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Deeper mechanistic understanding of lung adenocarcinoma (non–small cell lung carcinoma, or NSCLC), a leading cause of cancer-related deaths overall, may lead to more effective therapeutic strategies. In analyzing NSCLC clinical specimens and cell lines, we discovered a uniform decrease in miR-186 (MIR186) expression in comparison with normal lung tissue or epithelial cell lines. miR-186 expression correlated with patient survival, with median overall survival time of 63.0 or 21.5 months in cases exhibiting high or low levels of miR-186, respectively. Enforced overexpression of miR-186 in NSCLC cells inhibited proliferation by inducing G1–S checkpoint arrest. Conversely, RNA interference–mediated silencing miR-186 expression promoted cell-cycle progression and accelerated the proliferation of NSCLC cells. Cyclin D1 (CCND1), cyclin-dependent kinase (CDK)2, and CDK6 were each directly targeted for inhibition by miR-186 and restoring their expression reversed miR-186–mediated inhibition of cell-cycle progression. The inverse relationship between expression of miR-186 and its targets was confirmed in NSCLC tumor xenografts and clinical specimens. Taken together, our findings established a tumor-suppressive role for miR-186 in the progression of NSCLC. Cancer Res; 73(2); 756–66. ©2012 AACR.

Aim To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection (ABMR) after intestinal transplantation (ITx). Methods A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody (DSA), acute tissue damage, C4d deposition, and allograft dysfunction. Results Acute ABMR was identified in 18 (10.3%) out of 175 intestinal allografts with an average occurrence of 10 d (range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class I and/or II antigens with a detectable DSA. A positive cross-match was seen in 14 (77.8%) cases and twelve of 18 patients (66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibody as a significant independent risk factor. Despite initial improvement after therapy, eleven recipients (61.1%) lost transplant secondary to rejection. Of those, 9 (50%) underwent graft removal and 4 (22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo (range, 13.3-76.4), 8 (44.4%) recipients died. Conclusion Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes.

Twenty new 4,4'-dibenzoyl-1,1'-dibenzyl-1,3'-(decane-1,5-diyl)-piperazinium dihalides 5a-1 and 1,1'-dibenzyl-1,1'-(decane-1,5-diyl)piperazinium dihydrochloride dilialides 6a-1 were prepared and evaluated for their analgesic, sedative and anti-inflammatory activities. Structure-activity relationship studies indicated that the compounds 6e (Ar = 4-NO 2 C 6 H 5 ) and 6k (Ar = 3-Mc-C 6 H 5 ) exhibited higher activities than others. Compared with the corresponding compounds 6k and 61, the presence of benzoyl in the compound 5k and 5l exerted a contrary influeuce on the activities. 5h and 6h show the highest anti-inflammatory activity (59%, dose 20 mg/kg and 48%, dose 1 mg/kg) in the series 5 and 6, respectively.

Twenty new 4,4'-dibenzoyl-1,1'-dibenzyl-1,3'-(decane-1,5-diyl)-piperazinium dihalides 5a-1 and 1,1'-dibenzyl-1,1'-(decane-1,5-diyl)piperazinium dihydrochloride dilialides 6a-1 were prepared and evaluated for their analgesic, sedative and anti-inflammatory activities. Structure-activity relationship studies indicated that the compounds 6e (Ar = 4-NO 2 C 6 H 5 ) and 6k (Ar = 3-Mc-C 6 H 5 ) exhibited higher activities than others. Compared with the corresponding compounds 6k and 61, the presence of benzoyl in the compound 5k and 5l exerted a contrary influeuce on the activities. 5h and 6h show the highest anti-inflammatory activity (59%, dose 20 mg/kg and 48%, dose 1 mg/kg) in the series 5 and 6, respectively.

Publisher Summary This chapter provides an introduction, describes the Total Synthesis, biogenesis, and medicinal chemistry of camptothecin. Camptotheca acuminata Decne (Nyssaceae) is a tree distributed widely and abundantly in the southern part of China, and the crude alcoholic extract of C. acuminata show antitumor activity in animal tests. Camptothecin has two notable chemical properties: (1) its lack of significant alkalinity causes it to behave as a neutral molecule, and (2) the presence of the C-20 tertiary alcohol imparts an unusual electrophilicity to the lactone carbonyl group, perhaps via a strong intramolecular H bond. All the oxygenated camptothecin analogs showed antitumor activity in animal tests, and may be produced as a result of further metabolism in the plant. The principal effect of camptothecin on cultured mammalian cells is the potent inhibition of polynucleic acid biosynthesis. The drug affects the biosynthesis of ribosomal RNA more than other types of cellular RNA. It does not inhibit significantly protein biosynthesis. Camptothecin induces single-strand breaks in cellular DNA in intact HeLa cells as viewed by alkaline sucrose density gradient analysis; this effect is reversible. At present, camptothecin and 10-hydroxycamptothecin are used clinically only in the People's Republic of China.