Medicine and Health Sciences Commons^™

Successful Closed Reduction And Tooth-To-Tooth Wire-Fixation Of A Mandibular Singular Parasymphysis Fracture In A Male Collegiate Lacrosse Player, Steven Ross Murray, Coryann L. Leadford, Nathaniel Snyder, Robert W. Pettitt, Jeremy R. Hawkins

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

A 19-year-old male collegiate lacrosse player suffered an acute singular parasymphysis fracture of the mandible when he was struck in the facemask of his helmet by a lacrosse ball during practice. The fracture was confirmed via panoramic radiography and treated with a closed reduction under local anesthetic by looping a 26-gauge wire around the two right incisors and the right cuspid. This approach to managing the fracture was taken instead of an open reduction and plate application to be less invasive with the hope of a faster recovery and fewer complications. The fracture healed and aligned properly, and after six …

Reliability And Construct Validity Of The Single-Leg Landing Error Scoring System (Sl-Less) In Physically Active Females, Jennifer E. Earl-Boehm, Madison Mach, Erin Lally, Maegan O'Connor, Hayley Ericksen

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

PURPOSE Single-leg landings are common in sport and often result in injury, however a rubric to evaluate biomechanics during single-leg jump landing (SLL) does not exist. The Single-Leg Landing Error Scoring System (SL-LESS) is a rubric developed to evaluate movement during SLL. The purpose of this study was to 1) determine inter- and intra-rater reliability of the SL-LESS, 2) and determine the content and construct validity of the SL-LESS when evaluating SLL

METHOD 28 healthy females completed SLL on two days while 2D and 3D data were recorded. 3D angles were trunk flexion/lateral-flexion, pelvic tilt/contralateral drop, hip flexion/adduction, and knee …

Leadership And Management Curricula Trends In Athletic Training Education, Stephanie Wise, Matthew R. Kutz

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

Purpose: Leadership and management skills both are needed by athletic trainers. However, most professional education emphasizes management-related behaviors. The purpose of this study was to differentiate between leadership and management behaviors taught in athletic training programs and explore the pedagogical strategies used in teaching those behaviors. Method: A cross-sectional exploratory design was used to survey Athletic Training Program Directors (PDs). The Leadership and Management Education Assessment Instrument (LMEAI) was developed for this investigation. The LMEAI collected standard demographic characteristics of respondents and used a 5-point Likert scale (1 = extremely important to 5 = not at all important) to assess …

Quality Of Cardiopulmonary Resuscitation Performed Over Hockey Shoulder Pads: A Simulation Study, Jennifer Longo, Katie J. Lyman, Thomas A. Hanson, Adam G. Estabrooks

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

Purpose: Athletic trainers (ATs) must be prepared to manage cardiac arrest events in all athletes, including those participating in equipment-intensive sports. The goal of this study was to determine if first responders, specifically ATs, were able to perform high-quality cardiopulmonary resuscitation (CPR) over hockey shoulder pads. Methods: A sample of 50 ATs completed a one-minute, compression-only CPR proficiency test on a medium-fidelity manikin (Resusci Anne QCPR). Once deemed proficient, each participant completed CPR according to 2020 AHA guidelines on the manikin fitted with hockey shoulder pads for 8 minutes and 59 seconds. The primary measures of interest were the percentage …

Post-Activation Performance Enhancement Through Variable Loading Maintains Power Output Over Five Sets In Highly Trained Athletes, Robert Rocanelli, Morgan Siegel, Pedro Yunes, Pete Bommarito, Monique Mokha

Journal for Sports Neuroscience

The goal was to examine the acute effects of five sets of variable loading (VL) on the post-activation performance enhancement (PAPE) response during a live training session in highly trained athletes. PAPE is the phenomenon where acute improvements in power production in light loaded movements occur post near maximal loaded muscle contraction. PAPE may be induced with VL where resistance in the form of chains or bands is added to the bar as it displaces in the concentric phase. Participants were American football players from a variety of field positions (n=12, height =188 ± 0.01 cm, total body mass = …

