Abstract Thymic hyperplasia (TH) after chemotherapy is an infrequent phenomenon in adults. This study analyzed the incidence and metabolic activity of TH on (18)F fluorodeoxyglucose ((18)F FDG) positron emission tomography / computed tomography (PET/CT) in this population. By reviewing 471 PET/CT recordings of 211 adults with lymphoma, increased FDG uptake within an enlarged thymus regarded as TH was observed in 27 patients aged 18-53 years. FDG uptake in hyperplasic thymus was mild and diffuse, with a maximum standard uptake value (SUVmax) of 2.6±0.9. Its intensity varied with different occurring times following chemotherapy. In addition, by comparing the recovery of T cell subsets in patients with TH (n=20) and without TH (n=28), no impact of the presence of TH was found on the repopulation of total CD4(+) and CD8(+) T cells within the first year after treatment. These data may be helpful to avoid misinterpretation of increased thymic uptake in adults.
Closed plasma can overcome difficulties of maintaining plasma and excessive energy consumption in open environment. For plasma stealth technology, a closed plasma generator was designed. Using microsecond pulse generator and argon as working gas, discharge experiments were carried out under low pressure environment. The emission spectrum of Ar at different position in discharge chamber was measured. By using collisional-radiative modal (CRM), the distribution of plasma parameters was studied. At a given electron temperature and density with specified discharge parameters, corresponding population distribution could be obtained by CRM. By comparing the line ratio of argon 2p levels acquired from CRM with the line ratio from spectrum measured, the plasma parameters were confirmed after obtaining the minimum difference value. Using the line ratio of argon 2p9 to 2p1 from CRM while the range of electron density was 1-5 eV, the calculating error was analyzed. The results reveal that, the electron density of the closed plasma reaches a magnitude of 10(11) cm(-3) and shows a gradient distribution with small variational amplitude, and the distribution is beneficial to the application of plasma stealth.
Introduction: Infections caused by antibiotic-resistant bacteria pose an increasing risk for clinical treatment. Macrolide-lincosamide-streptogramin B is becoming increasingly ineffective due to the methylation at the binding site of bacteria. Despite great efforts on the natural product, erythromycin, only one derivative, that is, telithromycin, capable of fighting against resistant bacteria has so far been marketed. However, the 3'-dimethylamino group is readily metabolized to a nitroso group, which would inhibit CYP3A4, a very important metabolic enzyme responsible for nearly half of all marketed drugs. Areas covered: Modifications at C-10 of erythromycin were seldom reported. This invention disclosed novel ketolides that had a side chain comprising additional nitrogen atoms in place of the original 10-methyl group. Surprisingly, introduction of the side chain at C-10 led to reduced cytochrome inhibition and increased metabolic stability. As a result, the limited ability to inhibit CYP3A4 would relieve the drug-drug interaction and improve the safety of drug co-administration. Expert opinion: This invention opens a new avenue for future modifications to the erythromycin family. It remains unclear how the side chain effected on reduction of CYP inhibition. To fully identify structure-activity relationships, the MIC data of the derivatives on gram-negative bacteria is desirable.
To exacted analysis each time interval in isovolumic relaxation time (IVRT) of normal subjects through observin the changes of cardiac structure and hemodynamics during the IVRT. Then to provide the evidence of cardiac resynchronization therapy.
A prior study showed blood type A/AB to be associated with an increased risk of nasopharyngeal carcinoma (NPC) compared to subjects with blood type O. However, the relationship between ABO blood groups and prognosis of NPC patients is still questionable. In addition, whether Epstein-Barr virus (EBV) infection is associated with prognosis of NPC patients with different ABO blood groups is unclear.
Arabidopsis thaliana plants that lack ceramide kinase, encoded by ACCELERATED CELL DEATH5 (ACD5), display spontaneous programmed cell death late in development and accumulate substrates of ACD5. Here, we compared ceramide accumulation kinetics, defense responses, ultrastructural features, and sites of reactive oxygen species (ROS) production in wild-type and acd5 plants during development and/or Botrytis cinerea infection. Quantitative sphingolipid profiling indicated that ceramide accumulation in acd5 paralleled the appearance of spontaneous cell death, and it was accompanied by autophagy and mitochondrial ROS accumulation. Plants lacking ACD5 differed significantly from the wild type in their responses to B. cinerea, showing earlier and higher increases in ceramides, greater disease, smaller cell wall appositions (papillae), reduced callose deposition and apoplastic ROS, and increased mitochondrial ROS. Together, these data show that ceramide kinase greatly affects sphingolipid metabolism and the site of ROS accumulation during development and infection, which likely explains the developmental and infection-related cell death phenotypes. The acd5 plants also showed an early defect in restricting B. cinerea germination and growth, which occurred prior to the onset of cell death. This early defect in B. cinerea restriction in acd5 points to a role for ceramide phosphate and/or the balance of ceramides in mediating early antifungal responses that are independent of cell death.
Increased levels of monocyte-platelet aggregates (MPAs) are reported to be highly correlated with cardiovascular events. In this study, the MPA levels in different monocyte subsets and the associations between MPA levels, HIV-1 viremia and monocyte activation were evaluated during HIV-1 infection. The results showed that the percentages of MPAs in all three monocyte subsets were higher in HIV-1-infected subjects than in healthy controls, and were associated with the plasma viral load in the non-classical and intermediate monocyte subsets. The plasma levels of sCD14 and sCD163 were upregulated in HIV-1 infection and were positively associated with viral loads and negatively associated with CD4 counts. P-selectin glycoprotein ligand-1 (PSGL-1) was shown to be expressed at significantly lower levels on all three monocyte subsets and was negatively correlated with the sCD163 level. The MPA level was correlated with the levels of plasma sCD163 but negatively correlated with CD163 and PSGL-1 on all three monocyte subsets. An elevated immune activation status was correlated with increased MPA formation, underlying the potential interaction between monocyte activation and MPA formation. This interaction may be related to a higher thromboembolic risk in patients infected with HIV-1.Cellular & Molecular Immunology advance online publication, 11 August 2014; doi:10.1038/cmi.2014.66.
New iridium tetrazolate complexes containing o-, m-, or p-carboranyl substitution in different positions of a phenylpyridine ligand have been prepared. The carborane isomers and the effect of their substitution position in the tuning of optical properties have been examined. The neutral complexes with the carboranyl substituent on the phenyl ring in meta position relative to the metal exhibit redshifted emission bands in contrast to blueshifts for those with carboranyl in para position. All cationic complexes display evidently blueshifted dual-peak emission compared with the carborane-free complex (c-TZ) with a broad single-peak emission. Introduction of carborane leads to a blueshift over 70?nm relative to c-TZ. Carboranes also significantly improve phosphorescence efficiency (?P ) and lifetime (?), that is, ?P =0.64 versus 0.21 (c-TZ) and ?=880?ns versus 241?ns (c-TZ). The unique hydrophilic nido-carborane-based Ir(III) complex nido-o-1 shows the largest phosphorescence efficiency (abs ?P =0.57) among known water-soluble iridium complexes, long emission lifetime (?=4.38??s), as well as varying emission efficiency and lifetime with O2 content in aqueous solution. Therefore, nido-o-1 has been used as an excellent oxygen-sensitive phosphor for intracellular O2 sensing and hypoxia imaging.
The gene regulation network (GRN) is a high-dimensional complex system, which can be represented by various mathematical or statistical models. The ordinary differential equation (ODE) model is one of the popular dynamic GRN models. High-dimensional linear ODE models have been proposed to identify GRNs, but with a limitation of the linear regulation effect assumption. In this article, we propose a sparse additive ODE (SA-ODE) model, coupled with ODE estimation methods and adaptive group LASSO techniques, to model dynamic GRNs that could flexibly deal with nonlinear regulation effects. The asymptotic properties of the proposed method are established and simulation studies are performed to validate the proposed approach. An application example for identifying the nonlinear dynamic GRN of T-cell activation is used to illustrate the usefulness of the proposed method.
