Medical Specialties Commons^™

Structural Insights Into The Molecular Mechanism Of High-Level Ceftazidime-Avibactam Resistance Conferred By Cmy-185, Akito Kawai, William C Shropshire, Masahiro Suzuki, Jovan Borjan, Samuel L Aitken, William C Bachman, Christi L Mcelheny, Micah M Bhatti, Ryan K Shields, Samuel A Shelburne, Yohei Doi

Faculty, Staff and Student Publications

β-Lactamases can accumulate stepwise mutations that increase their resistance profiles to the latest β-lactam agents. CMY-185 is a CMY-2-like β-lactamase and was identified in an Escherichia coli clinical strain isolated from a patient who underwent treatment with ceftazidime-avibactam. CMY-185, possessing four amino acid substitutions of A114E, Q120K, V211S, and N346Y relative to CMY-2, confers high-level ceftazidime-avibactam resistance, and accumulation of the substitutions incrementally enhances the level of resistance to this agent. However, the functional role of each substitution and their interplay in enabling ceftazidime-avibactam resistance remains unknown. Through biochemical and structural analysis, we present the molecular basis for the enhanced …

Drug Resistance Assessed In A Phase 3 Clinical Trial Of Maribavir Therapy For Refractory Or Resistant Cytomegalovirus Infection In Transplant Recipients, Sunwen Chou, Sophie Alain, Carlos Cervera, Roy F Chemaly, Camille N Kotton, Jens Lundgren, Genovefa A Papanicolaou, Marcus R Pereira, Jingyang J Wu, Rose Ann Murray, Neil E Buss, Martha Fournier

Faculty, Staff and Student Publications

Background: This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56% and 24%, respectively, cleared cytomegalovirus DNA at week 8 (treatment responders).

Methods: Baseline and posttreatment plasma samples were tested for mutations conferring drug resistance in viral genes UL97, UL54, and UL27.

Results: At baseline, genotypic testing revealed resistance to ganciclovir, foscarnet, or cidofovir in 56% of patients receiving maribavir and 68% receiving IAT, including 9 newly phenotyped mutations. Among them, 63% (maribavir) and 21% (IAT) were treatment responders. Detected baseline maribavir resistance mutations were UL27 L193F (n …

Multifaceted Roles For Stat3 In Gammaherpesvirus Latency Revealed Through In Vivo B Cell Knockout Models, Chad H Hogan, Shana M Owens, Glennys V Reynoso, Yifei Liao, Thomas J Meyer, Monika A Zelazowska, Bin Liu, Xiaofan Li, Anna K Grosskopf, Camille Khairallah, Varvara Kirillov, Nancy C Reich, Brian S Sheridan, Kevin M Mcbride, Benjamin E Gewurz, Heather D Hickman, J Craig Forrest, Laurie T Krug

Faculty, Staff and Student Publications

Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor signal transducer and activator of transcription 3 (STAT3). To better understand the role of STAT3 during gammaherpesvirus latency and the B cell response to infection, we used the model pathogen murine gammaherpesvirus 68 (MHV68). Genetic deletion of STAT3 in B cells of CD19cre/+Stat3f/f mice reduced peak MHV68 latency approximately sevenfold. However, infected CD19cre/+Stat3f/f mice exhibited disordered germinal centers and heightened virus-specific CD8 T cell responses compared to wild-type (WT) littermates. To circumvent the systemic immune alterations observed in …

Synergic Effect Of Cai2 And Lii On Ionic Conductivity Of Solution-Based Synthesized Li7p3s11 Solid Electrolyte†, Tran Anh Tu, Tran Viet Toan, Luu Tuan Anh, Le Van Thang, Nguyen Huu Huy Phuc

Faculty, Staff and Student Publications

Li7P3S11 doped with CaX2 (X = Cl, Br, I) and LiI solid electrolytes were successfully prepared by liquid-phase synthesis using acetonitrile as the reaction medium. Their structure was investigated using XRD, Raman spectroscopy and SEM-EDS. The data obtained from complex impedance spectroscopy was analyzed to study the ionic conductivity and relaxation dynamics in the prepared samples. The XRD results suggested that a part of CaX2 and LiI incorporated into the structure of Li7P3S11, while the remaining part existed at the grain boundary of the Li7P3S11 particle. The Raman peak positions of PS43- and P2S74- ions in samples 90Li7P3S11-5CaI2 and 90Li7P3S11-5CaI2-5LiI …

