Cell-cycle analysis and micronuclei frequency reveals G0/G1 blockers as weak micronuclei inducers

Micronuclei (MN) formation is generally attributed to error in DNA synthesis or mitosis, which are represented by the S or G₂/M phase respectively, in the cell-cycle histogram. Interestingly, many of the known anticancer drugs target these cell-cycle phases to elicit cytotoxicity. Here, we attempted to identify whether any correlation exists between the cell-cycle effect and MN induction potential using various treatments. In addition, we tracked down MN in cycling cells to assess its final fate. We treated SiHa cells with various known drugs and correlated their effects on cell-cycle and MN frequency. MN-tracking studies were performed in peripheral mononuclear and siHa cells upon staining with Giemsa and ethidium bromide respectively. We observed MN induction by all the tested drugs irrespective of their basic effect on cell cycle. However, MN induction was more with drugs which interfere with the S or G₂/M than the G₀/G₁ phase. Our results indicate G₀/G₁ blockers to be comparatively safer drugs. Additionally, our results show that expulsion out of cells may be one of the main fates of drug-induced MN.     

HCMV INFECTION: MODULATING THE CELL CYCLE AND CELL DEATH

Human cytomegalovirus (HCMV) is a member of the Herpesviridae family and is recognized as a significant pathogen to certain subgroups of the human population. It has become apparent that HCMV manipulation of the host cell cycle as well as the immune response promotes the replication and propagation of the virus. The ability of HCMV to modulate components of the host immune system and the response to infection most likely contributes to the pathology associated with this virus. This review will address the mechanisms HCMV has adapted to modulate the cell cycle to promote viral replication as well as the different ways it can prevent the “death” of an infected cell.     

UBE2S drives elongation of K11-linked ubiquitin chains by the Anaphase-Promoting Complex

The Anaphase-Promoting Complex (APC) is an E3 ubiquitin ligase that regulates mitosis and G1 by sequentially targeting cell-cycle regulators for ubiquitination and proteasomal degradation. The mechanism of ubiquitin chain formation by APC and the resultant chain topology remains controversial. By using a single-lysine APC substrate to dissect the topology of ubiquitinated substrates, we find that APC-catalyzed ubiquitination has an intrinsic preference for the K11 linkage of ubiquitin that is essential for substrate degradation. K11 specificity is determined by an E2 enzyme, UBE2S/E2-EPF, that elongates ubiquitin chains after the substrates are pre-ubiquitinated by UbcH10 or UbcH5. UBE2S copurifies with APC; dominant-negative Ube2S slows down APC substrate degradation in functional cell-cycle extracts. We propose that Ube2S is a critical, unique component of the APC ubiquitination pathway.     

Cycles,phase synchronization,and entrainment in single-species phytoplankton populations

Complex dynamics, such as population cycles, can arise when the individual members of a population become synchronized. However, it is an open question how readily and through which mechanisms synchronization-driven cycles can occur in unstructured microbial populations. In experimental chemostats we studied large populations (>10⁹ cells) of unicellular phytoplankton that displayed regular, inducible and reproducible population oscillations. Measurements of cell size distributions revealed that progression through the mitotic cycle was synchronized with the population cycles. A mathematical model that accounts for both the cell cycle and population-level processes suggests that cycles occur because individual cells become synchronized by interacting with one another through their common nutrient pool. An external perturbation by direct manipulation of the nutrient availability resulted in phase resetting, unmasking intrinsic oscillations and producing a transient collective cycle as the individuals gradually drift apart. Our study indicates a strong connection between complex within-cell processes and population dynamics, where synchronized cell cycles of unicellular phytoplankton provide sufficient population structure to cause small-amplitude oscillations at the population level.     

妇幼专科医院与综合医院患者被褥细菌学调查对比

目的 通过对妇幼专科医院与综合医院患者住院期间使用中的床单、被套、棉胎、枕芯和床褥物体表面细菌学调查,分析妇幼专科医院与综合医院患者床上用品细菌分布,对两所医院菌群特点进行对比,探索适合不同疾病人群的床上用品安全使用时间及合理的更换周期.方法 采用中华人民共和国卫生部<消毒技术规范>2002版GB15982-1995A3规定方法,对妇幼专科医院和综合医院患者使用中的床单、被套、棉胎、枕套、枕芯、床褥物体表面采样,进行实验室细菌学调查,并对其细菌分布状况进行对比分析.结果 上述使用中的床上用品表皮葡萄球菌检出率最高;床褥、枕芯污染情况较其他严重;床上用品使用时间污染结果,从第四日起明显升高.两院患者床上用品细菌分布及菌群特点没有显著差异.结论 床褥、枕芯等不同细菌检出率有显著性差异(P<0.01);不同床上物品差异有显著性意义(P<0.01);医院被服污染,从第.四日起明显升高,经统计学处理,差异有显著性意义(P<0.01).这一方面,表皮葡萄球菌和其他常见致病菌两组情况-致.     

Gene therapy for arthritis

An accumulating body of evidence shows that gene therapy can be successfully used to treat animal models of arthritis. Based on this success, a clinical trial of gene therapy for rheumatoid arthritis has been initiated. We review the methods and genes used for the previous gene transfer experiments, including our own. Retroviral ex vivo gene transfer and adenoviral in vivo gene transfer were utilized most frequently. Most of the gene transfer strategies aimed at suppression of synovial inflammation, while our study attempted to convert a phenotype of synovial cells. Gene transfer could be used for part of the future therapy for RA. In basic research studies, gene transfer is of great help in defining new target molecules to treat arthritis. Received: February 21, 2000     

IRC‐083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells

CDC25 phosphatases are key actors in cyclin‐dependent kinases activation whose role is essential at various stages of the cell cycle. CDC25 expression is upregulated in a number of human cancers. CDC25 phosphatases are therefore thought to represent promising novel targets in cancer therapy. Here, we report the identification and the characterization of IRC‐083864, an original bis‐quinone moiety that is a potent and selective inhibitor of CDC25 phosphatases in the low nanomolar range. IRC‐083864 inhibits cell proliferation of a number of cell lines, regardless of their resistance to other drugs. It irreversibly inhibits cell proliferation and cell cycle progression and prevents entry into mitosis. In addition, it inhibits the growth of HCT‐116 tumor spheroids with induction of p21 and apoptosis. Finally, IRC‐083864 reduced tumor growth in mice with established human prostatic and pancreatic tumor xenografts. This study describes a novel compound, which merits further study as a potential anticancer agent. © 2008 Wiley‐Liss, Inc.     

Effect of Phosphatidic Acid on Human Breast Cancer Cells Exposed to Doxorubicin

We previously demonstrated that phosphatidic acid (PA) induces chemotactic migration of highly metastatic breast cancer cells MDA-MB-231. The widely used anticancer drug doxorubicin was reported to induce apoptosis of cancer cells. Growth factors such as epidermal growth factor (EGF) and bioactive lipids such as lysophosphatidic acid (LPA) and sphingosine 1-phosphate (SPP) have been shown to enhance viability and to protect cancer cells against apoptosis. In this study, we investigated the effect of PA on MDA-MB-231 cells exposed to the anticancer drug doxorubicin. Cell migration toward PA was partially inhibited by doxorubicin treatment, and PA moderately diminished cell cycle arrest of cells exposed to doxorubicin. Although PA itself was not able to induce apoptosis of MDA-MB-231 cells, apoptosis of cells exposed to doxorubicin was markedly enhanced by PA treatment. Thus, PA is able to increase the apoptotic potential of doxorubicin, and may regulate the effects of doxorubicin used for chemotherapy.     

Natural cycle IVF in unexplained, endometriosis-associated and tubal factor infertility.

BACKGROUND: To elucidate possible differences between unexplained and minimal peritoneal endometriosis-associated infertility, we studied their outcome in natural cycle IVF (NIVF). METHODS: A prospective cohort study was carried out on unexplained (33 couples), minimal peritoneal endometriosis-associated (30 couples) and tubal factor (24 couples) infertility in 223 NIVF cycles, using human chorionic gonadotrophin (HCG) for ovulation induction. RESULTS: During the first NIVF attempt, follicular and luteal phase oestradiol, FSH, LH and progesterone concentrations, as well as endometrial thickness and follicular diameter were similar among the three groups. Periovulatory follicular growth monitored from day of HCG administration to oocyte aspiration was significantly lowered in unexplained infertility compared with minimal endometriosis-associated and tubal factor infertility. The fertilization rate, clinical pregnancy rate per initiated cycle, per successful oocyte retrieval and per embryo transfer, in minimal endometriosis (80.0, 10.4, 16.0 and 23.5% respectively) were similar to that in tubal factor infertility patients (68.6, 5.8, 11.4 and 16.0%) but significantly higher (P < 0.05) than that of the unexplained infertility group (62.2, 2.6, 5.4 and 8.7%). CONCLUSIONS: The significant reduction in follicular periovulatory growth, fertilization and pregnancy rates in unexplained infertility compared with minimal peritoneal endometriosis patients may be explained by sub-optimal follicular development with possibly reduced oocyte quality, intrinsic embryo quality factors or by impaired implantation. From a clinical point of view, NIVF is less suited to unexplained infertility treatment, but might represent an interesting treatment option for minimal peritoneal endometriosis-associated infertility.