Future Directions in Early Cystic Fibrosis Lung Disease Research: An NHLBI Workshop Report

Since the 1989 discovery that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), there has been substantial progress toward understanding the molecular basis for CF lung disease, leading to the discovery and development of new therapeutic approaches. However, the earliest impact of the loss of CFTR function on airway physiology and structure and its relationship to initial infection and inflammation are poorly understood. Universal newborn screening for CF in the United States represents an unprecedented opportunity for investigating CF clinical manifestations very early in life. Recently developed animal models with pulmonary phenotypic manifestations also provide a window into the early consequences of this genetic disorder. For these reasons, the National Heart, Lung, and Blood Institute (NHLBI) convened a working group of extramural experts, entitled “Future Research Directions in Early CF Lung Disease” on September 21–22, 2010, to identify future research directions of great promise in CF. The priority areas identified included (1) exploring pathogenic mechanisms of early CF lung disease; (2) leveraging newborn screening to elucidate the natural history of early lung disease; (3) developing a spectrum of biomarkers of early lung disease that reflects CF pathophysiology, clinical outcome, and response to treatment; (4) exploring the role of genetics/genomics (e.g., modifier genes, gene–environmental interactions, and epigenetics) in early CF pathogenesis; (5) defining early microbiological events in CF lung disease; and (6) elucidating the initial airway inflammatory, remodeling, and repair mechanisms in CF lung disease

Phosphorylation of a splice variant of collapsin response mediator protein 2 in the nucleus of tumour cells links cyclin dependent kinase-5 to oncogenesis

Background Cyclin-dependent protein kinase-5 (CDK5) is an unusual member of the CDK family as it is not cell cycle regulated. However many of its substrates have roles in cell growth and oncogenesis, raising the possibility that CDK5 modulation could have therapeutic benefit. In order to establish whether changes in CDK5 activity are associated with oncogenesis one could quantify phosphorylation of CDK5 targets in disease tissue in comparison to appropriate controls. However the identity of physiological and pathophysiological CDK5 substrates remains the subject of debate, making the choice of CDK5 activity biomarkers difficult. Methods Here we use in vitro and in cell phosphorylation assays to identify novel features of CDK5 target sequence determinants that confer enhanced CDK5 selectivity, providing means to select substrate biomarkers of CDK5 activity with more confidence. We then characterize tools for the best CDK5 substrate we identified to monitor its phosphorylation in human tissue and use these to interrogate human tumour arrays. Results The close proximity of Arg/Lys amino acids and a proline two residues N-terminal to the phosphorylated residue both improve recognition of the substrate by CDK5. In contrast the presence of a proline two residues C-terminal to the target residue dramatically reduces phosphorylation rate. Serine-522 of Collapsin Response Mediator-2 (CRMP2) is a validated CDK5 substrate with many of these structural criteria. We generate and characterise phosphospecific antibodies to Ser522 and show that phosphorylation appears in human tumours (lung, breast, and lymphoma) in stark contrast to surrounding non-neoplastic tissue. In lung cancer the anti-phospho-Ser522 signal is positive in squamous cell carcinoma more frequently than adenocarcinoma. Finally we demonstrate that it is a specific and unusual splice variant of CRMP2 (CRMP2A) that is phosphorylated in tumour cells. Conclusions For the first time this data associates altered CDK5 substrate phosphorylation with oncogenesis in some but not all tumour types, implicating altered CDK5 activity in aspects of pathogenesis. These data identify a novel oncogenic mechanism where CDK5 activation induces CRMP2A phosphorylation in the nuclei of tumour cells

The 2MASS Redshift Survey - Description and Data Release

We present the results of the 2MASS Redshift Survey (2MRS), a ten-year project to map the full three-dimensional distribution of galaxies in the nearby Universe. The 2 Micron All-Sky Survey (2MASS) was completed in 2003 and its final data products, including an extended source catalog (XSC), are available on-line. The 2MASS XSC contains nearly a million galaxies with Ks <= 13.5 mag and is essentially complete and mostly unaffected by interstellar extinction and stellar confusion down to a galactic latitude of |b|=5 deg for bright galaxies. Near-infrared wavelengths are sensitive to the old stellar populations that dominate galaxy masses, making 2MASS an excellent starting point to study the distribution of matter in the nearby Universe. We selected a sample of 44,599 2MASS galaxies with Ks =5 deg (>= 8 deg towards the Galactic bulge) as the input catalog for our survey. We obtained spectroscopic observations for 11,000 galaxies and used previously-obtained velocities for the remainder of the sample to generate a redshift catalog that is 97.6% complete to well-defined limits and covers 91% of the sky. This provides an unprecedented census of galaxy (baryonic mass) concentrations within 300 Mpc. Earlier versions of our survey have been used in a number of publications that have studied the bulk motion of the Local Group, mapped the density and peculiar velocity fields out to 50 Mpc, detected galaxy groups, and estimated the values of several cosmological parameters. Additionally, we present morphological types for a nearly-complete sub-sample of 20,860 galaxies with Ks = 10 deg.Comment: Accepted for publication in The Astrophysical Journal Supplement Series. The 2MRS catalogs and a version of the paper with higher-resolution figures can be found at http://tdc-www.harvard.edu/2mrs

Keratin proteins and carcinoembryonic antigen in synovial sarcomas: An immunohistochemical study of 24 cases

Twenty-four synovial sarcomas were examined for the presence of keratin proteins by an indirect immunoperoxidase method with paraffin-embedded tissues. Keratin proteins were identified in 16 of 24 cases (67 per cent). Both the pseudoglandular and spindle cell areas of all eight of the biphasic synovial sarcomas and the spindle cells of eight of the 16 monophasic synovial sarcomas contained keratin proteins. In spindle cell areas, staining was observed in single cells and small cords and clusters of cells in the absence of cleft formation or other evidence of a pseudoglandular component. The predominant cytologic staining pattern in all cases was peripheral, with localization of staining to the cell membrane or adjacent areas, but diffuse and focal cytoplasmic staining patterns were also observed. No staining for keratin proteins was seen in 101 control cases, including 52 sarcomas of various types. Carcinoembryonic antigen was also identified in four of the 24 synovial sarcomas by an indirect immunoperoxidase technique. The identification of keratin proteins may be helpful in the pathologic diagnosis of synovial sarcoma, particularly the spindle cell monophasic variant. © 1984 W. B. Saunders Co