Medical Genetics Commons^™

Shiny-Magec: A Bayesian R Shiny Application For Meta-Analysis Of Censored Adverse Events, Zihan Zhou, Zizhong Tian, Christine Peterson, Le Bao, Shouhao Zhou

Faculty, Staff and Student Publications

Accurate assessment of adverse event (AE) incidence is critical in clinical research for drug safety. While meta-analysis serves as an essential tool to comprehensively synthesize the evidence across multiple studies, incomplete AE reporting in clinical trials remains a persistent challenge. In particular, AEs occurring below study-specific reporting thresholds are often omitted from publications, leading to left-censored data. Failure to account for these censored AE counts can result in biased AE incidence estimates. We present an R Shiny application that implements a Bayesian meta-analysis model specifically designed to incorporate censored AE data into the estimation process. This interactive tool provides a …

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 …

Clemastine Ameliorates Cognitive Deficits In An Experimental Rat Model Of Chronic Cerebral Hypoperfusion, Xuemei Zong, Zhihai Huang, Fanfei Kong, Yu Feng, Yulan Zhang, Peibin Zou, Hung Wen Lin, David C Hess, Quanguang Zhang

Faculty, Staff and Student Publications

Chronic cerebral hypoperfusion (CCH) profoundly affects patient well-being and has been proposed as a risk factor for cognitive impairment and dementia. However, due to the limited understanding of the pathophysiology of CCH, there are currently no effective preventive or therapeutic approaches for CCH-associated cognitive impairment. Therefore, identifying new targets for CCH is essential to bridge this knowledge gap. In this study, we sought to determine whether enhanced myelination could prevent cognitive impairment associated with CCH. Experimental CCH was induced via bilateral common carotid artery occlusion (BCCAO) in rats, and clemastine, a well-established pro-myelinating agent, was administered to boost myelin renewal. …

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 …

Beyond Short Microhomologies: Mismatch-Compatible Pol Θ-Mediated Dna Damage Repair, Yuzhen Li, Richard D Wood

Faculty, Staff and Student Publications

DNA polymerase θ (Pol θ)-mediated end-joining (TMEJ), one of several pathways for repairing DNA double-strand breaks, is traditionally thought to initiate via anchoring at short, consecutive, and perfectly matched microhomologies (MHs). Emerging evidence indicates that Pol θ can utilize MHs containing mismatches both in vitro and in vivo. This revised definition of MH provides a mechanistic explanation for a broader spectrum of Pol θ-dependent repair outcomes. Here, we summarize recent findings on the revised definition of MHs utilized by Pol θ, assess the applicability of this concept across species, and compare TMEJ with other (micro)hom(e)ology-mediated repair pathways. We explore how …

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 …

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 …

Alpha 7 Nicotinic Acetylcholine Receptor Contributes To Long-Term Cognitive Recovery Following Ischemic Stroke, Dustin T Nguyen, Kate Mendoza, Cassandra Hall, Chunfeng Tan, Anjali Chauhan

Faculty, Staff and Student Publications

Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n0KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance …

Analysis Of Patients With Monocytic And Monocytic-Like Acute Myeloid Leukemia, Including Aml-M4 And Aml-M5, Treated With Venetoclax Plus Azacitidine, Marina Konopleva, Courtney D Dinardo, Yan Sun, Paul Jung, Sanam Loghavi, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A Pollyea

Faculty, Staff and Student Publications

No abstract provided.

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 …

Pharmacokinetic Modeling Strategies For Dynamic Hyperpolarized Urea Imaging, Keith A Michel, Collin J Harlan, Christopher M Walker, Matthew E Merritt, Yunyun Chen, Stephen Y Lai, James A Bankson

Faculty, Staff and Student Publications

Purpose: To evaluate pharmacokinetic modeling methods for quantification of tissue perfusion/permeability with hyperpolarized 13C urea.

Methods: Three models for quantitative analysis of dynamic HP urea imaging data were proposed and evaluated in numerical simulations and a thyroid cancer mouse model. A multicompartment model resembling the extended Tofts model for DCE-MRI (Model I) and two simplified models were used. The simplified models each eliminate a volume parameter representing vascular (Model II) or impermeable cellular space (Model III). Signal curves were generated from Model I, and models were fit to these synthetic data to quantify the effects of acquisition settings, bias in …

Lonp1 Variants Are Associated With Clinically Diverse Phenotypes, Randee E Young, Lu Qiao, Rebecca Hernan, David A Sweetser, Jessica L Waxler, Daryl A Scott, Tiana M Scott, Seema R Lalani, Mahshid S Azamian, Jill A Rosenfeld, Bret Bostwick, Lindsay C Burrage, Lance H Rodan, Bianca E Russell, Marina Dutra-Clarke, Michael Kruer, Somayeh Bakhtiarim, Hossein Darvish, David J Amor, Shamima Rahman, Karen Stals, Lisa Bradley, Susan Byrne, Leandra K Tolusso, Beatrix Wong, Laura Benedict, Kimberly Wallis, Kestutis Micke, Cindy Colson, Thomas Smol, Sabrina V Southwick, Kristen A Miller, Michelle L Kush, Odelia Chorin, Annick Rothschild, Wei Wang, Yufeng Shen, Wendy K Chung

Faculty, Staff and Students Publications

LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic …

Comparison Of Variant Callers Using 60 532 Multi-Ancestry Whole Genome Sequences, Hufeng Zhou, Zilin Li, Derek Shyr, Xihao Li, Haoyu Yang, Rounak Dey, Yushi Tang, Robert Maier, Eric Boerwinkle, Steve Buyske, Mark Daly, Adam Felsenfeld, Richard A Gibbs, Namrata Gupta, Ira M Hall, Tara Matise, Ginger A Metcalf, Albert Smith, Catherine Reeves, Heidi J Sofia, Nathan O Stitziel, Michael C Zody, Nhgri Genome Sequencing Program (Gsp) Consortium, Benjamin Neale, Xihong Lin

Faculty, Staff and Students Publications

Whole genome sequencing (WGS) studies play a pivotal role in studying the genetic underpinnings of human diseases and traits. High quality and reproducible variant calling is the cornerstone for the success of downstream analyses, including WGS association studies and polygenic risk prediction. This paper compares the data quality, performance, and concordance of two widely used WGS variant callers, the Genome Analysis Toolkit (GATK) and Variant Tool set that discovers short variants (VT), using 60 532 multi-ancestry whole genomes sequenced by the Centers for Common Disease Genomics (CCDGs) of the NHGRI Genome Sequencing Program. Our findings show that both QCed GATK …

Segmental And Multifocal Isolated Dystonias: Similarities And Differences, Hyder A Jinnah, Vittorio Velucci, Daniele Belvisi, Gamze Kilic-Berkmen, Joel S Perlmutter, Laura J Wright, Christine Klein, Jeanne S Feuerstein, Steven Bellows, Joseph Jankovic, Cynthia Comella, Richard L Barbano, Aparna Wagle Shukla, Stephen G Reich, Mark S Ledoux, Alberto J Espay, Kevin R Duque, Florence C F Chang, Victor S C Fung, Sarah Pirio-Richardson, Carmen Terranova, Emile S Moukheiber, Sarah Idrissi, Barbara Vitucci, Susan H Fox, Samuel Frank, Natividad Stover, Brian D Berman, Rachel Saunders-Pullman, William G Ondo, Christopher L Groth, Marcello Esposito, Laura Avanzino, Francesco Bono, Roberto Erro, Marcello Mario Mascia, Antonella Muroni, Alfredo Berardelli, Giovanni Defazio

Faculty, Staff and Students Publications

Background: Whether the traditional distinction between segmental and multifocal dystonia is clinically or scientifically useful remains unclear.

Objective: To evaluate whether idiopathic isolated adult-onset segmental and multifocal dystonia can be differentiated based on clinical features other than the contiguity of affected body regions.

Methods: We compared data on segmental and multifocal dystonia from two large dystonia databases established in the USA and Italy that used similar criteria for patient recruitment and assessment.

Results: Compared to segmental dystonia, multifocal dystonia was characterized by a higher proportion of men, a younger age at dystonia onset, a greater frequency of upper limb dystonia, …

Impulsivity In Cerebellar Ataxia: An Online, Multidimensional Assessment, Brooke Chasalow, Yakov Flaumenhaft, Yael De Picciotto, Chi-Ying R Lin, Leila Montaser-Kouhsari, William Saban

Faculty, Staff and Students Publications

While considered a motor control structure, the cerebellum contributes to non-motor functions, including impulsivity. However, whether it contributes to impulsivity in a domain-specific manner remains unknown. Studies on cerebellar ataxia (CA), a common model for cerebellar dysfunction, typically have small sample sizes, limiting robustness. In a multicenter cross-sectional study, we investigated the cerebellum's role in various forms of impulsivity by comparing large cohorts of CA to age- and education-matched neurotypical healthy (NH) controls. Additionally, to examine the ability to identify individuals with CA using impulsivity features alone, we developed supervised machine learning (ML) models. In experiment 1 (CA = 140, …

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 …

Rab4 Spatially And Functionally Converges With Rab7 In The Degradative Endolysosomal Network, Stephen M Farmer, Shiyu Xu, Yue Yu, Xin Ye, Haoyi Yang, Jing Cai, Beatriz Rios, Wen-Wen Lin, Daniela Covarrubias, Vicky Chuong, Lili Ye, German Zylberberg, Charissa Wang, Erin Furr-Stimming, Qingchun Tong, Oguz Kanca, Hugo J Bellen, Travis I Moore, Sheng Zhang

Faculty, Staff and Students Publications

Rab GTPases are key regulators of endosomal trafficking in eukaryotes. In mammalian cells, Rab4 and Rab7 were shown to localize to distinct compartments, with Rab4 on early endosomes for fast recycling and Rab7 on late endosomes for degradation. Here, we show that in Drosophila, endogenous Rab4 and Rab7 extensively colocalize across tissues and developmental stages. Recruited to the same compartments through mechanisms that do not require the activity of the other, they have opposing effects on endolysosomal size: Rab4 overexpression or Rab7 impairment leads to enlarged endolysosomes, whereas Rab4 loss or constitutively active Rab7 reduces their sizes. Rab4 deficiency suppresses …

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 …

Post-Dobbs Realities: Ethical Imperatives For Data Transparency And Trust In Maternal Health Care, Faith E Fletcher, Sophie L Schott, Kelley Akhiemokhali, Kari White

Center for Medical Ethics and Health Policy Staff Publications

No abstract provided.

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 …

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). …

Aggregation Of Gene Regulatory Information And Knowledge On Fair Principles Enables Discovery Of Pathogenic Gene Regulatory Variants, Keyang Yu, Haoquan Zhao, Andrea S Wilderman, Tierra R Farris, Jessie E Arce, David Chen, Andrew R Jackson, Yiran Guo, Qi Li, Bosko Jevtic, Dubravka Jevtic, Vuk Milinovic, Yuankun Zhu, Jeremy Costanza, Eric D Wenger, Christopher Nemarich, Lisa Anderson, Aleksandar Mihajlović, Kristin Ardlie, Shaine A Morris, Matthew E Roth, Deanne M Taylor, Adam C Resnick, Lilei Zhang, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

Motivation: Methods for sharing gene regulatory information and knowledge on FAIR principles, particularly in the context of tissue-specific gene regulation, remain poorly defined and implemented, hampering discovery and clinical genetic diagnosis.

Results: We specified FAIR principles for tissue-specific gene regulatory information and knowledge; implemented them by developing a registry of regulatory elements and aggregating FAIR gene regulatory information from several major sources; developed computational tools that utilize these FAIR resources; and demonstrated their utility by associating gene regulatory variants with major subtypes of congenital heart disease.

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 …

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 …

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 …

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 …