The awareness and acceptance of HPV vaccines among parents of primary and junior high school students in China: a meta-analysis.

The awareness and acceptance of the human papillomavirus (HPV) vaccines among Chinese primary and junior high school students is limited. A meta-analysis was conducted to evaluate the awareness of HPV and HPV vaccines, as well as the acceptance of HPV vaccines, providing evidence-based strategies to promote HPV vaccination. Based on the databases of CNKI, Wanfang, VIP, PubMed, Embase, and Cochrane library, the literatures about the awareness of HPV and HPV vaccines, as well as the acceptance of HPV vaccines among parents of primary and junior high school students were collected from the inception to June 2023. Subgroup analysis was used to find the source of heterogeneity. Publication bias was evaluated using funnel plots and Egger's test. Fifteen literatures with 21,853 participants were included. The pooled HPV awareness, HPV vaccine awareness and acceptance rates among parents of primary and junior high school students in China were 42.90% (95% CI: 33.34%-52.47%), 28.11% (95% CI: 18.20%-43.41%), and 55.29% (95% CI: 45.85%-64.36%), respectively. The survey period and the proportion of female parents were the heterogeneity in awareness of HPV and HPV vaccines, as well as acceptance of HPV vaccines by subgroup analysis. Additionally, regional distribution emerged as another significant source of heterogeneity in HPV vaccine acceptance. The primary cause for parents' reluctance to vaccinate their children was theirs worries about the safety of the vaccines (66.21%). Though the awareness of HPV and its vaccines was low among parents of primary and junior high school students in China, the acceptance of HPV vaccines was relatively high. Strengthening health education and publicity was crucial to enhance awareness and acceptance, promoting HPV vaccination for effective cervical cancer prevention.

Peripheral Blood Markers Correlate with the Progression of Active Tuberculosis Relative to Latent Control of Mycobacterium tuberculosis Infection in Macaques.

Despite a century of research into tuberculosis (TB), there is a dearth of reproducible, easily quantifiable, biomarkers that can predict disease onset and differentiate between host disease states. Due to the challenges associated with human sampling, nonhuman primates (NHPs) are utilized for recapitulating the closest possible modelling of human TB. To establish a predictive peripheral biomarker profile based on a larger cohort of rhesus macaques (RM), we analyzed results pertaining to peripheral blood serum chemistry and cell counts from RMs that were experimentally exposed to Mtb in our prior studies and characterized as having either developed active TB (ATB) disease or latent TB infection (LTBI). We compared lung CFU burdens and quantitative pathologies with a number of measurables in the peripheral blood. Based on our results, the investigations were then extended to the study of specific molecules and cells in the lung compartments of a subset of these animals and their immune responses. In addition to the elevated serum C-reactive protein (CRP) levels, frequently used to discern the level of Mtb infection in model systems, reduced serum albumin-to-globulin (A/G) ratios were also predictive of active TB disease. Furthermore, higher peripheral myeloid cell levels, particularly those of neutrophils, kynurenine-to-tryptophan ratio, an indicator of induced expression of the immunosuppressive molecule indoleamine dioxygenase, and an influx of myeloid cell populations could also efficiently discriminate between ATB and LTBI in experimentally infected macaques. These quantifiable correlates of disease were then used in conjunction with a regression-based analysis to predict bacterial load. Our results suggest a potential biomarker profile of TB disease in rhesus macaques, that could inform future NHP-TB research. Our results thus suggest that specific biomarkers may be developed from the myeloid subset of peripheral blood or plasma with the ability to discriminate between active and latent Mtb infection.

Meta-analysis and machine learning-augmented mixed effects cohort analysis of improved diets among 5847 medical trainees, providers and patients.

OBJECTIVE: We sought to produce the first meta-analysis (of medical trainee competency improvement in nutrition counseling) informing the first cohort study of patient diet improvement through medical trainees and providers counseling patients on nutrition. DESIGN: (Part A) A systematic review and meta-analysis informing (Part B) the intervention analysed in the world's largest prospective multi-centre cohort study on hands-on cooking and nutrition education for medical trainees, providers and patients. SETTINGS: (A) Medical educational institutions. (B) Teaching kitchens. PARTICIPANTS: (A) Medical trainees. (B) Trainees, providers and patients. RESULTS: (A) Of the 212 citations identified (n 1698 trainees), eleven studies met inclusion criteria. The overall effect size was 9·80 (95 % CI (7·15, 12·45) and 95 % CI (6·87, 13·85); P < 0·001), comparable with the machine learning (ML)-augmented results. The number needed to treat for the top performing high-quality study was 12. (B) The hands-on cooking and nutrition education curriculum from the top performing study were applied for medical trainees and providers who subsequently taught patients in the same curriculum (n 5847). The intervention compared with standard medical care and education alone significantly increased the odds of superior diets (high/medium v. low Mediterranean diet adherence) for residents/fellows most (OR 10·79, 95 % CI (4·94, 23·58); P < 0·001) followed by students (OR 9·62, 95 % CI (5·92, 15·63); P < 0·001), providers (OR 5·19, 95 % CI (3·23, 8·32), P < 0·001) and patients (OR 2·48, 95 % CI (1·38, 4·45); P = 0·002), results consistent with those from ML. CONCLUSIONS: The current study suggests that medical trainees and providers can improve patients' diets with nutrition counseling in a manner that is clinically and cost effective and may simultaneously advance societal equity.

A Novel Controlled PTEN-Knockout Mouse Model for Prostate Cancer Study.

Prostate cancer (PCa) is associated with advanced age, but how age contributes to prostate carcinogenesis remains unknown. The prostate-specific Pten conditional knockout mouse model closely imitates human PCa initiation and progression. To better understand how age impacts PCa in an experimental model, we have generated a spatially and temporally controlled Pten-null PCa murine model at different ages (aged vs. non-aged) of adult mice. Here, we present a protocol to inject the Cre-expressing adenovirus with luciferin tag, intraductally, into the prostate anterior lobes of Pten-floxed mice; Pten-loss will be triggered post-Cre expression at different ages. In vivo imaging of luciferin signal following viral infection confirmed successful delivery of the virus and Cre activity. Immunohistochemical staining confirmed prostate epithelial-specific expression of Cre recombinase and the loss of Pten and activation of P-Akt, P-S6, and P-4E-BP1. The Cre-expression, Pten ablation, and activated PI3K/AKT/mTOR pathways were limited to the prostate epithelium. All mice developed prostatic epithelial hyperplasia within 4 weeks after Pten ablation and prostatic intraepithelial neoplasia (PIN) within 8 weeks post-Pten ablation. Some PINs had progressed to invasive adenocarcinoma at 8-16 weeks post-Pten ablation. Aged mice exhibited significantly accelerated PI3K/AKT/mTOR signaling and increased PCa onset and progression compared to young mice. The viral infection success rate is ∼80%. This model will be beneficial for investigations of cancer-related to aging.

SET levels contribute to cohesion fatigue.

Chromosome instability (CIN) is a major hallmark of cancer cells and believed to drive tumor progression. Several cellular defects including weak centromeric cohesion are proposed to promote CIN, but the molecular mechanisms underlying these defects are poorly understood. In a screening for SET protein levels in various cancer cell lines, we found that most of the cancer cells exhibit higher SET protein levels than nontransformed cells, including RPE-1. Cancer cells with elevated SET often show weak centromeric cohesion, revealed by MG132-induced cohesion fatigue. Partial SET knockdown largely strengthens centromeric cohesion in cancer cells without increasing overall phosphatase 2A (PP2A) activity. Pharmacologically increased PP2A activity in these cancer cells barely ameliorates centromeric cohesion. These results suggest that compromised PP2A activity, a common phenomenon in cancer cells, may not be responsible for weak centromeric cohesion. Furthermore, centromeric cohesion in cancer cells can be strengthened by ectopic Sgo1 overexpression and weakened by SET WT, not by Sgo1-binding-deficient mutants. Altogether, these findings demonstrate that SET overexpression contributes to impaired centromeric cohesion in cancer cells and illustrate misregulated SET-Sgo1 pathway as an underlying mechanism.

Genome and transcriptome profiling of FBXW family in human prostate cancer.

F-box and WD repeat domain containing (FBXW) family of E3 ligases has 10 members that ubiquitinate substrate proteins for proteasome-mediated degradation. Publicly archived datasets from The Cancer Genome Atlas (TCGA), Prostate Cancer Transcriptome Atlas (PCTA), and cBioPortal were analyzed for mRNA expression and genetic alterations of 10 FBXW genes. We found that FBXW7 mRNA expression was significantly decreased in primary prostate cancers compared to normal prostate tissues, whereas mRNA expression of FBXW8-10 was significantly increased in primary prostate cancers compared to normal prostate tissues. FBXW7 mRNA expression was also significantly decreased in breast invasive carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and uterine corpus endometrial carcinoma. In contrast, FBXW7 mRNA expression was significantly increased in cholangiocarcinoma, colon adenocarcinoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, pheochromocytoma and paraganglioma, and thyroid carcinoma. Compared to normal tissues, FBXW5 mRNA expression was significantly increased in breast invasive carcinoma, cholangiocarcinoma, kidney chromophobe, kidney renal clear cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, prostate adenocarcinoma, thyroid carcinoma, and uterine corpus endometrial carcinoma, whereas FBXW5 mRNA expression was only significantly decreased in colon adenocarcinoma. There were not any significant differences in gene copy number gains, losses, or gene simple somatic mutations between primary prostate cancers and normal prostate tissues. The mRNA expression levels of FBXW5, 7, 8, 9, and 12 were significantly higher in metastatic castration-resistant prostate cancers (mCRPCs) than primary prostate cancers, whereas mRNA expression levels of FBXW1 and 4 were significantly lower in mCRPCs than primary prostate cancers. All 10 FBXW genes had significantly more overall gene alterations including gene amplifications in mCRPCs than primary prostate cancers. FBXW5 and 7 had significantly more gene deep deletions in mCRPCs than primary prostate cancers and FBXW7 had significantly more gene missense mutations in mCRPCs than primary prostate cancers. Our findings suggest that different FBXW genes have differential mRNA expression in prostate cancer and other cancer types and their gene amplifications are significantly more in mCRPCs than primary prostate cancers. FBXW7 mRNA expression is consistently decreased in primary prostate cancers compared to normal prostate tissues.

A novel gene panel for prediction of lymph-node metastasis and recurrence in patients with thyroid cancer.

BACKGROUND: Although well-differentiated papillary thyroid cancer may remain indolent, lymph node metastases and the recurrence rates are approximately 50% and 20%, respectively. No current biomarkers are able to predict metastatic lymphadenopathy and recurrence in early stage papillary thyroid cancer. Hence, identifying prognostic biomarkers predicting cervical lymph-node metastases would prove very helpful in determining treatment. METHODS: The database of the Cancer Genome Atlas included 495 papillary thyroid cancer samples. Using this database, we developed a machine learning model to define a gene signature that could predict lymph-node metastasis (N0 or N1). Kruskal-Wallis tests, univariate and multivariate logistic and Cox regression models, and Kaplan-Meier analyses were performed to correlate the gene signature with clinical outcomes. RESULTS: We identified a panel of 25 genes and constructed a risk score that can differentiate N0 and N1 papillary thyroid cancer samples (P < .001) with a sensitivity of 86%, a specificity of 62%, a positive predictive value of 93%, and a negative predictive value of 42%. This panel represents an independent biomarker to predict metastatic lymphadenopathy (OR = 8.06, P < .001) specifically in patients with T1 lesions (OR = 7.65, P = .002) and disease-free survival (HR = 2.64, P = .043). CONCLUSION: This novel 25-gene panel may be used as a potential prognostic marker for accurately predicting lymph-node metastasis and disease-free survival in patients with early-stage papillary thyroid cancer.

