Medical Specialties Commons^™

Phase I Trial Of Tti-101, A First-In-Class Oral Inhibitor Of Stat3, In Patients With Advanced Solid Tumors, Apostolia M Tsimberidou, David J Vining, Sukeshi P Arora, Sofia De Achaval, Jeffrey Larson, John Kauh, Carrie Cartwright, Rony Avritscher, Imran Alibhai, David J Tweardy, Ahmed O Kaseb

Faculty, Staff and Student Publications

Purpose: Signal transducer and activator of transcription 3 is a transcription factor that is essential for the survival and immune sequestration of cancer cells. We conducted a phase I study of TTI-101, a first-in-class, selective small-molecule inhibitor of signal transducer and activator of transcription 3, in patients with advanced metastatic cancer.

Patients and methods: Patients were treated with TTI-101 orally twice daily in 28-day cycles at four dose levels (DL): 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/day ("3+3" design). Three TTI-101 formulations were used in a stepwise manner (NCT03195699).

Results: Sixty-four patients were treated (median …

Ca-125 As A Biomarker In Renal Medullary Carcinoma: Integrated Molecular Profiling, Functional Characterization, And Prospective Clinical Validation, Sandra L Grimm, Menuka Karki, Kyle A Blum, Jean-Philippe Bertocchio, Rong He, Durga N Tripathi, Niki M Zacharias, Justin M Lebenthal, Rahul A Sheth, Priya Rao, Giannicola Genovese, Zhen Lu, Robert C Bast, Davis R Ingram, Rossana Lazcano, Khalida M Wani, Wei-Lien Wang, Alexander J Lazar, Nizar M Tannir, Cheryl L Walker, Cristian Coarfa, Pavlos Msaouel

Faculty, Staff and Student Publications

Purpose: Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC.

Experimental design: Integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA sequencing and histone chromatin immunoprecipitation sequencing. The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. …

Genetic Associations With C-Peptide Levels Before Type 1 Diabetes Diagnosis In At-Risk Relatives, Taylor M Triolo, Hemang M Parikh, Mustafa Tosur, Lauric A Ferrat, Lu You, Peter A Gottlieb, Richard A Oram, Suna Onengut-Gumuscu, Jeffrey P Krischer, Stephen S Rich, Andrea K Steck, Maria J Redondo

Children’s Nutrition Research Center Staff Publications

Objective: We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms are associated with C-peptide preservation before type 1 diabetes diagnosis.

Methods: We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known single nucleotide polymorphisms and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis.

Results: Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before …

Exploring Profiles Of Fathers Integrating Food And Physical Activity Parenting Practices, John A Jimenez-Garcia, Louise C Mâsse, Robert L Newton, Salma M Musaad, Alicia Beltran, Teresia M O'Connor

Children’s Nutrition Research Center Staff Publications

Objective: This study aims to identify fathers' profiles integrating food parenting practices (FPP) and physical activity parenting practices (PAPP).

Design: We analysed cross-sectional data. The fathers completed the reduced FPP and PAPP item banks and socio-demographic and family dynamics (co-parenting and household responsibility) questionnaires. We identified fathers' profiles via latent profile analysis. We explored the influence of social determinants, child characteristics and family dynamics on fathers' profiles using multinomial logistic regression.

Setting: Online survey in the USA.

Participants: Fathers of 5-11-year-old children.

Results: We analysed data from 606 fathers (age = 38 ± 8·0; Hispanic = 37·5 %). Most fathers …

Inflammation And Gut Barrier Function-Related Genes And Colorectal Cancer Risk In Western European Populations, Hannah B Mandle, Mazda Jenab, Marc J Gunter, Anne Tjønneland, Anja Olsen, Christina C Dahm, Jie Zhang, Pierre-Emmanuel Sugier, Joseph Rothwell, Gianluca Severi, Rudolf Kaaks, Verena A Katzke, Matthias B Schulze, Giovanna Masala, Sabina Sieri, Salvatore Panico, Carlotta Sacerdote, Catalina Bonet, Maria-Jose Sánchez, Pilar Amiano, José María Huerta, Marcela Guevara, Richard Palmqvist, Thyra Löwenmark, Aurora Perez-Cornago, Elisabete Weiderpass, Alicia K Heath, Amanda J Cross, Paolo Vineis, David J Hughes, Veronika Fedirko

Faculty, Staff and Student Publications

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N = 1374; colon = 871, rectum = 503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set …

Adding Metastasis-Directed Therapy To Standard-Of-Care Systemic Therapy For Oligometastatic Breast Cancer (Extend): A Multicenter, Randomized Phase 2 Trial, Jay P Reddy, Alexander D Sherry, Bryan Fellman, Suyu Liu, Tharakeswara Bathala, Cara Haymaker, Lorenzo Cohen, Benjamin D Smith, David Ramirez, Simona F Shaitelman, Stephen G Chun, Marina Medina-Rosales, Mediget Teshome, Abenaa Brewster, Carlos H Barcenas, Alexandre Reuben, Amol J Ghia, Ethan B Ludmir, Daniel Weed, Shalin J Shah, Melissa P Mitchell, Wendy A Woodward, Daniel R Gomez, Chad Tang

Faculty, Staff and Student Publications

PURPOSE: Prior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer.

METHODS AND MATERIALS: External Beam Radiation to Eliminate Nominal Metastatic Disease is a multicenter phase 2 randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomly assigned 1:1 to MDT (definitive local treatment …

Superior Preclinical Efficacy Of Co-Treatment With Brg1/Brm And Flt3 Inhibitor Against Aml Cells With Flt3 Mutations, Warren Fiskus, Christopher P Mill, Jessica Piel, Mike Collins, Murphy Hentemann, Branko Cuglievan, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Tapan M Kadia, Naval Daver, Koji Sasaki, Koichi Takahashi, Danielle Hammond, Patrick K Reville, Lauren B Flores, Sanam Loghavi, Xiaoping Su, Courtney D Dinardo, Kapil N Bhalla

Faculty, Staff and Student Publications

Although treatment with standard frontline therapies, including a FLT3 inhibitor (FLT3i) reduces AML burden and achieves clinical remissions, most patients with AML with FLT3 mutation relapse due to therapy-resistant stem/progenitor cells. The core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2) of the canonical (c) BAF (BRG1/BRM-associated factor) complex is a dependency in AML cells, including those harboring FLT3 mutations. We have previously reported that treatment with FHD-286, a BRG1/BRM ATPases inhibitor, induces differentiation and loss of viability of AML stem/progenitor cells. Findings of present studies demonstrate that treatment with FHD-286 induces lethality in AML cells, regardless of sensitivity or resistance to …

Effects Of Social Isolation On Locus Coeruleus Opioid Receptor Expression And Affective Behavior, John Tkaczynski, Jordan Riser, Maya Patel, Nicole Shellenbarger, Jin Park, Daniel Manvich, Daniel J Chandler

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Social isolation is a stressor that impairs homeostatic neuroendocrine functions and is associated with the development of several mood disorders characterized by persistent negative affect. Persistent feelings of loneliness have been growing public health concerns for several years and were greatly exacerbated by the onset of the COVID-19 pandemic. The problem has grown so severe the U.S. Surgeon General recently declared loneliness to be an epidemic health concern that is associated with poor mental and somatic health outcomes. Therefore, identifying mechanisms of neuroadaptation that contribute to the development of persistent negative affect is a critical step in the identifying better …

Precision Phenotyping For Curating Research Cohorts Of Patients With Unexplained Post-Acute Sequelae Of Covid-19, Alaleh Azhir, Jonas Hügel, Jiazi Tian, Jingya Cheng, Ingrid V Bassett, Douglas S Bell, Elmer V Bernstam, Maha R Farhat, Darren W Henderson, Emily S Lau, Michele Morris, Yevgeniy R Semenov, Virginia A Triant, Shyam Visweswaran, Zachary H Strasser, Jeffrey G Klann, Shawn N Murphy, Hossein Estiri

Faculty, Staff and Student Publications

BACKGROUND: Scalable identification of patients with post-acute sequelae of COVID-19 (PASC) is challenging due to a lack of reproducible precision phenotyping algorithms, which has led to suboptimal accuracy, demographic biases, and underestimation of the PASC.

