Faculty Bibliography

Activation of phosphoinositide 3-kinase (PI3K) signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified novel candidates functionally important to buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAP2K4 reduced both baseline and feedback MAPK/MEK signaling and showed synthetic lethality with buparlisib in vitro. A complex in/del frameshift in PIK3CA decreased sensitivity to buparlisib via NEK9/MAP2K4-dependent mechanisms. In summary, our study supports a role for NEK9 and MAP2K4 in mediating buparlisib resistance and demonstrates the value of unbiased omic analyses in uncovering resistance mechanisms to targeted therapy.

OBJECTIVES/OBJECTIVE:We identified the prevalence of nonmedical prescription drug use and its relationship to heroin and injection drug use in 4 nationally representative samples of adolescents. METHODS:We used the most recent data (2009-2015) from the Youth Risk Behavior Surveillance System (Ntotal= 61,132). Prevalence rates and 95% confidence intervals for prescription drug misuse, heroin use, and injection drug use were calculated across time points, sex, and race/ethnicity subgroups. Using odds ratios, we determined the likelihood of youth reporting nonmedical prescription drug use also reporting heroin and drug injection. RESULTS:In 2015, one in 6 adolescents reported recent prescription drug misuse. High rates of nonmedical prescription drug use persisted or increased among Hispanic boys, black boys, and "other" youth, while declining among white youth. Youth who used prescription drugs nonmedically at least once were 17.5 times more likely to have used heroin (CI: 13.7, 22.4) and 14.6 times more likely to have injected drugs (CI: 11.2, 19.2) in their lifetime. CONCLUSIONS:Public health programming focused on reducing prescription drug misuse also may reduce youth engagement in heroin and/or injection drug use. Preventive efforts to support communities of color in reducing rates of prescription drug misuse are crucial.

Background: Multiple bacterial species are capable of degrading oxalate in vitro. Certain taxa degrade oxalate as their sole source of energy and carbon (e.g. Oxalobacter formigenes), whereas others use oxalate as an auxiliary carbon source. For oxalate metabolism, it is not yet well-understood how genomic potential relates to transcriptional regulation. We asked whether the human gut could have a community of oxalatedegrading taxa working synergistically to diminish the effects of this toxic metabolite. Our hypothesis is that oxalate metabolism is regulated by a multi-organism oxalatedegrading community (oxalobiome) that is dominated by specialist oxalate degraders.
Method(s): We used data from 2 public databases: (i)8 healthy subjects in the USA; and (ii)471 healthy subjects in the Netherlands as part of the Human Functional Genomic Project (HFGP). Both collected fecal samples for metagenomic and/or metatranscriptomic high throughput sequencing. Using HUMAnN2 with customized settings, we profiled the metabolic activity of oxalate-degrading bacterial species. Output from these analyses was expressed as Reads per Kilobase per Million mapped reads (RPKM).
Result(s): We identified the oxalate degradation pathway (ODP) in the metagenome and metatranscriptome of all 8 subjects. Mean ODP is 35.3+/-28.1 and 90.1+/-43.5 RPKM in the metagenome and the metatranscriptome, respectively, indicating active expression. O. formigenes, E. coli, and unclassified bacteria were present in metagenomic and metatranscriptomic reads. B. dentium had detectable ODP in its genome but was not transcribing it. In the HFGP database, we identified ODP in 328 subjects of the 471 tested (70%) (Mean=18.1+/-2.1 RPKM). ODP was detected in B. animalis, B. dentium, B. pseudocatenulatum, E.coli/Shigella, L. acidophilus, L. gasseri, L. mucosae, O. formigenes and unclassified bacteria. ODP was examined in the metagenome of 265 females (Mean ODP= 21.7+/-3.3) and 200 males (Mean ODP=13.3+/-1.9 RPKM; p=0.04 by unpaired t test).
Conclusion(s): We have identified a community of bacteria with the potential to degrade oxalate in healthy humans and species actively transcribing ODP. These include E.coli, which might be a common contributor of oxalate degradation in humans. The sex differences in ODP is consistent with the ~ 2:1 male/female incidence and prevalence of calcium oxalate stones

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.

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.

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.

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.

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.