Coordinate kinematic models in the International Terrestrial Reference Frame releases

International audienceIn the latest International Terrestrial Reference System realization (ITRF2014) combination model, new types of displacements have been introduced by means of mathematical functions. The addition of these functions has led to the implementation of new constraints to define the reference frame. This work was anticipated by A. Dermanis (2008) who derived constraint equations for different kinematic models. This paper presents the fundamental theoretical concepts that have been used to derive the latest International Terrestrial Reference Frame (ITRF). A new physical interpretation of the partial inner constraints involving transformation parameters is presented to supplement earlier work. By reviewing the various possibilities that could have been implemented to enhance the ITRF coordinate variations, this paper justifies the ITRF2014 chosen kinematic model and why it still does not include functions suggested by Dermanis (2008)

Centro de Análise Sirgas - IBGE: novas estratégias de processamento e combinação, e a influência da mudança do referencial global nos resultados

Atualmente, o SIRGAS (Sistema de Referência Geocêntrico para as Américas) é realizado por uma rede GNSS (Global Navigation Satellite System) permanente denominada SIRGAS-CON, com cerca de 240 estações em funcionamento permanente, distribuídas na América do Sul, Central e Caribe. Os Centros de Análise SIRGAS foram estabelecidos com a finalidade de determinar sistematicamente as coordenadas das estações SIRGAS-CON, seguindo padrões estabelecidos internacionalmente, a fim de apoiar a manutenção do sistema e as atividades do Grupo de Trabalho SIRGAS-GT I (Sistema de Referência). Desde agosto de 2008 a Coordenação de Geodésia do Instituto Brasileiro de Geografia e Estatística-IBGE assumiu oficialmente as atividades de um Centro de Análise. Este é um trabalho cuja dedicação é crescente uma vez que o número de estações no continente Sul Americano vem aumentando rapidamente nos últimos anos. Desta atividade diária são geradas dentre outros resultados, as séries temporais das coordenadas de cada estação, possibilitando assim a determinação dos deslocamentos das estações em função da movimentação da crosta terrestre, os movimentos locais como subsidência e/ou soerguimento crustal, causados por fenômenos naturais, como por exemplo, terremotos, além de efeitos sazonais causados por fatores diversos. Paralelamente a atividade de processamento dos dados GNSS, o IBGE também realiza semanalmente a combinação das soluções semanais dos nove Centros de Processamento SIRGAS. Esta combinação tem por objetivo comparar os resultados com os obtidos pelo DGFI (Deutsches Geodätisches Forschungsinstitut), o qual disponibiliza a solução final semanal da rede SIRGAS-CON. Por se tratar de resultados precisos, a mudança em alguma informação no processamento pode acarretar alterações nas coordenadas determinadas e, conseqüentemente, descontinuidades nas séries temporais de cada estação. Recentemente, em 17 de abril de 2011 (semana GPS 1632), as órbitas (finais e rápidas), as correções dos relógios dos satélites e o modelo de calibração das antenas disponibilizado pelo International GNSS Service - IGS, passaram a estar referidos à nova realização do IGS, denominada IGS08. Conseqüentemente, a partir dessa data, os processamentos GPS que utilizam os produtos IGS terão seus resultados referidos a este novo sistema de referência, o que poderá acarretar descontinuidades nas coordenadas. O objetivo desse trabalho é apresentar a estratégia de processamento atualmente em operação, bem com uma nova estratégia visando à melhoria dos resultados. Outro objetivo é apresentar alguns resultados do processamento e combinação semanal realizados pelo IBGE, bem como esclarecer as alterações ocorridas com a adoção da nova versão da Rede de Referência Global para soluções GNSS, o IGS08 e uma análise preliminar da conseqüência desta mudança

Quality Evaluation of the Weekly Vertical Loading Effects Induced from Continental Water Storage Models

To remove continental water storage (CWS) signals from the GPS data, CWS mass models are needed to obtain predicted surface displacements. We compared weekly GPS height time series with five CWS models: (1) the monthly and (2) three-hourly Global Land Data Assimilation System (GLDAS); (3) the monthly and (4) one-hourly Modern- Era Retrospective Analysis for Research and Applications (MERRA); (5) the six-hourly National Centers for Environmental Prediction-Department of Energy (NCEP-DOE) global reanalysis products (NCEP-R-2). We find that of the 344 selected global IGS stations, more than 77% of stations have their weighted root mean square (WRMS) reduced in the weekly GPS height by using both the GLDAS and MERRA CWS products to model the surface displacement, and the best improvement concentrate mainly in North America and Eurasia.We find that the one-hourly MERRA-Land dataset is the most appropriate product for modeling weekly vertical surface displacement caused by CWS variations. The threehourly GLDAS data ranks the second, while the GLDAS and MERRA monthly products rank the third. The higher spatial resolution MERRA product improves the performance of the CWS model in reducing the scatter of the GPS height by about 2–6% compared with the GLDAS. Under the same spatial resolution, the higher temporal resolution could also improve the performance by almost the same magnitude. We also confirm that removing the ATML and NTOL effects from the weekly GPS height would remarkably improve the performance of CWS model in correcting the GPS height by at least 10%, especially for coastal and island stations. Since the GLDAS product has a much greater latency than the MERRA product, MERRA would be a better choice to model surface displacements from CWS. Finally, we find that the NCEP-R-2 data is not sufficiently precise to be used for this application. Further work is still required to determine the reason

Ovarian cancer immunotherapy: opportunities, progresses and challenges

Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer

p53 status and response to radiotherapy in rectal cancer: a prospective multilevel analysis

The aim of this study was to evaluate, in a prospective study, the predictive role of p53 status analysed at four different levels in identifying the response to preoperative radiotherapy in rectal adenocarcinoma. Before treatment, 70 patients were staged and endoscopic forceps biopsies from the tumour area were taken. p53 status was assessed by total cDNA sequencing, allelic loss analysis, immunohistochemistry, and p53 antibodies. Neoadjuvant treatment was based on preoperative radiotherapy or radiochemotherapy. Response to therapy was evaluated after surgery by both pathologic downstaging and histologic tumour regression grade. In all, 35 patients (50.0%) had p53 gene mutations; 44.4% of patients had an allelic loss; nuclear p53 overexpression was observed in 39 patients (55.7%); and p53 antibodies were detected in 11 patients (16.7%). In the multilevel analysis of p53 status, gene mutations correlated with both nuclear protein overexpression (P<0.0001) and loss of heterozygosity (P=0.013). In all, 29 patients (41.4%) were downstaged by pathologic analysis, and 19 patients (29.2%) were classified as tumour regression grade 1. Whatever the method of evaluation of treatment response, no correlation between p53 alterations and response to radiotherapy was observed. Our results do not support the use of p53 alterations alone as a predictive marker for response to radiotherapy in rectal carcinoma

Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients

The clinical significance of ERBB2 amplification/overexpression in gastric cancer remains unclear. In this study, we evaluated the ERBB2 status in 463 gastric carcinomas using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), and compared the findings with histopathological characteristics and with disease-specific survival. ERBB2 overexpression (2+ and 3+) and amplification (ratio ERBB2/CEP17⩾2) were found in 43 (9.3%) and 38 (8.2%) gastric carcinomas, respectively. Perfect IHC/FISH correlation was found for the 19 cases scored as 0 (all negative by FISH), and also for the 25 cases scored as 3+ (all positive by FISH). One out of six carcinomas scored as 1+ and 12 out of 18 carcinomas scored as 2+ were positive by FISH. ERBB2 amplification was associated with gastric carcinomas of intestinal type (P=0.007) and with an expansive growth pattern (P=0.021). ERBB2 amplification was detected in both histological components of two mixed carcinomas, indicating a common clonal origin. A statistically significant association was found between ERBB2 amplification and worse survival in patients with expansive gastric carcinomas (P=0.011). We conclude that ERBB2 status may have clinical significance in subsets of gastric cancer patients, and that further studies are warranted to evaluate whether patients whose gastric carcinomas present ERBB2 amplification/overexpression may benefit from therapy targeting this surface receptor

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P &lt; 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM (-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors