Medical Genetics Commons^™

Landmark-Based Auto-Contouring Of Clinical Target Volumes For Radiotherapy Of Nasopharyngeal Cancer, Carlos Sjogreen, Tucker J Netherton, Anna Lee, Moaaz Soliman, Skylar S Gay, Callistus Nguyen, Raymond Mumme, Ivan Vazquez, Dong Joo Rhee, Carlos E Cardenas, Mary K Martel, Beth M Beadle, Laurence Edward Court

Faculty, Staff and Student Publications

Background: The delineation of clinical target volumes (CTVs) for radiotherapy for nasopharyngeal cancer is complex and varies based on the location and extent of disease.

Purpose: The current study aimed to develop an auto-contouring solution following one protocol guidelines (NRG-HN001) that can be adjusted to meet other guidelines, such as RTOG-0225 and the 2018 International guidelines.

Methods: The study used 2-channel 3-dimensional U-Net and nnU-Net framework to auto-contour 27 normal structures in the head and neck (H&N) region that are used to define CTVs in the protocol. To define the CTV-Expansion (CTV1 and CTV2) and CTV-Overall (the outer envelope of …

Quantitative Evaluation Of 90y-Pet/Ct And 90y-Spect/Ct-Based Dosimetry Following Yttrium-90 Radioembolization, Srinivas Cheenu Kappadath, Eric Courtney Henry, Benjamin P Lopez, Armeen Mahvash

Faculty, Staff and Student Publications

Background: Following yttrium-90 radioembolization (90Y-RE), 90Y-PET/CT and 90Y-SPECT/CT imaging provide the means to calculate the voxelized absorbed dose distribution. Given the widespread use of the two imaging modalities and lack of well-established standardized dosimetry protocols for 90Y-RE, there is a clinical need to systematically investigate and evaluate differences in the performance of voxel-based dosimetry between 90Y-PET/CT and 90Y-SPECT/CT.

Purpose: To quantitatively analyze and compare 90Y-PET/CT and 90Y-SPECT/CT-based dosimetry following 90Y-RE.

Methods: 90Y-PET/CT and 90Y-SPECT/CT imaging was acquired for 35 patients following 90Y-RE with TheraSphere for the treatment of unresectable hepatocellular carcinoma. Dosimetry was performed using the local deposition method with …

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, Susana Campos, Joyce F Liu, Neil Horowitz, 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 …

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, Wu Li, Zhe Luo, Tian Qing, 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 …

Multi-Institutional Audit Of Flash And Conventional Dosimetry With A 3d Printed Anatomically Realistic Mouse Phantom, M Ramish Ashraf, Stavros Melemenidis, Kevin Liu, Veljko Grilj, Jeannette Jansen, Brett Velasquez, Luke Connell, Joseph B Schulz, Claude Bailat, Aaron Libed, Rakesh Manjappa, Suparna Dutt, Luis Soto, Brianna Lau, Aaron Garza, William Larsen, Lawrie Skinner, Amy S Yu, Murat Surucu, Edward E Graves, Peter G Maxim, Stephen F Kry, Marie-Catherine Vozenin, Emil Schüler, Billy W Loo

Faculty, Staff and Student Publications

Purpose: We conducted a multi-institutional dosimetric audit between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3-dimensional (3D) printed mouse phantom.

Methods and materials: A computed tomography (CT) scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene (∼1.02 g/cm3) and polylactic acid (∼1.24 g/cm3) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid (∼0.64 g/cm3). Hounsfield units (HU), densities, and print-to-print …

Errors In Genome Sequencing Result Disclosures: A Randomized Controlled Trial Comparing Neonatology Non-Genetics Healthcare Professionals And Genetic Counselors, Tanner F Coleman, Jada Pugh, Whitley V Kelley, Kelly M East, Veronica Greve, Candice R Finnila, Ava Henson, Bruce R Korf, Gregory S Barsh, Gregory M Cooper, Meagan E Cochran

Faculty, Staff and Student Publications

Purpose: We compared the rate of errors in genome sequencing (GS) result disclosures by genetic counselors (GC) and trained non-genetics healthcare professionals (NGHPs) in SouthSeq, a randomized trial utilizing GS in critically ill infants.

Methods: Over 400 recorded GS result disclosures were analyzed for major and minor errors. We used Fisher's exact test to compare error rates between GCs and NGHPs and performed a qualitative content analysis to characterize error themes.

Results: Major errors were identified in 7.5% of disclosures by NGHPs and in no disclosures by GCs. Minor errors were identified in 32.1% of disclosures by NGHPs and in …

A Comparison Of Methods For In Vivo Activity And Absorbed Dose Quantification With Pet/Ct Following Yttrium-90 Radioembolization, Eric Courtney Henry, Armeen Mahvash, Benjamin P Lopez, Srinivas Cheenu Kappadath

Faculty, Staff and Student Publications

Background: Yttrium-90 (90Y) positron emission tomography (PET)/computed tomography (CT) imaging is increasingly being used to perform tumor (T) and normal liver (NL) voxel dosimetry after 90Y-radioembolization (90Y-RE). Yet, the accuracy of in vivo 90Y-PET/CT imaging, subject to motion blur and co-registration inaccuracies, and 90Y-PET/CT dose quantification, subject to availability of different voxel dosimetry algorithms, are not well understood.

Purpose: The purpose of this study was to investigate the accuracy of 90Y-PET/CT-based activity estimates following 90Y-RE and characterize differences between 90Y-PET/CT-based voxel dosimetry algorithms.

Methods: Thirty-five patients underwent 90Y-PET/CT imaging after 90Y-RE with TheraSphere. The net administered 90Y activity (Aadmin) was …

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

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.

Lifr Regulates Cholesterol-Driven Bidirectional Hepatocyte-Neutrophil Cross-Talk To Promote Liver Regeneration, Yalan Deng, Zilong Zhao, Marisela Sheldon, Yang Zhao, Hongqi Teng, Consuelo Martinez, Jie Zhang, Chunru Lin, 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 …

Panel Stacking Is A Threat To Consensus Statement Validity, Kasper P Kepp, Preben Aavitsland, Marcel Ballin, Francois Balloux, Stefan Baral, Kevin Bardosh, Howard Bauchner, Eran Bendavid, Raj Bhopal, Daniel T Blumstein, Paolo Boffetta, Florence Bourgeois, Adam Brufsky, Peter J Collignon, Sally Cripps, Ioana A Cristea, Nigel Curtis, Benjamin Djulbegovic, Oliver Faude, Maria Elena Flacco, Gordon H Guyatt, George Hajishengallis, Lars G Hemkens, Tammy Hoffmann, Ari R Joffe, Terry P Klassen, Despina Koletsi, Dimitrios P Kontoyiannis, Ellen Kuhl, Carlo La Vecchia, Tea Lallukka, John Lambris, Michael Levitt, Spyros Makridakis, Helena C Maltezou, Lamberto Manzoli, Ana Marusic, Clio Mavragani, David Moher, Ben W Mol, Taulant Muka, Florian Naudet, Paul W Noble, Anna Nordström, Peter Nordström, Nikolaos Pandis, Stefania Papatheodorou, Chirag J Patel, Irene Petersen, Stefan Pilz, Nikolaus Plesnila, Anne-Louise Ponsonby, Manuel A Rivas, Andrea Saltelli, Manuel Schabus, Michaéla C Schippers, Holger Schünemann, Marco Solmi, Andreas Stang, Hendrik Streeck, Joachim P Sturmberg, Lehana Thabane, Brett D Thombs, Athanasios Tsakris, Simon N Wood, John P A Ioannidis

Faculty, Staff and Student Publications

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members toward one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but nonfinancial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analyzing in depth a …

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, Eunji Jo, Heidi Russell, Robin Raesz-Martinez, 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 …

Targeting Nuclear Receptor Coactivator Src-1 Prevents Colorectal Cancer Immune Escape By Reducing Transcription And Protein Stability Of Pd-L1, Yilin Hong, Qiang Chen, Zinan Wang, Yong Zhang, Bei Li, Hanshi Guo, Chuanzhong Huang, Xu Kong, Pingli Mo, Nengming Xiao, Jianming Xu, Yunbin Ye, Chundong Yu

Faculty, Staff and Students Publications

Programmed death-ligand 1 (PD-L1) is overexpressed in multiple cancers and critical for their immune escape. It has previously shown that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability, yet its role in CRC immune escape is unclear. Here, we demonstrate that SRC-1 is positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibits PD-L1 expression in CRC cells and retards murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration of CD8

Psychosocial Outcomes Of Pain And Pain Management In Adults With Osteogenesis Imperfecta: A Qualitative Study, Whitney S Shepherd, Andrew D Wiese, Hannah E Cho, W Conor Rork, M Usman Baig, Kristin M Kostick, Dianne Nguyen, Erin M Carter, Members Of The Bbdc, Chaya N Murali, Marie-Eve Robinson, Sophie C Schneider, Brendan Lee, V Reid Sutton, Eric A Storch

Faculty, Staff and Students Publications

Objectives

Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and fractures, short stature, dental abnormalities, hearing loss, scoliosis, and chronic pain. Despite a growing literature on the functional outcomes of OI, limited research has explicitly examined the psychosocial outcomes of pain within OI.

Methods

Adults with OI (N=15) were interviewed to understand pain-related experiences through a thematic analysis of semi-structured interview data. Research team members, genetic research experts, and OI clinicians developed an interview guide focused on topics related to pain and mental health challenges. Participants’ transcripts were coded by two independent coders; codes were then merged …

Anti-Inflammatory And Anti-(Lymph)Angiogenic Properties Of An Abcb5+ Limbal Mesenchymal Stem Cell Population, Berbang Meshko, Thomas L. A. Volatier, Johanna Mann, Mark A. Kluth, Christoph Ganss, Markus H. Frank, Natasha Y. Frank, Bruce R. Ksander, Claus Cursiefen, Maria Notara

Research outputs 2022 to 2026

Corneal transparency and avascularity are essential for vision. The avascular cornea transitions into the vascularized conjunctiva at the limbus. Here, we explore a limbal stromal cell sub-population that expresses ABCB5 and has mesenchymal stem cell characteristics. Human primary corneal stromal cells were enriched for ABCB5 by using FACS sorting. ABCB5+ cells expressed the MSC markers CD90, CD73, and CD105. ABCB5+ but not ABCB5− cells from the same donor displayed evidence of pluripotency with a significantly higher colony-forming efficiency and the ability of trilineage differentiation (osteogenic, adipogenic, and chondrogenic). The ABCB5+ cell secretome demonstrated lower levels of the pro-inflammatory protein MIF …

Pnpla3, Obesity, And Heavy Alcohol Use In Cirrhosis Patients May Exert A Synergistic Increase Hepatocellular Carcinoma Risk, Aaron P Thrift, Fasiha Kanwal, Hyeyeun Lim, Hao Duong, Yanhong Liu, Amit G Singal, Saira Khaderi, Sumeet K Asrani, Christopher I Amos, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND & AIMS: In patients with cirrhosis, continued heavy alcohol consumption and obesity may increase risk of hepatocellular carcinoma (HCC). We examined whether germline susceptibility to hepatic steatosis not only independently predisposes to HCC but may also act synergistically with other risk factors.

METHODS: We analyzed data from 1911 patients in 2 multicenter prospective cohort studies in the United States. We classified patients according to alcohol consumption (current heavy vs not current heavy), obesity (body mass index ≥30 vs/m2), and PNPLA3 I148M variant status (carrier of at least one G risk allele vs noncarrier). We examined the independent and joint …

Phase Ii Study Of Samotolisib In Children And Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target Of Rapamycin Pathway Alterations: Pediatric Match Apec1621d, Theodore W Laetsch, Kathleen Ludwig, P Mickey Williams, Sinchita Roy-Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Joyce Mhlanga, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, Donald Williams Parsons

Faculty, Staff and Students Publications

Purpose: Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.

Methods: Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was …

Phylogenetically Diverse Bacterial Species Produce Histamine, Kristen A Engevik, Amber Hazzard, Brenton Puckett, Kathleen M Hoch, Sigmund J Haidacher, Anthony M Haag, Jennifer K Spinler, James Versalovic, Melinda A Engevik, Thomas D Horvath

Faculty, Staff and Students Publications

Histamine is an important biogenic amine known to impact a variety of patho-physiological processes ranging from allergic reactions, gut-mediated anti-inflammatory responses, and neurotransmitter activity. Histamine is found both endogenously within specialized host cells and exogenously in microbes. Exogenous histamine is produced through the decarboxylation of the amino acid L-histidine by bacterial-derived histidine decarboxylase enzymes. To investigate how widespread histamine production is across bacterial species, we examined 102,018 annotated genomes in the Integrated Microbial Genomes Database and identified 3,679 bacterial genomes (3.6 %) which possess the enzymatic machinery to generate histamine. These bacteria belonged to 10 phyla: Bacillota, Bacteroidota, Actinomycetota, Pseudomonadota, …

Satisfaction With Mode Of Delivery Of Genomic Sequencing Results In A Diverse National Sample Of Research Participants Through The Clinical Sequencing Evidence-Generating Research Consortium, Sarah Scollon, Jill O Robinson, Eunji Jo, Sabrina A Suckiel, Laura M Amendola, Ann Katherine M Foreman, Gail P Jarvik, Christine Rini, Tao Wang, Anne Slavotinek

Faculty, Staff and Students Publications

Purpose: Research that includes diverse patient populations is necessary to optimize implementation of telehealth.

Methods: As part of a Clinical Sequencing Evidence-Generating Research Consortium cross-site study, we assessed satisfaction with mode of return of results (RoR) delivery across a diverse sample of participants receiving genetic testing results in person vs telemedicine (TM).

Results: Ninety-eight percent of participants were satisfied with their mode of results delivery. Participants receiving results by TM were more likely to report a preference for receiving results in a different way and challenges with providers noticing difficulties with understanding. More than 90% reported satisfaction across all items …

Psychiatric Polygenic Risk Scores: Experience, Hope For Utility, And Concerns Among Child And Adolescent Psychiatrists, Amanda R Merner, Page M Trotter, Lauren A Ginn, Jason Bach, Katherine J Freedberg, Takahiro Soda, Eric A Storch, Stacey Pereira, Gabriel Lázaro-Muñoz

Center for Medical Ethics and Health Policy Staff Publications

Recent advances in psychiatric genetics have enabled the use of polygenic risk scores (PRS) to estimate genetic risk for psychiatric disorders. However, the potential use of PRS in child and adolescent psychiatry has raised concerns. This study provides an in-depth examination of attitudes among child and adolescent psychiatrists (CAP) regarding the use of PRS in psychiatry. We conducted semi-structured interviews with U.S.-based CAP (n=29) who possess expertise in genetics. The majority of CAP indicated that PRS have limited clinical utility in their current form and are not ready for clinical implementation. Most clinicians stated that nothing would motivate them to …

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, Alberto Lopez-Pastorini, Chenlei Zhang, Wei Chen, 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 …

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, Yujin Hoshida

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- …

Micronuclear Collapse From Oxidative Damage, Melody Di Bona, Yanyang Chen, Albert S Agustinus, Alice Mazzagatti, Mercedes A Duran, Matthew Deyell, Daniel Bronder, James Hickling, 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, Francesca Menchini, Marcio Meira, Alexander Shieh, 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 …

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 …

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. …

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 …