Medical Genetics Commons^™

Metabolomic Profiling Reveals Brain Lipid Alterations In Pex7-Deficient Models Of Rhizomelic Chondrodysplasia Punctata, Riya Sankhe, Meredith I Williams, Wedad Fallatah, Laura Mackay, Mary Layne Brown, Pranjali Bhagwat, Sarah H Elsea, Nancy Braverman, Michael F Wangler

Duncan NRI Faculty and Staff Publications

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisomal disorder characterized by skeletal shortening, intellectual disability, seizures, cataracts, and reduced lifespans. RCDP1 is caused by biallelic loss-of-function variants in PEX7, which encodes a protein required for importing select enzymes into the peroxisome matrix, including those essential for ether lipid synthesis (e.g., plasmalogens) and the branched-chain fatty acid catabolism. Plasmalogen deficiency is a hallmark of RCDP1 and other peroxisomal disorders, including RCDP types 2-5 (RCDP2-5) and Zellweger spectrum disorders (ZSD). Here, we performed comprehensive metabolomic profiling of clinical samples from RCDP patients and Pex7-deficient mouse models. We identified profound …

Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase As A Target For Combination Therapy, Yihui Chen, Rongzhang Dou, Monica J Hong, Hanwen Xu, Jody Vykoukal, Ricardo A León-Letelier, Yining Cai, Soyoung Park, Ehsan Irajizad, Fu Chung Hsiao, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Hiroyuki Katayama, Samir M Hanash

Faculty, Staff and Student Publications

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of …

Vesicle-Mediated Mitochondrial Clearance Presents An Actionable Metabolic Vulnerability In Triple-Negative Breast Cancer, Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death …

Targeting Kinesin Family Member 20a Sensitizes Stem-Like Triple-Negative Breast Cancer Cells To Standard Chemotherapy, Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC), being both aggressive and highly lethal, poses a major clinical challenge in terms of treatment. Its heterogeneity and lack of hormone receptors or HER2 expression further restrict the availability of targeted therapy. Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as a vulnerability for TNBC treatment. Here, we dissected the transcriptome of BCSCs and identified kinesin family member 20A (KIF20A) as a key regulator of BCSC survival and TNBC tumorigenesis. Genetic depletion or pharmacological inhibition of KIF20A impairs BCSC viability and tumor initiation and development in vitro and in vivo. …

Measurable Imaging-Based Changes In Enhancement Of Intrahepatic Cholangiocarcinoma After Radiotherapy Reflect Physical Mechanisms Of Response, Brian De, Prashant Dogra, Mohamed Zaid, Dalia Elganainy, Kevin Sun, Ahmed M Amer, Charles Wang, Michael K Rooney, Enoch Chang, Hyunseon C Kang, Zhihui Wang, Priya Bhosale, Bruno C Odisio, Timothy E Newhook, Ching-Wei D Tzeng, Hop S Tran Cao, Yun S Chun, Jean-Nicholas Vauthey, Sunyoung S Lee, Ahmed Kaseb, Kanwal Raghav, Milind Javle, Bruce D Minsky, Sonal S Noticewala, Emma B Holliday, Grace L Smith, Albert C Koong, Prajnan Das, Vittorio Cristini, Ethan B Ludmir, Eugene J Koay

Faculty, Staff and Student Publications

Escalated doses of radiotherapy associate with improved local control and overall survival (OS) in intrahepatic cholangiocarcinoma (iCCA), but personalization remains limited because conventional size-based CT criteria correlate poorly with outcomes. We hypothesized that quantitative enhancement measurements would better predict clinical outcomes and guide individualized RT optimization. In a retrospective cohort of 154 patients, we analyzed pre- and post-RT CT scans using quantitative European Association for Study of Liver (qEASL) to derive viable tumor volumes, comparing enhancement-based metrics with size-based RECIST and linking them to outcomes via survival and mathematical modeling. Change in enhancement volume was strongly associated with OS after …

Retrospective Review Of Metastatic Hormone Receptor-Positive Inflammatory Breast Cancer Patients Reveals Poor Responses To Cyclin Dependent Kinase 4/6 Inhibition, Azadeh Nasrazadani, Rebecca S Tidwell, Megumi Kai, Bora Lim, Vicente Valero, Debu Tripathy, Sadia Saleem, Bisrat G Debeb, Anthony Lucci, Wendy A Woodward, Rachel M Layman

Faculty, Staff and Student Publications

Background: Patients with inflammatory breast cancer (IBC) have aggressive biology and relatively inferior responses to standard-of-care (SOC) therapies. Understanding the efficacy of SOC therapies in IBC is critical to optimize outcomes. Our objective was to assess the progression-free survival (PFS) of metastatic hormone receptor-positive HER2-negative/low (HR+HER2-) IBC patients treated with CDK4/6 inhibitors (CDKIs) and hormonal therapy (HT).

Methods: Data from 58 IBC patients with metastatic HR + /HER2- IBC from a single institution were reviewed. The medians (95% confidence intervals) of overall survival (OS), PFS, and time on treatment (ToT) from the time of CDKI initiation were reported via the …

Circulating Tumor Dna Refines Risk Stratification Of Neoadjuvant Therapy-Resistant Breast Tumors, Mark Jesus M Magbanua, Nayelis A Manon, Denise M Wolf, Samuel Rivero-Hinojosa, Ziad Ahmed, Rosalyn W Sayaman, Antony Tin, Derrick Renner, Ekaterina Kalashnikova, Lamorna Brown-Swigart, Gillian L Hirst, Christina Yau, Wen Li, Claudine Isaacs, Rebecca A Shatsky, Amy S Clark, Alexandra Zimmer, Amy L Delson, Angel Rodriguez, Minetta C Liu, Paula R Pohlmann, Laura J Esserman, Hope S Rugo, Angela Demichele, Laura Van 'T Veer

Faculty, Staff and Student Publications

Early-stage breast cancers resistant to neoadjuvant therapy (NAT), characterized by high residual cancer burden (RCB) after treatment, have an increased risk of metastatic recurrence. Here, we show that circulating tumor DNA (ctDNA) detected using a tumor-informed test (1) can improve risk stratification of patients with NAT-resistant tumors (RCB-II/RCB-III) and (2) predict response to NAT. Stratification using ctDNA status at pretreatment or post-NAT and ctDNA dynamics identified NAT-resistant tumors with a significantly decreased risk of metastatic recurrence. ctDNA clearance as early as week 3 across receptor subtypes predicted favorable responses to NAT, including immunotherapies. Interestingly, less than a fifth of patients …

Precise Diagnosis Of Small Invasive Pulmonary Nodules Driven By Single-Cell Immune Signatures In Peripheral Blood, Yang Xia, Yin Zhu, Sai Zhang, Mo Zhou, Jiaqi Zhou, Guanxin Xu, Baiqin Zhao, Guofei Zhang, Qiyuan Wang, Bin Wang, Zexin Chen, Hongyu Shi, Xiuning Le, Tony Mok, Wei Chen, Junqiang Fan, Weiwei Yin, Wen Li

Faculty, Staff and Student Publications

Early detection of lung cancer is crucial for improving patient outcomes. However, accurately diagnosing invasive pulmonary nodules and predicting tumor invasiveness remain major clinical challenges. Given the established role of immune dysfunction in cancer development, we hypothesize that peripheral immune profiling could provide a strategy for managing pulmonary nodules. In this multi-center, prospective study, we combine peripheral immune profiling via mass cytometry with machine learning algorithms to develop an integrated pulmonary nodule management platform. This platform accurately distinguishes invasive from non-invasive pulmonary nodules (AUC = 0.952), outperforming established clinical and radiomics-based models. Furthermore, it effectively predicts tumor invasiveness, differentiating minimally …

Actin Dysregulation Induces Neuroendocrine Plasticity And Immune Evasion: A Vulnerability Of Small Cell Lung Cancer, Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit …

Hsp90 Buffers Deleterious Genetic Variations In Brca1, Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety …

Hif-2-Dependent Regulation Of Pthrp And Paraneoplastic Hypercalcemia In Aggressive Clear-Cell Renal Cell Carcinoma, Arijit Mal, Bingqing Xie, Zane Gray, Charlotte Small, Susmita G Ramanand, Yunpeng Gao, Vanina Toffessi Tcheuyap, Sashi Debnath, Alana Christie, Jeffrey Miyata, Brooklyn Jackson, Hua Zhong, Boning Gao, Jay Lohrey, Naim M Maalouf, Sangeetha M Reddy, John D Minna, Ivan Pedrosa, Xiankai Sun, Ram S Mani, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a …

Multi-Omic Profiling Provides Insights Into The Heterogeneity, Microenvironmental Features, And Biomarker Landscape Of Small-Cell Lung Cancer, Mingchao Xie, Miljenka Vuko, Shashank Saran, Siyu Liu, Andrew G Chambers, Hana Baakza, Helen K Angell, Felicia Ng, Carl M Gay, Robert J Cardnell, Felix J Segerer, Alma Andoni, Jaime Rodriguez-Canales, Paul M Waring, Markus Schick, J Carl Barrett, Lauren A Byers, Giulia Fabbri

Faculty, Staff and Student Publications

Background: Greater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.

