Synthesis and testing of anticonvulsant properties of 5-benzylidene derivatives of 3-o-, 3-m- I 3-p-chlorophenyl-2-thiohydantoin]

Ten new 3-(o-, 3-(m- and 3-(p-chlorophenyl)-5-benzylidene derivatives of 2-thiohydantoin were obtained. Their IR spectra were recorded. The obtained compounds were tested for anticonvulsant activity using the test of minimal and maximal pentetrazol shock in mice, and the MES test in rats.     

Sarcocystis gigantea lectin — mitogen and polyclonal B-cell activator

The present study further examined the in vitro response of human mononuclear cells (MNC) to theSarcocystis gigantea lectin (SGL). The results confirm our previous report that SGL is mitogenic for human MNC. We now report that SGL is not only a potent mitogen but also a polyclonal activator for human peripheral B cells. As was true for pokeweed mitogen (PWM, 2 g/ml), the addition of SGL (25 g protein/ml) to cultures of MNC caused lymphocyte proliferation and B-cell maturation, indicated by a marked increase in IgG and IgM production. As measured by the [³H]-thymidine incorporation assay, SGL induced significantly higher proliferative responses than PWM (P<0.01,n=24). The values obtained by SGL and PWM for IgG and IgM synthesis were essentially identical. As opposed to SGL, the sarcotoxin-containing fraction (SGTF) did not induce antibody formation or proliferative responses in human MNC.     

Synthesis andin vitro antitumor activity of isoazamitosene and isoiminoazamitosene derivatives

Seven isoazamitosene derivatives, mitomycin analogues, were synthesized and tested for cytotoxicities against leukemia and gastric cancer cell lines. Preparation of a pyrrolo[1,2-a]benzimidazole (3) (azamitosene ring system) was completed by utilizing the Lewis acid-catalized cyclization, witho-chloronitrotoluene as the starting material. Nitration of3 produced a mixture of two isomers (5-nitro isomer (4) and 7-nitro isomer (5)) in product ratio of 36∶52.4 was directly converted into quinone (7) by reduction and Fremy oxidaton. Finally, quinone derivatives (8, 9, 10, and11) were synthesized by 1,4-addition of7 with cyclic secondary amines. From above-mentioned5, 8-nitro compound (15) was prepared in 4 steps. At pH 3, Fremy oxidation of15 produced quinone (16), whereas iminoquinone derivatives (17a and17b) at pH 7. Isoazamitosene derivatives (8, 9, 10, and11), containing cyclic amino groups at the 7-position, showed potent cytotoxicity on P388, SNU-1, and KHH tumor cell lines. Among them,8 had stronger cytotoxicity against SNU-1 cell line than mitomycin and adriamycin. Considering these results, isoazamitosene derivatives may had unique cytotoxicity profiles. However, isoiminoazamitosene derivatives (17a and17b) revealed very weak cytotoxicity.     

Aspirin intolerance and the cyclooxygenase-leukotriene pathways

PURPOSE OF REVIEW: In up to 10% of patients with bronchial asthma, aspirin and other nonsteroidal antiinflammatory drugs precipitate asthmatic attacks. This is a hallmark of a distinct clinical syndrome that develops according to a characteristic sequence of symptoms. Here we discuss its clinical picture and management as related to the abnormalities in arachidonic acid transformations. RECENT FINDINGS: At the biochemical level, the characteristic feature is profound alteration in eicosanoid biosynthesis and metabolism. Major advances in the molecular biology of eicosanoids, exemplified by the cloning of cysteinyl-leukotriene receptors and discovery of a whole family of cyclooxygenase enzymes, offer new insights into mechanisms operating in aspirin-induced asthma. Clinical interest has been enhanced by the introduction into therapy of highly specific cyclooxygenase-2 inhibitors and antileukotriene drugs. SUMMARY: Recent studies have improved our understanding of mechanisms operating in asthma and unvieled the role of eicosanoid mediators in pulmonary disease.     

Ultrastructural and phenotypic analysis of in vitro erythropoiesis from human cord blood CD34<Superscript>+</Superscript> cells

Erythropoietin (EPO) induces erythropoiesis in vitro as well as in vivo, and the process of erythroid differentiation has been explored phenotypically and morphologically. However, morphological analysis of in vitro erythropoiesis of human hematopoietic progenitor cells at the ultrastructural level has not been reported before. In the present study, we have traced the ultrastructural changes of erythroid differentiation during ex vivo expansion of human cord blood (CB) CD34(+) cells in the presence of EPO by electron microscopy (EM), along with concurrent phenotypic analysis. CD34(+) cells purified from ten CBs by immunomagnetic selection were cultured in serum-free essential media in the presence of a combination of the several cytokines including EPO, thrombopoietin, flt3-ligand (FL), stem cell factor (SCF), granulocyte colony-stimulating factor, interleukin (IL)-3 and/or IL-11. Phenotypic analysis was performed by flow cytometric analysis for erythroid markers, including glycophorin C (GPC), Kell-related, glycophorin A (GPA), band 3, Lu(b), and RhD. Ultrastructural analysis was performed by electron-microscopic examination of the cultured cells stained with uranyl acetate and lead citrate. Phenotypic analysis revealed that in the absence of EPO, genuine erythroid fraction expressing the typical pattern of erythroid markers did not appear. The order of the above markers expressed in the cultured cells in the presence of EPO was GPC, Kell-related, GPA, band 3, Lu(b), and RhD, irrespective of the type of cytokine added. Of the cytokines used in combination with EPO, FL + IL-3 was the most efficient in inducing erythroid differentiation, which was followed by SCF + IL-3. EM examination demonstrated complete process of erythroid development from pronormoblasts to reticulocytes with nuclei having been extruded and mature erythrocytes. These results suggest that morphologically intact erythrocytes could be produced by ex vivo expansion of CB CD34(+) cells using EPO.     

Genes associated with venous thromboembolism in colorectal cancer patients

Essentials

• The underlying pathophysiological mechanisms behind cancer‐associated thrombosis are unknown.
• We compared expression profiles in tumor cells from patients with and without thrombosis.
• Tumors from patients with thrombosis showed significant differential gene expression profiles.
• Patients with thrombosis had a proinflammatory status and increased fibrin levels in the tumor.

Summary

Background

Venous thromboembolism (VTE) is a frequent complication in patients with cancer, and is associated with significant morbidity and mortality. However, the mechanisms behind cancer‐associated thrombosis are still incompletely understood.

Objectives

To identify novel genes that are associated with VTE in patients with colorectal cancer (CRC).

Methods

Twelve CRC patients with VTE were age‐matched and sex‐matched to 12 CRC patients without VTE. Tumor cells were isolated from surgical samples with laser capture microdissection approaches, and mRNA profiles were measured with next‐generation RNA sequencing.

Results

This approach led to the identification of new genes and pathways that might contribute to VTE in CRC patients. Application of ingenuity pathway analysis indicated significant links with inflammation, the methionine degradation pathway, and increased platelet function, which are all key processes in thrombus formation. Tumor samples of patients with VTE had a proinflammatory status and contained higher levels of fibrin and fibrin degradation products than samples of those without VTE.

Conclusion

This case–control study provides a proof‐of‐principle that tumor gene expression can discriminate between cancer patients with low and high risks of VTE. These findings may help to further unravel the pathogenesis of cancer‐related VTE. The identified genes could potentially be used as candidate biomarkers to select high‐risk CRC patients for thromboprophylaxis.