Genetic Phenomena Commons^™

Lifr Regulates Cholesterol-Driven Bidirectional Hepatocyte-Neutrophil Cross-Talk To Promote Liver Regeneration, Yalan Deng, Zilong Zhao, Marisela Sheldon, Yang Zhao, Hongqi Teng, Jie Zhang, Yutong Sun, Fan Yao, Michael A Curran, Hao Zhu, Li Ma

Faculty, Staff and Student Publications

Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 …

Psychological Distress And Mental Health Care Utilization Among Black Survivors Of Adolescent And Young Adult Cancer, Eunju Choi, Amy M Berkman, Aryce Battle, Andrea C Betts, John M Salsman, Clark R Andersen, Susan K Peterson, Qian Lu, Christabel K Cheung, J A Livingston, Michelle A T Hildebrandt, Susan K Parsons, David R Freyer, Michael E Roth

Faculty, Staff and Student Publications

Background: Survivors of adolescent and young adult (AYA) cancer experience significant psychological distress and encounter barriers to accessing mental health care. Few studies have investigated racial/ethnic disparities in psychological health outcomes among AYA survivors, and none have compared outcomes within a racially minoritized population.

Methods: National Health Interview Survey data (2010-2018) were analyzed that identified non-Hispanic Black (hereafter, Black) survivors of AYA cancer and age- and sex-matched Black noncancer controls. Sociodemographic factors, chronic health conditions, modifiable behaviors (smoking and alcohol use), and psychological outcomes were assessed with χ2 tests. Logistic regression models, adjusted for survey weights, were used to evaluate …

Feasibility And Acceptability Of A Nurse-Led Telehealth Intervention (Bolster) To Support Patients With Peritoneal Carcinomatosis And Their Caregivers: A Pilot Randomized Clinical Trial, Rachel A Pozzar, Andrea C Enzinger, Catherine Howard, Anna Tavormina, Ursula A Matulonis, Joyce F Liu, Panagiotis A Konstantinopoulos, Carolyn Krasner, Jaclyn A Wall, Kate Sciacca, Larissa A Meyer, Charlotta Lindvall, Alexi A Wright

Faculty, Staff and Student Publications

Objective: Patients with advanced gynecologic (GYN) and gastrointestinal (GI) cancers frequently develop peritoneal carcinomatosis (PC), which limits prognosis and diminishes health-related quality of life (HRQoL). Palliative procedures may improve PC symptoms, yet patients and caregivers report feeling unprepared to manage ostomies, catheters, and other complex needs. Our objectives were to (1) assess the feasibility of an efficacy trial of a nurse-led telehealth intervention (BOLSTER) for patients with PC and their caregivers; and (2) assess BOLSTER's acceptability, potential to improve patients' HRQoL and self-efficacy, and potential impact on advance care planning (ACP).

Methods: Pilot feasibility RCT. Recently hospitalized adults with advanced …

Proteomic Analysis Of Ferroptosis Pathways Reveals A Role Of Cept1 In Suppressing Ferroptosis, Xiaoguang Liu, Zhen Chen, Yuelong Yan, Fereshteh Zandkarimi, Litong Nie, Amber Horbath, Lavanya Kondiparthi, Chao Mao, Hyemin Lee, Li Zhuang, Masha Poyurovsky, Brent R Stockwell, Junjie Chen, Boyi Gan

Faculty, Staff and Student Publications

Ferroptosis has been recognized as a unique cell death modality driven by excessive lipid peroxidation and unbalanced cellular metabolism. In this study, we established a protein interaction landscape for ferroptosis pathways through proteomic analyses, and identified choline/ethanolamine phosphotransferase 1 (CEPT1) as a lysophosphatidylcholine acyltransferase 3 (LPCAT3)-interacting protein that regulates LPCAT3 protein stability. In contrast to its known role in promoting phospholipid synthesis, we showed that CEPT1 suppresses ferroptosis potentially by interacting with phospholipases and breaking down certain pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing phospholipids. Together, our study reveals a previously unrecognized role of CEPT1 in suppressing ferroptosis.

