Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

Xanafide, a DNA-intercalating agent and topoisomerase II inhibitor, has previously demonstrated comparable cytotoxicity to the parent drug amonafide (NSC 308847). The current study was conducted to investigate further the anti-proliferative effects of xanafide in human breast cancer cell lines, in vitro and in vivo. The in vitro activity of xanafide against MCF-7, MDA-MB-231, SKBR-3 and T47D cell lines was compared to that of paclitaxel, docetaxel, gemcitabine, vinorelbine and doxorubicin. In MCF-7, xanafide demonstrated comparable total growth inhibition (TGI) concentrations to the taxanes and lower TGI values than gemcitabine, vinorelbine and doxorubicin. MCF-7 (oestrogen receptor (ER)+/p53 wild-type) was the most sensitive cell line to xanafide. MDA-MB-231 and SKBR-3 exhibited similar sensitivity to xanafide. T47 D (ER+/p53 mutated), showed no response to this agent. The in vivo activity of xanafide was further compared to that of docetaxel in MCF-7 and MDA-MB-231 cell lines using the hollow fibre assay. Xanafide was slightly more potent than docetaxel, at its highest dose in MCF-7 cell line, whereas docetaxel was more effective than xanafide in MDA-MB-231 cell line. Our results show that there is no relationship between sensitivity of these cell lines to xanafide and cellular levels of both isoforms of topoisomerase II and suggest that ER and p53 status and their crosstalk may predict the responsiveness or resistance of breast cancer patients to xanafide

Myosin Va Participates in Acrosomal Formation and Nuclear Morphogenesis during Spermatogenesis of Chinese Mitten Crab Eriocheir sinensis

BACKGROUND: The Chinese mitten crab Eriocheir sinensis belongs to the Class Crustacea, Decapoda, Brachyura. The spermatozoon of this species is of aflagellated type, it has a spherical acrosome surrounded by the cup-shaped nucleus, which are unique to brachyurans. For the past several decades, studies on the spermatogenesis of the mitten crab mainly focus on the morphology. Compared with the extensive study of molecular mechanism of spermatogenesis in mammals, relatively less information is available in crustacean species. Myosin Va, a member of Class V myosin, has been implicated in acrosome biogenesis and vesicle transport during spermatogenesis in mammals. In the present study we demonstrate the expression and cellular localization of myosin Va during spermatogenesis in E. sinensis. METHODOLOGY/PRINCIPAL FINDINGS: Western blot demonstrated that myosin Va is expressed during spermatogenesis. Immunocytochemical and ultrastructural analyses showed that myosin Va mainly localizes in the cytoplasm in spermatocytes. At the early stage of spermiogenesis, myosin Va binds to the endoplasmic reticulum vesicle (EV) and proacrosomal granule (PG). Subsequently, myosin Va localizes within the proacrosomal vesicle (PV) formed by PG and EV fusion and locates in the membrane complex (MC) at the mid spermatid stage. At the late spermatid stage, myosin Va is associated with the shaping nucleus and mitochondria. In mature spermatozoon, myosin Va predominates in acrosomal tubule (AT) and nucleus. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that myosin Va may be involved in acrosome biogenesis and nuclear morphogenesis during spermatogenesis in E. sinensis. Considering the distribution and molecular characteristics of myosin Va, we also propose a hypothesis of AT formation in this species. It is the first time to uncover the role of myosin Va in crustacean spermatogenesis

Frequent Long-Range Epigenetic Silencing of Protocadherin Gene Clusters on Chromosome 5q31 in Wilms' Tumor

Wilms' tumour (WT) is a pediatric tumor of the kidney that arises via failure of the fetal developmental program. The absence of identifiable mutations in the majority of WTs suggests the frequent involvement of epigenetic aberrations in WT. We therefore conducted a genome-wide analysis of promoter hypermethylation in WTs and identified hypermethylation at chromosome 5q31 spanning 800 kilobases (kb) and more than 50 genes. The methylated genes all belong to α-, β-, and γ-protocadherin (PCDH) gene clusters (Human Genome Organization nomenclature PCDHA@, PCDHB@, and PCDHG@, respectively). This demonstrates that long-range epigenetic silencing (LRES) occurs in developmental tumors as well as in adult tumors. Bisulfite polymerase chain reaction analysis showed that PCDH hypermethylation is a frequent event found in all Wilms' tumor subtypes. Hypermethylation is concordant with reduced PCDH expression in tumors. WT precursor lesions showed no PCDH hypermethylation, suggesting that de novo PCDH hypermethylation occurs during malignant progression. Discrete boundaries of the PCDH domain are delimited by abrupt changes in histone modifications; unmethylated genes flanking the LRES are associated with permissive marks which are absent from methylated genes within the domain. Silenced genes are marked with non-permissive histone 3 lysine 9 dimethylation. Expression analysis of embryonic murine kidney and differentiating rat metanephric mesenchymal cells demonstrates that Pcdh expression is developmentally regulated and that Pcdhg@ genes are expressed in blastemal cells. Importantly, we show that PCDHs negatively regulate canonical Wnt signalling, as short-interfering RNA–induced reduction of PCDHG@ encoded proteins leads to elevated β-catenin protein, increased β-catenin/T-cell factor (TCF) reporter activity, and induction of Wnt target genes. Conversely, over-expression of PCDHs suppresses β-catenin/TCF-reporter activity and also inhibits colony formation and growth of cancer cells in soft agar. Thus PCDHs are candidate tumor suppressors that modulate regulatory pathways critical in development and disease, such as canonical Wnt signaling

Reported child sexual abuse in Bahrain: 2000-2009

<b>Background and Objective</b>: Child sexual abuse (CSA) is a common problem with severe short and long-term consequences to the abused child, the family and to society. The aim of this study was to evaluate the extent of CSA, and demographic and other characteristics of the abused and their families. <b>Design and Setting</b>: Retrospective and descriptive study based on a review of medical records of CSA cases from 2000-2009 at Sulmaniya Medical Complex, the main secondary and tertiary medical care facility in Bahrain. <b>Patients and Methods</b>: The review included demographic data, child and family characteristics, manifestations and interventions. <b>Results</b>: The 440 children diagnosed with CSA had a mean age of 8 years (range, 9 months to 17 years); 222 were males (50.5&#x0025;) and 218 were females (49.5&#x0025;). There was a steady increase in cases from 31 per year in 2000 to 77 cases in 2009. Children disclosed abuse in 26&#x0025; of cases, while health sector professionals recognized 53&#x0025; of the cases. Genital touching and fondling (62.5&#x0025;) were the most common form of CSA, followed by sodomy in 39&#x0025;. Gonorrhea was documented in 2&#x0025; of the cases and pregnancy in 4&#x0025; of the females. The illiteracy rate among the fathers and mothers was 9&#x0025; and 12&#x0025;, respectively, which is higher than the rate among the adult general population. Children came from all socio-economic classes. There was referral to police in 56&#x0025;, public prosecution in 31&#x0025; of the cases, but only 8&#x0025; reached the court. <b>Conclusion</b>: During ten years there has been a 2.5&#x0025; increase in reported cases of CSA. Improving the skill of professionals in identifying CSA indicators and a mandatory reporting law might be needed to improve the rate of recognition and referral of CSA cases. Further general population-based surveys are needed to determine more accurately the scope of CSA and the risk and protective factors in the family and community

Preparation of a New Oligomeric Surfactant: N,N,N′,N″,N″-Pentamethyl Diethyleneamine—N,N″-Di-[Tetradecylammonium Bromide] and the Study of its Thermodynamic Properties

A new oligomeric surfactant: N,N,N′,N″,N″-pentamethyl diethyleneamine-N,N″-di-[tetradecylammo-nium bromide] referred to as 14-2-N(CH3)-2-14 was synthesized, purified and characterized by Elemental Analysis, 1H and 13C NMR and Electrospray. The micellar properties of this compound were determined by electrical conductivity and surface tension methods. Optical microscopy was also employed to study the behavior of anhydrous surfactant and the binary water/surfactant system as a function of temperature. The critical micellar concentration (cmc), degree of counterion binding and thermodynamic parameters of micellization (standard molar Gibbs energy, enthalpy and entropy of micellization) were determined by electrical conductivity measurements in the temperature range [24-54 °C]. Surface tension measurements also provide information about the dependence of the surface tension at the cmc (γcmc), pC20 (negative logarithm of the surfactant's molar concentration C20, required to reduce the surface tension by 20 mN/m, the surface excess (γmax) at air/solution interface, the minimum area per surfactant molecule at the air/solution interface (Amin), surface pressure at the cmc (Πcmc), critical packing parameter(CPP) and the standard free energies of micellization (ΔG0m) and of adsorption (ΔG0ads).We would like to thank the CNRST (Morocco) for its financial help: Project number D13/31.Peer reviewe