Aim:Sperm chromatin/DNA integrity is essential for the accurate transmission of paternal genetic information,and normal sperm chromatin structure is important for sperm fertilizing ability.The routine examination of semen,which includes sperm concentration,motility and morphology,does not identify defects in sperm chromatin structure.The origin of sperm DNA damage and a variety of methods for its assessment are described.Evaluation of sperm DNA damage appears to be a useful tool for assessing male fertility potential both in vivo and in vitro.The possible impact of sperm DNA defects on the offspring is also discussed.(Asian J Androl 2006 Jan;8:11-29)

Sperm chromatin structure and male fertility:biological and clinical aspects

FOXO3a in cancer drug resistance.

Ankylosing spondylitis (AS) is a spinal arthritic disease that is often associated with human leukocyte antigen (HLA)-B27, while only part of HLA-B27 carriers become AS patients. T cells have been reported to play an important role in the pathology of AS. T-cell immunoglobulin and mucin-domain-containing molecule 3 (Tim-3) and programmed death-1 (PD-1) have been known to negatively regulate the immune response. In this study, we used flow cytometry to analyze the immunological differences of peripheral bloodfrom 21 patients with AS, 22 cases who didn't have AS but were found to be HLA-B27 positive (HLA-B27+ group), and 16 normal healthy individuals (Healthy group). The level of CD4+, CD8+ T cells,and Treg of each group was observed. The expression of Tim-3 and PD-1 and the production of IFN-γ, IL-6, TNF-α, IL-4, and IL-10 were examined as well. We found that the percentage of Treg in AS group was lower than that of healthy group. The expression of PD-1 on CD8+ T cells and Tim-3 on CD4+ T cells was lower in the AS group. AS group had lower IL-10 production by CD4+ T cells and higher IL-6 production by CD8+ T cells. The results of HLA-B27+ group were similar to that of the healthy group. These data suggested that patients with AS had an impairment in the ability to negatively regulate the immune response, which might be related to the etiology of AS. To further investigate the roles of Tim-3 and PD-1 on is a dysfunction of T cells in AS that is associated with PD-1 and Tim-3.

/pdf/the-immune-dysfunction-in-ankylosing-spondylitis-patients-3ok5wbd3ir.pdf

The immune dysfunction in ankylosing spondylitis patients

Conventional semen analysis is the standard of care to initially evaluate the fertility status of a male patient. However, it has some limitations and among these are failure to correctly identify the aetiology underlying fertility problems, intra- and inter-observer variability and incomplete information about sperm function. Considering these drawbacks, advanced semen tests have been developed to assess male infertility, including sperm function tests, oxidative stress (OS) and sperm DNA fragmentation (SDF) tests. This review illustrates the commonly utilised sperm function techniques, along with the assays used to assess SDF and OS and their diagnostic value.

/pdf/diagnostic-value-of-advanced-semen-analysis-in-evaluation-of-yxu1b1egvp.pdf

Diagnostic value of advanced semen analysis in evaluation of male infertility.

The role of endolysosomal trafficking in anticancer drug resistance

Autophagy is an essential metabolic pathway mediated by lysosomal degradation, which is involved in scavenging and recycling senescent or damaged organelles and biological macromolecules in eukaryotic cells. The present study explored the association between the autophagic activity and chemotherapy resistance of leukaemia cells, and the possibility of using autophagy inhibitors to combat leukemic drug resistance. It was found that the levels of basic autophagy in multidrug‑resistant leukaemia cells (K562/ADM) were significantly higher compared with sensitive cells (K562), and that Adriamycin (ADM) was capable of inducing autophagic activity in K562 and K562/ADM cells. K562 and K562/ADM cells were treated with a series of hydroxychloroquine (HCQ) concentrations to inhibit cellular autophagy and detect cell sensitivity to ADM. The results demonstrated that the sensitivity of K562 cells to ADM was mildly enhanced by HCQ, and that the sensitivity of K562/ADM cells to ADM was markedly strengthened by HCQ. In addition, more typical morphological changes associated with apoptosis emerged, and the ratio of Bax/Bcl‑2 and activity of caspase‑3 were markedly increased in K562/ADM cells treated with HCQ. Notably, the expression of mdr1 mRNA and P‑glycoprotein (P‑gp) in drug‑resistant K562/ADM cells was upregulated along with increasing autophagic activity induced by ADM. Furthermore, HCQ significantly reduced the increase in P‑gp expression by inhibiting autophagic activity. Collectively, these findings indicated that the inhibition of autophagy significantly promoted the sensitivity of K562/ADM cells to ADM by facilitating apoptosis. Furthermore, inhibition of autophagy attenuated the expression of P‑gp; therefore, P‑gp may be involved in autophagic regulation in drug‑resistant cells.

