Medical Genetics Commons^™

Bbox1 Restrains Tbk1-Mtorc1 Oncogenic Signaling In Clear Cell Renal Cell Carcinoma, Chengheng Liao, Lianxin Hu, Liwei Jia, Jin Zhou, Tao Wang, Kangsan Kim, Hua Zhong, Hongwei Yao, Lei Dong, Lei Guo, Qian Liang, Cheng Zhang, Fangzhou Zhao, Jun Fang, Hongyi Liu, Shina Li, Lin Xu, Jeremy M Simon, Srinivas Malladi, Payal Kapur, James Brugarolas, Ralph J Deberardinis, Qing Zhang

Faculty, Staff and Student Publications

Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential …

A Targeted Gene Expression Biomarker Predicts Clinic Low-Risk Meningioma Recurrence, Minh P Nguyen, Ramin A Morshed, Mark W Youngblood, Haley K Perlow, Calixto-Hope G Lucas, Akash J Patel, Joshua D Palmer, Craig M Horbinski, Stephen T Magill, William C Chen, David R Raleigh

Duncan NRI Faculty and Staff Publications

Background: Despite reassuring clinical and histological features, low-grade meningiomas can recur after surgery. Targeted gene expression profiling improves risk stratification of meningiomas, but the utility of this approach for clinical low-risk meningiomas is incompletely understood.

Methods: This was a multicenter retrospective cohort study of meningiomas from patients who were treated at 4 institutions from 1992 to 2023. Adult patients with newly diagnosed or recurrent World Health Organization (WHO) grade 1 meningiomas that were treated with gross total resection (GTR) or subtotal resection (STR), or newly diagnosed WHO grade 2 meningiomas that were treated with GTR, were included. A 34-gene expression …

Sex And Outcomes Of Patients With Microsatellite Instability-High And Braf V600e Mutated Metastatic Colorectal Cancer Receiving Immune Checkpoint Inhibitors, Vincenzo Nasca, Joseph Zhao, Javier Ros, Sara Lonardi, Koen Zwart, Romain Cohen, Marwan Fakih, Priya Jayachandran, Jeanine M L Roodhart, Jeroen Derksen, Rossana Intini, Francesca Bergamo, Giacomo Mazzoli, Filippo Ghelardi, Marta Ligero, Jitendra Jonnagaddala, Nicholas Hawkins, Robyn L Ward, Durgesh Wankhede, Hermann Brenner, Michael Hoffmeister, Marco Vitellaro, Lisa Salvatore, Claire Gallois, Pierre Laurent-Puig, Chiara Cremolini, Michael J Overman, Julien Taieb, David Tougeron, Thierry Andre, Jakob Nikolas Kather, Raghav Sundar, Javier Carmona, Elena Elez, Miriam Koopman, Filippo Pietrantonio

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICIs) are the gold standard therapy in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A significant proportion of patients show resistance, making the identification of determinants of response crucial. Growing evidence supports the role of sex in determining susceptibility to anticancer therapies, but data is lacking for patients with MSI-H CRC.

Methods: In this real-world cohort comprising 624 patients with MSI-H mCRC receiving ICIs, we investigated the impact of sex on patients' outcomes, overall and according to RAS-BRAF mutational status or type of treatment (anti-PD-(L)1 with or without anti-CTLA-4 agents). We …

Tigit Inhibitor M6223 As Monotherapy Or In Combination With Bintrafusp Alfa In Patients With Advanced Solid Tumors: A First-In-Human, Phase 1, Dose-Escalation Trial, Aung Naing, Meredith Mckean, Anthony Tolcher, Anja Victor, Ping Hu, Wei Gao, Marco A F Nogueira Filho, Thomas Kitzing, Stephan Gleicher, Daniel Holland, Emilia Richter, Keyvan Tadjalli-Mehr, Lillian L Siu

Faculty, Staff and Student Publications

Background: M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) is a bifunctional fusion protein that simultaneously blocks nonredundant immunosuppressive TGF-β and PD-(L)1 pathways.

Methods: This first-in-human, dose-escalation study in patients with advanced solid tumors (N=58; aged ≥18 years, ECOG PS≤1) evaluated M6223 alone (Part 1A, n=40; M6223 10-2400 mg every 2 weeks, n=32; M6223 2400 mg every 3 weeks, n=8) or with BA (Part 1B, n=18; M6223 300-1600 mg with BA 1200 mg; both every 2 weeks, intravenous). Primary objectives were safety, tolerability, …

Genomic And Phenotypic Correlates Of Mosaic Loss Of Chromosome Y In Blood, Yasminka A Jakubek, Xiaolong Ma, Adrienne M Stilp, Fulong Yu, Jason Bacon, Justin W Wong, Francois Aguet, Kristin Ardlie, Donna K Arnett, Kathleen Barnes, Joshua C Bis, Tom Blackwell, Lewis C Becker, Eric Boerwinkle, Russell P Bowler, Matthew J Budoff, April P Carson, Jiawen Chen, Michael H Cho, Josef Coresh, Nancy J Cox, Paul S De Vries, Dawn L Demeo, David W Fardo, Myriam Fornage, Xiuqing Guo, Michael E Hall, Nancy Heard-Costa, Bertha Hidalgo, Marguerite Ryan Irvin, Andrew D Johnson, Eric Jorgenson, Eimear E Kenny, Michael D Kessler, Daniel Levy, Yun Li, Joao A C Lima, Yongmei Liu, Adam E Locke, Ruth J F Loos, Mitchell J Machiela, Rasika A Mathias, Braxton D Mitchell, Joanne M Murabito, Josyf C Mychaleckyj, Kari E North, Peter Orchard, Stephen C J Parker, Yash Pershad, Patricia A Peyser, Katherine A Pratte, Bruce M Psaty, Laura M Raffield, Susan Redline, Stephen S Rich, Jerome I Rotter, Sanjiv J Shah, Jennifer A Smith, Aaron P Smith, Albert Smith, Margaret A Taub, Hemant K Tiwari, Russell Tracy, Bjoernar Tuftin, Alexander G Bick, Vijay G Sankaran, Alexander P Reiner, Paul Scheet, Paul L Auer

Faculty, Staff and Student Publications

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences …

Theranostic Nanoemulsions Suppress Macrophage-Mediated Acute Inflammation In Rats, Riddhi Vichare, Yalcin Kulahci, Rebecca Mccallin, Fatih Zor, Fatma Nurefsan Selek, Lu Liu, Caitlin Crelli, Anneliese Troidle, Michele Herneisey, James M Nichols, Andrew J Shepherd, Vijay S Gorantla, Jelena M Janjic

Faculty, Staff and Student Publications

In inflammatory diseases or following an injury, dysregulated inflammation is a common driver of pain and tissue damage. Macrophages are immune cells that contribute to the initiation, maintenance, and resolution of inflammation due to their phenotypic plasticity in response to signals from inflammatory microenvironments. Macrophages infiltrate and polarize toward a pro-inflammatory phenotype (M

Large-Bore Mechanical Thrombectomy Versus Catheter-Directed Thrombolysis In The Management Of Intermediate-Risk Pulmonary Embolism: Primary Results Of The Peerless Randomized Controlled Trial, Wissam A Jaber, Carin F Gonsalves, Stefan Stortecky, Samuel Horr, Orestis Pappas, Ripal T Gandhi, Keith Pereira, Jay Giri, Sameer J Khandhar, Khawaja Afzal Ammar, David M Lasorda, Brian Stegman, Lucas Busch, David J Dexter, Ezana M Azene, Nikhil Daga, Fakhir Elmasri, Chandra R Kunavarapu, Mark E Rea, Joseph S Rossi, Joseph Campbell, Jonathan Lindquist, Adam Raskin, Jason C Smith, Thomas M Tamlyn, Gabriel A Hernandez, Parth Rali, Torrey R Schmidt, Jeffrey T Bruckel, Juan C Camacho, Jun Li, Samy Selim, Catalin Toma, Sukhdeep Singh Basra, Brian A Bergmark, Bhavraj Khalsa, David M Zlotnick, Jordan Castle, David J O'Connor, C Michael Gibson, Peerless Committees And Investigators

Faculty, Staff and Student Publications

Background: There are a lack of randomized controlled trial data comparing outcomes of different catheter-based interventions for intermediate-risk pulmonary embolism.

Methods: PEERLESS is a prospective, multicenter, randomized controlled trial that enrolled 550 patients with intermediate-risk pulmonary embolism with right ventricular dilatation and additional clinical risk factors randomized 1:1 to treatment with large-bore mechanical thrombectomy (LBMT) or catheter-directed thrombolysis (CDT). The primary end point was a hierarchal win ratio composite of the following (assessed at the sooner of hospital discharge or 7 days after the procedure): (1) all-cause mortality, (2) intracranial hemorrhage, (3) major bleeding, (4) clinical deterioration and/or escalation to …

A Randomized, Double-Blind, Placebo-Controlled Trial Of Il-7 In Critically Ill Patients With Covid-19, Manu Shankar-Hari, Bruno Francois, Kenneth E Remy, Cristina Gutierrez, Stephen Pastores, Thomas Daix, Robin Jeannet, Jane Blood, Andrew H Walton, Reinaldo Salomao, Georg Auzinger, David Striker, Robert S Martin, Nitin J Anand, James Bosanquet, Teresa Blood, Scott Brakenridge, Lyle L Moldawer, Vidula Vachharajani, Cassian Yee, Felipe Dal-Pizzol, Michel Morre, Frederique Berbille, Marcel Van Den Brink, Richard Hotchkiss

Faculty, Staff and Student Publications

Background: Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients' ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function.

Methods: We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically ill, patients with lymphopenia who have COVID-19. The primary endpoint was to assess CYT107's effect on lymphocyte recovery with secondary clinical endpoints including …

Plant-Nanoparticles Enhance Anti-Pd-L1 Efficacy By Shaping Human Commensal Microbiota Metabolites, Yun Teng, Chao Luo, Xiaolan Qiu, Jingyao Mu, Mukesh K Sriwastva, Qingbo Xu, Minmin Liu, Xin Hu, Fangyi Xu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Maiying Kong, Zhanxu Liu, Xiang Zhang, Raobo Xu, Jun Yan, Michael L Merchant, Craig J Mcclain, Huang-Ge Zhang

Faculty, Staff and Student Publications

Diet has emerged as a key impact factor for gut microbiota function. However, the complexity of dietary components makes it difficult to predict specific outcomes. Here we investigate the impact of plant-derived nanoparticles (PNP) on gut microbiota and metabolites in context of cancer immunotherapy with the humanized gnotobiotic mouse model. Specifically, we show that ginger-derived exosome-like nanoparticle (GELN) preferentially taken up by Lachnospiraceae and Lactobacillaceae mediated by digalactosyldiacylglycerol (DGDG) and glycine, respectively. We further demonstrate that GELN aly-miR159a-3p enhances anti-PD-L1 therapy in melanoma by inhibiting the expression of recipient bacterial phospholipase C (PLC) and increases the accumulation of docosahexaenoic acid …

Safety And Tolerability Of Letetresgene Autoleucel (Gsk3377794): Pilot Studies In Patients With Advanced Non-Small Cell Lung Cancer, Mehmet Altan, Gilberto Lopes, T Jeroen N Hiltermann, Ramaswamy Govindan, Liza C Villaruz, Emiliano Calvo, Martin J Edelman, Muhammad Furqan, Joel Neal, Enriqueta Felip, Jennifer W Carlisle, John V Heymach, Róisín Eilish O'Cearbhaill, Marjorie Zauderer, Michael Chisamore, Ellie Corigliano, Ioanna Eleftheriadou, Stefan Zajic, Ben Jenkins, Sophia Goodison, Sunil Suchindran, Natalia Ramos-Hernandez, Nidale Tarek, Adam J Schoenfeld

Faculty, Staff and Student Publications

Purpose: The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02-positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1- and/or LAGE-1a-positive non-small cell lung cancer.

Patients and methods: Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non-small cell lung cancer.

Results: More than 2,500 patients were …

Phase I/Ii Study Of The Aurora Kinase A Inhibitor Alisertib And Pembrolizumab In Refractory, Rb-Deficient Head And Neck Squamous Cell Carcinomas, Faye M Johnson, Madison P O'Hara, Lacin Yapindi, Peixin Jiang, Hai T Tran, Alexandre Reuben, Weihong Xiao, Maura L Gillison, Xiaowen Sun, Alexander Khalaf, J Jack Lee, Jagannadha K Sastry, Soma Ghosh

Faculty, Staff and Student Publications

Purpose: Effective therapy for recurrent head and neck squamous cell carcinoma (HNSCC) that is refractory to chemotherapy and immunotherapy is a considerable need. Aurora kinase A inhibition leads to apoptosis and immunogenic cell death in preclinical models of human papilloma virus (HPV)-driven cancers.

Patients and methods: Alisertib was administered orally twice daily on days 1-7 and pembrolizumab on day 1 of a 21-day cycle to adults with advanced solid tumors (phase I) or with immunotherapy- and platinum-resistant, HPV-positive HNSCC (phase II).

Results: The recommended phase II alisertib dose was 40 mg, which had only the expected toxicity including cytopenia that …

The Landscape Of Ctdna In Appendiceal Adenocarcinoma, Michael G White, Mohammad A Zeineddine, Eleanor A Fallon, Fadl A Zeineddine, Julia Dansby, Saikat Chowdhury, Nicholas Hornstein, Abdelrahman Yousef, Mahmoud Yousef, Neal Bhutiani, Yue Gu, Bryan Kee, Arvind Dasari, Michael J Overman, Kanwal Raghav, Scott Kopetz, Abhineet Uppal, Melissa Taggart, Timothy Newhook, Keith Fournier, Beth Helmink, Leylah M Drusbosky, John Paul Shen

Faculty, Staff and Student Publications

Purpose: Appendiceal adenocarcinoma is a rare malignancy with distinct histopathologic subtypes and a natural history with metastasis primarily limited to the peritoneum. Little is known about the molecular pathogenesis of appendiceal adenocarcinoma relative to common tumors.

Experimental design: We analyzed molecular data for patients within the Guardant Health database with appendix cancer (n = 718). We then identified patients with appendiceal adenocarcinoma at our institution (from October 2004-September 2022) for whom ctDNA mutation profiling (liquid biopsy) was performed (n = 168) and extracted clinicopathologic and outcomes data. Of these 168 patients, 57 also had tissue-based tumor mutational profiling, allowing for …

Synaptic Alterations In Pyramidal Cells Following Genetic Manipulation Of Neuronal Excitability In Monkey Prefrontal Cortex, Guillermo Gonzalez-Burgos, Takeaki Miyamae, Yosuke Nishihata, Olga L Krimer, Kirsten Wade, Kenneth N Fish, Dominique Arion, Zhao-Lin Cai, Mingshan Xue, William R Stauffer, David A Lewis

Duncan NRI Faculty and Staff Publications

The primate dorsolateral prefrontal cortex (DLPFC) displays unique in vivo activity patterns, but how in vivo activity regulates DLPFC pyramidal neuron (PN) properties remains unclear. We assessed the effects of in vivo Kir2.1 overexpression, a genetic silencing tool, on synapses in monkey DLPFC PNs. We show for the first time that recombinant ion channel expression successfully modifies the excitability of primate cortex neurons, producing effects on synaptic properties apparently different from those in the rodent cortex.

Resilience And Coping: A Qualitative Analysis Of Cognitive And Behavioral Factors In Adults With Osteogenesis Imperfecta, Hannah E Cho, Whitney S Shepherd, Gianna M Colombo, Andrew D Wiese, W Conor Rork, Kristin M Kostick, Dianne Nguyen, Members Of The Bbdc, Chaya N Murali, Marie-Eve Robinson, Sophie C Schneider, Justin H Qian, Brendan Lee, V Reid Sutton, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Purpose: The aim of this qualitative study was to investigate resilience among adults with Osteogenesis Imperfecta (OI).

Materials and methods: Semi-structured interviews were conducted with 15 adults with OI. Transcripts were coded and subsequently abstracted, yielding themes specific to resilience and coping. Interview guides covered broad topics including pain challenges specific to OI, mental health issues related to OI, and priorities for future interventions for individuals with OI.

Results: Participants described resilience in the context of OI as the ability to grow from adversity, adapt to challenges resulting from OI-related injuries, and find identities apart from their condition. Psychological coping …

Figg At 5: An Update On Us Public Perspectives On Forensic Investigative Genetic Genealogy Five Years After Its Introduction To Criminal Investigations, Christi J Guerrini, Jill O Robinson, Mohamed I Elsaid, Whitney Bash Brooks, Ariel Levchenko, Stephanie M Fullerton, Sara Huston, Norah L Crossnohere, John F P Bridges, Jacklyn M Dahlquist, Louiza Kalokairinou, Diana Madden, Cece Moore, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

In 2018, after law enforcement announced it had used a technique called forensic investigative genetic genealogy (FIGG) to identify the Golden State Killer, we conducted a U.S. general population survey and found most respondents supported using FIGG to solve violent crimes. Since then, FIGG has helped close hundreds of criminal cases, but it also has weathered controversies. On FIGG's fifth anniversary, we conducted an expanded, follow-up survey with U.S.-based participants to determine if public opinion had changed and found continued support for FIGG across most applications. The same proportion (91 %) of respondents in the 2018 and 2023 surveys endorsed …

Plasma Proteomic Characterization Of Motoric Cognitive Risk And Mild Cognitive Impairment, Gabriela T Gomez, Sanish Sathyan, Jingsha Chen, Myriam Fornage, Pascal Schlosser, Zhongsheng Peng, Jenifer Cordon, Priya Palta, Kevin J Sullivan, Adrienne Tin, B Gwen Windham, Rebecca F Gottesman, Nir Barzilai, Sofiya Milman, Joe Verghese, Josef Coresh, Keenan A Walker

Faculty, Staff and Student Publications

INTRODUCTION: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by mobility and cognitive dysfunction. This study conducted a proteome-wide study of MCR and compared the proteomic signatures of MCR to that of mild cognitive impairment (MCI).

METHODS: Participants were classified as MCR using a memory questionnaire and 4-meter walk. We measured 4877 plasma proteins collected during late-life and midlife. Multivariable logistic regression related each protein to late-life MCR/MCI. MCR-associated proteins were replicated internally at midlife and in an external cohort.

RESULTS: Proteome-wide analysis (n = 4076) identified 25 MCR-associated proteins. Eight of these proteins remained associated with late-life MCR …

Chemoresistance-Motility Signature Of Molecular Evolution To Chemotherapy In Non-Muscle-Invasive Bladder Cancer And Its Clinical Implications, Mi-So Jeong, Seung-Woo Baek, Gi-Eun Yang, Jeong-Yeon Mun, Jeong Ah Kim, Tae-Nam Kim, Jong-Kil Nam, Yung-Hyun Choi, Ju-Seog Lee, In-Sun Chu, Sun-Hee Leem

Faculty, Staff and Student Publications

Non-muscle-invasive bladder cancer (NMIBC) often recurs and can progress to MIBC due to resistance to treatments like intravesical chemotherapy or Bacillus Calmette-Guérin (BCG). Therefore, we established the Gemcitabine-Resistant Cells (GRCs) to study the molecular evolution under external pressure. A 63-gene Chemoresistance-Motility (CrM) signature was created to identify stage-specific traits of GRCs. This signature was tested on 1846 samples using log-rank tests and Cox regression to evaluate clinical utility. Early and intermediate resistance stages showed increased cell motility and metastatic potential. FAK, PI3K-AKT, and TGFβ pathways were activated first, followed by MAPK signaling. Single-cell analysis and experiments utilizing the CrM signature …

Association Of Serum Endocannabinoid Levels With Pancreatitis And Pancreatitis-Related Pain, Marc T Goodman, Christina Lombardi, Alexa Torrens, Catherine Bresee, Jami L Saloman, Liang Li, Yunlong Yang, William E Fisher, Evan L Fogel, Christopher E Forsmark, Darwin L Conwell, Phil A Hart, Walter G Park, Mark Topazian, Santhi S Vege, Stephen K Van Den Eeden, Melena D Bellin, Dana K Andersen, Jose Serrano, Dhiraj Yadav, Stephen J Pandol, Daniele Piomelli

Faculty, Staff and Student Publications

No abstract provided.

Mayo Genetic Risk Models For Newly Diagnosed Acute Myeloid Leukemia Treated With Venetoclax + Hypomethylating Agent, Naseema Gangat, Azeem Elbeih, Nour Ghosoun, Kristen Mccullough, Fnu Aperna, Isla M Johnson, Maymona Abdelmagid, Aref Al-Kali, Hassan B Alkhateeb, Kebede H Begna, Michelle Elliott, Abhishek Mangaonkar, Aasiya Matin, Antoine N Saliba, Mehrdad Hefazi Torghabeh, Mark R Litzow, William Hogan, Mithun Shah, Mrinal M Patnaik, Animesh Pardanani, Talha Badar, Hemant Murthy, James Foran, Jeanne Palmer, Lisa Sproat, Nandita Khera, Cecilia Arana Yi, Samuel Yates, Abigail Sneider, Emily Dworkin, Anand A Patel, Alexandre Bazinet, Jayastu Senapati, Alex Bataller, Courtney Dinardo, Tapan Kadia, Ayalew Tefferi

Faculty, Staff and Student Publications

Patients with newly diagnosed acute myeloid leukemia (ND-AML) derive variable survival benefit from venetoclax + hypomethylating agent (Ven-HMA) therapy. The primary objective in the current study was to develop genetic risk models that are predictive of survival and are applicable at the time of diagnosis and after establishing treatment response. Among 400 ND-AML patients treated with Ven-HMA at the Mayo Clinic, 247 (62%) achieved complete remission with (CR) or without (CRi) count recovery. Multivariable analysis-derived hazard ratios (HR), including 1.8 for European LeukemiaNet (ELN) adverse karyotype, 4.7 for KMT2Ar, 1.7 for TP53

Forecasting Intraoperative Hypotension During Hepatobiliary Surgery, Juan P Cata, Bhavin Soni, Shreyas Bhavsar, Parvathy Sudhir Pillai, Tatiana A Rypinski, Anshuj Deva, Jeffrey H Siewerdsen, Jose M Soliz

Faculty, Staff and Student Publications

Prediction and avoidance of intraoperative hypotension (IOH) can lead to less postoperative morbidity. Machine learning (ML) is increasingly being applied to predict IOH. We hypothesize that incorporating demographic and physiological features in an ML model will improve the performance of IOH prediction. In addition, we added a "dial" feature to alter prediction performance. An ML prediction model was built based on a multivariate random forest (RF) trained algorithm using 13 physiologic time series and patient demographic data (age, sex, and BMI) for adult patients undergoing hepatobiliary surgery. A novel implementation was developed with an adjustable, multi-model voting (MMV) approach to …

A Phase Ib Trial Of Selinexor In Combination With Immune Checkpoint Blockade In Patients With Advanced Renal Cell Carcinoma, Omar Alhalabi, Mohamed A Gouda, Denái R Milton, Hassan Ahmed Momin, Bulent Yilmaz, Bettzy Stephen, Chinenye Lynette Ejezie, Justin Tyler Moyers, Serdar A Gurses, Jeffrey How, Siqing Fu, Jordi Rodon, David S Hong, Sarina A Piha-Paul, Vivek Subbiah, Ecaterina Elena Dumbrava, Daniel D Karp, Filip Janku, Funda Meric-Bernstam, Nizar M Tannir, Aung Naing

Faculty, Staff and Student Publications

Background: Selinexor (SEL) is a nuclear exportin 1 inhibitor that blocks the transport of nuclear proteins, including tumor suppressors, to the cytoplasm. Preclinical data suggest that the combination of SEL with checkpoint blockade may result in improved response to immunotherapy.

Methods: NCT02419495 was a multiarm phase IB study of SEL in combination with other standard regimens in patients with advanced malignancies. Arm M utilized twice weekly oral SEL and intravenous nivolumab (NIVO). Arm N utilized weekly oral SEL with NIVO plus ipilimumab (IPI). The primary objective of this study was to evaluate the safety of SEL + NIVO and SEL …

Frailty And Sleep In Adult Survivors Of Childhood Cancer: A Childhood Cancer Survivor Study Report, Lauren C Daniel, Margaret M Lubas, Huiqi Wang, Mariana Szklo-Coxe, Kirsten K Ness, Annalynn M Williams, Daniel A Mulrooney, Rebecca Howell, Wendy Leisenring, Yutaka Yasui, Leslie L Robison, Gregory T Armstrong, Eric J Chow, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

Background: Young adult survivors of childhood cancer exhibit rates of frailty similar to adults several decades older without a cancer history. Frailty has been associated with sleep disturbances in non-cancer populations, but the relationship has not been examined in childhood cancer survivors who are known to exhibit elevated rates of sleep problems.

Aims: Examine associations between frailty and poor sleep quality in long-term survivors of childhood cancer.

Methods: This study utilized data from 9044 participants (> 5 years from diagnosis, Mage = 40.8 years [SD = 9.5]) in the Childhood Cancer Survivor Study. Survivors' frailty status, chronic health conditions (CHC), …

Stereotactic Body Radiotherapy Vs Sorafenib Alone In Hepatocellular Carcinoma: The Nrg Oncology/Rtog 1112 Phase 3 Randomized Clinical Trial, Laura A Dawson, Kathryn A Winter, Jennifer J Knox, Andrew X Zhu, Sunil Krishnan, Chandan Guha, Lisa A Kachnic, Michael T Gillin, Theodore S Hong, Timothy D Craig, Terence M Williams, Ali Hosni, Eric Chen, Anne M Noonan, Eugene J Koay, Rishi Sinha, Michael I Lock, Nitin Ohri, Jennifer A Dorth, Guila Delouya, Anand Swaminath, Jennifer Moughan, Christopher H Crane

Faculty, Staff and Student Publications

Importance: Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy.

Objective: To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone.

Design, setting, and participants: This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, …

Human Hypofunctional Ncf1 Variants Promote Pulmonary Fibrosis In The Bleomycin-Induced Mouse Model And Patients With Systemic Sclerosis Via Expansion Of Spphuman Hypofunctional Ncf1 Variants Promote Pulmonary Fibrosis In The Bleomycin-Induced Mouse Model And Systemic Sclerosis Patients Via Expansion Of Spp1+ Monocytes-Derived Macrophages, Xinran Yuan, Xiaodong Qin, Kenji Takemoto, Jian Zhao, Matthew Sanderson, Xue Xu, Yu Zhang, Kristi L Helke, Bethany Jacobs Wolf, Joel M Guthridge, Judith A James, Xiaodong Zhou, Shervin Assassi, Carol Feghali-Bostwick, Dandan Wang, Lingyun Sun, Betty P Tsao

Faculty, Staff and Student Publications

Objective: We assessed the role of a systemic lupus erythematosus causal hypofunctional variant, neutrophil cytosolic factor 1 (NCF1)-p.Arg90His (p.R90H) substitution, in systemic sclerosis (SSc).

Methods: Association of NCF1-H90 with SSc was performed in case-control cohorts, bleomycin (BLM)-treated Ncf1-R90 C57BL/6 wildtype and Ncf1-H90 knock-in (KI) littermates. Peripheral blood mononuclear cell (PBMC) subsets were analysed by cytometry by time-of-flight.

Results: The NCF1-H90 allele is associated with risk for diffuse cutaneous SSc (dcSSc) in Chinese and European Americans, and lung fibrosis in Chinese patients with SSc (OR=2.09, p=7.96E-10). Low copy number of NCF1 associated with lung fibrosis in European Americans (OR=4.33, p=2.60E-2). BLM-treated …

Association Of Systemic Inflammation And Long-Term Dysfunction In Covid-19 Patients: A Prospective Cohort, Felipe Dal-Pizzol, Bruno Kluwe-Schiavon, Henrique Ritter Dal-Pizzol, Gabriele Da Silveira Prestes, Diogo Dominguini, Carolina Saibro Girardi, Lucas Santos, José Cláudio Fonseca Moreira, Daniel Pens Gelain, Roger Walz, Tatiana Barichello, Cristiane Ritter

Faculty, Staff and Student Publications

COVID-19 has significant long-term impacts, including a chronic syndrome known as long-COVID, characterized by persistent symptoms post-recovery. The inflammatory response during acute infection is hypothesized to influence long-term outcomes. This study aimed to identify inflammatory biomarkers predictive of functional outcomes one year after hospital discharge. A prospective cohort study was conducted with 213 COVID-19 patients admitted to ICUs in Southern Brazil between June and November 2020. After exclusions and follow-ups, 109 patients were evaluated for one-year post-discharge. Plasma levels of Th1 (TNF-α, INF-γ, IL-12), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), and Th17 (IL-17, IL-22) cytokines were measured. Functional outcomes in …

Somatic Copy Number Deletion Of Chromosome 22q In Papillary Thyroid Carcinoma, Olivia W Lee, Danielle M Karyadi, Stephen W Hartley, Weyin Zhou, Mitchell J Machiela, Shahriar A Zamani, Liudmyla Yu Zurnadzhy, John N Weinstein, Young Joo Park, Jeong-Sun Seo, Gerry A Thomas, Tetiana I Bogdanova, Mykola D Tronko, Lindsay M Morton, Stephen J Chanock

Faculty, Staff and Student Publications

Deletion of the long q arm of chromosome 22 (22qDEL) is the most frequently identified recurrent somatic copy number alteration observed in papillary thyroid carcinoma (PTC). Since its role in PTC is not fully understood, we conducted a pooled analysis of genomic characteristics and clinical correlates in 1094 primary tumors from four published PTC genomic studies. The majority of PTC cases with 22qDEL exhibited arm-level loss of heterozygosity (86%); nearly all PTC cases with 22qDEL had losses in 22q12 and 13, which together constitute 70% of the q arm. Our analysis confirmed that 22qDEL occurs more frequently with RAS point …

Recurrence-Free Survival Prediction For Anal Squamous Cell Carcinoma After Chemoradiotherapy Using Planning Ct-Based Radiomics Model, Shanshan Tang, Kai Wang, David Hein, Gloria Lin, Nina N Sanford, Jing Wang

Faculty, Staff and Student Publications

Objectives: Approximately 30% of non-metastatic anal squamous cell carcinoma (ASCC) patients will experience recurrence after chemoradiotherapy (CRT), and currently available clinical variables are poor predictors of treatment response. We aimed to develop a model leveraging information extracted from radiation pretreatment planning CT to predict recurrence-free survival (RFS) in ASCC patients after CRT.

Methods: Radiomics features were extracted from planning CT images of 96 ASCC patients. Following pre-feature selection, the optimal feature set was selected via step-forward feature selection with a multivariate Cox proportional hazard model. The RFS prediction was generated from a radiomics-clinical combined model based on an optimal feature …

Mutational And Co-Mutational Landscape Of Early Onset Colorectal Cancer, Jumanah Yousef Alshenaifi, Guglielmo Vetere, Giulia Maddalena, Mahmoud Yousef, Michael G White, John Paul Shen, Eduardo Vilar, Christine Parseghian, Arvind Dasari, Van Karlyle Morris, Ryan Huey, Michael J Overman, Robert Wolff, Kanwal P Raghav, Jason Willis, Kristin Alfaro, Andy Futreal, Y Nancy You, Scott Kopetz

Faculty, Staff and Student Publications

Introduction: Colorectal cancer (CRC) incidence and mortality before 50 have been rising alarmingly in the recent decades.

Methods: Using a cohort of 10,000 patients, this study investigates the clinical, mutational, and co-mutational features of CRC in early-onset (EOCRC, < 50 years) compared to late-onset (LOCRC, ≥ 50 years).

Results: EOCRC was associated with a higher prevalence of Asian and Hispanic patients, rectal or left-sided tumors (72% vs. 59%), and advanced-stage disease. Molecular analyses revealed differences in mutation patterns, with EOCRC having higher frequencies of TP53 (74% vs. 68%, p < 0.01) and SMAD4 (17% vs. 14%, p = 0.015), while BRAF (5% vs. 11%, p < 0.001) and NOTCH1 (2.7% vs. 4.1%, p = 0.01) mutations …

A Phase 2 Basket Study Of Talabostat, A Small-Molecule Inhibitor Of Dipeptidyl Peptidases, Administered In Combination With Pembrolizumab In Patients With Advanced Solid Cancers, Jibran Ahmed, Filip Janku, Daniel D Karp, Sarina A Piha-Paul, Apostolia M Tsimberidou, Timothy Anthony Yap, Bettzy Stephen, Yali Yang, Serdar Gurses, Qian Liu, Juhee Song, Funda Meric-Bernstam, Aung Naing

Faculty, Staff and Student Publications

Background: Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP8/9), has shown synergistic activity with immune checkpoint inhibitors in preclinical studies. This open label, phase 2 basket trial assessed the antitumor activity of combining talabostat and pembrolizumab (anti-programmed death-1 antibody) in advanced solid tumor patients.

Methods: The primary objective was assessment of dose-limiting toxicity (DLT) rates in the first six patients (lead-in stage) and response rate (efficacy stage; included cohort A [checkpoint inhibitor (ICI) naive] and cohort B [ICI pretreated]) for the study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune RECIST …

Angiotensin-(1-9) Improves The Cardioprotective Effects Of Del Nido Cardioplegia Against Ischemia/Reperfusion Injury, Evelyn Mendoza-Torres, Gina Sanchez, Wendy Rosales, María Clara Ospino, Luis Antonio Díaz-Ariza, Yuliet Montoya, John Bustamante, Jaime A Riquelme, Mario Chiong, Sergio Lavandero

Faculty, Staff and Student Publications

Del Nido cardioplegia (DNC), a blood-and-crystalloid solution containing high and low concentrations of potassium and calcium, respectively, is used as a single-dose antegrade infusion to induce immediate cardiac arrest in the surgery of patients with cardiovascular diseases requiring extracorporeal circulation. Adding cardioprotective molecules may further reduce the damage-triggered ischemia/reperfusion (I/R) injury. Angiotensin-(1-9) (Ang-(1-9)) and angiotensin-(1-7) (Ang-(1-7)), members of the counter-regulatory renin-angiotensin system, have shown cardioprotective effects in cardiac hypertrophy and I/R models. This study aimed to evaluate the effects of Ang-(1-9) and Ang-(1-7), as adjuvants of the DNC, on cardioprotection and ventricular function in isolated rat hearts subjected to I/R …