Prognostic value of NDRG1 and SPARC protein expression in breast cancer patients

An increasing number of studies have shown altered expression of secreted protein acidic and rich in cysteine (SPARC) and N-myc down-regulated gene (NDRG1) in several malignancies, including breast carcinoma; however, the role of these potential biomarkers in tumor development and progression is controversial. In this study, NDRG1 and SPARC protein expression was evaluated by immunohistochemistry on tissue microarrays containing breast tumor specimens from patients with 10 years of follow-up. NDRG1 and SPARC protein expression was determined in 596 patients along with other prognostic markers, such as ER, PR, and HER2. The status of NDRG1 and SPARC protein expression was correlated with prognostic variables and patient clinical outcome. Immunostaining revealed that 272 of the 596 cases (45.6%) were positive for NDRG1 and 431 (72.3%) were positive for SPARC. Statistically significant differences were found between the presence of SPARC and NDRG1 protein expression and standard clinicopathological variables. Kaplan-Meier analysis showed that NDRG1 positivity was directly associated with shorter disease-free survival (DFS, P < 0.001) and overall survival (OS, P < 0.001). In contrast, patients expressing low levels of SPARC protein had worse DFS (P = 0.001) and OS (P = 0.001) compared to those expressing high levels. Combined analysis of the two markers indicated that DFS (P < 0.001) and OS rates (P < 0.001) were lowest for patients with NDRG1-positive and SPARC-negative tumors. Furthermore, NDRG1 over-expression and SPARC down-regulation correlated with poor prognosis in patients with luminal A or triple-negative subtype breast cancer. On multivariate analysis using a Cox proportional hazards model, NDRG1 and SPARC protein expression were independent prognostic factors for both DFS and OS of breast cancer patients. These data indicate that NDRG1 over-expression and SPARC down-regulation could play important roles in breast cancer progression and serve as useful biomarkers to better define breast cancer prognosis.

Osteonectin/SPARC induction by ectopic beta(3) integrin in human radial growth phase primary melanoma cells

Expression of the beta(3) integrin subunit in melanoma in situ has been found to correlate with tumor thickness, the ability to invade and metastasize, and poor prognosis. Transition from the radial growth phase (RGP) to the vertical growth phase (VGP) is a critical step in melanoma progression and survival and is distinguished by the expression of beta(3), integrin. The molecular pathways that operate in melanoma cells associated with invasion and metastasis were examined by ectopic induction of the beta(3), integrin subunit in RGP SBcl2 and WM1552C melanoma cells, which converts these cells to a VGP phenotype. We used cDNA representational difference analysis subtractive hybridization between beta(3)-Positive and -negative melanoma cells to assess gene expression profile changes accompanying RGP to VGP transition. Fourteen fragments from known genes including osteonectin (also known as SPARC and BM-40) were identified after three rounds of representational difference analysis. Induction of osteonectin was confirmed by Northern and Western blot analysis and immunohistochemistry and correlated in organotypic cultures with the beta(3)-induced progression from RGP to VGP melanoma. Expression of osteonectin was also associated with reduced adhesion to vitronectin, but not to fibronectin. Osteonectin expression was not blocked when melanoma cells were cultured with anti-alpha(v)beta(3) LM609 mAb, mitogen-activated protein kinase, or protein kinase C inhibitors, indicating that other signaling pathway(s) operate through a(v)beta(3) integrin during conversion from RGP to VGP.

Role of SPARC in Bone Remodeling and Cancer‐Related Bone Metastasis

There is a growing socioeconomic recognition that clinical bone diseases such as bone infections, bone tumors and osteoporotic bone loss mainly associated with ageing, are major issues in today0s society. SPARC (secreted protein, acidic and rich in cysteine), a matricellular glycoprotein, may be a promising therapeutic target for preventing or treating bone‐related diseases. In fact, SPARC is associated with tissue remodeling, repair, development, cell turnover, bone mineralization and may also participate in growth and progression of tumors, namely cancer‐related bone metastasis. Yet, the function of SPARC in such biological processes is poorly understood and controversial. The main objective of this work is to review the current knowledge related to the activity of SPARC in bone remodeling, tumorigenesis, and bone metastasis. Progress in understanding SPARC biology may provide novel strategies for bone regeneration and the development of anti‐angiogenic, anti‐proliferative, or counter‐adhesive treatments specifically against bone metastasis.

Mutations in the SPARC-Related Modular Calcium-Binding Protein 1 Gene, SMOC1, Cause Waardenburg Anophthalmia Syndrome.

Waardenburg anophthalmia syndrome, also known as microphthalmia with limb anomalies, ophthalmoacromelic syndrome, and anophthalmia-syndactyly, is a rare autosomal-recessive developmental disorder that has been mapped to 10p11.23. Here we show that this disease is heterogeneous by reporting on a consanguineous family, not linked to the 10p11.23 locus, whose two affected children have a homozygous mutation in SMOC1. Knockdown experiments of the zebrafish smoc1 revealed that smoc1 is important in eye development and that it is expressed in many organs, including brain and somites.

The GCM–Reality Intercomparison Project for SPARC (GRIPS): scientific issues and initial results

To investigate the effects of the middle atmosphere on climate, the World Climate Research Programme is supporting the project "Stratospheric Processes and their Role in Climate" (SPARC). A central theme of SPARC, to examine model simulations of the coupled troposphere—middle atmosphere system, is being performed through the initiative called GRIPS (GCM—Reality Intercomparison Project for SPARC). In this paper, an overview of the objectives of GRIPS is given. Initial activities include an assessment of the performance of middle atmosphere climate models, and preliminary results from this evaluation are presented here. It is shown that although all 13 models evaluated represent most major features of the mean atmospheric state, there are deficiencies in the magnitude and location of the features, which cannot easily be traced to the formulation (resolution or the parameterizations included) of the models. Most models show a cold bias in all locations, apart from the tropical tropopause region where they can be either too warm or too cold. The strengths and locations of the major jets are often misrepresented in the models. Looking at three—dimensional fields reveals, for some models, more severe deficiencies in the magnitude and positioning of the dominant structures (such as the Aleutian high in the stratosphere), although undersampling might explain some of these differences from observations. All the models have shortcomings in their simulations of the present—day climate, which might limit the accuracy of predictions of the climate response to ozone change and other anomalous forcing.

SPARC Data Initiative: Comparison of water vapor climatologies from international satellite limb sounders

Within the SPARC Data Initiative, the first comprehensive assessment of the quality of 13 water vapor products from 11 limb-viewing satellite instruments (LIMS, SAGE II, UARS-MLS, HALOE, POAM III, SMR, SAGE III, MIPAS, SCIAMACHY, ACE-FTS, and Aura-MLS) obtained within the time period 1978-2010 has been performed. Each instrument's water vapor profile measurements were compiled into monthly zonal mean time series on a common latitude-pressure grid. These time series serve as basis for the "climatological" validation approach used within the project. The evaluations include comparisons of monthly or annual zonal mean cross sections and seasonal cycles in the tropical and extratropical upper troposphere and lower stratosphere averaged over one or more years, comparisons of interannual variability, and a study of the time evolution of physical features in water vapor such as the tropical tape recorder and polar vortex dehydration. Our knowledge of the atmospheric mean state in water vapor is best in the lower and middle stratosphere of the tropics and midlatitudes, with a relative uncertainty of. 2-6% (as quantified by the standard deviation of the instruments' multiannual means). The uncertainty increases toward the polar regions (+/- 10-15%), the mesosphere (+/- 15%), and the upper troposphere/lower stratosphere below 100 hPa (+/- 30-50%), where sampling issues add uncertainty due to large gradients and high natural variability in water vapor. The minimum found in multiannual (1998-2008) mean water vapor in the tropical lower stratosphere is 3.5 ppmv (+/- 14%), with slightly larger uncertainties for monthly mean values. The frequently used HALOE water vapor data set shows consistently lower values than most other data sets throughout the atmosphere, with increasing deviations from the multi-instrument mean below 100 hPa in both the tropics and extratropics. The knowledge gained from these comparisons and regarding the quality of the individual data sets in different regions of the atmosphere will help to improve model-measurement comparisons (e.g., for diagnostics such as the tropical tape recorder or seasonal cycles), data merging activities, and studies of climate variability.

SPARC Data Initiative: A comparison of ozone climatologies from international satellite limb sounders

A comprehensive quality assessment of the ozone products from 18 limb-viewing satellite instruments is provided by means of a detailed intercomparison. The ozone climatologies in form of monthly zonal mean time series covering the upper troposphere to lower mesosphere are obtained from LIMS, SAGE I/II/III, UARS-MLS, HALOE, POAM II/III, SMR, OSIRIS, MIPAS, GOMOS, SCIAMACHY, ACE-FTS, ACE-MAESTRO, Aura-MLS, HIRDLS, and SMILES within 1978–2010. The intercomparisons focus on mean biases of annual zonal mean fields, interannual variability, and seasonal cycles. Additionally, the physical consistency of the data is tested through diagnostics of the quasi-biennial oscillation and Antarctic ozone hole. The comprehensive evaluations reveal that the uncertainty in our knowledge of the atmospheric ozone mean state is smallest in the tropical and midlatitude middle stratosphere with a 1σ multi-instrument spread of less than ±5%. While the overall agreement among the climatological data sets is very good for large parts of the stratosphere, individual discrepancies have been identified, including unrealistic month-to-month fluctuations, large biases in particular atmospheric regions, or inconsistencies in the seasonal cycle. Notable differences between the data sets exist in the tropical lower stratosphere (with a spread of ±30%) and at high latitudes (±15%). In particular, large relative differences are identified in the Antarctic during the time of the ozone hole, with a spread between the monthly zonal mean fields of ±50%. The evaluations provide guidance on what data sets are the most reliable for applications such as studies of ozone variability, model-measurement comparisons, detection of long-term trends, and data-merging activities.

Characterizing sampling bias in the trace gas climatologies of the SPARC Data Initiative

Monthly zonal mean climatologies of atmospheric measurements from satellite instruments can have biases due to the nonuniform sampling of the atmosphere by the instruments. We characterize potential sampling biases in stratospheric trace gas climatologies of the Stratospheric Processes and Their Role in Climate (SPARC) Data Initiative using chemical fields from a chemistry climate model simulation and sampling patterns from 16 satellite-borne instruments. The exercise is performed for the long-lived stratospheric trace gases O3 and H2O. Monthly sampling biases for O3 exceed 10% for many instruments in the high-latitude stratosphere and in the upper troposphere/lower stratosphere, while annual mean sampling biases reach values of up to 20% in the same regions for some instruments. Sampling biases for H2O are generally smaller than for O3, although still notable in the upper troposphere/lower stratosphere and Southern Hemisphere high latitudes. The most important mechanism leading to monthly sampling bias is nonuniform temporal sampling, i.e., the fact that for many instruments, monthly means are produced from measurements which span less than the full month in question. Similarly, annual mean sampling biases are well explained by nonuniformity in the month-to-month sampling by different instruments. Nonuniform sampling in latitude and longitude are shown to also lead to nonnegligible sampling biases, which are most relevant for climatologies which are otherwise free of biases due to nonuniform temporal sampling.

The SPARC Data Initiative: Comparison of upper troposphere/lower stratosphere ozone climatologies from limb-viewing instruments and the nadir-viewing Tropospheric Emission Spectrometer

We present the first comprehensive intercomparison of currently available satellite ozone climatologies in the upper troposphere/lower stratosphere (UTLS) (300–70 hPa) as part of the Stratosphere-troposphere Processes and their Role in Climate (SPARC) Data Initiative. The Tropospheric Emission Spectrometer (TES) instrument is the only nadir-viewing instrument in this initiative, as well as the only instrument with a focus on tropospheric composition. We apply the TES observational operator to ozone climatologies from the more highly vertically resolved limb-viewing instruments. This minimizes the impact of differences in vertical resolution among the instruments and allows identification of systematic differences in the large-scale structure and variability of UTLS ozone. We find that the climatologies from most of the limb-viewing instruments show positive differences (ranging from 5 to 75%) with respect to TES in the tropical UTLS, and comparison to a “zonal mean” ozonesonde climatology indicates that these differences likely represent a positive bias for p ≤ 100 hPa. In the extratropics, there is good agreement among the climatologies regarding the timing and magnitude of the ozone seasonal cycle (differences in the peak-to-peak amplitude of <15%) when the TES observational operator is applied, as well as very consistent midlatitude interannual variability. The discrepancies in ozone temporal variability are larger in the tropics, with differences between the data sets of up to 55% in the seasonal cycle amplitude. However, the differences among the climatologies are everywhere much smaller than the range produced by current chemistry-climate models, indicating that the multiple-instrument ensemble is useful for quantitatively evaluating these models.

The SPARC Data Initiative: comparisons of CFC-11, CFC-12, HF and SF6 climatologies from international satellite limb sounders

A quality assessment of the CFC-11 (CCl3F), CFC-12 (CCl2F2), HF, and SF6 products from limb-viewing satellite instruments is provided by means of a detailed intercomparison. The climatologies in the form of monthly zonal mean time series are obtained from HALOE, MIPAS, ACE-FTS, and HIRDLS within the time period 1991–2010. The intercomparisons focus on the mean biases of the monthly and annual zonal mean fields and aim to identify their vertical, latitudinal and temporal structure. The CFC evaluations (based on MIPAS, ACE-FTS and HIRDLS) reveal that the uncertainty in our knowledge of the atmospheric CFC-11 and CFC-12 mean state, as given by satellite data sets, is smallest in the tropics and mid-latitudes at altitudes below 50 and 20 hPa, respectively, with a 1σ multi-instrument spread of up to ±5 %. For HF, the situation is reversed. The two available data sets (HALOE and ACE-FTS) agree well above 100 hPa, with a spread in this region of ±5 to ±10 %, while at altitudes below 100 hPa the HF annual mean state is less well known, with a spread ±30 % and larger. The atmospheric SF6 annual mean states derived from two satellite data sets (MIPAS and ACE-FTS) show only very small differences with a spread of less than ±5 % and often below ±2.5 %. While the overall agreement among the climatological data sets is very good for large parts of the upper troposphere and lower stratosphere (CFCs, SF6) or middle stratosphere (HF), individual discrepancies have been identified. Pronounced deviations between the instrument climatologies exist for particular atmospheric regions which differ from gas to gas. Notable features are differently shaped isopleths in the subtropics, deviations in the vertical gradients in the lower stratosphere and in the meridional gradients in the upper troposphere, and inconsistencies in the seasonal cycle. Additionally, long-term drifts between the instruments have been identified for the CFC-11 and CFC-12 time series. The evaluations as a whole provide guidance on what data sets are the most reliable for applications such as studies of atmospheric transport and variability, model–measurement comparisons and detection of long-term trends. The data sets will be publicly available from the SPARC Data Centre and through PANGAEA (doi:10.1594/PANGAEA.849223).

LPS Induces Greater Bone and PDL Loss in SPARC-null Mice

Individuals with periodontal disease have increased risk of tooth loss, particularly in cases with associated loss of alveolar bone and periodontal ligament (PDL). Current treatments do not predictably regenerate damaged PDL. Collagen I is the primary component of bone and PDL extracellular matrix. SPARC/Osteonectin (SP/ON) is implicated in the regulation of collagen content in healthy PDL. In this study, periodontal disease was induced by injections of lipopolysaccharide (LPS) from Aggregatibacter actinomycetemcomitans in wild-type (WT) and SP/ON-null C57/B16 mice. A 20-mu g quantity of LPS was injected between the first and second molars 3 times a week for 4 weeks, whereas PBS control was injected into the contralateral maxilla. LPS injection resulted in a significant decrease in bone volume fraction in both genotypes; however, significantly greater bone loss was detected in SP/ON-null maxilla. SP/ON-null PDL exhibited more extensive degradation of connective tissue in the gingival tissues. Although total cell numbers in the PDL of SP/ON-null were not different from those in WT, the inflammatory infiltrate was reduced in SP/ON-null PDL. Histology of collagen fibers revealed marked reductions in collagen volume fraction and in thick collagen volume fraction in the PDL of SP/ON-null mice. SP/ON protects collagen content in PDL and in alveolar bone in experimental periodontal disease.

Avaliação da expressão gênica de MMPs e TIMPs modulados por RECK e SPARC durante o desenvolvimento ovariano e a foliculogênese em ratas

O remodelamento da matriz extracelular (MEC), um importante componente dos organismos multicelulares, relaciona-se diretamente com o desenvolvimento embrionário, a angiogênese, a morfogênese de órgãos e a formação de cartilagens. Especificamente nos ovários, este remodelamento permite a ocorrência dos diversos eventos observados no ciclo ovariano, a citar: o crescimento folicular, a ovulação e a formação e regressão do corpo lúteo. A reorganização tecidual advinda destes eventos é regulada, em parte, pela ação de enzimas proteolíticas conhecidas como metaloproteinases de matriz (MMPs) e de seus inibidores (TIMPs e RECK) (revisado por Curry et al., 2003). Atualmente, o remodelamento da MEC pelo sistema MMPs/TIMPs é fortemente correlacionado com a expressão de alguns genes, tais como o gene Basigin (BSG), que induz a expressão de MMPs durante o ciclo ovariano em ratos (Smedts et al., 2005), ou o gene SPARC, que modula a expressão do TGF-β, fator de crescimento este associado ao aumento da agressividade tumoral (Podhajcer et al., 2008). A expressão do gene RECK foi descrita em diversos processos de remodelamento tecidual fisiológicos. Porém, uma diminuição em sua expressão, juntamente com o aumento na expressão das MMPs, tem sido associada com tumores mais agressivos e metastáticos (Meng et al., 2008). No entanto, apesar de RECK e SPARC estarem amplamente associados com remodelamento tecidual em diversas patologias, ainda não foi descrita a associação destes com remodelamento tecidual promovido pelo sistema MMPs/TIMPs que ocorre naturalmente durante a dinâmica ovariana. Considerando este quadro, o trabalho aqui proposto tem por objetivo analisar a expressão gênica de algumas MMPs- (-2, -9, -13, -14 e -19), e alguns de seus inibidores (TIMPs -1, -2, e -3 e RECK) e correlacioná-la com a expressão de SPARC e BSG durante a foliculogênese ovariana de ratas... (Resumo completo, clicar acesso eletrônico abaixo)

Modelado y generación flexible de núcleos de procesador SPARC para aplicaciones específicas

Doctorado en Ingeniería de Telecomunicación. Programa de Doctorado : Ingeniería Electrónica