The 2011 measles outbreak in Tokyo. An analysis of surveillance data.

OBJECTIVES: The study was conducted with the intention of establishing a strategy to eliminate measles on the basis of an analysis of the epidemiological profile of measles cases reported in Tokyo during the year 2011. METHODS: We investigated measles cases reported to the Tokyo Metropolitan Government in 2011, recorded as part of the National Epidemiological Surveillance of Infectious Diseases. Factors analyzed included age, vaccination status for each patient, cases for which records were discarded after laboratory confirmation, genotype of the measles virus and relationships between dates of specimen collection and results of polymerase chain reaction (PCR) and IgM antibody tests. RESULTS: A total of 178 measles cases were reported in Tokyo during 2011, and the majority of cases (128, 71.9%) were reported during the peak period from epiweeks 13 to 24. The largest age group reported was one to four years of age (40, 22.5%) followed by groups of 20-29 and 30-39 years of age (both 34, 19.1%). Most cases were sporadic, with only six outbreaks occurring. Even then, the numbers of cases for each outbreak was less than five. More than half of the patients in all age groups, except for the 1-4-year-old group, had not been vaccinated or did not have a record of vaccination. Genotypes D4 and D9 of measles virus were detected in most cases. However, genotype D5, which had been circulating in Japan before 2008, was not detected. CONCLUSION: Imported viruses were the cause of measles cases reported in Tokyo during 2011. The disease control was better than that in 2007 and 2008 because of the swift and appropriate responses to the occurrences. It is also possible that there has been an increase in the proportion of people with immunity to measles. Increasing the rate of immunization, performing effective surveillance, and confirming suspicious measles cases by using molecular methods are important for achieving the elimination of measles.

SAP155-mediated c-myc suppressor far-upstream element-binding protein-interacting repressor splicing variants are activated in colon cancer tissues.

The c-myc transcriptional suppressor, far-upstream element (FUSE)-binding protein (FBP)-interacting repressor (FIR), is alternatively spliced in colorectal cancer tissue (Matsushita et al., Cancer Res 2006). Recently, the knockdown of SAP155 pre-mRNA-splicing factor, a subunit of SF3b, was reported to disturb FIR pre-mRNA splicing and yield FIRΔexon2, an exon 2-spliced variant of FIR, which lacks c-myc repression activity. In the present study, novel splicing variants of FIR, Δ3 and Δ4, were also generated by SAP155 siRNA, and these variants were found to be activated in human colorectal cancer tissue. Furthermore, the expression levels of FIR variant mRNA were examined in the peripheral blood of colorectal cancer patients and healthy volunteers to assess its potency for tumor detection. As expected, circulating FIR variant mRNA in the peripheral blood of cancer patients were significantly overexpressed compared to that in healthy volunteers. In particular, the area under the receiving operating characteristic curve of FIR, FIRΔexon2 or FIRΔexon2/FIR, was greater than those of conventional carcinoembryonic antigen or carbohydrate antigen 19-9. In addition, FIRΔexon2 or FIR mRNA expression in the peripheral blood was significantly reduced after operative removal of colorectal tumors. Thus, circulating FIR and FIRΔexon2 mRNA are potential novel screening markers for colorectal cancer testing with conventional carcinoembryonic antigen and or carbohydrate antigen 19-9. Taken together, our results indicate that overexpression of FIR and its splicing variants in colorectal cancer directs feed-forward or addicted circuit c-myc transcriptional activation. Clinical implications for colorectal cancers of novel FIR splicing variants are also discussed in the present paper.

SAP155-mediated splicing of FUSE-binding protein-interacting repressor serves as a molecular switch for c-myc gene expression.

The Far UpStream Element (FUSE)-binding protein-interacting repressor (FIR), a c-myc transcriptional suppressor, is alternatively spliced removing the transcriptional repression domain within exon 2 (FIRΔexon2) in colorectal cancers. SAP155 is a subunit of the essential splicing factor 3b (SF3b) subcomplex in the spliceosome. This study aims to study the significance of the FIR-SAP155 interaction for the coordination of c-myc transcription, pre-mRNA splicing, and c-Myc protein modification, as well as to interrogate FIRΔexon2 for other functions relating to altered FIR pre-mRNA splicing. Knockdown of SAP155 or FIR was used to investigate their reciprocal influence on each other and on c-myc transcription, pre-mRNA splicing, and protein expression. Pull down from HeLa cell nuclear extracts revealed the association of FIR, FIRΔexon2, and SF3b subunits. FIR and FIRΔexon2 were coimmunoprecipitated with SAP155. FIR and FIRΔexon2 adenovirus vector (Ad-FIR and Ad-FIRΔexon2, respectively) were prepared to test for their influence on c-myc expression. FIR, SAP155, SAP130, and c-myc were coordinately upregulated in human colorectal cancer. These results reveal that SAP155 and FIR/FIRΔexon2 form a complex and are mutually upregulating. Ad-FIRΔexon2 antagonized Ad-FIR transcriptional repression of c-myc in HeLa cells. Because FIRΔexon2 still carries RRM1 and RRM2 and binding activity to FUSE, it is able to displace repression competent FIR from FUSE in electrophoretic mobility shift assays, thus thwarting FIR-mediated transcriptional repression by FUSE. Thus aberrant FIRΔexon2 production in turn sustained c-Myc expression. In conclusion, altered FIR and c-myc pre-mRNA splicing, in addition to c-Myc expression by augmented FIR/FIRΔexon2-SAP155 complex, potentially contribute to colorectal cancer development.

c-myc suppressor FBP-interacting repressor for cancer diagnosis and therapy.

Based on the genetic background of cancer, we have been trying to develop novel diagnostic and therapeutic strategies against human cancers. c-myc gene activation has been detected in many human cancers, indicating a key role of c-myc in tumor development. Thus targeting c-myc gene suppression is a promising strategy for cancer treatment. Recently, an interaction between FIR (FUSE-Binding Protein-Interacting Repressor) and TFIIH/p89/XPB helicase was found to repress c-myc transcription and so might be important for suppressing tumor formation. Previously, we have shown that the expression of splicing variant of FIR is elevated in colorectal cancer tissues and promotes tumor development by disabling FIR-repression to sustain high levels of c-Myc, opposing apoptosis in cancer cells. In this study, FIR recombinant adenovirus vector induces tumor growth suppression against tumor xenografts in animal model experiment. Together, one clue to the development of cancer diagnosis and therapies directed against c-Myc may go through FIR and its splicing variant.

[Clinical application of alternative splicing form of c-myc suppressor FUSE-binding protein-interacting repressor for cancer detection and treatment].

Development of useful biomarkers is pivotal for prediction of micro-metastasis, recurrence probability and/or prognosis of the patients. Recent studies have revealed that cancer-specific alternative splicing can be valuable for cancer cell detection. Among them, FUSE-binding protein-interacting repressor, FIR, has been reported to repress c-myc transcription and its exon2-spliced variant, FIRDelta(exon)2, is unable to repress c-myc by competing with authentic FIR in vivo and in vitro. Moreover FIRDelta(exon)2 was frequently discovered in human primary colorectal cancers, but not in the adjacent normal tissues, indicating its cancer-related expression. Thus, the expression level of FIRDelta(exon)2 mRNA in the colorectal cancer tissues as tumor marker candidates is examined. Further, to determine the interacting proteins, FIR-flag or FIRDelta(exon)2-flag stably expressing HeLa cells have been established by G418 selection and nuclear proteins were co immunoprecipitated with flag-conjugated magnetic beads. Those co-immunoprecipitated proteins with FIR or FIRDelta(exon)2 are candidates of tumor makers. In addition, substances that interfers FIR mRNA splicing should be anti-cancer drugs. Together, FIR splicing variant, FIRDelta(exon)2 mRNA or proteins and its interacting proteins are applicable for novel screening tumor markers in colorectal cancer detection.