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- Initial therapy, persistence and regimen change in a cohort of newly treated type 2 diabetes patients. [JOURNAL ARTICLE]
- Br J Clin Pharmacol 2014 Dec 17.
To describe the utilisation of antidiabetic agents , in terms of persistence and regimen change in the management of a cohort of newly treated type 2 diabetes patients and to investigate associated socio-demographic and treatment factors.A population-based retrospective cohort study was conducted using the national pharmacy claims database in Ireland. Subjects were analysed for persistence and regimen change. Cox proportional-hazards regression examined associations of socio-demographic and treatment factors on treatment patterns. Hazard ratios (HR) and 95% CIs are presented.20947 subjects were identified in the study over a 2 year period. Most were initiated on metformin (76%) or sulphonylureas (22%) and 77% were persistent with therapy 12 months after initiation. The likelihood of non-persistence was significantly lower in the youngest (40-49) age groups (ref 60-69) (HR 1.62 [CI 1.42-1.84]) and those on sulphonylureas (HR 1.49 [1.36-1.64]). The likelihood of receiving a regimen change was significantly lower in the older (80+) age groups (HR 0.63 [0.56-0.71]), females (HR 0.91 [0.86-0.95], and those with pre-existing CVD (1 vs 0 CVD medicines) (HR 0.82 [0.74-0.90]), and higher in those on sulphonylureas (HR 1.83 [1.73-1.94]) CONCLUSIONS: Type of treatment, pre-existing CVD and demographic factors are shown to be associated with the observed treatment patterns. Guideline recommended agents were widely used on treatment initiation though a substantial minority were not initiated on the recommended first line agent. Use of guideline recommended agents was not as evident during treatment progression. Further optimisation of initial and subsequent antidiabetic agent prescribing may be possible.
- Multifunctional NaYF4:Yb, Er@mSiO2@Fe3O4-PEG nanoparticles for UCL/MR bioimaging and magnetically targeted drug delivery. [JOURNAL ARTICLE]
- Nanoscale 2014 Dec 18.
A low toxic multifunctional nanoplatform, integrating both mutimodal diagnosis methods and antitumor therapy, is highly desirable to assure its antitumor efficiency. In this work, we show a convenient and adjustable synthesis of multifunctional nanoparticles NaYF4:Yb, Er@mSiO2@Fe3O4-PEG (MFNPs) based on different sizes of up-conversion nanoparticles (UCNPs). With strong up-conversion fluorescence offered by UCNPs, superparamagnetism properties attributed to Fe3O4 nanoparticles and porous structure coming from the mesoporous SiO2 shell, the as-obtained MFNPs can be utilized not only as a contrast agent for dual modal up-conversion luminescence (UCL)/magnetic resonance (MR) bio-imaging, but can also achieve an effective magnetically targeted antitumor chemotherapy both in vitro and in vivo. Furthermore, the UCL intensity of UCNPs and the magnetic properties of Fe3O4 in the MFNPs were carefully balanced. Silica coating and further PEG modifying can improve the hydrophilicity and biocompatibility of the as-synthesized MFNPs, which was confirmed by the in vitro/in vivo biocompatibility and in vivo long-time bio-distributions tests. Those results revealed that the UCNPs based magnetically targeted drug carrier system we synthesized has great promise in the future for multimodal bio-imaging and targeted cancer therapy.
- Ginsenoside Rg3 Inhibits Melanoma Cell Proliferation through Down-Regulation of Histone Deacetylase 3 (HDAC3) and Increase of p53 Acetylation. [JOURNAL ARTICLE]
- PLoS One 2014; 9(12):e115401.
Malignant melanoma is an aggressive and deadly form of skin cancer, and despite recent advances in available therapies, is still lacking in completely effective treatments. Rg3, a monomer extracted from ginseng roots, has been attempted for the treatment of many cancers. It is reported that the expressions of histone deacetylase 3 (HDAC3) and p53 acetylation correlate with tumor cell growth. However, the antitumor effect of Rg3 on melanoma and the mechanism by which it regulates HDAC3 expression and p53 acetylation remain unknown. We found high expression of HDAC3 in human melanoma tissues to be significantly correlated to lymph node metastasis and clinical stage of disease (p<0.05). In melanoma cells, Rg3 inhibited cell proliferation and induced G0/G1 cell cycle arrest. Rg3 also decreased the expression of HDAC3 and increased the acetylation of p53 on lysine (k373/k382). Moreover, suppression of HDAC3 by either siRNA or a potent HDAC3 inhibitor (MS-275) inhibited cell proliferation, increased p53 acetylation and transcription activity. In A375 melanoma xenograft studies, we demonstrated that Rg3 and HDAC3 short hairpin RNA (shHDAC3) inhibited the growth of xenograft tumors with down-regulation of HDAC3 expression and up-regulation of p53 acetylation. In conclusion, Rg3 has antiproliferative activity against melanoma by decreasing HDAC3 and increasing acetylation of p53 both in vitro and in vivo. Thus, Rg3 serves as a potential therapeutic agent for the treatment of melanoma.
- Naturally occurring phenethyl isothiocyanate-induced inhibition of gastric cancer cell growth by disruption of microtubules. [JOURNAL ARTICLE]
- J Gastroenterol Hepatol 2014 Dec.:99-106.
Phenethyl isothiocyanate (PEITC) derives from vegetables commonly consumed by man and has been demonstrated as a promising chemopreventive agent against several types of cancer. However, the potential in preventing gastric cancer as well as the underlying mechanisms are to date not fully understood. The present study aimed at elucidating the cellular effects induced by PEITC in gastric cancer cells leading to apoptosis.The human gastric cancer cell lines Kato-III and MKN74 were employed. Cell proliferation was assayed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Morphology and migration were investigated through a contrast microscope. Cell cycle distribution was analyzed using flow cytometry of PI-stained cells. Microtubules were studied by confocal detection of Kato-III cells transfected to express GFP-tagged microtubules. Commercial kits were employed to study the effect of PEITC on apoptosis, caspase-3 activity, and glutathione content in MKN74 cells.Kato-III and MKN74 cells responded, with different sensitivity, dose- and time-dependently in inhibition of cell proliferation to PEITC treatment. Further, PEITC induced aberrated cell morphologies and inhibited migration of MKN74 cells. Kato-III cells treated with PEITC accumulated in G2 /M phase and displayed a loss of microtubuli with the subsequent formation of apoptotic bodies. Although weak responses, MKN74 cells also accumulated in G2 /M phase, became apoptotic, increased caspase-3 activity, and suffered a reduction of glutathione pool.Our findings demonstrate that PEITC induces disintegration of microtubules in human gastric cancer cells contributing to cell cycle arrest and ultimately apoptosis, contributing to an increased understanding of PEITC-induced inhibition of gastric cancer cell growth.
- S-allyl cysteine alleviates nonsteroidal anti-inflammatory drug-induced gastric mucosal damages by increasing cyclooxygenase-2 inhibition, heme oxygenase-1 induction, and histone deacetylation inhibition. [JOURNAL ARTICLE]
- J Gastroenterol Hepatol 2014 Dec.:80-92.
Nonsteroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, are associated with gastric mucosal damages including ulcer directly or indirectly. This study was aimed to document the preventive effects of an organosulfur constituent of garlic, S-allyl cysteine (SAC), against NSAIDs-induced gastric damages, as well the elucidation of its pharmacological actions, such as anti-inflammatory, anti-oxidative, and cytoprotective actions.Different doses of SAC were administrated intragastrically before the indomethacin administration. After killing, in addition to gross and pathological evaluations of ulcer, the expressions of inflammatory mediators, including cyclooxygenase-2, prostaglandin E2 , IL-1β, tumor necrosis factor-α, IL-6, and anti-oxidant capacity, were analyzed by Western blot analysis or ELISA, respectively. Transferase deoxytidyl uridine end labeling assay, periodic acid and Schiff staining, F4/80 staining, and CD31 staining were compared among doses of SAC. Detailed documentation of in vitro biological actions of SAC, including NF-κB, histone deacetylator inhibition, phase 2 enzyme, and MAPKs, was performed.SAC was very effective in preventing indomethacin-induced gastric damages in a low dose through significant decreases in macrophage infiltration as well as restorative action. Indomethacin-induced expressions of inflammatory mediators were all significantly attenuated with SAC in accordance with histone deacetylator inhibition. In addition, SAC significantly increased the total anti-oxidant concentration and mucus secretion, and allows for a significant induction of HO-1. However, these preventive effects of SAC were dependent on dosage of SAC; higher dose above 10 μM paradoxically aggravated NSAID-induced inflammation.Synthetic SAC can be promising therapeutics agent to provide potent anti-inflammatory, anti-oxidative, and mucosa protective effects against NSAID-induced damages.
