Faculty Bibliography

The presence of chlamydia, gonorrhea, or syphilis infection is a significant risk factor for HIV acquisition and transmission and disproportionately impacts men who have sex with men (MSM) and transgender women. While HIV preexposure prophylaxis (PrEP) reduces HIV risk, its use may influence sexual behaviors, potentially increasing sexually transmitted infection (STI) exposure. Conversely, PrEP users are often more engaged in care, regularly screened and treated for STIs, and may access other prevention tools such as doxycycline postexposure prophylaxis. Studies on the relationship between PrEP use and STIs have shown mixed results. This cross-sectional analysis included 392 participants (381 cisgender MSM; 11 transgender women) enrolled in the US-based Multicenter AIDS Cohort Study/WIHS Combined Cohort Study between 2021 and 2024 who were sexually active in the year prior to STI testing and HIV negative at their most recent study visit. We assessed whether bacterial STI positivity (i.e., laboratory-confirmed chlamydia and gonorrhea at the urethral, pharyngeal, and/or rectal sites and/or current/past syphilis infection) differed by current PrEP use (yes/no). Multi-variable logistic regression models included sociodemographic and behavioral covariates that were associated with bacterial STI positivity at p < 0.05, with the most parsimonious models selected based on the lowest Akaike Information Criterion. Overall, 32.7% reported current PrEP use. Syphilis was the most prevalent STI (6.8%), followed by chlamydia (3.2%) and gonorrhea (2.1%); 11.7% of PrEP users tested positive for at least one STI, compared with 6.1% of non-PrEP users. Among PrEP users, 37.9% reported stopping or decreasing condom use, and 31.6% reported an increased number of sex partners after initiating PrEP. In both bivariate and multi-variable models, PrEP use was associated with higher odds of gonorrhea positivity (adjusted odds ratio = 4.70, 95% confidence interval [CI]: 1.10-20.04, p = 0.037) and greater odds of being positive for at least one STI (crude odds ratio = 1.94, 95% CI: 1.06-3.90, p = 0.041). No significant differences were observed for chlamydia and syphilis by PrEP use status. Overall, these findings suggest that current PrEP users (vs. non-PrEP users) have an increased odds of bacterial STI positivity, particularly gonorrhea, in a diverse, multi-city cohort of HIV negative, sexually active MSM and transgender women in the United States PrEP remains highly effective in preventing HIV, and our results underscore the importance of integrated sexual health services that support ongoing STI screening and prevention alongside PrEP use among sexual and gender minorities.

Perineural invasion (PNI), defined by cancer spreading or invading into the nerve, links to severe pain, recurrence, and poor prognosis. PNI contributes to nerve damage, Schwann cell activation, and sensory neuron dysfunction. Soluble tumor necrosis factor α (solTNFα) binds to TNFR1 to drive inflammation and nerve injury, playing a key role in cancer progression and pain. This study, using a mouse sciatic nerve PNI model, explored whether blocking solTNFα-TNFR1 signaling via TNFR1 knockout or pharmacological inhibition by XPro1595 could reduce PNI-associated pain. Data showed that XPro1595, but not TNFR1 knockout, reduced tumor burden, alleviated mechanical allodynia, and improved muscle function and locomotion, primarily in females. Histological analysis in females showed that XPro1595 increased the number of myelin and dendritic cells while reducing axonal damage that resulted from PNI. In the tumor zone outside the nerve truck, XPro1595 reduced T cell and increased macrophage and dendritic cell numbers. Transcriptomic analysis revealed that XPro1595 in females with PNI upregulated mitochondrial, myelination, motor function, and immune regulation gene pathways while it downregulated inflammatory, extracellular matrix, and tumor progression pathways. Overall, we demonstrated that XPro1595 exhibited antitumor, neuroprotective, and analgesic properties in female mice, likely by promoting neuronal regeneration and mitochondrial function, while reducing inflammation and extracellular remodeling.

