Distinct Cytoplasmic Expression of KL-6 Mucin in Chromophobe Renal Cell Carcinoma: A Comparative Immunohistochemical Study with Other Renal Epithelial Cell Tumors

信州大学博士（医学）・学位論文・平成25年1月30日授与（乙第1152号）・福島 万奈The presence of cytoplasmic sialyl glycoproteins is a conspicuous feature in chromophobe renal cell carcinoma (RCC). We compared the immunohistochemical expression of sialyl glycoproteins in chromophobe RCC with that in other types of renal tumors. Formalin-fixed, paraffin-embedded tissues of surgically resected renal tumors (chromophobe RCC, 14 cases [10 cases of classic type and 4 cases of eosinophilic variant]; oncocytoma, 7 cases; and clear cell RCC, 9 cases) and kidneys from immature infants (4 cases) were immunostained with antibodies against sialyl glycoproteins (anti-KL-6 and anti-sialyl MUC1 antibodies). Cytoplasmic expression of KL-6 and sialyl MUC1 was distinctive in the chromophobe RCC and renal oncocytoma cells, and in the intercalated cells in collecting duct epithelia. Apical-surface staining of these sialyl glycoproteins was predominantly observed in clear RCC, in the epithelia of the distal tubule and collecting duct, and in the neonatal renal proximal tubule, but not in those of the adult renal proximal tubule. The above-mentioned observations provide additional evidence for similar phenotypic profiles of chromophobe RCC and renal oncocytoma, and the intercalated cells in collecting ducts and the oncofetal expression of sialyl glycoproteins in clear cell RCC. KL-6 is a potential tumor marker for renal tumors.ArticleACTA HISTOCHEMICA ET CYTOCHEMICA. 45(5) 301-308 (2012)journal articl

Analyzing the Relationship Between Poverty and Work: Exploring ways to solve the problem of the working poor (Japanese)

International comparison analyses have clarified that the relative poverty rate among working households in Japan is high. Based on this fact, this study analyzed the relationship between poverty and work, using the Keio Household Panel Survey 2004-2010 (KHPS). Our study showed that households where the head of the household is working as a temporary worker have a higher probability of being in poverty than households where the head of the household is unemployed and not engaged in any other income-earning activity. However, concerning the poverty dynamic, households where the head of the household is working in any capacity including temporary work are more likely to exit from poverty than households where the head of the household is not working. Needless to say, households where the head of the household is working as a regular worker have the least probability of falling into poverty, and shifting from temporary work to regular work is an effective solution for the working poor. Because of this fact, our study also analyzed the probability of shifting from temporary workers to regular workers. Results for women showed that those who invest in self-development are more likely to make the shift from temporary workers to regular workers; accordingly, investing in human capital—for instance, in the form of self-training—is important for making this shift. Moreover, among the unemployed who are in poverty, those receiving unemployment benefits and investing in job-training are more likely to get out from poverty than those not eligible for unemployment benefits. This implies that it is necessary to build a support system for those who are not eligible for unemployment benefits.

Secure and effective gene delivery system of plasmid DNA coated by polynucleotide

Polynucleotides are anionic macromolecules which are expected to transfer into the targeted cells through specific uptake mechanisms. So, we developed polynucleotides coating complexes of plasmid DNA (pDNA) and polyethylenimine (PEI) for a secure and efficient gene delivery system and evaluated their usefulness. Polyadenylic acid (polyA), polyuridylic acid (polyU), polycytidylic acid (polyC), and polyguanylic acid (polyG) were examined as the coating materials. pDNA/PEI/polyA, pDNA/PEI/polyU, and pDNA/PEI/polyC complexes formed nanoparticles with a negative surface charge although pDNA/PEI/polyG was aggregated. The pDNA/PEI/polyC complex showed high transgene efficiency in B16-F10 cells although there was little efficiency in pDNA/PEI/polyA and pDNA/PEI/polyU complexes. An inhibition study strongly indicated the specific uptake mechanism of pDNA/PEI/polyC complex. Polynucleotide coating complexes had lower cytotoxicity than pDNA/PEI complex. The pDNA/PEI/polyC complex showed high gene expression selectively in the spleen after intravenous injection into mice. The pDNA/PEI/polyC complex showed no agglutination with erythrocytes and no acute toxicity although these were observed in pDNA/PEI complex. Thus, we developed polynucleotide coating complexes as novel vectors for clinical gene therapy, and the pDNA/PEI/polyC complex as a useful candidate for a gene delivery system

Genetic Polymorphisms of IL-17F and TRAF3IP2 Could Be Predictive Factors of the Long-Term Effect of Infliximab against Crohn’s Disease

Background. We aimed to identify certain genes related to response to infliximab (IFX) and biomarkers to predict the IFX effect for Japanese Crohn\u27s disease (CD) patients by performing an association study of single nucleotide polymorphisms (SNPs) in candidate genes in the interleukin-(IL-) 17 signaling pathway with response to IFX after 1 year of treatment. Methods. A total of 103 patients were divided into two groups, responders and nonresponders. Twenty-eight tag SNPs in 5 genes were genotyped. The frequencies of alleles and genotypes of each SNP were compared between responders and nonresponders in three different inheritance models. A genetic test was performed using a combination of the associated SNPs as biomarkers. Results. Multivariate logistic regression analysis indicated that the four variable factors, concomitant use of immunomodulators, penetrating disease, a G/G genotype of rs766748 in IL-17F, and a C/C or C/A genotype of rs1883136 in TRAF3IP2, independently contributed to response to IFX after 1 year of treatment. Genetic test using the polymorphisms of these genes perfectly predicted the responder and nonresponder CD patients with both concomitant use of immunomodulators and penetrating disease. Conclusion. IL17F and TRAF3IP2 are one of IFX-related genes, useful as biomarkers of IFX response, and may be target molecules for new therapeutic drugs

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

P301S Mutant Human Tau Transgenic Mice Manifest Early Symptoms of Human Tauopathies with Dementia and Altered Sensorimotor Gating

Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions

前立腺癌におけるHNK-1(Leu-7)抗原の予後因子としての検討 免疫組織化学的検討

前立腺癌組織におけるHNK-1抗原の発現を抗HNK-1抗体を用いてABC法での免疫組織化学的に検討した。HNK-1抗原は52例中49例に陽性で, その反応性は癌の組織分化度と相関した。高分化癌で陽性癌細胞の比率が最も高く, 低分化癌でもっとも低かった。進行癌での反応性は弱くなる傾向があったが, 各臨床病期間に統計学的に有意な反応性の違いはなかった。内分泌療法を受けた33例のstage D2症例について, HNK-1抗原が3分の2以上陽性のグループが3分の2未満のグループに比べて有意に良好な生存率と非進展率を示したThe anti-HNK-1 (Leu-7) monoclonal antibody (MAb) was revealed to be reactive with noncancerous and cancerous prostatic epithelial cells, although this antibody was originally found to be reactive against natural killer cells. However, the prognostic significance of HNK-1 antigen in prostatic cancer patients remains unknown. The expression of HNK-1 antigen on prostatic cancer was investigated immunohistochemically using the avidin-biotin-peroxidase complex (ABC) method with the anti-HNK-1 monoclonal antibody. Of the 52 patients with prostatic cancer, 49 patients (94%) showed reactivity to anti-HNK-1 MAb and the immunoreaction was associated with the histological differentiation of prostatic cancer. Well differentiated cancer showed the highest percentage of positively stained cancer cells and poorly differentiated cancer showed the lowest percentage. No statistically significant differences existed between groups classified by stage, although the more advanced cancers tended to have weaker reactions. The five-year survival rate and interval free of progression were then studied using the Kaplan-Meier method on 33 patients with stage D2 disease who had received endocrine therapy. The findings indicated that a high survival rate and a longer interval free of progression were associated with a higher fraction of positively stained cancer cells. In conclusion, the expression of HNK-1 antigen on prostatic cancer may be a useful prognostic factor in patients with prostatic cancer

Distinct Cytoplasmic Expression of KL-6 Mucin in Chromophobe Renal Cell Carcinoma: A Comparative Immunohistochemical Study with Other Renal Epithelial Cell Tumors

The presence of cytoplasmic sialyl glycoproteins is a conspicuous feature in chromophobe renal cell carcinoma (RCC). We compared the immunohistochemical expression of sialyl glycoproteins in chromophobe RCC with that in other types of renal tumors. Formalin-fixed, paraffin-embedded tissues of surgically resected renal tumors (chromophobe RCC, 14 cases [10 cases of classic type and 4 cases of eosinophilic variant]; oncocytoma, 7 cases; and clear cell RCC, 9 cases) and kidneys from immature infants (4 cases) were immunostained with antibodies against sialyl glycoproteins (anti-KL-6 and anti-sialyl MUC1 antibodies). Cytoplasmic expression of KL-6 and sialyl MUC1 was distinctive in the chromophobe RCC and renal oncocytoma cells, and in the intercalated cells in collecting duct epithelia. Apical-surface staining of these sialyl glycoproteins was predominantly observed in clear RCC, in the epithelia of the distal tubule and collecting duct, and in the neonatal renal proximal tubule, but not in those of the adult renal proximal tubule. The above-mentioned observations provide additional evidence for similar phenotypic profiles of chromophobe RCC and renal oncocytoma, and the intercalated cells in collecting ducts and the oncofetal expression of sialyl glycoproteins in clear cell RCC. KL-6 is a potential tumor marker for renal tumors

Perioperative dynamics and significance of plasma-free amino acid profiles in colorectal cancer

Abstract Background For early detection of cancer, we have previously developed the AminoIndex Cancer Screening (AICS) system, which quantifies 6 plasma-free amino acids (PFAAs) in blood samples. Herein, we examined the usefulness of the AICS in patients with colorectal cancer (CRC) by comparing the preoperative and postoperative PFAA profiles. Methods Our study cohort consisted of 62 patients who had undergone curative resection for CRC at our cancer center, with no recurrence at the time of the study. Blood samples were collected from fasted patients within 1 week before the resection and at 0.5–6.5 years post-resection. Following plasmapheresis, the PFAA levels were measured via liquid chromatography/mass spectrometry, and the AICS values were computed (the higher the value, the greater the probability of cancer). Risk was calculated from the AICS value and ranked as A, B, or C, with rank C representing the highest risk. All patients in our study were rank B + C. Results The postoperative AICS value was lower than the preoperative value in 57 of the 62 patients; the rank was also lower postoperatively (49 patients, p < 0.001). The decline in both was stage-independent, even occurring in patients with right-sided tumors or poorly differentiated adenocarcinomas. For comparative purposes, the levels of 2 tumor markers (carbohydrate antigen 19–9 and carcinoembryonic antigen) were also examined; these were within the reference ranges in 70–80% of patients preoperatively and in 80–90% postoperatively. Conclusion We suggest that tumor-bearing conditions alter the PFAA profiles, which may be used to predict prognosis and monitor for recurrence in CRC patients after tumor resection. Trial registration This trial has been retrospectively registered at UMIN-CTR R000028005, Oct 06, 2016

The Effectiveness and Applicability of Compensatory Cognitive Training for Japanese Patients with Schizophrenia: A Pilot Study

Although cognitive remediation or training for schizophrenia has been developed, few studies on the subject have focused on Japanese patients. The aim of the present study was to examine the effectiveness and applicability of compensatory cognitive training (CCT) in Japanese patients with schizophrenia. Twenty-six participants diagnosed with schizophrenia were assigned to either the CCT plus treatment as usual group (n=13) or the treatment as usual alone group (n=13). CCT is a 12-session, manualized, group-based training that coaches compensatory strategies in four cognitive domains (prospective memory, attention, verbal memory, and executive functions). Cognitive, functional, and clinical symptom measures were implemented at baseline, after treatment, and at 3-month follow-up. Mixed design analyses of variance with group and time for each measure demonstrated that effects of CCT on verbal memory, processing speed, and social functioning at postintervention were significant, and the effects on processing speed were maintained at follow-up. Our study suggests that CCT has beneficial effects on cognitive performance, improving functional outcomes in Japanese patients with schizophrenia. Additionally, the high degrees of attendance rates and level of satisfaction rated by the CCT participants ensure the applicability of this methodology to this population