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Articles by Jun Liang in JoVE

 JoVE Biology

Using RNA-mediated Interference Feeding Strategy to Screen for Genes Involved in Body Size Regulation in the Nematode C. elegans

1Department of Science, Borough of Manhattan Community College, City Universtiy of New York (CUNY), 2Department of Biology, Queens College, The City University of New York (CUNY), 3Biochemistry Program, The Graduate Center, Queens College, The City University of New York (CUNY)


JoVE 4373

We demonstrate how to use the RNAi feeding technique to knock down target genes and score body size phenotype in C. elegans. This method could be used for a large scale screen to identify potential genetic components of interest, such as those involved in body size regulation by DBL-1/TGF-β signaling.

Other articles by Jun Liang on PubMed

Insulin-cell Penetrating Peptide Hybrids with Improved Intestinal Absorption Efficiency

Cell-penetrating peptide (CPP) was linked to insulin to form insulin-CPP hybrids. The intestinal absorption efficiency of CPP hybridized insulin was 6-8 times increased compared to normal insulin as tested on Caco-2 cell monolayer, a widely used in vitro model for intestinal absorption. Insulin-CPP hybrid transportation seemed to be through an active and transcytosis-like mechanism. Importantly, insulin in hybrids kept intact after they passed through the Caco-2 cell monolayer. This study provides a new clue for oral insulin development.

The Minimal Functional Sequence of Protamine

Despite its nearly universal applications, protamine, a mixture of four major peptides with different sequences, is associated with clinically significant side effects. Through a well-designed enzyme digestion method, various low molecular weight protamine peptides were obtained. Among them, two low molecular weight protamine peptides with the same or even more potent heparin neutralization abilities as native protamine were identified through both in vitro and in vivo tests. In addition, in vivo experiments showed that compared to native protamine, these two low molecular weight protamine peptides were less toxic and would be safer for clinical use.

Synthesis of Doxorubicin-peptide Conjugate with Multidrug Resistant Tumor Cell Killing Activity

Cell penetrating peptide TAT was introduced into doxorubicin structure. Synthesized doxorubicin-TAT conjugate showed different intracellular distribution pattern and cell killing activity from those of free doxorubicin. Unlike free doxorubicin, doxorubicin-TAT conjugate was highly permeable to drug-resistant cells and was able to kill drug-resistant tumor cells efficiently.

[Present Studies of the Relationship Between Taste and Brain Functions]

Construction and Characterization of a T-PA Mutant for Use in ATTEMPTS: a Drug Delivery System for Achieving Targeted Thrombolysis

To resolve the bleeding risk associated with thrombolytic therapy, we have designed an approach, termed ATTEMPTS (Antibody Targeted Triggered Electrically Modified Prodrug Type Strategy), to deliver t-PA to the clot site in an inactive form and then trigger its conversion to the active form, so that it would selectively activate the clot bound plasminogen while alleviating the bleeding risk. This delivery system was composed of a large protein complex, consisting of two components: (i) a heparin-modified, negatively charged fibrin-targeting antibody; and (ii) a cationic peptide-modified, positively charged t-PA. Both in vitro and in vivo studies have confirmed the feasibility of this targeted drug delivery approach. A site-specific thrombolysis was observed in animals, without concomitant depletion of the coagulation factors -- the phenomenon in conventional thrombolytic therapy that contributes to the bleeding risk. Despite promise, the chemical conjugation method employed previously in the preparation of the cationic peptide-modified t-PA also revealed several major shortcomings. The primary drawback was that the number of the cationic peptides and the location at which these peptides were attached to a t-PA molecule could not be regulated by using the chemical conjugation method. As a consequence, the resultant modified t-PA possessed a wide range of heparin-binding strength, rendering the inhibition of t-PA activity by heparin binding ineffective. In this paper, we present a new strategy in producing the desired modified t-PA, utilizing the genetic engineering approach. A computer simulation-guided rational design strategy was adopted to identify the most desirable site in t-PA (i.e. the 37-loop) for incorporation of the heparin-binding peptide sequence. By altering the amino acid composition via mutation at three locations, i.e. Ser(300) to Cys, Gly(302) to Arg, and Glu(303) to Arg, a highly cationic nanomer sequence consisting of (297)KHRRCPRRR(304) and possessing a well-demonstrated heparin-binding domain was established within the 37-loop. To ensure the binding of heparin to this specifically modified domain, a cysteine residue (i.e. Cys(300)) was created to allow for site-specific conjugation of an additional heparin-binding peptide (i.e. the LMWP peptide previously developed in our laboratory) to this domain via the chemical conjugation method. In vitro fibrinolysis assays showed that both the t-PA mutant and the LMWP-attached t-PA mutant exhibited a fibrinolytic potency similar to that of the wild type t-PA. Inhibition studies using small chromogenic substrates demonstrated that the activity of mutant tPA-LMWP could be significantly inhibited by heparin binding. In conclusion, using computer simulation and molecular biology approaches, a mutated t-PA that meets the needs of the ATTEMPTS system, in providing a safe thrombolytic therapy, could be readily prepared.

[The Value of Serum Phosphorus Level Analysis in Assessing Clinical Characteristics of Hepatitis B Patients]

[Preliminary Results of Three-dimensional Conformal Radiotherapy for Small-cell Lung Cancer]

To evaluate the feasibility, therapeutic effects and complications of three-dimensional conformal radiotherapy (3DCRT) for small-cell lung cancer (SCLC).

[A Randomized Trial Comparing Oxaliplatin Plus Vinorelbine Versus Cisplatin Plus Vinorelbine for the Treatment of Patients with Advanced Non-small-cell Lung Cancer]

To evaluate the difference of efficacy, side-effects and quality of life in advanced non-small-cell lung cancer (NSCLC) patients treated with oxaliplatin plus vinorelbine or cisplatin plus vinorelbine.

[Construction of Two Hepatocellular Carcinoma Cell Models for the Expression of HBV X Gene with Different Selection Characteristics]

To construct 2 hepatocellular carcinoma (HCC) cell models for the expression of HBV X gene with different selection characteristics.

Progesterone Regulates Mouse Dendritic Cells Differentiation and Maturation

Progesterone, an important factor in the maintenance of gestation in humans and animals, has been demonstrated to lower immune response during pregnancy [Siiteri PK, Stites DP, Immunologic and endocrine interrelationships in pregnancy, Biol Reprod, (1982); Watnick AS, Russo RA, Survival of skin homografts in uteri of pregnant and progesterone-estrogen treated rats, Proc Soc Exp Biol Med, (1968)], which is one of many hypotheses trying to explain fetal tolerance. Because dendritic cells (DCs) play an important role in the initiation of immune response, we examined the effects of progesterone on the differentiation and maturation of DCs derived from mouse bone marrow cells. Our data suggest that progesterone may be involved in the maternal immune response by modulating DC differentiation, maturation and function.

[SPECT Lung Perfusion Scans in Predicting Radiation Pneumonitis in Lung Cancer Patients]

To evaluate single photon emission computed tomography (SPECT) lung perfusion in predicting radiation pneumonitis in lung cancer patients.

[Study of Effects of HBV X Gene and As2O3 on Expression and Activity of P53 in HepG2 Cells with ShRNA]

To delineate the effects of HBV X gene and of As(2)O(3) on p53 expression and activity in HepG2 cells by shRNA-mediated RNA interference (RNAi).

[Effectiveness and Safety of Recombinant Human Interleukin-11 in the Treatment of Chemotherapy-induced Thrombocytopenia]

To investigate the effectiveness and safety of domestically produced recombinant human interleukin 11 (rhIL-11) for the treatment of chemotherapy- induced thrombocytopenia.

[A Case of Severe HIV Occupational Exposure and Its Treatment]

Improvement in Sonochemical Degradation of 4-chlorophenol by Combined Use of Fenton-like Reagents

Studies on the sonolysis of a wide range of organic compounds have demonstrated that ultrasonic irradiation has potential for decomposition of organic pollutants in hazardous wastewater. However, the ultrasonic irradiation alone cannot provide high enough rate of decomposition to be used practically. One of the solutions to increase the degradation efficiency is to combine the ultrasound application with other advanced chemical oxidation processes (AOPs). In this study, in order to increase the efficiency of ultrasonically assisted degradation of organic pollutants in water, we examined effects of three kinds of solid Fe-containing catalysts, namely iron powder, basic oxygen furnace (BOF) slag and mill scale on the degradation rate of 4-CP (4-chlorophenol) in aqueous solutions containing hydrogen peroxide. In the experiments, 4-CP was considered as a model organic compound. All three Fe-containing matters when react with hydrogen peroxide are involved in the Fenton-like reaction system, which is one of the promising AOPs. The results showed that both the iron powder and mill scale additions can accelerate the degradation of 4-CP, although the effect is dependent on the solution pH. All 4-CP could be decomposed for 2 min at pH=3 and for 1h at pH=5.6. On the other hand, the BOF slag had no catalysis effect on the 4-CP degradation because of higher concentration of calcium and lower concentration of iron.

Characterization of a Cryptic Plasmid from Bacillus Sphaericus Strain LP1-G

A cryptic plasmid from Bacillus sphaericus strain LP1-G, designated as pLG, was sequenced and characterized. It was an 11,066bp circular molecule, with G+C content of 37%. The plasmid pLG was predicted to encode 23 putative ORFs, and ORF 21 shared the highest identity with Rep of pGI1 and pBMB9741, members of rolling-circle replication (RCR) pC194-family. Sequence analysis revealed a pC194-type double strand origin (dso) and a single strand origin (sso) like sequence located upstream and downstream of ORF 21, respectively. Moreover, Mung bean nuclease analysis and Southern hybridization confirmed the existence of single stranded DNA (ssDNA) intermediates, indicating that pLG belongs to the RCR pC194-family. Accumulation of multiple ssDNA intermediates in native strain LP1-G and decline of ssDNA and supercoiled DNA in rifampicin-treated strain implied that a special mechanism might be employed by pLG. Furthermore, the copy number of pLG in its original host was determined and about 58 copies of the plasmid exist in each cell. Subcloning and transformation experiments proved that the minimal replicon of pLG was within a 1.6-kb fragment, which was composed of rep gene and dso. These data are a good basis for the understanding of replication mechanisms and genetics of this B. sphaericus plasmid.

Role of P-glycoprotein in the Intestinal Absorption of Glabridin, an Active Flavonoid from the Root of Glycyrrhiza Glabra

Glabridin is a major constituent of the root of Glycyrrhiza glabra, which is commonly used in the treatment of cardiovascular and central nervous system diseases. This study aimed to investigate the role of P-glycoprotein (PgP/MDR1) in the intestinal absorption of glabridin. The systemic bioavailability of glabridin was approximately 7.5% in rats, but increased when combined with verapamil. In single-pass perfused rat ileum with mesenteric vein cannulation, the permeability coefficient of glabridin based on drug disappearance in luminal perfusates (P(lumen)) was approximately 7-fold higher than that based on drug appearance in the blood (P(blood)). Glabridin was mainly metabolized by glucuronidation, and the metabolic capacity of intestine microsomes was 1/15 to 1/20 of that in liver microsomes. Polarized transport of glabridin was found in Caco-2 and MDCKII monolayers. Addition of verapamil in both apical (AP) and basolateral (BL) sides abolished the polarized transport of glabridin across Caco-2 cells. Incubation of verapamil significantly altered the intracellular accumulation and efflux of glabridin in Caco-2 cells. The transport of glabridin in the BL-AP direction was significantly higher in MDCKII cells overexpressing PgP/MDR1 than in the control cells. Glabridin inhibited PgP-mediated transport of digoxin with an IC(50) value of 2.56 microM, but stimulated PgP/MDR1 ATPase activity with a K(m) of 25.1 microM. The plasma AUC(0-24h) of glabridin in mdr1a(-/-) mice was 3.8-fold higher than that in wild-type mice. These findings indicate that glabridin is a substrate for PgP and that both PgP/MDR1-mediated efflux and first-pass metabolism contribute to the low oral bioavailability of glabridin.

Enriched Selenium and Its Effects on Growth and Biochemical Composition in Lactobacillus Bulgaricus

Se-enriched Lactobacillus bulgaricus (L. bulgaricus) was generated by administration of sodium selenite (0, 1, 4, 8, 16, 32, and 64 mg/L, respectively) in MRS medium and enriched selenium manifestation in L. bulgaricus was investigated using transmission electron microscopy and energy-dispersive X-ray spectrometry and alterations of essential elements and amino acids in the organism were evaluated. We demonstrate that administration of sodium selenite in the dosage of 1-16 mg/L is suitable for selenium enrichment in L. bulgaricus and can enhance nutritive value in the organism by elevating the contents of essential elements including P, Mg, Mn, Zn, Ca, and total amino acids as well as reducing selenite to insoluble elemental selenium, an electron-dense and amorphous Se (0) granule, thereby depositing it both in the cytoplasm and in the extracellular space of L. bulgaricus. Thus, Se-enriched Lactobacillus can provide a potential dietary source of nontoxic selenium and functional regulator used for food and medical industry.

Transcriptional Repressor and Activator Activities of SMA-9 Contribute Differentially to BMP-related Signaling Outputs

In the nematode Caenorhabditis elegans, the BMP-related growth factor DBL-1 regulates body size and male tail morphogenesis via a conserved receptor/Smad signaling pathway. Smads are transcription factors, but rely on transcription cofactors for appropriate regulation of target genes in response to TGF-beta- and BMP-related signals. In the DBL-1 pathway, sma-9 encodes multiple zinc finger transcription factors homologous to Drosophila Schnurri, which functions in Dpp/BMP signaling. We have studied the molecular functions of SMA-9 as a model for transcription cofactor-dependent regulation of gene expression. Using SMA-9 fusions to known transcriptional activators and repressors, we demonstrate that SMA-9 acts primarily as a transcriptional repressor in body size regulation in vivo. In contrast, both activator and repressor functions contribute to male tail patterning. We further show that different SMA-9 regions have intrinsic repressor and activator activities using a yeast transcription assay. We use microarray analysis to identify transcriptional target genes in body size regulation. Consistent with the importance of repression in mediating body size regulation, we find more repressed genes than activated genes in this pool. Finally, we identify five transcriptional targets with body size and/or male tail patterning phenotypes, including transcription factors related to Runx and fos and signaling molecules related to hedgehog and patched. Our results thus suggest that SMA-9 products function differentially as transcriptional repressors and activators in DBL-1/BMP pathway regulated body size and male tail morphogenesis.

Tanshinone IIB, a Primary Active Constituent from Salvia Miltiorrhza, Exhibits Neuro-protective Activity in Experimentally Stroked Rats

Tanshinone IIB (TSB) is a major active constituent of the root of Salvia miltiorrhiza (Danshen) used in the treatment of acute stroke. Danshen extracts and TSB have shown marked neuron-protective effects in mouse studies but there is a lack of clinical evidence for the neuron-protective effects of Danshen and its active ingredients. This study investigated the neuron-protective effects of TSB in experimentally stroked rats. TSB at 5 and 25 mg/kg by intraperitoneal injection significantly reduced the focal infarct volume, cerebral histological damage and apoptosis in rats subjected to middle cerebral artery occlusion (MCAO) compared to MCAO rats receiving vehicle. This study demonstrated that TSB was effective in reducing stroke-induced brain damage and may represent a novel drug candidate for further development. Further mechanistic studies are needed for the neuron-protective activity of TSB.

Design of New Oxazaphosphorine Anticancer Drugs

The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, beta-D-glucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a beta-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)-bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.

The Schizosaccharomyces Pombe Cdc7 Protein Kinase Required for Septum Formation is a Client Protein of Cdc37

Cdc37 is an essential molecular chaperone found in fungi and metazoa whose main specificity is for certain protein kinases. Cdc37 can act as an Hsp90 cochaperone or alone; in yeasts, the interaction with Hsp90 is weak and appears not to be essential for Cdc37 function. Numerous genetic interactions between Cdc37 and likely client proteins have been observed in yeasts, but biochemical confirmation has been reported in only a few cases. We and others have generated and characterized temperature-sensitive cdc37 alleles in S. pombe and have used them to investigate the cellular roles of Cdc37: previous work has shown that mitotic Cdc2 is a major client. In this paper, we describe a screen for mutations synthetically lethal with a cdc37ts mutant with the aim of identifying genes encoding further client proteins of Cdc37. Ten such strains were isolated, and genomic libraries were screened for rescuing plasmids. In one case, a truncated cdc7 gene was identified. Further experiments showed that the mutation in this strain was indeed in cdc7. Cdc7 is a protein kinase required for septum initiation, and we show that its kinase activity is greatly reduced when Cdc37 function is impaired. Cdc7 normally locates to the spindle pole body during mitosis, and this appears to be unaffected in the cdc37ts mutant. Other evidence suggests that, in addition to mitosis and septum initiation, Cdc37 may also be required for septum cleavage.

Role of P-glycoprotein in the Intestinal Absorption of Tanshinone IIA, a Major Active Ingredient in the Root of Salvia Miltiorrhiza Bunge

The extracts from the roots of Salvia miltiorrhiza Bunge (Danshen) are widely and traditionally used in the treatment of angina pectoris, acute myocardial infarct, hyperlipidemia and stroke in China and other Asian countries. In this study, we have investigated the role of P-glycoprotein (P-gp) in the intestinal absorption of tanshinone IIA (TSA), a major active constituent of Danshen, using several in vitro and in vivo models. The oral bioavailability of TSA was about 2.9-3.4% in rats, with non-linear pharmacokinetics when its dosage increased. In a single pass rat intestinal perfusion model, the permeability coefficients (P(app)) based on TSA disappearance from the luminal perfusates (P(lumen)) were 6.2- to 7.2-fold higher (P < 0.01) than those based on drug appearance in mesenteric venous blood (P(blood)). The P(blood), but not P(lumen), was significantly increased when co-perfused with verapamil, or quinidine (both P-gp inhibitors). The uptake and efflux of TSA in confluent Caco-2 cells were significantly altered in the presence of verapamil, quinidine, MK-571, or probenecid. The transport of TSA across Caco-2 monolayers was pH-, temperature- and ATP-dependent. Furthermore, the transport from the apical (AP) to basolateral (BL) side of the Caco-2 monolayers was 3.3- to 8.5-fold lower than that from the BL to AP side, but such a polarized transport was attenuated by co-incubated verapamil or quinidine. A polarized transport was also observed in the control MDCKII cells and more apparent in MDR1-MDCKII monolayers, with the P(app) values of TSA in the BL-AP direction being 7- to 9-fold higher in MDR1-MDCKII monolayers than those in the control MDCKII cells. Moreover, TSA significantly inhibited P-gp-mediated transport of digoxin in P-gp-overexpressing membrane vesicles with an IC(50) of 2.6 microM, but stimulated vanadate-sensitive P-gp ATPase activity with estimated K(m) and V(max) values of 10.70 +/- 0.69 microM and 67.65 +/- 1.31 nmol/min/mg protein, respectively. TSA was extensively metabolized to tanshinone IIB (TSB), and two other oxidative metabolites in rat liver microsomes, but the formation rate of TSB in rat intestinal microsomes was only about 1/10 of that in liver microsomes. These findings indicate that TSA is a substrate and reversing agent for P-gp; and P-gp-mediated efflux of TSA into the gut lumen and the first-pass metabolism contribute to the low oral bioavailability. Further studies are needed to explore the role of other drug transporters and first-pass metabolism in the low bioavailability of TSA.

Transport of Cryptotanshinone, a Major Active Triterpenoid in Salvia Miltiorrhiza Bunge Widely Used in the Treatment of Stroke and Alzheimer's Disease, Across the Blood-brain Barrier

Cryptotanshinone (CTS), a major constituent from the roots of Salvia miltiorrhiza (Danshen), is widely used in the treatment of coronary heart disease, stroke and less commonly Alzheimer's disease. Our recent study indicates that CTS is a substrate for P-glycoprotein (PgP/MDR1/ABCB1). This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models. A polarized transport of CTS was found in rat primary microvascular endothelial cell (RBMVEC) monolayers, with facilitated efflux from the abluminal side to luminal side. Addition of a PgP (e.g. verapamil and quinidine) or multi-drug resistance protein 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake of CTS into the cerebrum increased from 0.52 +/- 0.1% at 1 min to 11.13 +/- 2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose. Co-perfusion of a PgP/MDR1 (e.g. verapamil) or MRP1/2 inhibitor (e.g. probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21% of those in plasma, and were significantly increased when coadministered with verapamil or probenecid in rats. The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid (a neurotoxin) were about 2- to 2.5-fold higher than the control rats. Moreover, the brain levels in mdr1a(-/-) and mrp1(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice, respectively. Taken collectively, these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents, suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1. Further studies are needed to explore the role of other drug transporters in restricting the brain penetration of CTS and the clinical relevance.

