Life Sciences Commons^™

Understanding The Treatment Paradigm And The Sequencing Of Antiglaucoma Fixed-Dose Combinations In A Tertiary Center In South India, Ronnie George, Praggya Mishra, Balekudaru Shantha, Lingam Vijaya, Nitin Maksane, Neha Gurha

Student and Faculty Publications

PURPOSE: To analyze the medical management of primary open-angle glaucoma (POAG) and ocular hypertension (OHT) and the placement of fixed-drug combination drugs (FDC) in the treatment paradigm at a tertiary eye care center in South India.

METHODS: Retrospective study (January 2011-December 2015) of newly diagnosed POAG and OHT patients (≥18 years) with ≥5 years follow-up. Primary outcome included percentage use of different antiglaucoma drugs (at initiation) and FDCs at the first, second, and third progression (sequencing). Secondary outcomes: Percentage discontinuation for different FDCs, efficacy parameters (decrease in intraocular pressure (IOP)/visual field), adverse events, and the median number of antiglaucoma medications …

Clinical Features And Genomic Epidemiology Of Bloodstream Infections Due To Enterococcal Species Other Than Enterococcus Faecalis Or E Faecium In Patients With Cancer, Dierdre B Axell-House, Patrycja A Ashley, Stephanie L Egge, Truc T Tran, Claudia Pedroza, Meng Zhang, An Q Dinh, Shelby R Simar, Pranoti V Sahasrabhojane, William R Miller, Samuel A Shelburne, Blake M Hanson, Cesar A Arias

Student and Faculty Publications

BACKGROUND: Non–Enterococcus faecium, non–E. faecalis (NFF) enterococci are a heterogeneous group of clinically pathogenic enterococci that include species with intrinsic low-level vancomycin resistance. Patients with cancer are at increased risk for bacteremia with NFF enterococci, but their clinical and molecular epidemiology have not been extensively described.

METHODS: We conducted a retrospective review of all patients (n = 70) with NFF bacteremia from 2016 to 2022 at a major cancer center. The main outcomes assessed were 30-day mortality, microbiological failure (positive blood cultures for ≥4 days), and recurrence of bacteremia (positive blood cultureclearance). Whole-genome sequencing was performed on all …

Us Filipino Adults Have Elevated Prevalence Of Hypertension Across The Adult Lifespan: Findings From A Cross-Sectional Electronic Health Record Study, Nancy P Gordon, Irvin C Lien, Jamal S Rana, Joan C Lo

Student and Faculty Publications

INTRODUCTION: The prevalence of hypertension increases with age and differs by race and ethnicity. Among U.S. Asian adults, prevalence is higher for Filipino adults than for other major Asian subgroups, but whether this disparity exists across the adult lifespan is unknown. This study examined hypertension prevalence by age decade, comparing Filipino adults with South Asian, Chinese, Black, Hispanic, and White adults.

METHODS: This cross-sectional study used 2015-2016 electronic health record data from a Northern California integrated healthcare delivery system for 1,839,603 adults aged 30-79 years, including 128,124 Filipino adults. Hypertension was defined by diagnosis codes. Sex-specific prevalence was calculated by …

Associations Between Radiation Oncologist Demographic Factors And Segmentation Similarity Benchmarks: Insights From A Crowd-Sourced Challenge Using Bayesian Estimation, Kareem A Wahid, Onur Sahin, Suprateek Kundu, Diana Lin, Anthony Alanis, Salik Tehami, Serageldin Kamel, Simon Duke, Michael V Sherer, Mathis Rasmussen, Stine Korreman, David Fuentes, Michael Cislo, Benjamin E Nelms, John P Christodouleas, James D Murphy, Abdallah S R Mohamed, Renjie He, Mohammed A Naser, Erin F Gillespie, Clifton D Fuller

Student and Faculty Publications

PURPOSE: The quality of radiotherapy auto-segmentation training data, primarily derived from clinician observers, is of utmost importance. However, the factors influencing the quality of clinician-derived segmentations are poorly understood; our study aims to quantify these factors.

METHODS: Organ at risk (OAR) and tumor-related segmentations provided by radiation oncologists from the Contouring Collaborative for Consensus in Radiation Oncology data set were used. Segmentations were derived from five disease sites: breast, sarcoma, head and neck (H&N), gynecologic (GYN), and GI. Segmentation quality was determined on a structure-by-structure basis by comparing the observer segmentations with an expert-derived consensus, which served as a reference …

Genetic Evidence For Functional Diversification Of Gram-Negative Intermembrane Phospholipid Transporters, Ashutosh K Rai, Katsuhiro Sawasato, Haley C Bennett, Anastasiia Kozlova, Genevieve C Sparagna, Mikhail Bogdanov, Angela M Mitchell

Student and Faculty Publications

The outer membrane of gram-negative bacteria is a barrier to chemical and physical stress. Phospholipid transport between the inner and outer membranes has been an area of intense investigation and, in E. coli K-12, it has recently been shown to be mediated by YhdP, TamB, and YdbH, which are suggested to provide hydrophobic channels for phospholipid diffusion, with YhdP and TamB playing the major roles. However, YhdP and TamB have different phenotypes suggesting distinct functions. It remains unclear whether these functions are related to phospholipid metabolism. We investigated a synthetic cold sensitivity caused by deletion of fadR, a transcriptional regulator …

Targeting Sinonasal Undifferentiated Carcinoma With A Combinatory Immunotherapy Approach, Austin T K Hoke, Yoko Takahashi, Michelle R Padget, Javier Gomez, Moran Amit, Jared Burks, Diana Bell, Tongxin Xie, Patrick Soon-Shiong, James W Hodge, Ehab Y Hanna, Nyall R London

Student and Faculty Publications

PURPOSE: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal cavity with poor prognosis and limited treatment options. To investigate the potential for SNUC sensitivity to combinatory immunotherapy, we performed in vitro studies with SNUC cell lines and used multi-spectral immunofluorescence to characterize the in vivo patient SNUC tumor immune microenvironment (TIME).

EXPERIMENTAL DESIGN: Human-derived SNUC cell lines were used for in vitro studies of tumor cell susceptibility to natural killer (NK) cell-based immunotherapeutic strategies. Tumor samples from 14 treatment naïve SNUC patients were examined via multi-spectral immunofluorescence and clinical correlations assessed.

RESULTS: Anti-PD-L1 blockade enhanced NK …

Evolution And Adaptation To Temperature In Thermotogota, Anne Amelia Farrell

Dartmouth College Ph.D Dissertations

Life thrives across incredibly diverse environmental conditions, yet most organisms are restricted to growing within a narrow range around their optimum growth temperature (OGT). The evolutionary events leading to changes in OGT are poorly understood, and it is uncertain if specific genes are required to thrive at a particular temperature. The bacterial phylum Thermotogota is an excellent model for the evolution of OGT. It comprises mesophilic, thermophilic, and hyperthermophilic members that collectively grow between 20°C and 90°C.

In this work, I analyze the history of OGT in the Thermotogota phylum and show how horizontal gene transfer contributes to the evolution …

Prediction Accuracy Of Soil Chemical Parameters By Field- And Laboratory-Obtained Vis-Nir Spectra After External Parameter Orthogonalization, Konrad Metzger, Frank Liebisch, Juan M Herrera, Thomas Guillaume, Luca Bragazza

Student and Faculty Publications

One challenge in predicting soil parameters using in situ visible and near infrared spectroscopy is the distortion of the spectra due to soil moisture. External parameter orthogonalization (EPO) is a mathematical method to remove unwanted variability from spectra. We created two different EPO correction matrices based on the difference between spectra collected in situ and, respectively, spectra collected from the same soil samples after drying and sieving and after drying, sieving and finely grinding. Spectra from 134 soil samples recorded with two different spectrometers were split into calibration and validation sets and the two EPO corrections were applied. Clay, organic …

Using Patient-Specific 3d Modeling And Simulations To Optimize Microwave Ablation Therapy For Liver Cancer, Amirreza Heshmat, Caleb S O'Connor, Jessica Albuquerque Marques Silva, Iwan Paolucci, Aaron Kyle Jones, Bruno C Odisio, Kristy K Brock

Student and Faculty Publications

Microwave ablation (MWA) of liver tumors presents challenges like under- and over-ablation, potentially leading to inadequate tumor destruction and damage to healthy tissue. This study aims to develop personalized three-dimensional (3D) models to simulate MWA for liver tumors, incorporating patient-specific characteristics. The primary objective is to validate the predicted ablation zones compared to clinical outcomes, offering insights into MWA before therapy to facilitate accurate treatment planning. Contrast-enhanced CT images from three patients were used to create 3D models. The simulations used coupled electromagnetic wave propagation and bioheat transfer to estimate the temperature distribution, predicting tumor destruction and ablation margins. The …

The Kat Module Of The Saga Complex Maintains The Oncogenic Gene Expression Program In Mycn- Amplified Neuroblastoma, Clare F Malone, Nathaniel W Mabe, Alexandra B Forman, Gabriela Alexe, Kathleen L Engel, Ying-Jiun C Chen, Melinda Soeung, Silvi Salhotra, Allen Basanthakumar, Bin Liu, Sharon Y R Dent, Kimberly Stegmaier

Student and Faculty Publications

Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. Here, we used functional genomic screens to identify multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies for MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We characterized the DNA recruitment sites of the SAGA complex in neuroblastoma and the consequences of loss of SAGA complex lysine acetyltransferase (KAT) activity on histone acetylation and gene expression. We demonstrate that loss of SAGA complex KAT activity is associated with reduced MYCN binding on chromatin, suppression of …

Molecular Classification And Biomarkers Of Outcome With Immunotherapy In Extensive-Stage Small-Cell Lung Cancer: Analyses Of The Caspian Phase 3 Study, Mingchao Xie, Miljenka Vuko, Jaime Rodriguez-Canales, Johannes Zimmermann, Markus Schick, Cathy O'Brien, Luis Paz-Ares, Jonathan W Goldman, Marina Chiara Garassino, Carl M Gay, John V Heymach, Haiyi Jiang, J Carl Barrett, Ross A Stewart, Zhongwu Lai, Lauren A Byers, Charles M Rudin, Yashaswi Shrestha

Student and Faculty Publications

BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial.

METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue …

Validation Of A Blood-Based Protein Biomarker Panel For A Risk Assessment Of Lethal Lung Cancer In The Physicians' Health Study, Lulu Song, Ehsan Irajizad, Andrew Rundle, Howard D Sesso, John Michael Gaziano, Jody V Vykoukal, Kim-Anh Do, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Frederica Perera, Samir Hanash

Student and Faculty Publications

This study aimed to assess a four-marker protein panel (4MP)'s performance, including the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19, for predicting lung cancer in a cohort enriched with never- and ever-smokers. Blinded pre-diagnostic plasma samples collected within 2 years prior to a lung cancer diagnosis from 25 cases and 100 sex-, age-, and smoking-matched controls were obtained from the Physicians' Health Study (PHS). The 4MP yielded AUC performance estimates of 0.76 (95% CI: 0.61-0.92) and 0.69 (95% CI: 0.56-0.82) for predicting lung cancer within one year and within two years of diagnosis, respectively. …

Innovation In Bioinformatics: Recent Tools, Database And Involvement Of Artificial Intelligence, Aziz Ahmed, Mohd Shuaib, Abdulbasid Banga, Rizwan Ahmad

Indonesian Journal of Medical Chemistry and Bioinformatics

Bioinformatics has evolved in recent years into a crucial subject and a well-liked research area that is interconnected with many approaches and disciplines. The capacity of bioinformatics and its approaches to tackle challenging biological problems and promote research and development. There are various tools and database which are used in bioinformatics. AI is the capacity of a computational system to carry out various activities associated with intellectual beings and as a computer system's imitation of human intelligence processes. The bioinformatics applications with artificial intelligence have the capacity to annotate the data in the direction of logical conclusions. By combining AI …

An International Phantom Study Of Inter-Site Variability In Technetium-99m Image Quantification: Analyses From The Target Radioembolization Study, Grace Keane, Rob Van Rooij, Marnix Lam, S Cheenu Kappadath, Bilal Kovan, Stephanie Leon, Matthew Dreher, Kirk Fowers, Hugo De Jong

Student and Faculty Publications

BACKGROUND: Personalised multi-compartment dosimetry based on [

RESULTS: Regarding the LSF, inter-site variation with planar site-specific protocols was minimal, as determined by comparing computed LSF between sites (interquartile range 9.6-10.1%). A standardised protocol did not improve variation (interquartile range 8.4-9.0%) but did improve mean accuracy compared to the site-specific protocols (5.0% error for standardised protocol vs 8.8% error for site-specific protocols). Regarding the CRC, inter-system variation was notable for site-specific SPECT protocols and could not be improved by the standardised protocol (CRC interquartile range for 37 mm sphere 0.5-0.7 and 0.6-0.8 respectively), however the standardised protocol did improve accuracy of …

Metabolic Alterations And Cellular Responses To Β-Hydroxybutyrate Treatment In Breast Cancer Cells, Hadas Fulman-Levy, Raichel Cohen-Harazi, Bar Levi, Lital Argaev-Frenkel, Ifat Abramovich, Eyal Gottlieb, Sarah Hofmann, Igor Koman, Elimelech Nesher

Student and Faculty Publications

BACKGROUND: The ketogenic diet (KD), based on high fat (over 70% of daily calories), low carbohydrate, and adequate protein intake, has become popular due to its potential therapeutic benefits for several diseases including cancer. Under KD and starvation conditions, the lack of carbohydrates promotes the production of ketone bodies (KB) from fats by the liver as an alternative source of metabolic energy. KD and starvation may affect the metabolism in cancer cells, as well as tumor characteristics. The aim of this study is to evaluate the effect of KD conditions on a wide variety of aspects of breast cancer cells …

Loss Of Lpar6 And Cab39l Dysregulates The Basal-To-Luminal Urothelial Differentiation Program, Contributing To Bladder Carcinogenesis, Sangkyou Lee, Jolanta Bondaruk, Yishan Wang, Huiqin Chen, June Goo Lee, Tadeusz Majewski, Rachel D Mullen, David Cogdell, Jiansong Chen, Ziqiao Wang, Hui Yao, Pawel Kus, Joon Jeong, Ilkyun Lee, Woonyoung Choi, Neema Navai, Charles Guo, Colin Dinney, Keith Baggerly, Cathy Mendelsohn, David Mcconkey, Richard R Behringer, Marek Kimmel, Peng Wei, Bogdan Czerniak

Student and Faculty Publications

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two …

A Multicenter Study Of Venetoclax-Based Treatment For Patients With Richter Transformation Of Chronic Lymphocytic Leukemia, Paul J Hampel, Mahesh Swaminathan, Kerry A Rogers, Erin M Parry, Jan A Burger, Matthew S Davids, Wei Ding, Alessandra Ferrajoli, Jonathan M Hyak, Nitin Jain, Saad S Kenderian, Yucai Wang, William G Wierda, Jennifer A Woyach, Sameer A Parikh, Philip A Thompson

Student and Faculty Publications

Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and …

Outcomes And Pattern Of Care For Spinal Myxopapillary Ependymoma In The Modern Era-A Population-Based Observational Study, Chenyang Wang, Michael K Rooney, Christopher Alvarez-Breckenridge, Thomas H Beckham, Caroline Chung, Brian S De, Amol J Ghia, David Grosshans, Nazanin K Majd, Mary F Mcaleer, Susan L Mcgovern, Robert Y North, Arnold C Paulino, Subha Perni, Jay P Reddy, Laurence D Rhines, Todd A Swanson, Claudio E Tatsui, Martin C Tom, Debra N Yeboa, Jing Li

Student and Faculty Publications

(1) Background: Myxopapillary ependymoma (MPE) is a rare tumor of the spine, typically slow-growing and low-grade. Optimal management strategies remain unclear due to limited evidence given the low incidence of the disease. (2) Methods: We analyzed data from 1197 patients with spinal MPE from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2020). Patient demographics, treatment modalities, and survival outcomes were examined using statistical analyses. (3) Results: Most patients were White (89.9%) with a median age at diagnosis of 42 years. Surgical resection was performed in 95% of cases. The estimated 10-year overall survival was 91.4%. Younger age (hazard ratio …

Reports Of Autosomal Recessive Disease And Consanguineous Mating Within The Human Population, Johnathon L. Schluter

Master's Theses

It is anecdotally evident when investigating published reports of autosomal recessive disease that a substantial number of cases are the result of related (consanguineous) mating. This research seeks to quantify the percent of manuscripts describing autosomal recessive diseases published between 2000 and 2020 in which consanguineous mating is indicated. We analyzed 602 peer-reviewed manuscripts to identify the percentage of cases presented in which consanguineous mating was indicated, the underlying genes (novel gene or new mutation) and geographical region. These papers were accessed through a specific set of parameters on the free access PubMed Central (PMC) database. A total of 552 …

Brain Cell-Type Shifts In Alzheimer’S Disease, Autism, And Schizophrenia Interrogated Using Methylomics And Genetics, Chloe X Yap, Daniel D Vo, Matthew G Heffel, Arjun Bhattacharya, Cindy Wen, Yuanhao Yang, Kathryn E Kemper, Jian Zeng, Zhili Zheng, Zhihong Zhu, Eilis Hannon, Dorothea Seiler Vellame, Alice Franklin, Christa Caggiano, Brie Wamsley, Daniel H Geschwind, Noah Zaitlen, Alexander Gusev, Bogdan Pasaniuc, Jonathan Mill, Chongyuan Luo, Michael J Gandal

Student and Faculty Publications

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial …

Validation Of Human Telomere Length Multi-Ancestry Meta-Analysis Association Signals Identifies Pop5 And Kbtbd6 As Human Telomere Length Regulation Genes, Rebecca Keener, Surya B Chhetri, Carla J Connelly, Margaret A Taub, Matthew P Conomos, Joshua Weinstock, Bohan Ni, Benjamin Strober, Stella Aslibekyan, Paul L Auer, Lucas Barwick, Lewis C Becker, John Blangero, Eugene R Bleecker, Jennifer A Brody, Brian E Cade, Juan C Celedon, Yi-Cheng Chang, L Adrienne Cupples, Brian Custer, Barry I Freedman, Mark T Gladwin, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Carmen R Isasi, Jill M Johnsen, Eimear E Kenny, Charles Kooperberg, Ryan L Minster, Take Naseri, Satupa'itea Viali, Sergei Nekhai, Nathan Pankratz, Patricia A Peyser, Kent D Taylor, Marilyn J Telen, Baojun Wu, Lisa R Yanek, Ivana V Yang, Christine Albert, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, Joshua C Bis, Thomas W Blackwell, Eric Boerwinkle, Esteban G Burchard, April P Carson, Zhanghua Chen, Yii-Der Ida Chen, Dawood Darbar, Mariza De Andrade, Patrick T Ellinor, Myriam Fornage, Bruce D Gelb, Frank D Gilliland, Jiang He, Talat Islam, Stefan Kaab, Sharon L R Kardia, Shannon Kelly, Barbara A Konkle, Rajesh Kumar, Ruth J F Loos, Fernando D Martinez, Stephen T Mcgarvey, Deborah A Meyers, Braxton D Mitchell, Courtney G Montgomery, Kari E North, Nicholette D Palmer, Juan M Peralta, Benjamin A Raby, Susan Redline, Stephen S Rich, Dan Roden, Jerome I Rotter, Ingo Ruczinski, David Schwartz, Frank Sciurba, M Benjamin Shoemaker, Edwin K Silverman, Moritz F Sinner, Nicholas L Smith, Albert V Smith, Hemant K Tiwari, Ramachandran S Vasan, Scott T Weiss, L Keoki Williams, Yingze Zhang, Elad Ziv, Laura M Raffield, Alexander P Reiner, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Hematology And Hemostasis Working Group, Topmed Structural Variation Working Group, Marios Arvanitis, Carol W Greider, Rasika A Mathias, Alexis Battle

Student and Faculty Publications

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of …

Selective Refueling Of Car T Cells Using Ada1 And Cd26 Boosts Antitumor Immunity, Yue Hu, Abhijit Sarkar, Kevin Song, Sara Michael, Magnus Hook, Ruoning Wang, Andras Heczey, Xiaotong Song

Student and Faculty Publications

Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor β1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor …

Age-Specific Induction Of Mutant P53 Drives Clonal Hematopoiesis And Acute Myeloid Leukemia In Adult Mice, Rasoul Pourebrahim, Rafael Heinz Montoya, Hiroki Akiyama, Lauren Ostermann, Shayuan Khazaei, Muharrem Muftuoglu, Natalia Baran, Ran Zhao, Tom Lesluyes, Bin Liu, Joseph D Khoury, Mihai Gagea, Peter Van Loo, Michael Andreeff

Student and Faculty Publications

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem …

Il-2-Free Tumor-Infiltrating Lymphocyte Therapy With Pd-1 Blockade Demonstrates Potent Efficacy In Advanced Gynecologic Cancer, Jing Guo, Chunyan Wang, Ning Luo, Yuliang Wu, Wei Huang, Jihui Zhu, Weihui Shi, Jinye Ding, Yao Ge, Chunhong Liu, Zhen Lu, Robert C Bast, Guihai Ai, Weihong Yang, Rui Wang, Caixia Li, Rong Chen, Shupeng Liu, Huajun Jin, Binghui Zhao, Zhongping Cheng

Student and Faculty Publications

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer.

METHODS: Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, …

Developing A Membrane-Proximal Cd33-Targeting Car T Cell, Ruby Freeman, Sanam Shahid, Abdul G Khan, Serena C Mathew, Sydney Souness, Erin R Burns, Jasmine S Um, Kento Tanaka, Winson Cai, Sarah Yoo, Andrew Dunbar, Young Park, Devin Mcavoy, Kinga K Hosszu, Ross L Levine, Jaap Jan Boelens, Ivo C Lorenz, Renier J Brentjens, Anthony F Daniyan

Student and Faculty Publications

BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.

METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.

RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both …

Advances In Data-Driven Life Sciences Research, Haiping Jiang, Chunchun Gao, Wenhao Liu, Yungui Yang, Xin Li

Bulletin of Chinese Academy of Sciences (Chinese Version)

The field of life sciences is rapidly evolving, driven by advancements in experimental techniques and vast biological big data which gradually arise and play an increasingly important role in life science research. First of all, biological big data has diversity and complexity, including genomic data, epigenomic data, proteomic data and other types. These data provide researchers with more comprehensive information and help reveal the laws behind life phenomena. Second, new data-driven developments and applications in life sciences cover many fields such as gene editing, precision medicine, drug development, etc., providing unprecedented possibilities for human health and quality of life. However, …

A Novel Positive-Contrast Magnetic Resonance Imaging Line Marker For High-Dose-Rate (Hdr) Mri-Assisted Radiosurgery (Mars), Li Wang, Yao Ding, Teresa L Bruno, R Jason Stafford, Eric Lin, Tharakeswara K Bathala, Jeremiah W Sanders, Matthew S Ning, Jingfei Ma, Ann H Klopp, Aradhana Venkatesan, Jihong Wang, Karen S Martirosyan, Steven J Frank

Student and Faculty Publications

Magnetic resonance imaging (MRI) can facilitate accurate organ delineation and optimal dose distributions in high-dose-rate (HDR) MRI-Assisted Radiosurgery (MARS). Its use for this purpose has been limited by the lack of positive-contrast MRI markers that can clearly delineate the lumen of the HDR applicator and precisely show the path of the HDR source on T1- and T2-weighted MRI sequences. We investigated a novel MRI positive-contrast HDR brachytherapy or interventional radiotherapy line marker, C4:S, consisting of C4 (visible on T1-weighted images) complexed with saline. Longitudinal relaxation time (T1) and transverse relaxation time (T2) for C4:S were measured on a 1.5 T …

Phase 1b Study Of Batiraxcept In Combination With Durvalumab In Patients With Platinum-Resistant Ovarian Cancer, Anne Knisely, Emily M Hinchcliff, Elisabeth Gardiner, Reshma Rangwala, Kathryn Lito, Bryan Fellman, Ying Yuan, Anil K Sood, Shannon N Westin, Karen H Lu, Amir A Jazaeri

Student and Faculty Publications

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71–2.40), and median overall survival (OS) was 4.53 …

Integrative Molecular Analyses Of The Md Anderson Prostate Cancer Patient-Derived Xenograft (Mda Pca Pdx) Series, Nicolas Anselmino, Estefania Labanca, Peter D A Shepherd, Jiabin Dong, Jun Yang, Xiaofei Song, Subhiksha Nandakumar, Ritika Kundra, Cindy Lee, Nikolaus Schultz, Jianhua Zhang, John C Araujo, Ana M Aparicio, Sumit K Subudhi, Paul G Corn, Louis L Pisters, John F Ward, John W Davis, Elba S Vazquez, Geraldine Gueron, Christopher J Logothetis, Andrew Futreal, Patricia Troncoso, Yu Chen, Nora M Navone

Student and Faculty Publications

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer.

EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived …

Ire1Α Determines Ferroptosis Sensitivity Through Regulation Of Glutathione Synthesis, Dadi Jiang, Youming Guo, Tianyu Wang, Liang Wang, Yuelong Yan, Ling Xia, Rakesh Bam, Zhifen Yang, Hyemin Lee, Takao Iwawaki, Boyi Gan, Albert C Koong

Student and Faculty Publications

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α's endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is …