Mycobacterium tuberculosis sensor kinase DosS modulates the autophagosome in a DosR-independent manner.

Dormancy is a key characteristic of the intracellular life-cycle of Mtb. The importance of sensor kinase DosS in mycobacteria are attributed in part to our current findings that DosS is required for both persistence and full virulence of Mtb. Here we show that DosS is also required for optimal replication in macrophages and involved in the suppression of TNF-α and autophagy pathways. Silencing of these pathways during the infection process restored full virulence in MtbΔdosS mutant. Notably, a mutant of the response regulator DosR did not exhibit the attenuation in macrophages, suggesting that DosS can function independently of DosR. We identified four DosS targets in Mtb genome; Rv0440, Rv2859c, Rv0994, and Rv0260c. These genes encode functions related to hypoxia adaptation, which are not directly controlled by DosR, e.g., protein recycling and chaperoning, biosynthesis of molybdenum cofactor and nitrogen metabolism. Our results strongly suggest a DosR-independent role for DosS in Mtb.

Identifying Multi-Omics Causers and Causal Pathways for Complex Traits.

The central dogma of molecular biology delineates a unidirectional causal flow, i.e., DNA → RNA → protein → trait. Genome-wide association studies, next-generation sequencing association studies, and their meta-analyses have successfully identified ~12,000 susceptibility genetic variants that are associated with a broad array of human physiological traits. However, such conventional association studies ignore the mediate causers (i.e., RNA, protein) and the unidirectional causal pathway. Such studies may not be ideally powerful; and the genetic variants identified may not necessarily be genuine causal variants. In this article, we model the central dogma by a mediate causal model and analytically prove that the more remote an omics level is from a physiological trait, the smaller the magnitude of their correlation is. Under both random and extreme sampling schemes, we numerically demonstrate that the proteome-trait correlation test is more powerful than the transcriptome-trait correlation test, which in turn is more powerful than the genotype-trait association test. In conclusion, integrating RNA and protein expressions with DNA data and causal inference are necessary to gain a full understanding of how genetic causal variants contribute to phenotype variations.

Genetic alterations of interleukin-17 and related genes in human prostate cancer.

Interleukin-17 (IL-17) has been shown to promote development of hormone-naïve prostate cancer (HNPC) and castration-resistant prostate cancer (CRPC) as well as lymph node metastasis in mouse models. Gene alterations of IL-17 family of cytokines and their downstream genes in human prostate cancer have not been investigated. We studied 7 datasets archived in cBioPortal and queried gene alterations in a total of 1303 cases of human prostate cancers. 35 genes were examined, including IL-17 family of cytokines and receptors, IL-17-downstream genes, and genes related to IL-17-downstream genes. We found that 34/35 (97%) genes had significantly more alterations in metastatic prostate cancer (with alteration rates ranging from 3.42% to 13.01%) than primary prostate cancer (with alteration rates ranging from 0.40% to 2.96%). 15/35 (43%) genes had significantly more alterations in primary CRPC than primary HNPC. 34/35 (97%) genes had significantly more alterations in metastatic CRPC than primary HNPC. Only three genes (S100A7, S100A8, and S100A9) had significantly more alterations in metastatic CRPC than primary CRPC. The gene alterations were mostly gene amplifications (97%), while gene deep deletions, missense mutations, and truncating mutations were very rare. 7/35 (20%) genes had significantly more alterations in primary neuroendocrine prostate cancer (NEPC) than primary adenocarcinoma (AC). 23/35 (66%) genes had significantly more alterations in metastatic NEPC than metastatic AC. Only three genes (S100A7, S100A8, and S100A9) had significantly more alterations in metastatic NEPC than metastatic AC with neuroendocrine features. Most of the gene alterations in metastatic NEPC were gene amplifications (80%), while gene deep deletions, missense mutations, and truncating mutations were very rare. Our findings suggest that gene amplifications of IL-17 and related genes are more frequently found in metastatic CRPC and NEPC than primary hormone-naïve prostate adenocarcinomas, implying that IL-17 and related genes may play important roles in the progression from HNPC to CRPC and from primary location to metastasis as well as in development of metastatic NEPC.

Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment.

BACKGROUND: Previous studies on the role of TP53 mutation in breast cancer treatment response and survival are contradictory and inconclusive, limited by the use of different endpoints to determine clinical significance and by small sample sizes that prohibit stratification by treatment. METHODS: We utilized large datasets to examine overall survival according to TP53 mutation status in patients across multiple clinical features and treatments. RESULTS: Confirming other studies, we found that in all patients and in hormone therapy-treated patients, TP53 wild-type status conferred superior 5-year overall survival, but survival curves crossed at 10 or more years. In contrast, further stratification within the large dataset revealed that in patients receiving chemotherapy and no hormone therapy, wild-type TP53 status conferred remarkably poor overall survival. This previously unrecognized inferior survival is consistent with p53 inducing arrest/senescence instead of apoptosis. Addition of hormone therapy to chemotherapy improved survival notably in patients with TP53 wild-type tumors, but not mutant, suggesting hormone therapy could eradicate arrested/senescent cells. Testing this, we found that estrogen receptor-positive, TP53 wild-type breast cancer cells that were made senescent by doxorubicin treatment were sensitive to tamoxifen. CONCLUSIONS: The poor survival of chemotherapy-treated patients with TP53 wild-type tumors may be improved by strategies to eliminate senescent cells, including the addition of hormone therapy when appropriate.

Machine Learning-Augmented Propensity Score-Adjusted Multilevel Mixed Effects Panel Analysis of Hands-On Cooking and Nutrition Education versus Traditional Curriculum for Medical Students as Preventive Cardiology: Multisite Cohort Study of 3,248 Trainees over 5 Years.

BACKGROUND: Cardiovascular disease (CVD) annually claims more lives and costs more dollars than any other disease globally amid widening health disparities, despite the known significant reductions in this burden by low cost dietary changes. The world's first medical school-based teaching kitchen therefore launched CHOP-Medical Students as the largest known multisite cohort study of hands-on cooking and nutrition education versus traditional curriculum for medical students. METHODS: This analysis provides a novel integration of artificial intelligence-based machine learning (ML) with causal inference statistics. 43 ML automated algorithms were tested, with the top performer compared to triply robust propensity score-adjusted multilevel mixed effects regression panel analysis of longitudinal data. Inverse-variance weighted fixed effects meta-analysis pooled the individual estimates for competencies. RESULTS: 3,248 unique medical trainees met study criteria from 20 medical schools nationally from August 1, 2012, to June 26, 2017, generating 4,026 completed validated surveys. ML analysis produced similar results to the causal inference statistics based on root mean squared error and accuracy. Hands-on cooking and nutrition education compared to traditional medical school curriculum significantly improved student competencies (OR 2.14, 95% CI 2.00-2.28, p < 0.001) and MedDiet adherence (OR 1.40, 95% CI 1.07-1.84, p = 0.015), while reducing trainees' soft drink consumption (OR 0.56, 95% CI 0.37-0.85, p = 0.007). Overall improved competencies were demonstrated from the initial study site through the scale-up of the intervention to 10 sites nationally (p < 0.001). DISCUSSION: This study provides the first machine learning-augmented causal inference analysis of a multisite cohort showing hands-on cooking and nutrition education for medical trainees improves their competencies counseling patients on nutrition, while improving students' own diets. This study suggests that the public health and medical sectors can unite population health management and precision medicine for a sustainable model of next-generation health systems providing effective, equitable, accessible care beginning with reversing the CVD epidemic.

A meta-analysis of associations of LEPR Q223R and K109R polymorphisms with Type 2 diabetes risk.

BACKGROUND: Leptin receptor (LEPR) plays a pivotal role in the control of body weight, energy metabolism, and insulin sensitivity. Various genetic association studies were performed to evaluate associations of LEPR genetic variants with type 2 diabetes (T2D) susceptibility. METHODS: A comprehensive search was conducted to identify all eligible case-control studies for examining the associations of LEPR single nucleotide polymorphisms (SNPs) Q223R (rs1137101) and K109R (rs1137100) with T2D risk. Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were used to measure the magnitudes of association. RESULTS: For Q223R, 13 studies (11 articles) consisting of a total of 4030 cases and 2844 controls, and for K109R 7 studies (7 articles) consisting of 3319 cases and 2465 controls were available. Under an allele model, Q223R was not significantly associated with T2D risk (OR = 1.09, 95% CI: 0.80-1.48, P-value = 0.5989), which was consistent with results obtained under four genotypic models (ranges: ORs 1.08-1.20, 95% CIs: 0.58-2.02 to 0.64-2.26; P-values, 0.3650-0.8177, which all exceeded multiplicity-adjusted α = 0.05/5 = 0.01). In addition, no significant association was found between K109R and T2D risk based on either an allele model (OR = 0.93, 95% CI: 0.85-1.03, P-value = 0.1868) or four genotypic models (ranges: ORs 0.81-0.99, 95% CIs: 0.67-0.86 to 0.97-1.26, P-values, 0.0207-0.8804 which all exceeded multiplicity-adjusted α of 0.01). The magnitudes of association for these two SNPs were not dramatically changed in subgroup analyses by ethnicity or sensitivity analyses. Funnel plot inspections as well as Begg and Mazumdar adjusted rank correlation test and Egger linear regression test did not reveal significant publication biases in main and subgroup analyses. Bioinformatics analysis predicted that both missense SNPs were functionally neutral and benign. CONCLUSIONS: The present meta-analysis did not detect significant genetic associations between LEPR Q223R and K109R polymorphisms and T2D risk.

LAG-3 potentiates the survival of Mycobacterium tuberculosis in host phagocytes by modulating mitochondrial signaling in an in-vitro granuloma model.

CD4+ T-cell mediated Th1 immune responses are critical for immunity to TB. The immunomodulatory protein, lymphocyte activation gene-3 (LAG-3) decreases Th1-type immune responses in T-cells. LAG-3 expression is significantly induced in the lungs of macaques with active TB and correlates with increased bacterial burden. Overproduction of LAG-3 can greatly diminish responses and could lead to uncontrolled Mtb replication. To assess the effect of LAG-3 on the progression of Mtb infection, we developed a co-culture system wherein blood-derived macrophages are infected with Mtb and supplemented with macaque blood or lung derived CD4+ T-cells. Silencing LAG-3 signaling in macaque lung CD4+ T-cells enhanced killing of Mtb in co-cultures, accompanied by reduced mitochondrial electron transport and increased IFN-γ expression. Thus, LAG-3 may modulate adaptive immunity to Mtb infection by interfering with the mitochondrial apoptosis pathway. Better understanding this pathway could allow us to circumvent immune features that promote disease.

KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment.

