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Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.

Purpose To investigate whether a history of non–muscle-invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. Patients and Methods A total of 282 patients who were diagnosed with cT2-T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n = 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n = 51). Results The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P = .004). Five-year recurrence-free survival and cancer-specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P = .039) and 76.1% versus 61.6% (P = .005), respectively. Progressive MIBC (hazard ratio, 2.170; P = .008) was independently associated with cancer death. In the primary MIBC group, the 5-year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P = .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. Conclusion MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy.

The microvascular density detected by markers of endothelial cells (ECs), such as CD31 and CD34, is considered to be a biomarker for angiogenesis, and it is generally associated with the malignant potential of solid tumors. However, there is a conflicting relationship between the microvascular density and prognosis in clear-cell renal cell carcinoma (ccRCC) patients. It may be explained by the suggestion that the microvascular density cannot fully reflect the angiogenic activity in ccRCC, as the markers of ECs are expressed by both quiescent and activated ECs. To investigate the real angiogenic activity, we examined vasohibin-1 (VASH1), a recently identified regulator of angiogenesis, which was demonstrated to be specifically expressed by ECs of newly formed blood vessels. Expression of VASH1 and CD34 were immunohistochemically examined in 116 primary untreated ccRCCs, 10 metastatic untreated ccRCCs, and 9 metastatic ccRCCs treated with sunitinib. ECs in the tumor microvessels were sporadically immunostained for VASH1, although no VASH1 staining was observed in the non-neoplastic renal tissues. CD34 was ubiquitously expressed by all ECs in both ccRCC and non-neoplastic renal tissues. Multivariate Cox analysis indicated that an elevated VASH1 density, but not microvascular density, was a significant and independent predictor of overall survival (odds ratio, 7.71; P=0.003). The microvascular density was significantly decreased in the sunitinib-treated metastases compared with untreated tumors (P=0.001). On the other hand, the VASH1 density was significantly higher in the metastatic ccRCCs treated with sunitinib compared with non-treated ones (P=0.010), indicating that VASH1 may be associated with the resistance of ECs to sunitinib treatment. Thus, VASH1 expression may reflect the actual activity of angiogenesis, and VASH1 can serve as a new prognostic and predictive biomarker in patients with ccRCC.

Relative dose intensity (RDI) is a simple index for evaluation of the amount of drug administered per unit time. We retrospectively investigated the prognostic impact of RDI for patients with metastatic renal cell carcinoma (mRCC) treated with second-line targeted therapy.We enrolled 168 patients with mRCC. We assessed RDI at 4 weeks after second-line targeted therapy induction.The median follow-up after second-line targeted therapy was 18.1 months. The median time-to-treatment-failure (TTF) and overall survival (OS) were 4.9 and 25.4 months, respectively. In the Kaplan-Meier analysis, the median OS of patients with second-line RDI 0.7 was significantly shorter than those with RDI ≥ 0.7 (12.1 vs. 31.3 months; P = .030). In the subgroup analysis, second-line RDI was definitely prognostic in the poor-risk group of the International Metastatic Renal Cell Carcinoma Database Consortium criteria, showing second-line RDI was an independent predictor for both TTF (hazard ratio [HR], 3.6; 95% confidence interval [CI], 1.6-8.0; P = .002) and OS (HR, 3.1; 95% CI, 1.1-8.4; P = .026). Also, assessing the type of second-line regimen, the multivariate analysis showed that second-line RDI was an independent prognostic indicator of TTF (HR, 1.7; 95% CI, 1.0-2.9; P = .040) and OS (HR, 2.7; 95% CI, 1.3-5.7; P = .009) in patients treated with everolimus. In this group, the median TTF and OS of patients with RDI 0.7 were 2.4 and 11.1 months, and those with RDI ≥ 0.7 were 5.3 and 25.9 months, respectively.The results suggest that second-line RDI may be a prognostic predictor for patients with mRCC treated with second-line targeted therapy, particularly in both the International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and everolimus-treated group.

