Digital Commons Network^™

Response To "Pulmonary Hypertension As A Determinant Of In-Hospital Mortality In Copd: Insights And Methodological Considerations", Trishna Parikh, Saad Afzal Khan, Adishwar Rao, Bela Patel, Bindu Akkanti

Faculty, Staff and Student Publications

No abstract provided.

Social Roles And Emotional Distress Are Associated With Successful Aging In Adult Childhood Cancer Survivors, Samah Hayek, Kimberly A Miller, Michael E Roth, Michelle A T Hildebrandt, David R Freyer, Joel Milam

Faculty, Staff and Student Publications

Childhood cancer survivors (CCS) face complex long-term health consequences resulting from intensive treatments that may impact their aging trajectory. This study assessed the associations between social role attainment, emotional distress, and indicators of successful aging (SA) among adult CCS, considering treatment intensity. SA, is a multidimensional concept encompassing physical, cognitive, and psychosocial well-being, provides a framework for understanding and optimizing outcomes in this population. This cross-sectional study utilized data from Project Forward, a cohort, of 1,248 adult CCS diagnosed between 1996 and 2010. Participants were identified through the Los Angeles County Cancer Surveillance Program and completed a comprehensive self-report survey …

Concordance Analysis Of Dna And Rna Profiling: The Md Anderson Impact2 Study In Precision Oncology, Stephanie T Schmidt, Mehmet A Baysal, Siqing Fu, David S Hong, Sarina A Piha-Paul, Aung Naing, Jordi Rodon Ahnert, Timothy A Yap, Ecaterina Elena Dumbrava, Jennifer Beck, Funda Meric-Bernstam, Apostolia Maria Tsimberidou

Faculty, Staff and Student Publications

DNA profiling is an established method for cancer treatment selection, while RNA profiling remains investigational. We explored associations between DNA and RNA alterations and between the number of genes with altered expression and overall survival (OS) using patient data from IMPACT2 (NCT02152254), a randomized study evaluating molecular profiling for guiding cancer therapy across tumor types. Molecular profiling, including DNA next-generation sequencing, was performed on all 829 patients in the IMPACT2 study. RNA profiling was performed by Tempus for 253 of 829 patients. We evaluated the concordance between DNA and RNA profiling, analyzed OS in 217 treated patients with …

Risk Stratification Of Low-Dose Cytarabine And Venetoclax In Patients With Aml Ineligible For Intensive Chemotherapy, Andrew H Wei, Panayiotis Panayiotidis, Pau Montesinos, Kamel Laribi, Vladimir Ivanov, Inho Kim, Jan Novak, Rebecca Champion, Walter Fiedler, Maria Pagoni, Julie Bergeron, Stephen B Ting, Jing-Zhou Hou, Takahiro Yamauchi, Jianxiang Wang, Stephen A Strickland, Michael R Savona, Tara L Lin, Anoop Enjeti, Ing Soo Tiong, Sangmin Lee, Gail J Roboz, Relja Popovic, Qi Jiang, Zihuan Liu, Yan Sun, Wellington Mendes, Brenda Chyla, Courtney D Dinardo

Faculty, Staff and Student Publications

Prognostic risk categorization aids treatment selection for patients with acute myeloid leukemia (AML). Although the European LeukemiaNet (ELN) classifications (2017 and 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, their application to patients receiving less intensive therapy, such as azacitidine plus venetoclax, has been less satisfactory. In response, a 4-gene classifier that stratifies older patients with AML unfit for intensive chemotherapy into those with higher benefit (wild type), intermediate benefit (FLT3-internal tandem duplication [ITD] or NRAS/KRAS mutation), or lower benefit (TP53 mutation) after azacitidine plus venetoclax treatment was developed. We hypothesized that this 4-gene …

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 …

Direct Synthesis Of Bicyclo[1.1.1]Pentane (Bcp) Boronates From Carboxylic Acids, Yongchen Wang, Jess C Tang, Gang Wu, Julian G West

Faculty, Staff and Student Publications

Bicyclo[1.1.1]pentane (BCP) boronic esters are crucial intermediates for accessing BCP-containing drugs with improved pharmacokinetic profiles, yet their synthesis typically relies on pre-formed redox-active esters derived from carboxylic acids. Here we report a general, single-step method for the direct conversion of carboxylic acids into BCP boronic esters. Upon irradiation of carboxylic acids with [1.1.1]propellane and bis(pinacolato)diboron (B2pin2) in dimethyl sulfoxide (DMSO), BCP boronates are obtained in good yields, which are further enhanced by the addition of an iron catalyst. Mechanistic studies suggest that photolytic cleavage of a B2pin2–DMSO complex initiates decarboxylation via hydrogen atom transfer (HAT), while iron catalysis enables a …

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 …

Cerebral Hypoperfusion Causes Behavioral Changes And Impairs The Rod Photoreceptor Pathway In The Retina Of Aged Mice, Spencer Talmage Barney, Daniela Becerril, Sheelu Monga, Samantha Flores, Audrey Lee, Marlon Fraga Mattos, Ross M Perez, Frank W Blixt, Michael Maniskas, Shuning Huang, Hongyu Wu, Chunfeng Tan, Louise D Mccullough, Elizabeth Zuniga-Sanchez, Jose Felix Moruno-Manchon

Faculty, Staff and Student Publications

Gradual reduction of cerebral blood flow occurs with aging, and it is a major cause of vascular dementia, a group of dementias with a cerebrovascular component. Interestingly, patients who have suffered a vascular insult may develop retinopathy, which may occur as an early symptom of vascular dementia. Several rodent models using young animals have been generated to mimic retinopathy caused by cerebral hypoperfusion; however, given that aging is an important factor in developing vascular dementia and hypoperfusion retinopathy, we propose to use aged (17-month-old) mice in a model of cerebral hypoperfusion. In this model, we implant two metallic micro-coils (0.16 …

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 …

Dasatinib Resensitizes Braf/Mek Inhibitor Efficacy In Patient-Derived Xenografts From Patients With Progression On Braf/Mek Inhibitor Treatment, Vito W Rebecca, Min Xiao, Andrew Kossenkov, Tetiana Godok, Gregory Schuyler Brown, Dylan Fingerman, Gretchen M Alicea, Meihan Wei, Hongkai Ji, Marie Portuallo, Jeremy Bravo, Vissy Elad, Yeqing Chen, Eneda Toska, Mitchell E Fane, Kasey L Couts, Jessie Villanueva, Katherine Nathanson, Keerthana M Arun, Govind Warrier, Xiangfan Yin, Jianyi Ding, Qin Liu, Yogesh Goyal, Y N Vashisht Gopal, Michael A Davies, Meenhard Herlyn

Faculty, Staff and Student Publications

Although BRAF/MEK inhibitor (BRAFi/MEKi) therapy initially shows high efficacy in patients with BRAFV600 E/K cutaneous melanoma, resistance develops in over 75% of cases. We tested robustness of the umbrella trial strategy in this population by analyzing relationships between genomic status of a gene and associated downstream consequences at the protein level. The results revealed weak relationships among mutations, copy-number amplification, and protein expression and activation. An in vivo compound repurposing screen using 11 clinically relevant agents from an NCI-portfolio with pan-RTK, non-RTK, and/or PI3K-mTOR specificity identified dasatinib as most capable of restoring sensitivity to BRAFi/MEKi in patient-derived xenograft (PDX) …

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, …

Perinatal And Maternal Outcomes By Indication For Delivery In The Second Trimester, Kristen A Cagino, Paula L Mcgee, Maged M Costantine, Michael W Varner, Alan T N Tita, Monica Longo, Barbara J Stoll, John M Thorp, Uma M Reddy, William A Grobman, Dwight J Rouse, Hyagriv N Simhan, Jennifer L Bailit, Lorraine Dugoff, George R Saade, Baha M Sibai

