Empowerment: Trait Relatedness

The purpose of this study was to determine whether the extent that variances in the level of empowerment can be influenced by the willingness of supervisor to empower, the willingness of subordinates to be empowered and the subordinators’ age. The results indicate that there is a positive relationship between subordinates’ empowerment level and the subordinates’ willingness to be empowered; but there is no significant relationship between subordinates’ empowerment level and the supervisors’ willingness to empower

Fetal haemoglobin response to hydroxycarbamide treatment and sar1a promoter polymorphisms in sickle cell anaemia

The hydroxycarbamide (HC)-inducible small guanosine triphosphate (GTP)-binding protein, secretion-associated and RAS-related (SAR) protein has recently been shown to play a pivotal role in HBG induction and erythroid maturation by causing cell apoptosis and G1/S-phase arrest. Our preliminary analysis indicated that HC inducibility is transcriptionally regulated by elements within the SAR1A promoter. This study aimed to assess whether polymorphisms in the SAR1A promoter are associated with differences Hb F levels or HC therapeutic responses among sickle cell disease (SCD) patients. We studied 386 individuals with SCD comprised of 269 adults treated with or without HC and 117 newborns with SCD identified from a newborn screening program. Three previously unknown single nucleotide polymorphisms (SNPs) in the upstream 5′UTR (−809 C>T, −502 G>T and −385 C>A) were significantly associated with the fetal haemoglobin (HbF) response in Hb SS patients treated with HC (P < 0·05). In addition, four SNPs (rs2310991, −809 C>T, −385 C>A and rs4282891) were significantly associated with the change in absolute HbF after 2 years of treatment with HC. These data suggest that variation within SAR1A regulatory elements might contribute to inter-individual differences in regulation of HbF expression and patient responses to HC in SCD

von Hippel-Lindau Disease-Associated Hemangioblastomas Are Derived from Embryologic Multipotent Cells

BACKGROUND: To determine the origin of the neoplastic cell in central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL) and its role in tumor formation and distribution, we characterized and differentiated neoplastic cells from hemangioblastomas removed from VHL patients. METHODS AND FINDINGS: A total of 31 CNS hemangioblastomas from 25 VHL patients were resected and analyzed. Tumor cells from the hemangioblastomas were characterized, grown, and differentiated into multiple lineages. Resected hemangioblastomas were located in the cerebellum (11 tumors), brainstem (five tumors), and spinal cord (15 tumors). Consistent with an embryologically derived hemangioblast, the neoplastic cells demonstrated coexpression of the mesodermal markers brachyury, Flk-1 (vascular endothelial growth factor-2), and stem cell leukemia (Scl). The neoplastic cells also expressed hematopoietic stem cell antigens and receptors including CD133, CD34, c-kit, Scl, erythropoietin, and erythropoietin receptor. Under specific microenvironments, neoplastic cells (hemangioblasts) were expanded and differentiated into erythrocytic, granulocytic, and endothelial progenitors. Deletion of the wild-type VHL allele in the hematopoietic and endothelial progeny confirmed their neoplastic origin. CONCLUSIONS: The neoplastic cell of origin for CNS hemangioblastomas in VHL patients is the mesoderm-derived, embryologically arrested hemangioblast. The hematopoietic and endothelial differentiation potential of these cells can be reactivated under suitable conditions. These findings may also explain the unique tissue distribution of tumor involvement

Target selection for the SUNS and DEBRIS surveys for debris discs in the solar neighbourhood

Debris discs - analogous to the Asteroid and Kuiper-Edgeworth belts in the Solar system - have so far mostly been identified and studied in thermal emission shortward of 100 um. The Herschel space observatory and the SCUBA-2 camera on the James Clerk Maxwell Telescope will allow efficient photometric surveying at 70 to 850 um, which allow for the detection of cooler discs not yet discovered, and the measurement of disc masses and temperatures when combined with shorter wavelength photometry. The SCUBA-2 Unbiased Nearby Stars (SUNS) survey and the DEBRIS Herschel Open Time Key Project are complimentary legacy surveys observing samples of ~500 nearby stellar systems. To maximise the legacy value of these surveys, great care has gone into the target selection process. This paper describes the target selection process and presents the target lists of these two surveys.Comment: 67 pages with full tables, 7 figures, accepted to MNRA

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (&gt;6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly

Getting It Right: Being Smarter about Clinical Trials

A major NIH meeting led to recommendations for conducting better clinical trials

Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin : The Randomized, Controlled EMPA-VISION Trial

Acknowledgments The authors express their gratitude toward the Oxford cardiovascular magnetic resonance nursing team, specifically Judith DeLos Santos, Catherine Krasopoulos, Marion Galley, and Claudia Nunes; and the diabetes trials unit team, particularly Irene Kennedy, for her organization skills. The authors also thank the team of the computed tomography suite at the Manor Hospital Oxford as well as all patients who participated in this trial. Drs Holman and Neubauer are Emeritus National Institute for Health Research senior investigators. The views expressed are those of the author(s) and not necessarily those of the National Health Service, National Institute for Health and Care Research, or Department of Health. Sources of Funding Boehringer Ingelheim is the sponsor of the EMPA-VISION study and was involved in early stages of its study design. Boehringer Ingelheim employees (Drs Lee and Massey) also supported preparation of this manuscript. Dr Neubauer acknowledges support from the Oxford British Heart Foundation Centre of Research Excellence. Drs Holman and Neubauer were supported by the Oxford National Institute for Health Research Biomedical Research Centre. Drs Rodgers and Valkovič are funded by Sir Henry Dale Fellowships from the Wellcome Trust and the Royal Society [098436/Z/12/B and 221805/Z/20/Z, respectively]. Dr Valkovič also gratefully acknowledges support of the Slovak Grant Agencies VEGA (Vedecká grantová agentúra) [2/0003/20] and APVV (Slovak Research and Development Agency) [No. 19–0032]. Dr Miller acknowledges support from the Novo Foundation (NNF21OC0068683).Peer reviewedPublisher PD