Chulabhorn Research Institute

About: Chulabhorn Research Institute is a facility organization based out in Bangkok, Thailand. It is known for research contribution in the topics: Mutant & Xanthomonas campestris. The organization has 503 authors who have published 1191 publications receiving 28872 citations.

Gut microbiome–mediated bile acid metabolism regulates liver cancer via NKT cells

Abstract: INTRODUCTION Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related deaths. The liver intimately cross-talks with the gut and performs many essential functions related to digestion, metabolism of nutrients, and clearance of bacterial metabolites. Diseased livers are often associated with altered gut bacterial composition, or dysbiosis, and it has been suggested that gut bacterial products contribute to malignant transformation of hepatocytes. The liver is exposed to the gut microbiome through the portal vein and is an immunological organ that is heavily populated by immune cells. Emerging studies have shown that gut commensal bacteria are important regulators of antitumor immunity. Although it has been established that the gut microbiome influences the efficacy of cancer immunotherapy, the role of gut bacteria in antitumor surveillance in the liver is poorly understood. RATIONALE The liver is exposed to gut bacterial metabolites and products by way of blood from the intestine, which comprises 70% of the whole liver blood supply. Changes in the gut microbiome may affect immune cell function in the liver, and commensal bacteria can mediate the metabolism of primary into secondary bile acids, which recirculate back into the liver through the enterohepatic circulation. Given that bile acids are known to be involved in liver cancer development, we focused on the role of bile acids in immunosurveillance of tumors growing in the liver. We altered gut bacteria and examined changes of hepatic immune cells and antitumor immunity directed against liver tumors. Uncovering how the gut microbiome uses bile acids to shape immunity to liver cancer may have future therapeutic applications. RESULTS Using one primary liver model and three liver metastasis models, we found that altering commensal gut bacteria induced a liver-selective antitumor effect. A selective increase of hepatic CXCR6 + natural killer T (NKT) cells was observed, independent of mouse strain, gender, or presence of liver tumors. The accumulated hepatic NKT cells showed an activated phenotype and produced more interferon-γ upon antigen stimulation. In vivo studies using both antibody-mediated cell depletion and NKT-deficient mice confirmed that NKT cells mediated the inhibition of tumor growth in the liver. Further investigation showed that NKT cell accumulation was regulated by the expression of CXCL16, the solo ligand for CXCR6, on liver sinusoidal endothelial cells, which form the lining of liver capillaries and the first barrier for the blood coming from the gut entering the liver. Primary bile acids increased CXCL16 expression, whereas secondary bile acids showed the opposite effect. Removing gram-positive bacteria by antibiotic treatment with vancomycin, which contains the bacteria mediating primary-to-secondary bile acid conversion, was sufficient to induce hepatic NKT cell accumulation and decrease liver tumor growth. Feeding secondary bile acids or colonization of bile acid–metabolizing bacteria, reversed both NKT cell accumulation and inhibition of liver tumor growth in mice with altered gut commensal bacteria. In nontumor liver tissue from human patients with primary liver cancer, primary bile acid chenodeoxycholic acid (CDCA) levels correlated with CXCL16 expression, whereas an inverse correlation was observed with secondary bile acid glycolithocholate (GLCA), suggesting that the finding may apply to humans. CONCLUSION We describe a mechanism by which the gut microbiome uses bile acids as messengers to control a chemokine-dependent accumulation of hepatic NKT cells and antitumor immunity in the liver, against both primary and metastatic liver tumors. These findings not only have possible implications for future cancer therapeutic studies but also provide a link between the gut microbiome, its metabolites, and immune responses in the liver.

IPCS framework for analyzing the relevance of a noncancer mode of action for humans.

Abstract: Structured frameworks are extremely useful in promoting transparent, harmonized approaches to the risk assessment of chemicals. One area where this has been particularly successful is in the analysis of modes of action (MOAs) for chemical carcinogens in experimental animals and their relevance to humans. The International Programme on Chemical Safety (IPCS) recently published an updated version of its MOA framework in animals to address human relevance (cancer human relevance framework, or HRF). This work has now been extended to noncancer effects, with the eventual objective of harmonizing framework approaches to both cancer and noncancer endpoints. As in the cancer HRF, the first step is to determine whether the weight of evidence based on experimental observations is sufficient to establish a hypothesized MOA. This comprises a series of key events causally related to the toxic effect, identified using an approach based on the Bradford Hill criteria. These events are then compared qualitatively and, next, quantitatively between experimental animals and humans. The output of the analysis is a clear statement of conclusions, together with the confidence, analysis, and implications of the findings. This framework provides a means of ensuring a transparent evaluation of the data, identification of key data gaps and of information that would be of value in the further risk assessment of the compound, such as on dose-response relationships, and recognition of potentially susceptible subgroups, for example, based on life-stage considerations.

MultiPhen: joint model of multiple phenotypes can increase discovery in GWAS.

Abstract: The genome-wide association study (GWAS) approach has discovered hundreds of genetic variants associated with diseases and quantitative traits. However, despite clinical overlap and statistical correlation between many phenotypes, GWAS are generally performed one-phenotype-at-a-time. Here we compare the performance of modelling multiple phenotypes jointly with that of the standard univariate approach. We introduce a new method and software, MultiPhen, that models multiple phenotypes simultaneously in a fast and interpretable way. By performing ordinal regression, MultiPhen tests the linear combination of phenotypes most associated with the genotypes at each SNP, and thus potentially captures effects hidden to single phenotype GWAS. We demonstrate via simulation that this approach provides a dramatic increase in power in many scenarios. There is a boost in power for variants that affect multiple phenotypes and for those that affect only one phenotype. While other multivariate methods have similar power gains, we describe several benefits of MultiPhen over these. In particular, we demonstrate that other multivariate methods that assume the genotypes are normally distributed, such as canonical correlation analysis (CCA) and MANOVA, can have highly inflated type-1 error rates when testing case-control or non-normal continuous phenotypes, while MultiPhen produces no such inflation. To test the performance of MultiPhen on real data we applied it to lipid traits in the Northern Finland Birth Cohort 1966 (NFBC1966). In these data MultiPhen discovers 21% more independent SNPs with known associations than the standard univariate GWAS approach, while applying MultiPhen in addition to the standard approach provides 37% increased discovery. The most associated linear combinations of the lipids estimated by MultiPhen at the leading SNPs accurately reflect the Friedewald Formula, suggesting that MultiPhen could be used to refine the definition of existing phenotypes or uncover novel heritable phenotypes.

Nucleophilic transition metal based cyclization of allenes

Abstract: Allenes bearing a pro-nucleophile can be cyclized on treatment with a wide variety of transition metal catalysts and reagents: palladium, cobalt, ruthenium, silver, rhodium, lanthanides, gold. The nucleophilic groups can be nitrogen, oxygen or carbon based and can form rings of various sizes, often with good control of stereochemistry. A variety of mechanisms can be proposed for these reactions and the metal complex can be used to introduce a variety of functional groups during cyclization. Several heterocyclic natural products have been prepared using a selection of these reactions.