Medical Specialties Commons^™

Early Skeletal Muscle Loss In Adolescent And Young Adult Cancer Patients Treated With Anthracycline Chemotherapy, Savannah V Wooten, Fei Wang, Michael E Roth, Guanshu Liu, J Andrew Livingston, Behrang Amini, Susan C Gilchrist, Michelle Hildebrandt, Eugenie S Kleinerman

Faculty, Staff and Student Publications

BACKGROUND: Early skeletal muscle loss has been observed in adolescent and young adult (AYA) sarcoma patients undergoing treatment. Identification of individuals within the AYA populace that are at greatest risk of anthracycline-induced skeletal muscle loss is unknown. Moreover, investigations which seek out underlying causes of skeletal muscle degradation during chemotherapy are critical for understanding, preventing, and reducing chronic health conditions associated with poor skeletal muscle status.

METHODS: Computed tomography (CT) scans were used to investigate changes in skeletal muscle of 153 AYA sarcoma and Hodgkin lymphoma patients at thoracic vertebra 4 after anthracycline treatment. Images were examined at three time …

A Framework For Standardised Tissue Sampling And Processing During Resection Of Diffuse Intracranial Glioma: Joint Recommendations From Four Rano Groups, Philipp Karschnia, Marion Smits, Guido Reifenberger, Emilie Le Rhun, Benjamin M Ellingson, Norbert Galldiks, Michelle M Kim, Jason T Huse, Oliver Schnell, Patrick N Harter, Malte Mohme, Expert Rater Panel, Louisa Von Baumgarten, Nathalie L Albert, Raymond Y Huang, Minesh P Mehta, Martin Van Den Bent, Michael Weller, Michael A Vogelbaum, Susan M Chang, Mitchel S Berger, Joerg-Christian Tonn

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Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, …

Effect Of The Covid-19 Pandemic On The Epidemiology Of Pediatric Traumatic Brain Injury In Brazil, Leopoldo Mandic Ferreira Furtado, José Aloysio Da Costa Val Filho, Victor Da Silva Pereira, Yasmin S Coimbra, Vitor Hugo R Caldas, Anne R Magalhães, Bruna Athayde S De Carvalho, Saulo G Moreira, Antônio L Teixeira, Aline Silva De Miranda

Faculty, Staff and Student Publications

Aim: In response to the coronavirus 2019 disease (COVID-19) pandemic, governments worldwide implemented measures to prevent infection, resulting in restricted school activities, restricted children’s freedom of movement, and increased risk of violence and injuries at home, including traumatic brain injury (TBI), among children. In Brazil, the consequences of the COVID-19 pandemic on the causes, severity, and mortality of pediatric TBI have not yet been investigated. Thus, our study aimed to determine whether the COVID-19 pandemic has affected the epidemiology of pediatric TBI among Brazilian children.

Materials and methods: We investigated the patients with TBI aged <18 years who visited a tertiary trauma center in Brazil in 2019 and 2020. TBI-related variables, such as classification, mechanism, clinical manifestations, need for intervention, morbidity, and mortality, were recorded. Furthermore, we used a nationwide databank to collect information on mortality from external causes of trauma and violence in the pediatric population in 2019 and 2020. The Mann-Whitney test was used to compare quantitative variables related to the mechanisms and severity of TBI in both periods in order to determine the impact of the COVID-19 pandemic.

Results: Of the patients with …

A Human Mitofusin 2 Mutation Can Cause Mitophagic Cardiomyopathy, Antonietta Franco, Jiajia Li, Daniel P Kelly, Ray E Hershberger, Ali J Marian, Renate M Lewis, Moshi Song, Xiawei Dang, Alina D Schmidt, Mary E Mathyer, John R Edwards, Cristina De Guzman Strong, Gerald W Dorn

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Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15-20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal …

A New Ferrocene Derivative Blocks K-Ras Localization And Function By Oxidative Modification At His95, Kristen M Rehl, Jayaraman Selvakumar, Rhonda L Pitsch, Don Hoang, Kuppuswamy Arumugam, Sean W Harshman, Alemayehu A Gorfe, Kwang-Jin Cho

