Pseudomonas aeruginosa Invades Human Aortic Endothelial Cells and Induces Cell Damage In Vitro

Background: Cardiovascular diseases such as endocarditis are the second most common cause of death worldwide. Infective Endocarditis (IE) is the most severe infection of the heart associated with significant mortality and morbidity. The binding and invasion of Human Aortic Endothelial Cells (HAECs) by pathogenic microbes can play an important role in the pathogenesis of IE. Objective: Pseudomonas aeruginosa is an emerging pathogen that has been associated with IE. However, it is not known whether P. aeruginosa can bind and interact with HAECs. The aim of this study was to determine whether P. aeruginosa can bind and colonize HAECs. Methods: The invasion of HAECs by P. aeruginosa was assessed by gentamicin protection assay. Cytokine levels were determined by enzyme-linked Immunosorbent Assay (ELISA) kits. Cell damage was determined by Lactate Dehydrogenase (LDH) assay. Results: P. aeruginosa can bind and invade HAECs. Infection of HAECs with P. aeruginosa induces TNF-α IL-1β, IL-6 and IL-8 cytokine production leading to the generation of inflammatory milieu that can cause tissue damage as observed in human clinical cases of IE. We also observed that P. aeruginosa induces cell damage in HAECs. Conclusion: In this study, we demonstrate for first time that P. aeruginosa can invade and survive inside HAECs. This cell culture model can be of immense importance to determine the efficacy of drug targets against IE

Exploring racial disparities of actionable mutations in gynecologic cancers

e17098 Background: Next Generation Sequencing (NGS) guides targeted therapy and clinical trial enrollment for patients with gynecologic malignancies. South Florida is a key region to explore biomarkers and molecular alterations common in Hispanic (H) patients due to the high proportion of H individuals. While NGS testing is increasingly used in clinical practice to aid in treatment planning, ethnic minorities are at risk for health disparity including clinical trial enrollment. The objective of this study was to determine if frequently reported mutations are also common in a predominantly H population with gynecologic cancers. Methods: Clinicopathologic data was obtained from women treated at our institution from Jan. 2014 to Jan 2019 for gynecologic malignancies. Women with ovarian (OC), endometrial (EC), and cervical cancer (CC) with NGS results from Caris Life Sciences were included for analysis. Women self-report ethnicity based on initial hospital intake form. Mutations based on point mutations, indels, fusions and copy number variations were identified. Descriptive statistics are reported. IRB approval was obtained. Results: A total of 233 patients with 117 ovarian (OC), 24 cervical (CC) and 92 endometrial cancers (EC) were included. Among the 233 women, 96 (41%) were H, 137 (59%) identified as NH. There were 38 H and 48 NH patients with EC; 50 H and 62 NH OC patients; and 8 H and 13 NH CC patients. Among EC patients, TP53 appeared in 42% vs. 47%, PTEN 26% vs. 30% , PIK3CA 32% vs. 17%, CTNNB1 32% vs. 17% , and KRAS 16% vs. 21% of H and NH cases respectively. In the OC cohort, TP53 appeared in 74% vs. 75% , BRCA1/2 10% vs. 19%, KRAS 16% vs. 16% and PIK3CA 8% vs. 6% of H and NH cases respectively. In CC patients, TP53 appeared in 25% vs. 23%, KMT2C 12.5% vs. 7.6% and PIK3CA 0 vs. 38% of H and NH cases respectively. There were no statistical differences in the mutation rates between the two groups. Conclusions: There is limited data reported on the variation of mutations based on ethnicity in women with gynecologic cancers. Our study suggests there may be different driver mutations based on ethnicity. Future studies in larger cohorts are needed to further assess genomic differences, potential responses to treatment and further increase H population enrollment into clinical trials

Cell communication by tunneling nanotubes: Implications in disease and therapeutic applications

Intercellular communication is essential for the development and maintenance of multicellular organisms. Tunneling nanotubes (TNTs) are a recently recognized means of long and short distance communication between a wide variety of cell types. TNTs are transient filamentous membrane protrusions that connect cytoplasm of neighboring or distant cells. Cytoskeleton fiber-mediated transport of various cargoes occurs through these tubules. These cargoes range from small ions to whole organelles. TNTs have been shown to contribute not only to embryonic development and maintenance of homeostasis, but also to the spread of infectious particles and resistance to therapies. These functions in the development and progression of cancer and infectious disease have sparked increasing scrutiny of TNTs, as their contribution to disease progression lends them a promising therapeutic target. Herein, we summarize the current knowledge of TNT structure and formation as well as the role of TNTs in pathology, focusing on viral, prion, and malignant disease. We then discuss the therapeutic possibilities of TNTs in light of their varied functions. Despite recent progress in the growing field of TNT research, more studies are needed to precisely understand the role of TNTs in pathological conditions and to develop novel therapeutic strategies

Organ-on-chip models: Implications in drug discovery and clinical applications

Before a lead compound goes through a clinical trial, preclinical studies utilize two-dimensional (2D) in vitro models and animal models to study the pharmacodynamics and pharmacokinetics of that lead compound. However, these current preclinical studies may not accurately represent the efficacy and safety of a lead compound in humans, as there has been a high failure rate of drugs that enter clinical trials. All of these failures and the associated costs demonstrate a need for more representative models of human organ systems for screening in the preclinical phase of drug development. In this study, we review the recent advances in in vitro modeling including three-dimensional (3D) organoids, 3D microfabrication, and 3D bioprinting for various organs including the heart, kidney, lung, gastrointestinal tract (intestine-gut-stomach), liver, placenta, adipose, retina, bone, and brain as well as multiorgan models. The availability of organ-on-chip models provides a wealth of opportunities to understand the pathogenesis of human diseases and provide a potentially better model to screen a drug, as these models utilize a dynamic 3D environment similar to the human body. Although there are limitations of organ-on-chip models, the emergence of new technologies have refined their capability for translational research as well as precision medicine

Recent treatment modalities for cardiovascular diseases with a focus on stem cells, aptamers, exosomes and nanomedicine

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Due to the significant impact of CVD on humans, there is a need to develop novel treatment modalities tailored to major classes of cardiac diseases including hypertension, coronary artery disease, cardiomyopathies, arrhythmias, valvular disease and inflammatory diseases. In this article, we discuss recent advancements regarding development of therapeutic strategies based on stem cells, aptamers, exosomes, drug-eluting and dissolvable stents, immunotherapy and nanomedicine for the treatment of CVD. We summarize current research and clinical advances in cardiovascular therapeutics, with a focus on therapies that move beyond current oral- or sublingual-based regimens. This review article provides insight into current research and future treatment strategies that hold a great relevance for future clinical practice in pursuit of improving quality of life of patients suffering from CVD

Recent advancements in nanoparticle based drug delivery for gastrointestinal disorders

Introduction: The emergent field of nanoparticles has presented a wealth of opportunities for improving the treatment of human diseases. Recent advances have allowed for promising developments in drug delivery, diagnostics, and therapeutics. Modified delivery systems allow improved drug delivery over traditional pH, microbe, or receptor dependent models, while antibody association allows for more advanced imaging modalities. Nanoparticles have potential clinical application in the field of gastroenterology as they offer several advantages compared to the conventional treatment systems including target drug delivery, enhanced treatment efficacy, and reduced side effects. Areas covered: The aim of this review article is to summarize the recent advancements in developing nanoparticle technologies to treat gastrointestinal diseases. We have covered the application of nanoparticles in various gastrointestinal disorders including inflammatory bowel disease and colorectal cancer. We also have discussed how the gut microbiota affects the nanoparticle based drug delivery in the gastrointestinal tract. Expert opinion: Nanoparticles based drug delivery offers a great platform for targeted drug delivery for gastrointestinal disorders. However, it is influenced by the presence of microbiota, drug interaction with nanoparticles, and cytotoxicity of nanoparticles. With the advancements in nanoparticle technology, it may be possible to overcome these barriers leading to efficient drug delivery for gastrointestinal disorders based on nanoparticle platform

Recent Advances in Understanding the Pathogenesis of Cardiovascular Diseases and Development of Treatment Modalities

Cardiovascular Diseases (CVDs) are a leading cause of morbidity and mortality worldwide. The underlying pathology for cardiovascular disease is largely atherosclerotic in nature and the steps include fatty streak formation, plaque progression and plaque rupture. While there is optimal drug therapy available for patients with CVD, there are also underlying drug delivery obstacles that must be addressed. Challenges in drug delivery warrant further studies for the development of novel and more efficacious medical therapies. An extensive understanding of the molecular mechanisms of disease in combination with current challenges in drug delivery serves as a platform for the development of novel drug therapeutic targets for CVD. The objective of this article is to review the pathogenesis of atherosclerosis, first-line medical treatment for CVD, and key obstacles in an efficient drug delivery

Genetic basis of hearing loss in Spanish, Hispanic and Latino populations

Hearing loss (HL) is the most common neurosensory disorder affecting humans. The screening, prevention and treatment of HL require a better understanding of the underlying molecular mechanisms. Genetic predisposition is one of the most common factors that leads to HL. Most HL studies include few Spanish, Hispanic and Latino participants, leaving a critical gap in our understanding about the prevalence, impact, unmet health care needs, and genetic factors associated with hearing impairment among Spanish, Hispanic and Latino populations. The few studies which have been performed show that the gene variants commonly associated with HL in non-Spanish and non-Hispanic populations are infrequently responsible for hearing impairment in Spanish as well as Hispanic and Latino populations (hereafter referred to as Hispanic). To design effective screening tools to detect HL in Spanish and Hispanic populations, studies must be conducted to determine the gene variants that are most commonly associated with hearing impairment in this racial/ethnic group. In this review article, we summarize gene variants and loci associated with HL in Spanish and Hispanic populations. Identifying new genetic variants associated with HL in Spanish and Hispanic populations will pave the way to develop effective screening tools and therapeutic strategies for HL. •Genetic predisposition is one of the most common factor that leads to hearing loss.•Summarize gene variants associated with hearing loss in Hispanic and Spanish populations.•Identifying new gene variants associated with deafness will help in developing effective screening tools

Zika Virus: An Emerging Global Health Threat

Zika virus (ZIKV) is an emerging healthcare threat. The presence of the mosquito species across South and Central America in combination with complementary climates have incited an epidemic of locally transmitted cases of ZIKV infection in Brazil. As one of the most significant current public health concerns in the Americas, ZIKV epidemic has been a cause of alarm due to its known and unknown complications. At this point, there has been a clear association between ZIKV infection and severe clinical manifestations in both adults and neonates, including but not limited to neurological deficits such as Guillain-Barré syndrome (GBS) and microcephaly, respectively. The gravity of the fetal anomalies linked to ZIKV vertical transmission from the mother has prompted a discussion on whether to include ZIKV as a formal member of the TORCH [Toxoplasma gondii, other, rubella virus, cytomegalovirus (CMV), and herpes] family of pathogens known to breach placental barriers and cause congenital disease in the fetus. The mechanisms of these complex phenotypes have yet to be fully described. As such, diagnostic tools are limited and no effective modalities are available to treat ZIKV. This article will review the recent advancements in understanding the pathogenesis of ZIKV infection as well as diagnostic tests available to detect the infection. Due to the increase in incidence of ZIKV infections, there is an immediate need to develop new diagnostic tools and novel preventive as well as therapeutic modalities based on understanding the molecular mechanisms underlying the disease

Zika Virus: An Emerging Global Health Threat

Zika virus (ZIKV) is an emerging healthcare threat. The presence of the mosquito Aedes species across South and Central America in combination with complementary climates have incited an epidemic of locally transmitted cases of ZIKV infection in Brazil. As one of the most significant current public health concerns in the Americas, ZIKV epidemic has been a cause of alarm due to its known and unknown complications. At this point, there has been a clear association between ZIKV infection and severe clinical manifestations in both adults and neonates, including but not limited to neurological deficits such as Guillain-Barré syndrome (GBS) and microcephaly, respectively. The gravity of the fetal anomalies linked to ZIKV vertical transmission from the mother has prompted a discussion on whether to include ZIKV as a formal member of the TORCH [Toxoplasma gondii, other, rubella virus, cytomegalovirus (CMV), and herpes] family of pathogens known to breach placental barriers and cause congenital disease in the fetus. The mechanisms of these complex phenotypes have yet to be fully described. As such, diagnostic tools are limited and no effective modalities are available to treat ZIKV. This article will review the recent advancements in understanding the pathogenesis of ZIKV infection as well as diagnostic tests available to detect the infection. Due to the increase in incidence of ZIKV infections, there is an immediate need to develop new diagnostic tools and novel preventive as well as therapeutic modalities based on understanding the molecular mechanisms underlying the disease