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Strength And Conditioning Society (Scs) 7th Annual Meeting, Murcia, Spain, 2024, Pedro E. Alcaraz, Konstantinos Spyrou, Anthony J. Blazevich, Tomás T. Freitas, Elena Marín-Cascales, Aarón Manzanares Serrano

Research outputs 2022 to 2026

On behalf of the Strength and Conditioning Society (SCS), we are pleased to present the abstracts submitted for the SCS 7th Annual Meeting. The event was held at the Universidad Católica de Murcia (UCAM) headquarters in Murcia, Spain, on 9–11 October 2024, and comprised several invited sessions by international and national speakers on a variety of topics related to biochemistry and exercise physiology, strength and conditioning practices and their application to health, injury prevention, and sports performance. These included strength training in high-performance sports, sport science and training–competition load management in elite environments, biochemistry and exercise physiology and prescription, nutrition …

Investigating The Effect Of Fasting On Senescent Cells In Nothobranchius Furzeri Fish, Israel A. Akinola

Electronic Theses and Dissertations

Senescent cells (SCs) have been documented to accumulate with age in the organism. Recent studies have shown that reducing the number of SCs in an organism result in tissue rejuvenation and extension of life expectancy. Intermittent fasting is reported to have multiple health benefits and is speculated to reduce the burden of SCs. Nothobranchius furzeri are a new model organism for studying aging and for which there are short- and long-lived strains available. We hypothesize that long- and short-lived strains of N. furzeri will accumulate SCs at different rates; and that fasting will reduce the burden of SCs.

The results …

A Quantitative Study Teaching De-Escalation With Virtual Reality Simulation To Associate Nursing Students Measuring Effectiveness, Learning, And Confidence, Michele Rene Marbet

Doctoral Dissertations and Projects

Workplace violence against nurses is a critical global public health issue, as one in four nurses reportedly experience physical assault by patients. This quantitative quasi-experimental, pretest-posttest study aimed to assess the effectiveness of virtual reality simulation as a teaching strategy for de-escalation education in associate nursing students’ (N = 29) perception in learning and confidence. The study utilized the Simulation Effectiveness Tool-Modified (SET-M) instrument to measure outcomes guided by Kolb's experiential learning theory and the NLN Jeffries simulation theory. The learning variable demonstrated significant improvement as confirmed by paired t-test analysis (p < .01). For the effectiveness and confidence variables, which violated assumptions of normality, a comprehensive statistical approach was implemented. Analysis included parametric testing via paired t-tests, supplemented by nonparametric methods (Wilcoxon Signed-ranks test and Sign test) to ensure statistical rigor. The cumulative results across all three statistical tests consistently demonstrated significant improvements (p < .001). Effect size calculations revealed medium to large significance for all variables measured by Cohen’s d. The conclusive findings of this research included a rejection of all three null hypotheses, which suggests that virtual reality simulation is an effective teaching strategy for developing de-escalation skills, enhancing both learning and confidence among associate nursing students. Future studies are needed to further validate and expand upon the findings of the current research, potentially leading to more widespread adoption of virtual reality simulation in nursing education for teaching de-escalation.

Manganese-Induced Precocious Puberty Alters Mammary Epithelial Cell Proliferation In Female Rats, Alina M. Hamilton, Vinod K. Srivastava, Jill K. Hiney, William L. Dees, Robert K. Dearth

School of Integrative Biological & Chemical Sciences Faculty Publications

Precocious puberty (PP) is an established breast cancer risk factor. In the normal mammary gland, hormone receptor-positive (HR+) cells rarely proliferate. In breast cancer, proliferating epithelial cells are often HR+. It is not known if PP can modify this population of proliferating HR+ cells. Previously, we established a manganese-induced precocious puberty (MnPP) model to study the effects of PP on mammary gland development in female rats. Here, we characterized the distribution of HR+ proliferating mammary epithelial cells in prepubertal and adult rodents, in association with precocious puberty. Female rats were exposed daily to 10 mg/kg manganese chloride or saline (control) …

A Neuroimmune Circuit Mediates Chemo Brain Pathology, Daniel Ahmadi

McKelvey School of Engineering Graduate Student Theses & Dissertations

Chemotherapeutic agents, while effective in targeting malignant tumors, often reduce the patients’ quality of life by inducing fatigue, pain, and motivational deficits. These symptoms are collectively referred to as “chemo brain.” The mechanisms underlying these adverse effects, and specifically whether fatigue and motivational impairments share a common etiology, remain poorly understood. The neural–immune substrates of these symptoms remain obscure, in part because standard preclinical regimens either bypass key systemic signals or introduce local toxicity confounds. Here, I establish and validate a three‑day, low‑dose intravenous cisplatin protocol that avoids peritoneal inflammation and severe renal injury yet produces robust, reversible fatigue and …

Advancing Understanding And Therapeutic Strategies For Nut Sarcomas: Comprehensive Review Of The Literature And Two Cases, Carlos Torrado, Elise Nassif Haddad, Neeta Somaiah, Pavlos Msaouel, Alexander J Lazar, Sarina A Piha-Paul

Faculty, Staff and Student Publications

Soft tissue sarcomas (STSs) are a group of rare cancers, among which nuclear protein in testis (NUT) sarcomas represent an ultra-rare subset driven by NUTM1 gene fusions. This article presents two unique cases of NUT sarcomas and conducts a comprehensive review of the literature to include an additional 61 cases. Our review reveals that NUT sarcoma exhibits a slightly higher incidence among women (male-to-female ratio of 1:1.03) and tends to manifest at a relatively young age (median age of 40 years). The most prevalent NUT partner genes were the MAD family in 52% of patients (33 of 63 patients, including …

Using A Surgical Risk Predictor To Estimate Percutaneous Cryoablation Adverse Event Risk: A Single Center Comparative Analysis, Prisha Patel, Koustav Pal, Hadi Ahmed, Bill Tang, Iwan Paolucci, Mohammad Khavandi, Peiman Habibollahi, Ketan Shah, Steven Y Huang, Bruno C Odisio, Sanjay Gupta, Kamran Ahrar, Steven Yevich, Joshua D Kuban, Alda Tam, Rahul A Sheth

Faculty, Staff and Student Publications

Objective: To evaluate the relevance of established surgical risk calculators for predicting complications in patients undergoing percutaneous lung cryoablation (PLC).

Methods: The institution's database was queried for PLC procedures from March 2015 to May 2024, excluding those patients with concomitant local therapies or five or more lesions treated in a single setting. Demographics, frailty metrics as defined by the surgical literature, and procedural variables were collected. To evaluate the suitability of surgical risk estimate calculators, the requisite demographic data were input into the American College of Surgery surgical risk calculator; estimates for length of stay (LOS), serious complications, 30-day readmission, …

Natural History Models For Lung Cancer: A Scoping Review, Renu Sara Nargund, Sayaka Ishizawa, Maryam Eghbalizarch, Paul Yeh, Seyyed Mostafa Mousavi Janbeh Saray, Sara Nofal, Yimin Geng, Pianpian Cao, Edwin J Ostrin, Rafael Meza, Martin C Tammemägi, Robert J Volk, Maria A Lopez-Olivo, Iakovos Toumazis

Faculty, Staff and Student Publications

Introduction: Natural history models (NHMs) of lung cancer (LC) simulate the disease's natural progression providing a baseline for assessing the impact of interventions. NHMs have been increasingly used to inform public health policies, highlighting their utility. The objective of this scoping review was to summarize existing LC NHMs, identify their limitations, and propose a framework for future NHM development.

Methods: We searched MEDLINE, Embase, Web of Science, and IEEE Xplore from their inception to October 5, 2023, for peer-reviewed, full-length articles with an LC NHM. Model characteristics, their applications, data sources used, and limitations were extracted and narratively synthesized.

Results: …

Tumoral And Circulating Genomic Landscape Inform Survival Differences In Colorectal Carcinomatosis, Michael G White, Reed I Ayabe, Mohammad A Zeineddine, Fadl A Zeineddine, Abdelrahman M G Yousef, Mahmoud Yousef, Norman J Galbraith, J Bryan Iorgulescu, Christopher Scally, Keith Fournier, Timothy E Newhook, Nancy Y You, Jason Willis, Scott Kopetz, George J Chang, John Paul Shen, Abhineet Uppal

Faculty, Staff and Student Publications

Colorectal peritoneal metastases (CPM) are the third most common site of metastatic spread of colorectal cancer and are associated with worse survival than other sites of metastatic disease. In recent years tumoral circulating tumoral DNA (ctDNA) mutational status has been increasingly utilized in clinical decision making for metastatic colorectal cancer patients despite its utility in CPM being poorly understood. Here we describe standard of care performed mutational profiles and associated outcomes for unresectable CPM patients, with a contextual comparison to 160 unresected colorectal liver metastases (CLM) patients. Of 508 patients, 288 (57 %) had CPM alone and 220 (43 %) …

Phase Ii Trial Of Atezolizumab And Bevacizumab For Treatment Of Hpv-Positive Unresectable Or Metastatic Squamous Cell Carcinoma Of The Anal Canal, Van K Morris, Suyu Liu, Kangyu Lin, Haifeng Zhu, Seema Prasad, Armeen Mahvash, Priya Bhosale, Baohua Sun, Edwin R Parra, Ignacio Wistuba, Arjun Peddireddy, James Yao, Julia Mendoza-Perez, Mark Knafl, Scott E Woodman, Cathy Eng, Daniel Halperin

Faculty, Staff and Student Publications

Purpose: Anti-PD-L1 antibodies are associated with responses in < 25% of patients with metastatic human papillomavirus-associated malignancies. VEGF signaling causes immune evasion and immune suppression within the tumor. We evaluated the anti-PD-L1 antibody atezolizumab and anti-VEGF antibody bevacizumab for patients with unresectable, advanced anal cancer.

Patients and methods: For this phase II study, participants with previously treated, immunotherapy-naïve anal cancer received atezolizumab (1,200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST version 1.1). The primary endpoint was the best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pre- and on-treatment biopsies) using a log-rank test.

Results: Among 20 participants, the overall response rate was 11% [95% confidence interval (CI): 1.2-32]. Median progression-free survival and overall survival were 4.1 months (95% CI, 2.6-not …

Pd-L1 Testing, Treatment Patterns, And Clinical Outcomes Among Patients With Metastatic Nsclc At An Academic Medical Center, 2017-2021, Mehmet Altan, Dawen Sui, Cai Xu, George R Simon, Saliha T Sulihem, Donna Malveaux, Darcy Ponce, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, J Jack Lee, Jianjun Zhang, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Melissa L Santorelli, Thomas Burke, Loretta A Williams

Faculty, Staff and Student Publications

Introduction: Targeted therapies and immune checkpoint inhibitors (ICIs) have revolutionized the management of metastatic non-small cell lung cancer (NSCLC) over the past decade.

Methods: This single-center observational study was conducted to describe programmed death-ligand 1 (PD-L1) testing, choice of therapy, and outcomes for adult patients with stage IV NSCLC initiating first-line therapy from 2017 through 2020, with follow-up through June 2021. Patient characteristics and study assessments were described according to four histomolecular subtypes, defined by histologic characteristics and availability of standard-of-care therapies for molecular subgroups at the time of study conduct.

Results: Of 507 eligible patients with metastatic NSCLC, 85 …

Pembrolizumab In Patients With Advanced Miscellaneous Rare Cancers: Results From A Phase 2 Basket Trial, Mirella Nardo, Camila Braganca Xavier, Bettzy Stephen, Jeffrey A How, Justin Moyers, Vivek Subbiah, David S Hong, Aung Naing

Faculty, Staff and Student Publications

Introduction: Rare solid tumors account for one-quarter of cancers among adults in the United States, but few resources have been devoted to their treatment. We evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with rare solid tumors.

Methods: We conducted a phase 2 basket trial that included patients with rare, advanced tumors. Patients were enrolled in the study in nine tumor-specific and a 10th cohort of miscellaneous rare histologies. Patients received pembrolizumab 200 mg intravenously every 21 days. The primary endpoint was the non-progression rate at 27 weeks per immune-related Response Evaluation Criteria in Solid Tumors …

Multiparametric Mri Scoring System Of The Pancreas For The Diagnosis Of Chronic Pancreatitis, Temel Tirkes, Dhiraj Yadav, Darwin L Conwell, Xuandong Zhao, Anil K Dasyam, Vivek Gowdra Halappa, Aashish Patel, Zarine K Shah, Jordan Swensson, Naoki Takahashi, Sudhakar Venkatesh, Ashley Wachsman, Liang Li, Kristofer Jennings, Yunlong Yang, Phil A Hart, Stephen J Pandol, Walter G Park, Santhi Swaroop Vege, Mark Topazian, Paul R Territo, Scott A Persohn, Dana K Andersen, Evan L Fogel, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Background: Ductal features alone may not offer high diagnostic sensitivity or most accurate disease severity of chronic pancreatitis (CP).

Purpose: Diagnose CP based on multiparametric MRI and MRCP features.

Study type: Prospective.

Population: Between February 2019 and May 2021, 46 control (23 males, 49.3 ± 14.1 years), 45 suspected (20 males, 48.7 ± 12.5 years), and 46 definite (20 males, 53.7 ± 14.6 years) CP patients were enrolled at seven hospitals enrolled in the MINIMAP study. CP classification was based on imaging findings and clinical presentation.

Field strength and sequences: 1.5 T. T1-weighted (T1W) spoiled gradient echo, T1 map with …

From Epithelium To Therapy: Transitional Cells In Lung Fibrosis, Sarah Y Shin, Jichao Chen, Irit Milman Krentsis, Yair Reisner, Rodeo Abrencillo, Rahat Hussain, Danielle Wu, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

Patients with idiopathic pulmonary fibrosis and lung fibrosis secondary to infections such as influenza A and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have limited treatment options outside of supportive therapy and lung transplantation. Multiple lung stem cell populations have been implicated in the pathogenesis of lung fibrosis, and more progenitor cell populations continue to be discovered and characterized. In this review, we summarize the functions and differentiation pathways of various cells that constitute the lung epithelium. We then focus on two subpopulations of KRT5

Justification, Margin Values, And Analysis Populations For Oncologic Noninferiority And Equivalence Trials: A Meta-Epidemiological Study, Troy J Kleber, Alexander D Sherry, Andrew J Arifin, Gabrielle S Kupferman, Ramez Kouzy, Joseph Abi Jaoude, Timothy A Lin, Esther J Beck, Avital M Miller, Adina H Passy, Zachary R Mccaw, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

Background: Noninferiority and equivalence trials evaluate whether an experimental therapy's effect on the primary endpoint is contained within an acceptable margin compared with standard of care. The reliability and impact of this conclusion, however, is largely dependent on the justification for this design, the choice of margin, and the analysis population used.

Methods: A meta-epidemiological study was performed of phase 3 randomized noninferiority and equivalence oncologic trials registered at ClinicalTrials.gov. Data were extracted from each trial's registration page and primary manuscript.

Results: We identified 65 noninferiority and 10 equivalence trials that collectively enrolled 61 632 patients. Of these, 61 (81%) …

Enhancing The Safety And Efficacy Of Cell Therapy With Programmed Sense-And-Respond Function, Andrew J Walters, Xiaoyu Yang, Scott D Olson, Caleb J Bashor

Faculty, Staff and Student Publications

No abstract provided.

Race And Clinical Outcomes In Hormone Receptor-Positive, Her2-Negative, Node-Positive Breast Cancer In The Randomized Rxponder Trial, Yara Abdou, William E Barlow, Julie R Gralow, Funda Meric-Bernstam, Kathy S Albain, Daniel F Hayes, Nancy U Lin, Edith A Perez, Lori J Goldstein, Stephen K L Chia, Sukhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Anne F Schott, Steven Shak, Priyanka Sharma, Danika L Lew, Jieling Miao, Joseph M Unger, Debasish Tripathy, Gabriel N Hortobagyi, Lajos Pusztai, Kevin Kalinsky

Faculty, Staff and Student Publications

Background: The phase III RxPONDER trial has affected treatment for node-positive (1-3), hormone receptor-positive, HER2-negative breast cancer with a 21-gene recurrence score (RS) less than 26. We investigated how these findings apply to different racial and ethnic groups within the trial.

Methods: The trial randomly assigned women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS), with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathological characteristics, RS, and treatment.

Results: A total of 4048 …

A Biomarker Signature-Guided Clinical Trial Design For Precision Medicine, Yuan Li, Dejian Lai, Ruosha Li, Han Chen, Xuelin Huang, Jing Ning

Faculty, Staff and Student Publications

Targeted cancer therapies aim to effectively treat patients with specific biomarker profiles. Nevertheless, these therapies may not always precisely hit their intended targets, leading to uncertainty about the specific subset of patients who will benefit. To address this uncertainty, the identification of sensitive patient subsets in clinical trials becomes crucial. Our proposed phase IIB/III clinical trial design seeks to pinpoint a biomarker signature with precision, ensuring the accurate identification of patients who will respond to a specific treatment. This approach allows for the selective enrollment of sensitive patients to maximize benefits for trial participants. We incorporate Bayesian methodology to facilitate …

Chd1 Loss Reprograms Srebp2-Driven Cholesterol Synthesis To Fuel Androgen-Responsive Growth And Castration Resistance In Spop-Mutated Prostate Tumors, Feiyu Chen, Haoyan Li, Yin Wang, Ximing Tang, Kevin Lin, Qidong Li, Chenling Meng, Wei Shi, Javier Leo, Xin Liang, Jie Zhang, Vivien Van, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Maria G Raso, Ana Aparicio, Yue Lu, Daniel E Frigo, Boyi Gan, Di Zhao

Faculty, Staff and Student Publications

Despite undergoing castration, most individuals with prostate cancer (PCa) experience progression to castration-resistant PCa (CRPC), in which the androgen receptor (AR) remains an important driver. Concurrent genetic alterations in SPOP and CHD1 define a unique subtype of PCa, but their interactions in tumor progression and therapy response remain unclear. Here, we provide genetic evidence supporting that CHD1 loss accelerates disease progression and confers resistance to castration in males with SPOP-mutated PCa. By leveraging genetic engineering and multiomics, we uncovered a noncanonical function of CHD1 in lipid metabolism reprogramming via repressing the SREBP2 transcriptome. Loss of CHD1 induces cholesterol production, supplies …

Safety, Efficacy, And Adjacent-Level Fracture Risk Following Vertebral Augmentation And Radiofrequency Ablation For The Treatment Of Spine Metastases In Patients With Cancer, Jeremiah Stringam, Koustav Pal, Andrew Niekamp, Rahim Jiwani, Iwan Paolucci, Joshua D Kuban, Zeyad Metwalli, Steven Huang, Peiman Habibollahi, Stephen Chen, Steven Yevich, Milan Patel, Sumit K Subudhi, Matthew Campbell, Amol Ghia, Claudio Tatsui, Rahul A Sheth

Faculty, Staff and Student Publications

Purpose: To evaluate the safety and efficacy of vertebral augmentation (VA) and radiofrequency ablation (RFA) for treating pathologic spinal fractures in patients with cancer and adjacent fracture risk following treatment.

Materials and Methods: This single-institution retrospective study, conducted from January 2017 to September 2020, included patients with cancer who underwent percutaneous VA with or without spine RFA for pathologic spine compression fractures. The primary outcome was pain reduction, assessed using the 10-point visual analog scale before the procedure, at first follow-up, and 2–4 weeks after the procedure. Logistic regression was performed to identify factors associated with epidural cement leak.

Results: …

Defining The Optimal Radiation-Induced Lymphopenia Metric To Discern Its Survival Impact In Esophageal Cancer, Pim J J Damen, Max Peters, Brian Hobbs, Yiqing Chen, Uwe Titt, Remi Nout, Radhe Mohan, Steven H Lin, Peter S N Van Rossum

Faculty, Staff and Student Publications

Purpose: A detrimental association between radiation-induced lymphopenia (RIL) and oncologic outcomes in patients with esophageal cancer has been established. However, an optimal metric for RIL remains undefined but is important for the application of this knowledge in clinical decision-making and trial designs. The aim of this study was to find the optimal RIL metric discerning survival.

Methods and materials: Patients with esophageal cancer treated with concurrent chemoradiation therapy (CRT; 2004-2022) were selected. Studied metrics included absolute lymphocyte counts (ALCs) and neutrophil counts-and calculated derivatives-at baseline and during CRT. Multivariable Cox regression models for progression-free survival (PFS) and overall survival (OS) …

Oral Microbiome Profile Of The Us Population, Anil K Chaturvedi, Emily Vogtmann, Jianxin Shi, Yukiko Yano, Martin J Blaser, Nicholas A Bokulich, J Gregory Caporaso, Maura L Gillison, Barry I Graubard, Xing Hua, Autumn G Hullings, Lisa Kahle, Rob Knight, Shilan Li, Jody Mclean, Vaishnavi Purandare, Yunhu Wan, Neal D Freedman, Christian C Abnet

Faculty, Staff and Student Publications

Importance: The oral microbiome likely plays key roles in human health. Yet, population-representative characterizations are lacking.

Objective: To characterize the composition, diversity, and correlates of the oral microbiome in US adults.

Design, setting, and participants: This cross-sectional study analyzed data from the population-representative National Health and Nutrition Examination Survey (NHANES) from 2009 to 2012. Microbiome data were made publicly available in 2024. NHANES participants were aged 18 to 69 years and provided oral rinse samples in 1 of 2 consecutive NHANES cycles (2009-2010 and 2011-2012).

Exposures: Demographic, socioeconomic, behavioral, anthropometric, metabolic, and clinical characteristics.

Main outcomes and measures: Oral microbiome …

The Multilayered Transcriptional Architecture Of Glioblastoma Ecosystems, Masashi Nomura, Avishay Spitzer, Kevin C Johnson, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhfury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Roel G W Verhaak, Antonio Iavarone, Mario L Suvà, Itay Tirosh

Faculty, Staff and Student Publications

In isocitrate dehydrogenase wildtype glioblastoma (GBM), cellular heterogeneity across and within tumors may drive therapeutic resistance. Here we analyzed 121 primary and recurrent GBM samples from 59 patients using single-nucleus RNA sequencing and bulk tumor DNA sequencing to characterize GBM transcriptional heterogeneity. First, GBMs can be classified by their broad cellular composition, encompassing malignant and nonmalignant cell types. Second, in each cell type we describe the diversity of cellular states and their pathway activation, particularly an expanded set of malignant cell states, including glial progenitor cell-like, neuronal-like and cilia-like. Third, the remaining variation between GBMs highlights three baseline gene expression …

Deciphering The Longitudinal Trajectories Of Glioblastoma Ecosystems By Integrative Single-Cell Genomics, Avishay Spitzer, Kevin C Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G W Verhaak, Itay Tirosh, Mario L Suvà

Faculty, Staff and Student Publications

The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there …

Glutamate Gating Of Ampa-Subtype Iglurs At Physiological Temperatures, Anish Kumar Mondal, Elisa Carrillo, Vasanthi Jayaraman, Edward C Twomey

Faculty, Staff and Student Publications

Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission1. iGluRs are gated by glutamate, where on glutamate binding, they open their ion channels to enable cation influx into postsynaptic neurons, initiating signal transduction1,2. The structural mechanics of how glutamate gating occurs in full-length iGluRs is not well understood. Here, using the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype iGluR (AMPAR), we identify the glutamate-gating mechanism. AMPAR activation by glutamate is augmented at physiological temperatures. By preparing AMPARs for cryogenic-electron microscopy at these temperatures, we captured the glutamate-gating mechanism. Activation by glutamate initiates ion channel opening that involves all ion …

Rna Sculpting By The Primordial Helix-Clasp-Helix-Strand-Loop (Hch-Sl) Motif Enforces Chemical Recognition Enabling Diverse Kh Domain Functions, John A Tainer, Susan E Tsutakawa

Faculty, Staff and Student Publications

In all domains of life, the ancient K homology (KH) domain superfamily is central to RNA processes including splicing, transcription, posttranscriptional gene regulation, signaling, and translation. Proteins with 1 to 15 KH domains bind single-strand (ss) RNA or DNA with base sequence specificity. Here, we examine over 40 KH domain experimental structures in complex with nucleic acid (NA) and define a novel Helix-clasp-Helix-Strand-Loop (HcH-SL) NA recognition motif binding 4 to 5 nucleotides using 10 to 18 residues. HcH-SL includes and extends the Gly-X-X-Gly (GXXG) signature sequence "clasp" that brings together two helices as an ∼90° helical corner. The first helix …

A Comparison Of Carbon Ions Versus Protons For Integrated Mode Ion Imaging, Mikaël Simard, Ryan Fullarton, Lennart Volz, Christoph Schuy, Daniel G Robertson, Allison Toltz, Colin Baker, Sam Beddar, Christian Graeff, Charles-Antoine Collins Fekete

Faculty, Staff and Student Publications

Background: Incorporating image guidance into ion beam therapy is critical for minimizing beam range uncertainties and realizing the modality's potential. One promising avenue for image guidance is to capture transmission ion radiographs (iRads) before and/or during treatment. iRad image quality is typically maximized using a single-event imaging system, which involves tracking individual ions, albeit the approach is generally not suited to clinical beam settings. An alternative faster and clinically compatible method is integrated mode imaging, where individual pencil beam data is acquired, rather than single ion data. To evaluate the usefulness of transmission ion imaging for image guidance, it is …

Comic: A Bayesian Dose Optimization Design For Drug Combination In Multiple Indications With Application To Car-T Therapies, Kai Chen, Kentaro Takeda, Ying Yuan

Faculty, Staff and Student Publications

Project Optimus, initiated by the US Food and Drug Administration (FDA), seeks to shift the focus of dose finding and selection from the maximum tolerated dose to the optimal dose that offers the most favorable risk-benefit balance. However, applying this paradigm shift to drug combination trials presents challenges, particularly due to limited sample sizes and a large two-dimensional dose exploration space. These challenges are amplified when trials involve multiple indications. To address this, we developed a two-stage Bayesian dose optimization design, called COMIC (Combination Optimization in Multiple IndiCations), to efficiently identify Optimal Biological Dose Combinations (OBDC) for multiple indications. The …

Gene Promoters Are Genomically Encoded To Facilitate Histone Exchange/Incorporation, Blaine Bartholomew

Faculty, Staff and Student Publications

Gene promoters are intrinsically hardwired not only to facilitate transcription preinitiation complex formation but also the release of paused RNA polymerase by H2A.Z. A new PLOS Biology study reveals poly (dA) tracts at promoters positively stimulate H2A.Z incorporation by the SWR complex in yeast.

Lefitolimod In Combination With Ipilimumab In Patients With Advanced Solid Tumors: A Phase I Trial, Mirella Nardo, Mohamed A Gouda, Matthew J Reilley, Amadeo B Biter, Joann Lim, Stacie A Bean, Ly M Nguyen, Priya R Bhosale, Casey R Ager, Coline A Couillault, Sarina A Piha-Paul, Siqing Fu, Apostolia M Tsimberidou, Timothy A Yap, Aung Naing, Jordi Rodon, Vivek Subbiah, Daniel D Karp, Michael A Curran, David S Hong

Faculty, Staff and Student Publications

Introduction: TLR9 agonists are immunomodulators that have been of interest for combined use with cancer immunotherapy. TLR9 agonists, such as lefitolimod (MGN1703), significantly increased Th1 response in preclinical models and have demonstrated efficacy in early clinical trials. This trial assessed the safety and preliminary efficacy of the combination of lefitolimod and ipilimumab in patients with advanced solid tumors.

Methods: This was a single-center, open-label, investigator-initiated phase I trial conducted at The University of Texas MD Anderson Cancer Center. Patients received leftolimod either subcutaneously (at escalating doses of 15-120 mg) or intratumorally (at the maximum feasible dose) in combination with ipilimumab …