Genetic Phenomena Commons^™

International Guidelines On The Diagnosis And Treatment Of Nut Carcinoma, Yu Zhang, Qi Zhang, Yue Hao, Jia Luo, Yingshi Piao, Zhengbo Song, Luka Brcic, Aijun Liu, Jinpu Yu, Yasuhiro Tsutani, Wenzhao Zhong, Wenfeng Fang, Zhijie Wang, Shengxiang Ren, Athanasios G Papavassiliou, Yongchang Zhang, Jingjing Liu, Shirong Zhang, Xiuyu Cai, Ayten Kayi Cangir, Anwen Liu, Wen Li, Filippo Lococo, Ping Zhan, Hongbing Liu, Tangfeng Lv, Liyun Miao, Lingfeng Min, Helmut Popper, Yu Chen, Jingping Yuan, Feng Wang, Zhansheng Jiang, Gen Lin, Long Huang, Xingxiang Pu, Rongbo Lin, Kalevi Kairemo, Weifeng Liu, Chuangzhou Rao, Dongqing Lv, Zongyang Yu, Ashrafian Leanne, Xiaoyan Li, Chuanhao Tang, Hifzur R Siddique, Chengzhi Zhou, Junping Zhang, Junli Xue, Vishal Shelat, Hui Guo, Qian Chu, Rui Meng, Fatemeh Ardeshir, Jingxun Wu, Rui Zhang, Jin Zhou, Robert A Kratzke, Zhengfei Zhu, Yongheng Li, Hong Qiu, Fan Xia, Fiorella Calabrese, Yang Xia, Alessandro Wasum Mariani, Yuanyuan Lu, Xiaofeng Chen, Mark A Klein, Rui Ge, Enyong Dai, Axel H Schönthal, Yu Han, Zhenying Guo, Jian Zhang, Yinghua Ji, Xianbin Liang, Hongmei Zhang, Xuelei Ma, Marco Chiappetta, Xuewen Liu, Francoise Galateau Salle, Yu Yao, Malgorzata Szolkowska, Weiwei Pan, Fei Pang, Fan Wu, Stefan B Watzka, Liping Wang, Youcai Zhu, Li Lin, Aparna Sharma, Jianfei Tu, Xinqing Lin, Jing Cai, Ling Xu, Jisheng Li, Xiaodong Jiao, Kainan Li, Marjorie G Zauderer, Jia Wei, Huijing Feng, Lin Wang, Yingying Du, Wang Yao, Elizabeth Dudnik, Xuefei Shi, Xiaomin Niu, Dongmei Yuan, Yanwen Yao, Jianhui Huang, Yue Feng, Yinbin Zhang, Binbin Song, Wenfeng Li, Jianfei Fu, Marina K Baine, Pingli Sun, Hong Wang, Mingxiang Ye, Dong Wang, Zhaofeng Wang, Jing Wu, Yunyun Yang, Yuan Fang, Zhen Wang, Bin Wan, Donglai Lv, Huafei Chen, Shengjie Yang, Jing Kang, Jiatao Zhang, Chao Zhang, Lin Shi, Yina Wang, Mohamed Emam Sobeih, Bihui Li, Bin Lian, Lili Mao, Zhang Zhang, Ke Wang, Zhongwu Li, Zhefeng Liu, Nong Yang, Lin Wu, Xiaobing Chen, Gu Jin, Miao Li, Guansong Wang, Thomas U Marron, Jiandong Wang, Sanjay Popat, Meiyu Fang, Yong Fang, Daniel Mansilla, Yuan Li, Xiaojia Wang, Jing Chen, Yiping Zhang, Xixu Zhu, Yi Shen, Shenglin Ma, Aaron S Mansfield, Biyun Wang, Lu Si, Anja C Roden, Bjørn H Grønberg, Yong Song, Geoffrey I Shapiro, Christopher A French, Yuanzhi Lu, Qian Wang, Chunwei Xu

Faculty, Staff and Student Publications

Nuclear protein in testis (NUT) carcinoma (NC) represents a rare, clinically aggressive cancer defined by pathognomonic NUT Midline Carcinoma Family Member 1 (NUTM1) gene fusions, with bromodomain and extraterminal domain (BET) protein 4 (BRD4)-NUTM1 being the predominant oncogenic driver. Since its description in 1991, gradual advances have clarified the pathologic mechanisms of NC and its diagnostic methods; however, NC treatment remains a significant challenge. Moreover, diagnostic and treatment approaches for this cancer require further validation and standardization. These guidelines were developed by the Chinese Alliance of Research for NC (ChARN) based on current evidence in …

A Prognostic Matrix Gene Expression Signature Defines Functional Glioblastoma Phenotypes And Niches, Monika Vishnoi, Zeynep Dereli, Zheng Yin, Elisabeth K Kong, Meric Kinali, Ozgun Babur, Nourhan Abdelfattah, Xubin Li, Behnaz Bozorgui, Mary C Farach-Carson, Robert C Rostomily, Anil Korkut

Faculty, Staff and Student Publications

Interactions among tumor, immune, and vascular niches play major roles in glioblastoma (GBM) malignancy and treatment responses. The composition and heterogeneity of extracellular core matrix proteins (CMPs) that mediate such interactions are not well understood. Here, we present an analysis of the clinical relevance of CMP expression in GBM at bulk, single-cell, and spatial anatomical resolution. We show that CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, pro-tumor immune infiltration, and immune checkpoint expression. Matrisome expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells. Finally, we …

Racial, Ethnic, And Socioeconomic Survival Disparities In Early-Onset Metastatic Colorectal Cancer, Jennifer S Wang, Benny Johnson, Caitlin C Murphy

Faculty, Staff and Student Publications

Importance: Rates of metastatic colorectal cancer (mCRC) are rising among young adults. Disparities by race and ethnicity and neighborhood-level socioeconomic status (SES) among this population are understudied.

Objective: To examine the association of race and ethnicity and neighborhood-level SES with mortality among a community-based sample of young adults with mCRC.

Design, setting, and participants: This cohort study used a large electronic health record-derived database of young adults with cancer treated at 280 community-based US clinics between 2013 and 2021. Eligible patients were young adults aged 18 to 49 years diagnosed with de novo or recurrent mCRC. Patients were followed up …

Cholesterol Efflux Protein, Abca1, Supports Anticancer Functions Of Myeloid Immune Cells, Shruti V Bendre, Yu Wang, Basel Hajyousif, Rajendra K C, Shounak G Bhogale, Natalia Krawczynska, Erin Weisser, Avni Singh, Simon Han, Hannah Kim, Lara Kockaya, Anasuya Das Gupta, Adam T Nelczyk, Hashni Epa Vidana Gamage, Yifan Fei, Desirée Rodríguez-Casiano, Xingyu Guo, Haoyun Li, Ryan J Deaton, Fei Mo, Maria Sverdlov, Peter H Gann, Saurabh Sinha, Sahil Sahni, Kun Wang, Kevin Van Bortle, Emad Tajkorshid, Wendy A Woodward, Wonhwa Cho, Erik R Nelson

Faculty, Staff and Student Publications

Breast and other solid tumors respond poorly to immune therapy. Myeloid cells (MCs) such as macrophages contribute to resistance. Established clinical evidence links cholesterol to cancer outcomes, with MC function being regulated by cholesterol metabolism. We screened MC-expressed regulators of cholesterol homeostasis linked to survival and identified the cholesterol efflux protein ABCA1. ABCA1 activity increases anticancer functions of macrophages: enhancing tumor infiltration, decreasing angiogenic potential, reducing efferocytosis, and improving support of CD8+ T cell activity. Mechanistically, different AKT isoforms are involved, through both PI3K-dependent and PI3K-independent mechanisms. Highlighting the clinical relevance of our findings are correlations between ABCA1 in macrophages …

Peroxisomal Integrity In Demyelination-Associated Microglia Enables Cellular Debris Clearance And Myelin Renewal In Mice, Joseph A Barnes-Vélez, Xiaohong Zhang, Yaren L Peña Señeriz, Kiersten A Scott, Yinglu Guan

Faculty, Staff and Student Publications

Demyelination associated microglia (DMAM) orchestrate the regenerative response to demyelination by clearing myelin debris and promoting oligodendrocyte maturation. Peroxisomal metabolism has emerged as a candidate regulator of DMAMs, though the cell-intrinsic contribution in microglia remains undefined. Here we elucidate the role of peroxisome integrity in DMAMs, using cuprizone-mediated demyelination coupled with conditional KO of peroxisome biogenesis factor 5 (PEX5) in microglia. Absent demyelination, PEX5 conditional KO (PEX5cKO) had minimal impact on homeostatic microglia. However, during cuprizone-induced demyelination, the emergence of DMAMs unmasked a critical requirement for peroxisome integrity. At peak demyelination, PEX5cKO DMAMs exhibited increased lipid droplet burden and reduced …

Nf2 Loss Malignantly Transforms Human Pancreatic Acinar Cells And Enhances Cell Fitness Under Environmental Stress, Yi Xu, Michael H Nipper, Angel A Dominguez, Chenhui He, Francis E Sharkey, Han Xu, Lei Zheng, Yu Luan, Jun Liu, Pei Wang

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) occurs as a complex, multifaceted event driven by the interplay of tumor-permissive genetic mutations, the nature of the cellular origin, and microenvironmental stress. In this study, using primary human pancreatic acinar 3D organoids, we performed a CRISPR-KO screen targeting 199 potential tumor suppressors curated from clinical PDAC samples. Our data revealed significant enrichment of a list of candidate genes, with neurofibromatosis type 2 associated gene (NF2) emerging as the top target. Functional validation confirmed that loss of NF2 promoted the transition of PDAC to an invasive state, potentially through extracellular matrix modulation. NF2 inactivation …

Public Support For Alcohol-Control Policies And Political Ideology In The Us, Joël Fokom Domgue, Robert Yu, Ernest Hawk, Sanjay Shete

Faculty, Staff and Student Publications

This cross-sectional study examines the role of US adults’ political affiliation, perception about alcohol use and cancer, and sociodemographic and behavioral factors in banning outdoor alcohol advertising and adding cancer warnings on alcohol containers.

Sexually Dimorphic Effects Of Gpnmb Modulation On Vertebral Bone Mass Regulation And Intravertebral Disc Health, Hakem Altawil, Fayez Safadi

Williams Honors College, Honors Research Projects

Osteoporosis and vertebral degeneration are major contributors to musculoskeletal morbidity, yet the molecular mechanisms regulating vertebral bone and intervertebral disc (IVD) homeostasis remain incompletely understood. GPNMB (osteoactivin) has been identified as a regulator of bone remodeling, though its role in spine health is unclear. This study evaluated the effects of GPNMB deficiency on lumbar vertebral bone microarchitecture and IVD integrity in a sex-dependent context.

Six-month-old male and female wild-type (WT) and GPNMB knockout (KO) mice were analyzed using micro–computed tomography (µCT) of lumbar vertebrae (L4–L6) and histological assessment of the L5–L6 IVD. KO males exhibited increased bone volume fraction, bone …

Test-Retest Apparent Diffusion Coefficient Reproducibility In Head And Neck Cancer Using A 15-T Mr-Linac, Brigid A Mcdonald, Dina El-Habashy, Renjie He, Sam Mulder, Sarah Mirbahaeddin, Abdallah S R Mohamed, Sara Ahmed, Yao Ding, Jihong Wang, Stephen Y Lai, Alex Dresner, John Christodouleas, Clifton D Fuller

Faculty, Staff and Student Publications

Purpose

To evaluate the reproducibility of apparent diffusion coefficient (ADC) measurements in head and neck squamous cell carcinoma (HNSCC) using a 1.5-T MR-linac (MRI-guided linear accelerator) system.

Materials and Methods

In this retrospective study, conducted between February 2021 and January 2024, patients with HNSCC lesions underwent echo-planar imaging diffusion-weighted MRI on a 1.5-T MR-linac system at two time points before the start of radiation therapy. Mean and median ADC values and volumes were measured for each lesion. Absolute and percent reproducibility coefficients (RCs) were calculated. Linear regression analyses and F tests were performed to determine whether the lesion volume or …

Using Genetically Diverse Mice To Examine The Effects Of Environmental Enrichment Of The Transcriptome, Michael Richard Leonardo

Theses, Dissertations and Capstones

Environmental impoverishment is a model of early life stress with direct consequences across a wide range of neurological and physiological conditions. Neuron morphology and density as well as anxiety disorders and addiction have shown to have significant relationships with environmental impoverishment models. Conversely, environmental enrichment confers therapeutic benefits that are protective across these conditions. There is an observed spectrum of resistance or vulnerability to the effects of housing conditions across populations, indicating genetics as an influential factor. Understanding this interaction is critical for deepening our knowledge of how genes and environment interact in ways that confer resistance or vulnerability, and …

Cerebellar Motor And Non-Motor Contributions To Dystonia Pathophysiology And Treatment, Linda H Kim, Cheryl Brandenburg, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia is a complex neurological disorder characterized by sustained or intermittent abnormal movements and/or postures. However, dystonia's non-motor symptoms, particularly the sleep disturbances, are critical yet underexplored concerns that affect all ages. Here, we synthesize current knowledge on the motor and non-motor domains of dystonia, emphasizing the functional interconnections and plasticity within cerebellar motor, cognitive, and sleep-associated circuits to motivate more comprehensive and effective treatments that improve overall quality of life.

Refining Aicardi Syndrome Diagnostic Criteria: An Expert-Based Consensus Using A Modified Delphi Approach, Silvia Masnada, Valentina De Giorgis, Umberto Carugo, Nadia Bahi-Buisson, Mara Cavallin, Mark Corbett, Manuela Formica, Jozef Gecz, Natalia Petros, Emilio Perucca, Anna Pichiecchio, Paolo Fusar Poli, Elliott H Sherr, Ignatia B Van Den Veyver, Federico Zara, Martin Geroldinger, Pierangelo Veggiotti, Alexis Arzimanoglou

Duncan NRI Faculty and Staff Publications

Background and objectives: Aicardi syndrome (AIC) is a rare neurodevelopmental disorder historically characterised by the presence of chorioretinal lacunae, corpus callosum agenesis, infantile spasms and several supporting features that aid in diagnosis. However, the unclear aetiology and evolving diagnostic tools have led to ongoing reconsideration of the criteria, based on individual approaches. Our study aimed to establish, for the first time, an expert-based consensus on diagnostic criteria for AIC by integrating both existing and novel ones.

Methods: A geographically diverse and multidisciplinary group of expert physicians was invited to participate in a modified Delphi study, to achieve consensus on major, …

Reconsidering The Definition Of Triple-Negative Breast Cancer In The Immune Checkpoint Inhibitor Era: An Optimal Cut-Off Value For Hormone Receptor Percentage Of Her2-Negative Invasive Breast Cancer, Takeo Fujii, Toshiaki Iwase, Yu Shen, Jami Fukui, Naoto T Ueno

Faculty, Staff and Student Publications

The optimal cut-off values of estrogen receptor (ER) and progesterone receptor (PgR) expression to define the positivity of ER and PgR have been under discussion for over a decade but remain controversial. The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) and the St. Gallen International Expert Consensus recommended that breast cancers with ≥1% of ER or PgR expression should be considered hormone receptor (HR)-positive tumors but ER/PR expression of 1% to 10% should be reported as HR-low positive; however, among HER2-negative disease, data on the overall benefit of adjuvant endocrine therapies for patients with HR-low positive disease is …

Contemporary Opportunities And Potential Of Auger Electron-Emitting Theranostics, Seok-Yong Lee, H Charles Manning

Faculty, Staff and Student Publications

Recent breakthroughs in radiopharmaceutical (RP) therapy have emerged interest in employing Auger electron (AE)-emitting radionuclides as potential agents for precise theranostics. AE provides energy with exceptional localization due to their short tissue penetration range (TPR, < 10 nm), rendering them particularly effective for targeting nuclear DNA in tumor cells. In this context, AE-emitting radionuclide therapy (AE-emitting RLT) enables the targeted destruction of tumor cells while reducing harm to adjacent healthy tissue, a significant challenge in this field. Preclinical and early clinical investigations reveal the efficacy of AE-emitting RLTs in the theranostics of diverse malignancies, such as glioblastoma, prostate cancer, and neuroendocrine tumors. Notwithstanding these developments, challenges and limitations persist regarding dosimetry, delivery efficiency, and the treatment of radiotoxicity. A new paradigm is being developed to tackle the obstacles encountered by integrating molecular target markers (e.g., PARP) that function near the nucleus to improve the intranuclear delivery efficiency of AE-emitting radionuclides. Novel radiochemical methods such as these have facilitated the more stable and efficient labeling of biomolecules with AE-emitting radionuclides. Also, recent advances in DNA-molecular targeting, nanoparticles, nucleic acid/protein engineering, click- or bioorthogonal conjugation chemistry, and artificial intelligence (AI)-based structure modeling present concrete opportunities to overcome these limitations. Moreover, the integration of diagnostic imaging companion platforms employing theranostic radioisotope pairings facilitates real-time assessment of therapeutic efficacy and biodistribution, resulting in the formulation of enhanced treatment regimens. This review summarizes the prior development, recent advancements, barriers in clinical implementation, and future perspective of AE-emitting RLTs.

Freeze-Dried, Not Frozen: Lyophilized Mesenchymal Stromal Cell-Derived Extracellular Vesicles And Therapeutic Function In Neuroinflammatory Models, Janet R Ashley, Aidan M Collier, Scott D Olson, Charles S Cox

Faculty, Staff and Student Publications

Background: Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) offer a promising acellular therapy for immune modulation, but clinical translation is hindered by variability and storage constraints. Lyophilization (freeze-drying) could enable shelf-stable EV therapeutics, although its effects on biological activity remain incompletely defined.

Study design: We compared the immunomodulatory effects of frozen and lyophilized EVs from bone marrow (BM), adipose tissue (AD), and umbilical cord (UC) MSCs using lipopolysaccharide-stimulated rodent splenocytes and microglial models and human peripheral blood mononuclear cells (PBMCs). Variables included batch scale (small vs large), cytokine priming, and MSC source. Tumor necrosis factor alpha (TNF-α) secretion was measured …

A Gut-Activated Nhr-86-Cyp Pathway Mediates The Neuroprotective Effects Of Enterococcus Faecium Probiotics In A Nematode Model Of Amyotrophic Lateral Sclerosis, Yu Sang, Jie Ren, Alejandro Aballay

Faculty, Staff and Student Publications

Neurodegenerative diseases are often associated with oxidative stress, and while probiotics may influence neuronal health, the underlying mechanisms remain poorly understood. Using the sod-1 A4VM amyotrophic lateral sclerosis (ALS) model in Caenorhabditis elegans, we investigated the protective effects of the probiotic Enterococcus faecium against oxidative stress-induced neurodegeneration. Animals fed E. faecium showed reduced motor neuron degeneration under oxidative stress compared to those maintained on a standard Escherichia coli diet. Transcriptome analysis revealed a significant enrichment of oxidoreductase genes, including cytochrome P450 (cyp) genes. RNAi-mediated knockdown of cyp genes impaired E. faecium-mediated neuroprotection, and this loss correlated with increased reactive oxygen …

Dosimetric Effect Of Abdominal Compression In Online Adaptive Planning For Abdominal Cancers Treated With A 15 Tesla Magnetic Resonance-Guided Linear Accelerator, Moghadaseh Khaleghibizaki, Angela Sobremonte, Luis Perles, Surendra Prajapati, Ergys Subashi, Yao Ding, Kristy Brock, Roya Barati, Eugene Koay, Chad Tang, Jinzhong Yang

Faculty, Staff and Student Publications

Compression belts (CBs) are sometimes used to reduce respiratory motion during stereotactic body radiotherapy of abdominal cancers with magnetic resonance (MR)-guided online adaptive planning. This study evaluated the dosimetric effects of overriding the relative electron density (ED) value of CBs in creating synthetic computed tomography (CT) scans for MR-guided adaptive planning. We evaluated plans for 12 patients with abdominal cancer and identified that ED values between 0.2 and 0.3 achieved the best approximation of CB ED in dose calculation. Our study presented an approach to estimate appropriate ED overrides for CBs in MR-guided online adaptive planning.

Telethon Undiagnosed Disease Program: Structured Approach To Solving Rare Childhood-Onset Genetic Diseases, Annalaura Torella, Manuela Morleo, Carmine Spampanato, Raffaele Castello, Mariateresa Zanobio, Giulio Piluso, Pasquale Di Letto, Maria Elena Onore, Sarah Iffat Rahman, Francesco Musacchia, Michele Pinelli, Giuseppina Vitiello, Giulia De Riso, Angelo Selicorni, Milena Mariani, Cecilia Daolio, Valeria Capra, Marcello Scala, Francesca Nardecchia, Serena Galosi, Mario Mastrangelo, Filippo Manti, Donatella Milani, Corrado Romano, Donatella Greco, Claudia Ciaccio, Stefano D'Arrigo, Arianna De Laurentiis, Antonietta Coppola, Marcella Zollino, Domizia Pasquetti, Federica Francesca L'Erario, Albina Tummolo, Claudia Santoro, Livia Garavelli, Carla Marini, Stefania Bigoni, Alfonsina Tirozzi, Viviana Cetrangolo, Giancarlo Parenti, Diego Di Bernardo, Angela Peron, Silvia Maitz, Andrea Accogli, Gerarda Cappuccio, Sandro Banfi, Giorgio Casari, Andrea Ballabio, Nicola Brunetti-Pierri, Vincenzo Nigro, Telethon Undiagnosed Disease Study Group

Duncan NRI Faculty and Staff Publications

Purpose: Many children with severe genetic disorders remain undiagnosed despite advanced genomic technologies. Early diagnosis is vital for prognosis, genetic counseling, and targeted treatment development. This study aims to increase diagnostic rates in complex pediatric cases and foster research into disease mechanisms.

Methods: Launched in 2016, the Telethon Undiagnosed Diseases Program provides a structured, multicenter approach to rare disease diagnosis. Standardized case submission criteria ensured consistent clinical data collection. Children with severe, multisystemic disorders and prior negative genetic tests were eligible. After case approval, trio-based exome sequencing was performed, with regular reanalysis for unsolved cases until December 2024.

Results: Between …

Nampt Inhibition Uncovers Therapeutic Vulnerabilities To Venetoclax And Chemotherapy In Acute Myelogenous Leukemia, John R Sanchez, Chaomei Liu, Vishakha Pawar, Yanqing Huang, Daisy Diaz-Rohena, Priya Koppikar, Lisa St John, Vinay Puduvalli, Jeffrey Molldrem, Palaniraja Thandapani, Nitin Jain, Rosa Lapalombella, Deepa Sampath

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) cells depend on nicotinamide adenine dinucleotide (NAD

The Legacy Of A Gentleman Scientist: Pierre Hainaut, Christophe Arnoult, Laura D Attardi, Kerem Batsheva, Giovanni Blandino, Kathleen H Burns, David G Kirsch, Arnold J Levine, Guillermina Lozano, David Malkin, Gerry Melino, Moshe Oren, Carol Prives, Daniel Schramek

Faculty, Staff and Student Publications

No abstract provided.