Recent developments in molecular therapeutic approaches for rheumatoid arthritis

Rheumatoid arthritis is a debilitating systemic autoimmune disease characterized by chronic synovial inflammation, which results in the progressive destruction of diseased joints. Advances in understanding the disease pathogenesis have led to the clinical introduction of biological inhibitors of inflammation or articular destruction. However, frequency of administration, cost and systemic side effects have driven efforts to develop gene therapeutic transfer strategies. This article reviews recent progress in the application of viral and non-viral vectors to target therapeutic genes for in vivo delivery.     

Recent approaches to the standardization of cardiac markers

The development of commercial assays for the determination of cardiac proteins has been one of the most important innovations in the field of cardiovascular diagnostics in the last decade. Some assays are, however, inadequately appraised prior to their introduction to clinical use. This paper focuses on some important preanalytical, analytical and interpretative problems, and summarizes the status of the ongoing local and international standardization efforts. The most urgent issue at the moment is the development of international reference materials, which can be used for the calibration of different assays, thus decreasing between-assay biases. In order to achieve comparability of test results, another important item is the standardization of the epitopes of the antibodies used for the assay development. Efforts to improve the precision of cardiac marker assays are also warranted. Finally, the effect of storage time and temperature on apparent marker concentration and the possible influence of different anticoagulants on measured marker values should clearly be evaluated.     

Recent approaches to the standardization of cardiac markers

The development of commercial assays for the determination of cardiac proteins has been one of the most important innovations in the field of cardiovascular diagnostics in the last decade. Some assays are, however, inadequately appraised prior to their introduction to clinical use. This paper focuses on some important preanalytical, analytical and interpretative problems, and summarizes the status of the ongoing local and international standardization efforts. The most urgent issue at the moment is the development of international reference materials, which can be used for the calibration of different assays, thus decreasing between-assay biases. In order to achieve comparability of test results, another important item is the standardization of the epitopes of the antibodies used for the assay development. Efforts to improve the precision of cardiac marker assays are also warranted. Finally, the effect of storage time and temperature on apparent marker concentration and the possible influence of different anticoagulants on measured marker values should clearly be evaluated.     

Novel therapeutic options for cachexia and sarcopenia

ABSTRACT

Introduction: Cachexia and sarcopenia are conditions phenotypically characterized by muscle loss and represent a factor of poor prognosis, increasing patients’ morbidity and mortality. Cachectic and sarcopenic patients often suffer from low quality of life, presenting lower muscle strength and appetite loss, which makes research on novel treatment strategies to ameliorate clinical response including patient’s symptoms, the objective of scientific interest.

Areas covered: This article covers recent developments in the area of cachexia and sarcopenia treatment and therapeutic interventions, targeting central nervous system involvement, key inflammatory and muscle-specific metabolic pathways.

Expert opinion: A number of promising agents have being evaluated, such as enobosarm, a selected androgen receptor modulator, and anamorelin, a ghrelin agonist which have been recently studied in phase III trials. These and other agents (i.e., infliximab, tocilizumab, MABp1, bimagrumab) have shown significant impact on reversal of skeletal muscle loss, but limited effect on physical function.

In the last few years advancement in the number and type of potential treatments for cachexia and sarcopenia have been obtained and we have now available more data on measurable effects of several drugs on patients’ nutritional and metabolic parameters and outcomes.     

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Many remarkable advances have improved our understanding of the cellular and molecular events in the pathogenesis of atherosclerosis. Chief among these is the accumulating knowledge of how the immune system contributes to all phases of atherogenesis, including well-known inflammatory reactions consequent to intimal trapping and oxidation of LDL. Advances in our understanding of the innate and adaptive responses to these events have helped to clarify the role of inflammation in atherogenesis and suggested new diagnostic modalities and novel therapeutic targets. Here we focus on recent advances in understanding how adaptive immunity affects atherogenesis.     

Post-infarct cardiac rupture: recent insights on pathogenesis and therapeutic interventions

Ventricular wall rupture represents a catastrophic complication of myocardial infarction (MI) in the clinic while research has long been hampered due to absence of suitable animal models. Since late 1990s, the mouse has become a suitable model for human post-infarct cardiac rupture. Here we review the clinical features of post-infarct rupture, factors associated with a higher risk of rupture, and findings from clinical trials on the incidence of post-infarct rupture. The features of the mouse model of post-infarct cardiac rupture are discussed. Research using this model suggests acute ventricular remodeling as the fundamental change leading to rupture, and has defined several key factors that determine the risk of rupture. We then provide a comprehensive review of the progress of experimental research in this field focusing on recent findings from genetically modified mouse models and experimental therapeutic interventions that reveal molecular mechanisms of post-infarct rupture. Genetic and pharmacological interventions targeting key inflammatory mediators, regulatory factors of extracellular matrix collagen and healing process effectively reduced the risk of rupture. These findings convincingly demonstrate that cardiac inflammation, damage to extracellular matrix proteins or blunted fibrotic healing constitute the central mechanisms for the pathogenesis of cardiac rupture and acute ventricular remodeling. Studies using the mouse model have also identified novel molecular mechanisms and therapeutic targets as well as suitable interventional regimens providing useful clues for clinical translation.     

Recent approaches in standardization of cardiac markers

The development of commercial assays for the determination of new cardiac proteins has been one of the most important innovations in the field of cardiovascular diagnostics in the last decade. This significant and sudden advancement has however led to some analytical and interpretative problems. There are problems in test standardization, imprecision, interference and preanalytical variability. We also need to standardize utilization of biomarkers in diagnosis and management of acute cardiac syndromes and clearly define decision thresholds. Powerful tests, such as cardiac markers, on which critical decisions will rest, need highly reliable methods. The feeling is that some assays are inadequately appraised prior to their introduction in clinical use. More studies are needed to implement new devices in the laboratory routine, and only well documented assays should be used in hospital-based laboratories. The technology to address many analytic problems is at hand, but commitment on the part of manufacturers and their customers in the laboratory community is essential.     

New insights into the molecular mechanisms of the fibrinolytic system

Summary.  Fibrinolysis is regulated by specific molecular interactions between its main components. Activation of plasminogen by tissue-type plasminogen activator (t-PA) is enhanced in the presence of fibrin or at the endothelial cell surface. Urokinase-type plasminogen activator (u-PA) binds to a specific cellular u-PA receptor (u-PAR), resulting in enhanced activation of cell-bound plasminogen. Inhibition of fibrinolysis occurs at the level of plasminogen activation or at the level of plasmin. Assembly of fibrinolytic components at the surface of fibrin results in fibrin degradation. Assembly at the surface of cells provides a mechanism for generation of localized cell-associated proteolytic activity. This review includes novel proteins such a thrombin-activatable fibrinolysis inhibitor (TAFI) and discusses new insights into molecular mechanisms obtained from the rapidly growing knowledge of crystal structures of proteins.     

Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities

Chronic and excessive inflammation in skin and joints causes significant morbidity in psoriasis patients. As a prevalent T lymphocyte-mediated disorder, psoriasis, as well as the side effects associated with its treatment, affects patients globally. In this review, recent progress is discussed in the areas of genetics, the immunological synapse, the untangling of the cytokine web and signaling pathways, xenotransplantation models, and the growing use of selectively targeted therapies. Since psoriasis is currently incurable, new management strategies are proposed to replace previous serendipitous approaches. Such strategic transition from serendipity to the use of novel selective agents aimed at defined targets in psoriatic lesions is moving rapidly from research benches to the bedsides of patients with this chronic and debilitating disease.     

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

SARS-CoV-2–infected individuals may suffer a multi–organ system disorder known as “long COVID” or post-acute sequelae of SARS-CoV-2 infection (PASC). There are no standard treatments, the pathophysiology is unknown, and incidence varies by clinical phenotype. Acute COVID-19 correlates with biomarkers of systemic inflammation, hypercoagulability, and comorbidities that are less prominent in PASC. Macrovessel thrombosis, a hallmark of acute COVID-19, is less frequent in PASC. Female sex at birth is associated with reduced risk for acute COVID-19 progression, but with increased risk of PASC. Persistent microvascular endotheliopathy associated with cryptic SARS-CoV-2 tissue reservoirs has been implicated in PASC pathology. Autoantibodies, localized inflammation, and reactivation of latent pathogens may also be involved, potentially leading to microvascular thrombosis, as documented in multiple PASC tissues. Diagnostic assays illuminating possible therapeutic targets are discussed.     

New insights into molecular mechanisms of sunitinib-associated side effects

The introduction of targeted therapy represents a major advance in the treatment of tumor progression. Targeted agents are a novel therapeutic approach developed to disrupt different cellular signaling pathways. The tyrosine kinase inhibitor sunitinib specifically blocks multiple tyrosine kinase receptors that are involved in the progression of many tumors. Sunitinib is the current standard of care in first-line treatment of advanced renal cell carcinoma, and it is approved in imatinib-intolerant and imatinib-refractory gastrointestinal stromal tumors. However, it is increasingly evident that sunitinib may display collateral effects on other proteins beyond its main target receptors, eliciting undesirable and unexpected adverse events. A better understanding of the molecular mechanisms underlying these undesirable sunitinib-associated side effects will help physicians to maximize efficacy of sunitinib and minimize adverse events. Here, we focus on new insights into molecular mechanisms that may mediate sunitinib-associated adverse events.     

T cell tolerance to inhaled allergens: mechanisms and therapeutic approaches

Background: Specific immune response to allergens is decisive in the development of clinically healthy or allergic states. Objective: Recent developments in the mechanisms of allergen-specific peripheral tolerance can be used for future treatment modalities. Methods: This review focuses on recent developments in allergen tolerance. Results/conclusion: The balance between allergen-specific IL-10-secreting T regulatory cells (Tr1) and T helper 2 (Th2) cells appears to be decisive in the development of allergic and healthy immune response against allergens. Induction of IL-10- and TGF-β-producing Tr1 cells, IgG4-isotype-blocking antibodies, and suppressed mast cells, basophils and eosinophils represent major components of a relatively normalized immune response after allergen-specific immunotherapy and healthy immune response to aeroallergens in sensitized individuals.     

New insights into the cellular and molecular mechanisms of cold storage injury.

Solid organ grafts, but also other biologic materials requiring storage for a few hours to a few days, are usually stored under hypothermic conditions. To decrease graft injury during cold storage, organ preservation solutions were developed many years ago. However, since then, modern biochemical and cell biologic methods have allowed further insights into the molecular and cellular mechanisms of cold storage injury, including further insights into alterations of the cellular ion homeostasis, the occurrence of a mitochondrial permeability transition, and the occurrence of free-radical-mediated hypothermic injury and cold-induced apoptosis. These new aspects of cold storage injury, which are not covered by preservation solutions in current clinical use and offer the potential for improvement of organ and tissue preservation, are presented here.     

Long QT syndrome: novel insights into the mechanisms of cardiac arrhythmias

The congenital long QT syndrome is a rare disorder in which mutation carriers are at risk for polymorphic ventricular tachycardia and/or sudden cardiac death. Discovery and analysis of gene mutations associated with variants of this disorder have provided novel insight into mechanisms of cardiac arrhythmia and have raised the possibility of mutation-specific therapeutic intervention.     

RhoA/Rho-kinase in erectile tissue: mechanisms of disease and therapeutic insights

Penile erection is a complicated event involving the regulation of corpus cavernosal smooth muscle tone. Recently, the small monomeric G-protein RhoA and its downstream effector Rho-kinase have been proposed to be important players for mediating vasoconstriction in the penis. RhoA/Rho-kinase increases MLC (myosin light chain) phosphorylation through inhibition of MLCP (MLC phosphatase) thereby increasing Ca2+ sensitivity. This review will outline the RhoA/Rho-kinase signalling pathway, including the upstream regulators, guanine nucleotide exchange factors, GDP dissociation inhibitors and GTPase-activating proteins. We also summarize the current knowledge about the physiological roles of RhoA/Rho-kinase in both male and female erectile tissues and its aberrations contributing to erectile dysfunction in several disease states. Understanding the RhoA/Rho-kinase signalling pathway in the regulation of erection is important for the development of therapeutic interventions for erectile dysfunction.     

Update on new diagnostic and therapeutic approaches for sarcomas

Sarcomas represent a family of uncommon malignancies related by histopathology and developmental biology. Sarcomas arise from any of the mesodermal tissues anywhere in the body (muscles, tendons, adipose tissue, blood vessels, and joints) from cells of mesenchymal origin or in the peripheral nervous system, derived from the ectoderm. Mainly diagnosed in the extremities, sarcomas can be present also in soft tissues of the trunk, abdomen, and retroperitoneum, as well as the head and neck. During the last decade, improvements in diagnostic techniques have made it possible to identify and characterize a subset of sarcomas arising within the gastrointestinal tract known as gastrointestinal stromal tumors, which were previously commonly misclassified as leiomyosarcomas. Sarcomas are extremely heterogeneous, so expert histopathologic characterization is essential to choose the appropriate path of multidisciplinary treatment and predict possible clinical outcomes. The aim of this review is to provide a brief overview of the epidemiology, pathology, clinical presentation, and new approaches to the treatment of adult soft-tissue and bone sarcomas.