Service Dogs: A Scoping Review Of Interdisciplinary Research, K. Lynn Pierce, Nancy A. Dreschel

People and Animals: The International Journal of Research and Practice

Despite a long history of service dogs (SDs) being paired with human partners as a systematic intervention and increasing numbers of and roles for SDs, there remains a lack of empirical knowledge and professional guidance regarding the implementation of SDs into treatment plans for individuals with disabilities. The purpose of this scoping review was to review the peer-reviewed literature specific to SDs and their handlers, to identify successful search term strategies, and to determine in what disciplines research is being conducted. Terminology used in referring to service dogs continues to be a challenge. Through a series of preliminary searches, search …

Microplastics In Water, Their Effects On The Aquatic Ecosystem And Human Public Health, And The Proposed Solutions, Mohanad Abouserie

The Undergraduate Research Journal

We could be swallowing a credit card's weight in plastic every week. Microplastic water pollution is becoming a threat to both humans and aquatic creatures. In this research, microplastic water contamination is discussed, and divergent solutions are proposed. This paper attempts to investigate the causes and effects of such pollution and analyze the current solutions for this issue. The adopted research method is secondary research, where several studies are explored and analyzed. This study explains numerous causes for this issue like cosmetics, cleaning products, factories, and sewage. Consequently, this contamination can negatively impact the organs and metabolisms of the living …

Bisphenol-A And Phthalate Metabolism In Children With Neurodevelopmental Disorders, T Peter Stein, Margaret D Schluter, Robert A Steer, Xue Ming

Rowan-Virtua School of Osteopathic Medicine Departmental Research

BACKGROUND: The etiology of autism spectrum (ASD) and Attention Deficit/Hyperactivity (ADHD) disorders are multifactorial. Epidemiological studies have shown associations with environmental pollutants, such as plasticizers. This study focused on two of these compounds, the Bisphenol-A (BPA) and Diethylhexyl Phthalate (DEHP). The major pathway for BPA and DEHP excretion is via glucuronidation. Glucuronidation makes insoluble substances more water-soluble allowing for their subsequent elimination in urine.

HYPOTHESIS: Detoxification of these two plasticizers is compromised in children with ASD and ADHD. Consequently, their tissues are more exposed to these two plasticizers.

METHODS: We measured the efficiency of glucuronidation in three groups of children, …

Sctiger: A Deep-Learning Method For Inferring Gene Regulatory Networks From Single-Cell Gene Expression Data, Madison Dautle

Theses and Dissertations

Inferring gene regulatory networks (GRNs) from single-cell RNA-sequencing (scRNA-seq) data is an important computational question to reveal fundamental regulatory mechanisms. Although many computational methods have been designed to predict GRNs, none work on condition specific GRNs by directly using paired datasets of case versus control experiments, common in diverse biological research projects. We present a novel deep-learning based method, scTIGER, for GRN detection by using the co-dynamics of gene expression. scTIGER also employs cell type-based pseudotiming, an attention-based convolutional neural network method, and permutation-based significance testing to infer GRNs from gene modules. We first applied scTIGER to scRNA-seq datasets of …

Folate Conjugated Nanomedicines For Selective Inhibition Of Mtor Signaling In Polycystic Kidneys At Clinically Relevant Doses, Rajasekharreddy Pala, Ayan K. Barui, Ashraf M. Mohieldin, Jing Zhou, Surya M. Nauli

Pharmacy Faculty Articles and Research

Although rapamycin is a very effective drug for rodents with polycystic kidney disease (PKD), it is not encouraging in the clinical trials due to the suboptimal dosages compelled by the off-target side effects. We here report the generation, characterization, specificity, functionality, pharmacokinetic, pharmacodynamic and toxicology profiles of novel polycystic kidney-specific-targeting nanoparticles (NPs). We formulated folate-conjugated PLGA-PEG NPs, which can be loaded with multiple drugs, including rapamycin (an mTOR inhibitor) and antioxidant 4-hydroxy-TEMPO (a nephroprotective agent). The NPs increased the efficacy, potency and tolerability of rapamycin resulting in an increased survival rate and improved kidney function by decreasing side effects and …