Sugar-Binding And Split Domain Combinations In Repeats-In-Toxin Adhesins From Vibrio Cholerae And Aeromonas Veronii Mediate Cell-Surface Recognition And Hemolytic Activities, Mustafa Sherik, Robert Eves, Shuaiqi Guo, Cameron J Lloyd, Karl E Klose, Peter L Davies

Faculty, Staff and Student Publications

Many pathogenic Gram-negative bacteria use repeats-in-toxin adhesins for colonization and biofilm formation. In the cholera agent Vibrio cholerae, flagellar-regulated hemagglutinin A (FrhA) enables these functions. Using bioinformatic analysis, a sugar-binding domain was identified in FrhA adjacent to a domain of unknown function. AlphaFold2 indicated the boundaries of both domains to be slightly shorter than previously predicted and assisted in the recognition of the unknown domain as a split immunoglobulin-like fold that can assist in projecting the sugar-binding domain toward its target. The AlphaFold2-predicted structure is in excellent agreement with the molecular envelope obtained from small-angle X-ray scattering analysis of …

The Il6/Jak/Stat3 Signaling Axis Is A Therapeutic Vulnerability In Smarcb1-Deficient Bladder Cancer, Chandra Sekhar Amara, Karthik Reddy Kami Reddy, Yang Yuntao, Yuen San Chan, Danthasinghe Waduge Badrajee Piyarathna, Lacey Elizabeth Dobrolecki, David J H Shih, Zhongcheng Shi, Jun Xu, Shixia Huang, Matthew J Ellis, Andrea B Apolo, Leomar Y Ballester, Jianjun Gao, Donna E Hansel, Yair Lotan, H Courtney Hodges, Seth P Lerner, Chad J Creighton, Arun Sreekumar, W Jim Zheng, Pavlos Msaouel, Shyam M Kavuri, Nagireddy Putluri

Faculty, Staff and Student Publications

SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces …

Tumor- And Circulating-Free Dna Methylation Identifies Clinically Relevant Small Cell Lung Cancer Subtypes, Simon Heeke, Carl M Gay, Marcos R Estecio, Hai Tran, Benjamin B Morris, Bingnan Zhang, Ximing Tang, Maria Gabriela Raso, Pedro Rocha, Siqi Lai, Edurne Arriola, Paul Hofman, Veronique Hofman, Prasad Kopparapu, Christine M Lovly, Kyle Concannon, Luana Guimaraes De Sousa, Whitney Elisabeth Lewis, Kimie Kondo, Xin Hu, Azusa Tanimoto, Natalie I Vokes, Monique B Nilsson, Allison Stewart, Maarten Jansen, Ildikó Horváth, Mina Gaga, Vasileios Panagoulias, Yael Raviv, Danny Frumkin, Adam Wasserstrom, Aharona Shuali, Catherine A Schnabel, Yuanxin Xi, Lixia Diao, Qi Wang, Jianjun Zhang, Peter Van Loo, Jing Wang, Ignacio I Wistuba, Lauren A Byers, John V Heymach

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype …

Phase I Study Of Mtorc1/2 Inhibitor Sapanisertib (Cb-228/Tak-228) In Combination With Metformin In Patients With Mtor/Akt/Pi3k Pathway Alterations And Advanced Solid Malignancies, Vivek Subbiah, Niamh Coleman, Sarina A Piha-Paul, Apostolia M Tsimberidou, Filip Janku, Jordi Rodon, Shubham Pant, Ecaterina E Ileana Dumbrava, Siqing Fu, David S Hong, Shizhen Zhang, Ming Sun, Yunfang Jiang, Jason Roszik, Juhee Song, Ying Yuan, Funda Meric-Bernstam, Aung Naing

Faculty, Staff and Student Publications

BACKGROUND: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of 5'-AMP-activated protein kinase (AMPK) suggesting combination therapy may enhance antitumor activity of sapanisertib. We report preliminary safety, tolerability, and efficacy from the dose-escalation study of sapanisertib in combination with metformin in patients with advanced solid tumors.

METHODS: Patients with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without mTOR/AKT/PI3K pathway alterations, received sapanisertib 3 or 4 mg daily together with metformin once to three times daily (500-1,500 mg). All patients underwent 14-day …

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

Efficacy Of Supplemental Ultrasound-Guided Pericapsular Nerve Group (Peng) Block Combined With Lateral Femoral Cutaneous Nerve Block In Patients Receiving Local Infiltration Analgesia After Hip Fracture Surgery: A Prospective Randomized Controlled Trial, Seung-Hee Yoo, Min-Jin Lee, Min-Hyouk Beak, Won-Joong Kim

Faculty, Staff and Student Publications

No abstract provided.

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

Insights From The Histopathologic Analysis Of Acquired And Genetic Thoracic Aortic Aneurysms And Dissections, L Maximilian Buja, Bihong Zhao, Humaira Sadaf, Michelle Mcdonald, Ana M Segura, Li Li, Alana Cecchi, Siddharth K Prakash, Rana O Afifi, Charles C Miller, Anthony L Estrera, Dianna M Milewicz

Faculty, Staff and Student Publications

OBJECTIVE: The purpose of this study was to apply contemporary consensus criteria developed by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology to the evaluation of aortic pathology, with the expectation that the additional pathologic information may enhance the understanding and management of aortic diseases.

METHODS: A scoring system was applied to ascending aortic specimens from 42 patients with heritable thoracic aortic disease and known genetic variations and from 86 patients from a single year, including patients with known genetic variations (n = 12) and patients with sporadic disease (n = 74).

RESULTS: The various types …

Belzutifan, Hif-2Α Inhibitor, And Clear Cell Renal Cell Carcinoma With Somatic Von-Hippel-Lindau Loss-Of-Function Mutation, Kok Hoe Chan, Ningjing Li, Ran Lador, Mark Amsbaugh, Anneliese Gonzalez, Putao Cen

Faculty, Staff and Student Publications

The Von-Hippel-Lindau (VHL) gene, acting as a tumor suppressor, plays a crucial role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Approximately 90% of individuals with advanced ccRCC exhibit somatic mutations in the VHL gene. Belzutifan, orally administered small-molecule inhibitor of hypoxia-induced factor-2α, has demonstrated promising efficacy in solid tumors associated with germline loss-of-function mutations in VHL, including ccRCC. However, its impact on cases with somatic or sporadic VHL mutations remains unclear. Here, we present 2 cases where belzutifan monotherapy was employed in patients with advanced ccRCC and somatic loss-of-function mutations in VHL. Both patients exhibited a swift …

Optimizing Internet Of Things Fog Computing: Through Lyapunov-Based Long Short-Term Memory Particle Swarm Optimization Algorithm For Energy Consumption Optimization, Sheng Pan, Chenbin Huang, Jiajia Fan, Zheyan Shi, Junjie Tong, Hui Wang

Faculty, Staff and Student Publications

In the era of continuous development in Internet of Things (IoT) technology, smart services are penetrating various facets of societal life, leading to a growing demand for interconnected devices. Many contemporary devices are no longer mere data producers but also consumers of data. As a result, massive amounts of data are transmitted to the cloud, but the latency generated in edge-to-cloud communication is unacceptable for many tasks. In response to this, this paper introduces a novel contribution-a layered computing network built on the principles of fog computing, accompanied by a newly devised algorithm designed to optimize user tasks and allocate …

Thsd1 Suppresses Autophagy-Mediated Focal Adhesion Turnover By Modulating The Fak-Beclin 1 Pathway, Zhen Xu, Jiayi Lu, Song Gao, Yan-Ning Rui

Faculty, Staff and Student Publications

Focal adhesions (FAs) play a crucial role in cell spreading and adhesion, and their autophagic degradation is an emerging area of interest. This study investigates the role of Thrombospondin Type 1 Domain-Containing Protein 1 (THSD1) in regulating autophagy and FA stability in brain endothelial cells, shedding light on its potential implications for cerebrovascular diseases. Our research reveals a physical interaction between THSD1 and FAs. Depletion of THSD1 significantly reduces FA numbers, impairing cell spreading and adhesion. The loss of THSD1 also induces autophagy independently of changes in mTOR and AMPK activation, implying that THSD1 primarily governs FA dynamics rather than …

Factors Associated With Early Mortality In Acute Type A Aortic Dissection—A Single-Centre Experience, Panagiotis Doukas, Nicola Dalibor, András Keszei, Jelle Frankort, Julia Krabbe, Rachad Zayat, Michael J Jacobs, Alexander Gombert, Payam Akhyari, Arash Mehdiani

Faculty, Staff and Student Publications

BACKGROUND: Acute aortic dissection type A (AADA) is a surgical emergency with relevant mortality and morbidity despite improvements in current management protocols. Identifying patients at risk of a fatal outcome and controlling the factors associated with mortality remain of paramount importance.

METHODS: In this retrospective observational study, we reviewed the medical records of 117 patients with AADA, who were referred to our centre and operated on between 2005 and 2021. Preoperative, intraoperative, and postoperative variables were analysed and tested for their correlation with in-hospital mortality.

RESULTS: The overall survival rate was 83%. Preoperatively, factors associated with mortality were age ( …

Sox On Tumors, A Comfort Or A Constraint?, Junqing Jiang, Yufei Wang, Mengyu Sun, Xiangyuan Luo, Zerui Zhang, Yijun Wang, Siwen Li, Dian Hu, Jiaqian Zhang, Zhangfan Wu, Xiaoping Chen, Bixiang Zhang, Xiao Xu, Shuai Wang, Shengjun Xu, Wenjie Huang, Limin Xia

Faculty, Staff and Student Publications

The sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family, composed of 20 transcription factors, is a conserved family with a highly homologous HMG domain. Due to their crucial role in determining cell fate, the dysregulation of SOX family members is closely associated with tumorigenesis, including tumor invasion, metastasis, proliferation, apoptosis, epithelial-mesenchymal transition, stemness and drug resistance. Despite considerable research to investigate the mechanisms and functions of the SOX family, confusion remains regarding aspects such as the role of the SOX family in tumor immune microenvironment (TIME) and contradictory impacts the SOX family exerts on tumors. This review summarizes …

Functional Epas1/ Hif2a Missense Variant Is Associated With Hematocrit In Andean Highlanders, Elijah S Lawrence, Wanjun Gu, Ryan J Bohlender, Cecilia Anza-Ramirez, Amy M Cole, James J Yu, Hao Hu, Erica C Heinrich, Katie A O'Brien, Carlos A Vasquez, Quinn T Cowan, Patrick T Bruck, Kysha Mercader, Mona Alotaibi, Tao Long, James E Hall, Esteban A Moya, Marco A Bauk, Jennifer J Reeves, Mitchell C Kong, Rany M Salem, Gustavo Vizcardo-Galindo, Jose-Luis Macarlupu, Rómulo Figueroa-Mujíca, Daniela Bermudez, Noemi Corante, Eduardo Gaio, Keolu P Fox, Veikko Salomaa, Aki S Havulinna, Andrew J Murray, Atul Malhotra, Frank L Powel, Mohit Jain, Alexis C Komor, Gianpiero L Cavalleri, Chad D Huff, Francisco C Villafuerte, Tatum S Simonson

Faculty, Staff and Student Publications

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations …

Comprehensive Landscape Of Braf Variant Classes, Clonalities, And Co-Mutations In Metastatic Colorectal Cancer Using Ctdna Profiling, Benny Johnson, Van Morris, Xuemei Wang, Arvind Dasari, Kanwal Raghav, John Paul Shen, Michael S Lee, Ryan Huey, Christine Parseghian, Jason Willis, Robert Wolff, Leylah M Drusbosky, Michael J Overman, Scott Kopetz

Faculty, Staff and Student Publications

Although V600E accounts for the majority of the BRAF mutations in metastatic colorectal cancer (mCRC), non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile of BRAF variants in mCRC using a large genomic database of circulating tumor DNA (ctDNA) and analyzing clinical outcomes in a cohort of patients with atypical (non-V600) BRAF variants (aBRAF; class II, class III, unclassified). Overall, 1733 out of 14,742 mCRC patients in the ctDNA cohort had at least one BRAF variant. Patients with atypical BRAF variants tended to be younger and …

Risk Factors For Non-Healing Wounds—A Single-Centre Study, Daniel Wolny, Ladislav Štěpánek, Dagmar Horáková, Janet Thomas, Jana Zapletalová, Mihir Sanjay Patel

Faculty, Staff and Student Publications

Background: Chronic wounds present a significant clinical, social, and economic challenge. This study aimed to objectify the risk factors of healing outcomes and the duration of chronic wounds from various etiologies. Methods: Patients treated for non-healing wounds at the surgical outpatient clinic of the Olomouc Military Hospital were involved. Data from patients treated between 8/2021 and 9/2023 were selected. Patients were mostly treated as outpatients, with microbiological follow-up indicated in cases of advanced signs of inflammation. Results: There were 149 patients who met our selection criteria (the mean age was 64.4 years). Predominant causes of wounds involved diabetes (30.9%), post-trauma …

Prex1 Improves Homeostatic Proliferation To Maintain A Naive Cd4+ T Cell Compartment In Older Age, Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M Weyand, Jӧrg J Goronzy

Faculty, Staff and Student Publications

The human adult immune system maintains normal T cell counts and compensates for T cell loss throughout life, mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naive CD4+ T cell compartment into older age. Here, we describe that naive CD4+ T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 in older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic …

Impact Of An Integrated Health, Nutrition, And Early Child Stimulation And Responsive Care Intervention Package Delivered To Preterm Or Term Small For Gestational Age Babies During Infancy On Growth And Neurodevelopment: Study Protocol Of An Individually Randomized Controlled Trial In India (Small Babies Trial), Ranadip Chowdhury, Rukman Manapurath, Ingvild Fossgard Sandøy, Ravi Prakash Upadhyay, Neeta Dhabhai, Saijuddin Shaikh, Harish Chellani, Tarun Shankar Choudhary, Abhinav Jain, Jose Martines, Nita Bhandari, Tor A Strand, Sunita Taneja

Faculty, Staff and Student Publications

BACKGROUND: Preterm and term small for gestational age (SGA) babies are at high risk of experiencing malnutrition and impaired neurodevelopment. Standalone interventions have modest and sometimes inconsistent effects on growth and neurodevelopment in these babies. For greater impact, intervention may be needed in multiple domains-health, nutrition, and psychosocial care and support. Therefore, the combined effects of an integrated intervention package for preterm and term SGA on growth and neurodevelopment are worth investigating.

METHODS: An individually randomized controlled trial is being conducted in urban and peri-urban low to middle-socioeconomic neighborhoods in South Delhi, India. Infants are randomized (1:1) into two strata …

Three-Year Follow-Up Analysis Of Axicabtagene Ciloleucel In Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (Zuma-5), Sattva S Neelapu, Julio C Chavez, Alison R Sehgal, Narendranath Epperla, Matthew Ulrickson, Emmanuel Bachy, Pashna N Munshi, Carla Casulo, David G Maloney, Sven De Vos, Ran Reshef, Lori A Leslie, Olalekan O Oluwole, Ibrahim Yakoub-Agha, Rashmi Khanal, Joseph Rosenblatt, Ronald Korn, Weixin Peng, Christine Lui, Jacob Wulff, Rhine Shen, Soumya Poddar, A Scott Jung, Harry Miao, Sara Beygi, Caron A Jacobson

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR …

Neurovascular Complications Of Iatrogenic Fusarium Solani Meningitis, Nora Strong, Grant Meeks, Sunil A Sheth, Louise Mccullough, Julian A Villalba, Chunfeng Tan, Andrew Barreto, Audrey Wanger, Michelle Mcdonald, Peter Kan, Hashem Shaltoni, Jose Campo Maldonado, Victoria Parada, Ameer E Hassan, Sarah Reagan-Steiner, Tom Chiller, Jeremy A W Gold, Dallas J Smith, Luis Ostrosky-Zeichner

Faculty, Staff and Student Publications

A multinational outbreak of nosocomial fusarium meningitis occurred among immunocompetent patients who had undergone surgery with epidural anesthesia in Mexico. The pathogen involved had a high predilection for the brain stem and vertebrobasilar arterial system and was associated with high mortality from vessel injury. Effective treatment options remain limited; in vitro susceptibility testing of the organism suggested that it is resistant to all currently approved antifungal medications in the United States. To highlight the severe complications associated with fusarium infection acquired in this manner, we report data, clinical courses, and outcomes from 13 patients in the outbreak who presented with …

Evolving Therapies, Neurocognitive Outcomes, And Functional Independence In Adult Survivors Of Childhood Glioma, Chiara Papini, Sedigheh Mirzaei S, Mengqi Xing, Ingrid Tonning Olsson, Peter M K De Blank, Katharine R Lange, Ralph Salloum, Deokumar Srivastava, Wendy M Leisenring, Rebecca M Howell, Kevin C Oeffinger, Leslie L Robison, Gregory T Armstrong, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

Background: Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions to attainment of adult independence, remain unknown.

Methods: Adult survivors of childhood glioma diagnosed in 1970-1999 in the Childhood Cancer Survivor Study (n = 1284; median [minimum-maximum] 30 [18-51] years of age at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and chronic health conditions. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [with or without surgery], cranial radiation [with …

Targeting Dna2 Overcomes Metabolic Reprogramming In Multiple Myeloma, Natthakan Thongon, Feiyang Ma, Natalia Baran, Pamela Lockyer, Jintan Liu, Christopher Jackson, Ashley Rose, Ken Furudate, Bethany Wildeman, Matteo Marchesini, Valentina Marchica, Paola Storti, Giannalisa Todaro, Irene Ganan-Gomez, Vera Adema, Juan Jose Rodriguez-Sevilla, Yun Qing, Min Jin Ha, Rodrigo Fonseca, Caleb Stein, Caleb Class, Lin Tan, Sergio Attanasio, Guillermo Garcia-Manero, Nicola Giuliani, David Berrios Nolasco, Andrea Santoni, Claudio Cerchione, Carlos Bueso-Ramos, Marina Konopleva, Philip Lorenzi, Koichi Takahashi, Elisabet Manasanch, Gabriella Sammarelli, Rashmi Kanagal-Shamanna, Andrea Viale, Marta Chesi, Simona Colla

Faculty, Staff and Student Publications

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein …

Endovascular Thrombectomy Treatment Effect In Direct Vs Transferred Patients With Large Ischemic Strokes: A Prespecified Analysis Of The Select2 Trial, Amrou Sarraj, Michael D Hill, M Shazam Hussain, Michael G Abraham, Santiago Ortega-Gutierrez, Michael Chen, Scott E Kasner, Leonid Churilov, Deep K Pujara, Hannah Johns, Spiros Blackburn, Sophia Sundararajan, Yin C Hu, Nabeel A Herial, Ronald F Budzik, William J Hicks, Juan F Arenillas, Jenny P Tsai, Osman Kozak, Dennis J Cordato, Ricardo A Hanel, Teddy Y Wu, Pere Cardona Portela, Chirag D Gandhi, Fawaz Al-Mufti, Laith Maali, Daniel Gibson, Natalia Pérez De La Ossa, Joanna D Schaafsma, Jordi Blasco, Navdeep Sangha, Steven Warach, Timothy J Kleinig, Faris Shaker, Clark W Sitton, Thanh Nguyen, Johanna T Fifi, Pascal Jabbour, Anthony Furlan, Maarten G Lansberg, Georgios Tsivgoulis, Cathy Sila, Nicholas Bambakidis, Stephen Davis, Lawrence Wechsler, Greg W Albers, James C Grotta, Marc Ribo, Bruce C Campbell, Ameer E Hassan, Nirav Vora, Nathan W Manning, Andrew Cheung, Amin N Aghaebrahim, Andres J Paipa Merchán, Daniel Sahlein, Manuel Requena Ruiz, Lucas Elijovich, Adam Arthur, Faisal Al-Shaibi, Edgar A Samaniego, Kelsey R Duncan, Amanda Opaskar, Abhishek Ray, Wei Xiong, Jeffery Sunshine, Michael Degeorgia, Stavropoula Tjoumakaris, Vitor Mendes Pereira

Faculty, Staff and Student Publications

Importance: Patients with large ischemic core stroke have poor clinical outcomes and are frequently not considered for interfacility transfer for endovascular thrombectomy (EVT).

Objective: To assess EVT treatment effects in transferred vs directly presenting patients and to evaluate the association between transfer times and neuroimaging changes with EVT clinical outcomes.

Design, setting, and participants: This prespecified secondary analysis of the SELECT2 trial, which evaluated EVT vs medical management (MM) in patients with large ischemic stroke, evaluated adults aged 18 to 85 years with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) as …

Discovery And Clinical Proof-Of-Concept Of Rly-2608, A First-In-Class Mutant-Selective Allosteric Pi3kα Inhibitor That Decouples Antitumor Activity From Hyperinsulinemia, Andreas Varkaris, Ermira Pazolli, Hakan Gunaydin, Qi Wang, Levi Pierce, Alessandro A Boezio, Artemisa Bulku, Lucian Dipietro, Cary Fridrich, Adam Frost, Fabrizio Giordanetto, Erika P Hamilton, Katherine Harris, Michael Holliday, Tamieka L Hunter, Amanda Iskandar, Yongli Ji, Alexandre Larivée, Jonathan R Larochelle, André Lescarbeau, Fabien Llambi, Brenda Lormil, Mary M Mader, Brenton G Mar, Iain Martin, Thomas H Mclean, Klaus Michelsen, Yakov Pechersky, Erika Puente-Poushnejad, Kevin Raynor, Dipali Rogala, Ramin Samadani, Alison M Schram, Kelley Shortsleeves, Sweta Swaminathan, Shahein Tajmir, Gege Tan, Yong Tang, Roberto Valverde, Bryan Wehrenberg, Jeremy Wilbur, Bret R Williams, Hongtao Zeng, Hanmo Zhang, W Patrick Walters, Beni B Wolf, David E Shaw, Donald A Bergstrom, James Watters, James S Fraser, Pascal D Fortin, D Randal Kipp

Faculty, Staff and Student Publications

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor–positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor …

Assessment Of Human Leukocyte Antigen-Based Neoantigen Presentation To Determine Pan-Cancer Response To Immunotherapy, Jiefei Han, Yiting Dong, Xiuli Zhu, Alexandre Reuben, Jianjun Zhang, Jiachen Xu, Hua Bai, Jianchun Duan, Rui Wan, Jie Zhao, Jing Bai, Xuefeng Xia, Xin Yi, Chao Cheng, Jie Wang, Zhijie Wang

Faculty, Staff and Student Publications

Despite the central role of human leukocyte antigen class I (HLA-I) in tumor neoantigen presentation, quantitative determination of presentation capacity remains elusive. Based on a pooled pan-cancer genomic dataset of 885 patients treated with immune checkpoint inhibitors (ICIs), we developed a score integrating the binding affinity of neoantigens to HLA-I, as well as HLA-I allele divergence, termed the HLA tumor-Antigen Presentation Score (HAPS). Patients with a high HAPS were more likely to experience survival benefit following ICI treatment. Analysis of the tumor microenvironment indicated that the antigen presentation pathway was enriched in patients with a high HAPS. Finally, we built …

Benchmarking Signal Quality And Spatiotemporal Distribution Of Interictal Spikes In Prolonged Human Ieeg Recordings Using Cortec Wireless Brain Interchange, Amir Hossein Ayyoubi, Behrang Fazli Besheli, Michael M Quach, Jay R Gavvala, Alica M Goldman, Chandra Prakash Swamy, Eleonora Bartoli, Daniel J Curry, Sameer A Sheth, David J Francis, Nuri F Ince

Faculty, Staff and Student Publications

Neuromodulation through implantable pulse generators (IPGs) represents an important treatment approach for neurological disorders. While the field has observed the success of state-of-the-art interventions, such as deep brain stimulation (DBS) or responsive neurostimulation (RNS), implantable systems face various technical challenges, including the restriction of recording from a limited number of brain sites, power management, and limited external access to the assessed neural data in a continuous fashion. To the best of our knowledge, for the first time in this study, we investigated the feasibility of recording human intracranial EEG (iEEG) using a benchtop version of the Brain Interchange (BIC) unit …