Digital Commons Network^™

Cdk2 Inhibitor Blu-222 Synergizes With Cdk4/6 Inhibitors In Drug Resistant Breast Cancers Through P21/P27 Induction, Linjie Luo, Yan Wang, Tuyen Bui, Xiaoting Jiang, Mei-Kuang Chen, Xiayu Rao, Sepideh Mohammadhosseinpour, Mi Li, Serena Kim, Rachel Y Kim, Saba Kamaliasl, Carmen W Ulizio, Spyros Tsavachidis, Juliana Navarro-Yepes, Nicole M Kettner, Hannah Wingate, Funda Meric-Bernstam, Kelly K Hunt, Jing Wang, Kerrie Faia, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer, but resistance inevitably develops. In triple-negative breast cancer (TNBC), the efficacy of CDK4/6i remains uncertain. Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2- and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. Mechanistically, BLU-222, alone or with palbociclib, upregulated …

Disease-Specific And Overall Survival For Patients With Lacrimal Gland Adenoid Cystic Carcinoma In Recent Decades, Bita Esmaeli, Zhouxuan Li, Tracy J Lu, Hila Goldberg, Jing Ning, James Matthew Debnam, Steven Jay Frank, Renata Ferrarotto

Faculty, Staff and Student Publications

Purpose: To evaluate the presenting symptoms, and the overall survival (OS) and disease-specific survival (DSS) in patients with lacrimal gland adenoid cystic carcinoma (LGACC).

Methods: This retrospective single-centre cohort study included all consecutive patients with LGACC treated by the primary author from November 1998 through August 2024. Demographic data, presenting symptoms, the histological subtype of LGACC, type of surgical treatment, adjuvant radiotherapy or chemotherapy, T category at presentation and survival data were reviewed. Correlations between histological subtypes, T-category, type of surgery (eye sparing vs orbital exenteration), and DSS and OS were analysed.

Results: 52 patients had a median age of …

The Gene Encoding Ornithine Decarboxylase For Putrescine Biosynthesis Is Essential For The Viability Of Fusobacterium Nucleatum, Shiqi Xu, Bibek G C, Alex Phan, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum is a Gram-negative anaerobe associated with periodontitis and colorectal cancer. It secretes putrescine, a polyamine that promotes biofilm formation by oral co-colonizers and enhances the proliferation of cancer cells. However, the physiological importance of putrescine for F. nucleatum itself remains unexplored. Here, we show that putrescine biosynthesis, mediated by the ornithine decarboxylase gene oda, is essential for F. nucleatum viability. Deletion of oda was only possible when a functional copy was provided in trans, and CRISPR interference of oda expression resulted in complete growth defects. The essentiality of oda was conserved across multiple subspecies. Supplementation with …

Association Between The 2022 Aha/Acc/Hfsa Heart Failure Staging And Cardiovascular And Kidney Outcomes In Patients With Diabetes And Kidney Disease: A Post Hoc Analysis Of The Scored Randomized Controlled Trial, Ayodele Odutayo, Deepak L Bhatt, Vikas S Sridhar, Michael Szarek, Christopher P Cannon, Lawrence A Leiter, Darren K Mcguire, Julia B Lewis, Renato D Lopes, Benjamin M Scirica, Kausik K Ray, Michael J Davies, Phillip Banks, Manon Girard, Subodh Verma, Jacob A Udell, Bertram Pitt, Ph Gabriel Steg, David Z I Cherney

Faculty, Staff and Student Publications

Background: The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America heart failure (HF) classification incorporates cardiac biomarkers to identify early risk of HF. The HF stages may also guide the prognosis and management of cardiovascular and kidney-related events.

Methods: SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) was a randomized trial in diabetes with kidney disease comparing sotagliflozin versus placebo on cardiovascular death, HF hospitalizations, and urgent HF visits. SCORED participants were grouped by HF stage post hoc. Stage A: no …

Microfluidic Capillary Transit Velocity As A Functional Measure For Sickle Cell Disease And In Vitro-Derived Red Blood Cells, Solomon Oshabaheebwa, Yuxuan Du, Christopher L. Wirth, Zoe Sekyonda, Zoe Sekyonda, Bryan L. Benson, Payam Fadaei, Yusang B. Ley, Michael A. Suster, Pedram Mohseni, Umut A. Gurkan

Faculty Scholarship

Emerging therapies in sickle cell disease (SCD) aim to restore healthy red blood cell (RBC) function, but they often yield heterogeneous cellular responses. There are no proven techniques to evaluate restored rheological functionality and heterogeneity in these RBCs. We present a biomimetic microcapillary network, high-speed imaging, and computational algorithms to analyze RBC capillary velocity profiles of the entire sample population at single-cell resolution. Using peripheral RBCs from SCD patients and healthy donors, we showed that RBC capillary transit velocity correlated with cell shape, hydrodynamic adaptability, and elongation index. Healthy RBCs exhibited a velocity distribution skewed toward higher values, whereas RBCs …

From Evaluation To Elevation: Standardized Letter Of Evaluation Domains Tied To Future Emergency Medicine Chief Residents, Abagayle Bierowski, Zaid Tayyem, Casey Morrone, Carlos Rodriguez, Chaiya Laoteppitaks, Peter Tomaselli, Dimitrios Papanagnou, Xiao Chi Zhang

Department of Emergency Medicine Faculty Papers

INTRODUCTION: The Standardized Letter of Evaluation (SLOE) is a core component of emergency medicine (EM) residency applications, designed to assess clinical performance, professionalism, and leadership potential. While its utility in selecting residency candidates is well established, its association with future leadership roles, such as chief resident, remains unclear. Identifying early indicators of leadership potential could inform both recruitment and resident development efforts. In this study we aimed to evaluate whether medical students' SLOEs are associated with subsequent selection as chief residents, offering insight into the SLOE's potential to forecast future leadership within EM.

METHODS: We conducted a retrospective review of …

Maturity-Onset Diabetes Of The Young (Mody) In A Racially/Ethnically Diverse Pediatric Population, Shilpi Relan, Guido Alarcon, Danielle Guffey, Charles G Minard, Mary E Fang, Kelly Timmons, Rona Y Sonabend, Mustafa Tosur, Maria J Redondo, Jennifer E Posey

Faculty, Staff and Students Publications

Context: Current practice guidelines recommend considering a diagnosis of maturity-onset diabetes of the young (MODY) in patients with diabetes with an affected parent but without typical features of type 1 or type 2 diabetes.

Objective: To test if these criteria apply to a real-world cohort of racially/ethnically diverse children with diabetes.

Methods: We performed a retrospective case review of electronic medical records of youth diagnosed with MODY in a large academic pediatric hospital in Southwestern United States. Cases were ascertained based on the identification of a molecular diagnosis of MODY.

Results: We studied 50 genetically confirmed cases of MODY: 60% …

What Needs To Be Standardized For Reliable, Reproducible, And Robust Tractography?, Jon Haitz Legarreta, Simona Schiavi, Wei Tang, Garrett Banks, Matthew Cieslak, Kurt Schilling, Alberto De Luca, Jacques-Donald Tournier, John Kruper, Francois Rheault, Stamatios N Sotiropoulos, Franco Pestilli, Jelle Veraart, Joseph Yuan-Mou Yang, Maxime Descoteaux, Sarah Heilbronner, Ariel Rokem

Faculty, Staff and Students Publications

Tractography is a key component of efforts to map brain connectivity. As a rapidly evolving field of neuroscience, current tractography methods are diverse, often varying across research laboratories and different software pipelines. Therefore, it suffers from a lack of standardization, leading to inconsistencies in results, which can limit reproducibility and affect the robustness needed for research and clinical applications of these methods. Variability in data acquisition procedures, inconsistencies in spatial referencing schemes and implementations, and anatomical heterogeneity-at the individual level, across the lifespan, and across species-hinder comparative analyses. Additionally, the lack of consensus on best practices complicates the development of …

Low Intensity Vibration With Zoledronate Reduces Musculoskeletal Weakness And Adiposity In Estrogen Deprived Female Mice, Gabriel M Pagnotti, Trupti Trivedi, Laura E Wright, Sutha K John, Sreemala Murthy, Ryan R Pattyn, Monte S Willis, Yun She, Sukanya Suresh, Aji F Touray, William R Thompson, Clinton T Rubin, Khalid S Mohammad, Theresa A Guise

Faculty, Staff and Student Publications

Aromatase inhibitors are widely used in the treatment of hormone-sensitive breast cancer, but their suppression of estrogen production accelerates bone loss, increases fracture risk, and negatively impacts muscle and fat metabolism. Here, we demonstrate that daily low intensity vibration, serving as a non-drug mimetic for exercise, protects musculoskeletal health in skeletally immature, female mice under complete estrogen deprivation. Subsequent improvements in vertebral bone density are paralleled by greater and leaner skeletal muscle mass and function alongside reduced fat accretion and circulating metabolites. In mature, estrogen deprived mice, vibration enhances weekly bisphosphonate treatment, improving bone density, cortical thickness, and mechanical resistance …

The Evolution Of Public Health Statistical Modeling Approaches And How To Advance Their Incorporation Into Modern Arboviral Surveillance, Maggie Mccarter, Stella C W Self, Alex Ewing, Mufaro Kanyangarara, Sarah M Gunter, Melissa S Nolan

Faculty, Staff and Students Publications

Statistical modeling of infectious disease transmission patterns has been in existence since the mid-1700s, evolving in their utility as the scientific and technological revolutions progressed. Despite the expansion of emerging mathematical and statistical methodologies over the past 250 yr, their usage has largely remained restricted to academic settings. This forum article will discuss the evolution of disease modeling techniques, the most common types of models in use today, and recommendations on how key archetypes can be incorporated into future public health practice. With the recent global impetus to predict and forecast novel pathogens, this article raises the question: Why are …

The Use Of Artificial Intelligence In Decreasing Vaccine Skepticism And Hesitancy, Nathaniel Wolf, Nhan Nguyen, Rojelio Mejia

Faculty, Staff and Students Publications

Purpose of review: Recent advances in artificial intelligence (AI) coincide with decreases in confidence in vaccines. This review examines studies that analyze and mitigate vaccine skepticism by implementing artificial intelligence strategies in various ways.

Recent findings: Studies have explored public attitudes towards vaccines using AI to analyze language in social media postings and interactions, scrutinize AI responses to vaccine-related queries, and attempt to use AI to directly influence vaccine hesitancy. Findings show that AI can be effective in addressing vaccine hesitancy in various ways, including, but not limited to, directly interacting with vaccine-hesitant groups, identifying reasons for vaccine hesitancy, and …

B Lymphocytes Impede Tregs To Erode Islet Tolerance In Type 1 Diabetes, Christopher S Wilson, Blair T Stocks, Alexander C Falk, Daniel J Moore

Faculty, Staff and Students Publications

B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and …

Simulated Complex Cells Contribute To Object Recognition Through Representational Untangling, Mitchell B Slapik, Harel Z Shouval

Faculty, Staff and Student Publications

The visual system performs a remarkable feat: it takes complex retinal activation patterns and decodes them for object recognition. This operation, termed "representational untangling," organizes neural representations by clustering similar objects together while separating different categories of objects. While representational untangling is usually associated with higher-order visual areas like the inferior temporal cortex, it remains unclear how the early visual system contributes to this process-whether through highly selective neurons or high-dimensional population codes. This article investigates how a computational model of early vision contributes to representational untangling. Using a computational visual hierarchy and two different data sets consisting of numerals …

Losartan-Induced Angioedema: A Case Report And Review Of Literature, Leila C. Tou, Audrey Nourse, Rachel Cox, Spencer Stanford

Journal of Community Hospital Internal Medicine Perspectives

Angiotensin receptor blockers (ARBs) are frequently prescribed as alternatives to angiotensin-converting enzyme inhibitors (ACEIs), particularly in patients who experience ACEI-induced adverse effects including cough. Although ARBs are associated with a lower incidence of angioedema, rare cases have been reported in patients without prior ACEI exposure. Here, we describe a 58-year-old Black male who developed lip and facial swelling six months after starting losartan. His symptoms did not improve with antihistamines or corticosteroids but resolved after discontinuation of losartan, which was replaced with amlodipine without recurrence. This case emphasizes the need for clinician awareness of ARB-induced angioedema and the importance of …

Accuracy Of Frozen Section For Hpv-Associated Squamous Cell Carcinoma Of Unknown Primary, Sindhura Sridhar, Annie Moroco, Shravan Gowrishankar, Mitra Mehrad, Kim Ely, James Lewis, Madalina Tuluc, Stacey Gargano, Melanie Hicks, Kyle Mannion, Arielle Thal, Adam Luginbuhl, Joseph Curry, David Cognetti, Michael Topf

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

INTRODUCTION: Current guidelines for the management of metastatic squamous cell carcinoma of unknown primary (SCCUP) recommend submission of suspicious primary sites for frozen section analysis (FSA). This study aims to investigate the diagnostic accuracy of FSA for identification of HPV-associated SCCUP.

METHODS: A retrospective cohort study of patients with biopsy-proven p16-positive SCCUP who underwent diagnostic operation at two tertiary care institutions was performed. Sensitivity, specificity, PPV, and NPV of diagnostic FSA were assessed.

RESULTS: 77 patients were included in analysis. 66 patients underwent definitive TORS (diagnostic TORS operation with subsequent neck dissection after identification of the occult primary tumor), 7 …

Successful Bacteriophage Treatment Of A Recalcitrant Intra-Abdominal Infection Caused By Multi-Drug-Resistant Pseudomonas Aeruginosa In A 2-Year-Old Child, Sanchi Malhotra, Keiko C Salazar, Neema Pithia, Ishminder Kaur, Kristina Adachi, Nanda Ramachandar, Austin L Terwilliger, Anthony Maresso, Robert S Venick, Suzanne V Mcdiarmid, John S Bradley

Faculty, Staff and Students Publications

Antimicrobial resistance is life-threatening to complex pediatric patients who receive multiple courses of broad-spectrum antibiotics. Bacteriophages offer a safe treatment alternative when our antibiotic armamentarium is no longer sufficient. We describe successful use of bacteriophage therapy on a patient with a recalcitrant Pseudomonas aeruginosa infection after receiving a multi-organ transplant.

Radionuclide-Stimulated Dynamic Therapy Induces Complementary Immunogenic Necroptosis And Apoptosis Cancer Cell Death Pathways, Christopher Egbulefu, Kvar Black, Xinming Su, Partha Karmakar, Lemoyne Habimana-Griffin, Gail Sudlow, Julie Prior, Ezugo Onejeme, Alex Zheleznyak, Baogang Xu, Yalin Xu, Alison Esser, Matthew Mixdorf, Evan Moss, Brad Manion, Cody Hongsermeier, Nisha Gamadia, Nicole Blasi, Luke Stallings, Chidube Alagbaoso, Nathan Reed, Matthew M Gubin, Chieh-Yu Lin, Robert Schreiber, Katherine Weilbaecher, Samuel Achilefu

Faculty, Staff and Student Publications

Radionuclide-stimulated dynamic therapy (RaST) utilizes Cerenkov-radiating radiopharmaceuticals to activate light-sensitive drugs and materials, generating reactive oxygen species (ROS) that inhibit cancer progression. However, the underlying cell death mechanisms are not fully understood. Using ROS-regenerative nanophotosensitizers coated with a tumor-targeting transferrin-titanocene complex and radiolabeled 2-fluorodeoxyglucose, we found that RaST induced apoptosis and necroptosis, characterized by the activation of RIPK-1, RIPK-3, nuclear factor kappa B, and mixed lineage kinase domain-like pseudokinase, leading to membrane permeabilization, cytokine release, and the expression of immunogenic damage-associated molecular patterns. In immune-deficient breast tumor-bearing mice with adequate stroma and growth factors, RaST did not prevent tumor growth …

Comprehensive Metabolic Profiling Across Five Lifespan Stages In Murine Hippocampus And Cortex Reveals Sex-Related Variation In Age-Related Cognitive Decline, Xi Long, Wuping Liu, Changhan Chen, Qi Guo, Yidan Wang, Fang Yu, Yujin Zhang, Rodney E Kellems, Yang Xia

Faculty, Staff and Student Publications

This study employs Barnes maze behavioral assessments, untargeted liquid chromatography-mass spectrometry metabolomics, and 13C6-glucose isotopic tracing to systematically investigate cognitive function and metabolic profiles in hippocampal and cortical tissues of male and female mice across five distinct age-ranges. Behavioral analyses reveal significant cognitive decline in both sexes by 16-months-of-age, with females exhibiting more severe impairment by 23-months, demonstrating a sex-related variation. 13C6-glucose tracing analyses reveals that glucose is rapidly and preferentially metabolized toward the Tricarboxylic acid cycle over glycolysis and the pentose phosphate pathway (PPP), with metabolism rates increasing from juvenility to meet developmental demands and maintaining homeostasis into pre-elderly. …

Premature Aging In Serious Mental Illness, Breno S Diniz, Gabriel R Fries, Chia-Ling Kuo, Ming Xu, Eric J Lenze

Faculty, Staff and Student Publications

Serious mental illnesses (SMIs), including major depressive disorder, bipolar disorder, and schizophrenia, have long been linked to cognitive decline, multiple chronic medical conditions, and premature mortality. These factors significantly contribute to the severe disability seen in SMIs, extending beyond the severity of psychopathology and indicating a premature aging phenotype associated with these conditions. The mechanisms that underlie the relationship between SMIs and the premature aging phenotype are not well understood, but recent evidence suggests that individuals with SMIs may exhibit accelerated biological aging. In this review, we present a comprehensive analysis of the current literature, demonstrating the potential association of …

Foxo1 Inhibition And Fadd Knockdown Have Opposing Effects On Anticancer Drug-Induced Cytotoxicity And P21 Expression In Osteosarcoma Cells, Danielle Walker, Antanay Hall, Alexis Bonwell, Nancy Gordon, Danielle Robinson, Mario G Hollomon

Faculty, Staff and Student Publications

Forkhead box class O1 (FOXO1) and fas-associated death domain (FADD) regulate cell death pathways and homeostatic processes such as cell cycle progression and apoptosis. FADD phosphorylation promotes nuclear localization of FOXO1, and FOXO1 regulates FADD expression. Therefore, it is plausible that FOXO1 and FADD have synergistic or antagonistic effects on cell cycle regulation and the response to anticancer drug treatment in cancer cells. In the present study, we report that AS1842856-mediated inhibition of FOXO1 reverses anticancer drug-induced cytotoxicity, while FADD knockdown increases anticancer drug-induced cytotoxicity in osteosarcoma (OS). Reversed anticancer drug-induced cytotoxicity was accompanied by G2/M cell cycle arrest and …

Institutional Practices Drive Antibiotic Variability In Neonatal Intensive Care Units: Baseline Evidence To Inform National Stewardship Interventions In Oman, Abdullah Alqayoudhi, Manoj Malviya, Sathiya Murthi, Mohammed Rasik Nv, Adil Said Al-Wahaibi, Raya Al-Habsi, Said Al-Balushi, Talal Alwardi, Agha Hatif Shamsi, Halah Bait Raidan, Aamera Al-Majrafi, Preethi Kiran, Eyad Hani Abu Abu Alhaijaa, Kawther Al Amri, Khalfan Al Abdali, Mohammed S. Al Reesi, Nasser Al-Shafouri, Amal Al-Jabri, Sachin Shah, Said Al-Kindi, Zubair H. Aghai, Mohammed Al-Yahmadi, Amal Al-Maani

Department of Pediatrics Faculty Papers

Background: Antibiotic overuse in Neonatal Intensive Care Units (NICUs) is a major contributor to antimicrobial resistance and adverse neonatal outcomes. This study aims to evaluate baseline antibiotic utilization (AU), identify factors influencing variability, and assess the impact of neonatal characteristics and sepsis incidence. Methods: A multicenter retrospective analysis examined AU in seven NICUs from 2019 to 2023, involving 25,532 neonatal admissions during national antibiotic stewardship program implementation. Data encompassed neonatal clinical parameters, sepsis incidence, and AU metrics, including days of therapy (DOT) per 1000 patient-days. Statistical analyses included correlation assessments and multivariate regression to identify determinants of antibiotic use. Results: …

Associations Of Arsenic Exposure And Folate In Maternal Leukocyte Dna Methylation: A Case-Control Study Of Mothers With Spina-Bifida Affected Children, Amy M Inkster, Anne K Bozack, Bernardo Lemos, Tabitha Lumour-Mensah, Sudipta Kumar Mukherjee, Shekh Muhammad Ekramullah, D M Arman, Joynul Islam, Xingyan Wang, Liming Liang, Richard H Finnell, Maitreyi Mazumdar, Andres Cardenas

Faculty, Staff and Students Publications

No abstract provided.

Rare Heterozygous De Novo Variants In Rapgef2 Are Associated With A Neurodevelopmental Disorder, Ali H Bereshneh, Kirkland A Wilson, Xueyang Pan, Shabab B Hannan, Megan A Cooper, Jullianne Diaz, Eyby Leon, Tiana M Moses, Mahshid S Azamian, Daryl A Scott, Ping Yee Billie Au, Juan Pablo Appendino, Ingrid E Scheffer, Antony Kaspi, Melanie Bahlo, Michael S Hildebrand, Angela T Morgan, Ekanem Ekure, Joshua M Shulman, Friedhelm Hildebrandt, Jennifer E Posey, Paul Kruszka, Eric Vilain, Shinya Yamamoto, Oguz Kanca, Seth Berger, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Purpose: RAPGEF2 encodes a guanine nucleotide exchange factor (GEF) that activates small GTPases and has not been linked to a Mendelian disorder. RAPGEF2 is highly intolerant to loss-of-function variants. We report 5 de novo heterozygous variants in RAPGEF2 in unrelated individuals with developmental delay, attention deficit hyperactivity disorder, epilepsy, dysmorphic features, or other manifestations. We used a Drosophila model to assess the functional impact of the identified human variants.

Methods: We generated a Kozak-GAL4 null allele of the Drosophila ortholog of RAPGEF2, PDZ-GEF, and used the allele to determine the gene expression pattern as well as the loss-of-function phenotypes. We …

Single-Cell Rna Sequencing Suggests Different Progenitor Lineages Between Idh Mutant And Idhwt Glioma, Iyad Alnahhas, Allison Kayne, Mehak Khan, Wenyin Shi