Low Dose Radiation Increased the Therapeutic Efficacy of Cyclophosphamide on S(180) Sarcoma Bearing Mice

We examined whether low dose radiation (LDR) exposure (75 mGy) could increase the therapeutic efficacy of cyclophosphamide (CTX) by comparing the effects of tumor suppression, tumor cell apoptosis, cell cycle and proliferation of bone marrow in vivo. Kunming mice implanted with S(180) sarcoma cells were given 75 mGy whole body gamma-ray radiation exposure and CTX (300 mg/kg) by intraperitoneal injection 36 hours after LDR. Proliferation of bone marrow and tumor cells was analyzed by flow cytometry. Cytochrome c leakage from the tumor was measured by Western-blot. We discovered that tumor growth was significantly reduced in the group exposed to CTX add to LDR. The apoptosis of tumor cells increased significantly after LDR. The tumor cells were arrested in G(1) phase in the groups treated with CTX and CTX + LDR, but cell cycle was more significantly arrested in mice exposed to LDR followed by CTX than in mice exposed only to LDR or CTX chemotherapy. Concentration of bone marrow cells and proliferation index in CTX + LDR mice were higher than those in the untreated mice. LDR or CTX + LDR could induce greater cytochrome c levels and caspase-3 activity in tumors. These results suggest that low dose radiation can enhance the anti-tumor effect of the chemotherapy agent CTX markedly. Furthermore, LDR significantly protects hematopoetic function of the bone marrow, which is of practical significance on adjuvant chemotherapy.

Role of P-glycoprotein in Limiting the Brain Penetration of Glabridin, an Active Isoflavan from the Root of Glycyrrhiza Glabra

Glabridin is a major active constituent of Glycyrrhiza glabra which is commonly used in the treatment of cardiovascular and central nervous system (CNS) diseases. Recently, we have found that glabridin is a substrate of P-glycoprotein (PgP/MDR1). This study aimed to investigate the role of PgP in glabridin penetration across the blood-brain barrier (BBB) using several in vitro and in vivo models.

Improved Stability and Selectivity of Lytic Peptides Through Self-assembly

Widespread clinical applications of peptide drugs have been hindered by their low stability and selectivity. Peptides can be easily digested by various enzymes in the blood and thus show a short life-span. Meanwhile, peptide drugs can cause severe normal tissue damage due to their low selectivity. Therefore, for effective therapy, a high dosage of peptide is required which is usually in excess of the clinically and economically acceptable level. In this study, we have tried to design new lytic peptides which can self-assemble into peptide fibrils with defined nanostructures as observed under atomic force microscopy. Lytic peptides in self-assembled peptide fibrils will lose their cell lysis activity but become resistant to enzyme degradation. Such lytic peptide self-assembly has proven to be a reversible process which is controlled by surrounded environments. A concentration controlled sustained release of free and active lytic peptide from self-assembled peptide fibrils has been achieved. Self-assembled lytic peptides with enzyme resistance, sustained release, and prodrug feature may have great clinical application potentials.

Kinetic Analysis of 99mTc-sestamibi Evaluates the Protective Effects by Ischaemic Preconditioning on Ischaemic Myocardium in an Isolated Rabbit Heart

To analyse the kinetic changes of uptake, washout and retention of Tc-sestamibi in order to evaluate the protective effects and possible mechanism of ischaemic preconditioning and adenosine preconditioning on myocardium injured by ischaemia/reperfusion.

[Ligustrazine and Cimetidine Therapy for the Prevention of Henoch-Schonlein Purpura Nephritis in Children: a Follow-up Study of 380 Cases]

[The Study on Freezing Intercostal Nerves for the Relief of Postoperative Chest Pain]

To explore the best freezing time and the optimum analgesia modality.

[Preliminary Studies on Histological Changes After Repairing the Facial Nerve Defect with Acellular Facial Nerve]

To investigate the morphological changes after chemically extracted acellular nerve allografts transplant.

Involvement of P-glycoprotein and Multidrug Resistance Associated Protein 1 in the Transport of Tanshinone IIB, a Primary Active Diterpenoid Quinone from the Roots of Salvia Miltiorrhiza, Across the Blood-brain Barrier

Tanshinone IIB (TSB) is a major constituent of Salvia miltiorrhiza, which is widely used in treatment of cardiovascular and central nervous system (CNS) diseases such as coronary heart disease and stroke. This study aimed to investigate the role of various drug transporters in the brain penetration of TSB using several in vitro and in vivo mouse and rat models. The uptake and efflux of TSB in rat primary microvascular endothelial cells (RBMVECs) were ATP-dependent and significantly altered in the presence of a P-glycoprotein (P-gp) or multidrug resistance associated protein (Mrp1/2) inhibitor. A polarized transport of TSB was found in RBMVEC monolayers with facilitated efflux from the abluminal to luminal side. Addition of a P-gp inhibitor (e.g. verapamil) in both abluminal and luminal sides attenuated the polarized transport. In an in situ rat brain perfusion model, TSB crossed the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier at a greater rate than that for sucrose, and the brain penetration was increased in the presence of a P-gp or Mrp1/2 inhibitor. The brain levels of TSB were only about 30% of that in the plasma and it could be increased to up to 72% of plasma levels when verapamil, quinidine, or probenecid was co-administered in rats. The entry of TSB to CNS increased by 67-97% in rats subjected to middle cerebral artery occlusion or treatment with the neurotoxin, quinolinic acid, compared to normal rats. Furthermore, The brain levels of TSB in mdr1a(-/-) and mrp1(-/-) mice were 28- to 2.6-fold higher than those in the wild-type mice. TSB has limited brain penetration through the BBB due to the contribution of P-gp and to a lesser extent of Mrp1 in rodents. Further studies are needed to confirm whether these corresponding transporters in humans are involved in limiting the penetration of TSB across the BBB and the clinical relevance.

E-cadherin Gene Polymorphisms and Haplotype Associated with the Occurrence of Epithelial Ovarian Cancer in Chinese

E-cadherin plays an important role in the origin of epithelial ovarian cancer. However, the exact molecular mechanism by which this occurs is unknown. The polymorphisms located at the E-cadherin may contribute to an increased risk for certain cancers. In this paper, we studied the association between polymorphisms of E-cadherin and the risk of epithelial ovarian cancer.

In Vitro and in Vivo Neuroprotective Effect and Mechanisms of Glabridin, a Major Active Isoflavan from Glycyrrhiza Glabra (licorice)

Stroke is a life-threatening disease characterized by rapidly developing clinical signs of focal or global disturbance of cerebral function due to cerebral ischemia. A number of flavonoids have been shown to attenuate the cerebral injuries in stroked animal models. Glabridin, a major flavonoid of Glycyrrhiza glabra (licorice), possesses multiple pharmacological activities. This study aimed to investigate whether glabridin modulated the cerebral injuries induced by middle cerebral artery occlusion (MCAO) in rats and staurosporine-induced damage in cultured rat cortical neurons and the possible mechanisms involved. Our study showed that glabridin at 25mg/kg by intraperitoneal injection, but not at 5mg/kg, significantly decreased the focal infarct volume, cerebral histological damage and apoptosis in MCAO rats compared to sham-operated rats. Glabridin significantly attenuated the level of brain malonyldialdehyde (MDA) in MCAO rats, while it elevated the level of two endogenous antioxidants in the brain, i.e. superoxide dismutase (SOD) and reduced glutathione (GSH). Co-treatment with glabridin significantly inhibited the staurosporine-induced cytotoxicity and apoptosis of cultured rat cortical neurons in a concentration-dependent manner. Consistently, glabridin significantly reduced the DNA laddering caused by staurosporine in a concentration-dependent manner. Glabridin also suppressed the elevated Bax protein and caspase-3 proenzyme and decreased bcl-2 induced by staurosporine in cultured rat cortical neurons, facilitating cell survival. Glabridin also inhibited superoxide production in cultured cortical neurons exposed to staurosporine. These findings indicated that glabridin had a neuroprotective effect via modulation of multiple pathways associated with apoptosis. Further studies are warranted to further investigate the biochemical mechanisms for the protective effect of glabridin on neurons and the evidence for clinical use of licorice in the management of cerebral ischemia.

[Influence of Chronic Unpredictable Emotional Stress on the Ultrastructures of Temporomandibular Joint in Rats]

To study the influence of emotional stress on the ultrastructures of temporomandibular joint in rats.

[Association of Three Single Nucleotide Polymorphisms of the E-cadherin Gene with Susceptibility to Epithelial Ovarian Carcinoma]

To investigate the association of three single nucleotide polymorphisms (SNPs), i.e. -160C/A, -347G/GA and 3'UTR+ 54C/T, in the promoter region of E-cadherin gene (CDH1) with the risk of epithelial ovarian carcinoma.

[Spontaneous Perforation of the Colon in Three Newborn Infants]

Specific Interactions Between Diphenhydramine and Alpha-helical Poly(glutamic Acid)--a New Ion-pairing Complex for Taste Masking and PH-controlled Diphenhydramine Release

Formation of drug/excipient complex through ionic interactions has proven to be very effective for both controlled release and taste masking. Unfortunately, the ionic interactions between drugs and small molecule excipients are usually weak, and the stability of the formed complexes can be greatly influenced by solution ionic strength. In this study, we explored to formulate diphenhydramine (DPH), a very bitter tasting drug, using small molecular weight and carboxyl group containing polymers. Studies showed that DPH interacted with alpha-helical poly(glutamic acid) specifically to produce DPH/poly(glutamic acid) complexes, mostly spherical in shape with a diameter of around 1.0 microm. Other drugs with similar chemical structures as DPH, such as phenylephrine and pseudoephedrine, could not form complexes with poly(glutamic acid) or other polymers under the same conditions. Although DPH in DPH/poly(glutamic acid) complexes existed amorphously, it showed increased stability. In vitro studies using electronic tongue demonstrated that poly(glutamic acid) might be as effective as sucralose for DPH bitter taste blocking. In addition, DPH/poly(glutamic acid) complexes were not stable in neutral or weak acidic (pH>5) environments and dissolved rapidly and completely. Therefore, DPH/poly(glutamic acid) complex may serve as a new formulation for taste masking and controlled DPH release in gastrointestinal tract. This is the first report that small molecule drugs can interact with peptides of specific secondary structures to form stable complexes. In addition to greatly expanded ion-pairing excipient pool, application of peptides in drug formulation may also solve the selectivity and stability problems faced by current small molecule excipients.

Discovery of Potent and Cell-active Allosteric Dual Akt 1 and 2 Inhibitors

This paper describes the improvement of cell potency in a class of allosteric Akt 1 and 2 inhibitors. Key discoveries include identifying the solvent exposed region of the molecule and appending basic amines to enhance the physiochemical properties of the molecules. Findings from the structure-activity relationships are discussed.

The Design and Synthesis of Potent and Cell-active Allosteric Dual Akt 1 and 2 Inhibitors Devoid of HERG Activity

This letter details the attenuation of hERG in a class of Akt inhibitors through heteroatom insertions into aromatic rings. The development of a cell-active dual Akt 1 and 2 inhibitors devoid of hERG activity is discussed using structure-activity relationships.

[Plasma Thromboxane A2 and Prostaglandin I2 Levels and Their Ratio in Children with Henoch-Schonlein Purpura Nephritis]

To study the changes and roles of plasma thromboxane A2 (TXA2) and prostaglandin I2 (PGT2) levels and their ratio in Henoch-Schonlein purpura nephritis (HSPN) in children.

A Pentacyclic Aurora Kinase Inhibitor (AKI-001) with High in Vivo Potency and Oral Bioavailability

Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.

PTD-modified ATTEMPTS System for Enhanced Asparaginase Therapy: a Proof-of-concept Investigation

Macromolecular drugs such as proteins and gene products are presumably the most desirable therapeutic agents due to their unmatched substrate specificity and reaction efficiency. Yet, clinical use of these drugs has met with limited success, primarily due to the impermeable nature of the cell membrane that restricts cellular drug uptake to only small (<600 Da) and hydrophobic molecules. The recent discovery of the protein transduction domain (PTD) membrane-penetrating peptides, such as HIV-TAT, has finally offered the possibility of resolving this cell-membrane barrier for macromolecular drug delivery. Via covalent linkages, these PTD peptides have been shown to ferry the attached macromolecular species across membranes of all cell types, both in vitro and in vivo. Nevertheless, the lack of selectivity for PTD-mediated internalization restricts the application of this cell uptake method in clinical practice, due to concerns of inducing systemic toxicity caused by the carried drugs. Presented herein is a modified version of our previously established "ATTEMPTS" approach in delivery of macromolecular drugs, which integrates the cell-penetrating PTDs into a heparin/protamine-regulated delivery system. In vitro findings using asparaginase (ASNase) as a model macromolecular anti-tumor agent were able to validate the feasibility of this delivery system. The chemically constructed TAT-ASNase conjugates not only were able to translocate into the MOLT-4 cells and elicit the cytotoxic effects, but also this PTD-mediated intracellular drug uptake could be regulated (with on/off control) by the addition of heparin and protamine. This modified ATTEMPTS system therefore presents a new avenue of treatment of various types of cancers and other diseases with macromolecular drugs. In vitro characterization and a preliminary proof-of-concept animal investigation that demonstrates the feasibility of this PTD-mediated ASNase therapeutic system is subsequently described.

A Novel and Effective Hepatocyte Growth Factor Kringle 1 Domain and P53 Cocktail Viral Gene Therapy for the Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, yet effective therapeutic options for advanced HCC are limited. Kringle 1 domain of HGF (HGFK1) has been demonstrated as a potent anti-tumor molecule and p53 is a well established tumor suppressor. Recently we developed AAV transducing HGFK1 (AAV-HGFK1) as a gene therapy for HCC. Here we investigated the possibility of enhancing the effect of AAV-HGFK1 by combining it with Adv transducing p53 (Adv-p53). In vitro expression experiments suggested a small amount of Adv-p53 could increase the expression of AAV transgenes. AAV-HGFK1+Adv-p53 cocktail strongly inhibited the proliferation of microvascular endothelial cell (MEC) and two HCC cell lines, Hepa1-6 and McA-RH7777. In two orthotopic mice and rat HCC models the cocktail gene therapy also significantly reduced the tumor burdens and prolonged the survival time by inhibiting tumor angiogenesis and inducing tumor cell death. Significantly, tumor metastasis was completely prevented. AAV-HGFK1+Adv-p53 viral cocktail may be a promising cancer therapy for the treatment of HCC.

Novel Suppressors of Alpha-synuclein Toxicity Identified Using Yeast

The mechanism by which the Parkinson's disease-related protein alpha-synuclein (alpha-syn) causes neurodegeneration has not been elucidated. To determine the genes that protect cells from alpha-syn, we used a genetic screen to identify suppressors of the super sensitivity of the yeast Saccharomyces cerevisiae expressing alpha-syn to killing by hydrogen peroxide. Forty genes in ubiquitin-dependent protein catabolism, protein biosynthesis, vesicle trafficking and the response to stress were identified. Five of the forty genes--ENT3, IDP3, JEM1, ARG2 and HSP82--ranked highest in their ability to block alpha-syn-induced reactive oxygen species accumulation, and these five genes were characterized in more detail. The deletion of any of these five genes enhanced the toxicity of alpha-syn as judged by growth defects compared with wild-type cells expressing alpha-syn, which indicates that these genes protect cells from alpha-syn. Strikingly, four of the five genes are specific for alpha-syn in that they fail to protect cells from the toxicity of the two inherited mutants A30P or A53T. This finding suggests that alpha-syn causes toxicity to cells through a different pathway than these two inherited mutants. Lastly, overexpression of Ent3p, which is a clathrin adapter protein involved in protein transport between the Golgi and the vacuole, causes alpha-syn to redistribute from the plasma membrane into cytoplasmic vesicular structures. Our interpretation is that Ent3p mediates the transport of alpha-syn to the vacuole for proteolytic degradation. A similar clathrin adaptor protein, epsinR, exists in humans.

Daidzein As an Antioxidant of Lipid: Effects of the Microenvironment in Relation to Chemical Structure

Isoflavone daidzein (D, pK a1 = 7.47 +/- 0.02 and pK a2 = 9.65 +/- 0.07) was, through a study of the parent compound and its three methyl anisol derivatives 7-methyldaidzein (7-Me-D, pK a = 9.89 +/- 0.05), 4'-methyldaidzein (4'-Me-D, pK a = 7.43 +/- 0.03), and 7,4'-dimethyldaidzein (7,4'-diMe-D), found to retard lipid oxidation in liposomal membranes through two mechanisms: (i) radical scavenging for which the 4'-OH was more effective than the 7-OH group in agreement with the oxidation potentials: 0.69 V for 4'-OH and 0.92 V for 7-OH versus Ag/AgCl in acidic solution and 0.44 V for 4'-O(-) and 0.49 V for 7-O(-) in alkaline solution and (ii) change in membrane fluidity through incorporation of the isoflavones, in effect hampering radical mobility. The radical scavenging efficiency measured by the rate of the reaction with the ABTS(*)(+) in aqueous solution followed the order D > 7-Me-D > 4'-Me-D > 7,4'-diMe-D, as also found for antioxidant efficiency in liposomes when oxidation was initiated with the water-soluble AAPH radical and monitored as the formation of conjugate dienes. For oxidation initiated by the lipid-soluble AMVN radical, the antioxidant efficiency was ranked as 4'-Me-D > D > 7,4'-diMe-D > 7-Me-D, and change in fluorescence anisotropy of fluorescent probes bound to the membrane surface or inside the lipid bilayer confirmed the effects of isoflavones on the membrane fluidity, especially for 7,4'-diMe-D.

The ATTEMPTS Delivery Systems for Macromolecular Drugs

Aiming at successful targeted drug delivery - a system that possesses both targeting and prodrug features that can be activated once the system reaches the target site upon systemic administration - would be desired to reduce systemic toxicity. Previously we proposed a heparin/protamine-based system for delivery of protease drugs such as tissue-specific plasminogen activator (t-PA). This approach, termed 'antibody targeted, triggered, electrically modified prodrug-type strategy' (ATTEMPTS), would permit antibody-directed administration of inactive t-PA and allow a subsequent triggered release of the active t-PA at the target site. This system can be adapted to target tumor tissues when protein transduction domain (PTD) peptide such as TAT is incorporated in the ATTEMPTS construct. Both in vitro and preliminary in vivo studies using TAT-gelonin (TAT-Gel) and TAT-asparaginase (TAT-ASNase) conjugates have demonstrated that the on/off regulation of the membrane translocation activity of PTD at tumor target, followed by intracellular delivery of cytotoxic macromolecular drug, can be accomplished. Hence, the PTD-mediated delivery system derived from our previous ATTEMPTS approach is a system that incorporates all of the targeting function, prodrug feature, release mechanism and cell entry mechanism and could become a generic system for delivery of macromolecular drugs.

[A Clinical and Genetic Analysis of a Pedigree with Two 46,XY Patients Suffering from 17alpha-hydroxylase Deficiency]

To investigate the molecular defects of CYP17A1 gene in a pedigree with two 46,XY patients suffering from 17alpha-hydroxylase deficiency (17-OHD) and explore the steroid biosynthetic difference in carriers of 17-OHD before and after adrenocorticotrophic hormone (ACTH) test.

Primary Small Cell Carcinoma of the Esophagus

Primary small cell esophageal carcinoma (SCEC) is a rare and aggressive disease for which there is no recommended standard treatment at this time.

Variations in Canadian Rates of Hospitalization for Ambulatory Care Sensitive Conditions

[Effects of Simulated Acid Rain on Leaf Photosynthate, Growth, and Yield of Wheat]

With winter wheat variety Yamgmai 12 as test object, a field experiment was conducted to study the stress of simulated acid rain on its growth and development. The results showed that simulated acid rain had considerable effect on wheat growth and yield. When the pH of acid rain was < or = 3.5, the growth of leaf area as well as the mass of fresh leaf per unit area declined greatly, and the yield was significantly lower than CK. When pH was < or = 2.5, the plant height was obviously lowered, and the visible injury on leaf surface was observed. Under acid rain stress, the contents of leaf chlorophyll a, chlorophyll b, and carotenoid, especially chlorophyll a, decreased obviously. Acid rain also suppressed the synthesis of soluble sugar and reduced sugar, and the suppression was stronger at pH < or = 3.5, and became much stronger with increasing acidity. The total free amino acid and soluble protein contents in leaves decreased with increasing acidity, and were significantly lower than CK when the pH was < or = 3.5 and < or = 4.5, respectively.

[Distribution Characteristics of Benthic Algae in Intertidal Zone of Ma' an Archipelago of Zhejiang Province]

Based on the survey of benthic algae in the intertidal zone of Ma' an Archipelago from March to July 2007, the algal species composition, distribution, and temperature feature were studied. The dominant algal species in the study area were preliminarily analyzed by using similarity indices (S(c)) and index of relative importance (IRI(c)). A total of 31 species sampled in sublittoral area were identified, among which, 7 species of 5 genera belonged to Chlorophyta, 8 species of 5 genera belonged to Phaeophyta, and 16 species of 14 genera belonged to Rhodophyta. Topical and selective distribution species influenced by wave and tide were identified in the intertidal zone. Ulva pertusa and Sargassum thunbergii were found in all survey area. Rhodophyta was the dominant species, with the occurring frequency being up to 61.1%, and Chlorophyta showed quite uniformed horizontal distribution. In addition, 81% of sampled species were from low-tide zone, and some were extended from mid-tide zone to low-tide zone. The composition comparability between mid-tide and low-tide species was 0.47, and the convergence effect in mid-tide and low-tide zone was higher than that in high-tide and mid-tide zone. The sublittoral area of Ma' an Archipelago showed obvious vertical zoning character, with temperate species being absolute abundant, and the warm-water species dominant. The marine floral texture of Ma' an Archipelago belongs to warm temperate-subtropical transitional marine flora.

[Postoperative Three-dimensional Conformal Radiotherapy for Resected Non-small Cell Lung Cancer]

To investigate the association between survival and postoperative three-dimensional conformal radiotherapy (3DCRT) in patients with resected non-small cell lung cancer (NSCLC).

[Capecitabine Combined with Cisplatin As First-line Therapy in Chinese Patients with Advanced Gastric Carcinoma-a Phase II Clinical Study]

To evaluate the effectiveness and safety of the combination chemotherapy of capecitabine (X) with fractionated administration of cisplatin (C) in Chinese patients with advanced gastric cancer (AGC).

Preliminary in Vivo Evaluation of the Protein Transduction Domain-modified ATTEMPTS Approach in Enhancing Asparaginase Therapy

Asparaginase (ASNase) is an enzyme drug presently approved for the induction of remission in the treatment of patients with acute lymphoblastic leukemia (ALL). The cytotoxic effect of ASNase is derived from its ability to deplete asparagine, an essential amino acid required by certain types of leukemia cells for protein synthesis and survival. Despite its efficacy in enhancing disease remission rate and prolonging complete remission duration in ALL patients, ASNase therapy is nevertheless confounded by a number of serious toxic effects, particularly to organs associated with high protein production (e.g., liver, pancreas), due to the systemic depletion of asparagine. Presented herein is a modified version of our previously established ATTEMPTS protein delivery system that carries the potential to permit a tumor specific, intracellular delivery of ASNase, thereby allowing for a significant reduction of ASNase-induced systemic toxicity. In a previous paper, we already demonstrated the in vitro feasibility of this heparin/protamine-regulated, TAT-mediated system in delivering ASNase directly into ASNase-sensitive murine lymphoma cells. In this article, we further validated the in vivo applicability of this system in animals harboring ASNase-encapsulated L5178Y lymphoma cells. Preliminary results showed that animals inoculated with L5178Y cells containing TAT-ASNase exhibited an extended survival rate of approximately 13% over those harboring L5178Y cells without the encapsulation of ASNase. Furthermore, the TAT-ASNase-treated mice also displayed a significantly improved hematological and liver histological status than the control groups. These findings bring promise to the use of the modified ATTEMPTS delivery system in achieving enhanced ASNase therapy.

Allosteric Inhibitors of Akt1 and Akt2: Discovery of [1,2,4]triazolo[3,4-f][1,6]naphthyridines with Potent and Balanced Activity

A series of [1,2,4]triazolo[3,4-f][1,6]naphthyridine allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been shown to have potent dual Akt1 and 2 cell potency. The representative compound 13 provided potent inhibitory activity against Akt1 and 2 in vivo in a mouse model.

Functional SNPs in the SCGB3A2 Promoter Are Associated with Susceptibility to Graves' Disease

Graves' disease (GD) is one of the most common human autoimmune diseases, and recent data estimated a prevalence of clinical hyperthyroidism of 0.25-1.09% in the population. Several reports have linked GD to the region 5q12-q33; and a locus between markers D5s436 and D5s434 was specifically linked to GD susceptibility in the Chinese population. In the present study, association analysis was performed using a large number of single-nucleotide polymorphisms (SNPs) at this locus in 2811 patients with GD recruited from different geographic regions of China. The strongest associations with GD in the combined Chinese Han cohorts were mapped to two SNPs in the promoter (pSNP) of SCGB3A2 [SNP76, rs1368408, P = 1.43 x 10(-6), odds ratio (OR) = 1.28 and SNP75, -623 - -622, P = 7.62 x 10(-5), OR = 1.32, respectively], a gene implicated in immune regulation. On the other hand, pSNP haplotypes composed of the SNP76 (rs1368408)+SNP74 (rs6882292) or SNP76+SNP75 (-623 approximately -622, AG/T) variants are correlated with high disease susceptibility (P = 0.0007, and P = 0.0192, respectively) in this combined Chinese Han cohort. Furthermore, these haplotypes were associated with reduced SCGB3A2 gene expression levels in human thyroid tissue, while functional analysis revealed a relatively low efficiency of SCGB3A2 promoters of the SNP76+SNP75 and SNP76+SNP74 haplotypes in driving gene expression. These results suggest that the SCGB3A2 gene may contribute to GD susceptibility.

Response of ATP Sulfurylase and Serine Acetyltransferase Towards Cadmium in Hyperaccumulator Sedum Alfredii Hance

We studied the responses of the activities of adenosine-triphosphate (ATP) sulfurylase (ATPS) and serine acetyltransferase (SAT) to cadmium (Cd) levels and treatment time in hyperaccumulating ecotype (HE) Sedum alfredii Hance, as compared with its non-hyperaccumulating ecotype (NHE). The results show that plant growth was inhibited in NHE but promoted in HE when exposed to high Cd level. Cd concentrations in leaves and shoots rapidly increased in HE rather than in NHE, and they became much higher in HE than in NHE along with increasing treatment time and Cd supply levels. ATPS activity was higher in HE than in NHE in all Cd treatments, and increased with increasing Cd supply levels in both HE and NHE when exposed to Cd treatment within 8 h. However, a marked difference of ATPS activity between HE and NHE was found with Cd treatment for 168 h, where ATPS activity increased in HE but decreased in NHE. Similarly, SAT activity was higher in HE than in NHE at all Cd treatments, but was more sensitive in NHE than in HE. Both ATPS and SAT activities in NHE leaves tended to decrease with increasing treatment time after 8 h at all Cd levels. The results reveal the different responses in sulfur assimilation enzymes and Cd accumulation between HE and NHE. With increasing Cd stress, the activities of sulfur assimilation enzymes (ATPS and SAT) were induced in HE, which may contribute to Cd accumulation in the hyperaccumulator Sedum alfredii Hance.

A Class of 2,4-bisanilinopyrimidine Aurora A Inhibitors with Unusually High Selectivity Against Aurora B

The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.

Constructing Bioactive Peptides with PH-dependent Activities

Many bioactive peptides are featured by their arginine and lysine rich contents. In this study, lysine and arginine residues in lytic peptides were selectively replaced by histidines. Although resulting histidine-containing lytic peptides had decreased activity, they did show pH-dependent cytotoxicity. The activity of the constructed histidine-containing lytic peptides increased 2-8 times as the solution pH changed from 7.4 to 5.5. More importantly, these histidine-containing peptides maintain the same cell killing mechanism as their parent peptides by causing cell lysis. Both the activity and pH-sensitivity of histidine-containing peptides are tunable by adjusting histidine substitution numbers and positions. This study has presented a general strategy to create bioactive peptides with desired pH-sensitivity to meet the needs of various applications such as cancer treatments.

[Changes of the Ultrastructures of Temporomandibular Joint After Removal of Emotional Stress Factors in Rats]

To examine the changes of the ultrastructures of temporomandibular joint after removal of the emotional stress factors in rats.

Expression of RhoA and RhoC in Colorectal Carcinoma and Its Relations with Clinicopathological Parameters

Ras homologous (Rho) family GTPases play a pivotal role in the regulation of numerous cellular functions associated with malignant transformation and metastasis. To evaluate the role of these GTPases in colorectal cancer, the mRNA expression levels in matched sets of tumor and non-tumor tissues from surgical specimens were analyzed. The relationship between the mRNA levels in tumor tissues to the clinicopathological features was also assessed.

[Clinical and Molecular Genetic Analysis for 7 Patients from 5 Pedigrees with 17a-hydroxylase/17, 20 Lyase Deficiency]

To investigate the clinical and genetic characteristics of 7 patients from 5 families with 17a-hydroxylase/17,20 lyase deficiency (17OHD) and the CYP17A1 mutation in Chinese.

Serum Uric Acid and Prehypertension Among Chinese Adults

Raised blood pressure is emerging as an independent risk factor for cardiovascular diseases and diabetes. We examined the relation between serum uric acid and prehypertension and the modification effects of age, obesity, fasting glucose, and lipids in Chinese adults.

[Clinical Analysis of 126 Patients with Primary Small Cell Carcinoma of the Esophagus]

To investigate the prognostic factors and the principles of treatment of primary esophageal small cell carcinoma (SCEC) retrospectively.

A Splice Site Mutation Combined with a Novel Missense Mutation of LHCGR Cause Male Pseudohermaphroditism

Leydig cell hypoplasia (LCH) is a rare form of male pseudohermaphroditism caused by inactivating mutations in the luteinizing hormone receptor gene (LHCGR). The majority of LHCGR mutations are located in the coding sequence, resulting in impairment of either LH/CG binding or signal transduction. We report a Chinese family with two siblings (46, XY and 46, XX) carrying a missense mutation (c. 455 T>C, p. Ile152Thr) and a splice site mutation (c. 537-3 C>A). Computational analysis of the missense mutation in the three-dimensional structural model predicted it might influence the distribution of hydrogen bonds and intermolecular contacts between the hormone and receptor. Consistent with these findings, in vitro mutant analysis revealed a marked impairment of human chorionic gonadotropin binding and signal transduction. The splice-acceptor mutation (c. 537-3 C>A) resulted in abnormal splicing of LHCGR mRNA, skipping exon 7. This report expands the genotypic spectrum of LHCGR mutations, with relevant implications for the molecular analysis of this gene.

Smoking and Coronary Atherosclerosis: Follow-up Study in China

1. The aim of the present study was to explore the association between the total number of cigarettes smoked in life and the severity of and mortality due to coronary atherosclerosis. 2. The study population comprised 1096 consecutive patients (820 men and 276 women) who underwent coronary angiography for suspected or known coronary atherosclerosis. Anthropometric and plasma measurements (body mass index, blood pressure and blood lipid, blood glucose and pro-insulin levels) were made. The number of cigarettes smoked during previous years was estimated. The severity of coronary atherosclerosis was defined by the Gensini score system. 3. At baseline, a significant positive association was observed between the number of cigarettes smoked and Gensini score (r = 0.213; P = 0.000), pro-insulin (r = 0.072; P = 0.017), total leucocyte count (r = 0.179; P = 0.000) and neutrophil count (r = 0.164; P = 0.000), whereas an inverse correlation was found between the number of cigarettes smoked and High-density lipoprotein-cholesterol (r = -0.150; P = 0.000). 4. When participants were divided into five categories based on the baseline number of cigarettes smoked, an independent association between baseline number of cigarettes smoked and all-cause mortality was observed in a multivariate analysis of Cox proportional hazards models, with a hazard ratio (95% confidence interval) of 1.328 (1.086-1.623; P = 0.006) during a median follow up of 2.86 years. 5. The number of cigarettes smoked was a highly significant predictor of coronary atherosclerosis and an independent risk factor for mortality in subjects with atherosclerosis in this Chinese population.

The PH Sensitivity of Histidine-containing Lytic Peptides

Many bioactive peptides are featured by their unique amino acid compositions such as argine/lysine-rich peptides. However, histidine-rich bioactive peptides are hardly found. In this study, histidine-containing peptides were constructed by selectively replacing the corresponded lysine residues in a lytic peptide LL-1 with histidines. Interestingly, all resulting peptides demonstrated pH-dependent activities. The cell lysis activities of these peptides could be increased up to four times as the solution pHs dropped from pH = 7.4 to pH = 5.5. The pH sensitivity of a histidine-containing peptide was determined by histidine substitution numbers. Peptide derivatives with more histidines were associated with increased pH sensitivity. Results showed that not the secondary structures but pH-affected cell affinity changes were responsible for the pH-dependent activities of histidine-containing peptides. The histidine substitution approach demonstrated here may present a general strategy to construct bioactive peptides with desired pH sensitivity for various applications.

[Brief Analysis of the Characteristics of Hygienic Law System of the Qing Dynasty]

The Qing dynasty, the last feudal dynasty of Chinese history, the social formation of which had changed many times as well as the hygienic law formation changed accordingly. The legislative principles of consulting the hygienic law system of the Han and the Jin dynasty, the hygienic law with thoughts of concentration of authority and the rules of rites, the customary law with supplementary functions, the colonial nature of late hygienic law constituted the characteristics of hygienic law system of the Qing dynasty, which had certain reference values to current construction of hygienic law system.

[Study on the Constituents of Petroleum Ether Fraction of Buxus Microphylla]

To study the chemical constituents from the petroleum ether fraction of Buxus microphylla.

Evaluation of Photodynamic Therapy Using Topical Aminolevulinic Acid Hydrochloride in the Treatment of Condylomata Acuminata: a Comparative, Randomized Clinical Trial

To determine the safety and efficacy of photodynamic therapy (PDT) with topical application of 20% wt/vol aminolevulinic acid hydrochloride (ALA) in the treatment of condylomata acuminata (CA).

Reverse Facial-submental Artery Island Flap for the Reconstruction of Maxillary Defects After Cancer Ablation

This study assessed the reliability of the reverse facial-submental artery island flap for reconstructing maxillary defects. Twelve patients with cancer underwent surgical resection and sequential maxillary reconstruction using a reverse facial-submental artery island flap. There were 9 men and 3 women. The patients ranged in age from 42 to 73 years. Palate squamous cell carcinoma was present in 7 cases; and maxillary gingival squamous cell carcinoma, in 5 cases. The remaining defects were classified as class 1 in one case, class 2a in 8 cases, and class 3b in 3 cases. The sizes of the skin paddle varied from a minimum of 4 x 12 cm to a maximum of 5 x 12 cm. No flaps failed. There were no donor-site problems. The patients were followed up for 16 to 30 months; one case of tumor local recurrence was observed. The reverse facial-submental artery island flap is safe, quick, and simple to elevate. The flap can be used reliably for reconstructing maxillary defects.

Quantitative Analysis and Chromatographic Fingerprinting for the Quality Evaluation of Forsythia Suspensa Extract by HPLC Coupled with Photodiode Array Detector

A simple and reproducible HPLC-photodiode array detector method has been described for evaluating and controlling quality of Forsythia suspensa extract (FSE). First, by analysis of chromatographic fingerprints, the similarities of chromatograms of FSE samples from the same pharmaceutical company exceeded 0.999, 0.997 and 0.960, respectively, although they were much lower from different pharmaceutical companies. Second, by further comparing many batches of extract chromatograph charts with the corresponding reference herb materials, the "common peaks" 3, 5, 7 and 10 were defined as "marker peaks", which were identified as (+)-pinoresinol-beta-D-glucoside, forsythiaside, phillyrin and phillygenin, respectively. Third, four "marker peaks" were simultaneously determined based on fingerprint chromatogram for further controlling the quality of FSE quantitatively. Namely, the newly developed method was successfully applied to analyze 38 batches of FSE samples supplied by three pharmaceutical factories, which showed acceptable linearity, intra-day precision (RSD<2.76%), inter-day precision (RSD<3.43%) and the average recovery rates in the range of (95.38+/-2.96)% to (101.60+/-3.08)%. At last, hierarchical clustering analysis and Bayes discriminant analysis statistical methods were used to classify and differentiate the 38 FSE samples to provide the basis for guiding reasonable use of FSE and controlling its quality better.

Investigation of Gait Features for Stability and Risk Identification in Elders

Today, eldercare demands a greater degree of versatility in healthcare. Automatic monitoring devices and sensors are under development to help senior citizens achieve greater autonomy, and, as situations arise, alert healthcare providers. In this paper, we study gait patterns based on extracted silhouettes from image sequences. Three features are investigated through two different image capture perspectives: shoulder level, spinal incline, and silhouette centroid. Through the evaluation of fourteen image sequences representing a range of healthy to frail gait styles, features are extracted and compared to validation results using a Vicon motion capture system. The results obtained show promise for future studies that can increase both the accuracy of feature extraction and pragmatism of machine monitoring for at-risk elders.

Genetic Polymorphisms of GSTP1 Related to Response to 5-FU-oxaliplatin-based Chemotherapy and Clinical Outcome in Advanced Colorectal Cancer Patients

To determine whether genetic polymorphisms of GSTP1 Ile105Val (A-->G) predict chemosensitivity and clinical outcome in patients with advanced colorectal cancer, treated by 5-FU/oxaliplatin-based chemotherapy.

Thirty-two Cases of Vascular Headache Treated by Acupuncture Combined with Chinese Herbal Decoction

To compare the acupuncture plus oral administration of Chinese herbal decoction with simple oral administration of Chinese herbal decoction in the treatment of vascular headache.

Identification of Steroid Biosynthetic Defects in Genotype-proven Heterozygous Individuals for 17alpha-hydroxylase/17,20-lyase Deficiency

P450c17 deficiency (17alpha-hydroxylase/17,20-lyase deficiency, 17OHD) is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene mutations. The D487_F489 deletion in exon 8 and Y329fs in exon 6 are relatively frequent mutations of the CYP17A1 gene in China that completely abolish the enzyme activity of P450c17. However, little remains known about steroid biosynthetic functions in carriers with these mutations in a single allele of the CYP17A1 gene, who are assumed to have 50% P450c17 activity. We investigated adrenal steroidogenic function in genotype-proven heterozygotes carrying such mutations in the CYP17A1 gene in vivo.

Chemical Modification of the Insecticidal Briantheins X and Y

Manipulation of the allylic chloride functionality in briantheins X and Y provided 10 new analogues of these gorgonian diterpenes as part of a continuing study of structure-activity relationships in this family of insecticidal compounds. Modified Finkelstein reaction conditions led not only to halogen substitution products but also to rearrangement, dehydrohalogenation, and dehydration products. None of the new compounds showed superior insecticidal activity to brianthein X or Y, although most did result in lower weight gains versus controls.

Interactions Between Genetic Factors That Predict Diabetes and Dietary Factors That Ultimately Impact on Risk of Diabetes

The purpose of the present review is to summarize recent advances in investigations of interactions between established genetic and dietary risk factors for type 2 diabetes (T2D).

The Combination of ERCC1 and XRCC1 Gene Polymorphisms Better Predicts Clinical Outcome to Oxaliplatin-based Chemotherapy in Metastatic Colorectal Cancer

To evaluate the effect of excision repair cross-complementing group 1 (ERCC1) and X-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcome in patients receiving oxaliplatin-based regimens for metastatic colorectal cancer.

Cerebral Lipiodol Embolism Following Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma

Cerebral lipiodol embolism (CLE) is an extremely rare complication of transcatheter arterial chemoembolization for hepatocellular carcinoma (HCC). The authors present a case of CLE that occurred after the second hepatic arterial chemoembolization for HCC, and attempt to introduce several plausible mechanisms of CLE, after reporting the clinical and radiological findings and reviewing the medical literature.

Low-dose Metronomic Chemotherapy with Cisplatin: Can It Suppress Angiogenesis in H22 Hepatocarcinoma Cells?

