Novel Role of Prostate Apoptosis Response-4 Tumor Suppressor in B-Cell Chronic Lymphocytic Leukemia

Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Eμ-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)–approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors

Oxidative Stress-Induced JNK/AP-1 Signaling is a Major Pathway Involved in Selective Apoptosis of Myelodysplastic Syndrome Cells by Withaferin-A

Myelodysplastic syndromes (MDS) are a diverse group of malignant clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology in one or more hematopoietic lineages, and a risk of progression to acute myeloid leukemia (AML). Approximately 50% of MDS patients respond to current FDA-approved drug therapies but a majority of responders relapse within 2-3 years. There is therefore a compelling need to identify potential new therapies for MDS treatment. We utilized the MDS-L cell line to investigate the anticancer potential and mechanisms of action of a plant-derived compound, Withaferin A (WFA), in MDS. WFA was potently cytotoxic to MDS-L cells but had no significant effect on the viability of normal human primary bone marrow cells. WFA also significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through transcriptome analysis, we identified reactive oxygen species (ROS)-activated JNK/AP-1 signaling as a major pathway mediating apoptosis of MDS-L cells by WFA. We conclude that the molecular mechanism mediating selective cytotoxicity of WFA on MDS-L cells is strongly associated with induction of ROS. Therefore, pharmacologic manipulation of redox biology could be exploited as a selective therapeutic target in MDS

Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia

Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis. Cytogenetic complexity (>3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV. Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation. Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p). In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002). In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (

The PtdIns 3-Kinase/Akt Pathway Regulates Macrophage-Mediated ADCC against B Cell Lymphoma

Macrophages are important effectors in the clearance of antibody-coated tumor cells. However, the signaling pathways that regulate macrophage-induced ADCC are poorly defined. To understand the regulation of macrophage-mediated ADCC, we used human B cell lymphoma coated with Rituximab as the tumor target and murine macrophages primed with IFNγ as the effectors. Our data demonstrate that the PtdIns 3-kinase/Akt pathway is activated during macrophage-induced ADCC and that the inhibition of PtdIns 3-kinase results in the inhibition of macrophage-mediated cytotoxicity. Interestingly, downstream of PtdIns 3-kinase, expression of constitutively active Akt (Myr-Akt) in macrophages significantly enhanced their ability to mediate ADCC. Further analysis revealed that in this model, macrophage-mediated ADCC is dependent upon the release of nitric oxide (NO). However, the PtdIns 3-kinase/Akt pathway does not appear to regulate NO production. An examination of the role of the PtdIns 3-kinase/Akt pathway in regulating conjugate formation indicated that macrophages treated with an inhibitor of PtdIns 3-kinase fail to polarize the cytoskeleton at the synapse and show a significant reduction in the number of conjugates formed with tumor targets. Further, inhibition of PtdIns 3-kinase also reduced macrophage spreading on Rituximab-coated surfaces. On the other hand, Myr-Akt expressing macrophages displayed a significantly greater ability to form conjugates with tumor cells. Taken together, these findings illustrate that the PtdIns 3-kinase/Akt pathway plays a critical role in macrophage ADCC through its influence on conjugate formation between macrophages and antibody-coated tumor cells

Mixed ligand complexes of ruthenium (II) with α,β-unsaturated β –ketoamines

626-628Ruthenium (II) mixed ligand complexes of the type [RuH(CO)(LL )(PPh)3)2 ] and [RuCl(CO)(LL') (PPh)3)2 LL' =α,β-unsaturated-β-ketoaminate) have been synthes sed by the replace ent of Hand PPh3, by a bidentate ch lating ligand, α,β-unsaturated- β -ketoamine, from [RuH2(CO) (PPh)3)3 and [RuHCl(CO) (PPh)3)3 respectively. All the complexes have been assigned octahedral structures on the basis of elemental analyses, IR, 1H NMR and electronic spectral data

Patient’s Perception on Services of Indian Multispecialty Hospitals – A Tqm Approach

No Abstract

Chloro bridged binuclear ruthenium(II) <i>β</i>-diketonato complexes containing triphenylphosphine and triphenylarsine

490-492Binuclear ruthenium (II) complexes of the type [RuCl(EPh3)2 (βdk)2 (where E = P or As: βdk = β-diketonate) have been synthesized from the reactions of fluorinated β-diketones with [RuCI2(PPh3)2]n and [RuCl2(AsPh3)2]2. These complexes have been characterized by elemental analyses, IR, 1HNMR and electronic spectral data and an octahedral structure has been proposed for all the complexes

Role of macrophage-colony stimulating factor and osteoclast differentiation factor in osteoclastogenesis of bone marrow derived stem cells

995-1000<span style="font-size:14.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" color:black;mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:="" hi"="" lang="EN-IN">Macrophage colony stimulating factor (M-CSF) and osteoclast differentiation factor (ODF) regulate osteoclastogenesis in vivo. Regulation of osteoclast development in vitro by these cytokines has been reported in the present study. Simultaneous addition of ODF and M-CSF during initiation of bone marrow culture inhibited osteoclastogenesis. However, delayed addition of ODF (three days after initiation of the culture) resulted in dramatic increase in phenotypically and functionally mature osteoclast cells. Delayed addition of ODF beyond day three decreased osteoclastogenesis.  Further, removal of MCSF as early as day three inhibited ODF-indueed osteoclastogenesis. These studies provided evidence for the importance of co-ordrinated regulation of osteoclastogenesis by M-CSF and ODF.</span

Drilling Parameters Analysis on In-Situ Al/B₄C/Mica Hybrid Composite and an Integrated Optimization Approach Using Fuzzy Model and Non-Dominated Sorting Genetic Algorithm

In-situ hybrid metal matrix composites were prepared by reinforcing AA6061 aluminium alloy with 10 wt.% of boron carbide (B4C) and 0 wt.% to 6 wt.% of mica. Machinability of the hybrid aluminium metal matrix composite was assessed by conducting drilling with varying input parameters. Surface texture of the hybrid composites and morphology of drill holes were examined through scanning electron microscope images. The influence of rotational speed, feed rate and % of mica reinforcement on thrust force and torque were studied and analysed. Statistical analysis and regression analysis were conducted to understand the significance of each input parameter. Reinforcement of mica is the key performance indicator in reducing the thrust force and torque in drilling of the selected material, irrespective of other parameter settings. Thrust force is minimum at mid-speed (2000 rpm) with the lowest feed rate (25 mm/min), but torque is minimum at highest speed (3000 rpm) with lowest feed rate (25 mm/min). Multi-objective optimization through a non-dominated sorting genetic algorithm has indicated that 1840 rpm of rotational speed, 25.3 mm/min of feed rate and 5.83% of mica reinforcement are the best parameters for obtaining the lowest thrust force of 339.68 N and torque of 68.98 N.m. Validation through experimental results confirms the predicted results with a negligible error (less than 0.1%). From the analysis and investigations, it is concluded that use of Al/10 wt.% B4C/5.83 wt.% mica composite is a good choice of material that comply with European Environmental Protection Directives: 2000/53/CE-ELV for the automotive sector. The energy and production cost of the components can be very much reduced if the found optimum drill parameters are adopted in the production