Faculty Bibliography

Increased intestinal permeability and translocation of gut bacteria trigger various polyaetiological diseases associated with chronic inflammation and underlie a variety of poorly treatable pathologies. Previous studies have established a primary role of the microbiota composition and intestinal permeability in such pathologies. Using a rat model, we examined the effects of exposure to a bacteriophage cocktail on intestinal permeability and relative abundance of taxonomic units in the gut bacterial community. There was an increase in markers of impaired gut permeability, such as the lactulose/mannitol ratio, plasma endotoxin concentrations, and serum levels of inflammation-related cytokines, following the bacteriophage challenge. We observed significant differences in the alpha diversity of faecal bacterial species and found that richness and diversity index values increased following the bacteriophage challenge. There was a reduction in the abundance of Blautia, Catenibacterium, Lactobacillus, and Faecalibacterium species and an increase in Butyrivibrio, Oscillospira and Ruminococcus after bacteriophage administration. These findings provide novel insights into the role of bacteriophages as potentially pathogenic for mammals and their possible implication in the development of diseases associated with increased intestinal permeability.

BACKGROUND: Benzodiazepines are a widely prescribed psychoactive drug; in the U.S., both medical and nonmedical use of benzodiazepines has increased markedly in the past 15 years. Long-term use can lead to tolerance and dependence, and abrupt withdrawal can cause seizures or other life-threatening symptoms. Benzodiazepines are often used nonmedically in conjunction with other drugs, and with opioids in particular-a combination that can increase the risk for fatal and non-fatal overdose. This mixed-methods study examines nonmedical use of benzodiazepines among young adults in New York City and its relationship with opioid use. METHODS: For qualitative analysis, 46 90-minute semi-structured interviews were conducted with young adult opioid users (ages 18-32). Interviews were transcribed and coded for key themes. For quantitative analysis, 464 young adult opioid users (ages 18-29) were recruited using Respondent-Driven Sampling and completed structured interviews. Benzodiazepine use was assessed via a self-report questionnaire that included measures related to nonmedical benzodiazepine and opioid use. RESULTS: Participants reported using benzodiazepines nonmedically for a wide variety of reasons, including: to increase the high of other drugs; to lessen withdrawal symptoms; and to come down from other drugs. Benzodiazepines were described as readily available and cheap. There was a high prevalence (93%) of nonmedical benzodiazepine use among nonmedical opioid users, with 57% reporting regular nonmedical use. In bivariate analyses, drug-related risk behaviours such as polysubstance use, drug binging, heroin injection and overdose were strongly associated with regular nonmedical benzodiazepine use. In multivariate analysis, growing up in a middle-income household (earning between $51,000 and $100,000 annually), lifetime overdose experience, having ever used cocaine regularly, having ever been prescribed benzodiazepines, recent drug binging, and encouraging fellow drug users to use benzodiazepines to cope with opioid withdrawal were consistently strong predictors of regular nonmedical benzodiazepine use. CONCLUSION: Nonmedical benzodiazepine use may be common among nonmedical opioid users due to its drug-related multi-functionality. Harm reduction messages should account for the multiple functions benzodiazepines serve in a drug-using context, and encourage drug users to tailor their endorsement of benzodiazepines to peers to include safer alternatives.

Bullying is an intentional act that can wreak havoc in the life of an individual. With more than 1 billion users, YouTubeTM is a powerful medium for disseminating information. The purpose of this study was to describe the extent to which content related to bullying is present on YouTubeTM with respect to source, content, number of views, length, and year uploaded. Collectively, the videos in this sample were viewed more than half a billion times. The source of the most widely viewed videos was consumers, and none of the most widely viewed videos was posted by a governmental agency or a professional organization. The most common content in the videos was describing or depicting violence (n = 89). Over one-half addressed getting help (n = 56). Suicide was mentioned in 38 of the videos. Additional investment by professional agencies is warranted to improve understanding about ways to increase the dissemination of positive messages about bullying prevention, and about helping adolescents who are bullied on social media.

To evaluate and characterize the structure of temporal patterns of depression, smoking, unhealthy alcohol use, and other substance use among individuals receiving medical care, and to inform discussion about whether integrated screening and treatment strategies for these conditions are warranted. Using the Veterans Aging Cohort Study (VACS) we measured depression, smoking, unhealthy alcohol use and other substance use (stimulants, marijuana, heroin, opioids) and evaluated which conditions tended to co-occur within individuals, and how this co-occurrence was temporally structured (i.e. concurrently, sequentially, or discordantly). Current depression was associated with current use of every substance examined with the exception of unhealthy alcohol use. Current unhealthy alcohol use and marijuana use were also consistently associated. Current status was strongly predicted by prior status (p < 0.0001; OR = 2.99-22.34) however, there were few other sequential relationships. Associations in the HIV infected and uninfected subgroups were largely the same with the following exceptions. Smoking preceded unhealthy alcohol use and current smoking was associated with current depression in the HIV infected subgroup only (p < 0.001; OR = 1.33-1.41 and p < 0.001; OR = 1.25-1.43). Opioid use and current unhealthy alcohol use were negatively associated only in the HIV negative subgroup (p = 0.01; OR = 0.75). Patterns of depression, smoking, unhealthy alcohol use, and other substance use were temporally concordant, particularly with regard to depression and substance use. These patterns may inform future development of more integrated screening and treatment strategies.

With combined technological advancements in high-throughput next-generation sequencing and deep mass spectrometry-based proteomics, proteogenomics, i.e., the integrative analysis of proteomic and genomic data, has emerged as a new research field. Early efforts in the field were focused on improving protein identification using sample-specific genomic and transcriptomic sequencing data. More recently, integrative analysis of quantitative measurements from genomic and proteomic studies have identified novel insights into gene expression regulation, cell signaling, and disease. Many methods and tools have been developed or adapted to enable an array of integrative proteogenomic approaches and in this article, we systematically classify published methods and tools into four major categories, (1) Sequence-centric proteogenomics; (2) Analysis of proteogenomic relationships; (3) Integrative modeling of proteogenomic data; and (4) Data sharing and visualization. We provide a comprehensive review of methods and available tools in each category and highlight their typical applications.

Nonmedical prescription opioid use has become widespread. It can lead to heroin use, drug injection and HIV infection. We describe young adult opioid users' sexual risk behavior, partnerships and settings. 464 youth aged 18-29 who reported opioid use in the past 30 days were recruited using Respondent-Driven Sampling. Eligible participants completed a computer-assisted, interviewer-administered risk questionnaire and were tested for STIs and HIV. Participants (33% female; 66% white non-Hispanic) almost all had sex in the prior 90 days; 42% reported more than one partner. Same-sex sex was reported by 3% of men and 10% of women. Consistent condom use was rare. Seven percent reported group sex participation in the last 90 days but lifetime group sex was common among men and women. Young opioid users' unprotected sex, multiple partners and group sex puts them and others at high HIV and STI risk.

Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities.

OBJECTIVE: To inform the design of a combination intervention strategy targeting HIV-infected unhealthy alcohol users in Maharashtra, India, that could be tested in future randomized control trials. METHODS: Using probabilistic compartmental simulation modeling we compared intervention strategies targeting HIV-infected unhealthy alcohol users on antiretroviral therapy (ART) in Maharashtra, India. We tested interventions targeting four behaviors (unhealthy alcohol consumption, risky sexual behavior, depression and antiretroviral adherence), in three formats (individual, group based, community) and two durations (shorter versus longer). A total of 5,386 possible intervention combinations were tested across the population for a 20-year time horizon and intervention bundles were narrowed down based on incremental cost-effectiveness analysis using a two-step probabilistic uncertainty analysis approach. RESULTS: Taking into account uncertainty in transmission variables and intervention cost and effectiveness values, we were able to reduce the number of possible intervention combinations to be used in a randomized control trial from over 5,000 to less than 5. The most robust intervention bundle identified was a combination of three interventions: long individual alcohol counseling; weekly Short Message Service (SMS) adherence counseling; and brief sex risk group counseling. CONCLUSIONS: In addition to guiding policy design, simulation modeling of HIV transmission can be used as a preparatory step to trial design, offering a method for intervention pre-selection at a reduced cost.

Inhibition of VLDL secretion reduces plasma levels of atherogenic apolipoprotein B (apoB) lipoproteins but can also cause hepatic steatosis. Approaches targeting apoB synthesis, which lies upstream of VLDL secretion, have potential to effectively reduce dyslipidemia but can also lead to hepatic accumulation of unsecreted triglycerides (TG). Here, we found that treating mice with apoB antisense oligonucleotides (ASOs) for 6 weeks decreased VLDL secretion and plasma cholesterol without causing steatosis. The absence of steatosis was linked to an increase in ER stress in the first 3 weeks of ASO treatment, followed by development of ER autophagy at the end of 6 weeks of treatment. The latter resulted in increased fatty acid (FA) oxidation that was inhibited by both chloroquine and 3-methyl adenine, consistent with trafficking of ER TG through the autophagic pathway before oxidation. These findings support the concept that inhibition of apoB synthesis traps lipids that have been transferred to the ER by microsomal TG transfer protein (MTP), inducing ER stress. ER stress then triggers ER autophagy and subsequent lysosomal lipolysis of TG, followed by mitochondrial oxidation of released FA, leading to prevention of steatosis. The identification of this pathway indicates that inhibition of VLDL secretion remains a viable target for therapies aiming to reduce circulating levels of atherogenic apoB lipoproteins.