Lack of efficacy of troglitazone at clinically achievable concentrations, with or without 9-cis retinoic acid or cytotoxic agents, for hepatocellular carcinoma cell lines

[[abstract]]Although the PPARgamma agonist troglitazone has been shown to induce growth inhibition of hepatocellular carcinoma (HCC) cells at high concentration, this study indicates troglitazone does not significantly inhibit the growth of HCC cells at clinically achievable concentrations (1-10 muM), and this lack of activity could not be improved by the addition of 9-cis-retinoic acid. Furthermore, no synergistic effect was found between troglitazone and cytotoxic anticancer agents

Formation of Amyloid-Like Fibrils by Y-Box Binding Protein 1 (YB-1) Is Mediated by Its Cold Shock Domain and Modulated by Disordered Terminal Domains

YB-1, a multifunctional DNA- and RNA-binding nucleocytoplasmic protein, is involved in the majority of DNA- and mRNA-dependent events in the cell. It consists of three structurally different domains: its central cold shock domain has the structure of a β-barrel, while the flanking domains are predicted to be intrinsically disordered. Recently, we showed that YB-1 is capable of forming elongated fibrils under high ionic strength conditions. Here we report that it is the cold shock domain that is responsible for formation of YB-1 fibrils, while the terminal domains differentially modulate this process depending on salt conditions. We demonstrate that YB-1 fibrils have amyloid-like features, including affinity for specific dyes and a typical X-ray diffraction pattern, and that in contrast to most of amyloids, they disassemble under nearly physiological conditions

Trust development and horizontal collaboration in logistics: A theory based evolutionary framework

Purpose: The purpose of this article is to provide academicians and practitioners alike with a theory-based framework regarding horizontal collaboration in logistics. The proposed tool is based on an incremental perspective, according to two main dimensions: mutual trust among partners and the extent of the cooperation

Differentiation therapy of acute promyelocytic leukemia using all-trans retinoic acid.

BACKGROUND AND METHODS: Patients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor-alpha (RAR-alpha). Since this receptor has been shown to be involved with growth and differentiation of myeloid cells in vitro, and since recent clinical studies have reported that tretinoin (all-trans-retinoic acid) induces complete remission in patients with acute promyelocytic leukemia we studied the effects of tretinoin on cellular maturation and molecular abnormalities in patients undergoing the induction of remission with this agent. RESULTS: Eleven patients with acute promyelocytic leukemia were treated with tretinoin administered orally at a dose of 45 mg per square meter of body-surface area per day. Nine of the 11 patients entered complete remission. In two patients, complete remission was preceded by striking leukocytosis that then resolved despite continued drug treatment. Serial studies of cellular morphologic features, cell-surface immunophenotypic analysis, and fluorescence in situ hybridization with a chromosome 17 probe revealed that clinical response was associated with maturation of the leukemic clone. All patients who responded to treatment who were tested by Northern blot analysis had expression of aberrant RAR-alpha. As patients entered complete remission, the expression of the abnormal RAR-alpha message decreased markedly; however, it was still detectable in several patients after complete morphologic and cytogenetic remission had been achieved. CONCLUSIONS: Tretinoin is a safe and highly effective agent for inducing complete remission in patients with acute promyelocytic leukemia. Clinical response to this agent is associated with leukemic-cell differentiation and is linked to the expression of an aberrant RAR-alpha nuclear receptor. Molecular detection of the aberrant receptor may serve as a useful marker for residual leukemia in patients with this disease

Positive and negative cis-regulatory elements directing postfertilization maternal mRNA translational control in mouse embryos

Mechanisms providing for temporally complex patterns of maternal mRNA translation after fertilization are poorly understood. We employed bioinformatics analysis to compare populations of mRNAs enriched specifically on polysomes at the metaphase II (MII) stage oocyte and late one-cell stages and a detailed deletion/truncation series to identify elements that regulate translation. We used the Bag4 3′ untranslated region (UTR) as a model. Bioinformatics analysis revealed one conserved motif, subsequently confirmed by functional studies to be a key translation repressor element. The deletion/truncation studies revealed additional regulatory motifs, most notably a strong translation activator element of <30 nt. Analysis of mRNA secondary structure suggests that secondary structure plays a key role in translation repression. Additional bioinformatics analysis of the regulated mRNA population revealed a diverse collection of regulatory motifs found in small numbers of mRNAs, highlighting a high degree of sequence diversity and combinatorial complexity in the overall control of the maternal mRNA population. We conclude that translational control after fertilization is driven primarily by negative regulatory mechanisms opposing strong translational activators, with stage-specific release of the inhibitory influences to permit recruitment. The combination of bioinformatics analysis and deletion/truncation studies provides the necessary approach for dissecting postfertilization translation regulatory mechanisms