Biomedical Informatics Commons^™

Mechanisms And Metabolic Consequences Of Adipocyte Progenitor Replicative Senescence, Tonghui Lin, Aftab Mohammad, Mikhail G Kolonin, Kristin L Eckel-Mahan

Faculty, Staff and Student Publications

In recent decades, obesity has become a worldwide epidemic. As a result, the importance of adipose tissue (AT) as a metabolically active storage depot for lipids and a key mediator of body-wide metabolism and energy balance has been increasingly recognized. Emerging from the studies of AT in metabolic disease is a recognition of the importance of the adipocyte progenitor cell (APC) population of AT being the gatekeeper of adipocyte function. APCs have the capability to self-renew and undergo adipogenesis to propagate new adipocytes capable of lipid storage, which is important for maintaining a healthy fat pad, devoid of dysfunctional lipid …

A Metabolite-Based Liquid Biopsy For Detection Of Ovarian Cancer, Johannes F Fahrmann, Seyyed Mahmood Ghasemi, Chae Y Han, Ranran Wu, Jennifer B Dennison, Jody Vykoukal, Joseph Celestino, Karen Lu, Zhen Lu, Charles Drescher, Kim-Anh Do, Samir Hanash, Robert C Bast, Ehsan Irajizad

Faculty, Staff and Student Publications

Serial CA125 and second line transvaginal ultrasound (TVS) screening in the UKCTOCS indicated a shift towards detection of earlier stage ovarian cancer (OvCa), but did not yield a significant mortality reduction. There remains a need to establish additional biomarkers that can complement CA125 for even earlier and at a larger proportion of new cases. Using a cohort of plasma samples from 219 OvCa cases (59 stage I/II and 160 stage III/IV) and 409 female controls and a novel Sensitivity Maximization At A Given Specificity (SMAGS) method, we developed a blood-based metabolite-based test consisting of 7 metabolites together with CA125 for …

Whole Genome And Reverse Protein Phase Array Landscapes Of Patient Derived Osteosarcoma Xenograft Models, Chia-Chin Wu, Licai Huang, Zhongting Zhang, Zhenlin Ju, Xingzhi Song, E Anders Kolb, Wendong Zhang, Jonathan Gill, Min Ha, Malcolm A Smith, Peter Houghton, Christopher L Morton, Raushan Kurmasheva, John Maris, Yael Mosse, Yiling Lu, Richard Gorlick, P Andrew Futreal, Hannah C Beird

Faculty, Staff and Student Publications

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds …

Neutralization Escape, Infectivity, And Membrane Fusion Of Jn1-Derived Sars-Cov-2 Slip, Flirt, And Kp2 Variants, Pei Li, Julia N Faraone, Cheng Chih Hsu, Michelle Chamblee, Yi-Min Zheng, Claire Carlin, Joseph S Bednash, Jeffrey C Horowitz, Rama K Mallampalli, Linda J Saif, Eugene M Oltz, Daniel Jones, Jianrong Li, Richard J Gumina, Kai Xu, Shan-Lu Liu

Faculty, Staff and Student Publications

We investigate JN.1-derived subvariants SLip, FLiRT, and KP.2 for neutralization by antibodies in vaccinated individuals, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients, or class III monoclonal antibody S309. Compared to JN.1, SLip, KP.2, and especially FLiRT exhibit increased resistance to bivalent-vaccinated and BA.2.86/JN.1-wave convalescent human sera. XBB.1.5 monovalent-vaccinated hamster sera robustly neutralize FLiRT and KP.2 but have reduced efficiency for SLip. All subvariants are resistant to S309 and show decreased infectivity, cell-cell fusion, and spike processing relative to JN.1. Modeling reveals that L455S and F456L in SLip reduce spike binding for ACE2, while R346T in FLiRT and KP.2 strengthens …

Trim44, A Novel Prognostic Marker, Supports The Survival Of Proteasome-Resistant Multiple Myeloma Cells, Trung Vu, Yuqin Wang, Annaliese Fowler, Anton Simieou, Nami Mccarty

Faculty, Staff and Student Publications

TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a Multiple Myeloma Research Foundation (MMRF) cohort of 858 patients, persisting across primary and recurrent MM cases. TRIM44 expression notably increases in advanced MM stages, indicating its potential role in disease progression. Single-cell RNA sequencing across MM stages showed significant TRIM44 upregulation in smoldering MM (SMM) and MM compared to normal bone marrow, especially in patients with t(4;14) …

Meti: Deep Profiling Of Tumor Ecosystems By Integrating Cell Morphology And Spatial Transcriptomics, Jiahui Jiang, Yunhe Liu, Jiangjiang Qin, Jianfeng Chen, Jingjing Wu, Melissa P Pizzi, Rossana Lazcano, Kohei Yamashita, Zhiyuan Xu, Guangsheng Pei, Kyung Serk Cho, Yanshuo Chu, Ansam Sinjab, Fuduan Peng, Xinmiao Yan, Guangchun Han, Ruiping Wang, Enyu Dai, Yibo Dai, Bogdan A Czerniak, Andrew Futreal, Anirban Maitra, Alexander Lazar, Humam Kadara, Amir A Jazaeri, Xiangdong Cheng, Jaffer Ajani, Jianjun Gao, Jian Hu, Linghua Wang

Faculty, Staff and Student Publications

Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance …

Non-Coding Rnas In Peritoneal Carcinomatosis: From Bench To Bedside, Julia Bohosova, Nida Sarosh Ashraf, Ondrej Slaby, George A Calin

Faculty, Staff and Student Publications

Peritoneal carcinomatosis represents an advanced stage of tumors within the peritoneal cavity. Once considered an incurable terminal cancer metastasis, contemporary medicine is on the hunt for certain potentially curative options alongside the present day’s palliative disease management. However, for most patients, peritoneal carcinomatosis continues to pose a fatal late-stage prognosis with a grim future outlook. Over the past two decades, non-coding RNAs have garnered significant attention due to their undeniable significance in regulating cellular processes across all levels. Disruption of the intricate regulation led by non-coding RNAs has been demonstrated to have a substantial impact on various human diseases, particularly …

The Icf Syndrome Protein Cdca7 Harbors A Unique Dna Binding Domain That Recognizes A Cpg Dyad In The Context Of A Non-B Dna, Swanand Hardikar, Ren Ren, Zhengzhou Ying, Jujun Zhou, John R Horton, Matthew D Bramble, Bin Liu, Yue Lu, Bigang Liu, Luis Della Coletta, Jianjun Shen, Jiameng Dan, Xing Zhang, Xiaodong Cheng, Taiping Chen

Faculty, Staff and Student Publications

CDCA7, encoding a protein with a carboxyl-terminal cysteine-rich domain (CRD), is mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a disease related to hypomethylation of juxtacentromeric satellite DNA. How CDCA7 directs DNA methylation to juxtacentromeric regions is unknown. Here, we show that the CDCA7 CRD adopts a unique zinc-binding structure that recognizes a CpG dyad in a non-B DNA formed by two sequence motifs. CDCA7, but not ICF mutants, preferentially binds the non-B DNA with strand-specific CpG hemi-methylation. The unmethylated sequence motif is highly enriched at centromeres of human chromosomes, whereas the methylated motif is distributed throughout …

Lung Cell Transplantation For Pulmonary Fibrosis, Irit Milman Krentsis, Yangxi Zheng, Chava Rosen, Sarah Y Shin, Christa Blagdon, Einav Shoshan, Yuan Qi, Jing Wang, Sandeep K Yadav, Esther Bachar Lustig, Elias Shetzen, Burton F Dickey, Harry Karmouty-Quintana, Yair Reisner

Faculty, Staff and Student Publications

Idiopathic pulmonary fibrosis is a major cause of death with few treatment options. Here, we demonstrate the therapeutic efficacy for lung fibrosis of adult lung cell transplantation using a single-cell suspension of the entire lung in two distinct mouse systems: bleomycin treatment and mice lacking telomeric repeat-binding factor 1 expression in alveolar type 2 (AT2) cells (SPC-Cre TRF1fl/fl), spontaneously developing fibrosis. In both models, the progression of fibrosis was associated with reduced levels of host lung progenitors, enabling engraftment of donor progenitors without any additional conditioning, in contrast to our previous studies. Two months after transplantation, engrafted progenitors …

Therapeutic Antisense Oligonucleotides In Oncology: From Bench To Bedside, Elif Çakan, Olivia D Lara, Anna Szymanowska, Emine Bayraktar, Arturo Chavez-Reyes, Gabriel Lopez-Berestein, Paola Amero, Cristian Rodriguez-Aguayo

Faculty, Staff and Student Publications

Advancements in our comprehension of tumor biology and chemoresistance have spurred the development of treatments that precisely target specific molecules within the body. Despite the expanding landscape of therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA therapeutics have emerged as a promising frontier in this realm, offering novel avenues for intervention such as RNA interference and the utilization of antisense oligonucleotides (ASOs). ASOs represent a versatile class of therapeutics capable of selectively targeting messenger RNAs (mRNAs) and silencing disease-associated proteins, thereby disrupting pathogenic processes at the molecular level. Recent advancements in chemical modification …

Active Learning Pipeline To Identify Candidate Terms For A Cdss Ontology, Xia Jing, Rohan Goli, Keerthana Komatineni, Shailesh Alluri, Nina Hubig, Hua Min, Yang Gong, Dean F Sittig, Paul Biondich, David Robinson, Christian Nøhr, Arild Faxvaag, Adam Wright, Timothy Law, Lior Rennert, Ronald Gimbel

Faculty, Staff and Student Publications

Ontology is essential for achieving health information and information technology application interoperability in the biomedical fields and beyond. Traditionally, ontology construction is carried out manually by human domain experts (HDE). Here, we explore an active learning approach to automatically identify candidate terms from publications, with manual verification later as a part of a deep learning model training and learning process. We introduce the overall architecture of the active learning pipeline and present some preliminary results. This work is a critical and complementary component in addition to manually building the ontology, especially during the long-term maintenance stage.

Perceptions Of Hiv-Related Comorbidities And Usability Of A Virtual Environment For Cardiovascular Disease Prevention Education In Sexual Minority Men With Hiv: Formative Phases Of A Pilot Randomized Controlled Trial, S Raquel Ramos, Harmony Reynolds, Constance Johnson, Gail Melkus, Trace Kershaw, Julian F Thayer, Allison Vorderstrasse

Faculty, Staff and Student Publications

Background: Sexual minority men with HIV are at an increased risk of cardiovascular disease (CVD) and have been underrepresented in behavioral research and clinical trials.

Objective: This study aims to explore perceptions of HIV-related comorbidities and assess the interest in and usability of a virtual environment for CVD prevention education in Black and Latinx sexual minority men with HIV.

Methods: This is a 3-phase pilot behavioral randomized controlled trial. We report on formative phases 1 and 2 that informed virtual environment content and features using qualitative interviews, usability testing, and beta testing with a total of 25 individuals. In phase …

Sexannodb, A Knowledgebase Of Sex-Specific Regulations From Multi-Omics Data Of Human Cancers, Mengyuan Yang, Yuzhou Feng, Jiajia Liu, Hong Wang, Sijia Wu, Weiling Zhao, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

Background

Sexual differences across molecular levels profoundly impact cancer biology and outcomes. Patient gender significantly influences drug responses, with divergent reactions between men and women to the same drugs. Despite databases on sex differences in human tissues, understanding regulations of sex disparities in cancer is limited. These resources lack detailed mechanistic studies on sex-biased molecules.

Methods

In this study, we conducted a comprehensive examination of molecular distinctions and regulatory networks across 27 cancer types, delving into sex-biased effects. Our analyses encompassed sex-biased competitive endogenous RNA networks, regulatory networks involving sex-biased RNA binding protein-exon skipping events, sex-biased transcription factor-gene regulatory networks, …

A Data Pipeline For Enhancing Quality Of Maude-Based Studies, Yuheng Shi, Yue Yu, Yubo Feng, Yang Gong

Faculty, Staff and Student Publications

The increasing use of MAUDE reports in patient safety research highlights the importance of understanding the processing and dissemination of open-access MAUDE data. However, the absence of a structured data pipeline undermines the reproducibility and transparency of studies relying on MAUDE data. In response, we conducted a comprehensive analysis of a recent study on endoscopic clips, assessing methodologies and results. We advocate for implementing an extract, transform, and load (ETL) pipeline, utilizing openFDA and integrating keyword search strategies and data visualization techniques. This approach aims to enhance the quality of MAUDE-based studies, ensuring their reproducibility and transparency. Moreover, ETL serves …

Challenges And Opportunities Of Artificial Intelligence In Cdss And Patient Safety, Yang Gong, Hua Min, Xia Jing, Ping Yu

Faculty, Staff and Student Publications

Ensuring patient safety in healthcare involves training professionals and implementing clinical decision support systems (CDSS) and health IT solutions to reduce errors and adverse events. The integration of artificial intelligence (AI) into health IT has revolutionized clinical settings by enabling real-time insights and personalized recommendations. However, the use of health IT can lead to unintended consequences that are not adequately addressed during training and implementation. These consequences can hinder the maximization of benefits and limit equitable access to healthcare. In this paper, we explore the impact of AI on CDSS and health IT, discuss the challenges in educating clinical informaticians, …

Loss Of Symmetric Cell Division Of Apical Neural Progenitors Drives Dennd5a-Related Developmental And Epileptic Encephalopathy, Emily Banks, Vincent Francis, Sheng-Jia Lin, Fares Kharfallah, Vladimir Fonov, Maxime Lévesque, Chanshuai Han, Gopinath Kulasekaran, Marius Tuznik, Armin Bayati, Reem Al-Khater, Fowzan S Alkuraya, Loukas Argyriou, Meisam Babaei, Melanie Bahlo, Behnoosh Bakhshoodeh, Eileen Barr, Lauren Bartik, Mahmoud Bassiony, Miriam Bertrand, Dominique Braun, Rebecca Buchert, Mauro Budetta, Maxime Cadieux-Dion, Daniel G Calame, Heidi Cope, Donna Cushing, Stephanie Efthymiou, Marwa Abd Elmaksoud, Huda G El Said, Tawfiq Froukh, Harinder K Gill, Joseph G Gleeson, Laura Gogoll, Elaine S-Y Goh, Vykuntaraju K Gowda, Tobias B Haack, Mais O Hashem, Stefan Hauser, Trevor L Hoffman, Jacob S Hogue, Akimoto Hosokawa, Henry Houlden, Kevin Huang, Stephanie Huynh, Ehsan G Karimiani, Silke Kaulfuß, G Christoph Korenke, Amy Kritzer, Hane Lee, James R Lupski, Elysa J Marco, Kirsty Mcwalter, Arakel Minassian, Berge A Minassian, David Murphy, Juanita Neira-Fresneda, Hope Northrup, Denis M Nyaga, Barbara Oehl-Jaschkowitz, Matthew Osmond, Richard Person, Davut Pehlivan, Cassidy Petree, Lynette G Sadleir, Carol Saunders, Ludger Schoels, Vandana Shashi, Rebecca C Spillmann, Varunvenkat M Srinivasan, Paria N Torbati, Tulay Tos, Maha S Zaki, Dihong Zhou, Christiane Zweier, Jean-François Trempe, Thomas M Durcan, Ziv Gan-Or, Massimo Avoli, Cesar Alves, Gaurav K Varshney, Reza Maroofian, David A Rudko, Peter S Mcpherson

Faculty, Staff and Student Publications

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells …

The Dna Repair Pathway As A Therapeutic Target To Synergize With Trastuzumab Deruxtecan In Her2-Targeted Antibody-Drug Conjugate-Resistant Her2-Overexpressing Breast Cancer, Jangsoon Lee, Kumiko Kida, Jiwon Koh, Huey Liu, Ganiraju C Manyam, Young Jin Gi, Dileep R Rampa, Asha S Multani, Jing Wang, Gitanjali Jayachandran, Dae-Won Lee, James M Reuben, Aysegul Sahin, Lei Huo, Debu Tripathy, Seock-Ah Im, Naoto T Ueno

Faculty, Staff and Student Publications

Background: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo. …

Transcriptome Profiling Of Pediatric Extracranial Solid Tumors And Lymphomas Enables Rapid Low-Cost Diagnostic Classification, Kofi B Opoku, Teresa Santiago, Priya Kumar, Sophia M Roush, Yuri Fedoriw, Tamiwe Tomoka, Vasiliki Leventaki, Larissa V Furtado, Nickhill Bhakta, Thomas B Alexander, Jeremy R Wang

Faculty, Staff and Student Publications

Approximately 80% of pediatric tumors occur in low- and middle-income countries (LMIC), where diagnostic tools essential for treatment decisions are often unavailable or incomplete. Development of cost-effective molecular diagnostics will help bridge the cancer diagnostic gap and ultimately improve pediatric cancer outcomes in LMIC settings. We investigated the feasibility of using nanopore whole transcriptome sequencing on formalin-fixed paraffin embedded (FFPE)-derived RNA and a composite machine learning model for pediatric solid tumor diagnosis. Transcriptome cDNA sequencing was performed on a heterogenous set of 221 FFPE and 32 fresh frozen pediatric solid tumor and lymphoma specimens on Oxford Nanopore Technologies' sequencing platforms. …

Analysis Of Serum Exosome Metabolites Identifies Potential Biomarkers For Human Hepatocellular Carcinoma, Tingting Zhao, Yan Liang, Xiaolan Zhen, Hong Wang, Li Song, Didi Xing, Hui Li

Faculty, Staff and Student Publications

Currently, the clinical cure rate for primary liver cancer remains low. Effective screening and early diagnosis of hepatocellular carcinoma (HCC) remain clinical challenges. Exosomes are intimately associated with tumor development and their contents have the potential to serve as highly sensitive tumor-specific markers. A comprehensive untargeted metabolomics study was conducted using exosome samples extracted from the serum of 48 subjects (36 HCC patients and 12 healthy controls) via a commercial kit. An ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) strategy was used to identify the metabolic compounds. A total of 18 differential metabolites were identified using the non-targeted metabolomics approach of UPLC-QTOF-MS/MS. …

Clinical And Genomic-Based Decision Support System To Define The Optimal Timing Of Allogeneic Hematopoietic Stem-Cell Transplantation In Patients With Myelodysplastic Syndromes, Cristina Astrid Tentori, Caterina Gregorio, Marie Robin, Nico Gagelmann, Carmelo Gurnari, Somedeb Ball, Juan Carlos Caballero Berrocal, Luca Lanino, Saverio D'Amico, Marta Spreafico, Giulia Maggioni, Erica Travaglino, Elisabetta Sauta, Manja Meggendorfer, Lin-Pierre Zhao, Alessia Campagna, Victor Savevski, Armando Santoro, Najla Al Ali, David Sallman, Francesc Sole, Guillermo Garcia-Manero, Ulrich Germing, Nicolaus Kroger, Shahram Kordasti, Valeria Santini, Guillermo Sanz, Wolfgang Kern, Uwe Platzbecker, Maria Diez-Campelo, Jaroslaw P Maciejewski, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Amer M Zeidan, Gastone Castellani, Rami Komrokji, Francesca Ieva, Matteo Giovanni Della Porta, Genomed4all And Synthema Consortiums

Faculty, Staff and Student Publications

Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M).

Patients and methods: We studied a retrospective population of 7,118 patients, stratified into training and validation …

Impacts Of Interleukin-10 Promoter Genotypes On Prostate Cancer, Yu-Ting Chin, Chung-Lin Tsai, Hung-Huan Ma, Da-Chuan Cheng, Chia-Wen Tsai, Yun-Chi Wang, Hou-Yu Shih, Shu-Yu Chang, Jian Gu, Wen-Shin Chang, Da-Tian Bau

Faculty, Staff and Student Publications

Prostate cancer (PCa) is a multifactorial disease influenced by genetic, environmental, and immunological factors. Genetic polymorphisms in the interleukin-10 (IL-10) gene have been implicated in PCa susceptibility, development, and progression. This study aims to assess the contributions of three IL-10 promoter single nucleotide polymorphisms (SNPs), A-1082G (rs1800896), T-819C (rs3021097), and A-592C (rs1800872), to the risk of PCa in Taiwan. The three IL-10 genotypes were determined using PCR-RFLP methodology and were evaluated for their contributions to PCa risk among 218 PCa patients and 436 non-PCa controls. None of the three IL-10 SNPs were significantly associated with the risks of …

Association Of Social Determinants, Lifestyle, And Metabolic Factors With Mortality In Chinese Adults: A Nationwide 10-Year Prospective Cohort Study, Jieli Lu, Mian Li, Jiang He, Yu Xu, Ruizhi Zheng, Jie Zheng, Guijun Qin, Yingfen Qin, Yuhong Chen, Xulei Tang, Zhen Ye, Min Xu, Tiange Wang, Lixin Shi, Qing Su, Xuefeng Yu, Li Yan, Zhiyun Zhao, Qin Wan, Gang Chen, Zhengnan Gao, Guixia Wang, Feixia Shen, Xuejiang Gu, Zuojie Luo, Li Chen, Xinguo Hou, Yanan Huo, Qiang Li, Hong Qiao, Yinfei Zhang, Tianshu Zeng, Chunyan Hu, Qiuyu Cao, Xiaojing Jia, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Hongyan Qi, Xueyan Wu, Di Zhang, Meng Dai, Donghui Li, Shenghan Lai, Lulu Chen, Jiajun Zhao, Yiming Mu, Weiguo Hu, Guang Ning, Ruying Hu, Yufang Bi, Weiqing Wang, 4c Study Group

Faculty, Staff and Student Publications

Nationwide estimates of the impact of common modifiable risk factors on mortality remain crucial. We aim to assess the influence of social determinants, lifestyle, and metabolic factors on mortality in 174,004 adults aged ≥40 years from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. We reveal that 17 modifiable factors are independently associated with mortality, accounting for 64.8% of all-cause mortality, 77.4% of cardiovascular mortality, and 44.8% of cancer mortality. Low education emerges as the leading factor for both all-cause and cancer mortality, while hypertension is predominant for cardiovascular mortality. Moreover, low gross domestic product per capita and high …

Effect Of The Implementation Of A Multiple-Behavior Self-Monitoring Intervention On Dietary Intake In Type 2 Diabetes: Secondary Data Analysis, Jisook Ko, Jing Wang, Ngozi Mbue, Susan Schembre, Stanley Cron

Faculty, Staff and Student Publications

Background: An electronic diary embedded in a mobile device to monitor lifestyle can be as effective as traditional methods. However, the efficacy of self-monitoring multiple behaviors for dietary intake has not been well studied in people with diabetes.

Objective: This study aimed to compare the effect of using technology-assisted self-monitoring versus paper diaries on changes in dietary intake.

Methods: This is a secondary analysis of data collected from 39 people with type 2 diabetes as part of a 3-month pilot clinical trial. Changes in energy intake and the contribution of total fat intake and total carbohydrate intake to total calories …

Epcam-Targeted Betulinic Acid Analogue Nanotherapy Improves Therapeutic Efficacy And Induces Anti-Tumorigenic Immune Response In Colorectal Cancer Tumor Microenvironment, Debasmita Dutta, Ashique Al Hoque, Brahamacharry Paul, Jun Hyoung Park, Chinmay Chowdhury, Mohiuddin Quadir, Soumyabrata Banerjee, Arghadip Choudhury, Soumik Laha, Nayim Sepay, Priyanka Boro, Benny Abraham Kaipparettu, Biswajit Mukherjee

Faculty, Staff and Students Publications

Background: Betulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) …

The Complex Molecular Epileptogenesis Landscape Of Glioblastoma, Victoria Soeung, Ralph B Puchalski, Jeffrey L Noebels

Faculty, Staff and Students Publications

The cortical microenvironment surrounding malignant glioblastoma is a source of depolarizing crosstalk favoring hyperexcitability, tumor expansion, and immune evasion. Neosynaptogenesis, excess glutamate, and altered intrinsic membrane currents contribute to excitability dyshomeostasis, yet only half of the cases develop seizures, suggesting that tumor and host genomics, along with location, rather than mass effect, play a critical role. We analyzed the spatial contours and expression of 358 clinically validated human epilepsy genes in the human glioblastoma transcriptome compared to non-tumor adult and developing cortex datasets. Nearly half, including dosage-sensitive genes whose expression levels are securely linked to monogenic epilepsy, are strikingly enriched …

Simulation Of Crispr-Cas9 Editing On Evolving Barcode And Accuracy Of Lineage Tracing, Fengshuo Liu, Xiang Zhang, Yipeng Yang

Faculty, Staff and Students Publications

We designed a simulation program that mimics the CRISPR-Cas9 editing on evolving barcode and double strand break repair procedure along with cell divisions. Emerging barcode mutations tend to build upon previously existing mutations, occurring sequentially with each generation. This process results in a unique mutation profile in each cell. We sample the barcodes in leaf cells and reconstruct the lineage, comparing it to the original lineage tree to test algorithm accuracy under different parameter settings. Our computational simulations validate the reasonable assumptions deduced from experimental observations, emphasizing that factors such as sampling size, barcode length, multiple barcodes, indel probabilities, and …

Cutaneous Squamous Cell Carcinoma Of The Head And Neck: Pathological Features And What They Mean For Prognosis And Treatment, Uma Ramesh, Elizabeth Chiang, Haleigh Stafford, Jane Buell, Frank Materia, Moran Amit, Dan Yaniv

Faculty, Staff and Student Publications

Simple Summary

Cutaneous squamous cell carcinoma (cSCC) of the head and neck, although treatable, can be highly aggressive. Certain pathological features of cSCC can drastically impact prognosis. Therefore, the presence of a few such features is considered in both staging and treating cSCC. In this review, we summarize the current literature regarding pathological prognostic indicators of cSCC, including depth of invasion, surgical margins, perineural invasion, lymphovascular invasion, extranodal extension, tumor grade, tumor subtype, premalignant lesions, and molecular markers. Furthermore, we characterize the impact of each indicator on clinical outcomes of head and neck cSCC, their role in dictating adjuvant therapy …

Synergistic Activation By Glass And Pointed Promotes Neuronal Identity In The Drosophila Eye Disc, Hongsu Wang, Komal Kumar Bollepogu Raja, Kelvin Yeung, Carolyn A Morrison, Antonia Terrizzano, Alireza Khodadadi-Jamayran, Phoenix Chen, Ashley Jordan, Cornelia Fritsch, Simon G Sprecher, Graeme Mardon, Jessica E Treisman

Faculty, Staff and Students Publications

The integration of extrinsic signaling with cell-intrinsic transcription factors can direct progenitor cells to differentiate into distinct cell fates. In the developing Drosophila eye, differentiation of photoreceptors R1-R7 requires EGFR signaling mediated by the transcription factor Pointed, and our single-cell RNA-Seq analysis shows that the same photoreceptors require the eye-specific transcription factor Glass. We find that ectopic expression of Glass and activation of EGFR signaling synergistically induce neuronal gene expression in the wing disc in a Pointed-dependent manner. Targeted DamID reveals that Glass and Pointed share many binding sites in the genome of developing photoreceptors. Comparison with transcriptomic data shows …

Trim44 Enhances Autophagy Via Sqstm1 Oligomerization In Response To Oxidative Stress, Yuqin Wang, Lin Lyu, Trung Vu, Nami Mccarty

Faculty, Staff and Student Publications

The deubiquitinase tripartite motif containing 44 (TRIM44) plays a critical role in linking the proteotoxic stress response with autophagic degradation, which is significant in the context of cancer and neurological diseases. Although TRIM44 is recognized as a prognostic marker in various cancers, the complex molecular mechanisms through which it facilitates autophagic degradation, particularly under oxidative stress conditions, have not been fully explored. In this study, we demonstrate that TRIM44 significantly enhances autophagy in response to oxidative stress, reducing cytotoxicity in cancer cells treated with arsenic trioxide. Our research emphasizes the critical role of the posttranslational modification of sequestosome-1 (SQSTM1) and …

Injectable, Reversibly Thermoresponsive Captopril-Laden Hydrogel For The Local Treatment Of Sensory Loss In Diabetic Neuropathy, Amit Chandra Das, James M Nichols, Caitlin V Crelli, Lu Liu, Riddhi Vichare, Hoang Vu Pham, Caitlyn M Gaffney, Fisher R Cherry, Peter M Grace, Andrew J Shepherd, Jelena M Janjic

Faculty, Staff and Student Publications

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. …