Medicine and Health Sciences Commons^™

Proteomics Analysis Of Plasma From Middle-Aged Adults Identifies Protein Markers Of Dementia Risk In Later Life, Keenan A Walker, Jingsha Chen, Liu Shi, Yunju Yang, Myriam Fornage, Linda Zhou, Pascal Schlosser, Aditya Surapaneni, Morgan E Grams, Michael R Duggan, Zhongsheng Peng, Gabriela T Gomez, Adrienne Tin, Ron C Hoogeveen, Kevin J Sullivan, Peter Ganz, Joni V Lindbohm, Mika Kivimaki, Alejo J Nevado-Holgado, Noel Buckley, Rebecca F Gottesman, Thomas H Mosley, Eric Boerwinkle, Christie M Ballantyne, Josef Coresh

Faculty, Staff and Student Publications

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that …

Integrating Genetics And Metabolomics From Multi-Ethnic And Multi-Fluid Data Reveals Putative Mechanisms For Age-Related Macular Degeneration, Xikun Han, Ines Lains, Jun Li, Jinglun Li, Yiheng Chen, Bing Yu, Qibin Qi, Eric Boerwinkle, Robert Kaplan, Bharat Thyagarajan, Martha Daviglus, Charlotte E Joslin, Jianwen Cai, Marta Guasch-Ferré, Deirdre K Tobias, Eric Rimm, Alberto Ascherio, Karen Costenbader, Elizabeth Karlson, Lorelei Mucci, A Heather Eliassen, Oana Zeleznik, John Miller, Demetrios G Vavvas, Ivana K Kim, Rufino Silva, Joan Miller, Frank Hu, Walter Willett, Jessica Lasky-Su, Peter Kraft, J Brent Richards, Stuart Macgregor, Deeba Husain, Liming Liang

Faculty, Staff and Student Publications

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal …

Women With Large Vessel Occlusion Acute Ischemic Stroke Are Less Likely To Be Routed To Comprehensive Stroke Centers, Muhammad Bilal Tariq, Iman Ali, Sergio Salazar-Marioni, Ananya S Iyyangar, Hussain M Azeem, Swapnil Khose, Victor Lopez, Rania Abdelkhaleq, Louise D Mccullough, Sunil A Sheth, Youngran Kim

Faculty, Staff and Student Publications

Background Prehospital routing of patients with large vessel occlusion (LVO) acute ischemic stroke (AIS) to centers capable of performing endovascular therapy may improve clinical outcomes. Here, we explore whether distance to comprehensive stroke centers (CSCs), stroke severity, and sex are associated with direct-to-CSC prehospital routing in patients with LVO AIS. Methods and Results In this cross-sectional study, we identified consecutive patients with LVO AIS from a prospectively collected multihospital registry throughout the greater Houston area from January 2019 to June 2020. Primary outcome was prehospital routing to CSC and was compared between men and women using modified Poisson regression including …

Reversal Of Dual Epigenetic Repression Of Non-Canonical Wnt-5a Normalises Diabetic Corneal Epithelial Wound Healing And Stem Cells, Ruchi Shah, Tanya M Spektor, Daniel J Weisenberger, Hui Ding, Rameshwar Patil, Cynthia Amador, Xue-Ying Song, Steven T Chun, Jake Inzalaco, Sue Turjman, Sean Ghiam, Jiho Jeong-Kim, Sasha Tolstoff, Sabina V Yampolsky, Onkar B Sawant, Yaron S Rabinowitz, Ezra Maguen, Pedram Hamrah, Clive N Svendsen, Mehrnoosh Saghizadeh, Julia Y Ljubimova, Andrei A Kramerov, Alexander V Ljubimov

Faculty, Staff and Student Publications

AIMS/HYPOTHESIS: Diabetes is associated with epigenetic modifications including DNA methylation and miRNA changes. Diabetic complications in the cornea can cause persistent epithelial defects and impaired wound healing due to limbal epithelial stem cell (LESC) dysfunction. In this study, we aimed to uncover epigenetic alterations in diabetic vs non-diabetic human limbal epithelial cells (LEC) enriched in LESC and identify new diabetic markers that can be targeted for therapy to normalise corneal epithelial wound healing and stem cell expression.

METHODS: Human LEC were isolated, or organ-cultured corneas were obtained, from autopsy eyes from non-diabetic (59.87±20.89 years) and diabetic (71.93±9.29 years) donors. The …

Psychosocial Impacts Of The Covid-19 Pandemic On Women With Spinal Cord Injury, Heather B Taylor, Rosemary B Hughes, Diana Gonzalez, Muna Bhattarai, Susan Robinson-Whelen

Faculty, Staff and Student Publications

This study represents the first known research addressing the impact of the COVID-19 pandemic on women with spinal cord injury (SCI) in the United States. Women in this population face unique barriers that put them at elevated risk for compromised quality of life, risk that was magnified by physical and social restrictions imposed during the pandemic. This qualitative study examined the perceptions of women with SCI and the effect of the pandemic on their lives. The predominantly White and relatively well-educated sample of 105 women with traumatic SCI was diverse in age, injury characteristics, and geographic representation. Recruited across the …

Impact Of Mir196a-2 Genotypes On Colorectal Cancer Risk In Taiwan, Te-Cheng Yueh, Yun-Chi Wang, Yu-Ting Chin, Yi-Chih Hung, Mei-Chin Mong, Ya-Chen Yang, Jen-Sheng Pei, Jian Gu, Chia-Wen Tsai, Da-Tian Bau, Wen-Shin Chang

Faculty, Staff and Student Publications

We aimed to investigate the association between genotypes for

New Insights About Immune Populations In Gastrointestinal Gvhd, Eiko Hayase, Robert R Jenq

Faculty, Staff and Student Publications

Jarosch et al.have deeply characterized immune cell infiltrates in gastrointestinal (GI) biopsies from individuals with GI graft-versus-host disease (GI-GvHD) using single-cell RNA sequencing and ChipCytometry. Individuals with severe GI-GvHD demonstrated increased clonally expanded cytotoxic CD8 T cells in GI biopsies.

Efficacy And Safety Of Elamipretide In Individuals With Primary Mitochondrial Myopathy: The Mmpower-3 Randomized Clinical Trial, Amel Karaa, Enrico Bertini, Valerio Carelli, Bruce H Cohen, Gregory M Enns, Marni J Falk, Amy Goldstein, Gráinne Siobhan Gorman, Richard Haas, Michio Hirano, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Costanza Lamperti, Anna Lehman, Nicola Longo, Maria Judit Molnar, Sumit Parikh, Han Phan, Robert D S Pitceathly, Russell Saneto, Fernando Scaglia, Serenella Servidei, Mark Tarnopolsky, Antonio Toscano, Johan L K Van Hove, John Vissing, Jerry Vockley, Jeffrey S Finman, David A Brown, James A Shiffer, Michelango Mancuso, Mmpower-3 Trial Investigators

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM.

METHODS: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints …

Timigp: Inferring Cell-Cell Interactions And Prognostic Associations In The Tumor Immune Microenvironment Through Gene Pairs, Chenyang Li, Baoyi Zhang, Evelien Schaafsma, Alexandre Reuben, Linghua Wang, Mary Jo Turk, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Determining the prognostic association of different immune cell types in the tumor microenvironment is critical for understanding cancer biology and developing new therapeutic strategies. However, this is challenging in certain cancer types, where the abundance of different immune subsets is highly correlated. In this study, we develop a computational method named TimiGP to overcome this challenge. Based on bulk gene expression and survival data, TimiGP infers cell-cell interactions that reveal the association between immune cell relative abundance and prognosis. As demonstrated in metastatic melanoma, TimiGP prioritizes immune cells critical in prognosis based on the identified cell-cell interactions. Highly consistent results …

A Polycistronic System For Multiplexed And Precalibrated Expression Of Multigene Pathways In Fungi, Qun Yue, Jie Meng, Yue Qiu, Miaomiao Yin, Liwen Zhang, Weiping Zhou, Zhiqiang An, Zihe Liu, Qipeng Yuan, Wentao Sun, Chun Li, Huimin Zhao, István Molnár, Yuquan Xu, Shuobo Shi

Faculty, Staff and Student Publications

Synthetic biology requires efficient systems that support the well-coordinated co-expression of multiple genes. Here, we discover a 9-bp nucleotide sequence that enables efficient polycistronic gene expression in yeasts and filamentous fungi. Coupling polycistronic expression to multiplexed, markerless, CRISPR/Cas9-based genome editing, we develop a strategy termed HACKing (Highly efficient and Accessible system by CracKing genes into the genome) for the assembly of multigene pathways. HACKing allows the expression level of each enzyme to be precalibrated by linking their translation to those of host proteins with predetermined abundances under the desired fermentation conditions. We validate HACKing by rapidly constructing highly efficient Saccharomyces …

Ancestry-Driven Metabolite Variation Provides Insights Into Disease States In Admixed Populations, Kaylia M Reynolds, Andrea R V R Horimoto, Bridget M Lin, Ying Zhang, Nuzulul Kurniansyah, Bing Yu, Eric Boerwinkle, Qibin Qi, Robert Kaplan, Martha Daviglus, Lifang Hou, Laura Y Zhou, Jianwen Cai, Saame Raza Shaikh, Tamar Sofer, Sharon R Browning, Nora Franceschini

Faculty, Staff and Student Publications

BACKGROUND: Metabolic pathways are related to physiological functions and disease states and are influenced by genetic variation and environmental factors. Hispanics/Latino individuals have ancestry-derived genomic regions (local ancestry) from their recent admixture that have been less characterized for associations with metabolite abundance and disease risk.

METHODS: We performed admixture mapping of 640 circulating metabolites in 3887 Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Metabolites were quantified in fasting serum through non-targeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Replication was performed in 1856 nonoverlapping HCHS/SOL participants with metabolomic data.

RESULTS: By leveraging local ancestry, this …

The Checkpoint Inhibitor Pd-1h/Vista Controls Osteoclast-Mediated Multiple Myeloma Bone Disease, Jing Fu, Shirong Li, Huihui Ma, Jun Yang, Gabriel M Pagnotti, Lewis M Brown, Stephen J Weiss, Markus Y Mapara, Suzanne Lentzsch

Faculty, Staff and Student Publications

Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone …

Anti-Mir-93-5p Therapy Prolongs Sepsis Survival By Restoring The Peripheral Immune Response, Mihnea P Dragomir, Enrique Fuentes-Mattei, Melanie Winkle, Keishi Okubo, Recep Bayraktar, Erik Knutsen, Aiham Qdaisat, Meng Chen, Yongfeng Li, Masayoshi Shimizu, Lan Pang, Kevin Liu, Xiuping Liu, Simone Anfossi, Huanyu Zhang, Ines Koch, Anh M Tran, Swati Mohapatra, Anh Ton, Mecit Kaplan, Matthew W Anderson, Spencer J Rothfuss, Robert Silasi, Ravi S Keshari, Manuela Ferracin, Cristina Ivan, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Constantin Georgescu, Pinaki P Banerjee, Rafet Basar, Ziyi Li, David Horst, Catalin Vasilescu, Maria Teresa S Bertilaccio, Katayoun Rezvani, Florea Lupu, Sai-Ching Yeung, George A Calin

Faculty, Staff and Student Publications

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture-induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and …

Anoctamin 4 Channel Currents Activate Glucose-Inhibited Neurons In The Mouse Ventromedial Hypothalamus During Hypoglycemia, Longlong Tu, Jonathan C Bean, Yang He, Hailan Liu, Meng Yu, Hesong Liu, Nan Zhang, Na Yin, Junying Han, Nikolas A Scarcelli, Kristine M Conde, Mengjie Wang, Yongxiang Li, Bing Feng, Peiyu Gao, Zhao-Lin Cai, Makoto Fukuda, Mingshan Xue, Qingchun Tong, Yongjie Yang, Lan Liao, Jianming Xu, Chunmei Wang, Yanlin He, Yong Xu

Faculty, Staff and Student Publications

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons - namely, glucose-inhibited (GI) neurons - paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood …

Long-Term Outcomes In Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib: Focus On Hypertension And Cardiovascular Toxicity, Max J Gordon, Jade E Jones, Binsah George, Christine Peterson, Jan A Burger, Nitin Jain, Michael Keating, William G Wierda, Jean-Bernard Durand, Alessandra Ferrajoli

Faculty, Staff and Student Publications

BACKGROUND: Continuous ibrutinib administration is needed to maintain efficacy in patients with chronic lymphocytic leukemia (CLL) and, as such, long-term toxicity is a concern. The authors report the 5-year follow-up of patients with CLL who received treatment with ibrutinib with a focus on hypertension and cardiovascular toxicities.

METHODS: Patient characteristics were assessed, including blood pressure, cardiovascular disease, disease progression, and death. Univariate logistic regression analysis assessed the relation of patient characteristics and the development of new or worsened hypertension. The incidence of hypertensive outcomes was evaluated using competing risk. Survival was estimated using the Kaplan-Meier method.

