Digital Commons Network^™

Influence Of Pregabalin Maintenance On Cannabis Effects And Related Behaviors In Daily Cannabis Users, Joshua A Lile, Joseph L Alcorn, Lon R Hays, Thomas H Kelly, William W Stoops, Michael J Wesley, Philip M Westgate

Faculty, Staff and Student Publications

No medications are approved for cannabis use disorder (CUD), though a small clinical trial demonstrated that the voltage-dependent calcium channel (VDCC) ligand gabapentin reduced cannabis use in treatment seekers. VDCCs are modulated by cannabinoid (CB) ligands, and there are shared effects between CB agonists and VDCC ligands. This overlapping neuropharmacology and the initial clinical results supported the evaluation of pregabalin, a "next-generation" VDCC ligand, as a CUD medication. Two separate placebo-controlled, double-blind, counterbalanced, within-subjects human laboratory studies tested placebo and 300 (N = 2 females, 11 males; Experiment [EXP] 1) or 450 (N = 3 females, 11 males; …

Cost-Effectiveness Frameworks For Comparing Genome And Exome Sequencing Versus Conventional Diagnostic Pathways: A Scoping Review And Recommended Methods, Bart S Ferket, Zach Baldwin, Priyanka Murali, Akila Pai, Kathleen F Mittendorf, Heidi V Russell, Flavia Chen, Frances L Lynch, Kristen Hassmiller Lich, Lucia A Hindorff, Renate Savich, Anne Slavotinek, Hadley Stevens Smith, Bruce D Gelb, David L Veenstra

Faculty, Staff and Student Publications

PURPOSE: Methodological challenges have limited economic evaluations of genome sequencing (GS) and exome sequencing (ES). Our objective was to develop conceptual frameworks for model-based cost-effectiveness analyses (CEAs) of diagnostic GS/ES.

METHODS: We conducted a scoping review of economic analyses to develop and iterate with experts a set of conceptual CEA frameworks for GS/ES for prenatal testing, early diagnosis in pediatrics, diagnosis of delayed-onset disorders in pediatrics, genetic testing in cancer, screening of newborns, and general population screening.

RESULTS: Reflecting on 57 studies meeting inclusion criteria, we recommend the following considerations for each clinical scenario. For prenatal testing, performing comparative analyses …

Maternal Occupational Exposure To Chemicals And Child Cognitive Function, Jennifer Ish, Elaine Symanski, David Gimeno Ruiz De Porras, Maribel Casas, George L Delclos, Mònica Guxens, Jesús M Ibarluzea, Carmen Iñiguez, Aitana Lertxundi, Marisa Rebagliato, Michael D Swartz, Kristina W Whitworth

Faculty, Staff and Student Publications

BACKGROUND: Limited data exist regarding child neurodevelopment in relation to maternal occupational exposure to endocrine-disrupting chemicals (EDCs).

METHODS: We included 1058 mother-child pairs from the INfancia y Medio Ambiente (INMA) project (2003-2008). Using a job-exposure matrix, exposure probability scores for ten EDC groups were assigned to each mother based on her longest held job during pregnancy. At the child's 5-year visit, the McCarthy Scales of Children's Abilities was administered, yielding the general cognitive index and scales for specific cognitive domains. We analyzed region-specific associations between EDC exposures and each outcome separately using adjusted linear regression and combined region-specific effect estimates …

Preconditioning By Voluntary Wheel Running Attenuates Later Neuropathic Pain Via Nuclear Factor E2-Related Factor 2 Antioxidant Signaling In Rats, Suzanne M Green-Fulgham, Michael E Harland, Jayson B Ball, Jiahe Li, Michael J Lacagnina, Heather D'Angelo, Renee A Dreher, Kendal F Willcox, Sabina A Lorca, Andrew J Kwilasz, Steven F Maier, Linda R Watkins, Peter M Grace

Faculty, Staff and Student Publications

Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases the formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain by supporting redox homeostasis after sciatic nerve injury in male and female rats. We show that 6 weeks of voluntary wheel running suppresses neuropathic pain development induced by chronic constriction injury across both sexes. This attenuation was associated with reduced nitrotyrosine immunoreactivity-a marker for peroxynitrite-at the sciatic nerve injury site. Our data suggest …

Mismatch Repair And Microsatellite Instability Testing For Immune Checkpoint Inhibitor Therapy: Guideline From The College Of American Pathologists In Collaboration With The Association For Molecular Pathology And Fight Colorectal Cancer, Angela N Bartley, Anne M Mills, Eric Konnick, Michael Overman, Christina B Ventura, Lesley Souter, Carol Colasacco, Zsofia K Stadler, Sarah Kerr, Brooke E Howitt, Heather Hampel, Sarah F Adams, Wenora Johnson, Cristina Magi-Galluzzi, Antonia R Sepulveda, Russell R Broaddus

Faculty, Staff and Student Publications

Context.—: The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status.

Objective.—: To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy.

Design.—: The College of American Pathologists convened an expert panel to perform a systematic review …

Targeting The Alk-Cdk9-Tyr19 Kinase Cascade Sensitizes Ovarian And Breast Tumors To Parp Inhibition Via Destabilization Of The P-Tefb Complex, Yu-Yi Chu, Mei-Kuang Chen, Yongkun Wei, Heng-Huan Lee, Weiya Xia, Ying-Nai Wang, Clinton Yam, Jennifer L Hsu, Hung-Ling Wang, Wei-Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao-Chun Wang, Jinsong Liu, Shannon N Westin, Sanghoon Lee, Anil K Sood, Liuqing Yang, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor …

Crucial Nuances In Understanding (Mis)Associations Between The Neonatal Microbiome And Cesarean Delivery, Alexa M Sassin, Grace J Johnson, Alison N Goulding, Kjersti M Aagaard

Faculty, Staff and Students Publications

As rates of Cesarean delivery and common non-communicable disorders (NCDs), such as obesity, metabolic disease, and atopy/asthma, have concomitantly increased in recent decades, investigators have attempted to discern a causal link. One line of research has led to a hypothesis that Cesarean birth disrupts the presumed normal process of colonization of the neonatal microbiome with vaginal microbes, yielding NCDs later in life. However, a direct link between a disrupted microbiota transfer at time of delivery and acute and/or chronic illness in infants born via Cesarean has not been causally established. Microbiota seeding from maternal vaginal or stool sources has been …

Variability In Energy Expenditure Is Much Greater In Males Than Females, Lewis G Halsey, Susan B Racette, Et Al.

2020-Current year OA Pubs

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether …

Identification Of An Early Survival Prognostic Gene Signature For Localized Osteosarcoma Patients, Harry Mackay, Chathura J Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, Cristian Coarfa, Robert A Waterland

Faculty, Staff and Students Publications

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and …

Sex-Specific Epigenetic Development In The Mouse Hypothalamic Arcuate Nucleus Pinpoints Human Genomic Regions Associated With Body Mass Index, Harry Mackay, Chathura J Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, Cristian Coarfa, Robert A Waterland

Duncan NRI Faculty and Staff Publications

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and …

Integration Of Mouse Ovary Morphogenesis With Developmental Dynamics Of The Oviduct, Ovarian Ligaments, And Rete Ovarii, Jennifer Mckey, Dilara N Anbarci, Corey Bunce, Alejandra E Ontiveros, Richard R Behringer, Blanche Capel

Faculty, Staff and Student Publications

Morphogenetic events during the development of the fetal ovary are crucial to the establishment of female fertility. However, the effects of structural rearrangements of the ovary and surrounding reproductive tissues on ovary morphogenesis remain largely uncharacterized. Using tissue clearing and lightsheet microscopy, we found that ovary folding correlated with regionalization into cortex and medulla. Relocation of the oviduct to the ventral aspect of the ovary led to ovary encapsulation, and mutual attachment of the ovary and oviduct to the cranial suspensory ligament likely triggered ovary folding. During this process, the rete ovarii (RO) elaborated into a convoluted tubular structure extending …

Temporal Lobe White Matter Asymmetry And Language Laterality In Epilepsy Patients, Nikolaos Soldatos, Huy Pham, Walid D Fakhouri, Binh Ngo, Panagiotis Lampropoulos, Tiffany Tran, Robin Weltman

Faculty, Staff and Student Publications

(1) Background: Several studies showed a sustained temperature of 47 °C or 50 °C for one minute resulted in vascular stasis and bone resorption with only limited bone regrowth over a 3–4-week healing period. The purpose of the present study was to evaluate the temperature changes (ΔΤ) that occur during the preparation of dental implant osteotomies using MIS® straight drills versus Densah® burs in a clockwise (cutting) drilling protocol. (2) Methods: Two hundred forty (240) osteotomies of two different systems’ drills were prepared at 6 mm depth at 800, 1000, and 1200 revolutions per minute (RPM), in fresh, unembalmed tibiae, …

Contrast-Enhanced Microct Evaluation Of Degeneration Following Partial And Full Width Injuries To The Mouse Lumbar Intervertebral Disc, Remy E Walk, Hong Joo Moon, Simon Y Tang, Munish C Gupta

2020-Current year OA Pubs

A targeted injury to the mouse intervertebral disc (IVD) is often used to recapitulate the degenerative cascade of the human pathology. Since injuries can vary in magnitude and localization, it is critical to examine the effects of different injuries on IVD degeneration. We thus evaluated the degenerative progression resulting from either a partial- or full-width injury to the mouse lumbar IVD using contrast-enhanced micro-computed tomography and histological analyses. A lateral-retroperitoneal surgical approach was used to access the lumbar IVD, and the injuries to the IVD were produced by either incising one side of the annulus fibrosus or puncturing both sides …

Bet Inhibition Induces Vulnerability To Mcl1 Targeting Through Upregulation Of Fatty Acid Synthesis Pathway In Breast Cancer, Gonghong Yan, Augustin Luna, Heping Wang, Behnaz Bozorgui, Xubin Li, Maga Sanchez, Zeynep Dereli, Nermin Kahraman, Goknur Kara, Xiaohua Chen, Caishang Zheng, Daniel Mcgrail, Nidhi Sahni, Yiling Lu, Ozgun Babur, Murat Cokol, Bora Lim, Bulent Ozpolat, Chris Sander, Gordon B Mills, Anil Korkut

Faculty, Staff and Student Publications

Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation …

Untold Story Of Human Cervical Cancers: Hpv-Negative Cervical Cancer, Jae-Eun Lee, Yein Chung, Siyeon Rhee, Tae-Hyung Kim

Pathology Research and Scholarship

Cervical cancer is the fourth most common malignancy in women worldwide. Although infection from human papillomavirus (HPV) has been the leading cause of cervical cancer, HPV-negative cervical cancer accounts for approximately 3-8% of all cases. Previous research studies on cervical cancer have focused on HPV-positive cervical cancer due to its prevalence, resulting in HPV-negative cervical cancer receiving considerably less attention. As a result, HPV-negative cervical cancer is poorly understood. Its etiology remains elusive mainly due to limitations in research methodology such as lack of defined markers and model systems. Moreover, false HPV negativity can arise from inaccurate diagnostic methods, which …

Associations Between Maternal Reports Of Periconceptional Fever From Miscellaneous Causes And Structural Birth Defects, Nithya Lakshmi Mohan Dass, Lorenzo D Botto, Sarah C Tinker, Mark A Canfield, Richard H Finnell, Michael Shayne Gallaway, Syed Shahrukh Hashmi, Adrienne T Hoyt, Wendy N Nembhard, Dorothy K Waller, National Birth Defects Prevention Study

Faculty, Staff and Students Publications

BACKGROUND: Associations between birth defects and fevers attributed to colds, influenza, and urinary tract infections (UTIs) have been observed in previous studies. Our aim was to study associations between birth defects and fevers attributed to other causes.

METHODS: We analyzed data from 34,862 participants in the National Birth Defects Prevention Study, a multistate case-control study of major structural birth defects. Using multivariable logistic regression, we assessed the association between maternal report of fever during early pregnancy due to causes other than colds, influenza, or UTI and 36 categories of birth defects.

RESULTS: Maternal reports of fever due to other causes …

Integrated Imaging And Molecular Analysis To Decipher Tumor Microenvironment In The Era Of Immunotherapy, Jia Wu, Aaron T Mayer, Ruijiang Li

Faculty, Staff and Student Publications

Radiological imaging is an integral component of cancer care, including diagnosis, staging, and treatment response monitoring. It contains rich information about tumor phenotypes that are governed not only by cancer cellintrinsic biological processes but also by the tumor microenvironment, such as the composition and function of tumor-infiltrating immune cells. By analyzing the radiological scans using a quantitative radiomics approach, robust relations between specific imaging and molecular phenotypes can be established. Indeed, a number of studies have demonstrated the feasibility of radiogenomics for predicting intrinsic molecular subtypes and gene expression signatures in breast cancer based on MRI. In parallel, promising results …

The Insulin Receptor Regulates The Persistence Of Mechanical Nociceptive Sensitization In Flies And Mice, Tatiana V Karpinets, Xiaogang Wu, Travis Solley, Molly B El Alam, Travis T Sims, Kyoko Yoshida-Court, Erica Lynn, Mustapha Ahmed-Kaddar, Greyson Biegert, Jingyan Yue, Xingzhi Song, Huandong Sun, Joseph F Petrosino, Melissa P Mezzari, Pablo Okhuysen, Patricia J Eifel, Anuja Jhingran, Lilie L Lin, Kathleen M Schmeler, Lois Ramondetta, Nadim Ajami, Robert R Jenq, Andrew Futreal, Jianhua Zhang, Ann H Klopp, Lauren E Colbert

Faculty, Staff and Student Publications

Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi …

Cannabis Use And Sinonasal Symptoms In Us Adults, Francis Reyes Orozco, Matthew Lin, Kevin Hur

Faculty, Staff and Student Publications

IMPORTANCE: Cannabis is the most commonly used illicit substance in the US and worldwide. Understanding the association between cannabis use and sinonasal symptoms may help clinicians and patients better understand the symptomatology associated with cannabis use.

OBJECTIVE: To assess the association between frequency of cannabis use and presence of sinonasal symptoms in a nationally representative sample of US adults.

DESIGN, SETTING, AND PARTICIPANTS: This population-based, retrospective cross-sectional study included adults aged 20 to 69 years who had completed data on sinonasal symptoms and substance use for the 2013 to 2014 National Health and Nutrition Examination Survey. The data were analyzed …

Revisiting Sex Differences In The Acquisition And Extinction Of Threat Conditioning In Humans, Zhenfu Wen, Jamie Fried, Edward F Pace-Schott, Sara W Lazar, Mohammed R Milad

Faculty, Staff and Student Publications

Findings pertaining to sex differences in the acquisition and extinction of threat conditioning, a paradigm widely used to study emotional homeostasis, remain inconsistent, particularly in humans. This inconsistency is likely due to multiple factors, one of which is sample size. Here, we pooled functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) data from multiple studies in healthy humans to examine sex differences during threat conditioning, extinction learning, and extinction memory recall. We observed increased functional activation in males, relative to females, in multiple parietal and frontal (medial and lateral) cortical regions during acquisition of threat conditioning and extinction …

Trends In The Diversity Of Pediatric Faculty: 2000 To 2020, Emma A Omoruyi, Colin J Orr, Greg Russell, Kimberly Montez

Faculty, Staff and Student Publications

OBJECTIVE: Academic medicine diversity is important for addressing health disparities and training the next generation. A recent study highlighted the lack of diversity among pediatric trainees over time. However, trends in US pediatric faculty diversity have not been clearly illuminated. The aim of this study is to evaluate pediatric faculty diversity trends and compare racial/ethnic representation between pediatric faculty and the US population.

METHODS: Repeat cross-sectional study of the Association of American Medical Colleges Faculty Roster of pediatric faculty from 2000 to 2020. Trends in sex, race, ethnicity, and rank were compared with the Cochran-Armitage test. Data on faculty race/ethnicity …

Mrnip Interacts With Sex Body Chromatin To Support Meiotic Progression, Spermatogenesis, And Male Fertility In Mice, Samina Kazi, Julio M Castañeda, Audrey Savolainen, Yiding Xu, Ning Liu, Huanyu Qiao, Ramiro Ramirez-Solis, Kaori Nozawa, Zhifeng Yu, Martin M Matzuk, Renata Prunskaite-Hyyryläinen

Faculty, Staff and Students Publications

Meiosis has a principal role in sexual reproduction to generate haploid gametes in both sexes. During meiosis, the cell nucleus hosts a dynamic environment where some genes are transcriptionally activated, and some are inactivated at the same time. This becomes possible through subnuclear compartmentalization. The sex body, sequestering X and Y chromosomes during male meiosis and creating an environment for the meiotic sex chromosome inactivation (MSCI) is one of the best known and studied subnuclear compartments. Herein, we show that MRNIP forms droplet‐like accumulations that fuse together to create a distinct subnuclear compartment that partially overlaps with the sex body …

A Rare Case Of Vulvar Discharge Associated With Exogenous Oestrogen Exposure In A Spayed Weimaraner Bitch, Francesca Ivaldi, Camille Ogdon, Firdous A Khan

Faculty, Staff and Students Publications

OBJECTIVE: This report documents a rare case of vulvar discharge associated with exogenous oestrogen exposure in a large-breed dog.

CASE DESCRIPTION: A 4-year-old spayed Weimaraner bitch was presented for evaluation of inappetence and intermittent sanguineous vulvar discharge. Physical examination, vaginal cytology, haematological, and ultrasonographic findings were indicative of a uterine stump pyometra. A celiotomy was performed, and the uterine stump appeared grossly cystic and thickened. Histopathological evaluation of the removed uterine stump and ovarian pedicles revealed cystic endometrial hyperplasia and no ovarian tissue. Fifteen days after surgery, the patient presented again with a sanguineous vulvar discharge. Vaginal cytology revealed predominantly …

Exposure Contrasts Of Pregnant Women During The Household Air Pollution Intervention Network Randomized Controlled Trial, Michael Johnson, Lindsay J Underhill, Et Al.

2020-Current year OA Pubs

BACKGROUND: Exposure to

OBJECTIVES: This paper reports exposure reductions achieved by a liquified petroleum gas (LPG) stove and fuel intervention for pregnant mothers in the Household Air Pollution Intervention Network (HAPIN) randomized controlled trial.

METHODS: The HAPIN trial included 3,195 households primarily using biomass for cooking in Guatemala, India, Peru, and Rwanda. Twenty-four-hour exposures to

RESULTS: Median postrandomization exposures of particulate matter (PM) with aerodynamic diameter

DISCUSSION: Postintervention

Spatiotemporal Correlation Analysis Of Hydraulic Fracturing And Stroke In The United States, Chuanbo Hu, Bin Liu, Shuo Wang, Zhenduo Zhu, Amelia Adcock, James Simpkins, Xin Li

2020-Current year OA Pubs

Hydraulic fracturing or fracking has led to a rapid growth of oil and gas production in the United States, but the impact of fracking on public health is an important but underresearched topic. We designed a methodology to study spatiotemporal correlations between the risk of fracking and stroke mortality. An annualized loss expectancy (ALE) model is applied to quantify the risk of fracking. The geographically and temporally weighted regression (GTWR) model is used to analyze spatiotemporal correlations of stroke mortality, fracking ALE, and nine other socioeconomic- and health-related factors. The analysis shows that fracking ALE is moderately correlated with stroke …

Heritable Vaginal Bacteria Influence Immune Tolerance And Relate To Early-Life Markers Of Allergic Sensitization In Infancy, Kathryn E. Mccauley, Elze Rackaityte, Brandon Lamere, Douglas W. Fadrosh, Kei E. Fujimura, Ariane R. Panzer, Din L. Lin, Kole V. Lynch, Joanna Halkias, Ventura F. Mendoza, Trevor D. Burt, Casper Bendixsen, Kathrine Barnes, Haejin Kim, Kyra Jones, Dennis R. Ownby, Christine C. Johnson, Christine M. Seroogy, James E. Gern, Homer A. Boushey, Susan V. Lynch

Allergy & Immunology Articles

Maternal asthma status, prenatal exposures, and infant gut microbiota perturbation are associated with heightened risk of atopy and asthma risk in childhood, observations hypothetically linked by intergenerational microbial transmission. Using maternal vaginal (n = 184) and paired infant stool (n = 172) samples, we identify four compositionally and functionally distinct Lactobacillus-dominated vaginal microbiota clusters (VCs) that relate to prenatal maternal health and exposures and infant serum immunoglobulin E (IgE) status at 1 year. Variance in bacteria shared between mother and infant pairs relate to VCs, maternal allergy/asthma status, and infant IgE levels. Heritable bacterial gene pathways associated with infant IgE …

Poziotinib Inhibits Her2-Mutant-Driven Therapeutic Resistance And Multiorgan Metastasis In Breast Cancer, Rashi Kalra, Ching Hui Chen, Junkai Wang, Ahmad Bin Salam, Lacey E Dobrolecki, Alaina Lewis, Christina Sallas, Clayton C Yates, Carolina Gutierrez, Balasubramanyam Karanam, Meenakshi Anurag, Bora Lim, Matthew J Ellis, Shyam M Kavuri

Faculty, Staff and Student Publications

The pan-HER tyrosine kinase inhibitor (TKI) neratinib is therapeutically active against metastatic breast cancers harboring activating HER2 mutations, but responses are variable and often not durable. Here we demonstrate that recurrent HER2 mutations have differential effects on endocrine therapy responsiveness, metastasis, and pan-HER TKI therapeutic sensitivity. The prevalence and prognostic significance may also depend on whether the HER2 mutant has arisen in the context of lobular versus ductal histology. The most highly recurrent HER2 mutant, L755S, was particularly resistant to neratinib but sensitive to the pan-HER TKI poziotinib, alone or in combination with fulvestrant. Poziotinib reduced tumor growth, diminished multiorgan …

Comparing Outcomes For Community-Acquired Pneumonia Between Females And Males: Results From The University Of Louisville Pneumonia Study, Pavani Nathala, Simrat Sarai, Vidyulata Salunkhe, Mahder A. Tella, Stephen P. Furmanek, Forest W. Arnold

The University of Louisville Journal of Respiratory Infections

Introduction: Male sex is currently considered to be a risk factor for worsened community-acquired pneumonia (CAP) outcomes compared to female sex; hence, female sex equates to a lower score on the Pneumonia Severity Index. There is no recent update on sex-based outcomes of patients with CAP. The objective of this study was to compare the outcomes of CAP between females and males.

Methods: This was a secondary analysis of the University of Louisville Pneumonia Study database. It was a prospective population-based cohort study of all hospitalized adults with CAP who were residents of Jefferson County in the city of Louisville, …

The Value Of In Vivo Reflectance Confocal Microscopy As An Assessment Tool In Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study, Sabrina R Ramnarine, Patrick M Dougherty, Roman Rolke, Linda J Williams, Christi Alessi-Fox, Andrew J Coleman, Caterina Longo, Lesley A Colvin, Marie T Fallon

Faculty, Staff and Student Publications

Background: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN.

Patients and methods: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical …

Gonadal Sex Patterns P21-Induced Cellular Senescence In Mouse And Human Glioblastoma, Lauren Broestl, Nicole M Warrington, Lucia Grandison, Tamara Abou-Antoun, Olivia Tung, Saraswati Shenoy, Miranda M Tallman, Gina Rhee, Wei Yang, Jasmin Sponagel, Lihua Yang, Najla Kfoury-Beaumont, Cameron M Hill, Sulaiman A Qanni, Diane D Mao, Albert H Kim, Sheila A Stewart, Monica Venere, Jingqin Luo, Joshua B Rubin

2020-Current year OA Pubs

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in wildtype and transformed murine …