Genetic Phenomena Commons^™

Temporal Recording Of Mammalian Development And Precancer, Mirazul Islam, Yilin Yang, Alan J Simmons, Vishal M Shah, Krushna Pavan Musale, Yanwen Xu, Naila Tasneem, Zhengyi Chen, Linh T Trinh, Paola Molina, Marisol A Ramirez-Solano, Iannish D Sadien, Jinzhuang Dou, Andrea Rolong, Ken Chen, Mark A Magnuson, Jeffrey C Rathmell, Ian G Macara, Douglas J Winton, Qi Liu, Hamim Zafar, Reza Kalhor, George M Church, Martha J Shrubsole, Robert J Coffey, Ken S Lau

Faculty, Staff and Student Publications

Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations1,2, an alternative solution leverages irreversible genetic changes, such as naturally occurring mutations, to create indelible marks that enables retrospective temporal ordering3–5. Using a multipurpose, single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, with incorporation of cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during mouse embryonic development, unconventional developmental relationships between cell …

A Protein Expression Atlas On Tissue Samples And Cell Lines From Cancer Patients Provides Insights Into Tumor Heterogeneity And Dependencies, Jun Li, Wei Liu, Kamalika Mojumdar, Hong Kim, Zhicheng Zhou, Zhenlin Ju, Shwetha V Kumar, Patrick Kwok-Shing Ng, Han Chen, Michael A Davies, Yiling Lu, Rehan Akbani, Gordon B Mills, Han Liang

Faculty, Staff and Student Publications

The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) are foundational resources in cancer research, providing extensive molecular and phenotypic data. However, large-scale proteomic data across various cancer types for these cohorts remain limited. Here, we expand upon our previous work to generate high-quality protein expression data for approximately 8,000 TCGA patient samples and around 900 CCLE cell line samples, covering 447 clinically relevant proteins, using reverse-phase protein arrays. These protein expression profiles offer profound insights into intertumor heterogeneity and cancer dependency and serve as sensitive functional readouts for somatic alterations. We develop a systematic protein-centered strategy …

The Five Homologous Ciar-Controlled Ccn Srnas Of Streptococcus Pneumoniae Modulate Zn-Resistance, Nicholas R De Lay, Nidhi Verma, Dhriti Sinha, Abigail Garrett, Maximillian K Osterberg, Daisy Porter, Spencer Reiling, David P Giedroc, Malcolm E Winkler

Faculty, Staff and Student Publications

Zinc is a vital transition metal for all bacteria; however, elevated intracellular free Zn levels can result in mis-metalation of Mn-dependent enzymes. For Mn-centric bacteria such as Streptococcus pneumoniae that primarily use Mn instead of Fe as an enzyme cofactor, Zn is particularly toxic at high concentrations. Here, we report our identification and characterization of the function of the five homologous, CiaRH-regulated Ccn sRNAs in controlling S. pneumoniae virulence and metal homeostasis. We show that deletion of all five ccn genes (ccnA, ccnB, ccnC, ccnD, and ccnE) from S. pneumoniae strains D39 (serotype 2) and TIGR4 (serotype 4) causes Zn …

Il-22 Resolves Masld Via Enterocyte Stat3 Restoration Of Diet-Perturbed Intestinal Homeostasis, Peng Zhang, Junlai Liu, Allen Lee, Irene Tsaur, Masafumi Ohira, Vivian Duong, Nicholas Vo, Kosuke Watari, Hua Su, Ju Youn Kim, Li Gu, Mandy Zhu, Shabnam Shalapour, Mojgan Hosseini, Gautam Bandyopadhyay, Suling Zeng, Cristina Llorente, Haoqi Nina Zhao, Santosh Lamichhane, Siddharth Mohan, Pieter C Dorrestein, Jerrold M Olefsky, Bernd Schnabl, Pejman Soroosh, Michael Karin

Faculty, Staff and Student Publications

The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs. MASLD pathogenesis is linked to obesity, diabetes, "gut-liver axis" alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes. This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance. Exogenous …

Methods For Pragmatic Randomized Clinical Trials Of Pain Therapies: Immpact Statement, David Hohenschurz-Schmidt, Dan Cherkin, Andrew S C Rice, Robert H Dworkin, Dennis C Turk, Michael P Mcdermott, Matthew J Bair, Lynn L Debar, Robert R Edwards, Scott R Evans, John T Farrar, Robert D Kerns, Michael C Rowbotham, Ajay D Wasan, Penney Cowan, Mckenzie Ferguson, Roy Freeman, Jennifer S Gewandter, Ian Gilron, Hanna Grol-Prokopczyk, Smriti Iyengar, Cornelia Kamp, Barbara I Karp, Bethea A Kleykamp, John D Loeser, Sean Mackey, Richard Malamut, Ewan Mcnicol, Kushang V Patel, Kenneth Schmader, Lee Simon, Deborah J Steiner, Christin Veasley, Jan Vollert

