Wnt signaling and gastrointestinal tumorigenesis in mouse models

The canonical Wnt signaling plays important roles in embryonic development and tumorigenesis. For the latter, induced mutations in mice have greatly contributed to our understanding of the molecular mechanisms of cancer initiation and progression. Here, I will review recent reports on gastrointestinal cancer model mice, with an emphasis on the roles of the Wnt signal pathway. They include: mouse models for familial adenomatous polyposis; modifying factors that affect mouse intestinal polyposis, including the genes that help cancer progression; Wnt target genes that affect mouse intestinal polyposis; and a mouse model of gastric cancer that mimics Helicobacter pyroli infection.     

Influenza vaccination in severely multiply handicapped persons/children

BACKGROUND: Many reports about the preventative effects of inactivated influenza vaccine have been published, targeting persons with underlying medical conditions. However, the effectiveness for severely multiply handicapped persons/children (SMHPs) is not yet well established. METHODS: The study group consisted of 79 SMHPs (36 males and 43 females, aged 18-66 years), with long-term hospitalization in Niigata National Hospital. We compared serum antibody responses before and after two-doses vaccination. RESULTS: Before vaccination for the 2004-2005 season, SMHPs showed continuously high HAI titer in A/New Caledonia/20/99(H1N1)-strain from March to October in 2004. The seroprotection rates were increased after the first dose, but no remarkable change was seen after the second dose in all three strains. Subjects less than 30 years old (< or = 29 group) had a high antibody titers against all three strains compared with subjects aged >40 years old. On the other hand, in the seroconversion rates, there were no significant differences in age, gender, and severity of symptoms. CONCLUSIONS: According to our study, SMHPs are low responders except < or = 29 group and the influenza vaccine effectiveness is more affected by their age than severity of symptoms. We suggest a recommendation for influenza vaccination especially in SMHPs; inactivated influenza virus vaccine (one dose) should be performed during the previous fall. In addition, further studies are needed about chemoprophylaxis, which can prevent influenza outbreaks in SMHPs.     

Fulminant Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder with hemophagocytosis following autologous peripheral blood stem cell transplantation for relapsed angioimmunoblastic T-cell lymphoma

Post-transplant lymphoproliferative disorder (PTLD) is a complication that can develop after either solid-organ or hematopoietic stem cell transplantation (HSCT). T-cell PTLD is a rare disorder, especially following autologous HSCT. Here we report a case of T-cell PTLD which occurred after autologous peripheral blood stem cell transplantation (PBSCT) for relapsed angioimmunoblastic T-cell lymphoma (AILT). Three months after the transplant, the patient developed fever with elevated plasma Epstein-Barr virus (EBV)-PCR values. The patient subsequently developed pneumonitis, hepatomegaly and marked pancytopenia due to hemophagocytosis. The patient died of multi-organ failure, despite antiviral and steroid pulse therapy. Our post-mortem study confirmed the marked proliferation of EBV-infected T-cells that differed from the original AILT clone and macrophages/histiocytes were observed in the marrow, liver, lymph nodes and lungs. Phagocytosis was most evident in the bone marrow. The patient's AILT remained in complete remission. To the best of our knowledge, this is the first case of fulminant EBV-associated T-cell lymphoproliferative disorder (LPD) following autologous HSCT.     

Hyperplastic gastric tumors with spasmolytic polypeptide-expressing metaplasia caused by tumor necrosis factor-alpha-dependent inflammation in cyclooxygenase-2/microsomal prostaglandin E synthase-1 transgenic mice

We showed recently that Helicobacter infection induces expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in the mouse stomach, and that transgenic mice expressing both cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (K19-C2mE mice) develop hyperplastic gastric tumors with inflammatory histopathology. To investigate possible roles of proinflammatory cytokines and acquired immunity in the gastric hyperplasia of K19-C2mE mice, we introduced knockout mutations for tumor necrosis factor-alpha (TNF-alpha; Tnf), interleukin-1 receptor-alpha chain (Il1r1), and Rag2 genes, respectively. Among the compound mutants, only the Tnf (-/-) K19-C2mE mice showed significant suppression of hyperplastic tumors with reduced cell proliferation. In contrast, tumorigenesis remained unaffected in either compound mutants of K19-C2mE containing Il1r1 or Rag2 mutation, indicating that neither interleukin-1beta signaling nor T cell/B cell response was required for the development of hyperplastic tumors. Importantly, spasmolytic polypeptide/trefoil factor 2-expressing metaplasia (SPEM) in the K19-C2mE stomach was also suppressed in the Tnf (-/-) K19-C2mE mice, indicating that TNF-alpha-dependent inflammation is responsible for SPEM development. Because gastric metaplasia to the SPEM lineage is considered as a preneoplastic lesion of gastric cancer, it is possible that inhibition of TNF-alpha-dependent inflammation, together with eradication of Helicobacter, can be an effective prevention strategy for gastric cancer.