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Early pregnancy is associated with a reduction in a woman's lifetime risk for breast cancer. However, different studies have demonstrated an increase in breast cancer risk in the years immediately following pregnancy. Early and long-term risk is even higher if the mother age is above 35 years at the time of first parity. The proinflammatory microenvironment within the mammary gland after pregnancy renders an "ideal niche" for oncogenic events. Signaling pathways involved in programmed cell death and tissue remodeling during involution are also activated in breast cancer. Herein, the major signaling pathways involved in mammary gland involution, signal transducer and activator of transcription (STAT3), nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGFβ), and retinoid acid receptors (RARs)/retinoid X receptors (RXRs), are reviewed as part of the complex network of signaling pathways that crosstalk in a contextual-dependent manner. These factors, also involved in breast cancer development, are important regulatory nodes for signaling amplification after weaning. Indeed, during involution, p65/p300 target genes such as MMP9, Capn1, and Capn2 are upregulated. Elevated expression and activities of these proteases in breast cancer have been extensively documented. The role of these proteases during mammary gland involution is further discussed. MMPs, calpains, and cathepsins exert their effect by modification of the extracellular matrix and intracellular proteins. Calpains, activated in the mammary gland during involution, cleave several proteins located in cell membrane, lysosomes, mitochondria, and nuclei favoring cell death. Besides, during this period, Capn1 is most probably involved in the modulation of preadipocyte differentiation through chromatin remodeling. Calpains can be implicated in cell anchoring loss, providing a proper microenvironment for tumor growth. A better understanding of the role of any of these proteases in tumorigenesis may yield novel therapeutic targets or prognostic markers for breast cancer.

This article will review the impact of the recently developed MassARRAY technology on our understanding of cancer biology and treatment. Analysis of somatic mutations is a useful tool in selecting personalized therapy, and for predicting the outcome of many solid tumors. Here, we review the literature on the application of MassARRAY technology (Sequenom Hamburg, Germany) to determine the mutation profile of solid tumors from patients. We summarize the use of commercially available panels of mutations - such as OncoCarta™ or other combinations - and their concordance with results obtained by using other technologies, such as next generation sequencing.

Psoriasis is a common but complex chronic inflammatory skin Disease. Array-based studies can help identify therapeutic targets.To reproducibly assess single-gene transcriptional changes in psoriatic skin.We evaluated 210 top candidate genes from a first psoriasis study group (population 1), and then confirmed differential expression in a second independent psoriasis study group (population 2).One hundred and thirty-eight differentially expressed genes were replicated in the 2 studies, of which 57 have not previously been reported as associated with psoriasis. This is significantly greater than the 10 expected false positives. Lesional skin vs uninvolved areas showed inflammatory and cell regulation changes.Previously undescribed psoriasis-associated genes revealed in this study may provide potential future targets for development and assessment of novel therapeutic agents for psoriasis.

In the HLA-G locus, the 3'-untranslated region (3'-UTR) begins in the mid exon 6, and ends in exon 8. The occurrence of a 14-bp deletion within exon 8, the only mutation known until now in the 3'-UTR, has been considered a risk factor for disease and allograft rejection. To describe the polymorphism within this region, direct sequencing analysis was performed on 120 DNA samples from Portugal and Guinea-Bissau. Results indicate that exon 8 is less conserved than the coding exons. Nine single nucleotide polymorphisms and the previously described 14-bp deletion were found within exon 8 of both populations. Molecular diversity was higher in the Guinean samples than in the Portuguese; however, little differentiation was found among the populations, suggesting that local selection on exon 8 sequence variation is absent. The screening for sequence motifs suggests that polymorphism on this region may be involved in HLA-G post-transcriptional regulation and, therefore, in phenotype variation.

Caspase recruitment domain-containing protein 14 mutations are the first monogenic defect causing psoriasis and pityriasisi rubra pilaris (PRP), linking psoriasis and PRP into one disease spectrum. Interestingly the disease responds well to the treatment with anti-p40 antibody (Ustekinumab) blocking IL-12 and IL-23. The mutant protein is mainly expressed in keratinocytes, leading us to explore whether keratinocyte dysfunction triggers the inflammatory phenotype through the recruitment of hematopoietic cells to the skin. CAR14 mutant keratinocytes produced high level of IL-8 to Toll-like receptor 3, 5, 9, IL-1a/b, IL-36, and TNF stimulation than control cells. IL-17A synergizes with Poly IC, Flagellin, and TNF, but not with IL-12/23, suggesting that Ustekinumab may not directly block keratinocytes but indirectly through inhibit IL-17A produced from likely hematopoietic cells. Using siRNA knock down assay of CMB (CARD-MALT1-BCL10) complex, we show that IL-17A induced IL-8 production is MALT1-dependent; thus raising the question what is the role of CARD14 in IL-17 mediated signal. Our data suggests that while IL-12/23 does not activate keratinocytes, IL-17A is a potent activator and even synergistically with other cytokine stimulant from hematopoietic cells during skin inflammation.

VNTR regions are informative genetic markers for linkage mapping and individual identification. Using PCR, we have developed a procedure for the enzymatic amplification of the VNTR located in the 16th intron of the human retinoblastoma (RB1) gene. We have also prepared a nonisotopically labeled oligonucleotide probe which facilitates detection of the amplification products. In examining 250 individuals from four different populations, we have detected 11 alleles ranging from 650 to 1,800 bp in size. The core repeat is approximately 50 bp in length. On the basis of the observed allele frequencies for Caucasian, African-American, and Hispanic populations from the United States and for the Mexican Hispanic population, the heterozygosities have been calculated to be 62%, 75%, 61%, and 50%, respectively. The observed genotype frequencies do not deviate from the values expected under Hardy-Weinberg equilibrium. The effect of varying primer sequences, annealing temperature, and cycle number on the amplification are also discussed. Amplification of this marker may also prove useful for detecting the heterozygosity loss that is associated with tumor formation in retinoblastoma.

The immunoglobulin kappa light chain (IgK) locus may play a significant role in the pathology of both infectious and autoimmune diseases. Most of the work on IgK genetics has been conducted using immunological techniques for allelic typing and sequence analysis. This is restricted by availability of reagents and can be both expensive and time-consuming. PCR primers were designed to amplify the kappa constant gene (Ck), and four allele-specific oligonucleotides (ASOs) were used to distinguish the alleles in the amplified PCR products. Direct sequencing of PCR products was performed to confirm that the primers specifically amplified the Ck region and the ASOs differentiated the Km alleles. Sequencing of an average of 209 nucleotides of DNA from 50 individuals revealed no variation except at codon 191, which is known to be involved in a frequent polymorphism. An analysis of 347 different individual DNAs from 10 human populations was conducted to determine Km allelic frequencies within these populations and to apply this type of data collection to population studies.

Chromosome 13q has been suggested as the site of a gene predisposing to human breast cancer, because loss of heterozygosity of alleles on this chromosome has been observed in some ductal breast tumors and because two breast cancer lines are altered at the retinoblastoma gene (RB1) at 13q14. To test this possibility, linkage of breast cancer susceptibility to 14 loci on chromosome 13q loci was assessed in extended families in which breast cancer is apparently inherited as an autosomal dominant trait. RB1 was excluded as the site of a breast cancer gene by a lod score of Z = -7.60 at close linkage for 13 families. Multipoint analysis yielded negative lod scores throughout the region between 13q12 and 13q34; over most of this distance, Z less than -2.0. Therefore, chromosome 13q appears to be excluded as the site of primary lesion for breast cancer in these families. In addition, comparison of tumor versus normal tissues of nonfamilial breast cancer patients revealed an alteration at the 5' end of RB1 in a mucoid carcinoma but no alterations of RB1 in five informative ductal adenocarcinomas. Linkage data and comparisons of tumor and normal tissues suggest that changes in the RBI locus either are secondary alterations associated with progression of some tumors or occur by chance.