Biomedical Informatics Commons^™

Cell Cycle Progression Of Under-Replicated Cells, Min Huang, Chang Yang, Litong Nie, Huimin Zhang, Dandan Zhu, Chao Wang, Jeong-Min Park, Mrinal Srivastava, Elina Mosa, Siting Li, Mengfan Tang, Xu Feng, Sarah J Keast, Fabio Stossi, Junjie Chen

Faculty, Staff and Student Publications

Cell cycle checkpoints are the regulatory mechanisms that secure the strict order of cellular events for cell division that ensure genome integrity. It has been proposed that mitosis initiation depends on the completion of DNA replication, which must be tightly controlled to guarantee genome duplication. Contrary to these conventional hypotheses, we showed here that cells were able to enter mitosis without completion of DNA replication. Although DNA replication was not completed in cells upon depletion of MCM2, CDC45 or GINS4, these under-replicated cells progressed into mitosis, which led to cell death. These unexpected results challenge current model and suggest the …

A Regularized Bayesian Dirichlet-Multinomial Regression Model For Integrating Single-Cell-Level Omics And Patient-Level Clinical Study Data, Yanghong Guo, Lei Yu, Lei Guo, Lin Xu, Qiwei Li

Faculty, Staff and Student Publications

The abundance of various cell types can vary significantly among patients with varying phenotypes and even those with the same phenotype. Recent scientific advancements provide mounting evidence that other clinical variables, such as age, gender, and lifestyle habits, can also influence the abundance of certain cell types. However, current methods for integrating single-cell-level omics data with clinical variables are inadequate. In this study, we propose a regularized Bayesian Dirichlet-multinomial regression framework to investigate the relationship between single-cell RNA sequencing data and patient-level clinical data. Additionally, the model employs a novel hierarchical tree structure to identify such relationships at different cell-type …

Causal Models And Prediction In Cell Line Perturbation Experiments, James P Long, Yumeng Yang, Shohei Shimizu, Thong Pham, Kim-Anh Do

Faculty, Staff and Student Publications

In cell line perturbation experiments, a collection of cells is perturbed with external agents and responses such as protein expression measured. Due to cost constraints, only a small fraction of all possible perturbations can be tested in vitro. This has led to the development of computational models that can predict cellular responses to perturbations in silico. A central challenge for these models is to predict the effect of new, previously untested perturbations that were not used in the training data. Here we propose causal structural equations for modeling how perturbations effect cells. From this model, we derive two estimators for …

Genetics And Biology Of Pancreatic Ductal Adenocarcinoma, Haoqiang Ying, Alec C Kimmelman, Nabeel Bardeesy, Raghu Kalluri, Anirban Maitra, Ronald A Depinho

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and …

Sstr2-Targeted Theranostics In Hepatocellular Carcinoma, Majid Momeny, Solmaz Aghaamiri, Servando Hernandez Vargas, Belkacem Acidi, Sukhen C Ghosh, Tyler M Bateman, Jack T Adams, Vahid Khalaj, Ahmed O Kaseb, Hop S Tran Cao, Ali Azhdarinia

Faculty, Staff and Student Publications

Background: While the clinical use of radiolabeled somatostatin analogs is well established in neuroendocrine tumors, there is growing interest in expanding their application to other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the potential utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC).

Methods: SSTR2 expression in HCC cell lines and clinical samples was evaluated using qRT-PCR, Western blot analysis, and a public dataset. 67Ga-DOTATATE uptake was measured, 177Lu-DOTATATE cytotoxicity was assessed, and 68Ga-DOTATATE tumor targeting was evaluated in HCC animal models and a patient via PET/CT imaging.

Results: SSTR2 expression was confirmed in HCC cell lines and clinical samples. …

Targeted Inhibition Of Aurora Kinase A Promotes Immune Checkpoint Inhibition Efficacy In Human Papillomavirus-Driven Cancers, Soma Ghosh, Madison P O'Hara, Pragya Sinha, Tuhina Mazumdar, Lacin Yapindi, Jagannadha K Sastry, Faye M Johnson

Faculty, Staff and Student Publications

Background: Human papillomavirus (HPV)-driven cancers include head and neck squamous cell carcinoma and cervical cancer and represent approximately 5% of all cancer cases worldwide. Standard-of-care chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICIs) are associated with adverse effects and limited responses in patients with HPV-driven cancers. The integration of targeted therapies with ICIs may improve outcomes. In a previous study, we demonstrated that Aurora kinase A (AURKA, Aurora A) inhibitors lead to apoptosis of human HPV-positive cancer cells in vitro and in vivo. Here, we explored the potential of Aurora A inhibition to enhance response to ICIs in immune-competent …

Development Of Sacb-Based Counterselection For Efficient Allelic Exchange In Fusobacterium Nucleatum, Peng Zhou, Bibek G C, Bo Hu, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum, prevalent in the oral cavity, is significantly linked to overall human health. Our molecular comprehension of its role in oral biofilm formation and its interactions with the host under various pathological circumstances has seen considerable advancements in recent years, primarily due to the development of various genetic tools for DNA manipulation in this bacterium. Of these, counterselection-based unmarked in-frame mutation methods have proved notably effective. Under suitable growth conditions, cells carrying a counterselectable gene die, enabling efficient selection of rare, defined allelic exchange mutants. The sacB gene from Bacillus subtilis, encoding levansucrase, is a widely used …

Advancing De Novo Lipogenesis: Genetic And Metabolic Insights, Sean M Hartig, Mark A Herman

Faculty, Staff and Students Publications

De novo lipogenesis (DNL) is the process whereby cells synthesize fatty acids from acetyl-CoA, contributing to steatosis in fatty liver disease. Two new studies, using genetic mouse models, metabolomics, and pharmacology, identified alternative pathways in DNL and unexpected physiological effects when targeting key enzymes in this pathway.

Microtubules Sequester Acetylated Yap In The Cytoplasm And Inhibit Heart Regeneration, Shijie Liu, Vaibhav Deshmukh, Fansen Meng, Yidan Wang, Yuka Morikawa, Jeffrey D Steimle, Rich Gang Li, Jun Wang, James F Martin

Faculty, Staff and Students Publications

Background: The Hippo pathway effector YAP (Yes-associated protein) plays an essential role in cardiomyocyte proliferation and heart regeneration. In response to physiological changes, YAP moves in and out of the nucleus. The pathophysiological mechanisms regulating YAP subcellular localization after myocardial infarction remain poorly defined.

Methods: We identified YAP acetylation at site K265 by in vitro acetylation followed by mass spectrometry analysis. We used adeno-associated virus to express YAP-containing mutations that either abolished acetylation (YAP-K265R) or mimicked acetylation (YAP-K265Q) and studied how acetylation regulates YAP subcellular localization in mouse hearts. We generated a cell line with YAP-K265R mutation and investigated the …

The Gip Receptor Activates Futile Calcium Cycling In White Adipose Tissue To Increase Energy Expenditure And Drive Weight Loss In Mice, Xinxin Yu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G Straub, Valentina Pirro, Margo P Emont, Brian A Droz, Kyla Ai Collins, Chanmin Joung, Mackenzie J Pearson, Corey M James, Gopal J Babu, Vissarion Efthymiou, Ashley Vernon, Mary Elizabeth Patti, Yu A An, Evan D Rosen, Matthew P Coghlan, Ricardo J Samms, Philipp E Scherer, Christine M Kusminski

Faculty, Staff and Student Publications

Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced …

Rpa And Rad27 Limit Templated And Inverted Insertions At Dna Breaks, Yang Yu, Xin Wang, Jordan Fox, Qian Li, Yang Yu, P J Hastings, Kaifu Chen, Grzegorz Ira

Faculty, Staff and Students Publications

Formation of templated insertions at DNA double-strand breaks (DSBs) is very common in cancer cells. The mechanisms and enzymes regulating these events are largely unknown. Here, we investigated templated insertions in yeast at DSBs using amplicon sequencing across a repaired locus. We document very short (most ∼5-34 bp), templated inverted duplications at DSBs. They are generated through a foldback mechanism that utilizes microhomologies adjacent to the DSB. Enzymatic requirements suggest a hybrid mechanism wherein one end requires Polδ-mediated synthesis while the other end is captured by nonhomologous end joining (NHEJ) or by alternative end joining (Alt-EJ). This process is exacerbated …

Yap Overcomes Mechanical Barriers To Induce Mitotic Rounding And Adult Cardiomyocyte Division, Yuka Morikawa, Jong H Kim, Rich Gang Li, Lin Liu, Shijie Liu, Vaibhav Deshmukh, Matthew C Hill, James F Martin

Faculty, Staff and Students Publications

Background: Many specialized cells in adult organs acquire a state of cell cycle arrest and quiescence through unknown mechanisms. Our limited understanding of mammalian cell cycle arrest is derived primarily from cell culture models. Adult mammalian cardiomyocytes, a classic example of cell cycle arrested cells, exit the cell cycle postnatally and remain in an arrested state for the life of the organism. Cardiomyocytes can be induced to re-enter the cell cycle by YAP5SA, an active form of the Hippo signaling pathway effector YAP.

Methods: We performed clonal analyses to determine the cell cycle kinetics of YAP5SA cardiomyocytes. We also performed …

Scproatlas: An Atlas Of Multiplexed Single-Cell Spatial Proteomics Imaging In Human Tissues, Tiangang Wang, Xuanmin Chen, Yujuan Han, Jiahao Yi, Xi Liu, Pora Kim, Liyu Huang, Kexin Huang, Xiaobo Zhou

Faculty, Staff and Student Publications

Spatial proteomics can visualize and quantify protein expression profiles within tissues at single-cell resolution. Although spatial proteomics can only detect a limited number of proteins compared to spatial transcriptomics, it provides comprehensive spatial information with single-cell resolution. By studying the spatial distribution of cells, we can clearly obtain the spatial context within tissues at multiple scales. Spatial context includes the spatial composition of cell types, the distribution of functional structures, and the spatial communication between functional regions, all of which are crucial for the patterns of cellular distribution. Here, we constructed a comprehensive spatial proteomics functional annotation knowledgebase, scProAtlas (https://relab.xidian.edu.cn/scProAtlas/#/), …

Aspdb: An Integrative Knowledgebase Of Human Protein Isoforms From Experimental And Ai-Predicted Structures, Yuntao Yang, Himansu Kumar, Yuhan Xie, Zhao Li, Rongbin Li, Wenbo Chen, Chiamaka S Diala, Meer A Ali, Yi Xu, Albon Wu, Sayed-Rzgar Hosseini, Erfei Bi, Hongyu Zhao, Pora Kim, W Jim Zheng

Faculty, Staff and Student Publications

Alternative splicing is a crucial cellular process in eukaryotes, enabling the generation of multiple protein isoforms with diverse functions from a single gene. To better understand the impact of alternative splicing on protein structures, protein-protein interaction and human diseases, we developed ASpdb (https://biodataai.uth.edu/ASpdb/), a comprehensive database integrating experimentally determined structures and AlphaFold 2-predicted models for human protein isoforms. ASpdb includes over 3400 canonical isoforms, each represented by both experimentally resolved and predicted structures, and >7200 alternative isoforms with AlphaFold 2 predictions. In addition to detailed splicing events, 3D structures, sequence variations and functional annotations, ASpdb uniquely offers comparative analyses and …

Metsdb: A Knowledgebase Of Cancer Metastasis At Bulk, Single-Cell And Spatial Levels, Sijia Wu, Jiajin Zhang, Yanfei Wang, Xinyu Qin, Zhaocan Zhang, Zhennan Lu, Pora Kim, Xiaobo Zhou, Liyu Huang

Faculty, Staff and Student Publications

Cancer metastasis, the process by which tumour cells migrate and colonize distant organs from a primary site, is responsible for the majority of cancer-related deaths. Understanding the cellular and molecular mechanisms underlying this complex process is essential for developing effective metastasis prevention and therapy strategies. To this end, we systematically analysed 1786 bulk tissue samples from 13 cancer types, 988 463 single cells from 17 cancer types, and 40 252 spots from 45 spatial slides across 10 cancer types. The results of these analyses are compiled in the metsDB database, accessible at https://relab.xidian.edu.cn/metsDB/. This database provides insights into alterations in …

Crisprofft: Comprehensive Database Of Crispr/Cas Off-Targets, Grant Wang, Xiaona Liu, Aoqi Wang, Jianguo Wen, Pora Kim, Qianqian Song, Xiaona Liu, Xiaobo Zhou

Faculty, Staff and Student Publications

The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR-associated protein) programmable nuclease system continues to evolve, with in vivo therapeutic gene editing increasingly applied in clinical settings. However, off-target effects remain a significant challenge, hindering its broader clinical application. To enhance the development of gene-editing therapies and the accuracy of prediction algorithms, we developed CRISPRoffT (https://ccsm.uth.edu/CRISPRoffT/). Users can access a comprehensive repository of off-target regions predicted and validated by a diverse range of technologies across various cell lines, Cas enzyme variants, engineered sgRNAs (single guide RNAs) and CRISPR editing systems. CRISPRoffT integrates results of off-target analysis from 74 studies, encompassing …

Plural Molecular And Cellular Mechanisms Of Pore Domain, Timothy J Abreo, Emma C Thompson, Anuraag Madabushi, Kristen L Park, Heun Soh, Nissi Varghese, Carlos G Vanoye, Kristen Springer, Jim Johnson, Scotty Sims, Zhigang Ji, Ana G Chavez, Miranda J Jankovic, Bereket Habte, Aamir R Zuberi, Cathleen M Lutz, Zhao Wang, Vaishnav Krishnan, Lisa Dudler, Stephanie Einsele-Scholz, Jeffrey L Noebels, Alfred L George, Atul Maheshwari, Anastasios Tzingounis, Edward C Cooper

Faculty, Staff and Students Publications

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. Kcnq2G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal …

Cansar 2024-An Update To The Public Drug Discovery Knowledgebase, Phillip W Gingrich, Rezvan Chitsazi, Ansuman Biswas, Chunjie Jiang, Li Zhao, Joseph E Tym, Kevin M Brammer, Jun Li, Zhigang Shu, David S Maxwell, Jeffrey A Tacy, Ioan L Mica, Michael Darkoh, Patrizio Di Micco, Kaitlyn P Russell, Paul Workman, Bissan Al-Lazikani

Faculty, Staff and Student Publications

canSAR (https://cansar.ai) continues to serve as the largest publicly available platform for cancer-focused drug discovery and translational research. It integrates multidisciplinary data from disparate and otherwise siloed public data sources as well as data curated uniquely for canSAR. In addition, canSAR deploys a suite of curation and standardization tools together with AI algorithms to generate new knowledge from these integrated data to inform hypothesis generation. Here we report the latest updates to canSAR. As well as increasing available data, we provide enhancements to our algorithms to improve the offering to the user. Notably, our enhancements include a revised ligandability classifier …

Urban Sensing In The Era Of Large Language Models, Ce Hou, Fan Zhang, Yong Li, Haifeng Li, Gengchen Mai, Yuhao Kang, Ling Yao, Wenhao Yu, Yao Yao, Song Gao, Min Chen, Yu Liu

Faculty, Staff and Student Publications

Urban sensing has become increasingly important as cities evolve into the centers of human activities. Large language models (LLMs) offer new opportunities for urban sensing based on commonsense and worldview that emerged through their language-centric framework. This paper illustrates the transformative impact of LLMs, particularly in the potential of advancing next-generation urban sensing for exploring urban mechanisms. The discussion navigates through several key aspects, including enhancing knowledge transfer between humans and LLM, urban mechanisms awareness, and achieve automated decision-making with LLM agents. We emphasize the potential of LLMs to revolutionize urban sensing, offering a more comprehensive, efficient, and in-depth understanding …

Dimensionality Reduction For Visualizing Spatially Resolved Profiling Data Using Spasne, Yuansheng Zhou, Chen Tang, Xue Xiao, Xiaowei Zhan, Tao Wang, Guanghua Xiao, Lin Xu

Faculty, Staff and Student Publications

Background: Spatially resolved profiling technologies to quantify transcriptomes, epigenomes, and proteomes have been emerging as groundbreaking methods for comprehensive molecular characterizations. Dimensionality reduction and visualization is an essential step to analyze and interpret spatially resolved profiling data. However, state-of-the-art dimensionality reduction methods for single-cell sequencing data, such as the t-distributed stochastic neighbor embedding (t-SNE) and uniform manifold approximation and projection (UMAP), were not tailored for spatially resolved profiling data.

Results: Here we developed a spatially resolved t-SNE (SpaSNE) method to integrate both spatial and molecular information. We applied it to a variety of public spatially resolved profiling datasets that were …

Intrinsic Adaptive Plasticity In Mouse And Human Sensory Neurons, Lisa A Mcilvried, John Smith Del Rosario, Melanie Y Pullen, Andi Wangzhou, Tayler D Sheahan, Andrew J Shepherd, Richard A Slivicki, John A Lemen, Theodore J Price, Bryan A Copits, Robert W Gereau

Faculty, Staff and Student Publications

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory …

The Association Of The Chemotherapy Response Score And Homologous Recombination Deficiency In Patients Undergoing Interval Tumor Reductive Surgery Following Neoadjuvant Chemotherapy, Roni Nitecki Wilke, Jinsong Liu, Shannon Neville Westin, Bryan M Fellman, Travis T Sims, Melissa Pham, Kelly Rangel, Esther Sey, Jose Alejandro Rauh-Hain, Karen H Lu, Anil K Sood, Nicole D Fleming

Faculty, Staff and Student Publications

Objectives: In patients undergoing interval tumor reductive surgery, a good response to neoadjuvant chemotherapy may limit available tumor for homologous recombination deficiency testing. The objective of this study was to assess whether the chemotherapy response score predicts homologous recombination status.

Methods: We identified patients with advanced epithelial ovarian cancer (diagnosed January 2019 to 20 June 2023) who received neoadjuvant chemotherapy, underwent interval surgery, and for whom a chemotherapy response score was reported (1=no or minimal tumor response, 2=appreciable tumor response, 3=complete or near complete response with no residual tumor). Comparisons were made using ANOVAs or Kruskal-Wallis test for continuous variables …

Circakb: A Comprehensive Knowledgebase Of Circadian Genes Across Multiple Species, Xingchen Zhu, Xiao Han, Zhijin Li, Xiaobo Zhou, Seung-Hee Yoo, Zheng Chen, Zhiwei Ji

Faculty, Staff and Student Publications

Circadian rhythms, which are the natural cycles that dictate various physiological processes over a 24-h period, have been increasingly recognized as important in the management and treatment of various human diseases. However, the lack of sufficient data and reliable analysis methods have been a major obstacle to understanding the bidirectional interaction between circadian variation and human health. We have developed CircaKB, a comprehensive knowledgebase of circadian genes across multiple species. CircaKB is the first knowledgebase that provides systematic annotations of the oscillatory patterns of gene expression at a genome-wide level for 15 representative species. Currently, CircaKB contains 226 time-course transcriptome …

Heterorepur: Efficient Modeling Of Heterogeneous Disease Graph For Depression Drug Repurposing Using Heterogeneous Graph Neural Networks, Ko-Hong Lin, Tongtong Huang, Kai Zhang, Xiaoqian Jiang, Yejin Kim

Faculty, Staff and Student Publications

Objective Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders, yet existing treatments often result in suboptimal responses and encounter high recurrence rate. Repositioning existing medications, which often significantly reduces the required time and budget, has been demonstrated to be a promising strategy for drug discovery of multiple central nervous system (CNS) disorders. However, an efficient modeling strategy of heterogeneous semantic information among biological networks has yet to be developed for drug repurposing.

Material and Methods In this study, we proposed HeteroRepur, by integrating heterogeneous graph neural networks to learn interaction features of Depression Drug Repurposing Graph …

Couple-Based Lifestyle Intervention For Minority Prostate Cancer Survivors: A Randomized Feasibility Trial, Dalnim Cho, Yisheng Li, Karen Basen-Engquist, Chiara Acquati, Nga T T Nguyen, Hilary Ma, Curtis A Pettaway, Lorna H Mcneill

Faculty, Staff and Student Publications

Background: Black and Hispanic prostate cancer (PCa) survivors, who face a high burden of comorbid conditions and often engage in low levels of physical activity and healthy eating, remain significantly underrepresented in lifestyle intervention studies.

Purpose: Given the significance of spousal influence, we developed a culturally tailored lifestyle intervention for these survivors and their spouses and assessed its feasibility, acceptability, and impact on behavioral change.

Methods: Survivor-spouse couples were randomly assigned to an intervention group (n = 22), which received 12 health-coaching calls over 6 months, or a usual-care control group (n = 9). Assessments were conducted at baseline (T1), …

Cyclin E1/Cdk2 Activation Defines A Key Vulnerability To Wee1 Kinase Inhibition In Gynecological Cancers, Daehwan Kim, Heekyung Chung, Wen Liu, Kangjin Jeong, Tugba Y Ozmen, Furkan Ozmen, Matthew J Rames, Sangyub Kim, Xiao Guo, Nathan Jameson, Petrus R De Jong, Steven Yea, Laurie Harford, Jiali Li, Cara A Mathews, Deborah B Doroshow, Vincent J Charles, Doris Kim, Kimberlee Fischer, Ahmed A Samatar, Adrian Jubb, Kevin D Bunker, Kimberly Blackwell, Fiona Simpkins, Funda Meric-Bernstam, Gordon B Mills, Olivier Harismendy, Jianhui Ma, Mark R Lackner

Faculty, Staff and Student Publications

Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib. We found that ovarian cancer cell lines with high levels of endogenous Cyclin E1 expression or forced overexpression were exquisitely sensitive to azenosertib and these results extended to in vivo models of ovarian and uterine serous carcinoma. Models with high Cyclin …

Early Treatment Discontinuation In Patients With Deficient Mismatch Repair Or Microsatellite Instability High Metastatic Colorectal Cancer Receiving Immune Checkpoint Inhibitors, Julien Taieb, Margherita Ambrosini, Emily Alouani, Sara Lonardi, Frank A Sinicrope, Marie Decraecker, Alice Boileve, Emilie Hafliger, Thibault Mazard, Simon Pernot, Pauline Parent, Javier Ros, Michael J Overman, Priya Jayachandran, Vincenzo Nasca, Lisa Salvatore, Rosine Guimbaud, Chiara Cremolini, David Tougeron, Filippo Pietrantonio

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD).

Methods: To assess whether ETD is associated with similar outcomes compared …

Comprehensive Characterization Of The Transcriptional Landscape In Alzheimer’S Disease (Ad) Brains, Chengxuan Chen, Zhao Zhang, Yuan Liu, Wei Hong, Hande Karahan, Jun Wang, Wenbo Li, Lixia Diao, Meichen Yu, Andrew J Saykin, Kwangsik Nho, Jungsu Kim, Leng Han

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the leading dementia among the elderly with complex origins. Despite extensive investigation into the AD-associated protein-coding genes, the involvement of noncoding RNAs (ncRNAs) and posttranscriptional modification (PTM) in AD pathogenesis remains unclear. Here, we comprehensively characterized the landscape of ncRNAs and PTM events in 1460 samples across six brain regions sourced from the Mount Sinai/JJ Peters VA Medical Center Brain Bank Study and Mayo cohorts, encompassing 33,321 long ncRNAs, 92,897 enhancer RNAs, 53,763 alternative polyadenylation events, and 900,221 A-to-I RNA editing events. We additionally identified 25,351 aberrantly expressed ncRNAs and altered PTM events associated with AD …

Atrx Silences Cartpt Expression In Osteoblastic Cells During Skeletal Development, Yi-Ting Chen, Ming-Ming Jiang, Carolina Leynes, Mary Adeyeye, Camilla F Majano, Barakat Ibrahim, Urszula Polak, George Hung, Zixue Jin, Denise G Lanza, Lan Liao, Brian Dawson, Yuqing Chen-Evenson, Oscar E Ruiz, Richard J Gibbons, Jason D Heaney, Yangjin Bae, Brendan Lee

Faculty, Staff and Students Publications

ATP-dependent chromatin remodeling protein ATRX is an essential regulator involved in maintenance of DNA structure and chromatin state and regulation of gene expression during development. ATRX was originally identified as the monogenic cause of X-linked α-thalassemia mental retardation (ATR-X) syndrome. Affected individuals display a variety of developmental abnormalities and skeletal deformities. Studies from others investigated the role of ATRX in skeletal development by tissue-specific Atrx knockout. However, the impact of ATRX during early skeletal development has not been examined. Using preosteoblast-specific Atrx conditional knockout mice, we observed increased trabecular bone mass and decreased osteoclast number in bone. In vitro coculture …

Novel Computational And Artificial Intelligence Models In Cancer Research, Li Liu, Fuhai Li, Xiaoming Liu, Kai Wang, Zhongming Zhao

Faculty, Staff and Student Publications

The ICIBM 2023 marked the 11th annual conference of its kind, with the ICIBM recently becoming the official conference of the International Association for Intelligent Biology and Medicine (IAIBM), showcasing cutting-edge advancements at the intersection of computation and biomedical research. A summary of the ICIBM 2023 program is provided by Li et al. [1]. As in previous years, cancer research remained a prominent focus, with numerous presentations highlighting innovative approaches to understanding and treating this complex disease. To summarize these contributions, selected works have been compiled in this Special Issue, “Novel Computational and Artificial Intelligence Models in Cancer …