Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1.

Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds.

Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein-Protein Interaction Modulator with the Potential of Treating Hematological Malignancies.

Avoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy.

Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity.

Mining the Microbiome and Microbiota-Derived Molecules in Inflammatory Bowel Disease.

The intestinal microbiota is a complex community that consists of an ecosystem with a dynamic interplay between bacteria, fungi, archaea, and viruses. Recent advances in model systems have revealed that the gut microbiome is critical for maintaining homeostasis through metabolic digestive function, immune regulation, and intestinal barrier integrity. Taxonomic shifts in the intestinal microbiota are strongly correlated with a multitude of human diseases, including inflammatory bowel disease (IBD).

The Impact of Deployment and Combat Exposure on Physical Health Among Military Personnel: A Systematic Review of Incidence, Prevalence, and Risks.

Objectives: The impact of deployment and combat on mental health of military personnel is well described. Less evidence is available to demonstrate and summarize the incidence, prevalence, and risks of these exposures on physical health. This study aims to (1) systematically review the available literature to determine the incidence and prevalence of physical health conditions among military personnel during and after deployment and (2) investigate the risks of deployment and combat exposure on physical health.

Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease.

We describe a series of potent and highly selective small-molecule MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC: 0.01 µM) in a biochemical assay measuring MALT1 enzymatic activity, as well as in cellular assays: Jurkat T cell activation (0.

Epidemiology and Financial Burden of Musculoskeletal Injuries as the Leading Health Problem in the Military.

Introduction: Musculoskeletal injuries (MSIs) have direct impact on occupational readiness and task performance in military populations. Until this date, no epidemiologic data have been published concerning MSI incidence in the Netherlands Armed Forces (NAF). The aim of this study was to assess the MSI incidence and related costs in the NAF.

Challenges in managing urinary tract infection and the potential of a point-of-care test guided care in primary care: an international qualitative study.

Background: Little is known about clinicians' experiences of using a point-of-care test (POCT) to inform management of urinary tract infection (UTI) in general practice.

Aim: To explore experiences of using the Flexicult test to inform management of UTI and views on requirements for an optimal POCT to inform successful implementation.

Design & Setting: Telephone interviews with 35 primary care clinicians and healthcare professionals in Wales, England, Spain, and the Netherlands, who had participated in a trial of the Flexicult POCT for UTI based on urine culture.

Talking about human papillomavirus and cancer: development of consultation guides through lay and professional stakeholder coproduction using qualitative, quantitative and secondary data.

Background: High-risk human papillomaviruses (HPVs) cause all cervical cancer and the majority of vulvar, vaginal, anal, penile and oropharyngeal cancers. Although HPV is the most common sexually transmitted infection, public awareness of this is poor. In addition, many clinicians lack adequate knowledge or confidence to discuss sexual transmission and related sensitive issues.

Loving-Kindness Meditation Effects on Well-Being and Altruism: A Mixed-Methods Online RCT.

Background: Evidence suggests that facilitating empathy could improve individuals' well-being. Loving-kindness meditation (LKM) could be a facilitator, and online delivery a cost-effective format.

Methods: We conducted an internet-based randomised controlled trial recruiting 809 adults to test whether an LKM course improves well-being through evoking pleasant emotions, psychological resources, and altruism compared to a light physical exercise course (LE).

Motivational interviewing competencies among UK family nurse partnership nurses: a process evaluation component of the building blocks trial.

Background: Motivational Interviewing (MI) is a person-centred counselling approach to behaviour change which is increasingly being used in public health settings, either as a stand-alone approach or in combination with other structured programmes of health promotion. One example of this is the Family Nurse Partnership (FNP) a licensed, preventative programme for first time mothers under the age of 20, delivered by specialist family nurses who are additionally trained in MI. The Building Blocks trial was an individually randomised controlled trial comparing effectiveness of Family Nurse Partnership when added to usual care compared to usual care alone within 18 sites in England.

Talking about human papillomavirus and cancer: protocol for a patient-centred study to develop scripted consultations.

Introduction: Persistent infection with sexually transmitted, high-risk human papillomavirus (HPV) types is the cause of all cervical cancers and some anogenital and oropharyngeal cancers. HPV is an extremely common asymptomatic infection but little known and poorly understood by the public. Patients with HPV-related cancers have new and challenging information needs due to the complex natural history of HPV and the stigma of sexual transmission.

A feasibility study to inform the design of a randomised controlled trial to identify the most clinically effective and cost-effective length of Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer-Associated Thrombosis (ALICAT).

Background: Venous thromboembolism is common in cancer patients and requires anticoagulation with low-molecular-weight heparin (LMWH). Current data recommend LMWH for anticoagulation as far as 6 months, yet guidelines recommend LMWH beyond 6 months in patients who have ongoing or active cancer. This recommendation, based on expert consensus, has not been evaluated in a clinical study.

Effectiveness of a nurse-led intensive home-visitation programme for first-time teenage mothers (Building Blocks): a pragmatic randomised controlled trial.

Background: Many countries now offer support to teenage mothers to help them to achieve long-term socioeconomic stability and to give a successful start to their children. The Family Nurse Partnership (FNP) is a licensed intensive home-visiting intervention developed in the USA and introduced into practice in England that involves up to 64 structured home visits from early pregnancy until the child's second birthday by specially recruited and trained family nurses. We aimed to assess the effectiveness of giving the programme to teenage first-time mothers on infant and maternal outcomes up to 24 months after birth.

BMI, waist circumference at 8 and 12 years of age and FVC and FEV1 at 12 years of age; the PIAMA birth cohort study.

Background: In adults, overweight is associated with reduced lung function, in children evidence on this association is conflicting. We examined the association of body mass index (BMI) and waist circumference (WC) at age 12, and of persistently (at ages 8 and 12 years) high BMI and large WC, with forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) at age 12.

Methods: Height, weight, WC and FVC and FEV1 were measured during a medical examination in 1288 12-year-olds participating in the PIAMA birth cohort study.

Relationship of night and shift work with weight change and lifestyle behaviors.

Objective: To prospectively study the association of night and shift work with weight change and lifestyle behaviors.

Methods: Workers participating in the Netherlands Working Conditions Cohort Study (2008 and 2009) (N = 5951) reported night and shift work, weight and height. Groups included stable night or shift work, from day work to night or shift work, from night or shift work to day work, and no night or shift work in 2008 and 2009.

The effectiveness of interventions for ageing workers on (early) retirement, work ability and productivity: a systematic review.

Purpose: To systematically summarise the literature on the effects of interventions for ageing workers that address work-related measures of sustainable employability, i.e. (early) retirement, work ability and work productivity.

Effect of kindness-based meditation on health and well-being: a systematic review and meta-analysis.

Objective: Kindness-based meditation (KBM) is a rubric covering meditation techniques developed to elicit kindness in a conscious way. Some techniques, for example, loving-kindness meditation and compassion meditation, have been included in programs aimed at improving health and well-being. Our aim was to systematically review and meta-analyze the evidence available from randomized controlled trials (RCTs) comparing the effects of KBM on health and well-being against passive and active control groups in patients and the general population.

The association between indoor temperature and body mass index in children: the PIAMA birth cohort study.

Background: Several experimental studies showed consistent evidence for decreased energy expenditure at higher ambient temperatures. Based on this, an association between thermal exposure and body weight may be expected. However, the effect of thermal exposure on body weight has hardly been studied.

Time in bed, sleep quality and associations with cardiometabolic markers in children: the Prevention and Incidence of Asthma and Mite Allergy birth cohort study.

We investigated associations of time in bed and multiple sleep quality characteristics with cardiometabolic markers in children. Data from the prevention and incidence of asthma and mite allergy study, a population-based prospective birth-cohort study started in 1996-1997 in the Netherlands, were analysed. In total 1481 children aged 11-12 years completed a questionnaire (including questions on sleep) and underwent a medical examination.

The effectiveness and cost-effectiveness of the Family Nurse Partnership home visiting programme for first time teenage mothers in England: a protocol for the Building Blocks randomised controlled trial.

Background: The Nurse Family Partnership programme was developed in the USA where it is made available to pregnant young mothers in some socially deprived geographic areas. The related Family Nurse Partnership programme was introduced in England by the Department of Health in 2006 with the aim of improving outcomes for the health, wellbeing and social circumstances of young first-time mothers and their children.

Methods / Design: This multi-centre individually randomised controlled trial will recruit 1600 participants from 18 Primary Care Trusts in England, United Kingdom.

BMI and waist circumference; cross-sectional and prospective associations with blood pressure and cholesterol in 12-year-olds.

Objective: Childhood and adolescent overweight, defined by body mass index (BMI) are associated with an increased risk of cardiovascular disease in later life. Abdominal adiposity may be more important in associations with cardiovascular diseases but waist circumference (WC) has been rarely studied in children. We studied associations between BMI and WC and blood pressure (BP) and cholesterol in 12-year-old children and prospectively changes in BMI or WC status between age 8 and 12 years and BP and cholesterol at age 12.

Waist circumference, BMI, and lung function in 8-year-old children: the PIAMA birth cohort study.

Background: Body mass index (BMI) and waist circumference (WC) may be associated with lung function in children, as observed in adults.

Methods: Height, weight, waist circumference, and lung function (FVC and FEV1 ) were measured during a medical examination in 1,058 eight-year-old children participating in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study.

Results: After adjusting for height, age and other potential confounders large WC or high BMI (>90th percentile) were not associated with forced expiratory volume in 1 sec (FEV1) or forced vital capacity (FVC).

Effectiveness of multifaceted educational programme to reduce antibiotic dispensing in primary care: practice based randomised controlled trial.

Objective: To evaluate the effectiveness and costs of a multifaceted flexible educational programme aimed at reducing antibiotic dispensing at the practice level in primary care.

Design: Randomised controlled trial with general practices as the unit of randomisation and analysis. Clinicians and researchers were blinded to group allocation until after randomisation.