How I do it: Endoscopic diagnosis for superficial non-ampullary duodenal epithelial tumors

There are no reports on detailed endoscopic diagnosis of superficial non-ampullary duodenal epithelial tumors (SNADET) except for relatively small case series. Herein, we conducted a prospective observational study to investigate the relationship between endoscopic findings and histopathological diagnosis of SNADET. A total of 163 SNADET diagnosed using magnified endoscopic examination with image-enhanced endoscopy (IEE-ME) were prospectively registered in this study. We investigated location, size, macroscopic type, color, and IEE-ME findings including surface structure (closed- or open-loop) and presence of white opaque substance (WOS) in SNADET. We analyzed association between these findings and histopathological diagnosis of SNADET based on the Vienna classification (VCL) using logistic regression analysis. In univariate analysis, lesion size, superficial structure, and WOS deposition showed statistical significance, and the oral side of the lesion location showed statistical tendency for association with VCL C4/5. In multivariate analysis, lesion size (odds ratio [OR], 2.92; 95% CI, 1.94–4.39; P < 0.05) and negative WOS (OR, 5.59; 95% CI, 1.72–18.1; P < 0.05) were significantly associated with VCL C4/5 lesions. Superficial structures with a closed-loop pattern on the surface showed statistical tendency for predicting VCL C4/5 lesions (OR, 2.15; 95% CI, 0.86–5.37; P = 0.10). Based on these findings, we concluded that negative WOS by IEE-ME and lesion size were independent predictors of VCL C4/5 SNADET. These factors may help us to understand of pathophysiology of SNADET and to select appropriate therapeutic strategies.     

Peculiar mechanisms of graft recovery through anti-inflammatory responses after rat lung transplantation from donation after cardiac death

BackgroundAlthough lung transplantation from donation after cardiac death (DCD), especially uncontrolled DCD, is limited by warm ischemic periods, the molecular mechanism of warm ischemia–reperfusion-injury (IRI) has not been well elucidated. The purpose of this study was to clarify the particular longitudinal mechanisms of molecular factors involved in warm IRI.MethodsCold ischemic-time (CIT)-group lungs were retrieved and subjected to 3-h of cold preservation, whereas warm ischemic-time (WIT)-group lungs were retrieved after 3-h of warm ischemia. Orthotopic rat lung transplantation was performed and the grafts were reperfused for 1 or 4-h. The graft functions, gene expression, and activation of inflammatory molecules in the grafts were analyzed. Exhaled-carbon-monoxide-concentration (ExCO-C) was measured during reperfusion.ResultsOnly the WIT-group showed obvious primary graft dysfunction at 1-h reperfusion, but the graft function was recovered during 4-h reperfusion. Most of pro-inflammatory cytokines and stress-induced molecules showed different expression and activation patterns between CIT and WIT groups. In the WIT-group, the expressions of anti-inflammatory molecules, IL-10 and HO-1, were significantly increased at 1-h reperfusion compared to the CIT-group, and these high levels were maintained through 4-h reperfusion. Furthermore, ExCO-C levels in the WIT-group increased immediately after reperfusion compared to the CIT-group.ConclusionsThis study indicates that warm IRI may involve a different mechanism than cold IRI and anti-inflammatory pathways may play important roles in the graft recovery after lung transplantation from uncontrolled DCD.     

RANKL-induced DC-STAMP is essential for osteoclastogenesis

Osteoclasts are bone-resorbing, multinucleated giant cells that are essential for bone remodeling and are formed through cell fusion of mononuclear precursor cells. Although receptor activator of nuclear factor-kappaB ligand (RANKL) has been demonstrated to be an important osteoclastogenic cytokine, the cell surface molecules involved in osteoclastogenesis are mostly unknown. Here, we report that the seven-transmembrane receptor-like molecule, dendritic cell-specific transmembrane protein (DC-STAMP) is involved in osteoclastogenesis. Expression of DC-STAMP is rapidly induced in osteoclast precursor cells by RANKL and other osteoclastogenic stimulations. Targeted inhibition of DC-STAMP by small interfering RNAs and specific antibody markedly suppressed the formation of multinucleated osteoclast-like cells. Overexpression of DC-STAMP enhanced osteoclastogenesis in the presence of RANKL. Furthermore, DC-STAMP directly induced the expression of the osteoclast marker tartrate-resistant acid phosphatase. These data demonstrate for the first time that DC-STAMP has an essential role in osteoclastogenesis.     

Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

l-cysteine derivatives as selective KSP inhibitors. Here, we report further optimizations using docking modeling in the L5 allosteric binding site, which led to the discovery of several high affinity derivatives with two fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth of HCT116 cells in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model in vivo.