Biomedical subjects

Tomoaki Fujioka

Publications and source records attributed to Tomoaki Fujioka.

At least 19 recordsLinked to original sources

PubMed2007

Validation study of the prediction system for clinical response of M-VAC neoadjuvant chemotherapy.

To predict the efficacy of the M-VAC neoadjuvant chemotherapy for invasive bladder cancers, we previously established the method to calculate the prediction score on the basis of expression profiles of 14 predictive genes. This scoring system had clearly distinguished the responder group from the non-responder group. To further validate the clinical significance of the system, we applied it to 22 additional cases of bladder cancer patients and found that the scoring system correctly predicted clinical response for 19 of the 22 test cases. The group of patients with positive predictive scores had significantly longer survival than that with negative scores. When we compared our results with a previous report describing the prognosis of the patients with cystectomy alone, the results imply that patients with positive scores are likely to benefit from M-VAC neoadjuvant chemotherapy, but that the chemotherapy would shorten the lives of patients with negative scores. We are confident that our prediction system to M-VAC therapy should provide opportunities for achieving better prognosis and improving the quality of life of patients. Taken together, our data suggest that the goal of 'personalized medicine', prescribing the appropriate treatment regimen for each patient, may be achievable by selecting specific sets of genes for their predictive values according to the approach shown here.

Aged↗

PubMed2006

Eight year experience with Studer ileal neobladder.

BACKGROUND: We reviewed our experience with orthotopic continent urinary reconstruction after radical cystectomy to assess the feasibility of Studer ileal neobladder for patients who are relatively advanced in age. METHODS: Between June 1997 and January 2005, 31 consecutive male patients (mean age: 64 years) underwent lower urinary tract reconstruction after radical cystoprostatectomy. Perioperative and late complications, functional outcome of the neobladder, urinary continence, upper urinary tract status and renal function with the metabolic balance were evaluated in all patients. RESULTS: There was no perioperative death, and perioperative and late complication rates were 22.8% and 3.3%, respectively. All 31 patients were able to void urine. Although the mean maximal functional capacity of the neobladder was 122 ml at 1 month after surgery, the mean capacities were increased to 247 ml at 6 months and 321 ml at 1 year after the operation. Urodynamic results at 3 years showed unchanged characteristics as to micturition pattern and volume of residual urine and neobladder pressure remained low. Of 31 patients, 29 (93.5%) showed excellent or good continent status during the daytime and 9 (29%) were completely dry at night in 6 months after surgery. Even at 3 years after the operation, only 1 patient out of 21 evaluated required single pad during nighttime. In a subgroup of five patients (24%) older than 70 years, the status of continence was satisfactory at 3 years after the reconstruction, and only one patient required a pad during the night at that point. Renal function levels and metabolic status were comparable before surgery and 3 years after surgery. Moreover, pyelography revealed normal condition of the upper urinary tract 1 month postoperatively in almost all cases. CONCLUSIONS: These data provide evidence that Studer ileal neobladder is a satisfactory surgical technique for selected patients at our institute. Even for patients older than 70 years, this urinary diversion procedure is safe in terms of morbidity and efficacious as indicated by functional outcome.

Age Factors↗

PubMed2006

Expression of novel molecules, MICAL2-PV (MICAL2 prostate cancer variants), increases with high Gleason score and prostate cancer progression.

PURPOSE: The aim of this study is to identify novel molecular targets for development of novel treatment or diagnostic markers of prostate cancer through genome-wide cDNA microarray analysis of prostate cancer cells purified by laser microdissection. EXPERIMENTAL DESIGN AND RESULTS: Here, we identified molecule interacting with CasL-2 prostate cancer variants (MICAL2-PV), novel splicing variants of MICAL2, showing overexpression in prostate cancer cells. Immunohistochemical analysis using an antibody generated specific to MICAL2-PV revealed that MICAL2-PV was expressed in the cytoplasm of cancer cells with various staining patterns and intensities, whereas it was not or hardly detectable in adjacent normal prostate epithelium or prostatic intraepithelial neoplasia. Interestingly, immunohistochemical analysis of 105 prostate cancer specimens on the tissue microarray indicated that MICAL2-PV expression status was strongly correlated with Gleason scores (P < 0.0001) or tumor classification (P < 0.0001). Furthermore, the expression levels of MICAL2-PVs were also concordant to those of c-Met, a marker of tumor progression, with statistical significance (P = 0.0018). To investigate its potential of molecular therapeutic target for prostate cancers, we knocked down endogenous MICAL2-PVs in prostate cancer cells by small interfering RNA, which resulted in the significant reduction of prostate cancer cell viability. CONCLUSIONS: Our findings suggest that MICAL2-PV is likely to be involved in cancer progression of prostate cancer and could be a candidate as a novel molecular marker and/or target for treatment of prostate cancers with high Gleason score.

Adaptor Proteins, Signal Transducing↗

PubMed2006

A randomized comparative study of endocrine monotherapy and a combination of estramustine phosphate with the endocrine therapy in patients with untreated stage D prostate cancer.

BACKGROUND: We investigated the clinical efficacy and the prolongation of survival with combination therapy of estramustine phosphate (EMP) and endocrine therapy in untreated patients with progressive prostate cancer. METHODS: We randomly divided 57 patients with untreated stage D prostate cancer into two groups, an endocrine monotherapy group and a group receiving combination treatment, consisting of endocrine therapy plus EMP. Treatment was continued until deterioration. RESULTS: There were no significant differences in the improvement rating for subjective/objective symptoms or in progression-free survival between the two groups. However, overall survival was significantly prolonged in the combination therapy group (log-rank test, P = 0.0394; generalized Wilcoxon's test, P = 0.0145). In particular, overall survival was significantly prolonged, compared to that in the endocrine monotherapy group, in patients in the combination therapy group who were less than 74 years old, those with a performance status (PS) of 1 to 3, a pretreatment prostate-specific antigen (PSA) level of more than 20 ng/ml, moderately or poorly differentiated carcinoma, or a partial response (PR) based on the PSA level 12 weeks after the start of treatment. There was no significant difference in the incidence of side effects between the combination therapy and the endocrine monotherapy groups. CONCLUSION: A combination of EMP with endocrine therapy may be useful for initial treatment in younger patients (aged 73 or younger) and in patients at high risk of progressive prostate cancer.

Aged↗

PubMed2006

Stability of the BK polyomavirus genome in renal-transplant patients without nephropathy.

To clarify the stability of the BK polyomavirus (BKPyV) genome in renal transplant (RT) recipients, three to five complete BKPyV genomes from each of six RT recipients with surviving renal allografts were molecularly cloned. The complete sequences of these clones were determined and compared in each patient. No nucleotide difference was detected among clones in two patients, and a few nucleotide variations were found among those in four patients. In each of these patients a parental sequence (usually the major sequence), from which variant sequences (usually minor sequences) with nucleotide substitutions would have been generated, were identified. A comparison between the parental and variant sequences in each patient identified a single nucleotide substitution in each variant sequence. From these findings, it was concluded that the genome of BKPyV is stable in RT recipients without nephropathy, with only minor nucleotide substitutions in the coding region.

BK Virus↗

PubMed2006

Extraskeletal mesenchymal chondrosarcoma of the kidney.

A 61-year-old woman was referred for evaluation of an incidental mass found on the right kidney. Abdominal ultrasonography and computed tomography showed a 3-cm tumor with calcification and peripheral enhancement. Under the diagnosis of renal cell carcinoma, a transabdominal right radical nephrectomy was performed. The pathological diagnosis was extraskeletal mesenchymal chondrosarcoma of the kidney. No recurrence or metastasis occurred during a 6-year follow up. Primary renal chondrosarcoma is extremely rare, this being only the fifth case reported in the English literature, and the patient's extended survival is attributed to the small size of the tumor, as well as early diagnosis and treatment.

Bone Neoplasms↗

PubMed2006

Neonatal abdominal wall urinoma due to rupture of anterior urethral diverticulum.

An anterior urethral valve with diverticulum is an uncommon cause of congenital urethral obstruction and urinary extravasation compared with a posterior urethral valve. We report a neonate presenting with an abdominal wall urinoma caused by rupture of an anterior urethral diverticulum. Urine drainage via urethral catheter was effective to resolve the abdominal urinoma. Voiding cystourethrogram performed 6 months after an endoscopic incision of the distal margin of the diverticulum revealed a normal urethra with smooth voiding. To our knowledge, no similar case has been reported previously.

Abdominal Wall↗

PubMed2006

Myxoma of the kidney.

A 62-year-old man had a right renal mass incidentally diagnosed by ultrasonography. Magnetic resonance imaging revealed a well-defined right renal mass with homogenous low-signal intensity on the T(1)-weighted pulse sequence and heterogeneous high-signal intensity on the T(2)-weighted pulse sequence. A right nephrectomy was performed. The histological examination showed a myxoma, which is a very uncommon neoplasm in the kidney. Eight cases have been reported previously.

Diagnosis, Differential↗

PubMed2006

Comparative analysis of the S-intergenic region in class-II S haplotypes of self-incompatible Brassica rapa (syn. campestris).

In the Brassica self-incompatibility (SI) system, a pollen determinant, SP11, is involved in dominance/recessive relationships in pollen SI phenotypes. In order to gain some insights into the genomic structure around the SP11 and the mechanisms that give dominance/recessive relationships, we characterized the genomic region containing SP11 and SRK genes in three pollen recessive class-II S haplotypes. The direction of transcription of S genes was completely conserved among class-II S haplotypes. However, the region between SP11 and SRK (S-intergenic region) was highly polymorphic without short repetitive sequences. In addition, we found a sequence similarity between the short repetitive sequence and 5'-upstream region of SP11. This sequence similarity was found to be potentially related to the expression of dominance relationships through the change of chromatin structure.

Base Sequence↗

PubMed2006

Antiproliferative activity of root extract from gentian plant (Gentiana triflora) on cultured and implanted tumor cells.

We describe a novel pharmacological activity of the gentian root, an ingredient of Chinese medicines. Root extract from Gentiana triflora triggered cell death of human Daudi cells in culture. In addition, daily administration of the extract to mice inhibited growth of implanted solid tumors. Extract treatment of cultured cells resulted in the appearance of shranken, fragmented, or condensed cell and nuclear morphologies, and in chromosomal DNA degradation. But, the extract-treated cells did not show DNA fragmentation, which exhibits a nucleosome ladder, suggesting that extract-triggered cell death is not mediated through a typical apoptotic pathway.

Animals↗

PubMed2005

Genetic variations in the gene encoding TFAP2B are associated with type 2 diabetes mellitus.

To search a gene(s) conferring susceptibility to type 2 diabetes mellitus, we genotyped nearly 60,000 gene-based SNPs for Japanese patients and found evidence that the gene at chromosome 6p12 encoding transcription-factor-activating protein 2beta (TFAP2B) was a likely candidate in view of significant association of polymorphism in this gene with type 2 diabetes. Extensive analysis of this region identified that several variations within TFAP2B were significantly associated with type 2 diabetes [a variable number of tandem repeat locus: chi(2)=10.9, P=0.0009; odds ratio=1.57, 95% CI 1.20-2.06, intron 1+774 (G/T); chi(2)=11.6, P=0.0006; odds ratio=1.60, 95% CI 1.22-2.09, intron 1+2093 (A/C); chi(2)=12.2, P=0.0004; odds ratio=1.61, 95% CI 1.23-2.11]. The association of TFAP2B with type 2 diabetes was also observed in the UK population. These results suggest that TFAP2B might be a new candidate for conferring susceptibility to type 2 diabetes and contribute to the pathogenesis of type 2 diabetes.

Base Sequence↗

PubMed2005

PCOTH, a novel gene overexpressed in prostate cancers, promotes prostate cancer cell growth through phosphorylation of oncoprotein TAF-Ibeta/SET.

Through genome-wide cDNA microarray analysis coupled with microdissection of prostate cancer cells, we identified a novel gene, prostate collagen triple helix (PCOTH), showing overexpression in prostate cancer cells and its precursor cells, prostatic intraepithelial neoplasia (PIN). Immunohistochemical analysis using polyclonal anti-PCOTH antibody confirmed elevated expression of PCOTH, a 100-amino-acid protein containing collagen triple-helix repeats, in prostate cancer cells and PINs. Knocking down PCOTH expression by small interfering RNA (siRNA) resulted in drastic attenuation of prostate cancer cell growth, and concordantly, LNCaP derivative cells that were designed to constitutively express exogenous PCOTH showed higher growth rate than LNCaP cells transfected with mock vector, suggesting the growth-promoting effect of PCOTH on prostate cancer cell. To investigate the biological mechanisms of this growth-promoting effect, we applied two-dimensional differential gel electrophoresis (2D-DIGE) to analyze the phospho-protein fractions in LNCaP cells transfected with PCOTH. We found that the phosphorylation level of oncoprotein TAF-Ibeta/SET was significantly elevated in LNCaP cells transfected with PCOTH than control LNCaP cells, and these findings were confirmed by Western blotting and in-gel kinase assay. Furthermore, knockdown of endogenous TAF-Ibeta expression by siRNA also attenuated viability of prostate cancer cells as well. These findings suggest that PCOTH is involved in growth and survival of prostate cancer cells thorough, in parts, the TAF-Ibeta pathway, and that this molecule should be a promising target for development of new therapeutic strategies for prostate cancers.

Cell Growth Processes↗

PubMed2005

Hypoxia-inducible protein 2 (HIG2), a novel diagnostic marker for renal cell carcinoma and potential target for molecular therapy.

To identify molecules to serve as diagnostic markers for renal cell carcinoma (RCC) and as targets for novel therapeutic drugs, we investigated genome-wide expression profiles of RCCs using a cDNA microarray. We subsequently confirmed that hypoxia-inducible protein-2 (HIG2) was expressed exclusively in RCCs and fetal kidney. Induction of HIG2 cDNA into COS7 cells led to secretion of the gene product into culture medium and resulted in enhancement of cell growth. Small interfering RNA effectively inhibited expression of HIG2 in human RCC cells that endogenously expressed high levels of the protein and significantly suppressed cell growth. Moreover, addition of polyclonal anti-HIG2 antibody into culture medium induced apoptosis in RCC-derived cell lines. By binding to an extracellular domain of frizzled homologue 10 (FZD10), HIG2 protein enhanced oncogenic Wnt signaling and its own transcription, suggesting that this product is likely to function as an autocrine growth factor. ELISA analysis of clinical samples identified secretion of HIG2 protein into the plasma of RCC patients even at an early stage of tumor development, whereas it was detected at significantly lower levels in healthy volunteers or patients with chronic glomerulonephritis. The combined evidence suggests that this molecule represents a promising candidate for development of molecular-targeting therapy and could serve as a prominent diagnostic tumor marker for patients with renal carcinomas.

Animals↗

PubMed2005

Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide gene expression profiling.

PURPOSE: Neoadjuvant chemotherapy for invasive bladder cancer, involving a regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), can improve the resectability of larger neoplasms for some patients and offer a better prognosis. However, some suffer severe adverse drug reactions without any effect, and no method yet exists for predicting the response of an individual patient to chemotherapy. Our purpose in this study is to establish a method for predicting response to the M-VAC therapy. EXPERIMENTAL DESIGN: We analyzed gene expression profiles of biopsy materials from 27 invasive bladder cancers using a cDNA microarray consisting of 27,648 genes, after populations of cancer cells had been purified by laser microbeam microdissection. RESULTS: We identified dozens of genes that were expressed differently between nine "responder" and nine "nonresponder" tumors; from that list we selected the 14 "predictive" genes that showed the most significant differences and devised a numerical prediction scoring system that clearly separated the responder group from the nonresponder group. This system accurately predicted the drug responses of 8 of 9 test cases that were reserved from the original 27 cases. Because real-time reverse transcription-PCR data were highly concordant with the cDNA microarray data for those 14 genes, we developed a quantitative reverse transcription-PCR-based prediction system that could be feasible for routine clinical use. CONCLUSIONS: Our results suggest that the sensitivity of an invasive bladder cancer to the M-VAC neoadjuvant chemotherapy can be predicted by expression patterns in this set of genes, a step toward achievement of "personalized therapy" for treatment of this disease.

Aged↗

PubMed2005

Perinephric angiomyolipoma: a unique development pattern surrounding the kidney.

We report a case of a 31-year-old man with extrarenal angiomyolipoma of the perinephric space. He presented with asymptomatic macrohematuria. Computed tomography of the abdomen revealed a large perinephric mass which was separated from the right kidney and its unique growth appeared to have surrounded the kidney. Extrarenal angiomyolipomas of the perinephric fat are rare and they should be considered in the differential diagnosis of a retroperitoneal mass where asymptomatic macrohematuria was presented at the onset.

Adult↗

PubMed2005

Cardiovascular risk factors in hemodialysis patients: results from baseline data of kaleidoscopic approaches to patients with end-stage renal disease study.

BACKGROUND: The prevalence of cardiovascular risk factors and the prevalence of comorbidities in adult hemodialysis patients in Japan are not fully understood. METHODS: In "Kaleidoscopic Approaches to Patients with End-stage Renal Disease Study" (The KAREN Study, 2003), trained research stuff examined 1,214 adult hemodialysis patients (mean age, 61.2 years; 779 males and 435 females) of 1,506 patients in northern areas of Iwate Prefecture. Cardiovascular risk factors and the prevalence of comorbidities in hemodialysis patients were compared with those in the general population using direct age-adjustment methodology and standardized morbidity ratios (SMRs). RESULTS: In hemodialysis patients, common causes of end-stage renal disease were chronic glomerulonephritis (29.8%), diabetic nephropathy (24.5%), and other diseases. Prevalence and SMR of myocardial infarction were 5% and 9.6, respectively, and those of stroke were 13% and 5.7. The prevalences of hypertension and diabetes mellitus were 87% and 29%, respectively. Mean systolic blood pressure and mean diastolic blood pressure were 155 mmHg and 85 mmHg, respectively. Mean levels of total serum cholesterol, high-density lipoprotein cholesterol, and albumin in patients with end-stage renal disease were lower than those of the general population (160.6 vs. 203.3 mg/dL, 48.5 vs. 59.7 mg/dL, and 3.7 vs. 4.4 g/dL, respectively). Mean levels of C-reactive protein were higher than those of the general population (3.80 vs. 1.16 mg/L). CONCLUSION: Hemodialysis patients have a high prevalence of cardiovascular risk factors and comorbidities. Levels of nutrition-related markers were lower, and C-reactive protein levels were higher, in hemodialysis patients than in the general population.

Adult↗

PubMed2004

Association of a single-nucleotide polymorphism in the immunoglobulin mu-binding protein 2 gene with immunoglobulin A nephropathy.

Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis worldwide. The pathogenesis of IgA nephropathy is unknown, but it is certain that some genetic factors are involved in susceptibility to the disease. Employing a large-scale, case-control association study using gene-based single-nucleotide polymorphism (SNP) markers, we previously reported four candidate genes. We report here an additional significant association between IgA nephropathy and an SNP located in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2) at chromosome 11q13.2-q13.4. The association (chi2 =17.1, p = 0.00003; odds ratio of 1.85 with 95% confidence interval of 1.39-2.50 in a dominant association model) was found using DNA from 465 affected individuals and 634 controls. The SNP (G34448A) caused an amino acid substitution from glutamine to lysine (E928K). As the gene product is involved in immunoglobulin-class switching and patients with the A allele revealed higher serum levels of IgA (p = 0.048), the amino acid change might influence a class switch to increase serum IgA levels, resulting in a higher risk of IgA nephropathy.

Adult↗

PubMed2004

Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs.

To characterize the molecular feature in prostate carcinogenesis and the putative transition from prostatic intraepithelial neoplasia (PIN) to invasive prostate cancer (PC), we analyzed gene-expression profiles of 20 PCs and 10 high-grade PINs with a cDNA microarray representing 23,040 genes. Considering the histological heterogeneity of PCs and the minimal nature of PIN lesions, we applied laser microbeam microdissection to purify populations of PC and PIN cells, and then compared their expression profiles with those of corresponding normal prostatic epithelium also purified by laser microbeam microdissection. A hierarchical clustering analysis separated the PC group from the PIN group, except for three tumors that were morphologically defined as one very-high-grade PIN and two low-grade PCs, suggesting that PINs and PCs share some molecular features and supporting the hypothesis of PIN-to-PC transition. On the basis of this hypothesis, we identified 21 up-regulated genes and 63 down-regulated genes commonly in PINs and PCs compared with normal epithelium, which were considered to be involved in the presumably early stage of prostatic carcinogenesis. They included AMACR, OR51E2, RODH, and SMS. Furthermore, we identified 41 up-regulated genes and 98 down-regulated genes in the transition from PINs to PCs; those altered genes, such as POV1, CDKN2C, EPHA4, APOD, FASN, ITGB2, LAMB2, PLAU, and TIMP1, included elements that are likely to be involved in cell adhesion or the motility of invasive PC cells. The down-regulation of EPHA4 by small interfering RNA in PC cells lead to attenuation of PC cell viability. These data provide clues to the molecular mechanisms underlying prostatic carcinogenesis, and suggest candidate genes the products of which might serve as molecular targets for the prevention and treatment of PC.

Cell Division↗