Medical Specialties Commons^™

Z-Scores Outperform Similar Methods For Analyzing Crispr Paralog Synthetic Lethality Screens, Juihsuan Chou, Nazanin Esmaeili Anvar, Reem Elghaish, Junjie Chen, Traver Hart

Faculty, Staff and Student Publications

Genetic screens offer a promising strategy for identifying tumor-specific therapeutic targets, but single-gene knockout screens often miss functionally redundant paralogs. Multiplex Cas9 and Cas12a CRISPR systems have been deployed to assay genetic interactions, but analysis pipelines vary considerably. Here we evaluate data from four in4mer CRISPR/Cas12a screens in cancer cell lines, using delta log fold change, Z-transformed dLFC, and rescaled dLFC approaches to identify synthetic lethal interactions. Both ZdLFC and RdLFC provide more consistent identification of synthetic lethal pairs across cell lines compared to the unscaled dLFC method, while ZdLFC benefits from not requiring a training set of known interactors.

Differential Efficacy Of Bevacizumab And Erlotinib In Preclinical Models Of Renal Medullary Carcinoma And Fumarate Hydratase-Deficient Renal Cell Carcinoma, Niki M Zacharias, Manuel Ozambela, Menuka Karki, Rong He, Pankaj K Chauhan, Pedro I Pesquera, Andres E Hernandez Gonzalez, Oscar Ochoa, Alberto Pieretti, Huiqin Chen, Carolyn De La Cerda, Zhiyuan Yu, Abha Grover, Samantha Hicks-Peña, Natalie W Fowlkes, Lei Wang, Tapati Maity, Priya Rao, Giannicola Genovese, Nizar M Tannir, Jose A Karam, Pavlos Msaouel

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare and highly aggressive cancers. Although the combination of vascular endothelial growth factor (VEGF) inhibition by bevacizumab and epidermal growth factor receptor (EGFR) inhibition by erlotinib is clinically used for both diseases, the differential effect of each component has not been investigated. Transcriptomic profiling revealed that RMC and FH-deficient tumor tissues demonstrate increased EGFR but not VEGF expression compared with adjacent normal kidney. Subsequent in vitro studies revealed that RMC and FH-deficient cell lines are sensitive to erlotinib treatment, whereas clear cell RCC cell lines are resistant. …

Structural And Functional Characterization Of Creb-Binding Protein (Crebbp) As A Histone Propionyltransferase, Guiling Cui, Marie Ley, Ariel E Mechaly, Linh-Chi Bui, Christina Michail, Jérémy Berthelet, Julien Dairou, Haopeng Yang, Guillaume Chevreux, Gautier Moroy, Michael R Green, Ahmed Haouz, Fernando Rodrigues Lima

Faculty, Staff and Student Publications

In addition to histone acetylation, histone lysine propionylation (such as the H3K18Pr mark) has recently attracted significant attention as a common and abundant modification linking the cellular metabolic state and gene expression. CREB-binding protein (CREBBP) and EP300 are key histone acetyltransferases that play a critical role in gene expression through their catalytic activity. Although CREBBP and EP300 are homologous enzymes with high structural similarities, they exhibit both redundant and specific functions. Dissecting the shared and divergent properties of CREBBP and EP300 is thus important to understand their roles. However, despite the importance of CREBBP, most mechanistic and structural studies have …

Cat: A Conditional Association Test For Microbiome Data Using A Permutation Approach, Yushu Shi, Liangliang Zhang, Kim-Anh Do, Robert R Jenq, Christine B Peterson

Faculty, Staff and Student Publications

In microbiome analysis, researchers often seek to identify taxonomic features associated with an outcome of interest. However, microbiome features are intercorrelated and linked by phylogenetic relationships, making it challenging to assess the association between an individual feature and an outcome. This paper proposes a novel conditional association test, CAT, that can account for other features and phylogenetic relatedness when testing the association between a feature and an outcome. CAT adopts a permutation approach, measuring the importance of a feature in predicting the outcome by permuting operational taxonomic unit/amplicon sequence variant counts belonging to that feature from the data and quantifying …

Pol Θ-Mediated End-Joining Uses Microhomologies Containing Mismatches, Yuzhen Li, Ngoc K Dang, Wei He, Mark Returan, Denisse Carvajal-Maldonado, Adele T Guerin, Han Xu, Bin Liu, Richard D Wood

Faculty, Staff and Student Publications

DNA polymerase theta (Pol θ) initiates repair of DNA double-strand breaks by pairing single strands at short "microhomologies". It is important to understand microhomology selection, as some cancer cells rely on Pol θ for survival. Here, we investigate end-joining by purified human Pol θ, employing DNA sequencing of products generated from oligonucleotide libraries having diverse 3' ends. Pol θ overwhelmingly selects short internal microhomologies found within 15 nucleotides of the terminus of single-stranded DNAs, restricting deletion size during end-joining. Significantly, we find that the selected microhomologies are usually interrupted by mismatches and that base pairing within 6 nucleotides of the …

Immature Acta2r179c/+ Smooth Muscle Cells Cause Moyamoya-Like Cerebrovascular Lesions In Mice Prevented By Boosting Oxphos, Anita Kaw, Suravi Majumder, Jose E Esparza Pinelo, Ting Wu, Zbigniew Starosolski, Zhen Zhou, Albert J Pedroza, Xueyan Duan, Kaveeta Kaw, Angie D Gonzalez, Ripon Sarkar, Michael P Fischbein, Philip L Lorenzi, Lin Tan, Sara A Martinez, Iqbal Mahmud, Laxman Devkota, L Maximilian Buja, Heinrich Taegtmeyer, Ketan B Ghaghada, Sean P Marrelli, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

ACTA2 pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusions of the distal internal carotid arteries, but the mechanisms of pathogenesis are unknown and no preventive treatments exist. Here we show that Acta2R179C/+ smooth muscle cells (SMCs) fail to fully differentiate and maintain stem cell-like features, including increased migration and glycolytic flux compared to wildtype (WT) SMCs. Increasing mitochondrial respiration with nicotinamide riboside (NR) drives differentiation and decreases migration of Acta2R179C/+ SMCs. Carotid artery injury of Acta2SMC-R179C/+ mice leads to premature death, intraluminal SMC accumulation leading to MMD-like occlusive lesions, neurologic symptoms, …

The Landscape Of Malignant Transition: Unraveling Cancer Cell-Of-Origin And Heterogeneous Tissue Microenvironment, Ruihan Luo, Jiajia Liu, Tiangang Wang, Weiling Zhao, Yanfei Wang, Jianguo Wen, Hongyu Wang, Shanli Ding, Xiaobo Zhou

Faculty, Staff and Student Publications

Understanding disease progression and sophisticated tumor ecosystems is imperative for investigating tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous microenvironments during malignant transitions by leveraging data from 1396 samples spanning 13 major tissues. Within transitional stem-like subpopulations highly enriched in precancers and cancers, we identified 30 recurring cellular states strongly linked to malignancy, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing dynamics in stem-cell crosstalk with the microenvironment along the pseudotime axis, we found differential roles of ANXA1 at different stages of tumor development. In precancerous stages, reduced …

Crispr-Cas9 Mediated Proteinase 3 Autoantigen Deletion As A Treatment Strategy For Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis, Uwe Jerke, Claudia Eulenberg-Gustavus, Dimitrios Laurin Wagner, Adrian Schreiber, Ralph Kettritz

Faculty, Staff and Students Publications

Introduction: Proteinase 3 (PR3) is a major autoantigen in patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Here, we performed a proof-of-principle study using ex vivo CRISPR-Cas9 guided gene editing to eliminate the PR3 autoantigen as an alternative to suppressing the autoimmune response to PR3.

Methods: A ribonucleoprotein (RNP) complex of Cas9 protein and a PR3-specific single guide-RNA was transfected into human CD34+ hematopoietic stem and progenitor cells (HSPC) by electroporation. Effects on PR3 protein abundance, neutrophil differentiation, and ANCA-dependent and -independent neutrophil responses were assessed.

