Digital Commons Network^™

Formation Of An Expanding Memory Representation In The Hippocampus, Sachin P Vaidya, Guanchun Li, Raymond A Chitwood, Yiding Li, Jeffrey C Magee

Faculty, Staff and Students Publications

How brain networks connected by labile synapses store new information without catastrophically overwriting previous memories remains poorly understood. To examine this, we tracked the same population of hippocampal CA1 place cells (PCs) as mice learned a task for 7 days. We found evidence of memory formation as both the number of PCs maintaining a stable place field and the stability of individual PCs progressively increased across the week until most of the representation was composed of long-term stable PCs. The stable PCs disproportionately represented task-related learned information, were retrieved earlier within a behavioral session and showed a strong correlation with …

Unfolding The Mystery Of Autoimmunity: The Environmental Determinants Of Diabetes In The Young (Teddy) Study, Marian Rewers, Daniel Agardh, Suzanne Bennett Johnson, Ezio Bonifacio, Helena Elding Larsson, Patricia Gesualdo, William Hagopian, Michael J Haller, Heikki Hyöty, Randi Johnson, Richard Mcindoe, Eoin Mckinney, Jessica Melin, Åke Lernmark, Richard E Lloyd, Kristian F Lynch, Jill M Norris, Stephen S Rich, Roswith Roth, Desmond Schatz, Jorma Toppari, Eric Triplett, Kendra Vehik, Suvi M Virtanen, Anette-G Ziegler, Beena Akolkar, Jeffrey P Krischer, Teddy Study Group

Faculty, Staff and Students Publications

In 2025, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health celebrates 75 years of leadership in diabetes research. The NIDDK serves people of the U.S. affected by or at risk for many chronic diseases, including diabetes and other endocrine, metabolic, and digestive disorders, by funding innovative research to develop better treatment and prevention and a cure for these conditions. Autoimmunity that leads to type 1 diabetes or celiac disease or thyroid autoimmunity affects 1 in 20 children and adolescents in the U.S. While treatments are available, prevention of these common autoimmune …

Copy Number Flexibility Facilitates Heteroresistance To Increasing Antibiotic Pressure And Threatens The Beta-Lactam Pipeline, Jacob E Choby, Tugba Ozturk, Carter N Abbott, Christina Nnabuife, Jennifer M Colquhoun, Sarah W Satola, Philip N Rather, Timothy Palzkill, David S Weiss

Faculty, Staff and Students Publications

Our understanding of the rapid adaptation of bacteria to resist novel drugs is growing beyond known mechanisms such as mobile genetic elements and mutation selection. Heteroresistance (HR) is a form of antibiotic resistance where a phenotypically unstable minority resistant subpopulation co-exists with a susceptible population. We sought to uncover the mechanism of heteroresistance to cefiderocol, a novel β-lactam developed to resist β-lactamases including extended-spectrum-β-lactamases (ESBLs), which has been recently reported but poorly understood. We observe HR to cefiderocol among clinical isolates collected before its use. The resistant subpopulation in Enterobacter is a continuum; increasing copy number of a gene encoding …

Metabolomic Data May Support The Development Of Personalized Nutrition Approaches To Type 2 Diabetes Management, Danielle J Lee, Shragvi Balaji, Jerome I Rotter, Alexis C Wood

Faculty, Staff and Students Publications

Diet is a major modifiable risk factor for type 2 diabetes (T2D), and suboptimal diets continue to contribute substantially to the population burden of T2D. Personalized nutrition proponents argue that specializing recommendations to interindividual differences in diet-health relationships will yield reductions in disease risk. However, how to personalize diet, and to whom, to reduce T2D risk remains unclear. Metabolites offer promise in this respect, as they capture (in part) dietary intake after the processes of digestion, processing, and absorption. The incorporation of metabolite data into diet-health studies therefore offers the opportunity to examine how the effects of food on the …

Clinical Assessment On Days 1-14 For The Characterization Of Traumatic Brain Injury: Recommendations From The 2024 Ninds Traumatic Brain Injury Classification And Nomenclature Initiative Clinical/Symptoms Working Group, David K Menon, Noah D Silverberg, Adam R Ferguson, Thomas J Bayuk, Shubhayu Bhattacharyay, David L Brody, Scott A Cota, Ari Ercole, Anthony Figaji, Guoyi Gao, Christopher C Giza, Fiona Lecky, Rebekah Mannix, Ana Mikolić, Kasey E Moritz, Claudia S Robertson, Abel Torres-Espin, Spyridoula Tsetsou, John K Yue, Hibah O Awad, Kristen Dams-O'Connor, Adele Doperalski, Andrew I R Maas, Michael A Mccrea, Nsini Umoh, Geoffrey T Manley

Faculty, Staff and Students Publications

The current classification of traumatic brain injury (TBI) primarily uses the Glasgow Coma Scale (GCS) to categorize injuries as mild (GCS 13-15), moderate (GCS 9-12), or severe (GCS ≤8). However, this system is unsatisfactory, as it overlooks variations in injury severity, clinical needs, and prognosis. A recent report by the National Academies of Sciences, Engineering, and Medicine (USA) recommended updating the classification system, leading to a workshop in 2024 by the National Institute of Neurological Disorders and Stroke. This resulted in the development of a new clinical, biomarker, imaging, and modifier (CBI-M) framework, with input from six working groups, including …

Intracranial Injury Following Nasogastric Tube Placement After Skull Base Surgery: A Case Report And Systematic Review, Gabrielle Wolter, Zain U Naqvi, Ali Jalali, Tran Locke, K Kelly Gallagher, Meha G Fox

Faculty, Staff and Students Publications

Inadvertent intracranial nasogastric tube placement is a recognized risk following skull base fracture, but prior skull base surgery also poses a significant and underrecognized risk for this potentially fatal complication. We report the case of a 75-year-old female admitted with Clostridioides difficile colitis, six months after endoscopic endonasal resection of a pituitary macroadenoma. A systematic review identified 10 prior cases of intracranial tube placement following skull base or sinonasal surgery, including nasotracheal and feeding tube insertions. Literature suggests that using small-bore flexible tubes and preserving anatomical barriers, such as the position of the middle turbinate and intact bony structures like …

Immediate Skin-To-Skin Contact And Postpartum Hemorrhagic Morbidity, Rachel L Wiley, Ipsita Ghose, Dana R Canfield, Minhazur R Sarker, Hector Mendez-Figueroa, Suneet Chauhan

Faculty, Staff and Students Publications

Objective: To examine rates of postpartum hemorrhagic (PPH) morbidity among patients who did and did not have immediate skin-to-skin contact (SSC).

Methods: This study was a retrospective cohort of all non-anomalous, term singleton vaginal births at a Level IV center over 2 years. Exclusion criteria included COVID-19. Immediate SSC was defined as at least 60 min of direct contact initiated between parturient and neonate within 10 min of birth. The primary outcome was a composite of maternal morbidity related to PPH compared among those with and without immediate SSC. We used multivariable Poisson regression adjusted for possible confounders with robust …

Bridging Cell Morphological Behaviors And Molecular Dynamics In Multi-Modal Spatial Omics With Morphlink, Jing Huang, Chenyang Yuan, Jiahui Jiang, Jianfeng Chen, Sunil S Badve, Yesim Gokmen-Polar, Rossana L Segura, Xinmiao Yan, Alexander Lazar, Jianjun Gao, Bing Yao, Michael Epstein, Linghua Wang, Jian Hu

Faculty, Staff and Student Publications

Multi-modal spatial omics data are invaluable for exploring complex cellular behaviors in diseases from both morphological and molecular perspectives. Current analytical methods primarily focus on clustering and classification, and do not adequately examine the relationship between cell morphology and molecular dynamics. Here, we present MorphLink, a framework designed to systematically identify disease-related morphological-molecular interplays. MorphLink has been evaluated across a wide array of datasets, showcasing its effectiveness in extracting and linking interpretable morphological features with various molecular measurements in spatial omics analyses. These linkages provide a transparent view of cellular behavior heterogeneity within tissue regions with similar cell type compositions, …

Utility Of The Us Preventive Services Task Force For Preeclampsia Risk Assessment And Aspirin Prophylaxis, Thomas F Mcelrath, Arun Jeyabalan, Arkady Khodursky, Alison B Moe, Manfred Lee, Maneesh Jain, Laura Goetzl, Elizabeth F Sutton, Pamela M Simmons, George R Saade, Antonio Saad, Luis D Pacheco, Esther Park-Hwang, Antonina I Frolova, Ebony B Carter, Ai-Ris Y Collier, Daniel G Kiefer, Vincenzo Berghella, Rupsa C Boelig, Michal A Elovitz, Cynthia Gyamfi-Bannerman, Joseph R Biggio, Kara Rood, William A Grobman, Carrie Haverty, Morten Rasmussen

Faculty, Staff and Student Publications

Importance: The US Preventive Services Task Force (USPSTF) guidelines on preeclampsia risk assessment and aspirin prophylaxis (AP) have not been evaluated for clinical utility.

Objective: To evaluate which characteristics in the USPSTF guidelines identify risk status and the association of preeclampsia risk with AP recommendations.

Design, setting, and participants: This observational cohort study enrolled from July 2020 to March 2023 with data analysis performed from October to December 2024. Enrollment occurred at 11 centers throughout the US or via direct-to-participant recruitment. Pregnant participants aged 18 years or older with a singleton pregnancy less than 22 weeks' gestation were selected via …

Author Correction: Autologous T Cell Therapy For Prame+ Advanced Solid Tumors In Hla-A*02+ Patients: A Phase 1 Trial, Martin Wermke, Dejka M Araujo, Manik Chatterjee, Apostolia M Tsimberidou, Tobias A W Holderried, Amir A Jazaeri, Ran Reshef, Carsten Bokemeyer, Winfried Alsdorf, Katrin Wetzko, Peter Brossart, Katrin Aslan, Linus Backert, Sebastian Bunk, Jens Fritsche, Swapna Gulde, Silvana Hengler, Norbert Hilf, Mohammad B Hossain, Jens Hukelmann, Mamta Kalra, Delfi Krishna, M Alper Kursunel, Dominik Maurer, Andrea Mayer-Mokler, Regina Mendrzyk, Ali Mohamed, Karine Pozo, Arun Satelli, Marilena Letizia, Heiko Schuster, Oliver Schoor, Claudia Wagner, Hans-Georg Rammensee, Carsten Reinhardt, Harpreet Singh-Jasuja, Steffen Walter, Toni Weinschenk, Jason J Luke, Cedrik M Britten

Faculty, Staff and Student Publications

No abstract provided.

Targeting Cdk2 And Other Novel Cell Cycle Targets For Breast Cancer Therapy, Mei-Kuang Chen, Linjie Luo, Nicole Massoumi, Khandan Keyomarsi

Faculty, Staff and Student Publications

Introduction: The dysregulation of cyclin-dependent kinases (CDKs) is a key driver of cancer progression, making them attractive therapeutic targets. In CDK4/6 inhibitor (CDK4/6i)-resistant breast cancer, targeting CDK2 offers a promising approach. CDK2 is frequently hyperactivated due to cyclin E1 overexpression or retinoblastoma protein loss, acting as a mechanism that sustains proliferation despite CDK4/6 inhibition. CDK2 inhibitors (CDK2i) show strong anti-tumor activity, particularly in combination with CDK4/6i or immune checkpoint inhibitors.

Areas covered: This review explores the biological roles of CDK2 and its regulatory mechanisms. The review highlights the latest advancements in CDK2i, their mechanisms of action, and their potential in …

Institutional Learning Curve And Factors Of Prolonged Operation Time Of Robotic Distal Pancreatectomy: An Analysis Of An Initial 117 Cases, Yuki Hirata, Laura Prakash, Jess Maxwell, Rebecca Snyder, Michael Kim, Hop Tran Cao, Ching-Wei D Tzeng, Jefferey E Lee, Matthew H G Katz, Naruhiko Ikoma

Faculty, Staff and Student Publications

Background: The granular methods by which centers can safely implement and effectively expand robotic distal pancreatectomy (RDP), including those related to appropriate patient selection during the learning curve period, remain unclear. This study aimed to verify that our strategic robotic surgical oncology program effectively implemented RDP as standard practice and to identify factors associated with prolonged operation time.

Materials and methods: We performed a detailed analysis of the intraoperative and short-term outcomes of consecutive patients (October 2018-September 2023) undergoing RDP at our center, beginning with the first patient in our program. Operation time was analyzed using a cumulative sum chart …

Ovarian Cancer Risk And Survival According To Tumor Sex Hormone Receptor Expression: An Ovarian Cancer Association Consortium And Ovarian Tumor Tissue Analysis Consortium Pooled Analysis, Zhuxuan Fu, Lauren Borho, Sarah E Taylor, Linda E Kelemen, Anna Defazio, Penelope M Webb, Martin Köbel, Nicola S Meagher, Renhua Na, Antonis C Antoniou, Alison H Brand, Catherine J Kennedy, Nikilyn Nevins, Paul D P Pharoah, Yurii B Shvetsov, Stacey J Winham, Jennifer Alsop, Matthias W Beckmann, Adelyn Bolithon, Jessica Boros, David D L Bowtell, James D Brenton, Michael E Carney, Anita Chudecka-Głaz, Linda S Cook, Cezary Cybulski, Peter A Fasching, Sian Fereday, Renée T Fortner, María J García, Ellen L Goode, Marc T Goodman, Jacek Gronwald, Arndt Hartmann, Brenda Y Hernandez, Estrid Høgdall, David G Huntsman, Allan Jensen, Mercedes Jimenez-Linan, Janine M Joseph, Beth Y Karlan, Ewa Kaznowska, Susanne K Kjaer, Tomasz Kluz, Jennifer M Koziak, Jenny Lester, Teri A Longacre, Maria Lycke, Valerie Mcguire, Kirsten B Moysich, Rachel A Murphy, Sandra Orsulic, Susan J Ramus, Cristina Rodríguez-Antona, Joseph H Rothstein, Spinder Samra, Weiva Sieh, Helen Steed, Karin Sundfeldt, Aline Talhouk, Jan Uciński, Chen Wang, Nicolas Wentzensen, Alice S Whittemore, Lynne R Wilkens, Thomas Songer, Maria Mori Brooks, Lu Tang, Francesmary Modugno

Faculty, Staff and Student Publications

Objective: Many epithelial ovarian cancer (EOC) risk factors relate to sex hormones. The association between these factors and the expression of androgen receptor (AR), estrogen receptor-α (ER), and progesterone receptor (PR) in tumors is unknown.

Method: We linked epidemiologic, AR/ER/PR tumor expression, and survival data from 19 studies in the Ovarian Cancer Association Consortium (OCAC; 4762 cases, 20,888 controls) and the Ovarian Tumor Tissue Analysis (OTTA) consortium (5737 cases). We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) between hormonally-linked factors and tumor AR/ER/PR expression using polytomous logistic regression. We assessed survival by AR/ER/PR tumor expression overall and …

Involved But Not Essential: Cognitive Activity In Periventricular Nodules And Neuropsychological Outcomes Following Their Ablation, Yosefa A Modiano, Oscar Woolnough, Ryan M Mccormack, Kathryn Snyder, Ellery Wheeler, Samden D Lhatoo, Nuria Lacuey, Sandipan Pati, Katherine Harris, Jay Gavvala, Jessica A Johnson, Nitin Tandon

Faculty, Staff and Student Publications

Objective: Periventricular nodular heterotopia (PVNH) is a malformation of cortical development with high rates of epilepsy. The extent to which nodules participate in normal cerebral functions in addition to pathological processes is unclear. The authors assessed the functional utility (i.e., cognitive impacts) of surgically ablated epileptogenic PVNH tissue via comprehensive neuropsychological testing.

Methods: The sample included 32 patients with PVNH who underwent presurgical neuropsychological evaluation and a subsample of 16 patients who underwent MR-guided laser interstitial thermal therapy (MRgLITT) of nodules, with postsurgical neuropsychological testing. In 11 patients in whom intracranial recordings were performed, reading and naming tasks were tested …

Heat Shock Induces Alternative Polyadenylation Through Dynamic Dna Methylation And Chromatin Looping, Emily E Fink, Yi Zhang, Briana Santo, Anwita Siddavatam, Rosie Ou, Vishal Nanavaty, Byron H Lee, Angela H Ting

Faculty, Staff and Student Publications

Alternative cleavage and polyadenylation (APA) is a gene regulatory mechanism used by cells under stress to upregulate proteostasis-promoting transcripts, but how cells achieve this remains poorly understood. Previously, we elucidated a DNA methylation-regulated APA mechanism, in which gene body DNA methylation enhances distal poly(A) isoform expression by blocking CCCTC-binding factor (CTCF) binding and chromatin loop formation at APA control regions. We hypothesized that DNA methylation-regulated APA is one mechanism cells employ to induce proteostasis-promoting poly(A) isoforms. At the DNAJB6 cochaperone locus, acute heat shock resulted in binding of stress response transcription factors heat shock factor 1, ATF6, and YY1 at …

Diagnostic Guidance For Chronic Complex Regional Pain Syndrome Type I And Type Ii From The American Society Of Interventional Physicians (Asipp), Christopher Gharibo, Miles Day, Steve M Aydin, Alan D Kaye, Salahadin Abdi, Sudhir Diwan, Lisa V Doan, Danielle Feng, Kris Ferguson, Kirolos Georges, Andrew Kaufman, Nebojsa Nick Knezevic, Sean Li, Franzes A Liongson, Devi Nampiaparampil, Annu Navani, Mahendra Sanapati, Michael E Schatman, Amol Soin, Peter S Staats, Giustino Varrassi, Jing Wang, Laxmaiah Manchikanti

Faculty, Staff and Student Publications

Background: Complex Regional Pain Syndrome (CRPS) is a challenging and often disabling condition marked by persistent pain, most commonly in a limb following injury or surgery. It presents with a wide array of symptoms, including intense pain, swelling, alterations in skin color and temperature, motor dysfunction, and trophic changes such as skin and tissue atrophy. While the precise cause of CRPS is not fully understood, it is thought to stem from abnormal nervous system activity, leading to heightened pain sensitivity and inflammatory responses. A thorough understanding of CRPS is essential for accurate diagnosis, effective treatment, and enhancing patients' quality of …

Incomplete Toxicity Reporting And Use Of Toxicity-Minimizing Language In Phase Iii Oncology Trials, Avital M Miller, Adina H Passy, Alexander D Sherry, Ramez Kouzy, Joseph Abi Jaoude, Timothy A Lin, Gabrielle S Kupferman, Esther J Beck, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

Purpose: This study aimed to determine complete toxicity reporting (CTR), and the use of subjective toxicity-minimizing language (TML) among phase III oncology trials.

Methods: Two-arm superiority-design phase III oncology trials published from 2002 to 2020 were reviewed for toxicity data. CTR was defined as reporting total adverse events (TAEs), total serious adverse events (SAEs), total deaths, and study therapy discontinuations because of toxicity. Guideline concordance was defined according to guidelines published in the BMJ (defined as reporting total SAEs, total deaths, and study therapy discontinuations because of toxicity). TML was defined as a set of terms that subjectively downplay the …

Renal G Protein-Coupled Estrogen Receptor 1 Regulates The Epithelial Sodium Channel Promoting Natriuresis To A Greater Extent In Females, Victoria L Nasci, Jean C Bopassa, Elena Mironova, Megan Rhoads, Ravneet Singh, Dennis P Buehler, David M Pollock, Oleh M Pochynyuk, James D Stockand, Eman Y Gohar

Faculty, Staff and Student Publications

Hypertension prevalence is lower in women than men. Enhanced renal sodium (Na+) handling in females has been implicated in sex-differences in hypertension. Epithelial Na+ channel (ENaC) is a key contributor to Na+ homeostasis and is regulated by estrogen. Recent evidence suggests G protein-coupled estrogen receptor 1 (GPER1) evokes a female-specific natriuresis that involves endothelin-1 (ET-1). ET-1 has been shown to downregulate ENaC activity, but whether GPER1 regulates ENaC to modulate natriuresis is unknown. We tested the hypothesis that renal GPER1 functionally interacts with ENaC to promote natriuresis in a sex-specific manner. RNAscope confirmed co-expression of GPER1 and ENaC in rat …

Long-Term Cytoreduction Outcomes With Or Without Heated Intraperitoneal Chemotherapy For Colorectal Peritoneal Metastases, Michael G White, Paula Marincola Smith, Neal Bhutiani, Beth Helmink, Norman Galbraith, Scott Kopetz, Michael Overman, Paul Mansfield, Keith Fournier, Abhineet Uppal

Faculty, Staff and Student Publications

Background: Patients with peritoneal metastases from colorectal adenocarcinoma (CRC) benefit from cytoreductive surgery (CRS). However, the role of heated intraperitoneal chemotherapy (HIPEC) remains unclear. We studied associations between HIPEC, peritoneal disease-free survival (PDFS), and overall survival (OS) in patients with CRC undergoing CRS.

Study design: All patients with CRC undergoing CRS between 2008 and 2023 were retrospectively identified at our center. Patient clinicodemographic factors were determined by chart review. OS and PDFS were evaluated using the Kaplan-Meier method. Associations between clinical factors and survival were determined using Cox proportional hazard models.

Results: A total of 147 patients were identified with …

Practical Considerations For Using The Tite-Boin Design To Handle Late-Onset Toxicity Or Fast Accrual In Phase I Trials, Kai Chen, Ting-Yu Chen, Yiming Zhang, Ruitao Lin, Ying Yuan

Faculty, Staff and Student Publications

Conducting phase I trials is particularly challenging when dealing with late-onset dose-limiting toxicity (DLT) or when patient accrual is rapid relative to the DLT assessment window. In such cases, a new cohort may be ready for enrollment before the DLT assessments are complete for the current cohort, complicating dose assignment decisions. The time-to-event Bayesian optimal interval (TITE-BOIN) design was developed to address this issue by enabling real-time dose assignment for new cohorts, even when some enrolled patients' DLT data are still pending. This design has been increasingly adopted in practice. Upon reviewing trial protocols utilizing TITE-BOIN, we observed considerable variation …

Outcomes And Toxicity Following 3 Or More Definitive Courses Of Thoracic Radiation Therapy For Non-Small Cell Lung Cancer, Abigael Odwuor, Percy Lee, Joe Y Chang, Saumil Gandhi, Zhongxing Liao, Steven H Lin, Aileen Chen, Quynh-Nhu Nguyen, Michael S O'Reilly, Stephen G Chun, Julianna Bronk, David Qian, Matthew S Ning

Faculty, Staff and Student Publications

Purpose: Salvage re-irradiation is increasingly utilized to manage non-small cell lung cancer (NSCLC) locoregional recurrence or new lung primaries in previously treated areas. There is sparse information on efficacy and toxicity profile. We report a large experience of patients treated with multiple courses of definitive radiation for new and recurrent NSCLC.

Methods and materials: Medical records of patients who underwent ≥ 3 definitive thoracic radiation therapy (RT) courses for new or recurrent NSCLC at our cancer center from 2012 through 2021 were retrospectively reviewed following institutional review board approval. Toxicity was graded per Common Terminology Criteria for Adverse Events (CTCAE) …

Oatp1b1/1b3 Deficiency Exacerbates Hyperbilirubinemia In Erythropoietic Protoporphyria, Ruizhi Gu, Fu-Ying Qin, Luxuan Wang, Jiaojiao Zhang, Jacob Emerson, Qing Ma, Jie Lu, Karl E Anderson, Junmei Wang, Xiaochao Ma

Faculty, Staff and Student Publications

Erythropoietic protoporphyria (EPP) is caused by loss-of-function mutations in ferrochelatase (FECH), leading to the accumulation of its substrate, protoporphyrin IX (PPIX). PPIX is primarily produced in the bone marrow and transported to the liver for excretion. Because PPIX is hydrophobic, its elevated levels can cause bile duct blockage, cholestatic liver injury, and even liver failure. However, the specific transporter responsible for PPIX uptake into hepatocytes remains unclear. The OATP1B1/1B3 transporters, which are expressed in hepatocytes, facilitate the uptake of coproporphyrin III, a structural analog of PPIX. Additionally, OATP1B1/1B3 mediates the uptake of bilirubin, a biomarker of liver injury, from plasma …

Myh11 Rare Variant Augments Aortic Growth And Induces Cardiac Hypertrophy And Heart Failure With Pressure Overload, Zhen Zhou, Kgosi Hughes, Nisha Saif, Hyoseon Kim, Michael P Massett, Mingjie Zheng, Alana C Cecchi, Dongchuan Guo, David R Murdock, Ping Pan, Jelita S Clinton, Jun Wang, John M Greally, Dianna M Milewicz

Faculty, Staff and Student Publications

Smooth muscle cell-specific myosin heavy chain, encoded by MYH11, is selectively expressed in smooth muscle cells (SMCs). Pathogenic variants in MYH11 predispose to a number of disorders, including heritable thoracic aortic disease associated with patent ductus arteriosus, visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Rare variants of uncertain significance occur throughout the gene, including MYH11 p.Glu1892Asp, and we sought to determine if this variant causes thoracic aortic disease in mice. Genomic editing was used to generate Myh11E1892D/E1892D mice. Wild-type (WT) and mutant mice underwent cardiovascular phenotyping with and without transverse aortic constriction (TAC). Myh11E1892D/E1892D and WT mice displayed …

Mutation Dynamics From Diagnosis To Relapse In Acute Myeloid Leukemia With Chromosomal 7 Deletions, Eitan Kugler, Enes Dasdemir, Alex Bataller, Bofei Wang, Courtney D Dinardo, Naval Daver, Musa Yilmaz, Nicholas J Short, Gautam Borthakur, Tapan M Kadia, Koji Sasaki, Danielle Hammond, Alexandre Bazinet, Ehsan Irajizad, Beenu Thakral, Sherry Pierce, Patrick Reville, Farhad Ravandi, Hussein A Abbas

Faculty, Staff and Student Publications

Monosomy 7 and 7q deletions (-7/del(7q)) are the most common adverse cytogenetic event in acute myeloid leukemia (AML), linked to high relapse rates. We analyzed 115 AML patients with -7/del(7q) who achieved remission after induction therapy to characterize the mutational landscape from diagnosis to relapse. Median overall survival (OS) was 10.4 months, with improved survival in patients without TP53 mutation (13.04 vs. 8.6 months) or complex karyotype (12.4 vs. 8.6 months). TP53 mutations were most frequent (67% of cases at diagnosis) and persisted in 97% of patients at relapse. At time of relapse, patients with TP53 mutations had fewer co-occurring …

A Visual-Omics Foundation Model To Bridge Histopathology With Spatial Transcriptomics, Weiqing Chen, Pengzhi Zhang, Tu N Tran, Yiwei Xiao, Shengyu Li, Vrutant V Shah, Hao Cheng, Kristopher W Brannan, Keith Youker, Li Lai, Longhou Fang, Yu Yang, Nhat-Tu Le, Jun-Ichi Abe, Shu-Hsia Chen, Qin Ma, Ken Chen, Qianqian Song, John P Cooke, Guangyu Wang

Faculty, Staff and Student Publications

Artificial intelligence has revolutionized computational biology. Recent developments in omics technologies, including single-cell RNA sequencing and spatial transcriptomics, provide detailed genomic data alongside tissue histology. However, current computational models focus on either omics or image analysis, lacking their integration. To address this, we developed OmiCLIP, a visual-omics foundation model linking hematoxylin and eosin images and transcriptomics using tissue patches from Visium data. We transformed transcriptomic data into 'sentences' by concatenating top-expressed gene symbols from each patch. We curated a dataset of 2.2 million paired tissue images and transcriptomic data across 32 organs to train OmiCLIP integrating histology and transcriptomics. Building …

Local Control After Adjuvant Radiosurgery For Spinal Metastasis Treated With Decompression And Posterior Segmental Stabilization: A Comparison Between Carbon Fiber/Polyetheretherketone-Based And Metallic Implants, Romulo A Andrade-Almeida, Francisco Call-Orellana, Juan P Zuluaga-Garcia, Esteban Ramirez-Ferrer, Gil Kimchi, Brian S De, Alexandre B Guimaraes, Christopher A Alvarez-Breckenridge, Jing Li, Amol J Ghia, Laurence Rhines, Martin C Tom, Chenyang Wang, Thomas H Beckham, Behrang Amini, Robert Y North, Claudio E Tatsui

Faculty, Staff and Student Publications

Purpose: Carbon fiber-reinforced polyetheretherketone (CFRP) spinal implants are gaining popularity in the surgical management of spinal metastasis because of their physical and radiographic properties, which facilitate adjuvant radiation planning and tumor surveillance. Their impact on clinical outcomes is still under investigation. We evaluated the role of hardware material (CFRP vs titanium) in local control and hardware durability in metastatic cases receiving decompressive surgery and adjuvant spinal stereotactic radiosurgery (SSRS).

Methods and materials: This single-institution, retrospective cohort study was approved by the local institutional review board. Patients who underwent decompressive surgery with posterior segmental instrumentation followed by treatment with SSRS for …

Histone Lysine Methyltransferases Mll3 And Mll4 Direct Gene Expression To Produce Platelets Efficiently, Guozhen Gao, Josimar Dornelas Moreira, Prosun Das, Kevin Lin, Kai Ge, Taiping Chen, Yue Lu, Margarida A Santos

Faculty, Staff and Student Publications

Circulating blood platelets are responsible for maintaining hemostasis. They are released into blood vessels from mature megakaryocytes. Although several transcription factors have been reported to orchestrate the transcriptional programs required for platelet production, how chromatin regulators control these processes is still poorly understood. MLL3 and MLL4 are the main lysine methyltransferases responsible for the deposition of H3K4me1 histone marks at enhancers. MLL3 and MLL4 typically form complexes with other co-factors, such as PTIP. Recently, we showed that loss of PTIP leads to decreased platelet numbers in mice. Here, we find that, although MLL3/4 double deficiency does not alter megakaryopoiesis and …

Blood Bacterial Dna Signatures In A Prospective Cohort Of Patients With Masld Cirrhosis, Suet-Ying Kwan, Lillian I Dolapchiev, Caren I Sanchez, Tiffany L Calderone, Jessica I Sanchez, Megha B Bhongade, Ahmed El Sabagh, Darrel W Cleere, Nakul Gupta, Prasun K Jalal, David W Victor, Laura Beretta

Faculty, Staff and Student Publications

Background: Predictive biomarkers are needed to identify individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), at high risk for HCC. Our study aimed to determine whether the detection of circulating bacterial DNA could be associated with HCC development in MASLD patients with liver cirrhosis.

Methods: We developed a multicenter prospective cohort of patients with cirrhosis undergoing surveillance for HCC by contrast-enhanced magnetic resonance imaging. In a nested cohort study, we performed 16S rRNA sequencing of cell-free DNA extracted from 343 longitudinal plasma samples collected from 151 MASLD patients with cirrhosis. Among the 151 patients, 25 developed HCC during follow-up.

Results: …

Kap1 Promotes Gastric Adenocarcinoma Progression By Activating Hippo/Yap1 Signaling Via Binding To Hnrnpab, Shumei Song, Yibo Fan, Gengyi Zou, Longfei Huo, Janani Kumar, Yuan Li, Ruiping Wang, Enyu Dai, Jiankang Jin, Ailing W Scott, Shan Shao, Melissa Pool Pizzi, Jody V Vykoukal, Hiroyuki Katayama, Samir Hanash, George A Calin, Xing Zhang, Min Gyu Lee, Zhenning Wang, Yuan-Hung Lo, Qiong Gan, Rebecca E Waters, Feng Yin, Linghua Wang, Xiaodong Cheng, Jaffer A Ajani, Shilpa S Dhar

Faculty, Staff and Student Publications

Gastric adenocarcinoma (GAC) remains a significant global health challenge, with over a million new cases annually. Peritoneal carcinomatosis (PC), detected in ∼20 % of cases at diagnosis and ∼45 % later, is uniformly fatal, with limited treatment options. This study investigated the role of KAP1 in GAC progression, focusing on its interaction with YAP1 and cancer stemness traits. Analysis of over 596 primary GACs and 72 PC samples revealed that high nuclear KAP1 expression correlates with poor prognosis. KAP1 knockdown reduced oncogenic activity and stemness traits in GAC cells. Mechanistically, KAP1 positively regulates YAP1 transcription by binding to its promoter …

Tumour And Microenvironment Crosstalk In Nsclc Progression And Response To Therapy, Zahraa Rahal, Roy El Darzi, Seyed Javad Moghaddam, Tina Cascone, Humam Kadara

Faculty, Staff and Student Publications

The treatment landscape of non-small-cell lung cancer (NSCLC) is evolving rapidly, driven by advances in the development of targeted agents and immunotherapies. Despite this progress, some patients have suboptimal responses to treatment, highlighting the need for new therapeutic strategies. In the past decade, the important role of the tumour microenvironment (TME) in NSCLC progression, metastatic dissemination and response to treatment has become increasingly evident. Understanding the complexity of the TME and its interactions with NSCLC can propel efforts to improve current treatment modalities, overcome resistance and develop new treatments, which will ultimately improve the outcomes of patients. In this Review, …