METHODS: In a retrospective case-control study, we developed a precision phenotyping algorithm for identifying cohorts of patients with PASC. We used longitudinal electronic health records data from over 295,000 patients from 14 hospitals and 20 community health centers in Massachusetts. The algorithm employs an attention mechanism to simultaneously exclude sequelae that prior conditions can explain and include infection-associated chronic conditions. We performed independent chart reviews …

Tunneling Nanotube-Like Structures Regulate Distant Cellular Interactions During Heart Formation, Lianjie Miao, Yangyang Lu, Anika Nusrat, Guizhen Fan, Shaohua Zhang, Luqi Zhao, Chia-Ling Wu, Hongyan Guo, Trang Le Nu Huyen, Yi Zheng, Zhen-Chuan Fan, Weinian Shou, Robert J Schwartz, Yu Liu, Ashok Kumar, Haixin Sui, Irina I Serysheva, Alan R Burns, Leo Q Wan, Bin Zhou, Sylvia M Evans, Mingfu Wu

Faculty, Staff and Student Publications

In the developing mammalian heart, the endocardium and the myocardium are separated by so-called cardiac jelly. Communication between the endocardium and the myocardium is essential for cardiac morphogenesis. How membrane-localized receptors and ligands achieve interaction across the cardiac jelly is not understood. Working in developing mouse cardiac morphogenesis models, we used a variety of cellular, imaging, and genetic approaches to elucidate this question. We found that myocardium and endocardium interacted directly through microstructures termed tunneling nanotube-like structures (TNTLs). TNTLs extended from cardiomyocytes (CMs) to contact endocardial cells (ECs) directly. TNTLs transported cytoplasmic proteins, transduced signals between CMs and ECs, and …

Strategies To Improve Antibody-Mediated Protection Against Herpes Simplex Virus Infections, Matthew D. Slein

Dartmouth College Ph.D Dissertations

No efficacious vaccine exists for herpes simplex virus and the global burden of disease remains high. Antibodies can serve as potent therapeutics to protect high risk populations such as neonates. Although rare, neonatal HSV (nHSV) infections can result in significant mortality and lifelong neurological morbidity even with antiviral therapy. While HSV-specific maternally derived antibodies significantly reduce the risk of neonatal disease in humans, the mechanisms by which they mediate protection have yet to be described. Using a mouse model of neonatal HSV (nHSV) infections we aimed to determine the mechanisms of antibody-mediated protection using monoclonal antibodies (mAbs) targeting two of …

Exploration Of Working Memory Retrieval Stage For Mild Cognitive Impairment: Time-Varying Causality Analysis Of Electroencephalogram Based On Dynamic Brain Networks, Yi Jiang, Zhiwei Guo, Xiaobo Zhou, Ning Jiang, Jiayuan He

Faculty, Staff and Student Publications

Background: Mild Cognitive Impairment (MCI) is an intermediate stage between the expected cognitive decline of normal aging and Alzheimer's disease (AD). Its management is crucial for it helps intervene and slow the progression of cognitive decline to AD. However, the understanding of the MCI mechanism is not completely clear. As working memory (WM) damage is a common symptom of MCI, this study focused on the core stage of WM, i.e., the memory retrieval stage, to investigate information processing and the causality relationships among brain regions based on electroencephalogram (EEG) signals.

Method: 21 MCI and 20 normal cognitive control (NC) participants …

Efficacy And Safety Of Venetoclax Plus Azacitidine For Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes, Jacqueline S Garcia, Uwe Platzbecker, Olatoyosi Odenike, Shaun Fleming, Chun Yew Fong, Uma Borate, Meagan A Jacoby, Daniel Nowak, Maria R Baer, Pierre Peterlin, Brenda Chyla, Huipei Wang, Grace Ku, David Hoffman, Jalaja Potluri, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study investigated safety and efficacy of venetoclax, a selective B-cell lymphoma 2 inhibitor, at the recommended phase 2 dose (RP2D; 400 mg for 14 days per 28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days per 28-day cycle) for treatment-naive HR MDS. Safety was the primary outcome, and complete remission (CR) rate was the primary efficacy outcome. Secondary outcomes included rates of modified overall response (mOR), hematologic improvement (HI), overall survival (OS), and time to next treatment (TTNT). …

Deep Learning Models Based On Pretreatment Mri And Clinicopathological Data To Predict Responses To Neoadjuvant Systemic Therapy In Triple-Negative Breast Cancer, Zhan Xu, Zijian Zhou, Jong Bum Son, Haonan Feng, Beatriz E Adrada, Tanya W Moseley, Rosalind P Candelaria, Mary S Guirguis, Miral M Patel, Gary J Whitman, Jessica W T Leung, Huong T C Le-Petross, Rania M Mohamed, Bikash Panthi, Deanna L Lane, Huiqin Chen, Peng Wei, Debu Tripathy, Jennifer K Litton, Vicente Valero, Lei Huo, Kelly K Hunt, Anil Korkut, Alastair Thompson, Wei Yang, Clinton Yam, Gaiane M Rauch, Jingfei Ma

Faculty, Staff and Student Publications

Purpose: To develop deep learning models for predicting the pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) in patients with triple-negative breast cancer (TNBC) based on pretreatment multiparametric breast MRI and clinicopathological data.

Methods: The prospective institutional review board-approved study [NCT02276443] included 282 patients with stage I-III TNBC who had multiparametric breast MRI at baseline and underwent NAST and surgery during 2016-2021. Dynamic contrast-enhanced MRI (DCE), diffusion-weighted imaging (DWI), and clinicopathological data were used for the model development and internal testing. Data from the I-SPY 2 trial (2010-2016) were used for external testing. Four variables with a …

Efficacy And Safety Of Venetoclax Plus Azacitidine For Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes, Jacqueline S Garcia, Uwe Platzbecker, Olatoyosi Odenike, Shaun Fleming, Chun Yew Fong, Uma Borate, Meagan A Jacoby, Daniel Nowak, Maria R Baer, Pierre Peterlin, Brenda Chyla, Huipei Wang, Grace Ku, David Hoffman, Jalaja Potluri, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study investigated safety and efficacy of venetoclax, a selective B-cell lymphoma 2 inhibitor, at the recommended phase 2 dose (RP2D; 400 mg for 14 days per 28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days per 28-day cycle) for treatment-naive HR MDS. Safety was the primary outcome, and complete remission (CR) rate was the primary efficacy outcome. Secondary outcomes included rates of modified overall response (mOR), hematologic improvement (HI), overall survival (OS), and time to next treatment (TTNT). …

Cranial Radiation Disrupts Dopaminergic Signaling And Connectivity In The Mammalian Brain, Die Zhang, Riya Thomas, Thanh Thai Lam, Ines Veselinovic, David R Grosshans

Faculty, Staff and Student Publications

Cognitive impairment is a common and challenging side effect of cranial radiation therapy for brain tumors, though its precise mechanisms remain unclear. The mesocortical dopaminergic pathway, known to play a key role in cognitive function, is implicated in several neuropsychiatric disorders, yet its involvement in radiation-induced cognitive dysfunction is unexplored. Here, with using in vivo multi-electrode array recordings of both anesthetized and free-moving rats to monitor the firing activities of dopamine neurons in the ventral tegmental area (VTA) and local field potentials in both the prefrontal cortex (PFC) and VTA, as well as the immunofluorescence assays and western blotting, we …

Influence Of Marching Band Experience On Eating Disorder Risk And Perceived Stress In Collegiate Marching Artists, Kalor Greve, Jaclyn B. Caccese, Matthew P. Brancaleone

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Introduction: Collegiate marching artists face severe and prevalent stressors that may contribute to poor mental health and unhealthy habits. The purpose of this study was to determine the effect of sex and years of participation in collegiate marching band on the relationship between eating disorder risk and perceived stress levels. Methods: Marching artists from an NCAA Division I university completed the Eating Disorder Questionnaire-6 (EDEQ-6) and Perceived Stress Scale (PSS-10) to obtain disordered eating behaviors and perceived stress levels, respectively. Spearman rank correlations were used to determine the relationship between PSS-10 scores and global and subscale EDEQ-6 scores, …

Retention Of Cpr Knowledge And Skills Among Ncaa Division Iii Athletic Coaches: A Prospective Cohort Study, Allison Hanstine, Jaclyn Tate, Chyrsten Gessel

