Medical Pharmacology Commons^™

Characterizing The Monomer-Dimer Equilibrium Of Ubch8/Ube2l6: A Combined Saxs And Nmr Study, Kerem Kahraman, Scott A. Robson, Oktay Göcenler, Cansu M. Yenici, Cansu D. Tozkoparan Ceylan, Jennifer M. Klein, Volker Dötsch, Emine Sonay Elgin, Arthur L. Haas, Joshua J. Ziarek, Çağdaş Dağ

School of Medicine Faculty Publications

Interferon-stimulated gene-15 (ISG15) is an interferon-induced protein with two ubiquitin-like (Ubl) domains linked by a short peptide chain and is a conjugated protein of the ISGylation system. Similar to ubiquitin and other Ubls, ISG15 is ligated to its target proteins through a series of E1, E2, and E3 enzymes known as Uba7, Ube2L6/UbcH8, and HERC5, respectively. Ube2L6/UbcH8 plays a central role in ISGylation, underscoring it as an important drug target for boosting innate antiviral immunity. Depending on the type of conjugated protein and the ultimate target protein, E2 enzymes have been shown to function as monomers, dimers, or both. UbcH8 …

Clinical Practice Guideline-Inconsistent Chemotherapy-Induced Vomiting Prophylaxis In Pediatric Cancer Patients In Community Settings: A Children's Oncology Group Study, Aaron J. Sugalski, Allison C. Grimes, Michelle M. Nuño, Subhash Ramakrishnan, Melissa P. Beauchemin, Paula D. Robinson, Nancy Santesso, Alexandra M. Walsh, Andrea R. Wrightson, Lolie C. Yu, Susan K. Parsons, Lillian Sung, L. Lee Dupuis

School of Medicine Faculty Publications

Background: This study aimed to determine the proportion of patients receiving clinical practice guideline (CPG)-inconsistent care related to chemotherapy-induced vomiting (CIV) prophylaxis, and to describe the association between CPG-inconsistent care and site size. The association between delivery of CPG-inconsistent care and patient outcomes (CIV control, admission prolongation, and unplanned healthcare visits) was also described. Methods: This was a retrospective study conducted at Children's Oncology Group (COG) National Cancer Institute Community Oncology Research Program (NCORP) sites. Eligible patients received highly (HEC) or moderately emetogenic chemotherapy (MEC) as inpatients from January 2014 through December 2015, and were previously enrolled in a COG …

The Il-6 Hypothesis In Covid-19: A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study To Evaluate The Efficacy And Safety Of Free Il-6 Sequestration By The Monoclonal Antibody Sirukumab In Severe And Critical Covid-19, Robert L. Gottlieb, Meredith Clement, Paul Cook, Audra Deveikis, Kap Sum Foong, Philip Robinson, Jihad Slim, Cedric W. Spak, Annemie Buelens, Katleen Callewaert, Sandra De Meyer, Wai Ling Mo, Inge Verbrugge, Liesbeth Van Wesenbeeck, Yanli Zhuang, Jason W. Chien, Magda Opsomer, Erika Van Landuyt

School of Medicine Faculty Publications

Background: Upregulation of IL-6 has been associated with worse prognosis in COVID-19 patients. Impact on IL-6 signalling has mostly been limited to clinical outcomes in IL-6 receptor antagonist trials. Methods: We performed a phase 2, randomised, double-blind, placebo-controlled trial (NCT04380961) of US-based hospitalised adults (< 85 years) with laboratory-confirmed SARS-CoV-2 infection and severe (low levels of supplemental oxygen) or critical disease (high levels of oxygen supplementation). Patients received sirukumab 5 mg/kg or placebo single dose IV on Day 1 plus standard of care. The primary endpoint was time to sustained clinical improvement up to Day 28 based on an ordinal scale. Secondary endpoints included clinical improvement, all-cause mortality, and safety. Following an interim analysis, the protocol was amended to only recruit patients with critical COVID-19. Findings: From May 2020 to March 2021, 209 patients were randomised; 112 had critical disease (72 sirukumab, 40 placebo) at baseline. Median time to sustained clinical improvement in critical patients was 17 and 23 days in the sirukumab and placebo groups (HR, 1∙1; 95% CI, 0∙66–1∙88; p > 0∙05). At Day 28, 59∙4% versus 55∙0% of patients achieved clinical improvement with sirukumab versus placebo and rates of all-cause mortality were 24∙6% versus 30∙0%, respectively. Rates of grade ≥ 3 adverse events were comparable between the sirukumab and placebo groups (25∙9% vs 32∙9%; all patients). Interpretation: In critical COVID-19 patients who received sirukumab, there …

Microrna-532-3p Modulates Colorectal Cancer Cell Proliferation And Invasion Via Suppression Of Foxm1, Ketakee Mahajan, Ani V. Das, Suresh K. Alahari, Ramesh Pothuraju, S. Asha Nair

School of Graduate Studies Faculty Publications

Colorectal cancer (CRC) is a heterogeneous disease and classified into various subtypes, among which transcriptional alterations result in CRC progression, metastasis, and drug resistance. Forkhead-box M1 (FOXM1) is a proliferation-associated transcription factor which is overexpressed in CRC and the mechanisms of FOXM1 regulation have been under investigation. Previously, we showed that FOXM1 binds to promoters of certain microRNAs. Database mining led to several microRNAs that might interact with FOXM1 3’UTR. The interactions between shortlisted microRNAs and FOXM1 3’UTR were quantitated by a dual-luciferase reporter assay. MicroRNA-532-3p interacted with the 3’UTR of the FOXM1 mRNA transcript most efficiently. MicroRNA-532-3p was ectopically …

Hydroxyurea In The Sickle Cell Disease Modern Era, Chazmyn Riley, Walter K. Kraft, Robin Miller

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

INTRODUCTION: Sickle cell disease is an inherited disorder characterized by hemoglobin S polymerization leading to vaso-occlusion and hemolytic anemia. These result in a variety of pathological events, causing both acute and chronic complications. Millions around the world are affected by sickle cell disease with predominance in sub-Saharan Africa. Hydroxyurea was the first drug approved for use in sickle cell disease to reduce the occurrence of painful crises and blood transfusions in patients with frequent, moderate to severe painful crises.

AREAS COVERED: With the development of new therapeutics, the role of hydroxyurea is evolving. This narrative review aims to provide clinical …

Epigenetic Mechanisms Differentially Regulate Blood Pressure And Renal Dysfunction In Male And Female Npr1 Haplotype Mice, Prerna Kumar, Kandasamy Neelamegam, Chandramohan Ramasamy, Ramachandran Samivel, Huijing Xia, Daniel R. Kapusta, Kailash N. Pandey

School of Graduate Studies Faculty Publications

We determined the epigenetic mechanisms regulating mean arterial pressure (MAP) and renal dysfunction in guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene-targeted mice. The Npr1 (encoding NPRA) gene-targeted mice were treated with class 1 specific histone deacetylase inhibitor (HDACi) mocetinostat (MGCD) to determine the epigenetic changes in a sex-specific manner. Adult male and female Npr1 haplotype (1-copy; Npr1+/−), wild-type (2-copy; Npr1+/+), and gene-duplicated heterozygous (3-copy; Npr1++/+) mice were intraperitoneally injected with MGCD (2 mg/kg) for 14 days. BP, renal function, histopathology, and epigenetic changes were measured. One-copy male mice showed significantly increased MAP, renal dysfunction, and fibrosis than 2-copy and 3-copy mice. …

Antibiotic Resistance In Livestock: A Literature Review Of Its Consequences And International Effort On Human Antimicrobial Agents Resistant Crisis, Ha Nguyen

Theses and Graduate Projects

Background: Despite their benefits, the overuse of antibiotics in livestock has resulted in negative consequences to human health and the augmenting of an antibiotic-resistant crisis. Countries worldwide have conducted analyses and confirmed the growth of bacterial strains immune to most antibiotics. The widespread use of antibiotics is shown in various sectors, including human medicine and agriculture, leading to the emergence of antibiotic-resistant bacterial strains.

Purpose: This comprehensive literature review focuses on finding the connection between the usage of antibiotics in livestock, the transfer of antibiotic resistance to humans through consumption and exposure, and international efforts to find solutions to antimicrobial …

Podocyte Cell-Specific Npr1 Is Required For Blood Pressure And Renal Homeostasis In Male And Female Mice: Role Of Sex-Specific Differences, Chandramohan Ramasamy, Kandasamy Neelamegam, Samivel Ramachandran, Huijing Xia, Daniel R. Kapusta, Farhad R. Danesh, Kailash N. Pandey

School of Graduate Studies Faculty Publications

Atrial and brain natriuretic peptides (ANP and BNP) bind to guanylyl cyclase A/natriuretic peptide receptor A (GC-A/NPRA), stimulating natriuresis and diuresis and reducing blood pressure (BP), but the role of ANP/NPRA signaling in podocytes (highly specialized epithelial cells covering the outer surfaces of renal glomerular capillaries) remains unclear. This study aimed to determine the effect of conditional deletion of podocyte-specific Npr1 (encoding NPRA) gene knockout (KO) in male and female mice. Tamoxifen-treated wild-type control (PD Npr1 f/f; WT), heterozygous (PD-Cre-Npr1 f/+; HT), and KO (PD-Cre-Npr1 f/-) mice were fed a normal-, low-, or high-salt diet for 4 wk. Podocytes isolated …

Non-Receptor Tyrosine Kinases: Their Structure And Mechanistic Role In Tumor Progression And Resistance, Abdulaziz M. Eshaq, Thomas W. Flanagan, Sofie Yasmin Hassan, Sara A. Al Asheikh, Waleed A. Al-Amoudi, Simeon Santourlidis, Sarah Lilly Hassan, Maryam O. Alamodi, Marcelo L. Bendhack, Mohammed O. Alamodi, Youssef Haikel, Mossad Megahed, Mohamed Hassan

School of Graduate Studies Faculty Publications

Protein tyrosine kinases (PTKs) function as key molecules in the signaling pathways in addition to their impact as a therapeutic target for the treatment of many human diseases, including cancer. PTKs are characterized by their ability to phosphorylate serine, threonine, or tyrosine residues and can thereby rapidly and reversibly alter the function of their protein substrates in the form of significant changes in protein confirmation and affinity for their interaction with protein partners to drive cellular functions under normal and pathological conditions. PTKs are classified into two groups: one of which represents tyrosine kinases, while the other one includes the …

Adhesion G Protein-Coupled Receptor Latrophilin 1 (Adgrl1): A Novel Regulator Of Glucose And Energy Homeostasis., Kavaljit H Chhabra

Pharmacology and Nutritional Sciences Faculty Publications

No abstract provided.

Differential Effect Of An Evolving Amyloid And Tau Pathology On Brain Phospholipids And Bioactive Lipid Mediators In Rat Models Of Alzheimer-Like Pathology, Sonia Do Carmo, Marie Audrey I. Kautzmann, Surjyadipta Bhattacharjee, Bokkyoo Jun, Carolyn Steinberg, Joshua T. Emmerson, Janice C. Malcolm, Quentin Bonomo, Nicolas G. Bazan, A. Claudio Cuello

School of Graduate Studies Faculty Publications

Background: Brain inflammation contributes significantly to the pathophysiology of Alzheimer’s disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved. Methods: In this study, we examined the cortical levels of DHA- and AA-derived bioactive …

Molecular Mechanism Of Bitter Taste Receptor Agonist-Mediated Relaxation Of Airway Smooth Muscle, Stanley Conaway, Weiliang Huang, Miguel A. Hernandez-Lara, Maureen A. Kane, Raymond B. Penn, Deepak A. Deshpande

Center for Translational Medicine Faculty Papers

G-protein-coupled receptors (GPCRs) belonging to the type 2 taste receptors (TAS2Rs) family are predominantly present in taste cells to allow the perception of bitter-tasting compounds. TAS2Rs have also been shown to be expressed in human airway smooth muscle (ASM), and TAS2R agonists relax ASM cells and bronchodilate airways despite elevating intracellular calcium. This calcium “paradox” (calcium mediates contraction by pro-contractile Gq-coupled GPCRs) and the mechanisms by which TAS2R agonists relax ASM remain poorly understood. To gain insight into pro-relaxant mechanisms effected by TAS2Rs, we employed an unbiased phosphoproteomic approach involving dual-mass spectrometry to determine differences in the phosphorylation of contractile-related …

Effect Of Resistance Training On Physical Function During Chemotherapy In Colon Cancer, Justin C. Brown, Shengping Yang, Stephanie L.E. Compton, Kristin L. Campbell, Elizabeth M. Cespedes Feliciano, Sara Quinney, Barbara Sternfeld, Bette J. Caan, Jeffrey A. Meyerhardt, Kathryn H. Schmitz

School of Medicine Faculty Publications

Background: The decline of physical function during chemotherapy predicts poor quality of life and premature death. It is unknown if resistance training prevents physical function decline during chemotherapy in colon cancer survivors. Methods: This multicenter trial randomly assigned 181 colon cancer survivors receiving postoperative chemotherapy to home-based resistance training or usual care control. Physical function outcomes included the short physical performance battery, isometric handgrip strength, and the physical function subscale of the Medical Outcomes Short-Form 36-item questionnaire. Mixed models for repeated measures quantified estimated treatment differences. Results: At baseline, participants had a mean (SD) age of 55.2 (12.8) years; 67 …

Silmitasertib (Cx-4945) Disrupts Erî±/Hsp90 Interaction And Drives Proteolysis Through The Disruption Of Ck2β Function In Breast Cancer Cells, Hogyoung Kim, Emma Elkins, Rahib Islam, Bo Cao, Nour Abbes, Kaela Battles, Sihyoung Kim, Sichan Kim, Christopher Williams

School of Graduate Studies Faculty Publications

Aberrant estrogen receptor (ERα) signaling mediates detrimental effects of tamoxifen including drug resistance and endometrial hyperplasia. ERα36, an alternative isoform of ERα, contributes to these effects. We have demonstrated that CK2 modulates ERα expression and function in breast cancer (BCa). Here, we assess if CX-4945 (CX), a clinical stage CK2 inhibitor, can disrupt ERα66 and ERα36 signaling in BCa. Using live cell imaging, we assessed the antiproliferative effects of CX in tamoxifen-sensitive and tamoxifen-resistant BCa cells in monolayer and/or spheroid cultures. CX-induced alterations in ERα66 and ERα36 mRNA and protein expression were assessed by RT-PCR and immunoblot. Co-immunoprecipitation was performed …

Adjunctive Therapy With An Oral H2s Donor Provides Additional Therapeutic Benefit Beyond Sglt2 Inhibition In Cardiometabolic Heart Failure With Preserved Ejection Fraction, Jake E. Doiron, Huijing Xia, Xiaoman Yu, Alexandra R. Nevins, Kyle B. Lapenna, Thomas E. Sharp, Traci T. Goodchild, Timothy D. Allerton, Mona Elgazzaz, Eric Lazartigues, Sanjiv J. Shah, Zhen Li, David J. Lefer

School of Graduate Studies Faculty Publications

Background and Purpose: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated. Experimental Approach: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or …

Perioperative Cannabis Use In Bariatric Patients: A Review Of Outcomes And Proposed Clinical Pathway For Management, Meghan H. Maceyko, Marc Neff, Jonathan Halevy, Marguerite Dunham

Jefferson Health - New Jersey Papers

Legalization of marijuana has led to increased prevalence of medical and recreational cannabis use, underscoring the importance for anesthesiologists, surgeons, and perioperative physicians to understand the effects of this drug in patient care. Bariatric surgical patients represent a unique target population to understand peri-operative cannabis use and its effects as these patients undergo an extensive preoperative psychological and nutritional evaluation. Standardized guidelines on cannabis use in bariatric surgery are lacking and many clinicians remain uncertain on how to handle cannabis use in the peri-operative period. Here, we summarize the data on cannabis use in bariatric patients, specifically exploring anesthetic considerations, …

The Latest Ic3d Classification Of Corneal Dystrophies—Overview And Changes Of The 3rd Edition, Tim Berger, Jayne S. Weiss, Walter Lisch, Berthold Seitz

School of Medicine Faculty Publications

The International Committee on Classification of Corneal Dystrophies (IC3D) was founded in 2005 to address difficulties arising from the outdated nomenclature for corneal dystrophies (CD) and to correct misconceptions in the literature. For each of the 22 CDs, a separate template was created to represent the current clinical, pathological and genetic knowledge of the disease. In addition, each template contains representative clinical photographs as well as light and electron microscopic images and, if available, confocal microscopic and coherence tomographic images of the respective CD. After the first edition was published in 2008, the revised version followed in 2015. The third …

Uses Of Herbal Extracts In Endodontology: A Literature Review, Reem Chamseddine, Roula S. Abiad

BAU Journal - Science and Technology

The use of natural herbal extracts in the field of dentistry, and specifically in endodontology had gained a high popularity in the past few years. The main objective of endodontic treatment is to prevent and eliminate the infection from the root canal, seize the invasion of microorganisms to periradicular tissues and preserve the natural dentition. Studies had shown that some herbs are better alternatives to traditional chemical irrigants or medicaments used in root canal treatment, based on their potential antimicrobial effect, smear layer removal capabilities, tissue dissolution effect, antioxidant, anti-inflammatory and regenerative properties. Aim: The purpose of this literature review …

Effects Of Exercise Or Metformin On Myokine Concentrations In Patients With Breast And Colorectal Cancer: A Phase Ii Multi-Centre Factorial Randomized Trial, Justin C. Brown, Guillaume Spielmann, Shengping Yang, Stephanie L.E. Compton, Lee W. Jones, Melinda L. Irwin, Jennifer A. Ligibel, Jeffrey A. Meyerhardt

School of Medicine Faculty Publications

Background: Physical activity and metformin pharmacotherapy are associated with improved clinical outcomes in breast and colorectal cancer survivors. Myokines are cytokines secreted from skeletal muscle that may mediate these associations. Methods: This hypothesis-generating analysis used biospecimens collected from a multi-centre 2 × 2 factorial randomized design of 116 patients with stage I–III breast and colorectal cancer who were randomized to 12 weeks of (1) aerobic exercise (moderate intensity titrated to 220 min/week); (2) metformin (850 mg daily for 2 weeks and then titrated to 850 mg twice per day); (3) aerobic exercise and metformin; or (4) control. Fourteen myokines were …

A Phase 3b, Open-Label, Single-Arm, Multicenter, Expanded-Access Study Of The Safety And Clinical Outcomes Of Stratagraft® Treatment In Adults With Deep Partial-Thickness Thermal Burns, James H. Holmes Iv, Angela L.F. Gibson, Tracee Short, Victor C. Joe, Jeffrey Litt, Joshua Carson, Jeffrey E. Carter, Lucy Wibbenmeyer, Helen Hahn, Janice M. Smiell, Randi Rutan, Richard Wu, Jeffrey W. Shupp

School of Medicine Faculty Publications

Background: A phase 3b, open-label, multicenter, expanded-access study (NCT04123548) evaluated safety and clinical outcomes of StrataGraft treatment in adults with deep partial-thickness thermal burns with intact dermal elements. Methods: Adult patients with 3 % to < 50 % total body surface area burns were treated with a single application of ≤ 1:1 meshed StrataGraft and followed for 24 weeks. Primary endpoint was count and percentage of patients with treatment-emergent adverse events (TEAEs). Secondary endpoints included confirmed wound closure (WC) at Week 12, durable WC at Week 24, time to WC, scar evaluation, and wound infection-related events. Results: Fifty-two patients with 96 treatment sites were enrolled. Pruritus was the most common TEAE (22 patients [42.3 %]). Twenty serious TEAEs occurred in 10 patients (19.2 %); none were related to StrataGraft. There were 4 (7.7 %) deaths (aspiration, myocardial infarction, self-injury, Gram-negative rod sepsis); none were related to StrataGraft. Confirmed WC was achieved by Week 12 in 33 patients (63.5 %; 95 % CI: 50.4–76.5 %) and 69 treatment sites (71.9 %; 95 % CI: 62.9–80.9 %). Durable WC was achieved by Week 24 in 29 patients (55.8 %; 95 % CI: 42.3–69.3 %) and 58 treatment sites (60.4 %; 95 % CI: 50.6–70.2 %). Conclusions: StrataGraft demonstrated clinical benefit. Safety data were consistent with previously reported findings.