Digital Commons Network^™

Spatial Profiling Reveals Distinct Molecular And Immune Evolution Of Mouse Lung Adenocarcinoma Precancers With Or Without Carcinogen Exposure, Bo Zhu, Muhammad Aminu, Pingjun Chen, Jian-Rong Li, Chuanpeng Dong, Chenyang Li, Yanhua Tian, Shao-Wei Lu, Hong Chen, Chenxi Ma, Xin Hu, Jie Ye, Andrew Y Liu, Beibei Huang, Frank R Rojas, Parra Cuentas Edwin Roger, Ou Shi, Monique B Nilsson, Alissa Poteete, Khaja B Khan, Wei Lu, Luisa M Solis Soto, Junya Fujimoto, Cara Haymaker, Ignacio I Wistuba, Zhubo Wei, Linghua Wang, Don L Gibbons, Ken Chen, Alexandre Reuben, Jason M Schenkel, John V Heymach, Chao Cheng, Jia Wu, Jianjun Zhang

Faculty, Staff and Student Publications

Tumor evolution involves genetic, transcriptional, and phenotypic alterations that shape cancer cell behavior and interactions with the microenvironment. While single‐cell technologies have advanced our understanding of this process, spatial dynamics remain incompletely characterized. Here, whole‐exome sequencing (WES), imaging mass cytometry (IMC), and spatial transcriptomics (ST) were integrated to study molecular evolution and immune responses in two lung adenocarcinoma (LUAD) mouse models: a genetically engineered model (129S4/Sv‐KrasLSL‐G12D, termed 129S4 K) and a carcinogen‐induced precancer model (129S4 U). Compared to 129S4 K, 129S4 U tumors exhibited higher mutational, neoantigen but lower copy number variation (CNV) burdens at matched developmental timepoints, consistent with …

Shiny-Magec: A Bayesian R Shiny Application For Meta-Analysis Of Censored Adverse Events, Zihan Zhou, Zizhong Tian, Christine Peterson, Le Bao, Shouhao Zhou

Faculty, Staff and Student Publications

Accurate assessment of adverse event (AE) incidence is critical in clinical research for drug safety. While meta-analysis serves as an essential tool to comprehensively synthesize the evidence across multiple studies, incomplete AE reporting in clinical trials remains a persistent challenge. In particular, AEs occurring below study-specific reporting thresholds are often omitted from publications, leading to left-censored data. Failure to account for these censored AE counts can result in biased AE incidence estimates. We present an R Shiny application that implements a Bayesian meta-analysis model specifically designed to incorporate censored AE data into the estimation process. This interactive tool provides a …

Frontotemporal Network Interactions Causally Support Rapid Concreteness Judgments During Reading, Elliot Murphy, Oscar Woolnough, Cale W Morse, Xavier Scherschligt, Nitin Tandon

Faculty, Staff and Student Publications

Neurobiological models of conceptual processing have been limited in spatiotemporal resolution, and uncertainty remains about the causal role of specific regions in concept representation. We utilized intracranial recordings in human neurosurgical patients with epilepsy (n = 19) during a concreteness judgement paradigm of single word reading. Concrete concepts showed greater high-frequency activation across a frontal and ventrotemporal network, while greater activation for abstract words was found in lateral posterior middle temporal cortex. Intercortical communications, measured by high-frequency partial direct coherence, revealed bidirectional frontal and ventral plus lateral temporal interactions. Words occupying the middle range of the concreteness scale (e.g., "profit") …

Large Language Models For Bioinformatics, Wei Ruan, Yanjun Lyu, Jing Zhang, Jiazhang Cai, Peng Shu, Yang Ge, Yao Lu, Shang Gao, Yue Wang, Peilong Wang, Lin Zhao, Tao Wang, Yufang Liu, Luyang Fang, Ziyu Liu, Zhengliang Liu, Yiwei Li, Zihao Wu, Junhao Chen, Hanqi Jiang, Yi Pan, Zhenyuan Yang, Jingyuan Chen, Shizhe Liang, Wei Zhang, Terry Ma, Yuan Dou, Jianli Zhang, Xinyu Gong, Qi Gan, Yusong Zou, Zebang Chen, Yuanxin Qian, Shuo Yu, Jin Lu, Kenan Song, Xianqiao Wang, Andrea Sikora, Gang Li, Xiang Li, Quanzheng Li, Yingfeng Wang, Lu Zhang, Yohannes Abate, Lifang He, Wenxuan Zhong, Rongjie Liu, Chao Huang, Wei Liu, Ye Shen, Ping Ma, Hongtu Zhu, Yajun Yan, Dajiang Zhu, Tianming Liu

Faculty, Staff and Student Publications

With the rapid advancements in large language model technology and the emergence of bioinformatics-specific language models (BioLMs), there is a growing need for a comprehensive analysis of the current landscape, computational characteristics, and diverse applications. This survey aims to address this need by providing a thorough review of BioLMs, focusing on their evolution, classification, and distinguishing features, alongside a detailed examination of training methodologies, datasets, and evaluation frameworks. We explore the wide-ranging applications of BioLMs in critical areas such as disease diagnosis, drug discovery, and vaccine development, highlighting their impact and transformative potential in bioinformatics. We identify key challenges and …

Tuscan: Tumor Segmentation And Classification Analysis In Spatial Transcriptomics, Chenxuan Zang, Charles C Guo, Yaohong Wang, Peng Wei, Ziyi Li

Faculty, Staff and Student Publications

The identification of tumor cells is pivotal for understanding tumor heterogeneity and the tumor microenvironment. Recent advances in spatially resolved transcriptomics (SRT) have revolutionized the way that transcriptomic profiles are characterized and have enabled the simultaneous quantification of transcript locations in intact tissue samples. SRT is a promising alternative method to study gene expression patterns in spatial domains. Nevertheless, the precise detection of tumor regions within intact tissue remains a great challenge. A common strategy for identifying tumor cells is via tumor-specific marker gene expression signatures, which are highly dependent on marker accuracy. Another effective approach is through aneuploid copy …

Severe Renal Phenotype Across A Multigenerational Tuberous Sclerosis Complex (Tsc) Family, Elena Tuller, Joshua A Samuels, Hope Northrup, Kate Richardson

Faculty, Staff and Student Publications

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the formation of hamartomas in the brain, kidney, and heart, along with other complex clinical manifestations, including TSC-associated neuropsychiatric disorder (TAND). Development of genotype-phenotype correlations within TSC can aid clinicians in providing prognostic data and improve clinical management. We present here a multigenerational family who has a pathogenic variant in TSC2 displaying a severe renal phenotype.

Methods: A 23-year-old Caucasian male (Patient 1) was determined to have a molecularly confirmed diagnosis of TSC at approximately 2 months of age. The nonsense pathogenic variant (c.1372C>T (p.Arg458*)) in …

An Adp Getaway Service, Not An Atp Tank: Insights Into The Phosphagen System In Neurons, Madeline P Marques, Kartik Venkatachalam

Faculty, Staff and Student Publications

No abstract provided.

Segmental Tracheal Resection For Thyroid Cancer: Perioperative Morbidity, Locoregional Control, And Survival, Anastasios Maniakas, David C Wilde, Isabelle Fournier, Emily K Hyde, Li Xu, Jennifer R Wang, Neil D Gross, Erich M Sturgis, Victoria Banuchi, Naifa L Busaidy, Maria E Cabanillas, Priyanka Iyer, Ramona Dadu, Steven G Waguespack, Mimi I Hu, G Brandon Gunn, Michael Kwon, Salmaan Ahmed, Michelle D Williams, Mark E Zafereo

Faculty, Staff and Student Publications

Background: Segmental tracheal resection is rarely needed for advanced thyroid cancer but is among the most complex, high-risk thyroid surgeries.

Methods: Retrospective study of patients undergoing segmental tracheal resection for thyroid cancer at MD Anderson Cancer Center (2005-2024).

Results: We identified 120 patients with a median follow-up of 4.6 years (range 0.02-16.38). Papillary thyroid cancer was most common (68%). The median number of tracheal rings resected was 4 (range 1-9). Seventeen (14%) patients had a new tracheostomy placed at the time of surgery, with 11 (9%) remaining trach-dependent at last follow-up. Twenty-six (22%) patients had a return to the operating …

Terraforming The Kras Lipid Landscape, Yong Zhou, John F Hancock

Faculty, Staff and Student Publications

No abstract provided.

Physical Activity In Osteosarcoma Patients During And Post Therapy: A Single Site Prospective Observational Study, Elysia R Cohen, Clark Andersen, Karen Moody, Maria C Swartz, Michael C Robertson, Alakh Rajan, Theresa Honey, Sandra Lugo, Grace Waterman, Keri Schadler

Faculty, Staff and Student Publications

PURPOSE: Osteosarcoma is the most common primary bone tumor in childhood and adolescence. Many patients face long-term impairments in their mobility and function after treatment, leading to a decrease in their quality of life. Exercise has been shown to improve functional recovery and improve quality of life in patients with cancer, though data specific to children with osteosarcoma are sparse. Exercise has also been shown to be feasible in patients undergoing chemotherapy, with numerous potential benefits to health and quality of life. To design the most effective exercise interventions for children and adolescents with osteosarcoma, we must first understand the …

Bone Marrow Endosteum Houses Hedgehog-Susceptible Dlx5-Expressing Osteoblast Precursor Cells, Keita Kondo, Yuki Matsushita, Shion Orikasa, Yuta Nakai, Aiko Kuroda, Shinsuke Ohba, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

The bone marrow endosteum provides a robust source of bone-making osteoblasts by housing various types of osteoblast precursor cells, including endosteal stem cells expressing fibroblast growth factor receptor 3 (Fgfr3) and their downstream progenitor cell populations. In fetal bone development, Dlx5 marks early perichondrial cells that populate the diaphyseal bone and marrow stroma in the postnatal stages. However, the location of Dlx5-expressing cells in the postnatal bone marrow and how they contribute to osteogenesis remain undefined. Here, we show that Dlx5

Phase I Trial Of Binimetinib Plus Hydroxychloroquine In Patients With Previously Treated Metastatic Pancreatic Cancer, S Daniel Haldar, Fen Saj, So Jung Hong, Rishi Surana, Lianchun Xiao, J Jack Lee, Brandon Smaglo, Dan Zhao, Huili Zhu, Ryan Huey, Jason Willis, M Pia Morelli, Michael Overman, Florencia Mcallister, Robert Wolff, Anirban Maitra, David Fogelman, Channing Der, Shubham Pant

Faculty, Staff and Student Publications

Background: Dual mitogen-activated protein kinase (MAPK) pathway and autophagy inhibition shows synergistic antitumor activity in preclinical models of RAS-mutant cancers. We hypothesized that autophagy blockade with hydroxychloroquine (HCQ) could overcome resistance to MEK inhibition with binimetinib (BINI) and provide clinical benefit in previously treated, KRAS-mutated, metastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: This investigator-led, single-arm, open-label, phase I dose escalation/expansion trial evaluated the safety and tolerability of BINI + HCQ in patients with previously treated, metastatic PDAC (NCT04132505). Key eligibility criteria: ECOG 0-1, adequate organ function, ≥ 1 prior line of therapy for metastatic disease, and presence of KRAS …

Endosteal Stem Cells At The Bone-Blood Interface: A Double-Edged Sword For Rapid Bone Formation: Bone Marrow Endosteal Stem Cells Provide A Robust Source Of Bone-Making Osteoblasts Both In Normal And Abnormal Bone Formation, Keita Kondo, Yuki Matsushita, Shion Orikasa, Yuta Nakai, Aiko Kuroda, Shinsuke Ohba, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non-endosteal perisinusoidal niche. Single-cell molecular profiling and in vivo cell lineage analyses play key roles in discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor-making cells when deleterious mutations occur in …

An Interoperable Vaccine Record: A Roadmap To Realization, Xia Jing, Arild Faxvaag, Christian G Nøhr, David Robinson, Paul G Biondich, Timothy D Law, Hua Min, Adam Wright, Yang Gong, Dean F Sittig

Faculty, Staff and Student Publications

Objectives: The objectives of this study were to educate the healthcare professional and the general public about interoperable vaccine records by elaborating on its definition, why we need one, what the challenges are, and what progress has been made in this direction.

Methods: The vaccination practices and vaccine record-keeping in the Nordic countries, the UK, and the USA are used as examples to demonstrate the necessity of interoperable vaccine records. The authors' expertise and experience in interoperability, medicine, and HealthIT, along with the literature, informed this paper's content, structure, and organization. Real-world examples and scenarios illustrate the reality …

From Wrist Data To Lifespan: Elucidating Inflammation-Driven Biological Aging Via Activity Rhythms Captured By Wearable Devices, Jinjoo Shim, Faraz Bishehsari, Mahboobeh Mahdavinia, Jamie M Zeitzer, Elgar Fleisch, Filipe Barata

Faculty, Staff and Student Publications

Systemic inflammation ("inflammaging") accelerates biological aging and drives cardiovascular, metabolic, and neurodegenerative disease. Circadian rhythms regulate the amplitude and timing of immune responses, yet their mechanistic role in inflammation and longevity remains unexplored. In 62,000 adults with 7-day wearable accelerometry, interpretable machine learning model identified rhythm amplitude, stability, and moderate-to-vigorous physical activity (MVPA) as dominant predictors of accelerated aging. In a subset of 1521 participants (35% male) with available data on the systemic immune-inflammation index (SII), we further examined the associations between behavioral rhythmicity and inflammation. Low amplitude and poor rhythm stability were associated with 0.31 and 0.18 SD higher …

Pretreatment Risk Model For Radiation-Induced Lymphopenia Is Associated With Adjuvant Durvalumab Efficacy In Patients With Unresectable Stage Iii Nsclc, Peter S N Van Rossum, Pim J J Damen, Francesco Cortiula, Brian P Hobbs, Lorenzo De Marchi, Radhe Mohan, Max Peters, Famke L Schneiders, Dirk De Ruysscher, Robin Wijsman, Joost J C Verhoeff, Ting Xu, Zhongxing Liao, Steven H Lin

Faculty, Staff and Student Publications

Introduction: Severe radiation-induced lymphopenia (RIL) during concurrent chemoradiotherapy (CCRT) for NSCLC has been associated with poorer outcomes and reduced immunotherapy efficacy. Because RIL often develops late during CCRT, identifying patients at risk before treatment may be clinically relevant. This study aimed to develop and validate a nomogram based on pretreatment predictors for severe RIL, and secondarily to explore associations between predicted RIL risk and adjuvant durvalumab-associated survival.

Methods: A retrospective development cohort of consecutive patients with NSCLC treated with CCRT (2010-2019) was established, along with an independent external validation cohort from other institutions. A multivariable logistic regression model was developed …

Winner's Curse Free Robust Mendelian Randomization With Summary Data, Zhongming Xie, Wanheng Zhang, Jingshen Wang, Chong Wu

Faculty, Staff and Student Publications

In the past decade, the increased availability of genome-wide association studies summary data has popularized Mendelian Randomization (MR) for conducting causal inference. MR analyses, incorporating genetic variants as instrumental variables, are known for their robustness against reverse causation bias and unmeasured confounders. Nevertheless, classical MR analyses using summary data may still produce biased causal effect estimates due to the winner’s curse and pleiotropy issues. To address these two issues and establish valid causal conclusions, we propose a unified robust Mendelian Randomization framework with summary data, which systematically removes the winner’s curse and screens out invalid genetic instruments with pleiotropic effects. …

Eepd1 Evolved A Unique Dna Clamping Dimer Protecting Reversed Replication Forks, Runze Shen, Altaf H Sarker, Yue Chen, Min Liu, Sunetra Roy, Andrew S Arvai, Albino Bacolla, Zamal Ahmed, Panagiotis Katsonis, Michal Hammel, Isao Kuraoka, Miaw-Sheue Tsai, Corydon Irie, Lukas Webb, Olivier Lichtarge, Chi-Lin Tsai, Susan E Tsutakawa, Katharina Schlacher, John A Tainer

Faculty, Staff and Student Publications

Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are canonically monomeric phosphodiesterases exemplified by APE1, DNase I, and TDP2 nucleases. While EEP family domain containing protein 1 (EEPD1) acts in DNA stress responses, its proposed nuclease activities are enigmatic. Here, we integrate hybrid structural methods, evolution, biochemistry, cancer genomics, plus molecular and cell biology to define EEPD1 structure, assembly, and function at stalled DNA replication forks. Results imply EEPD1 surprisingly requires both unique EEP domain dimer and distinctive tandem Helix-hairpin-Helix [(HhH)2] domains to clamp double-stranded (ds) DNA at reversed DNA replication forks for fork protection. Small-angle X-ray Scattering (SAXS), crystal, and cryo-EM structures unveil an …

Innovative Approaches For Lung Cancer Screening And Interception, Jianjun Zhang, Matthew D Park, Tej Pandya, Elaine Shum, Jia Wu, Simon Heeke, Ramin Salehi-Rad, Thomas U Marron, Zhubo Wei, Hui Li, Torsten G Blum, John V Heymach, Steven M Dubinett, Pan-Chyr Yang, Charles Swanton, Miriam Merad

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer-related deaths worldwide, partly because many patients are diagnosed at late stages, highlighting the urgent need for effective early detection and intervention strategies. Low-dose computed tomography (LDCT)-based screening reduces lung cancer mortality in high-risk populations defined by age and smoking history; however, the uptake of LDCT remains low among eligible individuals. Compounding this issue, modelling studies estimate that nearly half of lung cancers occur in individuals who do not meet eligibility criteria for LDCT-based lung cancer screening under current guidelines. Moreover, LDCT-based screening has inherent limitations, including a high rate of false-positive results …

Supt16h-Associated Neurodevelopmental Disorder And Neurocristopathy: Genetic And Phenotypic Spectrum, Eunhye Lee, Seungmin Sim, Hee-Jung Choi, Eugene Y Liang, Carolyn Le, Roya Bina, Ryan Cohen, Elizabeth George, Soo Yeon Kim, Gifty Bhat, Erin Falsey, Richard Sidlow, Kristin Clinard, Shay Ben-Shachar, Eleina England, Beatriz Menendez, Isabella Herman, Shelly Nielsen, Jaya Punetha, Priya Bhola, J Austin Hamm, Megan A Keeney, Nike Sitzman, Sara Berger, Lakshmi Mehta, Alison J Conn, Lilian Downie, Myla Ashfaq, Hope Northrup, Ange-Line Bruel, Sylvie Odent, Justin O Szot, Noelia Nunez Martinez, Sunju Park, Julie Refkin, Jean-Marc Good, Fabienne Maurer, Cédric Le Caignec, David J Coman, Erin Anderson, Linda J Richards, Ryan J Dean, Caleb Yang, Chulwon Choi, Byung Joon Hwang, Jin Sook Lee, William B Dobyns, Murim Choi, Elliott H Sherr, Jong-Hee Chae, Yun Kee, Emanuela Argilli

Faculty, Staff and Student Publications

SUPT16H encodes a subunit of the FACT (FAcilitates Chromatin Transcription) complex, a histone chaperone essential for maintaining chromatin integrity during transcription, replication, and DNA repair. Pathogenic de novo SUPT16H missense variants have previously been linked to neurodevelopmental disorders in eight individuals. Here, we expand the genotypic and phenotypic spectrum by identifying 24 additional individuals harboring ultrarare heterozygous missense or truncating variants, who share overlapping clinical features including intellectual disability, autism spectrum disorder, hypotonia, and characteristic craniofacial dysmorphism. To elucidate the underlying mechanisms, we generated a supt16h knockout zebrafish model using CRISPR/Cas9. The supt16h loss-of-function (LOF) model recapitulated key patient phenotypes …

Advances In Hpv Vaccination In People Living With Hiv: A Review, Megan Mooberry, J Brooks Jackson, Mary B Rysavy

Faculty, Staff and Student Publications

Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and is a leading cause of cervical, anal, penile, and oropharyngeal cancers. This review summarizes the epidemiology of HPV and the immunogenicity, clinical efficacy, and current HPV vaccination recommendations among people living with HIV (PLWH). PLWH experience a disproportionate burden of HPV-related infection and HPV-related malignancies. Although HPV vaccines have been shown to be highly effective, vaccination coverage among PLWH remains suboptimal, particularly in low- and middle-income countries. Barriers to vaccination include extended dosing schedules, limited awareness of the vaccine, and misinformation. Evidence indicates HPV vaccines are safe and …

Airway Secretory Cells Contain Both A Perinuclear Golgi Ribbon And Dispersed Golgi Satellites, Oanh N Hoang, Colin E Chan, Joshua M Brenner, Denisse Leza-Rincon, Ana M Jaramillo, Brendan Dolan, Adam W Aziz, Rodolfo A Cardenas, Gerardo J Cardenas, Eduardo D Galvez, Joshua B Hales, Emilia S Nunez-Pena, Boxuan Yang, Reid T Powell, Leoncio Vergara, Harry Karmouty-Quintana, Jesper M Magnusson, Gunnar C Hansson, Roberto Adachi, John D Dickinson, Christopher M Evans, Justin A Courson, Alan R Burns, Michael J Tuvim, Burton F Dickey

Faculty, Staff and Student Publications

Rationale: Finely tuned production and secretion of the polymeric mucins MUC5AC and MUCB are required for lung health, but knowledge of many details between their translation and their packaging into secretory granules is lacking.

Objective: To analyze the structure and function of the Golgi apparatus, a key site of mucin glycosylation, folding, polymerization and packaging, in airway epithelial secretory cells.

Methods: Lung tissue was obtained from mice stimulated or not with IL-13 to upregulate mucin production, and from normal human lungs. Golgi elements in mouse and human tissue were imaged by high-resolution immunofluorescence microscopy and electron microscopy. Tissue from mice …

External Validation Of The Proliferation Saturation Index Model In Predicting Tumour Volume Regression In Patients With Non-Small Cell Lung Cancer Undergoing Radiation Therapy, Sarah Barrett, Mohammad Zahid, Conor K Mcgarry, Heiko Enderling, Gerard M Walls, Laure Marignol

Faculty, Staff and Student Publications

Background: The Proliferation Saturation Index (PSI) model is a patient-specific mathematical model designed to simulate and predict tumour volume regression (TVR) during radiation therapy (RT) using early treatment response dynamics. This study validates the PSI model in an independent external cohort of patients with non-small cell lung cancer (NSCLC) using previously derived model parameters.

Methods: In a cohort of 71 patients, treated with definitive RT alone (55Gy/20#) tumour volume measurements extracted from 6 Cone Beam CT (CBCT) scans acquired on days 1, 2 and 3 and weekly thereafter. Model predictions of TVR at final CBCT (CBCT6) were made using tumour …

Hp1Β Recruits Ring1a To Ubiquitinate Histone H2a For Brca1-Mediated Resection Of Double-Stand Breaks, Vijaya Charaka, Raj K Pandita, Chi-Lin Tsai, Xiaoyan Wang, Sharmista Chakraborty, Kenneth S Ramos, Sandhik Nandi, Fransisca Leonard, Vipin Singh, Partha S Sarkar, Clayton R Hunt, John A Tainer, Chandrima Das, Tej K Pandita

Faculty, Staff and Student Publications

Efficient DNA double-strand break (DSB) repair by homologous recombination (HR), as initiated by BRCA1 recruitment orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we reveal Heterochromatin Protein1 beta (HP1β) promotes BRCA1 enrichment at DNA DSB sites in gene-rich regions, and this is impaired by HP1β depletion. We find that HP1β is specifically enriched at DSBs within gene-rich regions via its Chromo Shadow Domain (CSD) that interacts with both Chromatin Assembly Factor 1 and the RING1A ubiquitinase component of Polycomb Repressor Complex 1. The resulting protein complex facilitates BRCA1 recruitment by promoting …

Nci9673 (Part B): Etctn Randomized Phase Ii Study Of Nivolumab With Or Without Ipilimumab In Refractory, Metastatic Squamous Cell Carcinoma Of The Anal Canal, Van K Morris, Kristen K Ciombor, Lianchun Xiao, Joshua K Ochieng, Enrica Marmonti, Blase Polite, Benjamin A Weinberg, John C Krauss, John Hays, Sarbajit Mukherjee, Olivia Aranha, Syma Iqbal, Tony Shields, Al B Benson, Syed Kazmi, Christopher Lieu, Howard Hochster, Jennifer Whisenant, Cara Haymaker, Cathy Eng

Faculty, Staff and Student Publications

Purpose: In the previously completed NCI9673 (part A) single-arm study, the antiprogrammed death (PD)-ligand-1 antibody nivolumab demonstrated efficacy for patients with metastatic anal cancer. In NCI9673 (Part B), we evaluated the anticytotoxic T-cell lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in combination with nivolumab for patients with incurable anal cancer.

Methods: In this phase II NCI ETCTN trial, 100 patients with refractory, incurable anal cancer were randomly assigned to receive nivolumab (480 mg IV once every 4 weeks) alone or with ipilimumab (1 mg/kg IV once every 8 weeks). The primary end point was progression-free survival (PFS). Secondary endpoints included radiographic response, …

Adipocyte-Specific Deletion Of Sine Oculis Homeobox Homolog 1 Inhibits Lipolysis And Reduces Skin Fibrosis, Nancy Wareing, Tingting W Mills, Scott Collum, Minghua Wu, Lucy Revercomb, René Girard, Hui Liu, Alexes Daquinag, Mikhail Kolonin, Marka Lyons, Brian Skaug, Weizhen Bi, Meer A Ali, Haniyeh Koochak, Anthony R Flores, Yuntao Yang, W Jim Zheng, William R Swindell, Shervin Assassi, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

Dermal fibrosis is a cardinal feature of systemic sclerosis (SSc) for which there are limited Systemic sclerosis (SSc) is characterized by dermal fibrosis accompanied by loss of dermal white adipose tissue (DWAT), yet the mechanisms linking adipocyte depletion to fibroblast activation remain unclear. Here we identify the transcription factor SIX1 as a central regulator coupling adipogenic repression with profibrotic signaling. SIX1 expression was increased in skin biopsies from two independent SSc cohorts and localized to fibroblast and perivascular stromal cells. In mice, ubiquitous or adipocyte-specific deletion of Six1 preserved DWAT, reduced collagen accumulation, and selectively decreased pro-fibrotic mediators. In cultured …

Cml-Like Biology Is A Unifying Feature Of Myeloid/Lymphoid Neoplasms With Tyrosine Kinase Fusions In Lymphoid Blast Phase Comment On: Multilineage Involvement In Abl-Class Fusion-Positive Pediatric B-Cell Acute Lymphoblastic Leukemia: Cml-Like Biology, Wei J Wang, Shimin Hu

Faculty, Staff and Student Publications

No abstract provided.

The Link Between Weight Gain And Hippocampal Atrophy In Bipolar Disorder: A Longitudinal Investigation In 934 Participants, Julia Fraiha-Pegado, Sean R Mcwhinney, Martin Alda, Nina Alexander, Gerard Anmella, Christoph Abé, Luisa Altegoer, Francesco H Benedetti, Michael Berk, Erland Bøen, David J Bond, Brigitte Boye, Beatrice Bravi, Dara M Cannon, Emily L V Corkum, Emma Corley, Lorielle M F Dietze, Udo Dannlowski, Torbjorn Elvsåshagen, Paola Fuentes-Claramonte, Janice M Fullerton, Benjamin I Goldstein, Janik Goltermann, Dominik Grotegerd, Tim Hahn, Diego Hidalgo-Mazzei, Yanghee Im, Melody Kang, Andriana Karuk, Kody G Kennedy, Tilo Kircher, Anna Luisa Klahn, Anna Kraus, Mikael Landén, Elisabeth J Leehr, Rodrigo Machado-Vieira, Bradley J Macintosh, Ulrik F Malt, Elena Mazza, Colm Mcdonald, Susanne Meinert, Elisa Melloni, Phillip B Mitchell, Leila Nabulsi, Robert Nitsch, John O'Connor, Nils Opel, Maria C G Otaduy, Brownyn J Overs, Nadine Parker, Sara Poletti, Edith Pomarol-Clotet, Joaquim Radua, Gloria Roberts, Raymond Salvador, Chao Suo, Peter R Schofield, Maya Selitser, Kang Sim, Benjamin Straube, Lea Teutenberg, Sophia I Thomopoulos, Paula Usemann, Eduard Vieta, Lars T Westlye, Linzhi Wu, Lakshmi N Yatham, Paul M Thompson, Ole A Andreassen, Christopher R K Ching, Tomas Hajek, Enigma Bipolar Disorder And Bmix Working Groups

Faculty, Staff and Student Publications

Background: Obesity, which is common in bipolar disorder (BD), is associated with smaller hippocampal volumes. We do not know the role of weight/weight gain in relation to longitudinal hippocampal changes among individuals with BD.

Methods: In collaboration with the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-BD Working Group, we obtained T1-weighted magnetic resonance imaging and clinical data from 233 participants with BD and 701 healthy control participants (HCs) scanned twice, 2.84 ± 1.63 years apart on average. We estimated subcortical volumes using FreeSurfer longitudinal image processing stream and used linear mixed models to assess the bidirectional relationship between baseline …

Anti-Apoptotic Bcl-2 Binds To All Three Ip3r Isoforms, Thereby Limiting The Ca2+-Flux Properties Of Ip3r Homo-Tetramers, Ian De Ridder, Claire Cauwelier, Larry E Wagner Ii, Jens Loncke, Vikas Arige, Irina I Serysheva, David I Yule, Geert Bultynck

Faculty, Staff and Student Publications

Anti-apoptotic B-cell lymphoma 2 (BCL-2) controls inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca²+ signalling. As cells typically express all three IP3R isoforms in variable abundances that assemble in hetero-tetrameric channels, the specific effects of BCL-2 on each isoform remain unclear. Here, we employed a reductionist approach using HEK293 cells triple-IP3R knockout reconstituted with a single IP3R isoform to elucidate the impact of BCL-2 on Ca2+ signalling by homo-tetrameric IP3R channels. Co-immunoprecipitation experiments demonstrated that BCL-2 interacts with each IP3R isoform. Live-cell Ca²+ imaging revealed that BCL-2 overexpression suppresses Ca²+ signals evoked by any of the three IP3R isoforms. Moreover, BCL-2 overexpression impaired …

Tumor Microenvironment Transcriptional Activity Enables Robust Stratification Of Chemotherapy Response In Triple-Negative Breast Cancer, Yaoyi Dai, Xiaoxi Pan, Shuai Guo, Shuangxi Ji, Shaolong Cao, Matthew D Montierth, Yujie Jiang, Jeffrey T Chang, Leming Shi, Shabnam Shalapour, Gloria V Echeverria, Lucy Yates, Johan Staaf, Bora Lim, Yinyin Yuan, Wenyi Wang

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) exhibits heterogeneous treatment responses, yet molecular subtypes based on predefined biological pathways show limited prognostic value. We introduce tumor-specific total mRNA expression (TmS), a pathway-agnostic deconvolution metric derived from matched RNA/DNA sequencing, as a robust stratification tool. Analyzing 575 TNBC patients across Western and East Asian populations, TmS outperforms established subtypes in predicting chemotherapy outcomes, stratifying patients into high TmS with favorable prognosis and low TmS with poor prognosis. Stromal enrichment with immune exclusion emerges as a universal feature of chemotherapy-resistant low-TmS tumors across all cohorts. Population-specific features distinguish Asian cohorts: high-TmS tumors exhibit cell cycle-driven …