Life Sciences Commons^™

Perioperative Durvalumab Plus Chemotherapy Plus New Agents For Resectable Non-Small-Cell Lung Cancer: The Platform Phase 2 Neocoast-2 Trial, Tina Cascone, Laura Bonanno, Florian Guisier, Amelia Insa, Moishe Liberman, Lorenzo Livi, Romain Corre, Dong-Wan Kim, Maria Rosario Garcia Campelo, Mariano Provencio Pulla, Byoung Yong Shim, Giulio Metro, Jaafar Bennouna, Agata A Bielska, Alula R Yohannes, Yun He, Adam Dowson, Gozde Kar, Lara Mcgrath, Rakesh Kumar, Italia Grenga, Jonathan Spicer, Patrick M Forde

Faculty, Staff and Student Publications

In the phase II NeoCOAST-2 platform study, 202 patients with untreated, resectable stage IIA–IIIB non-small-cell lung cancer (NSCLC) were randomized to receive neoadjuvant durvalumab plus platinum-doublet chemotherapy with oleclumab, a CD73 inhibitor (Arm 1), or with monalizumab, a NKG2A inhibitor (Arm 2), or neoadjuvant durvalumab plus single-agent platinum chemotherapy with the TROP-2 antibody–drug conjugate (ADC) datopotamab deruxtecan (Arm 4), followed by surgical resection and adjuvant durvalumab with oleclumab or monalizumab (Arms 1 and 2) or durvalumab alone (Arm 4). Primary endpoints were pathological complete response (pCR) rate and safety; secondary endpoints included feasibility of surgery and major pathological response (mPR) …

Bayesian Counterfactual Machine Learning Individualizes Radiation Modality Selection To Mitigate Immunosuppression, Duo Yu, Michael J Kane, Yiqing Chen, Steven H Lin, Radhe Mohan

Faculty, Staff and Student Publications

Purpose: Lymphocytes play critical roles in cancer immunity and tumor surveillance. Radiation-induced lymphopenia (RIL) is a common side effect observed in patients with cancer undergoing chemoradiation therapy (CRT), leading to impaired immunity and worse clinical outcomes. Although proton beam therapy (PBT) has been suggested to reduce RIL risk compared with intensity-modulated radiation therapy (IMRT), this study used Bayesian counterfactual machine learning to identify distinct patient profiles and inform personalized radiation modality choice.

Methods: A novel Bayesian causal inferential technique is introduced and applied to a matched retrospective cohort of 510 patients with esophageal cancer undergoing CRT to identify patient profiles …

A Phase 2 Trial Of Cpx-351 Combined With Venetoclax In Relapsed Or Refractory Acute Myeloid Leukemia, Tapan M Kadia, Wei-Ying Jen, Alex Bataller, Alexandre Bazinet, Gautam Borthakur, Wei Qiao, Koichi Takahashi, Ghayas C Issa, Courtney D Dinardo, Guillermo Montalban-Bravo, Naveen Pemmaraju, Andrew Tran, Vanthana Bharathi, Sanam Loghavi, Amin M Alousi, Uday Popat, Naval G Daver, Farhad Ravandi, Hagop M Kantarjian

Faculty, Staff and Student Publications

Outcomes in patients with relapsed/refractory (RR) AML are poor. We sought to investigate if CPX-531 in combination with venetoclax (CPX + VEN) was tolerable and effective in RR AML. This was a single institution phase 1b/2 trial of CPX + VEN. Patients aged ≥ 18 years with RR AML who were fit for intensive chemotherapy were eligible. Prior venetoclax exposure was allowed. The phase 1b portion followed a 3 + 3 design to identify the recommended phase 2 dose (RP2D) for the expansion cohort. At the starting dose level of −1, prolonged myelosuppression was observed, leading to dose level −2 …

White Matter Abnormalities And Cognition In Aging And Alzheimer Disease, Christopher Peter, Aditi Sathe, Niranjana Shashikumar, Kimberly R Pechman, Abigail W Workmeister, Yuankai Huo, Jesse Mez, Logan C Dumitrescu, Katherine A Gifford, Corey J Bolton, Leslie S Gaynor, Shannon L Risacher, Lori L Beason-Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Duygu Tosun-Turgut, Mohamad Habes, Di Wang, Arthur W Toga, Paul M Thompson, Panpan Zhang, Kurt G Schilling, Marilyn Albert, Walter Kukull, Sarah A Biber, Bennett A Landman, Barbara B Bendlin, Sterling C Johnson, Julie Schneider, Lisa L Barnes, David A Bennett, Angela L Jefferson, Susan M Resnick, Andrew J Saykin, Paul K Crane, Michael L Cuccaro, Timothy J Hohman, Derek B Archer, Dimitrios Zaras, Yisu Yang, Alaina Durant, Praitayini Kanakaraj, Michael E Kim, Chenyu Gao, Nancy R Newlin, Karthik Ramadass, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Seo-Eun Choi, Brandon Klinedinst, Michael L Lee, Phoebe Scollard, Emily H Trittschuh, Elizabeth A Sanders

Faculty, Staff and Student Publications

Importance: There has yet to be a large-scale study quantifying the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD).

Objective: To investigate the associations between tract-specific white matter microstructure and cognitive performance and decline in aging and AD-related cognitive impairment.

Design setting and participants: This prognostic study of aging and AD, a secondary data analysis of multisite cohort studies, acquired data from 9 cohorts between September 2002 and November 2022. Participants were eligible if they had diffusion-weighted magnetic resonance imaging (dMRI) data, domain-specific cognitive composite z scores, demographic and clinical data, were …

The Significance Of Detecting An Unusual Myeloblast Immunophenotype In A Presumptive Clinical Diagnosis Of Myelodysplastic Syndromes, Fnu Sameeta, Wei Wang, Fatima Zahra Jelloul, Okechukwu V Nwogbo, Beenu Thakral, Shaoying Li, Guilin Tang, Fuli Jia, L Jeffrey Medeiros, Sanam Loghavi, Jeffrey L Jorgensen, Sa A Wang

Faculty, Staff and Student Publications

Context.—: Blasts in myelodysplastic syndromes (MDSs) typically have a primitive myeloid immunophenotype (CD34+CD117+CD13+CD33+HLA-DR+). On rare occasions, blasts were found to be CD34 negative or minimally expressed in a presumptive MDS.

Objective.—: To investigate the occurrence of these cases, and to examine any unique molecular genetic features, and clinical relevance.

Design.—: More than 2000 flow cytometry immunophenotyping tests for MDS performed during a 5-year period were retrospectively reviewed. Chronic myelomonocytic leukemia and overt acute myeloid leukemia (AML) (≥20% blasts) were excluded.

Results.—: Approximately 800 cases had abnormal myeloblasts consistent with myeloid neoplasms; 96% of cases showed a typical primitive phenotype, but …

Associations Between Prostate Cancer And Dementia: A Nationwide Study In Sweden, Casey Crump, Pär Stattin, James D Brooks, Jan Sundquist, Jingkai Wei, Weiva Sieh, Kristina Sundquist

Faculty, Staff and Student Publications

Background and objective: Prostate cancer (PC) and dementia may commonly co-occur; yet, prior evidence for bidirectional associations is inconsistent. This study aims to determine the associations between PC and dementia in large population-based studies, which may further inform clinical care.

Methods: To assess the dementia risk in men with PC, a national cohort study was conducted in 178 746 men diagnosed with PC in 1998-2017 and 1 787 460 age-matched control men in Sweden without prior dementia. Cox regression was used to estimate hazard ratios (HRs) for Alzheimer's disease (AD) and vascular dementia (VaD) through 2018. Subanalyses explored differences by …

12/15-Lipooxygenase Inhibition Reduces Microvessel Constriction And Microthrombi After Subarachnoid Hemorrhage In Mice, Ari Dienel, Sung Ha Hong, Hussein A Zeineddine, Sithara Thomas, Shafeeque C M, Kiara Torres, Andrew Dunn, P Kumar T, Gadiparthi N Rao, Spiros L Blackburn, Devin W Mcbride

Faculty, Staff and Student Publications

Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus, 12/15-LOX is an important target to prevent delayed cerebral ischemia. SAH was induced in C57BL/6 and 12/15-LOX−/− mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed …

Efficacy And Safety Of Oral Decitabine/Cedazuridine In The Chronic Myelomonocytic Leukaemia Subpopulations From Phase 2 And 3 Studies, Michael R Savona, Olatoyosi Odenike, Gail J Roboz, Harshad Amin, Amy E Dezern, Kim-Hien Dao, Bhavana Bhatnagar, Rena Buckstein, Brian Leber, Mary-Margaret Keating, Somedeb Ball, Aram Oganesian, Yuri Sano, Harold N Keer, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

DNA methyltransferase inhibitors (DNMTis) are commonly used in treating chronic myelomonocytic leukaemia (CMML); however, data from prospective studies of DNMTis in CMML are limited. The present analysis evaluated the efficacy, safety and pharmacodynamics of the oral DNMTi decitabine/cedazuridine in the subset of patients with CMML from the phase 2 and 3 trials, which led to the approval of this agent for myelodysplastic syndromes and CMML in the United States and Canada. Potential prognostic factors also were analysed. In all, 34 patients with CMML were screened and 33 were treated. Most patients (76% [n = 25]) had myelodysplastic type-CMML and 77% …

Inhibition Of Methylthioadenosine Phosphorylase Protects From Experimental Acute Kidney Injury, Afaf Saliba, Yidong Chen, Jonathan W Nelson, Abhinav Vetcha, Wei Wei Wang, Nagarjunachary Ragi, Hamid Rabb, W Brian Reeves, Kumar Sharma

Faculty, Staff and Student Publications

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in purine metabolism that may influence cellular responses to injury. We evaluated the effects of prophylactic MTAP inhibition in mouse models of ischemia-reperfusion and cisplatin-induced acute kidney injury (AKI). MTAP inhibition was confirmed by accumulation of methylthioadenosine (MTA). Treated mice showed reduced renal injury and decreased tubular damage. Transcriptomic analysis revealed protection from inflammatory and stress pathways, while maintaining oxidative phosphorylation, fatty acid metabolism, and epithelial integrity-related genes. Analysis of human single-cell RNA-seq data from the Kidney Precision Medicine Project indicated that MTAP is highly expressed in kidney injury marker-positive adaptive proximal tubule …

Single-Cell Proteomic Analysis Reveals Multiple Myeloma Heterogeneity And The Dynamics Of The Tumor Immune Microenvironment In Precursor And Advanced States, Mohamed Kamal, Stephanie N Shishido, Jeremy Mason, Krina Patel, Elisabet E Manasanch, Peter Kuhn

Faculty, Staff and Student Publications

Multiple myeloma (MM) is an aggressive hematologic malignancy arising from plasma cell (PC) proliferation in the bone marrow, progressing from its precursor states MGUS and SMM. Despite therapeutic advances, MM remains incurable, underscoring the need for better risk stratification and early detection. Tumor heterogeneity and dynamic immune microenvironment changes drive progression, yet bulk analyses overlook rare subpopulations critical to disease evolution and resistance. This study employed multiplexed targeted proteomics to characterize bone marrow aspirates (BMA) from 22 patients to observe the change in the distribution of PCs and tumor immune microenvironment (TiME) cells across MM disease states and controls. Bone …

Transcriptomic Analysis Of Localized High-Risk Prostate Cancer Improves Prognostication And Identifies Benefit From Adding Docetaxel To Definitive Radiotherapy With Androgen Suppression In The Nrg Oncology/Rtog 0521 Phase 3 Trial, Ryan M Phillips, James A Proudfoot, Elai Davicioni, Yang Liu, Daniel E Spratt, Jeff M Simko, Robert B Den, Alan Pollack, Seth A Rosenthal, A Oliver Sartor, Christopher J Sweeney, Gerhardt Attard, Leslie Longoria, Samir Patel, Michael W Straza, Jason A Efstathiou, Amit B Shah, Karen E Hoffman, Joseph P Rodgers, Howard M Sandler, Felix Y Feng, Phuoc T Tran

Faculty, Staff and Student Publications

Background and objective: NRG/RTOG 0521 randomized men with high-risk localized prostate cancer (PC) to androgen suppression (AS) and definitive radiotherapy (RT) ± docetaxel-based chemotherapy (CT). The overall survival (OS) benefit with CT initially reported was lost on longer follow-up. The Decipher genomic classifier (GC) measures multiple transcripts relevant to docetaxel action. Basal/luminal differentiation portends differential response to AS and CT for high-risk localized and metastatic hormone-sensitive PC. We validated the Decipher GC in pretreatment biopsy samples for risk stratification and examined basal-luminal subtyping to predict docetaxel response.

Methods: Decipher GC scores and basal-luminal cellular subtypes were generated for specimens from …

Non-Mutated Human Tau Stimulates Alzheimer’S Disease-Relevant Neurodegeneration In A Microglia-Dependent Manner, Yuanyuan Fan, Estrella Escobar, Constance L Atkins, Shuning Huang, Juan J Herrera, Wenbo Li, Clare Pridans, Xiaobo Zhou, Cynthia Ju, Wei Cao

Faculty, Staff and Student Publications

The accumulation of abnormal, non-mutated tau protein is a key pathological hallmark of Alzheimer's disease (AD). Despite its strong association with disease progression, the mechanisms by which tau drives neurodegeneration in the brain remain poorly understood. Here, we selectively expressed non-mutated or mutated human microtubule-associated protein tau (hMAPT) in neurons across the mouse brain and observed neurodegeneration in the hippocampus, especially associated with non-mutated human tau. Single-nuclei RNA sequencing confirmed a selective loss of hippocampal excitatory neurons by the wild-type tau and revealed the upregulation of neurodegeneration-related pathways in the affected populations. The accumulation of phosphorylated tau was accompanied by …

A Data Assimilation Framework For Predicting The Spatiotemporal Response Of High-Grade Gliomas To Chemoradiation, Hugo J M Miniere, David A Hormuth, Ernesto A B F Lima, Maguy Farhat, Bikash Panthi, Mihir D Shanker, Sara Thrower, Jodi Goldman, Sophia Ty, Caroline Chung, Thomas E Yankeelov

Faculty, Staff and Student Publications

Background: High-grade gliomas are highly invasive and respond variably to chemoradiation. Accurate, patient-specific predictions of tumor response could enhance treatment planning. We present a novel computational platform that assimilates MRI data to continually predict spatiotemporal tumor changes during chemoradiotherapy.

Methods: Tumor growth and response to chemoradiation was described using a two-species reaction-diffusion model of enhancing and non-enhancing regions of the tumor. Two evaluation scenarios were used to test the predictive accuracy of this model. In scenario 1, the model was calibrated on a patient-specific basis (n = 21) to weekly MRI data during the course of chemoradiotherapy. A data assimilation …

Melanoma Antigens In Pediatric Medulloblastoma Contribute To Tumor Heterogeneity And Species-Specificity Of Group 3 Tumors, Rebecca R J Collins, Rebecca R Florke Gee, Sima Tozandehjani, Tara Bayat, Maria Camila Hoyos Sanchez, Barbara Breznik, Samuel T Peters, Jon P Connelly, Shondra M Pruett-Miller, Martine F Roussel, Dinesh Rakheja, Heather S Tillman, Patrick Ryan Potts, Klementina Fon Tacer

Faculty, Staff and Student Publications

Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB (G3 MB) subtype accounts for about 25% of MB and is associated with the worst outcomes. Herein, we report that more than half of G3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are cancer-testis antigens, aberrantly expressed in several adult cancers, and associated with poorer prognosis and therapy resistance; however, their role in pediatric cancers is mostly unknown. This study aimed to determine whether MAGEs are activated and important in pediatric MB. We obtained formalin-fixed paraffin-embedded tumor samples of 34 patients, …

Use Of Cholic Acid In Smith-Lemli-Opitz Syndrome (Slos): Real-World Patient Outcomes, Edwin Ferren, Paul R Hillman, Amy Kritzer, Joseph Ray, Alvaro Serrano, Paige Roberts, Tiziano Pramparo, Pamela Vig, Robert D Steiner

Faculty, Staff and Student Publications

Background: Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by biallelic pathogenic variants in DHCR7, which encodes the enzyme 7-dehydrocholesterol reductase (DHCR7). SLOS is a multisystemic disorder affecting various aspects of health, including growth, development, behavior, and quality of life, underscoring the need for safe, efficacious interventions that limit disease burden. DHCR7 enzyme deficiency leads to a "metabolic block" resulting in decreased cholesterol production and accumulation of its precursor 7-dehydrocholesterol and the secondary isomer 8-dehydrocholesterol. Reduced cholesterol synthesis, in turn, leads to decreased levels of cholic acid (CA), an endogenous bile acid synthesized from cholesterol and …

Machine-Learning Driven Strategies For Adapting Immunotherapy In Metastatic Nsclc, Maliazurina B Saad, Qasem Al-Tashi, Lingzhi Hong, Vivek Verma, Wentao Li, Shenduo Li, Carol C Wu, Brett W Carter, Girish S Shroff, Tina Cascone, Xiuning Le, Yasir Y Elamin, Mehmet Altan, Simon Heeke, Ajay Sheshadri, Joe Y Chang, Percy P Lee, Zhongxing Liao, Don L Gibbons, Ara A Vaporciyan, J Jack Lee, Ignacio I Wistuba, Cara Haymaker, Seyedali Mirjalili, David Jaffray, Justin F Gainor, Yanyan Lou, Alessandro Di Federico, Federica Pecci, Mark Awad, Biagio Ricciuti, John V Heymach, Natalie I Vokes, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs), either as monotherapy (ICI-Mono) or combined with chemotherapy (ICI-Chemo), improves survival in advanced non-small cell lung cancer (NSCLC). However, prospective guidance for choosing between these options remains limited, and single-feature biomarkers like PD-L1 prove inadequate. We develop a machine learning model using clinicogenomic data from four cohorts (MD Anderson n = 750; Mayo Clinic n = 80; Dana-Farber n = 1077; Stand Up To Cancer n = 393) to predict individual benefit from adding chemotherapy. Benefit scores are calculated using five distinct functions derived from 28 genomic and 6 clinical features. Our integrated model, A-STEP (Attention-based …

Imaging Efficacy And Safety Of Low Dose Intraventricular Tissue Plasminogen Activator In Aneurysmal Subarachnoid Hemorrhage: Case Series, Collin Liu, William W Wroe, Hussein A Zeineddine, Bryden Dawes, Michael Giordano, Ching-Jen Chen, Aaron M Gusdon, Huimahn A Choi, Spiros L Blackburn

Faculty, Staff and Student Publications

Introduction: Free hemoglobin's release into CSF from blood breakdown is a primary instigator of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Early clearance of subarachnoid blood with intrathecal (IT) fibrinolytics has shown potential to decrease incidence of DCI. However, the dosage of fibrinolytic needed is not known. We investigated the ability of low dose tissue plasminogen activator (tPA) to rapidly remove subarachnoid clot.

Material and methods: We performed a single center retrospective review of aSAH patients who received IT tPA. Dosing consistent with the CLEAR III trial for IVH was utilized-tPA (1 mg) administered every 8 h via …

The Histone H3 Lysine 36 Demethylase Kdm2a/Fbxl11 Controls Polycomb-Mediated Gene Repression And Germ Cell Development In Male Mice, Michael T Bocker, Grigorios Fanourgakis, Kristie Wetzel, Pavel A Komarov, Hélène Royo, Sunwoo Chun, Hubertus Kohler, Taiping Chen, Xiaohong Mao, Mark A Labow, Reginald A Valdez, Michael B Stadler, Dirk G De Rooij, Paola Capodieci, John Tallarico, Antoine H F M Peters, Thomas B Nicholson

Faculty, Staff and Student Publications

KDM2A/FBXL11 is a Jumonji-domain containing lysine demethylase catalyzing the removal of mono- and di-methyl modifications of histone H3 lysine 36 (H3K36me1/2). While Kdm2a is required for mouse embryogenesis, its role in adult physiology has been largely unexplored. Using conditional deletion approaches, we demonstrate that Kdm2a deficiency leads to testicular atrophy and male infertility. Although spermatogonial stem cells remain unaffected, proliferating and differentiating spermatogonia exhibit delayed cell cycle progression and apoptosis. RNA-sequencing of purified spermatogonia and spermatocytes reveals Kdm2a-dependent repression of over 750 genes during spermatogonial differentiation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrates increased H3K36me2 levels at CpG-rich gene promoters …

Timing Of Nodal Metastasis In Patients With Eyelid Sebaceous Carcinoma And Implications For Surveillance And Survival, Tracy Lu, Casey Anthony, Xinyang Jiang, Jing Ning, Ryan Goepfert

Faculty, Staff and Student Publications

Background/aims: Sebaceous carcinoma (SC) is a rare cancer with periocular predilection. Studies focused on patterns and timing of nodal metastasis are scarce.Our aim is to report patterns of regional nodal metastasis in patients with eyelid SC, including results of sentinel lymph node biopsy (SLNB).

Methods: All consecutive patients with eyelid SC treated during 1999-2023 were retrospectively reviewed.All subjects had standard of care surgery for eyelid SC and regional lymph node evaluation using physical examination and ultrasonography (US) at baseline and during the surveillance period. 38 patients with negative findings on US had SLNB to rule out microscopic metastasis.The frequency and …

An Alternative Neural Basis Underlying Leptin Resistance, Hongli Li, Cunjin Su, Yuanzhong Xu, Mette Q Ludwig, Jon Davis

Faculty, Staff and Student Publications

Overconsumption of a palatable Western diet, a condition linked to central leptin resistance, contributes extensively to the current obesity epidemic. In this context, intensive efforts have focused on detailing the molecular mechanisms underlying leptin resistance. Here, we demonstrate that chronic inhibition of hypothalamic arcuate GABAergic neurons (ArcGABA) effectively reduced diet-induced obesity (DIO). Interestingly, palatable food exposure increased the activity level of ArcGABA neurons, which do not express the leptin receptor (non-LepR neurons; nonresponsive to leptin). Chronic activation of ArcGABA non-LepR neurons led to massive obesity, which was associated with normal leptin-induced pSTAT3 signaling but phenotypic leptin resistance; i.e., high leptin …

Belumosudil Reduces Oral Chronic Graft-Versus-Host Disease Tissue Inflammation And Fibrosis: A Rockstar Companion Study, Rubina Sharma, Noa G Holtzman, Iskra Pusic, Corey Cutler, Nathaniel Treister, Amin S Alousi, Ayesha Javaid, Francis Boksa, Drashty P Mody, Ana C Costa-Da-Silva, Olivier Schueller, Sandrine Macé, Yu Yao, Ran Ji, Beifang Hu, Kathy Marshall, Bruce R Blazar, Stephanie J Lee, Steven Z Pavletic, Jacqueline W Mays

Faculty, Staff and Student Publications

Belumosudil (KD025), an oral, selective, Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Previous studies demonstrated that ROCK2 inhibition reduces blood interleukin-17 (IL-17) activity and promotes regulatory T-cell (Treg cell) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 patients with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSGs], and skin) and the peripheral blood. After belumosudil treatment, reduction in …

Detection Of Oncogenic Fusions In Colorectal Cancer Using A Partner-Agnostic Next-Generation Sequencing Approach, Andrew J Pellatt, Reagan M Barnett, Sante Gnerre, Kristin Edwards, Jason A Willis, Kanwal Raghav, Arvind Dasari, M Pia Morelli, Alisha Bent, Madhulika Eluri, Nicholas Hornstein, Leylah M Drusbosky, Scott Kopetz, Van K Morris

Faculty, Staff and Student Publications

Background: Gene fusions exist with low prevalence in colorectal cancer (CRC), and the clinical utility of fusion testing in advanced CRC remains unclear. We sought to identify oncogenic fusions in patients with advanced CRC using a fusion partner-agnostic circulating tumor DNA (ctDNA) assay to better understand their clinical relevance.

Methods: We performed a retrospective analysis using de-identified data from 18,558 patients with advanced CRC who underwent ctDNA next-generation sequencing with Guardant360® from 2017 to 2022. These samples were subsequently reanalyzed with a partner-agnostic bioinformatics method to identify both clonal and non-clonal fusions. We analyzed for associations between fusions and MSI-H …

Longitudinal Analysis Of Gut Microbiome And Metabolome Correlates Of Response And Toxicity With Idecabtagene Vicleucel, Satabdi Saha, Lubna Rehman, Abdur Rehman, Faezeh Darbaniyan, Donna M Weber, Mahmoud Gaballa, Hans C Lee, Chia-Chi Chang, Reetakshi Arora, Meghan Menges, Salvatore Corallo, Marco L Davila, Frederick L Locke, Mark R Tanner, Sattva S Neelapu, Elizabeth J Shpall, Christopher R Flowers, Robert Z Orlowski, Robert R Jenq, Michael D Jain, Christine Peterson, Doris K Hansen, Neeraj Y Saini, Krina K Patel

Faculty, Staff and Student Publications

Increasing evidence suggests that the gut microbiome may influence the responses and toxicities associated with chimeric antigen receptor T-cell (CAR-T) therapy. We conducted whole-genome shotgun sequencing on stool samples (N = 117) collected at various times from patients with multiple myeloma (n = 33) who underwent idecabtagene vicleucel (ide-cel) anti-B-cell maturation antigen CAR-T therapy. We observed a significant decrease in bacterial diversity after ide-cel infusion, along with significant differences in the bacterial composition linked to therapy response and toxicities. Specifically, we found significant enrichment of Flavonifractor plautii, Bacteroides thetaiotaomicron, Blautia fecis, and Dysosmobacter species in ide-cel responders. A notable finding …

Patient-Centered, Theory-Based, Online Intervention To Promote A Physically Active Lifestyle For People With Multiple Sclerosis: Protocol For A Randomized Controlled Trial, Chungyi Chiu, Vaishnavi Sridharan, Mojtaba Khaliji, Md Refat Uz Zaman Sajib, Xiaotian Gao, Kathleen Zackowski

Children’s Nutrition Research Center Staff Publications

Background: People with multiple sclerosis (MS) experience life challenges due to the nature of disease progression. Although an active lifestyle has been shown effective for symptom and relapse management, most people with MS lead a sedentary lifestyle and do not reach the recommended physical activity (PA) guidelines.

Objective: This study aims to test the preliminary efficacy of a codeveloped, online self-management intervention based on the health action process approach (HAPA) adapted for people with MS to cultivate a physically active lifestyle.

Methods: The 8-week intervention program was developed using community-based participatory research based on the HAPA. The program includes increasing …

Serum Metabolomic Profiling Of Incident Type 2 Diabetes Mellitus In The Multi-Ethnic Study Of Atherosclerosis And Rotterdam Study, Xuanwei Jiang, Fang Zhu, Gonçalo Graça, Xihao Du, Jinjun Ran, Fariba Ahmadizar, Alexis C Wood, Yanqiu Zhou, Denise M Scholtens, Ali Farzaneh, M Arfan Ikram, Alan Kuang, Carel W Le Roux, Meghana D Gadgil, Marilyn C Cornelis, Kent D Taylor, Xiuqing Guo, Mohsen Ghanbari, Laura J Rasmussen-Torvik, Russell P Tracy, Alain G Bertoni, Jerome I Rotter, David M Herrington, Philip Greenland, Maryam Kavousi, Victor W Zhong

Children’s Nutrition Research Center Staff Publications

Objective: This study aimed to investigate serum metabolomic biomarkers associated with incident type 2 diabetes mellitus (T2DM) and evaluate their performance in improving T2DM risk prediction.

Methods: Untargeted proton nuclear magnetic resonance (1H NMR) spectroscopy-based metabolomics analyses were conducted in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 3460; discovery cohort) and The Rotterdam Study (RS; n = 1556; replication cohort). Multivariable cause-specific hazards models were used to analyze the associations between 23 571 serum metabolomic spectral variables and incident T2DM. Replicated metabolites required an false discovery rate-adjusted P < .01 in MESA, P < .05 in RS, and consistent direction of association. Pathway and network analyses were conducted to elucidate biological mechanisms underlying T2DM development. The utility of the replicated metabolites in improving T2DM risk prediction was assessed based on the Framingham Diabetes Risk Score. A 2-sample Mendelian randomization was conducted to assess causal associations.

Results: Nineteen metabolites were significantly associated with incident T2DM. Pathway analyses …

Sensory Neuron-Expressed Fgf13 Controls Nociceptive Signaling In Diabetic Neuropathy Models, Aditya K Singh, Matteo Bernabucci, Nolan M Dvorak, Zahra Haghighijoo, Jessica Di Re, Feni K Kadakia, Olumarotimi O Folorunso, Paul A Wadsworth, Cynthia M Tapia, Pingyuan Wang, Jigong Wang, Haiying Chen, Yu Xue, Jully Singh, Kali Hankerd, Isaac J Gamez, Makenna Kager, Vincent Truong, Patrick Walsh, Stephanie I Shiers, Nishka Kuttanna, Hanyue Liao, Margherita Marchi, Erika Salvi, Ilaria D'Amato, Daniela D'Amico, Parsa Arman, Catharina G Faber, Rayaz A Malik, Marina De Tommaso, Dan Ziegler, Krishna Rajarathnam, Thomas A Green, Peter M Grace, Matthew R Sapio, Michael J Iadarola, Gregory D Cuny, Diana S Chow, Giuseppe Lauria Pinter, Steve Davidson, Dustin P Green, Jun-Ho La, Jin Mo Chung, Jia Zhou, Theodore J Price, Elizabeth Salisbury, Subo Yuan, Fernanda Laezza

Faculty, Staff and Student Publications

Nociception involves complex signaling, yet intrinsic mechanisms bidirectionally regulating this process remain unexplored. Here, we show that the fibroblast growth factor 13 (FGF13)/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception, and that the FGF13/Nav1.7 ratio is upregulated in type 2 diabetic neuropathy (T2DN). PW164, an FGF13/Nav1.7 channel C-terminal tail domain (CTD) PPI interface inhibitor, which reduces complex assembly, selectively suppressed Na+ currents sensitized by capsaicin-induced activation of TRPV1 channels in human induced pluripotent stem cell-derived (hIPSC-derived) sensory neurons and inhibited mechanical and thermal hyperalgesia in mice. FGF13 silencing mimics PW164 activity in culture and in vivo. Conversely, ZL192, an FGF13 …

Antitumor Efficacy Of Intermittent Low-Dose Erlotinib Plus Sulindac Via Mhc Upregulation And Remodeling Of The Immune Cell Niche, Chakrapani Tripathi, Jorge E Tovar Perez, Sabeeta Kapoor, Ahmed Muhsin, Wan Mohaiza Dashwood, Melek Demirhan, Altaf Mohammed, Shizuko Sei, Jacklyn Thompson, Mahira Zaheer, Krishna M Sinha, Powel H Brown, Michelle I Savage, Eduardo Vilar, Praveen Rajendran, Roderick H Dashwood

Faculty, Staff and Student Publications

A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon-γ signaling as a key pathway. In this study, we combine intermittent low-dose ERL ± SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor-associated immune modulation. At clinically relevant doses, short-term (16 weeks) and long-term (46 weeks) ERL ± SUL administration results in near-complete tumor suppression in Pirc colon and duodenum (p < 0.0001). We identify a low-dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice-weekly oral gavage (SUL125 + ERL5 × 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL ± SUL upregulates the corresponding MHC and immune-associated factors in a subset of Pirc colon polyps, Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient-derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 × 2 increases tumor-associated Cd4+ T cells by ~2.6-fold (p < 0.05), with no apparent effect on Cd8+ T cells. The treatment also increases tumor-associated Cd68+ cells (p < 0.05) and decreases Foxp3+ (p < 0.01) and Arg1+ (p < 0.05) cells. Thus, intermittent low-dose ERL + SUL treatment enhances tumor-associated MHC expression and remodels the immune cell niche toward a more permissive "helper" immune microenvironment. We conclude that early immune-interception strategies targeting interferon-γ signaling may benefit FAP patients at drug doses below the clinical standard of care.

Synergistic Activity Of Combined Flt3-Itd And Mdm2 Inhibition With Quizartinib And Milademetan In Flt3-Itd Mutant/Tp53 Wild-Type Acute Myeloid Leukemias, Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Fumie Tanzawa, Dale L Bixby, Harry P Erba, Nikolai Podoltsev, Gary J Schiller, Prasanna Kumar, Arnaud Lesegretain, Takeshi Isoyama, Takahiko Seki, Naval Daver, Michael Andreeff

Faculty, Staff and Student Publications

Purpose: Acute myeloid leukemia (AML) is characterized by frequent mutations in FMS-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild-type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. In this study, we investigated the antileukemic efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3 internal tandem duplication (FLT3-ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase I clinical trial.

Experimental design: Preclinical studies used human and murine cell lines carrying FLT3-ITD and/or tyrosine kinase domain mutations, TP53 WT/knockdown, leukemia cell xenograft models, …

Ctdna Analysis In Erbb2-Amplified Colorectal Cancer: Biomarker Analysis Of The Mypathway Trial, Funda Meric-Bernstam, Kanwal Pratap Singh Raghav, Christopher J Sweeney, Charles Swanton, David R Spigel, Howard A Burris, Carin R Espenschied, Jessica M Grindheim, Julia Malato, Katja Schulze, Richard Price, Razelle Kurzrock

Faculty, Staff and Student Publications

Purpose: A combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P + T), has antitumor activity in HER2-positive colorectal cancer. Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and ctDNA ERBB2 status and ctDNA monitoring for early response and resistance are unknown.

Patients and methods: Eighty-five patients with ERBB2-amplified and/or -overexpressed colorectal cancer were treated with P + T in the MyPathway trial; 42 had ctDNA testing at cycle (C) 1 day (D) 1, and 38 had longitudinal plasma tested for ctDNA. We analyzed the ctDNA versus tissue ERBB2 concordance, genomic co-alterations, and ctDNA …

The Overlooked Impact Of Background Diet And Adherence In Nutrition Trials, Javier I Ottaviani, Hagen Schroeter, Dennis M Bier, John W Erdman, Howard D Sesso, Joann E Manson, Gunter G C Kuhnle

Children’s Nutrition Research Center Staff Publications

Randomised controlled trials in nutrition (RCTN) face unique challenges, including the considerable influence of the background diet and the challenge of assuring intervention adherence by participants. The impact of these factors on the outcome of RCTNs has been difficult to quantify, but nutritional biomarkers represent a valuable tool to address these challenges. Using flavanols as a model dietary intervention and a set of recently validated flavanol biomarkers, we here investigated the impact of background diet and adherence on the outcomes of a subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS, NCT 02422745). We found that 20% of participants …