iTRAQ-based quantitative proteomics reveals biomarkers/pathways in psoriasis that can predict the efficacy of methotrexate.

BACKGROUND: Methotrexate (MTX) is the first-line medicine to treat psoriasis. So far, there has been less research on protein biomarkers to predict its efficacy by the proteomic technique. OBJECTIVES: To evaluate differentially expressed proteins in peripheral mononuclear cells (PBMCs) between good responders (GRs) and non-responders (NRs) after MTX treatment, compared with normal controls (NCs). METHODS: We quantified protein expression of PBMCs with four GRs and four NRs to MTX and four NCs by isobaric tags for relative and absolute quantification (iTRAQ), analysing and identifying proteins related to efficacy of MTX in 18 psoriatic patients. RESULTS: A total of 3177 proteins had quantitative information, and 403 differentially expressed proteins (fold change ≥1.2, P < 0.05) were identified. Compared to NCs, upregulated proteins (ANXA6, RPS27A, EZR, XRCC6), participating in the activation of NF-κB, the JAK-STAT pathway and neutrophil degranulation were detected in GRs. The proteins (GPV, FN1, STOM), involving platelet activation, signalling and aggregation as well as neutrophil degranulation were significantly downregulated in GRs. These proteins returned to normal levels after MTX treatment. Furthermore, Western blotting identified the expression of ANXA6 and STAT1 in PBMCs, which were significantly downregulated in GRs, but not in NRs. CONCLUSIONS: We identified seven differentially expressed and regulated proteins (ANXA6, GPV, FN1, XRCC6, STOM, RPS27A and EZR) as biomarkers to predict MTX efficacy in NF-κB signalling, JAK-STAT pathways, neutrophil degranulation, platelet activation, signalling and aggregation.

Ambra1 inhibits paclitaxel-induced apoptosis in breast cancer cells by modulating the Bim/mitochondrial pathway.

Cancer cells often evade apoptosis induced by anti-cancer drugs, which reduces the efficacy of the drugs. Autophagy/Beclin 1 regulator 1 (Ambra1) is a crucial proautophagic protein. It also plays an important role in the execution of apoptosis. However, the mechanism by which Ambra1 regulates apoptosis has not been fully clarified. Moreover, whether Ambra1 participates in the regulation of paclitaxel-induced apoptosis in breast cancer cells is not clear. Here, we show that Ambra1 inhibits paclitaxel-induced apoptosis in breast cancer cells. Moreover, Bim and mitochondria are key effectors of Ambra1 in this process. Thus, Ambra1 is a protein that makes breast cancer cells resistant to apoptosis by modulating the Bim/mitochondrial pathway. Therefore, Ambra1 may be a potential target for the treatment of breast cancer.

The association and interaction analysis of hypertension and uric acid on cardiovascular autonomic neuropathy.

BACKGROUND: The purpose of this study was to evaluate associations among hypertension (HTN) and uric acid (UA) with cardiovascular autonomic neuropathy (CAN), and to estimate the extent to which synergistic effects of HTN and UA affect the outcome in a Chinese population. METHOD: We conducted a large-scale, population-based study to analyze the association and interaction of the two factors for CAN in a sample of 2092 Chinese people. Univariate and multiple linear regression (MLR) analysis were employed to detect these relationships. Interaction on an additive scale can be calculated by using the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S). RESULT: After adjusting for confounding factors, MLR showed that HTN was independently associated with CAN (P < 0.001). A significant interaction effect of UA and HTN on CAN was detected (P = 0.035; RETI = 1.483, 95 % CI 0.415-2.551; AP = 0.360, 95 % CI -0.043 to 0.76 and S = 1.908, 95 % CI 0.152-3.66). CONCLUSION: Our findings suggest that HTN is independently and significantly associated with CAN and offer evidence to support the hypothesis that HTN and UA have interaction effects to influence the progression of CAN.

Effects of stathmin 1 silencing by siRNA on sensitivity of esophageal cancer cells Eca-109 to paclitaxel.

We investigated the effects of stathmin 1 (STMN1) silencing by small interfering (siRNA) on the sensitivity of esophageal cancer cells Eca-109 to paclitaxel. STMN1 siRNA was transiently transfected into Eca-109 cells. The effects of transfection were detected by quantitative polymerase chain reaction and western blotting. The effects of STMN1 silencing by siRNA on the sensitivity of esophageal cancer cells Eca-109 to paclitaxel was tested by MTT and colony formation assays. Hoechst 33258 nuclear staining was used to investigate the differences in Eca-109 cell apoptosis induced by paclitaxel. STMN1 siRNA was successfully transfected and the expression of STMN1 was inhibited. The sensitivity of STMN1 siRNA-transfected Eca-109 cells to paclitaxel was significantly increased (P < 0.01). The apoptosis of Eca-109 cells significantly increased following treatment with paclitaxel (P < 0.01). STMN1 silencing by siRNA may enhance the sensitivity of esophageal cancer cells Eca-109 to paclitaxel and induce apoptosis.

Correlation analysis between single nucleotide polymorphism of DRD1 gene and stereotyped behavior of blue fox.

This study was performed to investigate the correlation between stereotyped behavior of the blue fox and single nucleotide polymorphisms (SNPs) of the DRD1 gene. We choose the DRD1 gene as a major gene for investigating the correlation of gene polymorphism and self-biting disease by means of direct sequencing. Part of the DRD1 gene exon of the blue fox was cloned; the length of the whole sequence was 864 bp. Four SNPs were detected and analyzed by the chi-square analysis; the results showed that the gene polymorphism of T206C in the DRD1 gene had a significant correlation with self-biting (P < 0.01). Therefore, marker-assistant selection on self-biting of blue foxes using these SNPs can be applied to select healthy individuals.

Mutation analysis of a Chinese pedigree with triphalangeal thumb-polysyndactyly syndrome.

Triphalangeal thumb-polysyndactyly syndrome (TPTPS) is an autosomal dominant limb disorder with triphalangeal thumbs, polysyndactyly, and syndactyly. In this study, we describe a four-generation Han Chinese family with eight affected members. Haplotype analysis, Affymetrix SNP 6.0 arrays, qPCR, and gap-PCR were performed. Haplotyping results linked the disease-causing region to the 7q36 region that includes the zone of polarizing activity-regulatory sequence. A 442-kb duplication was found on chromosome 7 that co-segregated with the disease phenotype. The extent of the duplication was determined by qPCR, and the breakpoints were identified by gap-PCR and direct sequencing. This mutation was not detected in normal members in the same family. Our data therefore suggest that this novel microduplication, between 155,913,768 and 156,355,553 bp on chromosome 7, could be considered the cause of TPTPS in this kindred.

Agreement between patient and proxy assessments of oral health-related quality of life after stroke: an observational longitudinal study.

This study aimed to assess agreement between patient and proxy assessment of patients' oral health-related quality of life (OHRQoL) during the acute stroke phase and 6 months after hospital discharge. As part of an observational longitudinal study, 161 consecutive patients hospitalized after stroke and their caregivers (CGs) were monitored during acute stroke and 6 months after hospital discharge. Patient-CG agreement of health-related quality of life as assessed by the General Oral Health Assessment Index (GOHAI) and Medical Outcomes Study 12-item Short Form (SF-12) which comprises physical (PCS-12) and mental component summaries (MCS-12) was determined by comparison and correlation analyses. Complete data were available for 65 patients and CGs. Compared with acute stroke, there were improvements in GOHAI and SF-12 scores from patient's and CG's perspective at 6-month follow-up. Caregivers overestimated the impact of stroke on MCS-12 over a period of time (P < 0.01) and underestimated the impact on GOHAI during acute stroke (P < 0.001) and on PCS-12 6 months later (P < 0.05). Patient-CG agreement was substantial to excellent during acute stroke [intra-class correlation coefficient (ICC 0.69-0.86)] and fair-to-moderate 6 months later (ICC 0.28-0.60). Agreement was adequate between patients' and CGs' assessment of patient OHRQoL during acute stroke but it was less reliable 6 months after hospital discharge. These findings suggest that proxy assessment of OHRQoL after stroke is effective in assessing stroke-related oral impairments that affect life quality without placing additional burden on stroke patients themselves to assess OHRQoL.