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Objective/Context: It is crucial for athletic coaches to be proficient in cardiopulmonary resuscitation (CPR) knowledge and skill performance for the health and safety of their athletes. This research aimed to assess CPR knowledge and CPR skill retention five months post-training among athletic coaches. In addition, the study assessed whether the number of years certified in CPR had an association with CPR skill performance scores five months post-training. Design and Setting: As a part of a master’s thesis, this prospective cohort study was performed over a five-month period to align with the research timeline. Participants: The study was conducted among 19 …

A Pilot Study: Effects Of 5-Week Hamstring Training On Functional Movement Screen Scores., Julie Landrigan, Colin Tomes

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Introduction. The Functional Movement Screen (FMS) can be used by clinicians to assess movement and asymmetries in their clients. Understanding FMS composite and subtest scores can be a useful way for clinicians to monitor risk of injury. The purpose of this study was to identify if eccentric hamstring stretching and Nordic hamstring curls could improve movement, FMS scores, and active straight leg raise range of motion. Methods. Participants consisted of a convenience sample of high-school athletes. All subjects participated in the intervention, performing the FMS screen pre- and post-Nordic curls and stretching. Results. This pilot study suggests that the …

Normative Performance Test Metrics In Professional Female Club Soccer, Andy Seraphin, Christi Edson, Cory Price, Barrett Jones, Amanda Jagielo, Justin Mullner

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Objective: To establish normative ranges in common performance tests for professional women’s club soccer. Setting:1^st division professional women’s soccer club in the United States

Participants: Twenty-eight healthy professional women’s soccer players (Age: 27.8 ± 5.1 years; Body Mass: 66.2 ± 6.7 kg). Main Outcome Measures: Countermovement Jump, Isometric Mid-Thigh Pull, and Nordic Hamstring Curl tests were performed to obtain lower body compound strength, power, and eccentric hamstring strength. Paired-samples t tests were used to determine between-limbs differences for each outcome measure. Results: Jump height had a mean of 28.9 ± 4.2 cm. Peak vertical force (IMTP) had a …

Control Of Clostridioides Difficile Virulence And Physiology By The Flagellin Homeostasis Checkpoint Flic-Fliw-Csra In The Absence Of Motility, Duolong Zhu, Katherine J Wozniak, Firas Midani, Shaohui Wang, Xingmin Sun, Robert A Britton

Faculty, Staff and Students Publications

Mutations affecting Clostridioides difficile flagellin (FliC) have been shown to be hypervirulent in animal models and display increased toxin production and alterations in central metabolism. The regulation of flagellin levels in bacteria is governed by a tripartite regulatory network involving fliC, fliW, and csrA, which creates a feedback system to regulate flagella production. Through genomic analysis of C. difficile clade 5 strains (non-motile), we identified they have jettisoned many of the genes required for flagellum biosynthesis yet retain the major flagellin gene fliC and regulatory gene fliW. We therefore investigated the roles of fliC, fliW …

Alpha-Frequency Stimulation Strengthens Coupling Between Temporal Fluctuations In Alpha Oscillation Power And Default Mode Network Connectivity, Yijia Ma, Joshua A Brown, Chaowen Chen, Mingzhou Ding, Wei Wu, Wen Li

Faculty, Staff and Student Publications

Alpha (8–12 Hz) oscillations and default mode network (DMN) activity dominate the brain's intrinsic activity in the temporal and spatial domains, respectively. They are thought to play crucial roles in the spatiotemporal organization of the complex brain system. Relatedly, both have been implicated, often concurrently, in diverse neuropsychiatric disorders, with accruing electroencephalogram (EEG)/magnetoencephalogram and functional magnetic resonance imaging (fMRI) data linking these two neural activities both at rest and during key cognitive operations. Prominent theories and extant findings thus converge to suggest a mechanistic relationship between alpha oscillations and the DMN. Here, we leveraged simultaneous EEG–fMRI data acquired before and …

Advancing Drug Development In Myelodysplastic Syndromes, Alain Mina, Kathy L Mcgraw, Lea Cunningham, Nina Kim, Emily Y Jen, Katherine R Calvo, Lori A Ehrlich, Peter D Aplan, Guillermo Garcia-Manero, James M Foran, Jacqueline S Garcia, Amer M Zeidan, Amy E Dezern, Rami Komrokji, Mikkael A Sekeres, Bart Scott, Rena Buckstein, Sara Tinsley-Vance, Amit Verma, Tanya Wroblewski, Steven Pavletic, Kelly Norsworthy

