The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Renal cell carcinoma(RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis

Surveillance of sentinel node-positive melanoma patients with reasons for exclusion from MLST-II: multi-institutional propensity score matched analysis

Background In sentinel lymph node (SLN)-positive melanoma, two randomized trials demonstrated equivalent melanoma-specific survival with nodal surveillance vs completion lymph node dissection (CLND). Patients with microsatellites, extranodal extension (ENE) in the SLN, or >3 positive SLNs constitute a high-risk group largely excluded from the randomized trials, for whom appropriate management remains unknown. Study design SLN-positive patients with any of the three high-risk features were identified from an international cohort. CLND patients were matched 1:1 with surveillance patients using propensity scores. Risk of any-site recurrence, SLN-basin-only recurrence, and melanoma-specific mortality were compared. Results Among 1,154 SLN-positive patients, 166 had ENE, microsatellites, and/or >3 positive SLN. At 18.5 months median follow-up, 49% had recurrence (vs 26% in patients without high-risk features, p ConclusionsSLN-positive patients with microsatellites, ENE, or >3 positive SLN constitute a high-risk group with a 2-fold greater recurrence risk. For those managed with nodal surveillance, SLN-basin recurrences were more frequent, but all-site recurrence and melanoma-specific mortality were comparable to patients treated with CLND. Most recurrences were outside the SLN-basin, supporting use of nodal surveillance for SLN-positive patients with microsatellites, ENE, and/or >3 positive SLN.Kristy K Broman, Tasha M Hughes, Lesly A Dossett, James Sun, Michael J Carr, Dennis A Kirichenko ... et al

Modelagem de dados de covariância de fluxo turbulento na floresta amazônica: uma comparação entre os modelos "folha-grande" e "sol/sombra" para a torre C-14 em Manaus. I. Fotossíntese do dossel

In this study, we concentrate on modelling gross primary productivity using two simple approaches to simulate canopy photosynthesis"big leaf" and "sun/shade" models. Two approaches for calibration are usedscaling up of canopy photosynthetic parameters from the leaf to the canopy level and fitting canopy biochemistry to eddy covariance fluxes. Validation of the models is achieved by using eddy covariance data from the LBA site C14. Comparing the performance of both models we conclude that numerically (in terms of goodness of fit) and qualitatively, (in terms of residual response to different environmental variables) sun/shade does a better job. Compared to the sun/shade model, the big leaf model shows a lower goodness of fit and fails to respond to variations in the diffuse fraction, also having skewed responses to temperature and VPD. The separate treatment of sun and shade leaves in combination with the separation of the incoming light into direct beam and diffuse make sun/shade a strong modelling tool that catches more of the observed variability in canopy fluxes as measured by eddy covariance. In conclusion, the sun/shade approach is a relatively simple and effective tool for modelling photosynthetic carbon uptake that could be easily included in many terrestrial carbon models.Neste trabalho foi modelada a produtividade primária bruta através de duas técnicas simples para simular a fotossíntese no dossel: os modelos "folha-grande" e "sol/sombra". Para calibrar os modelos foram utilizados os parâmetros de fotossíntese da folha, estendidos à escala do dossel e um ajuste da bioquímica do dossel em relação à covariância de vórtices turbulentos. Os modelos foram validados com as medidas feitas através da técnica de covariância de vórtices turbulentos da estação C14 do projeto LBA. Ao comparar o desempenho de ambos os modelos, conclui-se que o modelo "sol/sombra" apresenta melhores resultados numericamente (do ponto de vista da qualidade do ajuste aos dados da estação C14) e qualitativamente (segundo a resposta residual às diferentes variáveis ambientais). Comparado ao modelo "sol/sombra", o modelo "folha-grande" tem menos precisão e não responde bem às variações na fração difusa da luz. O modelo "folha-grande" também apresenta resultados assimétricos em relação à temperatura do ar e ao déficit da pressão de vapor. O tratamento separado de folhas expostas ao sol e de folhas sombreadas, combinado à separação da incidência de luz direta e difusa, faz do modelo "sol/sombra" uma ferramenta de modelagem útil, capaz de reproduzir melhor a variabilidade de fluxos no dossel medidos pela técnica de covariância de vórtices turbulentos. Neste trabalho, mostramos também a importância de boas estimativas de radiação difusa e a necessidade de aprimoramento de tais medidas na região amazônica. Discutimos igualmente as dificuldades de mudança de escala desde a folha para o dossel e a importância de dados representativos para serem parametrizados nestes tipos de modelo. Em conclusão, o modelo "sol/sombra" mostrou-se relativamente simples e eficaz para modelar a fixação de carbono pela fotossíntese e poderia facilmente ser incluído em diferentes modelos de ciclo do carbono terrestre

The ATLAS semiconductor tracker end-cap module

The challenges for the tracking detector systems at the LHC are unprecedented in terms of the number of channels, the required readout speed and the expected radiation levels. The ATLAS Semiconductor Tracker (SCT) end-caps have a total of about 3 million electronics channels each reading out every 25 ns into its own on-chip 3:3 ms buffer. The highest anticipated dose after 10 years operation is 1:4 1014 cm2 in units of 1 MeV neutron equivalent (assuming the damage factors scale with the non-ionising energy loss). The forward tracker has 1976 double-sided modules, mostly of area �70 cm2, each having 2 768 strips read out by six ASICs per side. The requirement to achieve an average perpendicular radiation length of 1.5% X0, while coping with up to 7W dissipation per module (after irradiation), leads to stringent constraints on the thermal design. The additional requirement of 1500e equivalent noise charge (ENC) rising to only 1800e ENC after irradiation, provides stringent design constraints on both the high-density Cu/Polyimide flex read-out circuit and the ABCD3TA read-out ASICs. Finally, the accuracy of module assembly must not compromise the 16 mm ðrfÞ resolution perpendicular to the strip directions or 580 mm radial resolution coming from the 40 mrad front-back stereo angle. A total of 2210 modules were built to the tight tolerances and specifications required for the SCT. This was 234 more than the 1976 required and represents a yield of 93%. The component flow was at times tight, but the module production rate of 40–50 per week was maintained despite this. The distributed production was not found to be a major logistical problem and it allowed additional flexibility to take advantage of where the effort was available, including any spare capacity, for building the end-cap modules. The collaboration that produced the ATLAS SCT end-cap modules kept in close contact at all times so that the effects of shortages or stoppages at different sites could be rapidly resolved