[Evaluation on the confidence of refusing unprotected sex behavior and related factors among college students in Zhejiang province].

Objective: To understand the confidence-related factors of refusing unprotected sex behavior among college students in Zhejiang province. Methods: Stratified cluster random sampling method was conducted among college students from 13 colleges and universities in Zhejiang province, from October to November, 2018. A total of 3 718 students who self-reported "ever having had sexual contacts" were enrolled. Chi-square test was used to compare the confidence of rejecting unprotected sex under different demographic characteristics, sexual attitude/behaviors and different intervention approaches. Multivariate logistic regression model was used to analyze the related factors. Results: A total of 3 718 college students were involved in this study with average age as (20.17±1.38) years old and 70.5% (2 620/3 718) were male. The proportions of having confidence to refuse unprotected sex behavior were 74.9% (1 963/2 620) of male and 77.9% (896/1 098) of female students, respectively. According to the results from multivariate logistic regression analysis, factors that related to the confidence of refusing unprotected sex behavior in male students would include, did not accept casual sex behavior (compared with accepted students, OR=2.247, 95%CI: 1.828-2.762), did not accept homosexual behavior (compared with accepted students, OR=1.810, 95%CI: 1.302- 2.516), having casual sex behavior in the past one year (compared with having no sex behavior, OR=1.345, 95%CI: 1.051-1.721), aware of the availability of HIV self-test reagents service in college (compared with did not knew, OR=1.381, 95%CI: 1.011-1.887), having taken the HIV infection risk self-assessment in college (compared with did not take, OR=1.707, 95%CI: 1.374-2.121). In female students, the factors would include: being urban resident (compared with rural residence, OR=1.816, 95%CI: 1.225-2.693), 21 years old or above (compared with 20 years old or below, OR=1.469, 95%CI: 1.075-2.007), having taken the HIV infection risk self-assessment in college (compared with did not take, OR=1.597, 95%CI: 1.093-2.333), etc. Conclusions: Both male and female college students had higher confidence in refusing unprotected sex behavior. For male students, refusing casual or homosexual contacts, having casual sex in the recent year, knowing HIV self-test reagents service and having had HIV-related risk self-assessment in college as related factors. However, for female students; city residence, 21 years old and above, and having a HIV infection risk self- assessment in college appeared as related factors. Sexual health education should be strengthened to reduce unprotective sex behavior and to promote HIV infection risk self-assessment among the college students.

[Immunohistochemical study of lung tissues from patients with idiopathic pulmonary fibrosis].

Immunohistochemical analysis using 24 different monoclonal and polyclonal antibodies was applied to lung biopsy and autopsy material from 9 patients with idiopathic pulmonary fibrosis (IPF) and 6 patients without lung disorders as control. Lymphoid, non-lymphoid cells and their subsets as well as extracellular matrix (fibronectin, laminin and collagens type I, III and IV) were observed in lung interstitium. Our results suggest that local B and T lymphoid immune responses are occurring in IPF. Extracellular matrix alterations are closely linked with the local immune responses.

ApoG2 as the most potent gossypol derivatives inhibits cell growth and induces apoptosis on gastric cancer cells.

Gastric cancer is one of the most common types of malignancies and proteins from the Bcl-2 family are highly expressed in human gastric cancer. Apogossypolone (ApoG2), the most potent gossypol derivative, has been defined as a novel small-molecule inhibitor of anti-apoptotic Bcl-2 family proteins. However, whether or not it can inhibit the growth and proliferation of gastric cancer cell lines has not been demonstrated to date. Here, we assessed the effects of anti-growth of ApoG2 on gastric cancer cell lines in vitro and explored the possible molecular mechanisms of ApoG2. Using the MTT assay and flow cytometry, we found that ApoG2 has the significant anti-growth effect on MKN28, MKN45 and AGS cell lines in a time- and dose-dependent manner. Compared to (-)-gossypol, MTT assay and flow cytometry results showed that anti-growth effect of ApoG2 is inferior, but the colony formation ability of ApoG2 is superior. Furthermore, western blot results revealed that ApoG2 inhibits the growth and proliferation of gastric cancer cells by down-regulating of Bcl-2 protein expression, up-regulating of Bax and activating of Caspase-3. Taken together, albeit the ApoG2 inferior to (-)-gossypol in many ways on gastric cancer in vitro, our results suggest that ApoG2 could effectively inhibit the growth and proliferation of gastric cancer cell lines through the mitochondrial pathway of apoptosis.

