SRT1720 inhibits bladder cancer cell progression by impairing autophagic flux.

Bladder cancer (BC) is the most common cancer of the urinary tract, with poor survival, high recurrence rates, and lacking of targeted drugs. In this study, we constructed a library to screen compounds inhibiting bladder cancer cells growth. Among them, SRT1720 was identified to inhibit bladder cancer cell proliferation in vitro and in vivo. SRT1720 treatment also suppressed bladder cancer cells migration, invasion and induced apoptosis. Mechanism studies shown that SRT1720 promoted autophagosomes accumulation by inducing early-stage autophagy but disturbed the late-stage of autophagy by blocking fusion of autophagosomes and lysosomes. SRT1720 appears to induce autophagy related proteins expression and alter autophagy-related proteins acetylation to impede the autophagy flux. LAMP2, an important lysosomal associated membrane protein, may mediate SRT1720-inhibited autophagy flux as SRT1720 treatment significantly deacetylated LAMP2 which may influence its activity. Taken together, our results demonstrated that SRT1720 mediated apoptosis and autophagy flux inhibition may be a novel therapeutic strategy for bladder cancer treatment.

Time trend of pancreatic cancer mortality in the Western Pacific Region: age-period-cohort analysis from 1990 to 2019 and forecasting for 2044.

BACKGROUND: Pancreatic cancer poses a serious medical problem worldwide. Countries in the Western Pacific Region are facing public health challenges from cancer. This study assesses the time trends of pancreatic cancer mortality in the Western Pacific Region from 1990 to 2019 and predicts its trend to 2044. METHODS: Mortality data were obtained from the Global Health Data Exchange. We used an age-period-cohort model to estimate age, period and birth cohort effects on pancreatic cancer mortality from 1990 to 2019 by calculating net drift, local drift, age-specific rate, period rate ratio, and cohort rate ratio. We also predict pancreatic cancer mortality to 2044 in Western Pacific countries. RESULTS: Overall, there were 178,276 (95% uncertain interval: 157,771 to 198,636) pancreatic cancer deaths in the Western Pacific Region in 2019, accounting for 33.6% of all deaths due to pancreatic cancer worldwide. There were significant increases in pancreatic cancer disability-adjusted life years between 1990 and 2019 in the Western Pacific Region, mainly due to population growth and aging. Pancreatic cancer mortality increased with age. The period effect showed an increasing trend of mortality for both sexes over the study period. Compared to the reference period (2000 to 2004), the rate ratio was elevated in both males and females in the period of 2015 to 2019. There was an overall increasing rate ratio from early birth cohorts to recent cohorts. Deaths may continue to increase in the next 25 years in the ten countries, while most countries have seen their age-standardized rate forecasts fall. CONCLUSION: The mortality of pancreatic cancer is still high in the Western Pacific Region. Countries/territories should focus on pancreatic cancer prevention and early cancer screening in high-risk populations. Specific public health methods and policies aimed at reducing risk factors for pancreatic cancer are also needed.

Age-period-cohort analysis of pancreatitis epidemiological trends from 1990 to 2019 and forecasts for 2044: a systematic analysis from the Global Burden of Disease Study 2019.

Objective: Pancreatitis poses a serious medical problem worldwide. This study aims to explore the epidemiological trends of pancreatitis from 1990 to 2019, analyze the association between disease burden and age, period and birth cohort, and subsequently present a forecast of pancreatitis incidence and deaths. Methods: Epidemiologic data were gathered from the Global Health Data Exchange query tool. Joinpoint regression model was used to calculate the average annual percentage changes (AAPCs). Age-period-cohort analysis was utilized to estimate the independent effects of age, period and birth cohort. We also predicted the global epidemiological trends to 2044. Results: Globally, the incident cases and deaths of pancreatitis increased 1.63-and 1.65-fold from 1990 to 2019, respectively. Joinpoint regression analysis showed that the age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR) decreased over the past three decades. The age effect indicates that older people have higher age-specific incidence and death rates. The period effect on incidence and deaths showed downward trends from 1990 to 2019. The cohort effect demonstrated that incidence and death risk peaked in the earlier birth cohort and were lower in the latest birth cohort. Incident cases and deaths of pancreatitis may significantly increase in the next 25 years. The ASIRs were predicted to slightly increase, while the ASDRs were predicted to decrease. Conclusion: Epidemiologic patterns and trends of pancreatitis across age, period and birth cohort may provide novel insight into public health. Limitations of alcohol use and prevention strategies for pancreatitis are necessary to reduce future burden.

The Global, Regional and National Burden of Pancreatic Cancer Attributable to Smoking, 1990 to 2019: A Systematic Analysis from the Global Burden of Disease Study 2019.