Results: Gene editing introduced a frame shift in exon 2 of PRTN3. Consequently, PR3 …

Integrative Analysis Reveals The Prognostic Effects Of Epigenetic Regulators In Bladder Cancer, Venugopalareddy Mekala, Yupei Lin, Xiang Wang, Naail Chowdhury, Jianrong Li, Chao Cheng

Faculty, Staff and Students Publications

Background: Epigenetic regulatory genes (epiRG) are pivotal in the epigenetic regulation of the human genome, primarily through DNA and histone modifications. These genes are frequently mutated in human cancers, particularly bladder cancer (BC). However, the functional impact of epiRG mutations on patient outcomes remains poorly understood.

Methods: In this study, we developed gene signatures for the most frequent genomic aberrations of epiRG using The Cancer Genome Atlas Bladder Carcinoma (TCGA-BLCA) dataset and validated these signatures with independent tumor expression profiles for prognostic relevance. Furthermore, we evaluated the role of these signature scores in the immune system within the tumor microenvironment …

Functional Regulation Of Macrophages By Ces1d-Mediated Lipid Signaling In Immunometabolism, Long J Shao, Fathima Elizondo, Feng Gao, Rabie Habib, Xin Li, Katherine Pham, Jazmin Ysaguirre, Maryam Elizondo, Shirindokht Shirazi, Kristin L Eckel-Mahan, Sean Hartig, Huaizhu Wu, Kai Sun

Faculty, Staff and Student Publications

Objective: Macrophage accumulation in metabolically active tissues during obesity is common in both animals and humans, but the lipid signaling mechanisms that trigger macrophage inflammation remain unclear. This study investigates the role of Ces1d, an unconventional lipase, in regulating macrophage inflammation under nutritional stress.

Methods: A myeloid-specific Ces1d knockout (LysM-Cre-Ces1d floxed/floxed, KO) mouse model was used for the studies. For in vitro tests, bone marrow-derived macrophages (BMDMs) from control (Ces1d floxed/floxed, WT) and KO mice were assessed for migration, polarization, and activation. For in vivo experiments, WT and KO mice were induced to obesity via a high-fat diet (HFD) and …

First-In-Human Phase 1 Study Of Khk2455 Monotherapy And In Combination With Mogamulizumab In Patients With Advanced Solid Tumors, Timothy A Yap, Olivier Rixe, Capucine Baldini, Ursa Brown-Glaberman, Sergey Efuni, David S Hong, Christophe Massard, Jameel Muzaffar, Andreea Varga, Emrullah Yilmaz, Yuta Ikawa, Lisa H Shiue, Yi Liu, Matthew W Hruska, Henry Zhao, Akihiro Tokunaga, Solmaz Sahebjam

Faculty, Staff and Student Publications

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that degrades tryptophan (Trp) to kynurenine (Kyn), which suppresses effector T cells and reduces antitumor activity. KHK2455 is a long-acting selective IDO1 inhibitor that blocks the heme component of the IDO holoenzyme. Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody targeting CCR4. KHK2455 + mogamulizumab demonstrated enhanced antitumor activity in preclinical studies, which led to a first-in-human, two-part, multicenter, open-label, phase 1, dose-escalation, cohort-expansion trial (ClinicalTrials.gov identifier NCT02867007) evaluating the safety/tolerability, pharmacokinetics, and IDO1 activity of KHK2455 alone and in combination with mogamulizumab in patients with treatment-refractory advanced solid tumors. …

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 …

Mtap Immunohistochemistry As A Surrogate Marker Of Cdkn2a Loss In Brain Tumors: A Meta-Analysis And Literature Review, Antonio Dono, Diego Pichardo-Rojas, Leonardo Mendoza Mora, Pavel S Pichardo-Rojas, Luis A Marin-Castañeda, Abril Carrillo, Adrian Coria Medrano, Yoshua Esquenazi, Leomar Y Ballester

Faculty, Staff and Student Publications

Given the known relationship between CDKN2A homozygous deletion (HD) and worsened outcomes in both meningiomas and IDH-mutant astrocytomas, it is paramount to identify CDKN2A HD for accurate risk stratification of patients. Multiple array platforms can detect CDKN2A HD. However, these methods are expensive and are not readily available at every institution. To address this, we conducted a meta-analysis and literature review to evaluate 5'-methylthioadenosine phosphorylase (MTAP) expression determined by immunohistochemistry (IHC) as a surrogate of CDKN2A HD. Our study analyzed 7 cohort studies, 3 of which focused on meningiomas encompassing a total of 87 patients; and 4 studies were conducted …

Mechanisms Of Experience-Dependent Place-Cell Referencing In Hippocampal Area Ca1, Fish Kunxun Qian, Yiding Li, Jeffrey C Magee

Faculty, Staff and Students Publications

Hippocampal CA1 place cells (PCs) encode both space- and goal-referenced information to support a cognitive map. The mechanism of this referencing and the role of experience remain poorly understood. Here we longitudinally recorded PC activity while head-fixed mice performed a spatial learning task on a treadmill. In a familiar environment, the CA1 representation consisted of PCs that were referenced to either specific spatial locations or a reward goal in approximately equal proportions; however, the CA1 representation became predominately goal-referenced upon exposure to a novel environment, as space-referenced PCs adaptively switched reference frames. Intracellular membrane potential recordings revealed that individual CA1 …

Pediatric Cancer Predisposition And Surveillance Update: Summary Perspective And Future Directions, Garrett M Brodeur, Lisa R Diller, Kim E Nichols, Sharon E Plon, Christopher C Porter, David Malkin

Faculty, Staff and Students Publications

An increasing number of studies suggest that a significant proportion of children with cancer harbor an underlying predisposition to malignancy, and it is likely that this proportion will only increase. Targeted surveillance for these individuals would likely improve outcomes. Historically, however, for most predisposition syndromes, there were no standardized surveillance protocols for early detection of cancer in predisposed individuals. Therefore, the Pediatric Cancer Working Group of the American Association for Cancer Research convened a workshop in 2016 to develop consensus surveillance recommendations (published in 2017) for children and adolescents with the most common cancer predisposition syndromes. These recommendations provided a …

Functional Assays In Drosophila Facilitate Classification Of Variants Of Uncertain Significance Associated With Rare Diseases, Jung-Wan Mok, Shelley B Gibson, Haley A Dostalik, Shinya Yamamoto

Faculty, Staff and Students Publications

Individuals living with rare diseases often undergo a frustrating and expensive diagnostic odyssey. Clinical geneticists who analyze exome or genome sequencing data from rare disease patients often encounter a list of variants of uncertain significance (VUS) in known disease-causing genes or rare variants in genes of uncertain significance (GUS) that are difficult to interpret, even with the integration of the latest bioinformatic tools. In this Perspective, we review how studies using the fruit fly Drosophila melanogaster have facilitated rare disease diagnosis by uncovering the clinical relevance of GUS and classifying rare variants into specific allelic categories (loss-of-function or gain-of-function, Muller's …

Endothelium- And Fibroblast-Derived C-Type Natriuretic Peptide Prevents The Development And Progression Of Aortic Aneurysm, Aisah A Aubdool, Amie J Moyes, Cristina Perez-Ternero, Reshma S Baliga, Jaspinder Singh Sanghera, M Taaha Syed, Kareemah Jaigirdar, Anmolpreet K Panesar, Janice C Tsui, Yanming Li, Hernan G Vasquez, Ying H Shen, Scott A Lemaire, Juliette Raffort, Ziad Mallat, Hong S Lu, Alan Daugherty, Adrian J Hobbs

Faculty, Staff and Students Publications

Background: Thoracic (TAA) and abdominal (AAA) aortic aneurysm are life-threatening diseases characterized by dilation, inflammation, and structural weakness; development of pharmacological therapies is desperately needed. CNP (C-type natriuretic peptide) plays a key role in vascular homeostasis, mediating vasodilator, anti-inflammatory, and antiatherogenic actions. Since such processes drive AA, we determined the role of endogenous CNP in offsetting pathogenesis.

Methods: Tissue from patients with AA was analyzed to determine the consequences on CNP signaling. Ascending and suprarenal aortic diameters were assessed at baseline and following Ang II (angiotensin II; 1.44 mg/kg per day) infusion in wild-type, endothelium-restricted (ecCNP-/-), fibroblast-restricted (fbCNP-/-), global CNP …

Non-Invasive Tools For Analysis Of Plasma Membrane Protein Topology In Living Cells, Daria Savenkova, Leysan Bulatova, Vera Skripova, Ramziya Kiyamova, Mikhail Bogdanov

Faculty, Staff and Student Publications

Membrane protein topology studies offer guidance to membrane protein structure, folding, and function, serving as a credible scaffold for designing site-directed mutagenesis and biochemical experiments, helping to identify functionally significant extracellular and intracellular regions, modeling three-dimensional structures, and building reliable mechanistic models. Membrane protein structure as a function of given lipid composition and physiological state of the cell is best probed in whole intact cells. A described simple and advanced immunofluorescence protocol applied to the transmembrane orientation of extramembrane domains permits a topology analysis of plasma membrane proteins in their native state in living unperturbed eucaryotic cells. The accessibility of …

Long Akap18 Isoforms Anchor Ubiquitin Specific Proteinases And Coordinate Calcium Reuptake At The Sarcoplasmic Reticulum, Taeyeop Park, Katherine Forbush, Yong Li, Oscar Vivas, Kacey J Rosenthal, Jerome Falcone, Cassandra J Wong, James E Bruce, Claudia Moreno, Carmen W Dessauer, John D Scott

Faculty, Staff and Student Publications

Subcellular targeting of signaling enzymes influences where and when various modes of intracellular communication operate. Macromolecular complexes of signal transduction and signal termination elements favor reversible control of repetitive processes. This includes adrenergic stimulation of excitation–contraction coupling in the heart. Long isoforms of A-kinase anchoring protein 18 (AKAP18γ and δ) modulate this process via regulation of calcium uptake into the sarcoplasmic reticulum through the Ca2+ATPase 2a (SERCA2a). AKAP18 proximity-proteomic screening in cardiomyocytes identifies networks for protein kinase A (PKA) and ubiquitin-specific proteinases (USPs). A 2′phosphoesterase domain on AKAP18 interfaces with the USP4 isoform at the Z bands of sarcomeres. PKA …

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 …

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 …

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 …

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 …

The Landscape Of Malignant Transition: Unraveling Cancer Cell-Of-Origin And Heterogeneous Tissue Microenvironment, Ruihan Luo, Jiajia Liu, Tiangang Wang, Weiling Zhao, Yanfei Wang, Jianguo Wen, Hongyu Wang, Shanli Ding, Xiaobo Zhou

Faculty, Staff and Student Publications

Understanding disease progression and sophisticated tumor ecosystems is imperative for investigating tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous microenvironments during malignant transitions by leveraging data from 1396 samples spanning 13 major tissues. Within transitional stem-like subpopulations highly enriched in precancers and cancers, we identified 30 recurring cellular states strongly linked to malignancy, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing dynamics in stem-cell crosstalk with the microenvironment along the pseudotime axis, we found differential roles of ANXA1 at different stages of tumor development. In precancerous stages, reduced …

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 …

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 …

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 …

Bayesian Inference Of Fitness Landscapes Via Tree-Structured Branching Processes, Xiang Ge Luo, Jack Kuipers, Kevin Rupp, Koichi Takahashi, Niko Beerenwinkel

Faculty, Staff and Student Publications

Motivation: The complex dynamics of cancer evolution, driven by mutation and selection, underlies the molecular heterogeneity observed in tumors. The evolutionary histories of tumors of different patients can be encoded as mutation trees and reconstructed in high resolution from single-cell sequencing data, offering crucial insights for studying fitness effects of and epistasis among mutations. Existing models, however, either fail to separate mutation and selection or neglect the evolutionary histories encoded by the tumor phylogenetic trees.

Results: We introduce FiTree, a tree-structured multi-type branching process model with epistatic fitness parameterization and a Bayesian inference scheme to learn fitness landscapes from single-cell …

The Long-Term Effects Of Chemotherapy On Normal Blood Cells, Emily Mitchell, My H Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I Hsu, Nina Friesgaard Øbro, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E Machado, E Joanna Baxter, George Follows, Daniel J Hodson, Ultan Mcdermott, Gary J Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A Goodell, David Kent, Elisa Laurenti, Peter J Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R Stratton

Faculty, Staff and Student Publications

Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3-80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes …