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1.  Genetic Analysis of Hedgehog Signaling in Ventral Body Wall Development and the Onset of Omphalocele Formation 
PLoS ONE  2011;6(1):e16260.
An omphalocele is one of the major ventral body wall malformations and is characterized by abnormally herniated viscera from the body trunk. It has been frequently found to be associated with other structural malformations, such as genitourinary malformations and digit abnormalities. In spite of its clinical importance, the etiology of omphalocele formation is still controversial. Hedgehog (Hh) signaling is one of the essential growth factor signaling pathways involved in the formation of the limbs and urogenital system. However, the relationship between Hh signaling and ventral body wall formation remains unclear.
Methodology/Principal Findings
To gain insight into the roles of Hh signaling in ventral body wall formation and its malformation, we analyzed phenotypes of mouse mutants of Sonic hedgehog (Shh), GLI-Kruppel family member 3 (Gli3) and Aristaless-like homeobox 4 (Alx4). Introduction of additional Alx4Lst mutations into the Gli3Xt/Xt background resulted in various degrees of severe omphalocele and pubic diastasis. In addition, loss of a single Shh allele restored the omphalocele and pubic symphysis of Gli3Xt/+; Alx4Lst/Lst embryos. We also observed ectopic Hh activity in the ventral body wall region of Gli3Xt/Xt embryos. Moreover, tamoxifen-inducible gain-of-function experiments to induce ectopic Hh signaling revealed Hh signal dose-dependent formation of omphaloceles.
We suggest that one of the possible causes of omphalocele and pubic diastasis is ectopically-induced Hh signaling. To our knowledge, this would be the first demonstration of the involvement of Hh signaling in ventral body wall malformation and the genetic rescue of omphalocele phenotypes.
PMCID: PMC3024424  PMID: 21283718
2.  Size dependent heat generation of magnetite nanoparticles under AC magnetic field for cancer therapy 
We have developed magnetic cationic liposomes (MCLs) that contained magnetic nanoparticles as heating mediator for applying them to local hyperthermia. The heating performance of the MCLs is significantly affected by the property of the incorporated magnetite nanoparticles. We estimated heating capacity of magnetite nanoparticles by measuring its specific absorption rate (SAR) against irradiation of the alternating magnetic field (AMF).
Magnetite nanoparticles which have various specific-surface-area (SSA) are dispersed in the sample tubes, subjected to various AMF and studied SAR.
Heat generation of magnetite particles under variable AMF conditions was summarized by the SSA. There were two maximum SAR values locally between 12 m2/g to 190 m2/g of the SSA in all ranges of applied AMF frequency and those values increased followed by the intensity of AMF power. One of the maximum values was observed at approximately 90 m2/g of the SSA particles and the other was observed at approximately 120 m2/g of the SSA particles. A boundary value of the SAR for heat generation was observed around 110 m2/g of SSA particles and the effects of the AMF power were different on both hand. Smaller SSA particles showed strong correlation of the SAR value to the intensity of the AMF power though larger SSA particles showed weaker correlation.
Those results suggest that two maximum SAR value stand for the heating mechanism of magnetite nanoparticles represented by hysteresis loss and relaxation loss.
PMCID: PMC2579422  PMID: 18928573
3.  Hyperthermic treatment of DMBA-induced rat mammary cancer using magnetic nanoparticles 
We have developed magnetite cationic liposomes (MCLs) and applied them as a mediator of local hyperthermia. MCLs can generate heat under an alternating magnetic field (AMF). In this study, the in vivo effect of hyperthermia mediated by MCLs was examined using 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancer as a spontaneous cancer model.
MCLs were injected into the mammary cancer and then subjected to an AMF.
Four rats in 20 developed mammary tumors at more than 1 site in the body. The first-developed tumor in each of these 4 rats was selected and heated to over 43°C following administration of MCLs by an infusion pump. After a series of 3 hyperthermia treatments, treated tumors in 3 of the 4 rats were well controlled over a 30-day observation period. One of the 4 rats exhibited regrowth after 2 weeks. In this rat, there were 3 sites of tumor regrowth. Two of these regrowths were reduced in volume and regressed completely after 31 days, although the remaining one grew rapidly. These results indicated hyperthermia-induced immunological antitumor activity mediated by the MCLs.
Our results suggest that hyperthermic treatment using MCLs is effective in a spontaneous cancer model.
PMCID: PMC2266920  PMID: 18298831
4.  Mice with a Targeted Mutation of Patched2 Are Viable but Develop Alopecia and Epidermal Hyperplasia†  
Molecular and Cellular Biology  2006;26(17):6609-6622.
Hedgehog (Hh) signaling plays pivotal roles in tissue patterning and development in Drosophila melanogaster and vertebrates. The Patched1 (Ptc1) gene, encoding the Hh receptor, is mutated in nevoid basal cell carcinoma syndrome, a human genetic disorder associated with developmental abnormalities and increased incidences of basal cell carcinoma (BCC) and medulloblastoma (MB). Ptc1 mutations also occur in sporadic forms of BCC and MB. Mutational studies with mice have verified that Ptc1 is a tumor suppressor. We previously identified a second mammalian Patched gene, Ptc2, and demonstrated its distinct expression pattern during embryogenesis, suggesting a unique role in development. Most notably, Ptc2 is expressed in an overlapping pattern with Shh in the epidermal compartment of developing hair follicles and is highly expressed in the developing limb bud, cerebellum, and testis. Here, we describe the generation and phenotypic analysis of Ptc2tm1/tm1 mice. Our molecular analysis suggests that Ptc2tm1 likely represents a hypomorphic allele. Despite the dynamic expression of Ptc2 during embryogenesis, Ptc2tm1/tm1 mice are viable, fertile, and apparently normal. Interestingly, adult Ptc2tm1/tm1 male animals develop skin lesions consisting of alopecia, ulceration, and epidermal hyperplasia. While functional compensation by Ptc1 might account for the lack of a strong mutant phenotype in Ptc2-deficient mice, our results suggest that normal Ptc2 function is required for adult skin homeostasis.
PMCID: PMC1592833  PMID: 16914743

Results 1-4 (4)