Medicine and Health Sciences Commons^™

Health Plan-Based Atherosclerosis Imaging For Members With Diabetics: Utilization And Impact On Subsequent Episodes Of Care., Subha V Raman, Alexander V Smolensky, Juhi Ramchandani, Purva Patel, Xin He, Tarek Aridi, John Salvas, Wasi Khatri, Jack Tiahnybik, Nihanth Damera, Keyur Vora, Rohan Dharmakumar

Heart and Vascular Articles

BACKGROUND: Quantitative coronary CT angiography plaque analysis (QCCTA) is a novel tool for atherosclerosis detection.

OBJECTIVES: The authors examined utilization of a health plan offering of QCCTA to diabetic members and the impact of utilization on health plan costs.

METHODS: Diabetic health plan members ≥40 years without prior myocardial infarction were offered QCCTA as a pilot benefit. Benefit utilizers were compared to eligible nonutilizers for incident cardiovascular episodes of care post-notification of eligibility.

RESULTS: Over 14 months, 2,064 of 38,079 health plan members were identified as eligible. Utilizers (19.1%) were predominantly White (76.4%) and female (72.6%) residing in communities with …

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 …

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% …

Iatrogenic Ptosis Mimicking Cranial Nerve Iii Palsy Following Cosmetic Botox Injection: A Case Report, Moath Alshanqity, Lujain Filimban, Sadaqah Wazzan

Saudi Toxicology Journal

We present a 40-year-old female who developed iatrogenic ptosis mimicking cranial nerve III palsy after undergoing a cosmetic treatment to treat periorbital hyperpigmentation. Within 48 hours of receiving what was believed to be tranexamic acid (TXA) injections, the patient developed isolated left ptosis and generalized headache. Stroke, cerebral venous thrombosis (CVT), subarachnoid hemorrhage (SAH), and cranial nerve injury were among the differential diagnoses upon presentation. No insult to the central nervous system was found during the initial workup, which included neuroimaging. Although TXA was initially suspected due to its prothrombotic potential and the patient’s history of pulmonary embolism, it has …

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 …

Genomics Define Malignant Transformation In Myeloma Precursor Conditions, Francesco Maura, P Leif Bergsagel, Bachisio Ziccheddu, Shaji Kumar, Kylee Maclachlan, Andriy Derkach, Juan-Jose Garces, Ross Firestone, Esteban Braggio, Yan Asmann, Michael Durante, Benjamin T Diamond, Marios Papadimitriou, Malin Hultcrantz, Alessio Marella, Giancarlo Castellano, Akihiro Maeda, Marta Lionetti, Antonio Matera, Stefania Pioggia, Matteo Claudio Da Vià, Claudio De Magistris, Daniel Leongamornlert, Danny Deavila, Praneeth Reddy Sudalagunta, Rafael Renatino Canevarolo, Erin M Siegel, Phaedra Agius, Jamie Teer, Andrew Mcpherson, Yusuke Yamashita, Ariosto S Silva, Patrick Blaney, Rachid Baz, Krina K Patel, Peter Campbell, Gareth Morgan, Rafael Fonseca, Ola Landgren, Robert Z Orlowski, Kenneth H Shain, Niccolo Bolli, Saad Usmani, S Vincent Rajkumar

Faculty, Staff and Student Publications

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify …

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 …

Hidden Malignancy: Ileocecal Intussusception As An Atypical First Presentation Of Diffuse Large B-Cell Lymphoma In Adulthood, Komal Harisinghani, Parth Adrejiya, Mohammad Abubaker, Oluchi Idenyi, Raman Babayeuski, Noor Qureshi, Ashok Kanugula, Sara Assaf, Daniel Assaf, Srikanth Maddika

Journal of Community Hospital Internal Medicine Perspectives

Intussusception is predominantly a pediatric condition, with only about 5% of all intussusception cases occurring in adults with primary intestinal lymphomas comprising 1%–4% of gastrointestinal malignancies, 90% of which are B-cell non-Hodgkin lymphomas (NHL). Diffuse large B-cell lymphoma (DLBCL), the most common subtype of NHL, often leads to intussusception without classical B symptoms. We present the case of a 33-year-old male with ileocolonic intussusception caused by a 4.8 × 5.3 × 5.5 cm enhancing mass. Histopathology and FISH confirmed DLBCL without MYC, BCL2, or BCL6 rearrangements, ruling out double- or triple-hit lymphoma. Following a right ileo-colectomy, R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, …

