Medical Specialties Commons^™

Efficacy And Safety Of Venetoclax Plus Azacitidine For Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes, Jacqueline S Garcia, Uwe Platzbecker, Olatoyosi Odenike, Shaun Fleming, Chun Yew Fong, Uma Borate, Meagan A Jacoby, Daniel Nowak, Maria R Baer, Pierre Peterlin, Brenda Chyla, Huipei Wang, Grace Ku, David Hoffman, Jalaja Potluri, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study investigated safety and efficacy of venetoclax, a selective B-cell lymphoma 2 inhibitor, at the recommended phase 2 dose (RP2D; 400 mg for 14 days per 28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days per 28-day cycle) for treatment-naive HR MDS. Safety was the primary outcome, and complete remission (CR) rate was the primary efficacy outcome. Secondary outcomes included rates of modified overall response (mOR), hematologic improvement (HI), overall survival (OS), and time to next treatment (TTNT). …

Efficacy And Safety Of Venetoclax Plus Azacitidine For Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes, Jacqueline S Garcia, Uwe Platzbecker, Olatoyosi Odenike, Shaun Fleming, Chun Yew Fong, Uma Borate, Meagan A Jacoby, Daniel Nowak, Maria R Baer, Pierre Peterlin, Brenda Chyla, Huipei Wang, Grace Ku, David Hoffman, Jalaja Potluri, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study investigated safety and efficacy of venetoclax, a selective B-cell lymphoma 2 inhibitor, at the recommended phase 2 dose (RP2D; 400 mg for 14 days per 28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days per 28-day cycle) for treatment-naive HR MDS. Safety was the primary outcome, and complete remission (CR) rate was the primary efficacy outcome. Secondary outcomes included rates of modified overall response (mOR), hematologic improvement (HI), overall survival (OS), and time to next treatment (TTNT). …

The Role Of Electrophysiologic Study In Device Selection For Leadless Atrial Pacing, Joshua R Hirsch, Jordan M Gales, Irakli Giorgberidze, Hamid Afshar

The Texas Heart Institute Journal

The AVEIR DR (Abbott Medical) was the first dual-chamber leadless pacing system approved by the US Food and Drug Administration. Many patients with sinus node dysfunction have physiologically normal atrioventricular conduction, so an atrial-only pacing system may be appropriate for them. Three patients with symptomatic sinus node dysfunction underwent device implantation with electrophysiologic study, including incremental atrial pacing until loss of 1:1 atrioventricular conduction (atrioventricular Wenckebach cycle length) and His-ventricular interval measurement. If the atrioventricular Wenckebach cycle length was no more than 400 milliseconds and the His-ventricular interval measurement was no more than 55 milliseconds, single-chamber atrial implantation was deemed …

The Dnase Trex1 Is A Substrate Of The Intramembrane Protease Spp With Implications For Disease Pathogenesis, Onur Kerem Tever, Torben Mentrup, Ivan Kingyue Chinn, Hitoshi Ishikuma, Regina Fluhrer, Marc Schmitz, Rebekka Wehner, Rayk Behrendt, Javier Chinen, Bernd Schröder

Faculty, Staff and Students Publications

Signal peptide peptidase (SPP) is an ER-resident aspartyl intramembrane protease cleaving proteins within type II-oriented transmembrane segments. Here, we identified the tail-anchored protein Three prime repair exonuclease 1 (TREX1) as a novel substrate of SPP. Based on its DNase activity, TREX1 removes cytosolic DNA acting as a negative regulator of the DNA-sensing cGAS/STING pathway. TREX1 loss-of-function variants cause Aicardi-Goutières syndrome (AGS), a type I interferonopathy. Cleavage of ER-bound TREX1 by SPP releases a cleavage product into the cytosol. Proteolysis depends on sequence determinants within the transmembrane segment and is modulated by different disease-associated TREX1 variants. The AGS-causing T303P variant greatly …