Low-dose chemotherapy drugs can suppress tumours by restraining tumour vessel growth and preventing the repair of damaged vascular endothelial cells. Cisplatin is a broad-spectrum, cell cycle-non-specific drug, but has serious side effects if used at high doses. There have been few reports on the anti-angiogenic effects of low-dose cisplatin and hence the effect of low-dose metronomic (LDM) chemotherapy on the proliferation and neovascularization of H22 hepatocarcinoma cells is discussed in this research. The influence of LDM chemotherapy with cisplatin on human umbilical vascular endothelial cells (HUVECs) and proliferation of the HepG(2) human hepatocarcinoma cell line were measured using MTT assays. The LDM group was treated with cisplatin 0.6 mg/kg/day; the control group with saline 0.2 ml; the maximum tolerated dose (MTD) group with cisplatin 9 mg/kg/day. Vascular endothelial growth factor (VEGF) and matrix metallopeptidase 2 (MMP-2) were detected using immunohistochemical staining. A chicken chorio-allantoic membrane (CAM) model was used to check the inhibitory effect of LDM chemotherapy with cisplatin on neovascularization in vivo. Low-dose cisplatin inhibited HUVEC proliferation in a dose- and time-dependent manner, but was ineffective in inhibiting HepG(2) cell proliferation. Tumour growth was delayed in mice receiving LDM cisplatin, without apparent body weight loss, compared with mice that received MTD cisplatin. Microvessel density and expression of VEGF and MMP-2 were much lower in mice receiving LDM cisplatin than in the control and MTD groups. Continuous low-dose cisplatin suppressed CAM angiogenesis in vivo. LDM chemotherapy with cisplatin can inhibit the growth of blood vessel endothelial cells in vitro and shows anti-angiogenic ability in vivo.

[Safety and Short-term Effect of Antithyroid Agents on Hyperthyroidism Patients Coexisting with Viral Hepatitis]

Identification of Molecular Targets Associated with Ethanol Toxicity and Implications in Drug Development

Alcohol dependence is a major disease burden of adults in modern society worldwide. There is no cure for alcohol dependence. In this study, we have examined the molecular targets of ethanol-induced toxicity in humans based on a systematic review of literature data and then discussed current and potential therapeutic targets for alcohol abuse and dependence. Using human samples with ethanol exposure, microarray analyses of gene expression have shown that numerous genes are up- and/or down-regulated by alcohol exposure. The ethanol-responsive genes mainly encode functional proteins such as proteins involved in nucleic acid binding, transcription factors, selected regulatory molecules, and receptors. These genes are also correlated with important biological pathways, such as angiogenesis, integrin signalling pathway, inflammation, wnt signaling pathway, platelet-derived growth factor signaling pathway, p53 pathway, epidermal growth factor receptor signaling pathway and apoptosis signaling pathway. Currently, only three medications were approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol abuse and alcohol dependence, including the aldehyde dehydrogenase inhibitor disulfiram, the micro-opioid receptor antagonist naltrexone, and the N-methyl-D-aspartate (NMDA) receptor inhibitor acamprosate (oral and injectable extended-release formulations). In addition, a number of agents are being investigated as novel treatments for alcohol abuse and dependence. These include selective 5-HT reuptake inhibitors (e.g. fluoxetine), 5-HT(1) receptor agonists (e.g. buspirone), 5-HT(2) receptor antagonists (e.g. ritanserin), 5-HT(3) receptor antagonists (e.g. ondansetron), dopamine receptor antagonists (e.g. aripiprazole and quetiapine), dopamine receptor agonists (e.g. bromocriptine), GABA(B) receptor agonists (e.g. baclofen), and cannabinoid-1 (CB(1)) receptor antagonists. Some of these agents have shown promising efficacy in initial clinical studies. However, further randomized studies with larger samples are warranted to establish their efficacy and safety profiles in the treatment of alcohol dependence.

Association of the CTLA4 Gene with Graves' Disease in the Chinese Han Population

To determine whether genetic heterogeneity exists in patients with Graves' disease (GD), the cytotoxic T-lymphocyte associated 4 (CTLA-4) gene, which is implicated a susceptibility gene for GD by considerable genetic and immunological evidence, was used for association analysis in a Chinese Han cohort recruited from various geographic regions. Our association study for the SNPs in the CTLA4 gene in 2640 GD patients and 2204 control subjects confirmed that CTLA4 is the susceptibility gene for GD in the Chinese Han population. Moreover, the logistic regression analysis in the combined Chinese Han cohort revealed that SNP rs231779 (allele frequencies p = 2.81x10(-9), OR = 1.35, and genotype distributions p = 2.75x10(-9), OR = 1.42) is likely the susceptibility variant for GD. Interestingly, the logistic regression analysis revealed that SNP rs35219727 may be the susceptibility variant to GD in the Shandong population; however, SNP, rs231779 in the CTLA4 gene probably independently confers GD susceptibility in the Xuzhou and southern China populations. These data suggest that the susceptibility variants of the CTLA4 gene varied between the different geographic populations with GD.

Role of Adjuvant Radiotherapy for Stage II Thymoma After Complete Tumor Resection

To determine whether patients with Masaoka stage II thymoma benefit from adjuvant radiation therapy after complete tumor resection.

[Brief Discussion on Changes of the Concept of Health]

The concept of health changes with the development of society. Through reviewing the course of people's health, it can be seen that the health is a target-state and a relative concept. Adapting the environment, adjusting the state of mind and maintaining hygiene are 3 experiences which can be learnt. Especially, adjusting the state of mind could be considered moral or wise.

The Feasibility of Facial-submental Artery Island Myocutaneous Flaps for Reconstructing Defects of the Oral Floor Following Cancer Ablation

The aim of the present study was to evaluate the feasibility of clinically applying facial-submental artery island flaps on primary reconstruction of oral floor defects following cancer ablation.

Umbilical Cord Mesenchymal Stem Cell Transplantation in Severe and Refractory Systemic Lupus Erythematosus

Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown marked therapeutic effects in a number of diseases in animal studies, based on their potential for self-renewal and differentiation. No data are available on the effectiveness of UC MSC transplantation (MSCT) in human autoimmune disease. This study was undertaken to assess the efficacy and safety of allogeneic UC MSCT in patients with severe and treatment-refractory systemic lupus erythematosus (SLE).

Genetic Polymorphism of GSTP1: Prediction of Clinical Outcome to Oxaliplatin/5-FU-based Chemotherapy in Advanced Gastric Cancer

The aim of this study was to evaluate the predictive value of the polymorphism Glutathione S-transferase P1 (GSTP1) Ile(105)Val on oxaliplatin/5-FU-based chemotherapy in advanced gastric cancer. Patients with advanced gastric cancer accepted oxaliplatin/5-FU-based chemotherapy as first-line chemotherapy were investigated. GSTP1 Ile(105)Val polymorphism was detected by TaqMan-MGB probe allelic discrimination method. Response to treatment was assessed by disease controlled rate. Time to progression, overall survival and toxicities were recorded. Final patient outcomes were as follows: the allele frequencies of GSTP1 were (105)Ile/(105)Ile 52%, (105)Ile/(105)Val 41% and (105)Val/(105)Val 7%. For patients with (105)Ile/(105)Ile and those with at least one (105)Val allele, disease control rate was 39% and 71% (P=0.026), respectively; median time to progression was 4.0 and 7.0 months (P=0.002); median overall survival time was 7.0 and 9.5 months (P=0.002). Neurological toxicity was more frequently occurred in patients with two (105)Ile alleles (P=0.005). In conclusion, patients with at least one (105)Val allele have better prognosis and response to oxaliplatin/5-FU-based regimen as first-line treatment for patients with advanced gastric cancer.

Mesenchymal Stem Cell Transplantation for Diffuse Alveolar Hemorrhage in SLE

A 19-year-old girl was diagnosed with systemic lupus erythematosus, based on findings of arthritis, malar rash, positive antinuclear antibody test and high levels of antibodies to double-stranded DNA. Two months after diagnosis, the patient presented with a sudden drop in blood hemoglobin level. Several days later, she developed bloody sputum, rapidly progressive dyspnea and hypoxemia. High-resolution CT showed diffuse alveolar infiltrates in both lung fields.

Allogenic Mesenchymal Stem Cells Transplantation in Refractory Systemic Lupus Erythematosus: a Pilot Clinical Study

To determine the safety and efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in refractory systemic lupus erythematosus (SLE).

CD4+ CD25+ but Not CD4+ Foxp3+ T Cells As a Regulatory Subset in Primary Biliary Cirrhosis

Increasing evidence indicates a role for regulatory T cells (Tregs) in the immune response and in autoimmune diseases, but the role of Tregs and cytokines in autoimmune hepatic diseases remains largely unclear and controversial, especially in patients with primary biliary cirrhosis (PBC). This study was undertaken to investigate Tregs and different cytokines in the liver and peripheral blood of PBC patients. We found that these patients demonstrated a reduction of CD4(+)CD25(+) T cells but elevated CD4(+)Foxp3(+) T cells in peripheral blood mononuclear cells (PBMCs) and CD4(+) T cells. The percentage of CD4(+)CD25(+) T cells in PBMCs was negatively correlated with elevated plasma interferon (IFN)-γ levels. A liver-specific analysis showed that the frequency of Foxp3(+) Tregs, transforming growth factor (TGF)-β1 and IFN-γ were increased in PBC patients. Our findings suggest that an imbalance between CD4(+)CD25(+) Tregs and cytotoxic cytokines plays a crucial role in the pathogenesis of PBC while the role of Foxp3 needs further investigation.

Two New Unusual Leucoagaricus Species (Agaricaceae) from Tropical China with Blue-green Staining Reactions

Most species of the genus Leucoagaricus have been described from temperate regions in North America and Europe, but little is known about the genus from tropical areas. In this report we describe two new species of Leucoagaricus, namely La. flavovirens and La. atroazureus, from tropical China. The two species are characterized by turning blue-green or dark blue where bruised and by unique phylogenetic placement. Two new combinations, namely La. viriditinctus and La. caerulescens, are proposed. A collection examined and cited under the name of La. viridiflavus by Kumar & Manimohan (2009b), who designated the neotype of the species, (Petch) TKA Kumar & Manimohan, was found to differ from La. flavovirens based on morphology and ITS sequence comparison. [corrected] A monophyletic group of four bluing species from Old World tropics is recovered but with poor measures of branch

[Association Between Genetic Polymorphisms of ERCC1, XRCC1, GSTP1 and Survival of Advanced Gastric Cancer Patients Treated with Oxaliplatin/5-Fu-based Chemotherapy]

To evaluate the association between the polymorphisms of excision repair cross complementation group 1 (ERCC1), X-ray repair cross complementing 1 (XRCC1), glutathione S-transferase Pi 1 (GSTP1) and the survival of advanced gastric cancer patients treated with oxaliplatin-based combination chemotherapy.

[Textual Research on Capital's Puji Tang (Relief Houses) in the Qing Dynasty]

Puji Tang (Relief Houses) was established in 1706 with the function of helping the poor, comforting and compensating people by medicine, therefore, which was supported by the Emperors of the Qing Dynasty. As a representation of medical relief organization of the Qing Dynasty, Puji Tang was developed from a folk relief organization to a government national organization. Because of the declination of the Qing Empire and the problems within its own organization, Puji Tang changed finally to an organization of reeducation through labor in 1907.

[Influence and Distribution of CD133 and CD34 Antigen Expression in Proximal Tubule Epithelial Cells During Ischemia/reperfusion Injury in Rats]

To study the influence and distribution in proximal tubule epithelial cells with the expressions of CD133 and CD34 in a rat model so as to provide a study basis for renal adult stem cell.

Hepatic Arterial Iodine-131-labeled Metuximab Injection Combined with Chemoembolization for Unresectable Hepatocellular Carcinoma: Interim Safety and Survival Data from 110 Patients

Few options are available to treat patients with hepatocellular carcinoma (HCC). It was tested whether the combination of iodine-131(¹³¹I)-metuximab with chemoembolization could improve outcomes in patients with intermediate HCC. Between April 2008 and April 2009, 110 patients with unresectable HCC were treated with 113 intra-arterial ¹³¹I-metuximab injections combined with chemoembolization (mean, 1.03 per patient; median, 1; range, 1-2), followed by 264 sessions of transcatheter arterial chemoembolization (mean, 2.4 per patient; median, 3; range, 1-6). The survival rates at 6, 12, and 18 months were 88.2%, 79.1%, and 57.4%, respectively, by the Kaplan-Meier method. Of these patients, 12% exhibited grade 3/4 bilirubin toxicity, 5% exhibited grade 3/4 white blood count toxicity, and 7% exhibited grade 3/4 platelet toxicity. Response rates based on World Health Organization and European Association for the Study of the Liver criteria were 42.73% and 61.82%, respectively. The combination of ¹³¹I-metuximab and chemoembolization appeared to extend survival in patients with unresectable HCC compared with historical controls, as well as being well tolerated by patients with Child-Pugh A and B. This combination may represent a promising treatment modality for patients with intermediate HCC.

[Serum Uric Acid and Prehypertension Among Chinese Adults]

The aim of this article is to discuss the relation between serum uric acid and prehypertension, and to evaluate the influence of age, obesity, fasting plasma glucose (FPG) and lipids in Chinese adults.

Micoletzkya Chinaae N. Sp. (Nematoda: Diplogastridae), a Potential Predacious Nematode and Ektaphelenchus Macrobulbosus (Nematoda: Ektaphelenchinae) Isolated from Simao Pine in South-western China

Detailed morphology of a new diplogastrid and a known ektaphelenchid species isolated from Simao pine in south-western China were illustrated and described/redescribed. Micoletzkya chinaae n. sp. is characterized by a relatively short body length (601-802 μm in female and 505-773 μm in male), undivided cheilorhabdia (forming an entire ring), dimorphic buccal cavity (eury- or stenostomatous), a large claw-like dorsal tooth and a large right subventral tooth in the stoma of eurystomatous form, typical diplogastrid pharynx, didelphic female gonads, nine pairs of genital papillae on male tail region with two ventral pairs (GP1 and GP2) closely associated, a unique gubernaculum morphology, and a long filiform tail in both sexes. The new diplogastrid belongs to the Group 1 category of Micoletzkya species sensuMassey, 1966, which is characterized by stoma equipped with a large dorsal and a large subventral tooth, and both teeth can cross near the center of the pharynx. The new species can be easily distinguished from other species within this group except for M. tomeaMassey, 1966 with the long filiform female and male tails. However, it shows great similarities to Mononchoides spp., Koerneria spp., Fictor spp., and Acrostichus members in some aspects. More morphological features as well as molecular data of this clade should be available before relationships between and within these genera can be better interpreted. The two large moveable teeth in eurystomatous worms indicate their potentially predacious habits, and re-isolation of this species is necessary. Morphology of south-western Chinese population of Ektaphelenchus macrobulbosus (Rühm,1956) Massey, 1974 conforms well to the previous descriptions except for a few minor variations. It is characterized by medium-long female and male bodies (676-791 and 613-685 μm, respectively), three incisures in the lateral field, offset cephalic region, knobless stylet 18-20 μm long, oblong median bulb with posteriorly situated valves, two to three rows of developing oocytes, short postuterine sac, absence of female rectum and anus, two pairs of subventral papillae on the male tail region, a cucullus (apophysis) present on the dorsal distal end of the spicule, and the conoid female and male tails.

Effect of Allogeneic Bone Marrow-derived Mesenchymal Stem Cells Transplantation in a PolyI:C-induced Primary Biliary Cirrhosis Mouse Model

Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune disease of unknown mechanism. We established a PBC animal model by injecting C57BL/6 mice with polyinosinic-polycytidylic acid sodium (polyI:C) to investigate the therapeutic effect of bone marrow-derived mesenchymal stem cells (BM-MSC) on this model. After 6 weeks of MSC infusion, serum aminotransferase and autoimmune antibodies declined, and histological examination by hematoxylin and eosin staining showed significant amelioration of monocytes infiltration around bile ducts of mice treated with BM-MSC. Interestingly, allogeneic BM-MSC transplantation markedly increased CD4(+)Foxp3(+) regulatory T cells in peripheral blood as well as in lymph nodes when analyzed by flow cytometry. Further examination showed serum TGF-β1 increased but IFN-γ decreased significantly in PBC mice treated with MSC, while with no obvious change in IL-10 expression. Our results for the first time suggested that BM-MSC transplantation could regulate systemic immune response and enhance recovery in liver inflammation of PBC mice, raising the possibility for clinical application of allogeneic MSC in treatment of early-stage PBC patients.

Chinese Medicine Tongxinluo Modulates Vascular Endothelial Function by Inducing ENOS Expression Via the PI-3K/Akt/HIF-dependent Signaling Pathway

To investigate the molecular mechanisms whereby the Chinese medicinal compound Tongxinluo improves vascular endothelial function through studying the induction of endothelial nitric oxide synthase (eNOS) and its upstream signaling pathway.

A New Regulatory Switch in a JAK Protein Kinase

Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over-stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhibitors of a JAK kinase has led to our characterization of a previously unknown kinase conformation arising from presentation of Tyr962 of TYK2 to an inhibitory small molecule via an H-bonding interaction. A small minority of protein kinase domains has a Tyrosine residue in this position within the αC-β4 loop, and it is the only amino acid commonly seen here with H-bonding potential. These discoveries will aid design of inhibitors that discriminate among the JAK family and more widely among protein kinases.

A New Method for Quantitative Determination of Two Uronic Acids by CZE with Direct UV Detection

A new method using capillary zone electrophoresis was developed for the rapid quantification of two common uronic acids, galacturonic acid and glucuronic acid, based on utilization of an alkaline background electrolyte with reversed electroosmotic flow (EOF) within 16 min. The method relies on in-capillary reaction and direct UV detection at the wavelength 270 nm. The optimum electrolyte solution was prepared of 130 mm sodium hydroxide, 36 mm disodium hydrogen phosphate dihydrate and 0.5 mm cetyltrimethylammonium bromide. EOF was reversed to detect uronic acids and to improve the separation of neutral sugars. The established method was validated and the results showed good linearity, high precision and satisfactory sensitivity. The newly developed method was successfully applied to analyze galacturonic acid and glucuronic acid content in Forsythia suspensa polysaccharides. The method is fast since only sample hydrolysis and dilution are required in the sample preparation.

Development and Application of a Rapid and Efficient CZE Method Coupled with Correction Factors for Determination of Monosaccharide Composition of Acidic Hetero-polysaccharides from Ephedra Sinica

Ephedrine alkaloids cannot account for all the effects of Ephedra sinica and the polysaccharides are also demonstrated to be one of the main bioactive constituents of E. sinica. However, no work has been reported on the analysis of monosaccharide composition of purified polysaccharides isolated from the stem of E. sinica.

A New Species of Lepiota from China

In this report we describe the three species in Lepiota sect. Lepiota occurring in tropical China. Lepiota attenuata is a new species and is characterized by a pileus with brownish yellow squamules and radially sulcate striate margin, penguin-shaped spores that are distinctively narrowed toward the apex and inflated submoniliform or catenulate elements in the pileus covering. We compared the type specimens of L. metulispora and L. thrombophora with tropical Chinese specimens; both taxa occur in the study area. Phylogenetic relationships among the tropical Chinese species and other closely related species in the genus were inferred based on DNA sequences of the nuclear ribosomal genes (ITS, LSU and IGS) and the mitochondrial small ribosomal RNA gene (mtSSU).

Deformation and Stress Distribution of the Human Foot After Plantar Ligaments Release: a Cadaveric Study and Finite Element Analysis

The majority of foot deformities are related to arch collapse or instability, especially the longitudinal arch. Although the relationship between the plantar fascia and arch height has been previously investigated, the stress distribution remains unclear. The aim of this study was to explore the role of the plantar ligaments in foot arch biomechanics. We constructed a geometrical detailed three-dimensional (3-D) finite element (FE) model of the human foot and ankle from computer tomography images. The model comprised the majority of joints in the foot as well as bone segments, major ligaments, and plantar soft tissue. Release of the plantar fascia and other ligaments was simulated to evaluate the corresponding biomechanical effects on load distribution of the bony and ligamentous structures. These intrinsic ligaments of the foot arch were sectioned to simulate different pathologic situations of injury to the plantar ligaments, and to explore bone segment displacement and stress distribution. The validity of the 3-D FE model was verified by comparing results with experimentally measured data via the displacement and von Mise stress of each bone segment. Plantar fascia release decreased arch height, but did not cause total collapse of the foot arch. The longitudinal foot arch was lost when all the four major plantar ligaments were sectioned simultaneously. Plantar fascia release was compromised by increased strain applied to the plantar ligaments and intensified stress in the midfoot and metatarsal bones. Load redistribution among the centralized metatarsal bones and focal stress relief at the calcaneal insertion were predicted. The 3-D FE model indicated that plantar fascia release may provide relief of focal stress and associated heel pain. However, these operative procedures may pose a risk to arch stability and clinically may produce dorsolateral midfoot pain. The initial strategy for treating plantar fasciitis should be non-operative.

Calcium Protects Roots of Sedum Alfredii H. Against Cadmium-induced Oxidative Stress

Sedum alfredii is a well-known Cd (cadmium) hyperaccumulator native to China. The impacts of exogenous Ca on Cd-induced oxidative stress and antioxidant systems in roots of S. alfredii were investigated by using cellular and biochemical approaches. Supplementation of the medium with higher Ca levels resulted in alleviated growth inhibition and decreased Cd concentration, as well as increased Ca concentration in roots. Cadmium induced lipid peroxidation and loss of plasma membrane integrity, reactive oxygen species overproduction, as well as ultrastructural changes of root cells were largely reversed by Ca supplementation in the medium. Calcium application significantly altered the Cd effects on antioxidant enzymes and non-enzyme antioxidants (non-protein thiols), and significantly increased glutathione (GSH) biosynthesis. The results suggest that Ca is able to protect the roots of S. alfredii against Cd toxicity by restoration of Cd-displaced Ca, alleviation of the metal induced oxidative stress, as well as promotion of GSH biosynthesis.

Postoperative Radiotherapy for Resected Pathological Stage IIIA-N2 Non-small Cell Lung Cancer: a Retrospective Study of 221 Cases from a Single Institution

For patients with resected pathological stage IIIA-N2 non-small cell lung cancer (NSCLC), the role of postoperative radiotherapy (PORT) is not well defined. In this single-institutional study, we re-evaluated the effect of PORT on overall survival (OS) as well as tumor control in this subgroup of patients.

Three-dimensional Conformal Radiation Therapy of Spontaneous Benign Prostatic Hyperplasia in Canines

The purpose of this study was to determine the effect and possible mechanism of three-dimensional conformal stereotactic radiation therapy (3D-CRT) for the treatment of spontaneous benign prostatic hyperplasia (BPH) in a canine model. Eight canines (7-15 years old) with spontaneous benign prostatic hyperplasia (prostate volume >18 cm3) were used as experimental models. The prostates were directly exposed to 3D-CRT at a total dose of 14 Gy. Serum prostate-specific antigen (PSA) and prostate acid phosphatase (PAP), prostate volume (measured by transrectal ultrasound), apoptosis index [AI, measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)], proliferation index [PI, measured by proliferating cell nuclear antigen (PCNA) expression], alpha-SMA, Bax, and bFGF were measured before and after radiation therapy. Histopathology of the prostate, rectum, and bladder tissue was also examined before and after irradiation. 3D-CRT treatment significantly decreased prostate volume, and the PI, PSA, and alpha-SMA, but significantly increased the AI, and had no effect on PAP. There was no evidence of Bax expression before or after irradiation. Irradiation led to no detectable symptoms of diarrhea or changes in stool, but did lead to minor bladder injury, based on light microscopy, scanning electron microscopy, and transmission electron microscopy. In our canine model, 3D-CRT is an effective, noninvasive treatment of BPH that is associated with minimal side effects. Our treatment appeared to reduce prostate size by treatment of the underlying pathological processes.

[Thoracic Radiation Therapy Improves the Prognosis for Patients with Extensive Stage Small-cell Lung Cancer]

To evaluate the effect of thoracic radiation therapy (TRT) on patients with extensive stage small-cell lung cancer (SCLC).

Analysis of Associations Between the Patterns of Global DNA Hypomethylation and Expression of DNA Methyltransferase in Patients with Systemic Lupus Erythematosus

To analyze associations between the patterns of global DNA hypomethylation and expression of DNA methyltransferase (DNMT1, DNMT3A, and DNMT3B) in patients with systemic lupus erythematosus (SLE) and to obtain a deeper understanding of the role that epigenetic mechanism may have on SLE.

Efficacy of Allogeneic Mesenchymal Stem Cell Transplantation in Patients with Drug-resistant Polymyositis and Dermatomyositis

To assess the safety and clinical efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in a small-scale pilot study with 10 patients with drug-resistant polymyositis (PM) or dermatomyositis (DM).

Association of Clinicopathologic Parameters with the Expression of Inducible Nitric Oxide Synthase and Vascular Endothelial Growth Factor in Mucoepidermoid Carcinoma

The roles that inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) play in tumorigenesis have been given special attention. In many tumors, their expression is upregulated. In addition, iNOS can stimulate the expression of VEGF. This study was carried out to investigate the expression of iNOS and VEGF as well as their relationship with angiogenesis and the clinicopathological characteristics of mucoepidermoid carcinoma (MEC).

Transparent Conductive Graphene Films Synthesized by Ambient Pressure Chemical Vapor Deposition Used As the Front Electrode of CdTe Solar Cells

Molecular Mechanism of Silymarin-induced Apoptosis in a Highly Metastatic Lung Cancer Cell Line Anip973

Silymarin, the main flavonoid constituent element extracted from Silybum marianum possessing antioxidant activity, is already known to be able to block the NF-κB activation process and result in cell apoptosis, implicating silymarin's potential to control cancer cell growth.

Lianqiaoxinoside B, a Novel Caffeoyl Phenylethanoid Glycoside from Forsythia Suspensa

Chemical investigation of the 70% ethanol extract of the unripe fruits of Forsythia suspensa resulted in the isolation of a novel caffeoyl phenylethanoid glycoside, lianqiaoxinoside B, together with the known compound forsythoside H. The new compound was elucidated to be 1'',2''-[β-(3,4,-dihydroxylphenyl)-α,β-dioxoethanol]-3''-O-caffeoyl-O-α-rhamnopyranosyl-(1→6)-O-β-glucopyranoside by extensive spectroscopic and chemical studies. Lianqiaoxinoside B and forsythoside H showed strong antioxidant and antimicrobial activities in vitro by the 2,2'-azinobis-3-ethylbenzothiazoline-6-sulphonate (ABTS) radical-scavenging assay and plate method. This study can be further extended to exploit for the possible application of caffeoyl phenylethanoid glycosides as the alternative antioxidants and antimicrobial agents of natural origin.

Susceptibility of Staphylococcus Aureus Biofilms to Reactive Discharge Gases

Formation of bacterial biofilms at solid-liquid interfaces creates numerous problems in both industrial and biomedical sciences. In this study, the susceptibility of Staphylococcus aureus biofilms to discharge gas generated from plasma was tested. It was found that despite distinct chemical/physical properties, discharge gases from oxygen, nitrogen, and argon demonstrated very potent and almost the same anti-biofilm activity. The bacterial cells in S. aureus biofilms were killed (>99.9%) by discharge gas within minutes of exposure. Under optimal experimental conditions, no bacteria and biofilm re-growth from discharge gas treated biofilms was found. Further studies revealed that the anti-biofilm activity of the discharge gas occurred by two distinct mechanisms: (1) killing bacteria in biofilms by causing severe cell membrane damage, and (2) damaging the extracellular polymeric matrix in the architecture of the biofilm to release biofilm from the surface of the solid substratum. Information gathered from this study provides an insight into the anti-biofilm mechanisms of plasma and confirms the applications of discharge gas in the treatment of biofilms and biofilm related bacterial infections.

[On Qi-huang Culture]

Qi-Huang is a short name for TCM, Qi-huang culture, i.e. the culture of TCM. The textual investigation on Qibo's biography and his cadastral records, as well as his contribution to life science is the key to clarify the cultural origins of TCM. Lacking of historical data, the study on Qibo is difficult to be extended profoundly. It is necessary to cut in from the aspect of culture and start field study. According to the historical records and the cultural relics discovered and unearthed, the fragment of Qibo's life was explored. It is thought that Xinmi is one of the important origins of Qi-huang culture. So it is important to grasp the concept of culture to expound and extend the Qi-huang culture, as well as extract the figures of the culture, all these are so important to study Qibo.

Study on the Relationship Between TSHR Gene and Thyroid Diseases

Thyroid stimulating hormone receptor (TSHR) is thought to play a critical role in the pathogenesis of certain thyroid diseases, including Graves' disease (GD), multinodular thyroid goiter (MTG), and Hashimoto's thyroiditis (HT). In order to understand whether single nucleotide polymorphisms in the TSHR gene contribute to thyroid diseases, we have conducted a case-control study in which, we examined 8 TSHR gene single-nucleotide polymorphisms in introns 1, 4, 5, 6 and exons 7 and 8, respectively, among patients with thyroid diseases. These included one family with GD (3 patients and 9 healthy members); 60 patients with familiar thyroid diseases (30 with GD, 20 with MTG, and 10 with HT patients), 48 sporadic patients with GD and 96 healthy control individuals. Direct sequencing of all 10 exons and part of introns of TSHR gene, in these patients as well as healthy controls revealed eight polymorphisms. A novel polymorphism in exon 8 AGA(Arg) → CGA(Arg). However, there were no significant differences between patients and controls in the incidence of these polymorphisms. These results suggest that the polymorphisms (polymorphism in intron 1 at 81 bp upstream of exon 2; polymorphism in intron 4 at 135 bp upstream of exon 5; polymorphism in intron 4 at 365 bp upstream of exon 5; polymorphism in intron 5 at 69 bp upstream of exon 6; means polymorphism in intron 6 at 13 bp downstream of exon 6; polymorphism in intron 6 at 187 bp upstream of exon 7; E7+16: polymorphism in 16 bp of exon 7; polymorphism in 40 bp of exon 8) of the TSHR gene may not contribute to the pathogenesis of thyroid diseases.

A Genome-wide Association Study Identifies Two New Risk Loci for Graves' Disease

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.

The Application of ZnO Luminescent Nanoparticles in Labeling Mice

Photoluminescent ZnO@polymer core-shell nanoparticles were used in mouse imaging through intradermal injections and intravenous injections, and the results proved that such ZnO fluorescence probes are nontoxic to live mice and have great potential in in vivo applications.

The Activity of a Small Lytic Peptide PTP-7 on Staphylococcus Aureus Biofilms

One of the most important features of bacterial biofilms is their resistance to antibiotics and to the host immune system. In this study, we have found that a small lytic peptide, PTP-7, is very potent to Gram-positive bacteria and is able to kill antibiotic sensitive and resistant Staphylococcus aureus indiscriminately. Further studies have revealed that despite being a cationic peptide, the antibacterial activity of PTP-7 was not affected by the negatively charged extracellular polymeric substance (EPS) of biofilms. PTP-7 could diffuse into the deep layer of S. aureus biofilms to kill bacteria inside biofilms efficiently and effectively. Neither the high concentrations of metal ions nor the acidic pH in biofilms affected the activity of peptide PTP-7. It seems that the unique sequence/structure together with the resistant bacteria killing ability of peptide PTP-7 confers its anti-biofilm activity. This study sheds new light on the treatment of bacterial biofilms, especially various biofilm related infections.

Efficacy and Safety of Bevacizumab Plus Chemotherapy in Chinese Patients with Metastatic Colorectal Cancer: a Randomized Phase III ARTIST Trial

The efficacy and safety of bevacizumab with modified irinotecan, leucovorin bolus, and 5-fluorouracil intravenous infusion (mIFL) in the first-line treatment of metastatic colorectal cancer (mCRC) has not been well evaluated in randomized clinical trials in Chinese patients. We conducted a phrase III trial in which patients with previously untreated mCRC were randomized 2:1 to the mIFL [irinotecan (125 mg/m(2)), leucovorin (20 mg/m(2)) bolus, and 5-fluorouracil intravenous infusion (500 mg/m(2)) weekly for four weeks every six weeks] plus bevacizumab (5 mg/kg every two weeks) group and the mIFL group, respectively. Co-primary objectives were progression-free survival (PFS) and 6-month PFS rate. In total, 214 patients were enrolled. Our results showed that addition of bevacizumab to mIFL significantly improved median PFS (4.2 months in the mIFL group vs. 8.3 months in the bevacizumab plus mIFL group, P < 0.001), 6-month PFS rate (25.0% vs. 62.6%, P < 0.001), median overall survival (13.4 months vs. 18.7 months, P = 0.014), and response rate (17% vs. 35%, P = 0.013). Grades 3 and 4 adverse events included diarrhea (21% in the mIFL group and 26% in the bevacizumab plus mIFL group) and neutropenia (19% in the mIFL group and 33% in the bevacizumab plus mIFL group). No wound-healing complications or congestive heart failure occurred. Our results suggested that bevacizumab plus mIFL is effective and well tolerated as first-line treatment for Chinese patients with mCRC. Clinical benefit and safety profiles were consistent with those observed in pivotal phase III trials with mainly Caucasian patients.

Genetic Polymorphisms of GSTP1 and XRCC1: Prediction of Clinical Outcome of Platinum-based Chemotherapy in Advanced Non-small Cell Lung Cancer (NSCLC) Patients

Platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of GSTP1 and XRCC1 involved in glutathione metabolic and DNA repair pathways may explain inter individual differences in chemosensitivity and clinical outcome in NSCLC patients treated with platinum-based regimens.

Antioxidants Modulate Molecular Mobility, Oxygen Permeability, and Microstructure in Zein Films

The effect of octyl gallate and propyl gallate on the molecular mobility, oxygen permeability, and microstructure of zein/glycerol films was studied. Films were cast from 70% ethanol/water containing 20% (w/w) glycerol and different amounts of the antioxidants propyl gallate or octyl gallate. The oxygen permeability and local mobility of these films were measured using phosphorescence from the dispersed triplet probe erythrosin B. Although both antioxidants increased the local mobility of the zein matrix to about the same extent, octyl gallate and to a lesser extent propyl gallate dramatically increased the permeability of the film to oxygen. Atomic force microscopy imaging indicated that propyl gallate induced aggregation of zein complexes, which could lead to a more condensed film. These results indicate that the addition of specific functional ingredients, such as antioxidants, to edible films may significantly affect the physical properties and structure and, thus, functional properties in ways that influence their eventual use.

Predictive Value of Preablation Stimulated Thyroglobulin and Thyroglobulin/thyroid-stimulating Hormone Ratio in Differentiated Thyroid Cancer

Recent studies have shown that thyroglobulin (Tg) concentration is a useful tumor marker in follow-up of differentiated thyroid cancer (DTC) patients after thyroidectomy and subsequent radioiodine (I-131) therapy. However, its role is controversial after total or near-total thyroidectomy before the first I-131 ablative treatment. So, we used thyroid-stimulating hormone (TSH) levels to normalize predictive values of Tg for DTC.

[Therapeutic Efficacy of Three-dimensional Conformal Radiation Therapy for Patients with Locally Advanced Non-small Cell Lung Cancer]

To compare the treatment results of three-dimensional conformal radiotherapy (3D-CRT) and conventional radiotherapy (2D) for patients with locally advanced non-small-cell lung cancer (NSCLC).

[Clinical Analysis of 79 Gastrointestinal Tract Stromal Tumor Cases]

(211)-Orientation Preference of Transparent Conducting In2O3:Sn Films and Its Formation Mechanism

Dominantly (211)-oriented In(2)O(3):Sn (ITO) transparent conducting oxide (TCO) films were first fabricated at high sputtering power in the weak reducing ambient with superior electrical and optical properties. The dependence of ITO film orientation on growth condition was systematically investigated, and the formation mechanism was studied by surface energy calculation and band structure simulation. The unique properties of the (211)-oriented films should be ascribed to the richest In-terminated surface of the (211) plane, which is tightly correlated with the comparably highest surface energy and highest conduction band surface comparing with the other two typical planes of (222) and (400). The as-prepared (211)-oriented ITO films with the In-rich ending atoms on the surface are of great significance for the transparent electrode applications.

Gene Expression Changes in the Pituitary Gland of Rats Exposed to Electromagnetic Pulses

We examined alterations in the expression of tumorigenesis-related genes in the pituitary gland of rats exposed to electromagnetic pulses (EMP).

Anti-tumor Effects of PEgr-1-endostatin-TNF-α Recombinant Plasmid Expression Induced by Ionizing Radiation

The aim of the present study was to investigate the anti-tumor effect of a pEgr-1-endostatin-TNF-α recombinant plasmid induced by ionizing radiation.

Polymorphism of DNA Repair Gene XRCC1 and Hepatocellular Carcinoma Risk in Chinese Population

We conducted a case-control study in China to clarify the association between the XRCC1-Arg399Gln polymorphism and HCC risk.

Multicenter Clinical Study for Evaluation of Efficacy and Safety of Transdermal Fentanyl Matrix Patch in Treatment of Moderate to Severe Cancer Pain in 474 Chinese Cancer Patients

Although a new matrix formulation fentanyl has been used throughout the world for cancer pain management, few data about its efficacy and clinical outcomes associated with its use in Chinese patients have been obtained. This study aimed to assess the efficacy and safety of the new system in Chinese patients with moderate to severe cancer pain.

Allogeneic Mesenchymal Stem Cell Transplantation in Seven Patients with Refractory Inflammatory Bowel Disease

In Vivo Reflectance Confocal Microscopy of Extramammary Paget Disease: Diagnostic Evaluation and Surgical Management

Extramammary Paget disease (EMPD) is a diagnostic challenge. In vivo reflectance confocal microscopy (RCM) has been reported to be useful for in vivo skin tumor evaluation. It may also assist in the surgical management of EMPD lesions.

Comparison of Setup Error Using Different Reference Images: a Phantom and Lung Cancer Patients Study

The purpose of this study was to compare setup errors obtained with kilovoltage cone-beam computed tomography (CBCT) and 2 different kinds of reference images, free-breathing 3D localization CT images (FB-CT) and the average images of 4-D localization CT images (AVG-CT) for phantom and lung cancer patients. This study also explored the correlation between the difference of translational setup errors and the gross tumor volume (GTV) motion. A respiratory phantom and 14 patients were enrolled in this study. For phantom and each patient, 3D helical CT and 4D CT images were acquired, and AVG-CT images were generated from the 4D CT. The setup errors were determined based on the image registration between the CBCT and the 2 different reference images, respectively. The data for both translational and rotational setup errors were analyzed and compared. The GTV centroid movement as well as its correlation with the translational setup error differences was also evaluated. In the phantom study, the AVG-CT method was more accurate than the FB-CT method. For patients, the translational setup errors based on FB-CT were significantly larger than those from AVG-CT in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions (p < 0.05). Translational setup errors differed by >1 mm in 32.6% and >2 mm in 12.9% of CBCT scans. The rotational setup errors from FB-CT were significantly different from those from AVG-CT in the LR and AP directions (p < 0.05). The correlation coefficient of the translational setup error differences and the GTV centroid movement in the LR, SI, and AP directions was 0.515 (p = 0.060), 0.902 (p < 0.001), and 0.510 (p = 0.062), respectively. For lung cancer patients, respiration may affect the on-line target position location. AVG-CT provides different reference information than FB-CT. The difference in SI direction caused by the 2 methods increases with the GTV movement. Therefore, AVG-CT should be the prefered choice of reference images.

Allogeneic Mesenchymal Stem Cells Transplantation in Patients with Refractory RA

This study aimed to determine the safety and efficacy of allogeneic mesenchymal stem cells transplantation (MSCT) in refractory rheumatoid arthritis (RA). Four patients with persistently active RA underwent MSCT. The outcome was evaluated by changes in the visual analog scale (VAS 100 mm) pain score, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and 28-joint disease activity score (DAS-28). Three of four patients received a reduction in ESR, DAS-28, and pain VAS score at 1 and 6 months after transplantation. Two of the three had a European League Against Rheumatism (EULAR) moderate response at 6 months but experienced a relapse at 7 and 23 months, respectively. Two patients had no EULAR response to MSCT. No one had achieved the DAS-28-defined remission in the follow-up period. No serious adverse events were reported. Allogeneic MSCT is a safe treatment in severe and resistant RA, but the effectiveness needs to be clarified.

Ligand- and Protein-based Modeling Studies of the Inhibitors of Human Cytochrome P450 2D6 and a Virtual Screening for Potential Inhibitors from the Chinese Herbal Medicine, Scutellaria Baicalensis (Huangqin,Baikal Skullcap)

We have previously examined the binding patterns of various substrates to human cytochrome P450 2D6 (CYP2D6) using a series of molecular modeling methods. In this study, we further explored the binding modes of various types of inhibitors to CYP2D6 using a combination of ligand- and protein-based modeling approaches. Firstly, we developed and validated a pharmacophore model for CYP2D6 inhibitors, which consisted of two hydrophobic features and one hydrogen bond acceptor feature. Secondly, we constructed and validated a quantitative structure-activity relationship (QSAR) model for CYP2D6 inhibitors which gave a poor to moderate prediction accuracy. Thirdly, a panel of CYP2D6 inhibitors were subject to molecular docking into the active site of wild-type and mutated CYP2D6 enzyme. We demonstrated that 8 residues in the active site (Leu213, Glu216, Ser217, Gln244, Asp301, Ser304, Ala305, and Phe483) played an important role in the binding to the inhibitors via hydrogen bond formation and/or π-π stacking interaction. Apparent changes in the binding modes of the inhibitors have been observed with Phe120Ile, Glu216Asp, Asp301Glu mutations in CYP2D6. Finally, we screened for potential binders/inhibitors from the Chinese herbal medicine Scutellaria baicalensis (Huangqin, Baikal Skullcap) using the established pharmacophore model for CYP2D6 inhibitors and molecular docking approach. Overall, 18 out of 40 compounds from S. baicalensis were mapped to the pharmacophore model of CYP2D6 inhibitors and most herbal compounds from S. baicalensis could be docked into the active site of CYP2D6. Our study has provided insights into the molecular mechanisms of interaction of synthetic and herbal compounds with human CYP2D6 and further benchmarking studies are needed to validate our modeling and virtual screening results.

Computational and in Vitro Studies on the Inhibitory Effects of Herbal Compounds on Human Cytochrome P450 1A2

Human CYP1A2 is an important enzyme for drug metabolism and procarcinogen activation. This study aimed to explore the binding mode of ligands with CYP1A2 and to screen potential inhibitors from a library of herbal compounds using computational and in vitro approaches. The heme prosthetic group and six residues (Thr124, Phe125, Phe226, Phe260, Gly316, and Ala317) in the active site of CYP1A2 were identified as important residues for ligand binding using the LIGPLOT program. Ala317 in helix I immediately above heme was highly conserved in most human CYPs with known crystal structures. In molecular docking, 19 of the 56 herbal compounds examined were identified as potential inhibitors of CYP1A2. Up to 21 of the 56 herbal compounds were hit by the pharmacophore model of CYP1A2 inhibitors developed and validated in this study. In the in vitro inhibition study, 8 herbal compounds were identified as moderate to potent inhibitors of CYP1A2. Five of the 8 herbal compounds predicted to be potential inhibitors were confirmed as CYP1A2 inhibitors in the in vitro study. A combination of computational and in vitro approaches, represent a useful tool to identify potential inhibitors for CYP1A2 from herbal compounds.

Pharmacophore, QSAR, and Binding Mode Studies of Substrates of Human Cytochrome P450 2D6 (CYP2D6) Using Molecular Docking and Virtual Mutations and an Application to Chinese Herbal Medicine Screening

The highly polymorphic human cytochrome P450 2D6 (CYP2D6) metabolizes about 25% of currently used drugs. In this study, we have explored the interaction of a large number of substrates (n = 120) with wild-type and mutated CYP2D6 by molecular docking using the CDOCKER module. Before we conducted the molecular docking and virtual mutations, the pharmacophore and QSAR models of CYP2D6 substrates were developed and validated. Finally, we explored the interaction of a traditional Chinese herbal formula, Fangjifuling decoction, with CYP2D6 by virtual screening. The optimized pharmacophore model derived from 20 substrates of CYP2D6 contained two hydrophobic features and one hydrogen bond acceptor feature, giving a relevance ratio of 76% when a validation set of substrates were tested. However, our QSAR models gave poor prediction of the binding affinity of substrates. Our docking study demonstrated that 117 out of 120 substrates could be docked into the active site of CYP2D6. Forty one out of 117 substrates (35.04%) formed hydrogen bonds with various active site residues of CYP2D6 and 53 (45.30%) substrates formed a strong π-π interaction with Phe120 (53/54), with only carvedilol showing π-π interaction with Phe483. The active site residues involving hydrogen bond formation with substrates included Leu213, Lys214, Glu216, Ser217, Gln244, Asp301, Ser304, Ala305, Phe483, and Phe484. Furthermore, the CDOCKER algorithm was further applied to study the impact of mutations of 28 active site residues (mostly non-conserved) of CYP2D6 on substrate binding modes using five probe substrates including bufuralol, debrisoquine, dextromethorphan, sparteine, and tramadol. All mutations of the residues examined altered the hydrogen bond formation and/or aromatic interactions, depending on the probe used in molecular docking. Apparent changes of the binding modes have been observed with the Glu216Asp and Asp301Glu mutants. Overall, 60 compounds out of 130 from Fangjifuling decoction matched our pharmacophore model for CYP2D6 substrates. Fifty four out of these 60 compounds could be docked into the active site of CYP2D6 and 24 of 54 compounds formed hydrogen bonds with Glu216, Asp301, Ser304, and Ala305 in CYP2D6. These results have provided further insights into the factors that determining the binding modes of substrates to CYP2D6. Screening of high-affinity ligands for CYP2D6 from herbal formula using computational models is a useful approach to identify potential herb-drug interactions.

Transcriptional Repressor Snail and Metastasis in Hepatocellular Carcinoma

We aimed to elucidate the effect of Snail transcriptional factor on invasion and metastasis and related molecular mechanisms in HCC.

Neuroprotective Effect of Ginkgolide K on Glutamate-induced Cytotoxicity in PC 12 Cells Via Inhibition of ROS Generation and Ca(2+) Influx

Glutamate is considered to be responsible for the pathogenesis of cerebral ischemia disease. [Ca(2+)](i) influx and reactive oxygen species (ROS) production are considered to be involved in glutamate-induced apoptosis process. In this study, we investigated the neuroprotective effects of ginkgolide K in the glutamate-induced rat's adrenal pheochromocytoma cell line (PC 12 cells) and the possible mechanism. Glutamate cytotoxicity in PC 12 cells was accompanied by an increment of malondialdehyde (MDA) content and lactate dehydrogenase (LDH) release, as well as Ca(2+) influx, bax/bcl-2 ratio, cytochrome c release, caspase-3 protein and ROS generation, and reduction of cell viability and mitochondrial membrane potential (MMP). Moreover, treatment with glutamate alone resulted in decrease activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity. However, pretreatment with ginkgolide K significantly reduced MDA content, LDH release, as well as Ca(2+) influx, cytochrome c release, bax/bcl-2 ratio, caspase-3 protein and ROS production, and attenuated the decrease of cells viability and MMP. In addition, ginkgolide K remarkedly up-regulated SOD and GSH-PX activities. All these findings indicated that ginkgolide K protected PC12 cells against glutamate-induced apoptosis by inhibiting Ca(2+) influx and ROS production. Therefore, the present study supports the notion that ginkgolide K may be a promising neuroprotective agent for the treatment of cerebral ischemia disease.

Alkylboronic Esters from Copper-catalyzed Borylation of Primary and Secondary Alkyl Halides and Pseudohalides

Easy access: An unprecedented copper-catalyzed cross-coupling reaction of the title compounds with diboron reagents is described (see scheme; Ts = 4-toluenesulfonyl). This reaction can be used to prepare both primary and secondary alkylboronic esters having diverse structures and functional groups. The resulting products would be difficult to access by other means.

Clinical Features and Management Outcomes of Severe Hand, Foot and Mouth Disease

This study was designed to describe the clinical features and management outcomes of severe hand, foot and mouth disease (HFMD).

Structural Properties and 4f → 5d Absorptions in Ce-doped LuAlO₃: a First-principles Study

The structural properties and the 4f → 5d absorptions of Ce-doped LuAlO(3) have been studied using the density functional theory-based generalized gradient approximation PBE + U (PBE: Perdew, Burke and Ernzerhof) and wavefunction-based embedded cluster calculations, respectively. The PBE or PBE + U calculations reveal that the substitution of Ce for Lu induces a strongly anisotropic distortion of the local atomic structure around the dopant site, which is largely insensitive to the value of U for the Ce 4f states. The calculated electronic structures depend explicitly on the value of U, and a value of U ≈ 6 eV is determined by comparison with experimental x-ray photoelectron data for CeAlO(3). On the basis of the PBE-optimized structure, CASSCF/CASPT2 (complete-active-space self-consistent-field/second-order perturbation theory) embedded cluster calculations for the Ce(3+) 4f → 5d transitions yield energy and intensity patterns in fairly good agreement with those estimated from the experimental absorption spectrum. A Mulliken spin population analysis for the 5d(1) states shows that the origins of the states are significantly different from being caused by the cubic crystal field, confirming an earlier conclusion as regards the origin of the 5d(1) states based on semiempirical molecular orbital calculations. The importance of spin-orbit effects on the energies and wavefunctions of the Ce 5d(1) states is highlighted.

Effects of Risperidone and Haloperidol on Superoxide Dismutase and Nitric Oxide in Schizophrenia

Oxidative stress may be involved in the pathophysiology of schizophrenia. No double-blind study has compared the effects of typical and atypical antipsychotics on both antioxidant enzyme activity and nitric oxide (NO) levels in schizophrenic patients. Seventy-eight inpatients with chronic schizophrenia were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol using a double-blind design. Clinical efficacy was determined using the Positive and Negative Syndrome Scale. Blood superoxide dismutase (SOD) and plasma NO levels were measured in patients and 30 normal controls. Our results showed that following a 2-week washout period, levels of SOD and NO were significantly increased in patients with schizophrenia compared to normal controls. Both risperidone and haloperidol equivalently reduced the elevated blood SOD levels in schizophrenia, but neither medication reduced the elevated plasma NO levels in schizophrenia. Low blood SOD levels at baseline predicted greater symptom improvement during treatment, and greater change in SOD was correlated with greater symptom improvement. These results suggest that both typical and atypical antipsychotic drugs may at least partially normalize abnormal free radical metabolism in schizophrenia, and some free radical parameters at baseline may predict antipsychotic responses of schizophrenic patients.

Lytic Peptides with Improved Stability and Selectivity Designed for Cancer Treatment

Lytic peptides are a group of membrane-acting peptides, which have excellent activity to drug-resistant cells. In this study, the stability and tumor selectivity of newly designed pH-activated lytic peptides were studied. We found that despite varied secondary structures, pH-induced structure changes could not be directly linked to the activity and pH sensitivity of peptides. On the contrary, formation of aggregates had great impacts on peptide binding and insertion into the lipid bilayer of cell membrane. It was found that the pH controlled peptide aggregation and dissolution was responsible for the pH-dependent membrane lysis activity of peptides. One peptide (PTP-7c) formed stable amyloid fibrils, which did not completely dissolve under acidic conditions. As a result, PTP-7c had the lowest membrane lysis and cell killing activities among tested lytic peptides. As solid tumors have consistently low extracellular pHs, peptides with acid-activation features showed improved selectivity to cancer cells. In addition, self-assembled lytic peptides were found to become more stable and showed dramatically increased half lives (up to 11 h) in human plasma. These new lytic peptides with good stability and acid-activated cell lysis activity will have wide biomedical applications especially for the treatment of cancers in which drug resistance has developed.

Low BDNF is Associated with Cognitive Impairment in Chronic Patients with Schizophrenia

Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. Schizophrenia has a range of cognitive deficits that may evolve from decreased BDNF, and this study examines this association of BDNF with cognitive deficits in schizophrenia.

Inhibition of AKT2 Enhances Sensitivity to Gemcitabine Via Regulating PUMA and NF-κB Signaling Pathway in Human Pancreatic Ductal Adenocarcinoma

Invasion, metastasis and resistance to conventional chemotherapeutic agents are obstacles to successful treatment of pancreatic cancer, and a better understanding of the molecular basis of this malignancy may lead to improved therapeutics. In the present study, we investigated whether AKT2 silencing sensitized pancreatic cancer L3.6pl, BxPC-3, PANC-1 and MIAPaCa-2 cells to gemcitabine via regulating PUMA (p53-upregulated modulator of apoptosis) and nuclear factor (NF)-κB signaling pathway. MTT, TUNEL, EMSA and NF-κB reporter assays were used to detect tumor cell proliferation, apoptosis and NF-κB activity. Western blotting was used to detect different protein levels. Xenograft of established tumors was used to evaluate primary tumor growth and apoptosis after treatment with gemcitabine alone or in combination with AKT2 siRNA. Gemcitabine activated AKT2 and NF-κB in MIAPaCa-2 and L3.6pl cells in vitro or in vivo, and in PANC-1 cells only in vivo. Gemcitabine only activated NF-κB in BxPC-3 cells in vitro. The presence of PUMA was necessary for gemcitabine-induced apoptosis only in BxPC-3 cells in vitro. AKT2 inhibition sensitized gemcitabine-induced apoptosis via PUMA upregulation in MIAPaCa-2 cells in vitro, and via NF-κB activity inhibition in L3.6pl cells in vitro. In PANC-1 and MIAPaCa-2 cells in vivo, AKT2 inhibition sensitized gemcitabine-induced apoptosis and growth inhibition via both PUMA upregulation and NF-κB inhibition. We suggest that AKT2 inhibition abrogates gemcitabine-induced activation of AKT2 and NF-κB, and promotes gemcitabine-induced PUMA upregulation, resulting in chemosensitization of pancreatic tumors to gemcitabine, which is probably an important strategy for the treatment of pancreatic cancer.

Meta-analysis Identifies Common Variants Associated with Body Mass Index in East Asians

Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10(-8)), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10(-7). Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.

Cigarette Smoking in Male Patients with Chronic Schizophrenia in a Chinese Population: Prevalence and Relationship to Clinical Phenotypes

The high prevalence of smoking in schizophrenia of European background may be related to smoking's reducing clinical symptoms and medication side effects. Because smoking prevalence and its associations with clinical phenotypes are less well characterized in Chinese than European patients with schizophrenia, we assessed these smoking behaviors using clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence (FTND) in 776 Chinese male schizophrenia and 560 control subjects. Patients also were rated on the Positive and Negative Symptom Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS). We found that the schizophrenia patients had a higher lifetime incidence of smoking (79% vs 63%), were more likely to be heavy smokers (61% vs 31%), and had lower smoking cessation rates (4% vs 9%) (all p<0.0001) than controls. Among the schizophrenia patients smoking prevalence increased with age, with the largest difference from controls in the age cohort of 55-75 years: 75% vs 46% (p<0.0001). Among the schizophrenia smokers 73% started to smoke before the onset of their illness by an average of 7.6 years. The patients with schizophrenia who were current smokers scored significantly lower on the PANSS negative symptom subscore (p<0.005), and on the SAES symptom scale (p<0.04; Bonferroni corrected p>0.05) than the non-smoking patients. These results suggest that Chinese males with schizophrenia smoke more frequently than the general population. Further, smokers with schizophrenia may display fewer negative symptoms and possibly less parkinsonism than non-smokers with schizophrenia.

Highly Sensitive Determination of Capsaicin Using a Carbon Paste Electrode Modified with Amino-functionalized Mesoporous Silica

Mesoporous silica (MS) and amino-functionalized mesoporous silica (NH(2)-FMS) were prepared and characterized using the techniques of transmission electron microscopy (TEM) and nitrogen adsorption-desorption. Voltammetry was used to investigate the electrochemical behavior of capsaicin at the amino-functionalized mesoporous silica, which was modified through carbon paste electrode (NH(2)-FMS/CPE). NH(2)-FMS/CPE showed better performance for the electrochemical oxidation of capsaicin, when compared with bare carbon paste electrode (CPE) and mesoporous silica modified carbon paste electrode (MS/CPE). We optimized the experimental conditions influencing the determination of capsaicin. Under optimal conditions, the oxidation peak current was proportional to capsaicin concentration in the range of 0.040-0.40 μmol L(-1)and 0.40-4.0 μmol L(-1), when the detection limit was 0.020 μmol L(-1) (S/N=3). The above method was successfully applied to determine capsaicin in hot pepper samples, yielding satisfactory results. The spiked recoveries were in the range of 93.1-100.7%.

Lower Serum Interleukin-2 Levels in Schizophrenic Patients with Tardive Dyskinesia

We determined serum interleukin-2 (IL-2) levels between schizophrenic patients with (n=45) and without tardive dyskinesia (TD; n=45) compared to normal controls (n=50). TD patients had lower serum IL-2 levels than non-TD patients, but higher IL-2 levels than normal controls. IL-2 was associated with the negative symptoms of schizophrenia, but not with TD severity. Immune disturbance may be involved in the pathophysiology of TD.

Randomized Phase II Study of Concurrent Cisplatin/etoposide or Paclitaxel/carboplatin and Thoracic Radiotherapy in Patients with Stage III Non-small Cell Lung Cancer

OBJECTIVE: To evaluate the activity and safety of concurrent thoracic radiotherapy (TRT) plus weekly paclitaxel/carboplatin (PC) regimen compared with widely used cisplatin/etoposide (PE) regimen in patients with unresectable stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to receive the following treatments: PE arm, cisplatin (50mg/m(2)) on days 1, 8, 29, and 36 and etoposide (50mg/m(2)) on days 1-5 and 29-33 plus 60Gy of TRT; PC arm, weekly concurrent carboplatin (AUC=2) and paclitaxel (45mg/m(2)) plus 60Gy of TRT. RESULTS: A total of 65 patients were randomized (PE arm, n=33; PC arm, n=32). The 3-year overall survival (OS) was significantly better in the PE arm than in the PC arm (33.1% vs. 13%, P=.04). The incidence of Grade 3/4 neutropenia was 78.1% in the PE arm and 51.5% in the PC arm (P=.05). The rate of Grade 2 or greater radiation pneumonitis was 25% in the PE arm and 48.5% in the PC arm (P=.09). CONCLUSIONS: Compared to PE regimen, weekly PC regimen cannot be recommended since it failed to achieve an improvement in either OS or PFS.

Study on the DNA Repair Gene XRCC1 and XRCC3 Polymorphism in Prediction and Prognosis of Hepatocellular Carcinoma Risk

Background/Aims: We conducted a case-control study in China to clarify the association between XRCC1-Arg399Gln polymorphism and HCC risk. Methodology: A total of 150 cases and 158 controls were selected from May 2008 to May 2010. XRCC1-Arg399Gln and XRCC3-Thr241Met polymorphisms were based upon duplex polymerase-chain-reaction with the confronting-two-pair primer (PCR-CTPP) method. All analysis was performed by using the STATA statistical package. Results: A significant increased risk of HCC was associated with XRCC1 399Arg/Gln, and a heavy risk of HCC was also found in individuals with XRCC3 241Met/Met genotypes. A significant association was found between positive HBsAg and Arg/Gln. XRCC3 Thr/Met genotypes had a significant positive association with HBsAg (+) and a heavy risk of HCC was found in HBsAg (+) individuals with XRCC3 Met/Met genotype. Individuals carrying XRCC1 Gln/Gln genotypes showed significantly lower median survival than XRCC1 Arg/Arg genotypes and significant hazard ratio (HR=1.38, 95% CI=1.04-1.84) was found. Meanwhile, we found a moderate HR for XRCC3 Thr/Met (HR=1.96, 95% CI=1.23-3.15) and a heavy HR for XRCC3 Met/Met (HR=2.98, 95% CI=1.77-7.54). Conclusions: In conclusion, we observed that XRCC1-Arg399Gln and XRCC3-Thr241Met polymorphism is associated with susceptibility to HCC and XRCC1 Gln allele and XRCC3 Met allele genotype showed significant poor prognosis of HCC.

Metabolic Monosaccharides Altered Cell Responses to Anticancer Drugs

Metabolic glycoengineering has been used to manipulate the glycochemistry of cell surfaces and thus the cell/cell interaction, cell adhesion, and cell migration. However, potential application of glycoengineering in pharmaceutical sciences has not been studied until recently. Here, we reported that Ac(4)ManNAc, an analog of N-acetyl-D-mannosamine (ManNAc), could affect cell responses to anticancer drugs. Although cells from different tissues and organs responded to Ac(4)ManNAc treatment differently, treated cells with increased sialic acid contents showed dramatically reduced sensitivity (up to 130 times) to anti-cancer drugs as tested on various drugs with distinct chemical structures and acting mechanisms. Neither increased P-glycoprotein activity nor decreased drug uptake was observed during the course of Ac(4)ManNAc treatment. However, greatly altered intracellular drug distributions were observed. Most intracellular daunorubicin was found in the perinuclear region, but not the expected nuclei in the Ac(4)ManNAc treated cells. Since sialoglycoproteins and gangliosides were synthesized in the Golgi, intracellular glycans affected intracellular signal transduction and drug distributions seem to be the main reason for Ac(4)ManNAc affected cell sensitivity to anticancer drugs. It was interesting to find that although Ac(4)ManNAc treated breast cancer cells (MDA-MB-231) maintained the same sensitivity to 5-Fluorouracil, the IC(50) value of 5-Fluorouracil to the same Ac(4)ManNAc treated normal cells (MCF-10A) was increased by more than 20 times. Thus, this Ac(4)ManNAc treatment enlarged drug response difference between normal and tumor cells provides a unique opportunity to further improve the selectivity and therapeutic efficiency of anticancer drugs.

[Therapeutic Efficacies of Bone Grafing for Calcaneal Intra-calcaneal Fractures]

To evaluate the efficacies of treating intra-calcaneal fractures with bone grafting.

Evaluation of DNA Repair Gene XRCC1 Polymorphism in Prediction and Prognosis of Hepatocellular Carcinoma Risk

We conducted a case-control study in China to clarify the association between XRCC1-Arg399Gln polymorphism and HCC risk. A total of 150 cases and 158 controls were selected from the the Affiliated Hospital of Qingdao University from May 2008 to May 2010. XRCC1-Arg399Gln polymorphism was based upon duplex polymerase-chain-reaction with the confronting-two-pair primer (PCR-CTPP) method. All analyses were performed using the STATA statistical package. A significantly increased risk was associated with the Arg/Gln genotype (adjusted OR 1.78, 95%CI=1.13-2.79) compared with genotype Arg/Arg. In contrast, the Gln/Gln genotype had non-significant increased risk of HCC with adjusted OR (95%CI) of 1.69 (0.93-2.66). A significant association was found between positive HBsAg and Arg/Gln, with an OR of 3.43 (95% CI=1.45-8.13). Patients carrying Gln/Gln genotypes showed significantly lower median survival than Arg/Arg genotypes (HR=1.38, 95% CI=1.04-1.84). Further Kaplan-Meier analysis showed decreased median survival in Arg/Gln+Gln/Gln genotype carriers in comparison to Arg/Arg carriers (HR=1.33, 95% CI=1.02-1.76). In conclusion, we observed that XRCC1-Arg399Cln polymorphism is associated with susceptibility to HCC, and XRCC1 Gln allele genotype showed significant prognostic associations.

Risk Factors for Radiation-induced Lung Toxicity in Patients with Non-small Cell Lung Cancer Who Received Postoperative Radiation Therapy

To evaluate the risk factors for radiation-induced lung toxicity (RILT) from post-operative radiation therapy (PORT) in patients with non-small cell lung cancer (NSCLC).

Activity and Selectivity of Histidine-containing Lytic Peptides to Antibiotic-resistant Bacteria

Lytic peptides are a group of membrane-acting peptides that are active to antibiotic-resistant bacteria but demonstrate high toxicity to tissue cells. Here, we reported the construction of new lytic peptide derivatives through the replacement of corresponding lysine/arginine residues in lytic peptide templates with histidines. Resulting lytic peptides had the same lethality to antibiotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus, but showed greatly improved selectivity to bacteria. When incubated with co-cultured bacteria and tissue cells, these histidine-containing lytic peptide derivatives killed bacteria selectively but spared co-cultured human cells. Membrane insertion and peptide-quenching studies revealed that histidine protonation controlled peptide interactions with cell membranes determined the bacterial selectivity of lytic peptide derivatives. Compared with parent peptides, lytic peptide derivatives bound to bacteria strongly and inserted deeply into the bacterial cell membrane. Therefore, histidine-containing lytic peptides represent a new group of antimicrobial peptides for bacterial infections in which the antibiotic resistance has developed.

Randomized Phase II Trial of First-line Treatment with Pemetrexed-cisplatin, Followed Sequentially by Gefitinib or Pemetrexed, in East Asian, Never-smoker Patients with Advanced Non-small Cell Lung Cancer

Treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors or chemotherapy have shown improved survival outcomes in East Asian, never-smoker patients with non-small cell lung cancer (NSCLC). However, treatment sequence has not been optimized in patients with unknown EGFR mutation status. This trial compared first-line chemotherapy with pemetrexed (P)-cisplatin (C), followed by either gefitinib (G) or P maintenance.

Genetic Polymorphism of XRCC1 Correlated with Response to Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer

To examine the association between genetic polymorphisms of XRCC1 Arg399Gln(G→A) and response to oxaliplatin-based chemotherapy in advanced colorectal cancer. XRCC1 genotypes of totally 99 patients(37 stage III, 62 stage IV)with advanced colorectal cancer treated with oxaliplatin-based chemotherapy were detected by TaqMan-MGB probe allelic discrimination method. And clinical response of 62 patients in stage IVafter 2 to 3 cycles of chemotherapy were evaluated. Also time to progress (TTP) of all patients were evaluated. Of the genotype frequencies in all patients, up to 52.53 % were G/G genotype, 9.09 % were A/A genotype, and 38.38 % were G/A genotype. The response rate (CR+PR) of 62 patients in stage IV was 61.29 % (19/31). Patients with G/G genotype showed enhanced respond to chemotherapy compared to those with G/A+A/A (x(2) = 5.6, P = 0.029; OR = 3.845, 95 %CI = 1.231 ~ 12.01, P = 0.018). Individuals with the G/G genotype had a TTP of 10.0 (8.88-11.12) months, those with the G/A+A/A genotype had an TTP of 5.0(4.26-5.74) months. The log-rank test was marginally significant (x(2) = 29.20, P < 0.01). The Cox proportional hazards model, adjusted for stage, performance status, and chemotherapy regimen, showed that only XRCC1 G/G genotypes increases the OR significantly (OR = 3.555; 95 % CI, 2.119 ~ 5.963; P < 0.01). The results suggest that XRCC1 Arg399Gln polymorphisms is associated with the response to oxaliplatin-based chemotherapy and time to progression in advanced colorectal cancer in Chinese population. It is proposed that the XRCC1 Arg399Gln polymorphism should be routinely detected to screen patients who are more likely benefit from oxaliplatin-based treatment.

Prognostic Significance of Snail Expression in Hilar Cholangiocarcinoma

Many patients with hilar cholangiocarcinoma (HC) have a poor prognosis. Snail, a transcription factor and E-cadherin repressor, is a novel prognostic factor in many cancers. The aim of this study was to evaluate the relationship between snail and E-cadherin protein expression and the prognostic significance of snail expression in HC. We examined the protein expression of snail and E-cadherin in HC tissues from 47 patients (22 males and 25 females, mean age 61.2 years) using immunohistochemistry and RT-PCR. Proliferation rate was also evaluated in the same cases by the MIB1 index. High, low and negative snail protein expression was recorded in 18 (38%), 17 (36%), and 12 (26%) cases, respectively, and 40.4% (19/47) cases showed reduced E-cadherin protein expression in HC samples. No significant correlation was found between snail and E-cadherin protein expression levels (P = 0.056). No significant correlation was found between snail protein expression levels and gender, age, tumor grade, vascular or perineural invasion, nodal metastasis and invasion, or proliferative index. Cancer samples with positive snail protein expression were associated with poor survival compared with the negative expresser groups. Kaplan-Meier curves comparing different snail protein expression levels to survival showed highly significant separation (P < 0.0001, log-rank test). With multivariate analysis, only snail protein expression among all parameters was found to influence survival (P = 0.0003). We suggest that snail expression levels can predict poor survival regardless of pathological features and tumor proliferation. Immunohistochemical detection of snail protein expression levels in routine sections may provide the first biological prognostic marker.

Hepatic Artery Injection of ¹³¹I-labelled Metuximab Combined with Chemoembolization for Intermediate Hepatocellular Carcinoma: a Prospective Nonrandomized Study

Hepatocellular carcinoma (HCC) is the fifth and seventh most common cause of cancer in men and women, respectively. Transcatheter arterial chemoembolization (TACE) is the standardized therapy for the intermediate stage of HCC. However, the 3-year overall survival remains low (<30 %) in these patients. Thus, there is a critical need for the development of treatment modalities to improve the survival rate. This study aimed to evaluate whether the combination of (131)I-metuximab with chemoembolization could improve treatment efficiency.

Influence of Irrigation on Incision and Coagulation of 2.0-μm Continuous-wave Laser: an Ex Vivo Study

Several lasers are suitable for laparoscopic surgery but with remarkable smoke formation, which compromises surgical visibility and safety. Slow irrigation eliminates laser smoke efficiently, but gives rise to the concern of reducing the laser incision and coagulation efficiency.

Anticancer Effect of Tert-butyl-2(4,5-dihydrogen-4,4,5,5-tetramethyl-3-O-1H-imidazole-3-cationic-1-oxyl-2)-pyrrolidine-1-carboxylic Ester on Human Hepatoma HepG2 Cell Line

Tert-butyl-2(4,5-dihydrogen-4,4,5,5-tetramethyl-3-O-1H-imidazole-3-cationic-1-oxyl-2)-pyrrolidine-1-carboxylic ester (L-NNP) is a stable nitroxyl nitroxide radical, which have displayed cytotoxicity on human breast cancer MCF-7 and MDA-MB-231 cell lines. In the present study, we investigated the selective cytotoxicity of L-NNP on isogenetic human hepatoma HepG2 and normal L-02 cell lines. Cell growth inhibition, intracellular reactive oxygen species production, the mitochondrial membrane potential loss, malondialdehyde generation and glutathione levels were analyzed. The expression of Bax, Bcl-2 and NF-κBp65 proteins was also examined. The anticancer activity was evaluated in a HepG2 cell xenograft nude mice model. The results showed that 10, 20, 40 μg/ml L-NNP exposure for 48 h caused 52%, 82% and 91% cell growth inhibition of HepG2 cells, compared with 5%, 10% and 15% that of L-02 cells (p < 0.01). Concentrations of 10, 20, 40 μg/ml L-NNP induced cell death by increasing the generation of intracellular reactive oxygen species and MDA, by depolarizing the mitochondrial membrane potential, and by decreasing intracellular GSH levels in HepG2 cells. Western blot assay showed that Bax, Bcl-2 and NF-κBp65 might be implicated in L-NNP-induced selective HepG2 cell death. L-NNP was also found to inhibit HepG2 hepatoma growth and extend the life span of nude mice model (p < 0.01). The pretreatment and co-treatment of 10 mM N-acetyl-cysteine alleviated L-NNP exposure induced intracellular reactive oxygen species increase and cell growth inhibition demonstrated that L-NNP exhibited neoplasm-selective cytotoxicity and pro-apoptotic activities via reactive oxygen species mediated oxidative damage in HepG2 cells. It might be promising for developing a new class of anticancer agent for liver cancer.

A Gold Nanoparticles-modified Aptamer Beacon for Urinary Adenosine Detection Based on Structure-switching/fluorescence-"turning On" Mechanism

A novel small molecule probe, aptamer beacon (AB), was introduced for adenosine (Ade) recognition and quantitative analysis. The Ade aptamer was engineered into an aptamer beacon by adding a gold nanoparticle-modified nucleotide sequence which is complementary to aptamer sequence (FDNA) at the 3'-end of FDNA. The fluorescence signal "turning on" was observed when AB was bound to Ade, which is attributed to a significant conformational change in AB from a FDNA/QDNA duplex to a FDNA-Ade complex. The Ade measurement was carried out in 20 mmol L(-1) Tris-HCl buffer solution of pH 7.4, ΔF signal linearly correlated with the concentration of Ade over the range of 2.0×10(-8) to 1.8×10(-6) mol L(-1). The limit of detection (LOD) for Ade is 6.0×10(-9) mol L(-1) with relative standard deviations (R.S.D) of 3.64-5.36%, and the recoveries were 98.6%, 100%, 102% (n=6), respectively. The present method has been successfully applied to determine Ade in human urine samples, and the obtained results were in good agreement with those obtained by the HPLC method. Our investigation shows that the unique properties of the AB could provide a promising potential for small molecules detection, and be benefit to extend the application of aptamer beacon technique.

Prolonged Early G(1) Arrest by Selective CDK4/CDK6 Inhibition Sensitizes Myeloma Cells to Cytotoxic Killing Through Cell Cycle-coupled Loss of IRF4

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.

Copper-catalyzed Cross-coupling of Nonactivated Secondary Alkyl Halides and Tosylates with Secondary Alkyl Grignard Reagents

Practical catalytic cross-coupling of secondary alkyl electrophiles with secondary alkyl nucleophiles under Cu catalysis has been realized. The use of TMEDA and LiOMe is critical for the success of the reaction. This cross-coupling reaction occurs via an S(N)2 mechanism with inversion of configuration and therefore provides a general approach for the stereocontrolled formation of C-C bonds between two tertiary carbons from chiral secondary alcohols.

Time to Disappearance of Thyroglobulin Antibodies and Influencing Factors in Patients with Papillary Thyroid Carcinoma

To investigate the time to disappearance of thyroglobulin antibodies (TgAb) and its influencing factors in papillary thyroid carcinoma (PTC) patients with positive TgAb after radioiodine ((131)I) ablation.

Primary Care Physicians' Response to Pandemic Influenza in Hong Kong: a Mixed Quantitative and Qualitative Study

The current study was conducted to use a developed framework to appraise the public primary care response to pandemic 2009 influenza A H1N1 virus in Hong Kong in 2009.

Risk Factors of Brain Metastases in Completely Resected Pathological Stage IIIA-N2 Non-small Cell Lung Cancer

Brain metastases (BM) is one of the most common failures of locally advanced non-small cell lung cancer (LA-NSCLC) after combined-modality therapy. The outcome of trials on prophylactic cranial irradiation (PCI) has prompted us to identify the highest-risk subset most likely to benefit from PCI. Focusing on patients with completely resected pathological stage IIIA-N2 (pIIIA-N2) NSCLC, we aimed to assess risk factors of BM and to define the highest-risk subset.

The Effects of Nrf2 on Tumor Angiogenesis: a Review of the Possible Mechanisms of Action

To date, preclinical and clinical data have shown that various cancer patients benefit from antiangiogenic therapy because of the important role of angiogenesis in the tumor development process. NF-E2-related factor 2 (Nrf2) is recognized as a key transcription factor of genes coding for various antioxidant and cytoprotective enzymes, and Nrf2 plays important roles during tumor progression. Recent studies have begun to explore the role of Nrf2 in tumor angiogenesis, which may be to promote the advancement of tumor antiangiogenic therapy. This article reviews the Nrf2-related pathways involved in tumor angiogenesis and summarizes the possible mechanisms of Nrf2 action as a pro-angiogenic factor in tumor progression.

Hemoglobin A1c Levels and Aortic Arterial Stiffness: the Cardiometabolic Risk in Chinese (CRC) Study

The American Diabetes Association (ADA) recently published new clinical guidelines in which hemoglobin A1c (HbA1c) was recommended as a diagnostic test for diabetes. The present study was to investigate the association between HbA1c and cardiovascular risk, and compare the associations with fasting glucose and 2-hour oral glucose tolerance test (2 h OGTT).

[The Characteristics and Influence of the Health Culture of Tibetan Medicine]

The Tibetan people's knowledge on preserving health is an important part of Tibetan medical culture. Most of the Tibetans live on the plateau where it is cold with decreased oxygen. They are devout Buddhists and they have developed a variety of healthy folk customs. These factors form the health culture of Tibetan medicine and demonstrate the plateau characteristics of health, psychology health and health customs. The health culture of Tibetan medicine has far-reaching influence because of the spread of Buddhism. Therefore it is worth exploring and carrying forward.

Inhibition of Hepatocellular Carcinoma Cell Growth by an Anti-insulin-like Growth Factor-I Receptor Monoclonal Antibody

Hepatocellular carcinoma (HCC) overexpresses insulin-like growth factor-I receptor (IGF-IR), as compared with normal hepatocytes. Since IGF-1R-mediated signaling promotes survival, oncogenic transformation and tumor growth and spread, it represents a potential target for treating HCC. Here, we have generated a murine anti-IGF-1R antibody, 4F2, that recognizes the IGF-IRα subunit and blocks in vitro IGF-I and IGF-II-induced cell proliferation of SMMC-7721 and Bel-7402 HCC cell lines. 4F2 can inhibit IGF-IR autophosphorylation, IRS-1 phosphorylation and the activation of the major downstream signaling molecules AKT and mitogen-activated protein kinase. Additionally, we observed a moderate increase in apoptosis as demonstrated by detection of changes in the expression of the pro-apoptotic and anti-apoptotic proteins Bax and Bcl-2 after 4F2 treatment. Combined treatment with 4F2 and doxorubicin was more effective in reducing cell proliferation and promoting apoptosis than either agent alone. These data support that therapeutic anti-IGF-IR antibodies are potential new agents for treating HCC.

Discovery and Preclinical Pharmacology of a Selective ATP-competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors

The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.

Peptide Self-assembly on Cell Membranes to Induce Cell Lysis

Self-assembling into aggregates with defined structures is a common phenomenon for many peptides at high concentrations. In this study, we found that when PTP-7b (FLGALFKALSHLL), a concentration-dependent self-assembling peptide, bound to tissue cells and accumulated on cell surfaces, it migrated and self-assembled into exosome-like aggregates at certain locations on the cell membranes. Studies using confocal microscopy and scanning electron microscopy revealed that peptide PTP-7b induced cell tissue damage through a new cell lysis mechanism that involved peptide self-assembly on cell surfaces, extracting lipids from cell membranes, and transporting peptides into the cytoplasm. Peptide self-assembly attributed greatly to peptide-cell interactions and thus the biological activity of a peptide. Because peptide self-assembly was a slow process, PTP-7b-induced cell lysis showed a biphasic behavior: a gradual viability decrease was followed by a rapid decline. These results suggest that peptide self-assembly could be equally as important as charge and secondary structure of a peptide in determining the anticancer and antibacterial activities of therapeutic peptides.

[Operative Treatment of Displaced Intra-calcaneal Fractures]

To explore the clinical efficacies of displaced intra-calcaneal fractures with operative treatment.

Antisense Oligonucleotide Against Clusterin Regulates Human Hepatocellular Carcinoma Invasion Through Transcriptional Regulation of Matrix Metalloproteinase-2 and E-cadherin

Secreted clusterin (sCLU) has been shown to be overexpressed in metastatic hepatocellular carcinoma (HCC) tissue, and its overexpression in HCC cells increases cell migration and the formation of liver metastatic tumor nodules in vivo. In this study, we tested the hypothesis that sCLU plays a role in the invasiveness of human HCC and may be associated with its metastatic spread. HCCLM3, a human hepatocellular carcinoma cell line, was transiently transfected with an antisense oligonucleotide (ASO) against sCLU (OGX-011). HepG2 liver hepatocellular cells were transiently transfected with the pc.DNA3.1-sCLU plasmid to overexpress sCLU, and subsequently evaluated for effects on invasion and the expression of molecules involved in invasion. We observed that suppression of the sCLU gene significantly reduced the invasive capability of the highly invasive HCCLM3 cells, and vice versa in the low invasive HepG2 cell line. The results revealed that knockdown of sCLU by OGX-011 resulted in a significant increase in the expression of E-cadherin and a decrease in matrix metalloproteinase-2 (MMP-2) gene transcription. Overexpression of sCLU by transfection with pc.DNA3.1-sCLU significantly decreased the expression of E-cadherin and increased MMP-2 gene transcription. These data were further verified by reverse transcription-PCR and Western blot analysis. A significant reduction in MMP-2 expression and an increase in E-cadherin expression in sCLU-knockdown HCCLM3 cells were observed, as well as a significant increase in MMP-2 expression and a decrease in E-cadherin expression in HepG2 cells overexpressing sCLU. These data indicate a role for sCLU in augmenting MMP-2 transcription and decreasing E-cadherin expression. Our data show the involvement of sCLU in human HCC invasion, and demonstrate that silencing sCLU gene expression inhibits the invasion of human HCC cells by inhibiting MMP-2 expression and promoting E-cadherin expression. Thus, OGX-011 could be an effective therapeutic agent for HCC.

