Suppression of Lung Adenocarcinoma Progression by Nkx2-1

Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS and inactivation of the p53 pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras[superscript LSL-G12D/+];p53[superscript flox/flox] mice initiates lung adenocarcinoma development4. Although tumours are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 (also called Ttf-1 or Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limitsmetastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically restricted chromatin regulator Hmga2. Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability and increased metastatic proclivity. Thus, the oncogenic and suppressive functions ofNkx2-1 in the sametumourNational Institutes of Health (U.S.) (grant U01-CA84306 )National Institutes of Health (U.S.) (grant K99-CA151968)Howard Hughes Medical InstituteLudwig Center for Molecular OncologyNational Cancer Institute (U.S.) (Cancer Center Support (core) grant P30-CA14051

Photons and local probes

Experiments using photons as a probe provide an excellent energy resolution. The wavelength of the light, however, sets a lower limit to the probed area perpendicular to the direction of propagation. This limit is of the order of the wavelength of the light. Scanning probe microscopes, on the other hand, have a superb spatial resolution. The energy of the interaction can only be acquired with modest sensitivty and resolution. Therefore, the combination of photons and local probes might provide the best of the two worlds. In this article we explore the possibilities of combining optical and SPM techniques. Near field optical microscopy using the aperture probe is used to investigate the emission properties of vertical cavity surface emitting laser diodes (VCSEL). Mode patterns put into relation to the topography of the emission area serve to diagnose the performance of the device. In contrast to classical optical microscopy techniques, our method is able to simultaneously decompose lasing transversal modes by their wavelength with lateral superresolution. Similarly, the comparison of the emission location of nanometer sized thin luminescent layers with the shape of the overgrown structure reveals variations of the bandgap and its position. Subtle differences in images obtained with internal and external collection modes provide clues to the diffusion of the charge carriers. Finally scanning force microscopy (SFM) is used to detect near field light by a mechanism based on optical modulation of the image force between a semiconducting probe tip and a glass surface due to the surface photo-voltage (SPV). This technique, which has a lateral resolution of better than 70 nm, allows the simultaneous detection of minute optical powers as small as 0.1 pW/#sq root#(Hz) in air and of charges. The technique is applied to the measurement of optical and charge gratings of a photorefractive material. (orig.)SIGLEAvailable from TIB Hannover: DtF QN1(64,22) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Proba-V cloud detection Round Robin: Validation results and recommendations

This paper discusses results from 12 months of a Round Robin exercise aimed at the inter-comparison of different cloud detection algorithms for Proba-V. Clouds detection is a critical issue for satellite optical remote sensing, since potential errors in cloud masking directly translates into significant uncertainty in the retrieved downstream geophysical products. Cloud detection is particularly challenging for Proba-V due to the presence of a limited number of spectral bands and the lack of thermal infrared bands. The main objective of the project was the inter-comparison of several cloud detection algorithms for Proba-V over a wide range of surface types and environmental conditions. Proba-V Level 2a products have been distributed to six different algorithm providers representing companies and research institutes in several European countries. The considered cloud detection approaches are based on different strategies: Neural Network, Discriminant Analysis, Multi-spectral and Multi-textural Thresholding, Self-Organizing Feature Maps, Dynamic Thresholding, and physically-based retrieval of Cloud Optical Thickness. The results from all algorithms were analysed and compared against a reference dataset, consisting of a large number (more than fifty thousands) of visually classified pixels. The quality assessment was performed according to a uniform methodology and the results provide clear indication on the potential best-suited approach for next Proba-V cloud detection algorithm

Effect of interferon-α on progression of cirrhosis to hepatocellular carcinoma: A retrospective cohort study

Background. There is debate about whether interferon-α treatment lowers the risk of progression to hepatocellular carcinoma in patients with chronic viral hepatitis and cirrhosis and whether any effect is limited to certain subgroups. We investigated these issues by retrospective analysis of data for 913 patients from Italy and Argentina. Methods. 21 centres reported patients from their records who had chronic viral hepatitis and Child's A cirrhosis, were positive for HBsAg or hepatitis-C-virus antibodies (anti-HCV), and had been screened yearly for at least 3 years by ultrasonography and α-1-fetoprotein testing. Prognostic risk factors for hepatocellular carcinoma defined by multivariate Cox regression analysis and individual observation time were used for group matching and conditional logistic regression analysis of the independent interferon-α treatment effect. Findings. After group matching, the number of patients was reduced to 637. Age, male sex, and portal hypertension were significant risk factors for hepatocellular carcinoma (each p < 0.001); hepatic inflammation (p = 0.21) and iron storage (p = 0.18) were also included in the model. 66 (19%) of 356 untreated patients and 29 (10%) of 281 treated patients developed hepatocellular carcinoma (relative risk 1.99 [95% CI 1.09-3.64]); the corresponding proportions for anti-HCV-positive patients were 48 (18.5%) of 259 versus 21 (9.1%) of 232 (3.14 [1.46-6. 80]), and those for hepatitis-B-virus-infected (HBV) patients were 18 (10%) of 97 and eight (16%) of 49 (0.98 [0.33-2.92]). Among anti-HCV patients without HBV markers, 29 (20%) of 129 untreated and six (5%) of 116 treated patients developed hepatocellular carcinoma (6.28 [1.65-2.38]). Interpretation. Interferon treatment lowered the rate of progression to hepatocellular carcinoma two fold. The risk reduction was apparently greater for patients with chronic hepatitis C and no evidence of HBV infection. Future studies should stratify HCV-infected patients by HBV status