A novel mutation in the miR-128b gene reduces miRNA processing and leads to glucocorticoid resistance of MLL-AF4 Acute Lymphocytic Leukemia cells

MLL-AF4 Acute Lymphocytic Leukemia has a poor prognosis, and the mechanisms by which these leukemias develop are not understood despite intensive research based on well-known concepts and methods. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate expression of target mRNA transcripts. We recently reported that ectopic expression of miR-128b together with miR-221, two of the miRNAs downregulated in MLL-AF4 ALL, restores glucocorticoid resistance through downregulation of the MLL-AF4 chimeric fusion proteins MLL-AF4 and AF4-MLL that are generated by chromosomal translocation t(4;11). Here we report the identification of new mutations in miR-128b in RS4;11 cells, derived from MLL-AF4 ALL patient. One novel mutation significantly reduces the processing of miR-128b. Finally, this base change occurs in a primary MLL-AF4 ALL sample as an acquired mutation. These results demonstrate that the novel mutation in miR-128b in MLL-AF4 ALL alters the processing of miR-128b and that the resultant downregulation of mature miR-128b contributes to glucocorticoid resistance through the failure to downregulate the fusion oncogenes.National Institutes of Health (U.S.) (NIH Grant R01 DK068348)Netherlands Organization for Scientific ResearchDutch Cancer SocietyJapan Society for the Promotion of Scienc

Selecting Forecasting Methods

I examined six ways of selecting forecasting methods: Convenience, “what’s easy,” is inexpensive, but risky. Market popularity, “what others do,” sounds appealing but is unlikely to be of value because popularity and success may not be related and because it overlooks some methods. Structured judgment, “what experts advise,” which is to rate methods against prespecified criteria, is promising. Statistical criteria, “what should work,” are widely used and valuable, but risky if applied narrowly. Relative track records, “what has worked in this situation,” are expensive because they depend on conducting evaluation studies. Guidelines from prior research, “what works in this type of situation,” relies on published research and offers a low-cost, effective approach to selection. Using a systematic review of prior research, I developed a flow chart to guide forecasters in selecting among ten forecasting methods. Some key findings: Given enough data, quantitative methods are more accurate than judgmental methods. When large changes are expected, causal methods are more accurate than naive methods. Simple methods are preferable to complex methods; they are easier to understand, less expensive, and seldom less accurate. To select a judgmental method, determine whether there are large changes, frequent forecasts, conflicts among decision makers, and policy considerations. To select a quantitative method, consider the level of knowledge about relationships, the amount of change involved, the type of data, the need for policy analysis, and the extent of domain knowledge. When selection is difficult, combine forecasts from different methods

The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection.

Background Stage I non-small cell lung cancer (NSCLC) is potentially curable, and surgery is considered to be the standard of care for patients with good performance status and minimal co-morbidity. However, a significant proportion of patients with stage I NSCLC have a poorer performance status and significant medical co-morbidity that make them at higher risk of morbidity and mortality from surgery. Stereotactic ablative radiotherapy (SABR), which uses modern radiotherapeutic techniques to deliver large doses of radiation, has shown superiority over conventional radiotherapy in terms of local control and toxicity and is a standard of care for patients with stage I NSCLC who are at too high risk for surgery. However, it is not known whether surgery or SABR is the most effective in patients with stage I NSCLC who are suitable for surgery but are less fit and at higher risk surgical complications. Previous randomised studies have failed to recruit in this setting, and therefore, a feasibility study is required to see whether a full randomised control trial would be possible. Methods/design SABRTooth is a UK-based, multi-centre, open-label, two-group individually (1:1) randomised controlled feasibility study in patients with peripheral stage I NSCLC considered to be at higher risk from surgical resection. The study will assess the feasibility of conducting a definitive large-scale phase III trial. The primary objective is to assess recruitment rates to provide evidence that, when scaled up, recruitment to a large phase III trial would be possible; the target recruitment being 54 patients in total, over a 21-month period. There are multiple secondary and exploratory objectives designed to explore the optimum recruitment and data collection strategies to help optimise the design of a future phase III trial. Discussion To know whether SABR is a better, equivalent or inferior alternative to surgery for higher risk patients is a key question in lung cancer. Other studies comparing SABR to surgery have closed early due to poor recruitment, and therefore, the SABRTooth feasibility study has been designed around the UK National Health Service (NHS) cancer pathway incorporating many design features in order to maximise recruitment for a future definitive phase III trial

