Pitavastatin and metformin synergistically activate apoptosis and autophagy in pancreatic cancer cells.

Pancreatic cancer is the seventh leading cause of cancer-related deaths globally. Metformin is the standard first-line of treatment for hyperglycemia in Type 2 diabetes, whereas pitavastatin is a cholesterol-lowering drug used to prevent cardiovascular diseases. Both these agents evidently exert anticancer effects on pancreatic cancer; however, it remains unclear whether cotreatment using them has additive or synergistic anticancer effects on pancreatic cancer. Thus, we herein used the ASPC-1 and PANC-1 cells and treated them with metformin and/or pitavastatin. We performed the cell viability assay, transwell migration assay, and cell cycle analysis using flow cytometry. Western blotting was used to determine protein levels. We found that cotreatment with metformin (30 mM) and pitavastatin (10 µM) significantly reduced cell viability; caused G0/G1 cell cycle arrest; upregulated the expression levels of Bax, PCNA, cleaved PARP-1, cleaved caspase-3, LC3 II, and p27 Kip1 /p21Cip1 ; and inhibited cell migration. The combination index value for cell viability indicated a synergistic interaction between metformin and pitavastatin. Moreover, cotreating the cells with metformin (30 mM) and pitavastatin (10 µM) could preserve mitochondrial function, activate AMPK, and inhibit PI3K/mTOR than treatment with metformin or pitavastatin alone. These findings clearly indicated that metformin plus pitavastatin had a synergistic anticancer effect on pancreatic cancer cells, potentially caused due to the activation of AMPK and inhibition of PI3K/mTOR signaling. Altogether, our results provide that use of metformin plus pitavastatin maybe serve as a chemotherapeutic agent for human pancreatic cancer in future.

Synergistic Anticancer Effects of Gemcitabine with Pitavastatin on Pancreatic Cancer Cell Line MIA PaCa-2 in vitro and in vivo.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with an overall 5-year survival rate of 9.3%, and this malignancy is expected to become the second leading cause of cancer-related death by 2030. Gemcitabine resistance develops within weeks of PDAC patient's chemotherapeutic initiation. Statins, including pitavastatin, have been indicated to have anticancer effects in numerous human cancer cell lines. Thus, in this study, we hypothesized that a combination of gemcitabine and pitavastatin may have a greater anticancer effect than gemcitabine alone on the human pancreatic carcinoma cell line MIA PaCa-2. METHODS: The anticancer effects of gemcitabine with pitavastatin were evaluated using human MIA PaCa-2 cell line in vitro and in vivo Balb/c murine xenograft tumor model. Cell viability was assessed with CCK-8, and cell migration was stained by crystal violet. Cell cycle distribution, apoptosis and mitochondrial membrane potential were examined by flow cytometry. Activation of drug transporters (hENTs, hCNTs), intracellular drug activating (dCK) and inhibition of inactivating enzymes (RRMs) pathways were assessed by Western blotting analysis. Molecular mechanisms and signaling pathways of apoptosis, necrosis and autophagy also were assessed by Western blotting. RESULTS: We observed that gemcitabine and pitavastatin synergistically suppressed the proliferation of MIA PaCa-2 cells through causing sub-G1 and S phase cell cycle arrest. Activation of apoptosis/necrosis was confirmed by annexin V/propidium iodide double staining, which showed increasing levels of active caspase 3, cleaved poly(ADP-ribose) polymerase and the RIP1-RIP3-MLKL complex. Moreover, gemcitabine-pitavastatin-mediated S phase arrest downregulated cyclin A2/CDK2 and upregulated p21/p27 in MIA PaCa-2 cells. Furthermore, this combination improved drug cellular metabolism pathway, mitochondria function and activated autophagy as part of the cell death mechanism. In vivo, gemcitabine-pitavastatin effectively inhibited tumor growth in a nude mouse mode of Mia PaCa-2 xenografts without observed adverse effect. CONCLUSION: Combined gemcitabine-pitavastatin may be an effective novel treatment option for pancreatic cancer.