Immunoprevention Strategies For Colorectal Cancer In Lynch Syndrome Carriers, Charles M Bowen, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

The immune revolution that swept the field of oncology in the mid-2010s with the advent of checkpoint inhibitors has led to a paradigm shift in approaches toward adapting new cancer prevention modalities. Cancer vaccines have emerged from this era with astounding potential as a durable intervention to prevent cancers especially for patients with hereditary susceptibilities such as Lynch syndrome carriers. This review covers new insights in the immunoprevention landscape for patients living with Lynch syndrome including highlights ranging from clinical trials exploring the use of chemoprevention agents to boost immune cellularity to investigative studies using novel vaccine approaches to induce …

Mitochondrial Complex I Promotes Kidney Cancer Metastasis, Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Hieu S Vu, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, Mckenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis Mcdaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J Deberardinis

Faculty, Staff and Student Publications

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human …

Determinant Of 30-Day Mortality Of Pulmonary Legionellosis: Do Coinfections Matter?, Takahiro Matsuo, Sebastian Wurster, Ying Jiang, Jeffrey Tarrand, Scott E Evans

Faculty, Staff and Student Publications

We retrospectively reviewed 64 cases of cancer with pulmonary legionellosis (Legionella pneumophila in 73%). Nearly all patients received Legionella-active antibiotics, yet 30-day mortality was 23%. Independent predictors of 30-day mortality were hyponatremia, bilateral lung involvement, and Sequential Organ Failure Assessment score ≥5. Lung coinfections were common (31%) but did not significantly increase mortality.

Comparing The Diagnostic Yield Of Germline Exome Versus Panel Sequencing In The Diverse Population Of The Texas Kidscanseq Pediatric Cancer Study, Lauren R Desrosiers-Battu, Tao Wang, Jacquelyn Reuther, George Miles, Hongzheng Dai, Heidi Russell, Alva Recinos, Stephanie Gutierrez, Amy Thomas, Emily Berenson, Jessica Corredor, Kimberly Nugent, Rachel Wyatt Castillo, Rebecca Althaus, Rebecca Littlejohn, Shawn Gessay, Gail Tomlinson, Jonathan Gill, Juan Carlos Bernini, Kelly Vallance, Timothy Griffin, Sarah Scollon, Frank Y Lin, Christine Eng, Shashikant Kulkarni, Susan G Hilsenbeck, Angshumoy Roy, Amy L Mcguire, D Williams Parsons, Sharon E Plon

Faculty, Staff and Student Publications

Purpose: To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population.

Patients and methods: The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel. The results were categorized by participants demographics, the presence of pathogenic or likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) in cancer predisposition genes (CPGs). Pediatric actionable CPGs were defined as those with cancer surveillance recommendations during childhood.

Results: Cancer P/LP variants were reported by at least one platform in 103 of …

Clonal Evolution Of Pancreatobiliary Neoplasms, Huamin Wang, Olca Basturk

Faculty, Staff and Student Publications

No abstract provided.

Small Molecules Targeting Micrornas: New Opportunities And Challenges In Precision Cancer Therapy, Ancuta Jurj, Beatrice Fontana, Gabriele Varani, George A Calin

Faculty, Staff and Student Publications

Noncoding RNAs, especially miRNAs, play a pivotal role in cancer initiation and metastasis, underscoring their susceptibility to precise modulation via small molecule inhibitors. This review examines the innovative strategy of targeting oncogenic miRNAs with small drug-like molecules, an approach that can reshape the cancer treatment landscape. We review the current understanding of the multifaceted roles of miRNAs in oncogenesis, highlighting emerging therapeutic paradigms that have the potential to expand cancer treatment options. As research on small molecule inhibitors of miRNA is still in its early stages, ongoing investigative efforts and the development of new technologies and chemical matter are essential …

Multi-Scale Variational Autoencoder For Imputation Of Missing Values In Untargeted Metabolomics Using Whole-Genome Sequencing Data, Chen Zhao, Kuan-Jui Su, Chong Wu, Xuewei Cao, Qiuying Sha, Zhe Luo, Chuan Qiu, Lan Juan Zhao, Anqi Liu, Lindong Jiang, Xiao Zhang, Hui Shen, Weihua Zhou, Hong-Wen Deng

Faculty, Staff and Student Publications

Background: Missing data is a common challenge in mass spectrometry-based metabolomics, which can lead to biased and incomplete analyses. The integration of whole-genome sequencing (WGS) data with metabolomics data has emerged as a promising approach to enhance the accuracy of data imputation in metabolomics studies.

Method: In this study, we propose a novel method that leverages the information from WGS data and reference metabolites to impute unknown metabolites. Our approach utilizes a multi-scale variational autoencoder to jointly model the burden score, polygenetic risk score (PGS), and linkage disequilibrium (LD) pruned single nucleotide polymorphisms (SNPs) for feature extraction and missing metabolomics …

Single-Center Clinical Experience Of Extended Sleeve Lobectomy (Esl) Versus Standard Sleeve Lobectomy (Sl), Haoyou Wang, Wei Wang, Peng Zu, Gregor J Kocher, Mara B Antonoff, Chenlei Zhang, Hongxu Liu

Faculty, Staff and Student Publications

Background: Sleeve lobectomy (SL) and extended SL (ESL), which aim to preserve pulmonary function and enhance the quality of life of patients while ensuring oncological outcomes, are valuable surgical options for the treatment of centrally located non-small cell lung cancer (NSCLC). This study aimed to compare perioperative adverse events and long-term survival between SL and ESL in NSCLC patients, providing a comprehensive review of surgical outcomes, complications, and survival to assess the roles of SL and ESL in thoracic oncology.

Methods: This single-center retrospective study assessed the outcomes of NSCLC patients who underwent SL or ESL from June 2014 to …

Management Targeted Genetic Evaluation Of An Idiopathic Neuropathy Cohort Through Attrv Amyloidosis Screening, Kristy A. Fisher, Santiago Diaz, Jeffrey Gelblum, Charles Brock, Niraja Suresh, Meghan Towne

HCA Healthcare Journal of Medicine

Background

While the reported prevalence of polyneuropathies is 1%-3%, the incidence of hereditary transthyretin amyloidosis in the United States is estimated to be 1 in 100 000 individuals. Polyneuropathies are known to be difficult to treat and lead to significant morbidity. The aim of pain management is symptomatic treatment, with varying approaches to progression prevention being based on the causative pathophysiology.

We assessed the prevalence of hereditary amyloid transthyretin variant (ATTRv) amyloidosis, a progressive autosomal dominant multisystem disease caused by the abnormal formation and extracellular deposition of transthyretin protein fibrils in various tissues, in an idiopathic polyneuropathy population by using …

Micronuclear Collapse From Oxidative Damage, Melody Di Bona, Yanyang Chen, Albert S Agustinus, Alice Mazzagatti, Mercedes A Duran, Daniel Bronder, Christy Hong, Lorenzo Scipioni, Giulia Tedeschi, Sara Martin, Jun Li, Aušrinė Ruzgaitė, Nadeem Riaz, Parin Shah, Edridge K D'Souza, D Zack Brodtman, Simone Sidoli, Bill Diplas, Manisha Jalan, Nancy Y Lee, Alban Ordureau, Benjamin Izar, Ashley M Laughney, Simon Powell, Enrico Gratton, Stefano Santaguida, John Maciejowski, Peter Ly, Thomas M Jeitner, Samuel F Bakhoum

Faculty, Staff and Student Publications

Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and …

Identification Of A0 Minimum Ablative Margins For Colorectal Liver Metastases: Multicentre, Retrospective Study Using Deformable Ct Registration And Artificial Intelligence-Based Autosegmentation, Iwan Paolucci, Jessica Albuquerque Marques Silva, Yuan-Mao Lin, Gregor Laimer, Valentina Cignini, Marcio Meira, Caleb O'Connor, Kyle A Jones, Carlo Gazzera, Paolo Fonio, Kristy K Brock, Marco Calandri, Marcos Menezes, Reto Bale, Bruno C Odisio

Faculty, Staff and Student Publications

Background: Several ablation confirmation software methods for minimum ablative margin assessment have recently been developed to improve local outcomes for patients undergoing thermal ablation of colorectal liver metastases. Previous assessments were limited to single institutions mostly at the place of development. The aim of this study was to validate the previously identified 5 mm minimum ablative margin (A0) using autosegmentation and biomechanical deformable image registration in a multi-institutional setting.

Methods: This was a multicentre, retrospective study including patients with colorectal liver metastases undergoing CT- or ultrasound-guided microwave or radiofrequency ablation during 2009-2022, reporting 3-year local disease progression (residual unablated tumour …

Stie: Single-Cell Level Deconvolution, Convolution, And Clustering In In Situ Capturing-Based Spatial Transcriptomics, Shijia Zhu, Naoto Kubota, Shidan Wang, Tao Wang, Guanghua Xiao

Faculty, Staff and Student Publications

In in situ capturing-based spatial transcriptomics, spots of the same size and printed at fixed locations cannot precisely capture the randomly-located single cells, therefore inherently failing to profile transcriptome at the single-cell level. To this end, we present STIE, an Expectation Maximization algorithm that aligns the spatial transcriptome to its matched histology image-based nuclear morphology and recovers missing cells from ~70% gap area, thereby achieving the real single-cell level and whole-slide scale deconvolution, convolution, and clustering for both low- and high-resolution spots. STIE characterizes cell-type-specific gene expression and demonstrates outperforming concordance with true cell-type-specific transcriptomic signatures than the other spot- …

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, Bin Liu, 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 …

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, Dileep R Rampa, 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, Vasiliki Leventaki, 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. …

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, Juan Carlos Caballero Berrocal, 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 …