RESULTS: Three hundred patients …

Phase 1b Study Of Combined Selinexor And Eribulin For The Treatment Of Advanced Solid Tumors And Triple-Negative Breast Cancer, Blessie Elizabeth Nelson, Sadia Saleem, Senthil Damodaran, Neeta Somaiah, Sarina Piha-Paul, Julia Ann Moore, Bulent Yilmaz, Deby Ogbonna, Daniel D Karp, Ecaterina Dumbrava, Apostolia M Tsimberidou, David S Hong, Jordi Rodon Ahnert, Denái R Milton, Xiaofeng Zheng, Daniel J Booser, Nuhad K Ibrahim, Anthony P Conley, Priya Bhosale, Cristhiam M Rojas Hernandez, Debasish Tripathy, Aung Naing, Funda Meric-Bernstam

Faculty, Staff and Student Publications

BACKGROUND: Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination.

METHODS: The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort.

RESULTS: Patients with TNBC (N = 19), sarcoma (N = 9), …

Five-Year Patient-Reported Outcomes In Nrg Oncology Rtog 0938, Evaluating Two Ultrahypofractionated Regimens For Prostate Cancer, Himanshu R Lukka, Snehal Deshmukh, Deborah W Bruner, Jean-Paul Bahary, Colleen A F Lawton, Jason A Efstathiou, Rajat J Kudchadker, Lee E Ponsky, Samantha A Seaward, Ian S Dayes, Darindra D Gopaul, Jeff M Michalski, Guila Delouya, Irving D Kaplan, Eric M Horwitz, Mack Roach, Felix Y Feng, Stephanie L Pugh, Howard M Sandler, Lisa A Kachnic

Faculty, Staff and Student Publications

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores.

METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions …

Actionability Classification Of Variants Of Unknown Significance Correlates With Functional Effect, Amber Johnson, Patrick Kwok-Shing Ng, Michael Kahle, Julia Castillo, Bianca Amador, Yujia Wang, Jia Zeng, Vijaykumar Holla, Thuy Vu, Fei Su, Sun-Hee Kim, Tara Conway, Xianli Jiang, Ken Chen, Kenna R Mills Shaw, Timothy A Yap, Jordi Rodon, Gordon B Mills, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Genomically-informed therapy requires consideration of the functional impact of genomic alterations on protein expression and/or function. However, a substantial number of variants are of unknown significance (VUS). The MD Anderson Precision Oncology Decision Support (PODS) team developed an actionability classification scheme that categorizes VUS as either "Unknown" or "Potentially" actionable based on their location within functional domains and/or proximity to known oncogenic variants. We then compared PODS VUS actionability classification with results from a functional genomics platform consisting of mutant generation and cell viability assays. 106 (24%) of 438 VUS in 20 actionable genes were classified as oncogenic in functional …

Presence Of Circulating Tumor Cells Predates Imaging Detection Of Relapse In Patients With Stage Iii Melanoma, Anthony Lucci, Sridevi Addanki, Yi-Ju Chiang, Salyna Meas, Vanessa N Sarli, Joshua R Upshaw, Mayank Manchem, Sapna P Patel, Jennifer A Wargo, Jeffrey E Gershenwald, Merrick I Ross

Faculty, Staff and Student Publications

Stage III melanoma includes nodal metastasis or in-transit disease. Five-year survival rates vary between 32% and 93%. The identification of high-risk patients is important for clinical decision making. We demonstrated previously that ≥1 circulating tumor cells (CTCs) at baseline was associated with recurrence. In this study, we investigated how frequently CTCs were identified prior to radiologically detected recurrence. Stage III patients (n = 325) had imaging at baseline and q 3 months. Baseline and q 6-12 months blood draws (7.5 mL) were performed to identify CTCs up to 3.5 years from diagnosis. CTC assessment was performed using the immunomagnetic …

Analysis Of Performance And Failure Modes Of The Iroc Proton Liver Phantom, Hunter Mehrens, Paige Taylor, Paola Alvarez, Stephen Kry

Faculty, Staff and Student Publications

Purpose: To analyze trends in institutional performance and failure modes for the Imaging and Radiation Oncology Core’s (IROC’s) proton liver phantom.

Materials and Methods: Results of 66 phantom irradiations from 28 institutions between 2015 and 2020 were retrospectively analyzed. Univariate analysis and random forest models were used to associate irradiation conditions with phantom results. Phantom results included pass/fail classification, average thermoluminescent dosimeter (TLD) ratio of both targets, and percentage of pixels passing gamma of both targets. The following categories were evaluated in terms of how they predicted these outcomes: irradiation year, treatment planning system (TPS), TPS algorithm, treatment machine, number …

An Observational Study To Develop A Predictive Model For Bacterial Pneumonia Diagnosis In Severe Covid-19 Patients-C19-Pneumoscore, Eloisa Sofia Tanzarella, Joel Vargas, Marco Menghini, Stefania Postorino, Francesca Pozzana, Maria Sole Vallecoccia, Francesco Lorenzo De Matteis, Federico Franchi, Amato Infante, Luigi Larosa, Maria Antonietta Mazzei, Salvatore Lucio Cutuli, Domenico Luca Grieco, Alessandra Bisanti, Simone Carelli, Gianmarco Lombardi, Edoardo Piervincenzi, Gabriele Pintaudi, Tommaso Pirronti, Mario Tumbarello, Massimo Antonelli, Gennaro De Pascale

Faculty, Staff and Student Publications

In COVID-19 patients, antibiotics overuse is still an issue. A predictive scoring model for the diagnosis of bacterial pneumonia at intensive care unit (ICU) admission would be a useful stewardship tool. We performed a multicenter observational study including 331 COVID-19 patients requiring invasive mechanical ventilation at ICU admission; 179 patients with bacterial pneumonia; and 152 displaying negative lower-respiratory samplings. A multivariable logistic regression model was built to identify predictors of pulmonary co-infections, and a composite risk score was developed using β-coefficients. We identified seven variables as predictors of bacterial pneumonia: vaccination status (OR 7.01; 95% CI, 1.73-28.39); chronic kidney disease …

Resistance To Human Immunodeficiency Virus 1 Infection Conferred By A Compound Ccr5Δ32 And Ccr5 C20s Heterozygote, Bashar Alkhatib, Mary Jabari, Shymaa Bilasy, Husni Abdul-Rahman, Kamal Sandhu, Stephen Lai, Ghalib Alkhatib

Faculty, Staff and Student Publications

We analyzed findings in a same-gender couple discordant in their human immunodeficiency virus (HIV) status. The HIV+ partner was homozygous for CCR5 while his receptive HIV- partner was a CCR5Δ32 heterozygote with a C20S missense mutation in his CCR5 allele. The cells from the HIV- partner showed significant resistance to R5 fusion/infection and had no chemotactic response to CCL4 (macrophage inflammatory protein 1β). We demonstrated abundant CCR5-specific RNA in the HIV- partner's cells but no detectable CCR5 protein. CCR5 promoter region cloned from each partner's DNA indicated no significant impact on RNA transcription. The compound effect of CCR5Δ32 and C20S …

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants, Dhruv Chachad, Lalit R Patel, Carlos Vera Recio, Rasoul Pourebrahim, Elizabeth M Whitley, Wenyi Wang, Xiaoping Su, An Xu, Dung-Fang Lee, Guillermina Lozano

Faculty, Staff and Student Publications

Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function (GOF) activities, such as promoting increased metastatic incidence compared with p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. To understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma …

Bicc1 Drives Pancreatic Cancer Progression By Inducing Vegf-Independent Angiogenesis, Chongbiao Huang, Hui Li, Yang Xu, Chao Xu, Huizhi Sun, Zengxun Li, Yi Ge, Hongwei Wang, Tiansuo Zhao, Song Gao, Xiuchao Wang, Shengyu Yang, Peiqing Sun, Zhe Liu, Jing Liu, Antao Chang, Jihui Hao

Faculty, Staff and Student Publications

VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent …

Adenosine Metabolized From Extracellular Atp Ameliorates Organ Injury By Triggering A2br Signaling, Taha Kelestemur, Zoltán H Németh, Pal Pacher, Jennet Beesley, Simon C Robson, Holger K Eltzschig, György Haskó

Faculty, Staff and Student Publications

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A

METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A

RESULTS: T/HS upregulated the expression of CD39, CD73, and the A

CONCLUSION: In conclusion, the CD39-CD73-A

Adenosine Metabolized From Extracellular Atp Ameliorates Organ Injury By Triggering A2br Signaling, Taha Kelestemur, Zoltán H Németh, Pal Pacher, Jennet Beesley, Simon C Robson, Holger K Eltzschig, György Haskó

Faculty, Staff and Student Publications

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A

METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A

RESULTS: T/HS upregulated the expression of CD39, CD73, and the A

CONCLUSION: In conclusion, the CD39-CD73-A

Determinants Of Covid-19 Vaccination Decision-Making Behaviors Among Pregnant Women In Sub-Saharan Africa: A Scoping Review, Sylvia Ayieko, Kimberly Baker, Sarah E Messiah, Brianna Lewis, Christine Markham

Faculty, Staff and Student Publications

Despite the availability of the coronavirus disease 2019 (COVID-19) vaccination, uptake among pregnant women in Sub-Saharan Africa has been low. This scoping review aimed to identify and characterize determinants influencing COVID-19 vaccination decision-making behaviors among pregnant women in Sub-Saharan Africa. We searched five online databases for articles on COVID-19 vaccination among pregnant women in Sub-Saharan Africa. We identified studies published in English between March 2020 and April 2023 that assessed vaccine-specific issues, psychosocial constructs, and contextual factors associated with COVID-19 vaccination decision-making behaviors. Of the fourteen studies identified, over half (57.1%) were cross-sectional; three used qualitative research methods; and three …

Mettl3-Mediated M6a Modification Of Linc00839 Maintains Glioma Stem Cells And Radiation Resistance By Activating Wnt/Β-Catenin Signaling, Jianxing Yin, Fangshu Ding, Zhangchun Cheng, Xin Ge, Yanhui Li, Ailiang Zeng, Junxia Zhang, Wei Yan, Zhumei Shi, Xu Qian, Yongping You, Zhiliang Ding, Jing Ji, Xiefeng Wang

Faculty, Staff and Student Publications

Long noncoding RNAs (lncRNAs) are involved in glioma initiation and progression. Glioma stem cells (GSCs) are essential for tumor initiation, maintenance, and therapeutic resistance. However, the biological functions and underlying mechanisms of lncRNAs in GSCs remain poorly understood. Here, we identified that LINC00839 was overexpressed in GSCs. A high level of LINC00839 was associated with GBM progression and radiation resistance. METTL3-mediated m6A modification on LINC00839 enhanced its expression in a YTHDF2-dependent manner. Mechanistically, LINC00839 functioned as a scaffold promoting c-Src-mediated phosphorylation of β-catenin, thereby inducing Wnt/β-catenin activation. Combinational use of celecoxib, an inhibitor of Wnt/β-catenin signaling, greatly sensitized GSCs to …

The Impact Of Covid-19 On The Financial Performance Of Largest Teaching Hospitals, Karima Lalani, Jeffrey Helton, Francine R Vega, Marylou Cardenas-Turanzas, Tiffany Champagne-Langabeer, James R Langabeer

Faculty, Staff and Student Publications

The COVID-19 pandemic disrupted hospital operations. Anecdotal evidence suggests financial performance likewise suffered, yet little empirical research supports this claim. This study aimed to explore the impact of the pandemic on the financial performance of the most prominent academic hospitals in the United States. Data from the 115 largest major teaching hospitals in the United States were extracted from the American Hospital Directory for three years (2019-2021). We hypothesized that the year and region would moderate the relationship between a hospital's return on assets (financial performance) and specific operational variables. We found evidence through descriptive statistics and multivariate moderated regressions …

A Global Study For Acute Myeloid Leukemia With Rarg Rearrangement, Hong-Hu Zhu, Ya-Zhen Qin, Zhang-Lin Zhang, Yong-Jing Liu, Li-Jun Wen, M James You, Cheng Zhang, Esperanza Such, Hong Luo, Hong-Jian Yuan, Hong-Sheng Zhou, Hong-Xing Liu, Reng Xu, Ji Li, Jian-Hu Li, Jian-Ping Hao, Jie Jin, Liang Yu, Jing-Ying Zhang, Li-Ping Liu, Le-Ping Zhang, Rui-Bin Huang, Shu-Hong Shen, Su-Jun Gao, Wei Wang, Xiao-Jing Yan, Xin-You Zhang, Xin Du, Xiao-Xia Chu, Yan-Fang Yu, Yi Wang, Ying-Chang Mi, Ying Lu, Zhen Cai, Zhan Su, David Christopher Taussig, Suzanne Macmahon, Edward D Ball, Huan-You Wang, John S Welch, C Cameron Yin, Gautam Borthakur, Miguel A Sanz, Hagop M Kantarjian, Jin-Yan Huang, Jiong Hu, Su-Ning Chen

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and …