Asciminib add-on to imatinib demonstrates sustained high rates of ongoing therapy and deep molecular responses with prolonged follow-up in the ASC4MORE study.

Background: Up to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate-competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy.

Anticipatory anxiety and participation in cancer screening. A systematic review.

Objectives: To synthesize current evidence on the association between anticipatory anxiety, defined as apprehension-specific negative affect that may be experienced when exposed to potential threat or uncertainty, and cancer screening to better inform strategies to maximize participation rates.

Methods: Searches related to cancer screening and anxiety were conducted in seven electronic databases (APA PsycINFO, Scopus, Web of Science, Embase, Cochrane Library, PubMed, CINAHL), with potentially eligible papers screened in Covidence. Data extraction was conducted independently by multiple authors.

Long-term Outcomes of Testosterone Treatment in Men: A T4DM Postrandomization Observational Follow-up Study.

Context: The T4DM study randomized 1007 men with impaired glucose tolerance or newly diagnosed diabetes to testosterone undecanoate (TU, 1000 mg) or matching placebo (P) injections every 12 weeks for 24 months with a lifestyle program with testosterone (T) treatment reducing diabetes diagnosis by 40%.

Background: The long-term effects on new diagnosis of diabetes, cardiovascular and prostate disease, sleep apnea, weight maintenance trajectory and androgen dependence were not yet described.

Methods: A follow-up email survey after a median of 5.

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results.

Asciminib is approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10-200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.

Molecular response in newly diagnosed chronic-phase chronic myeloid leukemia: prediction modeling and pathway analysis.

Tyrosine kinase inhibitor therapy revolutionized chronic myeloid leukemia treatment and showed how targeted therapy and molecular monitoring could be used to substantially improve survival outcomes. We used chronic myeloid leukemia as a model to understand a critical question: why do some patients have an excellent response to therapy, while others have a poor response? We studied gene expression in whole blood samples from 112 patients from a large phase III randomized trial (clinicaltrials gov. Identifier: NCT00471497), dichotomizing cases into good responders (BCR::ABL1 ≤10% on the International Scale by 3 and 6 months and ≤0.

Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL.

Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.

Development of asciminib, a novel allosteric inhibitor of BCR-ABL1.

Chronic myeloid leukemia (CML) is driven by a translocation event between chromosomes 9 and 22, leading to the formation of a constitutively active BCR-ABL1 oncoprotein. Approved tyrosine kinase inhibitors (TKIs) for CML inhibit BCR-ABL1 by competitively targeting its adenosine triphosphate (ATP)-binding site, which significantly improves patient outcomes. However, resistance to and intolerance of TKIs remains a clinical challenge.

A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs.

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily.

Mental Health and Psychosocial Challenges in the COVID-19 Pandemic: Food for Thought for Cardiovascular Health Care Professionals.

Background: The coronavirus disease (COVID-19) pandemic has produced substantial health challenges from the perspective of both its direct health complications and the disruption to delivery of standard care for individuals with a range of acute and chronic health issues. In parallel, the widespread application of social isolation initiatives in most countries raises the potential for significant mental health consequences and psychosocial impacts. This has major implications for cardiovascular health care professionals and the management of their patients.

Optimising Secondary Prevention and Cardiac Rehabilitation for Atherosclerotic Cardiovascular Disease During the COVID-19 Pandemic: A Position Statement From the Cardiac Society of Australia and New Zealand (CSANZ).

Background: The coronavirus disease 2019 (COVID-19) pandemic has introduced a major disruption to the delivery of routine health care across the world. This provides challenges for the use of secondary prevention measures in patients with established atherosclerotic cardiovascular disease (CVD). The aim of this Position Statement is to review the implications for effective delivery of secondary prevention strategies during the COVID-19 pandemic.

Characterizing localized reentry with high-resolution mapping: Evidence for multiple slow conducting isthmuses within the circuit.

Background: Reentrant circuits are considered to be critically dependent on a single protected slow conducting isthmus.

Objective: The purpose of this study was to investigate conduction properties and electrogram (EGM) characteristics of the entire circuit in localized atrial reentrant circuits using high-resolution mapping.

