Medical Specialties Commons^™

A Transdiagnostic, Multi-Modal Approach To Understanding Apathy: Methodological And Analytical Framework, Yunglin Gazes, Hideo Suzuki, Lee-Anne Morris, Seonjoo Lee, Zekai Jin, Edward D Huey, Bryan B Chen, Campbell Le Heron, Sarah R Heibronner, Nora Vanegas-Arroyave

Faculty, Staff and Students Publications

Apathy is characterized by loss of motivation and manifests as a reduction of goal-directed behavior. Apathy is highly prevalent across neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), and is an important contributor to the disability and reduce quality of life in these conditions. The treatment of apathy remains challenging due to a lack of specific therapies, largely attributed to an incomplete understanding of its cognitive and neuroanatomical underpinnings, crucial for developing targeted interventions. Apathy can be mechanistically studied through effort-based decision-making (EBDM) paradigms, where individuals choose between low- and high-effort tasks for varying reward magnitudes. Anatomically, apathy …

The State Of Educational Research In Cardiothoracic Surgery: A Review Of The Literature, Amirtha Shekar, Victoria Hart, John Treffalls, Travis J Miles, Todd K Rosengart, Marc R Moon, Joseph S Coselli, Lauren M Barron, Shawn S Groth, Shanda H Blackmon, Ravi K Ghanta, Dawn S Hui, Subhasis Chatterjee

Faculty, Staff and Students Publications

Objective: Evolving training paradigms in cardiothoracic surgery (CTS) are changing the educational needs of integrated residents and traditional fellows. Educational research is important for evaluating specialty training. This study assessed CTS education articles to analyze their prevalence, content, and reach.

Methods: In a cross-sectional observational study of education articles published on North American CTS programs from January 2013 through December 2023, articles were identified by querying PubMed, other databases, and journals. Articles that passed an initial abstract review underwent full-text review. Articles were organized by content into 9 categories: curriculum, simulation, trainee assessment, program evaluation, wellness/burnout, diversity/inclusion, mentorship/career, outcomes, and …

Rescue Bare-Metal Device Placement To Treat Iatrogenic Acute Type A Aortic Dissection During Transcatheter Aortic Valve Replacement, Hiroaki Osada, José G Diez, Ahmed Khouqeer, Susan Y Green, Marc R Moon, Vicente Orozco-Sevilla, Joseph S Coselli

Faculty, Staff and Students Publications

No abstract provided.

A Model For Developing Subspecialty Clinical Practice Guidelines: The Geriatric Emergency Department Guidelines 20, Satheesh Gunaga, Christopher R Carpenter, Maura Kennedy, Lauren T Southerland, Alexander X Lo, Sangil Lee, Kirby Swan, Fabrice Mowbray, Rachel M Skains, Teresita M Hogan, Martin F Casey, Kei Ouchi, Naomi R George, Kerstin De Wit, Cameron J Gettel, Katherine Selman, Luna C Ragsdale, Anita N Chary, James D Van Oppen, Glenn Arendts, Charles L Maddow, Katherine M Hunold, Katren R Tyler, Danya Khoujah, Ula Hwang, Shan Liu

Faculty, Staff and Students Publications

The original consensus-based Geriatric Emergency Department (GED) Guidelines, published in 2014, established a framework of core principles for delivering high-quality, age-appropriate emergency care for older adults. In response to significant advances in geriatric emergency medicine research and evolving clinical priorities, we developed the GED Guidelines 2.0 to ensure continued relevance, clinical utility, and evidence-based rigor. This concept paper describes the systematic and iterative process undertaken to update the guidelines, including the formation of multidisciplinary working groups and the application of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Unlike the original GED Guidelines, our approach prioritized methodological transparency, …

Gene Therapy Cm-Yapon Protects The Mouse Heart From Myocardial Infarction, Fansen Meng, Jeffrey D Steimle, Elizabeth Straight, Rich G Li, Yuka Morikawa, Zohaib Iqbal, Bing Xie, Jun Wang, Wyatt G Paltzer, Yi Zhao, Chang-Ru Tsai, Lin Liu, Maggie Lim, Rita A Schack, Daniel Ramirez, Katherine Carlson, Vaibhav Deshmukh, Jason M Karch, Robia G Pautler, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Myocardial infarction (MI) affects millions of people worldwide, causing irreversible injury to the heart and impairing cardiac function1. In both mouse and pig MI models, activating YAP in cardiomyocytes (CMs) stimulates regenerative repair2,3. Here we developed an adeno-associated virus 9 (AAV9)-based therapy, termed CM-YAPon, which enables transient expression of an active YAP variant (YAP5SA) in CMs following exposure to the small molecule LMI070. A single LMI070 dose in mice triggers YAP5SA expression, CM cell cycle re-entry, and reprogramming of the cardiac microenvironment. YAP5SA induction after MI rapidly improves cardiac function while pre-MI induction confers …

Alternative Splicing Of The Snap23 Microexon Is Regulated By Mbnl, Qki, And Rbfox2 In A Tissue-Specific Manner And Is Altered In Striated Muscle Diseases, Gabrielle M Gentile, R Eric Blue, Grant A Goda, Bryan B Guzman, Rachel A Szymanski, Eunice Y Lee, Nichlas M Engels, Emma R Hinkle, Hannah J Wiedner, Aubriana N Bishop, Jonathan T Harrison, Hua Zhang, Xander H T Wehrens, Daniel Dominguez, Jimena Giudice

Faculty, Staff and Students Publications

The reprogramming of alternative splicing networks during development is a hallmark of tissue maturation and identity. Alternative splicing of microexons (small, genomic regions ≤ 51 nucleotides) functionally regulate protein-protein interactions in the brain and is altered in several neuronal diseases. However, little is known about the regulation and function of alternatively spliced microexons in striated muscle. Here, we investigated alternative splicing of a microexon in the synaptosome-associated protein 23 (Snap23) encoded gene. We found that inclusion of this microexon is developmentally regulated and tissue-specific, as it occurs exclusively in adult heart and skeletal muscle. The alternative region is …

Lilrb4 Regulates Circadian Disruption-Induced Mammary Tumorigenesis Via Non-Canonical Wnt Signaling Pathway, Olajumoke Ogunlusi, Mrinmoy Sarkar, Kayla Carter, Arhit Chakrabarti, Devon J Boland, Tristan Nguyen, James Sampson, Christian Nguyen, Danielle Fails, Yava Jones-Hall, Loning Fu, Gus Wright, Da Mi Kim, James J Cai, Bani Mallick, Alex C Keene, Jeff R Jones, Tapasree Roy Sarkar

Faculty, Staff and Students Publications

Epidemiological studies have shown that circadian rhythm disruption (CRD) is associated with the risk of breast cancer. However, the role of CRD in mammary gland morphology and aggressive basal mammary tumorigenesis and the molecular mechanism underlying CRD-induced carcinogenesis remain unknown. To investigate the effect of CRD on aggressive tumorigenesis, a genetically engineered mouse model of aggressive breast cancer was used. The impact of CRD on the tumor microenvironment was investigated using the tumors from LD12:12 and CRD mice via scRNA-seq, flow cytometry, multiplexing immunostaining, and realtime PCR. The effect of LILRB4-immunotherapy on CRD-induced tumorigenesis was also investigated. Here we investigated …

Biochemical And Clinical Response To A Sulfur-Restricted Diet In Ethylmalonic Encephalopathy, Steven H Lang, Andres Caceres Salgado, Matthew T Snyder, Brandy Rawls-Castillo, Aaron Williams, Charul Gijavanekar, Sarah H Elsea, Xia Wang, Mary Elizabeth M Tessier, Claudia Soler-Alfonso, Fernando Scaglia

Faculty, Staff and Students Publications

Introduction: Ethylmalonic encephalopathy (EE) is an often-severe inborn error of metabolism caused by biallelic variants in the ETHE1 gene leading to impaired detoxification of hydrogen sulfide (H2S). H2S is produced both exogenously by anerobic intestinal bacteria as well as by the endogenous catabolism of the sulfur-containing amino acids methionine and cysteine. Existing therapies including metronidazole, N-acetylcysteine (NAC), and orthotopic liver transplantation (OLT) have been pursued with the objective of reducing or detoxifying exogenously produced H2S. However, strategies to reduce endogenously produced H2S using a methionine and cysteine restricted diet are an understudied therapeutic avenue.

Methods: We performed an open-label, …

Clinical Exome Sequencing Efficacy And Phenotypic Expansions Involving Non-Isolated Congenital Anomalies Of Kidney And Urinary Tract (Cakut+), E Andres Rivera-Munoz, Xiaonan E Zhao, Jill A Rosenfeld, Pamela N Luna, Chad A Shaw, Jennifer E Posey, Daryl A Scott

Faculty, Staff and Students Publications

Congenital Anomalies of Kidney and Urinary Tract (CAKUT) can occur in isolation or in conjunction with one or more non-CAKUT associated congenital anomalies or neurodevelopmental disorders (CAKUT+). A molecular cause is not identified in most individuals with CAKUT+. This is due, in part, to uncertainty regarding the efficacy of genetic testing and an incomplete understanding of the genes that cause CAKUT+. Here, we use data from 515 individuals with CAKUT+ (n = 500) or isolated CAKUT (n = 15) to determine the efficacy of clinical exome sequencing (cES) and to identify new phenotype expansions that involve CAKUT. We determined that …

Genetics Services In Latin America: A Descriptive Study Of Availability And Utilization Of Genetics In Healthcare, Ryan J German, Erin Atkinson, Eric A Storch, Claudia Soler-Alfonso, Sonia Margarit, Philip J Lupo, Stacey Pereira

Faculty, Staff and Students Publications

Genetic services are expanding globally, but access remains limited in low-resource regions such as Latin America. Understanding current service availability, barriers, and facilitators is critical to guide capacity building and improve patient care. We conducted a cross-sectional survey of healthcare professionals providing genetic services in Latin America. The survey, available in Spanish and English, assessed genetic services, referral patterns, testing availability, barriers, facilitators, and perceived needs. Descriptive statistics summarized quantitative data, and thematic analysis was applied to open-ended responses. Eighty-five respondents from 18 countries reported broad clinical activity across pediatric, cancer, and adult-onset genetic conditions. Commonly ordered tests included karyotype, …

Bridging The Gap: From Early Recognition To Timely Referral For Cardiac Implantable Electronic Devices Infections, M Rizwan Sohail, Sarwat Khalil, Molly L Paras, Christopher B Granger, Andrew Uehlin, Yu-Rong Gao, Zerelda Esquer Garrigos

Faculty, Staff and Students Publications

An increasing number of patients are living with cardiac implantable electronic devices (CIEDs). When a patient with a CIED is hospitalized with concern for infection or positive blood cultures from any source, recognizing and managing a possible CIED infection is critical due to its significant morbidity and mortality risk. Internists are often the first to evaluate these patients and must consider the possibility of an underlying device infection. Gram-positive bacteremia carries a high risk of CIED infection, often necessitating cardiac imaging. In contrast, hematogenous seeding with gram-negative bacteremia is infrequent. Patients with clinical or imaging evidence of device infection should …

Frequency, Duration, And Cost Of Pulmonary Exacerbations Among Patients With Bronchiectasis, Maitreyee Mohanty, Claudia Leiras, Haiyan Sun, Reina Rau, John Fastenau, Joseph Feliciano, Sunjay R Devarajan

Faculty, Staff and Students Publications

Background: In administrative claims database studies of bronchiectasis, pulmonary exacerbations are usually defined using a fixed period for their start and end, which prevents assessment of exacerbation duration and thereby limits assessment of exacerbation characteristics. Here, we applied a novel cost-based algorithm to characterize exacerbations.

Methods: This cohort study used the Merative MarketScan Commercial Claims and Encounters database, 1-Jan-2016 to 31-Dec-2022. Patients ≥18 years with bronchiectasis (≥2 outpatient or ≥1 inpatient claim with bronchiectasis; no cystic fibrosis) had 12 months of continuous enrollment before (baseline) and ≥12 months after (follow-up) index (first bronchiectasis claim). Cost-based exacerbations were identified by compound …

Modeling Reemergence Of Vaccine-Eliminated Infectious Diseases Under Declining Vaccination In The United States, Mathew V Kiang, Kate M Bubar, Yvonne Maldonado, Peter J Hotez, Nathan C Lo

Faculty, Staff and Students Publications

(Abstracted from JAMA 2025;333(24):2176-2187) The development of childhood vaccine protocols has led to the elimination of many infectious diseases from the United States, including measles, rubella, diphtheria, and polio, by maintaining herd immunity. In recent years, especially since the COVID-19 pandemic, vaccination rates have declined due to policy changes, misinformation, distrust, and broader societal shifts.

Differential Microrna Profiling Of Blood L1cam And Bulk Extracellular Vesicles In Bipolar Disorder, Gabriel R Fries, Salahudeen Mirza, Jun Wang, Camila N C Lima, Wei Zhang, Marcela Carbajal Tamez, Giselli Scaini, Jair C Soares, Joao Quevedo

Faculty, Staff and Student Publications

Objective: This preliminary study aimed to identify microRNA (miRNA) signatures associated with bipolar disorder (BD) by profiling blood-derived extracellular vesicles (EVs) of both putative neuronal origin and from all sources.

Method: In two parallel studies of individuals with BD and controls (CON), we characterized miRNA expression profiles of blood EVs selected for L1CAM, a putative marker of neuronal origin (n = 20 BD/20 CON), as well as bulk EVs (n = 21 BD/20 CON). For each study, analyses identified miRNAs differentially expressed between groups, followed by functional interrogation and testing for associations with clinical features.

Results: Results of …

Stage- And Smoking-Associated Microrna Expression In Lung Adenocarcinoma, Min Huang, Yimin Ge, Huiqin Chen, Caimiao Wei, David Cogdell, Cristina Ivan, Meng Chen, Wei Zhang, George A Calin, Ming Guo

Faculty, Staff and Student Publications

Background: Altered expression of microRNAs (miRNAs) is implicated in lung carcinogenesis, but little research has investigated the association of miRNA alterations with lung cancer stage or smoking status. To identify such alterations in lung adenocarcinoma, we conducted miRNA profiling.

Methods: Lung adenocarcinoma specimens and paired nonneoplastic lung tissues from 58 patients who had received no preoperative therapy and underwent tumor resection from 1991 to 2006 were collected from tumor tissue banks. Thirty (52%) of the tumors were stage I and 28 (48%) stage II or higher. Twenty-five (43%) patients were nonsmokers and 33 (57%) were smokers. To identify miRNAs of …

Application Of The Surgical Apgar Score To Predict Intensive Care Unit Admission And Post-Operative Outcomes In Cesarean Hysterectomy For Placenta Accreta Spectrum, Emily Root, Jacqueline Curbelo, Patrick Ramsey, Jessian L Munoz

Faculty, Staff and Students Publications

Background and Objective: Placenta Accreta Spectrum (PAS) encompasses a continuum of abnormal placentation conditions associated with significant maternal and fetal morbidity. Management of PAS requires coordinated cesarean hysterectomy. Associated morbidities include blood transfusion, coagulopathy, and intensive care unit (ICU) admission. Accurate prediction of ICU admission allows for enhanced multidisciplinary management, coordination of care and utilization of resources. Scoring systems exist in other surgical specialties that can predict the likelihood of ICU admission, but these have not been applied to an obstetric population. The SAS is a 10-point scale that has been validated for the prediction of ICU-level care requirements within …

The Gut Microbiome In Stevens-Johnson Syndrome And Sjögren's Disease: Correlations With Dry Eye, Luciana Frizon, Talita Trevizani Rocchetti, André Frizon, Rafael Jorge Alves De Alcântara, Cintia S De Paiva, José Álvaro Pereira Gomes

Faculty, Staff and Students Publications

Changes in gut microbial composition may influence mucosal immune responses and contribute to systemic autoimmune manifestations. In this pilot exploratory study, we investigated and compared the gut microbiome in patients with Stevens–Johnson syndrome (SJS), patients with Sjögren’s disease (SjD), and healthy controls, using next-generation sequencing (NGS), and assessed correlations with dry eye parameters. The study included 10 patients with SJS matched by age and sex to 10 healthy controls, and 10 patients with SjD matched to an additional set of 10 healthy controls. Dry eye parameters were employed to evaluate dry eye disease (DED). Microbiome profiles were determined using next-generation …

Developmental Stage-Dependent Transcriptomic Responses To Neonatal Intraventricular Hemorrhage, Elizabeth Wallace-Anthony, Miriam Zamorano, Hemendra J Vekaria, Braden B Oldham, Kiara P Umpornpun, Scott D Olson, Stefano Berto, Brandon A Miller

Faculty, Staff and Student Publications

Neonatal intraventricular hemorrhage (IVH) is a major complication of preterm birth, yet how developmental stage influences the brain's response to injury remains unclear. We performed single-nucleus RNA sequencing on rat brains 24 h after IVH at postnatal day 2 (PND2) or day 5 (PND5) to define transcriptional responses across cell types. We identified 42 distinct cell populations and found that PND5 brains exhibited a markedly stronger immune and inflammatory response to IVH, with a threefold increase in differentially expressed genes compared to PND2. Microglia were the most perturbed cell type at both stages, showing increased oxidative stress and polarization toward …

Benchmarking Dna Foundation Models For Genomic And Genetic Tasks, Haonan Feng, Lang Wu, Bingxin Zhao, Chad Huff, Jianjun Zhang, Jia Wu, Lifeng Lin, Peng Wei, Chong Wu

Faculty, Staff and Student Publications

The rapid evolution of DNA foundation models promises to revolutionize genomics, yet comprehensive evaluations are lacking. Here, we present a comprehensive, unbiased benchmark of five models (DNABERT-2, Nucleotide Transformer V2, HyenaDNA, Caduceus-Ph, and GROVER) across diverse genomic and genetic tasks including sequence classification, gene expression prediction, variant effect quantification, and topologically associating domain (TAD) region recognition, using zero-shot embeddings. Our analysis reveals that mean token embedding consistently and significantly improves sequence classification performance, outperforming other pooling strategies. Model performance varies among tasks and datasets; while general purpose DNA foundation models showed competitive performance in pathogenic variant identification, they were less …

Radiologist-Validated Automatic Lumbar T1-Weighted Spinal Mri Segmentation Tool Via An Attention U-Net Algorithm, Aryan Kalluvila, Ethan Wang, Michael C Hurley, Colbey Freeman, Jason M Johnson

Faculty, Staff and Student Publications

Background/Objectives: Spinal MRI segmentation has become increasingly important with the prevalence of disc herniation and vertebral injuries. Artificial intelligence can help orthopedic surgeons and radiologists automate the process of segmentation. Currently, there are few tools for T1-weighted spinal MRI segmentation, with most focusing on T2-weighted imaging. This paper focuses on creating an automatic lumbar spinal MRI segmentation tool for T1-weighted images using deep learning.

Methods: An Attention U-Net was employed as the main algorithm because the architecture has shown success in other segmentation applications. Segmentation loss functions were compared, focusing on the difference between BCE and MSE loss. Two board-certified …

Mecp2 Interacts With The Super Elongation Complex To Regulate Transcription, Jun Young Sonn, Wonho Kim, Marta Iwanaszko, Yuki Aoi, Yan Li, Guantong Qi, Luke Parkitny, Janice L Brissette, Lorin Weiner, Juan Botas, Ismael Al-Ramahi, Ali Shilatifard, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss-of-function mutations in methyl-CpG binding protein 2 (MECP2) cause Rett syndrome. While we know that MeCP2 binds to methylated cytosines on DNA, the full breadth of the molecular mechanisms by which MeCP2 regulates gene expression remains incompletely understood. Here, using a genetic modifier screen, we identify the super elongation complex, a P-TEFb–containing elongation factor that releases promoter-proximally paused RNA polymerase II, as a genetic interactor of MECP2. MeCP2 physically interacts with SEC subunits and directly binds AFF4, the scaffold of the SEC, via the transcriptional repression domain. Furthermore, MeCP2 facilitates the binding of AFF4 on a subset …

Microbial Associations And Viruses On The Risk Of Celiac Disease (Mavric): A Longitudinal Post-Hoc Case-Cohort Study, Kristian F Lynch, Eric W Triplett, Heikki Hyöty, Angelica P Ahrens, Jutta E Laiho, Joseph F Petrosino, Richard E Lloyd, Daniel Agardh

Faculty, Staff and Students Publications

Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity (CDA), was confirmed in 704 of the 6132 genetically at-risk TEDDY children. Celiac disease onset (CD-onset) was defined as the age CDA developed when followed by a biopsy-proven diagnosis. A competing risk analysis on …

Mucosal Melanoma: Mechanisms Of Its Etiology, Progression, Resistance And Therapy, Sofie-Yasmin Hassan, Thomas W. Flanagan, Sarah-Lilly Hassan, Sybille Facca, Youssef Haikel, Mohamed Hassan

School of Graduate Studies Faculty Publications

Mucosal melanoma (MM) is a rare, aggressive cancer whose incidence has increased continuously over the years. This subtype of melanoma arises from melanocytes on hairless surfaces, typically in the respiratory tract, gastrointestinal (GI) tract, and urogenital tract. The most common sites of occurrence include the head and neck, the anorectal region, and the vulvovaginal region, while the rare sites of MM are the urinary tract and the upper and lower GI tract, including the esophagus, duodenum and the gallbladder. MM arises in melanocytes of the ectodermal mucosa that originate from neural crest cells and migrate through embryonic mesenchyme to their …

A Phase 1/2 Study Of Ds-1594 Menin Inhibitor In Relapsed/Refractory Acute Leukemias, Jayastu Senapati, Marina Konopleva, Ghayas C Issa, Elias Jabbour, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Naveen Pemmaraju, Nicholas J Short, Musa Yilmaz, Indraneel Deshmukh, Joie Alvarez, Sanam Loghavi, Guilin Tang, Hussein A Abbas, Michael Andreeff, Kapil Bhalla, Narasimha M Midde, Nabil Said, Amy Noyalis, Derek E Mires, Jing Ning, Lianchun Xiao, Farhad Ravandi, Guillermo Garcia-Manero, Hagop M Kantarjian, Naval G Daver

Faculty, Staff and Student Publications

Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and …

Soluble Immune Factor Profiles In Blood And Csf Associated With Lrrk2 Mutations And Parkinson's Disease, Roshni Jaffery, Yuhang Zhao, Sarfraz Ahmed, Jackson G Schumacher, Jae Ahn, Leilei Shi, Yujia Wang, Yukun Tan, Jiayin Zhang, Ken Chen, Hussein Tawbi, Jian Wang, Michael A Schwarzschild, Weiyi Peng, Xiqun Chen

Faculty, Staff and Student Publications

Mutations in LRRK2, a leading genetic cause of Parkinson's disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incompletely defined. This study utilized a large cohort of serum samples (n = 651) and matched CSF samples (n = 129) from LRRK2 mutation carriers and non-carriers, with and without PD, to assess immune regulators using Luminex immunoassay. After correction for multiple comparisons, LRRK2 mutations were associated with significantly elevated serum levels of SDF-1 alpha and TNF-RII, while CSF markers such as BAFF, CD40L, and IL-27 were nominally reduced. Regardless of …

Delphi Panel On Neuromodulation As A Treatment Strategy For Dry Eye Disease: Unlocking The Potential Of Natural Tear Production, Esen Akpek, Lyndon Jones, Kelly K Nichols, Lisa M Nijm, Stephen Pflugfelder

Faculty, Staff and Students Publications

Purpose: Chronic tear deficiency, through reduced production and/or increased evaporation, is regarded as a root cause of dry eye disease (DED). The goal of treating DED is restoration of the tear film ultimately resulting in ocular surface homeostasis. Multiple therapeutic prescription drugs to manage DED exist with varying speed of onset, overall magnitude of efficacy, and tolerability. Neuromodulation is an emerging treatment modality offering direct stimulation of natural tear production. A modified Delphi study was conducted to explore the role of neuromodulation as a treatment for DED.

Methods: Twenty DED experts participated in three rounds of structured electronic Delphi questionnaires. …

Predicting The Response Of Triple Negative Breast Cancer To Neoadjuvant Systemic Therapy Via Biology-Based Modeling And Habitat Analysis, Casey E Stowers, Chengyue Wu, Clinton Yam, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Despite being the standard-of-care treatment, neoadjuvant therapy (NAT) attains a complete response only in approximately half of the patients with triple negative breast cancer. Thus, methods to predict and optimize patient response to NAT are needed. Previously, we employed patient-specific MRI data to calibrate a biology-based mathematical model that describes cell movement, proliferation, and death due to drug at the tumor level and cell proliferation at an image voxel level. We now extend our approach by using MRI data to group voxels into "habitats" whereby tumor cells of a habitat share the same proliferation. With this approach, we now calibrate …

Loss Of Idh1 And Idh2 Mutations During The Evolution Of Metastatic Chondrosarcoma, William Cross, Iben Lyskjær, Christopher Davies, Abigail Bunkum, Ana Maia Rocha, Tom Lesluyes, Fernanda Amary, Roberto Tirabosco, Cristina Naceur-Lombardelli, Mariam Jamal-Hanjani, Charles Swanton, Nischalan Pillay, Simone Zaccaria, Adrienne M Flanagan, Peter Van Loo

Faculty, Staff and Student Publications

Driver mutations in IDH1 and IDH2 are initiating events in the evolution of chondrosarcoma and several other cancer types. Here, we present evidence that mutant IDH1 is recurrently lost in metastatic central chondrosarcoma. This may reflect either relaxed positive selection for the mutant IDH1 locus, or negative selection for the hypermethylation phenotype later in tumor evolution. This finding highlights the challenge for therapeutic intervention by mutant IDH1 inhibitors in chondrosarcoma.

Interplay Of Menopause, Coronary Artery Calcium Score And Cardiovascular Disease Risk, Tanisha Mishra, Diksha Sanjana Pasnoor, Murtaza Gandhi, Nida Mohamed, Shaylika Chauhan, Kokou Adompreh-Fia, Kesha Mayank Doshi, Prerana Sevella, Rupak Desai

Abington Jefferson Health Papers

BACKGROUND: Postmenopausal women face an increased risk of cardiovascular disease (CVD) due to estrogen withdrawal, which exacerbates traditional cardiovascular risk factors such as dyslipidemia, glucose intolerance, and hypertension. Coronary Artery Calcium Score (CACS), a well-established marker of subclinical atherosclerosis, has emerged as a key predictor of adverse cardiovascular events. Despite the recognized association between menopause and heightened CVD risk, there remains a paucity of literature exploring the specific role of menopause in influencing CACS and its implications for cardiovascular morbidity and mortality.

AIM: To examine the interplay between menopause, CACS, and cardiovascular health by synthesizing existing literature.

METHODS: A comprehensive …

Transcription-Replication Collisions Trigger High-Fidelity Replication Reset, Matthew B Cooke, Kobie T Welch, Laura Deus Ramirez, Katelin M Hagstrom, Alice X Wen, Jennifer A Halliday, Susan M Rosenberg, Christophe Herman

Faculty, Staff and Students Publications

Double-stranded DNA ends arise from external agents or cellular processes like transcription-replication collisions (TRCs), threatening genome stability. Here, we performed genomic CRISPRi screens to uncover DNA end formation factors in Escherichia coli. We discovered that translation-transcription decoupling causes DNA end formation through a TRC-dependent pathway, which is lethal when DNA end processing by RecBCD is disrupted, but not when recombination is disrupted. We find that TRCs cause replisome stalling followed by "rear-ending" from trailing replisomes which generates free DNA ends, rather than strand breaks. Surprisingly, these DNA ends are resolved through a process we call "replication reset", where the stalled …