RESUMO
The systemic immune-inflammation index (SIII) is a marker studied in multiple types of urologic cancer. This systematic review evaluates the association between SIII values with overall survival (OS) and progression-free survival (PFS) in testicular cancer. We searched observational studies in five databases. The quantitative synthesis was performed using a random-effects model. The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). The only measure of the effect was the hazard ratio (HR). A sensitivity analysis was performed according to the risk of bias in the studies. There were 833 participants in a total of 6 cohorts. We found that high SIII values were associated with worse OS (HR = 3.28; 95% CI 1.3-8.9; p < 0.001; I2 = 78) and PFS (HR = 3.9; 95% CI 2.53-6.02; p < 0.001; I2 = 0). No indication of small study effects was found in the association between SIII values and OS (p = 0.5301). High SIII values were associated with worse OS and PFS. However, further primary studies are suggested to enhance the effect of this marker in different outcomes of testicular cancer patients.
RESUMO
BRCA1 has been found to be absent or miss localized in the cytoplasm in a relevant proportion of breast cancer tumors with no germline mutations. BRCA1 main function is in the nucleus, and its interaction with BARD1 is relevant for its nuclear translocation and retention. Our aim was to analyze the sub-cellular localization of BRCA1 and BARD1 in breast cancer tumors, and determine the level of expression of their splice variants BRCA1-Δ11q and BARD1-α and BARD1-ß. BRCA1 and BARD1 expressions were performed by immunohistochemistry and immunofluorescence in 103 breast cancer tumors. Colocalization was determined by confocal microscopy. Transcript variants were determined by qRT-PCR. We found BRCA1 localized in the cytoplasm with BARD1 in 51.4 % of tumors. An exclusive nuclear localization of both proteins was observed in 7/103 tumors (6.8 %). Indeed, these tumors displayed an apparent nucleolar colocalization of BARD1 and BRCA1. In relation to splice variants, there is a tendency to an overexpression of BARD1-α mRNA (30 % of tumors) and a decreased expression of BARD1-ß (41 %). BRCA1 full-length was downregulated in 63 % of tumors, and 37 % showed BRCA1-Δ11q variant overexpressed. Our findings contribute to a better understanding of the expression and sub-cellular localization of BRCA1 in breast cancer tumors. Interaction of BRCA1 and BARD1 seems to be not affected in 58.2 % of tumors, which showed colocalization of both proteins. The absence of BRCA1 in 41 % of tumors reveals a BRCAness phenotype, constituting an excellent marker for therapy sensitivity, to platinum drugs or PARP inhibitors.
Assuntos
Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Processamento Alternativo , Neoplasias da Mama/patologia , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Humanos , Ligação Proteica , Isoformas de Proteínas , Transporte ProteicoRESUMO
Promoter hypermethylation is gaining strength as one of the main mechanisms through which tumor suppressor genes are silenced during tumor progression. Three tumor suppressor genes are frequently found methylated in their promoter, in concordance with absence of expression, RASSF1A, SLIT2, and WIF1. In addition, a previous array-CGH analysis from our group showed that these genes are found in deleted genomic regions observed in hereditary breast cancer tumors. In the present work we analyzed the methylation status of these three tumor suppressor gene promoters in 47 hereditary breast cancer tumors. Promoter methylation status analysis of hereditary breast tumors revealed high methylation frequencies for the three genes (67% RASSF1A, 80% SLIT2, and 72% WIF1). Additionally, the presence of methylated PCR products was associated with absence of protein expression for the three genes and statistically significant for RASSF1A and WIF1. Interestingly, methylation of all the three genes was found in 4 out of 6 grade I invasive ductal carcinoma tumors. Association between RASSF1A methylation and DCIS tumors was found. These results suggest that silencing of these tumor suppressor genes is an early event in hereditary breast cancer, and could be a marker for pre-malignant phenotypes.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/genética , Mama/patologia , Inativação Gênica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas do Tecido Nervoso/genética , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/genética , Sequência de Bases , Mama/metabolismo , Neoplasias da Mama/patologia , DNA/genética , DNA/isolamento & purificação , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Regiões Promotoras GenéticasRESUMO
OBJECTIVE: To determine the prevalence of AZFc subdeletions in infertile Chilean men with severe spermatogenic impairment. DESIGN: Prospective analysis. SETTING: University infertility clinic. PATIENT(S): Ninety-five secretory azo/oligozoospermic men without AZFc Y chromosome microdeletions: 71 whose testicular histology showed severe spermatogenic impairment and 24 who exhibited reduced testicular volume and elevated serum FSH levels. As controls, we studied 77 men (50 fertile and/or normozoospermic, and 27 with azoospermia and normal spermatogenesis). INTERVENTION(S): Peripheral blood was drawn to obtain genomic DNA for polymerase chain reaction (PCR) digestion assays of DAZ-sequence nucleotide variants and for AZFc-STS PCR after a complete testicular characterization (biopsy, hormonal, and physical evaluation). MAIN OUTCOME MEASURE(S): DAZ genes and AZFc subdeletion types. RESULT(S): In cases we observed two "gr/gr" subdeletions (2.1%), one with absence of DAZ1/DAZ2 (g1/g2 subtype), and the other with absence of DAZ3/DAZ4 (r2/r4 subtype). Additionally, we found a g1/g3 subdeletion in a patient with Sertoli-cell-only syndrome. In controls, we observed two gr/gr subdeletions with absence of DAZ1/DAZ2 (2.6%) in a fertile/normozoospermic and in an obstructive azoospermic man. CONCLUSION(S): AZFc subdeletions do not seem to cause severe impairment of spermatogenesis. Moreover, gr/gr-DAZ1/DAZ2 subdeletions do not appear to affect fertility in Chilean men.