Two risk models, the Memorial Sloan Kettering Cancer Center (MSKCC) model and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, have been studied in metastatic renal cell carcinoma (mRCC) treated with targeted therapy.To validate externally the predictive accuracies of the MSKCC and IMDC models for prognosis in mRCC patients treated with first-line and subsequent second-line targeted therapy.A total of 311 patients were assessed retrospectively.All patients underwent targeted therapy.Survival outcomes were assessed using Kaplan-Meier analysis. The predictive ability was evaluated using the c-index.Regarding to the first-line targeted therapy, the 3-yr overall survival (OS) rates of the MSKCC (p0.001) and IMDC models (p0.001) were 76.2% and 77.3%, respectively, in the favorable-risk group; 46.7% and 47.9%, respectively, in the intermediate-risk group; and 13.4% and 15.6%, respectively, in the poor-risk group. The c-indexes were 0.68 for the MSKCC model and 0.69 for the IMDC model in a first-line setting. Regarding the second-line targeted therapy, the 1-yr OS rates of the MSKCC (p0.001) and IMDC models (p0.001) were 80.9% and 90.5%, respectively, in the favorable-risk group; 71.4% and 70.6%, respectively, in the intermediate-risk group; and 31.7% and 24.6%, respectively, in the poor-risk group. The c-indexes were 0.66 for the MSKCC model and 0.65 for the IMDC model in the second-line setting. The study is limited by its retrospective nature.The results may assist physicians in providing more appropriate patient counseling and imply the need for a future prognostic tool in mRCC treated with targeted therapy.Both risk models were useful for the risk stratification in metastatic renal cell carcinoma (mRCC) patients treated with first-line and second-line targeted therapy; however, it might be necessary to further update or optimize the models for our Japanese cohort of mRCC patients.

Background Previous studies showed the prognostic impact of preoperative levels of neutrophil-to-lymphocyte ratio (NLR), plasma fibrinogen, and serum C-reactive protein (CRP) in surgically treated upper tract urothelial carcinoma; however, few papers have discussed the proper use of these indices. Objective To investigate whether combinations of these three markers, as a cumulative marker score (CMS), improve the accuracy of prognostic models following radical nephroureterectomy (RNU). Design, setting, and participants A total of 394 patients from multiple institutions were included. Median follow-up was 30 mo. Intervention All patients underwent RNU without neoadjuvant chemotherapy. Outcome measurements and statistical analysis Associated outcomes were assessed using multivariate analysis. The CMS was defined as the number of elevated levels of preoperative NLR, plasma fibrinogen, and serum CRP. Results and limitations Multivariate analyses revealed that an increasing CMS was independently associated with high rates of disease recurrence, cancer-specific mortality, and all-cause mortality following RNU. Addition of the CMS to a model that included standard clinicopathologic predictors significantly improved predictive accuracy by 2.7% for disease recurrence, 3.9% for cancer-specific mortality, and 4.0% for all-cause mortality, which were the highest among other prognostic models using each marker alone or combinations of two. The study is limited by its retrospective nature. Conclusions Although the use of each inflammatory marker alone may be as predictive as clinicopathologic indices for prognosis, combinations like CMS can provide more accurate prognostic models following RNU. Patient summary Elevation of blood-based inflammatory markers may be useful for predicting prognosis because of their low cost and accessibility. Among blood-based indices, we examined the efficacy of preoperative neutrophil-to-lymphocyte ratio, plasma fibrinogen, and serum C-reactive protein levels. Although use of each marker alone provides additional prognostic information, the combination of all three markers would be more predictive than any single marker or combinations of two.

Few studies have discussed the prognostic impact of serum C-reactive protein (CRP) level in upper tract urothelial carcinoma (UTUC).To investigate whether the perioperative level of CRP provides additional prognostic information following radical nephroureterectomy (RNU).A total of 564 patients with UTUC from a retrospective multi-institutional cohort were included. The median follow-up was 32 mo.All patients underwent RNU without neoadjuvant chemotherapy, while 106 patients (18.8%) received adjuvant chemotherapy.Associations between perioperative CRP level and outcome were assessed using multivariate analysis. A serum CRP level0.50mg/dl was defined as elevated.Preoperative CRP (pre-CRP) level was elevated in 136 patients (24.1%). Multivariate analysis showed that pre-CRP elevation was an independent predictor of subsequent disease recurrence (hazard ratio [HR]: 1.47 for CRP 0.51-2.00; HR: 1.89 for CRP2.00). Five-year recurrence-free survival rates were 69.2% in patients with pre-CRP levels ≤ 0.50 mg/dl, 54.3% in patients with pre-CRP levels between 0.51 and 2.00 mg/dl, and 35.4% in patients with pre-CRP levels2.00 mg/dl (p0.001). Similar results were found in cancer-specific mortality, showing that pre-CRP elevation was an independent predictor of worse outcome (HR: 1.74 for CRP 0.51-2.00; HR: 2.31 for CRP2.00). In a subgroup analysis of the elevated pre-CRP group, postoperative normalisation of CRP level was an independent predictor of better outcome. This study is limited by its retrospective nature as well as its heterogeneous group of patients and variable follow-up protocols resulting from the multi-institution design.Serum CRP may become a possible biomarker in UTUC, suggesting that patients with an elevated pre-CRP level could be predicted to have subsequent disease recurrence and cancer-specific mortality, while postoperative normalisation of CRP level was an independent predictor for prognosis.

Caldicellulosiruptor bescii is a cellulolytic/hemicellulolytic anaerobe, which extracellularly secretes various proteins, including multidomain cellulases with two-catalytic domains, for plant biomass degradation. Degradation by C. bescii cells has been well characterized, but degradation by the cell-free extracellular cellulase/hemicellulase system (CEC) of C. bescii has not been as well studied. In the present study, C. bescii CEC was prepared from cell-free culture supernatant, and the degradation properties for defined substrates and non-pretreated plant biomass were characterized. Four multidomain cellulases (Cbes_1857, Cbes_1859, Cbes_1865, and Cbes_1867), composed of the glycoside hydrolase families 5, 9, 10, 44, and 48, were the major enzymes identified in the CEC by mass spectrometry. The CEC degraded xylan, mannose-based substrates, β-1,4-linked glucans, including microcrystalline cellulose (Avicel), and non-pretreated timothy grass and rice straw. However, degradation of chitin, pectin, dextran, and wheat starch was not observed. The optimum temperatures for degradation activities were 75°C for timothy grass and Avicel, 85°C for carboxylmethyl cellulose, and >85°C for xylan. The optimum pH for these substrates was 5–6. The degradation activities were compared with a CEC derived from the fungus Trichoderma reesei, the most common enzyme used for plant biomass saccharification. The amounts of degraded Avicel, timothy grass, and rice straw by C. bescii CEC were 2.2–2.4-fold larger than those of T. reesei CEC. The high hydrolytic activity of C. bescii CEC might be attributed to the two-catalytic domain architecture of the cellulases.

Arabinoxylans may account for up to 25% of the mass of grass cell walls. The interactions of these polysaccharides with themselves and with cellulose and lignin is believed to affect the walls physical properties and increase the walls resistance to biochemical conversion to fermentable sugars. Arabinoxylans have a backbone composed of 1,4-linked β- d -xylosyl residues, some of which are substituted at O -2 or O -3 with single arabinofuranosyl (Ara f ) residues. The Ara f residues are likely transferred from UDP-Ara f to the xylan backbone by arabinofuranosyltransferases. UDP-Ara f is itself formed from UDP-arabinopyranose (UDP-Ara p ) by UDP-arabinopyranose mutase (UAM). In this study, RNA interference (RNAi) was used to suppress UAM expression in rice plants and thereby reduce the amounts of UDP-Ara f available for cell wall synthesis. Several of the transgenic plants had reduced proportions of Ara f in their walls together with a decrease in the extent of substitution of the xylan backbone, and a reduction of between 25% and 80% in ferulic acid and p -coumaric acid contents of the cell walls. Those transgenic plants with >25% reduction in the amounts of Ara f were dwarfed and infertile.

Plants use UDP-arabinofuranose (UDP-Araf) to donate Araf residues in the biosynthesis of Araf-containing complex carbohydrates. UDP-Araf itself is formed from UDP-arabinopyranose (UDP-Arap) by UDP-arabinopyranose mutase (UAM). However, the mechanism by which this enzyme catalyzes the interconversion of UDP-Arap and UDP-Araf has not been determined. To gain insight into this reaction, functionally recombinant rUAMs were reacted with UDP-Glc or UDP-Araf. The glycosylated recombinant UAMs were fragmented with trypsin, and the glycopeptides formed were then identified and sequenced by LC-MS/MS. The results of these experiments, together with site-directed mutagenesis studies, suggest that in functional UAMs an arginyl residue is reversibly glycosylated with a single glycosyl residue, and that this residue is required for mutase activity. We also provide evidence that a DXD motif is required for catalytic activity.

Purpose The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model has been designed for prognostification in patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy. One factor is neutrophil count; however, increasing evidence has suggested the superiority of neutrophil-to-lymphocyte ratio (NLR) for predicting outcome. In this study, we evaluate the prognostic effect of NLR levels on patients with mRCC treated with targeted therapy, and then we compare the predictive accuracy of the IMDC risk model and its modified one by using NLR, instead of neutrophil count. Patients and method A total of 277 patients are included for the analysis. All patients underwent targeted therapies and associated outcome are assessed using multivariate analysis. Results Pretreatment NLR levels are elevated in 30.3% and 23.1% of patients in the first-line and subsequent second-line setting, respectively. Kaplan-Meier curves reveal that elevated pretreatment NLR is significantly associated with poor overall survival (OS) since first-line (P Conclusion Changes in NLR levels could be predictive for prognosis in patients with mRCC treated with first-line and second-line targeted therapy. The addition of NLR significantly improves the predictive accuracy of the IMDC risk model in the first-line and subsequent second-line setting.

Background and objective Few studies have addressed the predictive value of positive urine cytology for prognosis in patients with upper tract urothelial carcinoma (UTUC). We investigated whether the status of preoperative urine cytology could provide additional prognostic information following radical nephroureterectomy (RNU). Materials and methods The study included 474 patients with primary nonmetastatic UTUC (pTa-4N0M0) from a retrospective multi-institutional cohort. The median follow-up period was 35 months. Associations between the status of urine cytologic evaluation and outcomes were analyzed using multivariate Cox regression models. Urine cytology was evaluated preoperatively using voided samples. Disease recurrence was defined as any relapse in nonbladder lesions and was coded separately from intravesical recurrence. Results Positive urine cytology was detected in 184 patients (38.8%) preoperatively. Disease recurrence occurred in 127 patients, while intravesical recurrence occurred in 219 patients; 83 patients died of UTUC during follow-up. Kaplan-Meier analysis revealed that only the incidence of intravesical recurrence was significantly associated with the status of urine cytologic evaluation (P = 0.024); the intravesical recurrence-free survival rates at 1 and 3 years following RNU were 61.4% and 46.2% in patients with positive urine cytology and 71.1% and 51.6% in their counterparts, respectively. Multivariate analysis showed that gender (hazard ratio [HR] = 1.74, 95% confidence interval [CI]; 1.28–2.43), tumor multifocality in RNU specimens (HR = 1.64, 95% CI; 1.09–2.47), and positive urine cytology (HR = 1.41, 95% CI; 1.08–1.85) were independent risk factors for subsequent intravesical recurrence. Conclusions The results showed the prognostic value of positive urine cytology in patients with primary UTUC, and preoperative positive urine cytology may be associated with a significant increase in the prevalence of intravesical recurrence following RNU.