OBJECTIVE: Pancreatic cancer poses a serious medical problem worldwide. Studies have reported the relationship between smoking and cancer. This study aimed to evaluate the burden of pancreatic cancer attributable to smoking and its global, regional and national trends, patterns and alterations from 1990 to 2019. METHODS: Data were extracted from the Global Health Data Exchange query tool, including deaths, disability-adjusted life-years (DALYs) and age-standardized rates (ASRs). Measures were stratified by sex, age, region, country/territory and sociodemographic index (SDI). We used Joinpoint regression to determine the secular trend of ASRs by calculating the average annual percentage change (AAPC). RESULTS: In 2019, smoking risk-related deaths and DALYs accounted for 21.3% and 21.1% of global pancreatic cancer, respectively. There were 113,384 (95% UI 98,830 to 128,466) deaths of smoking-attributable pancreatic cancer worldwide in 2019, of which 64.1% were in males. The disease burden was higher in males than in females. High-income regions or large population regions had the higher disease burden. East Asia carried the highest number of smoking-attributable pancreatic cancer deaths and DALYs. The Caribbean had the fastest increasing rate (AAPC = 3.849, 95% CI 3.310 to 4.391) of age-standardized death rate over the past 30 years. In 2019, China had the highest number of deaths, which was followed by the USA and Japan. There was a trend of increasing ASDR along with increases in SDI. CONCLUSION: Variations existed in the smoking risk-related pancreatic cancer burden among different sexes, age groups, regions and countries/territories. The burden of smoking-attributable pancreatic cancer should be considered an important health issue. Future strategies should include comprehensive policies to control tobacco use.

Neutrophils in pancreatic cancer: Potential therapeutic targets.

Pancreatic cancer is a digestive system malignancy and poses a high mortality worldwide. Traditionally, neutrophils have been thought to play a role in acute inflammation. In contrast, their importance during tumor diseases has been less well studied. Generally, neutrophils are recruited into the tumor microenvironment and exert inflammation and tumor-promoting effects. As an essential part of the tumor microenvironment, neutrophils play diverse roles in pancreatic cancer, such as angiogenesis, progression, metastasis and immunosuppression. Additionally, neutrophils can be a new potential therapeutic target in cancer. Inhibitors of cytokines, chemokines and neutrophil extracellular traps can exert antitumor effects. In this review, we describe the role of neutrophils in the development and progression of pancreatic cancer, discuss their potential as therapeutic targets, and aim to provide ideas for improving the prognosis of patients with this malignant tumor disease.

Clinical outcomes of patients with hepatic insufficiency undergoing transcatheter aortic valve implantation: a systematic review and meta-analysis.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is currently a common treatment in high-risk aortic stenosis patients, but the impact of hepatic insufficiency on prognosis after TAVI is debatable and whether TAVI is superior to surgical aortic valve replacement (SAVR) in patients with hepatic insufficiency is uncertain. OBJECTIVE: To investigate the effect of abnormal liver function on the outcome and safety after TAVI and whether TAVI is superior to SAVR in patients with hepatic insufficiency. METHODS: PubMed, Embase, the Cochrane Library and Web of Science were systematically searched from inception up to 26 November 2021. Studies were eligible if mortality and complications after TAVI in patients with and without hepatic insufficiency, or mortality and complications for TAVI versus SAVR in patients with hepatic insufficiency were reported. The Newcastle-Ottawa scale (NOS) was used to evaluate the quality of each study. This meta-analysis was registered with PROSPERO (CRD42021253423) and was carried out by using RevMan 5.3 and Stata 14.0. RESULTS: This meta-analysis of 21 studies assessed a total of 222,694 patients. Hepatic insufficiency was associated with higher short-term (in-hospital or 30-day) mortality [OR = 1.62, 95% CI (1.18 to 2.21), P = 0.003] and 1-2 years mortality [HR = 1.64, 95% CI (1.42 to 1.89), P < 0.00001] after TAVI. Between TAVI and SAVR in patients with hepatic insufficiency, there was a statistically significant difference in in-hospital mortality [OR = 0.46, 95% CI (0.27 to 0.81), P = 0.007], the occurrence rate of blood transfusions [OR = 0.29, 95% CI (0.22 to 0.38), P < 0.00001] and the occurrence rate of acute kidney injury [OR = 0.55, 95% CI (0.33 to 0.91), P = 0.02]. CONCLUSIONS: TAVI patients with hepatic insufficiency may have negative impact both on short-term (in-hospital or 30-day) and 1-2-years mortality. For patients with hepatic insufficiency, TAVI could be a better option than SAVR.