Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia: Russian Multicenter Clinical Trial

Background. Recent advances in the treatment of relapsed/refractory acute lymphoblastic leukemia (R/R ALL) are attributed to the implementation of immunotherapy methods which include blinatumomab, the bispecific engager of a patient’s endogenous T-cells (Blincyto™, Amgen®) (BC). Aim. To assess BC efficacy and toxicity in the treatment of R/R ALL patients with persistence of minimal tumor clone before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Materials & Methods. The trial included 66 B-ALL patients with CD19+ aged 18 to 72 years, 23 (35 %) of them with measurable minimal residual disease (MRD+) and 43 (65 %) with R/R ALL. In 18 (27 %) patients BC was administered after prior allo-HSCT. Results. In the overall group 2-year overall survival (OS) and disease-free survival (DFS) in patients with response to BC treatment were 53 % and 38 % respectively. In the R/R ALL group complete remission (CR) was achieved in 29 (67 %) patients including 24 (83 %) patients with negative MRD. CR rate was higher in standard cytogenetic risk group (73 %) in comparison with high-risk group (59 %). In patients with more or less than 50 % blast cells in bone marrow CR rate was 85 % and 61 %, respectively. When BC was administered after prior allo-HSCT and without it CR rate was 80 % and 60 %, respectively. In R/R ALL patients with response to BC 2-year OS and DFS were 40 % and 26 %, respectively, in the MRD+ group of ALL patients they were 66 % and 51 %, respectively. Relapse rate was lower in the group with allo-HSCT than in the group without it, i.e. 21 % vs. 55 %. Adverse events of grade 3–4 were observed in 25 (38 %) patients. In 11 (16 %) patients BC therapy had to be discontinued, in 5 (7 %) patients it was terminated prior to the scheduled date. Conclusion. BC efficacy is higher in the MRD+ group and in R/R ALL patients with smaller tumor mass. BC treatment after allo-HSCT yields remissions in most patients and can be combined with immune-adoptive therapy

Cardiotrophin-1 and components of metabolic syndrome: what is the role in the development of atrial fibrillation?

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Pavlov University Introduction. The cardiotrophin-1 (CT-1) is a cytokine from the interleukin-6 family associated with pathology of the cardiovascular system, contributing to myocardial remodeling and the development of fibrosis in patients with hypertension. CT-1 is involved in the regulation of energy processes and the metabolism of adipose tissue, as well as in the regulation of lipid and carbohydrate metabolism. Revealed an increase in the deposition of type I collagen in the atrial myocardium against the background of dilatation of the left atrium and an increase in the expression of CT-1. The role of CT-1 in the development of AF is currently being actively studied. Purpose. To determine the concentration of cardiotrophin-1 (CT-1) in patients with metabolic syndrome (MS) and atrial fibrillation (AF) with an assessment of the relationship with the parameters of obesity and metabolic disorders. Methods. In a one-stage case-control study, 352 patients aged 35 to 65 years were included: patients with MS (n = 223), of which 107 patients with AF, and comparison groups consisted of patients with AF without MS (n = 69) and practically healthy examined without cardiovascular diseases and metabolic disorders (n = 60). Results. It was found that the concentration of CT-1 in serum in patients with AF is higher than in patients with MS without AF (766,2 (539,2-1032,3) and 590,2 (480,1-922,3) pg/ml, p = 0,005) and higher than in healthy subjects (780,2 (550,2-1050,3) and 410,1 (290,2-549,2) pg/ml, p &amp;lt; 0,0001). It was found that in patients with AF and MS, the concentration of CT-1 in the blood serum is higher than in patients with AF without MS (851,2 (589,1-1146,3) and 681,1 (480,1-823,2) pg/ml, p = 0,004). CT-1 positively correlates with the concentration of glucose in blood plasma (r = 0,423, p = 0.002) and triglycerides (r = 0,207, p = 0,003), as well as with the waist circumference (r = 0,265, p &amp;lt; 0.001) and the thickness of epicardial fat (r = 0,351, p &amp;lt; 0,001). Using ROC analysis, it was found that with an increase in the concentration of CT-1 in blood serum more than 638,1 pg/ml, the probability of AF increased by 4 times (OR = 4.0, 95%CI 2,31-6,94, p &amp;lt; 0,0001). Conclusion. An increase of serum CT-1 concentration is associated with heart remodeling and obesity in patients with MS and probably has a pathogenetic role in increasing the risk of AF in this cohort of patients. </jats:sec

Entry inhibitors: New advances in HCV treatment

Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and causes chronic liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although current antiviral therapy comprising direct-acting antivirals (DAAs) can achieve a quite satisfying sustained virological response (SVR) rate, it is still limited by viral resistance, long treatment duration, combined adverse reactions, and high costs. Moreover, the currently marketed antivirals fail to prevent graft reinfections in HCV patients who receive liver transplantations, probably due to the cell-to-cell transmission of the virus, which is also one of the main reasons behind treatment failure. HCV entry is a highly orchestrated process involving initial attachment and binding, post-binding interactions with host cell factors, internalization, and fusion between the virion and the host cell membrane. Together, these processes provide multiple novel and promising targets for antiviral therapy. Most entry inhibitors target host cell components with high genetic barriers and eliminate viral infection from the very beginning of the viral life cycle. In future, the addition of entry inhibitors to a combination of treatment regimens might optimize and widen the prevention and treatment of HCV infection. This review summarizes the molecular mechanisms and prospects of the current preclinical and clinical development of antiviral agents targeting HCV entry

Therapeutic strategies targeting connexins

The connexin family of channel-forming proteins is present in every tissue type in the human anatomy. Connexins are best known for forming clustered intercellular channels, structurally known as gap junctions, where they serve to exchange members of the metabolome between adjacent cells. In their single-membrane hemichannel form, connexins can act as conduits for the passage of small molecules in autocrine and paracrine signalling. Here, we review the roles of connexins in health and disease, focusing on the potential of connexins as therapeutic targets in acquired and inherited diseases as well as wound repair, while highlighting the associated clinical challenges