/pdf/hydroxychloroquine-reverses-the-drug-resistance-of-leukemic-9swag7c5f5.pdf

Hydroxychloroquine reverses the drug resistance of leukemic K562/ADM cells by inhibiting autophagy

The aim of this retrospective study was to compare the immune tolerance status of patients suffered from unexplained spontaneous abortion (URSA) before and after treatment with paternal lymphocyte induced immunization (PLII) four times, and its relationship to the pregnancy outcome. 168 URSA patients were included in the present study. Among 168 couples, 138 couples were conceived again, of whom 86 were successfully pregnant till 20 gestational weeks, 31 cases again failed in the first trimester, 21 cases were still under follow-up, another 30 cases still had not conceived. Both the level of one way mixed lymphocyte culture blocking efficiency (MLC-BE) and anti-idio blocking antibody (BE-Ab2) were markedly elevated in succeeded group after PLII. In contrast, although a significant increase could be observed in the failed group after treatment, the elevation of BE-Ab2 was much lower than that in successful group. PLII therapy significantly up-regulated the percentage of peripheral CD4(+)CD25(+)CD127(-) regulatory T cells (Tregs) in successfully pregnant women; however, there was no significant change of Tregs in pregnancy loss cases although receiving PLII therapy. These results suggested a positive correlation between higher frequency of Tregs and rate of successful pregnancies. The sensitivity and specificity of combination of Tregs with MLC-BE and BE-Ab2 were 81.8% and 81.3%, respectively. Therefore, the percentage of Tregs in peripheral blood may hopefully serve as a potential biomarker for monitoring the efficacy of therapy in URSA patients. Combination of Tregs with MLC-BE and BE-Ab2 may expect to better evaluate the efficacy of PLII in URSA patients.

Combination of CD4(+)CD25(+)CD127(-) regulatory T cells with MLC-BE and BE-Ab2: an efficient evaluation of the therapy of paternal lymphocyte induced immunization in unexplained recurrent spontaneous abortion patients.

Patients with acute myeloid leukemia (AML) often have a poor prognosis due to drug resistance, which is regarded as a tough problem during the period of clinical therapeutics. It has been reported that autophagy, an important event in various cellular processes, plays a crucial role in mediating drug-resistance to cancer cells. Our study attempts to comparatively investigate the differences of basic and induced autophagic activity between drug-sensitive and multidrug-resistant AML cells. The level of basic autophagy in K562/ADM cells was higher than that in K562 cells, which could be characterized by more cytosolic contents-packaged autophagic vacuoles in K562/ADM cells when compared to that in K562 cells. The observation of MDC staining showed that the fluorescent intensity of autophagosomes in K562/ADM cells was stronger than that in K562 cells. The expression of Beclin1 and the ratio of LC3-II to LC3-I were distinctly higher in K562/ADM cells, however, P62 protein was relatively lower in K562/ADM cells. Furthermore, we found that nutrient depletion could induce autophagic activity of both cell lines. However, autophagic activity of K562/ADM cells was always maintained at a higher level in contrast with K562 cells. ADM (Adriamycin) was also capable of inducing autophagic activity of K562 and K562/ADM cells, but the autophagic alteration in K562 cells appeared earlier. Taken together, our findings suggest that autophagy exerts an important effect on formation and maintenance of drug-resistance in AML cells.

http://www.jstage.jst.go.jp/article/irdr/6/4/6_2017.01069/_pdf

Differences of basic and induced autophagic activity between K562 and K562/ADM cells.

The objective of this study is to evaluate the predictive value of sperm DNA fragmentation Index (DFI) in unexplained recurrent spontaneous abortion (RSA) and to investigate its correlation with conventional sperm parameters. Besides, we aimed to reveal the necessity of establishing a DFI clinical threshold of each laboratory for the prognostic diagnosis of RSA and establish our own DFI threshold. Semen samples were collected from male partners of RSA patients (n = 139) and healthy recent fathers (control, n = 200). DFI was tested using SCSA and conventional semen analysis was performed using an automatic semen analyzer. The DFI value and distribution were compared between the two groups using corresponding statistical software. The diagnostic threshold value was established by ROC curve. The correlation between DFI and the conventional semen parameters of the 139 cases was further analyzed using Student's t test and Mann-Whitney U test. Our result showed that DFI was significantly higher in RSA patients compared with normal donor controls. We established our own DFI threshold at 13.59%. There was only a weak partial correlation between DFI values and conventional sperm analysis parameters. Our present study suggested that DFI might be used as a valuable predictor for RSA independent of conventional sperm parameters. Additionally, we recommend that each laboratory should establish its own clinical DFI threshold for more precise prediction of RSA and we recommend that sperm DNA fragmentation test should be included in complete sperm quality assessment in addition to conventional semen analysis for RSA male partners.

Sperm DNA fragmentation valued by SCSA and its correlation with conventional sperm parameters in male partner of recurrent spontaneous abortion couple.

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Hydroxychloroquine reverses the drug resistance of leukemic K562/ADM cells by inhibiting autophagy

Combination of CD4(+)CD25(+)CD127(-) regulatory T cells with MLC-BE and BE-Ab2: an efficient evaluation of the therapy of paternal lymphocyte induced immunization in unexplained recurrent spontaneous abortion patients.

Differences of basic and induced autophagic activity between K562 and K562/ADM cells.

Sperm DNA fragmentation valued by SCSA and its correlation with conventional sperm parameters in male partner of recurrent spontaneous abortion couple.