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Ras proteins are membrane-bound GTPases that regulate essential cellular processes at the plasma membrane (PM). Constitutively active mutations of K-Ras, one of the three Ras isoforms in mammalian cells, are frequently found in human cancers. Ferrocene derivatives, which elevate cellular reactive oxygen species (ROS), have shown to block the growth of non-small cell lung cancers harboring oncogenic mutant K-Ras. Here, we tested a novel ferrocene derivative on the growth of pancreatic ductal adenocarcinoma and non-small cell lung cancer. Our compound, which elevated cellular ROS levels, inhibited the growth of K-Ras-driven cancers, and abrogated the PM binding and signaling of K-Ras …

Differences In The Circulating Proteome In Individuals With Versus Without Sickle Cell Trait, Yanwei Cai, Nora Franceschini, Aditya Surapaneni, Melanie E Garrett, Usman A Tahir, Li Hsu, Marilyn J Telen, Bing Yu, Hua Tang, Yun Li, Simin Liu, Robert E Gerszten, Josef Coresh, Joann E Manson, Genevieve L Wojcik, Charles Kooperberg, Paul L Auer, Matthew W Foster, Morgan E Grams, Allison E Ashley-Koch, Laura M Raffield, Alex P Reiner

Faculty, Staff and Student Publications

BACKGROUND: Sickle cell trait affects approximately 8% of Black individuals in the United States, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests that sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including kidney failure. The mechanisms underlying these associations remain poorly understood. We used proteomic profiling to gain insight into the pathobiology of sickle cell trait.

METHODS: We measured proteomics ( N =1285 proteins assayed by Olink Explore) using baseline plasma samples from 592 Black participants with sickle cell trait and 1:1 …

Loss Of Adar1 In Macrophages In Combination With Interferon Gamma Suppresses Tumor Growth By Remodeling The Tumor Microenvironment, Weiwei Lin, Yikai Luo, Jie Wu, Haowan Zhang, Ge Jin, Chahua Guo, Hang Zhou, Han Liang, Xiaoyan Xu

Faculty, Staff and Student Publications

Background: ADAR1, the major enzyme for RNA editing, has emerged as a tumor-intrinsic key determinant for cancer immunotherapy efficacy through modulating interferon-mediated innate immunity. However, the role of ADAR1 in innate immune cells such as macrophages remains unknown.

Methods: We first analyzed publicly accessible patient-derived single-cell RNA-sequencing and perturbed RNA sequencing data to elucidate the ADAR1 expression and function in macrophages. Subsequently, we evaluated the combined effects of ADAR1 conditional knockout in macrophages and interferon (IFN)-γ treatment on tumor growth in three distinct disease mouse models: LLC for lung cancer, B16-F10 for melanoma, and MC38 for colon cancer. To gain …

Genome-Wide Interaction Analysis Of Folate For Colorectal Cancer Risk, Emmanouil Bouras, Andre E Kim, Yi Lin, John Morrison, Mengmeng Du, Demetrius Albanes, Elizabeth L Barry, James W Baurley, Sonja I Berndt, Stephanie A Bien, Timothy D Bishop, Hermann Brenner, Arif Budiarto, Andrea Burnett-Hartman, Peter T Campbell, Robert Carreras-Torres, Graham Casey, Tjeng Wawan Cenggoro, Andrew T Chan, Jenny Chang-Claude, David V Conti, Michelle Cotterchio, Matthew Devall, Virginia Diez-Obrero, Niki Dimou, David A Drew, Jane C Figueiredo, Graham G Giles, Stephen B Gruber, Marc J Gunter, Tabitha A Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R Huyghe, Amit D Joshi, Eric S Kawaguchi, Temitope O Keku, Anshul Kundaje, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M Lynch, Bharuno Mahesworo, Satu Männistö, Victor Moreno, Neil Murphy, Polly A Newcomb, Mireia Obón-Santacana, Jennifer Ose, Julie R Palmer, Nikos Papadimitriou, Bens Pardamean, Andrew J Pellatt, Anita R Peoples, Elizabeth A Platz, John D Potter, Lihong Qi, Conghui Qu, Gad Rennert, Edward Ruiz-Narvaez, Lori C Sakoda, Stephanie L Schmit, Anna Shcherbina, Mariana C Stern, Yu-Ru Su, Catherine M Tangen, Duncan C Thomas, Yu Tian, Caroline Y Um, Franzel Jb Van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Jun Wang, Emily White, Alicja Wolk, Michael O Woods, Cornelia M Ulrich, Li Hsu, W James Gauderman, Ulrike Peters, Konstantinos K Tsilidis

Faculty, Staff and Student Publications

Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC.

Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.

Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) …

Citrate Phosphate Dextrose Alters Coagulation Dynamics Ex Vivo, Jacob B Schriner, Atharwa Mankame, Scott D Olson, Charles S Cox, Brijesh S Gill

Faculty, Staff and Student Publications

INTRODUCTION: Citrate-phosphate-dextrose (CPD) is the most common anticoagulant for blood product storage in the United States. It was developed to prolong shelf life, though there is little research regarding its impact on function following transfusion. We used flow cytometry (FC), thromboelastography (TEG), and a clot contraction assay called the zFlex platform to measure platelet activation and global clot formation in blood samples anticoagulated with either CPD or in a standard blue top citrate (BTC) tube.

METHODS: Samples were obtained through venipuncture of the antecubital fossa from healthy donors who had not recently taken antiplatelet medication. Samples for FC analysis were …

Clonal Hematopoiesis Of Indeterminate Potential (Chip) And Incident Type 2 Diabetes Risk, Deirdre K Tobias, Alisa K Manning, Jennifer Wessel, Sridharan Raghavan, Kenneth E Westerman, Alexander G Bick, Daniel Dicorpo, Eric A Whitsel, Jason Collins, Adolfo Correa, L Adrienne Cupples, Josée Dupuis, Mark O Goodarzi, Xiuqing Guo, Barbara Howard, Leslie A Lange, Simin Liu, Laura M Raffield, Alex P Reiner, Stephen S Rich, Kent D Taylor, Lesley Tinker, James G Wilson, Peitao Wu, April P Carson, Ramachandran S Vasan, Myriam Fornage, Bruce M Psaty, Charles Kooperberg, Jerome I Rotter, James Meigs, Joann E Manson

Faculty, Staff and Student Publications

OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.

RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, …

Time To Endoscopy Or Colonoscopy Among Adults Younger Than 50 Years With Iron-Deficiency Anemia And/Or Hematochezia In The Vha, Joshua Demb, Lin Liu, Caitlin C Murphy, Chyke A Doubeni, Maria Elena Martinez, Samir Gupta

Faculty, Staff and Student Publications

IMPORTANCE: to date, the diagnostic test completion rate and the time to diagnostic endoscopy or colonoscopy among adults with iron-deficiency anemia (IDA) and/or hematochezia have not been well characterized.

OBJECTIVE: to evaluate the diagnostic test completion rate and the time to diagnostic testing among veterans younger than 50 years with IDA and/or hematochezia.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted within the Veterans Health Administration between October 1, 1999, and December 31, 2019, among US veterans aged 18 to 49 years from 2 separate cohorts: those with a diagnosis of IDA (n = 59 169) and those with …

Clinical Outcome And Therapeutic Impact On Neuroendocrine Neoplasms Of The Breast: A National Cancer Database Study, Libo Yang, Heather Lin, Yu Shen, Madhuchhanda Roy, Constance Albarracin, Qingqing Ding, Lei Huo, Hui Chen, Bing Wei, Hong Bu, Isabelle Bedrosian, Yun Wu

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Purpose: Neuroendocrine neoplasms (NENs) of the breast are rare and not well-studied. NEN are subcategorized as well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC). The objectives of the current study were to review the clinicopathologic features of NENs, therapeutic efficacy of current systemic therapy and clinical outcomes of NEN of the breast.

Methods: Between 2004 and 2015, 420 NET, 205 NEC, 146 Adenocarcinoma with NE differentiation (ACNED) and 1,479,520 of invasive carcinoma, not otherwise specified (IC-NOS) of the breast were identified in the National Caner Database. Overall survival was compared among groups using Kaplan-Meier method and Log-rank test. …

Remotely Delivered Cancer Genetic Testing In The Making Genetic Testing Accessible (Magenta) Trial: A Randomized Clinical Trial, Elizabeth M Swisher, Nadine Rayes, Deborah Bowen, Christine B Peterson, Barbara M Norquist, Tara Coffin, Kathleen Gavin, Deborah Polinsky, Jamie Crase, Jamie N Bakkum-Gamez, Stephanie V Blank, Mark F Munsell, Denise Nebgen, Gini F Fleming, Olufunmilayo I Olopade, Sherman Law, Alicia Zhou, Douglas A Levine, Alan D'Andrea, Karen H Lu

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Importance: Requiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress.

Objective: To assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing.

Design, setting, and participants: Making Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest. Participants were recruited via social and traditional media, and enrollment occurred between April 27, 2017, and September 29, 2020. Participants were women aged 30 years or older, English-speaking, US …

Next-Generation Chimeric Antigen Receptors For T- And Natural Killer-Cell Therapies Against Cancer, Ye Li, Katayoun Rezvani, Hind Rafei

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Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor-specific antigens that can be targeted without cross-reactivity against normal tissues. This may lead to unwanted on-target off-tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, …

Stepwise Requirements For Polymerases Δ And Θ In Theta-Mediated End Joining, Susanna Stroik, Juan Carvajal-Garcia, Dipika Gupta, Alyssa Edwards, Adam Luthman, David W Wyatt, Rachel L Dannenberg, Wanjuan Feng, Thomas A Kunkel, Gaorav P Gupta, Mark Hedglin, Richard Wood, Sylvie Doublié, Eli Rothenberg, Dale A Ramsden

Faculty, Staff and Student Publications

Timely repair of chromosomal double-strand breaks is required for genome integrity and cellular viability. The polymerase theta-mediated end joining pathway has an important role in resolving these breaks and is essential in cancers defective in other DNA repair pathways, thus making it an emerging therapeutic target1 It requires annealing of 2-6 nucleotides of complementary sequence, microhomologies, that are adjacent to the broken ends, followed by initiation of end-bridging DNA synthesis by polymerase θ. However, the other pathway steps remain inadequately defined, and the enzymes required for them are unknown. Here we demonstrate requirements for exonucleolytic digestion of unpaired 3' tails …

Methods For Objective Assessment Of Skin Involvement In Systemic Sclerosis, Ruhani Desai, Harshdeep Chawla, Kirill Larin, Shervin Assassi

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Purpose of review: Skin fibrosis is the most prominent disease manifestation of systemic sclerosis (SSc). Although the treatment for other SSc manifestations has expanded over the years, there is limited progress in identifying effective treatment options for SSc skin involvement. This is in part due to limitations in the utilized outcome measures for assessment of skin fibrosis. This review focuses on different emerging assessment tools for SSc skin involvement and their potential use for clinical care and multicenter trials.

Recent findings: Durometer and other device-based methodologies requiring application of direct pressure to the affected skin have been studied in SSc. …

Plasma Biomarkers For Brain Injury In Extracorporeal Membrane Oxygenation, Shrey Kapoor, Anna Kolchinski, Aaron M Gusdon, Lavienraj Premraj, Sung-Min Cho

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Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients with refractory cardiorespiratory failure. Despite its benefits, ECMO carries a significant risk of neurological complications, including acute brain injury (ABI). Although standardized neuromonitoring and neurological care have been shown to improve early detection of ABI, the inability to perform neuroimaging in a timely manner is a major limitation in the accurate diagnosis of neurological complications. Therefore, blood-based biomarkers capable of detecting ongoing brain injury at the bedside are of great clinical significance. This review aims to provide a concise review of the current literature on plasma biomarkers for ABI in …

Iron Overload Induces Cerebral Endothelial Senescence In Aged Mice And In Primary Culture In A Sex-Dependent Manner, Brian Noh, Maria Pilar Blasco-Conesa, Syed Mushfiqur Rahman, Sheelu Monga, Rodney Ritzel, Gary Guzman, Yun-Ju Lai, Bhanu Priya Ganesh, Akihiko Urayama, Louise D Mccullough, Jose Felix Moruno-Manchon

Faculty, Staff and Student Publications

Iron imbalance in the brain negatively affects brain function. With aging, iron levels increase in the brain and contribute to brain damage and neurological disorders. Changes in the cerebral vasculature with aging may enhance iron entry into the brain parenchyma, leading to iron overload and its deleterious consequences. Endothelial senescence has emerged as an important contributor to age-related changes in the cerebral vasculature. Evidence indicates that iron overload may induce senescence in cultured cell lines. Importantly, cells derived from female human and mice generally show enhanced senescence-associated phenotype, compared with males. Thus, we hypothesize that cerebral endothelial cells (CEC) derived …

Clinical And Molecular Features Of Long-Term Response To Immune Checkpoint Inhibitors In Patients With Advanced Non-Small Cell Lung Cancer, Rohit Thummalapalli, Biagio Ricciuti, Chaitanya Bandlamudi, Daniel Muldoon, Hira Rizvi, Arielle Elkrief, Jia Luo, Joao V Alessi, Federica Pecci, Giuseppe Lamberti, Alessandro Di Federico, Lingzhi Hong, Jianjun Zhang, John V Heymach, Don L Gibbons, Andrew J Plodkowski, Vignesh Ravichandran, Mark T A Donoghue, Chad Vanderbilt, Marc Ladanyi, Charles M Rudin, Mark G Kris, Gregory J Riely, Jamie E Chaft, Matthew D Hellmann, Natalie I Vokes, Mark M Awad, Adam J Schoenfeld

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PURPOSE: We sought to identify features of patients with advanced non-small cell lung cancer (NSCLC) who achieve long-term response (LTR) to immune checkpoint inhibitors (ICI), and how these might differ from features predictive of short-term response (STR).

EXPERIMENTAL DESIGN: We performed a multicenter retrospective analysis of patients with advanced NSCLC treated with ICIs between 2011 and 2022. LTR and STR were defined as response ≥ 24 months and response < 12 months, respectively. Tumor programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), next-generation sequencing (NGS), and whole-exome sequencing (WES) data were analyzed to identify characteristics enriched in patients achieving LTR compared with STR and non-LTR.

RESULTS: Among 3,118 patients, 8% achieved LTR and 7% achieved STR, with 5-year overall survival (OS) of 81% and 18% among LTR and STR patients, respectively. High TMB (≥50th percentile) enriched …

Disparities In Screening Mammography Utilization Among Hispanic Women In Rural Texas From 2002 To 2018, Zhaoli Liu, Yong-Fang Kuo, Sharon H Giordano

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PURPOSE: To examine the trends of racial/ethnic and urban-rural disparities in screening mammography use with a focus on Hispanic women in rural Texas, as well as to further investigate barriers to mammography screening practices.

METHODS: A serial cross-sectional study was conducted on screening mammography including eligible female respondents (≥ 40 years) from the Texas Behavioral Risk Factor Surveillance System survey from 2002 to 2018.

FINDINGS: Weighted descriptive analyses showed persistent racial/ethnic and urban-rural disparities in mammography screening rates among eligible women (≥ 40 years) in Texas. Overall, the mammography screening rates for women in rural areas were significantly lower than …

Post-Zygotic Rescue Of Meiotic Errors Causes Brain Mosaicism And Focal Epilepsy, Katherine E Miller, Adithe C Rivaldi, Noriyuki Shinagawa, Sahib Sran, Jason B Navarro, Jesse J Westfall, Anthony R Miller, Ryan D Roberts, Yassmine Akkari, Rachel Supinger, Mark E Hester, Mohammad Marhabaie, Meethila Gade, Jinfeng Lu, Olga Rodziyevska, Meenakshi B Bhattacharjee, Gretchen K Von Allmen, Edward Yang, Hart G W Lidov, Chellamani Harini, Manish N Shah, Jeffrey Leonard, Jonathan Pindrik, Ammar Shaikhouni, James E Goldman, Christopher R Pierson, Diana L Thomas, Daniel R Boué, Adam P Ostendorf, Elaine R Mardis, Annapurna Poduri, Daniel C Koboldt, Erin L Heinzen, Tracy A Bedrosian

Faculty, Staff and Student Publications

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched …

Valosin-Containing Protein (Vcp/P97) Is Prognostically Unfavorable In Pediatric Aml, And Negatively Correlates With Unfolded Protein Response Proteins Ire1 And Grp78: A Report From The Children’S Oncology Group, Fieke W Hoff, Yihua Qiu, Brandon D Brown, Robert B Gerbing, Amanda R Leonti, Rhonda E Ries, Alan S Gamis, Richard Aplenc, Edward Anders Kolb, Todd A Alonzo, Soheil Meshinchi, Gaye N Jenkins, Terzah M Horton, Steven M Kornblau

Faculty, Staff and Student Publications

Purpose: The endoplasmic reticulum (ER) is the major site of protein synthesis and folding in the cell. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the main mechanisms of ER-mediated cell stress adaptation. Targeting the cell stress response is a promising therapeutic approach in acute myeloid leukemia (AML).

Experimental design: Protein expression levels of valosin-containing protein (VCP), a chief element of ERAD, were measured in peripheral blood samples from in 483 pediatric AML patients using reverse phase protein array methodology. Patients participated in the Children's Oncology Group AAML1031 phase 3 clinical trial that randomized patients to standard chemotherapy (cytarabine …

Performance Of Ct-Based Deep Learning In Diagnostic Assessment Of Suspicious Lateral Lymph Nodes In Papillary Thyroid Cancer: A Prospective Diagnostic Study, Guibin Zheng, Haicheng Zhang, Fusheng Lin, Mark Zafereo, Neil Gross, Peng Sun, Yang Liu, Haiqing Sun, Guochang Wu, Shujian Wei, Jia Wu, Ning Mao, Guojun Li, Guoyang Wu, Haitao Zheng, Xicheng Song

Faculty, Staff and Student Publications

Background: Preoperative evaluation of the metastasis status of lateral lymph nodes (LNs) in papillary thyroid cancer is challenging. Strategies for using deep learning to diagnosis of lateral LN metastasis require additional development and testing. This study aimed to build a deep learning-based model to distinguish benign lateral LNs from metastatic lateral LNs in papillary thyroid cancer and test the model's diagnostic performance in a real-world clinical setting.

Methods: This was a prospective diagnostic study. An ensemble model integrating a three-dimensional residual network algorithm with clinical risk factors available before surgery was developed based on computed tomography images of lateral LNs …

Impact Of Rural Residence On The Presentation, Management And Survival Of Patients With Non-Metastatic Muscle-Invasive Bladder Carcinoma, Furkan Dursun, Ahmed Elshabrawy, Hanzhang Wang, Dharam Kaushik, Michael A Liss, Robert S Svatek, John L Gore, Ahmed M Mansour

Faculty, Staff and Student Publications

Purpose: To assess the impact of rural and remote residence on the receipt of guidelines-recommended treatment, quality of treatment and overall survival (OS) in patients with non-metastatic muscle-invasive bladder cancer (MIBC).

Materials and methods: Patients with MIBC were identified using National Cancer Database. Patients were classified into three residential areas. Logistic regression models were used to assess associations between geographic residence and receipt of radical cystectomy (RC) or chemoradiation therapy (CRT). Models were fitted to assess quality benchmarks of RC and CRT.

Results: We identified 71,395 patients. Of those 58,874 (82.5%) were living in Metro areas, 8,534 (11.9%) in urban-rural …

Phase Ii Study Of Cladribine, Idarubicin, And Ara-C (Clia) With Or Without Sorafenib As Initial Therapy For Patients With Acute Myeloid Leukemia, Tapan M Kadia, Farhad Ravandi, Matteo Molica, Alex Bataller, Gautam Borthakur, Naval Daver, Elias Jabbour, Courtney D Dinardo, Naveen Pemmaraju, Nitin Jain, Alessandra Ferrajoli, Musa Ylimaz, Prithviraj Bose, Rebecca Slack Tidwell, Kayleigh R Marx, Caitlin R Rausch, Rashmi Kanagal-Shamanna, Sa Wang, Rabiul Islam, Richard Champlin, Elizabeth Shpall, Marina Konopleva, Guillermo Garcia-Manero, Hagop Kantarjian

Faculty, Staff and Student Publications

The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). …

Mitochondrial Health Index Correlates With Plasma Circulating Cell-Free Mitochondrial Dna In Bipolar Disorder, Rafaela C Cordeiro, Camila N C Lima, Gabriel R Fries, Giovana Zunta-Soares, Jair C Soares, João Quevedo, Giselli Scaini

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Although mitochondrial dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. An emerging paradigm suggests mitochondria play an important non-energetic role in adaptation to stress, impacting cellular resilience and acting as a source of systemic allostatic load. Known as mitochondrial allostatic load, this (phenomenon) occurs when mitochondria are unable to recalibrate and maintain cell homeostasis. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls. We will also explore whether lower …

Long-Term Utilization And Benefit Of Luspatercept In Transfusion-Dependent, Erythropoiesis-Stimulating Agent-Refractory Or -Intolerant Patients With Lower-Risk Myelodysplastic Syndromes With Ring Sideroblasts, Uwe Platzbecker, Valeria Santini, Rami S Komrokji, Amer M Zeidan, Guillermo Garcia-Manero, Rena Buckstein, Dimana Miteva, Karen Keeperman, Natalia Holot, Jose Alberto Nadal, Yinzhi Lai, Sadanand Vodala, Barbara Rosettani, Ana Carolina Giuseppi, Aylin Yucel, Pierre Fenaux

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No abstract provided.

A Case Report Of Anesthesia-Induced Diffuse Alveolar Hemorrhage Presenting To The Emergency Department, Daniel Yiu, Christopher Stephens, Jacquelyn Mccullough, Lesley Osborn

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Introduction: The inhaled anesthetic sevoflurane is an uncommon etiology of diffuse alveolar hemorrhage (DAH). As DAH typically presents in the inpatient, postoperative setting, it has been infrequently reported in the anesthesiology literature and, to our knowledge, has not been reported in the emergency medicine literature to date.

Case report: We describe the presentation of a young, healthy male in respiratory distress to a busy urban emergency department (ED) after an outpatient surgical procedure. We highlight the etiology of post-anesthesia DAH and the acute management of this rare diagnosis in the ED.

Conclusion: With outpatient surgical centers becoming an increasingly popular …

Ramipril For The Treatment Of Covid-19: Ramic, A Randomized, Double-Blind, Placebo-Controlled Clinical Trial, Daniel Q Huang, Veeral Ajmera, Christian Tomaszewski, Andrew Lafree, Ricki Bettencourt, Wesley K Thompson, Davey M Smith, Atul Malhotra, Ravindra L Mehta, Vaishal Tolia, Jeffrey Yin, Paul A Insel, Stone Leachman, Jinho Jung, Summer Collier, Lisa Richards, Kristin Woods, Maral Amangurbanova, Archana Bhatt, Xinlian Zhang, Oana M Penciu, Stuart Zarich, Tamrat Retta, Michelle S Harkins, J Pedro Teixeira, Brian Chinnock, Netanya S Utay, Jordan E Lake, Rohit Loomba

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Introduction: Retrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19.

Methods: Eligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a …

Animal Models In Systemic Sclerosis: An Update, Xiongjie Bi, Tingting Mills, Minghua Wu

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Purpose of review: Systemic sclerosis (SSc) is a multisystem autoimmune connective tissue disease characterized by early inflammation followed by excessive fibrosis in the skin and internal organs. Enhancing our comprehension of SSc pathogenesis is essential to develop effective therapeutic strategies. Animal models that mimic one or more aspects of SSc have been proven to be a valuable resource for investigating disease mechanisms. This review aims to provide an updated overview of the existing SSc animal models and the potentially relevant pathways to SSc pathogenesis.

Recent findings: This review focuses on the most recently generated and investigated animal models, which delve …