Methods: We explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.

Results: Multi-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest …

Dna Methylation Markers Of Insulin Resistance Surrogate Measures In The Atherosclerosis Risk In Communities (Aric) Study, Jeewoen Shin, Jan Bressler, Megan L Grove, Michael Brown, Elizabeth Selvin, James S Pankow, Myriam Fornage, Alanna C Morrison, Chloé Sarnowski

Faculty, Staff and Student Publications

Insulin resistance (IR) is a risk factor for cardiovascular diseases and type 2 diabetes. Associations between DNA methylation (DNAm) and IR have been less studied in African ancestry (AA) populations than those of European ancestry (EA). We aimed to identify associations between whole blood DNAm and IR in up to 1,811 AA and 964 EA participants from the Atherosclerosis Risk in Communities (ARIC) study. We quantified IR using three surrogate measures: the homeostasis model assessment of insulin resistance (HOMA-IR), the triglyceride-glucose index (TyG), and the triglyceride glucose-body mass index (TyG-BMI). We used ancestry-stratified linear regression models to conduct epigenome-wide association …

Functional Head Tremor: Contrasting Features With Other Tremor Etiologies, José Fidel Baizabal-Carvallo, Joseph Jankovic

Faculty, Staff and Students Publications

Background: Functional tremor (FT) is considered the most common phenomenology among patients with functional movement disorders (FMDs). Most patients have limb tremor, but they can also present with tremor involving the head and trunk.

Objectives and methods: We aimed to assess the clinical phenomenology of functional head tremor (FHT) and contrast it with features of HT observed in 125 patients with other tremor etiologies (OTE), including 71 patients with essential tremor (ET).

Results: There were 101 consecutive patients (68.3% females) with FT from which n = 36 (35.6%) had FHT. Yes-yes tremor was the most common directionality (47.2%). Functional trunk …

Clinical Exome Sequencing Efficacy And Phenotypic Expansions Involving Non-Isolated Congenital Anomalies Of Kidney And Urinary Tract (Cakut+), E Andres Rivera-Munoz, Xiaonan E Zhao, Jill A Rosenfeld, Pamela N Luna, Chad A Shaw, Jennifer E Posey, Daryl A Scott

Faculty, Staff and Students Publications

Congenital Anomalies of Kidney and Urinary Tract (CAKUT) can occur in isolation or in conjunction with one or more non-CAKUT associated congenital anomalies or neurodevelopmental disorders (CAKUT+). A molecular cause is not identified in most individuals with CAKUT+. This is due, in part, to uncertainty regarding the efficacy of genetic testing and an incomplete understanding of the genes that cause CAKUT+. Here, we use data from 515 individuals with CAKUT+ (n = 500) or isolated CAKUT (n = 15) to determine the efficacy of clinical exome sequencing (cES) and to identify new phenotype expansions that involve CAKUT. We determined that …

Differential Microrna Profiling Of Blood L1cam And Bulk Extracellular Vesicles In Bipolar Disorder, Gabriel R Fries, Salahudeen Mirza, Jun Wang, Camila N C Lima, Wei Zhang, Marcela Carbajal Tamez, Giselli Scaini, Jair C Soares, Joao Quevedo

Faculty, Staff and Student Publications

Objective: This preliminary study aimed to identify microRNA (miRNA) signatures associated with bipolar disorder (BD) by profiling blood-derived extracellular vesicles (EVs) of both putative neuronal origin and from all sources.

Method: In two parallel studies of individuals with BD and controls (CON), we characterized miRNA expression profiles of blood EVs selected for L1CAM, a putative marker of neuronal origin (n = 20 BD/20 CON), as well as bulk EVs (n = 21 BD/20 CON). For each study, analyses identified miRNAs differentially expressed between groups, followed by functional interrogation and testing for associations with clinical features.

Results: Results of …

Molecular And Immunological Features Associated With Long-Term Benefits In Metastatic Nsclc Patients Undergoing Immune Checkpoint Blockade, Pedro Rocha, Rafael Bach, Laura Masfarré, Sharia Hernandez, Nil Navarro-Gorro, Adrià Rossell, Xavier Villanueva, Mario Giner, Ignacio Sanchéz, Miguel Galindo, Raúl Del Rey-Vergara, Albert Iñañez, Beatriz Sanchéz-Espiridion, Wei Lu, Ariadna Acedo-Terrades, Pau Berenguer-Molins, Albert Sánchez-Font, Roberto Chalela, Victor Curull, Álvaro Taus, Max Hardy-Werbin, Mark Sausen, Andrew Georgiadis, James White, Jennifer B Jackson, Laura Moliner, Sergi Clavé, Beatriz Bellosillo, Ana Rovira, Ignacio Wistuba, Luisa M Solis Soto, Júlia Perera-Bel, Edurne Arriola

Faculty, Staff and Student Publications

Introduction: Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet.

Methods: A total of 49 patients with metastatic NSCLC treated with ICB were included. Long-term (LTR) and short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before ICB treatment initiation and early-on treatment. …

Mecom Fusion Partner And Bone Marrow Blast Percentage Influence Outcomes Of Patients With Mecom Rearranged Acute Myeloid Leukaemia, Wei-Ying Jen, Guilin Tang, Eitan Kugler, Jennifer Croden, Koji Sasaki, Alexandre Bazinet, Alex Bataller, Guillermo Montalban-Bravo, Gautam Borthakur, Gokce A Toruner, Sanam Loghavi, Nicholas J Short, Ghayas C Issa, Ian M Bouligny, Sherry Pierce, Uday Popat, Naveen Pemmaraju, Elias Jabbour, Guillermo Garcia-Manero, Kapil Bhalla, Farhad Ravandi, Naval G Daver, Courtney D Dinardo, Hagop M Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

MECOM rearrangements (MECOM-r) are acute myeloid leukaemia (AML)-defining, regardless of blast percentage or MECOM fusion partner. We sought to investigate if blast percentage or MECOM-r partner was associated with overall survival (OS). We included 152 adult patients with newly diagnosed MECOM-r and classified blast percentage into < 20% or ≥20% and MECOM-r partner into classic (GATA2::MECOM) or variant (others). Thirty-one per cent had < 20% blasts, with 69% having ≥20%; 57% had classic and 43% variant MECOM-r. Treatment was with intensive chemotherapy (IC) in 41% and low-intensity therapy (LIT) in 59%. Composite complete remission rates were similar between IC (50%) and LIT (48%, p = 0.99). The median OS was 17 months (95% confidence interval [CI], 12-not estimable [NE]) for < 20% blasts, compared with 9 months (95% CI, 6-10) for ≥20% blasts (p <  0.01). On multivariate analysis, ≥20% blasts were associated with worse OS (hazard ratio [HR] 1.9, [95% CI, 1.2-3.2], p <  0.01), independent of age, MECOM-r partner, additional cytogenetic abnormalities, treatment intensity, addition of venetoclax and stem cell transplant (SCT). HR for IC was 2.0 (95% CI, 1.1-3.7, p = 0.03). In < 20% blasts, variant MECOM-r was independently associated with a reduced hazard of death (HR 0.2 [95% CI, 0.1-0.8], p <  0.01). MECOM-r AML is a heterogenous entity; consideration should be given to LIT approaches.

Evidence For Improved Dna Repair In The Long-Lived Bowhead Whale, Denis Firsanov, Max Zacher, Xiao Tian, Todd L Sformo, Yang Zhao, Gregory Tombline, J Yuyang Lu, Zhizhong Zheng, Luigi Perelli, Enrico Gurreri, Li Zhang, Jing Guo, Anatoly Korotkov, Valentin Volobaev, Seyed Ali Biashad, Zhihui Zhang, Johanna Heid, Alexander Y Maslov, Shixiang Sun, Zhuoer Wu, Jonathan Gigas, Eric C Hillpot, John C Martinez, Minseon Lee, Alyssa Williams, Abbey Gilman, Nicholas Hamilton, Ekaterina Strelkova, Ena Haseljic, Avnee Patel, Maggie E Straight, Nalani Miller, Julia Ablaeva, Lok Ming Tam, Chloé Couderc, Michael R Hoopmann, Robert L Moritz, Shingo Fujii, Amandine Pelletier, Dan J Hayman, Hongrui Liu, Yuxuan Cai, Anthony K L Leung, Zhengdong Zhang, C Bradley Nelson, Lisa M Abegglen, Joshua D Schiffman, Vadim N Gladyshev, Carlo C Maley, Mauro Modesti, Giannicola Genovese, Mirre J P Simons, Jan Vijg, Andrei Seluanov, Vera Gorbunova

Faculty, Staff and Student Publications

At more than 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth1, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto’s paradox2. Here, to understand the mechanisms that underlie the cancer resistance of the bowhead whale, we examined the number of oncogenic hits required for malignant transformation of whale primary fibroblasts. Unexpectedly, bowhead whale fibroblasts required fewer oncogenic hits to undergo malignant transformation than human fibroblasts. …

Sahrang: Subarachnoid Hemorrhage Recovery And Galantamine: A Pilot Multicenter Randomized Placebo-Controlled Trial, Bosco Seong Kyu Yang, Jude P J Savarraj, Elena Moreno, Kevin E Immanuel, Georgene Hergenroeder, Glenda Torres, Jung Hwan Kim, Sophie Samuel, Claudia Pedroza, James C Grotta, Andrew Barreto, H Alex Choi

Faculty, Staff and Student Publications

Background: Subarachnoid hemorrhage (SAH) causes life-long neurologic dysfunction. Peripheral inflammatory processes as a reaction to brain injury have been shown to worsen outcomes after SAH. Galantamine has been shown to reduce proinflammatory microglial activities and improve synaptic connections. We hypothesize that galantamine treatment after SAH mitigates inflammation-mediated neuronal injury and improve outcomes. We conducted a pilot clinical trial to examine the tolerability and safety of galantamine in patients with SAH.

Methods: This prospective, multicenter, double-masked, randomized, placebo-controlled study contiguously screened and enrolled adult patients presenting with aneurysmal SAH with a Fisher grade of 3 within 72 h of symptom onset. …

Meniscal Repair In The Setting Of Revision Anterior Cruciate Ligament Reconstruction: 6-Year Follow-Up Results From The Mars Cohort, Jake A Fox, Laura J Huston, Amanda K Haas, Jacquelyn S Pennings, Christina R Allen, Daniel E Cooper, Thomas M Deberardino, Warren R Dunn, Brett Brick A Lantz, Kurt P Spindler, Michael J Stuart, Annunziato Ned Amendola, Christopher C Annunziata, Robert A Arciero, Bernard R Bach, Champ L Baker, Arthur R Bartolozzi, Keith M Baumgarten, Jeffrey H Berg, Geoffrey A Bernas, Stephen F Brockmeier, Robert H Brophy, Charles A Bush-Joseph, J Brad Butler V, James L Carey, James E Carpenter, Brian J Cole, Jonathan M Cooper, Charles L Cox, R Alexander Creighton, Tal S David, David C Flanigan, Robert W Frederick, Theodore J Ganley, Charles J Gatt, Steven R Gecha, James Robert Giffin, Sharon L Hame, Jo A Hannafin, Christopher D Harner, Norman Lindsay Harris, Keith S Hechtman, Elliott B Hershman, Rudolf G Hoellrich, David C Johnson, Timothy S Johnson, Morgan H Jones, Christopher C Kaeding, Ganesh V Kamath, Thomas E Klootwyk, Bruce A Levy, C Benjamin Ma, G Peter Maiers, Robert G Marx, Matthew J Matava, Gregory M Mathien, David R Mcallister, Eric C Mccarty, Robert G Mccormack, Bruce S Miller, Carl W Nissen, Daniel F O'Neill, Brett D Owens, Richard D Parker, Mark L Purnell, Arun J Ramappa, Michael A Rauh, Arthur C Rettig, Jon K Sekiya, Kevin G Shea, Orrin H Sherman, James R Slauterbeck, Matthew V Smith, Jeffrey T Spang, Col Ret Steven J Svoboda, Timothy N Taft, Joachim J Tenuta, Edwin M Tingstad, Armando F Vidal, Darius G Viskontas, Richard A White, James S Williams, Michelle L Wolcott, Brian R Wolf, James J York, Rick W Wright

Faculty, Staff and Student Publications

Background: Meniscal preservation has been demonstrated to contribute to long-term knee health and has been a successful intervention in isolation and in patients with anterior cruciate ligament reconstruction (ACLR). The long-term results of meniscal repair in the setting of revision ACLR have yet to be documented.

Purpose: To report the incidence of meniscal repair failures at the 6-year follow-up in a cohort of patients who underwent concurrent revision ACLR and primary meniscal repair.

Study design: Prospective cohort study; Level of evidence, 2.

Methods: All revision ACLRs with concomitant primary meniscal repair cases from a multicenter group between 2006 and 2011 …

Decoding Fibrosis In Nonresolvable Covid-19: A Role For Myeloid-Specific Hif1a Deletion, Kemly Philip, Hannah P Thompson, Scott D Collum, Isabella Lefebvre, Bindu Akkanti, Bihong Zhao, Rahat Hussain, Manish Patel, Michael R Blackburn, Tingting W Mills, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

A complication of viral lung infections is the development of pulmonary fibrosis. This phenomenon is most evident in patients with COVID-19, where in its most aggressive form patients developed nonresolvable (NR) COVID-19 requiring lung transplantation. NR-COVID-19 was characterized by the presentation of a fulminant fibrotic lung injury that progressed rapidly, even in patients with limited comorbidities. However, the mechanisms that led to this rapidly progressing form of fibrosis are not fully understood. A common clinical manifestation in the most severe cases of COVID-19 was the presence of "silent" hypoxemia. Thus, we hypothesized that a dysfunctional hypoxic response may result in …

Adherence To Breast Cancer Screening Guidelines Among Age-Eligible Us Women: Findings From Nhis 2021, Monalisa Chandra, Joël Fokom Domgue, Robert Yu, Sanjay Shete

Faculty, Staff and Student Publications

Background: Despite the proven benefits of early breast cancer detection in reducing mortality, adherence to breast cancer screening guidelines in the United States is suboptimal. In this study, we assessed the prevalence and factors associated with adherence to breast cancer screening guidelines.

Methods: Using nationally representative data from the National Health Interview Survey 2021, we included breast cancer screening-eligible women (aged 50-74). Descriptive statistics and population-weighted multivariable logistic regression were employed to examine breast cancer screening adherence per the United States Preventive Services Task Force guidelines, and its determinants in this population.

Results: Of the 6814 screening-eligible women included in …

Standardized Research Electronic Cigarette Acceptability Among Adult Men And Women Who Smoke Combustible Cigarettes, Jason D Robinson, Yong Cui, Maher Karam-Hage, Janice A Blalock, Sanjay Shete, George Kypriotakis, Peiying Yang, Paul M Cinciripini

Faculty, Staff and Student Publications

Objective: The U.S. electronic cigarette marketplace is diverse and has evolved rapidly. To provide a standardized research model, the U.S. National Institute on Drug Abuse developed the Standard Research E-Cigarette (SREC). This study characterized potential gender differences in product use, acceptability, reinforcement, and nicotine dependence symptoms when switching from combustible cigarettes (CCs) to nicotine and placebo SRECs.

Method: In total, 169 adults (82 women) who smoke were enrolled in this all-remote randomized double-blind crossover trial. During Weeks 1-2, participants used their usual brand cigarettes (UBCs). During Weeks 3-4 and 5-6, they were instructed to use the tobacco-flavored SREC (either nicotine …

Profiling The Preclinical Pharmacokinetics And Biodistribution Of A Platinum(Iv)-Based Oxaliplatin Prodrug Oxalitex And Their Significance To Antitumor Response, Guangan He, Gregory D Thiabaud, Kathryn A Shelton, Luke J Segura, Jonathan F Arambula, Jonathan L Sessler, Rick A Finch, Zahid H Siddik

Faculty, Staff and Student Publications

OxaliTEX (NOVO-111) is a novel gadolinium(III) texaphyrin-platinum(IV) complex that is under development for clinical trials. It was designed as a prodrug of oxaliplatin (1,2-diaminocyclohexane-platinum(II) oxalate) tethered to a tumor-affinic texaphyrin moiety to improve drug delivery to the tumor. However, oxaliTEX was not only more effective as an antitumor agent but also better tolerated in mice. To appreciate this higher therapeutic index and advance its preclinical development, studies were undertaken to profile its plasma pharmacokinetics, distribution to tumor and normal tissues, and pharmacodynamics of the p53/p21 molecular pathway. Nude mice, with or without a subcutaneous colorectal HCT-116 xenograft harboring a phenotypically …

Regional Brain Morphology And Current Antidepressant Use: Findings From 32 International Cohorts From The Enigma Major Depressive Disorder Working Group, Chaira Serrarens, Yara J Toenders, Elena Pozzi, André Aleman, Nina Alexander, Zeynep Başgöze, Vladimir Belov, Klaus Berger, Katharina Brosch, Robin Bülow, Geraldo Filho Busatto, Liliana P Capitão, Colm G Connolly, Baptiste Couvy-Duchesne, Kathryn R Cullen, Udo Dannlowski, Christopher G Davey, Greig I De Zubicaray, Danai Dima, Katharina Dohm, Verena Enneking, Tracy Erwin-Grabner, Ulrika Evermann, Cynthia H Y Fu, Paola Fuentes-Claramonte, Beata R Godlewska, Ali Saffet Gonul, Ian H Gotlib, Roberto Goya-Maldonado, Hans J Grabe, Nynke A Groenewold, Dominik Grotegerd, Oliver Gruber, Tim Hahn, Geoffrey Hall, Ben J Harrison, Walter Heindel, Marco Hermesdorf, Tiffany C Ho, Naho Ichikawa, Eri Itai, Neda Jahanshad, Hamidreza Jamalabadi, Alec J Jamieson, Andreas Jansen, Tilo Kircher, Bonnie Klimes-Dougan, Bernd Krämer, Axel Krug, Thomas M Lancaster, Elisabeth J Leehr, Meng Li, David E J Linden, Frank Macmaster, Katie L Mcmahon, Sarah E Medland, David M A Mehler, Susanne Meinert, Benson Mwangi, Igor Nenadić, Go Okada, Yasumasa Okamoto, Nils Opel, Julia-Katharina Pfarr, Edith Pomarol-Clotet, Maria J Portella, Ronny Redlich, Liesbeth Reneman, Jonathan Repple, Kai Ringwald, Elena Rodriguez-Cano, Pedro G P Rosa, Matthew D Sacchet, Philipp G Sämann, Raymond Salvador, Anouk Schrantee, Hotaka Shinzato, Kang Sim, Egle Simulionyte, Jair C Soares, Dan J Stein, Frederike Stein, Benjamin Straube, Lachlan T Strike, Florian Thomas-Odenthal, Sophia I Thomopoulos, Paul M Thompson, Marie-Jose Van Tol, Paula Usemann, Aslihan Uyar, Nic Van Der Wee, Steven Van Der Werff, Yolanda Vives-Gilabert, Henry Völzke, Martin Walter, Sarah Whittle, Katharina Wittfeld, Adrian Wroblewski, Mon-Ju Wu, Tony T Yang, Giovana B Zunta-Soares, Dick J Veltman, Lianne Schmaal, Laura S Van Velzen

Faculty, Staff and Student Publications

The understanding of how antidepressant (AD) use is associated with brain structure in individuals with major depressive disorder (MDD) remains incomplete. We aimed to examine the association between AD medication use and brain morphology in relation to age and sex by pooling structural neuroimaging and clinical data from 32 cohorts within the ENIGMA-MDD working group. Interaction effects of group (2076 cases with current AD use (AD), 1495 cases not currently taking AD (nAD) and 5125 healthy controls (HC)) with age and sex, and main effects of group on regional brain structure (cortical surface area and thickness, and subcortical volume) were …

Fludarabine Lymphodepletion Exposure Is Associated With Toxicities After Idecabtagene-Vicleucel In Relapsed/Refractory Multiple Myeloma: Real-World Experience From The Us Myeloma Immunotherapy Consortium, Karen Sweiss, Charlotte Wagner, Eric Anto, Tom Greene, Ryan Sun, Rebecca Gonzalez, Omar Castaneda Puglianini, Ciara Freeman, Filip Ionescu, Krina Patel, Christopher Ferreri, Mahmoud Gaballa, Leyla Shune, Joseph Mcguirk, Surbhi Sidana, Vanna Hovanky, Jack Khouri, Shahzad Raza, Faiz Anwer, Danai Dima, Hamza Hashmi, James Davis, Aimaz Afrough, Gurbakhash Kaur, Larry Anderson, Peter Forsberg, Megan Herr, Doris K Hansen, Mehmet Hakan Kocoglu, Douglas Sborov

Faculty, Staff and Student Publications

Background: Idecabtagene vicleucel (ide-cel) is a BCMA-directed CAR-T associated with high response rates in relapsed/refractory multiple myeloma (RRMM), yet responses are not durable and most patients experience toxicities. Fludarabine (Flu) is a key component of lymphodepletion but exhibits significant pharmacokinetic (PK) variability.

Objective: Given Flu exposure (AUC) predicts outcomes after CD19-directed CAR-T, we hypothesized it would predict outcomes after ide-cel. Our objective was to determine the association between fludarabine AUC and clinical outcomes after standard-of-care (SOC) ide-cel.

Study design: RRMM patients receiving ide-cel from 10 US Multiple Myeloma Immunotherapy Consortium centers were retrospectively analyzed. A population PK approach using cumulative …

Forecasting Chemoradiation Response Midtreatment For High-Grade Gliomas Through Patient-Specific Biology-Based Modeling, David A Hormuth, Maguy Farhat, Bikash Panthi, Holly Langshaw, Mihir D Shanker, Wasif Talpur, Sara Thrower, Jodi Goldman, Sophia Ty, Calliope Custer, Jeanne Kowalski, Thomas E Yankeelov, Caroline Chung

Faculty, Staff and Student Publications

Purpose: The entire course of radiation therapy (RT) for high-grade glioma (HGG) is currently derived from pre-RT magnetic resonance imaging (MRI). Although it is possible to adapt RT during the course of treatment, it is often guided only by anatomical changes to the tumor. This study seeks to determine if a biology-based mathematical model, parameterized by patient-specific, multiparametric MRI (mpMRI) data, can accurately forecast HGG response during RT.

Methods and materials: Twenty one patients with HGG planned for 6 weeks of concurrent RT and chemotherapy were imaged weekly with mpMRI during RT and at 1, 2, and 3 months post-RT. …

Evaluation Of Renal Masses With Cest Mri: Protocol Optimization And Preliminary Results, Xiaojing Wang, Jochen Keupp, Ivan E Dimitrov, Ananth Madhuranthakam, Durga Udayakumar, Mahsa Taherzadeh, Emin Albayrak, Orson W Moe, Payal Kapur, Robert E Lenkinski, Ivan Pedrosa, Elena Vinogradov

Faculty, Staff and Student Publications

Purpose: This study investigates the application of CEST MRI in human kidneys, with the overarching goal of developing CEST MRI for renal mass characterization. Here, the focus is on the development of a protocol and the proof-of-principle evaluation of CEST for the characterization of clear cell renal cell carcinoma (ccRCC).

Methods: Ten healthy volunteers and five patients diagnosed with ccRCC underwent CEST MRI scans at 3 T. The sequence performance was characterized in healthy volunteers and tested using three saturation power levels, B1rms = 0.7, 1.2, and 1.6 μT. We compared the magnetization transfer ratio asymmetry (MTRasym) values at 1.0, …

Utility Of Serum Matrix Metalloproteinase-7 As A Biomarker In Cholestatic Infants With Congenital Heart Disease, Sindhu Pandurangi, Michael E Kim, Nicolas Noriega, Bradley Conant, Jangdong Seo, Reena Mourya, Pranavkumar Shivakumar, Anna L Peters, Andrew Misfeldt, Meghan Chlebowski

Faculty, Staff and Student Publications

Background: Matrix metalloproteinase 7 (MMP-7) is a novel biomarker for diagnosis of biliary atresia (BA), the most common cholestatic liver disease in infancy. There is a pressing need to determine the utility of MMP-7 levels in infants with congenital heart disease (CHD) to avoid unnecessary invasive diagnostic procedures in this high-risk population. We investigated the utility of MMP-7 in discriminating BA from non-BA cholestasis in infants with CHD and whether MMP-7 elevation was present in infants requiring treatment for clinically significant PH.

Methods: This is a single-center cross-sectional study including infants < 180 days of age with cholestasis and serum MMP-7 levels collected from 2019 to 2023. Demographic data and descriptive statistics were summarized with medians with interquartile ranges and frequencies with percentages. Median MMP-7 levels were assessed via Wilcoxon rank-sum test.

Results: A total of 149 patients were included. Patients …