Regulatory T (T reg ) cells are essential for immune tolerance 1 but also drive immunosuppression in the tumour microenvironment (TME) 2 . Therapeutic targeting of T reg cells in cancer requires the identification of context-specific mechanisms for T reg cell function. Here we demonstrate that inhibition of sterol regulatory element-binding protein (SREBP)-dependent lipid synthesis and metabolic signalling in T reg cells unleashes effective antitumour immune responses without autoimmune toxicity. SREBP activity is upregulated in intratumoural T reg cells, and T reg cell-specific deletion of SCAP, an obligatory factor for SREBP activity, inhibits tumour growth and boosts anti-PD-1 immunotherapy, associated with uncontrolled IFN-γ production and impaired function of intratumoural T reg cells. Mechanistically, SCAP/SREBP signalling coordinates lipid synthetic programs and inhibitory receptor signalling in T reg cells. First, de novo fatty acid synthesis mediated by fatty acid synthase (FASN) contributes to functional maturation of T reg cells, and loss of FASN in T reg cells inhibits tumour growth. Second, T reg cells show enhanced Pdcd1 expression in tumours in a process dependent on SREBP activity that further signals to mevalonate metabolism-driven protein geranylgeranylation, and blocking PD-1 or SREBP signaling results in dysregulated PI3K activation in intratumoural T reg cells. Our findings establish that metabolic reprogramming enforces T reg cell functional specialization in tumours, pointing to new avenues to target T reg cells for cancer therapy.

Etiological variations in hepatocellular carcinoma (HCC) exist across different geographic areas. To gain better control of HCC, we retrospectively studied the secular trends and geographic variations in hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related HCCs in Taiwan. A total of 18,423 HCC cases enrolled in 8 medical centers from 1981 to 2001 were reviewed. Overall, 67% of male HCC in Taiwan was related to HBV infection whereas 55.2% of female HCC in Taiwan was related to HCV infection. The mean age of patients with HBV-related HCC was 53.2 6 13.6 years, while the mean age of patients with HCV-related HCC was 65.1 6 9.1 years (p < 0.001). The male/female ratio was 6.4 for HBV-related HCC, while it was 1.7 for the HCV-related HCC (p < 0.001). The percentage of HBV-related HCC progressively decreased from 81.5 to 66.2% in males, and from 66.7 to 41.4% in females over the study period. Our study demonstrates that the percentage of HBV-related HCC has progressively decreased over the last 20 years. The relative decrease in HBV-related HCC was not due to a decrease in HBV-related HCC death. Instead, it was caused by an increase in HCV-related HCC. Prevention of new HCV infection and the treatment of chronic hepatitis C should be the primary goals, which will result in better control of HCC in the future, even in an HBV-endemic area like Taiwan. ' 2006 Wiley-Liss, Inc.Key words: hepatocellular carcinoma; hepatitis B virus; hepatitis C virus; secular trend; geographic variation; Taiwan Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially in sub-Saharan Africa and Southeast Asia. Since 1984, it has been the leading cause of cancer death in Taiwan, 1 accounting for approximately 7,000 death annually. In addition, around 8,000 new HCC cases are diagnosed each year. 2 High-risk groups for HCC include patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), liver cirrhosis patients, and people with a family history of HCC. Chronic HBV and HCV infections are the 2 major etiologies of HCC in Taiwan. 3 About 15-20% of the general population in Taiwan are chronic carriers of hepatitis B surface antigen (HBsAg). 4 HBV carriers have a 20-to 98-fold increased risk of HCC, 5,6 especially among the hepatitis B e antigen (HBeAg)-positive group. 7 A recent prospective study has further confirmed that positivity for HBeAg is associated with an increased risk of HCC. 8 To combat HBV infection in Taiwan, a mass immunization program has been launched on July 1, 1984, aiming first at the prevention of perinatal mother-to-infant, chronic HBV infection. 9 This nationwide vaccination program has markedly decreased the HBV carrier rate 10 and childhood HBVrelated HCCs (B-HCCs). 11 An 80-85% decrease in HCC among Taiwanese adults up to 3-4 decades later is anticipated. 12 The prevalence of anti-HCV antibody (anti-HCV) is 2-4% among the general population of Taiwan, 13 while it ranges from 0.95 to 2.2% in Taiwanese blood donors. 13,14 The anti-HCV prevalen...

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Alzheimer's disease (AD) is the most common brain disorder worldwide. Aberrant tau hyperphosphorylation and accumulation play critical roles in the formation of neurofibrillary tangles highly associated with neuronal dysfunction and cognitive impairment in AD pathogenesis. Glycogen synthase kinase-3β (GSK3β) is a key kinase responsible for tau hyperphosphorylation. Selective inhibition of GSK3β is a promising strategy in AD therapy. Corn silks (CS, Zea mays L.) have been traditionally used as a medicinal herb and recently noted for their potentially cognitive benefits. However, the neuroprotective components of CS and their molecular mechanism have received little attention to date. As part of our effort screening phytochemicals against a broad panel of kinases targeting AD tauopathy, we found inhibition of GSK3β by CS extracts. Subsequent bioassay-guided fractionation led to the isolation and identification of two 6-C-glycosylflavones, isoorientin (1) and 3'-methoxymaysin (2), with selective inhibition against GSK3β in vitro. Enzyme kinetics and molecular docking studies demonstrated that 1 specifically inhibited GSK3β via an ATP noncompetitive mechanism, acting as a substrate competitive inhibitor of GSK3β. Further in vitro cellular studies demonstrated that 1 effectively attenuated tau phosphorylation mediated by GSK3β and was neuroprotective against β-amyloid-induced tau hyperphosphorylation and neurotoxicity in SH-SY5Y cells. The C-glycosylflavones represent new lead candidates with a novel mechanism of action for the development of AD phytopharmaceuticals.

If we encountered a young HCC patient, the patient will probably be a male HBV carrier. He would probably have larger tumor and is more likely to expire within 1 year than the older HCC patients. However, if the young HCC patient can survive for more than 1 year, he would probably have better survival in the following years than the older patients.

There are geographic variations in the survival rates of patients with HCC. Survival has been improving gradually over the past 20 years, probably due to earlier detection of HCC or to improved patient care.

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PTEN-PI3K and IL-7R–mTORC1–Myc are two discrete signaling axes driving B cell development.