Medical Genetics Commons^™

Nprl2 Gene Therapy Induces Effective Antitumor Immunity In Kras/Stk11 Mutant Anti-Pd1 Resistant Metastatic Non-Small Cell Lung Cancer (Nsclc) In A Humanized Mouse Model, Ismail M Meraz, Mourad Majidi, Renduo Song, Feng Meng, Lihui Gao, Qi Wang, Jing Wang, Elizabeth J Shpall, Jack A Roth

Faculty, Staff and Student Publications

Expression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11^mt NSCLC in humanized-mice. Humanized-mice were generated by transplanting fresh human cord blood-derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung-metastases were developed from KRAS/STK11^mt/aPD1R A549 cells and treated with NPRL2 w/wo pembrolizumab. NPRL2-treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. Antitumor effect was greater in humanized than non-humanized-mice. NPRL2 + pembrolizumab was not synergistic in KRAS/STK11^mt/aPD1R tumors but was …

Regression Modeling Of Cumulative Incidence Function For Left-Truncated Right-Censored Competing Risks Data: A Modified Pseudo-Observation Approach, Rong Rong, Jing Ning, Hong Zhu

Faculty, Staff and Student Publications

Statistical methods have been developed for regression modeling of the cumulative incidence function (CIF) given left-truncated right-censored competing risks data. Nevertheless, existing methods typically involve complicated weighted estimating equations or nonparametric conditional likelihood function and often require a restrictive assumption that censoring and/or truncation times are independent of failure time. The pseudo-observation (PO) approach has been used in regression modeling of CIF for right-censored competing risks data under covariate-independent censoring or covariate-dependent censoring. We extend this approach to left-truncated right-censored competing risks data and propose to directly model the CIF based on POs, under general truncation and censoring mechanisms. We …

Complete Genome Sequence Of A Penicillin-Resistant Fusobacterium Necrophorum Subsp Funduliforme Isolate From A Tonsillitis Patient, Bibek G C, Anders Jensen, Chenggang Wu

Faculty, Staff and Student Publications

We report the complete genome sequence of a penicillin-resistant Fusobacterium necrophorum subsp. funduliforme isolate, AJ79, from a tonsillitis patient. The AJ79 genome consists of a chromosome (2,440,359 bp) and plasmid (9,887 bp), providing insights into the genetic basis of penicillin resistance in F. necrophorum and its implications for treating tonsillitis.

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 …

Classification Of Non-Tcga Cancer Samples To Tcga Molecular Subtypes Using Compact Feature Sets, Kyle Ellrott, Christopher K Wong, Christina Yau, Mauro A A Castro, Jordan A Lee, Brian J Karlberg, Jasleen K Grewal, Vincenzo Lagani, Bahar Tercan, Verena Friedl, Toshinori Hinoue, Vladislav Uzunangelov, Lindsay Westlake, Xavier Loinaz, Ina Felau, Peggy I Wang, Anab Kemal, Samantha J Caesar-Johnson, Ilya Shmulevich, Alexander J Lazar, Ioannis Tsamardinos, Katherine A Hoadley, Cancer Genome Atlas Analysis Network, A Gordon Robertson, Theo A Knijnenburg, Christopher C Benz, Joshua M Stuart, Jean C Zenklusen, Andrew D Cherniack, Peter W Laird

Faculty, Staff and Student Publications

Molecular subtypes, such as defined by The Cancer Genome Atlas (TCGA), delineate a cancer's underlying biology, bringing hope to inform a patient's prognosis and treatment plan. However, most approaches used in the discovery of subtypes are not suitable for assigning subtype labels to new cancer specimens from other studies or clinical trials. Here, we address this barrier by applying five different machine learning approaches to multi-omic data from 8,791 TCGA tumor samples comprising 106 subtypes from 26 different cancer cohorts to build models based upon small numbers of features that can classify new samples into previously defined TCGA molecular subtypes-a …

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, …

Long-Read Sequencing Of 945 Han Individuals Identifies Structural Variants Associated With Phenotypic Diversity And Disease Susceptibility, Jiao Gong, Huiru Sun, Kaiyuan Wang, Yanhui Zhao, Yechao Huang, Qinsheng Chen, Hui Qiao, Yang Gao, Jialin Zhao, Yunchao Ling, Ruifang Cao, Jingze Tan, Qi Wang, Yanyun Ma, Jing Li, Jingchun Luo, Sijia Wang, Jiucun Wang, Guoqing Zhang, Shuhua Xu, Feng Qian, Fang Zhou, Huiru Tang, Dali Li, Chinese Pangenome Consortium (Cpc), Fritz J Sedlazeck, Li Jin, Yuting Guan, Shaohua Fan

Faculty, Staff and Students Publications

Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could …

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 …

The Application And Innovation Of Casgevy On Sickle Cell Disease, Emily Tackett, Le Thien Truc Pham, Hannah Salamie, Arin Wade, Allison Provenzale, Alexander Defranco, Ashley Jacob, Brianna Lu, Joshua Honaker, Amy Stockert

Pharmacy and Wellness Review

Casgevy, sickle cell anemia, SCA, sickle cell disease, SCD, CRISPR/Cas9, hydroxyurea, hemoglobin, Hb, l-glutamine, voxelotor, Crizanlizumab, Lyfgenia, stem cells, genetics, pharmacogenetics, pharmacogenomics

Therapeutic Targeting Of The Janus Kinase/Signal Transducer And Activator Of Transcription Pathway In Cutaneous T-Cell Lymphoma, Alisha Kashyap, Julia Dai, Xiao Ni

Faculty, Staff and Student Publications

Background/Objectives: Cutaneous T-cell lymphoma (CTCL) is a rare group of non-Hodgkin lymphomas characterized by the clonal expansion of malignant T cells. While current treatments can alleviate symptoms and significant progress has been made in treating leukemic CTCL, a definitive cure remains elusive. Dysregulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a key driver of CTCL pathogenesis. As a result, therapeutic strategies targeting JAK/STAT signaling have gained momentum, with the increasing use of JAK inhibitors and other agents that effectively suppress this pathway. These immune-modulating therapies have broad effects on physiological processes, inflammation, and …

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 …

Characterizing Features Affecting Local Ancestry Inference Performance In Admixed Populations, Jessica Honorato-Mauer, Nirav N Shah, Adam X Maihofer, Clement C Zai, Sintia Belangero, Caroline M Nievergelt, Marcos Santoro, Elizabeth G Atkinson

Faculty, Staff and Students Publications

In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using local ancestry inference (LAI). Accurate LAI is crucial to ensure that downstream analyses accurately reflect the genetic ancestry of research participants. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America's primary continental ancestries-African (AFR), Amerindigenous (AMR), and European (EUR). Simulating linkage-disequilibrium-informed admixed haplotypes under a variety of 2- and 3-way admixture models, we implemented a standard LAI pipeline, testing the impact of reference panel composition, DNA data type, demography, and …

Design And Implementation Of An Action Plan For Justice, Equity, Diversity, And Inclusion Within The Clinical Genome Resource, Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales

Faculty, Staff and Students Publications

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments …

Oncogenic Kras Mutations Confer A Unique Mechanotransduction Response To Peristalsis In Colorectal Cancer Cells, Abigail J Clevenger, Claudia A Collier, John Paul M Gorley, Sarah Colijn, Maygan K Mcfarlin, Spencer C Solberg, Scott Kopetz, Amber N Stratman, Shreya A Raghavan

Faculty, Staff and Student Publications

Colorectal cancer tumors start as polyps on the inner lining of the colorectum, in which they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in colorectal cancer cells. However, this malignant mechanotransductive response was confined to select colorectal cancer lines that harbored an oncogenic mutation in the Kirsten rat sarcoma virus (KRAS) gene. In this study, we explored the involvement of activating KRAS mutations on peristalsis-associated mechanotransduction in colorectal cancer. Peristalsis enriched cancer stem cell marker Leucine-rich repeat-containing G protein-coupled receptor 5 …

Proceedings Of The 1st Biannual Bridging The Gaps In Lung Cancer Conference, Narjust Florez, Sandip P Patel, Heather Wakelee, Lyudmila Bazhenova, Erminia Massarelli, Ravi Salgia, Brendon Stiles, Solange Peters, Jyoti Malhotra, Shirish M Gadgeel, Jorge J Nieva, Michelle Afkhami, Fred R Hirsch, Matthew Gubens, Tina Cascone, Benjamin Levy, Joshua Sabari, Hatim Husain, Patrick C Ma, Leah M Backhus, Puneeth Iyengar, Percy Lee, Russell Miller, Jacob Sands, Edward Kim

Faculty, Staff and Student Publications

Lung cancer is the leading cause of cancer death in the US and globally. The mortality from lung cancer has been declining, due to a reduction in incidence and advances in treatment. Although recent success in developing targeted and immunotherapies for lung cancer has benefitted patients, it has also expanded the complexity of potential treatment options for health care providers. To aid in reducing such complexity, experts in oncology convened a conference (Bridging the Gaps in Lung Cancer) to identify current knowledge gaps and controversies in the diagnosis, treatment, and outcomes of various lung cancer scenarios, as described here. Such …

Preclinical Efficacy Of Cdk7 Inhibitor-Based Combinations Against Myeloproliferative Neoplasms Transformed To Aml, Warren Fiskus, Christopher P Mill, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Andrew Dunbar, Christine E Birdwell, John A Davis, Kaberi Das, Hanxi Hou, Taghi Manshouri, Antrix Jain, Anna Malovannaya, Kevin Philip, Noor Alhamadani, Alicia Matthews, Katie Lin, Lauren B Flores, Sanam Loghavi, Courtney Dinardo, Xiaoping Su, Raajit K Rampal, Kapil N Bhalla

Faculty, Staff and Student Publications

Rising blast percentage or secondary acute myeloid leukemia (sAML) transformation in myeloproliferative neoplasms (MPNs) leads to JAK1/2 inhibitor (JAKi) therapy resistance and poor survival. Here, we demonstrate that treatment with the CDK7 inhibitor (CDK7i) SY-5609 depletes phenotypically characterized post-MPN sAML stem/progenitor cells. In cultured post-MPN sAML SET2, HEL and patient-derived (PD) post-MPN sAML cells, SY-5609 treatment inhibited growth and induced lethality while sparing normal cells. RNA-sequencing analysis after SY-5609 treatment reduced mRNA expression of MYC, MYB, CDK4/6, PIM1, and CCND1 but increased expression of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also reduced c-Myc, c-Myb, PIM1, and CDK4/6 …

Dna-Binding Affinity And Specificity Determine The Phenotypic Diversity In Bcl11b-Related Disorders, Ivana Lessel, Anja Baresic, Ivan K Chinn, Jonathan May, Anu Goenka, Kate E Chandler, Jennifer E Posey, Alexandra Afenjar, Luisa Averdunk, Maria Francesca Bedeschi, Thomas Besnard, Rae Brager, Lauren Brick, Melanie Brugger, Theresa Brunet, Susan Byrne, Oscar De La Calle-Martín, Valeria Capra, Paul Cardenas, Céline Chappé, Hey J Chong, Benjamin Cogne, Erin Conboy, Heidi Cope, Thomas Courtin, Wallid Deb, Robertino Dilena, Christèle Dubourg, Magdeldin Elgizouli, Erica Fernandes, Kristi K Fitzgerald, Silvana Gangi, Jaya K George-Abraham, Muge Gucsavas-Calikoglu, Tobias B Haack, Medard Hadonou, Britta Hanker, Irina Hüning, Maria Iascone, Bertrand Isidor, Irma Järvelä, Jay J Jin, Alexander A L Jorge, Dragana Josifova, Ruta Kalinauskiene, Erik-Jan Kamsteeg, Boris Keren, Elena Kessler, Heike Kölbel, Mariya Kozenko, Christian Kubisch, Alma Kuechler, Suzanne M Leal, Juha Leppälä, Sharon M Luu, Gholson J Lyon, Suneeta Madan-Khetarpal, Margherita Mancardi, Elaine Marchi, Lakshmi Mehta, Beatriz Menendez, Chantal F Morel, Sue Moyer Harasink, Dayna-Lynn Nevay, Vincenzo Nigro, Sylvie Odent, Renske Oegema, John Pappas, Matthew T Pastore, Yezmin Perilla-Young, Konrad Platzer, Nina Powell-Hamilton, Rachel Rabin, Aisha Rekab, Raissa C Rezende, Leema Robert, Ferruccio Romano, Marcello Scala, Karin Poths, Isabelle Schrauwen, Jessica Sebastian, John Short, Richard Sidlow, Jennifer Sullivan, Katalin Szakszon, Queenie K G Tan, Undiagnosed Diseases Network, Matias Wagner, Dagmar Wieczorek, Bo Yuan, Nicole Maeding, Dirk Strunk, Amber Begtrup, Siddharth Banka, James R Lupski, Eva Tolosa, Davor Lessel

Faculty, Staff and Students Publications

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. …

Design And Implementation Of An Action Plan For Justice, Equity, Diversity, And Inclusion Within The Clinical Genome Resource, Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales

Faculty, Staff and Students Publications

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments …

Bi-Allelic Kics2 Mutations Impair Kicstor Complex-Mediated Mtorc1 Regulation, Causing Intellectual Disability And Epilepsy, Rebecca Buchert, Martin D Burkhalter, Chrisovalantou Huridou, Linda Sofan, Timo Roser, Kirsten Cremer, Javeria Raza Alvi, Stephanie Efthymiou, Tawfiq Froukh, Sughra Gulieva, Ulviyya Guliyeva, Moath Hamdallah, Muriel Holder-Espinasse, Rauan Kaiyrzhanov, Doreen Klingler, Mahmoud Koko, Lars Matthies, Joohyun Park, Marc Sturm, Ana Velic, Stephanie Spranger, Tipu Sultan, Hartmut Engels, Holger Lerche, Henry Houlden, Alistair T Pagnamenta, Ingo Borggraefe, Yvonne Weber, Penelope E Bonnen, Reza Maroofian, Olaf Riess, Jonasz J Weber, Melanie Philipp, Tobias B Haack

Faculty, Staff and Students Publications

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and …

Braf Mutant Appendiceal Adenocarcinoma Differs From Colorectal Cancer But Responds To Braf-Targeted Therapy, Vinay K Pattalachinti, Emaan Haque, Mahmoud Yousef, Abdelrahman Yousef, Saikat Chowdhury, Michael Overman, Christine M Parseghian, Van K Morris, Bryan Kee, Ryan W Huey, Kanwal Raghav, Colin M Court, John Paul Shen

Faculty, Staff and Student Publications

Appendiceal Adenocarcinoma (AA) is a rare gastrointestinal cancer with no FDA-approved targeted therapies. Here, we retrospectively compare BRAF-mutant AA and colorectal cancer (CRC). BRAF mutation is rare in AA (3%). Unlike CRC, BRAFV600E AA is not associated with poor prognosis, female sex, microsatellite instability, mucinous histology, or poor differentiation. In both cancers, BRAFV600E but not atypical BRAF mutations are mutually exclusive with other Ras-activating mutations. BRAFV600E + EGFR inhibition shows efficacy in BRAFV600E AA (disease control rate = 80%, median progression-free survival = 7.1 months).

Brd7 Loss Reawakens Dormant Metastasis Initiating Cells In Lung By Forging An Immunosuppressive Niche, Jayanta Mondal, Junfeng Zhang, Feng Qing, Shunping Li, Dhiraj Kumar, Jason T Huse, Filippo G Giancotti

Faculty, Staff and Student Publications

Metastasis in cancer is influenced by epigenetic factors. Using an in vivo screen, we demonstrate that several subunits of the polybromo-associated BAF (PBAF) chromatin remodeling complex, particularly Brd7, are required for maintaining breast cancer metastatic dormancy in the lungs of female mice. Brd7 loss induces metastatic reawakening, along with modifications in epigenomic landscapes and upregulated oncogenic signaling. Breast cancer cells harboring Brd7 inactivation also reprogram the surrounding immune microenvironment by downregulating MHC-1 expression and promoting a pro-metastatic cytokine profile. Flow cytometric and single-cell analyses reveal increased levels of pro-tumorigenic inflammatory and transitional neutrophils, CD8+ exhausted T cells, and CD4+ stress …

Advanced External Beam Stereotactic Radiotherapy For Skull Base Reirradiation, He Wang, Fahed M Alsanea, Dong Joo Rhee, Xiaodong Zhang, Wei Liu, Jinzhong Yang, Zhifei Wen, Yao Zhao, Tyler D Williamson, Rachel A Hunter, Peter A Balter, Tina M Briere, Ronald X Zhu, Anna Lee, Amy C Moreno, Jay P Reddy, Adam S Garden, David I Rosenthal, Gary B Gunn, Jack Phan

Faculty, Staff and Student Publications

Background/objectives: Stereotactic body radiation therapy (SBRT) for skull base reirradiation is particularly challenging, as patients have already received substantial radiation doses to the region, and nearby normal organs may have approached their tolerance limit from prior treatments. In this study, we reviewed the characteristics and capabilities of four advanced external beam radiation delivery systems and four modern treatment planning systems and evaluated the treatment plan quality of each technique using skull base reirradiation patient cases.

Methods: SBRT plans were generated for sixteen skull base reirradiation patients using four modalities: the GK plan for the Elekta Leksell Gamma Knife Perfexion/ICON, the …

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 …

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

Diet Therapy Abates Mutant Apc And Kras Effects By Reshaping Plasma Membrane Cholesterol Nanodomains, Eunjoo Kim, Alfredo Erazo-Oliveras, Mónica Muñoz-Vega, Natividad R Fuentes, Michael L Salinas, Miranda J George, Roger S Zoh, Martha E Hensel, Bhimanagouda S Patil, Ivan Ivanov, Nancy D Turner, Robert S Chapkin

Faculty, Staff and Student Publications

Cholesterol-enriched plasma membrane domains are known to serve as signaling platforms in a diverse array of cellular processes. However, the link between cholesterol homeostasis and mutant APC-KRas-associated colorectal tumorigenesis remains to be established. Thus, we investigated the impact of Apc-Kras on 1) colonocyte plasma membrane cholesterol homeostasis, order, and receptor nanoclustering, 2) colonocyte cell proliferation, and 3) whether these effects are modulated by select membrane active dietaries (MADs). We observed that oncogenic APC-KRas increased membrane order by perturbing cholesterol homeostasis when cell proliferation is upregulated, in part by altering the expression of genes associated with cholesterol influx, export and de …

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 …

Cancer Cells Avoid Ferroptosis Induced By Immune Cells Via Fatty Acid Binding Proteins, Maria Angelica Freitas-Cortez, Fatemeh Masrorpour, Hong Jiang, Iqbal Mahmud, Yue Lu, Ailing Huang, Lisa K Duong, Qi Wang, Tiffany A Voss, Claudia S Kettlun Leyton, Bo Wei, Wai-Kin Chan, Kevin Lin, Jie Zhang, Efrosini Tsouko, Shonik Ganjoo, Hampartsoum B Barsoumian, Thomas S Riad, Yun Hu, Carola Leuschner, Nahum Puebla-Osorio, Jing Wang, Jian Hu, Michael A Davies, Vinay K Puduvalli, Cyrielle Billon, Thomas P Burris, Philip L Lorenzi, Boyi Gan, James W Welsh

Faculty, Staff and Student Publications

Background: Cancer creates an immunosuppressive environment that hampers immune responses, allowing tumors to grow and resist therapy. One way the immune system fights back is by inducing ferroptosis, a type of cell death, in tumor cells through CD8 + T cells. This involves lipid peroxidation and enzymes like lysophosphatidylcholine acyltransferase 3 (Lpcat3), which makes cells more prone to ferroptosis. However, the mechanisms by which cancer cells avoid immunotherapy-mediated ferroptosis are unclear. Our study reveals how cancer cells evade ferroptosis and anti-tumor immunity through the upregulation of fatty acid-binding protein 7 (Fabp7).

Methods: To explore how cancer cells resist immune cell-mediated …

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 …