Advancing Drug Development In Myelodysplastic Syndromes, Alain Mina, Kathy L Mcgraw, Lea Cunningham, Nina Kim, Emily Y Jen, Katherine R Calvo, Lori A Ehrlich, Peter D Aplan, Guillermo Garcia-Manero, James M Foran, Jacqueline S Garcia, Amer M Zeidan, Amy E Dezern, Rami Komrokji, Mikkael A Sekeres, Bart Scott, Rena Buckstein, Sara Tinsley-Vance, Amit Verma, Tanya Wroblewski, Steven Pavletic, Kelly Norsworthy

Faculty, Staff and Student Publications

Myelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges …

Avasimibe Abolishes The Efficacy Of Fluvastatin For The Prevention Of Cancer In A Spontaneous Mouse Model Of Breast Cancer, Anjana Bhardwaj, Alexander Koh, Rhea Bhala, Janvi Sandhu, Zhenlin Ju, Leslie Faye Cando, Jing Wang, Isabelle Bedrosian

Faculty, Staff and Student Publications

The cholesterol biosynthesis pathway is upregulated during breast cancer development and progression. Inhibition of the aberrantly upregulated cholesterol pathway by statins reduces breast tumor incidence and burden by 50% in SV40 C3(1) TAg mice, a mouse model of triple negative breast cancer. We hypothesized that fluvastatin's preventive efficacy could be further enhanced by co-targeting the statin-induced restorative feedback pathways that tightly control the cholesterol pathway and are involved in resistance to statins. Acyl-coenzyme A: cholesterol acyltransferase (

Hematopoietic Cell Transplant Compared With Standard Care In Adolescents And Young Adults With Sickle Cell Disease, Mark C Walters, Mary Eapen, Yiwen Liu, Fuad El Rassi, Edmund K Waller, John E Levine, John J Strouse, Joseph H Antin, Suhag H Parikh, Nitya Bakshi, Carlton Dampier, Jennifer J Jaroscak, Shayla Bergmann, Trisha Wong, Vamsi Kota, Betty Pace, Lazaros J Lekakis, Premal Lulla, Robert S Nickel, Kimberly A Kasow, Uday Popat, Wally Smith, Lolie Yu, Nancy Difronzo, Nancy Geller, Naynesh Kamani, Elizabeth S Klings, Kathryn Hassell, Adam Mendizabal, Keith Sullivan, Donna Neuberg, Lakshmanan Krishnamurti

Faculty, Staff and Students Publications

Disease-modifying therapies are standard of care (SOC) for sickle cell disease (SCD), but hematopoietic cell transplantation (HCT) has curative potential. We compared outcomes prospectively through 2 years after biologic assignment to a donor or no donor (SOC) arm based on the availability of an HLA-matched sibling or unrelated donor (BMT CTN 1503). A donor search was commenced after eligibility confirmation. The primary end point was a comparison of survival between the treatment arms 2 years after biologic assignment. Power calculations required 60 participants in the donor arm and 140 in the no donor arm to determine if early transplant-related mortality …

Simvastatin And Rifaximin In Decompensated Cirrhosis: A Randomized Clinical Trial, Elisa Pose, César Jiménez, Giacomo Zaccherini, Daniela Campion, Salvatore Piano, Frank Erhard Uschner, Koos De Wit, Olivier Roux, Kohilan Gananandan, Wim Laleman, Cristina Solé, Sonia Alonso, Berta Cuyàs, Xavier Ariza, Adrià Juanola, Ann T Ma, Laura Napoleone, Jordi Gratacós-Ginès, Marta Tonon, Enrico Pompili, Jordi Sánchez-Delgado, Andrew S Allegretti, Manuel Morales-Ruiz, Marta Carol, Martina Pérez-Guasch, Núria Fabrellas, Judit Pich, Claudia Martell, María Joyera, Gemma Domenech, José Ríos, Ferrán Torres, Miquel Serra-Burriel, Rubén Hernáez, Elsa Solà, Isabel Graupera, Hugh Watson, Germán Soriano, Rafael Bañares, Rajeshwar P Mookerjee, Claire Francoz, Ulrich Beuers, Jonel Trebicka, Paolo Angeli, Carlo Alessandria, Paolo Caraceni, Víctor M Vargas, Juan G Abraldes, Patrick S Kamath, Pere Ginès

Faculty, Staff and Students Publications

Importance: There are no useful treatments to prevent the development of severe complications of liver cirrhosis. Simvastatin and rifaximin have shown beneficial effects in liver cirrhosis.

Objective: To assess whether simvastatin combined with rifaximin improves outcomes in patients with decompensated cirrhosis.

Design, setting, and participants: Double-blind, placebo-controlled, phase 3 trial conducted among patients with decompensated cirrhosis in 14 European hospitals between January 2019 and December 2022. The last date of follow-up was December 2022.

Interventions: Patients were randomly assigned to receive simvastatin, 20 mg/d, plus rifaximin, 1200 mg/d (n = 117), or identical-appearing placebo (n = 120) for 12 months …

Metabolic Signatures In Adipose Tissue Linking Lipophilic Persistent Organic Pollutant Mixtures To Blood Pressure Five Years After Bariatric Surgery Among Adolescents, Shudi Pan, Zhenjiang Li, Douglas I Walker, Brittney O Baumert, Hongxu Wang, Jesse A Goodrich, Sarah Rock, Thomas H Inge, Todd M Jenkins, Stephanie Sisley, Scott M Bartell, Stavra Xanthakos, Xiangping Lin, Brooklynn Mcneil, Anna R Robuck, Catherine E Mullins, Michele A La Merill, Erika Garcia, Max T Aung, Sandrah P Eckel, Rob Mcconnell, David V Conti, Justin R Ryder, Lida Chatzi

Faculty, Staff and Students Publications

Persistent organic pollutants (POPs) are lipophilic environmental contaminants accumulated in the adipose tissue. Weight loss interventions, such as bariatric surgery, can mobilize POPs from adipose tissue into the bloodstream. We hypothesized that this mobilization could contribute to increases in blood pressure among 57 adolescents with severe obesity undergoing bariatric surgery. POPs and metabolic features were measured from visceral adipose tissue collected during surgery using gas and liquid chromatography, coupled with high-resolution mass spectrometry. Blood pressure was assessed at baseline, 6 months, and 5 years post-surgery. We used quantile g-computation to estimate associations of POP mixtures with blood pressure changes. With …

Vdac2 And Bak Scarcity In Liver Mitochondria Enables Targeting Hepatocarcinoma While Sparing Hepatocytes, Shamim Naghdi, Piyush Mishra, Soumya S. Roy, David Weaver, Ludivine Walter, Erika Davies, Anil N. Antony, Xuena Lin, Gisela Moehren, Mark A. Feitelson, Christopher A. Reed, Tullia Lindsten, Craig B. Thompson, Hien T. Dang, Jan B. Hoek, Erik S. Knudsen, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins …

Improved Patient-Reported Outcomes With Post-Transplant Cyclophosphamide: A Quality-Of-Life Evaluation And 2-Year Outcomes Of Bmt Ctn 1703., Shernan G Holtan, Javier Bolaños-Meade, Monzr M Al Malki, Juan Wu, Carrie L Kitko, Ran Reshef, Andrew R Rezvani, Brian C Shaffer, Melhem M Solh, Janny M Yao, Lyndsey Runaas, Hany Elmariah, Karilyn T Larkin, Najla El Jurdi, Mahasweta Gooptu, Alison W Loren, Aric C Hall, Amin M Alousi, Omer Jamy, William Clark, Leslie Kean, Ami S Bhatt, Miguel-Angel Perales, Kristy Applegate, Yvonne Adeduni Efebera, Eric Leifer, Richard J Jones, Mary M Horowitz, Deborah Mattila, Wael Saber, Mehdi Hamadani, Michael J Martens

Oncology Articles

The BMT CTN 1703 phase III trial confirmed that graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) results in superior GVHD-free, relapse-free survival (GRFS) compared with Tac/methotrexate (MTX) prophylaxis. This companion study assesses the effect of these regimens on patient-reported outcomes (PROs). Using the Lee Chronic GVHD Symptom Score and PROMIS subscales (physical function, GI symptoms, social role satisfaction) as primary end points and hemorrhagic cystitis symptoms and Lee subscales as secondary end points, responses from English and Spanish speakers were analyzed at baseline and days 100, 180, and 365 after transplant. PRO scores …

A Phase I/Ii Trial Of Avelumab Combinations With Ivuxolimab, Utomilumab, And Radiation Therapy In Patients With Advanced Gastrointestinal Malignancies, Jibran Ahmed, Anne Knisely, Carlos Torrado, Bettzy Stephen, Yali Yang, Juhee Song, Anas Alshawa, Abdulrazzak Zarifa, Anuja Jhingran, Eugene J Koay, Van Karlyle Morris, Milind Javle, Robert A Wolff, Funda Meric-Bernstam, Shubham Pant, Jordi Rodon, Aung Naing

Faculty, Staff and Student Publications

Background: Checkpoint agonists utomilumab (4-1BB agonist) and ivuxolimab (OX40 agonist) enhance Teffector cell function. Preclinical studies suggest that combining these drugs with avelumab (anti-PD-L1 antibody) can potentially synergize this effect. In addition, tissue abscopal effects of radiation therapy may improve antigen presentation, complementing PD-L1 blockade. We conducted a single institution, open-label, multi-arm, non-randomized, phase 1/2 clinical trial of avelumab in combination with ivuxolimab, with or without utomilumab, and radiation therapy in patients with advanced solid tumors. Herein, we present a subgroup analysis in patients with gastrointestinal (GI) tumors (pancreatic, colon, gastric, and hepatocellular).

Methods: The primary objectives of this study …

Suppression Of Stress Granule Formation Is A Vulnerability Imposed By Mutant P53., Elizabeth A. Thoenen, Atul Ranjan, Alejandro Parrales, Shigeto Nishikawa, Dan A. Dixon, Sugako Oka, Tomoo Iwakuma

Manuscripts, Articles, Book Chapters and Other Papers

Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53^null) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 …

Incidence And Correlates Of High-Grade Chemotherapy-Induced Peripheral Neuropathy In Patients With Lung Cancer, Mitchell S Von Itzstein, Sawsan Rashdan, Suzanne E Dahlberg, David E Gerber, Alan B Sandler, Joan H Schiller, David H Johnson, Yating Wang, Zhuoxin Sun, Suresh S Ramalingam

Faculty, Staff and Student Publications

Background: High-grade chemotherapy-induced peripheral neuropathy (CIPN) represents a dreaded toxicity of cancer treatments. In some cases, it may limit activities of daily living and become permanent. Because many prior studies of CIPN were conducted in breast cancer populations, less is known about CIPN in men. We therefore determined the incidence and correlates of high-grade CIPN in a large cohort of patients with lung cancer.

Methods: We collected data from the ECOG-ACRIN E1594 (comparison of 4 chemotherapy regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) and E4599 (carboplatin-paclitaxel ± concurrent and maintenance bevacizumab) clinical trials. We identified cases with grade ≥3 CIPN. Multivariable logistic …

Prophylaxis, Clinical Management, And Monitoring Of Datopotamab Deruxtecan-Associated Oral Mucositis/Stomatitis, Funda Meric-Bernstam, Aditya Bardia, Paolo Bossi, Giampaolo Bianchini, Frances Gatlin, Rajesh V Lalla, Barbara Melosky, Naoki Niikura, Timothy A Yap, Sophie S Kim, Rachana Rajagopalan, Rick M Fairhurst, Stephanie L Graff, Hope S Rugo

Faculty, Staff and Student Publications

Oral mucositis/stomatitis (hereafter stomatitis) is a common dose-limiting toxicity seen with various classes of cancer treatment. Symptoms associated with stomatitis, primarily oral pain, may impact patient quality of life and may lead to dose delay and reduction or treatment discontinuation. Datopotamab deruxtecan (Dato-DXd) is a novel trophoblast cell surface antigen 2-directed antibody-drug conjugate undergoing clinical investigation in multiple solid tumor types. Stomatitis is among the most reported adverse events associated with Dato-DXd, with most cases being grades 1-2. This article reviews the incidence of stomatitis seen with Dato-DXd, including in the phase III pivotal studies TROPION-Lung01 and TROPION-Breast01 (in patients …

Meta-Analysis On Sex Differences In Mortality And Neurodevelopment In Congenital Heart Defects, Alyssa K Crain, Zhia N Lim, Chloe J Sarfatis, Magela Arias, Travis Holder, Alvaro G Moreira, Antonio F Corno, Tina O Findley

Faculty, Staff and Student Publications

Given the increasing survival rates among congenital heart disease (CHD) patients and the growing emphasis on their quality of life, there is a need to comprehensively assess the impact of surgical interventions on neurodevelopmental outcomes. With increasing awareness in sex-related disparities in CHD, there is a need to explore potential differences in surgical mortality and neurodevelopmental outcomes between male and female patients. In this systematic review, we adhered to PRISMA guidelines and PROSPERO registration (#CRD42021225610). Articles published from 2015 to 2021 were searched using MeSH descriptors in three major databases (MEDLINE Ovid, Elsevier Embase, and Cochrane Library). Study selection criteria …

Multi-Ancestry Transcriptome-Wide Association Studies Of Cognitive Function, White Matter Hyperintensity, And Alzheimer's Disease, Dima L Chaar, Zheng Li, Lulu Shang, Scott M Ratliff, Thomas H Mosley, Sharon L R Kardia, Wei Zhao, Xiang Zhou, Jennifer A Smith

Faculty, Staff and Student Publications

Genetic variants increase the risk of neurocognitive disorders in later life, including vascular dementia (VaD) and Alzheimer's disease (AD), but the precise relationships between genetic risk factors and underlying disease etiologies are not well understood. Transcriptome-wide association studies (TWASs) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWASs on VaD and AD have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European ancestry (EA) …

Gatad2b O-Glcnacylation Regulates Breast Cancer Stem-Like Potential And Drug Resistance, Giang Le Minh, Jessica Merzy, Emily Esquea, Nusaiba Ahmed, Riley Young, Ryan Sharp, Tejsi Dhameliya, Bernice Agana, Mi-Hye Lee, Jennifer Bethard, Susana Comte-Walters, Lauren Ball, Mauricio Reginato

Kimmel Cancer Center Faculty Papers

The growth of breast tumors is driven and controlled by a subpopulation of cancer cells resembling adult stem cells, which are called cancer stem-like cells (CSCs). In breast cancer, the function and maintenance of CSCs are influenced by protein O-GlcNAcylation and the enzyme responsible for this post-translational modification, O-GlcNAc transferase (OGT). However, the mechanism of CSCs regulation by OGT and O-GlcNAc cycling in breast cancer is still unclear. Analysis of the proteome and O-GlcNAcome, revealed GATAD2B, a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, as a substrate regulated by OGT. Reducing GATAD2B genetically impairs mammosphere formation, decreases expression …

Condensed Low-Dose Total Skin Electron Beam Therapy For Mycosis Fungoides: An Institutional Retrospective Review And Subgroup Analysis Of Patients With Large Cell Transformation, Louis Cappelli, Megan Cappelli, Nilanjan Haldar, Tiara Paul, Jenna Mandel, Tingting Zhan, Neda Nikbakht, Wenyin Shi

Department of Dermatology and Cutaneous Biology Faculty Papers

Low-dose total skin electron beam therapy (TSEBT) is an effective treatment option for mycosis fungoides (MF) with proven palliative effects and reduced toxicity. Presented is an institutional analysis of survival/response rate and quality of life for MF patients with subgroup analysis of those possessing pathologic large cell transformation (LCT). This is a single institutional retrospective review of patients with mycosis fungicides treated from 2014 to 2023 with low-dose TSEBT. All patients received 12 Gy in 6 fractions every other day with the modified Stanford technique, with boosts to shadowed sites between treatments, completed in 2 weeks. Outcomes evaluated included clinical …

Molecular Model Of Tfiih Recruitment To The Transcription-Coupled Repair Machinery, Tanmoy Paul, Chunli Yan, Jina Yu, Susan E Tsutakawa, John A Tainer, Dong Wang, Ivaylo Ivanov

Faculty, Staff and Student Publications

Transcription-coupled repair (TCR) is a vital nucleotide excision repair sub-pathway that removes DNA lesions from actively transcribed DNA strands. Binding of CSB to lesion-stalled RNA Polymerase II (Pol II) initiates TCR by triggering the recruitment of downstream repair factors. Yet it remains unknown how transcription factor IIH (TFIIH) is recruited to the intact TCR complex. Combining existing structural data with AlphaFold predictions, we build an integrative model of the initial TFIIH-bound TCR complex. We show how TFIIH can be first recruited in an open repair-inhibited conformation, which requires subsequent CAK module removal and conformational closure to process damaged DNA. In …

Predictors Of Perioperative Stroke In Patients With Ischemic-Type Moyamoya Disease Treated With Surgical Revascularization: A Retrospective Multicenter Study, Basel Musmar, Joanna M. Roy, Hammam Abdalrazeq, Elias Atallah, Kareem El Naamani, Ching-Jen Chen, Roland Jabre, Hassan Saad, Jonathan A. Grossberg, Adam A. Dmytriw, Aman B. Patel, Mirhojjat Khorasanizadeh, Christopher S. Ogilvy, Ajith J. Thomas, Andre Monteiro, Adnan Siddiqui, Gustavo M. Cortez, Ricardo A. Hanel, Guilherme Porto, Alejandro M. Spiotta, Anthony J. Piscopo, David M. Hasan, Mohammad Ghorbani, Joshua Weinberg, Shahid M. Nimjee, Kimon Bekelis, Mohamed M. Salem, Jan-Karl Burkhardt, Akli Zetchi, Charles Matouk, Brian M. Howard, Rosalind Lai, Rose Du, Rawad Abbas, Georgios S Sioutas, Abdelaziz Amllay, Alfredo Munoz, Nabeel A Herial, Stavropoula I Tjoumakaris, Michael Reid Gooch, Robert H Rosenwasser, Pascal Jabbour

Department of Neurosurgery Faculty Papers

INTRODUCTION: Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive stenosis or occlusion of the internal carotid arteries and the development of collateral moyamoya vessels. Surgical revascularization is commonly used to prevent future ischemic events in ischemic-type MMD, but there remains a high rate of stroke perioperatively. This study aims to analyze the predictive factors for perioperative stroke in patients with ischemic-type MMD undergoing surgical revascularization using a large multicenter database.

METHODS: We conducted a multicenter retrospective study in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. This study included patients with ischemic-type …

Consensus Recommendations For An Integrated Diagnostic Approach To Peripheral Nerve Sheath Tumors Arising In The Setting Of Neurofibromatosis Type 1, Calixto-Hope G Lucas, Andrea M Gross, Carlos G Romo, Carina A Dehner, Alexander J Lazar, Markku Miettinen, Melike Pekmezci, Martha Quezado, Fausto J Rodriguez, Anat Stemmer-Rachamimov, David Viskochil, Arie Perry

Faculty, Staff and Student Publications

Consensus recommendations published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation and enable appropriate intervention …

Immunotherapy-Related Neurotoxicity In The Central Nervous System Of Children With Cancer, Jiasen He, Jeremy Connors, Andrew Meador, Shuo Xu, Heather Meador, Hong Jiang, Juan Fueyo, Candelaria Gomez-Manzano, Gregory K Friedman, Wafik Zaky, Zsila Sadighi, John M Slopis, Ali H Ahmad

Faculty, Staff and Student Publications

Significant gaps remain in our understanding of immunotherapy-related neurotoxicity in pediatric patients, largely because much of our knowledge comes from studies in adults. Accurately identifying the adverse effects of immunotherapy in children is also challenging, owing to variations in terminology and grading systems. Moreover, the manifestation of immunotherapy-related neurotoxicity differs greatly across different diseases, various modalities, dosages, and delivery methods. Combining immunotherapy with other treatments might improve outcomes but introduces new complexities and potential for increased toxicities. Additionally, pediatric patients with intracranial malignancy have unique responses to immunotherapies and distinct neurotoxicity compared to those with extracranial malignancy. Consequently, we must …

Cryptic Kmt2a::Afdn Fusion Due To Afdn Insertion Into Kmt2a In A Patient With Acute Monoblastic Leukemia, Qing Wei, Gokce A Toruner, Beenu Thakral, Keyur P Patel, Naveen Pemmaraju, Sa A Wang, Rashmi Kanagal-Shamanna, Guilin Tang, Ghayas C Issa, Sanam Loghavi, L Jeffrey Medeiros, Courtney Dinardo

Faculty, Staff and Student Publications

Background: KMT2A rearrangements occur in ~10% of acute myeloid leukemia (AML) cases and are critical for classification, risk stratification, and use of targeted therapy. However, insertions involving the KMT2A gene can evade detection using chromosomal analysis and/or fluorescence in situ hybridization (FISH).

Methods: We present a case of a 22-year-old woman with acute monoblastic leukemia harboring a cryptic KMT2A::AFDN fusion identified by RNA sequencing. Initial FISH showed a 3' KMT2A deletion, while conventional karyotyping and the automated bioinformatic pipeline for optical genome mapping (OGM) did not identify the canonical translocation.

Results: To resolve these discrepancies, metaphase KMT2A FISH (break-apart fusion …

Cryptic Kmt2a::Afdn Fusion Due To Afdn Insertion Into Kmt2a In A Patient With Acute Monoblastic Leukemia, Qing Wei, Gokce A Toruner, Beenu Thakral, Keyur P Patel, Naveen Pemmaraju, Sa A Wang, Rashmi Kanagal-Shamanna, Guilin Tang, Ghayas C Issa, Sanam Loghavi, L Jeffrey Medeiros, Courtney Dinardo

Faculty, Staff and Student Publications

Background: KMT2A rearrangements occur in ~10% of acute myeloid leukemia (AML) cases and are critical for classification, risk stratification, and use of targeted therapy. However, insertions involving the KMT2A gene can evade detection using chromosomal analysis and/or fluorescence in situ hybridization (FISH).

Methods: We present a case of a 22-year-old woman with acute monoblastic leukemia harboring a cryptic KMT2A::AFDN fusion identified by RNA sequencing. Initial FISH showed a 3' KMT2A deletion, while conventional karyotyping and the automated bioinformatic pipeline for optical genome mapping (OGM) did not identify the canonical translocation.

Results: To resolve these discrepancies, metaphase KMT2A FISH (break-apart fusion …

Clinical And Genetic Markers Of Vascular Toxicity In Glioblastoma Patients: Insights From Nrg Oncology Rtog-0825, Joshua D Strauss, Mark R Gilbert, Minesh Mehta, Ang Li, Renke Zhou, Melissa L Bondy, Erik P Sulman, Ying Yuan, Yanhong Liu, Elizabeth Vera, Merideth M Wendland, Volker W Stieber, Vinay K Puduvalli, Serah Choi, Nina L Martinez, H Ian Robins, Grant K Hunter, Chi-Fan Lin, Vivian A Guedes, Melissa A Richard, Stephanie L Pugh, Terri S Armstrong, Michael E Scheurer

Faculty, Staff and Students Publications

Background: Glioblastoma (GBM) is an aggressive form of brain cancer in which treatment is associated with toxicities that can result in therapy discontinuation or death. This analysis investigated clinical and genetic markers of vascular toxicities in GBM patients during active treatment.

Methods: In total, 591 non-Hispanic White GBM patients with clinical data were included in the analysis from NRG RTOG-0825. Genome-wide association studies (GWAS) were performed from genotyped blood samples (N = 367) by occurrence of thrombosis or hypertension (grade ≥ 2). A clinical prediction model was produced for each vascular toxicity. Significant GWAS variants were then added to the …

Genome-Wide Prediction Of Dominant And Recessive Neurodevelopmental Disorder-Associated Genes, Ryan S Dhindsa, Blake A Weido, Justin S Dhindsa, Arya J Shetty, Chloe F Sands, Slavé Petrovski, Dimitrios Vitsios, Anthony W Zoghbi

Duncan NRI Faculty and Staff Publications

Despite great progress, thousands of neurodevelopmental disorder (NDD) risk genes remain to be discovered. We present a computational approach that accelerates NDD risk gene identification using machine learning. First, we demonstrate that models trained solely on single-cell RNA sequencing data can robustly predict genes implicated in autism spectrum disorder (ASD), developmental and epileptic encephalopathy (DEE), and developmental delay (DD). Notably, we find differences in gene expression patterns of genes with monoallelic and bi-allelic inheritance patterns in the developing human cortex. We then integrate expression data with 300 orthogonal features, including intolerance metrics, protein-protein interaction data, and others, in a semi-supervised …

Roles Of Mir-223 In Platelet Function And High On-Treatment Platelet Reactivity: A Brief Report And Review, Shayan Askari, Lawrence E. Goldfinger

Cardeza Foundation for Hematologic Research

BACKGROUND: Platelets are highly enriched in microRNAs (miRNAs), which are genomically encoded 19-25 nucleotide non-coding RNAs that target complementary mRNAs through total or near-total base pairing. MiR-223 is among the most abundant miRNAs in human and murine platelets, but despite ongoing investigations in recent years, miR-223 roles in platelet physiology and its putative roles in high on-treatment platelet reactivity (HTPR) remain controversial, as studies showed varying findings.

OBJECTIVES: In the current hybrid review/report, we aim to compare studies that investigated miR-223 in platelet function and HTPR. Additionally, we briefly report our own findings on murine miR-223-deficient platelets.

METHODS: We have …

Structure-Function Relationship Of Ash1l And Histone H3k36 And H3k4 Methylation, Kendra R Vann, Rajal Sharma, Chih-Chao Hsu, Maeva Devoucoux, Adam H Tencer, Lei Zeng, Kevin Lin, Li Zhu, Qin Li, Catherine Lachance, Ruben Rosas Ospina, Qiong Tong, Ka Lung Cheung, Shuai Yang, Soumi Biswas, Hongwen Xuan, Jovylyn Gatchalian, Lorena Alamillo, Jianlong Wang, Suk Min Jang, Brianna J Klein, Yue Lu, Patricia Ernst, Brian D Strahl, Scott B Rothbart, Martin J Walsh, Michael L Cleary, Jacques Côté, Xiaobing Shi, Ming-Ming Zhou, Tatiana G Kutateladze

Faculty, Staff and Student Publications

The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1LBD), a plant homeodomain (ASH1LPHD) finger, and a bromo-adjacent homology (ASH1LBAH) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1LPHD recognizes H3K4me2/3, whereas the neighboring ASH1LBD and ASH1LBAH have DNA binding activities. The DNA binding function of ASH1LBAH is a driving force for the association of ASH1L with the linker DNA in the …

Identification Of Genes Associated With Testicular Germ Cell Tumor Susceptibility Through A Transcriptome-Wide Association Study, Emilio Ugalde-Morales, Rona Wilf, John Pluta, Alexander Ploner, Mengyao Fan, Mohammad Damra, Katja K Aben, Lynn Anson-Cartwright, Chu Chen, Victoria K Cortessis, Siamak Daneshmand, Alberto Ferlin, Marija Gamulin, Jourik A Gietema, Anna Gonzalez-Niera, Tom Grotmol, Robert J Hamilton, Mark Harland, Trine B Haugen, Russ Hauser, Michelle A T Hildebrandt, Robert Karlsson, Lambertus A Kiemeney, Jung Kim, Davor Lessel, Ragnhild A Lothe, Chey Loveday, Stephen J Chanock, Katherine A Mcglynn, Coby Meijer, Kevin T Nead, Jeremie Nsengimana, Maja Popovic, Thorunn Rafnar, Lorenzo Richiardi, Maria S Rocca, Stephen M Schwartz, Rolf I Skotheim, Kari Stefansson, Douglas R Stewart, Clare Turnbull, David J Vaughn, Sofia B Winge, Tongzhang Zheng, Alvaro N Monteiro, Kristian Almstrup, Peter A Kanetsky, Katherine L Nathanson, Fredrik Wiklund, Testicular Cancer Consortium

Faculty, Staff and Student Publications

Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis …