Validation of the risk stratification newly defined in the Japanese Urological Association guidelines 2019 for non-muscle invasive bladder cancer: A multi-institutional collaborative study.

OBJECTIVES: To validate the risk stratification newly defined in the Japanese Urological Association guidelines 2019 for non-muscle invasive bladder cancer and provide a more accurate stratification model for a heterogeneous intermediate-risk group. METHODS: A total of 1610 patients, who underwent transurethral resection, diagnosed with non-muscle invasive bladder cancer in nine collaborating hospitals were retrospectively reviewed. They were classified into low-risk, intermediate-risk, high-risk, and highest-risk groups, and recurrence-free survival, progression-free survival, cancer-specific survival, and overall survival were compared among the groups. The intermediate-risk group was subdivided into two groups based on the multivariable Cox regression model of recurrence and progression risk factors, and a revised risk model was created. RESULTS: The progression-free survival, cancer-specific survival, and overall survival were well stratified, while the recurrence-free survival of the intermediate-risk group was the shortest among the four groups (p < 0.001). The independent risk factors for recurrence and progression-free survival in the intermediate-risk group were as follows: age ≥ 70 years, sex, multiple tumors, tumor size ≥3 cm, and recurrent cases. The intermediate-risk group was subdivided into two groups: favorable intermediate-risk group and unfavorable intermediate-risk group. The revised risk model showed significant differences. CONCLUSION: We validated the Japanese Urological Association guidelines 2019 stratification model. The revised risk model provided a more accurate treatment selection for this disease subset.

A new risk stratification model for intravesical recurrence, disease progression, and cancer-specific death in patients with non-muscle invasive bladder cancer: the J-NICE risk tables.

BACKGROUND: The aim of this study is to establish new risk tables for the current clinical setting, enabling short- and long-term risk stratification for recurrence, progression, and cancer-specific death after transurethral resection in non-muscle invasive bladder cancer (NMIBC). Currently available risk tables lack input from the 2004 World Health Organization grading system and risk prediction for cancer-specific death. METHODS: This was a multi-institutional database study of 1490 patients diagnosed with NMIBC (the development cohort). A multivariate Fine and Gray subdistribution hazard model was used to assess the prognostic impact of various factors. Patients were classified into low-, intermediate-, and high-risk groups according to a sum of the weight of selected factors, and predicted cumulative rates were calculated. Internal validation was conducted using 200 bootstrap resamples to assess the optimism for the c-index and estimate a bias-corrected c-index. External validation of the developed risk table was performed on an independent dataset of 91 patients. RESULTS: The Japanese NIshinihon uro-onCology Extensive collaboration group (J-NICE) risk stratification table was derived from six, five, and two factors for recurrence, progression, and cancer-specific death, respectively. The internal validation bias-corrected c-index values were 0.619, 0.621, and 0.705, respectively. The application of the J-NICE table to an external dataset resulted in c-indices for recurrence, progression, and cancer-specific death of 0.527, 0.691, and 0.603, respectively. CONCLUSIONS: We propose a novel risk stratification model that predicts outcomes of treated NMIBC and may overcome the shortcomings of existing risk models. Further external validation is required to strengthen its clinical impact.

Comparison of the morphology of the rotator cuff muscles across age groups.

We aimed at investigating the morphological difference of the rotator cuff (RC) muscles among age groups from elementary school students to college students. The subjects included 10 college (22.6 ± 1.8 years), 10 high school (16.8 ± 0.6 years), 10 junior high school (13.9 ± 0.6 years), and 10 elementary school (10.4 ± 0.5 years) students. Consecutive oblique sagittal magnetic resonance T1 -weighted images of the dominant shoulder were acquired for each participant. Muscle length, maximal anatomical cross-sectional area (ACSA), the position of the maximal ACSA at full muscle length, muscle volume, and the individual-to-total RC muscle volume ratio for the supraspinatus, external rotators (infraspinatus and teres minor), and subscapularis were evaluated. The muscle length, maximal ACSA, and muscle volume in the RC muscles significantly increased with increasing age (P < 0.01), but there was no significant difference between college and high school students except in regard to the volume of the external rotators. There was no difference in the position of the maximal ACSA or the individual-to-total RC muscle volume ratio among the groups. The findings of this study show that the size of each RC muscle increases with increasing age, but the position of maximal ACSA and the proportion of each muscle to the total RC muscle volume are similar among age groups from elementary school students to college students.

[Case of primary retroperitoneal GIST (gastrointestinal stromal tumor) with rapid progression].

A 69-year-old man complaining of left abdominal pain was referred from a private clinic for retroperitoneal masses that were discovered on abdominal ultrasound in November 2010. CT scan showed retroperitoneal masses, located above the left kidney, measuring 10 cm. Para-aortic lymph nodes were swelling. We performed open biopsy to make the diagnosis in December 2010. The diagnosis was primary retroperitoneal GIST (gastrointestinal stromal tumor). We started imatinib 400 mg/day according to the Japan GIST guideline in January 2011. However the tumor pogressed rapidly, after 1 month the patient died.

Compact automated culture machine for human induced pluripotent stem cell maintenance and differentiation.

The technologies used to generate human induced pluripotent stem cell (iPSC) from somatic cells potentially enable the wide application of iPSC-derived differentiated cells in industrial research fields as a replacement for animals. However, as highly trained individuals are required to obtain reproducible results, this approach has limited social implementation. In the research field of iPSC, it is believed that documentable information is not enough for reproducing the quality of the differentiated cells. Therefore, automated culture machines for cell processing should make the starting of iPSC-using researches easier. We developed a programmable all-in-one automated culture machine, with dense and compact constitution that fits within a normal biosafety cabinet (200 mm wide, 233 mm height, and 110 mm depth). This instrument was fabricated using novel x-y-z-axes-rail-system, such as an overhead traveling crane, in a factory, which served as the main handling machinery. This machine enabled stable and efficient expansion of human iPSC under the feeder-free condition, without karyotype alterations, and simultaneously differentiated the cells into various cell types, including cardiomyocytes, hepatocytes, neural progenitors, and keratinocytes. Overall, this machine would facilitate the social implementation of human pluripotent stem cells and contribute to the accumulation of sharable knowledge for the standardization of the entire handling processes of iPSC in pharmaceutical, food, and cosmetic research.

Inositol 1,4,5-trisphosphate (IP3) receptor type1 (IP3R1) modulates the acquisition of cisplatin resistance in bladder cancer cell lines.

To investigate the molecules that regulate the acquisition of cis-diamminedichloroplatinum (II) (cisplatin) resistance, we performed cDNA microarrays using two pairs of parental and cisplatin-resistant bladder cancer cell lines. We found a markedly reduced expression of inositol 1,4,5-trisphosphate (IP3) receptor type1 (IP3R1), endoplasmic reticulum membrane protein, in cisplatin-resistant cells. The suppression of IP3R1 expression using small interfering RNA in parental cells prevented apoptosis and resulted in decreased sensitivity to cisplatin. Contrarily, overexpression of IP3R1 in resistant cells induced apoptosis and increased sensitivity to cisplatin. These results suggest that cisplatin-induced downregulation of IP3R1 expression was closely associated with the acquisition of cisplatin resistance in bladder cancer cells.

Gene expression analysis using a modified HiCEP method applicable to prokaryotes: a study of the response of Rhodococcus to isoniazid and ethambutol.

We established a novel method to analyze the gene expression of prokaryotes by modifying and optimizing the HiCEP (high coverage gene expression analysis) method, which was originally developed for eukaryotic gene expression profiling. Following the removal of abundant rRNA, the mRNA of prokaryotic cells was enzymatically polyadenylated and subjected to HiCEP analysis. This method was highly reproducible due to selective PCR that was performed by using adaptor specific primers. We confirmed induction of tipA and induction or suppression of cspA, which are genes that are obtained from distinctive actinomycetes and responded to thiostrepton and temperature stress, respectively. Further, we applied this method to explore the gene expression profile of Rhodococcus erythropolis in response to drugs that inhibit cell wall synthetic pathways, and we were able to identify 35 upregulated genes. Among these genes, we confirmed the upregulation of 22 genes by using RT-PCR (reverse transcriptase-polymerase chain reaction). Some of these genes are involved in the synthesis of mycolic acid and arabinogalactan, suggesting a cell response to drug treatment by regulation of the genes involved in cell wall synthesis. This method could prove to be a useful technique for gene expression analysis of prokaryotes, particularly nonmodel strains with unknown genome sequences.

A novel mechanism of nuclear factor kappaB activation through the binding between inhibitor of nuclear factor-kappaBalpha and the processed NH(2)-terminal region of Mig-6.

Mitogene-inducible gene-6 (Mig-6), an adaptor molecule containing the Cdc42/Rac interaction and binding (CRIB) domain, is rapidly induced by mitogenic and stressful stimuli, and sustained mig-6 expression is observed in chronic pathological conditions. The function of this molecule has remained elusive. We find that mig-6 is constitutively expressed in many human cancer cell lines, and Mig-6 is cleaved into the NH(2)-terminal region containing the CRIB domain and the remainder of the COOH-terminal region by limited proteolytic processing. We report here that full-length Mig-6, but not CRIB domain-deleted Mig-6 (DeltaMig-6) or uncleavable mutant of Mig-6 (Mig-6-S38A), induces transcriptional activation of nuclear factor of kappaB (NFkappaB), which is inhibited by inhibitor of kappaBalpha (IkappaBalpha), and that the processed NH(2)-terminal region of Mig-6 but not the full length is bound with IkappaBalpha through its NFkappaB binding region. These findings suggest that the processed CRIB domain of Mig-6 will compete with NFkappaB for IkappaBalpha and result in NFkappaB activation. This novel NFkappaB activation pathway provides new insights regarding tumorigenesis, and the specific inhibition of the cleavage of Mig-6 may be a target for clinical treatment.

Effects of strenuous exercise with eccentric muscle contraction: physiological and functional aspects of human skeletal muscle.

PURPOSE: we used magnetic resonance (MR) imaging and ultrasonography in combination with a dynamometer to assess physiological and functional aspects of the skeletal muscles after strenuous exercise that included eccentric contraction. METHODS: seven male subjects (mean age, 21.7 years) performed ankle plantar flexion that included eccentric contraction and underwent diffusion-weighted MR imaging for calculation of the apparent diffusion coefficient (ADC) of the triceps surae muscles. We used ultrasonography combined with a dynamometer to measure the displacement of the myotendinous junction (MTJ) of the medial gastrocnemius and maximal isometric force during ankle plantar flexion. We also assessed the level of muscle soreness of the calf using a visual analogue scale. We measured these parameters before exercise and one, 2, 3, 5, and 8 days after exercise and examined significant changes from the pre-exercise value using repeated-measures analysis of variance with Dunnett's test for each measurement parameter. RESULTS: one day after exercise, we observed increased muscle soreness (P<0.001) and decreased MTJ displacement (P<0.05); isometric force generation tended to decrease, but the change was not significant. Muscle soreness peaked 2 days after exercise (P<0.001) and remained significantly increased until 5 days after exercise (P<0.005). The medial gastrocnemius exhibited increased ADC value 3 days after exercise (P<0.005), but the lateral gastrocnemius and the soleus showed no significant changes throughout this study. CONCLUSION: our findings suggest that muscle damage induced by eccentric contraction manifests as muscle soreness and dysfunction early after exercise and later increases water diffusion within damaged muscle.

Effect of urea surface modification and photocatalytic cleaning on surface-assisted laser desorption ionization mass spectrometry with amorphous TiO2 nanoparticles.

We have investigated the effect of urea surface modification and the photocatalytic cleaning on surface-assisted laser desorption ionization mass spectrometry (SALDI-MS) with amorphous TiO2 nanoparticles for the reduction of the background noise and the improvement of the sensitivity. In the use of nanoparticles of high surface area, chemical background signals arising from ambient environments and organic contaminants can frequently be serious problems below 500 Da, possibly reducing the advantages of the matrix-free approach. In this study, removal of contaminants and enhanced SALDI efficiency were easily achieved with UV irradiation via the photocatalyst effect of TiO2 before SALDI-MS measurements. The surface cleaning achieved by the UV photocatalytic procedure reduced the background noise and increased the peak intensities of peptides. In addition, we found that urea surface modification of TiO2 nanoparticles increased the performance of the TiO2-SALDI-MS. (1) The urea-surface modification of TiO2 made it possible to produce proton-adduct forms without citrate buffer, resulting in low background noises below 500 Da, in contrast to the essential use of a citrate buffer in the bare TiO2-SALDI-MS. (2) The detection sensitivity of angiotensin I increased to 0.3 fmol with the urea-surface modification, as compared to the use of bare TiO2 nanoparticles (6 fmol). The urea-TiO2 could ionize proteins of more than 20,000 Da such as trypsinogen (600 fmol). (3) The urea modification of TiO2 had the advantage of selective detection of phosphopeptides without sample clean up, or prefractionation in tryptic digest products of bovine hemoglobin.

Dietary isoflavones may protect against prostate cancer in Japanese men.

We examined associations between nutritional and other lifestyle factors and the prevalence of prostate cancer in a case-control study of Japanese men. Two hundred patients and 200 age-matched controls (+/-5 y) were selected from 3 geographic areas of Japan. BMI, physical activity, occupation, family history of prostate cancer, and medical history were not associated with prostate cancer risk. Isoflavones and their aglycones (genistein and daidzein) were significantly associated with decreased risk. The odds ratio for the highest category (> or = 89.9 mg/d) compared with the lowest category (<30.5 mg/d) of isoflavone intake was 0.42 (95% CI = 0.24-0.72) and the linear trend was significant (P < 0.01). PUFA, (n-6) fatty acids, and magnesium were significantly associated with decreased risk but not after adjustment for isoflavone intake. Isoflavone intake was correlated with the intake of PUFA (r = 0.68, P < 0.001), (n-6) fatty acids (r = 0.69, P < 0.001), and magnesium (r = 0.56, P < 0.001), because soy products contain high levels of these nutrients. On the other hand, isoflavone significantly decreased the risk of prostate cancer regardless of adjustment by PUFA, (n-6) fatty acids or magnesium. In conclusion, our findings indicate that isoflavones might be an effective dietary protective factor against prostate cancer in Japanese men.

Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries.

We have developed an in silico method of selection of human full-length cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries. Fullness rates were increased to about 80% by combination of the oligo-capping method and ATGpr, software for prediction of translation start point and the coding potential. Then, using 5'-end single-pass sequences, cDNAs having the signal sequence were selected by PSORT ('signal sequence trap'). We also applied 'secretion or membrane protein-related keyword trap' based on the result of BLAST search against the SWISS-PROT database for the cDNAs which could not be selected by PSORT. Using the above procedures, 789 cDNAs were primarily selected and subjected to full-length sequencing, and 334 of these cDNAs were finally selected as novel. Most of the cDNAs (295 cDNAs: 88.3%) were predicted to encode secretion or membrane proteins. In particular, 165(80.5%) of the 205 cDNAs selected by PSORT were predicted to have signal sequences, while 70 (54.2%) of the 129 cDNAs selected by 'keyword trap' preserved the secretion or membrane protein-related keywords. Many important cDNAs were obtained, including transporters, receptors, and ligands, involved in significant cellular functions. Thus, an efficient method of selecting secretion or membrane protein-encoding cDNAs was developed by combining the above four procedures.

Multicentric papillary renal cell carcinoma associated with renal adenomatosis.

A case of multicentric papillary renal cell carcinoma (RCC) associated with renal adenomatosis in the bilateral kidneys is reported. Bilateral multiple renal cysts in a 46-year-old man were pointed out incidentally by ultrasonography. Some of the left renal lesions were considered to be RCC, and left radical nephrectomy was performed accordingly. The left kidney was occupied by numerous solid nodules, which ranged from yellow to tan in color, and some of the large ones had foci of hemorrhage and necrosis. Microscopically, most of the tumors showed papillary RCC associated with renal adenoma, while others consisted only of adenomas. Ten months later, multiple lesions of the right kidney, which were initially considered to be multiple cysts, were found to have become enlarged and some of them were diagnosed as RCC. Thus, right radical nephrectomy was also performed, and these tumors showed the same features as the left renal tumors. The patient's familial history was not remarkable. The kidneys revealed various histological features, ranging from dysplastic to adenoma or carcinoma, including transitional or overlapping features between them. The findings suggest an adenoma-carcinoma sequence in papillary RCC. It is worth considering such entities.

A case-control study of diet and prostate cancer in Japan: possible protective effect of traditional Japanese diet.

The age-adjusted incidence of prostate cancer is low in Japan, and it has been suggested that the traditional Japanese diet, which includes many soy products, plays a preventive role against prostate cancer. We performed a case-control study on dietary factors and prostate cancer in order to assess the hypothesis that the traditional Japanese diet reduces the risk of prostate cancer. Four geographical areas (Ibaraki, Fukuoka, Nara, and Hokkaido) of Japan were selected for the survey. Average daily intake of food from 5 years before the diagnosis was measured by means of a semi-quantitative food frequency questionnaire. We studied 140 cases and 140 individually age ( +/- 5 years)-matched hospital controls for analysis. Estimates of age-adjusted odds ratios (ORs) and linear trends were calculated by conditional logistic regression models with adjustment for cigarette smoking and total energy intake as confounding factors. Consumption of fish, all soybean products, tofu (bean curds), and natto (fermented soybeans) was associated with decreased risk. ORs of the fourth vs. first quartile and 95% confidence intervals (95%CIs) were 0.45 (0.20-1.02) for fish, 0.53 (0.24-1.14) for all soybean products, 0.47 (0.20-1.08) for tofu, and 0.25 (0.05-1.24) for natto. Consumption of fish and natto showed significantly decreasing linear trends for risk (P < 0.05). Consumption of meat was significantly associated with increased risk (the OR of the second vs. first quartile was 2.19, 95%CI 1.00-4.81). Consumption of milk, fruits, all vegetables, green-yellow vegetables, and tomatoes showed no association. Our results provide support to the hypothesis that the traditional Japanese diet, which is rich in soybean products and fish, might be protective against prostate cancer.