Medical Genetics Commons^™

Perioperative Nivolumab Versus Observation In Patients With Renal Cell Carcinoma Undergoing Nephrectomy (Prosper Ecog-Acrin Ea8143): An Open-Label, Randomised, Phase 3 Study, Mohamad E Allaf, Se-Eun Kim, Viraj Master, David F Mcdermott, Lauren C Harshman, Suzanne M Cole, Charles G Drake, Sabina Signoretti, Mahmut Akgul, Nicholas Baniak, Elsa Li-Ning, Matthew B Palmer, Hamid Emamekhoo, Nabil Adra, Hristos Kaimakliotis, Yasser Ged, Phillip M Pierorazio, E Jason Abel, Mehmet A Bilen, Kenneth Ogan, Helen H Moon, Krishna A Ramaswamy, Eric A Singer, Tina M Mayer, Jay Lohrey, Vitaly Margulis, Jessie Gills, Scott E Delacroix, Mark J Waples, Andrew C James, Peng Wang, Toni Choueiri, M Dror Michaelson, Anil Kapoor, Daniel Y Heng, Brian Shuch, Bradley C Leibovich, Primo N Lara, Judith Manola, Deborah Maskens, Dena Battle, Robert Uzzo, Gennady Bratslavsky, Naomi B Haas, Michael A Carducci

Faculty, Staff and Student Publications

Background: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only.

Methods: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or …

Updated Understanding Of The Protein-Dna Recognition Code Used By C2h2 Zinc Finger Proteins, Xing Zhang, Robert M Blumenthal, Xiaodong Cheng

Faculty, Staff and Student Publications

C2H2 zinc-finger (ZF) proteins form the largest family of DNA-binding transcription factors coded by mammalian genomes. In a typical DNA-binding ZF module, there are twelve residues (numbered from -1 to -12) between the last zinc-coordinating cysteine and the first zinc-coordinating histidine. The established C2H2-ZF "recognition code" suggests that residues at positions -1, -4, and -7 recognize the 5', central, and 3' bases of a DNA base-pair triplet, respectively. Structural studies have highlighted that additional residues at positions -5 and -8 also play roles in specific DNA recognition. The presence of bulky and either charged or polar residues at these five …

Structural Dynamics In Α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid Receptor Gating, Cuauhtemoc U Gonzalez, Vasanthi Jayaraman

Faculty, Staff and Student Publications

The ionotropic glutamate receptors (iGluRs) are comprised of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-d-aspartate receptor, kainate, and delta subtypes and are pivotal in neuronal plasticity. Recent structural studies on AMPA receptors reveal intricate conformational changes during activation and desensitization elucidating the steps from agonist binding to channel opening and desensitization. Additionally, interactions with auxiliary subunits, including transmembrane AMPA-receptor regulatory proteins, germ-cell-specific gene 1-like protein, and cornichon homologs, intricately modulate AMPA receptors. We discuss the recent high-resolution structures of these complexes that unveil stoichiometry, subunit positioning, and differences in specific side-chain interactions that influence these functional modulations.

Mc-Keyboard: A Practical Phase I Trial Design For Targeted Therapies And Immunotherapies Integrating Multiple-Grade Toxicities, Liyun Jiang, Zhulin Yin, Fangrong Yan, Ying Yuan

Faculty, Staff and Student Publications

In targeted therapies and immunotherapies, the occurrence of low-grade (e.g., grade 1-2) toxicities (LGT) is common, while dose-limiting toxicities (DLT) are relatively rare. As a result, conventional phase I trial designs, solely based on DLTs and disregarding milder toxicities, are problematic when evaluating these novel therapies.

Methods: To address this issue, we propose a novel phase I design called a multiple-constraint keyboard (MC-Keyboard) that integrates multiple toxicity constraints, accounting for both DLT and LGT, for precise dose escalation and de-escalation, and identification of the maximum tolerated dose (MTD). As a model-assisted design, an important feature of MC-Keyboard is that its …

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk For Breast Cancer, Xiaohui Sun, Shiv P Verma, Guochong Jia, Xinjun Wang, Jie Ping, Xingyi Guo, Xiao-Ou Shu, Jianhong Chen, Andriy Derkach, Qiuyin Cai, Xiaolin Liang, Jirong Long, Kenneth Offit, Jung H Oh, Anne S Reiner, Gordon P Watt, Meghan Woods, Yaohua Yang, Christine B Ambrosone, Stefan Ambs, Yu Chen, Patrick Concannon, Montserrat Garcia-Closas, Jian Gu, Christopher A Haiman, Jennifer J Hu, Dezheng Huo, Esther M John, Julia A Knight, Christopher I Li, Charles F Lynch, Lene Mellemkjær, Katherine L Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Andrew F Olshan, Tuya Pal, Julie R Palmer, Michael F Press, Maureen Sanderson, Dale P Sandler, Melissa A Troester, Wei Zheng, Jonine L Bernstein, Matthew F Buas, Xiang Shu

Faculty, Staff and Student Publications

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead …

Why Do Patients With Cancer Die?, Adrienne Boire, Katy Burke, Thomas R Cox, Theresa Guise, Mariam Jamal-Hanjani, Tobias Janowitz, Rosandra Kaplan, Rebecca Lee, Charles Swanton, Matthew G Vander Heiden, Erik Sahai

Faculty, Staff and Student Publications

Cancer is a major cause of global mortality, both in affluent countries and increasingly in developing nations. Many patients with cancer experience reduced life expectancy and have metastatic disease at the time of death. However, the more precise causes of mortality and patient deterioration before death remain poorly understood. This scarcity of information, particularly the lack of mechanistic insights, presents a challenge for the development of novel treatment strategies to improve the quality of, and potentially extend, life for patients with late-stage cancer. In addition, earlier deployment of existing strategies to prolong quality of life is highly desirable. In this …

Survival And Treatment Outcomes In Patients With Leptomeningeal Disease From Metastatic Melanoma, Chantal Saberian, Denái R Milton, Julie Simon, Rodabe N Amaria, Adi Diab, Jennifer Mcquade, Sapna P Patel, Hussein Tawbi, Cassian Yee, Michael K Wong, Ian E Mccutcheon, Michael A Davies, Sherise D Ferguson, Isabella C Glitza Oliva

Faculty, Staff and Student Publications

Background: Melanoma leptomeningeal disease (LMD) has a poor prognosis. However, the management of patients with advanced melanoma has evolved with time, including those with LMD. We reviewed a large cohort of melanoma LMD patients to assess factors associated with survival.

Methods: Retrospective clinical data was collected on patients diagnosed with LMD at MD Anderson Cancer Center from 2015 to 2020. Overall survival (OS) was determined from LMD diagnosis to date of death or last follow-up. The Kaplan-Meier method and log-rank test were used to estimate OS and to assess univariate group differences, respectively. Multivariable associations of survival with variables of …

A Rare Case Of Fabry's Disease-Induced Cardiomyopathy: A Case Report And Review Of The Literature, Ahmed Hussein, Aya Salih, Yousif Mohamed, Emma Thames, L Maximilian Buja

Faculty, Staff and Student Publications

Fabry's disease, also known as Anderson-Fabry Disease (AFD), is caused by mutations in the α galactosidase A (α GalA) gene found on the X chromosome. This condition results in an accumulation of sphingolipids, including globotriaosylceramide (Gb3), in cells throughout the body. The main effects of Fabry disease typically involve heart, kidney, and nervous system complications. A common cardiac dysfunction is left ventricular hypertrophy. In this case study, we share findings about cardiomyopathy resulting from Fabry disease to explain how this condition impacts the heart and the importance of a biopsy in making a diagnosis. A 57-year-old woman with end-stage renal …

T-Bet Suppresses Proliferation Of Malignant B Cells In Chronic Lymphocytic Leukemia, Philipp M Roessner, Isabelle Seufert, Vicente Chapaprieta, Ruparoshni Jayabalan, Hannah Briesch, Ramon Massoni-Badosa, Pavle Boskovic, Julian Benckendorff, Tobias Roider, Lavinia Arseni, Mariana Coelho, Supriya Chakraborty, Alicia M Vaca, Mariela Sivina, Markus Muckenhuber, Sonia Rodriguez-Rodriguez, Alice Bonato, Sophie A Herbst, Marc Zapatka, Clare Sun, Helene Kretzmer, Thomas Naake, Peter-Martin Bruch, Felix Czernilofsky, Elisa Ten Hacken, Martin Schneider, Dominic Helm, Deyan Y Yosifov, Joseph Kauer, Alexey V Danilov, Moritz Bewarder, Kristina Heyne, Christof Schneider, Stephan Stilgenbauer, Adrian Wiestner, Jan-Philipp Mallm, Jan A Burger, Dimitar G Efremov, Peter Lichter, Sascha Dietrich, José I Martin-Subero, Karsten Rippe, Martina Seiffert

Faculty, Staff and Student Publications

The T-box transcription factor T-bet is known as a master regulator of the T-cell response but its role in malignant B cells has not been sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with a genetic knockout of Tbx21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity, induced by inflammatory signals provided by the microenvironment, triggered T-bet expression, which affected promoter-proximal and distal chromatin coaccessibility and controlled a specific gene …

Leptomeningeal Carcinomatosis From Breast Cancer Initially Mimicking Cerebral Infarction On Mri, Nozomi Satani, Tomonori Matsuura, Satoru Yanagaki, Yojiro Ishikawa, Gou Watanabe, Hiroshi Fukuda, Takayuki Yamada

Faculty, Staff and Student Publications

A female patient in her early 50s with breast cancer underwent breast-conserving surgery, followed by radiation therapy. She developed multiple lung and bone metastases and was started on chemotherapy with bevacizumab and paclitaxel 3 years later. After 6 months of chemotherapy, she developed a decline in conversation and memory. Magnetic resonance imaging (MRI) was conducted and showed multiple cortical and subcortical lesions and nodules with restricted diffusion but with no contrast enhancement on gadolinium (Gd) enhanced T1-weighted image, raising a suspicion of Trousseau's syndrome. A follow-up MRI revealed unchanged signal intensity of the lesions but with minimal enlargement. The cerebrospinal …

Outcome Of 3q262/Mecom Rearrangements In Chronic Myeloid Leukemia, Hiroki Akiyama, Hagop Kantarjian, Elias Jabbour, Ghayas Issa, Fadi G Haddad, Nicholas J Short, Shimin Hu, Jo Ishizawa, Michael Andreeff, Koji Sasaki

Faculty, Staff and Student Publications

Study aims: To evaluate the outcomes of patients with 3q26.2/MECOM-rearranged chronic myeloid leukemia (CML).

Methods: We reviewed consecutive adult patients with 3q26.2/MECOM-rearranged CML between January 1, 1998 and February 16, 2023. Rearrangements of 3q26.2/MECOM were confirmed by conventional cytogenetics, and fluorescence in situ hybridization starting in 2015.

Results: We identified 55 patients with MECOM-rearranged CML, including 23 in chronic phase (CP) or accelerated phase (AP) and 32 in blast phase (BP). Nine patients (16%) achieved a major cytogenetic response (MCyR) or deeper. At a median follow-up of 89 months, median survival was 14 months. The 5-year survival rate was 19% …

Safety And Efficacy Of Percutaneous Image-Guided Ablation For Soft Tissue Sarcoma Metastases To The Liver, Ahmed Awad, Koustav Pal, Steven Yevich, Joshua D Kuban, Alda Tam, Bruno C Odisio, Sanjay Gupta, Peiman Habibollahi, Andrew J Bishop, Anthony Paul Conley, Neeta Somaiah, Dejka M Araujo, Maria Alejandra Zarzour, Ravin Ratan, Christina L Roland, Emily Z Keung, Steven Y Huang, Rahul A Sheth

Faculty, Staff and Student Publications

Purpose: To evaluate outcomes following percutaneous image-guided ablation of soft tissue sarcoma metastases to the liver.

Materials and methods: A single-institution retrospective analysis of patients with a diagnosis of metastatic soft tissue sarcoma who underwent percutaneous image-guided ablation of hepatic metastases between January 2011 and December 2021 was performed. Patients with less than 60 days of follow-up after ablation were excluded. The primary outcome was local tumor progression-free survival (LPFS). Secondary outcomes included overall survival, liver-specific progression-free survival. and chemotherapy-free survival.

Results: Fifty-five patients who underwent percutaneous ablation for 84 metastatic liver lesions were included. The most common histopathological subtypes …

Tumoral Interferon Beta Induces An Immune-Stimulatory Phenotype In Tumor-Associated Macrophages In Melanoma Brain Metastases, Julia Gellert, Dennis A Agardy, Swaminathan Kumar, Alexandros Kourtesakis, Tamara Boschert, Kristine Jähne, Michael O Breckwoldt, Lukas Bunse, Wolfgang Wick, Michael A Davies, Michael Platten, Theresa Bunse

Faculty, Staff and Student Publications

Type I interferons (IFN) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies such as radiotherapy by activating both innate and adaptive immune cells. Macrophages are one of the most abundant innate immune cells in the immune microenvironment of melanoma brain metastases (MBM) and can exert potent immune-suppressive functions. Here, we investigate the potential of tumoral type I IFNs to repolarize tumor-associated macrophages (TAM) in two murine MBM models and assess the effects of radiotherapy-induced type I IFN on TAMs in a transcriptomic MBM patient dataset. In mice, we describe a …

Auto-Segmentation Of Adult-Type Diffuse Gliomas: Comparison Of Transfer Learning-Based Convolutional Neural Network Model Vs Radiologists, Qi Wan, Jisoo Kim, Clifford Lindsay, Xin Chen, Jing Li, J Bryan Iorgulescu, Raymond Y Huang, Chenxi Zhang, David Reardon, Geoffrey S Young, Lei Qin

Faculty, Staff and Student Publications

Segmentation of glioma is crucial for quantitative brain tumor assessment, to guide therapeutic research and clinical management, but very time-consuming. Fully automated tools for the segmentation of multi-sequence MRI are needed. We developed and pretrained a deep learning (DL) model using publicly available datasets A (n = 210) and B (n = 369) containing FLAIR, T2WI, and contrast-enhanced (CE)-T1WI. This was then fine-tuned with our institutional dataset (n = 197) containing ADC, T2WI, and CE-T1WI, manually annotated by radiologists, and split into training (n = 100) and testing (n = 97) sets. The Dice similarity coefficient (DSC) was used to …

Grace Periods In Comparative Effectiveness Studies Of Sustained Treatments, Kerollos Nashat Wanis, Aaron L Sarvet, Lan Wen, Jason P Block, Sheryl L Rifas-Shiman, James M Robins, Jessica G Young

Faculty, Staff and Student Publications

Researchers are often interested in estimating the effect of sustained use of a treatment on a health outcome. However, adherence to strict treatment protocols can be challenging for individuals in practice and, when non-adherence is expected, estimates of the effect of sustained use may not be useful for decision making. As an alternative, more relaxed treatment protocols which allow for periods of time off treatment (i.e. grace periods) have been considered in pragmatic randomized trials and observational studies. In this article, we consider the interpretation, identification, and estimation of treatment strategies which include grace periods. We contrast natural grace period …

Acute Myeloid Leukemia With Mast Cell Differentiation Is Characterized By Interstitial Mast Cells, Complex Karyotype, Do Hwan Kim, Sa A Wang, Wei Wang, Guilin Tang, Shaoying Li, C Cameron Yin, Pei Lin, Marina Konopleva, M James You, Roberto N Miranda, Xiaoqiong Wang, Qing Wei, L Jeffrey Medeiros, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.

T-Cell-Rich Hodgkin Lymphoma With Features Of Classic Hodgkin Lymphoma And Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Borderline Category With Overlapping Morphologic And Immunophenotypic Features, Siba El Hussein, Hong Fang, Fatima Zahra Jelloul, Wei Wang, Sanam Loghavi, Roberto N Miranda, Jonathan W Friedberg, W Richard Burack, Andrew G Evans, Jie Xu, L Jeffrey Medeiros

Faculty, Staff and Student Publications

Context.—: It is known that a subset of cases of classic Hodgkin lymphoma (CHL) with B-cell-rich nodules (lymphocyte-rich CHL) exhibits morphologic and immunophenotypic features that overlap with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), raising diagnostic difficulties that can be resolved in most cases by performing an adequate battery of immunohistochemical studies.

Objective.—: To fully characterize cases of T-cell-rich Hodgkin lymphoma where a specific diagnosis of NLPHL (ie, pattern D) or CHL could not be made even after complete immunophenotypic investigation.

Design.—: The clinical, immunomorphologic, and molecular (when applicable) presentation of 3 cases of T-cell-rich Hodgkin lymphoma was thoroughly investigated.

Results.—: These …

A Joint Estro And Aapm Guideline For Development, Clinical Validation And Reporting Of Artificial Intelligence Models In Radiation Therapy, Coen Hurkmans, Jean-Emmanuel Bibault, Kristy K Brock, Wouter Van Elmpt, Mary Feng, Clifton David Fuller, Barbara A Jereczek-Fossa, Stine Korreman, Guillaume Landry, Frederic Madesta, Chuck Mayo, Alan Mcwilliam, Filipe Moura, Ludvig P Muren, Issam El Naqa, Jan Seuntjens, Vincenzo Valentini, Michael Velec

Faculty, Staff and Student Publications

Background and purpose: Artificial Intelligence (AI) models in radiation therapy are being developed with increasing pace. Despite this, the radiation therapy community has not widely adopted these models in clinical practice. A cohesive guideline on how to develop, report and clinically validate AI algorithms might help bridge this gap.

Methods and materials: A Delphi process with all co-authors was followed to determine which topics should be addressed in this comprehensive guideline. Separate sections of the guideline, including Statements, were written by subgroups of the authors and discussed with the whole group at several meetings. Statements were formulated and scored as …

Disparities In Exposure To Tobacco On Television Or Streaming Platforms, Henry K Onyeaka, Onyema G Chido-Amajuoyi, Itunu Sokale, Kobi V Ajayi, A Eden Evins, Hermioni L Amonoo, Sanjay Shete

Faculty, Staff and Student Publications

Importance: With the rise in popularity of streaming platforms concerns about exposure to tobacco advertising and promotion have emerged. While tobacco marketing and promotion through traditional television (TV) media channels has been extensively studied, less is known about exposure to tobacco through TV or streaming platforms and its associated factors.

Objective: To examine the prevalence and factors associated with exposure to tobacco products advertised, marketed, or promoted on TV or streaming platforms among US adults.

Design, setting, and participants: This cross-sectional study used data from the National Cancer Institute's Health Information National Trends Survey (HINTS 6), conducted from March 7 …

Smyd5 Methylation Of Rpl40 Links Ribosomal Output To Gastric Cancer, Juhyung Park, Jibo Wu, Krzysztof J Szkop, Jinho Jeong, Predrag Jovanovic, Dylan Husmann, Natasha M Flores, Joel W Francis, Ying-Jiun C Chen, Ana Morales Benitez, Emily Zahn, Shumei Song, Jaffer A Ajani, Linghua Wang, Kamini Singh, Ola Larsson, Benjamin A Garcia, Ivan Topisirovic, Or Gozani, Pawel K Mazur

Faculty, Staff and Student Publications

Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis1,2. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites. A biochemical-proteomics strategy identifies the monoubiquitin fusion protein partner rpL40 (ref. 3) as the principal physiological substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprogrammes …

Benchmarking Lung Cancer Screening Programmes With Adaptive Screening Frequency Against The Optimal Screening Schedules Derived From The Engage Framework: A Comparative Microsimulation Study, Mehdi Hemmati, Sayaka Ishizawa, Rafael Meza, Edwin Ostrin, Samir M Hanash, Mara Antonoff, Andrew J Schaefer, Martin C Tammemägi, Iakovos Toumazis

Faculty, Staff and Student Publications

Background: Lung cancer screening recommendations employ annual frequency for eligible individuals, despite evidence that it may not be universally optimal. The impact of imposing a structure on the screening frequency remains unknown. The ENGAGE framework, a validated framework that offers fully dynamic, analytically optimal, personalised lung cancer screening recommendations, could be used to assess the impact of screening structure on the effectiveness and efficiency of lung cancer screening.

Methods: In this comparative microsimulation study, we benchmarked alternative clinically relevant structured lung cancer screening programmes employing a fixed (annual or biennial) or adaptive (start with annual/biennial screening and then switch to …

Accelerated Tumor Progression After Covid-19 Infection In Patients With Glioblastoma: A Retrospective Case-Control Study, Timothy A Gregory, Stephanie R Knight, Ashley E Aaroe, Kaitlin N Highsmith, Zachary C Janatpour, Barbara J O'Brien, Nazanin K Majd, Monica E Loghin, Chirag B Patel, Shiao-Pei Weathers, Vinay K Puduvalli, Carlos Kamiya-Matsuoka

Faculty, Staff and Student Publications

Background: We observed rapid tumor progression following COVID-19 infection among patients with glioblastoma and sought to systematically characterize their disease course in a retrospective case-control study.

Methods: Using an institutional database, we retrospectively identified a series of COVID-19-positive glioblastoma cases and matched them by age and sex 1:2 to glioblastoma controls who had a negative COVID-19 test during their disease course. Demographic and clinical data were analyzed. Hyperprogression was defined using modified response evaluation criteria in solid tumors criteria. Time to progression and overall survival were estimated using the Kaplan-Meier method.

Results: Thirty-two glioblastoma cases with positive COVID-19 testing were …

Variability In Performance Of Genetic-Enhanced Dxa-Bmd Prediction Models Across Diverse Ethnic And Geographic Populations: A Risk Prediction Study, Yong Liu, Xiang-He Meng, Chong Wu, Kuan-Jui Su, Anqi Liu, Qing Tian, Lan-Juan Zhao, Chuan Qiu, Zhe Luo, Martha I Gonzalez-Ramirez, Hui Shen, Hong-Mei Xiao, Hong-Wen Deng

Faculty, Staff and Student Publications

BACKGROUND: Osteoporosis is a major global health issue, weakening bones and increasing fracture risk. Dual-energy X-ray absorptiometry (DXA) is the standard for measuring bone mineral density (BMD) and diagnosing osteoporosis, but its costliness and complexity impede widespread screening adoption. Predictive modeling using genetic and clinical data offers a cost-effective alternative for assessing osteoporosis and fracture risk. This study aims to develop BMD prediction models using data from the UK Biobank (UKBB) and test their performance across different ethnic and geographical populations.

METHODS AND FINDINGS: We developed BMD prediction models for the femoral neck (FNK) and lumbar spine (SPN) using both …

Antitumor Activity Of A Novel Lair1 Antagonist In Combination With Anti-Pd1 To Treat Collagen-Rich Solid Tumors, Bertha L Rodriguez, Jiawei Huang, Laura Gibson, Jared J Fradette, Hung-I H Chen, Kikuye Koyano, Czrina Cortez, Betty Li, Carmence Ho, Amir M Ashique, Vicky Y Lin, Suzanne Crawley, Julie M Roda, Peirong Chen, Bin Fan, Jeong Kim, James Sissons, Jonathan Sitrin, Daniel D Kaplan, Don L Gibbons, Lee B Rivera

Faculty, Staff and Student Publications

We recently reported that resistance to PD-1 blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Thus, we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. In this study, we report that LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist mAb, elicits myeloid inflammation and allogeneic T-cell responses by binding …

The T2-Flair Mismatch Sign In Oncologic Neuroradiology: History, Current Use, Emerging Data, And Future Directions, Samir A Dagher, Riley Hideo Lochner, Burak Berksu Ozkara, Donald F Schomer, Max Wintermark, Gregory N Fuller, F Eymen Ucisik

Faculty, Staff and Student Publications

The T2-Fluid-Attenuated Inversion Recovery (T2-FLAIR) mismatch sign is a radiogenomic marker that is easily discernible on preoperative conventional MR imaging. Application of strict criteria (adult population, cerebral hemisphere location, and classic imaging morphology) permits the noninvasive preoperative diagnosis of isocitrate dehydrogenase (IDH)-mutant 1p/19q-non-codeleted diffuse astrocytoma with near-perfect specificity, albeit with variably low sensitivity. This leads to improved preoperative planning and patient counseling. More recent research has shown that the application of less strict criteria compromises the near-perfect specificity of the sign but remains adequate for ruling out IDH-wildtype (glioblastoma) phenotype, which bears a far grimmer prognosis compared to IDH-mutant diffuse …

De Novo Variants In The Rnu4-2 Snrna Cause A Frequent Neurodevelopmental Syndrome, Yuyang Chen, Ruebena Dawes, Hyung Chul Kim, Alicia Ljungdahl, Sarah L Stenton, Susan Walker, Jenny Lord, Gabrielle Lemire, Alexandra C Martin-Geary, Vijay S Ganesh, Jialan Ma, Jamie M Ellingford, Erwan Delage, Elston N D'Souza, Shan Dong, David R Adams, Kirsten Allan, Madhura Bakshi, Erin E Baldwin, Seth I Berger, Jonathan A Bernstein, Ishita Bhatnagar, Ed Blair, Natasha J Brown, Lindsay C Burrage, Kimberly Chapman, David J Coman, Alison G Compton, Chloe A Cunningham, Precilla D'Souza, Petr Danecek, Emmanuèle C Délot, Kerith-Rae Dias, Ellen R Elias, Frances Elmslie, Care-Anne Evans, Lisa Ewans, Kimberly Ezell, Jamie L Fraser, Lyndon Gallacher, Casie A Genetti, Anne Goriely, Christina L Grant, Tobias Haack, Jenny E Higgs, Anjali G Hinch, Matthew E Hurles, Alma Kuechler, Katherine L Lachlan, Seema R Lalani, François Lecoquierre, Elsa Leitão, Anna Le Fevre, Richard J Leventer, Jan E Liebelt, Sarah Lindsay, Paul J Lockhart, Alan S Ma, Ellen F Macnamara, Sahar Mansour, Taylor M Maurer, Hector R Mendez, Kay Metcalfe, Stephen B Montgomery, Mariya Moosajee, Marie-Cécile Nassogne, Serena Neumann, Michael O'Donoghue, Melanie O'Leary, Elizabeth E Palmer, Nikhil Pattani, John Phillips, Georgia Pitsava, Ryan Pysar, Heidi L Rehm, Chloe M Reuter, Nicole Revencu, Angelika Riess, Rocio Rius, Lance Rodan, Tony Roscioli, Jill A Rosenfeld, Rani Sachdev, Charles J Shaw-Smith, Cas Simons, Sanjay M Sisodiya, Penny Snell, Laura St Clair, Zornitza Stark, Helen S Stewart, Tiong Yang Tan, Natalie B Tan, Suzanna E L Temple, David R Thorburn, Cynthia J Tifft, Eloise Uebergang, Grace E Vannoy, Pradeep Vasudevan, Eric Vilain, David H Viskochil, Laura Wedd, Matthew T Wheeler, Susan M White, Monica Wojcik, Lynne A Wolfe, Zoe Wolfenson, Caroline F Wright, Changrui Xiao, David Zocche, John L Rubenstein, Eirene Markenscoff-Papadimitriou, Sebastian M Fica, Diana Baralle, Christel Depienne, Daniel G Macarthur, Joanna M M Howson, Stephan J Sanders, Anne O'Donnell-Luria, Nicola Whiffin

Faculty, Staff and Students Publications

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of …

Fetal Malrotation With Midgut Volvulus: Prenatal Diagnosis And Planning, Jai Sidpra, Sniya Sudhakar, Asthik Biswas, Flavia Massey, Valentina Turchetti, Tracy Lau, Edward Cook, Javeria Raza Alvi, Hasnaa M Elbendary, Jerry L Jewell, Antonella Riva, Alessandro Orsini, Aglaia Vignoli, Zara Federico, Jessica Rosenblum, An-Sofie Schoonjans, Matthias De Wachter, Ignacio Delgado Alvarez, Ana Felipe-Rucián, Nourelhoda A Haridy, Shahzad Haider, Mashaya Zaman, Selina Banu, Najwa Anwaar, Fatima Rahman, Shazia Maqbool, Rashmi Yadav, Vincenzo Salpietro, Reza Maroofian, Rajan Patel, Rupa Radhakrishnan, Sanjay P Prabhu, Klaske Lichtenbelt, Helen Stewart, Yoshiko Murakami, Ulrike Löbel, Felice D'Arco, Emma Wakeling, Wendy Jones, Eleanor Hay, Sanjay Bhate, Thomas S Jacques, David M Mirsky, Matthew T Whitehead, Maha S Zaki, Tipu Sultan, Pasquale Striano, Anna C Jansen, Maarten Lequin, Linda S De Vries, Mariasavina Severino, Andrew C Edmondson, Lara Menzies, Philippe M Campeau, Henry Houlden, Amy Mctague, Stephanie Efthymiou, Kshitij Mankad

Faculty, Staff and Students Publications

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or …

Structure Of Adenylyl Cyclase 5 In Complex With Gβγ Offers Insights Into Adcy5-Related Dyskinesia, Yu-Chen Yen, Yong Li, Chun-Liang Chen, Thomas Klose, Val J Watts, Carmen W Dessauer, John J G Tesmer

Faculty, Staff and Student Publications

The nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein, Gαs, but their response to Gβγ regulation is isoform specific. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with Gβγ and a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C1b) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based …

Impact Of Pretreatment Body Mass Index On The Survival Of Head And Neck Cancer Patients, Zheng Yang, Jobran Mansour, Peng Sun, Peng Wei, Kristina R Dahlstrom, Mark Zafereo, Guojun Li, Neil D Gross

Faculty, Staff and Student Publications

Background: Differences in pretreatment body mass index (BMI) have been associated with survival in squamous cell carcinoma of head and neck (SCCHN). We examined effects of BMI on survival in SCCHN patients after stratifying patients by tumor human papillomavirus (HPV) status and subsite.

Methods: Totally 2204 SCCHN patients in a prospective study were included in this secondary analysis. Multivariable Cox models were used to evaluate associations between pretreatment BMI and overall survival, disease-specific survival, and disease-free survival.

Results: BMI was significantly higher among patients with HPV-positive tumors than HPV-negative tumors. BMI >25 kg/m2 was associated with improved survival, while BMI …

The Role Of The Cerebellum In Learning To Predict Reward: Evidence From Cerebellar Ataxia, Jonathan Nicholas, Christian Amlang, Chi-Ying R Lin, Leila Montaser-Kouhsari, Natasha Desai, Ming-Kai Pan, Sheng-Han Kuo, Daphna Shohamy

Faculty, Staff and Students Publications

Recent findings in animals have challenged the traditional view of the cerebellum solely as the site of motor control, suggesting that the cerebellum may also be important for learning to predict reward from trial-and-error feedback. Yet, evidence for the role of the cerebellum in reward learning in humans is lacking. Moreover, open questions remain about which specific aspects of reward learning the cerebellum may contribute to. Here we address this gap through an investigation of multiple forms of reward learning in individuals with cerebellum dysfunction, represented by cerebellar ataxia cases. Nineteen participants with cerebellar ataxia and 57 age- and sex-matched …