Biomarkers for heart failure: small molecules with high clinical relevance

Heart failure (HF) is a rising epidemic due to the ageing population and progress in all areas of medicine. Thus, research efforts are made to ensure a timely diagnosis, to improve prognosis and treatment of the disease and to facilitate risk prediction at the population level. Because of their noninvasive determination with mostly high sensitivity and accuracy, circulating blood biomarkers are becoming increasingly important for daily clinical practice. Natriuretic peptides, especially B‐type natriuretic peptide (BNP), N‐terminal pro‐B‐type natriuretic peptide (Nt‐proBNP) and midregional pro‐atrial natriuretic peptide (MR‐proANP) and cardiac troponins are established blood biomarkers in HF diagnosis and prognosis of HF‐related outcomes. Inflammatory molecules as C‐reactive protein (CRP) may have added value in anti‐inflammatory therapy guidance. Next‐generation biomarkers including soluble source of tumorigenicity 2 (sST2), growth differentiation factor‐15 (GDF‐15), galectin‐3 (Gal‐3) and diverse microribonucleic acids (miRNAs) may have additional benefit in assessment of cardiac remodeling or differentiation of HF subtypes. Multimarker approaches containing different combinations of established and novel biomarkers might improve HF risk prediction at the population level once they are used on top of clinical variables.     

Pathogenesis of post-traumatic OA with a view to intervention

Post-traumatic osteoarthritis (PTOA) subsequent to joint injury accounts for over 12% of the overall disease burden of OA, and higher in the most at-risk ankle and knee joints. Evidence suggests that the pathogenesis of PTOA may be related to inflammatory processes and alterations to the articular cartilage, menisci, muscle and subchondral bone that are initiated in the acute post-injury phase. Imaging of these early changes, as well as a number of biochemical markers, demonstrates the potential for use as predictors of future disease, and may help stratify patients on the likelihood of their developing clinical disease. This will be important in guiding future interventions, which will likely target elements of the inflammatory response within the joint, molecular abnormalities related to cartilage matrix degradation, chondrocyte function and subchondral bone remodelling. Until significant improvements are made, however, in identifying patients most at risk for developing PTOA – and therefore those who are candidates for therapy – primary prevention programmes will remain the most effective current management tools.     

Assessment and management of methotrexate hepatotoxicity in psoriasis patients: report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic

Experts in psoriasis, hepatology, pharmacokinetics and pharmacogenetics convened to discuss the safety and monitoring of methotrexate with respect to hepatotoxicity when used in the treatment of psoriasis. Methotrexate is an efficacious and cost‐effective treatment for psoriasis, but is associated with significant safety issues, particularly relating to hepatotoxicity. Current British, Dutch, German, EU and US guidelines for baseline evaluations, monitoring and prevention of hepatotoxicity in patients with psoriasis receiving methotrexate were evaluated. Liver safety monitoring is currently reliant upon multiple methods, including biopsy, serological tests for biomarkers such as type III procollagen amino terminal propeptide (PIIINP), and liver function tests based on liver enzymes. Monitoring of patients receiving long‐term therapy is expected to be improved by the utilization of serum biomarkers currently in development such as the Enhanced Liver Fibrosis (ELF) panel and other non‐invasive tests of hepatic architecture, such as fibroelastography, microbubbles and magnetic resonance imaging. Appropriate studies to determine optimal dosing to maximize efficacy and minimize toxicity, potentially utilizing pharmacogenetic principles, are clearly needed. Key questions for future research are identified including needs for optimal screening and monitoring, identification of appropriate biomarkers, assessment of relationships between dosing and safety, utility of liver biopsy, optimal dosing regimens (including route of administration), methods to measure methotrexate levels in blood, and use of methotrexate as a standardized active comparator in trials of experimental drugs used to treat psoriasis.     

Optical coherence tomography (OCT) study in Argentinean Huntington’s disease patients

Abstract

Background: Huntington’s disease (HD) is a genetic, rare and progressive neurodegenerative disorder that causes motor and cognitive impairment in midlife patients. Although retinal damage was observed in animal HD models and in patients with other neurodegenerative diseases, we still need confirmation of impairment in HD patients. Optical coherence tomography (OCT) is a non-invasive methodology that analyses the retinal nerve fibre layers (RNFL) and could reflect processes of neurodegeneration.

Methods: A cross-sectional study with 14?HD patients who underwent a spectral domain OCT. Results were compared with a control group. Demographic data were also obtained.

Results: Temporal and superior RNFL sectors in HD showed a significant RNFL thinning compared with a control group. However, no differences were identified in mean total RNFL thickness between HD patients and controls.

Conclusions: OCT is a rapid and non-invasive technique that can be investigated in larger cohorts of patients to assess its potential role as a biomarker in HD patients.     

Developments in the discovery of drugs for spinal muscular atrophy: successful beginnings and future prospects

Introduction: Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in a gene that produces a protein called survival motor neuron (SMN). SMN has an important role in snRNP assembly in all cells but that may not be its only role; the reasons for SMN deficiency resulting in neuromuscular dysfunction and motor neuron degeneration remain active areas of research. Besides increasing SMN, compensating for SMN deficiencies or neuroprotection may be therapeutic options for SMA. Age of onset and the rate of disease progression are variable and therapeutic strategies should be appropriate to subtypes of SMA patients.

Areas covered: The article discusses SMA, their targets and where these targets can be found. Additionally, the article reviews small molecules identified as disease modifiers and how these small molecules were discovered. The article also describes and discusses emerging concepts regarding the disease mechanisms. The author compiled this review using scientific literature, patent databases, company and patient association and government websites.

Expert opinion: Small molecules targeting various processes implicated in SMA are reaching the clinic. These molecules and targets, although not yet validated, are providing insight into the complexity of a ‘simple’ genetic disease such as SMA. SMA is not a single disease and so various therapeutic strategies are needed. Biomarkers and regulatory guidelines are required to select patients for clinical trials, decide when to initiate treatment and how to develop combinations of investigational drugs.     

Angiogenesis in salivary gland tumors: from clinical significance to treatment

Introduction: Salivary gland tumors (SGTs) represent a rare cancer entity, consisting of various morphological features that complicate diagnosis. Their diversity in terms of morphology and clinical course makes defining risk factors difficult, while the molecular steps responsible for SGT development remain unclear. Angiogenesis, a hallmark of cancer development, is considered as an attractive target.

Areas covered: This review aims to summarize the available research regarding angiogenesis in SGTs from clinical significance to treatment options.

Expert opinion: The available data suggest that microvessel density (MVD) evaluation may be capable of discriminating between benign and malignant SGTs, while the use of CD105 antibody seems to be the most suitable. Substantial evidence also suggests that MVD and VEGF expression could be used as prognostic factors in malignant SGTs. Although several agents have shown antiangiogenic activities in adenoid cystic carcinoma cells and xenograft tumors, limited effectiveness in the existing clinical trials was noted. Further studies are strongly recommended for the validation of already well-known and the identification of novel prognostic and predictive angiogenic markers. There is also a strong demand for relatively larger cohorts, homogenous samples referring to same histological SGT subtypes and including an equivalent number of low- and high-grade SGTs.