Genetic Phenomena Commons^™

Quantifying Rate-Limiting Genetic Variation In Breast And Ovarian Tumourigenesis, Kathleen E Houlahan, Mahad Bihie, Yves Greatti, Julián Grandvallet Contreras, Daniel J Fulop, Gonzalo Lopez, Marc Williams, Hsin-Hsiung Huang, Peter Van Loo, Paul C Boutros, Kuan-Lin Huang

Faculty, Staff and Student Publications

Background: The number and type of genetic alterations required to initiate breast and ovarian cancer remain unclear. While germline BRCA1/2 carriers show markedly elevated cancer risk, it is uncertain whether point mutations or copy number alterations constitute the rate-limiting events of tumourigenesis.

Methods: We developed a statistical framework extending prior incidence-mutation models to estimate the minimal number and type of driver events required for cancer initiation. Somatic mutation and copy-number data from >3000 breast and ovarian cancers in TCGA and METABRIC were compared between germline BRCA1/2 carriers and non-carriers matched on subtypes. Results were validated through analyses of evolutionary timing …

Cd44v9 As A Therapeutic Target For Antibody-Drug Conjugate In Advanced Breast Cancer, Dileep R Reddy, Mckenna E Flynn, Yasuaki Anami, Zhaoxuan Yang, Jayden Aleman, Minji Seo, Kyoji Tsuchikama, Jennifer A Maynard, Naoto T Ueno, Jangsoon Lee

Faculty, Staff and Student Publications

Antibody-drug conjugates (ADCs) have revolutionized breast cancer therapy. HER2 is the only validated biomarker guiding ADC therapy in breast cancer. However, their clinical benefit remains confined to HER2- and TROP2-targeted therapies. Tumor heterogeneity and acquired resistance often limit durable responses, underscoring the need for novel, tumor-specific ADC targets. CD44 variant isoform 9 (CD44v9), a splice variant of the CD44 family, is largely absent in normal tissues but enriched in aggressive breast cancers, where it contributes to stemness, redox regulation, and therapy resistance. In this study, we developed a chimeric monoclonal antibody against CD44v9 (clone SUM24.1, IgG1) and conjugated it to …

Large Language Models For Bioinformatics, Wei Ruan, Yanjun Lyu, Jing Zhang, Jiazhang Cai, Peng Shu, Yang Ge, Yao Lu, Shang Gao, Yue Wang, Peilong Wang, Lin Zhao, Tao Wang, Yufang Liu, Luyang Fang, Ziyu Liu, Zhengliang Liu, Yiwei Li, Zihao Wu, Junhao Chen, Hanqi Jiang, Yi Pan, Zhenyuan Yang, Jingyuan Chen, Shizhe Liang, Wei Zhang, Terry Ma, Yuan Dou, Jianli Zhang, Xinyu Gong, Qi Gan, Yusong Zou, Zebang Chen, Yuanxin Qian, Shuo Yu, Jin Lu, Kenan Song, Xianqiao Wang, Andrea Sikora, Gang Li, Xiang Li, Quanzheng Li, Yingfeng Wang, Lu Zhang, Yohannes Abate, Lifang He, Wenxuan Zhong, Rongjie Liu, Chao Huang, Wei Liu, Ye Shen, Ping Ma, Hongtu Zhu, Yajun Yan, Dajiang Zhu, Tianming Liu

Faculty, Staff and Student Publications

With the rapid advancements in large language model technology and the emergence of bioinformatics-specific language models (BioLMs), there is a growing need for a comprehensive analysis of the current landscape, computational characteristics, and diverse applications. This survey aims to address this need by providing a thorough review of BioLMs, focusing on their evolution, classification, and distinguishing features, alongside a detailed examination of training methodologies, datasets, and evaluation frameworks. We explore the wide-ranging applications of BioLMs in critical areas such as disease diagnosis, drug discovery, and vaccine development, highlighting their impact and transformative potential in bioinformatics. We identify key challenges and …

Tuscan: Tumor Segmentation And Classification Analysis In Spatial Transcriptomics, Chenxuan Zang, Charles C Guo, Yaohong Wang, Peng Wei, Ziyi Li

Faculty, Staff and Student Publications

The identification of tumor cells is pivotal for understanding tumor heterogeneity and the tumor microenvironment. Recent advances in spatially resolved transcriptomics (SRT) have revolutionized the way that transcriptomic profiles are characterized and have enabled the simultaneous quantification of transcript locations in intact tissue samples. SRT is a promising alternative method to study gene expression patterns in spatial domains. Nevertheless, the precise detection of tumor regions within intact tissue remains a great challenge. A common strategy for identifying tumor cells is via tumor-specific marker gene expression signatures, which are highly dependent on marker accuracy. Another effective approach is through aneuploid copy …

Defining A Quantitative Threshold For Adaptive Re-Planning Using A Percentile-Based Scoring System, Alexandra O Leone, Christine B Peterson, Anna Lee, Adam S Garden, G Brandon Gunn, Lauren L Mayo, Amy C Moreno, Steven J Frank, C David Fuller, Jay P Reddy, Karen Hoffman, Ivan Vazquez, Ming Yang, Joshua S Niedzielski, Laurence E Court, Thomas J Whitaker

Faculty, Staff and Student Publications

Background: Despite the frequent need for adaptive planning in head and neck proton therapy, no quantitative indicators have been identified to determine when a plan should be adapted. Here, we aimed to determine a quantitative threshold for the change in plan quality between the primary treatment plan and verification plans that correlates with the physician's decision to adapt.

Methods: Primary treatment and verification plans were extracted from the clinical treatment planning system for 167 patients who underwent intensity-modulated proton therapy for base of tongue, tonsillar, or oropharyngeal cancers, with and without nodal involvement, between 2016 and 2021. All plans were …

Optimizing Feasibility And Acceptability Of An Online Expressive Writing Intervention For Survivors Of Adolescent And Young Adult Cancer: A Pilot Randomized Trial Of Iterative Modifications And Outcomes, Eunju Choi, Yusi Aveva Xu, Celia Cy Wong-Meli, Michael E Roth, Yisheng Li, Qian Lu

Faculty, Staff and Student Publications

Objective: To evaluate the feasibility of an online expressive writing (EW) intervention for survivors of adolescent and young adult (AYA) cancer and determine whether iterative, theory-driven modifications can enhance response, adherence, and completion rates.

Methods: In this randomized pilot trial, survivors of AYA cancer were recruited through a hospital-based AYA oncology clinic and an online community. Forty participants were randomly assigned to the EW intervention or control group. To improve on lower-than-expected adherence and completion rates in a previous cohort, the protocol was iteratively revised using the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies (FRAME-IS). Modifications included …

Intraoperative Ultrasound Imaging Features Guiding Surgical Strategy In Spinal Cord Ependymoma Resection, Esteban Ramirez-Ferrer, Ian E Mccutcheon, Gil Kimchi, Behrang Amini, Romulo Andrade Almeida, Francisco Call-Orellana, Juan Pablo Zuluaga-Garcia, Robert Y North, Christopher A Alvarez-Breckenridge, Jeffrey S Weinberg, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Background and objectives: Preoperative imaging provides surgeons with an initial estimate of tumor infiltration and the likelihood of achieving an en-bloc resection in spinal cord ependymomas, yet the definitive decision is made intraoperatively. This study characterizes the intraoperative ultrasound (iUS) features that guide real-time surgical strategy and are associated with successful en-bloc removal.

Methods: A retrospective review of iUS images obtained during resection of spinal cord ependymomas was performed. The presence of a peritumoral halo representing the transition zone between the tumor and the spinal cord, the dorsal sagittal area of the spinal cord overlying the tumoral poles, the presence …

An Adp Getaway Service, Not An Atp Tank: Insights Into The Phosphagen System In Neurons, Madeline P Marques, Kartik Venkatachalam

Faculty, Staff and Student Publications

No abstract provided.

Sexual Toxicity After Chemoradiation For Anal Cancer Among Men Who Have Sex With Men: A Mixed-Methods Analysis, Beck O Gold, Angie Arzola, Benjamin R Schrank, Van K Morris, Christophe Marques, Jaime Gilliland, Thomas M Atkinson, Emma B Holliday

Faculty, Staff and Student Publications

Purpose: Chemoradiation (CRT) is the standard of treatment for localized anal squamous cell carcinoma (SCCA). Although cure rates are high, acute and late toxicities are common. There are increasing published data regarding vaginal stenosis and erectile dysfunction; however, the nature and impact of holistic sexual dysfunction after pelvic radiation, particularly among men who have sex with men (MSM), remains poorly characterized. This study aimed to: (1) explore patient-reported sexual health outcomes among MSM as measured by existing patient-reported outcome tools, and (2) assess the applicability of these existing tools for this population.

Methods and materials: MSM who are at least …

Barriers To Occupational And Physical Therapy Utilization For Children With Cancer, Maria C Swartz, Shiming Zhang, Donna Kelly, Clark R Andersen, Keri Schadler, Alakh P Rajan, Eduardo Gonzalez Villarreal, Stephanie J Wells, Amy Heaton, Karen Moody

Faculty, Staff and Student Publications

Introduction: Occupational and physical therapy (OT/PT) referrals and utilization barriers for childhood cancer patients have not been adequately examined. The current study investigated factors influencing referrals to and utilization of OT/PT services among children with cancer at an NIH-designated cancer center.

Methods: This retrospective cohort study included pediatric cancer patients (up to 18.99 years) presenting to the center over a 33.5-month period. Variables that could influence referrals to OT/PT were extracted from the electronic medical record (EMR) including OT and PT referrals (inpatient and outpatient), OT and PT consult completion, age at diagnosis, cancer type, sex, race/ethnicity, insurance, cancer treatment, …

Physical Activity In Osteosarcoma Patients During And Post Therapy: A Single Site Prospective Observational Study, Elysia R Cohen, Clark Andersen, Karen Moody, Maria C Swartz, Michael C Robertson, Alakh Rajan, Theresa Honey, Sandra Lugo, Grace Waterman, Keri Schadler

Faculty, Staff and Student Publications

PURPOSE: Osteosarcoma is the most common primary bone tumor in childhood and adolescence. Many patients face long-term impairments in their mobility and function after treatment, leading to a decrease in their quality of life. Exercise has been shown to improve functional recovery and improve quality of life in patients with cancer, though data specific to children with osteosarcoma are sparse. Exercise has also been shown to be feasible in patients undergoing chemotherapy, with numerous potential benefits to health and quality of life. To design the most effective exercise interventions for children and adolescents with osteosarcoma, we must first understand the …

A Comprehensive Biomechanical Material Characterization Of The Human Breast Fibro-Structural Support System, Aroj Bhattarai, Gregory P Reece, Kristy K Brock, Krishnaswamy Ravi-Chandar

Faculty, Staff and Student Publications

Breast surgery for aesthetic purposes, such as breast augmentation or breast reduction, and breast reconstruction after cancer treatment require an accurate structural (anatomical) and mechanical (functional) understanding of the breast components, including the fascial-ligamentous support system of the breast, to achieve optimal results. This paper aims to provide a comprehensive description of the mechanical behavior of the ligamentous and fascial connective tissues of the human female breast. Fasciae and ligaments obtained from 17 patients between 35 and 85 years of age who were undergoing mastectomy and three female cadavers were tested. Uniaxial tensile tests were conducted, and three constitutive models …

Fgl2-Knockout Tumor Cells Serve As A Vaccine Inducing Long-Duration Brain-Resident Memory T Cells That Reject Subsequent Intracranial Tumor Cell Challenges, Sheng Zhang, Yining Jin, Zhiliang Jia, Xueqing Xia, Yang Li, Qi Wang, Jing Wang, Jian Wang, Joya Chandra, Gregory K Friedman, Shulin Li

Faculty, Staff and Student Publications

The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients' mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (TRM) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this …

The Filamentous Ultrastructure Of The Popz Condensate Is Required For Its Cellular Function, Daniel Scholl, Tumara Boyd, Andrew P Latham, Alexandra Salazar, Asma M A M Khan, Steven Boeynaems, Alex S Holehouse, Gabriel C Lander, Andrej Sali, Donghyun Park, Ashok A Deniz, Keren Lasker

Duncan NRI Faculty and Staff Publications

Biomolecular condensates have key roles in regulating cellular processes. Yet, the relationship between atomic features and condensate function remains poorly understood. We studied this relationship using the polar organizing protein Z (PopZ). Here, we revealed hierarchical assembly of PopZ into a filamentous condensate by integrating cryo-electron tomography, biochemistry, single-molecule techniques and molecular dynamics simulations. The PopZ helical domain drives filamentation and condensation, while the disordered region inhibits them. Phase-dependent conformational changes prevent interfilament contacts in the dilute phase and expose client-binding sites in the dense phase. Perturbing filament formation in vitro alters the dynamics of scaffold and client proteins and …

Segmental Tracheal Resection For Thyroid Cancer: Perioperative Morbidity, Locoregional Control, And Survival, Anastasios Maniakas, David C Wilde, Isabelle Fournier, Emily K Hyde, Li Xu, Jennifer R Wang, Neil D Gross, Erich M Sturgis, Victoria Banuchi, Naifa L Busaidy, Maria E Cabanillas, Priyanka Iyer, Ramona Dadu, Steven G Waguespack, Mimi I Hu, G Brandon Gunn, Michael Kwon, Salmaan Ahmed, Michelle D Williams, Mark E Zafereo

Faculty, Staff and Student Publications

Background: Segmental tracheal resection is rarely needed for advanced thyroid cancer but is among the most complex, high-risk thyroid surgeries.

Methods: Retrospective study of patients undergoing segmental tracheal resection for thyroid cancer at MD Anderson Cancer Center (2005-2024).

Results: We identified 120 patients with a median follow-up of 4.6 years (range 0.02-16.38). Papillary thyroid cancer was most common (68%). The median number of tracheal rings resected was 4 (range 1-9). Seventeen (14%) patients had a new tracheostomy placed at the time of surgery, with 11 (9%) remaining trach-dependent at last follow-up. Twenty-six (22%) patients had a return to the operating …

Spatial Profiling Reveals Distinct Molecular And Immune Evolution Of Mouse Lung Adenocarcinoma Precancers With Or Without Carcinogen Exposure, Bo Zhu, Muhammad Aminu, Pingjun Chen, Jian-Rong Li, Chuanpeng Dong, Chenyang Li, Yanhua Tian, Shao-Wei Lu, Hong Chen, Chenxi Ma, Xin Hu, Jie Ye, Andrew Y Liu, Beibei Huang, Frank R Rojas, Parra Cuentas Edwin Roger, Ou Shi, Monique B Nilsson, Alissa Poteete, Khaja B Khan, Wei Lu, Luisa M Solis Soto, Junya Fujimoto, Cara Haymaker, Ignacio I Wistuba, Zhubo Wei, Linghua Wang, Don L Gibbons, Ken Chen, Alexandre Reuben, Jason M Schenkel, John V Heymach, Chao Cheng, Jia Wu, Jianjun Zhang

Faculty, Staff and Student Publications

Tumor evolution involves genetic, transcriptional, and phenotypic alterations that shape cancer cell behavior and interactions with the microenvironment. While single‐cell technologies have advanced our understanding of this process, spatial dynamics remain incompletely characterized. Here, whole‐exome sequencing (WES), imaging mass cytometry (IMC), and spatial transcriptomics (ST) were integrated to study molecular evolution and immune responses in two lung adenocarcinoma (LUAD) mouse models: a genetically engineered model (129S4/Sv‐KrasLSL‐G12D, termed 129S4 K) and a carcinogen‐induced precancer model (129S4 U). Compared to 129S4 K, 129S4 U tumors exhibited higher mutational, neoantigen but lower copy number variation (CNV) burdens at matched developmental timepoints, consistent with …

Prenatal Stress Induces Changes In Behavior, Hpa Axis, Inflammation, And Oxidative Stress In Adult Rats Offspring, Jorge M Aguiar-Geraldo, Jefté Peper-Nascimento, José Henrique Cararo, Taise Possamai-Della, Alexandra I Zugno, Anilkumar Pillai, João Quevedo, Samira S Valvassori

Faculty, Staff and Student Publications

Prenatal stress is related to the development of psychiatric disorders involving inflammation, oxidative stress, and hypothalamic-pituitary-adrenal (HPA) axis. Therefore, the aim of the present study was to evaluate the effects of prenatal stress on behavior, inflammation, oxidative stress, and the HPA-axis in the dams and their offspring treated with lithium. Thirteen pregnant Wistar rats were exposed to a prenatal chronic unpredictable stress protocol from the 14th day of gestation until birth. At the 60th postnatal day (PND), a treatment protocol was carried out in the offspring with lithium (intraperitoneally - 47.5 mg/kg) or saline for seven days (twice a day). …

Profiling The Genomic Landscape And Evolutionary History Of Polyploid Giant Cancer Cells In Undifferentiated Pleomorphic Sarcomas, Amy L Bowes, Sara Waise, Tom Lesluyes, Thomas Butters, Christie English, Haixi Yan, Annelien Verfaillie, Christopher Davies, Jianan Chen, Emma Nye, Richard Stone, Jiten Manji, Adrienne M Flanagan, Jonas Demeulemeester, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo

Faculty, Staff and Student Publications

Polyploid giant cancer cells (PGCCs), characterised by multinucleation and atypical nuclear morphology, are a common feature of undifferentiated pleomorphic sarcomas. While PGCCs may be a critical substrate for cancer evolution, their formation pathways and genomic consequences remain underexplored. In this study, we characterise PGCCs in ten pleomorphic sarcomas and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mononucleated or multinucleated bizarre, misshapen nuclei, and analysed them at single-cell resolution. Histopathological analysis showed that PGCCs were often randomly distributed throughout the tumour and did not appear in clusters, suggesting …

Profiling The Genomic Landscape And Evolutionary History Of Polyploid Giant Cancer Cells In Undifferentiated Pleomorphic Sarcomas, Amy L Bowes, Sara Waise, Tom Lesluyes, Thomas Butters, Christie English, Haixi Yan, Annelien Verfaillie, Christopher Davies, Jianan Chen, Emma Nye, Richard Stone, Jiten Manji, Adrienne M Flanagan, Jonas Demeulemeester, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo

Faculty, Staff and Student Publications

Polyploid giant cancer cells (PGCCs), characterised by multinucleation and atypical nuclear morphology, are a common feature of undifferentiated pleomorphic sarcomas. While PGCCs may be a critical substrate for cancer evolution, their formation pathways and genomic consequences remain underexplored. In this study, we characterise PGCCs in ten pleomorphic sarcomas and use topographic single-cell DNA sequencing (scDNA-seq) to investigate their genomic landscape. We selected PGCCs based on their nuclear morphology, including mononucleated or multinucleated bizarre, misshapen nuclei, and analysed them at single-cell resolution. Histopathological analysis showed that PGCCs were often randomly distributed throughout the tumour and did not appear in clusters, suggesting …

Bone Marrow Endosteum Houses Hedgehog-Susceptible Dlx5-Expressing Osteoblast Precursor Cells, Keita Kondo, Yuki Matsushita, Shion Orikasa, Yuta Nakai, Aiko Kuroda, Shinsuke Ohba, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

The bone marrow endosteum provides a robust source of bone-making osteoblasts by housing various types of osteoblast precursor cells, including endosteal stem cells expressing fibroblast growth factor receptor 3 (Fgfr3) and their downstream progenitor cell populations. In fetal bone development, Dlx5 marks early perichondrial cells that populate the diaphyseal bone and marrow stroma in the postnatal stages. However, the location of Dlx5-expressing cells in the postnatal bone marrow and how they contribute to osteogenesis remain undefined. Here, we show that Dlx5

Phase I Trial Of Binimetinib Plus Hydroxychloroquine In Patients With Previously Treated Metastatic Pancreatic Cancer, S Daniel Haldar, Fen Saj, So Jung Hong, Rishi Surana, Lianchun Xiao, J Jack Lee, Brandon Smaglo, Dan Zhao, Huili Zhu, Ryan Huey, Jason Willis, M Pia Morelli, Michael Overman, Florencia Mcallister, Robert Wolff, Anirban Maitra, David Fogelman, Channing Der, Shubham Pant

Faculty, Staff and Student Publications

Background: Dual mitogen-activated protein kinase (MAPK) pathway and autophagy inhibition shows synergistic antitumor activity in preclinical models of RAS-mutant cancers. We hypothesized that autophagy blockade with hydroxychloroquine (HCQ) could overcome resistance to MEK inhibition with binimetinib (BINI) and provide clinical benefit in previously treated, KRAS-mutated, metastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: This investigator-led, single-arm, open-label, phase I dose escalation/expansion trial evaluated the safety and tolerability of BINI + HCQ in patients with previously treated, metastatic PDAC (NCT04132505). Key eligibility criteria: ECOG 0-1, adequate organ function, ≥ 1 prior line of therapy for metastatic disease, and presence of KRAS …

Endosteal Stem Cells At The Bone-Blood Interface: A Double-Edged Sword For Rapid Bone Formation: Bone Marrow Endosteal Stem Cells Provide A Robust Source Of Bone-Making Osteoblasts Both In Normal And Abnormal Bone Formation, Keita Kondo, Yuki Matsushita, Shion Orikasa, Yuta Nakai, Aiko Kuroda, Shinsuke Ohba, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non-endosteal perisinusoidal niche. Single-cell molecular profiling and in vivo cell lineage analyses play key roles in discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor-making cells when deleterious mutations occur in …

Pretreatment Risk Model For Radiation-Induced Lymphopenia Is Associated With Adjuvant Durvalumab Efficacy In Patients With Unresectable Stage Iii Nsclc, Peter S N Van Rossum, Pim J J Damen, Francesco Cortiula, Brian P Hobbs, Lorenzo De Marchi, Radhe Mohan, Max Peters, Famke L Schneiders, Dirk De Ruysscher, Robin Wijsman, Joost J C Verhoeff, Ting Xu, Zhongxing Liao, Steven H Lin

Faculty, Staff and Student Publications

Introduction: Severe radiation-induced lymphopenia (RIL) during concurrent chemoradiotherapy (CCRT) for NSCLC has been associated with poorer outcomes and reduced immunotherapy efficacy. Because RIL often develops late during CCRT, identifying patients at risk before treatment may be clinically relevant. This study aimed to develop and validate a nomogram based on pretreatment predictors for severe RIL, and secondarily to explore associations between predicted RIL risk and adjuvant durvalumab-associated survival.

Methods: A retrospective development cohort of consecutive patients with NSCLC treated with CCRT (2010-2019) was established, along with an independent external validation cohort from other institutions. A multivariable logistic regression model was developed …

Development And Validation Of A Prognostic Risk Score For Patients With Cancer And Neutropenic Fever Presenting To The Emergency Department, Sandy Nath, Aiham Qdaisat, Andriy Derkach, Afia Babar, Deepti Zalavadia, Patrick Chaftari, Ziyi Li, Monica K Wattana, Joseph Schmeltz, Rocio Perez Johnston, Eduardo Ortiz, Kumar Alagappan, Adam Klotz, Sai-Ching Jim Yeung

Faculty, Staff and Student Publications

Objectives: Neutropenic fever (NF) is a life-threatening oncologic emergency associated with significant morbidity and mortality. Current predictive risk-stratification scores' limitations include outdated criteria, subjectivity, and low usage in the emergency department (ED). We sought to develop and externally validate a pragmatic, objective risk score to predict adverse outcomes in patients presenting to the ED with cancer and NF.

Methods: A retrospective cohort study was performed using data from 2 comprehensive cancer centers. The derivation cohort included adults presenting with NF to Memorial Sloan Kettering Cancer Center. External validation was conducted using data from the MD Anderson Cancer Center. The primary …

Social Roles And Emotional Distress Are Associated With Successful Aging In Adult Childhood Cancer Survivors, Samah Hayek, Kimberly A Miller, Michael E Roth, Michelle A T Hildebrandt, David R Freyer, Joel Milam

Faculty, Staff and Student Publications

Childhood cancer survivors (CCS) face complex long-term health consequences resulting from intensive treatments that may impact their aging trajectory. This study assessed the associations between social role attainment, emotional distress, and indicators of successful aging (SA) among adult CCS, considering treatment intensity. SA, is a multidimensional concept encompassing physical, cognitive, and psychosocial well-being, provides a framework for understanding and optimizing outcomes in this population. This cross-sectional study utilized data from Project Forward, a cohort, of 1,248 adult CCS diagnosed between 1996 and 2010. Participants were identified through the Los Angeles County Cancer Surveillance Program and completed a comprehensive self-report survey …

Eepd1 Evolved A Unique Dna Clamping Dimer Protecting Reversed Replication Forks, Runze Shen, Altaf H Sarker, Yue Chen, Min Liu, Sunetra Roy, Andrew S Arvai, Albino Bacolla, Zamal Ahmed, Panagiotis Katsonis, Michal Hammel, Isao Kuraoka, Miaw-Sheue Tsai, Corydon Irie, Lukas Webb, Olivier Lichtarge, Chi-Lin Tsai, Susan E Tsutakawa, Katharina Schlacher, John A Tainer

Faculty, Staff and Student Publications

Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are canonically monomeric phosphodiesterases exemplified by APE1, DNase I, and TDP2 nucleases. While EEP family domain containing protein 1 (EEPD1) acts in DNA stress responses, its proposed nuclease activities are enigmatic. Here, we integrate hybrid structural methods, evolution, biochemistry, cancer genomics, plus molecular and cell biology to define EEPD1 structure, assembly, and function at stalled DNA replication forks. Results imply EEPD1 surprisingly requires both unique EEP domain dimer and distinctive tandem Helix-hairpin-Helix [(HhH)2] domains to clamp double-stranded (ds) DNA at reversed DNA replication forks for fork protection. Small-angle X-ray Scattering (SAXS), crystal, and cryo-EM structures unveil an …

Concordance Analysis Of Dna And Rna Profiling: The Md Anderson Impact2 Study In Precision Oncology, Stephanie T Schmidt, Mehmet A Baysal, Siqing Fu, David S Hong, Sarina A Piha-Paul, Aung Naing, Jordi Rodon Ahnert, Timothy A Yap, Ecaterina Elena Dumbrava, Jennifer Beck, Funda Meric-Bernstam, Apostolia Maria Tsimberidou

Faculty, Staff and Student Publications

DNA profiling is an established method for cancer treatment selection, while RNA profiling remains investigational. We explored associations between DNA and RNA alterations and between the number of genes with altered expression and overall survival (OS) using patient data from IMPACT2 (NCT02152254), a randomized study evaluating molecular profiling for guiding cancer therapy across tumor types. Molecular profiling, including DNA next-generation sequencing, was performed on all 829 patients in the IMPACT2 study. RNA profiling was performed by Tempus for 253 of 829 patients. We evaluated the concordance between DNA and RNA profiling, analyzed OS in 217 treated patients with …

Winner's Curse Free Robust Mendelian Randomization With Summary Data, Zhongming Xie, Wanheng Zhang, Jingshen Wang, Chong Wu

Faculty, Staff and Student Publications

In the past decade, the increased availability of genome-wide association studies summary data has popularized Mendelian Randomization (MR) for conducting causal inference. MR analyses, incorporating genetic variants as instrumental variables, are known for their robustness against reverse causation bias and unmeasured confounders. Nevertheless, classical MR analyses using summary data may still produce biased causal effect estimates due to the winner’s curse and pleiotropy issues. To address these two issues and establish valid causal conclusions, we propose a unified robust Mendelian Randomization framework with summary data, which systematically removes the winner’s curse and screens out invalid genetic instruments with pleiotropic effects. …

Risk Stratification Of Low-Dose Cytarabine And Venetoclax In Patients With Aml Ineligible For Intensive Chemotherapy, Andrew H Wei, Panayiotis Panayiotidis, Pau Montesinos, Kamel Laribi, Vladimir Ivanov, Inho Kim, Jan Novak, Rebecca Champion, Walter Fiedler, Maria Pagoni, Julie Bergeron, Stephen B Ting, Jing-Zhou Hou, Takahiro Yamauchi, Jianxiang Wang, Stephen A Strickland, Michael R Savona, Tara L Lin, Anoop Enjeti, Ing Soo Tiong, Sangmin Lee, Gail J Roboz, Relja Popovic, Qi Jiang, Zihuan Liu, Yan Sun, Wellington Mendes, Brenda Chyla, Courtney D Dinardo

Faculty, Staff and Student Publications

Prognostic risk categorization aids treatment selection for patients with acute myeloid leukemia (AML). Although the European LeukemiaNet (ELN) classifications (2017 and 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, their application to patients receiving less intensive therapy, such as azacitidine plus venetoclax, has been less satisfactory. In response, a 4-gene classifier that stratifies older patients with AML unfit for intensive chemotherapy into those with higher benefit (wild type), intermediate benefit (FLT3-internal tandem duplication [ITD] or NRAS/KRAS mutation), or lower benefit (TP53 mutation) after azacitidine plus venetoclax treatment was developed. We hypothesized that this 4-gene …

Innovative Approaches For Lung Cancer Screening And Interception, Jianjun Zhang, Matthew D Park, Tej Pandya, Elaine Shum, Jia Wu, Simon Heeke, Ramin Salehi-Rad, Thomas U Marron, Zhubo Wei, Hui Li, Torsten G Blum, John V Heymach, Steven M Dubinett, Pan-Chyr Yang, Charles Swanton, Miriam Merad

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer-related deaths worldwide, partly because many patients are diagnosed at late stages, highlighting the urgent need for effective early detection and intervention strategies. Low-dose computed tomography (LDCT)-based screening reduces lung cancer mortality in high-risk populations defined by age and smoking history; however, the uptake of LDCT remains low among eligible individuals. Compounding this issue, modelling studies estimate that nearly half of lung cancers occur in individuals who do not meet eligibility criteria for LDCT-based lung cancer screening under current guidelines. Moreover, LDCT-based screening has inherent limitations, including a high rate of false-positive results …