The discovery of DNA damage response proteins such as γH2AX, ATM, 53BP1, RAD51, and the MRE11/RAD50/NBS1 complex, that accumulate and/or are modified in the vicinity of a chromosomal DNA double-strand break to form microscopically visible, subnuclear foci, has revolutionized the detection of these lesions and has enabled studies of the cellular machinery that contributes to their repair. Double-strand breaks are induced directly by a number of physical and chemical agents, including ionizing radiation and radiomimetic drugs, but can also arise as secondary lesions during replication and DNA repair following exposure to a wide range of genotoxins. Here we aim to review the biological meaning and significance of DNA damage foci, looking specifically at a range of different settings in which such markers of DNA damage and repair are being studied and interpreted.
Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.
Background: The prevalence of infertility and vitamin D deficiency is common in Pakistan. Therefore, our study aims were to assess and compare Vitamin D; 25-hydroxyvitamin (25OHD) and reproductive hormone levels in male fertile and infertile subjects with normal and abnormal sperm parameters. Furthermore, the study is aimed to explore the association of 25OHD levels with these sperm parameters in a selected population of Karachi, Pakistan.Methods: The cross-sectional study was carried out from August 2016 till December 2017, 313 study subjects were recruited from an Infertile Clinic from Islamabad, Pakistan, and the general population. First, we took the couples' history of parenting and then carried out a semen analysis and infertile and fertile male subjects were then subgrouped into “normal” and “altered sperm parameter/s.” Forward linear regression was done for selection of 25OHD as a significant predictor of sperm parameters.Results: The median values of the total count, motility, morphology as well as serum 25OHD were significantly higher in the group with “normal” (186) as compared to subjects (127) in “abnormal sperm parameters” group. The 25OHD levels were significantly high in males with “normal sperm parameters”; 80.90 ± 23.33 nmol/L vs. “altered sperm parameter/s,” 64.68 ± 24.21 nmol/L (mean ± SD) with p < 0.001. Serum testosterone level had a significant positive correlation with 25OHD while LH had a significant negative correlation with 25OHD (p < 0.001), and FSH level had a non-significant negative correlation with 25OHD. Results of regression model showed one unit increase of motility would give 0.15-unit positive significant impact on 25OHD; 20% variation in 25OHD was explained by the total count, motility, and morphology, while the model was adjusted for BMI.Conclusion: The impact of 25OHD levels on sperm parameters can be emphasized on the basis of detection of its high serum levels in “normal” subjects in both fertile as well as infertile males in comparison to subjects that had altered sperm parameters; total sperm count, motility, and normal morphology. The considerably positive association between 25OHD, testosterone, total count, motility, and morphology further accentuates its impact on normal spermatogenesis and the male reproductive functions required for acquiring fertility.
Though, Acanthamoeba does not express a homolog of the human mu-opioid receptor, but does shows evidence of the homologs for other known human targets of loperamide that are involved in Ca+2 uptake and Ca+2 signal transduction pathways. This suggests optimization of similar drug interactions with these targets may be useful in developing new approaches to control the growth of this parasite and possibly the diseases caused by it.
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