Increased Risk of Polycystic Ovary Syndrome and It's Comorbidities in Women with Autoimmune Thyroid Disease.

OBJECTIVE: To investigate the prevalence of polycystic ovary syndrome (PCOS) and its comorbidities in patients with autoimmune thyroid disease (AITD). POPULATION: In this cohort study, patients newly diagnosed as having Hashimoto thyroiditis (HT) or Grave disease (GD) were recruited into the AITD group. METHOD: The logistic regression model was used to investigate the association between exposure, endpoint, later diseases and treatment. MAIN OUTCOME MEASURES: We assessed the cumulative incidence using the Kaplan-Meier method and verified the difference by the log-rank test. RESULTS: The AITD group included 3599 GD patients and 1332 HT patients. PCOS risk in patients with AITD was higher than that in the control group (adjusted hazard ratio = 1.39; 95% confidence interval = 1.07-1.71). In patients with both AITD and PCOS, the odds ratios of diabetes, hyperlipidemia and coronary artery disease were 2.48, 2.05 and 2.63, respectively. CONCLUSIONS: The risks of PCOS and its comorbidities such as diabetes, dyslipidemia and cardiac artery disease are high in patients with AITD in Taiwan.

Graves' disease could increase polycystic ovary syndrome and comorbidities in Taiwan.

Background: To investigate the association between Graves' disease (GD) and polycystic ovary syndrome (PCOS) and its comorbidities.Methods: Logistic regression was performed to determine the association between the two conditions. Cumulative incidence curves were obtained using the Kaplan-Meier method and log-rank test. Hazard ratios were determined using the Cox proportional hazards regression model.Results: We included 5399 patients with GD as the study group and 10,798 patients without GD as the control group. The cumulative incidence curve of PCOS in patients with GD was significantly higher than that in patients without GD (p = .02). The adjusted hazard ratio for PCOS in patients with GD compared with patients without GD was 1.47 (95%CI = 1.09-1.98). The adjusted odds ratio of hyperlipidemia in patients with GD and PCOS was 2.18 (95%CI = 1.14-4.17) higher than that in patients with GD only.Conclusion: Our study demonstrated that women with GD could be at risk of developing PCOS; additionally, a higher incidence of comorbidities, including hyperlipidemia, was noted in women with GD and PCOS.

Fasting plasma glucose variability is an independent risk factor for diabetic retinopathy and diabetic macular oedema in type 2 diabetes: An 8-year prospective cohort study.

IMPORTANCE: Long-term stability in plasma glucose may affect the development of diabetic retinopathy (DR) and diabetic macular oedema (DMO). BACKGROUND: To investigate the associations between glycaemic variability and the development of DR and DMO in type 2 diabetes (T2D). DESIGN: An 8-year prospective cohort study. PARTICIPANTS: 2005 patients with T2D. METHODS: DR and DMO were detected with non-mydriatic fundus photography. MAIN OUTCOME MEASURES: The visit-to-visit variability of fasting glucose or HbA1c was calculated as the standard deviation (SD) or coefficient of variation (CV = SD/mean) of all records during the follow-up periods or before the onset of the targeted event. Cox regression analysis was used to evaluate the hazard ratios (HRs) for new-onset DR, proliferative diabetic retinopathy (PDR), and DMO. RESULTS: After adjusting for the baseline and mean follow-up values, the SD and CV of fasting glucose during the follow-up periods were both correlated with the development of PDR (SD: HR = 1.011, P = .005; CV: HR = 6.858, P < .001), and DMO (SD: HR = 1.008, P = .038; CV: HR = 4.027, P = .017). As for HbA1c, neither the SD nor CV was correlated with the development of DR, PDR, or DMO (P > .05 for all). CONCLUSIONS AND RELEVANCE: High visit-to-visit fasting glucose variability was associated with new-onset PDR and DMO, independent of baseline and mean follow-up fasting glucose and HbA1c in T2D. Long-term stability in plasma glucose is important for reducing the risk of the development and progression for DR and DMO.

Effect of diabetes mellitus on risk of latent TB infection in a high TB incidence area: a community-based study in Taiwan.

OBJECTIVE: To investigate the association between diabetes and latent tuberculosis infections (LTBI) in high TB incidence areas. DESIGN: Community-based comparison study. SETTING: Outpatient diabetes clinics at 4 hospitals and 13 health centres in urban and rural townships. A community-based screening programme was used to recruit non-diabetic participants. PARTICIPANTS: A total of 2948 patients with diabetes aged older than 40 years were recruited, and 453 non-diabetic participants from the community were enrolled. PRIMARY AND SECONDARY OUTCOME MEASURES: The interferon-gamma release assay (IGRA) and the tuberculin skin test were used to detect LTBI. The IGRA result was used as a surrogate of LTBI in logistic regression analysis. RESULTS: Diabetes was significantly associated with LTBI (adjusted OR (aOR)=1.59; 95% CI 1.11 to 2.28) and age correlated positively with LTBI. Many subjects with diabetes also had additional risk factors (current smokers (aOR=1.28; 95% CI 0.95 to 1.71), comorbid chronic kidney disease (aOR=1.26; 95% CI 1.03 to 1.55) and history of TB (aOR=2.08; 95% CI 1.19 to 3.63)). The presence of BCG scar was protective (aOR=0.66; 95% CI 0.51 to 0.85). Duration of diabetes and poor glycaemic control were unrelated to the risk of LTBI. CONCLUSION: There was a moderately increased risk of LTBI in patients with diabetes from this high TB incidence area. This finding suggests LTBI screening for the diabetics be combined with other risk factors and comorbidities of TB to better identify high-risk groups and improve the efficacy of targeted screening for LTBI.

Enhancing the Anticancer Activity of Antrodia cinnamomea in Hepatocellular Carcinoma Cells via Cocultivation With Ginger: The Impact on Cancer Cell Survival Pathways.

Antrodia cinnamomea (AC) is a medicinal fungal species that has been widely used traditionally in Taiwan for the treatment of diverse health-related conditions including cancer. It possesses potent anti-inflammatory and antioxidant properties in addition to its ability to promote cancer cell death in several human tumors. Our aim was to improve the anticancer activity of AC in hepatocellular carcinoma (HCC) through its cocultivation with ginger aiming at tuning the active ingredients. HCC cell lines, Huh-7 and HepG2 were used to study the in vitro anticancer activity of the ethanolic extracts of AC (EAC) alone or after the cocultivation in presence of ginger (EACG). The results indicated that the cocultivation of AC with ginger significantly induced the production of important triterpenoids and EACG was significantly more potent than EAC in targeting HCC cell lines. EACG effectively inhibited cancer cells growth via the induction of cell cycle arrest at G2/M phase and induction of apoptosis in Huh-7 and HepG2 cells as indicated by MTT assay, cell cycle analysis, Annexin V assay, and the activation of caspase-3. In addition, EACG modulated cyclin proteins expression and mitogen-activated protein kinase (MAPK) signaling pathways in favor of the inhibition of cancer cell survival. Taken together, the current study highlights an evidence that EACG is superior to EAC in targeting cancer cell survival and inducing apoptotic cell death in HCC. These findings support that EACG formula can serve as a potential candidate for HCC adjuvant therapy.

Therapeutic Potential of Sclareol in Experimental Models of Rheumatoid Arthritis.

Previous studies have shown that the natural diterpene compound, sclareol, potentially inhibits inflammation, but it has not yet been determined whether sclareol can alleviate inflammation associated with rheumatoid arthritis (RA). Here, we utilized human synovial cell line, SW982, and an experimental murine model of rheumatoid arthritis, collagen-induced arthritis (CIA), to evaluate the therapeutic effects of sclareol in RA. Arthritic DBA/1J mice were dosed with 5 and 10 mg/kg sclareol intraperitoneally every other day over 21 days. Arthritic severity was evaluated by levels of anti-collagen II (anti-CII) antibody, inflammatory cytokines, and histopathologic examination of knee joint tissues. Our results reveal that the serum anti-CII antibody, cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-17, as well as Th17 and Th1 cell population in inguinal lymph nodes, were significantly lower in sclareol-treated mice compared to the control group. Also, the sclareol treatment groups showed reduced swelling in the paws and lower histological arthritic scores, indicating that sclareol potentially mitigates collagen-induced arthritis. Furthermore, IL-1β-stimulated SW982 cells secreted less inflammatory cytokines (TNF-α and IL-6), which is associated with the downregulation of p38-mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and NF-κB pathways. Overall, we demonstrate that sclareol could relieve arthritic severities by modulating excessive inflammation and our study merits the pharmaceutical development of sclareol as a therapeutic treatment for inflammation associated with RA.

Association of Abnormal Renal Profiles and Proliferative Diabetic Retinopathy and Diabetic Macular Edema in an Asian Population With Type 2 Diabetes.

Importance: The comorbidity of chronic kidney disease and diabetic retinopathy (DR) is well known. However, to our knowledge, no cohort study has demonstrated the effect of chronic kidney disease on the development or progression of DR. Objective: To investigate the association of chronic kidney disease with the development of DR and diabetic macular edema (DME) in type 2 diabetes. Design, Setting, and Participants: This 8-year prospective cohort study that was conducted in 2 medical centers in Taiwan included 2135 patients with type 2 diabetes. Exposures: The baseline and mean follow-up renal profiles including serum creatinine level, estimated glomerular filtration rate (eGFR), and urinary albumin/creatinine ratio (ACR). Main Outcomes and Measures: Diabetic retinopathy and DME were detected with nonmydriatic fundus photography. Cox regression analyses was used to evaluate the hazard ratios (HRs) for the renal profiles of new-onset DR, proliferative DR, and DME. Results: The mean (SD) age of the study participants was 63.4 (11.9) years and 1025 (48%) were women. A higher serum creatinine level (HR of 2.358 for an increase of 1 mg/dL [to convert to micromoles per liter, multiply by 76.25]; 95% CI, 1.901-2.924; P < .001), an estimated glomerular filtration rate of less than 60 mL/min/1.73m2 (40-60: HR, 2.235; 95% CI, 1.351-4.035; P = .002; 30-45: HR, 2.625; 95% CI, 1.436-4.798; P = .002; <30: HR, 5.488; 95% CI, 2.739-10.993; P < .001), and a urinary albumin to creatinine ratio (ACR) of more than 30 mg/g (31-300: HR, 3.202; 95% CI, 2.029-5.053; P < .001; >300: HR, 6.652; 95% CI, 3.922-11.285; P < .001) at baseline were all associated with the development of proliferative DR. A baseline urinary ACR of more than 30 mg/g (31-300: HR, 1.563; 95% CI, 1.078-2.267; P = .02; >300: HR, 2.707; 95% CI, 1.640-4.470; -2.707; P < 0.001) was associated with the development of DME. After adjusting the baseline values, the mean follow-up renal profiles, including a higher serum creatinine level (HR, 2.369 per mg/dL; 95% CI, 1.704-3.293; P < .001), an estimated glomerular filtration rate of less than 30 mL/min/1.73m2 (HR, 4.215; 95% CI, 1.265-14.039; P = .02), and a urinary ACR of more than 30 mg/g (31-300: HR, 2.344; 95% CI, 1.200-4.503; P = .01; >300: HR, 4.193; 95% CI, 1.638-10.735; P = .003) were still correlated with new-onset PDR during the follow-up periods. Conclusions and Relevance: Abnormal renal profiles at baseline, including a high serum creatinine level, low estimated glomerular filtration rate, and high urinary ACR, were associated with the development of PDR in patients with type 2 diabetes. A high baseline urinary ACR was associated with DME. Abnormal mean follow-up renal profiles were still correlated with new-onset PDR after adjusting for baseline values. Aggressive treatment for chronic kidney disease may have a role in preventing the deterioration of DR.

Diabetes mellitus increased all-cause mortality rate among newly-diagnosed tuberculosis patients in an Asian population: A nationwide population-based study.

AIMS: To investigate the effect of diabetes mellitus (DM) on all-cause mortality among patients with newly-diagnosed tuberculosis (TB) in an Asian population. We also identified risk factors for mortality in these patients. METHODS: The data were obtained from the National Health Insurance Research Database and included 9831 newly-diagnosed TB individuals and 1627 TB mortality cases in the period of 2000-2010. The mortality data were divided into a DM group and a non-DM group. We measured the incidence density of mortality and identified the risk factors of mortality. RESULTS: The all-cause mortality of newly-diagnosed TB patients progressively increased with an average rate of 16.5% during 2000-2010. DM is an independent risk factor for all-cause mortality with HRs 1.17-1.27 by various models. TB patients with ages above 75years had the highest risk of mortality (HR=11.93) compared with those under 45 years. TB patients with heart failure, peripheral vascular disease, ischemic heart disease, cerebral vascular disease, hypertension, chronic kidney disease, pulmonary disease, liver disease, cancer, peptic ulcer disease, gout, and autoimmune disease had higher mortality compared to those without the aforementioned factors. CONCLUSIONS: The one-year all-cause mortality after TB diagnosis was high among TB patients in Taiwan and it tended to increase in the past decade. While treating these newly-diagnosed TB patients, it is crucial to detect the factors predisposing to death, such as old age, male gender, certain kinds of aforementioned factors and diabetes.

The Different Effects of Atorvastatin and Pravastatin on Cell Death and PARP Activity in Pancreatic NIT-1 Cells.

Statins have been widely used drugs for lowering low-density lipoprotein and for preventing heart attack and stroke. However, the increased risk for developing diabetes during extended stain use and the molecular mechanisms remain unclear. The objective of this study was to elucidate the signaling pathway and biological function between necrosis and autophagy induced by atorvastatin (AS) and pravastatin (PS). Here we observed that atorvastatin (AS) can increase intracellular reactive oxygen species (ROS) and induce necrotic cell death and autophagy in NIT-1 cells, whereas pravastatin (PS) does not cause ROS and cell death but also induces autophagy. PARP1 exhibited a dual role in modulating necrosis and autophagy in AS- and PS-treated NIT-1 cells through RIP1-RIP3-MLKL pathway and PARP1-AMPK-mTOR pathway. Lastly, AS treatment induced mitochondrial morphology injury significantly more than PS treatment did. Thus, the PARP1 activation should be considered in the development of effective statin therapies for diabetes. Future studies may examine specific mechanisms and pathways in mitochondria, autophagy, and oxidative stress in vivo.

Increased incidence of rheumatoid arthritis in multiple sclerosis: A nationwide cohort study.

Past studies have shown inconsistent results on whether there is an association between multiple sclerosis (MS) and rheumatoid arthritis. To investigate the possible relationship between the 2 autoimmune diseases, we performed a nationwide cohort study utilizing the National Health Insurance Research Database and the Registry of Catastrophic Illness.A total of 1456 newly diagnosed patients with MS and 10,362 control patients were matched for age, sex, and initial diagnosis date. Patients with MS had a higher incidence of rheumatoid arthritis (age-adjusted standardized incidence ratio: 1.72; 95% confidence interval = 1.01-2.91). There was a positive correlation in being diagnosed with rheumatoid arthritis in patients previously diagnosed with MS when stratified by sex and age. The strength of this association remained statistically significant after adjusting for sex, age, and smoking history (hazard ratio: 1.78, 95% confidence interval = 1.24-2.56, P = 0.002).In conclusion, this study demonstrates that a diagnosis of MS increased the likelihood of a subsequent diagnosis of rheumatoid arthritis in patients, independent of sex, age, and smoking history.

Allopurinol and the incidence of bladder cancer: a Taiwan national retrospective cohort study.

Our aim is to investigate the risk association between allopurinol use and cancer incidence among gout patients using clinical evidence. Newly diagnosed male patients with gout, 20 years or older, were included after excluding those who had a diagnosis of type 2 diabetes, and were followed up for 12 years in a retrospective cohort study of one million outpatients of a national database. The gout patients were matched to male controls by age and first diagnosis date of gout disease. We then estimated the risk associations between incident cancers and duration of allopurinol use by Cox hazard regression, age-adjusted standardized incidence ratio, and incidence per 1000 person-years. A total of 24 050 gout patients and 76 129 controls were included. The incidence of all-cause cancers for gout patients and controls was 8.26 cases and 7.49 cases/1000 person-years, respectively; it was markedly increased in gout patients who used allopurinol for over 90 days. The hazard ratio of all-cause cancers was 1.21 (95% confidence interval=1.03-1.42, P=0.019) after adjustment for age and 2.26 for bladder cancer (95% confidence interval=1.32-3.87, P=0.003) on comparing those who used allopurinol for over 90 days with nonusers. Meanwhile, other cancers did not show the same significant result. We concluded that those who used allopurinol for a long duration had a higher occurrence of both bladder cancer and all-cause cancers in clinical evidence.

Colchicine Significantly Reduces Incident Cancer in Gout Male Patients: A 12-Year Cohort Study.

Patients with gout are more likely to develop most cancers than subjects without gout. Colchicine has been used for the treatment and prevention of gouty arthritis and has been reported to have an anticancer effect in vitro. However, to date no study has evaluated the relationship between colchicine use and incident cancers in patients with gout. This study enrolled male patients with gout identified in Taiwan's National Health Insurance Database for the years 1998 to 2011. Each gout patient was matched with 4 male controls by age and by month and year of first diagnosis, and was followed up until 2011. The study excluded those who were diagnosed with diabetes or any type of cancer within the year following enrollment. We calculated hazard ratio (HR), aged-adjusted standardized incidence ratio, and incidence of 1000 person-years analyses to evaluate cancer risk. A total of 24,050 male patients with gout and 76,129 male nongout controls were included. Patients with gout had a higher rate of incident all-cause cancers than controls (6.68% vs 6.43%, P = 0.006). A total of 13,679 patients with gout were defined as having been ever-users of colchicine and 10,371 patients with gout were defined as being never-users of colchicine. Ever-users of colchicine had a significantly lower HR of incident all-cause cancers than never-users of colchicine after adjustment for age (HR = 0.85, 95% CI = 0.77-0.94; P = 0.001). In conclusion, colchicine use was associated with a decreased risk of incident all-cause cancers in male Taiwanese patients with gout.

Reduced incidence of Crohn's disease in systemic sclerosis: a nationwide population study.

BACKGROUND: To date, there has been no studies to evaluate the incidence of Crohn's disease in systemic sclerosis patients. The goals of this study were to evaluate the incidence of Crohn's disease and its relationship with sex and age in patients with systemic sclerosis. METHODS: We enrolled patients with systemic sclerosis and controls from Taiwan's Registry of Catastrophic Illness Database and National Health Insurance Research Database. Every systemic sclerosis patient was matched to at most three controls by sex, age, month and year of initial diagnosis of systemic sclerosis. The standardized incidence ratio (SIR) of Crohn's disease in systemic sclerosis patients, and 95% confidence interval (95% CI) were calculated. Cox hazard regression was used to calculate the hazard ratio (HR). RESULTS: The study enrolled 2,829 patients with systemic sclerosis and 8,257 controls. Male and female patients with systemic sclerosis both had lower rates of incident Crohn's disease (SIR: 0.18, 95% CI = 0.05-0.62; SIR: 0.10, 95% CI = 0.05-0.21, respectively). The risk of incident Crohn's disease in systemic sclerosis was still lower than in controls when we stratified the patients according to their ages. In Cox hazard regression, the hazard rates of Crohn's disease were lower in systemic sclerosis patients after adjusting for genders and ages (HR: 0.12, 95% CI = 0.06-0.21, p < 0.001). CONCLUSIONS: Systemic sclerosis is associated with decreased incidence of, irrespective of sex and age of the patients.

The Association Between Body Mass Index and All-Cause Mortality in Patients With Type 2 Diabetes Mellitus: A 5.5-Year Prospective Analysis.

Abundances of study in different population have noted that obese cardiovascular disease (CVD) patients have a better prognosis than leaner patients, which refer to the phenomenon of obesity paradox. However, data on the association between body mass index (BMI) and mortality among Asian patients are limited, especially in patients with type 2 diabetes mellitus (T2DM). We investigate the association between BMI and all-cause mortality in Taiwanese patients with T2DM to define the optimal body weight for health.We conducted a longitudinal cohort study of 2161 T2DM patients with a mean follow-up period of 66.7 ±â€Š7.5 months. Using Cox regression models, BMI was related to the risk of all-cause mortality after adjusting all confounding factors.A U-shaped association between BMI and all-cause mortality was observed among all participants. Those with BMIs <22.5 kg/m had a significantly elevated all-cause mortality as compared with those with BMIs 22.5 to 25.0 kg/m, (BMIs 17.5-20.0 kg/m: hazard ratio 1.989, P < 0.001; BMIs 20.0-22.5 kg/m: hazard ratio 1.286, P = 0.02), as did those with BMIs >30.0 kg/m (BMIs 30.0-32.5 kg/m: hazard ratio 1.670, P < 0.001; BMIs 32.5-35.0 kg/m: hazard ratio, 2.632, P < 0.001). This U-shaped association remained when we examined the data by sex, age, smoking, and kidney function.Our study found a U-shaped relationship between all-cause mortality and BMI in Asian patients with T2DM, irrespective of age, sex, smoking, and kidney function. BMI <30 kg/m should be regarded as a potentially important target in the weight management of T2DM.

17ß-estradiol inhibits mesenchymal stem cells-induced human AGS gastric cancer cell mobility via suppression of CCL5- Src/Cas/Paxillin signaling pathway.

Gender differences in terms of mortality among many solid organ malignancies have been proved by epidemiological data. Estrogen has been suspected to cast a protective effect against cancer because of the lower mortality of gastric cancer in females and the benefits of hormone replacement therapy (HRT) in gastric cancer. Hence, it suggests that 17ß-estradiol (E2) may affect the behavior of cancer cells. One of the key features of cancer-related mortality is metastasis. Accumulating evidences suggest that human bone marrow mesenchymal stem cells (HBMMSCs) and its secreted CCL-5 have a role in enhancing the metastatic potential of breast cancer cells. However, it is not clear whether E2 would affect HBMMSCs-induced mobility in gastric cancer cells. In this report, we show that CCL-5 secreted by HBMMSCs enhanced mobility in human AGS gastric cancer cells via activation of Src/Cas/Paxillin signaling pathway. Treatment with specific neutralizing antibody of CCL-5 significantly inhibited HBMMSCs-enhanced mobility in human AGS gastric cancer cells. We further observe that 17ß-estradiol suppressed HBMMSCs-enhanced mobility by down-regulating CCL5-Src/Cas/paxillin signaling pathway in AGS cells. Collectively, these results suggest that 17ß-estradiol treatment significantly inhibits HBMMSCS-induced mobility in human AGS gastric cancer cells.

Randomized controlled trials in bariatric surgery.

To fill a void in the literature, we performed a literature search and subsequently reviewed randomized controlled trials (RCTs) in the field of obesity surgery that were published over the past 40 years. All RCTs published in the English between January 1972 and December 2011 were identified through a literature search using the PubMed database. The following search terms were used: "bariatric surgery", "obesity surgery", and "weight reducing surgery". Studies of basic science and anesthesia-related pain management were excluded. The extracted trials were divided into four groups: comparisons of different interventions, intraoperative surgical techniques, preoperative evaluation, and postoperative care. The literature search produced 753 manuscripts, of which 168 met the eligibility criteria. Among 168 papers, 32 % compared different interventions, 48 % assessed intraoperative surgical techniques, 18 % assessed postoperative care, and the remaining 2 % assessed preoperative evaluation. The RCTs were published in 47 different journals, most commonly in Obesity Surgery (28.6 %) and the Annals of Surgery (11.9 %). Trials were conducted in 25 different countries, with the greatest contribution from the USA (35.1 %). There was a progressive increase in published trials from 1972 to 2011, with 119 RCTs (70.8 %) being published over the last decade. A trend for an increasing number of published RCTs in the field of bariatric surgery was observed over the recent years. Although data from large, adequately powered, long-term RCTs are still lacking, any surgical intervention appears to be more effective than medical care for the treatment of morbid obesity.

Maxillary brown tumor as initial presentation of parathyroid adenoma: a case report.

Brown tumor is a rare late-stage skeletal change caused by long-term stimulation of excess parathyroid hormone. It is not neoplastic, but a reparative cellular process. Common sites of brown tumor are the ribs, clavicle, long bones and pelvic girdle. Solitary maxillary brown tumor as initial presentation of primary hyperparathyroidism is rare; it is often accompanied by brown tumors of the other facial bones. Here, we present the first case of solitary maxillary brown tumor in a 29-year-old ethnic Chinese woman with initial presentation of a large tumor filling the left maxillary sinus. Underlying long-standing primary hyperparathyroidism caused by a large parathyroid adenoma was finally diagnosed. Brown tumor tends to be misdiagnosed as malignancy, and delayed diagnosis of the underlying hyperparathyroidism is common. Our case validates the suggestion that young women have a higher probability of brown tumor. Biopsy of the suspicious bone tumor and blood tests for calcium and parathyroid hormone level are crucial and essential to reach the correct diagnosis. Most brown tumors show spontaneous regression after parathyroidectomy. However, direct excision of the brown tumor may be indicated to avoid the risk of facial deformity and orbital compression at a special anatomical site, as in our case.

The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese.

OBJECTIVE: To investigate the association between type 2 diabetes, glucose-lowering therapies (monotherapy with either metformin, sulphonylurea or insulin) and cancer risk in Taiwan. METHODS: Using Taiwan's National Health Research Institutes database of 1,000,000 random subjects from 2000-2008, we found 61777 patients with type 2 diabetes (age ≥20 years) and 677378 enrollees with no record of diabetes. RESULTS: After adjusting for age and sex, we found patients with diabetes to have significantly higher risk of all cancers (OR: 1.176; 95% CI: 1.149-1.204, P < 0.001). Diabetic patients treated with insulin or sulfonylureas had significantly higher risk of all cancers, compared to those treated with metformin (OR: 1.583; 95% CI: 1.389-1.805, P < 0.001 and OR: 1.784; 95% CI: 1.406-2.262, P < 0.001). Metformin treatment was associated with a decreased risk of colon and liver cancer compared to sulphonylureas or insulin treatment. Sulfonylureas treatment was associated with an increased risk of breast and lung cancer compared to metformin therapy. CONCLUSIONS: Taiwanese with type 2 diabetes are at a high risk of breast, prostate, colon, lung, liver and pancreatic cancer. Those treated with insulin or sulfonylureas monotherapy are more likely to develop colon and liver cancer than those treated with metformin.