Medicine and Health Sciences Commons^™

Acquired Genomic Alterations On First-Line Chemotherapy With Cetuximab In Advanced Colorectal Cancer: Circulating Tumor Dna Analysis Of The Calgb/Swog-80405 Trial (Alliance), Kanwal Raghav, Fang-Shu Ou, Alan P Venook, Federico Innocenti, Ryan Sun, Heinz-Josef Lenz, Scott Kopetz

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Acquired genomic alterations (Acq-GAs), specifically RAS, BRAF, and EGFR-ectodomain mutations and ERBB2 and MET amplifications, are recognized as major mechanisms of resistance to later-line anti-EGFR-antibody therapy in metastatic colorectal cancer (mCRC). However, data regarding …

Resistance Mechanisms To Anti–Epidermal Growth Factor Receptor Therapy In Ras/Raf Wild-Type Colorectal Cancer Vary By Regimen And Line Of Therapy, Christine M Parseghian, Ryan Sun, Melanie Woods, Stefania Napolitano, Hey Min Lee, Jumanah Alshenaifi, Jason Willis, Shakayla Nunez, Kanwal P Raghav, Van K Morris, John P Shen, Madhulika Eluri, Alexey Sorokin, Preeti Kanikarla, Eduardo Vilar, Marko Rehn, Agnes Ang, Teresa Troiani, Scott Kopetz

Faculty, Staff and Student Publications

Purpose: Acquired resistance to anti-epidermal growth factor receptor (EGFR) inhibitor (EGFRi) therapy in colorectal cancer (CRC) has previously been explained by the model of acquiring new mutations in KRAS/NRAS/EGFR, among other MAPK-pathway members. However, this was primarily on the basis of single-agent EGFRi trials and little is known about the resistance mechanisms of EGFRi combined with effective cytotoxic chemotherapy in previously untreated patients.

Methods: We analyzed paired plasma samples from patients with RAS/BRAF/EGFR wild-type metastatic CRC enrolled in three large randomized trials evaluating EGFRi in the first line in combination with chemotherapy and as a single agent in third …

Prediction Of Pathologic Complete Response To Neoadjuvant Systemic Therapy In Triple Negative Breast Cancer Using Deep Learning On Multiparametric Mri, Zijian Zhou, Beatriz E Adrada, Rosalind P Candelaria, Nabil A Elshafeey, Medine Boge, Rania M Mohamed, Sanaz Pashapoor, Jia Sun, Zhan Xu, Bikash Panthi, Jong Bum Son, Mary S Guirguis, Miral M Patel, Gary J Whitman, Tanya W Moseley, Marion E Scoggins, Jason B White, Jennifer K Litton, Vicente Valero, Kelly K Hunt, Debu Tripathy, Wei Yang, Peng Wei, Clinton Yam, Mark D Pagel, Gaiane M Rauch, Jingfei Ma

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Neoadjuvant systemic therapy (NAST) followed by surgery are currently standard of care for TNBC with 50-60% of patients achieving pathologic complete response (pCR). We investigated ability of deep learning (DL) on dynamic contrast enhanced (DCE) MRI and diffusion weighted imaging acquired early during NAST to predict TNBC patients' pCR status in the breast. During the development phase using the images of 130 TNBC patients, the DL model achieved areas under the receiver operating characteristic curves (AUCs) of 0.97 ± 0.04 and 0.82 ± 0.10 for the training and the …

Brain Nuclear Receptors And Cardiovascular Function, Mengjie Wang, Yongjie Yang, Yong Xu

Faculty, Staff and Students Publications

Brain-heart interaction has raised up increasing attentions. Nuclear receptors (NRs) are abundantly expressed in the brain, and emerging evidence indicates that a number of these brain NRs regulate multiple aspects of cardiovascular diseases (CVDs), including hypertension, heart failure, atherosclerosis, etc. In this review, we will elaborate recent findings that have established the physiological relevance of brain NRs in the context of cardiovascular function. In addition, we will discuss the currently available evidence regarding the distinct neuronal populations that respond to brain NRs in the cardiovascular control. These findings suggest connections between cardiac control and brain dynamics through NR signaling, which …

Substrate Electronics Dominate The Rate Of Reductive Dehalogenation Promoted By The Flavin-Dependent Iodotyrosine Deiodinase, Jeffrey M Carlson, Ayzsa Tannis, Kate R Woodworth, Megan R Reynolds, Neha Shinde, Breanne Anderson, Keivon Hobeheidar, Aisha Praag, Kristen Campbell, Cynthia Carpentieri, Teri Willabus, Elizabeth Burkhardt, Elizabeth Torrone, Kevin P O'Callaghan, Kathryn Miele, Dana Meaney-Delman, Suzanne M Gilboa, Emily O'Malley Olsen, Van T Tong

Faculty, Staff and Student Publications

Despite universal prenatal syphilis screening recommendations and availability of effective antibiotic treatment, syphilis prevalence during pregnancy and the incidence of congenital syphilis have continued to increase in the United States (1,2). Concurrent increases in methamphetamine, injection drug, and heroin use have been described in women with syphilis (3). CDC used data on births that occurred during January 1, 2018-December 31, 2021, from two states (Arizona and Georgia) that participate in the Surveillance for Emerging Threats to Pregnant People and Infants Network (SET-NET) to describe the prevalence of substance use among pregnant persons with syphilis by congenital syphilis pregnancy outcome (defined …

Svhound: Detection Of Regions That Harbor Yet Undetected Structural Variation, Luis F Paulin, Muthuswamy Raveendran, R Alan Harris, Jeffrey Rogers, Arndt Von Haeseler, Fritz J Sedlazeck

Faculty, Staff and Students Publications

BACKGROUND: Recent population studies are ever growing in number of samples to investigate the diversity of a population or species. These studies reveal new polymorphism that lead to important insights into the mechanisms of evolution, but are also important for the interpretation of these variations. Nevertheless, while the full catalog of variations across entire species remains unknown, we can predict which regions harbor additional not yet detected variations and investigate their properties, thereby enhancing the analysis for potentially missed variants.

RESULTS: To achieve this we developed SVhound ( https://github.com/lfpaulin/SVhound ), which based on a population level SVs dataset can predict …

A Pleiotropic Chemoreceptor Facilitates The Production And Perception Of Mating Pheromones, Cassondra L Vernier, Nicole Leitner, Kathleen M Zelle, Merrin Foltz, Sophia Dutton, Xitong Liang, Sean Halloran, Jocelyn G Millar, Yehuda Ben-Shahar

2020-Current year OA Pubs

Optimal mating decisions depend on the robust coupling of signal production and perception because independent changes in either could carry a fitness cost. However, since the perception and production of mating signals are often mediated by different tissues and cell types, the mechanisms that drive and maintain their coupling remain unknown for most animal species. Here, we show that in

Treatment Outcomes And Roles Of Transplantation And Maintenance Rituximab In Patients With Previously Untreated Mantle Cell Lymphoma: Results From Large Real-World Cohorts, Peter Martin, Jonathon B Cohen, Michael Wang, Anita Kumar, Brian Hill, Diego Villa, Jeffrey M Switchenko, Brad Kahl, Kami Maddocks, Natalie S Grover, Keqin Qi, Lori Parisi, Katherine Daly, Angeline Zhu, Gilles Salles

2020-Current year OA Pubs

PURPOSE: Commonly used first-line (1L) treatments for mantle cell lymphoma include high-dose cytarabine-based induction followed by autologous stem-cell transplant (ASCT) for younger patients and several chemoimmunotherapy regimens for older patients. Continuous debates exist on the role of ASCT in younger patients and maintenance rituximab (MR) after bendamustine plus rituximab (BR).

METHODS: Retrospective data from 4,216 patients with mantle cell lymphoma in the Flatiron Health electronic record-derived deidentified database diagnosed between 2011 and 2021, mostly in US community oncology settings, were evaluated for treatment patterns and outcomes. The efficacy findings with ASCT and MR were validated in an independent cohort of …

Synthetic Biology Design As A Paradigm Shift Toward Manufacturing Affordable Adeno-Associated Virus Gene Therapies, Logan Thrasher Collins, Selvarangan Ponnazhagan, David T Curiel

2020-Current year OA Pubs

Gene therapy has demonstrated enormous potential for changing how we combat disease. By directly engineering the genetic composition of cells, it provides a broad range of options for improving human health. Adeno-associated viruses (AAVs) represent a leading gene therapy vector and are expected to address a wide range of conditions in the coming decade. Three AAV therapies have already been approved by the FDA to treat Leber's congenital amaurosis, spinal muscular atrophy, and hemophilia B. Yet these therapies cost around $850,000, $2,100,000, and $3,500,000, respectively. Such prices limit the broad applicability of AAV gene therapy and make it inaccessible to …

Fluorescence Angiography With Dual Fluorescence For The Early Detection And Longitudinal Quantitation Of Vascular Leakage In Retinopathy, Benjamin Pomeroy, Alexander W Venanzi, Wei Li, Abigail S Hackam, Midhat H Abdulreda

Faculty, Staff and Students Publications

BACKGROUND: Diabetic retinopathy (DR) afflicts more than 93 million people worldwide and is a leading cause of vision loss in working adults. While DR therapies are available, early DR development may go undetected without treatment due to the lack of sufficiently sensitive tools. Therefore, early detection is critically important to enable efficient treatment before progression to vision-threatening complications. A major clinical manifestation of early DR is retinal vascular leakage that may progress from diffuse to more localized focal leakage, leading to increased retinal thickness and diabetic macular edema (DME). In preclinical research, a hallmark of DR in mouse models is …

Identifying Biomarkers Of Differential Chemotherapy Response In Tnbc Patient-Derived Xenografts With A Ctd/Wgcna Approach, Varduhi Petrosyan, Shunqiang Li, Et Al.

2020-Current year OA Pubs

Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, …

Identifying Biomarkers Of Differential Chemotherapy Response In Tnbc Patient-Derived Xenografts With A Ctd/Wgcna Approach, Varduhi Petrosyan, Lacey E Dobrolecki, Lillian Thistlethwaite, Alaina N Lewis, Christina Sallas, Ramakrishnan R Srinivasan, Jonathan T Lei, Vladimir Kovacevic, Predrag Obradovic, Matthew J Ellis, C Kent Osborne, Mothaffar F Rimawi, Anne Pavlick, Maryam Nemati Shafaee, Heidi Dowst, Antrix Jain, Alexander B Saltzman, Anna Malovannaya, Elisabetta Marangoni, Alana L Welm, Bryan E Welm, Shunqiang Li, Gerburg M Wulf, Olmo Sonzogni, Chen Huang, Suhas Vasaikar, Susan G Hilsenbeck, Bing Zhang, Aleksandar Milosavljevic, Michael T Lewis

Faculty, Staff and Students Publications

Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, …

Approach To The Patient: Pharmacological Therapies For Fracture Risk Reduction In Adults With Osteogenesis Imperfecta, Winnie Liu, Brendan Lee, Sandesh C S Nagamani, Lindsey Nicol, Frank Rauch, Eric T Rush, V Reid Sutton, Eric Orwoll

Faculty, Staff and Students Publications

Context

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. The effectiveness of medications used for fracture reduction in adults with OI is understudied and practice recommendations are not well established. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis. Oral and intravenous bisphosphonates have been shown to improve bone mineral density (BMD) in adults with OI and are commonly used; however, conclusive data confirming fracture protection are lacking. Similarly, teriparatide appears to increase BMD, an effect …

Delivering Occupation-Based Practice In Stroke Rehabilitation Of Hospital Settings: Thai Occupational Therapists’ Experiences, Anuchart Kaunnil, Veerawat Sansri, Surachart Thongchoomsin, Kannika Permpoonputtana, Sutinun Juntorn, Kathryn Jarvis, Cristina Reyes Smith, Michael Palapal Sy, Jiranan Griffiths, Chutikorn Nopparat, Peeradech Thichanpiang

The Qualitative Report

Occupation-based practice (OBP) is central to the practice of occupational therapists where occupations or meaningful activities become the focus of the assessment, intervention, and outcomes measurement process. Although occupational therapists practising in Thailand claim that they engage in OBP, this claim warrants empirical investigation. This study aimed to investigate the experiences and perceptions of hospital-based occupational therapists of OBP within stroke rehabilitation. Utilizing a qualitative design, fourteen occupational therapists were recruited through purposive sampling. Data were collected through semi-structured interviews until data saturation was reached. Each interview was recorded and transcribed verbatim, and data were analyzed using thematic analysis. Five …

Impact Of The Covid-19 Pandemic On Burnout And Perceived Workplace Quality Among Addiction Treatment Providers, Andrea Fentem, Raven Riordan, Christine Doroshenko, Xiao Li, Erin Kasson, Devin Banks, Rachel P Winograd, Patricia Cavazos-Rehg

2020-Current year OA Pubs

BACKGROUND: This study examines the impact of the COVID-19 pandemic on work satisfaction, work-related stress, and perceived work quality among substance use treatment providers to better understand challenges faced among this group during the pandemic.

METHODS: Participants of this study were 91 addiction treatment providers (e.g., therapists, physicians, community support specialists, administrative staff) recruited from various treatment facilities (e.g., inpatient and outpatient settings). Mixed method analyses were conducted to assess self-reported burnout, sources of work-related stress, and perceived work quality during the pandemic. Responses from providers reporting COVID-19 related decreases in work quality were compared to responses from providers who …

Personalized Therapeutics For Katp-Dependent Pathologies, Colin G Nichols

2020-Current year OA Pubs

Ubiquitously expressed throughout the body, ATP-sensitive potassium (K

Mental Health In Pilots Ages 19-26: What Are The New Pilots Telling Us?, Jason T. Lorenzon, Diana Semilia

National Training Aircraft Symposium (NTAS)

Mental Health is stigma that reaches all professional pilots. After spending a considerable amount of money, a pilot is always afraid of losing his/her medical certification. This leads many pilots to not be honest and forthcoming about his/her own health situation or if he/she is forthcoming with any medical deficiency, the regulatory framework at the Federal Aviation Administration may put a further burden on the pilot to provide additional medical documentation, or the FAA may even amend, revoke, or suspend a pilot's medical certificate.

The Federal Aviation Administration (FAA) regulations,14 CFR Parts 61 and 67 and internal protocols creates a …

2023-01-19_Michiganoverview_Misc, Michigan Department Of Health & Human Services

Michigan COVID-19 MIS-C Data

The MIS-C Data page was obtained from Michigan's COVID-19 data page: https://www.michigan.gov/coronavirus/stats/mis-c-reporting.

This report is created by the Michigan Department of Health & Human Services from data self-reported by health care providers and local health departments. Data is updated on the first and third Thursdays of the month.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition in children and adolescents under 21 years of age where multiple organ systems become inflamed or dysfunctional which occurs in association with illness. Children with MIS-C may have a fever and various symptoms, including abdominal (gut) pain, vomiting, diarrhea, neck pain, rash, …

Medical School Watercooler Newsletter - January 19, 2023, Lindsey Lyle

Watercooler Newsletter

This is the January 19, 2023 edition of the Frederick P. Whiddon College of Medicine's newsletter - Watercooler.

Contents include:

• Researches publish novel findings that could improve management of prostate cancer
• Meet a Med Student: Grace Dunbar
• New members selected for gold humanism in medicine honor society

Analyses Of Orthopaedic Surgery Residency Interviews, Alexander J Adams, Matthew Sherman, James J. Purtill

Rothman Institute Papers

Interviews are a critical component of orthopaedic surgery residency selection for both the applicant and the program. Some institutions no longer report Alpha Omega Alpha (AOA) designation or class rank, and US Medical Licensing Examination (USMLE) Step 1 recently switched to pass/fail scoring. During the coronavirus disease 2019 (COVID-19) pandemic, all Accreditation Council for Graduate Medical Education programs conducted virtual interviews and subinternship rotations were restricted. These changes offer significant challenges to the residency match process. The purpose of this study was to examine the residency applicant interview and ranking process at a large urban academic university setting. We hypothesized …

Understanding The Experiences Of Latino Medical Students In A Learning Medical Environment, Leslie García

Dissertations and Theses

Very little is known about the experiences and perceptions of underrepresented minority (URiM) medical students in the U.S. allopathic medical schools. The limited literature posits URiMs experience more adverse experiences in the learning environment and have different learning outcomes in comparison to their White peer counterparts. Latino medical students represent 7.1% of all entering medical students across all U.S. medical schools. While they represent the largest ethnic minority in the United States within parity lack representation among the physician workforce [sic]. There is a dearth of knowledge of what factors contribute to the success of Latino medical students progressing in …

Investigating Stigma During The Early Stages Of A Pandemic Through The Lens Of Covid-19, Zach Thornton, Bethany Hodge, Sheridan Langford

The University of Louisville Journal of Respiratory Infections

Background: Individuals face stigma associated with numerous health conditions. Stigma can arise rapidly during the early spread of a new disease, adding to the burden felt by those affected. COVID-19 can be used as an example to study stigma during the early phases of a pandemic. This narrative review is a descriptive analysis that tracks the ways in which COVID-19 stigma was discussed in the scholarly literature during the first year of the pandemic to understand how stigma was viewed in the context of a rapidly spreading pandemic.

Methods: PubMed was used as a non-exhaustive sample of the literature. Searches …

The Importance Of Occupational Health Service In The Era Of Vuca And The Dissemination Of Related Research Results, Muchtaruddin Mansyur

Occupational and Environmental Medicine Journal of Indonesia

Worldwide have been facing the era of dynamic life with the rapidly changing global situation for decades. This era is colored by volatility, uncertainty, complexity, and ambiguity (VUCA) situation that is aggravated by the COVID-19 pandemic. We have all experienced the VUCA situation with the COVID-19 Pandemic that has lasted over 2 years. The United Nations Development Programme (UNDP)1 report should be a common reference for dealing with situations that are not just uncertain but also called “uncertainty complexes”. So-called because its dimensions take on a new form that has never been seen before in human history. The complexity of …

A Work-Related Thyrotoxic Periodic Paralysis In A Worker Exposed To Heat Stress: A Case Report, Shanti Puji Lestari, Muchtaruddin Mansyur

Occupational and Environmental Medicine Journal of Indonesia

Thyrotoxic Periodic Paralysis (TPP) is an uncommon disorder, characterized by the triad of acute hypokalemia, muscle paralysis, and thyrotoxicosis. Attacks are typically transient, last hours to days, and may be triggered by many conditions, including exposure to heat stress in both indoor and outdoor activities. Indoor workers, especially those working around furnaces, ovens, smelters, and boilers, are at a higher heat stress risk, even higher risk if they have other individual factors such as obesity, dehydration, slower heat acclimation, consume certain medications and presence of underlying diseases. A 48-year-old man presented a sudden onset weakness in all four limbs, associated …

A Cohort Retrospective Study Of Framingham Score And Ecg Abnormality Among Coal Mining Workers, Faizal Ablansah Anandita, Isman Firdaus, Rino Alvani Gani, Retno Asti Werdhani, Muchtaruddin Mansyur

Occupational and Environmental Medicine Journal of Indonesia

Introduction. ECG is widely used for detecting cardiovascular disease in coal mine worker’s medical check-up. As the study has proven, coal mine workers have a double cardiovascular risk from their workplace hazard and their own medical risks as individuals. An early detection and risk assessment method is needed to predict ECG abnormalities in the future. This study will analyze the relationship between ECG abnormality and Framingham Risk Score on coal mine workers’. Methods. We examine ECG result from medical check-up of male coal worker during 2018 and 2021. Using Minnesota Code, we determine ECG abnormality categories in the 2021 result, …

The Effect Of Physical Training Program For Fitness Improvement On Sickness Absence Of Workers At A Chemical Company In Indonesia, Anita Johan, Aria Kekalih, Nuri Purwito Adi, Ambar W. Roestam, Dewi S. Soemarko

Occupational and Environmental Medicine Journal of Indonesia

Introduction. Sickness absence, which can be caused by an unhealthy lifestyle, is an important productivity parameter for the company. Therefore, there are many wellness programs developed in the workplace in an effort to improve workers’ health, fitness, and productivity. The aim of this study was to assess the effect of a physical training program for fitness improvement (VO2 max value) on sickness absence. Methods. This study was conducted by observing the results of the workers' physical training program in the chemical company during 2018, using a cohort retrospective design. SPSS Statistics version 22.0 was used for analysis, with the chi-square …

The Analysis Of Risk Factors Affecting The Proportion Of Standard Threshold Shift Among Manufacturing Workers, Firly Ratsmita, Muhammad Ilyas, Liem Jen Fuk, Dewi S. Soemarko, Levina Chandra

Occupational and Environmental Medicine Journal of Indonesia

Introduction. About 82% of cases of hearing loss due to employment occur in workers in the manufacturing sector. The prevalence of hearing loss has a permanent impact that can be detected by standard threshold shift (STS). The aim of the study was to determine the relationship between individual and occupational risk factors on the proportion of STS. Methods. The research was a cross-sectional study on employees with noise exposure. The independent variables include individual factors such as age, history of hypertension, history of diabetes mellitus, smoking, body mass index, and occupational factors such as the history of chemical exposures, working …

Could Hypertension In Radiographers Associated With Low Ionizing Radiation Exposure? An Evidence-Based Case Report, Rita I. Wijaya, Levina C Khoe, Muchtaruddin Mansyur

Occupational and Environmental Medicine Journal of Indonesia

Low-dose ionizing radiation exposure (

Development Of Food-Based Recommendation And Nutrient-Dense Meal For Female Shift Workers In West Java, Indonesia, Shanti Puji Lestari, Nuri Purwito Adi, Umi Fahmida, Dian Kusuma Dewi, Muchtaruddin Mansyur

Occupational and Environmental Medicine Journal of Indonesia

Introduction. Some manufacturing industries employ not only male workers but also female workers, who are required to undergo shift work. Given the altered eating habits as well as metabolic and endocrine profiles of shift workers, this will affect their nutritional needs. Considering that anemia that occurs in female workers is primarily nutritional anemia, this becomes a challenge in the field of occupational nutrition, especially in terms of preparing food for female workers in accordance with their nutritional needs. The aim of the study is to develop a set of FBR for female shift workers using the Linear Programming (LP) approach. …

Hypoxia Truncates And Constitutively Activates The Key Cholesterol Synthesis Enzyme Squalene Monooxygenase, Hudson W Coates, Isabelle M Capell-Hattam, Ellen M Olzomer, Ximing Du, Rhonda Farrell, Hongyuan Yang, Frances L Byrne, Andrew J Brown

Faculty, Staff and Student Publications

Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates …