Description: Introduction As the accurate diagnosis and treatment of gestational diabetes mellitus (GDM) is of increasing importance; new diagnostic approaches for the assessment of GDM in early pregnancy were recently suggested. We evaluate the diagnostic power of an ‘early’ oral glucose tolerance test (OGTT) 75 g and glycosylated fibronectin (glyFn) for GDM screening in a normal cohort. Methods and analysis In a prospective cohort study, 748 singleton pregnancies are recruited in 6 centres in Switzerland, Austria and Germany. Women are screened for pre-existing diabetes mellitus and GDM by an ‘early’ OGTT 75 g and/or the new biomarker, glyFn, at 12–15 weeks of gestation. Different screening strategies are compared to evaluate the impact on detection of GDM by an OGTT 75 g at 24–28 weeks of gestation as recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG). A new screening algorithm is created by using multivariable risk estimation based on ‘early’ OGTT 75 g and/or glyFn results, incorporating maternal risk factors. Recruitment began in May 2014. Ethics and dissemination This study received ethical approval from the ethics committees in Basel, Zurich, Vienna, Salzburg and Freiburg. It was registered under http://www.ClinicalTrials.gov (NCT02035059) on 12 January 2014. Data will be presented at international conferences and published in peer-reviewed journals. Trial registration number NCT02035059.

Description: Acute myelogenous leukemia stem cells (AML–LSC) give rise to the leukemic bulk population and maintain disease. Relapse can arise from residual LSCs that have distinct sensitivity and dependencies when compared with the AML bulk. AML–LSCs are driven by genetic and epigenomic changes, and these alterations influence prognosis and clonal selection. Therapies targeting these molecular aberrations have been developed and show promising responses in advanced clinical trials; however, so far success with LSCs has been limited. Besides the genetic diversity, AML–LSCs are critically influenced by the microenvironment, and a third crucial aspect has recently come to the fore: A group of evolutionarily conserved signaling pathways such as canonical Wnt signaling, Notch signaling, or the Hedgehog pathway can be essential for maintenance of AML–LSC but may be redundant for normal hematopoietic stem cells. In addition, early reports suggest also regulators of cell polarity may also influence hematopoietic stem cells and AML biology. Interactions between these pathways have been investigated recently and suggest a network of signaling pathways involved in regulation of self-renewal and response to oncogenic stress. Here, we review how recent discoveries on regulation of AML–LSC-relevant evolutionarily conserved pathways may open opportunities for novel treatment approaches eradicating residual disease. Clin Cancer Res; 21(2); 240–8. ©2015 AACR .

Description: Purpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study, we investigated the potential of targeting the catalytic class I A PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types. Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or downregulation by siRNA. Results: Overexpression of the PI3K isoforms p110-α and p110-β and the antiapoptotic protein Bcl-2 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110-α with RNA interference or selective pharmacologic inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo , whereas targeting p110-β was less effective. Inhibition of p110-α also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mTOR pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1. A DNA microarray analysis revealed that p110-α inhibition profoundly affected the balance of pro- and antiapoptotic Bcl-2 family proteins. Finally, p110-α inhibition led to impaired SCLC tumor formation and vascularization in vivo . Conclusion: Together our data show the key involvement of the PI3K isoform p110-α in the regulation of multiple tumor-promoting processes in SCLC. Clin Cancer Res; 19(1); 96–105. ©2012 AACR .

Description: Objective Diarrhoea is a significant contributer to morbidity and is among the leading causes of death of children living in poverty. As such, the incidence, duration and severity of diarrhoeal episodes in the household are often key variables of interest in a variety of community-based studies. However, there currently exists no means of defining diarrhoeal severity that are (A) specifically designed and adapted for community-based studies, (B) associated with poorer child outcomes and (C) agreed on by the majority of researchers. Clinical severity scores do exist and are used in healthcare settings, but these tend to focus on relatively moderate-to-severe dehydrating and dysenteric disease, require trained observation of the child and, given the variability of access and utilisation of healthcare, fail to sufficiently describe the spectrum of disease in the community setting. Design Longitudinal cohort study. Setting Santa Clara de Nanay, a rural community in the Northern Peruvian Amazon. Participants 442 infants and children 0–72 months of age. Main outcome measures Change in weight over 1-month intervals and change in length/height over 9-month intervals. Results Diarrhoeal episodes with symptoms of fever, anorexia, vomiting, greater number of liquid stools per day and greater number of total stools per day were associated with poorer weight gain compared with episodes without these symptoms. An instrument to measure the severity was constructed based on the duration of these symptoms over the course of a diarrhoeal episode. Conclusions In order to address limitations of existing diarrhoeal severity scores in the context of community-based studies, we propose an instrument comprised of diarrhoea-associated symptoms easily measured by community health workers and based on the association of these symptoms with poorer child growth. This instrument can be used to test the impact of interventions on the burden of diarrhoeal disease.

Description: Background High-resolution ultrasonography is a new and promising technique to evaluate peripheral and spinal nerves. Its validity as a diagnostic tool in neurological diseases has been demonstrated in adults. Up to now no reference values have been published in children and adolescents although this technique would be ideal in this population as it is fast and non-invasive. Methods/design Our aim is to generate ultrasonographic reference values for several peripheral nerves (median, ulnar, radial, tibial, sural, peroneal and tibial nerve) as well as for the spinal nerves C5 and C6 and the vagus nerve in children and adolescents. In an observational prospective study, we will recruit 205 children and adolescents aged between ≥2 and ≤18 years without neuromuscular symptoms/signs and without a history of neuromuscular disease. After the collection of demographic and anthropometric data (height, weight, body mass index, age, gender and handedness) and a neurologic examination, a high-resolution ultrasonography of peripheral and spinal nerves at several anatomic landmarks will be performed. These data will be used to estimate age-dependent percentile curves and to evaluate inter-rater, intrarater and interequipment reliability of the measurements. Ethics and dissemination This study was approved by the local ethics committee (EKNZ 2015-210). The findings from this study will be disseminated through peer-reviewed publications and conference presentations. Trial registration number NCT02570802, pre-results publication.