Neuropeptide Y Promoter Polymorphism Modifies Effects of a Weight-loss Diet on 2-year Changes of Blood Pressure: the Preventing Overweight Using Novel Dietary Strategies Trial

Neuropeptide Y (NPY) is implicated in the regulation of blood pressure (BP), and NPY pathways in the hypothalamus are sensitive to dietary fat. We evaluated the potential effect of a functional variant rs16147 located in the NPY gene promoter region on the association between 2-year diet intervention and change in multiple BP measures in the randomized Preventing Overweight Using Novel Dietary Strategies Trial. The NPY rs16147 was genotyped in 723 obese adults who were randomly assigned to 1 of 4 diets differing in the target percentages of energy derived from fat, protein, and carbohydrate. The changes of 4 BP phenotypes, including systolic BP, diastolic BP, pulse pressure, and mean arterial pressure, during 2-year diet intervention were analyzed. In the total participants and participants with hypertension, we observed significant and consistent interactions between rs16147 genotype and dietary fat intake on changes in multiple BP phenotypes at 2 years (all P for interactions <0.05). The risk allele (C allele) was associated with a greater reduction of BP phenotypes in response to low-fat diet, whereas an opposite genetic effect was observed in response to high-fat diet. In addition, the C allele was related to greater changes in 4 BP phenotypes in hypertensive compared with nonhypertensive participants. Our data suggest that NPY rs16147 may modulate the association between dietary fat intake and changes in BP phenotypes, and the C allele exerts a long-term beneficial effect on lowering BP in response to low-fat diet in obese and hypertensive subjects.

Proteomic Response to Acupuncture Treatment in Spontaneously Hypertensive Rats

Previous animal and clinical studies have shown that acupuncture is an effective alternative treatment in the management of hypertension, but the mechanism is unclear. This study investigated the proteomic response in the nervous system to treatment at the Taichong (LR3) acupoint in spontaneously hypertensive rats (SHRs). Unanesthetized rats were subject to 5-min daily acupuncture treatment for 7 days. Blood pressure was monitored over 7 days. After euthanasia on the 7(th) day, rat medullas were dissected, homogenized, and subject to 2D gel electrophoresis and MALDI-TOF analysis. The results indicate that blood pressure stabilized after the 5th day of acupuncture, and compared with non-acupoint treatment, Taichong-acupunctured rat's systolic pressure was reduced significantly (P<0.01), though not enough to bring blood pressure down to normal levels. The different treatment groups also showed differential protein expression: the 2D images revealed 571 ± 15 proteins in normal SD rats' medulla, 576 ± 31 proteins in SHR's medulla, 597 ± 44 proteins in medulla of SHR after acupuncturing Taichong, and 616 ± 18 proteins in medulla of SHR after acupuncturing non-acupoint. In the medulla of Taichong group, compared with non-acupoint group, seven proteins were down-regulated: heat shock protein-90, synapsin-1, pyruvate kinase isozyme, NAD-dependent deacetylase sirtuin-2, protein kinase C inhibitor protein 1, ubiquitin hydrolase isozyme L1, and myelin basic protein. Six proteins were up-regulated: glutamate dehydrogenase 1, aldehyde dehydrogenase 2, glutathione S-transferase M5, Rho GDP dissociation inhibitor 1, DJ-1 protein and superoxide dismutase. The altered expression of several proteins by acupuncture has been confirmed by ELISA, Western blot and qRT-PCR assays. The results indicate an increase in antioxidant enzymes in the medulla of the SHRs subject to acupuncture, which may provide partial explanation for the antihypertensive effect of acupuncture. Further studies are warranted to investigate the role of oxidative stress modulation by acupuncture in the treatment of hypertension.

Influence of Glycerol on Molecular Mobility and Hydrogen Bond Network in Amorphous Glucose Matrix

The effect of glycerol on molecular mobility and hydrogen bonding in amorphous glucose matrix was studied. Phosphorescence from erythrosin B (Ery B) was used to characterize the temperature dependence of mobility in glucose/glycerol films over the temperature range from 100 °C down to -10 °C. Analysis of emission energy and excited state decay kinetics from Ery B provided information about thermally activated modes of matrix dipolar relaxation around and collisions with the excited triplet state of the probe. Both the average rate of matrix mobility and the width of the distribution of matrix mobility rates largely scaled with the effect of glycerol on the glass transition temperature of the glucose/glycerol mixture. The IR hydrogen bond bandwidth increased at higher glycerol content, suggesting that the strength of the bond became more widely distributed with the added glycerol. An increase with temperature in the hydrogen bond peak frequency indicated the transformation of associated hydroxyl to free hydroxyl. These results support a model in which glycerol plasticizes the glucose matrix at mole ratios of 0.1 and above while providing no evidence for the antiplasticization seen in other sugar matrices.

Integrin αvβ3 Imaging of Radioactive Iodine-refractory Thyroid Cancer Using 99mTc-3PRGD2

Integrin α(v)β(3) has been proposed as a potential imaging target for radiolabeled RGD peptides and a molecular marker for the estimation of tumor angiogenesis, yet it has not been applied in differentiated thyroid cancer (DTC) patients with radioactive iodine-refractory (RAIR) lesions. The current study was conducted to assess the potential of integrin α(v)β(3) imaging in the detection of RAIR DTC lesions using (99m)Tc-PEG(4)-E[PEG(4)-c(RGDfK)](2) ((99m)Tc-3PRGD2), thus providing a feasible antiangiogenetic therapeutic target.

Associations Between Aberrant DNA Methylation and Transcript Levels of DNMT1 and MBD2 in CD4+T Cells from Patients with Systemic Lupus Erythematosus

BACKGROUND/OBJECTIVES: It seems that global DNA hypomethylation in CD4+T cells is linked to the pathogenesis of systemic lupus erythematosus (SLE). However, the underlying mechanism by which SLE patients show hypomethylated DNA remains unclear. This study explored the relationship between DNA methylation patterns and expression levels of DNA methyltransferases (DNMT1) and MBD2 in CD4+T cells of SLE patients. METHODS: CD4+T cells were obtained from 30 patients with SLE and 18 normal controls. The global DNA methylation levels in CD4+T cells were evaluated by the Methyflash DNA methylation quantification kit. The mRNA levels of DNMT1 and MBD2 were quantified by quantitative real-time polymerase chain reaction. RESULTS: SLE patients had significantly lower global DNA methylation levels than controls, and the global DNA methylation was inversely correlated with the SLE disease activity index (SLEDAI). The mRNA levels of DNMT1 in SLE patients were significantly lower than that of controls and there was no correlation between DNMT1 mRNA levels and SLEDAI but there was a positive correlation between DNMT1 mRNA levels and global DNA methylation. The mRNA levels of MBD2 in SLE patients were significantly higher than in controls, and there was positive correlation between MBD2 mRNA levels and SLEDAI and an inverse correlation between MBD2 mRNA levels and global DNA methylation. CONCLUSIONS: Global DNA hypomethylation may play a pivotal role in the pathogenesis of SLE. Abnormal expression levels of DNMT1 and MBD2 mRNA may be important causes of the global hypomethylation observed in CD4+T cells in SLE.

Allogenic Mesenchymal Stem Cell Transplantation Ameliorates Nephritis in Lupus Mice Via Inhibition of B-cell Activation

Recent evidence indicates that bone marrow-derived mesenchymal stem cells (BM-MSCs) possess immunosuppressive properties both in vitro and in vivo. We have previously demonstrated that transplantation of human MSCs can significantly improve the autoimmune conditions in MRL/lpr mice. The current study aimed to determine the mechanisms by which murine BM-MSC transplantation (MSCT) ameliorates nephritis in MRL/lpr mice. In this study, we found that MSCT can significantly prolong the survival of MRL/lpr mice. Eight weeks after transplantation, MSCT treated mice showed significantly smaller spleens than control animals, with fewer MZ, T1, T2, activated B cells and plasma cells. Moreover, serum levels of BAFF and IL-10 in MSCT-treated mice decreased significantly compared to those in the control group, while levels of serum TGF-β were increased. Notably, decreased BAFF expression in both spleen and kidney was accompanied by decreased production of antidsDNA autoantibodies and proteinuria in MSCT-treated mice. Since BAFF is mainly expressed by T cells and dendritic cells, we incubated BM-MSCs and DCs together, and found that the production of BAFF by DCs were suppressed by MSCs. Thus, our findings suggest that MSCT may suppress the excessive activation of B cells via inhibiting BAFF production in MRL/lpr mice.

Allogeneic Mesenchymal Stem Cell Transplantation in Severe and Refractory Systemic Lupus Erythematosus: 4 Years Experience

Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitors and are capable of differentiating into several tissues of mesenchymal origin. We have shown that bone marrow derived MSCs from both SLE patients and lupus prone MRL/lpr mice are defective structurally and functionally. Here we observe the long-term safety and efficacy of allogeneic MSC transplantation (MSCT) in treatment-resistant SLE patients. Eighty-seven patients with persistently active SLE who were refractory to standard treatment or had life-threatening visceral involvement were enrolled. Allogeneic bone marrow or umbilical cord derived MSCs were harvested and infused intravenously (1×10⁶ cells/kg of body weight). Primary outcomes were rates of survival, disease remission and relapse, as well as transplantation related adverse events. Secondary outcomes included SLE disease activity index (SLEDAI) and serologic features. During the 4 years follow up and with a mean follow up period of 27 months, the overall rate of survival was 94% (82/87). Complete clinical remission rate was 28% at 1 year (23/83), 31% at 2 years (12/39), 42% at 3 years (5/12) and 50% at 4 years (3/6). Rates of relapse were 12% (10/83) at 1 year, 18% (7/39) at 2 years, 17% (2/12) at 3 years and 17% (1/6) at 4 years. The overall rate of relapse was 23% (20/87). Disease activity declined as revealed by significant changes in SLEDAI score, levels of serum autoantibodies, albuminand complements. A total of 5 patients (6%) died after MSCT from non-treatment-related events in 4 years follow up, and no transplantation-related adverse event was observed. Allogeneic MSCT resulted in the induction of clinical remission and improvement in organ dysfunction in drug-resistant SLE patients. No transplantation-related adverse event was observed.

[Treatment of Anterior Cruciate Ligament Injury with Peroneus Longus Tendon]

To evaluate the effects of anterior cruciate ligament reconstruction with peroneus longus tendon and observe the clinical outcomes of ankle joint after the resection of peroneus longus tendon.

Synergistic Effects of Serum Uric Acid and Cardiometabolic Risk Factors on Early Stage Atherosclerosis: the Cardiometabolic Risk in Chinese Study

To comprehensively examine the associations of serum uric acid (SUA) with central and peripheral arterial stiffness in Chinese adults, and particularly assess the interactions between SUA and other cardiometabolic risk factors.

Combination Chemotherapy with Paclitaxel, Cisplatin and Fluorouracil for Patients with Advanced and Metastatic Gastric or Esophagogastric Junction Adenocarcinoma: a Multicenter Prospective Study

To evaluate the efficacy and toxicity of the combination regimen of paclitaxel, cisplatin and 5-FU (PCF) as first-line or second-line therapy in patients with advanced gastric and esophagogastric junction (EGJ) adenocarcinoma in China.

Transcriptional Regulatory Network for Psoriasis

Psoriasis is a common, chronic, intractable skin disease that affects approximately 2% of the world's population. Transcriptional regulation is one of the most fundamental processes in psoriasis. However, high-throughput functional analysis of multiple transcription factors and their target genes in psoriasis is still rare. Thus, the objective of our study was to interpret the mechanisms of psoriasis through the regulation network construction using the GSE14905 microarray data. The results showed E2F transcription factor 1 (E2F1), jun proto-oncogene (JUN), nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1), signal transducer and activator of transcription 1 (STAT1), STAT3 and SP3 were hinge points in our transcriptome network. Importantly, JUN may regulate activating transcription factor 3 expression to involve cell proliferation process; STAT1 and STAT3 can inhibit tissue inhibitor of metalloproteinases-3 expression to modulate the cell adhesion molecule pathway; NF-κB and E2F1 can downregulate cyclin D1, but upregulate proliferating cell nuclear antigen expression to promote the cell cycle pathway. In addition, the regulation network between transcription factors and pathways revealed that NF-κB1 could promote the Toll-like receptor signaling pathway and that SP3 may inhibit the steroid hormone biosynthesis pathway in psoriasis. This transcriptional regulation analysis may provide a better understanding of molecular mechanism and some potential therapeutic targets in the treatment of human psoriasis.

Effect of Quorum Quenching on the Reactor Performance, Biofouling and Biomass Characteristics in Membrane Bioreactors

Enzymatic quorum quenching has recently been shown to be a promising approach to mitigate biofouling in membrane filtration processes. However, its universal effectiveness and mechanisms need further research. In this study, acylase was immobilized into sodium alginate capsules for enzymatic quorum quenching in MBRs operated at typical sludge concentrations (MLSS ≈ 10 g/L) for extended period of time. The results showed that quorum quenching influenced sludge characteristics and biofouling, while not impacting pollutant degradation. Better sludge settleability, smaller sludge particle size, less SMP and EPS production, lower apparent viscosity and higher zeta potential of mixed liquor were observed with quorum quenching. Quorum quenching also influenced the characteristics, behavior and function of SMP and EPS, which weakened biofilm formation ability but enhanced membrane filterability.

MicroRNA-29b Contributes to DNA Hypomethylation of CD4+ T Cells in Systemic Lupus Erythematosus by Indirectly Targeting DNA Methyltransferase 1

The mechanism of DNA hypomethylation in systemic lupus erythematosus (SLE) has not been fully elucidated. Recent studies showed that miR-29b could regulate DNA methylation by targeting the DNA methylation machinery. However, the role of miR-29b in T cell aberrant DNA hypomethylation of SLE still remains unclear.

Human Umbilical Cord Mesenchymal Stem Cells Derived from Wharton's Jelly Differentiate into Cholinergic-like Neurons in Vitro

In Alzheimer's disease patients, dysfunction of the cholinergic neurons is one of the causes of cognitive disorders. Although there is still no effective cure for theses diseases and conditions, some promising strategies are currently available to replace these damaged cells. Wharton's jelly mesenchymal stem cells (WJ-MSCs) derived from umbilical cord appeared as a promising cell source for cell replacement therapy. However, the capacity of WJ-MSCs to differentiate into cholinergic-like neurons remains undetermined. In this study, we examined whether WJ-MSCs could differentiate into cholinergic-like neurons in vitro. After induction, the spindle-shaped or fibroblast-like WJ-MSCs changed into bulbous cells. The induced cells positively expressed cholinergic neuron's markers, and an acetylcholine secretion of the induced WJ-MSCs was significantly elevated. These results demonstrated that WJ-MSCs had capability to differentiate into cholinergic-like neurons.

Differential Expression of the Na(+)/I(-) Symporter Protein in Thyroid Cancer and Adjacent Normal and Nodular Goiter Tissues

The ability of differentiated thyroid cancer and adjacent thyroid cells to concentrate iodine is dependent on their expression of a functional NA(+)/I(-) symporter (NIS). Thyroid cancer is insensitive to (131)I treatment if the thyroid cells lack the ability to concentrate iodide. Thus, in this study, we aimed to determine whether the NIS protein was differentially expressed in thyroid cancer and various surrounding tissues. We recruited 114 cases of papillary thyroid carcinoma (PTC) and divided them into two groups: 60 patients of 9 males and 51 females with a mean age of 49.55 years who had PTC with surrounding nodular goiter tissue (simplified as G(NG)), and 54 patients of 8 males and 46 females with a mean age of 45.78 years who had PTC with surrounding normal tissue (G(normal)) after total or near total thyroidectomy. Formalin-fixed and paraffin-embedded tissue sections were prepared for immunohistochemical staining of the NIS protein and semi-quantitative analysis. The NIS protein was expressed in the basolateral membrane of the normal epithelium, while PTC and nodular goiter cells expressed NIS in the cytoplasm and basolateral membrane. The expression levels of the NIS protein were higher in the adjacent normal tissues compared with those of the surrounding nodular goiter tissues (P=0.002) and expression levels of the NIS protein were higher in PTC tissues compared with the surrounding nodular goiter tissues (P=0.008). The data from this study indicate that cancer-surrounding tissues may play a significant role in mediating the sensitivity of PTC patients to radioactive iodine treatment.

RNAi Functionalized Collagen-chitosan/silicone Membrane Bilayer Dermal Equivalent for Full-thickness Skin Regeneration with Inhibited Scarring

Scar inhibition of dermal equivalent is one of the key issues for treatment of full thickness skin defects. To yield a bioactive RNAi functionalized matrix for skin regeneration with inhibited scarring, collagen-chitosan/silicone membrane bilayer dermal equivalent (BDE) was combined with trimetylchitosan (TMC)/siRNA complexes which could induce suppression of transforming growth factor-β1 (TGF-β1) pathway. The RNAi-BDE functioned as a reservoir for the incorporated TMC/siRNA complexes, enabling a prolonged siRNA release. The seeded fibroblasts in the RNAi-BDE showed good viability, internalized the TMC/siRNA complexes effectively and suppressed TGF-β1 expression constantly until 14 d. Application of the RNAi-BDE on the full-thickness skin defects of pig backs confirmed the in vivo inhibition of TGF-β1 expression by immunohistochemistry, real-time quantitative PCR and western blotting during 30 d post surgery. The levels of other scar-related factors such as collagen type I, collagen type III and α-smooth muscle actin (α-SMA) were also down-regulated. In combination with the ultra-thin skin graft transplantation for 73 d, the regenerated skin by RNAi-BDE had an extremely similar structure to that of the normal one. Our study reflects the latest paradigm of tissue engineering by incorporating the emerging biomolecule siRNA. The 3-D scaffolding materials for siRNA delivery may have general implications in generation of bioactive matrix as well.

Salvianic Acid A Protects L-02 Cells Against γ-irradiation-induced Apoptosis Via the Scavenging of Reactive Oxygen Species

Salvianic acid A (SAA) is the main hydrophilic active ingredient of Salvia miltiorrhiza bunge, which has long been used to treat liver and heart disease in China. In the present study, we investigated the radioprotective effects of SAA against γ-radiation-induced apoptosis in cultured human embryo liver L-02 cells. The results demonstrated that SAA markedly inhibited γ-radiation induced apoptosis, decreased DNA damage, and increased the intracellular antioxidative ability of the L-02 cells. SAA exhibited radioprotection by decreasing the generation of reactive oxygen species, inhibiting the release of mitochondrial cytochrome C, blocking the activation of caspase-3, and down regulating the expression of Bax and P53 and up regulating the expression of Bcl-2. This indicated that SAA pretreatment inhibited the caspase-dependent mitochondria apoptosis pathway. The radioprotection of the SAA pretreatment was also evidenced by an increased survival ratio, maintaining the antioxidant enzyme levels in the liver, inhibition of oxidative stress, and relative low liver and renal toxicity compared with estriol exposure. In conclusion, SAA may be an effective radioprotector against γ-radiation induced apoptosis in L-02 cells and damage in mice, the antioxidant potency of SAA might be correlated with the beneficial radioprotectant effects observed.

Genetic Polymorphism of XRCC1 Correlated with Response to Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer

In this study, we investigated the association between genetic polymorphisms of XRCC1 Arg399Gln (G→A) and response to oxaliplatin-based chemotherapy in advanced colorectal cancer. XRCC1 genotypes of totally 99 patients (37 stage III and 62 stage IV) with advanced colorectal cancer treated with oxaliplatin-based chemotherapy were detected by the TaqMan-MGB probe allelic discrimination method, and clinical response of 62 patients in stage IV after 2 to 3 cycles of chemotherapy were evaluated. Also, time to progression (TTP) of all patients was evaluated. The results showed that of the genotype frequencies in all patients, up to 52.53% were G/G genotype, 9.09% were A/A genotype, and 38.38% were G/A genotype. The response rate (CR + PR) of 62 patients in stage IV was 61.29% (19/31). Patients with G/G genotype showed enhanced response to chemotherapy compared with those with G/A + A/A (x(2) = 5.6, p = .029; Odds Ratio (OR) = 3.845, 95% Confidence Interval (CI) = 1.231 ∼ 12.01, p = .018). Individuals with the G/G genotype had a TTP of 10.0 (8.88-11.12) months, and those with the G/A + A/A genotype had a TTP of 5.0 (4.26-5.74) months. The Log-Rank test was marginally significant (x(2) = 29.20, p < .01). The Cox proportional hazards model, adjusted for stage, performance status, and chemotherapy regimen showed that only XRCC1 G/G genotype increases the OR significantly (OR = 3.555; 95% CI, 2.119 ∼ 5.963; p < .01). These results indicate that XRCC1 Arg399Gln polymorphism is associated with response to oxaliplantin-based chemotherapy and TTP in advanced colorectal cancer in Chinese population. It is proposed that the XRCC1 Arg399Gln polymorphism should be routinely detected to screen patients who are more likely to benefit from oxaliplantin-based treatment.

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