Department of Neurology Faculty Papers

Introduction Single-cell RNA sequencing has elucidated the heterogeneity in cancer. Single-cell glioblastoma (GBM) analyses have also proposed the resemblance of GBM cells to radial glia and outer radial glia (oRG) supporting the hypothesis that remnants of developmental tissue get reactivated in cancer. A recent study isolated neural progenitor cells (NPCs) from developing fetal human brain (gestational week 17-19) and classified NPCs based on their expression of THY1 (CD90), CD24 and EGFR. Ventricular radial glia are THY1⁻CD24⁻EGFR⁺ whereas oRG are THY1⁻CD24⁻EGFR⁻. Early neuron precursors are CD24⁺THY1⁻EGFR …

Rnai-Based Screen For Pigmentation In Drosophila Melanogaster Reveals Regulators Of Brain Dopamine And Sleep, Samantha L Deal, Danqing Bei, Shelley B Gibson, Harim Delgado-Seo, Yoko Fujita, Kyla Wilwayco, Elaine S Seto, Amita Sehgal, Shinya Yamamoto

Faculty, Staff and Students Publications

The dopaminergic system has a large role in behavior and neurological disease, and understanding dopamine level regulation in vivo is critical. To identify dopamine regulators, we utilized Drosophila melanogaster cuticle pigmentation, where dopamine is a precursor to melanin. We measured dopamine from known pigmentation mutants (e.g., tan, ebony, black) and performed an RNAi-based screen to identify additional regulators. We found 153 hits, enriched for developmental signaling pathways and mitochondria-associated proteins. From 35 prioritized candidates, 11 affected head dopamine levels. Effects on brain dopamine were mild, even knocking down the rate-limiting synthesis enzyme Tyrosine hydroxylase (TH), suggesting …

Onset And Exacerbation Of Obsessive-Compulsive Disorder In The Perinatal Period, Jack Samuels, Mary Kimmel, Janice Krasnow, Rashelle Musci, Paul S Nestadt, Lauren M Osborne, Eric A Storch, Jonathan S Abramowitz, Gerald Nestadt

Faculty, Staff and Students Publications

Purpose: Obsessive-compulsive disorder (OCD) can emerge during pregnancy and the postpartum and may adversely affect mother and newborn. However, little is known about potential risk factors for the onset of OCD in the perinatal period. Therefore, we investigated the onset of diagnosed DSM-5 OCD in women followed from the second trimester of pregnancy to 6-months postpartum.

Methods: We followed 256 women from the 20-24th week of pregnancy to 6-month postpartum. Participants had psychiatric diagnostic interviews at baseline and 6-month postpartum and completed self-report instruments. We compared women with and without incident OCD on sociodemographic characteristics and clinical features.

Results: Of …

Role Of The Etv5/P38 Signaling Axis In Aggressive Thyroid Cancer Cells, Jerry H Houl, Rozita Bagheri-Yarmand, Muthusamy Kunnimalaiyaan, Paola Miranda Mendez, Joseph L Kidd, Ali Dadbin, Andrea Ruiz-Jurado, Parag A Parekh, Ying C Henderson, Nikhil S Chari, Aatish Thennavan, Reid T Powell, Clifford C Stephan, Xiao Zhao, Anastasios Maniakas, Roza Nurieva, Naifa L Busaidy, Maria E Cabanillas, Ramona Dadu, Mark Zafereo, Jennifer R Wang, Stephen Y Lai, Marie-Claude Hofmann

Faculty, Staff and Student Publications

Patients with poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) face a much poorer prognosis than those with differentiated thyroid cancers. Around 25% of PDTCs and 35% of ATCs carry the BRAFV600E mutation, which constitutively activates the MAPK pathway, a key driver of cell growth. Although combining BRAF and MEK inhibitors can shrink tumors, resistance often develops. The exact cause of this resistance remains unclear. We previously found that in PDTC and ATC cells, the BRAFV600E mutation is strongly linked to the expression of ETV5, a transcription factor downstream of the MAPK pathway. In the current study, we …

Emt-Induced Stem Cell And Mesenchymal Programs Can Be Decoupled Via Cell Division And Esrp1-Dependent Mechanisms, Petra Den Hollander, Maria Castaneda, Suhas V Vasaikar, Joanna Joyce Maddela, Claire Gould, Breanna R Demestichas, Robiya Joseph, Shivangi Agarwal, Abhijeet P Deshmukh, Alvina Zia, Shruti Shah, Tieling Zhou, Geraldine Raja, Paul Allegakoen, Nick A Kuburich, Mika Pietila, Chunxiao Fu, Jeffrey Chang, Chad J Creighton, William F Symmans, Rama Soundararajan, Sendurai A Mani

Faculty, Staff and Student Publications

Epithelial-to-mesenchymal transition (EMT) is known to induce both stemness and mesenchymal properties, and our findings reveal that these two programs can be uncoupled. During EMT, epithelial cells transition from symmetric divisions producing differentiated daughter cells to self-renewing daughter cells. When we block cell division and induce EMT, cells gain mesenchymal properties but not stemness, suggesting the importance of cell division for gaining stemness. We identified ESRP1 as a key regulator of EMT-driven stemness, which get downregulated during EMT in a cell division-dependent manner. Overexpression of ESRP1 prevents the gain of stemness without affecting the mesenchymal program. Only the stemness and …

Loss Of Payload Sensitivity And Other Mechanisms Of Resistance To T-Dxd In Her2-Mutant Nsclc: Implications For Subsequent Responsiveness To Her2 Tkis, Monique B Nilsson, Xiuning Le, Alissa Poteete, Xiaoxing Yu, Junqin He, Qian Huang, Yuji Shibata, Ximeng Liu, Cesar Moran, Ash A Alizadeh, Maximilian Diehn, Heather Wakelee, Diego Almanza, Scott Soltys, Takeshi Sugio, Jurik Mutter, Xiaoman Kang, Rui Wang, Soyeong Jun, Mohammad Shahrokh Esfahani, Hai Tran, Yuanxin Xi, Lingzhi Hong, Xiaofang Huo, Ashwani Kumar, Xiaoyang Ren, Kei Oguchi, Kazuhisa Minamiguchi, Caroline M Weipert, Jing Wang, Ralf Kittler, John V Heymach

Faculty, Staff and Student Publications

Introduction: Effective therapies are needed for patients with NSCLC with HER2-mutant tumors who progress on the HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), a standard-of-care treatment. A greater understanding of mechanisms mediating acquired T-DXd resistance and whether these tumors could benefit from HER2 tyrosine kinase inhibitors (TKIs) is needed.

Methods: Using preclinical models of acquired T-DXd resistance, LentiMutate scanning mutagenesis, and clinical analyses, we investigated mechanisms mediating acquired resistance to T-DXd and assessed the impact of each of these resistance mechanisms on cross-resistance to alternative HER2-targeting approaches.

Results: We determined that acquired resistance to T-DXd could occur through multiple mechanisms including …

Advances In Targeting Her2 Across Cancer Subtypes: A Pan-Tumor Approach, Taiwo Adesoye, Ecaterina E Dumbrava, Kanwal P S Raghav, Aysegul A Sahin, Hui Chen, Sunyoung S Lee, Milind M Javle, Shubham Pant, Omar Alhalabi, Xiuning Le, Vicente Valero, Paula R Pohlmann, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in multiple solid tumors, particularly breast and gastric cancers. Significant advancements have been made in the development of HER2-targeted therapies, including monoclonal antibodies, tyrosine kinase inhibitors, antibody-drug conjugates (ADC), and novel bispecific antibodies. These agents have revolutionized the treatment landscape for HER2-positive metastatic cancers, resulting in improved progression-free and overall survival, and quality of life for patients. Beyond breast and gastric cancers, HER2 expression/amplification has been observed in other solid tumors, such as colorectal, lung, bladder, ovarian, and biliary tract cancers, offering new opportunities for personalized therapy in …