Diagnostic utility of snail in metaplastic breast carcinoma

Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer characterized by coexistence of carcinomatous and sarcomatous components. Snail is a nuclear transcription factor incriminated in the transition of epithelial to mesenchymal differentiation of breast cancer. Aberrant Snail expression results in lost expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. We aimed to identify the utility of Snail, and of traditional immunohistochemical markers, in accurate MBC classification and to evaluate clinicopathologic characteristics and outcome

EMT and Stem Cell-Like Properties Associated with HIF-2α Are Involved in Arsenite-Induced Transformation of Human Bronchial Epithelial Cells

Arsenic is well-established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is not been determined if the epithelial-mesenchymal transition (EMT) and stem cell-like properties contribute in causing to carcinogen-induced malignant transformation and subsequent tumor formation.To investigate the molecular mechanisms underlying EMT and the emergence of cancer stem cell-like properties during neoplastic transformation of human bronchial epithelial (HBE) cells induced by chronic exposure to arsenite. HBE cells were continuously exposed to arsenite. Spheroid formation assays and analyses of side populations (SPs) were performed to confirm that arsenite induces the acquired EMT and cancer stem cell-like phenotype. Treated HBE cells were molecularly characterized by RT-PCR, Western blots, immunofluorescence, Southwestern assays, reporter assays, and chromatin immunoprecipitation.With chronic exposure to arsenite, HBE cells undergo an EMT and then acquire a malignant cancer stem cell-like phenotype. Twist1 and Bmi1 are involved in arsenite-induced EMT. The process is directly regulated by HIF-2α. The self-renewal genes, Oct4, Bmi1, and ALDH1, are necessary for arsenite-mediated maintenance of stem cells.EMT, regulated by HIF-2α, and the development of a cancer stem cell-like phenotype are associated with arsenite-induced transformation of HBE cells

Understanding the cancer stem cell

The last 15 years has seen an explosion of interest in the cancer stem cell (CSC). Although it was initially believed that only a rare population of stem cells are able to undergo self-renewing divisions and differentiate to form all populations within a malignancy, a recent work has shown that these cells may not be as rare as thought first, at least in some malignancies. Improved experimental models are beginning to uncover a less rigid structure to CSC biology, in which the concepts of functional plasticity and clonal evolution must be incorporated into the traditional models. Slowly the genetic programmes and biological processes underlying stem cell biology are being elucidated, opening the door to the development of drugs targeting the CSC. The aim of ongoing research to understand CSCs is to develop novel stem cell-directed treatments, which will reduce therapy resistance, relapse and the toxicity associated with current, non-selective agents

Expression of P. falciparum var Genes Involves Exchange of the Histone Variant H2A.Z at the Promoter

Plasmodium falciparum employs antigenic variation to evade the human immune response by switching the expression of different variant surface antigens encoded by the var gene family. Epigenetic mechanisms including histone modifications and sub-nuclear compartmentalization contribute to transcriptional regulation in the malaria parasite, in particular to control antigenic variation. Another mechanism of epigenetic control is the exchange of canonical histones with alternative variants to generate functionally specialized chromatin domains. Here we demonstrate that the alternative histone PfH2A.Z is associated with the epigenetic regulation of var genes. In many eukaryotic organisms the histone variant H2A.Z mediates an open chromatin structure at promoters and facilitates diverse levels of regulation, including transcriptional activation. Throughout the asexual, intraerythrocytic lifecycle of P. falciparum we found that the P. falciparum ortholog of H2A.Z (PfH2A.Z) colocalizes with histone modifications that are characteristic of transcriptionally-permissive euchromatin, but not with markers of heterochromatin. Consistent with this finding, antibodies to PfH2A.Z co-precipitate the permissive modification H3K4me3. By chromatin-immunoprecipitation we show that PfH2A.Z is enriched in nucleosomes around the transcription start site (TSS) in both transcriptionally active and silent stage-specific genes. In var genes, however, PfH2A.Z is enriched at the TSS only during active transcription in ring stage parasites. Thus, in contrast to other genes, temporal var gene regulation involves histone variant exchange at promoter nucleosomes. Sir2 histone deacetylases are important for var gene silencing and their yeast ortholog antagonises H2A.Z function in subtelomeric yeast genes. In immature P. falciparum parasites lacking Sir2A or Sir2B high var transcription levels correlate with enrichment of PfH2A.Z at the TSS. As Sir2A knock out parasites mature the var genes are silenced, but PfH2A.Z remains enriched at the TSS of var genes; in contrast, PfH2A.Z is lost from the TSS of de-repressed var genes in mature Sir2B knock out parasites. This result indicates that PfH2A.Z occupancy at the active var promoter is antagonized by PfSir2A during the intraerythrocytic life cycle. We conclude that PfH2A.Z contributes to the nucleosome architecture at promoters and is regulated dynamically in active var genes

Partner-Level Factors Associated with Insertive and Receptive Condomless Anal Intercourse Among Transgender Women in Lima, Peru

Condomless anal intercourse among transgender women (TW) in Peru has been shown to vary by the type of partner involved (e.g. primary vs. casual vs. transactional sex partner), but no previous studies have explored variations in partner-level patterns of condom use according to type of anal intercourse. We evaluated the relationship between partnership characteristics and condom use during insertive (IAI) versus receptive anal intercourse (RAI) among TW with recent, non-female partners. Condomless IAI was more common with transactional and casual sex partners and by TW who self-reported HIV-uninfected serostatus (p<0.05), alcohol use disorders, or substance use before sex. Condomless RAI was more common with primary partners and by TW who described their HIV serostatus as unknown (p<0.05). Examining partner-level differences between condomless IAI and RAI reveals distinct patterns of HIV/STI risk among TW, suggesting a need for HIV prevention strategies tailored to the specific contexts of partners, practices, and networks