Faculty, Staff and Student Publications

Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the …

Inhibition Of Hepatic Oxalate Overproduction Ameliorates Metabolic Dysfunction-Associated Steatohepatitis, Sandeep Das, Alexandra C Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H Pearson-Gallion, M Peyton Mckinney, Koral S E Richard, Jose A Gomez-Vidal, Chowdhury S Abdullah, Elizabeth D Cockerham, Joseph Eniafe, Andrew D Yurochko, Tarek Magdy, Christopher B Pattillo, Christopher G Kevil, Babak Razani, Md Shenuarin Bhuiyan, Erin H Seeley, Gretchen E Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T Garcia-Barrio, Philip L Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y Eugene Chen, Nirav Dhanesha, Paul T Thevenot, Ari J Cohen, Arif Yurdagul, Oren Rom

Faculty, Staff and Student Publications

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In …

Does Time To Initiation Of Adjuvant Radiotherapy Affect Reconstruction Outcomes After Endoscopic Resection Of Skull Base Malignancies?, Franco Rubino, Bledi Brahimaj, Ehab Y Hanna, Shirley Y Su, Jack Phan, David R Grosshans, Franco Demonte, Shaan M Raza

Faculty, Staff and Student Publications

Introduction and Objective It is unclear if the length of the time interval to initiation of adjuvant radiation therapy (RT) after endoscopic endonasal surgery affects reconstruction outcomes. In this study we present our experience with adjuvant RT after endoscopic endonasal procedures, to determine if the time to RT after surgery impacts post-RT reconstruction complication rates.

Methods A retrospective cohort study of 164 patients who underwent endoscopic endonasal surgery between 1998 and 2021 was conducted. Using Cox proportional hazard ratios (HRs), we evaluated several variables and the complications that occurred during the 1-year period after starting RT.

Results Seventy-eight (47.5%) and …

Multifocal, Multiphenotypic Tumours Arising From An Mtor Mutation Acquired In Early Embryogenesis, Clarissa N Pacyna, Madhanagopal Anandapadamanaban, Kevin W Loudon, Iain M Hay, Olga Perisic, Ruoyan Li, Matthew Byrne, Laura Allen, Kirsty Roberts, Yvette Hooks, Anne Y Warren, Grant D Stewart, Menna R Clatworthy, Sarah A Teichmann, Sam Behjati, Peter J Campbell, Roger L Williams, Thomas J Mitchell

Faculty, Staff and Student Publications

Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared MTOR mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. …

Dual Targeting Macrophages And Microglia Is A Therapeutic Vulnerability In Models Of Pten-Deficient Glioblastoma, Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B Heimberger, Peiwen Chen

Faculty, Staff and Student Publications

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent …

Small-Molecule Ccr4 Antagonists In Cutaneous T-Cell Lymphoma, José S Enriquez, Xiaohong Wang, Loka Reddy Velatooru, Wei Han, Pedram Bijani, Xiao Ni

Faculty, Staff and Student Publications

Mycosis fungoides (MF) and Sézary syndrome (SS) are two most common types of cutaneous T-cell lymphoma (CTCL). Despite advances in understanding the pathogenesis of MF and SS, effective treatments remain limited. CC chemokine receptor-4 (CCR4) is highly expressed on CTCL cells and serves as a great therapeutic target. Mogamulizumab, an FDA-approved anti-CCR4 antibody, has shown efficacy in treating MF/SS; however, its side effects have raised concerns, underscoring the need for more effective and less toxic CCR4-targeted therapies. Although small-molecule CCR4 antagonists have been studied in other diseases involving CCR4⁺ Th2 cells and regulatory T cells, their effects in CTCL …

Evaluating Dynamic And Predictive Discrimination For Recurrent Event Models: Use Of A Time-Dependent C-Index, Jian Wang, Xinyang Jiang, Jing Ning

Faculty, Staff and Student Publications

Interest in analyzing recurrent event data has increased over the past few decades. One essential aspect of a risk prediction model for recurrent event data is to accurately distinguish individuals with different risks of developing a recurrent event. Although the concordance index (C-index) effectively evaluates the overall discriminative ability of a regression model for recurrent event data, a local measure is also desirable to capture dynamic performance of the regression model over time. Therefore, in this study, we propose a time-dependent C-index measure for inferring the model's discriminative ability locally. We formulated the C-index as a function of time using …

Biomarker Trajectory For Earlier Detection Of Lung Cancer, Ehsan Irajizad, Johannes F Fahrmann, Iakovos Toumazis, Jody Vykoukal, Jennifer B Dennison, Yu Shen, Kim-Anh Do, Edwin J Ostrin, Ziding Feng, Samir Hanash

Faculty, Staff and Student Publications

Background: To determine whether an algorithm based on repeated measurements of a panel of four circulating protein biomarkers (4 MP) for lung cancer risk assessment results in improved performance over a single time measurement.

Methods: We conducted data analysis of the 4 MP consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in pre-diagnostic sera from 2483 ever-smoker participants (389 cases and 2094 randomly selected non-cases) in the Prostate, Lung, Colorectal, Ovarian (PLCO) Study who had at least two sequential blood collections over 6 years. A parametric empirical Bayes (PEB) algorithm, which …

Meta-Analysis Of Censored Adverse Events, Xinyue Qi, Shouhao Zhou, Christine B Peterson, Yucai Wang, Xinying Fang, Michael L Wang, Chan Shen

Faculty, Staff and Student Publications

Meta-analysis is a powerful tool for assessing drug safety by combining treatment-related toxicological findings across multiple studies, as clinical trials are typically underpowered for detecting adverse drug effects. However, incomplete reporting of adverse events (AEs) in published clinical studies is frequently encountered, especially if the observed number of AEs is below a pre-specified study-dependent threshold. Ignoring the censored AE information, often found in lower frequency, can significantly bias the estimated incidence rate of AEs. Despite its importance, this prevalent issue in meta-analysis has received little statistical or analytic attention in the literature. To address this challenge, we propose a Bayesian …

Genevic: Genetic Data Exploration And Visualization Via Intelligent Interactive Console, Anindita Nath, Savannah Mwesigwa, Yulin Dai, Xiaoqian Jiang, Zhongming Zhao

Faculty, Staff and Student Publications

The vast generation of genetic data poses a significant challenge in efficiently uncovering valuable knowledge. Introducing GENEVIC, an AI-driven chat framework that tackles this challenge by bridging the gap between genetic data generation and biomedical knowledge discovery. Leveraging generative AI, notably ChatGPT, it serves as a biologist’s “copilot.” It automates the analysis, retrieval, and visualization of customized domain-specific genetic information, and integrates functionalities to generate protein interaction networks, enrich gene sets, and search scientific literature from PubMed, Google Scholar, and arXiv, making it a comprehensive tool for biomedical research. In its pilot phase, GENEVIC is assessed using a curated database …

Feasibility Of Quantitative Relaxometry For Prostate Target Localization And Response Assessment In Magnetic Resonance-Guided Online Adaptive Stereotactic Body Radiotherapy, Ergys Subashi, Eve Locastro, Sarah Burleson, Aditya Apte, Michael Zelefsky, Neelam Tyagi

Faculty, Staff and Student Publications

Purpose: Multiparametric magnetic resonance imaging (MRI) is known to provide predictors for malignancy and treatment outcome. The inclusion of these datasets in workflows for online adaptive planning remains under investigation. We demonstrate the feasibility of longitudinal relaxometry in online MR-guided adaptive stereotactic body radiotherapy (SBRT) to the prostate and dominant intra-prostatic lesion (DIL).

Methods: Fifty patients with intermediate-risk prostate cancer were included in the study. The clinical target volume (CTV) was defined as the prostate gland plus 1 cm of seminal vesicles. The gross tumor volume (GTV) was defined as the DIL identified on multiparametric MRI. Online adaptive radiotherapy was …

Improving Access In Medical Physics Residency Programs For Physicists With Disabilities, Jessica M Fagerstrom, Grace Eliason, Hania Al-Hallaq, Brian A Taylor, Muhammad Ramish Ashraf, Natalie Viscariello

Faculty, Staff and Student Publications

Within the landscape of medical physics education, residency programs are instrumental in imparting hands-on training and experiential knowledge to early-career physicists. Ensuring access to educational opportunities for physicists with disabilities is a legal, ethical, and pragmatic requirement for programs, considering that a significant proportion of the United States population has a disability. Grounded in conceptual frameworks of competency-based medical education and the social model of disability, this work provides an introduction to some practical recommendations for medical physics residency programs. Strategies include embracing universal design principles, fostering partnerships with disability service offices, using inclusive language, developing and publicizing clear procedures …

Exploring Age And Gender Disparities In Cardiometabolic Phenotypes And Lipidomic Signatures Among Chinese Adults: A Nationwide Cohort Study, Xiaojing Jia, Hong Lin, Ruizhi Zheng, Shuangyuan Wang, Yilan Ding, Chunyan Hu, Mian Li, Yu Xu, Min Xu, Guixia Wang, Lulu Chen, Tianshu Zeng, Ruying Hu, Zhen Ye, Lixin Shi, Qing Su, Yuhong Chen, Xuefeng Yu, Li Yan, Tiange Wang, Zhiyun Zhao, Guijun Qin, Qin Wan, Gang Chen, Meng Dai, Di Zhang, Bihan Qiu, Xiaoyan Zhu, Jie Zheng, Xulei Tang, Zhengnan Gao, Feixia Shen, Xuejiang Gu, Zuojie Luo, Yingfen Qin, Li Chen, Xinguo Hou, Yanan Huo, Qiang Li, Yinfei Zhang, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Jiajun Zhao, Yiming Mu, Shenghan Lai, Donghui Li, Weiguo Hu, Guang Ning, Weiqing Wang, Yufang Bi, Jieli Lu, 4c Study Group

Faculty, Staff and Student Publications

Understanding sex disparities in modifiable risk factors across the lifespan is essential for crafting individualized intervention strategies. We aim to investigate age-related sex disparity in cardiometabolic phenotypes in a large nationwide Chinese cohort. A total of 254,670 adults aged 40 years or older were selected from a population-based cohort in China. Substantial sex disparities in the prevalence of metabolic diseases were observed across different age strata, particularly for dyslipidemia and its components. Generalized additive models were employed to characterize phenotype features, elucidating how gender differences evolve with advancing age. Half of the 16 phenotypes consistently exhibited no sex differences, while …

Targeting Multiple Receptor Tyrosine Kinases With Sitravatinib: A Phase 1b Study In Advanced Renal Cell Carcinoma And Castrate-Resistant Prostate Cancer, Shubham Pant, Byoung Chul Cho, Christos E Kyriakopoulos, Alexander Spira, Nizar Tannir, Theresa L Werner, Xiaohong Yan, Saskia Neuteboom, Richard Chao, Sanjay Goel

Faculty, Staff and Student Publications

Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also …

Late Subsequent Leukemia After Childhood Cancer: A Report From The Childhood Cancer Survivor Study (Ccss), Taumoha Ghosh, Geehong Hyun, Rikeenkumar Dhaduk, Miriam Conces, Michael A Arnold, Rebecca M Howell, Tara O Henderson, Aaron Mcdonald, Leslie L Robison, Yutaka Yasui, Kirsten K Ness, Gregory T Armstrong, Joseph P Neglia, Lucie M Turcotte

Faculty, Staff and Student Publications

Background: Subsequent short-latency leukemias are well-described among survivors of childhood cancer. However, late (5-14.9 years from diagnosis, LL) and very late (≥15 years from diagnosis, VLL) subsequent leukemias have not been well studied. We assessed risk factors, prevalence, and outcomes for LL and VLL in the Childhood Cancer Survivor Study cohort.

Methods: Subsequent leukemias, among 25,656 five-year survivors, were self-reported and confirmed by pathology review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, and relative risks (RR) were estimated using Cox regression for exposures.

Results: Seventy-seven survivors developed subsequent leukemia, 49 survivors with LL (median time from diagnosis 7.8 …

Autonomic Dysfunction Among Adult Survivors Of Childhood Cancer In The St Jude Lifetime Cohort Study, John D Groarke, Kirsten K Ness, Rikeenkumar Dhaduk, Juan C Plana, Jean Bernard Durand, Russell V Luepker, Vijaya M Joshi, Matthew Ehrhardt, Daniel A Mulrooney, Stephanie B Dixon, Anju Nohria, Daniel M Green, Rebecca M Howell, Deo Kumar Srivastava, John L Jefferies, Leslie L Robison, Melissa M Hudson, Gregory T Armstrong

Faculty, Staff and Student Publications

Background: The burden and functional significance of autonomic dysfunction among survivors of childhood cancer is unknown.

Objectives: We evaluated the prevalence, risk factors, and functional relevance of autonomic dysfunction in survivors.

Methods: We conducted a cross-sectional prospective evaluation of 1,041 adult survivors of childhood cancer treated with anthracyclines (31.1%), chest-directed radiation (13.5%), both (19.5%), or neither (35.9%), and 286 community control subjects enrolled in the SJLIFE (St Jude Lifetime Cohort Study). Four measures of autonomic dysfunction were evaluated: elevated resting heart rate, decreased heart rate reserve, decreased systolic blood pressure response to exercise, and delayed heart rate recovery. Logistic regression …