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Physical Activity And Sedentary Time Among Us Adolescents Before And During Covid-19: Findings From A Large Cohort Study, Ethan T Hunt, Keith Brazendale, Augusto C F De Moraes, Raja Malkani, Natalia I Heredia, Christopher D Pfledderer, Denver M Brown, Deanna M Hoelscher, Michael W Beets, Robert G Weaver Oct 2024

Physical Activity And Sedentary Time Among Us Adolescents Before And During Covid-19: Findings From A Large Cohort Study, Ethan T Hunt, Keith Brazendale, Augusto C F De Moraes, Raja Malkani, Natalia I Heredia, Christopher D Pfledderer, Denver M Brown, Deanna M Hoelscher, Michael W Beets, Robert G Weaver

Faculty, Staff and Student Publications

INTRODUCTION: Evidence suggests that adolescents engage in less physical activity during the summer break. Less is known regarding physical activity during the summer months of the COVID-19 pandemic.

METHODS: Utilizing data from the Adolescent Brain Cognitive Development study, the authors examined daily activity measured by Fitbit Charge 2 devices before and after the onset of the COVID-19 pandemic during school and summer months. Linear models estimated activity during pre-COVID-19 school, pre-COVID-19 summer, COVID-19 school, and COVID-19 summer.

RESULTS: Participants (N=7,179, aged 11.96 years, 51% female, 51% White) accumulated 8,671.0 (95% CI=8,544.7; 8,797.3) steps, 32.5 (95% CI=30.8, 32.3) minutes of moderate-to-vigorous …


Phenotypic Diversity Of Type Iii Secretion System Activity In Enteropathogenic Escherichia Coli Clinical Isolates, Carmen A Contreras, Tracy H Hazen, Carmen Guadarrama, Ramón Cervantes-Rivera, Theresa J Ochoa, Pablo Vinuesa, David A Rasko, Jose L Puente Oct 2024

Phenotypic Diversity Of Type Iii Secretion System Activity In Enteropathogenic Escherichia Coli Clinical Isolates, Carmen A Contreras, Tracy H Hazen, Carmen Guadarrama, Ramón Cervantes-Rivera, Theresa J Ochoa, Pablo Vinuesa, David A Rasko, Jose L Puente

Faculty, Staff and Student Publications

Introduction. Enteropathogenic Escherichia coli (EPEC) strains pose a significant threat as a leading cause of severe childhood diarrhoea in developing nations. EPEC pathogenicity relies on the type III secretion system (T3SS) encoded by the locus of enterocyte effacement (LEE), facilitating the secretion and translocation of bacterial effector proteins.

Gap Statement. While the regulatory roles of PerC (plasmid-encoded regulator) and GrlA (global regulator of LEE-activator) in ler expression and LEE gene activation are well-documented in the EPEC prototype strain E2348/69, understanding the variability in LEE gene expression control mechanisms among clinical EPEC isolates remains an area requiring further investigation.

Aim. This …


Genomic Biomarkers To Predict Response To Atezolizumab Plus Bevacizumab Immunotherapy In Hepatocellular Carcinoma: Insights From The Imbrave150 Trial, Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Sang-Hee Kang, Kena Park, Hyewon Park, Sunyoung S Lee, Ahmed O Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A Curran, Ji Hoon Kim, Ju-Seog Lee Oct 2024

Genomic Biomarkers To Predict Response To Atezolizumab Plus Bevacizumab Immunotherapy In Hepatocellular Carcinoma: Insights From The Imbrave150 Trial, Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Sang-Hee Kang, Kena Park, Hyewon Park, Sunyoung S Lee, Ahmed O Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A Curran, Ji Hoon Kim, Ju-Seog Lee

Faculty, Staff and Student Publications

Background/aims: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.

Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full …


Feasibility Of Quantitative Relaxometry For Prostate Target Localization And Response Assessment In Magnetic Resonance-Guided Online Adaptive Stereotactic Body Radiotherapy, Ergys Subashi, Eve Locastro, Sarah Burleson, Aditya Apte, Michael Zelefsky, Neelam Tyagi Oct 2024

Feasibility Of Quantitative Relaxometry For Prostate Target Localization And Response Assessment In Magnetic Resonance-Guided Online Adaptive Stereotactic Body Radiotherapy, Ergys Subashi, Eve Locastro, Sarah Burleson, Aditya Apte, Michael Zelefsky, Neelam Tyagi

Faculty, Staff and Student Publications

Purpose: Multiparametric magnetic resonance imaging (MRI) is known to provide predictors for malignancy and treatment outcome. The inclusion of these datasets in workflows for online adaptive planning remains under investigation. We demonstrate the feasibility of longitudinal relaxometry in online MR-guided adaptive stereotactic body radiotherapy (SBRT) to the prostate and dominant intra-prostatic lesion (DIL).

Methods: Fifty patients with intermediate-risk prostate cancer were included in the study. The clinical target volume (CTV) was defined as the prostate gland plus 1 cm of seminal vesicles. The gross tumor volume (GTV) was defined as the DIL identified on multiparametric MRI. Online adaptive radiotherapy was …


Small-Molecule Ccr4 Antagonists In Cutaneous T-Cell Lymphoma, José S Enriquez, Xiaohong Wang, Loka Reddy Velatooru, Wei Han, Pedram Bijani, Xiao Ni Oct 2024

Small-Molecule Ccr4 Antagonists In Cutaneous T-Cell Lymphoma, José S Enriquez, Xiaohong Wang, Loka Reddy Velatooru, Wei Han, Pedram Bijani, Xiao Ni

Faculty, Staff and Student Publications

Mycosis fungoides (MF) and Sézary syndrome (SS) are two most common types of cutaneous T-cell lymphoma (CTCL). Despite advances in understanding the pathogenesis of MF and SS, effective treatments remain limited. CC chemokine receptor-4 (CCR4) is highly expressed on CTCL cells and serves as a great therapeutic target. Mogamulizumab, an FDA-approved anti-CCR4 antibody, has shown efficacy in treating MF/SS; however, its side effects have raised concerns, underscoring the need for more effective and less toxic CCR4-targeted therapies. Although small-molecule CCR4 antagonists have been studied in other diseases involving CCR4+ Th2 cells and regulatory T cells, their effects in CTCL …


Evaluating Dynamic And Predictive Discrimination For Recurrent Event Models: Use Of A Time-Dependent C-Index, Jian Wang, Xinyang Jiang, Jing Ning Oct 2024

Evaluating Dynamic And Predictive Discrimination For Recurrent Event Models: Use Of A Time-Dependent C-Index, Jian Wang, Xinyang Jiang, Jing Ning

Faculty, Staff and Student Publications

Interest in analyzing recurrent event data has increased over the past few decades. One essential aspect of a risk prediction model for recurrent event data is to accurately distinguish individuals with different risks of developing a recurrent event. Although the concordance index (C-index) effectively evaluates the overall discriminative ability of a regression model for recurrent event data, a local measure is also desirable to capture dynamic performance of the regression model over time. Therefore, in this study, we propose a time-dependent C-index measure for inferring the model's discriminative ability locally. We formulated the C-index as a function of time using …


Mhc Hammer Reveals Genetic And Non-Genetic Hla Disruption In Cancer Evolution, Clare Puttick, Thomas P Jones, Michelle M Leung, Felipe Galvez-Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Oriol Pich, Carlos Martinez-Ruiz, Robert Bentham, Krijn K Dijkstra, James R M Black, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A Quezada, Tracerx Consortium, Charles Swanton, Nicholas Mcgranahan Oct 2024

Mhc Hammer Reveals Genetic And Non-Genetic Hla Disruption In Cancer Evolution, Clare Puttick, Thomas P Jones, Michelle M Leung, Felipe Galvez-Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Oriol Pich, Carlos Martinez-Ruiz, Robert Bentham, Krijn K Dijkstra, James R M Black, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A Quezada, Tracerx Consortium, Charles Swanton, Nicholas Mcgranahan

Faculty, Staff and Student Publications

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% …


Biomarker Trajectory For Earlier Detection Of Lung Cancer, Ehsan Irajizad, Johannes F Fahrmann, Iakovos Toumazis, Jody Vykoukal, Jennifer B Dennison, Yu Shen, Kim-Anh Do, Edwin J Ostrin, Ziding Feng, Samir Hanash Oct 2024

Biomarker Trajectory For Earlier Detection Of Lung Cancer, Ehsan Irajizad, Johannes F Fahrmann, Iakovos Toumazis, Jody Vykoukal, Jennifer B Dennison, Yu Shen, Kim-Anh Do, Edwin J Ostrin, Ziding Feng, Samir Hanash

Faculty, Staff and Student Publications

Background: To determine whether an algorithm based on repeated measurements of a panel of four circulating protein biomarkers (4 MP) for lung cancer risk assessment results in improved performance over a single time measurement.

Methods: We conducted data analysis of the 4 MP consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in pre-diagnostic sera from 2483 ever-smoker participants (389 cases and 2094 randomly selected non-cases) in the Prostate, Lung, Colorectal, Ovarian (PLCO) Study who had at least two sequential blood collections over 6 years. A parametric empirical Bayes (PEB) algorithm, which …


Meta-Analysis Of Censored Adverse Events, Xinyue Qi, Shouhao Zhou, Christine B Peterson, Yucai Wang, Xinying Fang, Michael L Wang, Chan Shen Oct 2024

Meta-Analysis Of Censored Adverse Events, Xinyue Qi, Shouhao Zhou, Christine B Peterson, Yucai Wang, Xinying Fang, Michael L Wang, Chan Shen

Faculty, Staff and Student Publications

Meta-analysis is a powerful tool for assessing drug safety by combining treatment-related toxicological findings across multiple studies, as clinical trials are typically underpowered for detecting adverse drug effects. However, incomplete reporting of adverse events (AEs) in published clinical studies is frequently encountered, especially if the observed number of AEs is below a pre-specified study-dependent threshold. Ignoring the censored AE information, often found in lower frequency, can significantly bias the estimated incidence rate of AEs. Despite its importance, this prevalent issue in meta-analysis has received little statistical or analytic attention in the literature. To address this challenge, we propose a Bayesian …


Technical Pitfalls For Fenestrated-Branched Endovascular Aortic Repair Following Petticoat, Aidin Baghbani-Oskouei, Emanuel R Tenorio, Marina Dias-Neto, Andrea Vacirca, Aleem K Mirza, Naveed Saqib, Bernardo C Mendes, Laura Ocasio, Thanila A Macedo, Gustavo S Oderich Oct 2024

Technical Pitfalls For Fenestrated-Branched Endovascular Aortic Repair Following Petticoat, Aidin Baghbani-Oskouei, Emanuel R Tenorio, Marina Dias-Neto, Andrea Vacirca, Aleem K Mirza, Naveed Saqib, Bernardo C Mendes, Laura Ocasio, Thanila A Macedo, Gustavo S Oderich

Faculty, Staff and Student Publications

Purpose: The Provisional Extension to Induce Complete Attachment Technique (PETTICOAT) uses a bare-metal stent to scaffold the true lumen in patients with acute or subacute aortic dissections. While it is designed to facilitate remodeling, some patients with chronic post-dissection thoracoabdominal aortic aneurysms (TAAAs) require repair. This study describes the technical pitfalls of fenestrated-branched endovascular aortic repair (FB-EVAR) in patients who underwent prior PETTICOAT repair.

Technique: We report 3 patients with extent II TAAAs who had prior bare-metal dissection stents treated by FB-EVAR. Two patients required maneuvers to reroute the aortic guidewire, which was initially placed in-between stent struts. This was …


Cross-Silo Federated Learning With Record-Level Personalized Differential Privacy, Junxu Liu, Jian Lou, Li Xiong, Jinfei Liu, Xiaofeng Meng Oct 2024

Cross-Silo Federated Learning With Record-Level Personalized Differential Privacy, Junxu Liu, Jian Lou, Li Xiong, Jinfei Liu, Xiaofeng Meng

Faculty, Staff and Student Publications

Federated learning (FL) enhanced by differential privacy has emerged as a popular approach to better safeguard the privacy of client-side data by protecting clients’ contributions during the training process. Existing solutions typically assume a uniform privacy budget for all records and provide one-size-fits-all solutions that may not be adequate to meet each record’s privacy requirement. In this paper, we explore the uncharted territory of cross-silo FL with record-level personalized differential privacy. We devise a novel framework named rPDP-FL, employing a two-stage hybrid sampling scheme with both uniform client-level sampling and non-uniform record-level sampling to accommodate varying privacy requirements.

A …


Enhanced Privacy Bound For Shuffle Model With Personalized Privacy, Yixuan Liu, Yuhan Liu, Li Xiong, Yujie Gu, Hong Chen Oct 2024

Enhanced Privacy Bound For Shuffle Model With Personalized Privacy, Yixuan Liu, Yuhan Liu, Li Xiong, Yujie Gu, Hong Chen

Faculty, Staff and Student Publications

The shuffle model of Differential Privacy (DP) is an enhanced privacy protocol which significantly amplifies the central DP guarantee by anonymizing and shuffling the local randomized data. Yet, deriving a tight privacy bound is challenging due to its complicated randomization protocol. While most existing works focused on uniform local privacy settings, this work focuses on a more practical personalized privacy setting. To bound the privacy after shuffling, we need to capture the probability of each user generating clones of the neighboring data points and quantify the indistinguishability between two distributions of the number of clones on neighboring datasets. Existing works …


Precurious: How Innocent Pre-Trained Language Models Turn Into Privacy Traps, Ruixuan Liu, Tianhao Wang, Yang Cao, Li Xiong Oct 2024

Precurious: How Innocent Pre-Trained Language Models Turn Into Privacy Traps, Ruixuan Liu, Tianhao Wang, Yang Cao, Li Xiong

Faculty, Staff and Student Publications

The pre-training and fine-tuning paradigm has demonstrated its effectiveness and has become the standard approach for tailoring language models to various tasks. Currently, community-based platforms offer easy access to various pre-trained models, as anyone can publish without strict validation processes. However, a released pre-trained model can be a privacy trap for fine-tuning datasets if it is carefully designed. In this work, we propose PreCurious framework to reveal the new attack surface where the attacker releases the pre-trained model and gets a black-box access to the final fine-tuned model. PreCurious aims to escalate the general privacy risk of both membership inference …


Cellular Prion Protein Acts As Mediator Of Amyloid Beta Uptake By Caveolin-1 Causing Cellular Dysfunctions In Vitro And In Vivo, Angela Da Silva Correia, Matthias Schmitz, Anna-Lisa Fischer, Susana Da Silva Correia, Franco L Simonetti, Gesine Saher, Roberto Goya-Maldonado, Amandeep Singh Arora, Andre Fischer, Tiago F Outeiro, Inga Zerr Oct 2024

Cellular Prion Protein Acts As Mediator Of Amyloid Beta Uptake By Caveolin-1 Causing Cellular Dysfunctions In Vitro And In Vivo, Angela Da Silva Correia, Matthias Schmitz, Anna-Lisa Fischer, Susana Da Silva Correia, Franco L Simonetti, Gesine Saher, Roberto Goya-Maldonado, Amandeep Singh Arora, Andre Fischer, Tiago F Outeiro, Inga Zerr

Faculty, Staff and Student Publications

Introduction: Cellular prion protein (PrPC) was implicated in amyloid beta (Aβ)-induced toxicity in Alzheimer's disease (AD), but the precise molecular mechanisms involved in this process are unclear.

Methods: Double transgenic mice were generated by crossing Prnp knockout (KO) with 5xFAD mice, and light-sheet microscopy was used for whole brain tissue analyses. PrPC-overexpressing cells were developed for in vitro studies, and microscopy was used to assess co-localization of proteins of interest. Surface-plasmon resonance (SPR) was used to investigate protein-binding characteristics.

Results: In vivo, PrPC levels correlated with reduced lifespan and cognitive and motor function, and its ablation disconnected behavior deficits from …


Impact Of Frailty And Delirium Among Older Adults Admitted With Acute Decompensated Heart Failure, Jorge A Irizarry-Caro, Manish Kumar, Qian Wang, Namit Rohant, Parag Goyal, Abdulla A Damluji, James N Kirkpatrick, Min Ji Kwak Oct 2024

Impact Of Frailty And Delirium Among Older Adults Admitted With Acute Decompensated Heart Failure, Jorge A Irizarry-Caro, Manish Kumar, Qian Wang, Namit Rohant, Parag Goyal, Abdulla A Damluji, James N Kirkpatrick, Min Ji Kwak

Faculty, Staff and Student Publications

Background: The presence of frailty or delirium among patients hospitalized for acute decompensated heart failure (ADHF) is associated with increased mortality and prolonged hospital stay.

Objectives: The purpose of this study was to assess the combined effect of frailty and delirium on in-hospital mortality and disposition at discharge among older adults hospitalized with ADHF.

Methods: We conducted a retrospective observational study using Nationwide Inpatient Sample data from the Agency for Healthcare Research and Quality from 2016 to 2018. Patients aged 65 years or older with a diagnosis of ADHF (both with preserved and reduced left ventricular ejection fraction) were included. …


Outcomes In Solid Organ Transplant Recipients Receiving Organs From A Donor With Fusarium Solani Species Complex Meningitis, Isabel S Griffin, Dallas J Smith, Pallavi Annambhotla, Jeremy A W Gold, Luis Ostrosky-Zeichner, Carol A Kauffman, Lalitha Gade, Anastasia Litvintseva, Daniel Zp Friedman, Angie G Nishio Lucar, Tarina C Parpia, Joshua Lieberman, Janet Bujan, Julie Corkrean, Mukul K Divatia, Kevin Grimes, Jiejian Lin, Constance Mobley, Mary R Schwartz, Bashar Hannawi, Anne Malilay, Anne O'Boye, Jeffrey Lysne, Mrinalini Venkata Subramani, Hayley Heckmann, Venice Servellita, Charles Chiu, Sridhar V Basavaraju Oct 2024

Outcomes In Solid Organ Transplant Recipients Receiving Organs From A Donor With Fusarium Solani Species Complex Meningitis, Isabel S Griffin, Dallas J Smith, Pallavi Annambhotla, Jeremy A W Gold, Luis Ostrosky-Zeichner, Carol A Kauffman, Lalitha Gade, Anastasia Litvintseva, Daniel Zp Friedman, Angie G Nishio Lucar, Tarina C Parpia, Joshua Lieberman, Janet Bujan, Julie Corkrean, Mukul K Divatia, Kevin Grimes, Jiejian Lin, Constance Mobley, Mary R Schwartz, Bashar Hannawi, Anne Malilay, Anne O'Boye, Jeffrey Lysne, Mrinalini Venkata Subramani, Hayley Heckmann, Venice Servellita, Charles Chiu, Sridhar V Basavaraju

Faculty, Staff and Student Publications

Background: Five organs (heart, right lung, liver, right, and left kidneys) from a deceased patient were transplanted into five recipients in four US states; the deceased patient was identified as part of a healthcare-associated fungal meningitis outbreak among patients who underwent epidural anesthesia in Matamoros, Mexico.

Methods: After transplant surgeries occurred, Fusarium solani species complex, a fungal pathogen with a high case-mortality rate, was identified in cerebrospinal fluid from the organ donor by metagenomic next-generation sequencing (mNGS) and fungal-specific polymerase chain reaction and in plasma by mNGS.

Results: Four of five transplant recipients received recommended voriconazole prophylaxis; four were monitored …


Neoadjuvant And Adjuvant Treatments For Early Stage Resectable Nsclc: Consensus Recommendations From The International Association For The Study Of Lung Cancer, Jonathan D Spicer, Tina Cascone, Murry W Wynes, Myung-Ju Ahn, Sanja Dacic, Enriqueta Felip, Patrick M Forde, Kristin A Higgins, Mark G Kris, Tetsuya Mitsudomi, Mariano Provencio, Suresh Senan, Benjamin J Solomon, Ming Sound Tsao, Masahiro Tsuboi, Heather A Wakelee, Yi-Long Wu, James Chih-Hsin Yang, Caicun Zhou, David H Harpole, Karen L Kelly Oct 2024

Neoadjuvant And Adjuvant Treatments For Early Stage Resectable Nsclc: Consensus Recommendations From The International Association For The Study Of Lung Cancer, Jonathan D Spicer, Tina Cascone, Murry W Wynes, Myung-Ju Ahn, Sanja Dacic, Enriqueta Felip, Patrick M Forde, Kristin A Higgins, Mark G Kris, Tetsuya Mitsudomi, Mariano Provencio, Suresh Senan, Benjamin J Solomon, Ming Sound Tsao, Masahiro Tsuboi, Heather A Wakelee, Yi-Long Wu, James Chih-Hsin Yang, Caicun Zhou, David H Harpole, Karen L Kelly

Faculty, Staff and Student Publications

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer …


Mutational Characteristics And Clinical Outcomes For Lung Adenocarcinoma With Egfr Germline Mutations, Kelsey Pan, Jennifer Owens, Yasir Elamin, Charles Lu, Mark Routbort, Jianjun Zhang, Frank Fossella, Marcelo V Negrao, Mehmet Altan, Jenny Pozadzides, Ferdinandos Skoulidis, Anne Tsao, Tina Cascone, John V Heymach, Edwin Ostrin, Xiuning Le Oct 2024

Mutational Characteristics And Clinical Outcomes For Lung Adenocarcinoma With Egfr Germline Mutations, Kelsey Pan, Jennifer Owens, Yasir Elamin, Charles Lu, Mark Routbort, Jianjun Zhang, Frank Fossella, Marcelo V Negrao, Mehmet Altan, Jenny Pozadzides, Ferdinandos Skoulidis, Anne Tsao, Tina Cascone, John V Heymach, Edwin Ostrin, Xiuning Le

Faculty, Staff and Student Publications

Introduction: Germline mutations driving lung cancer have been infrequently reported in the literature, with EGFR T790M being a known germline mutation identified in 1% of NSCLCs. Typically, a somatic EGFR mutation is acquired to develop lung adenocarcinoma. Osimertinib has become a standard-of-care treatment for EGFR T790M-positive lung cancer.

Methods: We perform a retrospective analysis through the Lung Cancer Moon Shot GEMINI database at the University of Texas MD Anderson Cancer Center. Of the patients that underwent cell-free DNA analysis, germline mutations were identified by those with high variant allelic fraction approximating 50%, followed by further confirmation on genetic testing.

Results: …


Multifocal, Multiphenotypic Tumours Arising From An Mtor Mutation Acquired In Early Embryogenesis, Clarissa N Pacyna, Madhanagopal Anandapadamanaban, Kevin W Loudon, Iain M Hay, Olga Perisic, Ruoyan Li, Matthew Byrne, Laura Allen, Kirsty Roberts, Yvette Hooks, Anne Y Warren, Grant D Stewart, Menna R Clatworthy, Sarah A Teichmann, Sam Behjati, Peter J Campbell, Roger L Williams, Thomas J Mitchell Oct 2024

Multifocal, Multiphenotypic Tumours Arising From An Mtor Mutation Acquired In Early Embryogenesis, Clarissa N Pacyna, Madhanagopal Anandapadamanaban, Kevin W Loudon, Iain M Hay, Olga Perisic, Ruoyan Li, Matthew Byrne, Laura Allen, Kirsty Roberts, Yvette Hooks, Anne Y Warren, Grant D Stewart, Menna R Clatworthy, Sarah A Teichmann, Sam Behjati, Peter J Campbell, Roger L Williams, Thomas J Mitchell

Faculty, Staff and Student Publications

Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared MTOR mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. …


Dual Targeting Macrophages And Microglia Is A Therapeutic Vulnerability In Models Of Pten-Deficient Glioblastoma, Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B Heimberger, Peiwen Chen Oct 2024

Dual Targeting Macrophages And Microglia Is A Therapeutic Vulnerability In Models Of Pten-Deficient Glioblastoma, Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B Heimberger, Peiwen Chen

Faculty, Staff and Student Publications

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent …


Challenges And Opportunities For Early Phase Clinical Trials Of Novel Drug-Radiotherapy Combinations: Recommendations From Nrg Oncology, The American Society For Radiation Oncology (Astro), The American College Of Radiology (Acr), The Sarah Cannon Research Institute, And The American College Of Radiation Oncology (Acro), Zachary S Zumsteg, Siddharth Sheth, Salma K Jabbour, Krishnan R Patel, Randall J Kimple, Terence M Williams, Meng Xu-Welliver, Pedro A Torres-Saavedra, Arta M Monjazeb, Jyoti Mayadev, Steven E Finkelstein, John M Buatti, Sandip P Patel, Steven H Lin Oct 2024

Challenges And Opportunities For Early Phase Clinical Trials Of Novel Drug-Radiotherapy Combinations: Recommendations From Nrg Oncology, The American Society For Radiation Oncology (Astro), The American College Of Radiology (Acr), The Sarah Cannon Research Institute, And The American College Of Radiation Oncology (Acro), Zachary S Zumsteg, Siddharth Sheth, Salma K Jabbour, Krishnan R Patel, Randall J Kimple, Terence M Williams, Meng Xu-Welliver, Pedro A Torres-Saavedra, Arta M Monjazeb, Jyoti Mayadev, Steven E Finkelstein, John M Buatti, Sandip P Patel, Steven H Lin

Faculty, Staff and Student Publications

NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug-drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug-radiotherapy combinations.


Mechanisms By Which The Intratumoral Microbiome May Potentiate Immunotherapy Response, Dalissa Negrón-Figueroa, Lauren E Colbert Oct 2024

Mechanisms By Which The Intratumoral Microbiome May Potentiate Immunotherapy Response, Dalissa Negrón-Figueroa, Lauren E Colbert

Faculty, Staff and Student Publications

No abstract provided.


Lower Intensity Therapy With Cladribine/Low Dose Cytarabine/Venetoclax In Older Patients With Acute Myeloid Leukemia Compares Favorably With Intensive Chemotherapy Among Patients Undergoing Allogeneic Stem Cell Transplantation, Jayastu Senapati, Hagop M Kantarjian, Alexandre Bazinet, Patrick Reville, Nicholas J Short, Naval Daver, Gautam Borthakur, Alex Bataller, Elias Jabbour, Courtney Dinardo, Fadi Haddad, Koji Sasaki, Uday Popat, Betul Oran, Amin M Alousi, Sanam Loghavi, Elizabeth Shpall, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M Kadia Oct 2024

Lower Intensity Therapy With Cladribine/Low Dose Cytarabine/Venetoclax In Older Patients With Acute Myeloid Leukemia Compares Favorably With Intensive Chemotherapy Among Patients Undergoing Allogeneic Stem Cell Transplantation, Jayastu Senapati, Hagop M Kantarjian, Alexandre Bazinet, Patrick Reville, Nicholas J Short, Naval Daver, Gautam Borthakur, Alex Bataller, Elias Jabbour, Courtney Dinardo, Fadi Haddad, Koji Sasaki, Uday Popat, Betul Oran, Amin M Alousi, Sanam Loghavi, Elizabeth Shpall, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M Kadia

Faculty, Staff and Student Publications

Background: Allogeneic stem cell transplantation (SCT) remains the best consolidative modality in most patients with acute myeloid leukemia (AML). Along with factors directly pertaining to SCT, pretransplantation disease control, performance status, and prior treatment-related complications are important factors that affect posttransplantation survival outcomes.

Methods: The authors compared the survival outcomes of patients ≥60 years of age treated on the phase 2 clinical trial of venetoclax (Ven) added to cladribine (CLAD) and low dose cytarabine (LDAC) alternating with azacitidine (CLAD/LDAC/Ven arm) (NCT03586609) who underwent allogeneic SCT in first remission to a retrospective cohort of patients ≥60 years of age …


Drug-Resistant Epilepsy In Tuberous Sclerosis Complex Is Associated With Tsc2 Genotype: More Findings From The Preventing Epilepsy Using Vigatrin (Prevent) Trial, Laura S Farach, Melissa A Richard, Aynara C Wulsin, Elizabeth M Bebin, Darcy A Krueger, Mustafa Sahin, Brenda E Porter, Tarrant O Mcpherson, Jurriaan M Peters, Sarah O'Kelley, Katherine S Taub, Rajsekar Rajaraman, Stephanie C Randle, William M Mcclintock, Mary Kay Koenig, Michael D Frost, Klaus Werner, Danielle A Nolan, Michael Wong, Gary Cutter, Hope Northrup, Kit Sing Au Oct 2024

Drug-Resistant Epilepsy In Tuberous Sclerosis Complex Is Associated With Tsc2 Genotype: More Findings From The Preventing Epilepsy Using Vigatrin (Prevent) Trial, Laura S Farach, Melissa A Richard, Aynara C Wulsin, Elizabeth M Bebin, Darcy A Krueger, Mustafa Sahin, Brenda E Porter, Tarrant O Mcpherson, Jurriaan M Peters, Sarah O'Kelley, Katherine S Taub, Rajsekar Rajaraman, Stephanie C Randle, William M Mcclintock, Mary Kay Koenig, Michael D Frost, Klaus Werner, Danielle A Nolan, Michael Wong, Gary Cutter, Hope Northrup, Kit Sing Au

Faculty, Staff and Student Publications

Background: Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE.

Methods: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to …


Collision Tumor: Multinodular And Vacuolating Neuronal Tumor With Isocitrate Dehydrogenase-Mutant Diffuse Astrocytoma, Vinodh A Kumar, Alejandro Perez, Angela L Young, Julia Jones, Barbara J O'Brien, Frederick F Lang, Jason T Huse, Gregory N Fuller Oct 2024

Collision Tumor: Multinodular And Vacuolating Neuronal Tumor With Isocitrate Dehydrogenase-Mutant Diffuse Astrocytoma, Vinodh A Kumar, Alejandro Perez, Angela L Young, Julia Jones, Barbara J O'Brien, Frederick F Lang, Jason T Huse, Gregory N Fuller

Faculty, Staff and Student Publications

Herein, we report a case of a collision tumor involving a multinodular and vacuolating neuronal tumor (MVNT) and a diffuse astrocytoma. A collision tumor between these two entities has not previously been reported. The patient is a 35-year-old woman who presented with new-onset hearing loss and ringing in her right ear. Magnetic resonance imaging identified a non-enhancing mass involving the gray matter and subcortical white matter of the left middle frontal gyrus. Additionally, tiny clustered nodules were noted along the underlying subcortical ribbon and superficial subcortical white matter of the left superior frontal gyrus. The patient underwent a left frontal …


Asxl1/Tet2 Genotype-Based Risk Stratification Outperforms Asxl1 Mutational Impact And Is Independent Of Mutant Variant Allele Fractions In Chronic Myelomonocytic Leukemia, Clifford M Csizmar, Mark Gurney, Rashmi Kanagal-Shamanna, Kelly Chien, Danielle Hammond, Terra L Lasho, Christy M Finke, Christopher Dean, Anuya Natu, Abhishek A Mangaonkar, Aref Al-Kali, Naseema Gangat, Ayalew Tefferi, Hassan Alkhateeb, Guillermo Garcia-Manero, Rami S Komrokji, Najla A Ali, Eric Padron, Guillermo Montalban-Bravo, Mrinal M Patnaik Oct 2024

Asxl1/Tet2 Genotype-Based Risk Stratification Outperforms Asxl1 Mutational Impact And Is Independent Of Mutant Variant Allele Fractions In Chronic Myelomonocytic Leukemia, Clifford M Csizmar, Mark Gurney, Rashmi Kanagal-Shamanna, Kelly Chien, Danielle Hammond, Terra L Lasho, Christy M Finke, Christopher Dean, Anuya Natu, Abhishek A Mangaonkar, Aref Al-Kali, Naseema Gangat, Ayalew Tefferi, Hassan Alkhateeb, Guillermo Garcia-Manero, Rami S Komrokji, Najla A Ali, Eric Padron, Guillermo Montalban-Bravo, Mrinal M Patnaik

Faculty, Staff and Student Publications

No abstract provided.


Downregulation Of Uba1 Expression In Myelodysplastic Neoplasm, Yue Wei, Hong Zheng, Ziyi Li, Pamela Pennington Lockyer, Faezeh Darbaniyan, Rashmi Kanagal-Shamanna, Hui Yang, Danielle Hammond, Guillermo Garcia-Manero Oct 2024

Downregulation Of Uba1 Expression In Myelodysplastic Neoplasm, Yue Wei, Hong Zheng, Ziyi Li, Pamela Pennington Lockyer, Faezeh Darbaniyan, Rashmi Kanagal-Shamanna, Hui Yang, Danielle Hammond, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

No abstract provided.


Pregnancy Outcomes In Patients With Hepatitis C Virus Infection, Brenna L Hughes, Grecio J Sandoval, George R Saade, Rebecca G Clifton, Uma M Reddy, Anna Bartholomew, Ashley Salazar, Edward K Chien, Alan T N Tita, John M Thorp, Torri D Metz, Ronald J Wapner, Vishaka Sabharwal, Hyagriv N Simhan, Geeta K Swamy, Kent D Heyborne, Baha M Sibai, William A Grobman, Yasser Y El-Sayed, Brian M Casey, Samuel Parry, George A Macones, Mona Prasad Oct 2024

Pregnancy Outcomes In Patients With Hepatitis C Virus Infection, Brenna L Hughes, Grecio J Sandoval, George R Saade, Rebecca G Clifton, Uma M Reddy, Anna Bartholomew, Ashley Salazar, Edward K Chien, Alan T N Tita, John M Thorp, Torri D Metz, Ronald J Wapner, Vishaka Sabharwal, Hyagriv N Simhan, Geeta K Swamy, Kent D Heyborne, Baha M Sibai, William A Grobman, Yasser Y El-Sayed, Brian M Casey, Samuel Parry, George A Macones, Mona Prasad

Faculty, Staff and Student Publications

Objective: To evaluate the risks of adverse maternal and neonatal outcomes associated with pregnancies complicated by hepatitis C virus (HCV) infection.

Methods: This is a secondary analysis of a multicenter prospective cohort study of HCV infection in pregnancy. Participants were screened for HCV infection with serum antibody tests, and each participant with a positive HCV result (case group) was matched with up to two individuals with negative HCV results (control group) prospectively by gestational age (±2 weeks) at enrollment. Maternal outcomes included gestational diabetes, abruption, preeclampsia or gestational hypertension, cholestasis, and preterm delivery. Neonatal outcomes included hyperbilirubinemia, admission to neonatal …


Incidence Of Ipsilateral Femoral Neck And Shaft Fractures In Pediatric And Adolescent Patients, Timothy C Borden, Layla A Haidar, Rohini M Vanodia, Sree M Vemu, Garrett S Dennis, Surya N Mundluru, Lindsay M Crawford, Jessica L Traver, Shiraz A Younas, Joshua L Gary, Mark L Prasarn, Timothy S Achor, John W Munz, Alfred A Mansour Oct 2024

Incidence Of Ipsilateral Femoral Neck And Shaft Fractures In Pediatric And Adolescent Patients, Timothy C Borden, Layla A Haidar, Rohini M Vanodia, Sree M Vemu, Garrett S Dennis, Surya N Mundluru, Lindsay M Crawford, Jessica L Traver, Shiraz A Younas, Joshua L Gary, Mark L Prasarn, Timothy S Achor, John W Munz, Alfred A Mansour

Faculty, Staff and Student Publications

Objectives: To identify the incidence, patient characteristics, and effectiveness of radiographic screening methods for detecting ipsilateral femoral neck and shaft fractures in pediatric and adolescent trauma patients.

Design: Retrospective cohort study.

Setting: This study was conducted at a tertiary pediatric trauma hospital.

Patient selection criteria: Patients younger than 18 years treated for a femoral shaft fracture between 2004 and 2018 were reviewed. Pathologic (metabolic bone disease or bone lesion), periprosthetic, and penetrating traumatic femoral shaft fractures were excluded.

Outcome measurements and comparisons: Patient demographics, mechanisms of injury, treatment methods, and associated injuries were analyzed. Pretreatment x-rays and computed tomography (CT) …


Percutaneous Sacral Screw Fixation Alone Sufficient For Mildly Displaced U-Type Sacral Fractures With Preserved Osseous Fixation Pathways, Augustine M Saiz, Patrick J Kellam, Adeet Amin, Zachary Arambula, Abhi Rashiwala, Joshua L Gary, Stephen J Warner, Milton Routt, Jonathan G Eastman Oct 2024

Percutaneous Sacral Screw Fixation Alone Sufficient For Mildly Displaced U-Type Sacral Fractures With Preserved Osseous Fixation Pathways, Augustine M Saiz, Patrick J Kellam, Adeet Amin, Zachary Arambula, Abhi Rashiwala, Joshua L Gary, Stephen J Warner, Milton Routt, Jonathan G Eastman

Faculty, Staff and Student Publications

Purpose: To describe U-type sacral fracture characteristics amenable to percutaneous sacral screw fixation.

Methods: U-type sacral fractures were identified from a trauma registry at a level 1 trauma center from 2014 to 2020. Patient demographics, injury mechanism, fracture characteristics, and fixation construct were retrospectively retrieved. Associations between fracture pattern and surgical fixation were identified.

Results: 82 U-type sacral fractures were reviewed. Six treated with lumbopelvic fixation (LPF) and 76 were treated with percutaneous sacral screws (PSS) alone. Patients receiving LBF had greater sacral fracture displacement in coronal, sagittal, and axial planes compared to patients receiving PSS alone (P < 0.05), negating osseous fixation pathways. All patients went onto sacral union and there were no implant failures or unplanned reoperations for either group.

Conclusion: If …