Faculty, Staff and Student Publications

Myelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges …

Avasimibe Abolishes The Efficacy Of Fluvastatin For The Prevention Of Cancer In A Spontaneous Mouse Model Of Breast Cancer, Anjana Bhardwaj, Alexander Koh, Rhea Bhala, Janvi Sandhu, Zhenlin Ju, Leslie Faye Cando, Jing Wang, Isabelle Bedrosian

Faculty, Staff and Student Publications

The cholesterol biosynthesis pathway is upregulated during breast cancer development and progression. Inhibition of the aberrantly upregulated cholesterol pathway by statins reduces breast tumor incidence and burden by 50% in SV40 C3(1) TAg mice, a mouse model of triple negative breast cancer. We hypothesized that fluvastatin's preventive efficacy could be further enhanced by co-targeting the statin-induced restorative feedback pathways that tightly control the cholesterol pathway and are involved in resistance to statins. Acyl-coenzyme A: cholesterol acyltransferase (

A Phase I/Ii Trial Of Avelumab Combinations With Ivuxolimab, Utomilumab, And Radiation Therapy In Patients With Advanced Gastrointestinal Malignancies, Jibran Ahmed, Anne Knisely, Carlos Torrado, Bettzy Stephen, Yali Yang, Juhee Song, Anas Alshawa, Abdulrazzak Zarifa, Anuja Jhingran, Eugene J Koay, Van Karlyle Morris, Milind Javle, Robert A Wolff, Funda Meric-Bernstam, Shubham Pant, Jordi Rodon, Aung Naing

Faculty, Staff and Student Publications

Background: Checkpoint agonists utomilumab (4-1BB agonist) and ivuxolimab (OX40 agonist) enhance Teffector cell function. Preclinical studies suggest that combining these drugs with avelumab (anti-PD-L1 antibody) can potentially synergize this effect. In addition, tissue abscopal effects of radiation therapy may improve antigen presentation, complementing PD-L1 blockade. We conducted a single institution, open-label, multi-arm, non-randomized, phase 1/2 clinical trial of avelumab in combination with ivuxolimab, with or without utomilumab, and radiation therapy in patients with advanced solid tumors. Herein, we present a subgroup analysis in patients with gastrointestinal (GI) tumors (pancreatic, colon, gastric, and hepatocellular).

Methods: The primary objectives of this study …

Advances In Extracellular Matrix-Associated Diagnostics And Therapeutics, Morten Karsdal, Thomas R Cox, Amelia L Parker, Nicholas Willumsen, Jannie Marie Bülow Sand, Gisli Jenkins, Henrik H Hansen, Anouk Oldenburger, Kerstin E Geillinger-Kaestle, Anna Thorsø Larsen, Darcey Black, Federica Genovese, Alexander Eckersley, Andrea Heinz, Alexander Nyström, Signe Holm Nielsen, Lucas Bennink, Lars Johannsson, Anne-Christine Bay-Jensen, Dana E Orange, Scott Friedman, Mads Røpke, Vincent Fiore, Detlef Schuppan, Florian Rieder, Benjamin Simona, Lee Borthwick, Mark Skarsfeldt, Haakan Wennbo, Paresh Thakker, Ruedi Stoffel, Graham W Clarke, Raghu Kalluri, Darren Ruane, Faiez Zannad, Joachim Høg Mortensen, Dovile Sinkeviciute, Fred Sundberg, Molly Coseno, Christian Thudium, Adam P Croft, Dinesh Khanna, Michael Cooreman, Andre Broermann, Diana Julie Leeming, Ali Mobasheri, Sylvie Ricard-Blum

Faculty, Staff and Student Publications

The extracellular matrix (ECM) is the common denominator of more than 50 chronic diseases. Some of these chronic pathologies lead to enhanced tissue formation and deposition, whereas others are associated with increased tissue degradation, and some exhibit a combination of both, leading to severe tissue alterations. To develop effective therapies for diseases affecting the lung, liver, kidney, skin, intestine, musculoskeletal system, heart, and solid tumors, we need to modulate the ECM's composition to restore its organization and function. Across diverse organ diseases, there are common denominators and distinguishing factors in this fibroinflammatory axis, which may be used to foster new …

Incidence And Correlates Of High-Grade Chemotherapy-Induced Peripheral Neuropathy In Patients With Lung Cancer, Mitchell S Von Itzstein, Sawsan Rashdan, Suzanne E Dahlberg, David E Gerber, Alan B Sandler, Joan H Schiller, David H Johnson, Yating Wang, Zhuoxin Sun, Suresh S Ramalingam

Faculty, Staff and Student Publications

Background: High-grade chemotherapy-induced peripheral neuropathy (CIPN) represents a dreaded toxicity of cancer treatments. In some cases, it may limit activities of daily living and become permanent. Because many prior studies of CIPN were conducted in breast cancer populations, less is known about CIPN in men. We therefore determined the incidence and correlates of high-grade CIPN in a large cohort of patients with lung cancer.

Methods: We collected data from the ECOG-ACRIN E1594 (comparison of 4 chemotherapy regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) and E4599 (carboplatin-paclitaxel ± concurrent and maintenance bevacizumab) clinical trials. We identified cases with grade ≥3 CIPN. Multivariable logistic …

Prophylaxis, Clinical Management, And Monitoring Of Datopotamab Deruxtecan-Associated Oral Mucositis/Stomatitis, Funda Meric-Bernstam, Aditya Bardia, Paolo Bossi, Giampaolo Bianchini, Frances Gatlin, Rajesh V Lalla, Barbara Melosky, Naoki Niikura, Timothy A Yap, Sophie S Kim, Rachana Rajagopalan, Rick M Fairhurst, Stephanie L Graff, Hope S Rugo

Faculty, Staff and Student Publications

Oral mucositis/stomatitis (hereafter stomatitis) is a common dose-limiting toxicity seen with various classes of cancer treatment. Symptoms associated with stomatitis, primarily oral pain, may impact patient quality of life and may lead to dose delay and reduction or treatment discontinuation. Datopotamab deruxtecan (Dato-DXd) is a novel trophoblast cell surface antigen 2-directed antibody-drug conjugate undergoing clinical investigation in multiple solid tumor types. Stomatitis is among the most reported adverse events associated with Dato-DXd, with most cases being grades 1-2. This article reviews the incidence of stomatitis seen with Dato-DXd, including in the phase III pivotal studies TROPION-Lung01 and TROPION-Breast01 (in patients …

Multi-Ancestry Transcriptome-Wide Association Studies Of Cognitive Function, White Matter Hyperintensity, And Alzheimer's Disease, Dima L Chaar, Zheng Li, Lulu Shang, Scott M Ratliff, Thomas H Mosley, Sharon L R Kardia, Wei Zhao, Xiang Zhou, Jennifer A Smith

Faculty, Staff and Student Publications

Genetic variants increase the risk of neurocognitive disorders in later life, including vascular dementia (VaD) and Alzheimer's disease (AD), but the precise relationships between genetic risk factors and underlying disease etiologies are not well understood. Transcriptome-wide association studies (TWASs) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWASs on VaD and AD have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European ancestry (EA) …

Molecular Model Of Tfiih Recruitment To The Transcription-Coupled Repair Machinery, Tanmoy Paul, Chunli Yan, Jina Yu, Susan E Tsutakawa, John A Tainer, Dong Wang, Ivaylo Ivanov

Faculty, Staff and Student Publications

Transcription-coupled repair (TCR) is a vital nucleotide excision repair sub-pathway that removes DNA lesions from actively transcribed DNA strands. Binding of CSB to lesion-stalled RNA Polymerase II (Pol II) initiates TCR by triggering the recruitment of downstream repair factors. Yet it remains unknown how transcription factor IIH (TFIIH) is recruited to the intact TCR complex. Combining existing structural data with AlphaFold predictions, we build an integrative model of the initial TFIIH-bound TCR complex. We show how TFIIH can be first recruited in an open repair-inhibited conformation, which requires subsequent CAK module removal and conformational closure to process damaged DNA. In …