Methods: Fifteen localized reentrant atrial tachycardias were studied with high-resolution mapping (Rhythmia).

Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis.

Treatment of patients with myelofibrosis with the type I JAK (Janus kinase) inhibitor ruxolitinib paradoxically induces JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn. We developed a time-dependent assay to mimic ruxolitinib withdrawal in primary JAK2 and CALR mutant myelofibrosis patient samples and observed notable activation of spontaneous STAT signaling in JAK2 samples after drug washout. Accumulation of ruxolitinib-induced JAK2 phosphorylation was dose dependent and correlated with rebound signaling and the presence of a JAK2 mutation.

Management of Severe Dyslipidaemia: Role of PCSK9 Inhibitors.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulation of LDL receptors on the hepatocyte surface and therefore is essential for effective removal of LDL particles from circulation. Genetic and biochemical studies have established that altered PCSK9 functionality influences both LDL cholesterol levels and cardiovascular risk. This has prompted development of inhibitory strategies targeting PCSK9.

A dual role for the N-terminal domain of the IL-3 receptor in cell signalling.

The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W.

Recommendations on Arresting Global Health Challenges Facing Adolescents and Young Adults.

Background: The health challenges faced by young people are more complex than adults and can compromise their full growth and development. Attention must be paid to the health of this age group, yet adolescents and youth remain largely invisible and often disappear from the major global datasets.

Objective: The aim of this paper is to discuss the global health challenges faced by adolescents and youth, global legislations and guidelines pertaining to this particular age group, recommendations to arrest these challenges, and research priorities.

Role of the β Common (βc) Family of Cytokines in Health and Disease.

The β common ([βc]/CD131) family of cytokines comprises granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5, all of which use βc as their key signaling receptor subunit. This is a prototypic signaling subunit-sharing cytokine family that has unveiled many biological paradigms and structural principles applicable to the IL-2, IL-4, and IL-6 receptor families, all of which also share one or more signaling subunits. Originally identified for their functions in the hematopoietic system, the βc cytokines are now known to be truly pleiotropic, impacting on multiple cell types, organs, and biological systems, and thereby controlling the balance between health and disease.

Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia.

Background: Imatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy.

Methods: In this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine.

Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia.

Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry-based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML.

Implications of Total to High-Density Lipoprotein Cholesterol Ratio Discordance With Alternative Lipid Parameters for Coronary Atheroma Progression and Cardiovascular Events.

The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio may quantify atherogenic lipoproteins beyond low-density lipoprotein cholesterol (LDL-C), non-HDL-C and apolipoprotein B (apoB). We analyzed pooled data from 9 trials involving 4,957 patients with coronary artery disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (ΔPAV) and 2-year major adverse cardiovascular event (MACE) rates when TC/HDL-C levels were discordant with LDL-C, non-HDL-C, and apoB. Discordance was investigated when lipid levels were stratified by View Article and Find Full Text PDF

eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures.

Alterations in the balance of inhibitory and excitatory synaptic transmission have been implicated in the pathogenesis of neurological disorders such as epilepsy. Eukaryotic elongation factor 2 kinase (eEF2K) is a highly regulated, ubiquitous kinase involved in the control of protein translation. Here, we show that eEF2K activity negatively regulates GABAergic synaptic transmission.

Role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle.

During induction of the autophagosomal degradation process, LC3-I is lipidated to LC3-II and associates to the cargo isolation membrane allowing for autophagosome formation. Lipidation of LC3 results in an increased LC3-II/LC3-I ratio, and this ratio is an often used marker for autophagy in various tissues, including skeletal muscle. From cell studies AMPK has been proposed to be necessary and sufficient for LC3 lipidation.

Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel.

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are muscle-related.

Evolving targets for lipid-modifying therapy.

The pathogenesis and progression of atherosclerosis are integrally connected to the concentration and function of lipoproteins in various classes. This review examines existing and emerging approaches to modify low-density lipoprotein and lipoprotein (a), triglyceride-rich lipoproteins, and high-density lipoproteins, emphasizing approaches that have progressed to clinical evaluation. Targeting of nuclear receptors and phospholipases is also discussed.