We found that the IASLC/ATS/ERS classification identified prognostic histologic subtypes of lung adenocarcinomas among Japanese patients. Histologic subtyping and molecular testing for EGFR and KRAS mutations can help predict patient prognosis and select those who require adjuvant chemotherapy.

Purpose: Human invariant natural killer T (NKT) cells are novel, distinct lymphocyte populations with a restricted T-cell receptor repertoire (Va24-Vh11). They play a pivotal role in immunoregulation and in antitumor activities. This study focused on Va24 + NKT cells in colorectal carcinomas and their clinicopathologic significance. Experimental Design: Va24 + NKT-cell infiltration immunohistochemistry was studied in a total of 103 colorectal carcinoma cases. The degree of NKT-cell infiltration in tumors was evaluated as low (<7 NKTcells/5 HPF) or high (z7 NKT cells/5 HPF). The correlation between the degree of infiltrated Va24 + NKTcells and clinicopathologic variables was studied statistically. Results: A small number of Va24 + NKT cells were found in the normal colorectal mucosa (2.6 F 3.7 cells/5 HPF); however, their number increased remarkably in colorectal carcinomas (15.2 F 16.3 cells/5 HPF; P = 0.0003) and a majority showed phenotype of activation. Higher NKT-cell infiltration was more frequent in women than in men (P = 0.034) and correlated with fewer lymph node metastases (P = 0.042). Patients with high NKT-cell infiltration showed higher overall (P = 0.018) as well as disease-free (P = 0.0006) survival rates. Intratumor NKT-cell infiltration was an independent prognostic factor for the overall (P = 0.033) and disease-free (P = 0.0064) survival rates. Conclusions: Increased infiltration of Va24+ NKT cells was observed in colorectal carcinomas. HigherVa24 + NKT-cell infiltration in colorectal carcinomas was an independent prognostic factor for favorable prognosis.

IgA regulates the composition and function of gut microbiota. Nakajima et al. show that a heavily glycosylated monoclonal IgA coats B. theta and induces Mucus-Associated Functional Factor in vivo to enhance symbiotic interactions with commensal bacteria to maintain gut homeostasis.

BackgroundIschemia-reperfusion (I/R) injury associated with living donor liver transplantation impairs liver graft regeneration. Mesenchymal stem cells (MSCs) are potential cell therapeutic targets for liver disease. In this study, we demonstrate the impact of MSCs against hepatic I/R injury and hepatectomy.Methodology/Principal FindingsWe used a new rat model in which major hepatectomy with I/R injury was performed. Male Lewis rats were separated into two groups: an MSC group given MSCs after reperfusion as treatment, and a Control group given phosphate-buffered saline after reperfusion as placebo. The results of liver function tests, pathologic changes in the liver, and the remnant liver regeneration rate were assessed. The fate of transplanted MSCs in the luciferase-expressing rats was examined by in vivo luminescent imaging. The MSC group showed peak luciferase activity of transplanted MSCs in the remnant liver 24 h after reperfusion, after which luciferase activity gradually declined. The elevation of serum alanine transaminase levels was significantly reduced by MSC injection. Histopathological findings showed that vacuolar change was lower in the MSC group compared to the Control group. In addition, a significantly lower percentage of TUNEL-positive cells was observed in the MSC group compared with the controls. Remnant liver regeneration rate was accelerated in the MSC group.Conclusions/SignificanceThese data suggest that MSC transplantation provides trophic support to the I/R-injured liver by inhibiting hepatocellular apoptosis and by stimulating regeneration.

Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4-related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. We previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, we identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti-laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, we confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.

We studied histological features and long-term outcomes in patients with progressive familial intrahepatic cholestasis type 1 (PFIC1) after liver transplantation (LT). Histological findings were correlated with the post-LT course and treatment in 11 recipients with PFIC1. Ages at LT varied from 1 to 18 years (median, 4 years). Macrovesicular steatosis was observed in 8 patients at a median of 60 days post-LT (range, 21-191 days). Severe steatosis progressed to steatohepatitis in 7 patients at a median of 161 days (range, 116-932 days). The patients were followed up for a median of 7.3 years (range, 2.3-16.1 years). Six showed bridging fibrosis, with 2 progressing to cirrhosis. One patient with cirrhosis died because of the rupture of a splenic artery aneurysm 13.6 years post-LT. Post-LT refractory diarrhea was present in all 8 having steatosis. Three without post-LT diarrhea showed no allograft steatosis. Bile adsorptive resin therapy reduced the diarrhea and steatosis. Patients with posttransplant steatosis typically had more severe mutations of the ATPase class I type 8B member 1 (ATP8B1) gene and were more likely to have systemic complications such as pancreatitis. In conclusion, allograft steatosis was present in patients with PFIC1, progressing to steatohepatitis and cirrhosis. Because expression of the familial intrahepatic cholestasis 1 gene occurs in several organs, including the small intestine, pancreas, and liver, and it is involved in enterohepatic bile acid circulation, post-LT steatosis may be due to a malfunction of the ATP8B1 product. Liver Transpl 15:610-618, 2009.

Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation-and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFa and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFa, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFa, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer.

In human inflammatory sites, PD-1hiCXCR5−CD4+ T cells are involved in the formation of ectopic lymphoid-like structures (ELSs) by the secretion of chemokine CXCL13, but how the transcription of CXCL13 is regulated in CD4+ T cells is still unclear. Here we show that Sox4 is a key transcription factor for CXCL13 production in human CD4+ T cells under inflammatory conditions. In vitro TGF-β+, IL-2-neutralizing culture conditions give rise to PD-1hiCXCR5−CD4+ T cells that preferentially express CXCL13, and transcriptome analysis and lentiviral overexpression indicate Sox4 association with the CXCL13 transcription. In vivo, Sox4 is significantly upregulated in synovial CD4+ T cells, when compared with blood CD4+ T cells, from patients with rheumatoid arthritis (RA), and further correlates with ELS formation in RA synovium. Overall, our studies suggest that Sox4 contributes to CXCL13 production and ELS formation at inflammatory sites in humans.