Faculty Bibliography

The cerebellum takes in a great deal of sensory information from the periphery and descending signals from the cerebral cortices. It has been debated whether the paramedian lobule (PML) in the rat and its paravermal regions that project to the interpositus nucleus (IPN) are primarily involved in motor execution or motor planning. Studies that have relied on single spike recordings in behaving animals have led to conflicting conclusions regarding this issue. In this study, we tried a different approach and investigated the correlation of field potentials and multi-unit signals recorded with multi-electrode arrays from the PML cortex along with the forelimb electromyography (EMG) signals in rats during behavior. Linear regression was performed to predict the EMG signal envelopes using the PML activity for various time shifts (±25, ±50, ±100, and ± 400 ms) between the two signals to determine a causal relation. The highest correlations (~0.5 on average) between the neural and EMG envelopes were observed for zero and small (±25 ms) time shifts and decreased with larger time shifts in both directions, suggesting that paravermal PML is involved both in processing of sensory signals and motor execution in the context of forelimb reaching behavior. EMG envelopes were predicted with higher success rates when neural signals from multiple phases of the behavior were utilized for regression. The forelimb extension phase was the most difficult to predict while the releasing of the bar phase prediction was the most successful. The high frequency (>300 Hz) components of the neural signal, reflecting multi-unit activity, had a higher contribution to the EMG prediction than did the lower frequency components, corresponding to local field potentials. The results of this study suggest that the paravermal PML in the rat cerebellum is primarily involved in the execution of forelimb movements rather than the planning aspect and that the PML is more active at the initiation and termination of the behavior, rather than the progression.

Metastatic disease remains the leading cause of death due to cancer, yet the mechanism(s) of metastasis and its timely detection remain to be elucidated. Neutrophil elastase (NE), a serine protease secreted by neutrophils, is a crucial mediator of chronic inflammation and tumor progression. In this study, we used the PyMT model (NE+/+ and NE-/-) of breast cancer to interrogate the tumor-intrinsic and -extrinsic mechanisms by which NE can promote metastasis. Our results showed that genetic ablation of NE significantly reduced lung metastasis and improved metastasis-free survival. RNA-sequencing analysis of primary tumors indicated differential regulation of tumor-intrinsic actin cytoskeleton signaling pathways by NE. These NE-regulated pathways are critical for cell-to-cell contact and motility and consistent with the delay in metastasis in NE-/- mice. To evaluate whether pharmacologic inhibition of NE inhibited pulmonary metastasis and phenotypically mimicked PyMT NE-/- mice, we utilized AZD9668, a clinically available and specific NE inhibitor. We found AZD9668 treated PyMT-NE+/+ mice showed significantly reduced lung metastases, improved recurrence-free, metastasis-free and overall survival, and their tumors showed similar molecular alterations as those observed in PyMT-NE-/- tumors. Finally, we identified a NE-specific signature that predicts recurrence and metastasis in patients with breast cancer. Collectively, our studies suggest that genetic ablation and pharmacologic inhibition of NE reduces metastasis and extends survival of mouse models of breast cancer, providing rationale to examine NE inhibitors as a treatment strategy for the clinical management of patients with metastatic breast cancer.

While there have been many descriptions of characteristic motion findings in left bundle branch block (LBBB), there are few published descriptions of such findings in right bundle branch block (RBBB). The purpose of this study was to assess the frequency of particular regional motion findings in cardiac magnetic resonance imaging (CMR) studies of patients with RBBB, compared with normal subjects. We focused on three distinctive motion patterns that can be seen in RBBB during early systole: delayed apex-ward motion of the RV base, "reverse septal flash", and "basal bulge". The presence and relative magnitude of these findings were independently scored by four experienced observers, in 3-chamber and 4-chamber CMR cines, for both normal subjects and patients with RBBB. These motion patterns were found to be strongly associated with the presence of RBBB. While only moderately sensitive, they were quite specific for RBBB, when present. In particular, with ROC analysis, a combined feature set of the findings in the 4-chamber view had an area under the curve of 0.81.This previously undescribed set of RBBB-associated early-systolic regional motion features (delayed apex-ward motion of the RV base, "reverse septal flash", and "basal bulge") is strongly suggestive of RBBB when present, particularly in the 4-chamber view. Although here evaluated with CMR, it is also likely to be associated with RBBB when seen with other cardiac imaging modalities.

Neurogenesis occurs in the adult brain in the hippocampal dentate gyrus, an area that contains neurons which are vulnerable to insults and injury, such as severe seizures. Previous studies showed that increasing adult neurogenesis reduced neuronal damage after these seizures. Because the damage typically is followed by chronic life-long seizures (epilepsy), we asked if increasing adult-born neurons would prevent epilepsy. Adult-born neurons were selectively increased by deleting the pro-apoptotic gene Bax from Nestin-expressing progenitors. Tamoxifen was administered at 6 weeks of age to conditionally delete Bax in Nestin-CreER^T2

BACKGROUND:Major depressive disorder (MDD) is one of the most prevalent and disabling illnesses worldwide. Treatment of MDD typically relies on trial-and-error to find an effective approach. Identifying early response-related biomarkers that predict response to antidepressants would help clinicians to decide, as early as possible, whether a particular treatment might be suitable for a given patient. METHODS:Data were from the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial. A whole-brain, voxel-wise, mixed-effects model was applied to identify early-treatment cerebral blood flow (CBF) changes as biomarkers of treatment response. We examined changes in CBF measured with arterial spin labeling 1-week after initiating double-masked sertraline/placebo. We tested whether these early 1-week scans could be used to predict response observed after 8-weeks of treatment. RESULTS:Response to 8-week placebo treatment was associated with increased cerebral perfusion in temporal cortex and reduced cerebral perfusion in postcentral region captured at 1-week of treatment. Additionally, CBF response in these brain regions was significantly correlated with improvement in Hamilton Depression Rating Scale score in the placebo group. No significant associations were found for selective serotonin reuptake inhibitor treatment. CONCLUSIONS:We conclude that early CBF responses to placebo administration in multiple brain regions represent candidate neural biomarkers of longer-term antidepressant effects.

OBJECTIVE/UNASSIGNED:The process of resident recruitment is costly, and our surgical residency program expends significant time on the resident selection process while balancing general duties and responsibilities. The aim of our study was to explore the relationship between otolaryngology-head and surgery (OHNS) residents' National Residency Matching Program (NRMP) rank-list position at our institution and their subsequent residency performance. STUDY DESIGN/UNASSIGNED:Retrospective cohort study. SETTING/UNASSIGNED:Single site institution. METHODS/UNASSIGNED:). RESULTS/UNASSIGNED: > .05). CONCLUSION/UNASSIGNED:Our results showed that there were no significant correlations between OHNS rank order and various measures of success in residency training, which aligns with existing literature. Further investigation of this relationship should be conducted to ensure the applicability of our findings.

The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I-II and 47 miRNAs were associated with higher Braak Stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.

INTRODUCTION/BACKGROUND:E-cigarettes (ECs) may be an effective harm reduction strategy for individuals with conditions like chronic obstructive pulmonary disease (COPD), asthma, coronary artery disease (CAD), and peripheral arterial disease (PAD) who smoke combustible cigarettes (CCs). Our aim was to examine how individuals with chronic conditions transition from CCs to ECs and its impact on health outcomes. METHODS:In a pilot randomized controlled trial (RCT), patients with COPD, asthma, CAD/PAD who currently smoke CCs and have not used nicotine replacement therapy (NRT) or ECs in the past 14 days were randomized to receive ECs or combination NRT with behavioral counselling. Disease symptoms, acceptability/satisfaction (TSQM-9) and feasibility, and cigarettes per day (CPD), and/or EC use were collected at baseline, 3-, and 6-months. Descriptive statistics and a linear regression were conducted to explore changes in CPD and chronic condition-specific assessments (CAT, SAQ-7, ACT) that assess COPD, asthma, and CAD/PAD symptom change. RESULTS:At 3-months, the EC group (n=63, mean CPD=9±11) reduced their CPD by 54% vs. 60% in the NRT group (n=58, mean CPD=7±6), p=0.56. At 6-months, 17.5% had switched completely to ECs while 23% quit smoking in the NRT arm. CAT scores showed a significant 6-point reduction in the EC arm (p=0.03). Participants scored an average of 69±27 for EC effectiveness, 87±23 for convenience, and 75±27 for overall satisfaction. CONCLUSIONS:This pilot study suggests that ECs may be a safer alternative for chronic condition patients using CCs and warrants further research on expected smoking cessation/reduction among individuals who use ECs. IMPLICATIONS/CONCLUSIONS:The findings from this pilot RCT hold significant implications with chronic conditions such as COPD, asthma, CAD and PAD who smoke CCs. The observed reduction in cigarettes per day and improvement in respiratory symptoms suggest that switching to ECs appears feasible and acceptable among those with chronic diseases. These results suggest that ECs may offer an alternative for individuals struggling to quit CC smoking through existing pharmacotherapies. This study supports further exploration of switching to ECs as a harm reduction strategy among CC users who have been unsuccessful at quitting by other means.