The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis

<p>Abstract</p> <p>Background</p> <p>The process of malignant transformation, progression and metastasis of melanoma is poorly understood. Gene expression profiling of human cancer has allowed for a unique insight into the genes that are involved in these processes. Thus, we have attempted to utilize this approach through the analysis of a series of primary, non-metastatic cutaneous tumors and metastatic melanoma samples.</p> <p>Methods</p> <p>We have utilized gene microarray analysis and a variety of molecular techniques to compare 40 metastatic melanoma (MM) samples, composed of 22 bulky, macroscopic (replaced) lymph node metastases, 16 subcutaneous and 2 distant metastases (adrenal and brain), to 42 primary cutaneous cancers, comprised of 16 melanoma, 11 squamous cell, 15 basal cell skin cancers. A Human Genome U133 Plus 2.0 array from Affymetrix, Inc. was utilized for each sample. A variety of statistical software, including the Affymetrix MAS 5.0 analysis software, was utilized to compare primary cancers to metastatic melanomas. Separate analyses were performed to directly compare only primary melanoma to metastatic melanoma samples. The expression levels of putative oncogenes and tumor suppressor genes were analyzed by semi- and real-time quantitative RT-PCR (qPCR) and Western blot analysis was performed on select genes.</p> <p>Results</p> <p>We find that primary basal cell carcinomas, squamous cell carcinomas and thin melanomas express dramatically higher levels of many genes, including <it>SPRR1A/B</it>, <it>KRT16/17</it>, <it>CD24</it>, <it>LOR</it>, <it>GATA3</it>, <it>MUC15</it>, and <it>TMPRSS4</it>, than metastatic melanoma. In contrast, the metastatic melanomas express higher levels of genes such as <it>MAGE</it>, <it>GPR19</it>, <it>BCL2A1</it>, <it>MMP14</it>, <it>SOX5</it>, <it>BUB1</it>, <it>RGS20</it>, and more. The transition from non-metastatic expression levels to metastatic expression levels occurs as melanoma tumors thicken. We further evaluated primary melanomas of varying Breslow's tumor thickness to determine that the transition in expression occurs at different thicknesses for different genes suggesting that the "transition zone" represents a critical time for the emergence of the metastatic phenotype. Several putative tumor oncogenes (<it>SPP-1</it>, <it>MITF</it>, <it>CITED-1</it>, <it>GDF-15</it>, <it>c-Met</it>, <it>HOX </it>loci) and suppressor genes (<it>PITX-1</it>, <it>CST-6</it>, <it>PDGFRL</it>, <it>DSC-3</it>, <it>POU2F3</it>, <it>CLCA2</it>, <it>ST7L</it>), were identified and validated by quantitative PCR as changing expression during this transition period. These are strong candidates for genes involved in the progression or suppression of the metastatic phenotype.</p> <p>Conclusion</p> <p>The gene expression profiling of primary, non-metastatic cutaneous tumors and metastatic melanoma has resulted in the identification of several genes that may be centrally involved in the progression and metastatic potential of melanoma. This has very important implications as we continue to develop an improved understanding of the metastatic process, allowing us to identify specific genes for prognostic markers and possibly for targeted therapeutic approaches.</p

Program for expectant and new mothers: a population-based study of participation

<p>Abstract</p> <p>Background</p> <p>The Manitoba Healthy Baby Program is aimed at promoting pre- and perinatal health and includes two components: 1) prenatal income supplement; 2) community support programs. The goal of this research was to determine the uptake of these components by target groups.</p> <p>Methods</p> <p>Data on participation in each of the two program components were linked to data on all hospital births in Manitoba between 2004/05 through 2007/08. Descriptive analyses of participation by maternal characteristics were produced. Logistic regression analyses were conducted to identify factors associated with participation in the two programs. Separate regressions were run for two groups of women giving birth during the study period: 1) total population; 2) those receiving provincial income assistance during the prenatal period.</p> <p>Results</p> <p>Almost 30% of women giving birth in Manitoba received the Healthy Baby prenatal income supplement, whereas only 12.6% participated in any community support programs. Over one quarter (26.4%) of pregnant women on income assistance did not apply for and receive the prenatal income supplement, despite all being eligible for it. Furthermore, 77.8% of women on income assistance did not participate in community support programs. Factors associated with both receipt of the prenatal benefit and participation in community support programs included lower SES, receipt of income assistance, obtaining adequate prenatal care, having completed high school and having depressive symptoms. Having more previous births was associated with higher odds of receiving the prenatal benefit, but lower odds of attending community support programs. Being married was associated with lower odds of receiving the prenatal benefit but higher odds of participating in community support programs.</p> <p>Conclusions</p> <p>Although uptake of the Healthy Baby program in Manitoba is greater for women in groups at risk for poorer perinatal outcomes, a substantial number of women eligible for this program are not receiving it; efforts to reach these women should be enhanced.</p

Transcriptomic Analysis of Human Retinal Detachment Reveals Both Inflammatory Response and Photoreceptor Death

Background Retinal detachment often leads to a severe and permanent loss of vision and its therapeutic management remains to this day exclusively surgical. We have used surgical specimens to perform a differential analysis of the transcriptome of human retinal tissues following detachment in order to identify new potential pharmacological targets that could be used in combination with surgery to further improve final outcome. Methodology/Principal Findings Statistical analysis reveals major involvement of the immune response in the disease. Interestingly, using a novel approach relying on coordinated expression, the interindividual variation was monitored to unravel a second crucial aspect of the pathological process: the death of photoreceptor cells. Within the genes identified, the expression of the major histocompatibility complex I gene HLA-C enables diagnosis of the disease, while PKD2L1 and SLCO4A1 -which are both down-regulated- act synergistically to provide an estimate of the duration of the retinal detachment process. Our analysis thus reveals the two complementary cellular and molecular aspects linked to retinal detachment: an immune response and the degeneration of photoreceptor cells. We also reveal that the human specimens have a higher clinical value as compared to artificial models that point to IL6 and oxidative stress, not implicated in the surgical specimens studied here. Conclusions/Significance This systematic analysis confirmed the occurrence of both neurodegeneration and inflammation during retinal detachment, and further identifies precisely the modification of expression of the different genes implicated in these two phenomena. Our data henceforth give a new insight into the disease process and provide a rationale for therapeutic strategies aimed at limiting inflammation and photoreceptor damage associated with retinal detachment and, in turn, improving visual prognosis after retinal surgery

Euclid preparation - VII. Forecast validation for Euclid cosmological probes

Aims. The Euclid space telescope will measure the shapes and redshifts of galaxies to reconstruct the expansion history of the Universe and the growth of cosmic structures. The estimation of the expected performance of the experiment, in terms of predicted constraints on cosmological parameters, has so far relied on various individual methodologies and numerical implementations, which were developed for different observational probes and for the combination thereof. In this paper we present validated forecasts, which combine both theoretical and observational ingredients for different cosmological probes. This work is presented to provide the community with reliable numerical codes and methods for Euclid cosmological forecasts. Methods. We describe in detail the methods adopted for Fisher matrix forecasts, which were applied to galaxy clustering, weak lensing, and the combination thereof. We estimated the required accuracy for Euclid forecasts and outline a methodology for their development. We then compare and improve different numerical implementations, reaching uncertainties on the errors of cosmological parameters that are less than the required precision in all cases. Furthermore, we provide details on the validated implementations, some of which are made publicly available, in different programming languages, together with a reference training-set of input and output matrices for a set of specific models. These can be used by the reader to validate their own implementations if required. Results. We present new cosmological forecasts for Euclid. We find that results depend on the specific cosmological model and remaining freedom in each setting, for example flat or non-flat spatial cosmologies, or different cuts at non-linear scales. The numerical implementations are now reliable for these settings. We present the results for an optimistic and a pessimistic choice for these types of settings. We demonstrate that the impact of cross-correlations is particularly relevant for models beyond a cosmological constant and may allow us to increase the dark energy figure of merit by at least a factor of three

Euclid preparation: V. Predicted yield of redshift 7<z<9 quasars from the wide survey

We provide predictions of the yield of 7 < z < 9 quasars from the Euclid wide survey, updating the calculation presented in the Euclid Red Book in several ways. We account for revisions to the Euclid near-infrared filter wavelengths; we adopt steeper rates of decline of the quasar luminosity function (QLF; Φ) with redshift, Φ ∝ 10k(z−6) , k = −0.72, and a further steeper rate of decline, k = −0.92; we use better models of the contaminating populations (MLT dwarfs and compact early-type galaxies); and we make use of an improved Bayesian selection method, compared to the colour cuts used for the Red Book calculation, allowing the identification of fainter quasars, down to JAB ∼ 23. Quasars at z > 8 may be selected from Euclid OY JH photometry alone, but selection over the redshift interval 7 < z < 8 is greatly improved by the addition of z-band data from, e.g., Pan-STARRS and LSST. We calculate predicted quasar yields for the assumed values of the rate of decline of the QLF beyond z = 6. If the decline of the QLF accelerates beyond z = 6, with k = −0.92, Euclid should nevertheless find over 100 quasars with 7.0 < z < 7.5, and ∼ 25 quasars beyond the current record of z = 7.5, including ∼ 8 beyond z = 8.0. The first Euclid quasars at z > 7.5 should be found in the DR1 data release, expected in 2024. It will be possible to determine the bright-end slope of the QLF, 7 < z < 8, M1450 < −25, using 8 m class telescopes to confirm candidates, but follow-up with JWST or E-ELT will be required to measure the faint-end slope. Contamination of the candidate lists is predicted to be modest even at JAB ∼ 23. The precision with which k can be determined over 7 < z < 8 depends on the value of k, but assuming k = −0.72 it can be measured to a 1σ uncertainty of 0.07

Euclid preparation: VII. Forecast validation for Euclid cosmological probes

Aims. The Euclid space telescope will measure the shapes and redshifts of galaxies to reconstruct the expansion history of the Universe and the growth of cosmic structures. The estimation of the expected performance of the experiment, in terms of predicted constraints on cosmological parameters, has so far relied on various individual methodologies and numerical implementations, which were developed for different observational probes and for the combination thereof. In this paper we present validated forecasts, which combine both theoretical and observational ingredients for different cosmological probes. This work is presented to provide the community with reliable numerical codes and methods for Euclid cosmological forecasts. Methods. We describe in detail the methods adopted for Fisher matrix forecasts, which were applied to galaxy clustering, weak lensing, and the combination thereof. We estimated the required accuracy for Euclid forecasts and outline a methodology for their development. We then compare and improve different numerical implementations, reaching uncertainties on the errors of cosmological parameters that are less than the required precision in all cases. Furthermore, we provide details on the validated implementations, some of which are made publicly available, in different programming languages, together with a reference training-set of input and output matrices for a set of specific models. These can be used by the reader to validate their own implementations if required. Results. We present new cosmological forecasts for Euclid. We find that results depend on the specific cosmological model and remaining freedom in each setting, for example flat or non-flat spatial cosmologies, or different cuts at non-linear scales. The numerical implementations are now reliable for these settings. We present the results for an optimistic and a pessimistic choice for these types of settings. We demonstrate that the impact of cross-correlations is particularly relevant for models beyond a cosmological constant and may allow us to increase the dark energy figure of merit by at least a factor of three

Euclid preparation: V. Predicted yield of redshift 7 < z < 9 quasars from the wide survey

We provide predictions of the yield of 7 8 may be selected from Euclid OY JH photometry alone, but selection over the redshift interval 7 7.5 should be found in the DR1 data release, expected in 2024. It will be possible to determine the bright-end slope of the QLF, 7 < z < 8, M1450 < −25, using 8 m class telescopes to confirm candidates, but follow-up with JWST or E-ELT will be required to measure the faint-end slope. Contamination of the candidate lists is predicted to be modest even at JAB ∼ 23. The precision with which k can be determined over 7 < z < 8 depends on the value of k, but assuming k = −0.72 it can be measured to a 1σ uncertainty of 0.07