- Initial clinical trial of a novel hemostat, TDM-621, in the endoscopic treatments of the gastric tumors. [JOURNAL ARTICLE]
- J Gastroenterol Hepatol 2014 Dec.:77-79.
The feasibility of TDM-621, the synthetic infectious agent-free peptides, was tested in hemostasis of the bleeding after endoscopic treatments of the gastric tumors.The patients who underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) were enrolled in the present study. The subject of hemostasis was the oozing after the EMR or ESD. The hemostatic effect, the secondary hemorrhage from one postoperative day to the day before discharge and operability were studied.The hemostatic effects were assessed in 12 patients. It was "remarkably effective" in 11 patients and "effective" in 1 patient. The operability was "very easy" in two patients, "easy" in eight patients and "acceptable" in two patients. No secondary hemorrhage was observed in all of 12 patients. No adverse effect considered to be related to TDM-621 was observed.It was shown that hemostasis using TDM-621 was feasible after endoscopic treatments of the gastric tumors without any technical trouble or adverse event.
- Acetic acid induces cell death: An in vitro study using normal rat gastric mucosal cell line and rat and human gastric cancer and mesothelioma cell lines. [JOURNAL ARTICLE]
- J Gastroenterol Hepatol 2014 Dec.:65-69.
We recently reported that topical application of acetic acid promptly caused tumor necrosis in a mouse model of gastric cancer. The aim of the present study was to examine whether acetic acid can directly induce cancer cell death.Rat gastric epithelial cell line (RGM-1), rat gastric carcinoma cell line (RGK-1), human gastric cancer cell line (KATO III), and human mesothelioma cell lines (ACC-MESO1 and MSTO-211H) were used. Acetic acid was added into the cell culture at different concentrations for different time periods. Cell death was analyzed by MTT assay, flow cytometry, and trypan blue exclusion test.Acetic acid promptly induced the cell death of RGM-1, RGK-1 cells, and KATO III cells in a concentration-dependent manner from 0.01% to 0.5%. Acetic acid at 0.5% for 1 min induced the cell death by 80%. RGK-1 cells were more sensitive to acetic acid than RGM-l cells. KATO III cells were more sensitive to acetic acid than RGK-1 cells. Acetic acid at 0.5% for 10 min induced almost complete cell death of ACC-MESO1 and MSTO-211H.Acetic acid is a powerful anticancer agent. Topical application of acetic acid may be a feasible approach for the treatments of gastric cancer and possibly other malignancies.
- Monitoring bypassing agent therapy - a prospective crossover study comparing thromboelastometry and thrombin generation assay. [JOURNAL ARTICLE]
- Haemophilia 2014 Dec 18.
The aim of this study was to evaluate the capability of thromboelastometry (ROTEM) and thrombin generation assay (TGA) to monitor the treatment response of bypassing agent (BPA) therapy and to study whether one method is superior to another. In a prospective crossover study haemophilia A patients with high titre inhibitors were included to receive a dose of 75 U kg(-1) activated prothrombin complex concentrates (aPCC) intravenously. Blood sampling was performed at baseline, 15, 30 min, 1, 2, 3 and 4 h post-infusion for TGA and ROTEM analysis. After a washout period of 14 days the subjects received recombinant FVIIa (rFVIIa) at a dose of 90 μg kg(-1) and similar blood sampling was performed. Healthy subjects were used as controls. Six haemophilia A patients with inhibitors were included. We found that TGA parameters endogenous thrombin potential (ETP) and peak thrombin increased 2-3 folds from baseline 15-30 min after infusion. ROTEM parameters MaxVel and maximum clot firmness increased to a level comparable to that of healthy controls. An individual difference in response was observed for different parameters among participants. ETP and peak thrombin were almost two-fold greater following aPCC infusion compared to rFVIIa, whereas ROTEM parameters showed no difference in response between the two products. The study showed that ROTEM and TGA have a great potential to evaluate the effect of BPA in haemophilia patients with inhibitors. TGA seemed to be more sensitive than ROTEM in reflecting the difference in treatment response between aPCC and rFVIIa. Additional prospective clinical studies are needed to clarify which assay and what parameters are clinically predictive.
- WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory properties via MKP-1 in lipopolysaccharide-stimulated RAW264.7 macrophages. [JOURNAL ARTICLE]
- Br J Pharmacol 2014 Dec 17.
Hydroxamate derivatives have been attracted considerable attention, due to their broad pharmacological properties. Recent studies reported their potential use in the treatment of cardiovascular diseases, arthritis or infectious diseases. However, the inhibitory mechanisms of hydroxamate derivatives in inflammation remain to be elucidated. In an effort to develop a novel pharmacological agent that could suppress abnormally activated macrophages, we investigated a novel aliphatic hydroxamate derivative, WMJ-S-001, and explored its anti-inflammatory mechanisms.RAW264.7 macrophages were exposed to lipopolysaccharide (LPS) in the absence or presence of WMJ-S-001. COX-2 expression and signaling molecules activated by LPS were assessed.The LPS-induced COX-2 expression was suppressed by WMJ-S-001. WMJ-S-001 inhibited p38MAPK, NF-κB subunit p65 and C/EBPβ phosphorylation in cells exposed to LPS. Treatment of cells with a p38MAPK inhibitor (p38MAPK inhibitor III) markedly inhibited LPS-induced p65 and C/EBPβ phosphorylation and COX-2 expression. LPS-increased p65 and C/EBPβ binding to the COX-2 promoter region was suppressed in the presence of WMJ-S-001. In addition, WMJ-S-001 suppression of p38MAPK, p65 and C/EBPβ phosphorylation, and subsequent COX-2 expression were restored in cells transfected with mitogen-activated protein kinase phosphatase-1 (MKP-1) dominant negative (DN) mutant. WMJ-S-001 also caused an increase in MKP-1 phosphatase activity in RAW264.7 macrophages.WMJ-S-001 may cause MKP-1 activation to dephosphorylate p38MAPK, resulting in the decrease in p65 and C/EBPβ binding to the COX-2 promoter region and COX-2 down-regulation in LPS-stimulated RAW264.7 macrophages. The present study suggests that WMJ-S-001 may be a potential drug candidate in alleviating LPS-associated inflammatory diseases.
- The therapeutic potential of a novel non-ATP-competitive fibroblast growth factor receptor 1 inhibitor on gastric cancer. [JOURNAL ARTICLE]
- Anticancer Drugs 2014 Dec 17.
Previous studies showed that fibroblast growth factor receptor 1 (FGFR1) is an attractive target in gastric cancer therapy. In the current study, we aimed to investigate whether the compound L6123, a novel non-ATP-competitive FGFR1 inhibitor, could show better antitumor activity than the leading compound, nordihydroguaiaretic acid (NDGA), in FGFR1-overexpressing gastric cancer cells. Using an MTT assay, we investigated the inhibitory effect of L6123 on the viability of three gastric cancer cells (MGC-803, SGC-7901, and BGC-823) overexpressing FGFR1, wild-type mouse embryonic fibroblast (MEF), and MEF expressing FGFR1, FGFR2, and FRS2α gene knockout (MEF). We studied the antitumor mechanism of L6123 against the gastric cancer cell line SGC-7901 by western blot analysis. The antitumor effects of L6123 on the gastric cancer cell line SGC-7901 were detected by flow cytometry, Hoechst staining, western blot analysis, and Transwell invasion assay. L6123 had lower IC50 in all three gastric cancer cells than NDGA and showed better inhibitory activity against MEF cells than against MEF cells. In the SGC-7901 gastric cell, L6123 inhibited the FGF2-induced phosphorylation of FGFR1/FRS2α/ERK1/2 in a dose-dependent manner, induced the activation of the apoptosis-related proteins, cleaved-PARP and cleaved-caspase-3, decreased the expression of pro-caspase-3 and Bcl-2, and induced tumor cell apoptosis. L6123 also dose-dependently reduced cell invasion ability, and showed better activity than NDGA at the same concentration. A novel non-ATP-competitive inhibitor L6123 showed excellent antigastric cancer activity by inhibiting the FGFR1 signaling pathway. Thus, we discovered a potential agent for the treatment of FGFR1-overexpressing gastric cancer.