In recent years, enterovirus 71 (EV71) has been a cause of numerous outbreaks of hand-foot-and-mouth disease, with severe neurological complications in the Asia-Pacific region. The reemergence in Taiwan of EV71 genotype B5 in 2008 resulted in the largest outbreak of EV71 in Taiwan in the past 11 years. Phylogenetic analyses indicated that dominant genotype changes from B to C or C to B occurred at least three times between 1986 and 2008. Furthermore, antigenic cartography of EV71 by using neutralization tests revealed that the reemerging EV71 genotype B5 strains formed a separate cluster which was antigenically distinct from the B4 and C genotypes. Moreover, analyses of full-length genomic sequences of EV71 circulating in Taiwan during this period showed the occurrence of intra-and interserotypic recombination. Therefore, continuous surveillance of EV71 including the monitoring of genetic evolution and antigenic changes is recommended and may contribute to the development of a vaccine for EV71.The genus Enterovirus ([EV] family Picornaviridae) contains numerous viruses that are pathogenic to humans. Human EVs (HEVs) have been classified into four species, HEV-A, HEV-B, HEV-C, and HEV-D, based on their sequence homologies (48). In contrast to other etiological agents of hand-foot-and-mouth disease that tend to cause mild and self-limiting disease, EV71 infection is often associated with other clinical manifestations including acute neurologic symptoms, such as poliomyelitis-like paralysis, encephalitis, aseptic meningitis, shock, and cardiac dysfunction (32).Since 1969, when EV71 was first isolated in California, EV71-associated outbreaks have been reported worldwide (42). EV71 infection reached epidemic proportions, causing sporadic cases or outbreaks and then becoming prevalent around the AsiaPacific region including Australia, Malaysia, Singapore, Japan, China, and Taiwan for the past 12 years (1, 16-18, 20, 25, 26, 28, 46, 53). Phylogenetic studies have classified EV71 into genotypes A, B, and C, which can be further subdivided into subgentotypes B1 to B5 and C1 to C5 (7,8,17,20,22,25,28,41,45,52,53). These reports indicated that the dominant EV71 strains circulating in the Asia-Pacific region varied genetically, suggesting that the virus was evolving.Intertypic or intratypic recombination of EV71 has been reported to occur frequently in the region encoding the nonstructural proteins and could potentially influence the replication, tissue tropism, and virulence of EV71 (10,11,18). These studies emphasized the importance of full-genome sequencing for the surveillance of EV71 evolution. Therefore, to analyze the evolution of EV71, we performed phylogenetic analysis of the Taiwan isolates from 1986 and from 1998 and 2008 based on the complete genomic sequences. In addition, neutralizing activities of human antiserum against the various subgenotypes of EV71 were investigated to evaluate the antigenic changes of EV71. We found evidence for intertypic and intratypic recombination and demonstrated variation in anti...

Given (1) the wide range of ALDH1A1 levels observed in malignant breast tissues, (2) that ALDH1A1 levels in primary breast tumor tissue, as well as those in normal breast tissue, directly reflect ALDH1A1 levels in metastatic breast tumor cells derived therefrom, and (3) the findings reported here, measurement of ALDH1A1 levels in primary breast malignancies and/or normal breast tissue prior to the initiation of chemotherapy is likely to be of value in predicting the therapeutic potential, or lack of potential, of cyclophosphamide and other oxazaphosphorines, e.g. ifosfamide, in the treatment of primary, as well as metastatic, breast cancer, thus providing a rational basis for the design of individualized therapeutic regimens for this disease. Failure to observe the expected inverse relationship between clinical responses to cyclophosphamide-based chemotherapeutic regimens and ALDH3A1 levels was probably because even the highest breast tumor tissue ALDH3A1 level thus far reported appears to be below the threshold level at which ALDH3A1-catalyzed detoxification of oxazaphosphorines becomes pharmacologically meaningful. However, ALDH3A1 levels in certain other malignancies, e.g. those of the alimentary tract and lung, may be of a sufficient magnitude in that regard.

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During a 6-week period in 2003, 56 residents and 26 staff developed respiratory illness in a long-term facility; 12 residents died. Seven of 13 respiratory specimens were culture-positive for rhinovirus; 6 of the isolates were serotype 82. In elderly populations, severe illness may be associated with organisms typically considered to be "benign," such as rhinovirus.

The type I insulin-like growth factor receptor (IGF1R) and insulin receptor (IR) are structurally and functionally related heterotetrameric receptors. Activation of IGF1R has been shown to regulate breast cancer cell biology, and it has become an attractive therapeutic target. Most strategies have focused on targeting IGF1R alone without affecting IR levels given the known physiologic functions of IR. Human breast cancer cell lines and tissues revealed mRNA expression of both IGF1R and IR. Because AB chains of IGF1R and IR form hybrid receptors, we hypothesized that agents solely targeting IGF1R may affect tumor biology mediated by IGF1R/IR hybrids and IR. We used small interfering RNA (siRNA) technology to specifically down-regulate IGF1R by 60% to 80% in the MDA-435/LCC6 cell line, which was sufficient to diminish activation of IGF1R by IGF-I. IGF1R down-regulation by siRNA did not affect IR levels but, interestingly, sensitized cells to insulin activation of downstream signaling pathways in several breast cancer cell lines. IGF1R siRNA treatment diminished hybrid receptor formation, suggesting that specific down-regulation of IGF1R resulted in enhanced holo-IR formation. In addition, IGF1R down-regulation increased insulin binding consistent with the formation of an increased number of holo-IR on the cell surface. Accordingly, insulinstimulated glucose uptake was enhanced on IGF1R downregulation. In conclusion, our data suggest that specific siRNA targeting of IGF1R alone in breast cancer increases insulin sensitivity. Because IR also activates signaling pathways similar to IGF1R in breast cancer cells, agents targeting both receptors may be necessary to disrupt the malignant phenotype regulated by this growth factor system. [Cancer Res 2007;67(1):391-7]