SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC50=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) ...within the JAK family (IC50=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC50=22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(V617F)-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2(V617F) patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.
Summary
The contribution of rapid weight gain (RWG) during infancy to later adiposity has received considerable investigation. The present systematic review and meta‐analysis aimed to update the ...literature on association between RWG and subsequent adiposity outcomes. Electronic searches were undertaken in EMBASE, MEDLINE, psycINFO, PubMed and ScienceDirect. Studies that examined the associations between RWG (a change in weight z‐scores > 0.67) during infancy (from birth to age 2 years) and subsequent adiposity outcomes were included. Random effects meta‐analysis was conducted to obtain the weighted‐pooled estimates of the odds of overweight/obesity for those with RWG. Seventeen studies were eligible for inclusion with the majority of studies (15/17) being of high/acceptable quality and reporting positive associations between RWG during infancy and later adiposity outcomes. RWG in infancy was associated with overweight/obesity from childhood to adulthood (pooled odds ratio = 3.66, 95% confidence interval: 2.59–5.17, I2 > 75%). Subgroup analyses revealed that RWG during infancy was associated with higher odds of overweight/obesity in childhood than in adulthood, and RWG from birth to 1 year was associated with higher odds of overweight/obesity than RWG from birth to 2 years. The present study supports that RWG during infancy is a significant predictor of adiposity in later life.
Background
The IL‐13 receptor α2 (IL‐13Rα2) is a receptor for IL‐13 which has conflicting roles in mediating IL‐13 responses in the lower airway, with little known about its impact on upper airway ...diseases. We sought to investigate the expression of IL‐13 receptors, IL‐13Rα1 and IL‐13Rα2, in chronically inflamed nasal epithelium, and explore IL‐13‐induced signaling pathways in an in vitro model of human nasal epithelial cells (hNECs).
Methods
The protein and mRNA expression levels of IL‐13 and its receptors in nasal biopsies of patients with nasal polyps (NP) and healthy controls were evaluated. We investigated goblet cell stimulation with mucus hypersecretion induced by IL‐13 (10 ng/mL, 72 hours) treatment in hNECs using a pseudostratified epithelium in air‐liquid interface (ALI) culture.
Results
There were significant increases in IL‐13, IL‐13Rα1, and IL‐13Rα2 mRNA and protein levels in NP epithelium with healthy controls as baseline. MUC5AC mRNA positively correlated with IL‐13Rα2 (r = .5886, P = .002) but not with IL‐13Rα1 in primary hNECs. IL‐13 treatment resulted in a significant increase in mRNA and protein levels of IL‐13Rα2 only in hNECs. IL‐13 treatment induced an activation of extracellular signal‐regulated kinases (ERK)1/2 and an upregulation of C‐JUN, where the IL‐13‐induced effects on hNECs could be attenuated by ERK1/2 inhibitor (50 μmol/L) or dexamethasone (10−4‐10−7 mol/L) treatment.
Conclusions
IL‐13Rα2 has a potential role in IL‐13‐induced MUC5AC and ciliary changes through ERK1/2 signal pathway in the nasal epithelium. IL‐13Rα2 may contribute to airway inflammation and aberrant remodeling which are the main pathological features of CRSwNP.
The increase in IL‐13Rα2 with IL‐13 treatment activates ERK1/2, which is associated with IL‐13‐induced MUC5AC upregulation and impaired ciliary function in hNECs. IL‐13‐induced effects on hNECs could be attenuated either by ERK1/2 inhibitor PD98059 or by dexamethasone treatment. IL‐13Rα2 has a potential role in airway inflammation and aberrant remodeling.
Objective
Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy ...and newborn anthropometric outcomes.
Design
Individual level meta‐analysis, which reduces heterogeneity across studies.
Setting
A consortium of eight population‐based studies (seven European and one US) comprising 72 694 participants.
Methods
Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self‐reported LTPA at either early (8–18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta‐analyses.
Main outcome measures
Birth weight, large‐for‐gestational age (LGA), macrosomia, small‐for‐gestational age (SGA), % body fat, and ponderal index at birth.
Results
Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2 = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA.
Conclusions
Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA.
Tweetable
In an individual participant meta‐analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.
Tweetable
In an individual participant meta‐analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.
TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3. It dose-dependently inhibits signaling pathways downstream of CDKs, JAK2 and FLT3 ...in cancer cells with the main targets being CDKs. TG02 is anti-proliferative in a broad range of tumor cell lines, inducing G1 cell cycle arrest and apoptosis. Primary cultures of progenitor cells derived from acute myeloid leukemia (AML) and polycythemia vera patients are very sensitive to TG02. Comparison with reference inhibitors that block only one of the main targets of TG02 demonstrate the benefit of combined CDK and JAK2/FLT3 inhibition in cell lines as well as primary cells. In vivo, TG02 exhibits favorable pharmacokinetics after oral dosing in xenograft models and accumulates in tumor tissues, inducing an effective blockade of both CDK and STAT signaling. TG02 induces tumor regression after oral dosing on both daily and intermittent schedules in a murine model of mutant-FLT3 leukemia (MV4-11) and prolongs survival in a disseminated AML model with wild-type FLT3 and JAK2 (HL-60). These data demonstrate that TG02 is active in various models of leukemia and provide a rationale for the ongoing clinical evaluation of TG02 in patients with advanced leukemias.
Sugar‐sweetened beverage (SSB) consumption is associated with adverse health outcomes. Improved understanding of the determinants will inform effective interventions to reduce SSB consumption. A ...total of 46,876 papers were identified through searching eight electronic databases. Evidence from intervention (n = 13), prospective (n = 6) and cross‐sectional (n = 25) studies on correlates/determinants of SSB consumption was quality assessed and synthesized. Twelve correlates/determinants were associated with higher SSB consumption (child's preference for SSBs, TV viewing/screen time and snack consumption; parents' lower socioeconomic status, lower age, SSB consumption, formula milk feeding, early introduction of solids, using food as rewards, parental‐perceived barriers, attending out‐of‐home care and living near a fast food/convenience store). Five correlates/determinants were associated with lower SSB consumption (parental positive modelling, parents' married/co‐habiting, school nutrition policy, staff skills and supermarket nearby). There was equivocal evidence for child's age and knowledge, parental knowledge, skills, rules/restrictions and home SSB availability. Eight intervention studies targeted multi‐level (child, parents, childcare/preschool setting) determinants; four were effective. Four intervention studies targeted parental determinants; two were effective. One (effective) intervention targeted the preschool environment. There is consistent evidence to support potentially modifiable correlates/determinants of SSB consumption in young children acting at parental (modelling), child (TV viewing) and environmental (school policy) levels.
AbstractObjective: To identify predictors of postnatal catch-up growth from birth to two years and its relation to size and obesity at five years.Design: Regional prospective cohort study.Setting: ...Avon longitudinal study of pregnancy and childhood, United Kingdom.Subjects: 848 full term singletons from a 10% random sample of the Avon longitudinal study of pregnancy and childhood.Main outcome measures: Maternal birth weight, prepregnancy weight, pregnancy weight gain, height, smoking, and parity, and paternal height. Weight and length of infants at birth, two years, and five years expressed as standard deviation (SD) scores from the UK reference scores for 1990. Percentage fat mass and total fat mass (estimated from skinfolds) and waist circumference at five years.Results: Size at birth was representative of the national reference. Overall, 30.7% (260 of 848) of infants showed a gain in SD score for weight greater than 0.67 SD scores between zero and two years, indicating clinically significant catch-up growth. These children had lower weight, length, and ponderal index at birth than other children, and were more often from primiparous pregnancies. They also had taller fathers than other children, and their mothers had lower birth weights and were more likely to smoke during pregnancy. Children who showed catch-up growth between zero and two years were heavier, taller, and fatter (body mass index, percentage body fat, and waist circumference) at five years than other children.Conclusions: In this contemporary well nourished cohort, catch-up growth was predicted by factors relating to intrauterine restraint of fetal growth. Children who showed catch-up growth between zero and two years were fatter and had more central fat distribution at five years than other children. Mechanisms that signal and regulate early catch-up growth in the postnatal period may influence associations between small size at birth and risks for disease in adulthood.
Movement is fundamental to human and animal life, emerging through interaction of complex neural, muscular, and skeletal systems. Study of movement draws from and contributes to diverse fields, ...including biology, neuroscience, mechanics, and robotics. OpenSim unites methods from these fields to create fast and accurate simulations of movement, enabling two fundamental tasks. First, the software can calculate variables that are difficult to measure experimentally, such as the forces generated by muscles and the stretch and recoil of tendons during movement. Second, OpenSim can predict novel movements from models of motor control, such as kinematic adaptations of human gait during loaded or inclined walking. Changes in musculoskeletal dynamics following surgery or due to human-device interaction can also be simulated; these simulations have played a vital role in several applications, including the design of implantable mechanical devices to improve human grasping in individuals with paralysis. OpenSim is an extensible and user-friendly software package built on decades of knowledge about computational modeling and simulation of biomechanical systems. OpenSim's design enables computational scientists to create new state-of-the-art software tools and empowers others to use these tools in research and clinical applications. OpenSim supports a large and growing community of biomechanics and rehabilitation researchers, facilitating exchange of models and simulations for reproducing and extending discoveries. Examples, tutorials, documentation, and an active user forum support this community. The OpenSim software is covered by the Apache License 2.0, which permits its use for any purpose including both nonprofit and commercial applications. The source code is freely and anonymously accessible on GitHub, where the community is welcomed to make contributions. Platform-specific installers of OpenSim include a GUI and are available on simtk.org.
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