Chronotherapeutic approaches that optimize the timing of therapy to enhance efficacy and minimize side effects are becoming mainstream. The widespread adoption of chronotherapeutic approaches is hindered by the lack of accessible, valid tools to determine circadian time. Building on evidence that gene expression profiles predict circadian time, this pilot study assessed associations between circadian phase predictions from a single blood sample, actigraphy-estimated sleep, and chronotype in a real-world setting. Twelve adults (mean age 51 y, 8 women) reporting short sleep (<7 h/night) and at risk for metabolic syndrome participated. CD14+ monocytes were isolated from 20 ml blood samples, pelleted, and stored at -80°C before RNA sequencing. Sleep was monitored over two weeks using the ActiGraph GT9X-BT, and chronotype preference was assessed with the Composite Scale of Morningness. Spearman's correlations analyzed correlations between predicted dim light melatonin onset (DLMO), sleep, and chronotype preference. Moderate-to-strong association was found between gene expression-based DLMO predictions and sleep, supporting the utility of peripheral blood mononuclear cell gene expression profiles for estimating circadian phase. This approach shows promise for improving chronotherapy implementation in middle-aged adults with chronic health conditions and short sleep. This study was part of a larger study that was registered with Clinicaltrials.gov as NCT03596983.

OBJECTIVE/UNASSIGNED:This longitudinal study aimed to examine the associations of sexual minority stress and outness with leukocyte telomere length across time among sexually minority men (SMM) with HIV who use methamphetamine. METHODS/UNASSIGNED:A sample of 91 SMM with HIV with biologically confirmed recent methamphetamine use completed measures of sexual minority stress and outness at the baseline visit in a randomized controlled trial. Telomere length was measured over 15 months using extracted leukocyte DNA Statistical analyses were performed using bivariate analyses and generalized estimation equations to examine the independent association between baseline outness and leukocyte telomere length, adjusting for chronological age and recent stimulant use. RESULTS/UNASSIGNED:Greater outness was significantly associated with longer telomere length (estimate = 0.008; CI: 0.001-0.008) after adjusting for chronological age and stimulant use. There was no evidence that stimulant use, intervention assignment, or race/ethnicity moderated the association between outness and greater leukocyte-telomere length. Sexual minority stress was not significantly associated with leukocyte-telomere length. CONCLUSION/UNASSIGNED:Findings are among the first to demonstrate that greater outness is associated with slower biological aging in SMM. Further research is needed to elucidate the bio-behavioral mechanisms linking outness and greater leukocyte-telomere length.

BACKGROUND:Poor sleep and frailty are prevalent among aging women with HIV (WWH). Although poor sleep quality has been associated with frailty in general aging populations, these relationships are not well characterized among WWH. METHODS:Among 1001 WWH and 371 women without HIV (WWoH) over age 40 years with Pittsburgh Sleep Quality Index (PSQI) and Fried Frailty Phenotype data, we analyzed relationships of poor sleep quality (PSQI>5) and sleep quality components with frailty. Separate hierarchical regression models evaluated associations between sleep and frailty status (prefrail vs. robust, frail vs robust) adjusting for: (1) study site and HIV status, (2) demographics, (3) substance use/Central Nervous System active medications, (4) comorbidities, and (5) depressive symptoms. RESULTS:Median age was 53 years; 9.2% were frail while 52.8% were prefrail. Poor sleep quality was frequent (52% WWH vs. 47% WWoH; p=0.07) and associated with double the frailty odds independent of HIV status, after adjusting for depressive symptoms (fully adjusted odds ratio AOR 1.99, 95% CI:1.14, 3.50, p=0.016). Sleep-associated daytime dysfunction and very poor sleep efficiency were independently associated with being frail. Poor self-rated sleep quality and higher use of sleep medications were independently associated with being prefrail. CONCLUSIONS:Among midlife WWH and WWoH, poor subjective sleep measures are independently associated with higher frailty odds. Longitudinal studies are needed to understand how aspects of sleep may impact progression from prefrailty to frailty after accounting for comorbidities and to elucidate the complex relationships between comorbidities and frailty, with sleep quality among midlife PWH.

OBJECTIVE:To determine if microbiome differences exist in head and neck squamous cell carcinoma (HNSCC) based on high-risk pathologic features, smoking, and outcomes using The Cancer Microbiome Atlas (TCMA). STUDY DESIGN/METHODS:Database study. SETTING/METHODS:Database review. METHODS:TCMA is a publicly available database containing curated, decontaminated microbial profiles for tumors from 1772 patients. The data were limited to microbiome profiles, survival, and clinicopathologic features for HNSCC patients. Phyloseq objects were created, low-read samples were removed, and differential abundance analysis (DAA) using Analysis of Compositions of Microbiomes with Bias Correction 2 (ANCOM-BC2) was performed. Statistical analysis was done in R (v4.3.1). RESULTS:One hundred fifty-six patients with HNSCC were included from TCMA with a mean age of 59 (std 13, min 19, and max 90), 72% male (n = 113), and 91% white (n = 140). Primary sites encompassed oral cavity (n = 106, 68%), oropharynx (n = 26, 17%), and larynx/hypopharynx (n = 24, 15%). For all HNSCC in TCMA, rates of lymphovascular invasion were 17% (n = 26), perineural invasion, 34% (n = 53), and microscopic or gross extranodal extension (ENE), 19% (n = 30). DAA revealed significant changes in bacterial genera based on high-risk pathologic features, smoking status, vital status, and disease-specific survival (DSS). Genera observed with ANCOM-BC2 include Scardovia, Alloscardovia, Lactobacillus, and Corynebacterium genera for vital status and DSS. CONCLUSION/CONCLUSIONS:Changes in the relative abundance of select intratumoral bacterial genera are associated with adverse pathologic features, DSS, and vital status in HNSCC. Shifts in the microbiome need further investigation to determine if they can provide any mechanistic insight or predictive role.

Methylome-wide association studies (MWASs) have identified many 5'-cytosine-phosphate-guanine-3' (CpG) sites associated with complex traits. Several methods have been developed to predict CpG methylation levels from genotypes when the direct measurements of methylation are unavailable. To date, the published methods have mostly used datasets from populations of European ancestry to train prediction models for methylations, which limits the generalizability of methylome-wide association study to non-European populations. To address this gap, we proposed a new model by incorporating local ancestry (LA) information, called LA Methylation Predictor with Preselection (LAMPP), to improve the prediction accuracy of DNA methylation in admixed populations. We showed that LAMPP outperformed the conventional model and other LA models in prediction accuracy using an admixed African American population. We further applied our model to identify significant CpG sites for seven complex traits. Together, our LAMPP model is a valuable tool to reveal epigenetic underpinnings of complex traits in the admixed populations.

BACKGROUND:Opioid addiction is a worldwide public health crisis. In the United States, for example, opioids cause more drug overdose deaths than any other substance. However, opioid addiction treatments have limited efficacy, meaning that additional treatments are needed. METHODS:To help address this problem, we used network-based machine learning techniques to integrate results from genome-wide association studies of opioid use disorder and problematic prescription opioid misuse with transcriptomic, proteomic, and epigenetic data from the dorsolateral prefrontal cortex of people who died of opioid overdose and control individuals. RESULTS:We identified 211 highly interrelated genes identified by genome-wide association studies or dysregulation in the dorsolateral prefrontal cortex of people who died of opioid overdose that implicated the Akt, BDNF (brain-derived neurotrophic factor), and ERK (extracellular signal-regulated kinase) pathways, identifying 414 drugs targeting 48 of these opioid addiction-associated genes. Some of the identified drugs are approved to treat other substance use disorders or depression. CONCLUSIONS:Our synthesis of multiomics using a systems biology approach revealed key gene targets that could contribute to drug repurposing, genetics-informed addiction treatment, and future discovery.

BACKGROUND:Oral squamous cell carcinoma (OSCC) is typically diagnosed at advanced stages, resulting in poor survival rates. Epigenetic alterations, especially DNA methylation, are important early and key contributors to OSCC pathogenesis, but comprehensive epigenetic analysis has traditionally been confounded by cancer tissue availability, with fresh-frozen tissues being the gold standard but difficult to obtain. METHODS:This study established and optimized a new workflow for the use of methylation capture sequencing (MC-seq) to analyze DNA methylation profiles in formalin-fixed paraffin-embedded (FFPE) tissues. Twelve OSCC patients were randomly selected from a prospective, multi-institutional study. Paired fresh-frozen and FFPE tissues were collected and processed for DNA extraction and MC-seq. Data were pre-processed using Bismark and methylKit pipelines. Methylation concordance between FFPE and fresh-frozen samples was assessed by comparing β-value correlation. RESULTS:DNA from FFPE and fresh-frozen OSCC samples showed minimal differences in fragmentation, with FFPE achieving high mapping efficiency (average 71.6%) and retaining an average of about 5 million CpG sites at 10× depth. The distributions of CpG in the methylome region, including promoter, exonic, intronic, and intergenic regions, showed similar patterns between sample types. Additionally, the methylation levels of all matched CpG sites in our 12-gene prognostic panel showed a strong correlation (r ≥ 0.97) between FFPE and fresh-frozen samples. CONCLUSION/CONCLUSIONS:Our findings indicate that FFPE samples are reliable for methylation capture sequencing, offering a new, scalable and reliable alternative to fresh-frozen samples for large-scale OSCC research.