Juvenile Myelomonocytic Leukemia: Molecular Pathogenesis Informs Current Approaches to Therapy and Hematopoietic Cell Transplantation

Juvenile myelomonocytic leukemia (JMML) is a rare childhood leukemia that has historically been very difficult to confidently diagnose and treat. The majority of patients ultimately require allogeneic hematopoietic cell transplantation (HCT) for cure. Recent advances in the understanding of the pathogenesis of the disease now permit over 90% of patients to be molecularly characterized. Pre-HCT management of patients with JMML is currently symptom-driven. However, evaluation of potential high-risk clinical and molecular features will determine which patients could benefit from pre-HCT chemotherapy and/or local control of splenic disease. Furthermore, new techniques to quantify minimal residual disease burden will determine whether pre-HCT response to chemotherapy is beneficial for long-term disease-free survival. The optimal approach to HCT for JMML is unclear, with high relapse rates regardless of conditioning intensity. An ongoing clinical trial in the Children’s Oncology Group will test if less toxic approaches can be equally effective, thereby shifting the focus to post-HCT immunomanipulation strategies to achieve long-term disease control. Finally, our unraveling of the molecular basis of JMML is beginning to identify possible targets for selective therapeutic interventions, either pre- or post-HCT, an approach which may ultimately provide the best opportunity to improve outcomes for this aggressive disease

Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington's Disease.

Huntington's disease (HD) patients suffer from a progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep/wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and fatigue during the day. The heterozygous Q175 mouse model of HD has been shown to phenocopy many HD core symptoms including circadian dysfunctions. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early intervention that improve circadian rhythmicity can benefit HD and delay disease progression. We determined the effects of time-restricted feeding (TRF) on the Q175 mouse model. At six months of age, the animals were divided into two groups: ad libitum (ad lib) and TRF. The TRF-treated Q175 mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle of the time when mice are normally active. After three months of treatment (when mice reached the early disease stage), the TRF-treated Q175 mice showed improvements in their locomotor activity rhythm and sleep awakening time. Furthermore, we found improved heart rate variability (HRV), suggesting that their autonomic nervous system dysfunction was improved. Importantly, treated Q175 mice exhibited improved motor performance compared to untreated Q175 controls, and the motor improvements were correlated with improved circadian output. Finally, we found that the expression of several HD-relevant markers was restored to WT levels in the striatum of the treated mice using NanoString gene expression assays

Mining Of Text In The Product Development Process

In the prevailing world economy, competition is keen and firms need to have an edge over their competitors for profitability and sometimes, even for the survival of the business itself. One way to help achieve this is the capability for rapid product development on a continual basis. However, this rapidity must be accomplished without compromising vital information and feedback that are necessary. The compromise in such information and feedback at the expense of speed may result in counter-productive outcomes, thereby offsetting or even negating whatever profits that could have been derived. New ways, tools and techniques must be found to deliver such information. The widespread availability of databases within the Product Development Process (PDP) facilitates the use of data mining as one of the tools. Thus far, most of the studies on data mining within PDP have emphasised on numerical databases. Studies focusing on textual databases in this context have been relatively few. The research direction is to study real-life cases where textual databases can be mined to obtain valuable information for PDP. One suitable candidate identified for this is “voice of the customer” databases.Singapore-MIT Alliance (SMA

Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease.

Cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with Huntington's disease (HD). Preclinical research requires mouse models that recapitulate disease symptoms and the Q175 knock-in model offers a number of advantages but potential autonomic dysfunction has not been explored. In this study, we sought to test the dual hypotheses that cardiovascular dysautonomia can be detected early in disease progression in the Q175 model and that this dysfunction varies with the daily cycle. Using radiotelemetry implants, we observed a significant reduction in the diurnal and circadian activity rhythms in the Q175 mutants at the youngest ages. By middle age, the autonomically driven rhythms in core body temperature were highly compromised, and the Q175 mutants exhibited striking episodes of hypothermia that increased in frequency with mutant huntingtin gene dosage. In addition, Q175 mutants showed higher resting heart rate (HR) during sleep and greatly reduced correlation between activity and HR HR variability was reduced in the mutants in both time and frequency domains, providing more evidence of autonomic dysfunction. Measurement of the baroreceptor reflex revealed that the Q175 mutant could not appropriately increase HR in response to a pharmacologically induced decrease in blood pressure. Echocardiograms showed reduced ventricular mass and ejection fraction in mutant hearts. Finally, cardiac histopathology revealed localized points of fibrosis resembling those caused by myocardial infarction. Thus, the Q175 mouse model of HD exhibits cardiovascular dysautonomia similar to that seen in HD patients with prominent sympathetic dysfunction during the resting phase of the activity rhythm

Changes in waist circumference independent of weight: Implications for population level monitoring of obesity

Population monitoring of obesity is most commonly conducted using body mass index (BMI). We test the hypothesis that because of increases in waist circumference (WC) independent of increases in weight, BMI alone detects an increasingly smaller proportion of the population with obesity. Methods: Australian adults with measured height, weight, and WC were selected from three nationally representative cross-sectional surveys (1989, 1999–2000, 2011–12; n = 8313, 5903 & 3904). Participants were defined as having obesity using classifications for an obese BMI (≥ 30 kg·m− 2) and substantially-increased-risk WC (≥ 88 cm [women], ≥ 102 cm [men]). Age-standardised prevalence of obesity according to BMI and/or WC, and the proportion of these detected by BMI and by WC were compared across surveys. Findings: Between 1989 and 2011–12, weight and WC increased by 5.4 kg and 10.7 cm (women), and by 7.0 kg and 7.3 cm (men). For women and men, 63% and 38% of increases in WC were independent of increases in weight. Over this period, the prevalence of obesity according to BMI and/or WC increased by 25.3 percentage-points for women (18.9% to 44.3%) and 21.1 percentage-points for men (17.1% to 38.2%). The proportion of these detected by BMI decreased for women by 20 percentage-points (77% to 57%) with no change for men. The proportion of these detected by WC increased for women and men by 10 percentage-points (87% to 97%) and 6 percentage-points (85% to 91%) respectively. Conclusion: BMI alone is detecting a decreasing proportion of those considered obese by BMI and/or WC. Renewed discussion regarding how we monitor obesity at the population level is required

Comparison of eccentric utilization ratio of elite karate (kata) with elite Wushu athletes

[EN] Karate and Wushu are gaining popularity as a sport globally. In Karate there are two events: Kata and Kumite

Coil-Assisted Retrograde Transvenous Obliteration (CARTO) for the Treatment of Portal Hypertensive Variceal Bleeding: Preliminary Results.

ObjectivesTo describe the technical feasibility, safety, and clinical outcomes of coil-assisted retrograde transvenous obliteration (CARTO) in treating portal hypertensive non-esophageal variceal hemorrhage.MethodsFrom October 2012 to December 2013, 20 patients who received CARTO for the treatment of portal hypertensive non-esophageal variceal bleeding were retrospectively evaluated. All 20 patients had at least 6-month follow-up. All patients had detachable coils placed to occlude the efferent shunt and retrograde gelfoam embolization to achieve complete thrombosis/obliteration of varices. Technical success, clinical success, rebleeding, and complications were evaluated at follow-up.ResultsA 100% technical success rate (defined as achieving complete occlusion of efferent shunt with complete thrombosis/obliteration of bleeding varices and/or stopping variceal bleeding) was demonstrated in all 20 patients. Clinical success rate (defined as no variceal rebleeding) was 100%. Follow-up computed tomography after CARTO demonstrated decrease in size with complete thrombosis and disappearance of the varices in all 20 patients. Thirteen out of the 20 had endoscopic confirmation of resolution of varices. Minor post-CARTO complications, including worsening of esophageal varices (not bleeding) and worsening of ascites/hydrothorax, were noted in 5 patients (25%). One patient passed away at 24 days after the CARTO due to systemic and portal venous thrombosis and multi-organ failure. Otherwise, no major complication was noted. No variceal rebleeding was noted in all 20 patients during mean follow-up of 384±154 days.ConclusionsCARTO appears to be a technically feasible and safe alternative to traditional balloon-occluded retrograde transvenous obliteration or transjugular intrahepatic portosystemic shunt, with excellent clinical outcomes in treating portal hypertensive non-esophageal variceal bleeding

Field responsive mechanical metamaterials.

Typically, mechanical metamaterial properties are programmed and set when the architecture is designed and constructed, and do not change in response to shifting environmental conditions or application requirements. We present a new class of architected materials called field responsive mechanical metamaterials (FRMMs) that exhibit dynamic control and on-the-fly tunability enabled by careful design and selection of both material composition and architecture. To demonstrate the FRMM concept, we print complex structures composed of polymeric tubes infilled with magnetorheological fluid suspensions. Modulating remotely applied magnetic fields results in rapid, reversible, and sizable changes of the effective stiffness of our metamaterial motifs