Medical Specialties Commons^™

Hormonal Therapies Up-Regulate Manf And Overcome Female Susceptibility To Immune Checkpoint Inhibitor Myocarditis, Yaohua Zhang, Chengcao Sun, Yajuan Li, Juan Qin, Kaushik Amancherla, Ying Jing, Qingsong Hu, Ke Liang, Zhao Zhang, Youqiong Ye, Lisa A Huang, Tina K Nguyen, Sergey D Egranov, Zilong Zhao, Andrew Wu, Yutao Xi, Jun Yao, Mien-Chie Hung, George A Calin, Jie Cheng, Bora Lim, Lorenz H Lehmann, Joe-Elie Salem, Douglas B Johnson, Michael A Curran, Dihua Yu, Leng Han, Radbod Darabi, Liuqing Yang, Javid J Moslehi, Chunru Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis …

The Single-Cell Immunogenomic Landscape Of B And Plasma Cells In Early-Stage Lung Adenocarcinoma, Dapeng Hao, Guangchun Han, Ansam Sinjab, Lorena Isabel Gomez-Bolanos, Rossana Lazcano, Alejandra Serrano, Sharia D Hernandez, Enyu Dai, Xuanye Cao, Jian Hu, Minghao Dang, Ruiping Wang, Yanshuo Chu, Xingzhi Song, Jianhua Zhang, Edwin R Parra, Jennifer A Wargo, Stephen G Swisher, Tina Cascone, Boris Sepesi, Andrew P Futreal, Mingyao Li, Steven M Dubinett, Junya Fujimoto, Luisa M Solis Soto, Ignacio I Wistuba, Christopher S Stevenson, Avrum Spira, Shabnam Shalapour, Humam Kadara, Linghua Wang

Faculty, Staff and Student Publications

Tumor-infiltrating B and plasma cells (TIB) are prevalent in lung adenocarcinoma (LUAD); however, they are poorly characterized. We performed paired single-cell RNA and B-cell receptor (BCR) sequencing of 16 early-stage LUADs and 47 matching multiregion normal tissues. By integrative analysis of ∼50,000 TIBs, we define 12 TIB subsets in the LUAD and adjacent normal ecosystems and demonstrate extensive remodeling of TIBs in LUADs. Memory B cells and plasma cells (PC) were highly enriched in tumor tissues with more differentiated states and increased frequencies of somatic hypermutation. Smokers exhibited markedly elevated PCs and PCs with distinct differentiation trajectories. BCR clonotype diversity …

Targeting The Eif2ak1 Signaling Pathway Rescues Red Blood Cell Production In Sf3b1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts, Vera Adema, Feiyang Ma, Rashmi Kanagal-Shamanna, Natthakan Thongon, Guillermo Montalban-Bravo, Hui Yang, Scott A Peslak, Feng Wang, Pamela Acha, Francesc Sole, Pamela Lockyer, Margherita Cassari, Jaroslaw P Maciejewski, Valeria Visconte, Irene Gañán-Gómez, Yuanbin Song, Carlos Bueso-Ramos, Matteo Pellegrini, Tuyet M Tan, Rafael Bejar, Jennifer S Carew, Stephanie Halene, Valeria Santini, Gheath Al-Atrash, Karen Clise-Dwyer, Guillermo Garcia-Manero, Gerd A Blobel, Simona Colla

Faculty, Staff and Student Publications

SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of …

Tp53-Mutated Myelodysplastic Syndrome And Acute Myeloid Leukemia: Biology, Current Therapy, And Future Directions, Naval G Daver, Abhishek Maiti, Tapan M Kadia, Paresh Vyas, Ravindra Majeti, Andrew H Wei, Guillermo Garcia-Manero, Charles Craddock, David A Sallman, Hagop M Kantarjian

Faculty, Staff and Student Publications

UNLABELLED: TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to either induction chemotherapy, hypomethylating agent-based regimens, or venetoclax-based therapies compared with non-TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches …

Broad-Acting Therapeutic Effects Of Mir-29b-Chitosan On Hypertension And Diabetic Complications, David M Jensen, Peng Han, Lingegowda S Mangala, Gabriel Lopez-Berestein, Anil K Sood, Jing Liu, Alison J Kriegel, Kristie Usa, Michael E Widlansky, Mingyu Liang

Faculty, Staff and Student Publications

MicroRNA miR-29 promotes endothelial function in human arterioles in part by targeting LYPLA1 and increasing nitric oxide production. In addition, miR-29 is a master inhibitor of extracellular matrix gene expression, which may attenuate fibrosis but could also weaken tissue structure. The goal of this study was to test whether miR-29 could be developed as an effective, broad-acting, and safe therapeutic. Substantial accumulation of miR-29b and effective knockdown of Lypla1 in several mouse tissues were achieved using a chitosan-packaged, chemically modified miR-29b mimic (miR-29b-CH-NP) injected systemically at 200 μg/kg body weight. miR-29b-CH-NP, injected once every 3 days, significantly attenuated angiotensin II-induced …

Stroke Genetics Informs Drug Discovery And Risk Prediction Across Ancestries, Aniket Mishra, Rainer Malik, Tsuyoshi Hachiya, Tuuli Jürgenson, Shinichi Namba, Daniel C Posner, Frederick K Kamanu, Masaru Koido, Quentin Le Grand, Mingyang Shi, Yunye He, Marios K Georgakis, Ilana Caro, Kristi Krebs, Yi-Ching Liaw, Felix C Vaura, Kuang Lin, Bendik Slagsvold Winsvold, Vinodh Srinivasasainagendra, Livia Parodi, Hee-Joon Bae, Ganesh Chauhan, Michael R Chong, Liisa Tomppo, Rufus Akinyemi, Gennady V Roshchupkin, Naomi Habib, Yon Ho Jee, Jesper Qvist Thomassen, Vida Abedi, Jara Cárcel-Márquez, Marianne Nygaard, Hampton L Leonard, Chaojie Yang, Ekaterina Yonova-Doing, Maria J Knol, Adam J Lewis, Renae L Judy, Tetsuro Ago, Philippe Amouyel, Nicole D Armstrong, Mark K Bakker, Traci M Bartz, David A Bennett, Joshua C Bis, Constance Bordes, Sigrid Børte, Anael Cain, Paul M Ridker, Kelly Cho, Zhengming Chen, Carlos Cruchaga, John W Cole, Phil L De Jager, Rafael De Cid, Matthias Endres, Leslie E Ferreira, Mirjam I Geerlings, Natalie C Gasca, Vilmundur Gudnason, Jun Hata, Jing He, Alicia K Heath, Yuk-Lam Ho, Aki S Havulinna, Jemma C Hopewell, Hyacinth I Hyacinth, Michael Inouye, Mina A Jacob, Christina E Jeon, Christina Jern, Masahiro Kamouchi, Keith L Keene, Takanari Kitazono, Steven J Kittner, Takahiro Konuma, Amit Kumar, Paul Lacaze, Lenore J Launer, Keon-Joo Lee, Kaido Lepik, Jiang Li, Liming Li, Ani Manichaikul, Hugh S Markus, Nicholas A Marston, Thomas Meitinger, Braxton D Mitchell, Felipe A Montellano, Takayuki Morisaki, Thomas H Mosley, Mike A Nalls, Børge G Nordestgaard, Martin J O'Donnell, Yukinori Okada, N Charlotte Onland-Moret, Bruce Ovbiagele, Annette Peters, Bruce M Psaty, Stephen S Rich, Jonathan Rosand, Marc S Sabatine, Ralph L Sacco, Danish Saleheen, Else Charlotte Sandset, Veikko Salomaa, Muralidharan Sargurupremraj, Makoto Sasaki, Claudia L Satizabal, Carsten O Schmidt, Atsushi Shimizu, Nicholas L Smith, Kelly L Sloane, Yoichi Sutoh, Yan V Sun, Kozo Tanno, Steffen Tiedt, Turgut Tatlisumak, Nuria P Torres-Aguila, Hemant K Tiwari, David-Alexandre Trégouët, Stella Trompet, Anil Man Tuladhar, Anne Tybjærg-Hansen, Marion Van Vugt, Riina Vibo, Shefali S Verma, Kerri L Wiggins, Patrik Wennberg, Daniel Woo, Peter W F Wilson, Huichun Xu, Qiong Yang, Kyungheon Yoon, Compass Consortium, Invent Consortium, Dutch Parelsnoer Initiative (Psi) Cerebrovascular Disease Study Group, Estonian Biobank, Precise4q Consortium, Finngen Consortium, Ninds Stroke Genetics Network (Sign), Megastroke Consortium, Siren Consortium, China Kadoorie Biobank Collaborative Group, Va Million Veteran Program, International Stroke Genetics Consortium (Isgc), Biobank Japan, Charge Consortium, Gigastroke Consortium, Iona Y Millwood, Christian Gieger, Toshiharu Ninomiya, Hans J Grabe, J Wouter Jukema, Ina L Rissanen, Daniel Strbian, Young Jin Kim, Pei-Hsin Chen, Ernst Mayerhofer, Joanna M M Howson, Marguerite R Irvin, Hieab Adams, Sylvia Wassertheil-Smoller, Kaare Christensen, Mohammad A Ikram, Tatjana Rundek, Bradford B Worrall, G Mark Lathrop, Moeen Riaz, Eleanor M Simonsick, Janika Kõrv, Paulo H C França, Ramin Zand, Kameshwar Prasad, Ruth Frikke-Schmidt, Frank-Erik De Leeuw, Thomas Liman, Karl Georg Haeusler, Ynte M Ruigrok, Peter Ulrich Heuschmann, W T Longstreth, Keum Ji Jung, Lisa Bastarache, Guillaume Paré, Scott M Damrauer, Daniel I Chasman, Jerome I Rotter, Christopher D Anderson, John-Anker Zwart, Teemu J Niiranen, Myriam Fornage, Yung-Po Liaw, Sudha Seshadri, Israel Fernández-Cadenas, Robin G Walters, Christian T Ruff, Mayowa O Owolabi, Jennifer E Huffman, Lili Milani, Yoichiro Kamatani, Martin Dichgans, Stephanie Debette

