Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Alcohol synergistically enhances the progression of liver disease and the risk for liver cancer caused by hepatitis C virus (HCV). However, the molecular mechanism of this synergy remains unclear. Here, we provide the first evidence that Toll-like receptor 4 (TLR4) is induced by hepatocyte-specific transgenic (Tg) expression of the HCV nonstructural protein NS5A, and this induction mediates synergistic liver damage and tumor formation by alcohol-induced endotoxemia. We also identify Nanog, the stem/progenitor cell marker, as a novel downstream gene up-regulated by TLR4 activation and the presence of CD133/Nanog-positive cells in liver tumors of alcohol-fed NS5A Tg mice. Transplantation of p53-deficient hepatic progenitor cells transduced with TLR4 results in liver tumor development in mice following repetitive LPS injection, but concomitant transduction of Nanog short-hairpin RNA abrogates this outcome. Taken together, our study demonstrates a TLR4-dependent mechanism of synergistic liver disease by HCV and alcohol and an obligatory role for Nanog, a TLR4 downstream gene, in HCV-induced liver oncogenesis enhanced by alcohol

A Bayesian Hierarchical Model for Relating Multiple SNPs within Multiple Genes to Disease Risk

A variety of methods have been proposed for studying the association of multiple genes thought to be involved in a common pathway for a particular disease. Here, we present an extension of a Bayesian hierarchical modeling strategy that allows for multiple SNPs within each gene, with external prior information at either the SNP or gene level. The model involves variable selection at the SNP level through latent indicator variables and Bayesian shrinkage at the gene level towards a prior mean vector and covariance matrix that depend on external information. The entire model is fitted using Markov chain Monte Carlo methods. Simulation studies show that the approach is capable of recovering many of the truly causal SNPs and genes, depending upon their frequency and size of their effects. The method is applied to data on 504 SNPs in 38 candidate genes involved in DNA damage response in the WECARE study of second breast cancers in relation to radiotherapy exposure

Genome-wide transcriptomic alterations induced by ethanol treatment in human dental pulp stem cells (DPSCs)

Human dental pulp stem cells (DPSCs) isolated from adult dental pulp are multipotent mesenchymal stem cells that can be directed to differentiate into osteogenic/odontogenic cells and also trans-differentiate into neuronal cells. The utility of DPSC has been explored in odontogenic differentiation for tooth regeneration. Alcohol abuse appears to lead to periodontal disease, tooth decay and mouth sores that are potentially precancerous. Persons who abuse alcohol are at high risk of having seriously deteriorated teeth, gums and compromised oral health in general. It is currently unknown if alcohol exposure has any impact on adult stem cell maintenance, stem cell fate determination and plasticity, and stem cell niche environment. Here we provide detailed experimental methods, analysis and information associated with our data deposited into Gene Expression Omnibus (GEO) under GSE57255. Our data provide transcriptomic changes that are occurring by EtOH treatment of DPSCs at 24-hour and 48-hour time point

Addition of Audiovisual Feedback During Standard Compressions Is Associated with Improved Ability

Introduction: A benefit of in-hospital cardiac arrest is the opportunity for rapid initiation of “high-quality” chest compressions as defined by current American Heart Association (AHA) adult guidelines as a depth 2-2.4 inches, full chest recoil, rate 100 -120 per minute, and minimal interruptions with a chest compression fraction (CCF) ≥ 60%. The goal of this study was to assess the effect of audiovisual feedback on the ability to maintain high-quality chest compressions as per 2015 updated guidelines.Methods: Ninety-eight participants were randomized into four groups. Participants were randomly assigned to perform chest compressions with or without use of audiovisual feedback (+/- AVF). Participants were further assigned to perform either standard compressions with a ventilation ratio of 30:2 to simulate cardiopulmonary resuscitation (CPR) without an advanced airway or continuous chest compressions to simulate CPR with an advanced airway. The primary outcome measured was ability to maintain high-quality chest compressions as defined by current 2015 AHA guidelines. Results: Overall comparisons between continuous and standard chest compressions (n=98) were without significant differences in chest compression dynamics (p’s >0.05). Overall comparisons between +/- AVF (n = 98) were significant for differences in average rate of compressions per minute (p= 0.0241) and proportion of chest compressions within guideline rate recommendations (p = 0.0084). There was a significant difference in the proportion of high quality-chest compressions favoring AVF (p = 0.0399). Comparisons between chest compression strategy groups +/- AVF were significant for differences in compression dynamics favoring AVF (p’s < 0.05).  Conclusion: Overall, AVF is associated with greater ability to maintain high-quality chest compressions per most-recent AHA guidelines. Specifically, AVF was associated with a greater proportion of compressions within ideal rate with standard chest compressions while demonstrating a greater proportion of compressions with simultaneous ideal rate and depth with a continuous compression strategy

Addition of Audiovisual Feedback During Standard Compressions Is Associated with Improved Ability

Introduction: A benefit of in-hospital cardiac arrest is the opportunity for rapid initiation of “high-quality” chest compressions as defined by current American Heart Association (AHA) adult guidelines as a depth 2–2.4 inches, full chest recoil, rate 100–120 per minute, and minimal interruptions with a chest compression fraction (CCF) ≥ 60%. The goal of this study was to assess the effect of audiovisual feedback on the ability to maintain high-quality chest compressions as per 2015 updated guidelines. Methods: Ninety-eight participants were randomized into four groups. Participants were randomly assigned to perform chest compressions with or without use of audiovisual feedback (+/− AVF). Participants were further assigned to perform either standard compressions with a ventilation ratio of 30:2 to simulate cardiopulmonary resuscitation (CPR) without an advanced airway or continuous chest compressions to simulate CPR with an advanced airway. The primary outcome measured was ability to maintain high-quality chest compressions as defined by current 2015 AHA guidelines. Results: Overall comparisons between continuous and standard chest compressions (n=98) were without significant differences in chest compression dynamics (p’s >0.05). Overall comparisons between +/− AVF (n = 98) were significant for differences in average rate of compressions per minute (p= 0.0241) and proportion of chest compressions within guideline rate recommendations (p = 0.0084). There was a significant difference in the proportion of high quality-chest compressions favoring AVF (p = 0.0399). Comparisons between chest compression strategy groups +/− AVF were significant for differences in compression dynamics favoring AVF (p’s < 0.05). Conclusion: Overall, AVF is associated with greater ability to maintain high-quality chest compressions per most-recent AHA guidelines. Specifically, AVF was associated with a greater proportion of compressions within ideal rate with standard chest compressions while demonstrating a greater proportion of compressions with simultaneous ideal rate and depth with a continuous compression strategy

Gene expression signatures affected by ethanol and/or nicotine in normal human normal oral keratinocytes (NHOKs)

It has been reported that nicotine/alcohol alters epigenetic control and leads to abrogated DNA methylation and histone modifications, which could subsequently perturb transcriptional regulation critically important in cellular transformation. The aim of this study is to determine the molecular mechanisms of nicotine/alcohol-induced epigenetic alterations and their mechanistic roles in transcriptional regulation in human adult stem cells. We hypothesized that nicotine/alcohol induces deregulation of epigenetic machinery and leads to epigenetic alterations, which subsequently affect transcriptional regulation in oral epithelial stem cells. As an initiating step we have profiled transcriptomic alterations induced by the combinatory administration of EtOH and nicotine in primary normal human oral keratinocytes. Here we provide detailed experimental methods, analysis and information associated with our data deposited into Gene Expression Omnibus (GEO) under GSE57634. Our data provide comprehensive transcriptomic map describing molecular changes induced by EtOH and nicotine on normal human oral keratinocytes

Opioid and naloxone prescribing following insertion of prompts in the electronic health record to encourage compliance with California state opioid law.

IMPORTANCE: Opioid addiction or dependency is a serious crisis in the US that affects public health as well as social and economic welfare. The State of California passed Assembly Bill (AB) 2760 in 2018 that mandates the coprescription of naloxone and opioids for patients with a high overdose risk. OBJECTIVE: To assess whether the AB 2760–based electronic prompts were associated with increased naloxone orders for opioid users and reduced opioid prescribing when integrated into the practitioner workflow. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used interrupted time series mixed models to evaluate data obtained from the regional integrated health care system Kaiser Permanente Southern California (KPSC) from January 1, 2018, to December 31, 2019. Clinician participants were continuously employed at KPSC during the study period and ordered an opioid analgesic for eligible patients in 2018. Patient participants were KPSC members aged 18 years or older who received an opioid analgesic prescription during the study period. A series of AB 2760–based electronic prompts were integrated into the KPSC electronic health record system on December 27, 2018. The prompts are triggered or activated when 1 or more opioid prescribing conditions, defined in the AB 2760, are met at outpatient visits. Data were analyzed from January 8, 2021, to September 15, 2021. EXPOSURES: Assembly Bill 2760–based electronic prompts for outpatient opioid prescriptions in the electronic health record system. MAIN OUTCOMES AND MEASURES: Primary outcomes were changes in outpatient naloxone order rates among patients who were prescribed opioids and changes in outpatient opioid prescribing rates. Secondary outcomes were total morphine milligram equivalents (MMEs) ordered per prescriber-month, prompts-targeted objectives, and unintended consequences. Risk for opioid abuse among 3 types of patients was also assessed. RESULTS: The 6515 eligible clinicians (mean [SD] age, 45.9 [9.43] years; 3604 men [55.3%]) included in the study served 500 711 unique patients in 1 903 289 outpatient encounters (mean [SD] age, 60.4 [15.67] years; 1 121 004 women [58.9%]) in which an opioid analgesic was prescribed. Naloxone order rate increased from 2.0% in December 2018 to 13.2% in January 2019 and then continued to increase to 27.1% in December 2019. Outpatient opioid prescribing rates decreased by 15.1% (rate ratio [RR], 0.85; 95% CI, 0.83-0.87) per prescriber-month when the electronic prompts were implemented. The postimplementation trend increased by 0.7% per prescriber-month (RR, 1.01; 95% CI, 1.01-1.01); the overall trend was still decreasing. The total MMEs per prescriber-month decreased by 7.8% (RR, 0.92; 95% CI, 0.89-0.96) after implementation of the prompts. The postimplementation trend tapered off. Other safe opioid prescribing measures also improved after implementation (decreases in concomitant muscle relaxants orders [RR, 0.94; 95% CI, 0.89-1.00], initial [RR, 0.86; 0.83-0.89] and renewal [RR, 0.65; 95% CI, 0.62-0.69] opioid orders, and long-term high-dose orders [RR, 0.96; 95% CI, 0.94-0.98]). CONCLUSIONS AND RELEVANCE: This study found an association between implementation of AB 2760–based prompts and increased naloxone order rate; improved opioid prescribing measures (ie, decreased concomitant muscle relaxants orders, initial and renewal opioid orders, and long-term high-dose orders), except monthly median MMEs; and reduced opioid prescribing. The findings suggest that opioid overdose risks can be mitigated by encouraging safe prescribing habits

Hepatitis C Virus Causes Uncoupling of Mitotic Checkpoint and Chromosomal Polyploidy through the Rb Pathway ▿ †

Hepatitis C virus (HCV) infection is associated with the development of hepatocellular carcinoma and probably also non-Hodgkin's B-cell lymphoma. The molecular mechanisms of HCV-associated carcinogenesis are unknown. Here we demonstrated that peripheral blood mononuclear cells obtained from hepatitis C patients and hepatocytes infected with HCV in vitro showed frequent chromosomal polyploidy. HCV infection or the expression of viral core protein alone in hepatocyte culture or transgenic mice inhibited mitotic spindle checkpoint function because of reduced Rb transcription and enhanced E2F-1 and Mad2 expression. The silencing of E2F-1 by RNA interference technology restored the function of mitotic checkpoint in core-expressing cells. Taken together, these data suggest that HCV infection may inhibit the mitotic checkpoint to induce polyploidy, which likely contributes to neoplastic transformation

Molecular effect of ethanol during neural differentiation of human embryonic stem cells in vitro

Potential teratogenic effects of alcohol on fetal development have been documented. Especially studies have demonstrated deleterious effect of ethanol exposure on neuronal development in animal models and on the maintenance and differentiation of neuronal precursor cells derived from stem cells. To better understand the molecular effect of alcohol on the process of neural differentiation, we have performed gene expression microarray analysis on human embryonic stem cells being directed to neural rosettes and neural precursor cells in the presence of ethanol treatment. Here we provide detailed experimental methods, analysis and information associated with our data deposited into Gene Expression Omnibus (GEO) under GSE56906. Our data provide scientific insight on potential molecular effects of fetal alcohol exposure on neural differentiation of early embryo development