Faculty Bibliography

The pancreas tumor microbiota may influence tumor microenvironment and influence survival in early-stage pancreatic ductal adenocarcinoma (PDAC); however, current studies are limited and small. We investigated the relationship of tumor microbiota to survival in 201 surgically resected patients with localized PDAC (Stages I-II), from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts. We characterized the tumor microbiome using RNA-sequencing data. We examined the association of the tumor microbiome with overall survival (OS), via meta-analysis with the Cox PH model. A microbial risk score (MRS) was calculated from the OS-associated microbiota. We further explored whether the OS-associated microbiota is related to host tumor immune infiltration. PDAC tumor microbiome α- and β-diversities were not associated with OS; however, 11 bacterial species, including species of Gammaproteobacteria, confirmed by extensive resampling, were significantly associated with OS (all Q < 0.05). The MRS summarizing these bacteria was related to a threefold change in OS (hazard ratio = 2.96 per standard deviation change in the MRS, 95% confidence interval = 2.26-3.86). This result was consistent across the two cohorts and in stratified analyses by adjuvant therapy (chemotherapy/radiation). Identified microbiota and the MRS also exhibited association with memory B cells and naïve CD4⁺ T cells, which may be related to the immune landscape through BCR and TCR signaling pathways. Our study shows that a unique tumor microbiome structure, potentially affecting the tumor immune microenvironment, is associated with poorer survival in resected early-stage PDAC. These findings suggest that microbial mechanisms may be involved in PDAC survival, potentially informing PDAC prognosis and guiding personalized treatment strategies.IMPORTANCEMuch of the available data on the PDAC tumor microbiome and survival are derived from relatively small and heterogeneous studies, including those involving patients with advanced stages of pancreatic cancer. There is a critical knowledge gap in terms of the tumor microbiome and survival in early-stage patients treated by surgical resection; we expect that advancements in survival may initially be best achieved in these patients who are treated with curative intent.

BACKGROUND:The diagnosis and treatment of tumors often depend on molecular-genetic data. However, rapid and iterative access to molecular data is not currently feasible during surgery, complicating intraoperative diagnosis and precluding measurement of tumor cell burdens at surgical margins to guide resections. METHODS:Here, we introduce Ultra-Rapid droplet digital PCR (UR-ddPCR), a technology that achieves the fastest measurement, to date, of mutation burdens in tissue samples, from tissue to result in 15 min. Our workflow substantially reduces the time from tissue biopsy to molecular diagnosis and provides a highly accurate means of quantifying residual tumor infiltration at surgical margins. FINDINGS/RESULTS: = 0.995). CONCLUSIONS:The technology and workflow developed here enable intraoperative molecular-genetic assays with unprecedented speed and sensitivity. We anticipate that our method will facilitate novel point-of-care diagnostics and molecularly guided surgeries that improve clinical outcomes. FUNDING/BACKGROUND:This study was funded by the National Institutes of Health and NYU Grossman School of Medicine institutional funds. Reagents and instruments were provided in kind by Bio-Rad.

Recurrent respiratory papillomatosis (RRP) is a chronic airway disease caused by Human Papillomavirus (HPV). INO-3107, DNA immunotherapy designed to elicit T-cells against HPV-6 and HPV-11, was evaluated in a 52-week Phase 1/2 study for efficacy, safety, and immunogenicity (NCT04398433). Thirty-two eligible adults with HPV-6 and/or HPV-11 RRP, requiring ≥2 surgical interventions in the year preceding dosing were enrolled between October 2020 and November 2021 and administered 4 INO-3107 doses by intramuscular injection followed by electroporation. The primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included surgical intervention frequency and change in RRP Severity Score (modified) post-INO-3107 and assessment of immune responses. 81% (26/32) of patients experienced surgery reduction following INO-3107 compared with the year prior to treatment. Blood assessments revealed HPV-6 and HPV-11 antigen-specific T-cell induction. RNA sequencing identified an inflammatory response in papillomas, inclusive of cytolytic CD8 + T-cell signatures. T-cell receptor sequencing revealed emergent T-cell clones in blood and confirmed trafficking to papillomas. Treatment-related adverse events (AEs) were reported in 13/32 (41%) patients, all low-grade. INO-3107 provides clinical benefit to HPV-6 and/or HPV-11-associated RRP adults and is well-tolerated. Importantly, treatment-induced peripheral T-cell responses traffic to airway tissue and are associated with clinical response.

Inhibitory interneurons are highly heterogeneous circuit elements often characterized by cell biological properties, but how these factors relate to specific roles underlying complex behavior remains poorly understood. Using chronic silicon probe recordings, we demonstrate that distinct interneuron groups perform different inhibitory roles within HVC, a song production circuit in the zebra finch forebrain. To link these functional subtypes to molecular identity, we performed two-photon targeted electrophysiological recordings of HVC interneurons followed by post hoc immunohistochemistry of subtype-specific markers. We find that parvalbumin-expressing interneurons are highly modulated by sensory input and likely mediate auditory gating, whereas a more heterogeneous set of somatostatin-expressing interneurons can strongly regulate activity based on arousal. Using this strategy, we uncover important cell-type-specific network functions in the context of an ethologically relevant motor skill.

Current models of eye movement control propose that motor neurons responsible for moving the eyes contribute to all eye movements, regardless of context. A recent study in larval zebrafish has instead identified specialized neural circuits, including subtypes of motor neurons, for two different types of fast eye movement, one for exploration and the other for hunting.

OBJECTIVES/OBJECTIVE:Recent studies suggest that hearing loss is associated with balance dysfunction and an increased risk of falls. The purpose of this study was to investigate whether adults with unilateral hearing loss (UHL) have an underlying vestibular dysfunction and whether vestibular testing explains balance function and fall risk. STUDY DESIGN/METHODS:Cross-sectional. SETTING/METHODS:Urban otology practice and a human motion laboratory. PATIENTS/METHODS:We recruited 41 healthy controls (mean age, 52 years; range, 22-78 years) and 29 adults with stable UHL (mean age, 53 years; range, 18-80 years) who denied symptoms of dizziness (Dizziness Handicap Inventory average, 1.86; range, 0-14). UHL occurred an average of 4 years (range from sudden loss, 4 months to 27.5 years) prior to testing. INTERVENTIONS/METHODS:We conducted the caloric portion of the videonystagmography test, video head impulse test (vHIT), and a battery of balance tests: standing on foam with eyes closed, timed up and go test, four square step test, 10-meter walk, and a virtual reality (VR) assessment of postural control. MAIN OUTCOME MEASURES/METHODS:Hearing was quantified by four-frequency pure-tone average (PTA). Caloric weakness was defined as asymmetry greater than 25%. Participants self-reported falls over the past 12 months and history of vertigo. Performance on balance tests was quantified by time to completion or duration of hold. Performance on the VR assessment was quantified by root-mean-square velocity of head sway. RESULTS:Proportion of unilateral caloric weakness was significantly higher in the UHL group (25%) than the control group (12%). Five participants with UHL refused caloric testing. vHIT gains of lateral canals were normal in both groups. The majority of participants in the UHL group experienced vertigo at the onset of hearing loss (72%). There were five fallers in the UHL group (17%) and three in the control group (7%). Participants with caloric weakness or vertigo at onset did not differ from those without in age or in any of the balance tests. Participants with history of falls differed in head sway and duration of hold standing on foam with eyes closed. CONCLUSIONS:Individuals with UHL are more likely to have caloric weakness than healthy controls; however, these findings are not correlated with functional outcomes or history of falls. Postural control testing using virtual reality or standing on foam with eyes closed may help detect those at a risk for falls.

INTRODUCTION/BACKGROUND:Tracheostomy is a commonly performed procedure in Otolaryngology and can be performed in different settings. We evaluate patient characteristics and cost efficacy of tracheostomy at the bedside versus operating room (OR). MATERIALS AND METHODS/METHODS:Retrospective chart review was performed for adult intensive care unit (ICU) patients who underwent tracheostomy from 2020 to 2023. Data and cost of procedures were analyzed using descriptive statistics. RESULTS:One hundred and sixty-five patients were included. One hundred and thirty-four (81.2%) patients underwent bedside tracheostomy. Age, sex, and BMI were not significantly different. Average time from consult to procedure and operative time was significantly shorter (p = 0.03; 0.008). There were no differences in postoperative complications, 30-day mortality, ICU length of stay (LOS), or overall LOS. Tracheostomy at the bedside offered a 73.1% cost reduction compared with performed in the OR. CONCLUSION/CONCLUSIONS:Advantages of bedside tracheostomy include decreased operative time, time from consult to procedure, and cost reduction for the hospital system. We advocate for consideration of bedside tracheostomy when appropriate.

OBJECTIVE:To investigate the effect of heated-cigarette smoking on voice. METHODS:Participants completed a survey including three sections: section-1 comprised demographic data, section-2 comprised visual analogue scale grading of voice changes and fatigue and section-3 consisted of the voice handicap index-10. RESULTS:< 0.05). CONCLUSION/CONCLUSIONS:Smokers of heated cigarettes have a significantly higher mean voice handicap index-10 score compared to non-smokers and higher grade of voice changes and fatigue.

Motor neurons have highly diverse anatomical, functional and molecular features, and differ significantly in their susceptibility in disease. Extraocular motor neurons, residing in the oculomotor, trochlear and abducens cranial nuclei (nIII, nIV and nVI), control eye movements. Recent work has begun to clarify the developmental mechanisms by which functional diversity among extraocular motor neurons arises. However, we know little about the role and consequences of extraocular motor neuron diversity in eye movement control. Here, we highlight recent work investigating the anatomical, functional and molecular features of extraocular motor neurons. Further, we frame hypotheses where studying ocular motor circuits in the larval zebrafish is poised to illuminate the consequences of motor neuron diversity for behavior.