Faculty, Staff and Student Publications

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary …

Lessons From The Failure To Complete A Trial Of Denosumab In Women With A Pathogenic Brca1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy, Meghna S Trivedi, Nadir Arber, Eitan Friedman, Judy E Garber, Kevin Holcomb, Neil S Horowitz, Jason D Wright, J Jack Lee, Lana A Vornik, Saba Abutaseh, Tawana Castile, Edward R Sauter, Eileen Dimond, Brandy M Heckman-Stoddard, Margaret House, Goli Samimi, Powel H Brown, Katherine D Crew

Faculty, Staff and Student Publications

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO …

Ovarian Steroid Cell Tumors, Not Otherwise Specified: Analysis Of Nine Cases With A Literature Review, Mengyan Lin, Kechun Bao, Lingjia Lu, Shuhang Xu, Yun Liang, Xiaodong Cheng, Fenfen Wang

Faculty, Staff and Student Publications

BACKGROUND: Ovarian steroid cell tumors (SCTs), not otherwise specified (NOS), are rare, with few large studies. The purpose of this study was to analyze the clinical features, prognosis, and treatment choices for these patients of different age groups.

METHODS: This was a retrospective study. We identified nine cases of ovarian steroid cell tumor, not otherwise specified, confirmed by post-operative histopathological examination, and analyzed clinical features, surgical procedures, and follow up outcomes. We also reviewed cases reports of ovarian steroid cell tumors, not otherwise specified.

RESULTS: A total of nine cases were included. The age range was 9-68 years (mean, 41.89 …

Risks Of Depression And Suicide After Diagnosis With Heart Failure: A National Cohort Study, Casey Crump, Jan Sundquist, Kenneth S Kendler, Weiva Sieh, Alexis C Edwards, Kristina Sundquist

Faculty, Staff and Student Publications

BACKGROUND: Heart failure (HF) has been associated with psychosocial distress, but other long-term mental health sequelae are unclear.

OBJECTIVES: In this study, the authors sought to determine risks of major depression and suicide, susceptible time periods, and sex-specific differences after HF diagnosis in a large population-based cohort.

METHODS: A national cohort study was conducted of all 154,572 persons diagnosed with HF at ages 18-75 years during 2002-2017 in Sweden and 1,545,720 age- and sex-matched population-based control subjects who were followed up for major depression and suicide ascertained from nationwide inpatient, outpatient, and death records through 2018. Poisson regression was used …

Ambulatory Monitoring Of Subglottal Pressure Estimated From Neck-Surface Vibration In Individuals With And Without Voice Disorders, Juan P Cortés, Jon Z Lin, Katherine L Marks, Víctor M Espinoza, Emiro J Ibarra, Matías Zañartu, Robert E Hillman, Daryush D Mehta

Faculty, Staff and Student Publications

The aerodynamic voice assessment of subglottal air pressure can discriminate between speakers with typical voices from patients with voice disorders, with further evidence validating subglottal pressure as a clinical outcome measure. Although estimating subglottal pressure during phonation is an important component of a standard voice assessment, current methods for estimating subglottal pressure rely on non-natural speech tasks in a clinical or laboratory setting. This study reports on the validation of a method for subglottal pressure estimation in individuals with and without voice disorders that can be translated to connected speech to enable the monitoring of vocal function and behavior in …

Risk Factors For Community-Acquired Bacterial Infection Among Young Infants In South Asia: A Longitudinal Cohort Study With Nested Case-Control Analysis, Nicholas E Connor, Mohammad Shahidul Islam, Luke C Mullany, Nong Shang, Zulfiqar A Bhutta, Anita K M Zaidi, Sajid Soofi, Imran Nisar, Pinaki Panigrahi, Kalpana Panigrahi, Radhanath Satpathy, Anuradha Bose, Rita Isaac, Abdullah H Baqui, Dipak K Mitra, Qazi Sadeq-Ur Rahman, Tanvir Hossain, Stephanie J Schrag, Jonas M Winchell, Melissa L Arvay, Maureen H Diaz, Jessica L Waller, Martin W Weber, Davidson H Hamer, Patricia Hibberd, A S M Nawshad Uddin Ahmed, Maksuda Islam, Mohammad Belal Hossain, Shamim A Qazi, Shams El Arifeen, Gary L Darmstadt, Samir K Saha

Faculty, Staff and Student Publications

OBJECTIVE: Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship.

METHODS: Five sites in Bangladesh, India and Pakistan enrolled mother-child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0-59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build …

Cardiovascular Outcomes In Patients With Chronic Kidney Disease And Covid-19: A Multi-Regional Data-Linkage Study, Emilie J Lambourg, Peter J Gallacher, Robert W Hunter, Moneeza Siddiqui, Eve Miller-Hodges, James D Chalmers, Dan Pugh, Neeraj Dhaun, Samira Bell

Faculty, Staff and Student Publications

BACKGROUND: Data describing cardiovascular outcomes in patients with coronavirus disease 2019 (COVID-19) and chronic kidney disease (CKD) are lacking. We compared cardiovascular outcomes of patients with and without COVID-19, stratified by CKD status.

METHODS: This retrospective, multi-regional data-linkage study utilised individual patient-level data from two Scottish cohorts. All patients tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Cohort 1 between 1 February 2020 and 31 March 2021 and in Cohort 2 between 28 February 2020 and 8 February 2021 were included.

RESULTS: Overall, 86 964 patients were tested for SARS-CoV-2. There were 36 904 patients (mean±sd age 61±21 …

Identification Of Novel Susceptibility Methylation Loci For Pancreatic Cancer In A Two-Phase Epigenome-Wide Association Study, Ziqiao Wang, Yue Lu, Myriam Fornage, Li Jiao, Jianjun Shen, Donghui Li, Peng Wei

Faculty, Staff and Student Publications

The role of DNA methylation and its interplay with gene expression in the susceptibility to pancreatic cancer (PanC) remains largely unexplored. To fill in this gap, we conducted an integrative two-phase epigenome-wide association study (EWAS) of PanC using genomic DNA from 44 cases and 556 controls (20 local controls and 536 public controls in the Framingham Heart Study) in phase 1 and 23 cases and 22 controls in phase 2. We validated the findings using pre-diagnostic blood samples from 13 cases and 26 controls in the Women's Health Initiative (WHI) Study. We further examined gene expression in peripheral leukocytes of …

Identification Of Key Genes Associated With Cancer Stem Cell Characteristics In Wilms’ Tumor Based On Bioinformatics Analysis, Cheng Su, Jie Zheng, Siyu Chen, Jinwei Tuo, Jinxia Su, Xiuyi Ou, Shaohua Chen, Congjun Wang

Faculty, Staff and Student Publications

BACKGROUND: Nephroblastoma, also known as Wilms' tumor (WT), remains one of the major causes of tumor-related deaths worldwide in children. Cancer stem cells (CSCs) are considered to be the main culprits in cancer resistance and disease recurrence, which are reported in multiple types of tumors. However, the research on CSCs in WT is limited. Therefore, our study aimed to identify the key genes related to CSCs in WT to provide new ideas for treating WT.

METHODS: The RNA-seq and clinical data of WT samples were obtained from the University of California Santa Cruz (UCSC) Xena database, which included 120 WT …

Anatomical Validation Of Automatic Respiratory Motion Correction For Coronary 18f-Sodium Fluoride Positron Emission Tomography By Expert Measurements From Four-Dimensional Computed Tomography, Martin Lyngby Lassen, Evangelos Tzolos, Tinsu Pan, Jacek Kwiecinski, Sebastien Cadet, Damini Dey, Daniel Berman, Piotr Slomka

Faculty, Staff and Student Publications

BACKGROUND: Respiratory motion correction is of importance in studies of coronary plaques employing

PURPOSE: To investigate the accuracy of the motion correction employed in a software (FusionQuant) used for evaluation of

METHODS: This study included 23 patients who undertook thoracic PET scans for the assessment of coronary plaques using

RESULTS: In total, 19 coronary plaques were identified in 16 patients. No statistical differences were observed for the maximum respiratory motion observed in x, y, and the 3D motion fields (magnitude and direction) between the CT and PET (X direction: 4D CT = 2.5 ± 1.5 mm, PET = 2.4 ± …

Bile Acids Regulate The Epithelial Na+ Channel In Native Tissues Through Direct Binding At Multiple Sites, Xue-Ping Wang, Viktor Tomilin, Andrew J Nickerson, Runze Tian, Merve Ertem, Abagail Mckernan, Xiaoguang Lei, Oleh Pochynyuk, Ossama B Kashlan

Faculty, Staff and Student Publications

Bile acids, originally known to emulsify dietary lipids, are now established signalling molecules that regulate physiological processes. Signalling targets several proteins that include the ion channels involved in regulating intestinal motility and bile viscosity. Studies show that bile acids regulate the epithelial sodium channel (ENaC) in cultured cell models and heterologous expression systems. ENaC plays both local and systemic roles in regulating extracellular fluids. Here we investigated whether bile acids regulate ENaC expressed in native tissues. We found that taurocholic acid and taurohyodeoxycholic acid regulated ENaC in both the distal nephron and distal colon. We also tested the hypothesis that …

Netie: Inferring The Evolution Of Neoantigen-T Cell Interactions In Tumors, Tianshi Lu, Seongoh Park, Yi Han, Yunguan Wang, Shawna Marie Hubert, P Andy Futreal, Ignacio Wistuba, John V Heymach, Alexandre Reuben, Jianjun Zhang, Tao Wang

Faculty, Staff and Student Publications

Neoantigens are the key targets of antitumor immune responses from cytotoxic T cells and play a critical role in affecting tumor progressions and immunotherapy treatment responses. However, little is known about how the interaction between neoantigens and T cells ultimately affects the evolution of cancerous masses. Here, we develop a hierarchical Bayesian model, named neoantigen-T cell interaction estimation (netie) to infer the history of neoantigen-CD8

International Delphi Consensus Guidelines For Follow-Up After Prophylactic Total Gastrectomy: The Life After Prophylactic Total Gastrectomy (Lag-Tg) Study, Geoffrey Roberts, Patrick R Benusiglio, Tanya Bisseling, Daniel Coit, Jeremy L Davis, Sam Grimes, Theresa A Guise, Richard Hardwick, Kirsty Harris, Paul Furman Mansfield, Jeremy Rossaak, Karen Chelcun Schreiber, Peter P Stanich, Vivian E Strong, Pardeep Kaurah

Faculty, Staff and Student Publications

BACKGROUND: Prophylactic total gastrectomy (PTG) remains the only means of preventing gastric cancer for people with genetic mutations predisposing to Hereditary Diffuse Gastric Cancer (HDGC), mainly in the CDH1 gene. The small but growing cohort of people undergoing PTG at a young age are expected to have a life-expectancy close to the general population, however, knowledge of the long-term effects of, and monitoring requirements after, PTG is limited. This study aims to define the standard of care for follow-up after PTG.

METHODS: Through a combination of literature review and two-round Delphi consensus of major HDGC/PTG units and physicians, and patient …

Immune Dysfunction Signatures Predict Outcomes And Define Checkpoint Blockade-Unresponsive Microenvironments In Acute Myeloid Leukemia, Sergio Rutella, Jayakumar Vadakekolathu, Francesco Mazziotta, Stephen Reeder, Tung-On Yau, Rupkatha Mukhopadhyay, Benjamin Dickins, Heidi Altmann, Michael Kramer, Hanna A Knaus, Bruce R Blazar, Vedran Radojcic, Joshua F Zeidner, Andrea Arruda, Bofei Wang, Hussein A Abbas, Mark D Minden, Sarah K Tasian, Martin Bornhäuser, Ivana Gojo, Leo Luznik

Faculty, Staff and Student Publications

Background

Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8⁺ T cells and whether they have prognostic relevance.

METHODS

We analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB).

Results

We show that senescent-like bone marrow CD8⁺ T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival …

An Automated Treatment Planning Framework For Spinal Radiation Therapy And Vertebral-Level Second Check, Tucker J Netherton, Callistus Nguyen, Carlos E Cardenas, Caroline Chung, Ann H Klopp, Lauren E Colbert, Dong Joo Rhee, Christine B Peterson, Rebecca Howell, Peter Balter, Laurence E Court

Faculty, Staff and Student Publications

Purpose: Complicating factors such as time pressures, anatomic variants in the spine, and similarities in adjacent vertebrae are associated with incorrect level treatments of the spine. The purpose of this work was to mitigate such challenges by fully automating the treatment planning process for diagnostic and simulation computed tomography (CT) scans.

Methods and materials: Vertebral bodies are labeled on CT scans of any length using 2 intendent deep-learning models-mirroring 2 different experts labeling the spine. Then, a U-Net++ architecture was trained, validated, and tested to contour each vertebra (n = 220 CT scans). Features from the CT and auto-contours were …

Antibody Therapeutics For Epithelial Ovarian Cancer, Mason Ruiz, Ningyan Zhang, Anil K Sood, Zhiqiang An

Faculty, Staff and Student Publications

INTRODUCTION: High-grade serous ovarian carcinoma (HGSC) is an aggressive subtype of epithelial ovarian carcinoma (EOC) and remains the most lethal gynecologic cancer. A lack of effective and tolerable therapeutic options and nonspecific symptoms at presentation with advanced stage of disease are among the challenges in the management of the disease.

AREAS COVERED: An overview of ovarian cancer, followed by a discussion of the current therapeutic regimes and challenges that arise during and after the treatment of EOC. We discuss different formats of antibody therapeutics and their usage in targeting validated targets implicated in ovarian cancer, as well as three emerging …

Contemporary Primary Treatment Of Women With Stage Ii-Iv Low-Grade Serous Ovarian/Peritoneal Cancer (Lgsoc): Determinants Of Relapse And Disease-Free Survival, David M Gershenson, Lauren P Cobb, Shannon N Westin, Yingao Zhang, Amir Jazaeri, Anais Malpica, Charlotte C Sun

Faculty, Staff and Student Publications

Objective: The purpose of the present study is to describe a cohort who received contemporary primary treatment for stage II-IV low-grade serous ovarian/peritoneal cancer (LGSOC), including patient characteristics and determinants of relapse and disease-free survival.

Methods: The study included 99 patients: 1) with pathologically confirmed stage II-IV LGSOC of the ovary or peritoneum, 2) who underwent primary treatment consisting of cytoreductive surgery and either a) platinum/taxane chemotherapy followed by aromatase inhibitor maintenance therapy or b) aromatase inhibitor monotherapy, and 3) for whom there was availability of clinical data. Descriptive statistics were used to characterize clinicodemographic features. Subgroups were compared for …

Impact Of Conditioning Chemotherapy On Lymphocyte Kinetics And Outcomes In Lbcl Patients Treated With Car T-Cell Therapy, Paolo Strati, Andrew P Jallouk, Ryan Sun, Jaihee Choi, Kaberi Das, Hua-Jay Cherng, Sairah Ahmed, Hun J Lee, Swaminathan P Iyer, Ranjit Nair, Loretta J Nastoupil, Raphael E Steiner, Chad D Huff, Yao Yu, Haleigh Mistry, Brittany Pulsifer, Mansoor Noorani, Neeraj Saini, Elizabeth J Shpall, Partow Kebriaei, Christopher R Flowers, Jason R Westin, Michelle A T Hildebrandt, Sattva S Neelapu

Faculty, Staff and Student Publications

Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 109/L (range, 0.01-2.75 × 109/L) and was significantly higher in patients who achieved complete response (p = 0.04). On …

Clinical Impact Of Ceftriaxone Resistance In Escherichia Coli Bloodstream Infections: A Multicenter Prospective Cohort Study, Pranita D Tamma, Lauren Komarow, Lizhao Ge, Julia Garcia-Diaz, Erica S Herc, Yohei Doi, Cesar A Arias, Owen Albin, Elie Saade, Loren G Miller, Jesse T Jacob, Michael J Satlin, Martin Krsak, W Charles Huskins, Sorabh Dhar, Samuel A Shelburne, Carol Hill, Keri R Baum, Minal Bhojani, Kerryl E Greenwood-Quaintance, Suzannah M Schmidt-Malan, Robin Patel, Scott R Evans, Henry F Chambers, Vance G Fowler, David Van Duin, Antibacterial Resistance Leadership Group

Faculty, Staff and Student Publications

Background

Ceftriaxone-resistant (CRO-R) Escherichia coli bloodstream infections (BSIs) are common.

Methods

This is a prospective cohort of patients with E coli BSI at 14 United States hospitals between November 2020 and April 2021. For each patient with a CRO-R E coli BSI enrolled, the next consecutive patient with a ceftriaxone-susceptible (CRO-S) E coli BSI was included. Primary outcome was desirability of outcome ranking (DOOR) at day 30, with 50% probability of worse outcomes in the CRO-R group as the null hypothesis. Inverse probability weighting (IPW) was used to reduce confounding.

Results

Notable differences between patients infected with CRO-R and CRO-S …

Optimisation Of Imaging Parameters During Ct Guided Interventional Procedures In Patients With Total Hip Arthroplasty, Anish Patel, Christine Azzopardi, Scott Evans, A Mark Davies, Steven James, Rajesh Botchu

Faculty, Staff and Student Publications

OBJECTIVE: To determine the optimal KV and mAs settings during CT guided injections in the presence of a total hip arthroplasty so that image quality is maintained whist keeping the dose as low as reasonably achievable.

METHODS: A total hip arthroplasty phantom with needles with differing gauges was scanned using different CT parameters (from low dose to high dose) and evaluating if this had any effect on needle conspicuity. Conspicuity was graded from 1 to 3 by 2 independent blinded reviewers.

RESULTS: Irrespective of the CT settings used (high dose or low dose parameters) needle conspicuity was not adversely affected …

The Safety Of Deutetrabenazine For Chorea In Huntington Disease: An Open-Label Extension Study, Samuel Frank, Claudia Testa, Mary C Edmondson, Jody Goldstein, Elise Kayson, Blair R Leavitt, David Oakes, Christine O'Neill, Christina Vaughan, Jacquelyn Whaley, Nicholas Gross, Mark Forrest Gordon, Juha-Matti Savola, Huntington Study Group/Arc-Hd Investigators And Coordinators

Faculty, Staff and Student Publications

BACKGROUND: Deutetrabenazine is approved in the USA, China, Australia, Israel, Brazil, and South Korea for the treatment of chorea associated with Huntington disease.

OBJECTIVE: We aimed to evaluate the long-term safety and tolerability of deutetrabenazine for the treatment of Huntington disease.

METHODS: This open-label, single-arm, multi-center study included patients who completed a double-blind study (Rollover) and patients who converted overnight from a stable tetrabenazine dose (Switch). Exposure-adjusted incidence rates (adverse events per person-year) were calculated. Efficacy was analyzed using a stable post-titration timepoint (8 weeks). Changes in the Unified Huntington's Disease Rating Scale total motor score and total maximal chorea …

A Multi-Omics Framework Reveals Strawberry Flavor Genes And Their Regulatory Elements, Zhen Fan, Denise M Tieman, Steven J Knapp, Philipp Zerbe, Randi Famula, Christopher R Barbey, Kevin M Folta, Rodrigo R Amadeu, Manbo Lee, Youngjae Oh, Seonghee Lee, Vance M Whitaker

Faculty, Staff and Student Publications

Flavor is essential to consumer preference of foods and is an increasing focus of plant breeding programs. In fruit crops, identifying genes underlying volatile organic compounds has great promise to accelerate flavor improvement, but polyploidy and heterozygosity in many species have slowed progress. Here we use octoploid cultivated strawberry to demonstrate how genomic heterozygosity, transcriptomic intricacy and fruit metabolomic diversity can be treated as strengths and leveraged to uncover fruit flavor genes and their regulatory elements. Multi-omics datasets were generated including an expression quantitative trait loci map with 196 diverse breeding lines, haplotype-phased genomes of a highly-flavored breeding selection, a …

Potential Focal Adhesion Kinase Inhibitors In Management Of Cancer: Therapeutic Opportunities From Herbal Medicine, Feiyu Chen, Zhangfeng Zhong, Cheng Zhang, Yuanjun Lu, Yau-Tuen Chan, Ning Wang, Di Zhao, Yibin Feng

Faculty, Staff and Student Publications

Focal adhesion kinase (FAK) is a multifunctional protein involved in cellular communication, integrating and transducing extracellular signals from cell-surface membrane receptors. It plays a central role intracellularly and extracellularly within the tumor microenvironment. Perturbations in FAK signaling promote tumor occurrence and development, and studies have revealed its biological behavior in tumor cell proliferation, migration, and adhesion. Herein we provide an overview of the complex biology of the FAK family members and their context-dependent nature. Next, with a focus on cancer, we highlight the activities of FAK signaling in different types of cancer and how knowledge of them is being used …

Diffuse Large B-Cell Lymphoma With Phenotype Switch, Anaplastic Features And Aberrant T-Cell Marker Expression During Disease Evolution, Xiaoqiong Wang, Pei Lin, Jie Xu, Shaoying Li

Faculty, Staff and Student Publications

No abstract provided.

Lenalidomide-Based Maintenance After Autologous Hematopoietic Stem Cell Transplantation For Patients With High-Risk Multiple Myeloma, Oren Pasvolsky, Denái R Milton, Mikael Rauf, Mark R Tanner, Qaiser Bashir, Samer Srour, Guilin Tang, Neeraj Saini, Jeremy Ramdial, Adeel Masood, Yago Nieto, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Maintenance therapy with single-agent lenalidomide (Len) after autologous hematopoietic stem cell transplantation (autoHCT) for multiple myeloma (MM) is associated with improved progression-free survival (PFS). However, MM patients with high-risk chromosomal abnormalities (HRMMs) may need a more intense regimen. We hypothesized that adding another antimyeloma drug to Len maintenance would lead to improved outcomes. We conducted this retrospective single-center chart review analysis of adult HRMM patients who underwent autoHCT between 2008 and 2018, followed by Len-based maintenance therapy. High-risk cytogenetics were defined as del(17p), t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization. We divided patients into those who …