A Rare Cause of Scrotal Swelling: Transitional Cell Carcinoma of the Bladder Presenting as a Testicular Metastasis

A 72-year-old Caucasian male who presented with haematuria in July of 2000 was found to have a large left-sided bladder tumour. He underwent a transurethral resection of the tumour and surveillance program. In October 2008 he underwent a transurethral resection of the prostate (TURP). Histology of the prostatic chippings showed poorly differentiated TCC with prostatic invasion. A CT of his chest abdomen and pelvis revealed no lymph node involvement or metastatic spread. He therefore underwent a cystoprostato-urethrectomy with ileal conduit formation, in December 2008. In May 2010 the decision was made to perform a left inguinal orchidectomy as he presented with a craggy mass of his left testis, and there were clinical concerns that this was a tumour. Histology revealed that the left testis had been wholly replaced by a tumour. Taking into account his previous urological history, the features of this tumour are consistent with metastatic TCC, which is very rare

In vitro modelling of epithelial and stromal interactions in non-malignant and malignant prostates

To study the effects of stromal epithelial cell interactions on prostate cancer metastasis, we have used primary human prostatic stromal cells derived from malignant and non-malignant tissues and established epithelial cell lines from normal (PNT1a and PNT2-C2) and tumour (PC-3, DU145 and LNCaP) origins. The effects of stromal cells on epithelial cell growth were studied in direct and indirect (using culture inserts) co-culture and by exposure to stromal cell-conditioned medium (assessed by MTT assay). The influence of stromal cells on epithelial cell invasion was measured using matrigel invasion chambers and on epithelial cell motility using time lapse microscopy. Results indicated that epithelial cell line growth was similarly unaffected or inhibited by stromal cells derived from malignant (n = 8) or non-malignant tissue (n = 8). In contrast, PNT2-C2 and PC-3 cells were found to be the least and the most invasive and motile epithelia respectively. Stromal cultures enhanced the invasion of both epithelial cells, but no differences were observed between the use of malignant and non-malignant tissues. All stromal cultures modestly stimulated PNT2-C2 motility but displayed a greater stimulation of PC-3 cell motility, while stromal cells derived from malignant tissue stimulated PNT2-C2 and PC-3 cell motility more than stromal cultures from non-malignant tissues. © 2000 Cancer Research Campaig

Microbes and masculinity: Does exposure to pathogenic cues alter women's preferences for male facial masculinity and beardedness?

Women’s preferences for men’s androgen dependent secondary sexual traits are proposed to be phenotypically plastic in response to exposure to pathogens and pathogen disgust. While previous studies report that masculinity in facial shape is more attractive to women who have recently been exposed to pathogenic cues and who are high in self-reported pathogen disgust, facial hair may reduce male attractiveness under conditions of high pathogens as beards are a possible breeding ground for disease carrying ectoparasites. In the present study, we test whether women’s preferences for beardedness and facial masculinity vary due to exposure to different pathogenic cues. Participants (N = 688, mean age + 1SD = 31.94 years, SD = 6.69, range = 18–67) rated the attractiveness of facial composite stimuli of men when they were clean-shaven or fully bearded. These stimuli were also manipulated in order to vary sexual dimorphism by ±50%. Ratings were conducted before and after exposure to one of four experimental treatments in which participants were primed to either high pathogens (e.g. infected cuts), ectoparasites (e.g. body lice), a mixture of pathogens and ectoparasites, or a control condition (e.g. innocuous liquids). Participants then completed the three-domain disgust scale measuring attitudes to moral, sexual and pathogen disgust. We predicted that women would prefer facial masculinity following exposure to pathogenic cues, but would show reduced preferences for facial hair following exposure to ectoparasites. Women preferred full beards over clean-shaven faces and masculinised over feminised faces. However, none of the experimental treatments influenced the direction of preferences for facial masculinity or beardedness. We also found no association between women’s self-reported pathogen disgust and their preferences for facial masculinity. However, there was a weak positive association between moral disgust scores and preferences for facial masculinity, which might reflect conservatism and preferences for gender typicality in faces. Women’s preferences for beards were positively associated with their pathogen disgust, which runs contrary to our predictions and may reflect preferences for high quality individuals who can withstand any costs of beardedness, although further replications are necessary before firm conclusions can be made. We conclude that there is little support for pathogenic exposure being a mechanism that underpins women’s directional preferences for masculine traits

The histone deacetylase inhibitor sodium valproate causes limited transcriptional change in mouse embryonic stem cells but selectively overrides Polycomb-mediated Hoxb silencing.

BACKGROUND: Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation and H3K4 hypermethylation in various cell types. They find clinical application as anti-epileptics and chemotherapeutic agents, but the pathways through which they operate remain unclear. Surprisingly, changes in gene expression caused by HDACi are often limited in extent and can be positive or negative. Here we have explored the ability of the clinically important HDACi valproic acid (VPA) to alter histone modification and gene expression, both globally and at specific genes, in mouse embryonic stem (ES) cells. RESULTS: Microarray expression analysis of ES cells exposed to VPA (1 mM, 8 h), showed that only 2.4% of genes showed a significant, >1.5-fold transcriptional change. Of these, 33% were down-regulated. There was no correlation between gene expression and VPA-induced changes in histone acetylation or H3K4 methylation at gene promoters, which were usually minimal. In contrast, all Hoxb genes showed increased levels of H3K9ac after exposure to VPA, but much less change in other modifications showing bulk increases. VPA-induced changes were lost within 24 h of inhibitor removal. VPA significantly increased the low transcription of Hoxb4 and Hoxb7, but not other Hoxb genes. Expression of Hoxb genes increased in ES cells lacking functional Polycomb silencing complexes PRC1 and PRC2. Surprisingly, VPA caused no further increase in Hoxb transcription in these cells, except for Hoxb1, whose expression increased several fold. Retinoic acid (RA) increased transcription of all Hoxb genes in differentiating ES cells within 24 h, but thereafter transcription remained the same, increased progressively or fell progressively in a locus-specific manner. CONCLUSIONS: Hoxb genes in ES cells are unusual in being sensitive to VPA, with effects on both cluster-wide and locus-specific processes. VPA increases H3K9ac at all Hoxb loci but significantly overrides PRC-mediated silencing only at Hoxb4 and Hoxb7. Hoxb1 is the only Hoxb gene that is further up-regulated by VPA in PRC-deficient cells. Our results demonstrate that VPA can exert both cluster-wide and locus-specific effects on Hoxb regulation.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Differential cytotoxic activity of a novel palladium-based compound on prostate cell lines, primary prostate epithelial cells and prostate stem cells

The outcome for patients with advanced metastatic and recurrent prostate cancer is still poor. Therefore, new chemotherapeutics are required, especially for killing cancer stem cells that are thought to be responsible for disease recurrence. In this study, we screened the effect of a novel palladium-based anticancer agent (Pd complex) against six different prostate cancer cell lines, and primary cultures from seven Gleason 6/7 prostate cancer, three Gleason 8/9 prostate cancer and four benign prostate hyperplasia patient samples, as well as cancer stem cells selected from primary cultures. MTT and ATP viability assays were used to assess cell growth and flow cytometry to assess cell cycle status. In addition, immunofluorescence was used to detect γH2AX nuclear foci, indicative of DNA damage, and Western blotting to assess the induction of apoptosis and autophagy. The Pd complex showed a powerful growth-inhibitory effect against both cell lines and primary cultures. More importantly, it successfully reduced the viability of cancer stem cells as first reported in this study. The Pd complex induced DNA damage and differentially induced evidence of cell death, as well as autophagy. In conclusion, this novel agent may be promising for use against the bulk of the tumour cell population as well as the prostate cancer stem cells, which are thought to be responsible for the resistance of metastatic prostate cancer to chemotherapy. This study also indicates that the combined use of the Pd complex with an autophagy modulator may be a more promising approach to treat prostate cancer. In addition, the differential effects observed between cell lines and primary cells emphasise the importance of the model used to test novel drugs including its genetic background, and indeed the necessity of using cells cultured from patient samples

Regulation of the stem cell marker CD133 is independent of promoter hypermethylation in human epithelial differentiation and cancer

BackgroundEpigenetic control is essential for maintenance of tissue hierarchy and correct differentiation. In cancer, this hierarchical structure is altered and epigenetic control deregulated, but the relationship between these two phenomena is still unclear. CD133 is a marker for adult stem cells in various tissues and tumour types. Stem cell specificity is maintained by tight regulation of CD133 expression at both transcriptional and post-translational levels. In this study we investigated the role of epigenetic regulation of CD133 in epithelial differentiation and cancer.MethodsDNA methylation analysis of the CD133 promoter was done by pyrosequencing and methylation specific PCR; qRT-PCR was used to measure CD133 expression and chromatin structure was determined by ChIP. Cells were treated with DNA demethylating agents and HDAC inhibitors. All the experiments were carried out in both cell lines and primary samples.ResultsWe found that CD133 expression is repressed by DNA methylation in the majority of prostate epithelial cell lines examined, where the promoter is heavily CpG hypermethylated, whereas in primary prostate cancer and benign prostatic hyperplasia, low levels of DNA methylation, accompanied by low levels of mRNA, were found. Moreover, differential methylation of CD133 was absent from both benign or malignant CD133+/α2β1integrinhi prostate (stem) cells, when compared to CD133-/α2β1integrinhi (transit amplifying) cells or CD133-/α2β1integrinlow (basal committed) cells, selected from primary epithelial cultures. Condensed chromatin was associated with CD133 downregulation in all of the cell lines, and treatment with HDAC inhibitors resulted in CD133 re-expression in both cell lines and primary samples.ConclusionsCD133 is tightly regulated by DNA methylation only in cell lines, where promoter methylation and gene expression inversely correlate. This highlights the crucial choice of cell model systems when studying epigenetic control in cancer biology and stem cell biology. Significantly, in both benign and malignant prostate primary tissues, regulation of CD133 is independent of DNA methylation, but is under the dynamic control of chromatin condensation. This indicates that CD133 expression is not altered in prostate cancer and it is consistent with an important role for CD133 in the maintenance of the hierarchical cell differentiation patterns in cancer

Differential cytotoxic activity of a novel palladium-based compound on prostate cell lines, primary prostate epithelial cells and prostate stem cells

The outcome for patients with advanced metastatic and recurrent prostate cancer is still poor. Therefore, new chemotherapeutics are required, especially for killing cancer stem cells that are thought to be responsible for disease recurrence. In this study, we screened the effect of a novel palladium-based anticancer agent (Pd complex) against six different prostate cancer cell lines, and primary cultures from seven Gleason 6/7 prostate cancer, three Gleason 8/9 prostate cancer and four benign prostate hyperplasia patient samples, as well as cancer stem cells selected from primary cultures. MTT and ATP viability assays were used to assess cell growth and flow cytometry to assess cell cycle status. In addition, immunofluorescence was used to detect gamma H2AX nuclear foci, indicative of DNA damage, and Western blotting to assess the induction of apoptosis and autophagy. The Pd complex showed a powerful growth-inhibitory effect against both cell lines and primary cultures. More importantly, it successfully reduced the viability of cancer stem cells as first reported in this study. The Pd complex induced DNA damage and differentially induced evidence of cell death, as well as autophagy. In conclusion, this novel agent may be promising for use against the bulk of the tumour cell population as well as the prostate cancer stem cells, which are thought to be responsible for the resistance of metastatic prostate cancer to chemotherapy. This study also indicates that the combined use of the Pd complex with an autophagy modulator may be a more promising approach to treat prostate cancer. In addition, the differential effects observed between cell lines and primary cells emphasise the importance of the model used to test novel drugs including its genetic background, and indeed the necessity of using cells cultured from patient samples.YÖKYorkshire Cancer Research Core GrantUK Research & Innovation (UKRI) Medical Research Council UK (MRC) European Commission (G0900871)UK Research & Innovation (UKRI) Medical Research Council UK (MRC) (G0900871

Mating strategies and the masculinity paradox: How relationship context, relationship status, and sociosexuality shape women's preferences for facial masculinity and beardedness

According to the dual mating strategy model, in short-term mating contexts women should forego paternal investment qualities in favor of mates with well-developed secondary sexual characteristics and dominant behavioral displays. We tested whether this model explains variation in women’s preferences for facial masculinity and beardedness in male faces. Computer-generated composites that had been morphed to appear +/-50% masculine were rated by 671 heterosexual women (M age = 31.72 years, SD = 6.43) for attractiveness when considering them as a short-term partner, long-term partner, a co-parent or a friend. They then completed the Revised Sociosexual Inventory (SOI-R) to determine their sexual openness on dimensions of desire, behavior, and attitudes. Results showed that women’s preferences were strongest for average facial masculinity, followed by masculinized faces, with feminized faces being least attractive. In contrast to past research, facial masculinity preferences were stronger when judging for co-parenting partners than for short-term mates. Facial masculinity preferences were also positively associated with behavioral SOI, negatively with desire, and were unrelated to global or attitudinal SOI. Women gave higher ratings for full beards than clean-shaven faces. Preferences for beards were higher for co-parenting and long-term relationships than short-term relationships, although these differences were not statistically significant. Preferences for facial hair were positively associated with global and attitudinal SOI, but were unrelated to behavioral SOI and desire. Although further replication is necessary, our findings indicate that sexual openness is associated with women’s preferences for men’s facial hair and suggest variation in the association between sociosexuality and women’s facial masculinity preferences