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 …

A Comparison Of Biological Therapies Vs Traditional Immunosuppressant In The Management Of Inflammatory Bowel Diseases: A Narrative Review, Umme Farwah Tahir Dr, Sadaf Noureen, Fnu Partab, Muhammad Waqas Afzal, Maham Afzal, Asad Mehmood, Fatima Afzal, Kaynat Hasan, Fnu Sameeha, Seerat Riaz, Sumyya Tariq, Abida Perveen

Journal of Community Hospital Internal Medicine Perspectives

Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is a chronic immune-mediated condition requiring long-term management. Traditional immunosuppressants, such as corticosteroids, thiopurines, and methotrexate, have been widely used but are associated with broad immunosuppressive effects and significant adverse events. The advent of biological therapies, including tumor necrosis factor (TNF) inhibitors, integrin inhibitors, and interleukin (IL)-12/23 inhibitors, has revolutionized IBD treatment by offering targeted immune modulation. Biologics have demonstrated superior efficacy in achieving and maintaining remission compared to traditional immunosuppressants, particularly in moderate to severe IBD. They provide targeted immune suppression, reducing systemic side effects, but are associated with …

A Strategy For Surge Management: Senior Residents On The Admitting Frontlines, Hamza Saifuddin, Oliver Yockey, Rachelle Pichot, Gwendolyn Brainard, Samantha Labay, Michael S. Wang

Journal of Community Hospital Internal Medicine Perspectives

Hospitals adapt to surges in a variety of ways, including expediting admitting and discharge procedures, hiring temporary staff and locums to meet increased demand, and temporarily expanding or creating facilities. To mitigate negative effects associated with surges, a small community-based hospital’s Internal Medicine (IM) residency program and hospitalist program collaborated by shifting senior residents into admitting physician roles with indirect supervision to meet increased surge needs. This shift allowed an admitting attending physician to shift to a newly created rounding service and, on average, the number of rounding services was increased from seven to nine. Over a fifteen-month period (five …

Empowering Residents In Community-Based Internal Medicine Programs: A Structured Framework Integrating Simulation Labs, Ai, And Gamification, Nirmay Sonar, Zaynah Sadiq, Bernie Sergent

Journal of Community Hospital Internal Medicine Perspectives

Community-based internal medicine residencies train nearly half of all U.S. IM residents and are essential for staffing underserved areas. These programs often face educational gaps due to limited resources, faculty development, and procedural training opportunities. We designed a 12-month quality initiative for 27 residents at a small community hospital blending new high-fidelity simulation drills (e.g. in-situ rapid-response and procedural labs), restructured didactics (gamified quizzes, NEJM Resident 360™, HumanDx cases), enhanced orientation (“intern survival guide”), research education, wellness retreats, community outreach and AI-driven, individualized case feedback. New interventions were implemented alongside existing activities, with targeted outcomes including clinical competency, board readiness, …

A Review Of 3d-Printed Medical Devices For Cancer Radiation Therapy., Radiah Pinckney, Santosh Kumar Parupelli, Peter Sandwall, Sha Chang, Salil Desai

Oncology Articles

This review explores the transformative role of three-dimensional (3D) printing in radiation therapy for cancer treatment, emphasizing its potential to deliver patient-specific, cost-effective, and sustainable medical devices. The integration of 3D printing enables rapid fabrication of customized boluses, compensators, immobilization devices, and GRID collimators tailored to individual anatomical and clinical requirements. Comparative analysis reveals that additive manufacturing surpasses conventional machining in design flexibility, lead time reduction, and material efficiency, while offering significant cost savings and recyclability benefits. Case studies demonstrate that 3D-printed GRID collimators achieve comparable dosimetric performance to traditional devices, with peak-to-valley dose ratios optimized for spatially fractionated radiation …

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. …

Prospective Comparison Of Wbc Spect/Ct And Conventional Mri For Diagnosing Osteomyelitis And Monitoring Treatment Response In Diabetic Foot Infections, Orhan Oz, Amber M. Sherwood, Peter A. Crisologo, Amanda L. Killeen, Kavita Bhavan, Javier La Fontaine, Katie L. Rubitschung, Helena Hwang, Robert W. Haley, Lawrence A. Lavery

School of Podiatric Medicine Publications

Aims/hypothesis: Osteomyelitis is a common complication of diabetic foot ulcers and a leading cause of lower limb amputations globally. Accurate diagnosis of diabetic foot osteomyelitis (DFO) is essential for effective infection management and improving prognosis. This study aimed to compare the performance of white blood cell (WBC)-single photon emission computed tomography (SPECT)/computed tomography (CT) and conventional MRI in the initial diagnosis of DFO and in detecting residual infection during treatment monitoring, using bone biopsy as the reference standard.