The efficiency of cellular uptake of triplex?forming oligodexinucleotides (TFO), and the inhibition of tissue factor (TF) is low. The aim of the present study was to improve the absorption of TFO, and increase the inhibition of TF induced by shear stress both in vitro and in vivo, by using an ultrasound?targeted microbubble destruction (UTMD)?based delivery system. TFO?conjugated lipid ultrasonic microbubbles (TFO?M) were first constructed and characterised. The absorption of TFO was observed by a fluorescence?based method, and the inhibition of TF by immunofluorescence and quantitative polymerase chain reaction. ECV304 human umbilical vein endothelial cells were subjected to fluid shear stress for 6 h after treatment with TFO conjugated lipid ultrasonic microbubbles without sonication (TFO?M group); TFO alone; TFO conjugated lipid ultrasonic microbubbles, plus immediate sonication (TFO+U group and TFO?M+U group); or mock treated with 0.9% NaCl only (SSRE group). The in vivo experiments were established in a similar manner to the in vitro experiments, except that TFO or TFO?M was injected into rats through the tail vein. Six hours after the preparation of a carotid stenosis model, the rats were humanely sacrificed. The transfection efficiency of TFO in the TFO?M+U group was higher as compared with the TFO?M and TFO+U group (P<0.01). The protein and mRNA expression of TF in the TFO?M+U group was significantly decreased both in vitro and in vivo (P<0.01), as compared with the TFO?M, TFO+U and SSRE groups. The UTMD?based TFO delivery system promoted the -absorption of TFO and the inhibition of TF, and was therefore considered to be favorable for preventing thrombosis induced by shear stress.
To decrease the methanol content of the sugar cane sprits, mutagenesis of ultraviolet (UV) coupled with diethyl sulfate (DES) was used to generate a mutant of Saccharomyces cerevisiae with lower methanol content. Meanwhile, the effects of the additions of pectinase, cellulase and glycine on the production of methanol in sugar cane spirits were evaluated.
Pseudomonas aeruginosa isolates that were initially carbapenem-susceptible and later became selective carbapenem-resistant following antimicrobial therapy were identified from individual cases during the same hospitalisation. Cross-resistance to other ?-lactams was not found and their susceptibilities remained identical in consecutive isolates. Real-time quantitative reverse transcription PCR was performed to investigate the role of OprD, an outer membrane protein regulating the entry of carbapenems, in the appearance of carbapenem-resistant-only P. aeruginosa (CROPA). Fifteen paired isolates of carbapenem-susceptible P. aeruginosa (CS-PA) and CROPA were identified. All of the cases had carbapenem exposure history within 1 month before the appearance of CROPA (mean 10 days). Reduced OprD expression was found in 93% (14/15) of the isolates, suggesting that oprD inactivation was the major contributor to selective carbapenem resistance. Of the 14 cases with CROPA due to oprD mutation, 71% (10/14) were persistent infection, as genotype analysis revealed that their paired strains were isogenic; 29% (4/14) represented re-infections as they were heterogenic, suggesting that oprD-deficient CROPA existed in the hospital and that carbapenem selective pressure promoted its spread to patients. We conclude that CROPA may occur soon after the use of carbapenems to treat CS-PA infections and that oprD mutation is the major mechanism of resistance in CROPA. Restriction of empirical use of carbapenems by antibiotic stewardship is important to halt the occurrence of CROPA.
GLP-1 and incretin mimetics, such as exenatide, have been shown to attenuate hepatocyte steatosis in vivo and in vitro, but the specific underlying mechanism is unclear. SIRT1, an NAD(+)-dependent protein deacetylase, has been considered as a crucial regulator in hepatic lipid homeostasis by accumulated studies. Here, we speculate that SIRT1 might mediate the effect of the GLP-1 receptor agonist exenatide (exendin-4) on ameliorating hepatic steatosis. After 8 weeks of exenatide treatment in male SIRT1(+/-) mice challenged with a high-fat diet and their wild-type (WT) littermates, we found that lipid deposition and inflammation in the liver, which were improved dramatically in the WT group, diminished in SIRT1(+/-) mice. In addition, the protein expression of SIRT1 and phosphorylated AMPK was upregulated, whereas lipogenic-related protein, including SREBP-1c and PNPLA3, was downregulated in the WT group after exenatide treatment. However, none of these changes were observed in SIRT1(+/-) mice. In HepG2 cells, exendin-4-reversed lipid deposition induced by palmitate was hampered when SIRT1 was silenced by SIRT1 RNA interference. Our data demonstrate that SIRT1 mediates the effect of exenatide on ameliorating hepatic steatosis, suggesting the GLP-1 receptor agonist could serve as a potential drug for nonalcoholic fatty liver disease (NAFLD), especially in type 2 diabetes combined with NAFLD, and SIRT1 could be a therapeutic target of NAFLD.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) derived from plasmacytoid dendritic cell precursors is a very rare, and characterized by cutaneous and bone marrow involvement and leukemic spread. The neoplasm presents with an aggressive behavior, and the clinical findings include cytopenia, particularly thrombocytopenia. The tumor cells are negative for antigens of T- and B- cell lines. However, these cells express CD4, CD56 and CD123, which are markers of plasmacytoid dendritic cells, and negative for Epstein-Barr virus (EBV). From this point of view, a 71-year-old man who was initially found to have a cutaneous mass on his face and thorax was reported here, and initially was diagnosed as "eczema". The skin rashes then became aggravated on a trial of low dose topical corticosteroid for 2 months. According to skin biopsy, the tumor cells reveal an immature blastic appearance and positive for CD4 and CD56, negative for CD3, CD20, indicating a diagnosis of BPDCN. Here, we report the dismal course of a patient with BPDCN without accepting further therapy, and only survived 3 months.
Accumulated evidence has revealed the presence of Notch receptor polymorphisms in non-tumorous diseases; however, few studies have investigated the association of Notch polymorphisms with breast cancer risk. A total of 100 invasive ductal carcinoma (IDC) and 50 ductal carcinoma in situ (DCIS) patients and 100 usual ductal hyperplasia (UDH) controls were genotyped for the following Notch receptor single nucleotide polymorphisms (SNPs) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry: Notch1, rs3124591; Notch2, rs11249433; Notch3, rs3815188, and rs1043994; and Notch4, rs367398, and rs520692. Immunohistochemistry was used to determine the effect of Notch polymorphisms on corresponding Notch protein expression in successfully genotyped patients. The frequency of rs3124591 TC genotype was significantly higher in IDC (24.7%, 20/81) and DCIS (30%, 12/40) patients than in UDH controls (8%, 8/97) (P = 0.002 and P = 0.011, respectively). However, the distribution of other SNP genotypes was not significantly different between IDC and DCIS patients and UDH controls. The frequency of TC genotype was significantly higher in poorly differentiated tumors than in well-differentiated and moderately differentiated tumors (P = 0.022). Importantly, a positive correlation between the rs3124591 TC genotype and high Notch1 protein expression was observed in DCIS patients (P = 0.043) but not in IDC patients. This is the first study to suggest an increased risk of IDC and DCIS of the breast for the Notch1 rs3124591 variant. Furthermore, given the inconsistent associations between the rs3124591 variant and Notch1 expression in IDC and DCIS, this variant may affect breast cancer risk through mechanisms in the latter stage other than alterations in Notch1 protein expression.
Inflammatory myofibroblastic tumour (IMT) is a relatively rare soft tissue malignancy. It exhibits locally aggressive behavior with a tendency for local recurrence and rare metastasis, and rare recurrent IMTs may show histological progression. The genetic hallmark of IMT is ALK rearrangement from chromosome arm 2p, but gene mutations involved in IMT remain poorly understood. The aim of the present study was to perform a pairwise comparison of the gene mutations occurring in primary and recurrent IMT from the same patient. We conducted a high-throughput analysis of 238 known mutations of 19 oncogenes in pairwise comparison primary and recurrent samples from 2 patients of IMT using Sequenom MassARRAY technology. Our results revealed 2 mutations in 2 recurrent lesion samples, including one in exon 11 of the KIT gene, resulting in a T-C substitution at position 1727 (L576P), the recurrent sample underwent histologic progression with "pleomorphic undifferentiated sarcoma-like" transformation; the other mutation was in exon 19 of the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene, resulting in a G-A substitution at position 1624 (E542K). Moreover, no any mutation was found in the primary lesion samples from 2 patients. Our findings suggest that variable genome changes might be present in IMT, especially during the progression from a primary tumour to recurrence. To the best of our knowledge, no such longitudinal study of IMT has been undertaken previously.
Chlorination is an effective approach for understanding the feature of multiple additions on fullerene cages. The chlorofullerenes obtained are versatile synthons for further derivatization. However, chlorofullerenes used for chemical reaction studies are mainly based on the skew-pentagonal-pyramidal (SPP) C60 Cl6 . In this work, a new isomer of C60 Cl10 that does not contain an SPP-C60 Cl6 substructure was identified. Its electrochemical properties give it unexpected cyclic voltammetric behavior at more negative potentials relative to other chlorofullerenes. Friedel-Crafts arylation shows good reactivity of this compound. These new findings challenge opinions of fullerene addition patterns and will break the monopoly of C60 Cl6 as a precursor for fullerene modifications.
Methanol, often generated in brewed wine, is highly toxic for human health. To decrease the methanol content of the brewed wine, atmospheric and room-temperature plasma (ARTP) was used as a new mutagenesis tool to generate a mutant of Saccharomy cescerevisiae with lower methanol content. Headspace gas chromatography was used to determine the identity and concentration of methanol with butyl acetate as internal standard in brewed wine. With 47.4% higher and 26.3% positive mutation rates were obtained, the ARTP jet exhibited a strong effect on mutation breeding of S. cerevisiae. The mutant S. cerevisiae S12 exhibited the lowest methanol content, which was decreased by 72.54% compared with that of the wild-type strain. Subsequently, the mutant S. cerevisiae S12 was used to ferment different combinations of malt and adjuncts for lower methanol content and higher alcoholic content. It was shown that the culture 6#, which was 60% malt, 20% wheat, and 20% corn, was the best combinations of malt and adjuncts, with the lowest methanol content (104.8 mg/L), and a relatively higher alcoholic content (15.3%, v/v). The optimal malt-adjunct culture 6#, treated with the glucoamylase dose of 0.04 U/mg of grain released the highest reducing sugars (201.6 mg/mL). It was indicated that the variation in reducing sugars among the combinations of malt and different adjuncts could be due to the dose of exogenous enzymes.
Midaortic syndrome (MAS) is a rare vascular anomaly characterized by segmental narrowing of the distal descending thoracic or abdominal aorta. Renal or visceral arteries may also be affected to varying degrees. MAS is often associated with renovascular hypertension, and requires early intervention. When medical therapy and percutaneous interventions fail to control hypertension, surgical treatment is required. We report a case of MAS that failed to respond to bilateral renal artery stenting, but treated with aortic bypass and orthotopic right renal autotransplantation with good outcome.
Analyses of supernatants from apoptotic cells have helped in the identification of many signals that modulate the states of cell activation and differentiation. However, the current knowledge about the soluble factors that are released during apoptosis is rather limited. Previous studies have shown that S5a and angiocidin (both encoded by PSMD4) induce human acute monocytic leukemia cells (THP-1 cells) to differentiate into macrophages, but the cell-surface receptor of S5a has not been identified. In this study, we show that apoptotic THP-1 cells release endogenous S5a that binds to death receptor-6 (DR6, also known as TNFRSF1), which was identified as an orphan receptor, to induce THP-1 cells to differentiate. Furthermore, we found that the NF-?B pathway is activated, and that the transcription factors WT1 (Wilms' tumor 1) and c-myb mediate S5a-induced THP-1 differentiation. We also show that differentiation is blocked by anti-DR6 antibody, DR6 siRNA, DR6-Fc, NF-?B inhibitor or WT1 siRNA treatment. Our findings indicate that the interaction between cells can determine their differentiation, and we provide evidence for a functional interaction between S5a and DR6, which provides a novel potential mechanism to induce the differentiation of cancer cells, especially during biotherapy for leukemia.
In a previous study, we showed early insulin therapy could improve ?-cell function in type 2 diabetic patients. However, the molecular mechanism was not clear. In the present study, we addressed this question by analyzing the pancreatic microvasculature in diabetic rats after insulin treatment.
The measurement of hepatitis C virus core antigen (HCV-coreAg) has been shown to be an indicator of active HCV infection. The aim of the present study was 1) to investigate the stability and effectiveness of HCV-coreAg and HCV-RNA quantification in HCV infection with or without HIV-1 coinfection, 2) to explore the association between the HCV-coreAg/HCV-RNA (Ag/RNA) ratio and the immune status in chronic HCV/HIV-1-coinfected patients.
The present study aimed to examine the changes in mesenteric lymph during the development of sepsis and to identify the distinct proteins involved, as targets for further study. The sepsis animal model was constructed by cecal ligation and puncture (CLP). The mesenteric lymph was collected from 28 adult male Sprague?Dawley rats, which were randomly divided into the following four groups (n=7 per group): CLP?6 h, CLP?24 h, sham?6 h and sham?24 h groups. Capillary high performance liquid chromatography?tandem mass spectrometry was performed to analyze the proteome in mesenteric lymph. A comprehensive bioinformatic analysis was then conducted to investigate the distinct proteins. Compared with the sham group, 158 distinct proteins were identified in the lymph samples from the CLP group. Five of these proteins associated with the same lipid metabolism pathway were selected, apolipoprotein E (ApoE), annexin A1 (Anxa1), neutrophil gelatinase?associated lipocalin (NGAL), S100a8 and S100a9. The expression of ApoE, Anxa1, NGAL, S100a8 and S100a9 were all elevated in the progression of sepsis. The five proteins were reported to be closely associated with disease development and may be a potential target for the diagnosis and treatment of sepsis. In conclusion, identifying proteome changes in mesenteric lymph provides a novel perspective to understand the pathological mechanisms underlying sepsis.
Several reports on the association between the BRCC5 gene polymorphism and ovarian cancer risk have been published recently, but the estimates of the risk vary widely. We thus performed a meta-analysis in an effort to determine the association. To identify the eligible studies, we searched the PubMed, Embase, and CNKI databases, and reviewed all original studies retrieved as well as their citations. The risk of ovarian cancer was estimated using odds ratio (OR) and its 95 % confidence interval (CI). Meta-analysis of seven comparisons revealed an obvious rise in the risk of ovarian cancer under the CC vs. GG contrast model (OR?=?1.52, 95 % CI?=?1.07-2.16, P OR?=?0.020). A similar increase was also indicated in the CC vs. GC?+?GG model (OR?=?2.10, 95 % CI?=?1.51-2.93, P OR?0.001). Our meta-analysis indicates that the BRCC5 polymorphism may be a candidate modifier of ovarian cancer risk in Caucasians.
Interferon regulatory factor 3 (IRF-3) plays an important role in host defense against viral and bacterial infection. IRF-3 includes a variety of spliced variants, which may regulate the transcription of IRF-3. We previously identified two novel IRF-3 spliced variants, Int2V1 and Int2V2, starting from intron 2 of the wild-type of IRF-3. However, the mechanism through which the IRF-3 spliced variants regulate transcription has not been elucidated. In this study, we demonstrated that the transcription factor Sp1 upregulates the basal transcriptional activity of IRF-3 Int2V1. By transient transfection analysis, we demonstrated that the overexpression of Sp1 led to positive regulation, whereas knocking down of the endogenous Sp1 resulted in repression of IRF-3 promoter activity. Electrophoretic gel mobility shift assays and chromatin immunoprecipitation assays demonstrated that Sp1 interacted with the IRF-3 promoter in vitro and in vivo. These results suggested that Sp1 positively regulated the transcription of a spliced variant of IRF-3 through directly binding to the Sp1 consensus binding site.
Spontaneous bacterial peritonitis is an important cause of morbidity and mortality in cirrhotic patients with ascites. The key step in the pathogenesis of spontaneous bacterial peritonitis is bacterial translocation from intestinal lumen to mesenteric lymph nodes, and from there to the systemic circulation and ascitic fluid. We aimed to study the ascitic microbiota of cirrhotic patients with or without spontaneous bacterial peritonitis.
Recently, microRNAs (miRNAs) have been shown to be involved in multiple biological pathways that can influence tumor progression and metastasis and they can serve as prognostic biomarkers in many cancers. The present study examined the prognostic significance of miR-215 in cervical cancer. The paraffin-embedded paired cervical scrape samples and tumor tissue samples from 302 patients with stage II cervical cancer were detected for the expression of miR-215 by using qRT-PCR. A miR-215-based classifier was established by using the Cox regression model. The prognostic and predictive accuracy of this classifier was determined in both the internal testing group of 138 patients, and the external independent group of 280 patients. Moreover, cervical cancer HeLa cells overexpressing miR-215 (HeLa-miR-215) were constructed and subcutaneously injected into the nude mice to examine the effect of miR-215 on tumor growth and metastasis in vivo. The results showed that the expression level of miR-215 was significantly higher in cervical cancer tissues than in paired normal tissues (P<0.0001). When patients were classified into high- and low-risk cancer progression groups according to miR-215 level, the 5-year disease-free survival in high- and low-risk groups were 43% (95% CI: 32.1-51.6) and 67% (95% CI: 48.6-77.3) (hazard ratio [HR] 2.02, 95% CI: 1.16-3.52; P=0.013) respectively. Moreover, the expression level of miR-215 was negatively associated with survival rate in patients at TNM stage T3 (HR: 3.317; 95% CI: 1.18-5.14, P=0.017) and TNM stage T4 (HR: 3.48; 95% CI: 1.49-4.45, P=0.008). Tumor volume in nude mice injected with HeLa-miR-215 cells was significantly larger than that in mice injected with control HeLa cells. It was concluded that the expression level of miR-215 is associated with cervical tumor progression and worse survival rate, suggesting that it may serve as a potential prognostic marker to identify patients at higher risk of recurrence.
Circulating monocyte subsets with distinct functions play important roles in hepatitis C virus (HCV) infection. However, the mechanisms have not been well studied. In this study, we analyzed the distributions and phenotypic characteristics of three circulating monocyte subsets-CD14(++)CD16(-), CD14(++)CD16(+) and CD14(+/dim)CD16(+)-in chronic HCV-infected patients, HCV spontaneous resolvers and healthy controls, and we evaluated the possible link between HCV viremia and disease progression. Our results indicated that the frequency of the CD14(++)CD16(+) monocyte subset was decreased, and negatively correlated with HCV RNA and core antigen levels during chronic HCV infection. PD-L1 expression and the PD-L1/CD86 ratio in CD14(++)CD16(+) monocytes were higher during chronic HCV infection than in spontaneous HCV resolvers and healthy controls. The PD-L1/CD86 ratio positively correlated with HCV viral load and core antigen levels. Finally, PD-L1 was significantly increased, while cytokine secretions were dramatically decreased upon Toll-like receptor (TLR) ligand binding and HCV JFH-1stimulation. These findings indicates the compromised immune status of the CD14(++)CD16(+) monocytes during chronic HCV infection and provides new insights into the specific role of the CD14(++)CD16(+) monocytes and their significance in chronic HCV infection.
Nanomaterials as tracing tags have been widely used in biosensors with high sensitivity and selectivity. In this work, a signal amplification electrochemical aptamer sensing strategy for the detection of protein was designed by combining the hybridization-inducing aggregate of DNA-functionalized silver nanoparticles (AgNPs) and differential pulse stripping voltammetry (DPSV) detection. The multiprobes containing hybridization DNA and aptamers were anchored onto the silver nanoparticles. The protein assay was prepared through the immobilization of capture aptamer that specifically recognizes platelet-derived growth factor (PDGF-BB) on gold nanoparticles modified screen-printed electrode (SPE) array. After a sandwich-type reaction, two kinds of DNA-modified AgNPs were simultaneously added on the electrode surface for specifically recognizing PDGF-BB and forming the AgNPs aggregate caused by in situ hybridization of DNA. Compared to the signal-labeled tag, the tracing aggregate tags showed a strong electroactivity for signal amplification through stripping detection of silver after preoxidation. By using the hybridization-inducing aggregate as electrochemical readouts, the sensor showed wide linear range and low detection limit. The hybridization-inducing AgNPs aggregate were further used as tracing tags in multiplied proteins assays for PDGF-BB and thrombin by using the SPE array chip as sensing platform. The cross-talk between different aptamer-modified electrodes on the same array was avoided because of the advantage of labeled AgNPs. The array detection was also applied in the logic gate operation. The proposed method described here is ideal for multianalytes determination in clinical diagnostics with good analytical performance.
Interferon regulatory factor 3 (IRF-3), an essential transcriptional regulator of the interferon (IFN) genes, is important in the host defense against viral and microbial infection. Epstein-Barr virus (EBV) immediate-early protein replication and transcription activator (Rta) and the transcription factor E2F1 are two important inhibitive factors, which repress IRF-3 expression. Numerous studies have identified that Rta can directly bind to the Rta-response element in promoters of its target genes and regulate their expression. In the present study, we demonstrated that Rta represses the expression of IRF-3 by E2F1 rather than through its traditional way. Transient transfection analysis and chromatin immunoprecipitation (ChIP) assays revealed that the overexpression of Rta elevated the expression of E2F1 and increased the binding of E2F1 to the promoter of IRF-3. The mutation of the E2F1?binding site and the knocking down of E2F1 by small interfering RNA (siRNA) can eradicate the inhibitory effect of Rta. These results suggested that Rta represses IRF-3 expression by increasing E2F1 binding to the IRF-3 promoter.
Cellular replacement therapy for diabetes mellitus (DM) has received much attention. In this study, we investigated the effect of transplantation of autologous bone marrow?derived mesenchymal stem cells (ABMSCs) in streptozotocin (STZ)?induced diabetic miniature pigs. Miniature pig BMSCs were cultured, labeled with superparamagnetic iron oxide (SPIO) and transplanted into the pancreas of diabetic miniature pigs through targeted intervention. Blood glucose levels, intravenous and oral glucose tolerance test (OGTT), serum insulin, C?peptide and islets histology were analyzed. These transplanted cells were then identified by magnetic resonance imaging (MRI). The results showed that transplantation of ABMSCs reversed STZ?induced diabetes in miniature pigs. Blood glucose levels, intravenous, OGTT, serum insulin and C?peptide were significantly recovered in the diabetic minipigs with the autologous BMSC (DMAB) transplantation group. In addition, the number of islets was significantly increased in this group compared to the diabetic minipig control (DMC) group with conventional therapy. These data suggested the implantation of autologous BMSCs for type 1 diabetes treatment can partially restore the function of islet ? cells and maintain blood glucose homeostasis. Transplanted autologous BMSCs may improve islet repairing by differentiating for new islets and change pancreatic microcirculation and be identified in a real?time manner using MRI in vivo.
High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances tumor control both locally and distantly. Unfortunately, local relapses often occur following IR treatment, indicating that IR-induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator programmed death-ligand 1 (PD-L1, also called B7-H1) can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. Here, we demonstrate that PD-L1 was upregulated in the tumor microenvironment after IR. Administration of anti-PD-L1 enhanced the efficacy of IR through a cytotoxic T cell-dependent mechanism. Concomitant with IR-mediated tumor regression, we observed that IR and anti-PD-L1 synergistically reduced the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which suppress T cells and alter the tumor immune microenvironment. Furthermore, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumors through the cytotoxic actions of TNF. Our data provide evidence for a close interaction between IR, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and radiotherapy.
Human papillomavirus (HPV) infection is a major risk factor for cervical cancer. However, only some high risk human papillomavirus (HR-HPV)-infected women progress to cervical cancer, host immunogenetic factors human leukocyte antigen (HLA) may account for viral antigens presenting individually or together in the progression to cervical cancer. This study examined the association between the development of invasive cervical cancer (ICC) and the determinant factors including HLA-DRB1*1501 and DQB1*0602, HR-HPV infection among Chinese Uighur and Han populations. Blood samples, cervical swabs and biopsies were obtained from 287 patients with ICC (192 Uighurs and 95 Hans) and 312 healthy controls (218 Uighurs and 94 Hans). HPV DNA was detected by PCR and HLA-DRB1*1501 and DQB1*0602 alleles were performed using PCR-SSP method. HPV16 infection rates was significantly higher among Uighur and Han with ICC as compared to healthy controls (OR = 58.317; 95% CI: 39.663-85.744; OR = 33.778; 95% CI: 12.581-90.691; P < 0.05 for all). HLA-DRB1*1501 (OR = 0.305; 95% CI: 0.115-0.813; P < 0.05) and HLA-DRB1*1501-DQB1*0602 haplotype frequencies (OR = 0.274; 95% CI: 0.086-0.874; P < 0.05) were significantly reduced in Han ICC. The HLA-DQB1*0602 frequency significantly decreased among Uighur women with ICC (OR = 0.482; 95% CI: 0.325-0.716; P < 0.05). Similar tendencies were observed for DQB1*0602 with HPV16-positive ICC (OR = 0.550; 95% CI: 0.362-0.837; P < 0.05). This study suggests that HLA-DRB1*1501 and DQB1*0602 alleles may influence the immune response to HPV16 infection and decrease the risk of ICC among Uighurs and Hans in Xinjiang, China.
Genetic information, such as single nucleotide polymorphism (SNP) data, has been widely recognized as useful in prediction of disease risk. However, how to model the genetic data that is often categorical in disease class prediction is complex and challenging. In this paper, we propose a novel class of nonlinear threshold index logistic models to deal with the complex, nonlinear effects of categorical/discrete SNP covariates for Schizophrenia class prediction. A maximum likelihood methodology is suggested to estimate the unknown parameters in the models. Simulation studies demonstrate that the proposed methodology works viably well for moderate-size samples. The suggested approach is therefore applied to the analysis of the Schizophrenia classification by using a real set of SNP data from Western Australian Family Study of Schizophrenia (WAFSS). Our empirical findings provide evidence that the proposed nonlinear models well outperform the widely used linear and tree based logistic regression models in class prediction of schizophrenia risk with SNP data in terms of both Types I/II error rates and ROC curves.
Tumor relapse after radiotherapy may be due to the upregulation of programmed cell death ligand 1 (PD-L1). We demonstrated that anti-PD-L1 antibody synergizes with radiation to control local and distal tumors. CD8(+)T cells mediated antitumor effects of the combination therapy by the reduction of myeloid-derived suppressor cells (MDSCs) via tumor-necrosis factor (TNF)-mediated signaling. Our study provides insight into immune- and radiation-based combinational therapies.
Small ubiquitin-like modifier (SUMO) proteins regulate many important eukaryotic cellular processes through reversible covalent conjugation to target proteins. In addition to its many well-known biological consequences, like subcellular translocation of protein, subnuclear structure formation, and modulation of transcriptional activity, we show here that SUMO-2 also plays a role in mRNA translation. SUMO-2 promoted formation of the active eukaryotic initiation factor 4F (eIF4F) complex by enhancing interaction between Eukaryotic Initiation Factor 4E (eIF4E) and Eukaryotic Initiation Factor 4G (eIF4G), and induced translation of a subset of proteins, such as cyclinD1 and c-myc, which essential for cell proliferation and apoptosis. As expected, overexpression of SUMO-2 can partially cancel out the disrupting effect of 4EGI-1, a small molecule inhibitor of eIF4E/eIF4G interaction, on formation of the eIF4F complex, translation of the cap-dependent protein, cell proliferation and apoptosis. On the other hand, SUMO-2 knockdown via shRNA partially impaired cap-dependent translation and cell proliferation and promoted apoptosis. These results collectively suggest that SUMO-2 conjugation plays a crucial regulatory role in protein synthesis. Thus, this report might contribute to the basic understanding of mammalian protein translation and sheds some new light on the role of SUMO in this process.
Most chronically-infected hepatitis C virus (HCV) patients have increased levels of iron in the liver. Iron overload reduces sustained responses to antiviral therapy, leading to more rapid progression to liver cirrhosis and the development of hepatocellular carcinoma. However, it is still unclear how HIV-1 infection affects iron status in patients chronically infected with HCV. The present study recruited 227 patients from a village in central China. These patients were either monoinfected with HCV (n?=?129) or coinfected with HCV/HIV-1 (n?=?98). Healthy controls (n?=?84) were also recruited from the same village. Indicators of iron status, such as serum levels of iron, ferritin, and transferrin, total iron-binding capacity (TIBC), transferrin saturation (Tfs), and hepcidin, were analyzed and compared across the three groups. The results showed that serum levels of iron (p?=?0.001) and ferritin (p?=?0.009) and the Tfs (p?=?0.002) were significantly higher in HCV-monoinfected patients than in the healthy controls; however, there were no differences in iron levels and Tfs between HCV/HIV-1 coinfected patients and healthy controls. Additionally, although serum hepcidin levels in HCV-monoinfected and HCV/HIV-1-coinfected patients were lower (p<0.001) than those in health controls, the levels in coinfected patients were higher (p?=?0.025) than those in HCV-monoinfected patients. Serum iron and ferritin levels in HCV-monoinfected patients were positively correlated with serum ALT/AST. Serum transferrin levels were negatively correlated with ALT/AST levels. The levels of iron in the serum of coinfected patients with a CD4+T-cell count <500/µl were lower than those in patients with a CD4+T-cell count ?500/µl, whereas serum hepcidin levels showed the opposite trend. Taken together, these results suggest that coinfection with HIV-1 alleviates iron accumulation caused by chronic HCV infection. Our study indicated that determining the status of serum iron and other iron-associated parameters will be helpful to understand the complexity of alternations in iron distribution in HCV/HIV-1-coinfected patients.
Sedation or anaesthesia is recommended for all patients undergoing bronchoscopy unless absolute contraindications exist. However, the widely used combination of propofol and opiates for moderate sedation (MS) in bronchoscopy results in a high incidence of hypoxaemia and a relatively high cough score during the procedure. In this study, we evaluated the efficacy and safety of target-controlled infusion (TCI) of propofol and remifentanil, together with the use of high frequency jet ventilation (HFJV), to achieve general anesthesia (GA) in diagnostic fibre-optic bronchoscopy.
In the present paper, a dielectric barrier discharge (DBD) plasma was generated at low pressure in a DBD device with the eletrode distance of 10cm and using Ar as working gas. The changes in electronic temperature and density in the discharge cavum were studied by means of emission spectrometry. The changes in electronic temperature measured by using corona model were obtained. The variations in electronic density were analyzed using 750.4 nm line intensity. It was found that the plasma electronic temperature and density is various at different positions in the discharge cavum. With the measuring point moving from cathode to anode, the electronic temperature firstly increases slowly, then decreases quickly. While the electronic density increases slowly at first, and then rapidly.
It was found in our previous study that berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. The aim of the present study was to clarify how BBR and FLC worked synergistically and the underlying mechanism. Antifungal time-kill curves indicated that the synergistic effect of the two drugs was BBR dose dependent rather than FLC dose dependent. In addition, we found that BBR accumulated in C. albicans cells, especially in the nucleus, and resulted in cell cycle arrest and significant change in the transcription of cell cycle-related genes. Besides BBR, other DNA intercalators, including methylene blue, sanguinarine, and acridine orange, were all found to synergize with FLC against FLC-resistant C. albicans. Detection of intracellular BBR accumulation by fluorescence measurement showed that FLC played a role in increasing intracellular BBR concentration, probably due to its effect in disrupting the fungal cell membrane. Similar to the case with FLC, other antifungal agents acting on the cell membrane were able to synergize with BBR. Interestingly, we found that the efflux of intracellular BBR was FLC independent but strongly glucose dependent and associated with the drug efflux pump Cdr2p. These results suggest that BBR plays a major antifungal role in the synergism of FLC and BBR, while FLC plays a role in increasing the intracellular BBR concentration.
This study investigated the expression of the phospholipase C epsilon 1 (PLCE1) and nuclear factor-kappaB (NF-?B)-related proteins in Kazakh patients with esophageal squamous cell carcinoma (ESCC). Tissue microarrays of 90 ethnic Kazakh patients with ESCC and exhibiting clinical characteristics were analyzed for protein expression of PLCE1, IKK?, IKB?, p50, and p65 by immunohistochemistry. Correlations between histoscores of PLCE1 and NF-?B-related proteins were determined using Spearmans rank correlation tests. Expression of PLCE1 and NF-?B-related proteins significantly increased in tumor tissues compared with normal esophageal tissues (P = 9.48 × 10(-7), 1.24 × 10(-5), 0.004, 0.003, and 2.83 × 10(-5), respectively). Upregulation of PLCE1 was significantly correlated with advanced tumor-node-metastasis stages (P = 0.018) and lymph node metastasis (P = 0.003). Overexpression of IKK? and IKB? was associated with ESCC stages I/II (P = 3.36 × 10(-4) and 0.022, respectively). Increased expression of p50 was significantly higher in patients with lymph node metastasis than without lymph node metastasis (P = 0.048). Elevated expression of p65 protein was significantly correlated with poor and moderately differentiated ESCC and depth of tumor invasion (P = 0.026 and 0.010, respectively). Significant positive correlations were observed between the expression of PLCE1 and NF-?B-related proteins, especially IKK? (r = 0.246 and P = 0.025) and p50 (r = 0.244 and P = 0.024). These results suggest, for the first time, that upregulation of PLCE1 is correlated with increased expression of NF-?B-related proteins in Kazakh patients with ESCC, suggesting that interaction between PLCE1 with the NF-?B signal pathway may be responsible for the carcinogenesis of ESCC, such as ESCC-related inflammation.
Abstract Increasing evidence has suggested that HIV infection severely damages the V?2V?2 (V?2) T cells that play an important role in the first-line host response to infectious disease. However, little is known about V?2 T cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) in HIV disease. We found that although the CD16(+) V?2 T cell subset hardly participated in phosphoantigen responses dominated by the CD16(-) V?2 T cell subset, the potency of the ADCC function of V?2 T cells was correlated with the frequency of the CD16(+) subset. Thus, two distinct and complementary V?2 T cell subsets discriminated by CD16 were characterized to explore the respective impacts of HIV-1 infection on them. HIV-1 disease progression was not only associated with the phosphoantigen responsiveness of the CD16(-) V?2 subset, but also with the ability of the CD16(+) V?2 subset to kill antibody-coated target cells. Furthermore, both of the two V?2 functional subsets could be partially restored in HIV-infected patients with antiretroviral therapy. Notably, in the context of an overall HIV-mediated V?2 T cell depletion, despite the decline of phosphoantigen-responsive CD16(-) V?2 cells, CD16(+) V?2 cell-mediated ADCC was not compromised but exhibited a functional switch with dramatic promotion of degranulation in the early phase of HIV infection and chronic infection with slower disease progression. Our study reveals functional characterizations of the two V?2 T cell subsets with different activation pathways during HIV-1 infection and provides a rational direction for activating the CD16(+) V?2 T cells capable of mediating ADCC as a means to control HIV-1 disease.
Sterol regulatory element binding protein-1c (SREBP-1c) is a master regulator of fatty acid synthase and controls lipogenesis. IRS-1 is the key insulin signalling mediator in skeletal muscle. In the present study, we investigated the role of SREBP-1c in the regulation of IRS-1 in skeletal muscle cells.
Few characteristic changes of linear electroencephalograph (EEG) have been reported in schizophrenia. The aim of the present study was to investigate the changes in temporal-spatial dimensional properties of EEG under different cognitive tasks in patients with schizophrenia.
Enormous efforts were focused on the 3-descladinosyl erythromycin derivatives which led to 3-keto (ketolides), 3-O-acyl (acylides), 3-O-carbamate (carbamolides), and 3-O-alkyl (alkylides) and cladinosyl-containing erythromycin derivatives such as 4"-O-acyl, 4"-O-carbamate, and 4"-O-alkyl derivatives as recently exemplified by macrolones (macrolide-quinolone hybrids). Ketolides acquire activity against MLSB-resistant pathogens via a featured arylalkyl extension suspended on the macrolide core, which interacts with a base pair formed by A752Ec and U2609Ec located in the nascent peptide release tunnel of the bacterial rRNA. A base pair formed by C2610Ec and G2505Ec probably is another novel binding site for 3-descladinosyl non-ketolides. It is believed that 4"-derived compounds perhaps interfere with the formation of polypeptide because the extension oriented into peptidyl transferase center (PTC) region. Although macrolones are hybrids of macrolides and quinolones, they do not have dual modes of action, and serve only as protein synthesis inhibitors.
Raman spectroscopy was used for experimental research on D2 signal to noise ratio (SNR) under different conditions. The 32 mW Ar+ laser was injected into the Raman quartz glass cells to study the effect of grating, laser power, exposure time and the gas pressure on D2 Raman spectra SNR. D2 Raman spectral signal to noise ratio is proportional to the laser power, exposure time and gas pressure. The standard curve of the pressure and SNR for this experimental apparatus was obtained. Three sets of random samples were used to verify the formula SNR(J 2 --> 2) = 10.6 x 10(-4) p+1.271 34. When the deuterium pressure is 21 280 Pa, the relative error is 4.8%. When the pressure increases to 67 235 Pa, the relative error is down to 1.46%.
A selective phosphorescent biothiols probe is synthesized based on Ir(III) complex 1, which has 2,2-biquinoline as the N^N ligand for realizing the satisfied two-photon absorption cross-section and two-functionalized 2-phenylpyridine ligands with an ?,?-unsaturated ketone moiety as the thiol reaction site. The one- and two-photon optical properties of 1 are investigated through UV-vis absorption spectrum and photoluminescence spectrum. This Ir(III) complex can act as an excellent one- and two-photon excited "OFF-ON" phosphorescent probe for biothiols based on the 1,4-addition of biothiol to ?,?-unsaturated ketones. Moreover, one- and two-photon-induced luminescent imagings of biothiols in living cells are also realized. Furthermore, the experiments of time-resolved photoluminescence technique and fluorescence lifetime imaging microscopy demonstrate that 1 is able to detect biothiols in the presence of strong background fluorescence. In addition, probe 1 is adsorbed into the shell of mesoporous silica nanoparticles with core-shell structure to form a nanoprobe, which can realize the ratiometric detection of biothiols in absolute water solution and living cells based on two phosphorescent signals.
Double-stranded (ds-) DNA molecules were stretched and ruptured on molecularly modified graphite surfaces with a scanning force microscope (SFM) exerting a force parallel to the surface. The stretching force was either large enough to break the molecule immediately or compensated by the elastic restoring force of the DNA backbone, which stabilized the molecular length. However, the size-stabilized molecules broke gradually from longer molecules to shorter ones with time. The breakage of different lengths of stabilized molecules was recorded in order to study time-dependent mechanical properties of the molecules under constant forces. From these data, a relatively high rate constant, k0 = (2.2 ± 0.1) × 10(-7) s(-1), was calculated. Moreover, we found a nonlinear stress-strain dependence of DNA on the surface which we attributed to DNA conformational transition. Assuming that the structural transition on the surface is similar to that in solution we estimated the forces needed to stretch the molecules and thereby verify the estimation of the activation energy barrier.
To explore the nonlinear interactions between covariates and an index variable, partially linear proportional hazards models have been proposed for censored survival data. However, specification of the partially linear structure was usually carried out in an ad-hoc manner by first fitting a full varying-coefficient model and visually examining the resulting fit to identify the linear part. In this article, we consider the problem of coefficient estimation and constant coefficient identification based on a double shrinkage approach. Variable selection is also considered in a coherent estimation framework, resulting in a double-penalization procedure. Under the mild assumptions, we establish asymptotic properties for the procedure such as consistency, sparesistency, constansistency, and asymptotic normality. We evaluate the performance of the proposed method by numerical simulations and demonstrate its application using a breast cancer data set.
Despite its efficacy and widespread use, radiation therapy is often associated with local or distal tumor relapse. We have recently found that CD8(+) T cells and their cytokines are essential for maintaining irradiated neoplasms under control. In line with this notion, enhancing T-cell functions by means of immune checkpoint inhibitors can tilt the balance toward tumor rejection.
Single-chain Fv fragments (scFvs) consist of the variable heavy-chain (VH) and variable light-chain (VL) domains, which are the smallest immunoglobulin fragments containing the whole antigen-binding site. Human soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) proves to acquire a potent pro-apoptotic activity only after selective binding to a predefined tumor cell surface antigen and has no off-target effects towards normal cells. Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor and overexpresses human multidrug resistance protein 3 (MRP3). In this study, we designed a novel fusion protein, termed scFvM58-sTRAIL, in which the MRP3-specific scFv antibody M58 was genetically fused to the N-terminus of human soluble TRAIL (sTRAIL). The recombinant scFvM58-sTRAIL fusion protein, expressed in Escherichia coli, was purified by chromatography and tested for cytotoxicity. scFvM58-sTRAIL showed a significant apoptosis-inducing activity towards MRP3-positive GBM cells in vitro. The pro-apoptotic activity of scFvM58-sTRAIL towards GBM cells was strongly inhibited in the presence of the parental scFvM58 antibody, suggesting that cytotoxic activity is MRP3-restricted. In a control experiment with MRP3-negative Jurkat cells, scFvM58-sTRAIL did not induce apparent apoptosis. In addition, through target antigen-restricted binding, scFvM58-sTRAIL was capable of activating not only TRAIL-R1 but also TRAIL-R2. In conclusion, our results suggest that fusion protein scFvM58-sTRAIL with specificity for MRP3 is a highly selective therapeutic agent and may provide an alternative therapy for human GBM.
The postprandial event known as the specific dynamic action is an evolutionarily conserved physiological set of metabolic responses to feeding. Its behavioral counterpart, a sequence of drinking, maintenance (e.g., grooming) and sleep-like behaviors known as the behavioral satiety sequence (BSS), has been thoroughly described in rodents and has enabled the refined evaluation of potential appetite modifiers. However, the presence and attributes of a BSS have not been systematically studied in non-mammalian species. Here, we describe the BSS induced in pigeons (Columba livia) by 1) the presentation of a palatable seed mixture (SM) food to free-feeding animals (SM+FF condition) and 2) re-feeding after a 24-h fasting period (FD24h+SM), which was examined by continuous behavioral recording for 2h. We then compare these patterns to those observed in free-feeding (FF) animals. A set of graphic representations and indexes, drawn from these behaviors (latency, time-to-peak, inter-peak intervals and the first intersection between feeding curves and those of other BSS-typical behaviors) were used to describe the temporal structure and sequential relationships between the pigeons BSS components. Cramér-von Mises-based statistical procedures and bootstrapping-based methods to compare pairs of complex behavioral curves were described and used for comparisons among the behavioral profiles during the free-feeding recordings and after fasting- and SM-induced BSS. FD24h+SM- and SM+FF-induced feeding were consistently followed by a similar sequence of increased bouts of drinking, followed by preening and then sleep, which were significantly different from that of FF birds. The sequential and temporal patterns of the pigeons BSS were not affected by differences in food intake or by dissimilarity in motivational content of feeding stimuli. The present data indicated that a BSS pattern can be reliably evoked in the pigeon, in a chronological succession and sequence that strongly resembled that observed in rodents and primates. This pattern can be quantitatively described and compared using different suitable and coordinated behavioral measures, enabling further studies on the comparative and evolutionary aspects of the mechanisms that shape the post-consummatory behavioral flux in amniotes.
SUMMARY: To explore the nonlinear interactions between covariates and an index variable, partially linear proportional hazards models have been proposed for censored survival data. However, specification of the partially linear structure was usually carried out in an ad-hoc manner by first fitting a full varying-coefficient model and visually examining the resulting fit to identify the linear part. In this article, we consider the problem of coefficient estimation and constant coefficient identification based on a double shrinkage approach. Variable selection is also considered in a coherent estimation framework, resulting in a double-penalization procedure. Under the mild assumptions, we establish asymptotic properties for the procedure such as consistency, sparesistency, constansistency, and asymptotic normality. We evaluate the performance of the proposed method by numerical simulations and demonstrate its application using a breast cancer data set.
Local failures following radiation therapy are multifactorial, and the contributions of the tumor and the host are complex. Current models of tumor equilibrium suggest that a balance exists between cell birth and cell death due to insufficient angiogenesis, immune effects, or intrinsic cellular factors. We investigated whether host immune responses contribute to radiation-induced tumor equilibrium in animal models. We report an essential role for immune cells and their cytokines in suppressing tumor cell regrowth in two experimental animal model systems. Depletion of T cells or neutralization of IFN-? reversed radiation-induced equilibrium, leading to tumor regrowth. We also demonstrate that PD-L1 blockade augments T cell responses, leading to rejection of tumors in radiation-induced equilibrium. We identify an active interplay between tumor cells and immune cells that occurs in radiation-induced tumor equilibrium and suggest a potential role for disruption of the PD-L1/PD-1 axis in increasing local tumor control.
This study was undertaken to determine whether twitch mouth pressure (TwPmo) can reliably assess diaphragm strength in patients with chronic obstructive pulmonary disease (COPD) using fully automatic trigger techniques. Fifteen patients with COPD were recruited. TwPmo, twitch oesophageal pressure (TwPes) and twitch transdiaphragmtic pressure (TwPdi) were generated by phrenic nerve stimulation and were measured using an inspiratory flow trigger (40 ml/s, Experiment 1) using an inspiratory pressure trigger (-5 cmH2O, Experiment 2) and using no trigger at functional residual capacity (Experiment 3). The correlation between TwPmo and TwPes was as follows: r=0.832; P<0.0001 (Experiment 1), r=0.900; P<0.0001 (Experiment 2); there was no significant correlation in Experiment 3. A Bland-Altman plot of the difference between TwPmo and TwPes showed the limits of agreement in Experiment (1) bias (range) 0.18 cmH2O (-2.05 to 2.41) and Experiment (2) bias (range) 0.32 cmH2O (-1.69 to 2.32). Measuring TwPmo using a fully automatic technique is a simple and convenient method for assessing diaphragm strength.
It is unknown which factors are associated with smoking cessation interventions initiated by hospital chest physicians in China. We examined physicians awareness of negative effects of smoking on smoking cessation advice given.
Patients with diabetes mellitus exhibit peripheral arterioles lesions that is associated with reduced blood flow. Here, we intended to assess the acral arterioles lesion in patients with type 2 diabetes based on the rate of blood flow by multigate spectral Doppler ultrasonography. Fifty-two patients with type 2 DM were divided into two groups. Group 1 included 13 men and 12 women with an average age of 60.60 ± 14.03 years and a duration of type 2 diabetes for 2.44 ± 1.50 years. Group 2 included 17 men and 11 women with an average age of 64.25 ± 10.84 years and type 2 diabetes for 12.57 ± 6.26 years. Age-matched control subjects (n = 52) were recruited (30 men and 22 woman, mean age of 61.19 ± 10.38 years). A multigate spectral Doppler algorithm was applied to the acral finger of the thumb of the right hand to test the arteriole diameter and hemodynamic parameters, including diameter of the acral finger arterioles (D), area of the blood flow profile of the acral finger arterioles (A max) and hemodynamic parameters. Patients with diabetes exhibited a significant reduction in the arteriole diameter (1.63 ± 0.18 and 1.57 ± 0.22 mm, respectively, P < 0.001 for both) compared to control subjects (2.09 ± 0.17 mm). A max were significantly reduced in patients with diabetes (61.35 ± 10.66 mm(2)/s for group 1 and 46.50 ± 6.59 mm(2)/s for group 2, P < 0.001 for both) compared to that in control subjects (77.93 ± 12.37 mm(2)/s). Furthermore, a significant difference in Amax was found between group 1 and group 2 (P < 0.001). The vascular resistance index (RI) was significantly higher in both patient groups 0.58 ± 0.06 for group 1 (P < 0.001) and 0.64 ± 0.07 for group 2 (P < 0.001) than that in control subjects (0.48 ± 0.04). The RI value of the acral finger arterioles differed significantly between group 1 and group 2 (P < 0.01). Diabetic patients exhibited a weak blood flow in the acral finger arterioles. The multigate spectral Doppler technology can be used to test blood flow in the acral finger arterioles and provide hemodynamic data for systematic analyses of the peripheral arteriole lesions in diabetes.
The diagnosis of pancreatic tumors is often complicated because of sampling and interpretive challenges. The current study was performed to determine the rates, types, and causes of diagnostic discrepancies.
Sevoflurane, an inhalational anesthetic, and cisplatin (DDP)-based chemotherapy have been widely used during lung cancer surgery. However, the effect of sevoflurane on the sensitivity of lung cancer cells to DDP chemotherapy remains unclear. In this study, the effects of combined treatment with sevoflurane and cisplatin on the growth and invasion of human lung adenocarcinoma A549 cell line have been investigated. The underlying mechanism has also been explored. In our experiment, A549 cells were treated with 2.5% sevoflurane, 10?mol/L DDP, or the co-treatment of sevoflurane and DDP for 4h, respectively. Cell proliferation was evaluated by the MTT assay and colony formation assay. Apoptosis was assessed by flow cytometry. Cell invasion was detected by Transwell assay. The expressions of X-linked inhibitor of apoptosis protein (XIAP), Survivin, matrix metalloproteinase (MMP)-2 and MMP-9 were determined by western blotting. Our results showed that sevoflurane combined with DDP resulted in a more pronounced inhibition of tumor cells growth and invasion as compared with either drug alone. Besides, XIAP, Survivin, MMP-2, and MMP-9 were downregulated more significantly by the co-treatment of the two drugs as compared to sevoflurane treatment or DDP treatment alone. Taken together, the growth-inhibitory and invasion-inhibitory synergy between sevoflurane and DDP in human adenocarcinoma A549 cell line was found in this study. Furthermore, we showed that the growth-inhibitory synergy between sevoflurane and DDP might be associated with the downregulation of XIAP and Survivin, and the invasion-inhibitory synergy between sevoflurane and DDP might be involved in the downregulation of MMP-2 and MMP-9.
Traditional cell-tracking methods fail to meet the needs of preclinical or clinical research. Thus, the aim of the present study was to establish a new method of double labeling bone marrow mesenchymal stem cells (BMSCs) from type 1 diabetic (T1D) minipigs with super-paramagnetic iron oxide (SPIO) and enhanced green fluorescent protein (eGFP) and tracing them using MRI in vitro.
With the depletion of global petroleum and its increasing price, biodiesel has been becoming one of the most promising biofuels for global fuels market. Researchers exploit oleaginous microorganisms for biodiesel production due to their short life cycle, less labor required, less affection by venue, and easier to scale up. Many oleaginous microorganisms can accumulate lipids, especially triacylglycerols (TAGs), which are the main materials for biodiesel production. This review is covering the related researches on different oleaginous microorganisms, such as yeast, mold, bacteria and microalgae, which might become the potential oil feedstocks for biodiesel production in the future, showing that biodiesel from oleaginous microorganisms has a great prospect in the development of biomass energy. Microbial oils biosynthesis process includes fatty acid synthesis approach and TAG synthesis approach. In addition, the strategies to increase lipids accumulation via metabolic engineering technology, involving the enhancement of fatty acid synthesis approach, the enhancement of TAG synthesis approach, the regulation of related TAG biosynthesis bypass approaches, the blocking of competing pathways and the multi-gene approach, are discussed in detail. It is suggested that DGAT and ME are the most promising targets for gene transformation, and reducing PEPC activity is observed to be beneficial for lipid production.
Orosomucoid 1-like 3 (ORMDL3) gene was strongly linked with the development of asthma in genetic association studies, and its expression could be significantly induced by allergen in airway epithelial cells of mice. However, the expression mechanism of ORMDL3 was still unclear. Here we have identified and characterized the mouse ORMDL3 gene promoter. Deletion constructs of the 5 ?anking region were fused to a luciferase reporter gene. After transient transfection in mouse fibroblast cell line NIH3T3, a CRE (-27/-20) binding CREB was identified in the core promoter region. Deletion or mutation of the CRE consensus sequence resulted in a significant loss of the promoter activity. EMSA and ChIP assays demonstrated the binding of CREB to the core promoter. Knocking down endogenous CREB led to a reduction in ORMDL3 expression. Conversely, overexpression of CREB up-regulated ORMDL3 expression. Moreover, forskolin, a PKA activator, could facilitate the phosphorylation of CREB, which in turn heightens ORMDL3 expression. H-89, a PKA-specific inhibitor, could significantly inhibit ORMDL3 expression. This study delineates the characterization of mouse ORMDL3 gene promoter and shows signaling pathway cAMP/PKA/CREB plays an important role in regulating ORMDL3 expression, which will be helpful for future animal model studies regarding the regulation or function of ORMDL3 gene.
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.
Increasing evidence indicates that antibody-dependent cellular cytotoxicity (ADCC) contributes to the control of HIV/SIV infection. However, little is known about the ADCC function of natural killer (NK) cells in non-human primate model. Here we demonstrated that ADCC function of NK cells was significantly compromised in chronic SIV/SHIV infection, correlating closely with the expression of Fc?RIIIa receptor (CD16) on NK cells. CD32, another class of IgG Fc receptors, was identified on NK cells with higher expression in the infected macaques and the blockade of CD32 impacted the ability of NK cells to respond to antibody-coated target cells. The inhibition of matrix metalloproteases (MMPs), a group of enzymes normally involved in tissue/receptor remodeling, could restore NK cell-mediated ADCC with increased CD16 expression on macaque NK cells. These data offer a clearer understanding of NK cell-mediated ADCC in rhesus macaques, which will allow us to evaluate the ADCC repertoire arising from preclinical vaccination studies in non-human primates and inform us in the future design of effective HIV vaccination strategies.
The applications of endohedral non-metallic fullerenes are limited by their low production rate. Recently, an explosive method developed in our group shows promise to prepare He@C?? at fairly high yield, but the mechanism of He inserting into C?? cage at explosive conditions was not clear. Here, ab initio molecular dynamics analysis has been used to simulate the collision between C?? molecules at high-temperature and high-pressure induced by explosion. The results show that defects formed on the fullerene cage by collidsion can effectively decrease the reaction barrier for the insertion of He into C??, and the self-healing capability of the defects was also observed.
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