Programmable shunt valves for the treatment of hydrocephalus: a systematic review.

OBJECTIVE: To evaluate the clinical effectiveness of programmable valves compared with non-programmable valves of hydrocephalus. METHODS: In this paper, the authors report a systematic review and meta-analysis of complications and revision rate for programmable valves and non-programmable implantation. Randomized or non-randomized controlled trials of hydrocephalus treated by programmable and non-programmable valves were considered for inclusion. RESULTS: Seven published reports of eligible studies involving 1702 participants meet the inclusion criteria. Compared with non-programmable, programmable valves had no significant difference in catheter-related complications [RR = 0.88, 95%CI (0.66,1.19), p = 0.10] and infection rate [RR = 1.25, 95%CI (0.92,1.69), p = 1.00]. There were significant differences in overall complications [RR = 0.80, 95%CI (0.67,0.96), p < 0.01], over-drainage or under-drainage complications [RR = 0.44, 95%CI (0.31,0.63), p < 0.01] and revision rate [RR = 0.56, 95%CI (0.45,0.69), p < 0.01] in favor of programmable valves. CONCLUSION: Although the studies seem to demonstrate a small advantage for the programmable shunts, the probable bias and the difficulties in patient selection are too important to make a general conclusion.

Reactive gliosis and neuroinflammation in rats with communicating hydrocephalus.

UNLABELLED: Reactive gliosis has been implicated in injury and recovery patterns associated with hydrocephalus. The roles that these mechanisms play in the pathophysiology of hydrocephalus are still not clear in terms of cytopathology and gene expression. In this paper, we investigated the relationship between reactive gliosis and neuroinflammation of hydrocephalic rats of different severity at both cellular and molecular levels. Therefore 35 adult SD (standard deviation) rats were randomly divided into the normal group (n=5), the sham operation group (n=5) and the model group (n=25). Hydrocephalic rat models were induced by intraventricular injections of 3% kaolin, and the ventricular dilatation was examined by MRI (magnetic resonance imaging) at 2-week postoperation. Then the model group was subdivided into the mild group (n=5), the moderate group (n=7) and the severe group (n=9) according to the degree of ventricular dilatation. While IL-18 (interlukin 18), GFAP (glial fibrillary acidic protein), and Iba-1 (ionized calcium binding adaptor molecule-1) were detected by ELISA (enzyme-linked immunosorbent assay), RT-PCR, immunohistochemistry, Western blot and correlation analysis were conducted at the same time. According to the result comparison between the normal group and the sham operation group, the ventricle of model group was obviously enlarged (P<0.01). The expression of GFAP and Iba-1 was increased (P<0.05) in brain tissue of the model group and IL-18 was also increased in CSF (cerebrosinal fluid) sample of model group. It was revealed by correlation analysis that the increase was positively correlated with the severity of ventricular dilatation. CONCLUSION: These results indicate that gliosis and inflammation continue to rise dramatically in experimental hydrocephalus and can be regarded as the main factors of hydrocephalus. Regulating the level of gliosis and alleviating inflammation may provide new therapeutic methods of hydrocephalus.

Design, synthesis, and primary activity evaluation of pyrrolidine derivatives as matrix metalloproteinase inhibitors.

A series of novel pyrrolidine derivatives was designed, synthesized, and assayed to determine the derivatives' activity against matrix metalloproteinase-2 (MMP-2) and aminopeptidase N (APN)/CD13. Preliminary biological tests showed that most compounds inhibit MMP-2 in a highly selective manner compared to APN. Compounds 9d, 9e, and 9g had better inhibitory activity than LY52 and could be used as lead compounds in the future.

QSAR studies of histone deacetylase (HDAC) inhibitors by CoMFA, CoMSIA, and molecular docking.

In order to develop highly potent antitumor agents, three-dimensional quantitative structure-activity relationship (3-D QSAR) studies were conducted using a series of thienyl-based hydroxamic acids. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were applied to provide the structural information for further chemical modification and optimization. ClogP was applied as an additional descriptor in the CoMFA analysis to study the effects of lipophilic parameters on the activity of these compounds, and it did improve the statistical significance of the model. Two molecules were designed based on the 3-D QSAR analysis, their activity values were predicted by the generated model, and their binding mode was elucidated by a docking approach compared to molecules in the dataset.

Oral carriage of yeasts and coliforms in stroke sufferers: a prospective longitudinal study.

AIM: To investigate prospectively the qualitative and quantitative changes in oral carriage of yeasts and coliforms in southern Chinese people suffering from stroke. MATERIALS AND METHODS: In 56 elderly people suffering from stroke in a rehabilitation unit of a general medical hospital in Hong Kong, oral microbiological sampling using a combined imprint culture, oral rinse approach and clinical assessment was made during the acute stroke phase, on hospital discharge and 6 months later. RESULTS: The oral carriage of yeasts increased significantly during acute stroke (P<0.05), whereas coliform carriage did not. A reduction in oral carriage of yeasts was found on hospital discharge and 6 months later and in coliforms at the 6-month assessment (P<0.05). Candida albicans and Klebsiella pneumoniae were the predominant yeast and coliform respectively. Stroke-related difficulty in tooth brushing and denture wearing were associated with higher oral yeast carriage (P<0.05). We also report here for the first time that the use of aspirin was associated with lower oral yeast carriage in people suffering from stroke. CONCLUSION: Oral yeast carriage was closely linked to the level of stroke-related functional disability that improved over time but had not totally resolved 6 months after hospital discharge. The oral reservoir of yeasts and coliforms in people suffering from stroke is noteworthy by care providers as K. pneumoniae may cause aspiration pneumonia.

Can caregivers be used in assessing oral health-related quality of life among patients hospitalized for acute medical conditions?

OBJECTIVES: To assess the agreement between patients' and caregivers' (CGs) assessment of patients' oral health-related quality of life (OHRQoL) during the acute stage of their hospitalization. METHODS: A sample of 161 consecutive patients admitted to hospital following stroke and their CGs. Patients and CGs were interviewed independently about the impact of oral health status on the life quality of the patient employing the General Oral Health Assessment Index (GOHAI). Agreement of impact was assessed by comparison (agreement at the group level) and correlation analyses (agreement of individual patient-CG pairs). RESULTS: The response rate was 76% with 121 pairs of patients and CGs participating. At the group level, variations in patient's own and CG GOHAI scores were found (P < 0.001). The CGs underestimated the impact of oral health on life quality, particularly with respect to aspects of psychosocial functioning compared with patients' own perceptions. However, the bias in reports was small (standardized difference = 0.43). The mean absolute difference in overall scores constituted 8% of the possible range of GOHAI scores. At the individual patient-CG pair level, the intraclass correlation coefficient for GOHAI scores was 0.73 (95% CI 0.61-0.82), indicating substantial agreement. CONCLUSION: At the group and individual level there was adequate agreement between patients' and CGs' assessment of patients' OHRQoL during the acute stage of their hospitalization. The findings have implications in the use of CGs as proxies in assessing oral health when patients' own assessment may be difficult to obtain.

3D-QSAR study with pharmacophore-based molecular alignment of hydroxamic acid-related phosphinates that are aminopeptidase N inhibitors.

3D-QSAR models for a series of aminopeptidase N inhibitors were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA).GALAHAD, a pharmacophore generation module involving a genetic algorithm, was used to generate the pharmacophore model of the series of inhibitors. Molecules both in the training set and test set were aligned to the pharmacophore model. Values for the CoMFA model were r(2) = 0.992, q(2) = 0.586, SEE = 0.111, and F (8, 10) = 191.263. Values for the CoMSIA model were r(2) = 0.990, q(2) = 0.776, SEE = 0.123, and F (7, 11) = 156.68. This model can help not only in improving current understanding of enzyme-ligand interactions but also in predicting the activity of derivatives and designing new compounds with better potency.