Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer.

The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt-like, lower crypt-like, CIMP-H-like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer-associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E-MTAB-990 and E-MTAB-1026. © 2013 Swiss Institute of Bioinformatics. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The 2010 May Flaring Episode of Cygnus X-3 in Radio, X-rays, and γ-rays

In 2009, Cygnus X-3 (Cyg X-3) became the first microquasar to be detected in the GeV γ-ray regime, via the satellites Fermi and AGILE. The addition of this new band to the observational toolbox holds promise for building a more detailed understanding of the relativistic jets of this and other systems. We present a rich data set of radio, hard and soft X-ray, and γ-ray observations of Cyg X-3 made during a flaring episode in 2010 May. We detect a ~3 day softening and recovery of the X-ray emission, followed almost immediately by a ~1 Jy radio flare at 15 GHz, followed by a 4.3σ γ-ray flare (E > 100 MeV) ~1.5 days later. The radio sampling is sparse, but we use archival data to argue that it is unlikely the γ-ray flare was followed by any significant unobserved radio flares. In this case, the sequencing of the observed events is difficult to explain in a model in which the γ-ray emission is due to inverse Compton scattering of the companion star's radiation field. Our observations suggest that other mechanisms may also be responsible for γ-ray emission from Cyg X-3.

Ein unbekanntes Fragment der "Alexandreis" Walters von Châtillon

Das im letzten Viertel des 12. Jahrhunderts entstandene Alexander-Epos Walters von Châtillon, schon im 13. Jahrhundert in den ,,status of a classic" (Colker) und überdies zum Schultext avanciert, gehört zu den am reichhaltigsten überlieferten Erzähltexten der lateinischen Literatur des Mittelalters. Der Beitrag kann ausser den in der Ausgabe Colkers (1987) nachgewiesenen 209 Textzeugen 15 weitere Handschriften und Fragmente belegen und zudem einen Neufund vorstellen: Im Archiv der Bürgergemeinde Frauenfeld, Schweiz, erhielt sich als einzelnes Doppelblatt ein glossiertes Fragment des Textes aus dem späten 13. oder frühen 14. Jahrhundert. Sein Layout verrät, dass es für die begleitende Kommentierung von vornherein angelegt war und vermutlich einem Schulbuch entstammt. Die erhaltenen Scholien scheinen dem ,,Standardkommentar" (Killermann) zur ,Alexandreis' nahezustehen, könnten aber auch Bezüge zum Kommentar des Geoffrey de Vitry aufweisen, der in einer mit seinem Namen auktorial verbundenen, aus Rheinau stammenden Handschrift erhalten ist. In vergleichsweise dichter räumlicher und zeitlicher Nähe zu diesem Textzeugen entstand die Handschrift, aus der das neue Frauenfelder Fragment stammt: Die Untersuchung der Akte, als deren Schutzumschlag das Doppelblatt aus der ,Alexandreis' diente, zeigt, dass sie sich seit dem frühen 15. Jahrhundert im jetzigen Kontext, den Beständen des heutigen Archivs der Frauenfelder Bürgergemeinde, befunden hat, das auf eine seit dem 13. Jahrhundert geführte Sammlung zurückgeht. Da zudem in Frauenfeld eine Lateinschule seit dem 14. Jahrhundert nachweisbar und schon im 13. Jahrhundert zu vermuten ist, liegt es nahe, dass der Fundort des neuen Textzeugen auch der seiner Entstehung oder doch zumindest seiner Benutzung im Unterricht war. Das Fragment bietet einen trotz schlechter Abschrift (mit häufigen Korrekturen durch den Glossator) unverkennbar guten Text, in kritischer Hinsicht dabei nur geringen Gewinn. Seine textgeschichtliche Verortung kann angesichts der nach wie vor weitgehend unaufgearbeiteten Überlieferung der ,Alexandreis' nur in groben Zügen vorgenommen werden. - Mit einem durch einen kritischen Apparat erschlossenen diplomatischen Abdruck und zwei Abbildungen des neuen Fragments.

Identification of a Poor-Prognosis BRAF-Mutant-Like Population of Patients With Colon Cancer.

PURPOSE Our purpose was development and assessment of a BRAF-mutant gene expression signature for colon cancer (CC) and the study of its prognostic implications. Materials and METHODS A set of 668 stage II and III CC samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial were used to assess differential gene expression between c.1799T>A (p.V600E) BRAF mutant and non-BRAF, non-KRAS mutant cancers (double wild type) and to construct a gene expression-based classifier for detecting BRAF mutant samples with high sensitivity. The classifier was validated in independent data sets, and survival rates were compared between classifier positive and negative tumors. Results A 64 gene-based classifier was developed with 96% sensitivity and 86% specificity for detecting BRAF mutant tumors in PETACC-3 and independent samples. A subpopulation of BRAF wild-type patients (30% of KRAS mutants, 13% of double wild type) showed a gene expression pattern and had poor overall survival and survival after relapse, similar to those observed in BRAF-mutant patients. Thus they form a distinct prognostic subgroup within their mutation class. CONCLUSION A characteristic pattern of gene expression is associated with and accurately predicts BRAF mutation status and, in addition, identifies a population of BRAF mutated-like KRAS mutants and double wild-type patients with similarly poor prognosis. This suggests a common biology between these tumors and provides a novel classification tool for cancers, adding prognostic and biologic information that is not captured by the mutation status alone. These results may guide therapeutic strategies for this patient segment and may help in population stratification for clinical trials.

Points to consider for prioritizing clinical genetic testing services: a European consensus process oriented at accountability for reasonableness.

Given the cost constraints of the European health-care systems, criteria are needed to decide which genetic services to fund from the public budgets, if not all can be covered. To ensure that high-priority services are available equitably within and across the European countries, a shared set of prioritization criteria would be desirable. A decision process following the accountability for reasonableness framework was undertaken, including a multidisciplinary EuroGentest/PPPC-ESHG workshop to develop shared prioritization criteria. Resources are currently too limited to fund all the beneficial genetic testing services available in the next decade. Ethically and economically reflected prioritization criteria are needed. Prioritization should be based on considerations of medical benefit, health need and costs. Medical benefit includes evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient-specific likelihood of being affected by the condition tested for. It may be subject to a finite time window. Health need includes the severity of the condition tested for and its progression at the time of testing. Further discussion and better evidence is needed before clearly defined recommendations can be made or a prioritization algorithm proposed. To our knowledge, this is the first time a clinical society has initiated a decision process about health-care prioritization on a European level, following the principles of accountability for reasonableness. We provide points to consider to stimulate this debate across the EU and to serve as a reference for improving patient management.

The 2010 May Flaring Episode of Cygnus X-3 in Radio, X-rays, and γ-rays

In 2009, Cygnus X-3 (Cyg X-3) became the first microquasar to be detected in the GeV γ-ray regime, via the satellites Fermi and AGILE. The addition of this new band to the observational toolbox holds promise for building a more detailed understanding of the relativistic jets of this and other systems. We present a rich data set of radio, hard and soft X-ray, and γ-ray observations of Cyg X-3 made during a flaring episode in 2010 May. We detect a ~3 day softening and recovery of the X-ray emission, followed almost immediately by a ~1 Jy radio flare at 15 GHz, followed by a 4.3σ γ-ray flare (E > 100 MeV) ~1.5 days later. The radio sampling is sparse, but we use archival data to argue that it is unlikely the γ-ray flare was followed by any significant unobserved radio flares. In this case, the sequencing of the observed events is difficult to explain in a model in which the γ-ray emission is due to inverse Compton scattering of the companion star's radiation field. Our observations suggest that other mechanisms may also be responsible for γ-ray emission from Cyg X-3.

Sublingual sugar for infant hypoglycaemia

Refers To Deborah L Harris, Philip J Weston, Matthew Signal, J Geoffrey Chase, Jane E Harding Dextrose gel for neonatal hypoglycaemia (the Sugar Babies Study): a randomised, double-blind, placebo-controlled trial The Lancet, Volume 382, Issue 9910, 21 December 2013-3 January 2014, Pages 2077-2083 Referred to by Jane E Harding, Deborah L Harris, Philip J Weston, Matthew Signal, Geoffrey Chase Sublingual sugar for infant hypoglycaemia - Authors' reply The Lancet, Volume 383, Issue 9924, 5-11 April 2014, Pages 1208-1209

The pseudo-high-risk prevention strategy

Key Messages: A fundamental failure of high-risk prevention strategies is their inability to prevent disease in the large part of the population at a relatively small average risk and from which most cases of diseases originate. The development of individual predictive medicine and the widening of high-risk categories for numerous (chronic) conditions lead to the application of pseudo-high-risk prevention strategies. Widening the criteria justifying individual preventive interventions and the related pseudo-high-risk strategies lead to treating, individually, ever healthier and larger strata of the population. The pseudo-high-risk prevention strategies raise similar problems compared with high-risk strategies, however on a larger scale and without any of the benefit of population-based strategies. Some 30 years ago, the strengths and weaknesses of population-based and high-risk prevention strategies were brilliantly delineated by Geoffrey Rose in several seminal publications (Table 1).1,2 His work had major implications not only for epidemiology and public health but also for clinical medicine. In particular, Rose demonstrated the fundamental failure of high-risk prevention strategies, that is, by missing a large number of preventable cases.

Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.

Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total Cbl was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCbl. Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders.

Peutz-Jeghers syndrome: a systematic review and recommendations for management

Peutz¿Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype¿phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.