Medical Specialties Commons^™

Histone H2a Lys130 Acetylation Epigenetically Regulates Androgen Production In Prostate Cancer, Thanh Nguyen, Dhivya Sridaran, Surbhi Chouhan, Cody Weimholt, Audrey Wilson, Jingqin Luo, Tiandao Li, John Koomen, Bin Fang, Nagireddy Putluri, Arun Sreekumar, Felix Y Feng, Kiran Mahajan, Nupam P Mahajan

Faculty, Staff and Students Publications

The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of …

A Novel Bioactive Peptide, T14, Selectively Activates Mtorc1 Signalling: Therapeutic Implications For Neurodegeneration And Other Rapamycin-Sensitive Applications, Sanskar Ranglani, Anna Ashton, Kashif Mahfooz, Joanna Komorowska, Alexandru Graur, Nadine Kabbani, Sara Garcia-Rates, Susan Greenfield

Faculty, Staff and Student Publications

T14 modulates calcium influx via the α-7 nicotinic acetylcholine receptor to regulate cell growth. Inappropriate triggering of this process has been implicated in Alzheimer's disease (AD) and cancer, whereas T14 blockade has proven therapeutic potential in in vitro, ex vivo and in vivo models of these pathologies. Mammalian target of rapamycin complex 1 (mTORC1) is critical for growth, however its hyperactivation is implicated in AD and cancer. T14 is a product of the longer 30mer-T30. Recent work shows that T30 drives neurite growth in the human SH-SY5Y cell line via the mTOR pathway. Here, we demonstrate that T30 induces an …

Celiac Disease And The Risk Of Cardiovascular Diseases, Yichen Wang, Bing Chen, Edward J Ciaccio, Hani Jneid, Salim S Virani, Carl J Lavie, Jessica Lebovits, Peter H R Green, Chayakrit Krittanawong

Faculty, Staff and Students Publications

Celiac disease (CD) is a chronic autoimmune disorder that affects the small intestine in genetically predisposed individuals. Previous studies have investigated the potential link between CD and cardiovascular disease (CVD); however, the findings have been inconsistent. We aimed to provide an updated review of the literature on the association between CD and CVD. PubMed was searched from inception to January 2023 using keywords including CD, cardiovascular disease, coronary artery disease, cardiac arrhythmia, heart failure, cardiomyopathy, and myocarditis. We summarized the results of the studies, including meta-analyses and original investigations, and presented them according to the different forms of CVD. Meta-analyses …

Microcalcification Crystallography As A Potential Marker Of Dcis Recurrence, Sarah B Gosling, Emily L Arnold, Samantha K Davies, Hannah Cross, Ihssane Bouybayoune, Doriana Calabrese, Jayakrupakar Nallala, Sarah E Pinder, Liping Fu, Esther H Lips, Lorraine King, Jeffrey Marks, Allison Hall, Lars J Grimm, Thomas Lynch, Donna Pinto, Hilary Stobart, E Shelley Hwang, Jelle Wesseling, Kalotina Geraki, Nicholas Stone, Iain D Lyburn, Charlene Greenwood, Keith D Rogers, Grand Challenge Precision Consortium

Faculty, Staff and Student Publications

Ductal carcinoma in-situ (DCIS) accounts for 20-25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite …

Medicaid Expansion, Chemotherapy Delays, And Racial Disparities Among Women With Early-Stage Breast Cancer, Mariana Chavez-Macgregor, Xiudong Lei, Catalina Malinowski, Hui Zhao, Ya-Chen Shih, Sharon H Giordano

Faculty, Staff and Student Publications

BACKGROUND: Medicaid expansion under the Affordable Care Act extends eligibility for participating states and has been associated with improved outcomes by facilitating access to care. Delayed initiation of adjuvant chemotherapy is associated with worse outcomes among patients with early-stage breast cancer (BC). The impact of Medicaid expansion in narrowing delays by race and ethnicity has not been studied, to our knowledge.

METHODS: This was a population-based study using the National Cancer Database. Patients diagnosed with primary early-stage BC between 2007 and 2017 residing in states that underwent Medicaid expansion in January 2014 were included. Time to chemotherapy initiation and proportion …

Early Postpartum Hba1c After Hyperglycemia First Detected In Pregnancy-Imperfect But Not Without Value, Ankia Coetzee, David R Hall, Mari Van De Vyver, Magda Conradie

Faculty, Staff and Student Publications

BACKGROUND: South African women of childbearing age are disproportionally affected by obesity and at significant risk of Type 2 Diabetes Mellitus (T2DM). Unless pregnant, they do not readily undergo screening for T2DM. With a local focus on improved antenatal care, hyperglycemia is often first detected in pregnancy (HFDP). This may erroneously be attributed to Gestational Diabetes Mellitus (GDM) in all without considering T2DM. Glucose evaluation following pregnancy is essential for early detection and management of women with T2DM in whom persistent hyperglycemia is to be expected. Conventional testing with an oral glucose tolerance test (OGTT) is cumbersome, prompting investigation for …

Targeting Neddylation And Sumoylation In Chemoresistant Triple Negative Breast Cancer, Wei Ruan, Jiwen Li, Seungwon Choi, Xinxin Ma, Yafen Liang, Ragini Nair, Xiaoyi Yuan, Tingting W Mills, Holger K Eltzschig

Faculty, Staff and Student Publications

Previous studies implicate extracellular adenosine signaling in attenuating myocardial ischemia and reperfusion injury (IRI). This extracellular adenosine signaling is terminated by its uptake into cells by equilibrative nucleoside transporters (ENTs). Thus, we hypothesized that targeting ENTs would function to increase cardiac adenosine signaling and concomitant cardioprotection against IRI. Mice were exposed to myocardial ischemia and reperfusion injury. Myocardial injury was attenuated in mice treated with the nonspecific ENT inhibitor dipyridamole. A comparison of mice with global Ent1 or Ent2 deletion showed cardioprotection only in Ent1-/- mice. Moreover, studies with tissue-specific Ent deletion revealed that mice with myocyte-specific Ent1 deletion (Ent1loxP/loxP …

Prediction Of Disease Progression To Upfront Pembrolizumab Monotherapy In Advanced Non-Small-Cell Lung Cancer With High Pd-L1 Expression Using Baseline Ct Disease Quantification And Smoking Pack Years, Ali Silver, Cheryl Ho, Qian Ye, Jianjun Zhang, Ian Janzen, Jessica Li, Montgomery Martin, Lang Wu, Ying Wang, Stephen Lam, Calum Macaulay, Barbara Melosky, Ren Yuan

Faculty, Staff and Student Publications

Health Canada approved pembrolizumab in the first-line setting for advanced non-small-cell lung cancer with PD-L1 ≥ 50% and no EGFR/ALK aberration. The keynote 024 trial showed 55% of such patients progress with pembrolizumab monotherapy. We propose that the combination of baseline CT and clinical factors can help identify those patients who may progress. In 138 eligible patients from our institution, we retrospectively collected their baseline variables, including baseline CT findings (primary lung tumor size and metastatic site), smoking pack years, performance status, tumor pathology, and demographics. The treatment response was assessed via RECIST 1.1 using the baseline and first follow-up …

Genome-Wide Analyses Characterize Shared Heritability Among Cancers And Identify Novel Cancer Susceptibility Regions, Sara Lindström, Lu Wang, Helian Feng, Arunabha Majumdar, Sijia Huo, James Macdonald, Tabitha Harrison, Constance Turman, Hongjie Chen, Nicholas Mancuso, Theo Bammler, Breast Cancer Association Consortium (Bcac), Steve Gallinger, Stephen B Gruber, Marc J Gunter, Loic Le Marchand, Victor Moreno, Kenneth Offit, Colorectal Transdisciplinary Study (Corect), Colon Cancer Family Registry Study (Ccfr), Genetics And Epidemiology Of Colorectal Cancer Consortium (Gecco), Immaculata De Vivo, Tracy A O'Mara, Amanda B Spurdle, Ian Tomlinson, Endometrial Cancer Association Consortium (Ecac), Rebecca Fitzgerald, Puya Gharahkhani, Ines Gockel, Janusz Jankowski, Stuart Macgregor, Johannes Schumacher, Jill Barnholtz-Sloan, Melissa L Bondy, Richard S Houlston, Robert B Jenkins, Beatrice Melin, Margaret Wrensch, Paul Brennan, David C Christiani, Mattias Johansson, James Mckay, Melinda C Aldrich, Christopher I Amos, Maria Teresa Landi, Adonina Tardon, International Lung Cancer Consortium (Ilcco), D Timothy Bishop, Florence Demenais, Alisa M Goldstein, Mark M Iles, Peter A Kanetsky, Matthew H Law, Ovarian Cancer Association Consortium (Ocac), Laufey T Amundadottir, Rachael Stolzenberg-Solomon, Brian M Wolpin, Pancreatic Cancer Cohort Consortium (Panscan), Alison Klein, Gloria Petersen, Harvey Risch, Pancreatic Cancer Case-Control Consortium (Panc4), The Practical Consortium, Stephen J Chanock, Mark P Purdue, Ghislaine Scelo, Paul Pharoah, Siddhartha Kar, Rayjean J Hung, Bogdan Pasaniuc, Peter Kraft

Faculty, Staff and Student Publications

BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.

METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel …

Germline Genetic Variants And Pediatric Rhabdomyosarcoma Outcomes: A Report From The Children’S Oncology Group, Bailey A Martin-Giacalone, Melissa A Richard, Michael E Scheurer, Javed Khan, Pagna Sok, Priya B Shetty, Stephen J Chanock, Shengchao Alfred Li, Meredith Yeager, Deborah A Marquez-Do, Donald A Barkauskas, David Hall, Matthew T Mcevoy, Austin L Brown, Aniko Sabo, Paul Scheet, Chad D Huff, Stephen X Skapek, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Philip J Lupo

Faculty, Staff and Student Publications

BACKGROUND: Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS.

METHODS: The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical …

Plumbing Mysterious Rnas In “Dark Genome” For The Conquest Of Human Diseases, Lisa A Huang, Chunru Lin, Liuqing Yang

Faculty, Staff and Student Publications

Next-generation sequencing has revealed that less than 2% of transcribed genes are translated into proteins, with a large portion transcribed into noncoding RNAs (ncRNAs). Among these, long noncoding RNAs (lncRNAs) represent the largest group and are pervasively transcribed throughout the genome. Dysfunctions in lncRNAs have been found in various diseases, highlighting their potential as therapeutic, diagnostic, and prognostic targets. However, challenges, such as unknown molecular mechanisms and nonspecific immune responses, and issues of drug specificity and delivery present obstacles in translating lncRNAs into clinical applications. In this review, we summarize recent publications that have explored lncRNA functions in human diseases. …

The Novel Uncompetitive Nmda Receptor Antagonist Esmethadone (Rel-1017) Has No Meaningful Abuse Potential In Recreational Drug Users, Megan J Shram, Jack E Henningfield, Glen Apseloff, Charles W Gorodetzky, Sara De Martin, Frank L Vocci, Frank L Sapienza, Thomas R Kosten, Jeff Huston, August Buchhalter, Judy Ashworth, Ryan Lanier, Franco Folli, Andrea Mattarei, Clotilde Guidetti, Stefano Comai, Cedric O'Gorman, Sergio Traversa, Charles E Inturrisi, Paolo L Manfredi, Marco Pappagallo

Faculty, Staff and Students Publications

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg …

Tebentafusp In Combination With Durvalumab And/Or Tremelimumab In Patients With Metastatic Cutaneous Melanoma: A Phase 1 Study, Omid Hamid, Jessica C. Hassel, Alexander N. Shoushtari, Friedegund Meier, Todd M. Bauer, April K.S. Salama, John M. Kirkwood, Paolo A. Ascierto, Paul C. Lorigan, Cornelia Mauch, Marlana Orloff, Thomas R. Jeffry Evans, Chris Holland, Ramakrishna Edukulla, Shaad E. Abedin, Mark R. Middleton

Department of Medical Oncology Faculty Papers

BACKGROUND: Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority …

Steroid Responsive Idiopathic Calcitriol Induced Hypercalcemia: A Case Report And Review Of The Literature, Omar El Fadel, Anshel Kenkare, Jingjing Zhang

Division of Internal Medicine Faculty Papers & Presentations

BACKGROUND: Idiopathic Calcitriol Induced Hypercalcemia is a rare cause of a common condition of hypercalcemia. Hypercalcemia is most commonly the result of hyperparathyroidism and together with hypercalcemia of malignancy accounts for over 95% of cases. Idiopathic Calcitriol Induced Hypercalcemia can mimic hypercalcemia secondary to granulomatous diseases like sarcoidosis, but with apparent absences of both imaging and physical exam findings consistent with the disease. We report here a 51-year-old man who presented with recurrent nephrolithiasis, hypercalcemia, and acute kidney injury.

CASE PRESENTATION: A 51-year-old man presented with severe back pain and mild hematuria. He had a history of recurrent nephrolithiasis over …

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

Targeting Cxcr4 Abrogates Resistance To Trastuzumab By Blocking Cell Cycle Progression And Synergizes With Docetaxel In Breast Cancer Treatment, Shuying Liu, Shelly M Xie, Wenbin Liu, Mihai Gagea, Ariella B Hanker, Nguyen Nguyen, Akshara Singareeka Raghavendra, Gloria Yang-Kolodji, Fuliang Chu, Sattva S Neelapu, Adriano Marchese, Samir Hanash, Johann Zimmermann, Carlos L Arteaga, Debasish Tripathy

Faculty, Staff and Student Publications

Background: Although trastuzumab and other HER2-targeted therapies have significantly improved survival in patients with HER2 overexpressed or amplified (HER2+) breast cancer, a significant proportion of patients do not respond or eventually develop clinical resistance. Strategies to reverse trastuzumab resistance remain a high clinical priority. We were the first to report the role of CXCR4 in trastuzumab resistance. The present study aims to explore the therapeutic potential of targeting CXCR4 and better understand the associated mechanisms.

Methods: Immunofluorescent staining, confocal microscopy analysis, and immunoblotting were used to analyze CXCR4 expression. BrdU incorporation assays and flow cytometry were used to analyze dynamic …

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

17Β-Estradiol Promotes Extracellular Vesicle Release And Selective Mirna Loading In Erα-Positive Breast Cancer, Rares Drula, Barbara Pardini, Xiao Fu, Mireia Cruz De Los Santos, Ancuta Jurj, Lan Pang, Sherien M El-Daly, Linda Fabris, Erik Knutsen, Mihnea P Dragomir, Recep Bayraktar, Yongfeng Li, Meng Chen, Filippo Del Vecchio, Léa Berland, Jessica Dae, Daniel Fan, Masayoshi Shimizu, Anh M Tran, Mercedes Barzi, Carlotta Pioppini, Angelica M Gutierrez, Cristina Ivan, Salyna Meas, Carolyn S Hall, Suresh K Alahari, Ioana Berindan-Neagoe, Muller Fabbri, Anthony Lucci, Banu Arun, Simone Anfossi, George A Calin

Faculty, Staff and Student Publications

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, …

Tubectomy With Delayed Oophorectomy As An Alternative To Risk-Reducing Salpingo-Oophorectomy In High-Risk Women To Assess The Safety Of Prevention: The Tuba-Wisp Ii Study Protocol, Miranda P Steenbeek, Majke H D Van Bommel, Joanna Inthout, Christine B Peterson, Michiel Simons, Kit C B Roes, Marleen Kets, Barbara M Norquist, Elizabeth M Swisher, Rosella P M G Hermens, Tuba-Wisp Ii Consortium, Karen H Lu, Joanne A De Hullu

Faculty, Staff and Student Publications

Background: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy.

Primary objective: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk.

Study hypothesis: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) …

Autolysosomal Exocytosis Of Lipids Protect Neurons From Ferroptosis, Isha Ralhan, Jinlan Chang, Matthew J Moulton, Lindsey D Goodman, Nathanael Y J Lee, Greg Plummer, H Amalia Pasolli, Doreen Matthies, Hugo J Bellen, Maria S Ioannou

Faculty, Staff and Students Publications

During oxidative stress neurons release lipids that are internalized by glia. Defects in this coordinated process play an important role in several neurodegenerative diseases. Yet, the mechanisms of lipid release and its consequences on neuronal health are unclear. Here, we demonstrate that lipid-protein particle release by autolysosome exocytosis protects neurons from ferroptosis, a form of cell death driven by lipid peroxidation. We show that during oxidative stress, peroxidated lipids and iron are released from neurons by autolysosomal exocytosis which requires the exocytic machinery VAMP7 and syntaxin 4. We observe membrane-bound lipid-protein particles by TEM and demonstrate that these particles are …

Systematic Assessment Of The Contribution Of Structural Variants To Inherited Retinal Diseases, Shu Wen, Meng Wang, Xinye Qian, Yumei Li, Keqing Wang, Jongsu Choi, Mark E Pennesi, Paul Yang, Molly Marra, Robert K Koenekoop, Irma Lopez, Anna Matynia, Michael Gorin, Ruifang Sui, Fengxia Yao, Kerry Goetz, Fernanda Belga Ottoni Porto, Rui Chen

Faculty, Staff and Students Publications

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined were subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these …

The Role Of Native Cysteine Residues In The Oligomerization Of Kcnq1 Channels, Alison Bates, Rebecca B Stowe, Elizabeth M Travis, Lauryn E Cook, Carole Dabney-Smith, Gary A Lorigan

Faculty, Staff and Student Publications

KCNQ1, the major component of the slow-delayed rectifier potassium channel, is responsible for repolarization of cardiac action potential. Mutations in this channel can lead to a variety of diseases, most notably long QT syndrome. It is currently unknown how many of these mutations change channel function and structure on a molecular level. Since tetramerization is key to proper function and structure of the channel, it is likely that mutations modify the stability of KCNQ1 oligomers. Presently, the C-terminal domain of KCNQ1 has been noted as the driving force for oligomer formation. However, truncated versions of this protein lacking the C-terminal …

Digital Health Technologies For Peripartum Depression Management Among Low-Socioeconomic Populations: Perspectives From Patients, Providers, And Social Media Channels, Alexandra Zingg, Tavleen Singh, Amy Franklin, Angela Ross, Sudhakar Selvaraj, Jerrie Refuerzo, Sahiti Myneni

Faculty, Staff and Student Publications

BACKGROUND: Peripartum Depression (PPD) affects approximately 10-15% of perinatal women in the U.S., with those of low socioeconomic status (low-SES) more likely to develop symptoms. Multilevel treatment barriers including social stigma and not having appropriate access to mental health resources have played a major role in PPD-related disparities. Emerging advances in digital technologies and analytics provide opportunities to identify and address access barriers, knowledge gaps, and engagement issues. However, most market solutions for PPD prevention and management are produced generically without considering the specialized needs of low-SES populations. In this study, we examine and portray the information and technology needs …

Cfp1 Governs Uterine Epigenetic Landscapes To Intervene In Progesterone Responses For Uterine Physiology And Suppression Of Endometriosis, Seung Chel Yang, Mira Park, Kwon-Ho Hong, Hyeonwoo La, Chanhyeok Park, Peike Wang, Gaizhen Li, Qionghua Chen, Youngsok Choi, Francesco J Demayo, John P Lydon, David G Skalnik, Hyunjung J Lim, Seok-Ho Hong, So Hee Park, Yeon Sun Kim, Hye-Ryun Kim, Haengseok Song

Faculty, Staff and Students Publications

Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent …

Real-World Utilization Of The Pill-In-The-Pocket Method For Terminating Episodes Of Atrial Fibrillation: Data From The Multinational Antiarrhythmic Interventions For Managing Atrial Fibrillation (Aim-Af) Survey, James A Reiffel, Carina Blomström-Lundqvist, Giuseppe Boriani, Andreas Goette, Peter R Kowey, Jose L Merino, Jonathan P Piccini, Sanjeev Saksena, A John Camm

Department of Medicine Faculty Papers

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Episodes may stop spontaneously (paroxysmal AF); may terminate only via intervention (persistent AF); or may persist indefinitely (permanent AF) (see European and American guidelines, referenced below, for more precise definitions). Recently, there has been renewed interest in an approach to terminate AF acutely referred to as 'pill-in-the-pocket' (PITP). The PITP is recognized in both the US and European guidelines as an effective option using an oral antiarrhythmic drug for acute conversion of acute/recent-onset AF. However, how PITP is currently used has not been systematically evaluated.

METHODS …

The Landscape Of Tolerated Genetic Variation In Humans And Primates, Hong Gao, Tobias Hamp, Jeffrey Ede, Joshua G Schraiber, Jeremy Mcrae, Moriel Singer-Berk, Yanshen Yang, Anastasia S D Dietrich, Petko P Fiziev, Lukas F K Kuderna, Laksshman Sundaram, Yibing Wu, Aashish Adhikari, Yair Field, Chen Chen, Serafim Batzoglou, Francois Aguet, Gabrielle Lemire, Rebecca Reimers, Daniel Balick, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien De Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Fabiano R De Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi Do Amaral, Mariluce Messias, Maria N F Da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Thomas Bataillon, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Monkol Lek, Shamil Sunyaev, Anne O'Donnell-Luria, Heidi L Rehm, Jinbo Xu, Jeffrey Rogers, Tomas Marques-Bonet, Kyle Kai-How Farh

Faculty, Staff and Students Publications

INTRODUCTION:

Millions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.

RATIONALE:

As a result of the short evolutionary distance between humans and nonhuman primates, …

Evaluating The Use Of Blood Pressure Polygenic Risk Scores Across Race/Ethnic Background Groups, Nuzulul Kurniansyah, Matthew O Goodman, Alyna T Khan, Jiongming Wang, Elena Feofanova, Joshua C Bis, Kerri L Wiggins, Jennifer E Huffman, Tanika Kelly, Tali Elfassy, Xiuqing Guo, Walter Palmas, Henry J Lin, Shih-Jen Hwang, Yan Gao, Kendra Young, Gregory L Kinney, Jennifer A Smith, Bing Yu, Simin Liu, Sylvia Wassertheil-Smoller, Joann E Manson, Xiaofeng Zhu, Yii-Der Ida Chen, I-Te Lee, C Charles Gu, Donald M Lloyd-Jones, Sebastian Zöllner, Myriam Fornage, Charles Kooperberg, Adolfo Correa, Bruce M Psaty, Donna K Arnett, Carmen R Isasi, Stephen S Rich, Robert C Kaplan, Susan Redline, Braxton D Mitchell, Nora Franceschini, Daniel Levy, Jerome I Rotter, Alanna C Morrison, Tamar Sofer

Faculty, Staff and Student Publications

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs …

A Global Catalog Of Whole-Genome Diversity From 233 Primate Species\, Lukas F K Kuderna, Hong Gao, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Thomas Bataillon, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien De Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idrissa S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Joshua G Schraiber, Fabiano R De Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi, Malu Messias, Maria N F Da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda D Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Jeffrey Rogers, Kyle Kai-How Farh, Tomas Marques Bonet

Faculty, Staff and Students Publications

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families …