Musculin/MyoR is a new member of basic helix-loop-helix transcription factors, and its expression is limited to skeletal muscle precursors. Here, we report that musculin/MyoR is expressed in adult kidney side population (SP) cells and can regulate their function. SP phenotype can be used to purify stem cell–rich fractions. Microarray analysis clarified that musculin/MyoR was exclusively expressed in kidney SP cells, and the cells resided in the renal interstitial space. Musculin/MyoR-positive cells were decreased in acute renal failure, but infusion of kidney SP cells increased musculin/MyoR-positive cells and improved renal function. Kidney SP cells in reversible acute renal failure expressed a high level of renoprotective factors and leukemia inhibitory factor (LIF), but not in irreversible chronic renal failure. In cultured kidney SP cells, LIF stimulated gene expression of renoprotective factors, and down-regulation of musculin/MyoR augmented LIF-induced gene expression. Our results suggest that musculin/MyoR may play important roles not only in developmental processes but also in regenerative processes in adult tissue.

CD1d and CD1d-restricted natural killer T (NKT) cells serve as a natural bridge between innate and adaptive immune responses to microbes. CD1d downregulation is utilized by a variety of microbes to evade immune detection. We demonstrate here that CD1d is downregulated in human papillomavirus (HPV)-positive cells in vivo and in vitro.CD1d immunoreactivity was strong in HPV-negative normal cervical epithelium but absent in HPV16-positive CIN1 and HPV6-positive condyloma lesions. We used two cell lines for in vitro assay; one was stably CD1d-transfected cells established from an HPV-negative cervical cancer cell line, C33A (C33A/CD1d), and the other was normal human vaginal keratinocyte bearing endogenous CD1d (Vag). Flow cytometry revealed that cell surface CD1d was downregulated in both C33A/CD1d and Vag cells stably transfected with HPV6 E5 and HPV16 E5. Although the steady-state levels of CD1d protein decreased in both E5-expressing cell lines compared to empty retrovirus-infected cells, CD1d mRNA levels were not affected. Confocal microscopy demonstrated that residual CD1d was not trafficked to the E5-expressing cell surface but colocalized with E5 near the endoplasmic reticulum (ER). In the ER, E5 interacted with calnexin, an ER chaperone known to mediate folding of CD1d. CD1d protein levels were rescued by the proteasome inhibitor, MG132, indicating a role for proteasome-mediated degradation in HPV-associated CD1d downregulation. Taken together, our data suggest that E5 targets CD1d to the cytosolic proteolytic pathway by inhibiting calnexin-related CD1d trafficking. Finally, CD1d-mediated production of interleukin-12 from the C33A/CD1d cells was abrogated in both E5-expressing cell lines. Decreased CD1d expression in the presence of HPV E5 may help HPV-infected cells evade protective immunological surveillance.There are approximately 100 identified genotypes (types) of human papillomavirus (HPV). Over 40 of these are classified as genital HPV subtypes that invade the reproductive organs, including the uterine cervix, vaginal wall, vulva, and penis. Genital HPV types are further subclassified into high-risk types that are commonly associated with cervical cancer and low-risk types that cause noninvasive condyloma acuminata. Although exact classification varies among researchers, subtypes 16,18,31,33,35,39, 45, 51, 52, 56, 58, 66, and 68 are typically classified as high risk and subtypes 6,11,40,42,43,44, 54, 61, and 72 as low risk (44). Genital HPV infection involves short-term virus proliferation, followed by the long-term latent presence of a small number of copies of the viral genome within the basal cells of the genital epithelium (44). Infections with high-risk HPV subtypes result in progression to genital tract cancers (most commonly cervical) in only a small percentage of infected women and typically after a long latency period. A high percentage of high-risk HPV DNA-positive infected women resolve their infections during the proliferative phase and thereby clear the virus or progress to latency with...

Dear Sir,Recently, pooled IARC studies 1,2 and meta-analyses 3,4 have showed that at least 13 human papillomavirus (HPV) types, including types 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68, are commonly associated with invasive cervical cancer (ICC). Based on HPV type prevalence data from these studies, current HPV vaccines against only HPV16/18 are considered to prevent a majority (>70%) of cervical cancer worldwide. 5,6 However, HPV data in East Asia have not been fully evaluated in previous pooled and meta-analyses. The present study thus focused on HPV type prevalence in Japan. We performed a meta-analysis of published data to obtain the representative results, and investigated HPV type prevalence and type-specific risks for cervical carcinogenesis in Japan. Furthermore, obtained data were compared with those in China, Korea and other regions.Source articles presenting HPV prevalence data among Japanese women were identified from National Library of Medicine (PubMed). For the meta-analysis, the following inclusion criteria were considered: (i) Studies were published between 1995 and 2005. (ii) Studies had to use PCR-based assays to identify at least 16 strains of HPV6,11,16,18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59 and 68. (iii) Studies had to include at least 20 HPV-positive women with squamous intraepithelial lesion (SIL), cervical intraepithelial neoplasia (CIN) or ICC. When data or data subsets from an identical study had been published in more than one article, only the publication with the largest sample size was included. However, data from different studies conducted by the same study group were included. Overall, a total of 14 Japanese studies were identified for the present study. [7][8][9][10][11][12][13][14][15][16][17][18][19][20] For some articles, additional typespecific data were obtained from the authors. 11,12,20 HPV type prevalence data were collected separately for squamous cell carcinoma (SCC) and for adeno-and adenosquamous carcinoma (ADC). Where histological data were not reported, ICC cases were classified as unspecified carcinoma (UC). On the basis of the pooled analysis of IARC studies, 2 HPV types were separated into 2 groups. High-risk HPVs considered as carcinogenic or probably carcinogenic included HPV16,18,26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73 and 82; all other HPV types were classified as low-risk types. To evaluate HPV genotype-specific risks for progression from LSIL (low grade SIL) to HSIL (high grade SIL) or more, prevalence ratios [(HSIL 1 ICC):LSIL] and 95% confidence intervals were calculated after adjusting for study area, specimen used for HPV DNA testing, and PCR primers. Logistic regression model was used for statistical adjustment, and the analysis was carried out using JMP 6.0J statistics package (SAS Institute, Cary, NC, USA). The p-values obtained in all tests were considered significant at <0.05.This analysis included 7,262 Japanese women (4,941 normal cytology, 475 LSIL, 720 HSIL and 1,126 ICC) from 14 Japanese HPV studie...

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Phenolic and catecholic compounds were synthesized, by combination with cysteine or cysteamine through thioether bond, and their antimelanoma and melanocytotoxic effects were evaluated. Among nine compounds tested, 4-S-cysteaminylphenol (CAP) resulted in an increase in the life span (% ILS) of melanoma-bearing mice and in the growth inhibition (% GI) of melanoma tissue. 4-S-Cysteinylphenol (CP) and its methyl ester form also showed some increase in % GI. The 2-S-isomers of CP and CAP and diphenolic derivatives of CP did not show any significant antimelanoma effect. In addition, the s.c. injection of 4-S-CAP and 4-S-CP, in particular 4-S-CAP, caused the depigmentation of black hair which was manifested by loss of functioning melanocytes, as seen under light microscopy. The 4-S-CAP appears to provide a basis for development of a new class of antimelanoma and melanocytotoxic agents that are more stable than catecholic compounds, which have been most widely utilized as a source of rational chemotherapy for malignant melanoma.

Recombinant proteins are an attractive choice as a safe alternative to traditional live attenuated vaccines. However, most small-size proteins are poorly immunogenic, and adjuvants, whose mode of action remain to be fully clarified, are needed for increasing their immunogenicity. Here, we report the effects of short solubility controlling peptide tags (SCP-tags) on the immunogenicity of DENV3 envelope protein domain 3 (3ED3; 103 residues, 11.46 kDa) in ICR and Swiss albino model mice. The attachment of a 4-Ile SCP-tag (C4I-tag) increased the hydrodynamic radius of 3ED3 from 2.2 ± 0.09 to 111 ± 146 nm as assessed by dynamic light scattering in phosphate buffered saline at 37 • C, indicating that the C4I-tag oligomerized 3ED3. Immunization at 30 µg/dose showed that the untagged 3ED3 was not or poorly immunogenic, whereas the C4I-tag increased its immunogenicity by up to 39-fold as assessed by the IgG level measured using ELISA. Moreover, the increased antibody level was sustained for over 6 months after immunization and a high number of effector and central memory T cells were generated. These observations provide solid and quantitative evidence for the hypothesis that subvisible aggregates with hydrodynamic radii of 100 nm can increase immunogenicity and that SCP-tag can establish a long-term, target-specific immune response in a way adequate for the development of a peptide/protein-based DENV vaccine.

The prevalence of cervical tolerogenic T cells correlates inversely with spontaneous regression of CIN. Cervical Tregs may play an important role in HPV-related neoplastic immunoevasion.