CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer

Triple-negative breast cancer (TNBC) occurs in approximately 15% of all breast cancer patients, and the incidence of TNBC is greatly increased in BRCA1 mutation carriers. This study aimed to assess the impact of BRCA1 promoter methylation with respect to breast cancer subtypes in sporadic disease. Tissue microarrays (TMAs) were constructed representing tumors from 303 patients previously screened for BRCA1 germline mutations, of which a subset of 111 sporadic tumors had previously been analyzed with respect to BRCA1 methylation. Additionally, a set of eight tumors from BRCA1 mutation carriers were included on the TMAs. Expression analysis was performed on TMAs by immunohistochemistry (IHC) for BRCA1, pRb, p16, p53, PTEN, ER, PR, HER2, CK5/6, CK8, CK18, EGFR, MUC1, and Ki-67. Data on BRCA1 aberrations and IHC expression was examined with respect to breast cancer-specific survival. The results demonstrate that CpG island hypermethylation of BRCA1 significantly associates with the basal/triple-negative subtype. Low expression of pRb, and high/intense p16, were associated with BRCA1 promoter hypermethylation, and the same effects were seen in BRCA1 mutated tumors. The expression patterns of BRCA1, pRb, p16 and PTEN were highly correlated, and define a subgroup of TNBCs characterized by BRCA1 aberrations, high Ki-67 (≥ 40%) and favorable disease outcome. In conclusion, our findings demonstrate that epigenetic inactivation of the BRCA1 gene associates with RB/p16 dysfunction in promoting TNBCs. The clinical implications relate to the potential use of targeted treatment based on PARP inhibitors in sporadic TNBCs, wherein CpG island hypermethylation of BRCA1 represents a potential marker of therapeutic response

Gene expression profiling of tumour epithelial and stromal compartments during breast cancer progression

The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in the evolution of breast cancer. There is some evidence to suggest that dynamic interactions between the neoplastic cells and the tumour microenvironment play an important role. Using the whole-genome cDNA-mediated annealing, selection, extension and ligation assay (WG-DASL, Illumina), we performed gene expression profiling on 87 formalin-fixed paraffin-embedded (FFPE) samples from 17 patients consisting of matched IDC, DCIS and three types of stroma: IDC-S ( 10 mm from IDC or DCIS). Differential gene expression analysis was validated by quantitative real time-PCR, immunohistochemistry and immunofluorescence. The expression of several genes was down-regulated in stroma from cancer patients relative to normal stroma from reduction mammoplasties. In contrast, neoplastic epithelium underwent more gene expression changes during progression, including down regulation of SFRP1. In particular, we observed that molecules related to extracellular matrix (ECM) remodelling (e.g. COL11A1, COL5A2 and MMP13) were differentially expressed between DCIS and IDC. COL11A1 was overexpressed in IDC relative to DCIS and was expressed by both the epithelial and stromal compartments but was enriched in invading neoplastic epithelial cells. The contributions of both the epithelial and stromal compartments to the clinically important scenario of progression from DCIS to IDC. Gene expression profiles, we identified differential expression of genes related to ECM remodelling, and specifically the elevated expression of genes such as COL11A1, COL5A2 and MMP13 in epithelial cells of IDC. We propose that these expression changes could be involved in facilitating the transition from in situ disease to invasive cancer and may thus mark a critical point in disease development

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients

Número de horas de cuidados de enfermagem em unidade de terapia intensiva de adultos Número de horas de cuidados de enfermería en unidad de terapia intensiva Number of nursing care hours in an intensive care unit

O adequado dimensionamento de pessoal de enfermagem nas Terapias Intensivas tem sido uma grande preocupação para os enfermeiros que nelas atuam a despeito dos diferentes modelos de classificação dos pacientes propostos, no âmbito nacional e internacional. No presente estudo de caso, os objetivos foram estabelecer o tempo médio despendido na assistência direta de enfermagem em uma Unidade de Terapia Intensiva geral e calcular o número médio de horas de assistência direta de enfermagem prestada a esses pacientes. Para tanto, primeiramente, classificaram-se os procedimentos de enfermagem desenvolvidos com pacientes da UTI, de acordo com a sua complexidade: baixa, média e alta. A seguir, cronometrou-se o tempo médio despendido na realização desses procedimentos, a fim de se encontrar o tempo médio de assistência direta de enfermagem prestada aos pacientes, durante um período de três meses consecutivos.<br>La dimensión adecuada del personal de enfermería en los centros de terapias intensivas ha sido una gran preocupación para los enfermeros que actúan en ellos, llevando en consideración los diferentes modelos de clasificación de los pacientes propuestos, tanto en el ámbito nacional como en el internacional. En este estudio, los objetivos fueron establecer el tiempo medio que se utilizó en la asistencia directa de enfermería en un centro de terapia intensiva (CTI) general y calcular el número medio de horas de asistencia directa dispendidas con estos pacientes. Para eso fueron clasificados primeramente los procesos de enfermería desarrollados con pacientes de CTI, de acuerdo con su complejidad: baja, media y alta. Enseguida se cronometró el tiempo medio que se gastó en la realización de estos procedimientos con la finalidad de encontrar el tiempo medio de la atención de enfermería dedicada a los pacientes, durante un periodo de tiempo de tres meses consecutivos.<br>The adequate sizing of the nursing staff in Intensive Care Units has been one of the main concerns for the nurses that work in them, in spite of different classification models for patients that have been proposed at the domestic and international levels. In the present case study, the goals were to establish the average time spent in direct nursing assistance in an ICU and to calculate the average number of hours of direct nursing assistance delivered to its patients. In order to do that, the first step was to classify the nursing procedures carried out with ICU patients according to their complexity: low, medium and high. Next, the average time spent in theses procedures was counted during a threemonth period, in order to find out the average time of direct nursing assistance delivered to patients