Thyroid disease is a favorable prognostic factor in achieving sustained virologic response in chronic hepatitis C undergoing combination therapy: A nested case control study

<p>Abstract</p> <p>Background</p> <p>Interferon-α in combination with ribavirin is the current gold standard for treatment of chronic hepatitis C. It is unknown if the development of autoimmune thyroid disease (TD) during treatment confers an improved chance of achieving sustained virologic response. The aim of this study is to assess the chance of achieving sustained virologic response (SVR) in patients who developed TD during treatment when compared with those who did not.</p> <p>Methods</p> <p>We performed a tertiary hospital-based retrospective nested case-control analysis of 19 patients treated for hepatitis C who developed thyroid disease, and 76 controls (matched for age, weight, gender, cirrhosis and aminotransferase levels) who did not develop TD during treatment. Multivariate logistic-regression models were used to compare cases and controls.</p> <p>Results</p> <p>The development of TD was associated with a high likelihood of achieving SVR (odds ratio, 6.0; 95% confidence interval, 1.5 to 24.6) for the pooled group containing all genotypes. The likelihood of achieving SVR was increased in individuals with genotype 1 HCV infection who developed TD (odds ratio, 5.2; 95% confidence interval, 1.2 to 22.3), and all genotype 3 patients who developed TD achieved SVR.</p> <p>Conclusions</p> <p>Development of TD during treatment for hepatitis C infection is associated with a significantly increased chance of achieving SVR. The pathophysiogical mechanisms for this observation remain to be determined.</p> <p>Trial Registration</p> <p><it>The Australian New Zealand Clinical Trials Registry (ANZCTR)</it>: <a href="http://www.anzctr.org.au/ACTRB12610000830099.aspx">ACTRB12610000830099</a></p

Effective Mechanical Advantage About the Ankle Joint and the Effect of Achilles Tendon Curvature During Toe-Walking

Data Availability Statement: The datasets generated for this study are available on request to the corresponding author.Copyright © 2020 Harkness-Armstrong, Debelle, Maganaris, Walton, Wright, Bass, Baltzopoulos and O’Brien. Aim: To study the causes of locomotor dysfunction, estimate muscle forces, or understand the influence of altered sarcomere and muscle properties and behaviours on whole body function, it is necessary to examine the leverage with which contractile forces operate. At the ankle joint, current methods to quantify this leverage for the plantarflexors do not account for curvature of the Achilles tendon, and so may not be appropriate when studying equinus gait. Thus, novel methodologies need to be developed and implemented to quantify the Achilles tendon moment arm length during locomotion. Methods: Plantarflexor internal moment arm length and effective mechanical advantage of 11 typically developed young adults were calculated throughout stance, while heel-toe walking and voluntarily toe-walking on an instrumented treadmill. Achilles tendon moment arm was defined in two-ways: (1) assuming a straight tendon, defined between the gastrocnemius medialis myotendinous junction and Achilles tendon insertion point, and (2) accounting for tendon curvature, by tracking the initial path of the Achilles tendon from the calcaneal insertion. Results: When accounting for tendon curvature, Achilles tendon moment arm length and plantarflexor effective mechanical advantage did not differ between walking conditions (p > 0.05). In contrast, when assuming a straight tendon, Achilles tendon moment arm length (p = 0.043) and plantarflexor effective mechanical advantage (p = 0.007) were significantly greater when voluntary toe-walking than heel-toe walking in late stance. Discussion: Assuming a straight Achilles tendon led to a greater Achilles tendon moment arm length and plantarflexor effective mechanical advantage during late stance, compared to accounting for tendon curvature. Consequently, plantarflexor muscle force would appear smaller when assuming a straight tendon. This could lead to erroneous interpretations of muscular function and fascicle force-length-velocity behaviour in vivo, and potentially inappropriate and ineffective clinical interventions for equinus gait.Liverpool John Moores University Ph.D. scholarship

Exoplanet phase curves: observations and theory

Phase curves are the best technique to probe the three dimensional structure of exoplanets' atmospheres. In this chapter we first review current exoplanets phase curve observations and the particular challenges they face. We then describe the different physical mechanisms shaping the atmospheric phase curves of highly irradiated tidally locked exoplanets. Finally, we discuss the potential for future missions to further advance our understanding of these new worlds.Comment: Fig.5 has been updated. Table 1 and corresponding figures have been updated with new values for WASP-103b and WASP-18b. Contains a table sumarizing phase curve observation

Mapping Exoplanets

The varied surfaces and atmospheres of planets make them interesting places to live, explore, and study from afar. Unfortunately, the great distance to exoplanets makes it impossible to resolve their disk with current or near-term technology. It is still possible, however, to deduce spatial inhomogeneities in exoplanets provided that different regions are visible at different times---this can be due to rotation, orbital motion, and occultations by a star, planet, or moon. Astronomers have so far constructed maps of thermal emission and albedo for short period giant planets. These maps constrain atmospheric dynamics and cloud patterns in exotic atmospheres. In the future, exo-cartography could yield surface maps of terrestrial planets, hinting at the geophysical and geochemical processes that shape them.Comment: Updated chapter for Handbook of Exoplanets, eds. Deeg & Belmonte. 17 pages, including 6 figures and 4 pages of reference

Cross-sectional analysis of baseline differences of candidates for rotator cuff surgery: a sex and gender perspective

<p>Abstract</p> <p>Background</p> <p>The word "sex" refers to biological differences between men and women. Gender refers to roles, behaviors, activities, and attributes that a given society considers appropriate for men and women. Traditionally, treatment decisions have been based on patient's sex without including the gender. Assessment of disability secondary to musculoskeletal problems would not be complete or accurate unless potentially relevant biological and non-biological aspects of being a man or woman are taken into consideration. The purposes of this study were to: 1) investigate the difference in pre-operative characteristics between men and women who were candidates for rotator cuff surgery; and, 2) assess the relationship between level of disability and factors that represent sex and factors that signify gender.</p> <p>Method</p> <p>This was a cross-sectional study. The primary outcome measure of disability was a disease-specific outcome measure, the Western Ontario Rotator Cuff (WORC) index, and independent variables were sex, age, hand dominance, shoulder side involvement, BMI, co-morbidity, medication use, work status, smoking habits, strength, range of motion, level of pathology, concurrent osteoarthritis, expectations for recovery, and participation restriction. Parametric, non-parametric, univariable, subgroup, and multivariable analyses were conducted.</p> <p>Results</p> <p>One hundred and seventy patients were included in the study. The mean age was 57 ± 11, 85 were females. Women reported higher levels of disability despite similar or lower levels of pathology. Scores of the WORC were strongly influenced by factors that represented "gender" such as participation restriction (F = 28.91, p < 0.0001) and expectations for improved activities of daily living (F = 5.80, p = 0.004). Painfree combined range of motion, which represented an interaction between "sex" and "gender" was also associated with disability after being adjusted for all other relevant baseline factors (F = 25.82, p < 0.0001).</p> <p>Conclusion</p> <p>Gender-related factors such as expectations and participation limitations have an independent impact on disability in men and women undergoing rotator cuff related surgery.</p

Gender differences in disability after sickness absence with musculoskeletal disorders: five-year prospective study of 37,942 women and 26,307 men

<p>Abstract</p> <p>Background</p> <p>Gender differences in the prevalence and occupational consequences of musculoskeletal disorders (MSDs) are consistently found in epidemiological studies. The study investigated whether gender differences also exist with respect to chronicity, measured as the rate of transition from sickness absence into permanent disability pension (DP).</p> <p>Methods</p> <p>Prospective national cohort study in Norway including all cases with a spell of sickness absence > eight weeks during 1997 certified with a MSD, 37,942 women and 26,307 men. The cohort was followed-up for five years with chronicity measured as granting of DP as the endpoint. The effect of gender was estimated in the full sample adjusting for sociodemographic factors and diagnostic distribution. Gender specific analyses were performed with the same explanatory variables. Finally, the gender difference was estimated for nine diagnostic subgroups.</p> <p>Results</p> <p>The crude rate of DP was 22% for women and 18% for men. After adjusting for all sociodemographic variables, a slightly higher female risk of DP remained. However, additional adjustment for diagnostic distribution removed the gender difference completely. Having children and working full time decreased the DP risk for both genders, whereas low socioeconomic status increased the risk similarly. There was a different age effect as more women obtained a DP below the age of 50. Increased female risk of chronicity remained for myalgia/fibromyalgia, back disorders and "other/unspecified" after relevant adjustments, whereas men with neck disorders were at higher risk of chronicity.</p> <p>Conclusions</p> <p>Women with MSDs had a moderately increased risk of chronicity compared to men, when including MSDs with a traumatic background. Possible explanations are lower income, a higher proportion belonging to diagnostic subgroups with poor prognosis, and a younger age of chronicity among women. When all sociodemographic and diagnostic variables were adjusted for, no gender difference remained, except for some diagnostic subgroups.</p