Medicine and Health Sciences Commons^™

The Somatic Mosaicism Across Human Tissues Network, Tim H H Coorens, Ji Won Oh, Yujin Angelina Choi, Nam Seop Lim, Boxun Zhao, Adam Voshall, Alexej Abyzov, Lucinda Antonacci-Fulton, Samuel Aparicio, Kristin G Ardlie, Thomas J Bell, James T Bennett, Bradley E Bernstein, Thomas G Blanchard, Alan P Boyle, Jason D Buenrostro, Kathleen H Burns, Fei Chen, Rui Chen, Sangita Choudhury, Harsha V Doddapaneni, Evan E Eichler, Gilad D Evrony, Melissa A Faith, Thomas G Fazzio, Robert S Fulton, Manuel Garber, Nils Gehlenborg, Soren Germer, Gad Getz, Richard A Gibbs, Raquel G Hernandez, Fulai Jin, Jan O Korbel, Dan A Landau, Heather A Lawson, Niall J Lennon, Heng Li, Yan Li, Po-Ru Loh, Gabor Marth, Michael J Mcconnell, Ryan E Mills, Stephen B Montgomery, Pradeep Natarajan, Peter J Park, Rahul Satija, Fritz J Sedlazeck, Diane D Shao, Hui Shen, Andrew B Stergachis, Hunter R Underhill, Alexander E Urban, Melissa W Vondran, Christopher A Walsh, Ting Wang, Tao P Wu, Chenghang Zong, Eunjung Alice Lee, Flora M Vaccarino

Center on Aging Staff Publications

From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues …

Clonal Evolution Of Hematopoietic Stem Cells After Autologous Stem Cell Transplantation, Hidetaka Uryu, Koichi Saeki, Hiroshi Haeno, Chiraag Deepak Kapadia, Ken Furudate, Jyoti Nangalia, Michael Spencer Chapman, Linda Zhang, Jennifer Padilla, Li Zhao, Joanne I Hsu, Chong Zhao, Shujuan Chen, Tomoyuki Tanaka, Zongrui Li, Satoko Ogata, Sarah Hanache, Hui Yang, Courtney Dinardo, Naval Daver, Naveen Pemmaraju, Nitin Jain, Farhad Ravandi, Jianhua Zhang, Xingzhi Song, Erika Thompson, Hongli Tang, Latasha Little, Curtis Gumbs, Robert Z Orlowski, Muzaffar Qazilbash, Kapil Bhalla, Simona Colla, Hagop Kantarjian, Rashmi Kanagal-Shamanna, Carlos Bueso-Ramos, Daisuke Nakada, Gheath Al-Atrash, Jeffery Molldrem, P Andrew Futreal, Elizabeth Shpall, Margaret Goodell, Guillermo Garcia-Manero, Koichi Takahashi

Faculty, Staff and Student Publications

The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal hematopoiesis is not well defined. We conducted whole-genome sequencing on 1,276 single-cell-derived hematopoietic stem and progenitor cell (HSPC) colonies from ten patients with multiple myeloma treated with chemotherapies and six normal donors. Melphalan treatment significantly increased the mutational burden, producing a distinctive mutation signature, whereas other chemotherapeutic agents had minimal effects. Consequently, the clonal diversity and architecture of post-treatment HSPCs resemble those observed in normal elderly individuals, particularly through the progression of oligoclonal hematopoiesis, thereby suggesting that chemotherapy accelerates clonal aging. Integrated …

Postoperative Delirium In Older Adults Undergoing Noncardiac Surgery, Heather L Lander, Andrew W Dick, Karen E Joynt Maddox, Mark A Oldham, Lee A Fleisher, Michael Mazzeffi, Stewart J Lustik, Jingjing Shang, Patricia W Stone, Marjorie S Gloff, Jacob Nadler, Isaac Wu, Raymond Zollo, Laurent G Glance

2020-Current year OA Pubs

IMPORTANCE: Understanding the association of postoperative delirium with adverse outcomes and the hospital-level variation of postoperative delirium is important for efforts to improve perioperative brain health.

