22q11 Gene dosage establishes an adaptive range for sonic hedgehog and retinoic acid signaling during early development

We asked whether key morphogenetic signaling pathways interact with 22q11 gene dosage to modulate the severity of cranial or cardiac anomalies in DiGeorge/22q1 deletion syndrome (22q11DS). Sonic hedgehog (Shh) and retinoic acid (RA) signaling is altered in the brain and heart—clinically significant 22q11DS phenotypic sites—in LgDel mouse embryos, an established 22q11DS model. LgDel embryos treated with cyclopamine, an Shh inhibitor, or carrying mutations in Gli3Xtj, an Shh-signaling effector, have morphogenetic anomalies that are either not seen, or seen at significantly lower frequencies in control or single-mutant embryos. Similarly, RA exposure or genetic loss of RA function via heterozygous mutation of the RA synthetic enzyme Raldh2 induces novel cranial anomalies and enhances cardiovascular phenotypes in LgDel but not other genotypes. These changes are not seen in heterozygous Tbx1 mutant embryos—a 22q11 gene thought to explain much of 22q11DS pathogenesis—in which Shh or RA signaling has been similarly modified. Our results suggest that full dosage of 22q11 genes beyond Tbx1 establish an adaptive range for morphogenetic signaling via Shh and RA. When this adaptive range is constricted by diminished dosage of 22q11 genes, embryos are sensitized to otherwise benign changes in Shh and RA signaling. Such sensitization, in the face of environmental or genetic factors that modify Shh or RA signaling, may explain variability in 22q11DS morphogenetic phenotypes

Specific Mesenchymal/Epithelial Induction of Olfactory Receptor, Vomeronasal, and Gonadotropin-Releasing Hormone (GnRH) Neurons

We asked whether specific mesenchymal/epithelial (M/E) induction generates olfactory receptor neurons (ORNs), vomeronasal neurons (VRNs), and gonadotropin-releasing hormone (GnRH) neurons, the major neuron classes associated with the olfactory epithelium (OE). To assess specificity of M/E-mediated neurogenesis, we compared the influence of frontonasal mesenchyme on frontonasal epithelium, which becomes the OE, with that of the forelimb bud. Despite differences in position, morphogenetic and cytogenic capacity, both mesenchymal tissues support neurogenesis, expression of several signaling molecules and neurogenic transcription factors in the frontonasal epithelium. Only frontonasal mesenchyme, however, supports OE-specific patterning and activity of a subset of signals and factors associated with OE differentiation. Moreover, only appropriate pairing of frontonasal epithelial and mesenchymal partners yields ORNs, VRNs, and GnRH neurons. Accordingly, the position and molecular identity of specialized frontonasal epithelia and mesenchyme early in gestation and subsequent inductive interactions specify the genesis and differentiation of peripheral chemosensory and neuroendocrine neurons.Molecular and Cellular Biolog

Whole-body integration of gene expression and single-cell morphology

Animal bodies are composed of cell types with unique expression programs that implement their distinct locations, shapes, structures, and functions. Based on these properties, cell types assemble into specific tissues and organs. To systematically explore the link between cell-type-specific gene expression and morphology, we registered an expression atlas to a whole-body electron microscopy volume of the nereid Platynereis dumerilii. Automated segmentation of cells and nuclei identifies major cell classes and establishes a link between gene activation, chromatin topography, and nuclear size. Clustering of segmented cells according to gene expression reveals spatially coherent tissues. In the brain, genetically defined groups of neurons match ganglionic nuclei with coherent projections. Besides interneurons, we uncover sensory-neurosecretory cells in the nereid mushroom bodies, which thus qualify as sensory organs. They furthermore resemble the vertebrate telencephalon by molecular anatomy. We provide an integrated browser as a Fiji plugin for remote exploration of all available multimodal datasets

Understanding missed opportunities for more timely diagnosis of cancer in symptomatic patients after presentation.

The diagnosis of cancer is a complex, multi-step process. In this paper, we highlight factors involved in missed opportunities to diagnose cancer more promptly in symptomatic patients and discuss responsible mechanisms and potential strategies to shorten intervals from presentation to diagnosis. Missed opportunities are instances in which post-hoc judgement indicates that alternative decisions or actions could have led to more timely diagnosis. They can occur in any of the three phases of the diagnostic process (initial diagnostic assessment; diagnostic test performance and interpretation; and diagnostic follow-up and coordination) and can involve patient, doctor/care team, and health-care system factors, often in combination. In this perspective article, we consider epidemiological 'signals' suggestive of missed opportunities and draw on evidence from retrospective case reviews of cancer patient cohorts to summarise factors that contribute to missed opportunities. Multi-disciplinary research targeting such factors is important to shorten diagnostic intervals post presentation. Insights from the fields of organisational and cognitive psychology, human factors science and informatics can be extremely valuable in this emerging research agenda. We provide a conceptual foundation for the development of future interventions to minimise the occurrence of missed opportunities in cancer diagnosis, enriching current approaches that chiefly focus on clinical decision support or on widening access to investigations.We acknowledge the helpful and incisive comments by Dr Rikke Sand Andersen (Aarhus University, Denmark) in conceptualising this piece and in drafts of the manuscript. The work is independent research supported by different funding schemes. GL was supported by a Post-Doctoral Fellowship by the National Institute for Health Research (PDF-2011-04-047) until the end of 2014 and by a Cancer Research UK Clinician Scientist Fellowship award (A18180) from 2015. HS is supported by the VA Health Services Research and Development Service (CRE 12-033; Presidential Early Career Award for Scientists and Engineers USA 14-274), the VA National Center for Patient Safety, the Agency for Health Care Research and Quality (R01HS022087) and in part by the Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (CIN 13–413). PV was supported by CaP, funded by The Danish Cancer Society and the Novo Nordisk Foundation.This is the final version of the article. It first appeared at http://dx.doi.org/10.1038/bjc.2015.4

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems