Portopulmonary Hypertension: From Bench to Bedside.
Ontology highlight
ABSTRACT:
SUBMITTER: Thomas C
PROVIDER: S-EPMC7670077 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Portopulmonary Hypertension: From Bench to Bedside.
Thomas Christopher C Glinskii Vladimir V de Jesus Perez Vinicio V Sahay Sandeep S
Frontiers in medicine 20201103
Portopulmonary hypertension (PoPH) is defined as pulmonary arterial hypertension (PAH) associated with portal hypertension and is a subset of Group 1 pulmonary hypertension (PH). PoPH is a cause of significant morbidity and mortality in patients with portal hypertension with or without liver disease. Significant strides in elucidating the pathogenesis, effective screening algorithms, accurate diagnoses, and treatment options have been made in past 20 years. Survival of PoPH has remained poor com ...[more]
Similar Datasets
Project description:Accuracy of sepsis prediction was obtained using cross-validation of gene expression data from 12 human spleen samples and from 16 mouse spleen samples. For blood studies, classifiers were constructed using data from a training data set of 26 microarrays. The error rate of the classifiers was estimated on seven de-identified microarrays, and then on a subsequent cross-validation for all 33 blood microarrays. Estimates of classification accuracy of sepsis in human spleen were 67.1%; in mouse spleen, 96%; and in mouse blood, 94.4% (all estimates were based on nested cross-validation). Lists of genes with substantial changes in expression between study and control groups were used to identify nine mouse common inflammatory response genes, six of which were mapped into a single pathway using contemporary pathway analysis tools. Keywords: genomics, diagnosis, microarray, calprotectin
2006-08-29 | GSE5663 | GEO
Project description:BackgroundPortopulmonary hypertension (POPH), pulmonary arterial hypertension that develops in the setting of portal hypertension, can lead to right-sided heart failure and death. Being female is a known risk factor for POPH, but little is known about the effect of sex on clinical manifestations, hemodynamics, treatment response, and survival.Research questionWe sought to characterize sex differences in clinical characteristics, pulmonary hemodynamics, treatment response, and survival in patients with POPH.Study design and methodsWe performed a retrospective cohort study of adult candidates for liver transplant (LT) who had POPH within the Organ Procurement and Transplantation Network database. Females and males were compared. Multivariate regression was performed to assess the association between sex and pulmonary vascular resistance (PVR) and survival. Patients were also stratified by age (50 years) to determine how age modifies the relationship between sex and hemodynamics and survival.ResultsWe included 190 adults (103 male, 87 female). Compared with men, women had a lower model for end-stage liver disease (MELD) score (12.1± 4.2 vs 13.8 ± 4.9; P = .01) and were more likely to have autoimmune liver disease. Women had a higher baseline PVR (610.6 ± 366.6 vs 461.0 ± 185.3 dynes-s-cm-5; P < .001) and posttreatment PVR (244.6 ± 119.5 vs 202.0 ± 87.7 dynes-s-cm-5; P = .008) and a greater treatment response (ΔPVR) (-359.3 ± 381.9 vs -260.2 ± 177.3 dynes-s-cm-5; P = .03). In multivariate analysis, female sex (or gender) remained associated with a higher baseline PVR (P = .008). Women and men had overall similar survival (P > .05). When patients were stratified by age, being female was independently associated with worse waiting list survival after adjusting for MELD and PVR in younger patients (HR, 6.61; 95% CI, 1.25-35.08; P = .03) but not in older patients.InterpretationCompared with male candidates, female candidates for LT who had POPH had a higher PVR and lower MELD score and were more likely to have autoimmune liver disease. Women and men had similar overall survival, but female sex (or gender) was associated with worse survival in younger patients.
| S-EPMC7893306 | biostudies-literature
Project description:In heart failure with reduced left ventricular ejection fraction (HFrEF), adrenergic activation is a key compensatory mechanism that is a major contributor to progressive ventricular remodeling and worsening of heart failure. Targeting the increased adrenergic activation with ?-adrenergic receptor blocking agents has led to the development of arguably the single most effective drug therapy for HFrEF. The pressure-overloaded and ultimately remodeled/failing right ventricle (RV) in pulmonary arterial hypertension (PAH) is also adrenergically activated, which raises the issue of whether an antiadrenergic strategy could be effectively employed in this setting. Anecdotal experience suggests that it will be challenging to administer an antiadrenergic treatment such as a ?-blocking agent to patients with established moderate-severe PAH. However, the same types of data and commentary were prevalent early in the development of ?-blockade for HFrEF treatment. In addition, in HFrEF approaches have been developed for delivering ?-blocker therapy to patients who have extremely advanced heart failure, and these general principles could be applied to RV failure in PAH. This review examines the role played by adrenergic activation in the RV faced with PAH, contrasts PAH-RV remodeling with left ventricle remodeling in settings of sustained increases in afterload, and suggests a possible approach for safely delivering an antiadrenergic treatment to patients with RV dysfunction due to moderate-severe PAH.
| S-EPMC4556494 | biostudies-other
Project description:The combination of microbubbles and ultrasound has emerged as a promising method for local drug delivery. Microbubbles can be locally activated by a targeted ultrasound beam, which can result in several bio-effects. For drug delivery, microbubble-assisted ultrasound is used to increase vascular- and plasma membrane permeability for facilitating drug extravasation and the cellular uptake of drugs in the treated region, respectively. In the case of drug-loaded microbubbles, these two mechanisms can be combined with local release of the drug following destruction of the microbubble. The use of microbubble-assisted ultrasound to deliver chemotherapeutic agents is also referred to as sonochemotherapy. In this review, the basic principles of sonochemotherapy are discussed, including aspects such as the type of (drug-loaded) microbubbles used, the routes of administration used in vivo, ultrasound devices and parameters, treatment schedules and safety issues. Finally, the clinical translation of sonochemotherapy is discussed, including the first clinical study using sonochemotherapy.
| S-EPMC4498442 | biostudies-other
Project description:The nature of biomedical research affords a broad range of investigational topics at the preclinical stage, not all of which may be explored in subsequent clinical studies. To provide a comprehensive perspective on the physiologic effects of the dipeptidyl peptidase-4 inhibitor linagliptin, this review will discuss the results of both preclinical and clinical research, summarizing data describing outcomes associated with its use.Clinical studies demonstrate an overall favorable safety profile, low risk for hypoglycemia, weight neutrality, primarily nonrenal clearance, and efficacy for glycosylated hemoglobin reduction, typically ranging from 0.6% to 0.8% depending on baseline levels. In addition to these characteristics, preclinical research on linagliptin has yielded several interesting findings such as improved wound healing, reduced hepatic fat content, decreased infarct size following myocardial infarction or intracranial stroke, and improved vascular function with decreased oxidative stress. In accordance with its preclinical profile, linagliptin is unique among available dipeptidyl peptidase-4 compounds because it does not require dose adjustment when used in patients with renal dysfunction. Reduction of albuminuria with linagliptin on top of inhibitors of the renin-angiotensin-aldosterone system in both preclinical and post hoc clinical analysis serves as the foundation for ongoing clinical trials.In addition to its efficacy for glycemic control, current literature points to other potential opportunities associated with linagliptin therapy. These results warrant further investigation and underscore the importance of translational study based on findings from preclinical research. Moving forward, we can expect that future research on linagliptin and other incretin-based therapies will continue to expand their applications beyond the maintenance of glycemic control in patients with type 2 diabetes.
| S-EPMC4018312 | biostudies-literature
Project description:Leukocyte recruitment to sites of infection or tissue damage plays a crucial role for the innate immune response. Chemokine-dependent signaling in immune cells is a very important mechanism leading to integrin activation and leukocyte recruitment. CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils. During the last years, several studies were performed investigating the role of CXCR2 in different diseases. Until now, many CXCR2 inhibitors are tested in animal models and clinical trials and promising results were obtained. This review gives an overview of the structure of CXCR2 and the signaling pathways that are activated following CXCR2 stimulation. We discuss in detail the role of this chemokine receptor in different disease models including acute lung injury, COPD, sepsis, and ischemia-reperfusion-injury. Furthermore, this review summarizes the results of clinical trials which used CXCR2 inhibitors.
| S-EPMC3426767 | biostudies-literature
Project description:Sentrin/small ubiquitin-like modifier (SUMO) is protein modification pathway that regulates multiple biological processes, including cell division, DNA replication/repair, signal transduction, and cellular metabolism. In this review, we will focus on recent advances in the mechanisms of disease pathogenesis, such as cancer, diabetes, seizure, and heart failure, which have been linked to the SUMO pathway. SUMO is conjugated to lysine residues in target proteins through an isopeptide linkage catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes. In steady state, the quantity of SUMO-modified substrates is usually a small fraction of unmodified substrates due to the deconjugation activity of the family Sentrin/SUMO-specific proteases (SENPs). In contrast to the complexity of the ubiquitination/deubiquitination machinery, the biochemistry of SUMOylation and de-SUMOylation is relatively modest. Specificity of the SUMO pathway is achieved through redox regulation, acetylation, phosphorylation, or other posttranslational protein modification of the SUMOylation and de-SUMOylation enzymes. There are three major SUMOs. SUMO-1 usually modifies a substrate as a monomer; however, SUMO-2/3 can form poly-SUMO chains. The monomeric SUMO-1 or poly-SUMO chains can interact with other proteins through SUMO-interactive motif (SIM). Thus SUMO modification provides a platform to enhance protein-protein interaction. The consequence of SUMOylation includes changes in cellular localization, protein activity, or protein stability. Furthermore, SUMO may join force with ubiquitin to degrade proteins through SUMO-targeted ubiquitin ligases (STUbL). After 20 yr of research, SUMO has been shown to play critical roles in most, if not all, biological pathways. Thus the SUMO enzymes could be targets for drug development to treat human diseases.
| S-EPMC7717128 | biostudies-literature
Project description:B7x is an immune checkpoint molecule which belongs to the B7 family of ligands which includes PD-L1, PD-L2, B7-H3 and HHLA2. B7x belongs to the Immunoglobulin superfamily and its protein structure is similar to other members with a N terminus peptide, IgV and IgC like extracellular domain with four cysteine residues. Its receptor is yet to be identified. B7x inhibits T cell proliferation and expansion by IL-2 dependent and non-IL-2 dependent pathways. Even though high levels of B7x mRNA can be detected in most tissues its protein expression is highly limited suggesting significant post translational control. In vivo data, show that B7x plays an important role in limiting autoimmunity in the peripheral tissues and fine-tuning autoimmune responses. B7x is highly expressed in various cancers and in prostate cancer its expression is corelated with poorer outcomes. Local production of IL-6 and IL-10 in various cancers promotes B7x expression and tumor immune evasion. B7x is especially expressed in PD-L1 negative tumors suggesting that this may be an important method of immune evasion in these tumors. Currently drug development, targeting B7x through various mechanisms including monoclonal antibodies and antibody drug conjugates are in development in cancers and increasing B7x expression with fusion proteins in autoimmune diseases is underway.
| S-EPMC6735664 | biostudies-literature
Project description:We previously showed that a single nucleotide polymorphism in S100A4 was associated with portopulmonary hypertension (PPHTN) in patients with advanced liver disease. We aimed to determine the association between plasma levels of S100A4 and PPHTN. We performed a case-control study of patients with advanced liver disease. Cases with PPHTN had mean pulmonary artery pressure >25 mmHg, pulmonary vascular resistance >240 dynes s cm(-5) and pulmonary capillary wedge pressure </=15 mmHg. Controls with liver disease had right ventricular systolic pressure <40 mmHg and normal right atrial and ventricular morphology by echocardiography. Plasma samples were assayed for S100A4. The study sample included 14 cases with PPHTN and 32 controls with liver disease. There was no difference in mean age between cases and controls (p = 0.52). Seventy-nine percent of cases were female compared with 44% of controls (p = 0.03). There was no difference in S100A4 levels between cases and controls (p = 0.58). Both groups had significantly higher S100A4 levels than healthy volunteers (p <0.05). There was no significant difference in plasma levels of S100A4 between PPHTN patients and controls with liver disease, although liver disease itself was associated with increased S100A4 levels.
| S-EPMC2819481 | biostudies-literature
Project description:BackgroundThe current Organ Procurement Transplantation Network policy grants Model for End-Stage Liver Disease (MELD) exception points to patients with portopulmonary hypertension (POPH), but potentially important factors, such as severity of liver disease and pulmonary hypertension, are not included in the exception score, and may affect survival. The purpose of this study was to identify significant predictors of waitlist mortality in patients with POPH.MethodsWe performed a retrospective cohort study of patients in the Organ Procurement and Transplantation Network database with hemodynamics consistent with POPH (defined as mean pulmonary arterial pressure >25 mm Hg and pulmonary vascular resistance [PVR] ≥240 dynes·s·cm) who were approved for a POPH MELD exception between 2006 and 2014. Using a Cox proportional hazards model, we identified predictors of waitlist mortality (or removal for clinical deterioration).ResultsOne hundred ninety adults were included. Age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.00-1.08; P = 0.0499), initial native MELD score (HR, 1.11; 95% CI, 1.05-1.17; P < 0.001), and initial PVR (HR, 1.12 per 100 dynes·s·cm; 95% CI, 1.02-1.23; P = 0.02) were the only significant univariate predictors of waitlist mortality and remained significant predictors in a multivariate model, which had a c-statistic of 0.71. PVR and mean pulmonary arterial pressure were not significant predictors of posttransplant mortality.ConclusionsBoth the severity of liver disease and POPH (as assessed by MELD and PVR, respectively) were significantly associated with waitlist, but not posttransplant, mortality in patients with approved MELD exceptions for POPH. Both factors should potentially be included in the POPH MELD exception score to more accurately reflect waitlist mortality risk.
| S-EPMC5481480 | biostudies-literature