Transparent electrodes that can maintain their electrical and optical properties stably against large mechanical deformations are essential in numerous applications of flexible and wearable electronics. In this paper, we report a comprehensive analysis of the electrical, optical, and mechanical properties of hybrid nanostructures based on graphene and metal nanotrough networks as stretchable and transparent electrodes. Compared to the single material of graphene or the nanotrough, the formation of this hybrid can improve the uniformity of sheet resistance significantly, that is, a very low sheet resistance (1 ?/sq) with a standard deviation of less than ±0.1 ?/sq, high transparency (91% in the visible light regime), and superb stretchability (80% in tensile strain). The successful demonstration of skin-attachable, flexible, and transparent arrays of oxide semiconductor transistors fabricated using hybrid electrodes suggests substantial promise for the next generation of electronic devices.
Purpose: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient derived xenografts (PDXs). Experimental Design: Immunohistochemistry and fluorescence in situ hybridization were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2 and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib or the combination of trastuzumab and lapatinib. Acute and chronic post treatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation. Results: HER2 gene amplification (24%) correlated significantly with HER2 protein over-expression (55%). All models were impervious to single agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2 amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant anti-tumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2 amplified models, and was associated with increased apoptosis and decreased proliferation.
Growth factor receptors, often carrying tyrosine kinase activities in their cytoplasmic domains, are overexpressed in many cancers. Coactivation of receptor tyrosine kinases (RTKs) plays a critical role in tumor response to targeted therapeutics. We examined concomitant overexpression of EGFR and MET in patients with HER2(+) and HER2(-) gastric cancers (GCs). Tissue microarray samples obtained from 1,589 GC patients who received R0 gastrectomy with extensive node dissection and adjuvant chemoradiationtherapy were analyzed by immunohistochemistry and fluorescence in situ hybridization. HER2(+) was observed in 169 patients (11%). Out of 169 HER2(+) patients, 15 (9%) were EGFR(+) and MET(+) , 29 (17%) were EGFR(+) , 37 (22%) were MET(+) and the remaining 88 patients (52%) were HER2(+) only, without concomitant EGFR or MET overexpression. Greater number of overexpressed RTKs correlated with younger age (p?0.001), larger tumor size (p = 0.027), intestinal histology (p?0.001) and shorter overall survival (p = 0.002). The mean overall survival was 113 months for HER2(-) /EGFR(-) /MET(-) and 63 months for HER2(+) /EGFR(+) /MET(+) subgroups. Patients with HER2(+) /EGFR(+) /MET(+) GCs had a substantial risk of death with a hazard ratio of 3.01 (95% CI: 1.54-5.90), compared with HER2(-) /EGFR(-) /MET(-) GC patients. Using patient-derived tumor cell models isolated from pericardial effusion of HER2(+) and MET(+) GC cases, we demonstrated that the combination of HER2-inhibitor (lapatinib) and MET-inhibitor offered a more profound inhibition in the ERK/AKT pathway and cell proliferation than lapatinib alone. Co-overexpression of RTKs was demonstrated in small subsets of GC associated with aggressive behavior and in these cases, combination therapy may be considered as potential treatment options.
Molar uprighting is an important adjunctive treatment in orthodontics: repositioning the tilted molar eliminates the potentially pathologic condition and simplifies the ultimate restorative procedure. Although various methods for molar uprighting have been applied successfully, they still have some limitations and disadvantages in tooth movement. This article reports on a new clinical technique for molar uprighting with nickel-titanium springs based on a setup model. Two patients treated with this system are shown.
ABSTRACT BACKGROUND. Lung cancer is the leading cause of cancer deaths in both genders worldwide, with an incidence only second to prostate cancer in men and breast cancer in women. The lethality of the disease highlights the urgent need for innovative therapeutic options. Immunotherapy can afford efficient and specific targeting of tumor cells, improving efficacy and reducing the side effects of current therapies. We have previously reported the aberrant expression of cancer/testis antigens (CTAs) in tumors of unrelated histological origin. In this study we investigated the expression and immunogenicity of the cancer/testis antigens (CTAs) Sperm Protein 17 (SP17), A-kinase anchor protein 4 (AKAP4) and Pituitary Tumor Transforming Gene 1 (PTTG1) in human non-small cell lung cancer (NSCLC) cell lines and primary tumors. METHODS. We used RT-PCR, immunofluorescence, flow cytometry, ELISA and cytotoxicity assays to determine the expression levels and immunogenicity of SP17, AKAP4 and PTTG1 in human NSCLC cell lines and primary tumors. RESULTS. We found that SP17, AKAP4 and PTTG1 are aberrantly expressed in NSCLC cancer cell lines and primary tumor tissues from patients, compared to normal lung cell lines and tissues. We established the immunogenicity of these CTAs by measuring CTA-specific autoantibodies in patients' sera and generating CTA-specific autologous cytotoxic lymphocytes (CTLs) from patients' peripheral blood mononuclear cells (PBMCs). CONCLUSIONS. Our results provide proof of principle that the CTAs SP17/AKAP4/PTTG1 are expressed in both human NSCLC cell lines and primary tumors and can elicit an immunogenic response in NSCLC patients. Based on our findings, further studies are warranted to explore the feasibility of developing CTA-specific immunotherapeutic strategies for NSCLC patients.
Complex interplay of innate and adaptive immune cells has been implicated in the establishment, maintenance, and progression of endometriosis. Defining the identity, activation state, and functional role of immune cells during lesion establishment will provide invaluable insight into the underlying mechanisms of disease. This study utilized a transgenic mouse model with conditional dendritic cell (DC) depletion (diphtheria toxin-treated B6.FVB-Itgax-hDTR-EGFP(tg)) and multiparametric flow cytometry to examine immune cell composition and activation state and to assess the functional role of DCs in endometriosis-like lesions. T cells and DCs were increased in lesions compared to native uteri and control splenocytes and demonstrated an activated phenotype (P < .05). Lesions in DC-depleted hosts demonstrated greater size (P < .001) and reduced expression of T-cell activation marker CD69 compared to controls (P < .05). Collectively, these results suggest that activated DCs within lesions activate T cells and result in the impairment of early lesion establishment.
The anti-inflammatory impact of three polyunsaturated fatty acids (3-PUFA) in endometriosis is incompletely understood. The effect of 3-PUFA on endometriosis-like lesions is evaluated as a potential anti-inflammatory treatment target.
The formation of epithelial tissues containing lumens requires not only the apical-basolateral polarization of cells, but also the coordinated orientation of this polarity such that the apical surfaces of neighboring cells all point toward the central lumen. Defects in extracellular matrix (ECM) signaling lead to inverted polarity so that the apical surfaces face the surrounding ECM. We report a molecular switch mechanism controlling polarity orientation. ECM signals through a ?1-integrin/FAK/p190RhoGAP complex to downregulate a RhoA/ROCK/Ezrin pathway at the ECM interface. PKC?II phosphorylates the apical identity-promoting Podocalyxin/NHERF1/Ezrin complex, removing Podocalyxin from the ECM-abutting cell surface and initiating its transcytosis to an apical membrane initiation site for lumen formation. Inhibition of this switch mechanism results in the retention of Podocalyxin at the ECM interface and the development instead of collective front-rear polarization and motility. Thus, ECM-derived signals control the morphogenesis of epithelial tissues by controlling the collective orientation of epithelial polarization.
Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity.
Objectives:The aim of this study was to investigate the effects of retraction force and anchorage reinforcement with orthodontic mini implants on occlusal force.Materials and Methods:A strain gauge was attached to the palatal surface of the maxillary right first molar on an en masse retraction model.Results:Occlusal forces were measured from this model, according to different retraction forces that were generated by elastic chain, under varied compressive forces (simulating masticatory forces). This retraction experiment was then performed again, after using anchorage reinforcement with an orthodontic mini implant. Occlusal force decreased as retraction force increased. The decrease showed a significant difference above 150g of retraction force (P < 0.05) and was more definite under compressive force higher than 150 N (P < 0.001). After anchorage reinforcement with the orthodontic mini implant, however, occlusal force did not significantly decrease with increasing retraction force. Significant differences in occlusal force were noted between the conditions with and without anchorage reinforcement when the applied retraction force was greater than 200g.Conclusion:Occlusal force tends to decrease during retraction, and this decrease can be prevented by anchorage reinforcement with orthodontic mini implants.Limitations:Further investigation on the actual masticatory process in humans is required for more clear clinical implication.
We were not aware of a well-validated patellofemoral joint-specific scoring system. We performed this study to develop and validate a scoring system (Samsung Medical Center [SMC] patellofemoral scoring system) suitable for the evaluation of patellofemoral joint status.
Postsurgical changes in the condylar position are of great importance to surgical stability, especially in asymmetric double-jaw surgery. The aims of this study were to evaluate positional changes of the condyle up to 12 months after surgery in patients with Class III malocclusion and to identify the factors affecting postsurgical condylar position.
This article describes the orthodontic treatment of a 25-year-old Korean female patient with anterior crowding, including palatally displaced lateral incisors. Her facial profile was satisfactory, but 3.5 mm of maxillary anterior crowding was observed. To correct this crowding, we decided to minimize the use of the conventional fixed orthodontic appliances and employed a less bulky and more aesthetic appliance for applying light continuous force. We determined the final positions of the maxillary teeth via a working model for diagnostic set up and achieved space gaining and alignment with simple Ni-Ti spring and stainless steel round tubes. Tooth alignment was achieved efficiently and aesthetically without the conventional brackets.
Globotriaosylceramide (Gb(3)) is a cell surface-expressed natural resistance factor for HIV infection, but, its expression in human T-cells remains unknown. Therefore, Gb(3) in resting or activated CD4(+) T-cells was assessed by flow cytometry and thin layer chromatography of cell extracts. We found the majority of CD4(+) T-cells, whether resting or activated, do not express Gb(3) at significant levels (<2% positive cells). Thus, HIV treatment or prevention strategies must focus on development of soluble Gb(3) analogues for inhibition of HIV infection.
The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r=0.465, P<0.0001), increased copy number gain (r=0.393, P=0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324-2.395; P<0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227-2.541; P=0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r=0.274, P=0.002), copy number gain or survival (P>0.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors.
Dill, a small annual herb, is widely used as a flavoring agent in dishes including salads. It has been demonstrated that dill extract and its essential oil show hypolipidemic effects in rats. However, the mechanism of these effects has not been elucidated yet. We found that dill seed extract (DSE) activated peroxisome proliferator-activated receptor-? (PPAR-?), an indispensable regulator for hepatic lipid metabolism, by luciferase assay. Thus, we performed DSE feeding experiments using diabetic obese model KK-Ay mice to examine the effects of DSE on PPAR-? activation in vivo. A 4-week feeding of DSE contained in a high-fat diet decreased plasma triacylglyceride and glucose levels and increased the mRNA expression levels of fatty acid oxidation-related genes in the liver. In addition, the DSE feeding as well as bezafibrate (a PPAR-? potent agonist) feeding increased oxygen consumption rate and rectal temperature. These results indicate that DSE suppresses high-fat diet-induced hyperlipidemia through hepatic PPAR-? activation.
Psoriasis is a multi-factorial disease with various clinical manifestations. We present a case of unilateral psoriasis associated with ipsilateral lymphedema that developed after mastectomy for breast cancer. A 42-year-old Korean woman was referred to our clinic with a 1-month history of multiple erythematous scaly patches on the right arm, back, and breast and was diagnosed with psoriasis by a skin biopsy. Three years previously, she had been diagnosed with breast cancer (T1N2), underwent a right quadrantectomy and axillary lymph node dissection, and completed adjuvant chemotherapy followed by high-dose adjuvant radiotherapy. She had started rehabilitation therapy on the right arm for secondary lymphedema 30 months previously. Because of the long interval between radiation and psoriasis, we speculated that changes in the local milieu caused by the lymphedema might be a causative factor. We hereby report a rare case of unilateral psoriasis following post-mastectomy lymphedema.
?-Transaminase (?-TA) is an industrially important enzyme for production of chiral amines. About 20 (S)-specific ?-TAs known to date show remarkably similar substrate selectivity characterized by stringent steric constraint precluding entry of a substituent larger than an ethyl group in the small binding pocket (S) and dual recognition of an aromatic substituent as well as a carboxylate group in the large pocket (L). The strictly defined substrate selectivity of the available ?-TAs remains a limiting factor in the production of structurally diverse chiral amines. In this work, we cloned, purified, and characterized three new ?-TAs from Ochrobactrum anthropi, Acinetobacter baumannii, and Acetobacter pasteurianus that were identified by a BLASTP search using the previously studied ?-TA from Paracoccus denitrificans. All the new ?-TAs exhibited similar substrate specificity, which led us to explore whether the molecular determinants for the substrate specificity are conserved among the ?-TAs. To this end, key active site residues were identified by docking simulation using the X-ray structure of the ?-TA from Pseudomonas putida. We found that the dual recognition in the L pocket is ascribed to Tyr23, Phe88*, and Tyr152 for hydrophobic interaction and Arg414 for recognition of a carboxylate group. In addition, the docking simulation indicates that Trp60 and Ile262 form the S pocket where the substituent size up to an ethyl group turns out to be sterically allowed. The six key residues were found to be essentially conserved among nine ?-TA sequences, underlying the molecular basis for the high similarity in the substrate selectivity.
Previously we have found that extracellular guanosine (Guo) has neuroprotective properties in in vitro and in vivo. Moreover, extracellular Guo significantly increased in the ipsilateral hemisphere within 2h following focal stroke in rats, and remained elevated for one week. Therefore, we hypothesized that Guo could be a potential candidate for a non-toxic neuroprotective agent. In the present study, we examined the effects of Guo on rats following permanent middle cerebral artery occlusion (MCAO). We also determined whether Guo can precondition neurons by modulating endoplasmic reticulum (ER) stress proteins. As most therapies employ a combination treatment regimen, we optimized the neuroprotection by combining pre- and post-MCAO treatments with Guo, attempting to reduce both ischemic cell death and improve functional recovery. A combination of 4mg/kg Guo given 30min pre-stroke and 8mg/kg Guo given 3, 24 and 48h post-stroke exerted the most significant decrease in infarct volume and sustainable improvement in neurological function. Moreover, these effects are not attributable to Guo metabolites. Measurements taken 6h post-MCAO from animals pre-treated with Guo did not reveal any significant changes in ER stress proteins (GRP 78 and 94) or HSP 70, but did reveal significantly increased levels of m-calpain. Thus, our data indicate that there is a treatment regimen for Guo as a neuroprotectant following ischemic stroke. The mechanism by which Guo confers neuroprotection may involve an increase in m-calpain, possibly resulting from a mild increase in intracellular calcium. M-calpain may be involved in the preconditioning response to ischemia by upregulating endogenous pro-survival mechanisms in neurons.
The cell surface-expressed glycosphingolipid (GSL), globotriaosylceramide (Gb(3)), is becoming increasingly important and is widely studied in the areas of verotoxin (VT)-mediated cytotoxicity, human immunodeficiency virus (HIV) infection, immunology and cancer. However, despite its diverse roles and implications, an optimized detection method for cell surface Gb(3) has not been determined. GSLs are differentially organized in the plasma membrane which can affect their availability for protein binding. To examine various detection methods for cell surface Gb(3), we compared four reagents for use in flow cytometry analysis. A natural ligand (VT1B) and three different monoclonal antibodies (mAbs) were optimized and tested on various human cell lines for Gb(3) detection. A differential detection pattern of cell surface Gb(3) expression, which was influenced by the choice of reagent, was observed. Two mAb were found to be suboptimal. However, two other methods were found to be useful as defined by their high percentage of positivity and mean fluorescence intensity (MFI) values. Rat IgM anti-Gb(3) mAb (clone 38-13) using phycoerythrin-conjugated secondary antibody was found to be the most specific detection method while the use of VT1B conjugated to Alexa488 fluorochrome was found to be the most sensitive; showing a rare crossreactivity only when Gb(4) expression was highly elevated. The findings of this study demonstrate the variability in detection of Gb(3) depending on the reagent and cell target used and emphasize the importance of selecting an optimal methodology in studies for the detection of cell surface expression of Gb(3).
The role of vitamin D in the inhibition of malignant cell proliferation in hematological malignancies is indicative of its future use in cancer therapy. An understanding of the biochemical mechanism by which vitamin D and its derivatives exert their effects will prove to be useful in the development of clinically applicable therapies involving vitamin D. While the use of vitamin D in clinical trials against acute myeloid leukemia and myelodysplastic syndrome has been met with few successes thus far, in vitro and in vivo studies as well as epidemiological correlations between vitamin D deficiency and cancer have implicated the great potential of the use of vitamin D derivatives in effective therapies against neoplastic diseases. For these reasons, a focus on current understanding of role of vitamin D and derivatives in hematologic malignancies is relevant and the goal for this review.
Although quantitative EEG parameters, such as spectral band powers, are sensitive to centrally acting drugs in dose- and time-related manners, changes of the EEG parameters are redundant. It is desirable to reduce multiple EEG parameters to a few components that can be manageable in a real space as well as be considered as parameters representing drug effects. We calculated factor loadings from normalized values of eight relative band powers (powers of 0.5, 1.0~2.0, 2.5~4.0, 4.5~5.5, 6.0~8.0, 8.5~12.0, 12.5~24.5, and 25~49.5 Hz bands expressed as ratios of the power of 0.5-49.5 Hz band) of EEG during pre-drug periods (11:00~12:00) by factor analysis and constructed a two-dimensional canonical space (reference canonical space) by canonical correlation analysis. Eight relative band powers of EEG produced by either physostigmine or yohimbine were reduced to two canonical scores in the reference canonical space. While changes of the band powers produced by physostigmine and yohimbine were too redundant to describe the difference between two drugs, locations of two drugs in the reference canonical space represented the difference between two drugs effects on EEG. Because the distance between two locations in the canonical space (Mahalanobis distance) indicates the magnitude of difference between two different sets of EEG parameters statistically, the canonical scores and the distance may be used to quantitatively and qualitatively describe the dose-dependent and time-dependent effects and also tell similarity and dissimilarity among effects. Then, the combination of power spectral analysis and statistical analysis may help to classify actions of centrally acting drugs.
Budd-Chiari syndrome has been described as a late complication of Behçets disease. Although the mortality rate associated with Behçets disease is low, it can escalate in the presence of Budd-Chiari syndrome and may be further complicated by intracardial thrombus formation. It is therefore important to detect and initiate management early in the disease course. The imaging modalities of choice should be minimally invasive as certain procedures may aggravate Behçets disease by initiating a thrombosis or aggravating an existing one. In Behçets disease-induced Budd-Chiari syndrome, cardiac investigation is crucial in the work-up in order to identify any cardiac involvement and determine the etiology of intracardial thrombus. Furthermore, the treatment should ultimately focus on controlling the activity of Behçets disease. We report an unusual case of Behçets disease presenting with Budd-Chiari syndrome complicated by intracardial thrombus in a young Korean man.
Trichogerminoma is a rare neoplasm which was first described in 1992 and there is still controversy over its inclusion into the spectrum of trichoblastoma. A 79-year-old woman presented with a 5-year history of an asymptomatic nodule on the left posterior neck. Histologically, the lesion revealed a well-demarcated deep dermal nodule surrounded by a pseudocapsule. The tumor was composed of lobules with basophilic cells and some of the lobules displayed a distinctive pattern of densely packed cell balls with peripheral condensation. Immunohistochemically, the tumor cells showed zonal CK5/6 immunoactivity in contrast with the negatively stained cell balls. These characteristics were compatible with the diagnosis of trichogerminoma. We report here on a rare case of a hair germ tumor called trichogerminoma.
Tubule formation in vitro using Madin-Darby canine kidney (MDCK) epithelial cells consists mainly of two processes. First, the cells undergo a partial epithelial-mesenchymal transition (pEMT), losing polarity and migrating. Second, the cells redifferentiate, forming cords and then tubules with continuous lumens. We have shown previously that extracellular signal-regulated kinase activation is required for pEMT. However, the mechanism of how the pEMT phase is turned off and the redifferentiation phase is initiated is largely unknown. To address the central question of the sequential control of these two phases, we used MDCK cells grown as cysts and treated with hepatocyte growth factor to model tubulogenesis. We show that signal transducer and activator of transcription (STAT)1 controls the sequential progression from the pEMT phase to the redifferentiation phase. Loss of STAT1 prevents redifferentiation. Constitutively active STAT1 allows redifferentiation to occur even when cells are otherwise prevented from progressing beyond the pEMT phase by exogenous activation of Raf. Moreover, tyrosine phosphorylation defective STAT1 partially restored cord formation in such cells, suggesting that STAT1 functions in part as nonnuclear protein mediating signal transduction in this process. Constitutively active or inactive forms of STAT1 did not promote lumen maturation, suggesting this requires a distinct signal.
There is an increasing interest in curcumin (Curcuma longa L.) as a cardiovascular disease (CVD) protective agent via decreased blood total cholesterol and low-density lipoprotein-cholesterol (LDL-cholesterol) level. The aim of this study was to investigate further the potential mechanism in the hypocholesterolemic effect of curcumin by measuring cholesterol 7a-hydroxylase (CYP7A1), a rate limiting enzyme in the biosynthesis of bile acid from cholesterol, at the mRNA level. Male Sprague-Dawley rats were fed a 45% high fat diet or same diet supplemented with curcumin (0.1% wt/wt) for 8 weeks. The curcumin diet significantly decreased serum triglyceride (TG) by 27%, total cholesterol (TC) by 33.8%, and LDL-cholesterol by 56%, respectively as compared to control group. The curcumin-supplemented diet also significantly lowered the atherogenic index (AI) by 48% as compared to control group. Hepatic TG level was significantly reduced by 41% in rats fed with curcumin-supplemented diet in comparison with control group (P < 0.05). Conversely, the curcumin diet significantly increased fecal TG and TC. The curcumin diet up-regulated hepatic CYP7A1 mRNA level by 2.16-fold, compared to control group p (P < 0.05). These findings suggested that the increases in the CYP7A1 gene expression may partially account for the hypocholesterolemic effect of curcumin.
Lymphoepithelioma-like carcinoma (LELC) is a rare subtype of gastric carcinoma (GC) with a better survival rate than other GCs; most cases of LELC are associated with Epstein-Barr virus (EBV) infection. We investigated whether the survival advantage of LELC is related to the EBV infection itself or to associated inflammatory immune responses.
Dopamine-releasing neurons of the substantia nigra pars compacta produce an extraordinarily dense and expansive plexus of innervation in the striatum converging with glutamatergic corticostriatal and thalamostriatal axon terminals at dendritic spines of medium spiny neurons. Here, we investigated whether glutamatergic signaling promotes arborization and growth of dopaminergic axons. In postnatal ventral midbrain cultures, dopaminergic axons rapidly responded to glutamate stimulation with accelerated growth and growth cone splitting when NMDA and AMPA/kainate receptors were activated. In contrast, when AMPA/kainate receptors were selectively activated, axon growth rate was decreased. To address whether this switch in axonal growth response was mediated by distinct calcium signals, we used calcium imaging. Combined NMDA and AMPA/kainate receptor activation elicited calcium signals in axonal growth cones that were mediated by calcium influx through L-type voltage-gated calcium channels and ryanodine receptor-induced calcium release from intracellular stores. AMPA/kainate receptor activation alone elicited calcium signals that were solely attributable to calcium influx through L-type calcium channels. We found that inhibitors of calcium/calmodulin-dependent protein kinases prevented the NMDA receptor-dependent axonal growth acceleration, whereas AMPA/kainate-induced axonal growth decrease was blocked by inhibitors of calcineurin and by increased cAMP levels. Our data suggest that the balance between NMDA and AMPA/kainate receptor activation regulates the axonal arborization pattern of dopamine axons through the activation of competing calcium-dependent signaling pathways. Understanding the mechanisms of dopaminergic axonal arborization is essential to the development of treatments that aim to restore dopaminergic innervation in Parkinsons disease.
Over the past few years, robot-assisted surgery has become increasingly popular, affecting virtually all surgical fields. It has been proven to overcome pitfalls of laparoscopic procedures, such as high complication rates and steep learning curve. We have, therefore, performed experimental anterior lumbar interbody fusion (ALIF) using retroperitoneal approach in swine model to test the feasibility of robot-assisted surgery in spinal surgery.
ADAM10, a member of a disintegrin and metalloprotease family, is an alpha-secretase capable of anti-amyloidogenic proteolysis of the amyloid precursor protein. Here, we present evidence for genetic association of ADAM10 with Alzheimers disease (AD) as well as two rare potentially disease-associated non-synonymous mutations, Q170H and R181G, in the ADAM10 prodomain. These mutations were found in 11 of 16 affected individuals (average onset age 69.5 years) from seven late-onset AD families. Each mutation was also found in one unaffected subject implying incomplete penetrance. Functionally, both mutations significantly attenuated alpha-secretase activity of ADAM10 (>70% decrease), and elevated Abeta levels (1.5-3.5-fold) in cell-based studies. In summary, we provide the first evidence of ADAM10 as a candidate AD susceptibility gene, and report two potentially pathogenic mutations with incomplete penetrance for late-onset familial AD.
The aim of this study was to determine whether serum levels of adipokines, including the ratio of serum adiponectin to leptin (A/L) levels could predict the severity of liver injury in patients with non-alcoholic fatty liver disease (NAFLD).
Collagen tripeptide (CTP) is a functional food material with several biological effects such as improving dry skin and wound and bone fracture healing. This study focused on the anti-photoaging effects of CTP on a hairless mouse model. To evaluate the effects of CTP on UVB-induced skin wrinkle formation in vivo, the hairless mice were exposed to UVB radiation with oral administration of CTP for 14 weeks. Compared with the untreated UVB control group, mice treated with CTP showed significantly reduced wrinkle formation, skin thickening, and transepidermal water loss (TEWL). Skin hydration and hydroxyproline were increased in the CTP-treated group. Moreover, oral administration of CTP prevented UVB-induced MMP-3 and -13 activities as well as MMP-2 and -9 expressions. Oral administration of CTP increased skin elasticity and decreased abnormal elastic fiber formation. Erythema was also decreased in the CTP-treated group. Taken together, these results strongly suggest that CTP has potential as an anti-photoaging agent.
Our previous genetic, pharmacological and analogue protection studies identified the glycosphingolipid, Gb(3) (globotriaosylceramide, Pk blood group antigen) as a natural resistance factor for HIV infection. Gb(3) is a B cell marker (CD77), but a fraction of activated peripheral blood mononuclear cells (PBMCs) can also express Gb(3). Activated PBMCs predominantly comprise CD4+ T-cells, the primary HIV infection target. Gb(3) is the sole receptor for Escherichia coli verotoxins (VTs, Shiga toxins). VT1 contains a ribosome inactivating A subunit (VT1A) non-covalently associated with five smaller receptor-binding B subunits. The effect of VT on PHA/IL2-activated PBMC HIV susceptibility was determined. Following VT1 (or VT2) PBMC treatment during IL2/PHA activation, the small Gb(3)+/CD4+ T-cell subset was eliminated but, surprisingly, remaining CD4+ T-cell HIV-1(IIIB) (and HIV-1(Ba-L)) susceptibility was significantly reduced. The Gb(3)-Jurkat T-cell line was similarly protected by brief VT exposure prior to HIV-1(IIIB) infection. The efficacy of the VT1A subunit alone confirmed receptor independent protection. VT1 showed no binding or obvious Jurkat cell/PBMC effect. Protective VT1 concentrations reduced PBMC (but not Jurkat cell) proliferation by 50%. This may relate to the mechanism of action since HIV replication requires primary T-cell proliferation. Microarray analysis of VT1A-treated PBMCs indicated up regulation of 30 genes. Three of the top four were histone genes, suggesting HIV protection via reduced gene activation. VT blocked HDAC inhibitor enhancement of HIV infection, consistent with a histone-mediated mechanism. We speculate that VT1A may provide a benign approach to reduction of (X4 or R5) HIV cell susceptibility.
The aims of this study were to use a 3-dimensional (3D) system to compare molar relationship assessments performed from the buccal and lingual aspects, and to measure differences in occlusal contact areas between Class II and Class I molar relationships.
Lung cancer is the main cause of cancer mortality worldwide. This is mainly due to the fact that it is diagnosed in advanced stage patients, which are no more surgically curable. Consequently, searching for novel treatments and new modalities for early diagnosis offers great promise to improve the clinical outcome. Recently, a new group of antigens, the cancer testis antigens, have been described as possible early diagnostic tools and therapeutic targets in cancer therapy.This review will report emerging evidences of cancer testis antigens deregulation in lung cancer and explore the state of the art of their currently known role and potential as markers for early diagnosis and disease progression and targets of an immunotherapeutic approach aiming to improve the cure rate of this tumor.
There have been conflicting results on seasonal variation in the occurrence of venous thromboembolism (VTE). It also has never been studied in Asian population. To address these issues, we investigated seasonal changes of the incidence of VTE in Korean population using 1,495 patients with VTE between January 2001 and December 2010. VTE occurred most frequently in the winter and least frequently in the summer (?2=11.83, P=0.008). In the subset analyses, the same trend was shown in the PE±DVT group, the unprovoked VTE group, and the VTE without malignancy group. The monthly occurrence rate peaked in December and was at its lowest in July (P=0.004). In conclusion, our study provides evidence that there is an increased risk for VTE in Korean population in the winter season.
Porous zirconia monolith modified with clindamycin phosphate (CLIP-ZM) was used as chiral stationary phase (CSP) to separate a set of six acidic and basic chiral compounds in capillary electrochromatography (CEC). Resolutions and chiral selectivity factors of the chiral compounds were measured in ACN/MeOH mobile phases of varying compositions of MeOH and ammonium acetate as the electrolyte. In contrast to the CE separations where only chiral separations of acidic compounds were achieved enantiomers of both acidic and basic compounds were separated with acidic compounds better resolved than basic ones by CEC on the CLIP-ZM CSP. Best chiral separations of the chiral compounds were obtained with an eluent containing 10mM ammonium acetate and 35 vol.% methanol.
Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor with intermediate malignancy. The purpose of this study was to evaluate the utility of p53, smooth muscle actin (SMA) and c-kit as immunohistochemical markers and toluidine blue staining for mast cell that can correlate with the clinical outcome and clarify role of mast cells in pathogenesis of tumor. We analysed data for 32 lesions from 31 patients. Fibrosarcomatous type DFSP showed high immunoreactivity for SMA compared with other subtypes (P = 0.026). No differences in p53 immunoreactivity were observed between subtypes. None of tumor cells were immunoreactive with c-kit. The mast cell counts showed a negative correlation with mitosis and tumor size (P < 0.05), implying that mast cells do not have a causative primary role in tumorigenesis but rather play a secondary role.
Postsurgical changes of the airway have become a great point of interest and often have been reported to be a predisposing factor for obstructive sleep apnea after mandibular setback surgery. The purpose of this study was to evaluate the 3-dimensional volumetric changes in the upper airway space of patients who underwent bimaxillary surgery to correct Class III malocclusions.
As the importance of patient safety has been broadly acknowledged, various improvement programmes have been developed. Many of the programmes with proven efficacy have been disseminated internationally. However, some of those attempts may encounter unexpected cross-cultural obstacles and may fail to harvest the expected success. Each country has different cultural background that has shaped the behavior of the constituents for centuries. It is crucial to take into account these cultural differences in effectively disseminating these programmes. As an organ transplantation requires tissue-compatibility between the donor and the recipient, there needs to be compatibility between the country where the program was originally developed and the nation implementing the program. Though no detailed guidelines exist to predict success, small-scale pilot tests can help evaluate whether a safety programme will work in a new cultural environment. Furthermore, a pilot programme helps reveal the source of potential conflict, so we can modify the original programme accordingly to better suit the culture to which it is to be applied. In addition to programme protocols, information about the cultural context of the disseminated programme should be conveyed during dissemination. Original programme designers should work closely with partnering countries to ensure that modifications do not jeopardise the original intention of the programme. By following this approach, we might limit barriers originating from cultural differences and increase the likelihood of success in cross-cultural dissemination.
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Journal of Visualized Experiments
What is Visualize?
JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
How does it work?
We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.