Cancer Stem Cells and Anti-tumor Immunity.

Cancer stem cells (CSCs) are correlated with poor clinical outcomes due to their contribution to chemotherapy resistance and the formation of metastasis. Multiple cell surface and enzymatic markers have been characterized to identify CSCs, which is important for diagnosis, therapy, and prognosis. This review underlines the role of CSCs and circulating tumor cells (CTCs) in tumor relapse and metastasis, the characteristics of CSC and CTC biomarkers, and the techniques used to detect these cells. We also summarized novel therapeutic approaches toward targeting CSCs, especially focusing on the role of immune checkpoint blockades (ICB), such as anti-programmed death 1 (anti-PD1) and antiprogrammed death ligand-1 (anti-PDL1) therapies. Additionally, we address an intriguing new mechanism of action for small molecular drugs, such as telomere-targeted therapy 6-thio-2'deoxyguanosine (6- thio-dG), and how it reshapes tumor microenvironment to overcome ICB resistance. There are indications, that personalized cancer therapy targeting CSC populations in conjunction with immune-mediated strategy hold promise for the removal of residual therapy-resistant CSCs in the near future.

Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.

Expressions of homeobox, collagen and estrogen genes in women with uterine prolapse.

OBJECTIVE: Genetic contribution is thought to be involved in the pathophysiology of pelvic organ prolapse (POP). We aimed to study the gene expression profiles of the genes HomeoboxA11 (HOXA11), HomeoboxA13 (HOXA13), Collagen Type I (COL1A), Collagen Type III (COL3A), estrogen receptor genes (ESR1 and ESR2) of round (RL) and uterosacral ligaments (USL) in postmenopausal women with uterine prolapse. STUDY DESIGN: Gene expressions of 32 postmenopausal women with prolapse were analysed according to gene expressions of 8 postmenopausal women without prolapse. Quantitative real-time PCR (qRT-PCR) method was used for the detection of expression levels of the genes. Student's t-Test and Mann-Whitney U test were used for statistical analysis. RESULTS: In the USL specimens of all women with uterine prolapse HOXA13 and ESR1 gene expressions were decreased compared to controls (0.5 fold, p = 0.04 and 0.82 fold, p = 0.04, respectively). In the RL specimens, ESR2 gene expression was decreased 0.7 fold in women with prolapse when compared to controls (p = 0.04). In the USL specimens of women with advanced stages of prolapse (stage ≥3), HOXA13 and COL3A gene expressions were decreased compared to controls (0.44 fold, p = 0.043 and 0.39 fold, p = 0.045, respectively). In the RL specimens, ESR2 gene expression was decreased 0.65 fold in women with prolapse when compared to controls (p = 0.052). CONCLUSION: The significant decrease in the expression of the genes HOXA13, COL3A in the USL and ESR2 in the RL especially in advanced stages of prolapse, implicate that these gene expressions may play a role in the development of uterine prolapse.

Genetic Polymorphisms in PRM1, PRM2, and YBX2 Genes are Associated with Male Factor Infertility.

AIMS: The etiology of infertility is still unknown in almost half of all male infertility patients. In sperm, DNA condensation differs from somatic and female gamete cells, with the protamine (PRM) gene and its transcription factor, Y-box binding protein 2 (YBX2), playing key roles in making the structure more compact. Protamine polymorphisms have been studied in different populations, but various results have been acquired. MATERIALS AND METHODS: In our study, we examined, for the first time in a Turkish population, the association between protamine gene alleles (PRM1 c.-190C>A, PRM1 c.197G>T, and PRM2 c.248C>T), and YBX2 (c.187T>C and c.1095 + 16A>G) and male infertility. This was accomplished using polymerase chain reaction-restriction fragment length polymorphism analyses of 100 infertile and 100 fertile Turkish men. Sperm DNA fragmentation analysis was performed using the Comet technique. RESULTS: We found that the AA and CA genotypes of the PRM1 c.-190C>A polymorphism had a significant association with infertility (p < 0.001) and the AA genotype was also highly significantly associated with high sperm DNA damage (p < 0.001). CONCLUSION: This study demonstrates that the PRM1 c.-190C>A polymorphism is associated with sperm DNA fragmentation, which may impact male infertility in the Turkish population. Further research with larger groups and in various other study populations will be required to clarify the impact of protamine and YBX2 gene polymorphisms on male infertility.

Apoptotic effects of salinomycin on human ovarian cancer cell line (OVCAR-3).

In this study, we studied the apoptotic and cytotoxic effects of salinomycin on human ovarian cancer cell line (OVCAR-3) as salinomycin is known as a selectively cancer stem cell killer agent. We used immortal human ovarian epithelial cell line (IHOEC) as control group. Ovarian cancer cells and ovarian epithelial cells were treated by different concentrations of salinomycin such as 0.1, 1, and 40 µM and incubated for 24, 48, and 72 h. Dimethylthiazol (MTT) cell viability assay was performed to determine cell viability and toxicity. On the other hand, the expression levels of some of the apoptosis-related genes, namely anti-apoptotic Bcl-2, apoptotic Bax, and Caspase-3 were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, Caspase-3 protein level was also determined. As a result, we concluded that incubation of human OVCAR-3 by 0.1 µM concentration of salinomycin for 24 h killed 40 % of the cancer cells by activating apoptosis but had no effect on normal cells. The apoptotic Bax gene expression was upregulated but anti-apoptotic Bcl-2 gene expression was downregulated. Active Caspase-3 protein level was increased significantly (p < 0.05).

Analysis of the correlation between sperm DNA integrity and conventional semen parameters in infertile men.

OBJECTIVE: A male factor is responsible in approximately 30-40% of couples receiving infertility treatment. Routinely, such couples undergo semen analysis including parameters such as sperm count, motility and morphology. Generally, the analysis of sperm DNA damage, shown to have a significant clinical importance by many studies, is recognized as an advanced test that is not included in routine infertility tests. Intracytoplasmic sperm injection method, commonly employed in the current infertility treatment protocols, lowers the fertilization rate, however, fertilization can occur even with a damaged DNA which is known to pose a risk in the subsequent pregnancy period. The relation between sperm morphology and the degree of sperm DNA damage has not yet been understood clearly. In this study, we aimed to investigate the association between routine semen analysis and sperm DNA integrity assay, another advanced but costly method. MATERIAL AND METHODS: The degree of DNA damage was compared with the results of semen analysis, based on the WHO criteria, in 399 male patients who received comet assay for sperm DNA integrity. The statistical correlation analyses were performed with Windows SPPS statistical package program. RESULTS: Accordingly, the sperm DNA damage was found to be correlated with all 3 parameters (sperm count, forward motility, and morphology) examined by the semen analysis (p<0.001). Total sperm DNA Damage Count was 226, 216, and 210 arbitrary units in patients with a sperm count <15 mil/mL, forward moving motility <32%, and normal morphology <4%, respectively. The difference with the normal individuals was statistically significant (p<0.001). CONCLUSION: In light of the comet assay results, higher degree of sperm DNA damage is associated with significant impairment of all seminal parameters.