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Deletion of Nrf2 leads to hepatic insulin resistance via the activation of NF-ÎºB in mice fed a high-fat diet. - Molecular medicine reports
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Insulin resistance (IR) is important in the development and progression of NAFLD. Nuclear erythroid 2â€‘related factorÂ 2 (Nrf2) has previously been reported to be a novel regulator in NAFLD. The present study determined that Nrf2 knockdown accelerated the onset of obesity and nonâ€‘alcoholic steatohepatitis (NASH), via the induction of hepatic IR in mice fed a highâ€‘fat diet (HFD), which was confirmed by an increase in total and hepatic weight in Nrf2â€‘nullâ€‘HFD mice, in addition to marked structural disorder in liver tissues from the Nrf2â€‘nullâ€‘HFD group analyzed by histopathological examination. Subsequently, it was demonstrated that hepatic IR in Nrf2â€‘nullâ€‘HFD mice was influenced by oxidative stress; this was confirmed by an increase in malondialdehyde levels and a decrease in glutathione levels. In addition, it was determined that the induction of hepatic IR by Nrf2 knockdown in HFD-treated mice was regulated by activation of the nuclear factorâ€‘ÎºB (NFâ€‘ÎºB) signaling pathway, as detected by an increase in the expression levels of nuclear NFâ€‘ÎºB, and its downstream effectors interleukinâ€‘6 and tumor necrosis factorâ€‘Î±. The present study provides insight into the function of Nrf2 in NAFLD, indicating that Nrf2 deletion may lead to hepatic IR by activation of NFâ€‘ÎºB, which is often associated with oxidative stress. Therefore, activation of Nrf2 may limit disease progression and act as a therapeutic approach for the treatment of NASH.
The prevalence and risk factors of stroke in patients with chronic schizophrenia. - Neuropsychiatric disease and treatment
To investigate the stroke risk and risk factors in patients with chronic schizophrenia.This study was a large-sample, cross-sectional survey. A total of 363 patients with chronic schizophrenia were selected from the Changping Traditional Chinese Medicine Hospital, Beijing, in August 2014. The patients were divided into either stroke group or control group based on the presence of stroke. Clinical evaluation included positive and negative syndrome scale assessment and a detailed questionnaire to collect the general information and disease-related conditions.The prevalence of stroke was 16.5% (60 cases). Stroke and control groups showed a significant difference in age, sex, smoking, combined medication, doses, negative factor score in positive and negative syndrome scale, body mass index, waist circumference, and systolic blood pressure. Multivariate analysis showed that a number of factors are significantly related to stroke, including age, sex, smoking, combined medication, doses, body mass index, and systolic blood pressure.The prevalence of stroke is relatively higher in Chinese patients with chronic schizophrenia. Chronic schizophrenia patients are more likely to suffer from stroke; meanwhile, a number of risk factors were identified, including old age, female sex, smoking history, combined medication with a variety of drugs, high doses, obesity, and high blood pressure.
Efficacy and Safety of Co-Administration of Sitagliptin with Insulin Glargine in type 2 diabetes. - Journal of diabetes
To compare therapeutic efficacy and safety of sitagliptin(DPP-4 inhibitor) combined with insulin glargine(GLâ€‰+â€‰sita) which premixed insulin aspart 30(NOV) for type 2 diabetes patients controlled by oral hypoglycemic drugs(HbA1c 7%-9%).This was a randomized study of 65 patients who were randomized(1:1) to the GLâ€‰+â€‰sita(nâ€‰=â€‰33) and NOV(nâ€‰=â€‰32) groups, treated with so-called fixed combination regimen or premixed insulin twice a day for 16â€‰weeks. The primary endpoint was the mean change in HbA1c. The second included fasting blood glucose, blood glucose profiles(7 time-points), target rate of HbA1c(<7% orâ€‰â‰¤â€‰6.5%), insulin dose, incidence of hypoglycemia, body weight.After 16â€‰weeks, there was no significant difference between the groups, although more patients achieved HbA1c <7.0% in the GLâ€‰+â€‰sita group. There was a significant difference in the body weight changes between the groups(GLâ€‰+â€‰sita, -0.45â€‰kg and NOV, 1.52â€‰kg; Pâ€‰<â€‰0.001). The MPG and MAGE were significantly lower in the GLâ€‰+â€‰Sita group(Pâ€‰<â€‰0.005 vs.NOV). The incidence of symptomatic hypoglycemia was significantly lower in the GLâ€‰+â€‰Sita group(2.85% vs.13.3%; Pâ€‰<â€‰0.001 vs.NOV).GLâ€‰+â€‰sita greatly improved HbA1c levels in the type 2 diabetes patients(HbA1c 7%-9%), with an efficacy that was equal effect to that of premixed insulin. GLâ€‰+â€‰sita treatment is a valuable option for the patients failed by oral hypoglycemic drugs.GLâ€‰+â€‰sita greatly improved HbA1c levels in the type 2 diabetes patients(HbA1c 7%-9%), with an efficacy that was equal effect to that of premixed insulin.GLâ€‰+â€‰sita treatment is a valuable option for the patients failed by oral hypoglycemic drugs.This article is protected by copyright. All rights reserved.
Surgical Intervention Improves Survival for Metastatic Non-Small Cell Lung Cancer Patients. - Medicine
Surgical intervention for stage IV non-small cell lung cancer (NSCLC) is still controversial. This study sought to evaluate the clinical effects of surgical intervention on survival in patients with stage IV NSCLCs and to identify the cohort benefitting the most from surgery.A retrospective study from the Surveillance, Epidemiology, and End Results database was performed to compare the survival of stage IV NSCLC patients who had undergone surgery with those who did not undergo surgery. Overall survival (OS) was evaluated using the Kaplan-Meier method and the log-rank test. The Cox proportional hazards model was used for multivariate analysis.The total number of eligible patients was 43,538, including 16.8% in the M1a stage and 83.2% in the M1b stage. The percentages of patients with no surgery (NONE), only metastatic tumor resection (MTR), only primary tumor resection (PTR), and both primary and metastatic tumor resection (PMTR) were 89.0%, 6.7%, 3.5%, and 0.8%, respectively; the corresponding 5-year survival rates were 2.0%, 4.0%, 13.0%, and 20.0%, respectively (Pâ€Š<â€Š0.001); and the corresponding OS rates were 11.1 months, 14.7 months, 29.4 months, and 34.9 months, respectively (Pâ€Š<â€Š0.001). Notably, the pairwise comparisons of 5-year survival rate and OS among the subgroups were all statistically significant. The multivariate analysis showed that surgical intervention was correlated with longer survival in patients with stage IV NSCLC. The stratified analysis showed significant differences in the OS on strata of the M1a stage and strata of the M1b stage. In the M1a stage, patients with PTR had significantly better OS than those with NONE (Pâ€Š<â€Š0.001) or MTR (Pâ€Š<â€Š0.001) but showed no significant differences compared with those with PMTR (Pâ€Š=â€Š0.174); patients with MTR did not have prolonged survival compared with patients with NONE (Pâ€Š=â€Š0.185), and they also did not have prolonged survival compared with patients with PMTR (Pâ€Š=â€Š0.052). In the M1b stage, pairwise comparisons of OS were all statistically significant among the subgroups (Pâ€Š<â€Š0.001).Surgical intervention can prolong survival to different degrees according to the modalities of surgery in stage IV NSCLC.
Tumor volume of resectable gastric adenocarcinoma on multidetector computed tomography: association with N categories. - Clinics (SaÌƒo Paulo, Brazil)
To determine whether the gross tumor volume of resectable gastric adenocarcinoma on multidetector computed tomography could predict the presence of regional lymph node metastasis and could determine N categories.A total of 202 consecutive patients with gastric adenocarcinoma who had undergone gastrectomy 1 week after contrast-enhanced multidetector computed tomography were retrospectively identified. The gross tumor volume was evaluated on multidetector computed tomography images. Univariate and multivariate analyses were performed to determine whether the gross tumor volume could predict regional lymph node metastasis, and the Mann-Whitney U test was performed to compare the gross tumor volume among N categories. Additionally, a receiver operating characteristic analysis was performed to identify the accuracy of the gross tumor volume in differentiating N categories.The gross tumor volume could predict regional lymph node metastasis (p<0.0001) in the univariate analysis, and the multivariate analyses indicated that the gross tumor volume was an independent risk factor for regional lymph node metastasis (p=0.005, odds ratio=1.364). The Mann-Whitney U test showed that the gross tumor volume could distinguish N0 from the N1-N3 categories, N0-N1 from N2-N3, and N0-N2 from N3 (all p<0.0001). In the T1-T4a categories, the gross tumor volume could differentiate N0 from the N1-N3 categories (cutoff, 12.3 cm3), N0-N1 from N2-N3 (cutoff, 16.6 cm3), and N0-N2 from N3 (cutoff, 24.6 cm3). In the T4a category, the gross tumor volume could differentiate N0 from the N1-N3 categories (cutoff, 15.8 cm3), N0-N1 from N2-N3 (cutoff, 17.8 cm3), and N0-N2 from N3 (cutoff, 24 cm3).The gross tumor volume of resectable gastric adenocarcinoma on multidetector computed tomography could predict regional lymph node metastasis and N categories.
Pharmacokinetics, Pharmacodynamics, and Safety of ASP015K (Peficitinib), a New Janus Kinase Inhibitor, in Healthy Subjects. - Clinical pharmacology in drug development
Two randomized, double-blind, placebo-controlled studies were reported, which had the objective to evaluate the pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a Janus Kinase (JAK) inhibitor in healthy subjects. The single-dose study included 7 male (3-300 mg) and 2 female groups (30 or 200 mg) (n = 8 [6 on ASP015K and 2 on placebo] /group). The multiple-dose study included 1 female and 3 male groups (n = 12 [9 on ASP015K and 3 on placebo] /group) who received ASP015K (30 - mg) or placebo every 12 hours (BID) for 14 days. In the single-dose study, plasma ASP015K concentration increased dose-proportionally. Food increased ASP015K exposure (AUCinf ) by 27%. Mean peak JAK inhibition increased with dose, from 6% at 4 hours (median) following ASP015K 3 mg to 93% (range: 89%-98%) at 2 hours (median) after ASP015K 300 mg. In the multiple-dose study, ASP015K plasma exposure reached steady state by day 3. On day 14, mean ASP015K peak concentration was 38%-65% higher than after first dose; peak JAK inhibition following 100 or 200 mg BID was > 85%. The most common adverse events (AEs) were neutropenia, headache, and abdominal pain; no serious AEs occurred. The safety findings at pharmacologically-effective doses of ASP015K support further clinical development. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
Prognostic Role of BRAF Mutation in Stage II/III Colorectal Cancer Receiving Curative Resection and Adjuvant Chemotherapy: A Meta-Analysis Based on Randomized Clinical Trials. - PloS one
Studies examining the prognostic value of the BRAF mutation on relapse-free survival (RFS), disease-free survival (DFS) and overall survival (OS) in stage II/III colorectal cancer (CRC) patients receiving curative resection and adjuvant chemotherapy so far showed discrepant results. Therefore, a meta-analysis of relevant studies was performed for clarification.Randomized trials of stage II/III colorectal cancer treated with curative resection followed by adjuvant chemotherapy were selected to conduct a meta-analysis. The necessary descriptive and statistical information such as hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from published survival data.Seven phase III randomized clinical trials (RCTs) including 1,035 BRAF mutation stage II/III CRC patients receiving curative resection and adjuvant chemotherapy were analyzed. Overall, BRAF mutation resulted in poorer OS (HR = 1.42, 95% CI: 1.25-1.60; P < 0.00001), and poorer DFS (HR = 1.26, 95% CI: 1.07-1.48, P = 0.006) compared with BRAF wild-type CRC. The prognostic role on RFS could not be elucidated in the meta-analysis because of limited data.BRAF mutation was significantly related with shorter DFS and OS among stage II/III CRC patients receiving adjuvant chemotherapy after curative resection. Its prognostic role for RFS needs to be further analyzed when more data is available.
The SNW Domain of SKIP is Required for its Integration into the Spliceosome and its Interaction with the Paf1 Complex in Arabidopsis. - Molecular plant
SKIP is a conserved protein from yeasts to plants and humans. In plant cells, SKIP is a bifunctional regulator that works in the nucleus as a splicing factor by integrating into the spliceosome and as a transcriptional activator by interacting with the Paf1 complex. In this study, we identified two nuclear localization signals in SKIP and confirmed that each is sufficient to target SKIP to the nucleus. The SNW domain of SKIP is required for both its function as a splicing factor by promoting integration into the spliceosome in response to stress, and its function as a transcriptional activator by controlling its interaction with the Paf1 complex to participates in flowering. Truncated proteins that included the SNW domain and the N- or C-terminus of SKIP were still able to carry out the functions of the full-length protein in gene splicing and transcriptional activation in Arabidopsis. In addition, we found that SKIP undergoes 26S proteasome-mediated degradation, and that the C-terminus of SKIP is required to maintain the stability of the protein in plant cells. Together, our findings demonstrate the structural domain organization of SKIP and they reveal the core domains and motifs underlying SKIP function in plants.Copyright Â© 2016 The Author. Published by Elsevier Inc. All rights reserved.
A Comparison of Tissue versus Swab Culturing of Infected Diabetic Foot Wounds. - International journal of endocrinology
Objective. To compare the efficacy of swabbing versus tissue biopsy for microbiological diagnosis of diabetic foot infection. Methods. This was a prospective trial. Fifty-six patients with diabetic foot infection were divided into the following 3 groups according to the PEDIS grading system: grade 2 (n = 10), grade 3 (n = 29), and grade 4 (n = 17). Two specimens were collected from each wound for microbial culturing after debridement, including a superficial swab and a deep tissue punch biopsy specimen. Results. Swab culturing identified all of the microorganisms isolated from the corresponding deep tissue specimens in 9/10 of grade 2 wounds (90.0%), and this proportion decreased to 12/29 (41.4%) and 7/17 (41.2%) for grades 3 and 4 wounds, respectively (p = 0.02). Moreover, the sensitivity for identifying Gram-negative bacteria, such as E. coli and Citrobacter, by swabbing was low (33.3%). In addition, some Gram-negative bacteria, such as Serratia and Ralstonia pickettii, were isolated from deep tissues but not from swabs. Conclusions. Swab culturing may be reliable for identification of pathogens in diabetic foot wounds classified as grade 2. However, it is advisable to culture deep tissue specimens for wounds of grade â‰¥3 because swab culturing is associated with a high risk of missing pathogens, especially Gram-negative bacteria.
High-throughput identification of novel conotoxins from the Chinese tubular cone snail (Conus betulinus) by multi-transcriptome sequencing. - GigaScience
The venom of predatory marine cone snails mainly contains a diverse array of unique bioactive peptides commonly referred to as conopeptides or conotoxins. These peptides have proven to be valuable pharmacological probes and potential drugs because of their high specificity and affinity to important ion channels, receptors and transporters of the nervous system. Most previous studies have focused specifically on the conopeptides from piscivorous and molluscivorous cone snails, but little attention has been devoted to the dominant vermivorous species.The vermivorous Chinese tubular cone snail, Conus betulinus, is the dominant Conus species inhabiting the South China Sea. The transcriptomes of venom ducts and venom bulbs from a variety of specimens of this species were sequenced using both next-generation sequencing and traditional Sanger sequencing technologies, resulting in the identification of a total of 215 distinct conopeptides. Among these, 183 were novel conopeptides, including nine new superfamilies. It appeared that most of the identified conopeptides were synthesized in the venom duct, while a handful of conopeptides were identified only in the venom bulb and at very low levels.We identified 215 unique putative conopeptide transcripts from the combination of five transcriptomes and one EST sequencing dataset. Variation in conopeptides from different specimens of C. betulinus was observed, which suggested the presence of intraspecific variability in toxin production at the genetic level. These novel conopeptides provide a potentially fertile resource for the development of new pharmaceuticals, and a pathway for the discovery of new conotoxins.
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