BACKGROUND: Type 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic ß cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic ß cells that regulates insulin production and processing. Because mutations of these genes could affect insulin secretion stimulated by sulfonylureas, the aim of this study is to assess associations between molecular variants of KCNJ11, ABCC8 and TCF7L2 genes and response to sulfonylurea treatment and to predict their potential functional effects. METHODS: Based on a comprehensive literature search, we found 13 pharmacogenetic studies showing that single nucleotide polymorphisms (SNPs) located in KCNJ11: rs5219 (E23K), ABCC8: rs757110 (A1369S), rs1799854 (intron 15, exon 16 -3C/T), rs1799859 (R1273R), and TCF7L2: rs7903146 (intron 4) were significantly associated with responses to sulfonylureas. For in silico bioinformatics analysis, SIFT, PolyPhen-2, PANTHER, MutPred, and SNPs3D were applied for functional predictions of 36 coding (KCNJ11: 10, ABCC8: 24, and TCF7L2: 2; all are missense), and HaploReg v4.1, RegulomeDB, and Ensembl's VEP were used to predict functions of 7 non-coding (KCNJ11: 1, ABCC8: 1, and TCF7L2: 5) SNPs, respectively. RESULTS: Based on various in silico tools, 8 KCNJ11 missense SNPs, 23 ABCC8 missense SNPs, and 2 TCF7L2 missense SNPs could affect protein functions. Of them, previous studies showed that mutant alleles of 4 KCNJ11 missense SNPs and 5 ABCC8 missense SNPs can be successfully rescued by sulfonylurea treatments. Further, 3 TCF7L2 non-coding SNPs (rs7903146, rs11196205 and rs12255372), can change motif(s) based on HaploReg v4.1 and are predicted as risk factors by Ensembl's VEP. CONCLUSIONS: Our study indicates that a personalized medicine approach by tailoring sulfonylurea therapy of T2D patients according to their genotypes of KCNJ11, ABCC8, and TCF7L2 could attain an optimal treatment efficacy.

Androgen receptor-deficient islet ß-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse.

AIMS: Testosterone action is mediated via the androgen receptor (AR). We have reported that male mice lacking AR selectively in ß-cells (ßARKO-/y) develop decreased glucose-stimulated insulin secretion (GSIS), producing glucose intolerance. We showed that testosterone action on AR in ß-cells amplifies the insulinotropic action of GLP-1 on its receptor via a cAMP-dependent protein kinase-A pathway. METHODS: To investigate AR-dependent gene networks in ß-cells, we performed a high throughput whole transcriptome sequencing (RNA-Seq) in islets from male ßARKO-/y and control mice. RESULTS: We identified 214 differentially expressed genes (DEGs) (158 up- and 56 down-regulated) with a false discovery rate (FDR) < 0.05 and a fold change (FC) > 2. Our analysis of individual transcripts revealed alterations in ß-cell genes involved in cellular inflammation/stress and insulin secretion. Based on 312 DEGs with an FDR < 0.05, the pathway analysis revealed 23 significantly enriched pathways, including cytokine-cytokine receptor interaction, Jak-STAT signaling, insulin signaling, MAPK signaling, type 2 diabetes (T2D) and pancreatic secretion. The gene ontology analysis confirmed the results of the individual DEGs and the pathway analysis in showing enriched biological processes encompassing inflammation, ion transport, exocytosis and insulin secretion. CONCLUSIONS: AR-deficient islets exhibit altered expression of genes involved in inflammation and insulin secretion demonstrating the importance of androgen action in ß-cell health in the male with implications for T2D development in men.

Identification of Novel Signal Transduction, Immune Function, and Oxidative Stress Genes and Pathways by Topiramate for Treatment of Methamphetamine Dependence Based on Secondary Outcomes.

BACKGROUND: Topiramate (TPM) is suggested to be a promising medication for treatment of methamphetamine (METH) dependence, but the molecular basis remains to be elucidated. METHODS: Among 140 METH-dependent participants randomly assigned to receive either TPM (N = 69) or placebo (N = 71) in a previously conducted randomized controlled trial, 50 TPM- and 49 placebo-treated participants had a total 212 RNA samples available at baseline, week 8, and week 12 time points. Following our primary analysis of gene expression data, we reanalyzed the microarray expression data based on a latent class analysis of binary secondary outcomes during weeks 1-12 that provided a classification of 21 responders and 31 non-responders with consistent responses at both time points. RESULTS: Based on secondary outcomes, 1,381, 576, 905, and 711 differentially expressed genes at nominal P values < 0.05 were identified in responders versus non-responders for week 8 TPM, week 8 placebo, week 12 TPM, and week 12 placebo groups, respectively. Among 1,381 genes identified in week 8 TPM responders, 359 genes were identified in both week 8 and week 12 TPM groups, of which 300 genes were exclusively detected in TPM responders. Of them, 32 genes had nominal P values < 5 × 10-3 at either week 8 or week 12 and false discovery rates < 0.15 at both time points with consistent directions of gene expression changes, which include GABARAPL1, GPR155, and IL15RA in GABA receptor signaling that represent direct targets for TPM. Analyses of these 300 genes revealed 7 enriched pathways belonging to neuronal function/synaptic plasticity, signal transduction, inflammation/immune function, and oxidative stress response categories. No pathways were enriched for 72 genes exclusively detected in both week 8 and week 12 placebo groups. CONCLUSION: This secondary analysis study of gene expression data from a TPM clinical trial not only yielded consistent results with those of primary analysis but also identified additional new genes and pathways on TPM response to METH addiction.

Sequencing-relative to hybridization-based transcriptomics approaches better define Mycobacterium tuberculosis stress-response regulons.

Mycobacterium tuberculosis (Mtb) infections cause tuberculosis (TB), an infectious disease which causes ∼1.5 million deaths annually. The ability of this pathogen to evade, escape and encounter immune surveillance is fueled by its adaptability. Thus, Mtb induces a transition in its transcriptome in response to environmental changes. Global transcriptome profiling has been key to our understanding of how Mtb responds to the different stress conditions it faces during its life cycle. While this was initially achieved using microarray technology, RNAseq is now widely employed. It is important to understand the correlation between the large amount of microarray based transcriptome data, which continues to shape our understanding of Mtb stress networks, and newer data being generated using RNAseq. We assessed how well the two platforms correlate using three well-defined stress conditions: diamide, hypoxia, and re-aeration. The data used here was generated by different individuals over time using distinct samples, providing a stringent test of platform correlation. While correlation between microarrays and sequencing was high upon diamide treatment, which causes a rapid reprogramming of the transcriptome, RNAseq allowed a better definition of the hypoxic response, characterized by subtle changes in the magnitude of gene-expression. RNAseq also allows for the best cross-platform reproducibility.

Adherence to low-carbohydrate and low-fat diets in relation to weight loss and cardiovascular risk factors.

OBJECTIVE: A low-carbohydrate diet can reduce body weight and some cardiovascular disease (CVD) risk factors more than a low-fat diet, but differential adherence may play a role in these effects. METHODS: Data were used from 148 adults who participated in a 12-month clinical trial examining the effect of a low-carbohydrate diet (<40 g/day) and a low-fat diet (<30% fat, <7% saturated fat) on weight and CVD risk factors. We compared attendance at counseling sessions, deviation from nutrient goals, urinary ketone presence, and composite scores representing the overall adherence based on the distribution of these individual indicators between two interventions. RESULTS: Composite scores were similar between the two groups. A one-interquartile-range increase in composite score representing better adherence to a low-carbohydrate diet was associated with 2.2 kg or 2.3 % greater weight loss, 1.1 greater reduction in percent fat mass, and 1.3 greater increase in proportion of lean mass. Indicators of adherence to a low-fat diet was not associated with changes in weight, fat mass or lean mass. CONCLUSIONS: Despite comparable adherence between groups, a low-carbohydrate diet was associated with greater reductions in body weight and improvement in body composition, while a low-fat diet was not associated with weight loss.