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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.

While chromosomal translocations have a fundamental role in the development of several human leukaemias, their role in solid tumour development has been somewhat more controversial. Recently, it was shown that up to 80% of prostate tumours harbour at least one such gene fusion, and that the most common fusion event, between the prostate-specific TMPRSS2 gene and the ERG oncogene, is a critical, and probably early factor in prostate cancer development. Here we demonstrate the presence and expression of this significant chromosomal rearrangement in prostate cancer stem cells. Moreover, we show that in the prostate epithelial hierarchy from both normal and tumour tissues, TMPRSS2 transcription is subjected to tight monoallelic regulation, which is retained upon asymmetric division and relaxed during epithelial cell differentiation. The presence and expression of TMPRSS2/ERG in prostate stem cells would provide ERG-driven survival advantages, allowing maintenance of this mutated genotype. The TMPRSS2/ERG gene fusion is frequently expressed in prostate cancers, however, its clinical significance is unclear. Polsen et al . show that this gene fusion is expressed monoallelically in prostate cancer stem cells, and may influence their self-renewal and maintenance.

BackgroundHuman prostate cancers display numerous DNA methylation changes compared to normal tissue samples. However, definitive identification of features related to the cells’ malignant status has been compromised by the predominance of cells with luminal features in prostate cancers.MethodsWe generated genome-wide DNA methylation profiles of cell subpopulations with basal or luminal features isolated from matched prostate cancer and normal tissue samples.ResultsMany frequent DNA methylation changes previously attributed to prostate cancers are here identified as differences between luminal and basal cells in both normal and cancer samples. We also identified changes unique to each of the two cancer subpopulations. Those specific to cancer luminal cells were associated with regulation of metabolic processes, cell proliferation and epithelial development. Within the prostate cancer TCGA dataset, these changes were able to distinguish not only cancers from normal samples, but also organ-confined cancers from those with extraprostatic extensions. Using changes present in both basal and luminal cancer cells, we derived a new 17-CpG prostate cancer signature with high predictive power in the TCGA dataset.ConclusionsThis study demonstrates the importance of comparing phenotypically matched prostate cell populations from normal and cancer tissues to unmask biologically and clinically relevant DNA methylation changes.

This study aimed to elucidate the role of ELF3, an ETS family member in normal prostate growth and prostate cancer. Silencing ELF3 in both benign prostate (BPH‐1) and prostate cancer (PC3) cell lines resulted in decreased colony‐forming ability, inhibition of cell migration and reduced cell viability due to cell cycle arrest, establishing ELF3 as a cell cycle regulator. Increased ELF3 expression in more advanced prostate tumours was shown by immunostaining of tissue microarrays and from analysis of gene expression and genetic alteration studies. This study indicates that ELF3 functions not only as a part of normal prostate epithelial growth but also as a potential oncogene in advanced prostate cancers. In the prostate, ELF3 is expressed in committed basal (CB) cells but not stem cells (SC), transit amplifying (TA) cells or luminal (L) cells. Using siRNA to knockdown ELF3 expression results in cell cycle arrest, reduced colony formation and reduced wound healing. ELF3 is expressed in some high grade cancers and there is evidence for ELF3 amplification in metastatic cancers.

Background: Objective identification of key miRNAs from transcriptomic data is difficult owing to the inherent inconsistencies within miRNA target-prediction algorithms and the promiscuous nature of miRNA-mRNA target relationship. Methods: An integrated database of miRNAs and their ‘relevant’ mRNA targets was generated from validated miRNA and mRNA microarray data sets generated from patient-derived prostate epithelial normal and cancer stem-like cells (SCs) and committed basal (CB) cells. The effect of miR-542-5p inhibition was studied to provide proof-of-principle for database utility. Results: Integration of miRNA-mRNA databases showed that signalling pathways and processes can be regulated by a single or relatively few miRNAs, for example, DNA repair/Notch pathway by miR-542-5p, P =0.008. Inhibition of miR-542-5p in CB cells (thereby achieving miR-542-5p expression levels similar to SCs) promoted efficient DNA repair and activated expression of Notch reporters, HES1 and Survivin, without inducing dedifferentiation into SCs. Conclusions: Our novel framework impartially identifies therapeutically relevant miRNA candidates from transcriptomic data sets.

In comparison to more differentiated cells, prostate cancer stem‐like cells are radioresistant, which could explain radio‐recurrent prostate cancer. Improvement of radiotherapeutic efficacy may therefore require combination therapy. We have investigated the consequences of treating primary prostate epithelial cells with gamma irradiation and photodynamic therapy (PDT), both of which act through production of reactive oxygen species (ROS). Primary prostate epithelial cells were cultured from patient samples of benign prostatic hyperplasia and prostate cancer prior to treatment with PDT or gamma irradiation. Cell viability was measured using MTT and alamar blue assay, and cell recovery by colony‐forming assays. Immunofluorescence of gamma‐H2AX foci was used to quantify DNA damage, and autophagy and apoptosis were assessed using Western blots. Necrosis and senescence were measured by propidium iodide staining and beta‐galactosidase staining, respectively. Both PDT and gamma irradiation reduced the colony‐forming ability of primary prostate epithelial cells. PDT reduced the viability of all types of cells in the cultures, including stem‐like cells and more differentiated cells. PDT induced necrosis and autophagy, whereas gamma irradiation induced senescence, but neither treatment induced apoptosis. PDT and gamma irradiation therefore inhibit cell growth by different mechanisms. We suggest these treatments would be suitable for use in combination as sequential treatments against prostate cancer. We determined the consequences of radiotherapy and photodynamic therapy on primary prostate epithelial cells cultured from patient tissue. Photodynamic therapy induced autophagy and necrosis, whereas radiotherapy induced senescence and neither treatment induced apoptosis. This provides evidence that photodynamic therapy could be used in combination with radiotherapy to overcome radio‐recurrent disease.

Mass spectrometric monitoring of albumin in uremia. Advanced glycation end products (AGEs) are a novel class of uremic toxins. In plasma, they are present in proteins and also in low molecular mass peptides. AGE-modified peptides are thought to bind and modify plasma proteins. Monitoring of the consequent increase in molecular mass of serum albumin may be used in surveillance of the clinical management of uremia. We investigated molecular mass changes of human serum albumin (HSA) glycated by glucose and methylglyoxal in vitro and of subjects with moderate renal impairment, end-stage renal disease (ESRD), ESRD on hemodialysis, and normal healthy controls by matrix-assisted laser desorption ionization mass spectrometry. Fatty acid-free HSA had a molecular mass of 66,446 ± 114 D. Mean (±SD) molecular mass increases were HSA minimally glycated by glucose 399 ± 88 D (N = 5, P < 0.001), HSA highly glycated by glucose 6780 ± 122 D (N = 5, P < 0.001), HSA minimally glycated by methylglyoxal 73 ± 121 D (N = 5, P > 0.05), and HSA without fatty acid removal 535 ± 90 D (N = 5, P < 0.001). For HSA of human subjects, mean (± SD) molecular mass increases were normal healthy controls 243 ± 97 D (N = 5), moderate renal impairment 350 ± 83 D (P > 0.05 with respect to controls, N = 5), ESRD 498 ± 128 (P < 0.02 with respect to controls, N = 3), and ESRD on hemodialysis 438 ± 85 D (P < 0.02 with respect to controls, N = 5). The mean molecular mass of albumin of all groups was increased significantly with respect to that of fatty acid free albumin (P < 0.001). Only ESRD was associated with a significant increase in the molecular mass of HSA in vivo. Since this mass increase was very low and much lower than reported for AGE-modified peptides, it may reflect AGE formation on HSA by α-oxoaldehydes that accumulate in uremia, rather than modification of albumin by AGE-modified peptides. The molecular mass of HSA in vivo was indicative of a minimal and not a high extent of glycation.

Polycystic ovary syndrome (PCOS) increases the risk of metabolic syndrome and non-alcoholic-fatty-liver disease (NAFLD). Vitamin D supplementation may exert positive effects on liver biochemistry in patients with NAFLD; however, its effects on PCOS are unknown. This randomized, double-blind, placebo-controlled study explored the effect of vitamin D supplementation on cardiovascular risk factors (high-sensitivity C-reactive protein (hs-CRP), weight, body mass index (BMI), lipid profile, glucose levels, insulin levels, the homeostatic model assessment-insulin resistance (HOMA-IR), hormones (free androgen index (FAI), testosterone, sex hormone binding globulin (SHBG), and liver markers (alanine aminotransferase (ALT), hyaluronic acid (HA), N-terminal pro-peptide of type III procollagen (PIIINP), tissue inhibitor of metallo-proteinases-1 (TIMP-1), and the enhanced liver fibrosis (ELF) score). Forty women with PCOS were recruited and randomized to vitamin D (3200 IU) or placebo daily for 3 months. All outcomes were measured at baseline and 3 months follow-up (FU). Greater increases in vitamin D levels were shown in the supplementation group (vitamin D, baseline: 25.6 ± 11.4 nmol/L, FU: 90.4 ± 19.5 nmol/L vs. placebo, baseline: 30.9 ± 11.1 nmol/L, FU: 47.6 ± 20.5 nmol/L, p < 0.001). Between groups comparisons (% baseline change) revealed significant differences in ALT (p = 0.042) and a weak effect indicating a greater reduction in the HOMA-IR in the vitamin D group (p = 0.051). No further between group differences were seen in other cardiovascular risk factor, liver markers, or hormones. This study supports beneficial effects of vitamin D supplementation on liver markers and modest improvements in insulin sensitivity in vitamin D deficient women with PCOS.

This study aimed to evaluate self-reported exposure to the Ringwood Mines/Landfill Superfund Site in relation to chronic health outcomes among members of the Ramapough Lunaape Turtle Clan nation and other local residents of Ringwood, New Jersey. Community surveys on personal exposure to the nearby Superfund site, self-reported health conditions, and demographics were conducted with 187 members of the Ramapough Lunaape Turtle Clan Nation and non-Native Americans residing in Ringwood, New Jersey from December 2015 to October 2016. Multiple logistic regression was performed to assess the association between ethnicity and a Superfund site exposure score developed for this study, as well as between exposure score and several chronic health conditions. Native Americans were 13.84 times (OR 13.84; 95% CI 4.32, 44.37) more likely to face exposure opportunities to Superfund sites as compared to non-Native Americans in the same New Jersey borough. For the entire surveyed cohort, increased Superfund site exposure routes was significantly associated with bronchitis (OR 4.10; 95% CI 1.18, 14.23). When the analyses were restricted to Native Americans, the association between self-reported Superfund site exposure and bronchitis remained significant (OR 17.42; 95% CI 1.99, 152.45). Moreover, the association between greater exposure score and asthma in this same population also reached statistical significance (OR 6.16; 95% CI 1.38, 27.49). This pilot study demonstrated a significant association between being a Ringwood resident of Native American ethnicity and self-declared opportunities for Superfund site exposure. It also showed a strong association between self-reported Superfund site exposure and the prevalence of bronchitis and asthma.

Laser beam welding has become an established joining technique in automotive manufacturing. Common solid-state lasers generate high-quality joints, but they provide low energy efficiency. By contrast, direct diode lasers (DDL) have superior energy efficiency, are cheaper to purchase and additionally require less utility space. To examine the overall performance of direct diode lasers in comparison to disk lasers, welding quality and energy consumption of the two lasers have to be evaluated. Additionally, for this contribution the stability of the DDL’s beam, like temporal variation of focus position and beam shape, is examined. It is found that a focus shift takes place for longer periods of emission, but the variation of the focus diameter in the initial focal plane is negligible. As expected, the direct diode laser consumes less energy than the disk laser for the same output power. Welding experiments are conducted using four different steel alloys that are exemplary for engineering materials used in automotive manufacturing. Metallographic analysis shows that weld seam depths and widths are on average larger using the disk laser. However even with the need for higher output powers to achieve equal seam geometries the DDL consumes less energy and thereby causes less costs.