OBJECTIVE: To examine (1) the association of postoperative delirium with 30-day mortality and complications and (2) hospital-level variation in postoperative delirium.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study examined hospitalizations among patients aged 65 years and older who underwent noncardiac surgery in US hospitals between January 1, 2017, and December 31, 2020. Data were analyzed between August 28, 2024, and April 10, 2025.

EXPOSURE: Postoperative delirium.

MAIN OUTCOMES AND MEASURES: The association of …

First-Trimester Antibiotic Use For Urinary Tract Infection And Risk Of Congenital Malformations, Sarah S Osmundson, Katelin B Nickel, Susan M. Shortreed, Sascha Dublin, Dustin Stwalley, Michael J Durkin, Paige D Wartko, John M Sahrmann, Ryan Colvin, Anne M Butler

2020-Current year OA Pubs

IMPORTANCE: Clinical guidelines recommend screening and treating bacteriuria in early pregnancy given that urinary tract infections (UTIs) can cause serious maternal and neonatal consequences. Evidence regarding antibiotic exposure during early pregnancy and risk of congenital malformations is limited and inconsistent.

OBJECTIVE: To compare the risk of congenital malformations following first-trimester exposure to different antibiotic agents used to treat UTI.

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study included commercially insured pregnant individuals aged 15 to 49 years who were treated for UTI and linked liveborn infants in the Merative MarketScan Commercial Database (2006-2022).

EXPOSURE: First-trimester antibiotic prescription fill of nitrofurantoin, …

History Of Hypoxia Exposure Aids Future Cell Invasion According To Cell Type And Collagen Density, José A Almeida, Diego B Avila, Gregory D Longmore, Amit Pathak

2020-Current year OA Pubs

In cancer progression, tumor microenvironments (TME) progressively become denser and hypoxic, and cell migrate toward higher oxygen levels as they invade across the tumor-stromal boundary. Although cell invasion dependence on optimal collagen density is well appreciated, it remains unclear whether past oxygen conditions alter future invasion phenotype of cells. Here, we show that normal human mammary epithelial cells (MCF10A) and leader-like human breast tumor cells (BT549) undergo higher rates of invasion and collagen deformation after past exposure to hypoxia, compared with normoxia controls. Upon increasing collagen density by ∼50%, cell invasion under normoxia reduced, as expected due to the increased …

Distinct Patterns Of Weight Gain, Age, And Subcortical Microstructure In Early Adolescence, Shana Adise, Zhaolong Adrian Li, Jonatan Ottino-González, Filip Morys, Peter A Chiarelli, Tamara Hershey

2020-Current year OA Pubs

IMPORTANCE: Associations between childhood obesity and brain microstructural differences have been observed. It remains unknown whether these associations are driven by sex-specific excessive weight gain. Restriction spectrum imaging characterizes brain tissue microstructural health via water diffusion, where the restricted normalized isotropic (RNI) compartment assesses neuronal and glial cellularity, which may reflect neuroinflammation, synaptic pruning, or both.

OBJECTIVE: To identify associations among RNI scaling factor values, normal neurodevelopment, and weight gain during early adolescence.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Adolescent Brain Cognitive Development (ABCD) Study, a 10-year, ongoing, multisite longitudinal cohort study conducted among youths …

Utility Of The Us Preventive Services Task Force For Preeclampsia Risk Assessment And Aspirin Prophylaxis, Thomas F Mcelrath, Antonina I Frolova, Et Al.

2020-Current year OA Pubs

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 …

Evaluation Of Internally Cooled Radiofrequency Ablation Targeting Multiple Shoulder Nerves For Chronic Shoulder Pain Relief And Function Restoration: A Prospective Study, Mitsukuni Yoshida, Peter K Park, Loc V Thang

2020-Current year OA Pubs

OBJECTIVE: Shoulder pain is a prevalent musculoskeletal disorder, affecting up to 70% of adults over their lifetimes. Recently, radiofrequency ablation (RFA) has gained attention as a treatment for joint pain. This study aims to evaluate the efficacy of internally cooled RFA (icRFA) in alleviating shoulder pain and improving both qualitative and quantitative measures of shoulder function.

DESIGN: Prospective cohort study.

SUBJECTS: Patients with chronic shoulder pain (n = 35) who responded positively to diagnostic blocks of the suprascapular nerve (SSN), axillary nerve (AN), and lateral pectoral nerve (LPN).

METHODS: Patients underwent icRFA targeting the SSN, AN, and LPN. Treatment response …

Genetic Structuring And Estimation Of Reproductive Adults In Onchocerca Volvulus: A Genome-Wide Analysis Across Hosts And Regions, Pawan Kumar, Young-Jun Choi, Kerstin Fischer, Shannon M. Hedtke, Anusha Kode, Nicholas Opoku, Lincoln Gankpala, Tony O. Ukety, Jöel Lonema Mande, Timothy J. C. Anderson, Warwick N. Grant, Peter U. Fischer, Makedonka Mitreva

2020-Current year OA Pubs

Genomic analysis of parasites can deepen our understanding of their transmission, population structure, and important biological characteristics. Onchocerciasis (river blindness), caused by the parasitic nematode Onchocerca volvulus, involves adult worms residing in subcutaneous nodules that produce larval-stage microfilariae (mf), which are routinely detected in the skin for diagnosis. Whole-genome studies of mf are limited; most analyses have focused on the mitochondrial genome. We conducted a genome-wide analysis with 94% median nuclear genome coverage, analyzing 171, 37, and 98 mf from 16, 3, and 5 individuals from Ghana, Liberia, and the Democratic Republic of Congo, respectively. These data were used to …

Bispecific Antibodies In Follicular Lymphoma, Imran A. Nizamuddin, Nancy L. Bartlett

2020-Current year OA Pubs

Bispecific antibodies, specifically anti-CD20 T-cell engaging constructs, are poised to alter the treatment paradigm for multiple B-cell malignancies, including follicular lymphoma. Two CD20xCD3 bispecific antibodies, mosunetuzumab and epcoritamab, are now approved in the United States for third-line or later treatment of follicular lymphoma. A third agent, odronextamab, remains under review by regulatory agencies. In pivotal phase II trials, these bispecific antibodies demonstrated overall response rates of approximately 80%, with complete response rates of 60-70%, the majority of which have been durable at 2 years. Important safety signals included risk of infections, neutropenia, and cytokine release syndrome, which occurred in approximately …

The Loss Of Opa1 Accelerates Intervertebral Disc Degeneration And Osteoarthritis In Aged Mice, Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K Boneski, Hiromi Sesaki, Ruteja A Barve, John A Collins, Makarand V Risbud

2020-Current year OA Pubs

Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and

Exploitable Mechanisms Of Antibody And Car Mediated Macrophage Cytotoxicity, Tianyi Liu, Alexander B Kim, Young Ah Goo, Minsoo Son, Jaenyeon Kim, Carl J Deselm, Et Al.

2020-Current year OA Pubs

Macrophages infiltrate solid tumors and either support survival or induce cancer cell death through phagocytosis or cytotoxicity. To uncover regulators of macrophage cytotoxicity towards cancer cells, we perform two co-culture CRISPR screens using CAR-macrophages targeting different tumor associated antigens. Both identify ATG9A as an important regulator of this cytotoxic activity. In vitro and in vivo, ATG9A depletion in cancer cells sensitizes them to macrophage-mediated killing. Proteomic and lipidomic analyses reveal that ATG9A deficiency impairs the cancer cell response to macrophage-induced plasma membrane damage through defective lysosomal exocytosis, reduced ceramide production, and disrupted caveolar endocytosis. Depleting non-cytotoxic macrophages using CSF1R inhibition …

Participation In Activities Among People With Long-Term Spinal Cord Injury In Sweden And The Usa - An Explorative Study Using Secondary Data Analysis, Jessica L Dashner, Ulrica Antepohl

2020-Current year OA Pubs

STUDY DESIGN: Secondary data analysis.

OBJECTIVE: To explore differences in participation, secondary health complications, and the use of assistive devices and personal assistance among people with long-term SCI in Sweden and the USA.

SETTING: Community dwelling individuals with SCI in Sweden and USA.

METHODS: Secondary analysis of data collected via PARTS-Mv3 among individuals living with SCI in Sweden (n = 73) and in the USA (n = 45). Descriptive analyses provided information regarding the participants, their participation in activities, and secondary health complications, together with the use of assistive devices and personal assistance.

RESULTS: Both samples included more males than …

Effect Of A Pay-It-Forward Strategy On Reducing Hpv Vaccine Delay And Increasing Uptake Among 15- To 18-Year-Old Girls In China: A Randomized Controlled Trial, Jing Li, Elvin H. Geng, Et Al.

2020-Current year OA Pubs

BACKGROUND: Catch-up human papillomavirus (HPV) vaccination is challenging in many low- and middle-income countries (LMICs). Pay-it-forward offers an individual a subsidized vaccine, then an opportunity to donate to help others access vaccinations. Our randomized control trial assessed the effectiveness of pay-it-forward in improving HPV vaccination among girls aged 15-18 years in China.

METHODS AND FINDINGS: This study was conducted from July 6, 2022, to June 9, 2023, in four community health centers (CHCs) in Chengdu, western China. Eligible participants were unvaccinated girls living in the service areas of CHCs. Participants were initially recruited via telephone and, after providing verbal consent, …

Incident Depression After Breast Cancer Among Older Asian, Native Hawaiian, And Pacific Islander Women, Alzina Koric, Chun-Pin Esther Chang, Yuan-Chin Amy Lee, Mei Wei, Catherine Lee, Jing Wang, Mia Hashibe

2020-Current year OA Pubs

BACKGROUND: Longitudinal studies examining mental health outcomes among older (≥66 years) Asian, Native Hawaiian, and Pacific Islander (ANHPI) women diagnosed with breast cancer are limited. We evaluated incident depression after breast cancer among specific groups of older ANHPI compared with older non-Hispanic White (NHW) women. Predictors of depression and the risk of death following early onset of depression after breast cancer were also evaluated.

METHODS: A cohort of 26 776 older ANHPI women in the United States diagnosed with breast cancer between 2000 and 2017 was identified from the SEER-Medicare linked claims. There were 6694 older ANHPI and 20 082 …

Medications To Reduce Breast Cancer Risk: A Network Meta-Analysis Of Randomized Controlled Trials, Ghazaleh Pourali, Minglu Liu, Supriya S Sherpa, Angela Hardi, Chongliang Luo, Adetunji T Toriola

2020-Current year OA Pubs

BACKGROUND: Given the rising incidence of breast cancer, especially in premenopausal women, there is an urgent need to identify additional risk-reducing medications to accelerate prevention, as only a few are currently approved. We, therefore, performed network meta-analysis (NMA) to identify and compare the efficacy of medications for primary breast cancer prevention.

METHODS: We performed a literature search completed on November 16, 2023, in Embase, Ovid-Medline, Scopus, and Cochrane Library for randomized controlled trials (RCTs) evaluating risk-reducing medications in women without a history of invasive breast cancer. Two reviewers independently screened and extracted data based on predefined criteria, following the Preferred …

Where Should The Cancer Control Interventions Target: A Geospatial Hotspot Analysis For Major Cancer Mortality 2018 To 2022 In The United States, Chongliang Luo, Saira Khan, Liyan Jin, Aimee S James, Graham A Colditz, Bettina F Drake

2020-Current year OA Pubs

BACKGROUND: Identifying changes in geographic disparities of cancer mortality reveals locations where cancer prevention and control efforts should be focused/targeted. We use recent cancer surveillance data to demonstrate the geographic disparity of major cancer mortality rates in the United States and its shift compared with previous data.

METHODS: This cross-sectional study used the 2018 to 2022 county-level mortality rates of colorectal, lung, breast, and prostate cancers from the Centers for Disease Control mortality data. Counties with suppressed death counts were imputed by spatial regression models. Getis-Ord Gi* statistics were used to evaluate the spatial clustering of county mortality. Identified hotspot …

Integrating Nonindividual Patient Features In Machine Learning Models Of Hospital-Onset Bacteremia, M Cristina Vazquez-Guillamet, Jingwen Zhang, Alice Bewley, Andrew Atkinson, Heidi Holtz, Ziqian Wang, Nicole Brougham, Chenyang Lu, Marin H Kollef, Philip Payne, David Warren, Victoria J Fraser

2020-Current year OA Pubs

IMPORTANCE: Hospital-onset bacteremia and fungemia (HOB) are common and potentially preventable complications of hospital care.

OBJECTIVE: To assess whether nonindividual patient features, which summarize interactions with other patients and health care workers (HCWs), can contribute to predictive and causal machine learning models for HOB.

DESIGN, SETTING, AND PARTICIPANTS: This prognostic study included adult patients admitted to Barnes-Jewish Hospital, an academic hospital in St Louis, Missouri, in 2021. Analyses were developed between October 2023 and August 2024 and in April 2025.

EXPOSURE: Individual patient features were extracted from electronic health records and used to engineer nonpatient features, including interactions with HCWs …

Eculizumab Treatment Of Tacrolimus-Associated Autoimmune Haemolytic Anaemia And Thrombotic Microangiopathy In A Child With Orthotopic Heart Transplant, Daniel Pike, Monica Hulbert, Alicia Kamsheh

2020-Current year OA Pubs

BACKGROUND: Tacrolimus is the standard immunosuppressant used in paediatric orthotopic heart transplantation, but it can be associated with rare and life-threatening haemolysis.

METHODS: Retrospective chart review was used for this case report.

RESULTS/CONCLUSION: We present the case of a 6-year-old heart transplant recipient who developed life-threatening haemolysis in the setting of mycoplasma infection while on tacrolimus immunosuppression that was treated successfully with eculizumab.

High-Frequency, At-Home Monitoring Of Drug Safety And Tolerability In Clinical Trials: Results From Studies Of Fluvoxamine For Covid-19 Treatment, Eric J Lenze, Madeline Nykamp, J Philip Miller, Angela Stevens, Julia Schweiger, Torie Gettinger, Michael Yingling, Yi Zhang, Ginger E Nicol, Charles F Zorumski, Angela M Reiersen

2020-Current year OA Pubs

Clinical trials are increasingly using remote monitoring techniques at the patient's home. We conducted a secondary analysis of remote safety and tolerability monitoring from two fully-remote clinical trials that tested fluvoxamine for the acute treatment of COVID-19. Both trials assessed pulse and blood pressure daily, and one study assessed symptoms daily via Ecological Momentary Assessment. On average, patients provided data on vital signs on 93% of the study days and provided data on side effects on 81% of the study days. With respect to safety, patients taking fluvoxamine had reduced pulse rate compared to placebo, with the greatest difference-5 points-at …

Molecular Profile Of Adult Primary Leptomeningeal Gliomatosis Aligns With Glioblastoma, Idh-Wildtype, Yi Zhu, Darin D Carabenciov, Derek R Johnson, Jorge A Trejo-Lopez, Aivi T Nguyen, Aditya Raghunathan, Giuseppe Lanzino, Cristiane M Ida, Cinthya J Zepeda-Mendoza, Surendra Dasari, Emilie Russler-Germain, Sonika Dahiya, Martha Quezado, Kenneth Aldape, Caterina Giannini

2020-Current year OA Pubs

Adult primary leptomeningeal gliomatosis (PLG) is a rare, rapidly progressive and fatal disease characterized by prominent leptomeningeal infiltration by a glial tumor without an identifiable parenchymal mass. The molecular profile of adult PLG has not been well-characterized. We report the clinical, pathological, and molecular findings of six adult PLG patients (five males and one female), median age 58 years. All cases exhibited pathological leptomeningeal enhancement at presentation. Leptomeningeal biopsy was diagnostic in five (of six) cases, revealing infiltration by an astrocytic glioma with mitotic activity, lacking microvascular proliferation or necrosis. One case was diagnosed at autopsy. All tumors were IDH-wildtype, …

Liger-Hn Phase Iii Trials Of Petosemtamab + Pembrolizumab And Petosemtamab Monotherapy In Recurrent Or Metastatic Hnscc, Jean-Pascal Machiels, Douglas Adkins, Et Al.

2020-Current year OA Pubs

Patients with recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) have limited treatment options and a dismal prognosis, especially when their cancer is resistant to standard treatments like anti-programmed cell death protein 1 and platinum-based therapies. Petosemtamab - a human, common light chain, bispecific antibody with enhanced antibody-dependent cellular cytotoxicity targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) - demonstrated antitumor activity in r/m HNSCC. In many tumor types, including HNSCC, EGFR is an oncogenic driver, while LGR5 is upregulated. LGR5 can potentiate the wingless-type integration site (WNT)/β-catenin signaling pathway in response to …

Adapt-Marketplace - A Web-Application For Xml-Based Template Sharing In Radiation Oncology, Dennis N Stanley, Joseph Harms, Gaurav N Rathi, Joel A Pogue, Ritish Nedunoori, John B Fiveash, Richard A Popple, Carlos E Cardenas

2020-Current year OA Pubs

PURPOSE: The adaption of radiotherapy (RT) plans in response to anatomical and physiological changes during treatment marks a significant shift toward personalized cancer care. However, the complexity of Online Adaptive Radiotherapy (OART) procedures often leads to variability in treatment quality across institutions. The development of planning templates, particularly through the Ethos treatment planning system (TPS) and Intelligent Optimization Engine (IOE) (Varian Medical Systems, Palo Alto, CA), plays a crucial role in standardizing and streamlining OART. To address the challenges of sharing and optimizing treatment templates across diverse clinical environments, we developed the ADaptive rAdiotherapy Planning Template (ADAPT-) Marketplace to facilitate …

Clinical Evaluation Of The Healgen Rapid Covid-19 Antigen Test As A Point-Of-Care Diagnostic Tool, Stephen A Young, Hua Zhang, Jose Rodriguez, David Mishkin, Ward Paine, Li Seyfried, Latisha Hargrove, Dennis L Broyles, Chermaen Lindberg, Anurag Purushothaman, Stacey House

2020-Current year OA Pubs

BACKGROUND: Development of readily available Rapid COVID-19 Antigen tests essential for promptly identifying SARS-CoV2 infection and preventing its spread.

METHODS: This study evaluated the clinical performance of the Healgen Rapid COVID-19 antigen test as a point-of-care diagnostic tool with 806 evaluable subjects who were within 6 days post-symptom onset. The results from the Healgen test were compared to the results from Emergency Use Authorization (EUA) approved SARS-CoV-2 RT-PCR tests.

RESULTS: Out of the 806 evaluable subjects, 140 tested positive and 640 tested negative for SARS-CoV-2 with the Healgen COVID-19 test, showing good agreement with the EUA RT-PCR results. There were …

Kpna2 Promotes Osteosarcoma Progression By Regulating The Alternative Splicing Of Ddx3x Mediated By Ybx1, Li Cao, Ke Jia, B A Van Tine, Yihan Yu, Yizhong Peng, Xuanzuo Chen, Qing Pan, Wenbo Yang, Zhicai Zhang, Zengwu Shao, Wei Wu

2020-Current year OA Pubs

Osteosarcoma (OS) is a rapidly progressive primary malignant bone tumor that occurs in children and adolescents aged between 15 and 19 years and adults aged over 60 years. As alternative splicing (AS) changes caused by abnormal splicing factors contribute to tumor progression, gene expression and AS analyses were performed on 44 osteosarcoma patients to create a genome-wide co-expression network of RNA-binding proteins (RBPs), AS events, and AS genes. A gain- or loss-of-function osteosarcoma cell model was established, and an interactive network analysis and enrichment analysis were performed. Karyopherin Subunit Alpha 2 (KPNA2) negatively correlated with patient survival. KPNA2 transports splicing …

Molecular Mechanisms Of Inverse Agonism Via Κ-Opioid Receptor-G Protein Complexes, Aaliyah S Tyson, Saif Khan, Zenia Motiwala, Gye Won Han, Zixin Zhang, Mohsen Ranjbar, Daniel Styrpejko, Nokomis Ramos-Gonzalez, Stone Woo, Kelly Villers, Delainey Landaker, Terry Kenakin, Ryan Shenvi, Susruta Majumdar, Cornelius Gati

2020-Current year OA Pubs

Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor-G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR-G

Sleep Variability And Time To Achieving Pregnancy: Findings From A Pilot Cohort Study Of Women Desiring Pregnancy, Peinan Zhao, Emily S Jungheim, Bronwyn S Bedrick, Leping Wan, Patricia T Jimenez, Ronald Mccarthy, Jessica Chubiz, Justin C Fay, Erik D Herzog, Siobhan Sutcliffe, Sarah K England

2020-Current year OA Pubs

OBJECTIVE: To determine whether chronodisruption is associated with achieving pregnancy.

DESIGN: Pilot prospective cohort study.

SETTING: Academic Medical Center.

SUBJECTS: One hundred eighty-three women desiring pregnancy were recruited from the local community of an academic medical center located in the Midwest and provided sleep information between February 1, 2015, and November 30, 2017.

EXPOSURE: Sleep and activity data were obtained via actigraphy watches worn continuously for 2 weeks to assess measures of chronodisruption, including sleep period onset, offset, midtime, and duration; as well as variability in each of these measures.

MAIN OUTCOME MEASURES: Time to becoming pregnant over 1-year of …

Reduced Risk Of Cesarean Delivery With Oxytocin Discontinuation In Active Labor: A Systematic Review And Meta-Analysis, Julia Whitley, Julia Burd, Michelle Doering, Jeannie Kelly, Antonina Frolova, Nandini Raghuraman

2020-Current year OA Pubs

OBJECTIVE: Our objective was to determine if oxytocin discontinuation in the active phase of labor impacts the rate of cesarean delivery compared to continuation of oxytocin.

DATA SOURCES: This study was a systematic review and meta-analysis of randomized controlled trials. A research librarian performed a database search using a combination of standardized terms and keywords related to oxytocin discontinuation and stages of labor from database inception until February 2024. This protocol was registered in The International Prospective Register of Systematic Reviews (PROSPERO).

STUDY ELIGIBILITY CRITERIA: Randomized controlled trials of pregnant patients who received oxytocin for induction or augmentation of labor, …

Landscape Of Cancer Associated Epcam Mutations: Molecular Modeling, Predictive Insights And Impact On Patient Survival, Priyanka S Dhotare, Audrey C Bochi-Layec, Timothy P Fleming, William E Gillanders, Ross M Bremner, Kailas D Sonawane, Narendra V Sankpal

2020-Current year OA Pubs

BACKGROUND: EpCAM (epithelial cell adhesion molecule) is a key regulator of epithelial cell-cell adhesion, signal transduction, tissue regeneration, and serves as a stem cell marker. It is frequently overexpressed in epithelial cancers and is linked to tumor progression, survival, and metastasis. However, the functional impact of EpCAM mutations in cancer remains poorly understood.

METHODS: To investigate the role of EpCAM mutations, we performed a comprehensive analysis of cancer cohorts from multiple genomic datasets, identifying novel somatic EpCAM mutations across diverse epithelial cancers. Using bioinformatics tools (SIFT, PolyPhen-2, Mutation Assessor) and molecular modeling, we assessed the potential impact of these mutations. …

Phase Ii Basket Trial Of Dual Anti-Ctla-4 And Anti-Pd-1 Blockade In Rare Tumors (Dart) Swog S1609: Pancreatic Neuroendocrine Neoplasm (Pnen) Cohort, Sandip Pravin Patel, Jillian Fisher, Young Kwang Chae, Luisa Solis Soto, Anup Kasi, Bhavana Konda, Mark Walshauser, Edwin Parra, Jiexin Zhang, Caroline Duault, Edgar Gonzalez-Kozlova, Ganiraju Manyam, Jianhua Zhang, Hong Chen, Dzifa Yawa Duose, Caddie Laberiano Fernandez, Raja Luthra, Gheath Al-Atrash, Seunghee Kim-Schulze, Holden T Maecker, Ignacio I Wistuba, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Christine M Magner, Helen X Chen, Elad Sharon, Megan Othus, Christopher W Ryan, Charles Blanke, Cara L Haymaker, Razelle Kurzrock

Faculty, Staff and Student Publications

Purpose: SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.

Experimental design: Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative …