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In search of new active molecules, a small focused library of new 1,2,3-triazoles derived from naphthols were efficiently prepared via the click chemistry approach. The synthesized triazole derivatives were evaluated for their antifungal, antioxidant and antitubercular activities. Furthermore, to rationalize the observed biological activity data, the molecular docking study has also been carried out against the active site of cytochrome P450 lanosterol 14α-demethylase of C. albicans to understand the binding affinity and binding interactions of enzyme and synthesized derivatives, which revealed a significant correlation between the binding score and biological activity for these compounds. The results of the in vitro and In Silico study suggest that the 1,2,3-triazole derivatives may possess the ideal structural requirements for the further development of novel therapeutic agents. [ABSTRACT FROM AUTHOR]

Background: Serum interleukin (IL)-6 levels correlate with disease outcomes in renal cell carcinoma (RCC) patients. Siltuximab, a chimeric, murine-human mAb against IL-6, was evaluated in a three-part phase I/II study in patients with progressive metastatic RCC.Methods: In part 1, 11 patients received 1, 3, 6, or 12mgkg-¹ at weeks 1, 4 and q2w × 2 thereafter; in part 2, 37 patients randomly received 3 or 6 mgkg-¹ q3w × 4; in part 3, 20 low-risk patients received 6mgkg-¹ q2w × 6. Modified WHO response criteria were assessed at weeks 7, 11, the 6-week follow-up, and when clinically indicated.Results: Siltuximab was well tolerated overall, with no maximum tolerated dose or immune response observed. In all, 5 out of 11, 17 out of 37, and 9 out of 20 patients in parts 1, 2, and 3, respectively, received extended treatment beyond 4-6 initial infusions. In part 2, stable disease (SD) (≥11weeks) or better was achieved by 11 out of 17 (65%) 3 mgkg-¹ treated patients (one partial response (PR) ~8 months, 10 SD) and 10 out of 20 (50%) 6mgkg-¹ treated patients (10 SD). In part 3, documented complete or PR was not observed, but 13 out of 20 (65%) patients achieved SD.Conclusion: Siltuximab stabilised disease in >50% of progressive metastatic RCC patients. One PR was observed. Given the favourable safety profile of siltuximab and poor correlation of tumour shrinkage with clinical benefit demonstrated for other non-cytotoxic therapies, further evaluation of dose-escalation strategies and/or combination therapy may be considered for patients with RCC. [ABSTRACT FROM AUTHOR]

A novel, immortalized, human bone marrow stroma-derived cell line TF274 is described which has the ability to form bone both in vitro and in vivo. Under basal conditions these cells expressed alkaline phosphatase (ALP) and type I collagen genes which are characteristic of the osteoblast phenotype. ALP levels were upregulated in the presence of osteotropic agents such as parathyroid hormone (PTH), transforming growth factor beta (TGF-beta), and BMP-2. In addition, PTH also increased cAMP levels in these cells. The capacity of these cells to form bone in vitro was evaluated by culturing them in the presence of L-ascorbic acid and beta-glycerophosphate. Matrix mineralization in these cultures was assessed by Alizarin Red staining and increased 45Ca uptake. Under these conditions mineralized nodule formation was observed in less than 2 weeks. Northern analysis of TF274 cells at various times during the mineralization process indicated a temporal expression of the osteocalcin gene that is typically associated with differentiating osteoblasts. The osteogenic nature of TF274 cells was confirmed in vivo using the severe combined immunodeficient (SCID) mouse model. Antibodies to human leukocyte antigens (HLA), class I antigens, and human OKa blood group antigen were used to demonstrate that the lesions formed were of human origin. By 21 days, the lesion consisted of a homogeneous focus of ALP-positive cells containing areas of mineralized bone lined with tartarate-resistant acid phosphatase (TRAP) positive osteoclasts. Thus, the TF274 cells exhibit osteogenic potential both in vitro and in vivo. This immortalized cell line represents a consistent source of cells that can be used to study human osteoblast differentiation both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Exposure of human monocytes (HM) to E. coli lipopolysacharide (LPS) results in measurable production of both IL-1β and TNFα in culture supernatants. It has previously been reported that the elevation of cAMP levels in HM selectively suppresses the LPS-induced TNFα but not IL-1β production. In this study we investigated whether the novel anti-inflammatory drug, SK&F 86002 [5-4(-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazole(2,1-b)thiazol] and related analogs of the pyridinyl imidazole class, inhibit IL-1 and TNF production via a cAMP-dependent mechanism. These compounds, when added together with LPS result in inhibition of IL-1 and TNF production with equal-rank-order potency. Although the pyridinyl imidazole compounds were found to be generally weak phosphodiesterase inhibitors, they did not affect cAMP levels in HM, alone or in the presence of LPS. In contrast, PGE, which significantly elevated intracellular cAMP levels, inhibited TNF but not IL-1 production at the transcriptional level. Taken together, these results suggest that the pyridinyl imidazoles inhibit the production of IL-1β and TNFα through pathways independent of cAMP elevating mechanisms. [ABSTRACT FROM AUTHOR]