Examining Pi3k-Signaling-Dependent Regulation Of Lens Organelle Free Zone Formation Via Immunolocalization And Immunoblotting In Chick Embryos, Rifah Gheyas, A. Sue Menko

Computational Medicine Center Faculty Papers

The elimination of lens organelles during development, required for mature lens function, is an autophagy-dependent mechanism induced through suppression of PI3K signaling. Here, we present a protocol for investigating the signaling pathways responsible for induction of the formation of this lens organelle free zone. We describe steps for preparation of lens organ culture and use of signaling pathway inhibitors. We then detail procedures for analyzing their impact using both confocal microscopy imaging of immunolabeled lens cryosections and immunoblot approaches. For complete details on the use and execution of this protocol, please refer to Gheyas et al. (2022).

Precision Modulation Of Dysbiotic Adult Microbiomes With A Human-Milk-Derived Synbiotic Reshapes Gut Microbial Composition And Metabolites, Julie E Button, Casey M Cosetta, Abigail L Reens, Sarah L Brooker, Aislinn D Rowan-Nash, Richard C Lavin, Russell Saur, Shuning Zheng, Chloe A Autran, Martin L Lee, Adam K Sun, Amin M Alousi, Christine B Peterson, Andrew Y Koh, David J Rechtman, Robert R Jenq, Gregory J Mckenzie

Faculty, Staff and Student Publications

Manipulation of the gut microbiome using live biotherapeutic products shows promise for clinical applications but remains challenging to achieve. Here, we induced dysbiosis in 56 healthy volunteers using antibiotics to test a synbiotic comprising the infant gut microbe, Bifidobacterium longum subspecies infantis (B. infantis), and human milk oligosaccharides (HMOs). B. infantis engrafted in 76% of subjects in an HMO-dependent manner, reaching a relative abundance of up to 81%. Changes in microbiome composition and gut metabolites reflect altered recovery of engrafted subjects compared with controls. Engraftment associates with increases in lactate-consuming Veillonella, faster acetate recovery, and changes in indolelactate and p-cresol …

Dosimetry Of A Novel 111indium-Labeled Anti-P-Cadherin Monoclonal Antibody (Ff-21101) In Non-Human Primates, Gregory Ravizzini, William Erwin, Louis De Palatis, Lucia Martiniova, Vivek Subbiah, Vincenzo Paolillo, Jennifer Mitchell, Asa P Mccoy, Jose Gonzalez, Osama Mawlawi

Faculty, Staff and Student Publications

P-cadherin is associated with a wide range of tumor types, making it an attractive therapeutic target. FF-21101 is a human-mouse chimeric monoclonal antibody (mAb) directed against human P-cadherin, which has been radioconjugated with indium-111 (111In) utilizing a DOTA chelator. We investigated the biodistribution of FF-21101(111In) in cynomolgus macaques and extrapolated the results to estimate internal radiation doses of 111In- and yttrium-90 (90Y)-FF-21101 for targeted radioimmunotherapy in humans. Whole-body planar and SPECT imaging were performed at 0, 2, 24, 48, 72, 96, and 120 h post-injection, using a dual-head gamma camera. Volumes of interest of identifiable source organs of radioactivity were …

Pathogen-Driven Crispr Screens Identify Trex1as A Regulator Of Dna Self-Sensing During Influenza Virus Infection, Cason R King, Yiping Liu, Katherine A Amato, Grace A Schaack, Clayton Mickelson, Autumn E Sanders, Tony Hu, Srishti Gupta, Ryan A Langlois, Judith A Smith, Andrew Mehle

Faculty, Staff and Student Publications

Host:pathogen interactions dictate the outcome of infection, yet the limitations of current approaches leave large regions of this interface unexplored. Here, we develop a novel fitness-based screen that queries factors important during the middle to late stages of infection. This is achieved by engineering influenza virus to direct the screen by programming dCas9 to modulate host gene expression. Our genome-wide screen for pro-viral factors identifies the cytoplasmic DNA exonuclease TREX1. TREX1 degrades cytoplasmic DNA to prevent inappropriate innate immune activation by self-DNA. We reveal that this same process aids influenza virus replication. Infection triggers release of mitochondrial DNA into the …

Exploring Acute Pancreatitis Clinical Pathways Using A Novel Process Mining Method, Xue Yang, Wei Huang, Weiling Zhao, Xiaobo Zhou, Na Shi, Qing Xia

Faculty, Staff and Student Publications

Mining process models of medical behavior from electronic medical records is an effective way to optimize clinical pathways. However, clinical medical behavior is an extremely complex field with high nonlinearity and variability, and thus we need to adopt a more effective method. In this study, we developed a fuzzy process mining method for complex clinical pathways. Firstly, we designed a multi-level expert classification system with fuzzy values to preserve finer details. Secondly, we categorized medical events into long-term and temporary events for more specific data processing. Subsequently, we utilized electronic medical record (EMR) data of acute pancreatitis spanning 9 years, …

The Use Of Prognostic Markers To Predict Disease Progression And Clinical Outcome In Monoclonal Gammopathy Of Undetermined Significance, Smouldering Multiple Myeloma And Multiple Myeloma., Róisín C. Mcmonagle

International Undergraduate Journal of Health Sciences

Multiple Myeloma (MM) is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smouldering Multiple Myeloma (SMM) precede MM, with variable risks and rates of disease progression. The continuing high relapse and death rate in MM cases has prompted research into more accurate prognostic markers to predict progression from MGUS and SMM to MM, as well as identify MM cases with aggressive disease, in order to begin early, targeted and effective therapeutic intervention. Many studies have focused on utilising current markers more effectively, including M-protein, serum-free light chain ratio, …

The Endosomal Escape Vehicle Platform Enhances Delivery Of Oligonucleotides In Preclinical Models Of Neuromuscular Disorders, Xiang Li, Mahboubeh Kheirabadi, Patrick G Dougherty, Kimberli J Kamer, Xiulong Shen, Nelsa L Estrella, Suresh Peddigari, Anushree Pathak, Sara L Blake, Emmanuelle Sizensky, Carmen Del Genio, Arti B Gaur, Mohanraj Dhanabal, Mahasweta Girgenrath, Natarajan Sethuraman, Ziqing Qian

Faculty, Staff and Student Publications

Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides. Canonical cell-penetrating peptides, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our endosomal escape vehicle technology capable of delivering therapeutic agent-conjugated cargo intracellularly. We demonstrated the therapeutic potential of …

Interaction Between Myelodysplasia-Related Gene Mutations And Ontogeny In Acute Myeloid Leukemia, Joseph G W Mccarter, David Nemirovsky, Christopher A Famulare, Noushin Farnoud, Abhinita S Mohanty, Zoe S Stone-Molloy, Jordan Chervin, Brian J Ball, Zachary D Epstein-Peterson, Maria E Arcila, Aaron J Stonestrom, Andrew Dunbar, Sheng F Cai, Jacob L Glass, Mark B Geyer, Raajit K Rampal, Ellin Berman, Omar I Abdel-Wahab, Eytan M Stein, Martin S Tallman, Ross L Levine, Aaron D Goldberg, Elli Papaemmanuil, Yanming Zhang, Mikhail Roshal, Andriy Derkach, Wenbin Xiao

Faculty, Staff and Student Publications

Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort …

Biosafety And Biohazard Considerations Of Hsv-1-Based Oncolytic Viral Immunotherapy., Elizabeth Robilotti, Nathalie C Zeitouni, Marlana Orloff

Department of Medical Oncology Faculty Papers

Oncolytic viral immunotherapies are agents which can directly kill tumor cells and activate an immune response. Oncolytic viruses (OVs) range from native/unmodified viruses to genetically modified, attenuated viruses with the capacity to preferentially replicate in and kill tumors, leaving normal tissue unharmed. Talimogene laherparepvec (T-VEC) is the only OV approved for patient use in the United States; however, during the last 20 years, there have been a substantial number of clinical trials using OV immunotherapies across a broad range of cancers. Like T-VEC, many OV immunotherapies in clinical development are based on the herpes simplex virus type 1 (HSV-1), with …

Disease Modeling And Gene Correction Of Lgmdr21 Ipscs Elucidates The Role Of Poglut1 In Skeletal Muscle Maintenance, Regeneration, And The Satellite Cell Niche, Jose L Ortiz-Vitali, Jianbo Wu, Nasa Xu, Annie W Shieh, Nima Niknejad, Megumi Takeuchi, Carmen Paradas, Chunru Lin, Hamed Jafar-Nejad, Robert S Haltiwanger, Sidney H Wang, Radbod Darabi

Faculty, Staff and Student Publications

Autosomal recessive limb-girdle muscular dystrophy 21 (LGMDR21) is caused by pathogenic variants in protein O-glucosyltransferase 1 (POGLUT1), which is responsible for O-glucosylation of specific epidermal growth factor (EGF) repeats found in ∼50 mammalian proteins, including Notch receptors. Previous data from patient biopsies indicated that impaired Notch signaling, reduction of muscle stem cells, and accelerated differentiation are probably involved in disease etiopathology. Using patient induced pluripotent stem cells (iPSCs), their corrected isotypes, and control iPSCs, gene expression profiling indicated dysregulation of POGLUT1, NOTCH, muscle development, extracellular matrix (ECM), cell adhesion, and migration as involved pathways. They also exhibited reduced in vitro …

Cell-Type-Specific Alternative Polyadenylation Promotes Oncogenic Gene Expression In Non-Small Cell Lung Cancer Progression, Kexin Huang, Yun Zhang, Xiaorui Shi, Zhiqin Yin, Weiling Zhao, Liyu Huang, Fu Wang, Xiaobo Zhou

Faculty, Staff and Student Publications

Disrupted alternative polyadenylation (APA) is frequently involved in tumorigenesis and cancer progression by regulating the gene expression of oncogenes and tumor suppressors. However, limited knowledge of tumor-type- and cell-type-specific APA events may lead to novel APA events and their functions being overlooked. Here, we compared APA events across different cell types in non-small cell lung cancer (NSCLC) and normal tissues and identified functionally related APA events in NSCLC. We found several cell-specific 3'-UTR alterations that regulate gene expression changes showed prognostic value in NSCLC. We further investigated the function of APA-mediated 3'-UTR shortening through loss of microRNA (miRNA)-binding sites, and …

Preface: Causes Of Obesity, Theories, Conjectures And Evidence, David B Allison, Thorkild I A Sørensen, Kevin D Hall, John R Speakman

Children’s Nutrition Research Center Staff Publications

No abstract provided.

Integrative Multi-Omic Cancer Profiling Reveals Dna Methylation Patterns Associated With Therapeutic Vulnerability And Cell-Of-Origin, Wen-Wei Liang, Rita Jui-Hsien Lu, Reyka G Jayasinghe, Steven M Foltz, Eduard Porta-Pardo, Yifat Geffen, Michael C Wendl, Rossana Lazcano, Iga Kolodziejczak, Yizhe Song, Akshay Govindan, Elizabeth G Demicco, Xiang Li, Yize Li, Sunantha Sethuraman, Samuel H Payne, David Fenyö, Henry Rodriguez, Maciej Wiznerowicz, Hui Shen, D R Mani, Karin D Rodland, Alexander J Lazar, Ana I Robles, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Student Publications

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A …

Global Proteomic Identifies Multiple Cancer-Related Signaling Pathways Altered By A Gut Pathobiont Associated With Colorectal Cancer, Ewa Pasquereau-Kotula, Giulia Nigro, Florent Dingli, Damarys Loew, Patrick Poullet, Yi Xu, Scott Kopetz, Jennifer Davis, Lucie Peduto, Catherine Robbe-Masselot, Philippe Sansonetti, Patrick Trieu-Cuot, Shaynoor Dramsi

Faculty, Staff and Student Publications

In this work, we investigated the oncogenic role of Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut bacterium associated with colorectal cancer (CRC). We showed that SGG UCN34 accelerates colon tumor development in a chemically induced CRC murine model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 revealed that 164 proteins and 725 phosphorylation sites were differentially regulated. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced by SGG UCN34, as ~ 90% of proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed up-regulation of …

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows …

Treatment Of Older Adults With Flt3-Mutated Aml: Emerging Paradigms And The Role Of Frontline Flt3 Inhibitors, Nicholas J Short, Daniel Nguyen, Farhad Ravandi

Faculty, Staff and Student Publications

FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3-mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3-mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3-mutated AML are unsuitable …

Krasg12d Inhibition Reprograms The Tumor Microenvironment Of Early And Advanced Pancreatic Cancer To Promote Fas-Mediated Killing By Cd8+ T Cells, Krishnan K Mahadevan, Kathleen M Mcandrews, Valerie S Lebleu, Sujuan Yang, Hengyu Lyu, Bingrui Li, Amari M Sockwell, Michelle L Kirtley, Sami J Morse, Barbara A Moreno Diaz, Michael P Kim, Ningping Feng, Anastasia M Lopez, Paola A Guerrero, Francesca Paradiso, Hikaru Sugimoto, Kent A Arian, Haoqiang Ying, Yasaman Barekatain, Lakshmi Kavitha Sthanam, Patience J Kelly, Anirban Maitra, Timothy P Heffernan, Raghu Kalluri

Faculty, Staff and Student Publications

The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 …

Collagene Enables Privacy-Aware Federated And Collaborative Genomic Data Analysis, Wentao Li, Miran Kim, Kai Zhang, Han Chen, Xiaoqian Jiang, Arif Harmanci

Faculty, Staff and Student Publications

Growing regulatory requirements set barriers around genetic data sharing and collaborations. Moreover, existing privacy-aware paradigms are challenging to deploy in collaborative settings. We present COLLAGENE, a tool base for building secure collaborative genomic data analysis methods. COLLAGENE protects data using shared-key homomorphic encryption and combines encryption with multiparty strategies for efficient privacy-aware collaborative method development. COLLAGENE provides ready-to-run tools for encryption/decryption, matrix processing, and network transfers, which can be immediately integrated into existing pipelines. We demonstrate the usage of COLLAGENE by building a practical federated GWAS protocol for binary phenotypes and a secure meta-analysis protocol. COLLAGENE is available at https://zenodo.org/record/8125935 …

Unfolding The Secrets Of Small Cell Lung Cancer Progression: Novel Approaches And Insights Through Rapid Autopsies, Zsolt Megyesfalvi, Simon Heeke, Benjamin J Drapkin, Anna Solta, Ildiko Kovacs, Kristiina Boettiger, Lilla Horvath, Busra Ernhofer, Janos Fillinger, Ferenc Renyi-Vamos, Clemens Aigner, Karin Schelch, Christian Lang, Gyorgy Marko-Varga, Carl M Gay, Lauren A Byers, Benjamin B Morris, John V Heymach, Peter Van Loo, Fred R Hirsch, Balazs Dome

Faculty, Staff and Student Publications

The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms.

Early Onset Horizontal Gaze Palsy And Progressive Scoliosis Due To A Noncanonical Splicing-Site Variant And A Missense Variant In The Robo3 Gene, Sheng Yi, Zailong Qin, Xunzhao Zhou, Junjie Chen, Shang Yi, Qiuli Chen, Limei Huang, Qinle Zhang, Biyan Chen, Jingsi Luo

Faculty, Staff and Student Publications

BACKGROUND: Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified.

METHODS: We described an HGPPS patient and performed whole-exome sequencing (WES) to identify the causative gene.

RESULTS: We identified a missense variant and a splice-site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention …