Life Sciences Commons^™

One Health Interventions And Challenges Under Rural African Smallholder Farmer Settings: A Scoping Review, Evanson R. Omuse, Honest Machekano, Bonoukpoè M. Sokame, Daniel M. Mutyambai, Thomas Dubois, Sevgan Subramanian, Frank Chidawanyika

All Peer-Reviewed Publications

The global human population is rapidly increasing, escalating interactions of people, animals and the environment. This has led to more convoluted health challenges, for which African smallholder farmers bear the brunt. The One Health (OH) approach recognises the interconnectedness of these health challenges and thus follows a transdisciplinary approach involving diverse stakeholders to address them. Although there have recently been global concerted efforts and studies on OH, an information gap exists in Africa, particularly regarding smallholder farmers and their needs. Additionally, evaluation frameworks and outcome metrics for OH initiatives are still unclear. Thus, this study was conducted to critically map …

Adoption Of Sustainable Land And Water Management Practices And Their Impact On Crop Productivity Among Smallholder Farmers In Sub-Saharan Africa, Cool Dady Mangole, Charles Mbogo Maina, Kelvin Mulungu, Maurice Tschopp, Nichole Harari, Roopa Suresh, Menale Kassie

All Peer-Reviewed Publications

Land degradation and water challenges threaten sub-Saharan Africa's agricultural productivity and food security. This study uses panel secondary data from the World Bank Living Standards Measurement Study—Integrated Surveys on Agriculture project to evaluate land degradation variations, the adoption of sustainable land and water management (SLWM) practices, and their impacts on crop yields among smallholder farmers in four sub-Saharan African countries: Tanzania, Malawi, Uganda, and Ethiopia. The study used a high-dimensional fixed effects model to control for time-invariant unobserved and time-varying observed household and plot-level confounders. The results indicate that while many households experienced land degradation and water problems, SLWM adoption …

Microbial Composition And Bioremediation In Frass Fertilizers From Insect-Based Agri-Food Waste Valorization, María Gómez-Brandón, Dennis Beesigamukama, Maraike Probst, Thomas Klammsteiner, Jian Qiang Su, Yong Guan Zhu, Chrysantus Mbi Tanga

All Peer-Reviewed Publications

Insect frass fertilizer is emerging as a sustainable and novel input for improving soil health and crop production; however, research attention on its safety and microbial properties remains limited. Here, we evaluated the levels of heavy metals, pathogens, diversity, abundance, composition and functional roles of bacteria and fungi in frass fertilizer produced by eight edible insect species. Our results revealed the absence of Salmonella spp. In the frass fertilizers produced by all insect species, while the levels of other pathogens and heavy metals were within permissible limits for organic fertilizers. We found that 79–86 % of the variations in bacterial …

Basal Autophagy Promotes Accurate Chromosome Segregation In Drosophila Oocytes And Declines During Oocyte Aging, Diana C. Hilpert

Dartmouth College Ph.D Dissertations

The frequency of trisomic pregnancies exponentially increases with advanced maternal age, a phenomenon known as the maternal age effect. The majority of these aneuploid pregnancies arise from meiotic segregation errors in the oocyte and premature loss of sister chromatid cohesion is a contributing factor. However, the mechanisms that lead to premature cohesion loss during oocyte aging are not fully understood.

Using Drosophila melanogaster as a model organism, work described in this dissertation demonstrates that basal levels of autophagy, a degradation process for damaged organelles and protein aggregates, are required during meiotic prophase for arm cohesion maintenance and accurate meiotic segregation …

Decoding The Plant Metabolome: A Metabolomics Approach To Guereza (Colobus Guereza) Feeding Ecology In Kibale National Park, Uganda, Emma Grace Thurau

Dissertations, Theses, and Capstone Projects

Plant metabolites, an elusive and diverse group of plant chemicals, represent a complex chemical interplay between plants and herbivores. Plants contain essential nutrients necessary for herbivore survival, yet herbivore consumption results in negative fitness consequences to a plant. This relationship has triggered a coevolutionary arms race in which plants have evolved chemical defenses to prevent herbivore consumption and herbivores, in response, have evolved their own counter-adaptations. This arms race has led to the diverse numbers of herbivores and plants observed today; therefore, these plant metabolites act as a signature of evolution through their influence on herbivore adaptations. Plant metabolites are …

Elucidating The Roles Of Eukaryotic Initiation Factors Involved In Dap5 Mediated Translation, Jacob Nk Quartey

Dissertations, Theses, and Capstone Projects

Translation initiation in eukaryotes is a highly regulated process essential for accurate protein synthesis. It is a dynamic process that involves a complex interplay between messenger RNAs (mRNAs), ribosomal subunits, and a host of initiation factors, ensuring precise start codon selection and the subsequent assembly of the translation machinery. This process has well been known to be mediated by the eukaryotic Initiation Factor (eIF4F), which consists of the cap binding protein eIF4E, the scaffolding protein eIF4GI, and the helicase factor eIF4A.The recognition and binding of eIF4E to the m⁷G cap structure of the mRNA is essential for the …

Parvalbumin Interneuron-Oligodendrocyte Interactions In The Infralimbic Cortex Promote Extracellular Plasticity Mechanisms After Safety Learning, Lucy Emma Denholtz

Dissertations, Theses, and Capstone Projects

The ability to differentiate between threat and safety cues is essential for adaptive behavior, yet this process is disrupted in psychiatric disorders, such as post-traumatic stress disorder (PTSD), where safety cues fail to downregulate fear expression. To better understand the neurobiological mechanisms of safety learning, I investigate how safety conditioning vs contextual fear conditioning modify behavioral and cellular mechanisms in the infralimbic (IL) region of the medial prefrontal cortex (mPFC) at several time points after learning. Through this work, I identify a novel mechanism whereby safety learning promotes learning dependent neuro-glial interactions that promote conditions for plasticity in the mPFC. …

Climate Change Threatens Water Resources For Major Field Crops In The Serbian Danube River Basin By The Mid-21st Century, Jamshid Jalali, Nishan Bhattarai, Jillian Greene, Tao Liu, Oskar Marko, Mirjana Radulović, Molly Sears, Sean A. Woznicki

Michigan Tech Publications

Study region: Serbian Danube River Basin Study focus: As climate change makes weather patterns more erratic, water supply for agriculture is becoming increasingly uncertain. This is concerning in the Serbian Danube River Basin, where crops are mainly rainfed and the growing season is becoming warmer and drier. Assessing the balance between future agricultural water demand and availability in a changing climate is critical to address agricultural water scarcity. To understand how changing climate will affect water availability during 2041–2070, we used the Soil and Water Assessment Tool+ hydrological model with field-scale crop rotations and irrigated extent data and forced with …

Computerized Diagnostic Decision Support Systems-Isabel Pro Versus Chatgpt-4 Part Ii, Joe M Bridges, Xiaoqian Jiang, Michael Ige, Oluwatoniloba Toyobo

Faculty, Staff and Student Publications

Objective: Does a Tree-of-Thought prompt and reconsideration of Isabel Pro's differential improve ChatGPT-4's accuracy; does increasing expert panel size improve ChatGPT-4's accuracy; does ChatGPT-4 produce consistent outputs in sequential requests; what is the frequency of fabricated references?

Materials and methods: Isabel Pro, a computerized diagnostic decision support system, and ChatGPT-4, a large language model. Using 201 cases from the New England Journal of Medicine, each system produced a differential diagnosis ranked by likelihood. Statistics were Mean Reciprocal Rank, Recall at Rank, Average Rank, Number of Correct Diagnoses, and Rank Improvement. For reproducibility, the study compared the initial expert panel run …

Associations Between Vitamin D Deficiency And Sociodemographic Factors, Lifestyle Behaviors, And Metabolic Conditions: A Cross-Sectional Study From The Hnnhs In Greece, Asmae Mohamad Sadek

Theses

Vitamin D deficiency (VDD) is a widespread global health concern associated with various sociodemographic, lifestyle, dietary, and metabolic factors. While previous studies examined VDD in Greece, few provided a comprehensive analysis across multiple determinants using representative national data. This study aimed to assess the prevalence and predictors of VDD among Greek adults and to examine its associations with sociodemographic, dietary, behavioral, and metabolic variables using data from the Hellenic National Nutrition and Health Survey (HNNHS). A cross-sectional analysis was conducted among 978 adults (≥19 years) from the HNNHS. Serum 25-hydroxyvitamin D [25(OH)D] concentrations < 20 ng/mL were defined as deficient and ≥20 ng/mL as normal. The median age of participants was 40.2 years, and 62.0% were female. The overall prevalence of VDD was 46.0%, with the highest rate observed among adults aged ≥60 years (62.2%). VDD was significantly associated with older age (p < 0.001), retirement status (62.9% among retired; p < 0.001), low and sedentary physical activity (32.7% and 32.6% vs. 50.8% among highly active; p < 0.001), higher HDL (median 52.0 vs. 49.0 mg/dL among VDD vs Normal; p = 0.001), elevated serum calcium (median 9.4 vs. 9.2 mg/dL among VDD vs Normal; p = 0.020), and lower insulin levels (median 7.5 vs. 8.0 μIU/mL among VDD vs Normal; p = 0.044). Dietary intake (total energy and macronutrients) and body composition were not significantly associated with VDD. In the multivariate model, significant independent predictors of VDD included being retired (AOR = 2.383; 95% CI: 1.596–3.558; p < 0.001), having higher serum calcium levels (AOR = 1.563; 95% CI: 1.078–2.266; p = 0.019), and higher HDL levels (AOR = 1.016; 95% CI: 1.005–1.027; p = 0.001). Physical activity level was also a key determinant; participants classified as sedentary or low active had significantly higher odds of deficiency compared to highly active individuals (AOR = 0.468; 95% CI: 0.319–0.690; p < 0.001). This counterintuitive result may be influenced by factors such as increased indoor physical activity, and warrants further investigation. Dietary intake and body composition were not significantly associated with VDD. The findings underscore the importance of incorporating sociodemographic and lifestyle factors into prevention strategies. Interventions should particularly focus on older adults, retired individuals, even if they have higher HDL and calcium levels, and are physically active.

A Scan Of Pleiotropic Immune Mediated Disease Genes Identifies Novel Determinants Of Baseline Fviii Inhibitor Status In Hemophilia A, Marcio Almeida, Vincent P. Diego, Kevin R. Viel, Bernadette W. Luu, Eron G. Manusov, Juan M. Peralta, Satish Kumar, Sarah Williams-Blangero, John Blangero, Tom Howard

School of Medicine Publications

Hemophilia-A (HA) is the X-linked bleeding disorder caused by heterogeneous factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that prevent intrinsic-pathway mediated coagulation-amplification. Severe-HA patients (HAPs) require life-long infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called “FVIII-inhibitors (FEIs)”. We investigated the genetics underlying the variable risk of FEI-development in 450 North American HAPs (206 and 244 respectively self-reporting black-African- or white-European-ancestry) by analyzing the genotypes of single-nucleotide-variations (SNVs) in candidate immune-mediated-disease (IMD)-genes using a binary linear-mixed model of genetic association with baseline-FEI-status, the dependent variable, while simultaneously accounting for their genetic relationships and heterogeneous-F8-mutations to …

Clearing Cloudy Or Coloured Water On Farms In Western Australia, Department Of Primary Industries And Regional Development, Western Australia

Natural resources factsheets

Cloudy or coloured water can be a nuisance when used for household purposes, and sometimes be unsuitable for livestock, irrigation, or crop spraying. The following is for general information only, it is recommended that people seek expert advice for treating cloudy or coloured water.

State And Transition Models For Mulga Rangelands Of Western Australia, Alison O'Donnell, Anna E. Richards, Suzanne Prober, Peter-Jon A. Waddell, Sarah Luxton, Ian Watson, Brett Abbott, Philip Thomas, Joshua E. Foster

Natural resources published reports

This report details a collaborative project between the Western Australian Department of Primary Industries and Regional Development and CSIRO that focused on developing State and Transition Models (STMs) for mulga rangelands in Western Australia. The overarching aim of the project was to improve the common understanding of the characteristics and dynamics of mulga rangeland ecosystems and the expected impacts of management. Specifically, the project aimed to collate expert knowledge and monitoring information using a nationally consistent framework to develop quantitative and dynamic STMs. The geographic scope of the project covers the extensive mulga rangelands of Western Australia, particularly the Gascoyne …

Encoding 3d Information In 2d Feature Maps For Brain Ct-Angiography, Uma M Lal-Trehan Estrada, Sunil Sheth, Arnau Oliver, Xavier Lladó, Luca Giancardo

Faculty, Staff and Student Publications

We propose learnable 3D pooling (L3P), a CNN module designed to compress 3D information into 2D feature maps using anisotropic convolutions and unidirectional max pooling. Specifically, we used L3P followed by a 2D network to generate predictions from 3D brain CT-Angiography (CTA) in the context of large vessel occlusion (LVO). To further demonstrate its versatility, we extended its application to 3D brain MRI analysis for brain age prediction. First, we designed an experiment to classify the LVO-affected hemisphere (left or right), projecting the input CTA into the sagittal plane, which allowed to assess the ability of L3P to encode the …

Building Community Through Data: The Value Of A Researcher Driven Open Science Ecosystem, Meredith C B Adams, Carla M Bann, Emine Ozgur Bayman, Maria Chao, Georgene W Hergenroeder, Charles Knott, Martin A Lindquist, Z David Luo, Rosemarie Martin, Maryann E Martone, John Mccarthy, Micah Mccumber, Sharon B Meropol, Ty A Ridenour, Lissette M Saavedra, Abeed Sarker, Kevin J Anstrom, Wesley K Thompson

Faculty, Staff and Student Publications

No abstract provided.

Multicancer Early Detection Tests At A Crossroads: Commercial Availability Ahead Of Definitive Evidence, Carmen E Guerra, Jennifer Keating Litton, Carolina E Viswanath, A Mark Fendrick

Faculty, Staff and Student Publications

Multicancer early detection tests (MCEDs), sometimes referred to as liquid biopsies, are tests that can screen for multiple cancers by analyzing blood, urine, and other bodily fluids for biomarkers released by cancer cells. These tests have the potential to change the cancer screening paradigm if they are shown to reduce cancer mortality. However, it is not yet known whether MCEDs reduce mortality. Randomized controlled trials, the gold standard for evaluating cancer screening programs, are currently evaluating the effectiveness of MCEDs. However, because cancer-specific and all-cause mortality are end points that can take years to reach, trials are being designed with …

An Enzyme-Linked Immunosorbent Assay (Elisa)-Based Activity Assay For Amp-Activated Protein Kinase (Ampk), Trezze P Nguyen, Shangze Lyu, Yang Liu

Faculty, Staff and Student Publications

AMP-activated protein kinase (AMPK) is the master regulator of cellular and organismal energy homeostasis, playing an essential role in modulating metabolism and other cellular processes. Substantial efforts have been made to develop pharmacological modulators of AMPK activity due to their therapeutic potential against various diseases. Measuring AMPK activity in vitro is a fundamental step for testing AMPK activators and inhibitors. Here, we report an enzyme-linked immunosorbent assay (ELISA)-based AMPK activity assay with simple steps and high sensitivity. This assay offers a robust, in-house alternative to the traditional radioactive methods and other approaches that rely on specialized reagents or commercial kits.

Aapm Task Group No 249b-Essentials And Guidelines For Clinical Medical Physics Residency Training Programs, Jonathon A Nye, Joseph P Dugas, William D Erwin, David P Gierga, Darryl G Kaurin, Stephanie M Leon, Ho-Ling Anthony Liu, Zheng Feng Lu, Alphonso W Magri, Lynn N Rill, Leah K Schubert, Beth A Schueler, Irina Vergalasova, John Vetter, Brian D Wichman, Amy Shu-Jung Yu, Dandan Zheng

Faculty, Staff and Student Publications

The establishment of guidelines and curriculum standards for medical physics residency training is a critical component of setting expectations and competencies for the profession. Since the last publication of these standards, residency training has become integrated into the eligibility criteria for most medical physics certification bodies. The rapid growth of medical physics requires periodic review of the curriculum to remove outdated approaches, update established knowledge, and add emerging technologies. The goal of this document is to provide a reference standard for residency training program directors, training mentors, and residents to guide creation and/or optimization of their program's curriculum. The document …

Outcomes After Palliative Radiation Therapy In Patients With Symptomatic Locoregionally Advanced Breast Cancer, Luisa E Jacomina, David M Swanson, Melissa P Mitchell, Wendy A Woodward, Benjamin D Smith, Karen E Hoffman, Chelain R Goodman, Haven R Garber, Susie X Sun, Timothy A Yap, Funda Meric-Bernstam, Isidora Y Arzu, Elizabeth S Bloom, Pamela J Schlembach, Eric A Strom, Michael C Stauder, Simona F Shaitelman

Faculty, Staff and Student Publications

Purpose: Symptomatic locoregionally advanced breast cancer (SLABC) can cause troublesome pain or wound complications that negatively impact quality of life. Although palliative radiation therapy (RT) can minimize tumor-related symptoms, how best to tailor RT to achieve the most meaningful and durable response is not well defined.

Methods and materials: This is a single institution, multi-site retrospective review of patients with SLABC treated between 2016 and 2023 with palliative RT to symptomatic disease in the breast, chest wall, and/or regional lymph node basins. Overall survival (OS), locoregional control (LC), clinical and radiographic treatment response, overall pain scores, and treatment-related toxicities were …

Bispecific Antibodies In Hematologic And Solid Tumors: Current Landscape And Therapeutic Advances, Lorenzo Guidi, Julian Etessami, Carmine Valenza, Augusto Valdivia, Funda Meric-Bernstam, Enriqueta Felip, Giuseppe Curigliano

Faculty, Staff and Student Publications

Bispecific antibodies (bsAbs) have emerged as a novel class of therapeutics, offering a dual-targeting strategy to enhance the therapeutic efficacy of monoclonal antibodies, which is often limited by tumor heterogeneity and the occurrence of resistance mechanisms. By simultaneously engaging two distinct antigens or pathways, bsAbs disrupt multiple signaling cascades simultaneously, preventing escape mechanisms and offering a more durable response. Furthermore, they can optimize immune activation, improving immune cell recruitment strategies. In particular, T-cell engager bsAbs facilitate immune cell-mediated tumor destruction by linking T cells to tumor antigens. Instead, dual immune checkpoint inhibitors (CPIs) enhance immune activation by blocking inhibitory signals. …

Functional Vs Structural Cortical Deficit Pattern Biomarkers For Major Depressive Disorder, Peter Kochunov, Bhim M Adhikari, David Keator, Daniel Amen, Si Gao, Nicole R Karcher, Demetrio Labate, Robert Azencott, Yewen Huang, Hussain Syed, Hongjie Ke, Paul M Thompson, Danny J J Wang, Braxton D Mitchell, Jessica A Turner, Theo G M Van Erp, Neda Jahanshad, Yizhou Ma, Xiaoming Du, William Burroughs, Shuo Chen, Tianzhou Ma, Jair C Soares, L Elliot Hong

Faculty, Staff and Student Publications

Importance: Major depressive disorder (MDD) is a severe mental illness characterized more by functional rather than structural brain abnormalities. The pattern of regional homogeneity (ReHo) deficits in MDD may relate to underlying regional hypoperfusion. Capturing this functional deficit pattern provides a brain pattern-based biomarker for MDD that is linked to the underlying pathophysiology.

Objective: To examine whether cortical ReHo patterns provide a replicable biomarker for MDD that is more sensitive than reduced cortical thickness and evaluate whether the ReHo MDD deficit pattern reflects regional cerebral blood flow (RCBF) deficit patterns in MDD and whether a regional vulnerability index (RVI) thus …

Multi-Institutional Study On Image Quality For A Novel Cbct Solution On O-Ring Linac, Luis Agulles-Pedrós, R Lee Macdonald, Amanda Jean Cherpak, Nayha Dixit, Lei Dong, Tianyu Zhao, Kundan Thind, Anthony Doemer, Boon-Keng Teo, Shiqin Su, Alexander Moncion, James L Robar

Faculty, Staff and Student Publications

INTRODUCTION: This work presents a multi-institutional study on image quality provided by a novel cone beam computed tomography (CBCT). The main goal is to investigate the consistency of imaging performance across multiple institutions.

METHODS: Phantoms for measuring relative electron density (RED) and image quality were sent to six institutions for imaging on Ethos and Halcyon units equipped with HyperSight CBCT. The imaging protocols included tube potential from 100 to 140 kVp and exposure from 80 to 800 mAs. Imaging performance was evaluated with regard to RED versus Hounsfield units (HU), uniformity, contrast-to-noise ratio (CNR), slice thickness, circular symmetry, modulation transfer …

Gut Microbiota In Immuno-Oncology: A Practical Guide For Medical Oncologists With A Focus On Antibiotics Stewardship, Arielle Elkrief, Bertrand Routy, Lisa Derosa, Laura Bolte, Jennifer A Wargo, Jennifer L Mcquade, Laurence Zitvogel

Faculty, Staff and Student Publications

The gut microbiota has emerged as a critical determinant of immune checkpoint inhibitor (ICI) efficacy, resistance, and toxicity. Retrospective and prospective studies profiling the taxonomic composition of intestinal microbes of patients treated with ICI have revealed specific gut microbial signatures associated with response. By contrast, dysbiosis, which can be caused by chronic inflammatory processes (such as cancer) or comedications, is a risk factor of resistance to ICI. Recent large-scale meta-analyses have confirmed that antibiotic (ATB) use before or during ICI therapy alters the microbiota repertoire and significantly shortens overall survival, even after adjusting for prognostic factors. These results underscore the …

A Gut-On-A-Chip Incorporating Human Faecal Samples And Peristalsis Predicts Responses To Immune Checkpoint Inhibitors For Melanoma, Mattia Ballerini, Serena Galiè, Punit Tyagi, Carlotta Catozzi, Hariam Raji, Amir Nabinejad, Angeli D G Macandog, Alessandro Cordiale, Bianca Ionela Slivinschi, Karol K Kugiejko, Martina Freisa, Paola Occhetta, Jennifer A Wargo, Pier F Ferrucci, Emilia Cocorocchio, Nicola Segata, Andrea Vignati, Andrey Morgun, Michela Deleidi, Teresa Manzo, Marco Rasponi, Luigi Nezi

Faculty, Staff and Student Publications

Patient responses to immune checkpoint inhibitors can be influenced by the gastrointestinal microbiome. Mouse models can be used to study microbiome-host crosstalk, yet their utility is constrained by substantial anatomical, functional, immunological and microbial differences between mice and humans. Here we show that a gut-on-a-chip system mimicking the architecture and functionality of the human intestine by including faecal microbiome and peristaltic-like movements recapitulates microbiome-host interactions and predicts responses to immune checkpoint inhibitors in patients with melanoma. The system is composed of a vascular channel seeded with human microvascular endothelial cells and an intestinal channel with intestinal organoids derived from human …

Therapeutic Hurdles In Acute Myeloid Leukemia: Leukemic Stem Cells, Inflammation And Immune Dysfunction, Bofei Wang, Patrick K Reville, Hussein A Abbas

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is an aggressive and highly heterogeneous hematological malignancy characterized by clonal expansion and differentiation arrest in myeloid progenitor cells. Despite advancements in chemotherapy, allogeneic hematopoietic stem cell transplantation, and post-remission maintenance therapies, the long-term survival remains unsatisfactory with high rates of relapse and refractory. These therapeutic challenges are mediated by multiple factors, including the complexity of the cellular hierarchies in AML, the interaction of leukemic stem cells (LSCs) with the bone marrow niche, inflammation, and immune evasion mechanisms. Further, the absence of specific surface markers that distinguish LSCs from normal hematopoietic stem cells, together with LSCs' …

Clinical Interrogation Of Tp53 Aberrations And Its Impact On Survival In Patients With Myeloid Neoplasms, Jayastu Senapati, Sanam Loghavi, Guillermo Garcia-Manero, Guillin Tang, Tapan Kadia, Nicholas J Short, Hussein A Abbas, Naszrin Arani, Courtney D Dinardo, Gautam Borthakur, Naveen Pemmaraju, Betul Oran, Elizabeth Shpall, Uday Popat, Richard Champlin, Sherry Pierce, Sankalp Arora, Ghayas Issa, Musa Yilmaz, Keyur Patel, Koichi Takahashi, Guillermo Montalban-Bravo, Danielle Hammond, Fadi G Haddad, Farhad Ravandi, Hagop M Kantarjian, Naval G Daver

Faculty, Staff and Student Publications

In myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with TP53 aberrations, dissecting the interaction amongst patient, disease and treatment factors are important for therapeutic decisions and prognostication. This retrospective analysis included patients with newly diagnosed MDS (>5% blasts) and AML with TP53 mutation(s) treated at MD Anderson Cancer Center. We factored patient age, TP53 aberration burden, therapy intensity and use of venetoclax in the AML subgroup, and allogeneic hematopoietic stem cell transplantation (HSCT) to interrogate outcomes. TP53 was annotated as high-risk (TP53HR) if >1 mutation, one mutation plus allelic deletion or a single mutation with variant allele frequency …

Externally Validated Digital Decision Support Tool For Time-To-Osteoradionecrosis Risk-Stratification Using Right-Censored Multi-Institutional Observational Cohorts, Laia Humbert-Vidan, Serageldin Kamel, Andrew Wentzel, Zaphanlene Kaffey, Moamen Abdelaal, Kyle B Spier, Natalie A West, G Elisabeta Marai, Guadalupe Canahuate, Xinhua Zhang, Melissa M Chen, Kareem A Wahid, Jillian Rigert, Seyedmohammadhossein Hosseinian, Andrew J Schaefer, Kristy K Brock, Mark Chambers, Adegbenga O Otun, Ruth Aponte-Wesson, Vinod Patel, Andrew Hope, Jack Phan, Adam S Garden, Steven J Frank, William H Morrison, Michael T Spiotto, David Rosenthal, Anna Lee, Renjie He, Mohamed A Naser, Erin Watson, Katherine A Hutcheson, Abdallah S R Mohamed, Vlad C Sandulache, Lisanne V Van Dijk, Amy C Moreno, Teresa Guerrero Urbano, Clifton D Fuller, Stephen Y Lai

Faculty, Staff and Student Publications

Background: Existing studies on osteoradionecrosis of the jaw (ORNJ) have primarily used cross-sectional data, assessing risk factors at a single time point. Determining the time-to-event profile of ORNJ has important implications to monitor oral health in head and neck cancer (HNC) long-term survivors.

Methods: Data were retrospectively obtained for a clinical observational cohort of 1129 patients (198 ORNJ cases) with HNC treated with radiotherapy (RT) at The University of Texas MD Anderson Cancer Center. A Weibull Accelerated Failure Time model was trained on previously identified dosimetric, clinical and demographic predictors. External validation was performed using an independent cohort of 265 …

Trem2 Depletion In Pancreatic Cancer Elicits Pathogenic Inflammation And Accelerates Tumor Progression Via Enriching Il-1Β+ Macrophages, Daowei Yang, Xinlei Sun, Hua Wang, Ignacio I Wistuba, Huamin Wang, Anirban Maitra, Yang Chen

Faculty, Staff and Student Publications

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a complex tumor microenvironment enriched with tumor-associated macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) is highly expressed by a subset of macrophages in PDAC. However, the functional role of TREM2 in PDAC progression remains elusive.

Methods: We generated a novel transgenic mouse model (KPPC;Trem2-/-) that enables the genetic depletion of TREM2 in the context of spontaneous PDAC development. Single-cell RNA-sequencing analysis was used to identify changes in the tumor immune microenvironment on TREM2 depletion. We evaluated the impacts of TREM2 depletion on the tumor immune microenvironment to elucidate the functions …

Gsk-3484862, A Dnmt1 Degrader, Promotes Dnmt3b Expression In Lung Cancer Cells, Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa Jr, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng

Faculty, Staff and Student Publications

DNA methylation alterations, including hypermethylation and silencing of tumor suppressor genes, contribute to cancer formation and progression. The FDA-approved nucleoside analogs azacytidine and decitabine are effective demethylating agents for hematologic malignancies but their general use has been limited by their toxicity and ineffectiveness against solid tumors. GSK-3484862, a dicyanopyridine-containing, DNMT1-selective inhibitor and degrader, offers a promising lead for developing novel demethylating therapeutics. Here, we demonstrate that GSK-3484862 treatment upregulates DNMT3B expression in lung cancer cell lines (A549 and NCI-H1299). Disrupting DNMT3B in NCI-H1299 sensitizes these cells to GSK-3484862, enhancing its inhibitory effects on cell viability and growth. GSK-3484862 treatment induces …

Nlrp3 Inflammasome Activation Expands The Immunosuppressive Myeloid Stroma And Antagonizes The Therapeutic Benefit Of Sting Activation In Glioblastoma, Spencer T Lea, Chao-Hsien Chen, Jun Wei, Ivana William, Inés Lopez Del Castillo, Michael A Curran

Faculty, Staff and Student Publications

Glioblastoma (GBM) is the most common and deadly primary brain malignancy and is clinically refractory to immunotherapy. Active NLRP3 inflammasome signaling and IL-1β secretion have been observed in GBM, and NLRP3-driven myeloid-derived suppressor cell (MDSC) recruitment can mediate cancer immune evasion. Agonists of the cytosolic double-stranded DNA-sensing stimulator of IFN gene (STING) pathway can mediate proinflammatory conversion of cancer MDSCs; however, secretion of the NLRP3 products IL-1β and IL-18 has also been observed in certain myeloid populations following STING activation. In this study, we aimed to determine both the potential mechanistic synergy between STING and NLRP3 agonists, and the effects …