Biological Activity of Some Cobalt(II) and Molybdenum(VI) Complexes: in vitro Cytotoxicity

Cytotoxicity and cell growth inhibition studies were performed for five distinct cobalt(ll) [Co2(acac)tpmc](ClO4)3, [Co2(dibzac)tpmc](ClO4)3, [Co2(hfac)tpmc](CIO4)2, [Co2(tmhd)tpmc](CIO4)3 and [Co2(ox)tpmc](CIO4)2.3H20 and five molybdenum(Vl) complexes, [MoO2(pipdtc)2], [MoO2(morphdtc)], [MoO2(timdtc)2], [MoO2(pzdtc)2] and [MoO2(N-Mepzdtc)2]. The former were tested in two leukemia cell lines: chronic myelogenic leukemia (K562) and human promyelocytic cell line (U937). They showed to have relatively high toxicity in K562 cells and a relatively low cytotoxicity in U937 cells, as assessed by both MTT and Trypan Blue assays. The five molybdenum complexes were tested in human promyelotic U937 cell line and they showed to have high toxicity

Space Deficits in Parkinson’s Disease Patients: Quantitative or Qualitative Differences from Normal Controls?

Twenty-seven patients with idiopathic Parkinson's disease (PD) and the same number of normal controls (NCs) were studied on a test battery including five conceptual categories of spatial ability. The two groups of subjects were matched for age, sex, years of education, socioeconomic status and non-verbal (Raven Standard Progressive Matrices) intelligence. A multivariate analysis of variance (MANOVA) showed that the PD patients performed less efficiently on almost all the tasks. A logistic regression analysis (LRA) classified 81.48% of the subjects into the PD group and 92.59% into NC group, indicating that left-right and back-front Euclidean orientation, three dimensional mental rotation and visuospatial immediate recognition memory of mirror image patterns discriminate well between the two groups. Application of a structural model (confirmatory factor analysis) demonstrated that both PD patients and the NC group stemmed from a homogeneous population, suggesting that the differences found between the two groups are of a quantitative rather than of a qualitative nature

Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro

Osteoclast (OC) development in response to nuclear factor kappa-Β ligand (RANKL) is critical for bone homeostasis in health and in disease. The early and direct chromatin regulatory changes imparted by the BET chromatin readers Brd2-4 and OC-affiliated transcription factors (TFs) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early OC development entails regulation of two alternative cell fate transcriptional programmes, OC vs macrophage, with repression of the latter following activation of the former. Both programmes are regulated in a non-redundant manner by increased chromatin binding of Brd2 at promoters and of Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, regulates OC development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TFs. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation

Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma

Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myeloma initiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia

The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma

Multiple myeloma is a malignancy of plasma cells (PC) initiated and driven by primary and secondary genetic events. Nevertheless, myeloma PC survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B cell development in both human and mouse cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma PC, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the PC lineage-defining transcription factor IRF4, and thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology

MAF functions as a pioneer transcription factor that initiates and sustains myelomagenesis

Deregulated expression of lineage-affiliated transcription factors (TFs) is a major mechanism of oncogenesis. However, how the deregulation of nonlineage affiliated TF affects chromatin to initiate oncogenic transcriptional programs is not well-known. To address this, we studied the chromatin effects imposed by oncogenic MAF as the cancer-initiating driver in the plasma cell cancer multiple myeloma. We found that the ectopically expressed MAF endows myeloma plasma cells with migratory and proliferative transcriptional potential. This potential is regulated by the activation of enhancers and superenhancers, previously inactive in healthy B cells and plasma cells, and the cooperation of MAF with the plasma cell-defining TF IRF4. Forced ectopic MAF expression confirms the de novo ability of oncogenic MAF to convert transcriptionally inert chromatin to active chromatin with the features of superenhancers, leading to the activation of the MAF-specific oncogenic transcriptome and the acquisition of cancer-related cellular phenotypes such as CCR1-dependent cell migration. These findings establish oncogenic MAF as a pioneer transcription factor that can initiate as well as sustain oncogenic transcriptomes and cancer phenotypes. However, despite its pioneer function, myeloma cells remain MAF-dependent, thus validating oncogenic MAF as a therapeutic target that would be able to circumvent the challenges of subsequent genetic diversification driving disease relapse and drug resistance

Ultrasound assisted casting of an AM60 based metal matrix nanocomposite, its properties, and recyclability

An AM60 magnesium alloy nanocomposite reinforced with 1 wt % of AlN nanoparticles was prepared using an ultrasound (US) assisted permanent-mould indirect-chill casting process. Ultrasonically generated cavitation and acoustic streaming promoted de-agglomeration of particle clusters and distributed the particles throughout the melt. Significant grain refinement due to nucleation on the AlN nanoparticles was accompanied by an exceptional improvement in properties: yield strength increased by 103%, ultimate tensile strength by 115%, and ductility by 140%. Although good grain refinement was observed, the large nucleation undercooling of 14 K limits further refinement because nucleation is prevented by the formation of a nucleation-free zone around each grain. To assess the industrial applicability and recyclability of the nanocomposite material in various casting processes, tests were performed to determine the effect of remelting on the microstructure. With each remelting, a small percentage of effective AlN nanoparticles was lost, and some grain growth was observed. However, even after the third remelting, excellent strength and ductility was retained. According to strengthening models, enhanced yield strength is mainly attributed to Hall-Petch strengthening caused by the refined grain size. A small additional contribution to strengthening is attributed to Orowan strengthening

Bio-psychosocial determinants of cardiovascular disease in a rural population on Crete, Greece: formulating a hypothesis and designing the SPILI-III study

Background: In 1988, the SPILI project was established in order to evaluate the cardiovascular disease (CVD) risk profile of the inhabitants of Spili, in rural Crete, Greece. The first reports from this project revealed that against the unfavourable risk factors’ profile observed, only a few men with a previous myocardial infarction were encountered. A follow-up study (SPILI II) was performed twelve years after the initial examination, and the unfavourable cardiovascular risk profile was re-confirmed. Presentation of the Hypothesis: This paper presents a hypothesis formulated on the basis of previous research to investigate if dynamic psycho-social determinants, including social coherence of the local community, religiosity and spirituality, are protective against the development of coronary heart disease in a well-defined population. Testing the Hypothesis: A follow-up examination of this Cretan cohort is currently being performed to assess the link between psychosocial factors and CVD. Psychosocial factors including sense of control, religiosity and spirituality are assessed in together with conventional CVD risk factors. Smoking and alcohol consumption, as well as dietary habits and activity levels are recorded. Oxidative stress and inflammatory markers, as well as ultrasound measurement of carotid intima media thickness, a preclinical marker of atherosclerosis, will also be measured. Implications of the hypothesis tested: The issue of the cardio-protective effect of psycho-social factors would be revisited based on the results of this Cretan cohort; nevertheless, further research is needed across different subpopulations in order to establish a definite relationship. A comprehensive approach based on the aspects of biosocial life may result in more accurate CVD risk management