Medical Genetics Commons^™

Proteomics In Orthopedic Research: Recent Studies And Their Translational Implications, George Li, Argyrios Stampas, Yoshihiro Komatsu, Xueqin Gao, Johnny Huard, Sheng Pan

Faculty, Staff and Student Publications

Proteomics is a growing field that offers insights into various aspects of disease processes and therapy responses. Within the field of orthopedics, there are a variety of diseases that have a poor prognosis due to a lack of targeted curative therapy or disease modifying therapy. Other diseases have been difficult to manage in part due to lack of clinical biomarkers that offer meaningful insight into disease progression or severity. As an emerging technology, proteomics has been increasingly applied in studying bone biology and an assortment of orthopedics related diseases, such as osteoarthritis, osteosarcoma and bone tumors, osteoporosis, traumatic bone injury, …

A First-In-Class Selective Inhibitor Of Egfr And Pi3k Offers A Single-Molecule Approach To Targeting Adaptive Resistance, Christopher E Whitehead, Elizabeth K Ziemke, Christy L Frankowski-Mcgregor, Rachel A Mumby, June Chung, Jinju Li, Nathaniel Osher, Oluwadara Coker, Veerabhadran Baladandayuthapani, Scott Kopetz, Judith S Sebolt-Leopold

Faculty, Staff and Student Publications

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal …

Genotype-By-Environment Interactions In Nonalcoholic Fatty Liver Disease And Chronic Illness Among Mexican Americans: The Role Of Acculturation Stress, Eron Manusov, Vincent Diego, Marcio Almeida, David Ortiz, Joanne E. Curran, Jacob Galan, Ana C. Leandro, Sandra Laston, John Blangero, Sarah Williams-Blangero

School of Medicine Publications

This study examines the complex interplay of genetic and environmental interactions that shape chronic illness risk. Evidence is mounting for the role of genetic expression and the immune response in the pathogenesis of chronic disease. In the Rio Grande Valley of south Texas, where 90% of the population is Mexican American, chronic illnesses (including obesity, diabetes, nonalcoholic liver disease, and depression) are reaching epidemic proportions. This study leverages an ongoing family study of the genetic determinants of risk for obesity, diabetes, hypertension, hyperlipidemia, and depression in a Mexican American population. Data collected included blood pressure, BMI, hepatic transaminases, HbA1c, depression …

Large-Scale Genotype Prediction From Rna Sequence Data Necessitates A New Ethical And Policy Framework, Mary A Majumder, Jeffrey T Leek, Kasper D Hansen, Afrooz Razi, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

Genotype prediction from RNA-seq data has become widespread. RNA-seq data, unlike DNA-seq data, are available as raw reads for many projects, with related protocols and consent terms typically inaccessible. However, there is a lack of clarity in current policy and inconsistency in practice with regard to the handling of these data. Here, we call for a framework for management of RNA-seq data and the predicted genotypes that includes registered access for RNA-seq data, controlled access for predicted genotypes, and a code of conduct for data access and use, as well as enhanced downstream protections.

Chick Embryo Chorioallantoic Membrane As A Platform For Assessing The In Vivo Efficacy Of Chimeric Antigen Receptor T-Cell Therapy In Solid Tumors, Allison J Nipper, Emilie A K Warren, Kershena S Liao, Hsuan-Chen Liu, Chieko Michikawa, Caroline E Porter, Gabrielle A Wells, Mariana Villanueva, Fabio Henrique Brasil Da Costa, Ratna Veeramachaneni, Hugo Villanueva, Masataka Suzuki, Andrew G Sikora

Faculty, Staff and Student Publications

The fertilized chicken egg chorioallantoic membrane (CAM), a highly vascularized membrane nourishing the developing embryo, also supports rapid growth of three-dimensional vascularized tumors from engrafted cells and tumor explants. Because murine xenograft models suffer limitations of time, cost, and scalability, we propose CAM tumors as a rapid, efficient screening tool for assessing anti-tumor efficacy of chimeric Ag receptor (CAR) T cells against solid tumors. We tested the efficacy of human epidermal growth factor receptor 2 (HER2)-specific CAR T cells against luminescent, HER2-expressing (FaDu, SCC-47) or HER2-negative (MDA-MB-468) CAM-engrafted tumors. Three days after tumor engraftment, HER2-specific CAR T cells were applied …

2023 American College Of Rheumatology (Acr)/American College Of Chest Physicians (Chest) Guideline For The Treatment Of Interstitial Lung Disease In People With Systemic Autoimmune Rheumatic Diseases, Sindhu R Johnson, Elana J Bernstein, Marcy B Bolster, Jonathan H Chung, Sonye K Danoff, Michael D George, Dinesh Khanna, Gordon Guyatt, Reza D Mirza, Rohit Aggarwal, Aberdeen Allen, Shervin Assassi, Lenore Buckley, Hassan A Chami, Douglas S Corwin, Paul F Dellaripa, Robyn T Domsic, Tracy J Doyle, Catherine Marie Falardeau, Tracy M Frech, Fiona K Gibbons, Monique Hinchcliff, Cheilonda Johnson, Jeffrey P Kanne, John S Kim, Sian Yik Lim, Scott Matson, Zsuzsanna H Mcmahan, Samantha J Merck, Kiana Nesbitt, Mary Beth Scholand, Lee Shapiro, Christine D Sharkey, Ross Summer, John Varga, Anil Warrier, Sandeep K Agarwal, Danielle Antin-Ozerkis, Bradford Bemiss, Vaidehi Chowdhary, Jane E Dematte D'Amico, Robert Hallowell, Alicia M Hinze, Patil A Injean, Nikhil Jiwrajka, Elena K Joerns, Joyce S Lee, Ashima Makol, Gregory C Mcdermott, Jake G Natalini, Justin M Oldham, Didem Saygin, Kimberly Showalter Lakin, Namrata Singh, Joshua J Solomon, Jeffrey A Sparks, Marat Turgunbaev, Samera Vaseer, Amy Turner, Stacey Uhl, Ilya Ivlev

Faculty, Staff and Student Publications

Objective: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs).

Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations.

Results: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong …

Impact Of Pretreatment Body Mass Index On The Survival Of Head And Neck Cancer Patients, Zheng Yang, Jobran Mansour, Peng Sun, Peng Wei, Kristina R Dahlstrom, Mark Zafereo, Guojun Li, Neil D Gross

Faculty, Staff and Student Publications

Background: Differences in pretreatment body mass index (BMI) have been associated with survival in squamous cell carcinoma of head and neck (SCCHN). We examined effects of BMI on survival in SCCHN patients after stratifying patients by tumor human papillomavirus (HPV) status and subsite.

Methods: Totally 2204 SCCHN patients in a prospective study were included in this secondary analysis. Multivariable Cox models were used to evaluate associations between pretreatment BMI and overall survival, disease-specific survival, and disease-free survival.

Results: BMI was significantly higher among patients with HPV-positive tumors than HPV-negative tumors. BMI >25 kg/m2 was associated with improved survival, while BMI …

Cerebellar Functions Beyond Movement And Learning, Linda H Kim, Detlef H Heck, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural …

Extraordinary Phase Transition Revealed In A Van Der Waals Antiferromagnet, Xiaoyu Guo, Wenhao Liu, Jonathan Schwartz, Suk Hyun Sung, Dechen Zhang, Makoto Shimizu, Aswin L N Kondusamy, Lu Li, Kai Sun, Hui Deng, Harald O Jeschke, Igor I Mazin, Robert Hovden, Bing Lv, Liuyan Zhao

Faculty, Staff and Student Publications

While the surface-bulk correspondence has been ubiquitously shown in topological phases, the relationship between surface and bulk in Landau-like phases is much less explored. Theoretical investigations since 1970s for semi-infinite systems have predicted the possibility of the surface order emerging at a higher temperature than the bulk, clearly illustrating a counterintuitive situation and greatly enriching phase transitions. But experimental realizations of this prediction remain missing. Here, we demonstrate the higher-temperature surface and lower-temperature bulk phase transitions in CrSBr, a van der Waals (vdW) layered antiferromagnet. We leverage the surface sensitivity of electric dipole second harmonic generation (SHG) to resolve surface …

Phase Ii Study Of Talazoparib In Advanced Cancers With Brca1/2, Dna Repair, And Pten Alterations, Sarina A Piha-Paul, Chieh Tseng, Cheuk Hong Leung, Ying Yuan, Daniel D Karp, Vivek Subbiah, David Hong, Siqing Fu, Aung Naing, Jordi Rodon, Milind Javle, Jaffer A Ajani, Kanwal P Raghav, Neeta Somaiah, Gordon B Mills, Apostolia M Tsimberidou, Xiaofeng Zheng, Ken Chen, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Cancer cells with BRCA1/2 deficiencies are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We evaluated the efficacy of talazoparib in DNA-Damage Repair (DDR)-altered patients. In this phase II trial, patients were enrolled onto one of four cohorts based on molecular alterations: (1) somatic BRCA1/2, (2) other homologous recombination repair pathway, (3) PTEN and (4) germline BRCA1/2. The primary endpoint was a clinical benefit rate (CBR): complete response, partial response or stable disease ≥24 weeks. 79 patients with a median of 4 lines of therapy were enrolled. CBR for cohorts 1-4 were: 32.5%, 19.7%, 9.4% and 30.6%, respectively. PTEN mutations correlated …

Adaptive Fine-Tuning Based Transfer Learning For The Identification Of Mgmt Promoter Methylation Status, Erich Schmitz, Yunhui Guo, Jing Wang

Faculty, Staff and Student Publications

Background. Glioblastoma Multiforme (GBM) is an aggressive form of malignant brain tumor with a generally poor prognosis. O 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been shown to be a predictive bio-marker for resistance to treatment of GBM, but it is invasive and time-consuming to determine methylation status. There has been effort to predict the MGMT methylation status through analyzing MRI scans using machine learning, which only requires pre-operative scans that are already part of standard-of-care for GBM patients. Purpose. To improve the performance of conventional transfer learning in the identification of MGMT promoter methylation status, we developed a 3D SpotTune …

Cerebellar Nuclei Cells Produce Distinct Pathogenic Spike Signatures In Mouse Models Of Ataxia, Dystonia, And Tremor, Meike E Van Der Heijden, Amanda M Brown, Dominic J Kizek, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared …

Targeting Astrogliosis In The Retrotrapezoid Nucleus: A Novel Approach To Ameliorate Respiratory Dysfunction And Alzheimer's Pathology In Mice, Zahid Iqbal, Ahmad El Hamamy, Ngoc Mai Le, Arya Ranjan, Yuxing Zhang, Li Qi, Bharti Manwani, Chunfeng Tan, Louise D Mccullough, Jun Li

Faculty, Staff and Student Publications

Alzheimer's disease (AD), a leading cause of dementia, is associated with significant respiratory dysfunctions. Our study explores the role of astrogliosis in the brainstem retrotrapezoid nucleus (RTN), a key breathing regulatory center, and its impact on breathing control and AD pathology in mice. Using Tg-2576 AD and wild-type mice, we investigated the effect of silencing the transforming growth factor-beta receptor II (TGFβR II) in the RTN. We performed behavioral tests, including the Barnes maze and novel object recognition test, along with whole-body plethysmography to assess breathing disorders. Our results showed that AD mice exhibited increased apneas and cognitive impairment, which …

Tert Activation Targets Dna Methylation And Multiple Aging Hallmarks, Hong Seok Shim, Jonathan Iaconelli, Xiaoying Shang, Jiexi Li, Zheng D Lan, Shan Jiang, Kayla Nutsch, Brittney A Beyer, Luke L Lairson, Adam T Boutin, Michael J Bollong, Peter G Schultz, Ronald A Depinho

Faculty, Staff and Student Publications

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, …

Glucose-6-Phosphate Dehydrogenase Deficiency As A Cause For Nonimmune Hydrops Fetalis And Severe Fetal Anemia: A Systematic Review, Neel S. Iyer, Matthew H. Mossayebi, Tracy J. Gao, Lylach Haizler-Cohen, Daniele Di Mascio, Rodney A. Mclaren, Huda B. Al-Kouatly

Department of Obstetrics and Gynecology Faculty Papers

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disorder that predisposes individuals to hemolysis due to an inborn error of metabolism. We performed a systematic literature review to evaluate G6PD deficiency as a possible etiology of nonimmune hydrops fetalis (NIHF) and severe fetal anemia.

METHODS: PubMed, OVID Medline, Scopus, and clinicaltrials.gov were queried from inception until 31 April 2023 for all published cases of NIHF and severe fetal anemia caused by G6PD deficiency. Keywords included "fetal edema," "hydrops fetalis," "glucose 6 phosphate dehydrogenase deficiency," and "fetal anemia." Cases with workup presuming G6PD deficiency as an etiology for NIHF and …

A Scaled Proteomic Discovery Study For Prostate Cancer Diagnostic Markers Using Proteograph, Matthew E K Chang, Jane Lange, Jessie May Cartier, Travis W Moore, Sophia M Soriano, Brenna Albracht, Michael Krawitzky, Harendra Guturu, Amir Alavi, Alexey Stukalov, Xiaoyuan Zhou, Eltaher M Elgierari, Jessica Chu, Ryan Benz, Juan C Cuevas, Shadi Ferdosi, Daniel Hornburg, Omid Farokhzad, Asim Siddiqui, Serafim Batzoglou, Robin J Leach, Michael A Liss, Ryan P Kopp, Mark R Flory

Faculty, Staff and Student Publications

There is a significant unmet need for clinical reflex tests that increase the specificity of prostate-specific antigen blood testing, the longstanding but imperfect tool for prostate cancer diagnosis. Towards this endpoint, we present the results from a discovery study that identifies new prostate-specific antigen reflex markers in a large-scale patient serum cohort using differentiating technologies for deep proteomic interrogation. We detect known prostate cancer blood markers as well as novel candidates. Through bioinformatic pathway enrichment and network analysis, we reveal associations of differentially abundant proteins with cytoskeletal, metabolic, and ribosomal activities, all of which have been previously associated with prostate …

Genetics Of Mdh In Humans, Adam Haberman, Celeste N. Peterson

Biology: Faculty Scholarship

Malate dehydrogenase (MDH) performs key roles in metabolism, but little is known about its function specifically in human health and disease. In this minireview, we describe the incomplete state of our knowledge of human MDH genetics. Humans have three MDH genes with a total of four validated isoforms. MDH1 and MDH2 are widely expressed, while MDH1B is only expressed in a small subset of tissues. Many mutations in MDH1 and MDH2 have been identified in patients, but only a few have been studied to determine what symptoms they cause. MDH1 has been associated with cancer and a neurodevelopmental disorder. MDH2 …

Bayesian Sequential Monitoring Strategies For Trials Of Digestive Cancer Therapeutics, Guillaume Mulier, Ruitao Lin, Thomas Aparicio, Lucie Biard

Faculty, Staff and Student Publications

Background: New therapeutics in oncology have presented challenges to existing paradigms and trial designs in all phases of drug development. As a motivating example, we considered an ongoing phase II trial planned to evaluate the combination of a MET inhibitor and an anti-PD-L1 immunotherapy to treat advanced oesogastric carcinoma. The objective of the paper was to exemplify the planning of an adaptive phase II trial with novel anti-cancer agents, including prolonged observation windows and joint sequential evaluation of efficacy and toxicity.

Methods: We considered various candidate designs and computed decision rules assuming correlations between efficacy and toxicity. Simulations were conducted …

An Investigation Into Aetiology, Detection And Treatment Of Neonatal Alloimmune Thrombocytopenia, Mairead Horan

International Undergraduate Journal of Health Sciences

NAIT is a rare disorder with a similar aetiology to HDN, however unlike its erythrocyte counterpart, thrombocyte immunisation can occur within the first pregnancy. (Giouleka et al., 2023). The most common antibodies implicated are HLA-1a. (Winkelhorst et al., 2017). 2.5% of the Caucasian population are HPA-1a negative, of this population 33% are HLA-DR-B3*0101 positive increasing the risk of producing an alloantibody upon encountering the HPA-1a antigen. The maternal system becomes alloimmunised to the foreign paternal antigens of the foetus/neonate, which cross the placenta causing low platelets of the foetus. (Giouleka et al., 2023).

A third of antigen-positive neonates born to …

Crispr-Cas9 And Cas12a Target Site Richness Reflects Genomic Diversity In Natural Populations Of Anopheles Gambiae And Aedes Aegypti Mosquitoes, Travis C Collier, Yoosook Lee, Derrick K Mathias, Víctor López Del Amo

Faculty, Staff and Student Publications

Due to limitations in conventional disease vector control strategies including the rise of insecticide resistance in natural populations of mosquitoes, genetic control strategies using CRISPR gene drive systems have been under serious consideration. The identification of CRISPR target sites in mosquito populations is a key aspect for developing efficient genetic vector control strategies. While genome-wide Cas9 target sites have been explored in mosquitoes, a precise evaluation of target sites focused on coding sequence (CDS) is lacking. Additionally, target site polymorphisms have not been characterized for other nucleases such as Cas12a, which require a different DNA recognition site (PAM) and would …

Biophysics Of Protein-Lipid Interactions, Paula A Bender, Vasanthi Jayaraman

Faculty, Staff and Student Publications

The biological phenomenon of protein-lipid interactions in cell membranes underlies the diversity of peripheral membrane protein function and physical properties of the membrane. To summarize novel findings in the field, this research highlight focuses on recent publications in Biophysical Journal.

Novel Immunomodulatory Properties Of Adenosine Analogs Promote Their Antiviral Activity Against Sars-Cov-2, Giulia Monticone, Zhi Huang, Peter Hewins, Thomasina Cook, Oygul Mirzalieva, Brionna King, Kristina Larter, Taylor Miller-Ensminger, Maria D. Sanchez-Pino, Timothy P. Foster, Olga V. Nichols, Alistair J. Ramsay, Samarpan Majumder, Dorota Wyczechowska, Darlene Tauzier, Elizabeth Gravois, Judy S. Crabtree, Jone Garai, Li Li, Jovanny Zabaleta, Mallory T. Barbier, Luis Del Valle, Kellie A. Jurado, Lucio Miele

School of Medicine Faculty Publications

The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case …

Trps1 Expression Is Frequently Seen In A Subset Of Cutaneous Mesenchymal Neoplasms And Tumors Of Uncertain Differentiation: A Potential Diagnostic Pitfall, Moon Joo Kim, Yi A Liu, Yunyi Wang, Jing Ning, Woo Cheal Cho

Faculty, Staff and Student Publications

Although extensively studied in cutaneous epithelial neoplasms, the TRPS1 immunoreactivity in cutaneous mesenchymal neoplasms and tumors of uncertain differentiation (CMNTUDs), such as atypical fibroxanthoma (AFX), remains largely unexplored. We assessed TRPS1 immunoreactivity in 135 CMNTUDs, comprising 46 fibrohistiocytic/fibroblastic tumors, 28 vascular tumors, 24 peripheral nerve sheath tumors (PNSTs), 21 tumors of uncertain differentiation, and 16 smooth muscle tumors. Additionally, we included selected cases of melanoma with spindled cell morphology or desmoplastic features (n = 9) and sarcomatoid squamous cell carcinoma (SSCC) (n = 5) to compare TRPS1 expression patterns with those of AFX. TRPS1 expression was prevalent in dermatofibromas (24/24), …

Nrg Oncology And Particle Therapy Co-Operative Group Patterns Of Practice Survey And Consensus Recommendations On Pencil-Beam Scanning Proton Stereotactic Body Radiation Therapy And Hypofractionated Radiation Therapy For Thoracic Malignancies, Wei Liu, Hongying Feng, Paige A Taylor, Minglei Kang, Jiajian Shen, Jatinder Saini, Jun Zhou, Huan B Giap, Nathan Y Yu, Terence S Sio, Pranshu Mohindra, Joe Y Chang, Jeffrey D Bradley, Ying Xiao, Charles B Simone, Liyong Lin

Faculty, Staff and Student Publications

Stereotactic body radiation therapy (SBRT) and hypofractionation using pencil-beam scanning (PBS) proton therapy (PBSPT) is an attractive option for thoracic malignancies. Combining the advantages of target coverage conformity and critical organ sparing from both PBSPT and SBRT, this new delivery technique has great potential to improve the therapeutic ratio, particularly for tumors near critical organs. Safe and effective implementation of PBSPT SBRT/hypofractionation to treat thoracic malignancies is more challenging than the conventionally fractionated PBSPT because of concerns of amplified uncertainties at the larger dose per fraction. The NRG Oncology and Particle Therapy Cooperative Group Thoracic Subcommittee surveyed proton centers in …

Clinical And Genomic Landscape Of Ras Mutations In Gynecologic Cancers, Ji Son, Yingao Zhang, Heather Lin, Oriol Mirallas, Pablo Alvarez Ballesteros, Mirella Nardo, Natalie Clark, R Tyler Hillman, Erick Campbell, Vijaykumar Holla, Amber M Johnson, Amadeo B Biter, Ying Yuan, Lauren P Cobb, David M Gershenson, Amir A Jazaeri, Karen H Lu, Pamela T Soliman, Shannon N Westin, Elizabeth D Euscher, Barrett C Lawson, Richard K Yang, Funda Meric-Bernstam, David S Hong

Faculty, Staff and Student Publications

Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications.

Experimental design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model.

Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and …

Author Correction: Brafv600e-Mutant Metastatic Nsclc: Disease Overview And Treatment Landscape, David Planchard, Rachel E Sanborn, Marcelo V Negrao, Aria Vaishnavi, Egbert F Smit

Faculty, Staff and Student Publications

No abstract provided.

Set-Based Tests For Genetic Association Studies With Interval-Censored Competing Risks Outcomes, Zhichao Xu, Jaihee Choi, Ryan Sun

Faculty, Staff and Student Publications

Over the past decade, massive genetic compendiums such as the UK Biobank have gathered extensive genetic and phenotypic data that hold the potential to provide unparalleled insight into the genetic etiologies of various complex diseases. However, much of the disease information is collected as time-to-event outcomes in interval-censored form, and conventional tools for genetic association analysis are often not available for this type of data. For example, set-based inference for common and rare variants analysis is a fundamental investigation in germline genetics studies, but there is a lack of approaches that can perform set-based testing when the interval-censored outcome of …

Patient-Reported Quality Of Life At Diagnosis In Adolescent And Young Adults With Cancer, Goldy C George, Clark Andersen, Xiaohui Tang, Elizabeth Rodriguez, Midhat Jafry, Maria C Swartz, Sairah Ahmed, Carlos H Barcenas, J Andrew Livingston, Michael E Roth, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

Background: The overall landscape of health-related quality of life (HRQoL) has not been thoroughly investigated in adolescents and young adults (AYAs) with cancer. Data are also lacking on how well HRQoL at the time of cancer diagnosis can prognosticate long-term survival in AYA survivors.

Patients and methods: We included 3,497 survivors of AYA cancer (age 15-39 years at diagnosis) who completed the Short-Form 12 Health Survey (SF-12) HRQoL questionnaire at diagnosis. Physical component summary (PCS) and mental component summary (MCS) scores were generated, with scores < 50 representing poor HRQoL. Differences in HRQoL by patient characteristics and tumor type were investigated using violin plots and t tests/analysis of variance. The effect of HRQoL on overall survival was assessed using Kaplan-Meier plots and Cox proportional hazards models.

Results: Overall mean PCS and MCS scores in this racially/ethnically diverse cohort (64% White, 19% …

Parg Is Essential For Polθ-Mediated Dna End-Joining By Removing Repressive Poly-Adp-Ribose Marks, Umeshkumar Vekariya, Leonid Minakhin, Gurushankar Chandramouly, Mrityunjay Tyagi, Tatiana Kent, Katherine Sullivan-Reed, Jessica Atkins, Douglas Ralph, Margaret Nieborowska-Skorska, Anna-Mariya Kukuyan, Hsin-Yao Tang, Richard T. Pomerantz, Tomasz Skorski

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase theta (Polθ)-mediated end-joining (TMEJ) repairs DNA double-strand breaks and confers resistance to genotoxic agents. How Polθ is regulated at the molecular level to exert TMEJ remains poorly characterized. We find that Polθ interacts with and is PARylated by PARP1 in a HPF1- independent manner. PARP1 recruits Polθ to the vicinity of DNA damage via PARylation dependent liquid demixing, however, PARylated Polθ cannot perform TMEJ due to its inability to bind DNA. PARG-mediated de-PARylation of Polθ reactivates its DNA binding and end-joining activities. Consistent with this, PARG is essential for TMEJ and the temporal recruitment of PARG to DNA …

Chronic Eosinophilic Leukemia With A Novel Jak1 Mutation Responds Well To The Jak1/2 Inhibitor Ruxolitinib, Qing Wei, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.