Translational Medical Research Commons^™

Editorial: Debates In Cardiovascular Pharmacology And Drug Discovery: 2022, Keman Xu, Fatma Saaoud, Ying Shao, Yifan Lu, Xiaohua Jiang, Sheng Wu, Jianxin Sun, Filipe Fernades Conti, Laisel Martinez, Roberto Vazquez-Padron, Hong Wang, Xiaofeng Yang

Center for Translational Medicine Faculty Papers

No abstract provided.

Reap-2: An Interactive Quantitative Tool For Robust And Efficient Dose-Response Curve Estimation, Xinying Fang, Xinyi Liu, Vernon M Chinchilli, Michael Wang, Hong-Gang Wang, Nikolay V Dokholyan, Chan Shen, J Jack Lee, Shouhao Zhou

Faculty, Staff and Student Publications

REAP-2 is an interactive dose-response curve estimation tool for Robust and Efficient Assessment of drug Potency. It provides user-friendly dose-response curve estimation for in vitro studies and conducts statistical testing for model comparisons with a redesigned user interface. We also make a major update of the underlying estimation method with penalized beta regression, which demonstrates great reliability and accuracy in dose estimation and uncertainty quantification. In this note, we describe the method and implementation of REAP-2 with a highlight on potency estimation and drug comparison.

Novel Therapy Targeting Mutant-Krasg12d And Galectin-1 In Pancreatic Cancer, Ana I. Martinez Bulnes, Nirnoy Dan, Poornima Devi Shaji, Swathi Holla, Murali M. Yallapu, Sheema Khan

Research Colloquium

Introduction: Although, surgical resection and chemotherapy are the gold standard for treating Pancreatic Ductal Adenocarcinoma (PDAC), low patient survival rate remains the problem. The activating point mutation of the KRAS on codon-12 is present in 70–95% of PDAC cases and so far, no success has been achieved to inhibit KRAS. KRASG12D regulates cell proliferation, differentiation, apoptosis. Recent preliminary and published studies show high Galectin-1 (Gal-1) levels in both pancreatic cancer and stromal cells, which modulate tumor microenvironment and metastasis. Additionally, genetic deletion of gal1 inhibits metastasis and improves survival in KRAS mouse model of PDAC (1). Therefore, our objective is …

A Novel Approach To Target Tumor Immune Microenvironment And Improve Checkpoint Immunotherapies, Poornima Devi Shaji, Ana Martinez, Melida Flores Cantu, Anupam Dhasmana, Meena Jaggi, Stephen W. Behrman, Murali M. Yallapu, Subhash C. Chauhan, Sheema Khan

Research Colloquium

Background: Pancreatic cancer remains 3^rd deadliest disease, with less than 7-10% survival rate. Little progress has been seen in patient’s outcome due to high desmoplasia and chemo-resistance. Immunotherapy has shown promising results in cancers, except pancreatic cancer due to their characteristic fibrotic tumor microenvironment. The therapies are unable to penetrate fibrotic tumor leading to insufficient availability of therapeutic drugs at the tumor site. A recently identified mucin, MUC13 is aberrantly expressed in pancreatic tumors but not in normal pancreas, that makes it an excellent protein tumor target. This study is unique as it utilizes MUC13Ab for targeting the pancreatic …

Novel Therapy Targeting Mutant-Krasg12d And Galectin-1 In Pancreatic Cancer, Ana I. Martinez Bulnes, Poornima Devi Shaji, Swathi Holla, Nirnoy Dan, Shabnam Malik, Murali M. Yallapu, Meena Jaggi, Stephen W. Behrman, Subhash C. Chauhan, Sheema Khan

Research Colloquium

Introduction: In pancreatic ductal adenocarcinoma (PDAC), low patient survival rate remains a problem. The activating point mutation of KRAS on codon-12 is present in 70–95% of PDAC cases and so far, no success has been achieved to inhibit KRAS. KRAS^G12D regulates cell proliferation, differentiation, apoptosis; recent preliminary and published studies show high Galectin-1 (Gal-1) levels in both PDAC and stromal cells, which modulate tumor microenvironment and metastasis. Therefore, we have developed a novel combination therapy for PDAC by targeting mutated KRAS^G12D and Gal-1 to target both proliferation and metastasis in PDAC. This includes the delivery of KRAS^{G12D …}

Global Impact Of Proteoglycan Science On Human Diseases, Christopher Xie, Liliana Schaefer, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

In this comprehensive review, we will dissect the impact of research on proteoglycans focusing on recent developments involved in their synthesis, degradation, and interactions, while critically assessing their usefulness in various biological processes. The emerging roles of proteoglycans in global infections, specifically the SARS-CoV-2 pandemic, and their rising functions in regenerative medicine and biomaterial science have significantly affected our current view of proteoglycans and related compounds. The roles of proteoglycans in cancer biology and their potential use as a next-generation protein-based adjuvant therapy to combat cancer is also emerging as a constructive and potentially beneficial therapeutic strategy. We will discuss …

A Multi-Modal Imaging Analysis Of Inter-Community Hub Nodes In Subjective Cognitive Decline Linking Longitudinal Hub Function Disruption To White Matter Integrity Kurtosis, Duncan Nowling

MUSC Theses and Dissertations

Subjective Cognitive Decline (SCD) has garnered much interest as a potential identifiable preclinical stage and indicator of risk for cognitive decline in Alzheimer’s Disease and related dementias (ADRD). Identification of individuals in this stage though is difficult, as they present with objectively normal cognitive evaluation scores, relying instead upon self-report of concern about decline in cognitive abilities. The use of non-invasive in-vivo imaging methods like BOLD functional imaging and diffusion tensor have allowed for complex mapping of both the functional and structural network features unique to this condition. This study furthers this network biomarker map of SCD by investigating the …

Communicating Unexpected Genetic Information With Family Members: A Multimethod Study Of Secondary Findings Recipients, Julie Chevalier Sapp

Doctor of Philosophy in Translational Health Sciences Dissertations

Background: Medically-actionable secondary genomic findings (SF) can be life- preserving or life-prolonging for recipients but this benefit can only extend to family members if this information is shared with relatives. How SF recipients communicate this important genetic information with relatives, barriers and facilitators to this process, and SF recipients’ lived experiences in communicating about their results over time remain largely unknown. Family communication is required for relatives of SF recipients to access cascade testing and the potential benefits of enhanced screening and management. Applying behavioral and implementation science theories and providing rich and deep descriptions of SF recipients’ lived experiences …

Reclaiming The Balance: Blocking Glutamine Uptake To Restrain Pulmonary Fibrosis, Gang Liu, Ross Summer

Center for Translational Medicine Faculty Papers

No abstract provided.

Early Development Of C3ar1-Targeting Chimeric Antigen Receptor T Cells For The Treatment Of Glioblastoma Multiforme, Cameron Fraser

Electronic Theses, Projects, and Dissertations

Glioblastoma multiforme is the most aggressive type of glioma, demonstrating extremely low long-term survival despite modern therapies. Chimeric antigen receptor T cells have shown extreme levels of success in the treatment of B cell lymphomas through persistent anti-tumor activity. Prior research has demonstrated the therapeutic potential in targeting the C3a-C3aR1 pathway as it acts in an autocrine loop, maintaining the proliferation and survival of cancer stem cells within the tumor. Here, we reorient the treatment to target C3aR1 for the treatment of glioblastoma multiforme. In order to achieve this, Jurkat immortalized T cells will express various chimeric antigen receptor designs …

Virtual Education Implementation For Children With Autism Spectrum Disorders Amidst The Covid-19 Pandemic, Monika Sinha-Bhamra

Doctor of Philosophy in Translational Health Sciences Dissertations

Background: The COVID-19 pandemic led to widespread school closures in the Washington DC metropolitan region, necessitating a shift from traditional in-person education to virtual platforms. The context was significantly influenced by the evolving pandemic and its impact on the region's COVID-19 positive rates, with the Washington DC region facing some of the highest positive rates in 2020. These escalating positive rates posed substantial challenges to planning and implementing in-person learning, primarily driven by concerns for public health and safety. The region's persistently low percentages of in-person learning made it one of the worst in the country regarding the provision of …

Tox3 Rs3803662 Polymorphism Is Associated With Breast Cancer Protection In Northeastern Mexican Woman, Orlando D. Solis-Coronado, Hazyadee F. Rodríguez-Gutiérrez, Monica P. Villarreal-Vela, Ricardo M. Cerda-Flores, Juan F. González-Guerrero, Oscar Vidal-Gutiérrez, Diana C. Pérez-Ibave, Maria Lourdes Garza-Rodríguez

Research Symposium

Introduction: Low penetrance genes are involved in breast cancer (BC) and confer risk for the development of this neoplasia. Different single nucleotide polymorphisms (SNPs) associated with BC have been identified, such as rs3803662 (TOX3), which is related to estrogen receptors in European and African-American women. The contribution of this variant in the Mexican population is unknown. The objective of this study was to evaluate, through a case-control design, the association of the SNP rs3803662 (TOX3), with the risk of BC in women from northeastern Mexico.

Methods: We included 434 cases and 228 controls. Genotyping was carried out using RFLPs. The …

Smoking And Drinking Activates Nf-Κb /Il-6 Axis To Promote Inflammation During Cervical Carcinogenesis, Vivek Kumar Kashyap, Prashanth Kb Nagesh, Ajay K. Singh, Andrew Massey, Godwin P. Darkwah, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan

Research Symposium

Background: High-risk strains of HPV are known to cause cervical cancer. Multiple clinical studies have emphasized that smoking and drinking are critical risk factors for cervical cancer and its high-grade precursors. In this study, we investigated the molecular mechanisms involved in the interplay of smoking and/or drinking with HPV infectivity and defined a systematic therapeutic approach for their attenuation in cervical cancer.

Methods: The impact of benzo[a]pyrene (B[a]P) and/or ethanol (EtOH) exposure on cervical cancer cells was assessed by measuring changes in cell proliferation, clonogenicity, biophysical properties, cell migration, and invasion. Expression of HPV16 E6/E7, NF-κB, cytokines, cell cycle, and …

Human Ipsc Derived Cardiomyocyte Model Reveals The Transcriptomic Bases Of Covid-19 Associated Myocardial Injury, Kashish Kumar, Satish Kumar, Erica De Leon, Joanne E. Curran, Sarah Williams-Blangero, John Blangero

Research Symposium

Background: Multi-organ complications have been the hallmark of severe COVID-19; cardiac injuries were reported in 20% to 30% of hospitalized COVID-19 patients, although the disease etiology remains poorly understood. This study leveraged genome-wide RNA-sequence data generated using induced pluripotent stem cell (iPSC) differentiated cardiomyocytes (CMs) and in vitro modeling of SARS-CoV-2 infection in CMs, to understand the molecular mechanisms of COVID-19 myocardial injuries for novel diagnostic and therapeutic development.

Methods: Raw RNA-sequence data sets, GSE165242 and GSE150392 were aligned to human genome assembly GRCh38 and gene expressions were quantified. Differentially expressed (DE) genes between experimental groups were identified using moderated …

Differential Gene Expression Between African American And Caucasian American Prostate Cancer, Daniel L. Shen, Gregory T. Maclennan, Sanjay Gupta

Research Symposium

Background: African-American (AA) men have higher incidence and mortality from prostate cancer compared to Caucasian-American (CA) men. Increasing evidence suggests that genetic and molecular alterations play important roles. We identified a 5 gene panel viz. p-Akt (Ser473), chemokine (C-X-C motif) receptor 4 (CXCR4), fatty acid synthase (FASN), interleukin-6 (IL-6) and matrix metallopeptidase 9 (MMP-9) highly expressed in prostate cancer and analyzed their expression in AA and CA cohorts.

Methods: IHC of p-Akt, CXCR4, FASN, IL-6 and MMP-9 were evaluated in RRP specimens (n=20) from each ethnic group exhibiting Gleason scores ranging from 6 through 9.

Results: Low to medium staining …

An Ngqd Based Diagnostic Tool For Pancreatic Cancer, Ryan Ketan Ajgaonkar, Bong Lee, Alina Valimukhametova, Anton Naumov, Giridhar Akkaraju

Research Symposium

Background: Pancreatic cancer remains difficult to detect at early stages which contributes to a poor five-yearsurvival rate. Therefore, early detection approaches based on novel technologies should be explored to address this critical health issue. Nanomaterials have recently emerged as frontrunners for diagnostic applications due to their small size in the 1-100 nm range, which facilitates one-on-one interactions with a variety of biomolecules like oligonucleotides and makes them suitable for a plethora of detection and delivery applications. In this work, the presence of specific pancreatic cancer miRNA (pre-miR-132) is detected utilizing the fluorescence properties of highly biocompatible nitrogen-doped graphene quantum dots …

Cell-Based Experimental Evidence To The Anti-Covid-19 Potential Of Ashwagandha And Honeybee Propolis Ingredients, Renu Wadhwa, Durai Sundar, Yoshiyuki Ishida, Keiji Terao, Sunil C. Kaul

Research Symposium

Background: The COVID-19 pandemic emerged in December 2019 by a novel strain of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has led to new endeavours in repurposing of existing drugs, anti-COVID-19 vaccine and drug development. Natural products, due to their general safety and wider availability, have attracted research and public attention. In this study, we report anti-COVID potential of compounds from honeybee propolis and Ayurvedic herb, Ashwagandha. Effect of active ingredients was studied on human cell surface receptors (ACE-2:Angiotensin Converting Enzyme-2/Spike protein and TMPRSS2:Transmembrane Protease Serine 2), critical for virus infection and virus main protease (Mpro, essential for virus replication), …

Epicutaneous Sensitization To The Phytocannabinoid Β-Caryophyllene Induces Pruritic Inflammation, Saadet Inan, Sara J Ward, Citlalli T Baltazar, Gabrielle A. Peruggia, Elham Javed, Ajay P. Nayak

Center for Translational Medicine Faculty Papers

In recent years, there has been increased accessibility to cannabis for recreational and medicinal use. Incidentally, there has been an increase in reports describing allergic reactions to cannabis including exacerbation of underlying asthma. Recently, multiple protein allergens were discovered in cannabis, yet these fail to explain allergic sensitization in many patients, particularly urticaria and angioedema. Cannabis has a rich chemical profile including cannabinoids and terpenes that possess immunomodulatory potential. We examined whether major cannabinoids of cannabis such as cannabidiol (CBD) and the bicyclic sesquiterpene beta-caryophyllene (β-CP) act as contact sensitizers. The repeated topical application of mice skin with β-CP at …

Proteomics-Based Approach For Detailing The Allergenic Profile Of Cannabis Chemotypes, Cali Loblundo, Jenna Severa, Gabrielle A Peruggia, Kristina Reid Black, Suman Chandra, Hemant Lata, Mahmoud Elsohly, Martin D Chapman, Deepak A. Deshpande, Ajay P. Nayak

Center for Translational Medicine Faculty Papers

Allergic sensitization to cannabis is an emerging public health concern and is difficult to clinically establish owing to lack of standardized diagnostic approaches. Attempts to develop diagnostic tools were largely hampered by the Schedule I restrictions on cannabis, which limited accessibility for research. Recently, however, hemp was removed from the classified list, and increased accessibility to hemp allows for the evaluation of its practical clinical value for allergy diagnosis. We hypothesized that the proteomic profile is preserved across different cannabis chemotypes and that hemp would be an ideal source of plant material for clinical testing. Using a proteomics-based approach, we …

Evaluation Of A Novel Lupus Anticoagulant Assay Designed To Reduce False Positive Results Due To Anticoagulation: A Retrospective Study At A Single Health System, Jessica D. Anderson, Tamara Sabih, Yuying Xing, Lili Zhao, Marc D. Smith

Conference Presentation Abstracts

Introduction: Lupus anticoagulants (LA) are antibodies directed against phospholipids/phospholipid-protein complexes involved in coagulation and are associated with thrombotic events and recurrent fetal loss. There is no gold standard test for LA, therefore at least two LA-specific tests are recommended before excluding LA. Potential testing methods involve dilute Russell viper venom time (dRVVT) and hexagonal phase phospholipid assays (HPPA); however, many of these tests are susceptible to interference with anticoagulant therapy which can lead to false positive results. In this study, we compared the performance of our current HPPA, StaClot LA (SCLA), with a novel assay reported to have relatively minimal …