Hepatocyte death results in a sterile inflammatory response that amplifies the initial insult and increases overall tissue injury. One important example of this type of injury is acetaminophen-induced liver injury, in which the initial toxic injury is followed by innate immune activation. Using mice deficient in Tlr9 and the inflammasome components Nalp3 (NACHT, LRR, and pyrin domain-containing protein 3), ASC (apoptosis-associated specklike protein containing a CARD), and caspase-1, we have identified a nonredundant role for Tlr9 and the Nalp3 inflammasome in acetaminophen-induced liver injury. We have shown that acetaminophen treatment results in hepatocyte death and that free DNA released from apoptotic hepatocytes activates Tlr9. This triggers a signaling cascade that increases transcription of the genes encoding pro-IL-1β and pro-IL-18 in sinusoidal endothelial cells. By activating caspase-1, the enzyme responsible for generating mature IL-1β and IL-18 from pro-IL-1β and pro-IL-18, respectively, the Nalp3 inflammasome plays a crucial role in the second step of proinflammatory cytokine activation following acetaminophen-induced liver injury. Tlr9 antagonists and aspirin reduced mortality from acetaminophen hepatotoxicity. The protective effect of aspirin on acetaminophen-induced liver injury was due to downregulation of proinflammatory cytokines, rather than inhibition of platelet degranulation or COX-1 inhibition. In summary, we have identified a 2-signal requirement (Tlr9 and the Nalp3 inflammasome) for acetaminophen-induced hepatotoxicity and some potential therapeutic approaches.

Background Worldwide, both the incidence and death rates of pancreatic cancer are increasing. Evaluation of pancreatic cancer burden and its global, regional, and national patterns is crucial to policy making and better resource allocation for controlling pancreatic cancer risk factors, developing early detection methods, and providing faster and more effective treatments. Methods Vital registration, vital registration sample, and cancer registry data were used to generate mortality, incidence, and disability-adjusted life-years (DALYs) estimates. We used the comparative risk assessment framework to estimate the proportion of deaths attributable to risk factors for pancreatic cancer: smoking, high fasting plasma glucose, and high body-mass index. All of the estimates were reported as counts and age-standardised rates per 100 000 person-years. 95% uncertainty intervals (UIs) were reported for all estimates. Findings In 2017, there were 448 000 (95% UI 439 000-456 000) incident cases of pancreatic cancer globally, of which 232 000 (210 000-221 000; 51•9%) were in males. The age-standardised incidence rate was 5•0 (4•9-5•1) per 100 000 person-years in 1990 and increased to 5•7 (5•6-5•8) per 100 000 person-years in 2017. There was a 2•3 times increase in number of deaths for both sexes from 196 000 (193 000-200 000) in 1990 to 441 000 (433 000-449 000) in 2017. There was a 2•1 times increase in DALYs due to pancreatic cancer, increasing from 4•4 million (4•3-4•5) in 1990 to 9•1 million (8•9-9•3) in 2017. The age-standardised death rate of pancreatic cancer was highest in the highincome super-region across all years from 1990 to 2017. In 2017, the highest age-standardised death rates were observed in Greenland (17•4 [15•8-19•0] per 100 000 person-years) and Uruguay (12•1 [10•9-13•5] per 100 000 personyears). These countries also had the highest age-standardised death rates in 1990. Bangladesh (1•9 [1•5-2•3] per 100 000 person-years) had the lowest rate in 2017, and São Tomé and Príncipe (1•3 [1•1-1•5] per 100 000 personyears) had the lowest rate in 1990. The numbers of incident cases and deaths peaked at the ages of 65-69 years for males and at 75-79 years for females. Age-standardised pancreatic cancer deaths worldwide were primarily attributable to smoking (21•1% [18•8-23•7]), high fasting plasma glucose (8•9% [2•1-19•4]), and high body-mass index (6•2% [2•5-11•4]) in 2017. Interpretation Globally, the number of deaths, incident cases, and DALYs caused by pancreatic cancer has more than doubled from 1990 to 2017. The increase in incidence of pancreatic cancer is likely to continue as the population ages. Prevention strategies should focus on modifiable risk factors. Development of screening programmes for early detection and more effective treatment strategies for pancreatic cancer are needed. Funding Bill & Melinda Gates Foundation.

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Based on this randomized controlled trial, autologous bone marrow MSC transplantation through peripheral vein probably has no beneficial effect in cirrhotic patients. Further studies with higher number of patients are warranted to better clarify the impact of MSC infusion through peripheral vein or portal vein in cirrhosis.