Methods: In this prospective clinical study, 47 patients with foot wounds suspicious for DFO underwent 99mTc-WBC SPECT/CT and MRI, followed by bone …

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 …

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 …

Real-Time Hemodynamic Deterioration Following Polymorphic Ventricular Tachycardia In A Patient With Preexisting Aicd Implanted With Lvad, Dhruvil Patel, Maya Guglin, Deepa Iyer, Chonyang Albert, Jagpreet Grewal, Kenneth Dulnuan

The VAD Journal

Ventricular arrhythmias (VAs) are common in patients with a left ventricular assist device (LVAD), but the literature remains inconclusive regarding the benefits of an automatic implantable cardioverter-defibrillator (AICD) in this population, especially in those with a preexisting device before LVAD implantation. Here, we report the acute hemodynamic consequences of polymorphic ventricular tachycardia in a patient with a preexisting biventricular AICD who was implanted with an LVAD (HeartMate 3). This case underscores the importance of considering AICD placement on a case-by-case basis and highlights the need for a well-designed study to establish its benefit in this population.

Cleft Feeding: Practical Tips For Pediatricians, Michael Smith, Leah Hunt, Brenda Fetter, Hannah J. Bergman

Pediatrics in Practice: A CME Podcast

Feeding infants with cleft lip and palate can be challenging. In this episode, a pediatric surgeon, occupational therapist, and speech pathologist share practical strategies for pediatricians—from pre- and post-surgery care to therapy techniques and key red flags. Learn how to guide families and collaborate effectively for the best outcomes.

Note: This episode is not awarded CME.

Click here to stream the podcast episode.

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 …

Glutamatergic Projection Neurons In The Basal Forebrain Underlie Learned Olfactory Associational Valence Assignments, Pey-Shyuan Chin, Zhuokun Ding, Mikhail Kochukov, Snigdha Srivastava, Elizabeth H Moss, Qingchun Tong, Benjamin R Arenkiel

Faculty, Staff and Student Publications

Sensory perception is shaped by experience, giving stimuli behavioral significance. Basal forebrain (BF) cholinergic neurons in mice, which are crucial for arousal and motivation, also regulate sensory processing. Within BF nuclei, glutamatergic (vGlut2BF) neurons receive cholinergic input and modulate behaviors, but their roles in encoding sensory significance remain unclear. Using in vivo calcium imaging, we found that vGlut2BF neurons initially poorly encoded odor identity. However, their response to conditioned odors increased following associative learning, and their population activity more distinctly encoded paired stimuli, reflecting emergent value representation. Furthermore, pairing stimulation or inhibition of vGlut2BF neurons with specific odors altered odor …

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 …

Aberrant Cd25 And Increased Cd123 Expression Are Common In Acute Myeloid Leukemia With Kmt2a Partial Tandem Duplication And Are Associated With Flt3 Internal Tandem Duplication, Qing Wei, Guilin Tang, Shaoying Li, Sa A Wang, Pei Lin, Wei Wang, Sanam Loghavi, Wei J Wang, L Jeffrey Medeiros, Jie Xu

Faculty, Staff and Student Publications

Background: KMT2A partial tandem duplication (PTD) occurs in approximately 5-10% of acute myeloid leukemia (AML) cases and is associated with poor prognosis. While its cytogenetic and molecular features are well described, the immunophenotypic characteristics of AML with KMT2A-PTD remain incompletely defined.

Methods: We identified 47 cases of AML with KMT2A-PTD by optical genome mapping. All cases underwent flow cytometric immunophenotypic analysis and next-generation sequencing using an 81-gene panel.

Results: The cohort included 32 men and 15 women with a median age of 67 years (range, 19-87). Thirty-eight cases were de novo AML, and nine were secondary to myelodysplastic …

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 …

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 …