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Transwell co-culture of AGS cells with HFE-145 cells markedly inhibited viability and proliferation of AGS cells. Following uptake of HFE-145-derived exosomes in recipient cells, GKN1 protein bound to HRas and inhibited the binding of HRas to b-Raf and c-Raf which subsequently downregulated HRas/Raf/MEK/ERK signaling pathways in AGS, MKN1 cells, and MKN1-derived xenograft tumor tissues. In addition, exosomal GKN1 protein suppressed both migration and invasion of gastric cancer cells by inhibiting epithelial-mesenchymal transition. CONCLUSIONS Gastric-specific uptake of exosomes derived from gastric epithelial cells requires integrin α6 and αX proteins in both gastric epithelial cells and exosomes. Exosomal GKN1 protein inhibits gastric carcinogenesis by downregulating HRas/Raf/MEK/ERK signaling pathways.BACKGROUND The majority of GISTs express mutationally activated KIT. Imatinib and sunitinib are approved KIT-inhibiting therapies. Their efficacy is usually hampered by the acquired multiple secondary drug-resistance KIT mutations. The most problematic resistance subset is GISTs with acquisition of secondary mutations in the KIT activation loop. Here, we establish the spectrum of activity of dasatinib against a comprehensive collection of clinically relevant KIT mutants associated with drug-sensitive and drug-resistant GIST. METHODS The cellular and in vitro activities of tyrosine kinase inhibitors (TKIs) against mutant KIT were assessed using a panel of engineered and GIST-derived cell lines. The in vivo activities of dasatinib were determined using TKI-resistant xenograft models. RESULTS In engineered and GIST-derived cell lines, dasatinib potently inhibited KIT with primary mutations in exon 11 or 9 and a range of secondary imatinib-resistant mutations in exons 13 and 14, encoding the ATP-binding pocket, and in exons 17 and 18, encoding the activation loop, with the exception of a substitution at codon T670. Our data show that dasatinib is more potent than imatinib or sunitinib at inhibiting the activity of drug-resistant KIT mutants. Dasatinib also induces regression in GIST-derived xenograft models containing these secondary mutations. A major determinant of the efficacy of dasatinib for the treatment of advanced GIST is the activity of this inhibitor against KIT mutants. CONCLUSION Dasatinib shows efficacy in cancer models, inhibiting a wide range of oncogenic primary and drug-resistant KIT mutants. These results have implications for the further development of dasatinib precision therapy in GIST patients.BACKGROUND Bile acids (BAs) are important in the metabolic effects of bariatric surgery. Most BAs are reabsorbed in the ileum and recycled back to the liver. We have reported that this enterohepatic circulation was shortened by duodenal-jejunal bypass (DJB), and the biliopancreatic (BP)-limb plays an important role in reabsorption of BAs. However, the mechanism of BA reabsorption in BP-limb remains uncertain. We aimed to investigate the mechanisms of BA reabsorption after DJB, especially focusing on carrier-mediated transport of BAs and the impact of the presence or absence of lipids on BA reabsorption. METHODS Otsuka-Long-Evans-Tokushima fatty rats or Sprague-Dawley rats were assigned to a control group and DJB group. BA levels in the divided small intestine were quantified with liquid chromatography-mass spectrometry. Labeled BA was injected and perfused with BA transporter inhibitors or mixture of lipids in the isolated BP-limb, and bile was sampled and analyzed. RESULTS Conjugated BA levels in the BP-limb were significantly higher than that of the control group. BA absorption tended to decrease by the apical sodium-dependent BA transporter inhibitor and was significantly decreased by the organic anion-transporting peptide (OATP) inhibitor. VE-821 nmr BA absorption tended to increase in the absence of lipid solutions compared with that in the presence of lipid solutions. CONCLUSION We attributed the increased BA reabsorption in the BP-limb to lack of food in the BP-limb, which contains concentrated BAs and no lipids. OATP played an important role in BA reabsorption in the BP-limb. Therefore, BAs would be reabsorbed in different manners after DJB.PURPOSE Obesity and cardiac failure are globally endemic and increasingly intersecting. Bariatric surgery may improve cardiac function and act as a bridge-to-transplantation. We aim to identify effects of bariatric surgery on severe heart failure patients and ascertain its role regarding cardiac transplantation. MATERIALS AND METHODS A retrospective study of a prospectively collected database identified heart failure patients who underwent bariatric surgery between 1 January 2008 and 31 December 2017. Patients were followed up 12 months post-operatively. Cardiac investigations, functional capacity, cardiac transplant candidacy, morbidity and length of stay were recorded. RESULTS Twenty-one patients (15 males, 6 females), mean age 48.7 ± 10, BMI 46.2 kg/m2 (37.7-85.3) underwent surgery (gastric band (18), sleeve gastrectomy (2), biliopancreatic diversion (1)). There were no loss to follow-up. There was significant weight loss of 26.0 kg (5.0-78.5, p  less then  0.001), significant improvement of left ventricular ejection fraction (LVEF) (10.0 ± 11.9%, p  less then  0.001) and significant reduction of 0.5 New York Heart Association (NYHA) classification (0-2, p  less then  0.001). Multivariate models delineated the absence of atrial fibrillation and pre-operative BMI  less then  49 kg/m2 as significant predictors (adjusted R-square 69%) for improvement of LVEF. Mean length of stay was 3.6 days and in-hospital morbidity rate was 42.9%. One patient subsequently underwent a heart transplant, and two patients were removed from the waitlist due to clinical improvements. CONCLUSION Bariatric surgery is safe and highly effective in obese patients with severe heart failure with substantial improvements in cardiac function and symptoms. A threshold pre-operative BMI of 49 kg/m2 and absence of atrial fibrillation may be significant predictors for improvement in cardiac function. There is a role for bariatric surgery to act as a bridge-to-transplantation or even ameliorate this requirement.
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