The Emerging Role of c-Met in Carcinogenesis and Clinical Implications as a Possible Therapeutic Target

Background. c-MET is a receptor tyrosine kinase receptor (RTK) for the hepatocyte growth factor (HGF). The binding of HGF to c-MET regulates several cellular functions: differentiation, proliferation, epithelial cell motility, angiogenesis, and epithelial-mesenchymal transition (EMT). Moreover, it is known to be involved in carcinogenesis. Comprehension of HGF-c-MET signaling pathway might have important clinical consequences allowing to predict prognosis, response to treatment, and survival rates based on its expression and dysregulation. Discussion. c-MET represents a useful molecular target for novel engineered drugs. Several clinical trials are underway for various solid tumors and the development of new specific monoclonal antibodies depends on the recent knowledge about the definite c-MET role in each different malignance. Recent clinical trials based on c-MET molecular targets result in good safety profile and represent a promising therapeutic strategy for solid cancers, in monotherapy or in combination with other target drugs. Conclusion. The list of cell surface receptors crosslinking with the c-MET signaling is constantly growing, highlighting the importance of this pathway for personalized target therapy. Research on the combination of c-MET inhibitors with other drugs will hopefully lead to discovery of new effective treatment options.

Atrial Functional Tricuspid Regurgitation as a Distinct Pathophysiological and Clinical Entity: No Idiopathic Tricuspid Regurgitation Anymore

Functional tricuspid regurgitation (FTR) is a strong and independent predictor of patient morbidity and mortality if left untreated. The development of transcatheter procedures to either repair or replace the tricuspid valve (TV) has fueled the interest in the pathophysiology, severity assessment, and clinical consequences of FTR. FTR has been considered to be secondary to tricuspid annulus (TA) dilation and leaflet tethering, associated to right ventricular (RV) dilation and/or dysfunction (the “classical”, ventricular form of FTR, V-FTR) for a long time. Atrial FTR (A-FTR) has recently emerged as a distinct pathophysiological entity. A-FTR typically occurs in patients with persistent/permanent atrial fibrillation, in whom an imbalance between the TA and leaflet areas results in leaflets malcoaptation, associated with the dilation and loss of the sphincter-like function of the TA, due to right atrium enlargement and dysfunction. According to its distinct pathophysiology, A-FTR poses different needs of clinical management, and the various interventional treatment options will likely have different outcomes than in V-FTR patients. This review aims to provide an insight into the anatomy of the TV, and the distinct pathophysiology of A-FTR, which are key concepts to understanding the objectives of therapy, the choice of transcatheter TV interventions, and to properly use pre-, intra-, and post-procedural imaging.

Efficacy of conservative physiotherapeutic approaches in hormonal-related headaches: a scoping review protocol.

ABSTRACT Introduction. Headache is one of the most common and disabling conditions worldwide, as described by the World Health Organization report. The risk of suffering from headache has been described to increase from twofold to threefold in adult women compared to men, depending on the studies. These gender differences have been linked to environmental, genetic, epigenetic, and hormonal aspects. Sex hormones can enhance headaches mainly through sensitization of the trigemino-vascular system and modulation of the blood vessel factors, with significant clinical consequences. International guidelines suggest several pharmacological and non-pharmacological treatments in the management of headache disorders as acute or preventive therapies. Few studies have been conducted on the efficacy and effectiveness of therapies in managing hormonal-related headaches to date. Therefore, this scoping review (ScR) aims to summarize the evidence regarding the efficacy of conservative physiotherapeutic approaches on this topic in the domain of gender medicine, which studies sex influences on pathophysiology, clinical signs, prevention, and therapy of diseases. Methods and analysis. The ScR will be performed following the 6-stage methodology suggested by Arksey and O Malley and the extensions to the original framework recommended by the Joanna Briggs Institute. MEDLINE, Cochrane Central, Scopus, CINHAL, Embase and PEDro databases will be searched. Additional records will be identified through searching in grey literature and the reference lists of all relevant studies. No study design, publication type, language nor date restrictions will be applied. Two reviewers will independently screen all abstracts and full-text studies for inclusion. The research team will develop a data collection form to extract the studies characteristics. A tabular and accompanying narrative summary of the information will be provided. This protocol received input from all authors who have expertise in research methodology and specific knowledge in the field. Ethics and dissemination. This study does not require ethical approval as we will not collect personal data. It will summarize information from publicly available studies in line with the nature of the study s methodology. Regarding dissemination activities, the results of this review will be submitted for publication in a peer-reviewed journal, presented at relevant conferences in the field and disseminated through working groups, webinars and partners. KEYWORDS Headache, menstruation, hormones, physical therapy, exercise therapy.

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

International practice variation in perioperative laboratory testing in glioblastoma patients—a retrospective cohort study

Purpose Although standard-of-care has been defined for the treatment of glioblastoma patients, substantial practice variation exists in the day-to-day clinical management. This study aims to compare the use of laboratory tests in the perioperative care of glioblastoma patients between two tertiary academic centers—Brigham and Women’s Hospital (BWH), Boston, USA, and University Medical Center Utrecht (UMCU), Utrecht, the Netherlands. Methods All glioblastoma patients treated according to standard-of-care between 2005 and 2013 were included. We compared the number of blood drawings and laboratory tests performed during the 70-day perioperative period using a Poisson regression model, as well as the estimated laboratory costs per patient. Additionally, we compared the likelihood of an abnormal test result using a generalized linear mixed effects model. Results After correction for age, sex, IDH1 status, postoperative KPS score, length of stay, and survival status, the number of blood drawings and laboratory tests during the perioperative period were 3.7-fold (p < 0.001) and 4.7-fold (p < 0.001) higher, respectively, in BWH compared to UMCU patients. The estimated median laboratory costs per patient were 82 euros in UMCU and 256 euros in BWH. Furthermore, the likelihood of an abnormal test result was lower in BWH (odds ratio [OR] 0.75, p < 0.001), except when the prior test result was abnormal as well (OR 2.09, p < 0.001). Conclusions Our results suggest a substantially lower clinical threshold for ordering laboratory tests in BWH compared to UMCU. Further investigating the clinical consequences of laboratory testing could identify over and underuse, decrease healthcare costs, and reduce unnecessary discomfort that patients are exposed to.

Men’s health and osteoporosis: modern treatment and prevention options

Osteoporosis (OP) has traditionally been seen as a pathology that mainly occurs in postmenopausal women and elderly men, and until recently, the problem of this disease among males has not been given sufficient priority. At the moment, however, OP in men is widely acknowledged to be an important issue of modern health care. Given the etiological and pathogenetic characteristics, two categories of OP have been identified: primary and secondary. In the structure of male OP, the secondary category of OP accounts for up to 40-60 % of all cases. Hypogonadism is one of the common causes of bone loss in men. Initially, males develop a larger bone mass compared to women and, accordingly, greater bone strength. Men over the age of 50 do not undergo rapid bone mass loss, as women do after menopause, and the bone mass decreases more gradually, in a linear manner. With ageing, the trabecular number (Tb.N) in men are relatively maintained with underlying more pronounced thinning of Tb. N associated with decreased osteoblast-forming activity. Although the prevalence of OP among men is significantly lower than among women, the clinical consequences of OP in men are of a great importance. The primary strategy of the anti-osteoporotic therapy is to prevent OP and low-traumatic fractures. According to the current guidelines for the treatment of OP in men, bisphosphonates (BP) are the drugs of choice. Zoledronic acid is a highly effective nitrogen-containing BP, the first drug to be injected once a year. Intravenous injection of zoledronic acid is as effective in reducing the risk of fractures in men as in women.

CFTR variants are associated with chronic bronchitis in smokers

IntroductionLoss of function variants in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF); however, there is evidence that reduction in CFTR function due to the presence of one deleterious variant can have clinical consequences. Here, we hypothesize that CFTR variants in individuals with a history of smoking are associated with COPD and related phenotypes.MethodsWhole genome sequencing was performed through the NHLBI TOPMed program in 8597 subjects from the COPDGene study, an observational study of current and former smokers. We extracted clinically annotated CFTR variants and performed single variant and variant-set testing for COPD and related phenotypes. Replication was performed in 2,118 subjects from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study.ResultsWe identified 301 coding variants within the CFTR gene boundary: 147 of these have been reported in individuals with CF, including 36 CF-causing variants. We found that CF causing variants were associated with chronic bronchitis in variant-set testing in COPDGene (one sided p-value=0.0025, OR=1.53) and in meta-analysis of COPDGene and ECLIPSE (one sided p-value=0.0060, OR=1.52). Single variant testing revealed that the F508del variant was associated with chronic bronchitis in COPDGene (one sided p-value=0.015, OR=1.47). In addition, we identified 32 subjects with two or more CFTR variants on separate alleles, and these subjects were enriched for COPD cases (p=0.010).ConclusionsCigarette smokers who carry one deleterious CFTR variant have higher rates of chronic bronchitis, while presence of two CFTR variants may be associated with COPD. These results indicate that genetically-mediated reduction in CFTR function contributes to COPD related phenotypes, in particular chronic bronchitis.

Antibody-dependent enhancement of virus infection and disease: implications in COVID-19

Antibody-dependent enhancement (ADE) can be seen in a variety of viruses. It has a deleterious impact on antibody treatment of viral infection. This effect was first discovered in the dengue virus, and it has since been discovered in the coronavirus. Over 213 million people have been affected by the rapid spread of the newly emerging coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). The new coronavirus offers a significant threat and has sparked widespread concern. ADE in dengue virus and other viruses are discussed with possible effect on COVID-19 treatment and vaccine development will need to consider this phenomenon to ensure it is mitigated and avoided altogether. In these case scenarios, the role of ADE and its clinical consequences remains to be explored for this newly detected virus.