Curcumin inhibits the cancer­associated fibroblast­derived chemoresistance of gastric cancer through the suppression of the JAK/STAT3 signaling pathway.

The present study aimed to investigate whether the Janus­activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a critical mechanism underlying the cancer­associated fibroblast (CAF)­induced chemoresistance of gastric cancer (GC). In addition, the present study tried to suggest a natural product to compromise the effects of CAF on the chemoresistance of GC. The results of cell proliferation assay revealed that the conditioned medium (CM) collected from CAFs further increased resistance to 5­fluorouracil (5­FU) in GC cell lines. Secretome analysis revealed that the levels of several secreted proteins, including C­C motif chemokine ligand 2, C­X­C motif chemokine ligand 1, interleukin (IL)­6 and IL­8, were increased in the CM from CAFs co­cultured with cancer cells compared to CM from cancer cells. Western blot analysis revealed that CAFs activated the JAK/STAT3 signaling pathway in cancer cells. The experimental models revealed that curcumin abrogated the CAF­mediated activation of the JAK/STAT3 signaling pathway in GC cells. In vivo data revealed the synergistic effects of curcumin with 5­FU treatment in xenograft GC tumors. These data strongly suggest that the suppression of the JAK/STAT3 signaling pathway counteracts the CAF­induced chemoresistance of GC cells. It is suggested that curcumin may be a suitable natural product which may be used to overcome chemoresistance by inhibiting the CAF­induced activation of the JAK/STAT3 signaling pathway in GC.

Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma.

BACKGROUND: The effects of cancer-associated fibroblasts (CAF) on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAF and GC cells have not been applied in a clinical setting. Here, we examined if inhibition for Axl receptor tyrosine kinase (AXL) can suppress CAF-induced aggressive phenotype in GC. METHODS: We investigated the function of CAF-derived growth arrest-specific 6 (GAS6), a major ligand of AXL, on the migration and proliferation of GC cells. The effect of the AXL inhibitor, BGB324, on the CAF-induced aggressive phenotype of GC cells was also investigated. In addition, we performed immunohistochemistry to examine the expression of phosphorylated AXL protein in 175 GC tissues and evaluated its correlation with the prognosis. RESULTS: The qPCR and western blot analysis showed that GAS6 expression was higher in CAF relative to other cells. We found that co-culture with CAF increased the phosphorylation of AXL (P-AXL), differentiation into a mesenchymal-like phenotype, and cell survival in GC cell lines. When the expression of AXL was genetically inhibited in GC cells, the effect of CAF was reduced. BGB324, a small molecule inhibitor of AXL, suppressed the effects of CAF on GC cell lines. In GC tissues, high levels of P-AXL were significantly associated with poor overall survival (P = 0.022). CONCLUSIONS: We concluded that CAF are a major source of GAS6 and that GAS6 promotes an aggressiveness through AXL activation in GC. We suggested that an AXL inhibitor may be a novel agent for GC treatment.

Laparoscopic Gastrectomy Using Instruments with a Minimal Diameter for Early Gastric Cancer: A Feasible Alternative to Conventional Laparoscopic Gastrectomy for Experienced Surgeons.

Background: The application of laparoscopic surgery using instruments that are 3 mm or less in diameter for patients with early gastric cancer (EGC) has not yet been established. We aimed to evaluate the feasibility and safety of laparoscopic gastrectomy using instruments with minimal diameter. Methods: We retrospectively analyzed 41 patients who underwent laparoscopic subtotal gastrectomy with D1-positive lymph node dissection for EGC. Among them, 17 patients underwent laparoscopic gastrectomy using instruments with a minimal diameter (experimental group), while 24 patients underwent conventional laparoscopic gastrectomy (control group). In the experimental group, we used two 3-mm trocars, one 5-mm trocar, and the GelPOINT® Advanced Access Platform. We compared operative outcomes between the two groups and assessed the learning curve of laparoscopic gastrectomy using instruments with minimal diameter. Results: The operative outcomes were similar between the two groups. The preoperative-to-postoperative day 2 ratio of neutrophil count in the experimental group was significantly lower than in the control group (2.07 versus 2.65; P = .038). Morbidity was not observed in the experimental group and 3 patients experienced complications in the control group, although it was not significantly different (P = .252). The operation time according to the accumulation of cases was stable without any significant change in the experimental group. Conclusions: Laparoscopic gastrectomy using instruments with minimal diameter is technically feasible and safe for EGC and could also be a good alternative to conventional laparoscopic gastrectomy to minimize the impact of surgical invasiveness when performed by experienced surgeons.

Long-Term Changes in the Distal Aorta after Aortic Arch Replacement in Acute DeBakey Type I Aortic Dissection.

BACKGROUND: We analyzed the long-term results of ascending aortic replacement and arch aortic replacement in acute DeBakey type I aortic dissections to measure the differences in the distal aortic changes with extension of the aortic replacement. METHODS: We reviewed 142 cases of acute DeBakey type I aortic dissections (1996-2015). Seventy percent of the cases were ascending aortic replacements, and 30% of the cases underwent total arch aortic replacement, which includes the aorta from the root to the beginning of the descending aorta with the 3 arch branches. Fourteen percent (20 cases) resulted in surgical mortality and 86% of cases that survived had a mean follow-up period of 6.6±4.6 years. Among these cases, 64% of the patients were followed up with computed tomography (CT) angiograms with the duration of the final CT check period of 4.9±2.9 years. RESULTS: There were 15 cases of reoperation in 13 patients. Of these 15 cases, 13 cases were in the ascending aortic replacement group and 2 cases were in the total arch aortic replacement group. Late mortality occurred in 13 cases; 10 cases were in the ascending aortic replacement group and 3 cases were in the total arch aortic replacement group. Eight patients died of a distal aortic problem in the ascending aortic replacement group, and 1 patient died of distal aortic rupture in the total arch aortic replacement group. The follow-up CT angiogram showed that 69.8% of the ascending aortic replacement group and 35.7% of the total arch aortic replacement group developed distal aortic dilatation (p=0.0022). CONCLUSION: The total arch aortic replacement procedure developed fewer distal remnant aortic problems from dilatation than the ascending aortic replacement procedure in acute type I aortic dissections.

Cardiac Usage of Reducible Poly(oligo-D-arginine) As a Gene Carrier for Vascular Endothelial Growth Factor Expression.

Developments of non-viral carriers have headed toward reducing cytotoxicity, which results from the use of conventional gene carriers, and enhancing gene delivery efficiency. Cys-(d-R9)-Cys repeated reducible poly(oligo-D-arginine) (rPOA) is one of the most efficient non-viral carriers for gene therapy; however, while its efficiency has been verified in the lung and brain, it is necessary to confirm its activity in each organ or tissue since there are differences of gene carrier susceptibility to among tissue types. We therefore tested the compatibility of rPOA in cardiac tissue by in vitro or in vivo experiments and confirmed its high transfection efficiency and low cytotoxicity. Moreover, substantial regenerative effects were observed following transfection with rPOA/pVEGF expression vector complexes (79% decreased infarct size) compared to polyethyleneimine (PEI) (34% decreased infarct size) in a rat myocardial infarction (MI) model. These findings suggest that rPOA efficiently enables DNA transfection in cardiac tissue and can be used as a useful non-viral therapeutic gene carrier for gene therapy in ischemic heart disease.

Iron oxide nanoparticle-mediated development of cellular gap junction crosstalk to improve mesenchymal stem cells' therapeutic efficacy for myocardial infarction.

Electrophysiological phenotype development and paracrine action of mesenchymal stem cells (MSCs) are the critical factors that determine the therapeutic efficacy of MSCs for myocardial infarction (MI). In such respect, coculture of MSCs with cardiac cells has windowed a platform for cardiac priming of MSCs. Particularly, active gap junctional crosstalk of MSCs with cardiac cells in coculture has been known to play a major role in the MSC modification through coculture. Here, we report that iron oxide nanoparticles (IONPs) significantly augment the expression of connexin 43 (Cx43), a gap junction protein, of cardiomyoblasts (H9C2), which would be critical for gap junctional communication with MSCs in coculture for the generation of therapeutic potential-improved MSCs. MSCs cocultured with IONP-harboring H9C2 (cocultured MSCs: cMSCs) showed active cellular crosstalk with H9C2 and displayed significantly higher levels of electrophysiological cardiac biomarkers and a cardiac repair-favorable paracrine profile, both of which are responsible for MI repair. Accordingly, significantly improved animal survival and heart function were observed upon cMSC injection into rat MI models compared with the injection of unmodified MSCs. The present study highlights an application of IONPs in developing gap junctional crosstalk among the cells and generating cMSCs that exceeds the reparative potentials of conventional MSCs. On the basis of our finding, the potential application of IONPs can be extended in cell biology and stem cell-based therapies.

Bioequivalence and pharmacokinetics of 70 mg alendronate sodium tablets by measuring alendronate in plasma.

The bioequivalence and pharmacokinetics of alendronate sodium tablets were examined by determining the plasma concentration of alendronate. Two groups, consisting of 24 healthy volunteers, each received a 70 mg reference alendronate sodium tablet and a test tablet in a 2x2 crossover study. There was a 6-day washout period between doses. The plasma alendronate concentration was monitored for 7 h after the dose, using HPLC-Fluorescence Detector (FD). The area under the plasma concentration-time curve from time 0 to the last sampling time at 7 h (AUC(0-7h) was calculated using the linear-log trapezoidal rule. The maximum plasma drug concentration (Cmax) and the time to reach Cmax (Tmax) were derived from the plasma concentration-time data. Analysis of variance was performed using logarithmically transformed AUC(0-7h) and Cmax, and untransformed Tmax. For the test medication versus the reference medication, the AUC(0-7h) were 87.63 +/- 29.27 vs. 102.44 +/- 69.96 ng x h x mL(-1) and the Cmax values were 34.29 +/- 13.77 vs. 38.47 +/- 24.39 ng x mL(-1), respectively. The 90% confidence intervals of the mean differences of the logarithmic transformed AUC(0-7h) and Cmax values were log 0.8234-log 1.1597 and log 0.8222-log 1.1409, respectively, satisfying the bioequivalence criteria guidelines of both the U.S. Food and Drug Administration and the Korea Food and Drug Administration. The other pharmacokinetic parameters for the test drug versus reference drug, respectively, were: t(1/2), 1.87 +/- 0.62 vs. 1.77 +/- 0.54 h; V/F, 2061.30 +/- 986.49 vs. 2576.45 +/- 1826.05 L; CL/F, 835.32 +/- 357.35 vs. 889.48 +/- 485.87 L x h(-1); K(el), 0.42 +/- 0.14 vs. 0.40 +/- 0.18 h(-1); Ka, 4.46 +/- 3.63 vs. 3.80 +/- 3.64 h(-1); and Tlag, 0.19 +/- 0.09 vs. 0.18 +/- 0.06 h. These results indicated that two alendronate formulations (70-mg alendronate sodium) were biologically equivalent and can be prescribed interchangeably.