Digital Commons Network^™

Higher Dose Corticosteroids In Patients Admitted To Hospital With Covid-19 Who Are Hypoxic But Not Requiring Ventilatory Support (Recovery): A Randomised, Controlled, Open-Label, Platform Trial

Faculty, Staff and Student Publications

BACKGROUND: Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group.

METHODS: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation

FINDINGS: Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen …

Shared Decision Making In Self-Care Management And Health Outcomes Of Adolescents And Young Adults With Sickle Cell Disease, Judith M. Odityo

Dissertations and Theses (Open Access)

Background: Shared decision making (SDM) is a model of care with a potential to guide disease self-care management and promote optimal health outcomes in adolescents and young adults (AYA) with sickle cell disease (SCD).

Aims: To identify the perceived involvement of AYA with SCD in the SDM process and examine its association with self-care management and health outcomes.

Methods: Data were collected from a major sickle cell center. Using a cross-sectional design, participants completed surveys and data were analyzed with descriptive statistics, analysis of variance, multiple linear regression, and correlational statistics.

Results: Participants (N=25) were on average age 22.72 (SD …

Noninvasive Screening Of Nonalcoholic Fatty Liver Disease Among People Living With Hiv, Essi M. Havor

Dissertations and Theses (Open Access)

Background: Nonalcoholic fatty liver disease (NAFLD) disproportionately affects up to 75% of people living with HIV (PLWH). Given the high HIV prevalence in Houston and Harris County, knowledge of the prevalence of NAFLD in PLWH is needed to inform prevention efforts. In addition, such knowledge is required to raise awareness among at-risk individuals and healthcare professionals.

Specific Aims: This cross-sectional study aimed (1) to examine the demographic, behavioral, clinical, and psychosocial characteristics of PLWH in Houston/Harris County, Texas, and to estimate the prevalence of NAFLD, (2) to determine factors associated with the severity of NAFLD, and (3) to identify specific …

Tmem106b Regulates Microglial Proliferation And Survival In Response To Demyelination, Jennifer Guo, Kenton Wu, Mariela Nunez Santos, Akshayakeerthi Arthanarisami, Alissa L Nana, Quynh Nguyen, Peter J Kim, Joanna L Jankowsky, William W Seeley, Fenghua Hu

Faculty, Staff and Students Publications

TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B …

Association Of Polymorphisms In Fshr, Inha, Esr1, And Bmp15 With Recurrent Implantation Failure, Ji-Young Hwang, Ji-Hyang Kim, Nam-Keun Kim

Faculty, Staff and Student Publications

Recurrent implantation failure (RIF) refers to two or more unsuccessful in vitro fertilization embryo transfers in the same individual. Embryonic characteristics, immunological factors, and coagulation factors are known to be the causes of RIF. Genetic factors have also been reported to be involved in the occurrence of RIF, and some single nucleotide polymorphisms (SNPs) may contribute to RIF. We examined SNPs in

Lessons Learned From All For Them: Best Practices For A Cross-Collaboration Approach To Hpv Vaccination In Public Schools, Diane Santa Maria, Sally W Vernon

Faculty, Staff and Student Publications

The Community Preventive Services Task Force endorses vaccination programs in schools to increase access to vaccinations. However, implementing a school-based approach requires substantial coordination, planning, and resources. All for Them (AFT) is a multilevel, multicomponent approach to increase HPV vaccination among adolescents attending public schools in medically underserved areas in Texas. AFT comprised a social marketing campaign, school-based vaccination clinics, and school nurse continuing education. Process evaluation metrics and key informant interviews to understand experiences with AFT program implementation informed lessons learned. Lessons emerged in six domains: strong champion, school-level support, tailored and cost-effective marketing approaches, mobile provider collaboration, community …

Correction: Deadly Combination Of Vaping-Lnduced Lung Injury And Influenza: Case Report, Kha Dinh, Klemen Petek, Ismael A Salas De Armas, Mehmet Akay, Biswajit Kar, Igor D Gregoric, L Maximilian Buja

Faculty, Staff and Student Publications

Following publication of the original article [1], In this article the title was incorrectly given as “Deadly combination of E-cigarettes has become a popular-lnduced lung injury and Influenza: case report” but should have been “Deadly combination of Vaping-lnduced lung injury and Influenza: case report”.

The original article has been updated.

Home-Based Tdcs For Apathy In Alzheimer’S Disease: A Protocol For A Randomized Double-Blinded Controlled Pilot Study, Robert Suchting

Faculty, Staff and Student Publications

BACKGROUND: Apathy is among the most common behavioral symptoms in dementia and is consistently associated with negative outcomes in Alzheimer's disease (AD). Despite its prevalence and clinical relevance, available pharmacological and non-pharmacological strategies to treat apathy in AD have been marked, respectively, by potentially severe side effects and/or limited efficacy. Transcranial direct current stimulation (tDCS) is a relatively novel non-pharmacological method of neuromodulation with promising results. Compared to previous tDCS formats, recent technological advances have increased the portability of tDCS, which creates the potential for caregiver-administered, home use. Our study aims to evaluate the feasibility, safety, and efficacy of home-based …

Exercise Reprograms The Inflammatory Landscape Of Multiple Stem Cell Compartments During Mammalian Aging, Jaime M Reyes, Jengmin Kang, Lei Tian, Mingqiang Wang, Alexander Lieu, Michelle Mao, Cristina Rodriguez-Mateo, Heather D Ishak, Mira Jeong, Joseph C Wu, Margaret A Goodell, Anne Brunet, Thomas A Rando

Faculty, Staff and Students Publications

Exercise has the ability to rejuvenate stem cells and improve tissue regeneration in aging animals. However, the cellular and molecular changes elicited by exercise have not been systematically studied across a broad range of cell types in stem cell compartments. We subjected young and old mice to aerobic exercise and generated a single-cell transcriptomic atlas of muscle, neural, and hematopoietic stem cells with their niche cells and progeny, complemented by whole transcriptome analysis of single myofibers. We found that exercise ameliorated the upregulation of a number of inflammatory pathways associated with old age and restored aspects of intercellular communication mediated …

Bi-Allelic Variants In Ints11 Are Associated With A Complex Neurological Disorder, Monika Weisz Hubshman, Oguz Kanca, Laura Schultz-Rogers, Yuri A Zarate, G Bradley Schaefer, Jorge Luis Granadillo De Luque, Daniel J Wegner, Benjamin Cogne, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Eric J Wagner, Lynn S Pais, Jennifer E Neil, Ganeshwaran H Mochida, Christopher A Walsh, Nurit Magal, Valerie Drasinover, Mordechai Shohat, Tanya Schwab, Chris Schmitz, Karl Clark, Anthony Fine, Brendan Lanpher, Ralitza Gavrilova, Pierre Blanc, Lydie Burglen, Alexandra Afenjar, Dora Steel, Manju A Kurian, Prab Prabhakar, Sophie Gößwein, Nataliya Di Donato, Enrico S Bertini, Undiagnosed Diseases Network, Michael F Wangler, Shinya Yamamoto, Marco Tartaglia, Eric W Klee, Hugo J Bellen

Faculty, Staff and Students Publications

The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog …

Glynac (Glycine And N-Acetylcysteine) Supplementation In Old Mice Improves Brain Glutathione Deficiency, Oxidative Stress, Glucose Uptake, Mitochondrial Dysfunction, Genomic Damage, Inflammation And Neurotrophic Factors To Reverse Age-Associated Cognitive Decline: Implications For Improving Brain Health In Aging

Faculty, Staff and Students Publications

Cognitive decline frequently occurs with increasing age, but mechanisms contributing to age-associated cognitive decline (ACD) are not well understood and solutions are lacking. Understanding and reversing mechanisms contributing to ACD are important because increased age is identified as the single most important risk factor for dementia. We reported earlier that ACD in older humans is associated with glutathione (GSH) deficiency, oxidative stress (OxS), mitochondrial dysfunction, glucose dysmetabolism and inflammation, and that supplementing GlyNAC (glycine and N-acetylcysteine) improved these defects. To test whether these defects occur in the brain in association with ACD, and could be improved/reversed with GlyNAC supplementation, we …

Osteoprogenitor-Gmp Crosstalk Underpins Solid Tumor-Induced Systemic Immunosuppression And Persists After Tumor Removal, Weijie Zhang, Elizabeth Valverde, Ling Wu, Hilda L Chan, Zhan Xu, Liqun Yu, Yang Gao, Igor Bado, Laura Natalee Michie, Charlotte Helena Rivas, Luis Becerra Dominguez, Sergio Aguirre, Bradley C Pingel, Yi-Hsuan Wu, Fengshuo Liu, Yunfeng Ding, David G Edwards, Jun Liu, Angela Alexander, Naoto T Ueno, Po-Ren Hsueh, Chih-Yen Tu, Liang-Chih Liu, Shu-Hsia Chen, Mien-Chie Hung, Bora Lim, Xiang H-F Zhang

Faculty, Staff and Students Publications

Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitors (OPs) expansion, hematopoietic stem cell dislocation and CD41− granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41− GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in hematopoietic program. Importantly, these effects persist …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Using Cancer Proteomics Data To Identify Gene Candidates For Therapeutic Targeting, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer …

Srsf1 Haploinsufficiency Is Responsible For A Syndromic Developmental Disorder Associated With Intellectual Disability, Kathleen Rooney, Yannis Duffourd, Pontus Leblanc, Emma Van Reempts, Frederic Tran Mau-Them, Ingrid M Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J Louie, Michael J Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley Mcconkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R Roeder, Tadahiro Mitani, Jennifer E Posey, Daniel Calame, Hagith Yonath, Jill A Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello

Faculty, Staff and Students Publications

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals …

Linking Social And Built Environmental Factors To Leisure-Time Physical Activity In Rural Cancer Survivors, Hannah Arem, Kathryn H Schmitz, Scherezade K Mama

Faculty, Staff and Student Publications

BACKGROUND: This study explored associations between social and built environmental factors and leisure-time physical activity (LTPA) in rural cancer survivors (RCS) and whether these associations differed by exercise stage of change (SOC).

METHOD: RCS (n = 219) completed questionnaires assessing LTPA, SOC, and social (social status, connectedness, support) and environmental (home environment, neighborhood environment) factors. Linear regression models examined associations between social and built environmental factors and LTPA and tested for moderation by SOC.

RESULTS: Half (50.7%) of RCS were physically active, and 49.3% were not active. Social factors positively associated with LTPA included subjective social status in the community …

A Vlp-Based Vaccine Displaying Hbha And Mtp Antigens Of Mycobacterium Tuberculosis Induces Potentially Protective Immune Responses In M Tuberculosis H37ra Infected Mice, Xiaoping Li, Yang Gong, Pu He, Yuqi Liu, Fei Li, Jixi Li, Zengjun Lu, Bingdong Zhu

Faculty, Staff and Student Publications

Heparin-binding hemagglutinin (HBHA) and M. tuberculosis pili (MTP) are important antigens on the surface of Mycobacterium tuberculosis. To display these antigens effectively, the fusion protein HBHA-MTP with a molecular weight of 20 kD (L20) was inserted into the receptor-binding hemagglutinin (HA) fragment of influenza virus and was expressed along with matrix protein M1 in Sf9 insect cells to generate influenza virus-like particles (LV20 in short). The results showed that the insertion of L20 into the envelope of the influenza virus did not affect the self-assembly and morphology of LV20 VLPs. The expression of L20 was successfully verified by transmission …

Igfbp2 Expressing Midlobular Hepatocytes Preferentially Contribute To Liver Homeostasis And Regeneration, Yu-Hsuan Lin, Yonglong Wei, Qiyu Zeng, Yunguan Wang, Chase A Pagani, Min Zhu, Meng-Hsiung Hsieh, Natasha Corbitt, Yu Zhang, Tripti Sharma, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Although midlobular hepatocytes in zone 2 are a recently identified cellular source for liver homeostasis and regeneration, these cells have not been exclusively fate mapped. We generated an Igfbp2-CreER knockin strain that specifically labels midlobular hepatocytes. During homeostasis over 1 year, zone 2 hepatocytes increased in abundance from occupying 21%-41% of the lobular area. After either pericentral injury with carbon tetrachloride or periportal injury with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), IGFBP2+ cells replenished lost hepatocytes in zones 3 and 1, respectively. IGFBP2+ cells also preferentially contributed to regeneration after 70% partial hepatectomy, as well as liver growth during pregnancy. Because IGFBP2 labeling increased …

Twas_Sim, A Python-Based Tool For Simulation And Power Analysis Of Transcriptome-Wide Association Analysis, Xinran Wang, Zeyun Lu, Arjun Bhattacharya, Bogdan Pasaniuc, Nicholas Mancuso

Faculty, Staff and Student Publications

Genome-wide association studies (GWASs) have identified numerous genetic variants associated with complex disease risk; however, most of these associations are non-coding, complicating identifying their proximal target gene. Transcriptome-wide association studies (TWASs) have been proposed to mitigate this gap by integrating expression quantitative trait loci (eQTL) data with GWAS data. Numerous methodological advancements have been made for TWAS, yet each approach requires ad hoc simulations to demonstrate feasibility. Here, we present twas_sim, a computationally scalable and easily extendable tool for simplified performance evaluation and power analysis for TWAS methods.

Software and documentation are available at https://github.com/mancusolab/twas_sim.

Loss Of Lgr5 Through Therapy-Induced Downregulation Or Gene Ablation Is Associated With Resistance And Enhanced Met-Stat3 Signaling In Colorectal Cancer Cells, Tressie A Posey, Joan Jacob, Ashlyn Parkhurst, Shraddha Subramanian, Liezl E Francisco, Kendra S Carmon

Faculty, Staff and Student Publications

Leucine-rich repeat-containing, G protein-coupled receptor 5 (LGR5) is highly expressed in colorectal cancer and cancer stem cells (CSCs) that play important roles in tumor initiation, progression, and metastasis. Loss of LGR5 has been shown to enhance therapy resistance. However, the molecular mechanisms that mediate this resistance remain elusive. In this study, we demonstrate conversion of LGR5+ colorectal cancer cells to an LGR5- state in response to chemotherapy, LGR5- targeted antibody-drug conjugates (ADCs), or LGR5 gene ablation led to activation of STAT3. Further investigation revealed increased STAT3 activation occurred as a result of increased mesenchymal epithelial transition (MET) factor receptor activity. …

Patterns Of Oncogene Coexpression At Single-Cell Resolution Influence Survival In Lymphoma, Michal Marek Hoppe, Patrick Jaynes, Fan Shuangyi, Yanfen Peng, Shruti Sridhar, Clementine Xin Liu, Limei Poon, Esther Hian Li Chan, Joanne Lee, Choon Kiat Ong, Tiffany Tang, Soon Thye Lim, Chandramouli Nagarajan, Nicholas F Grigoropoulos, Soo-Yong Tan, Susan Swee-Shan Hue, Sheng-Tsung Chang, Shih-Sung Chuang, Shaoying Li, Joseph D Khoury, Hyungwon Choi, Carl Harris, Alessia Bottos, Laura J Gay, Hendrik F P Runge, Ilias Moutsopoulos, Irina Mohorianu, Daniel J Hodson, Pedro Farinha, Anja Mottok, David W Scott, Jason J Pitt, Jinmiao Chen, Gayatri Kumar, Kasthuri Kannan, Wee Joo Chng, Yen Lin Chee, Siok-Bian Ng, Claudio Tripodo, Anand D Jeyasekharan

Faculty, Staff and Student Publications

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n …

Insights Into The Formation And Diversification Of A Novel Chiropteran Wing Membrane From Embryonic Development, Neal Anthwal, Daniel J Urban, Alexa Sadier, Risa Takenaka, Simon Spiro, Richard R Behringer, John J Rasweiler, Karen E Sears

Faculty, Staff and Student Publications

BACKGROUND: Through the evolution of novel wing structures, bats (Order Chiroptera) became the only mammalian group to achieve powered flight. This achievement preceded the massive adaptive radiation of bats into diverse ecological niches. We investigate some of the developmental processes that underlie the origin and subsequent diversification of one of the novel membranes of the bat wing: the plagiopatagium, which connects the fore- and hind limb in all bat species.

RESULTS: Our results suggest that the plagiopatagium initially arises through novel outgrowths from the body flank that subsequently merge with the limbs to generate the wing airfoil. Our findings further …

Usp36 Promotes Tumorigenesis And Drug Sensitivity Of Glioblastoma By Deubiquitinating And Stabilizing Alkbh5, Guoqiang Chang, Gloria S Xie, Li Ma, Peng Li, Linlin Li

Faculty, Staff and Student Publications

Background: ALKBH5 is aberrantly activated and exerts critical roles in facilitating the development of glioblastoma. However, the underlying activation mechanism by which ALKBH5 protein is increased in glioblastoma is not completely understood. Our study aimed to elucidate the signaling pathways involved in mediating ALKBH5 protein stability.

Methods: The contribution of deubiquitinating enzymes (DUB) to the fluctuation of ALKBH5 protein expression was globally profiled with western blot analysis. Mass spectrometry and immunoprecipitation were performed to identify the USP36 and ALKBH5 interaction. The effects of USP36 on the stability of ALKBH5 were detected with in vivo and in vitro ubiquitination assays. Cell …

Prognosticators For Patients With Pancreatic Ductal Adenocarcinoma Who Received Neoadjuvant Folfirinox Or Gemcitabine/Nab-Paclitaxel Therapy And Pancreatectomy, Yi Tat Tong, Zongshan Lai, Matthew H G Katz, Laura R Prakash, Hua Wang, Michael Kim, Jeffrey E Lee, Naruhiko Ikoma, Asif Rashid, Robert A Wolff, Dan Zhao, Eugene J Koay, Anirban Maitra, Huamin Wang

Faculty, Staff and Student Publications

Neoadjuvant FOLFIRINOX and gemcitabine/nab-paclitaxel (GemNP) therapies are increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). However, limited data are available on their clinicopathologic prognosticators. We examined the clinicopathologic factors and survival of 213 PDAC patients who received FOLFIRINOX with 71 patients who received GemNP. The FOLFIRINOX group was younger (p < 0.01) and had a higher rate of radiation (p = 0.049), higher rate of borderline resectable and locally advanced disease (p < 0.001), higher rate of Group 1 response (p = 0.045) and lower ypN stage (p = 0.03) than the GemNP group. Within FOLFIRINOX group, radiation was associated with decreased lymph node metastasis (p = 0.01) and lower ypN …

Dimeric P53 Mutant Elicits Unique Tumor-Suppressive Activities Through An Altered Metabolic Program, Jovanka Gencel-Augusto, Xiaoping Su, Yuan Qi, Elizabeth M Whitley, Vinod Pant, Vrutant Shah, Encarnacion Perez, Marta L Fiorotto, Iqbal Mahmud, Abhinav K Jain, Philip L Lorenzi, Nicholas E Navin, Ellen R Richie, Guillermina Lozano

Faculty, Staff and Student Publications

Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence …

Prognostic Validation Of A New Classification System For Extent Of Resection In Glioblastoma: A Report Of The Rano Resect Group, Tommaso Sciortino, Ramin A Morshed, Alexander F Haddad, Yalan Zhang, Sophia Stoecklein, Michael Weller, Michael A Vogelbaum, Juergen Beck, Nitin Tandon, Shawn Hervey-Jumper, Annette M Molinaro, Roberta Rudà, Lorenzo Bello, Oliver Schnell, Yoshua Esquenazi, Maximilian I Ruge, Stefan J Grau, Mitchel S Berger, Susan M Chang, Martin Van Den Bent, Joerg-Christian Tonn

Faculty, Staff and Student Publications

BACKGROUND: Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit.

METHODS: The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected.

RESULTS: We collected 1,008 patients with newly …

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant P53 Promotes Transactivation-Independent Mitochondrial Cell Death, Aleksandar Z Obradovic, Kaitlin Long, Paul M Hwang, Joshua D Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol Prives

Faculty, Staff and Student Publications

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. …

Colonizing And Virulence Factors In Enterotoxigenic Escherichia Coli From Peru, Maria J Pons

Faculty, Staff and Student Publications

Enterotoxigenic Escherichia coli (ETEC) ranks among the most relevant diarrheagenic pathogens. Efforts to design vaccines to fight ETEC have been focused on colonizing factors (CFs) and atypical virulence factors (AVF). An effective vaccine must account for differences in the regional prevalence of these CFs and AVFs to be truly effective in a given area. In the present study, the presence of 16 CFs and 9 AVFs, as well as the heat-stable (ST) variants (STh or STp), was established by polymerase chain reaction in 205 Peruvian ETEC isolates (120 from diarrhea cases and 85 from healthy controls). Ninety-nine (48.3%) isolates were …

Post-Traumatic Stress Disorder And Risk Of Degenerative Synucleinopathies: Systematic Review And Meta-Analysis, Melissa B Jones, Rachel Gates, Lakeshia Gibson, Dakota Broadway, Gursimrat Bhatti, Juliann Tea, Ana Guerra, Ruosha Li, Beatriz Varman, Mohamed Elammari, Ricardo E Jorge, Laura Marsh

Library Staff Publications

OBJECTIVE: A systematic review was conducted to answer whether adult-onset post-traumatic stress disorder (PTSD) is associated with increased risk of Parkinson's disease (PD) and related synucleinopathies.

DESIGN: A systematic search of Medline (Ovid), Embase (Elsevier), PsycInfo (Ovid), Cochrane Library (Wiley), and Web of Science (Clarivate) was performed using MeSH headings and equivalent terms for PTSD, PD, DLB, and related disorders.

SETTING: No restrictions.

PARTICIPANTS: Eligible articles were published in peer-reviewed journals, sampled adult human populations, and treated PTSD and degenerative synucleinopathies as exposures and outcomes, respectively.

MEASUREMENTS: Extracted data included diagnostic methods, sample characteristics, matching procedures, covariates, and effect estimates. …

Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy In Melanoma, Gabriele Romano, Francesca Paradiso, Peng Li, Pooja Shukla, Lindsay N Barger, John P Miller, Timothy L Helms, Alexander J Lazar, Jennifer A Wargo, Francesca Taraballi, James C Costello, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as …