Faculty, Staff and Student Publications

Perinatal and maternal morbidity in the setting of preterm birth may differ by delivery indication. We compared perinatal and maternal outcomes of second-trimester (240/7-276/7 weeks of gestation) deliveries indicated for preeclampsia with severe features (PE-SF), with those following preterm premature rupture of membranes (PPROM).Secondary analysis of an observational cohort study of singleton and twin preterm deliveries before 35 weeks' gestation at 33 hospitals across the United States. Singletons without congenital anomalies who were delivered due to PE-SF or PPROM from 240/7 to 276/7 weeks of gestation were included. The primary outcome was a composite of perinatal morbidity or death, defined …

A Phenomenological Approach To Spastic Movement Disorders: An International Expert Panel Consensus, Bo Biering-Sørensen, Jörg Wissel, Raymond Rosales, Rajiv Reebye, Jorge Jacinto, Gerard E Francisco, Peter Sanderson, Per Ertzgaard

Faculty, Staff and Student Publications

Background and objectives: Hyperkinetic movement disorders, characterized by complex and overlapping motor patterns, present significant challenges in classification and treatment. The inconsistency in definitions and descriptors complicates both research and clinical communication. This study aims to provide an overview of current terminology and definitions related to spasticity and other hyperkinetic movement disorders associated with central nervous system lesions. We propose a unified terminology and classification system for spastic movement disorders (SMD).

Methods: In this scoping review, definitions of spasticity, dystonia, tremor, chorea, hemiballismus, athetosis, myoclonus, and dyssynergia were reviewed, with emphasis on overlaps and diagnostic challenges among these disorders. The …

Cardiac Output-Guided Vs. Mean Arterial Pressure-Guided Hemodynamic Management In Craniotomy Patients With Cardiovascular Disease: A Randomized Trial, Na Chen, Minjing Yang, Renhua Li, Chunyan Ye, Lu Wang, Xingyang Liu, Jinghan Wu, Daniel I Sessler, E Wang

Faculty, Staff and Student Publications

We tested the primary hypothesis that cardiac output (CO)-guided versus mean arterial pressure (MAP)-guided hemodynamic management reduces the fraction of patients with 90-day Glasgow Outcome scores ≤ 4 (on a 1–5 scale, 5 better) after supratentorial brain tumor resections in adults with cardiovascular disease. 202 adults were randomized to intraoperative hemodynamic management guided by either CO or MAP. In patients assigned to CO guidance, clinicians targeted CO > 4 L/min and > 90% of baseline values using a combination of fluids and vasoactive agents. In patients assigned to MAP guidance, clinicians targeted MAP within ± 20% of baseline and ≥ 65 mmHg. …

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 …

Neurophysiological Connectomic Signatures Of Consciousness During Propofol-Induced General Anesthesia, Yuqin Li, Xiaoxiao Chen, Hui Zheng, Senqi Li, Qingyu Teng, Chengyu Wang, Fali Li, Zhongcong Xie, Daniel Sessler, Zhe Zhang, Peng Xu, Ti-Fei Yuan, Tao Xu

Faculty, Staff and Student Publications

General anesthesia induces reversible changes in consciousness through cortical activity and connectivity alterations, yet the functional connectome dynamics underlying propofol-induced unconsciousness remains unclear. We analyze high-density 128-channel electroencephalogram (EEG) from 31 surgical patients using source localization to identify neurobiological connectome signatures of propofol anesthesia. Propofol anesthesia increases delta and theta functional connectivity and decreases alpha, beta, and gamma connectivity. A classification model and dynamic analysis of consciousness loss reveals that alpha-band connectivity between parietal, occipital, and subcortical regions is critical for sustaining consciousness, with its disruption marking a key transition to unconsciousness. EEG from 46 additional patients under mild sedation …

Expectant Management Vs Medication For Patent Ductus Arteriosus In Preterm Infants: The Pda Randomized Clinical Trial, Matthew M Laughon, Sonia M Thomas, Kristi L Watterberg, Kathleen A Kennedy, Martin Keszler, Namisavayam Ambalavanan, Alexis S Davis, Jonathan L Slaughter, Ronnie Guillet, Tarah T Colaizy, C Michael Cotten, Megan A Dhawan, Carl L Bose, Jennifer Talbert, Sarah Smucny, William E Benitz, Matthew A Rysavy, Robin K Ohls, Mariana C Baserga, Sara B Demauro, Mambarambath Jaleel, Wesley M Jackson, Waldemar A Carlo, Karen M Puopolo, Anna Maria Hibbs, Anup Katheria, Pablo J Sánchez, Carl T D'Angio, Ravi M Patel, Beth Ann Johnson, Valerie Y Chock, Abhay J Bhatt, Stephanie L Merhar, Ryan Moore, Abbot R Laptook, Sarvin Ghavam, Janell Fuller, Shilpa Vyas-Read, Stephen D Kicklighter, Baiba Steinbrekera, Kathryn Anderson, Praveen K Chandrasekharan, Myra H Wyckoff, Cassandra Montoya, Abhik Das, Barbara Do, Samantha Chang, Rosemary D Higgins, Michele C Walsh

Faculty, Staff and Student Publications

Importance: The management of patent ductus arteriosus (PDA) in preterm infants is controversial.

Objective: To determine whether expectant management compared with active treatment of a protocol-defined PDA in preterm infants decreases the incidence of death or bronchopulmonary dysplasia (BPD).

Design, setting, and participants: A randomized clinical trial including infants born at 22 to 28 weeks' gestation and diagnosed with a protocol-defined PDA between the age of 48 hours and 21 days at screening. The trial was conducted from December 2018 to December 2024 at 33 hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. The …

Syndecan-1-Targeted Therapeutic Antibody Impairs Macropinocytosis And Elicits Antitumor Immunity In Pancreatic Cancer, Zecheng Yang, Madelaine S Theardy, Shuaitong Chen, Yongkun Wei, Mitsunobu Takeda, Yue Zeng, Xiaofei Wang, Jun Yao, Jennifer Li, Prapassorn Thirasastr, Jangho Park, Yangxi Zheng, Long T Vien, Khalida M Wani, Huamin Wang, Sisi Gao, Tim Heffernan, Lawrence Kwong, Ignacio I Wistuba, Laura Bover, Giulio F Draetta, Haoqiang Ying, Wantong Yao

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a 5-year survival rate of just 13%. While the development and early clinical use of small molecules targeting oncogenic KRAS mutations, key drivers of PDAC, have shown promise, resistance to these targeted therapies remains a significant challenge. We recently identified Syndecan-1 (SDC1), a highly expressed heparan sulfate proteoglycan, as a critical KRAS effector protein that promotes nutrient salvage and tumor growth. Here, we report the development of a human-specific monoclonal antibody (anti-SDC1 mAb) that inhibits PDAC cell proliferation in vitro and suppresses PDAC tumor growth in vivo. Mechanistically, …

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 …

Sting-Induced Blood-Brain Barrier Opening Combined With Radiotherapy Potentiates Antitumor Response In A High-Grade Glioma Model, Shashwat Tripathi, Hinda Najem, Lisa Hurley, Ruochen Du, Crismita Dmello, Heba Ali, Kathleen Mccortney, Karl J Habashy, Peng Zhang, Craig M Horbinski, Lara Leoni, Ryan J Avery, Rimas V Lukas, Timothy L Sita, David R Raleigh, Sean Sachdev, Roger Stupp, Maciej S Lesniak, David M Ashley, Daniele Procissi, Michael A Curran, Irina Balyasnikova, Amy B Heimberger

Faculty, Staff and Student Publications

Radiation therapy (RT) is the standard of care for glioblastoma but is not curative. Triggering the cGAS/stimulator of interferon genes (STING) pathway with potent agonists, such as 8803, exerts activity across high-grade glioma preclinical models. To determine if the combination of 8803 with RT warrants consideration in the up-front treatment setting and to clarify the underlying mechanisms of therapeutic activity, C57BL/6J mice harboring intracerebral CT-2A or QPP8v gliomas were treated with RT, intratumoral 8803, or both. The treatment with the combination resulted in 80% long-term survival in the CT-2A model but not in the radiation-resistant QPP8v model. This therapeutic effect …

Mutant Kras In Brain Endothelial Cells Promotes Vascular Inflammation And Impairs Vascular Integrity In Brain Arteriovenous Malformation, Jung-Eun Park, Bridger H Freeman, Hyejin Park, Sehee Kim, Adrian E Bafor, Ohnmar Myint, Song Gao, Zhen Xu, Jakob Körbelin, Jaroslaw Aronowski, Peng Roc Chen, Eunhee Kim, Eun S Park

Faculty, Staff and Student Publications

Somatic KRAS (KRASG12V) mutation in endothelial cells (EC) induces brain arteriovenous malformation (bAVM) that could lead to vascular instability and ultimately bleeding. However, the causes of bAVM instability remain unclear. Here we demonstrate that KRASG12V expressing cultured ECs (KRAS-G12V-EC) have increased expression of pro-inflammatory mediators and reduced expression of blood-brain-barrier (BBB) junction constituents. The conditioned medium from KRAS-G12V-EC can activate BV2-microglia (BV2-MG) and conditioned media from this primed BV2-MG can compromise the expression of EC-junction constituents when added to wild-type ECs. In an in vitro BBB model, KRAS-G12V-EC form a dysfunctional EC barrier that is further disrupted, leading to lower …

Automated Quantification Of Movement Qualities In The Human Upper Extremity After Stroke Using A Wearable Robot., Yoon No Gregory Hong, Kyoungsoon Kim, Sheng Li, Marcia K O'Malley, Ashish D Deshpande, Jinsook Roh

Faculty, Staff and Student Publications

Background: Stroke is a leading cause of long-term adult disability, with approximately 80% of survivors experiencing upper extremity (UE) motor impairments. Conventional tools like the Fugl-Meyer Assessment (FMA) are widely used but limited by ordinal scales and subjective visual observation. While wearable robotics offer high-resolution data, their clinical translation is hindered by a lack of standardized protocols and limited interpretability for clinical decision-making.

Objective: This study aimed to develop an objective, standardized, and clinically interpretable method to quantify UE motor qualities by integrating wearable robotic technology with traditional clinical assessment tasks.

Methods: Ten healthy individuals and ten stroke survivors performed …

Optimizing Electrode Placement And Information Capacity For Local Field Potentials In Cortex, Jace A Willis, Christopher E Wright, Ruoqian Zhu, Yilan Ruan, Joshua Stallings, Amada M Abrego, Takfarinas Medani, Promit Moitra, Arjun Ramakrishnan, Charles E Schroeder, Anand A Joshi, Nitin Tandon, Richard M Leahy, John C Mosher, John P Seymour

Faculty, Staff and Student Publications

Recent neurosurgery advancements include improved stereotactic targeting and increased density and specificity of electrophysiological evaluation. This study introduces a subject-specific, in silico modeling tool for optimizing electrode placement and maximizing coverage with a variety of devices. The basis for optimization is the Shannon-Hartley information capacity of field potentials derived from dipolar sources. The approach integrates subject-specific MRI data with finite element modeling (FEM) used to simulate the sensitivity of subdural and intracortical devices. Sensitivity maps, or lead fields, from these models enable the comparison of different electrode placements, contact sizes, contact configurations, and substrate properties, which are often overlooked factors. …

Clinical, Genetic, And Familial Features Of Pot1 Tumor Predisposition Syndrome, Courtney D Dinardo, Jennifer Croden, Hiam M Abdel-Salam, Tapan Kadia, Matteo Molica, Alexandre Bazinet, Prithviraj Bose, Abhishek Maiti, Fadi Haddad, Jan Burger, Hagop Kantarjian, William Wierda, Nitin Jain, Alessandra Ferrajoli

Faculty, Staff and Student Publications

Background: Protection of telomere 1 (POT1) tumor predisposition syndrome (POT1-TPD) is a hereditary leukemia syndrome that is identified in ∼5% of patients with chronic lymphocytic leukemia (CLL) and is characterized by a predisposition to other cancers, including gliomas, melanomas, and angiosarcomas. This study reports clinical and genetic characteristics of a large cohort of individuals with POT1-TPD.

Materials and methods: Individuals with pathogenic/likely pathogenic germline POT1 variants referred to the Hereditary Hematologic Malignancy Clinic at The University of Texas MD Anderson Cancer Center were included. Individuals with variants of uncertain significance were included if found to have telomeres >90th percentile of …