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The potential of the silica membrane reactors for use in the decomposition of hydrogen iodide (HI) was investigated by simulation with the aim of producing CO2-free hydrogen via the thermochemical water-splitting iodine-sulfur process. Simulation model validation was done using the data derived from an experimental membrane reactor. The simulated results showed good agreement with the experimental findings. The important process parameters determining the performance of the membrane reactor used for HI decomposition, namely, reaction temperature, total pressures on both the feed side and the permeate side, and HI feed flow rate were investigated theoritically by means of a simulation. It was found that the conversion of HI decomposition can be improved by up to four times (80%) or greater than the equilibrium conversion (20%) at 400 °C by employing a membrane reactor equipped with a tubular silica membrane. The features to design the membrane reactor module for HI decomposition of the thermochemical iodine-sulfur process were discussed under a wide range of operation conditions by evaluating the relationship between HI conversion and number of membrane tubes.

It is essential to understand the combined effects of elevated CO2 and temperature on phytoplankton-zooplankton link when attempting to predict climate change responses of freshwater ecosystems. Phytoplankton species differ in stoichiometric and fatty acids composition, and this may result in phytoplankton-mediated effect on zooplankton at elevated CO2 and temperature. Beyond the isolated analysis of CO2 or temperature effect, few studies have assessed zooplankton growth under the phytoplankton-mediated effects of elevated CO2 and temperature. In this study, three algal species (green alga, diatom, cyanobacteria) were fed on zooplankton Daphnia magna, under the conditions of CO2 concentrations of ambient (390 ppm) and elevated (1000 ppm) levels and temperatures at 20, 25 and 30 °C. Elevated CO2 increased the algal biomass, while it reduced the phosphorus (P) and ω3 polyunsaturated fatty acids (ω3 PUFAs) to carbon (C) ratios. Elevated temperature decreased the P/C ratios in all algal cultures and ω3 PUFAs/C ratios in the diatom and the cyanobacteria cultures. Phytoplankton-mediated effect of elevated CO2 reduced the growth of zooplankton fed on the green and the mixed three algae culture. The stimulation of zooplankton fed on the diatom and the cyanobacteria by elevated temperature can be offset by decreasing food P and ω3 PUFAs contents. The combined effects of elevated CO2 and temperature on the growth of daphnids were mainly mediated by ω3 PUFAs/C ratios in the phytoplankton. Rising temperature as a combined direct and indirectly phytoplankton-mediated effect on zooplankton may be able to ameliorate the negative effects of elevated CO2. The results indicated that the combined effects of increased CO2 and temperature increased the fatty acid content of the green alga but not the other algae. This study highlighted that climate change with simultaneously increasing temperature and CO2 may entangle the carbon transfer in freshwater planktonic communities.

Single cell analysis has gained attention as a means to investigate the heterogeneity of cells and amplify a cell with desired characteristics. However, obtaining a single cell from a large number of cells remains difficult because preparation of single-cell samples relies on conventional techniques such as pipetting that are labor intensive. In this study, we developed a system combining a 0.6-mm thin glass microfluidic device and machine vision approach to isolate single Euglena gracilis cells, as a model of microorganism with mobility, in a small/thin glass chamber. A single E. gracilis cell in a chamber was cultured for 4 days to monitor its multiplication. With this system, we successfully simplified preparation of single cells of interest and determined that it is possible to combine it with other analytical techniques to observe single cells continuously.

Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8

In general, the index lesion of prostate cancer has the largest tumor volume, the highest Grade Group (GG), and the highest stage (concordant cases). However, these factors sometimes do not coincide within one lesion (discordant cases). In such discordant cases, the largest tumor may not be of biological significance and the secondary tumor may more greatly impact the prognosis.We retrospectively reviewed the medical records of patients who underwent radical prostatectomy, and we identified 580 (85.3%) concordant cases and 100 (14.7%) discordant cases. The end point of this study was biochemical recurrence, and median followup was 4.2 years.Among discordant cases in which GGs of the largest tumor and the highest GG tumor differed, the majority (67 patients) had the largest tumor of GG 2, and we set them as the study cohort. On the other hand, we regarded 212 concordant cases with an index tumor of GG 2 as the control cohort. The study cohort comprised 48 (71.6%) patients with a secondary tumor of GG 3 and 19 (28.4%) with a secondary tumor of GG 4/5. Kaplan-Meier curves revealed that the 5-year biochemical recurrence-free survival rates were 76%, and 67%, respectively. The 5-year biochemical recurrence-free survival rate of the control cohort was 91%, which was significantly better than that of the study cohort (p=0.013 and p=0.014, respectively).Our study suggests that the prognosis of discordant cases is better determined by the secondary cancer lesion with the highest GG instead of the largest lesion.

Inducing apoptosis is an effective treatment for cancer. Conventional cytotoxic anticancer agents induce apoptosis primarily through activation of tumor suppressor p53 by causing DNA damage and the resulting regulation of B-cell leukemia/lymphoma-2 (BCL-2) family proteins. Therefore, the effects of these agents are limited in cancers where p53 loss-of-function mutations are common, such as triple-negative breast cancer (TNBC). Here, we demonstrate that ultraviolet (UV) light-induced p53-independent transcriptional activation of NOXA, a proapoptotic factor in the BCL-2 family, results in apoptosis induction. This UV light-induced NOXA expression was triggered by extracellular signal-regulated kinase (ERK) activity. Moreover, we identified the specific UV light-inducible DNA element of the NOXA promoter and found that this sequence is responsible for transcription factor Krüppel-like factor 4 (KLF4)-mediated induction. In p53-mutated TNBC cells, inhibition of KLF4 by RNA interference reduced NOXA expression. Furthermore, treatment of TNBC cells with a KLF4-inducing small compound, APTO-253, resulted in the induction of NOXA expression and NOXA-mediated apoptosis. Therefore, our results help to clarify the molecular mechanism of DNA damage-induced apoptosis and provide support for a possible treatment method for p53-mutated cancers.

We examined the antimicrobial susceptibility of 848 Escherichia coli isolates from 237 feces samples of wild sika deer (Cervus nippon) captured between 2016 and 2019 in 39 of the 47 prefectures of Japan. Five of the 237 wild sika deer (2.1%) carried E. coli with resistance to at least one antimicrobial, and all the resistant isolates showed resistance to tetracycline. The resistant isolates contained antimicrobial resistance genes that were similar to those in E. coli derived from humans and farm animals. Although wild sika deer are not currently likely to be a source for the transmission of antimicrobial resistance in Japan, they can potentially mediate antimicrobial resistance spread by coming into contact with humans, animals, and their surroundings.

Nudging is a method for eliciting a desired behavior. One approach to nudging involves information provision. When information presented for this purpose is designed from an evolutionary perspective, it may reveal a deeper level of rationality within human decision-making that might otherwise appear to be irrational. Based on insights from the evolution of altruism, we previously designed a message to remind people of the benefits they have received from the actions of relatives to realize industrialization. We then demonstrated that using this message in Japan was effective at moderating extreme risk-averse attitudes toward air pollution resulting from industrialization. However, the universality of the intervention effect, including whether it could be affected by exogenous factors, was not explored. Therefore, in the present study, we conducted a randomized controlled trial based on an online survey carried out in Japan, Canada, and the US. The intervention was shown to be effective in all the three countries, but the effect size varied according to segment. Although women showed more intervention effects than men in Japan and the US, no significant sex difference was observed in Canada. In terms of personality traits, higher agreeableness significantly contributed to the intervention effects. The influence of the COVID-19 pandemic, which necessitated many lifestyle changes, was found to weaken the intervention effect by increasing the message effect in the control group. We propose that this effect was caused by an increased perception of familial support in everyday life. These results suggest that the nudge message was universally effective, although the effect size might have been affected by cultural factors and social events.

Purpose The purpose of this study was to compare the high-resolution CT (HRCT) findings of pulmonary infectious and noninfectious complications with extensive ground-glass attenuation (GGA) in immunocompromised patients. Materials and methods One hundred fifty-two immunocompromised patients with pulmonary complications that showed extensive GGA (> 50% of the whole lung on HRCT) were included in this study. The diagnoses of the 152 patients were as follows: pneumocystis pneumonia (PCP), n = 82; drug-induced pneumonia, n = 38; bacterial pneumonia, n = 9; cytomegalovirus pneumonia, n = 6; idiopathic pneumonia syndrome, n = 6; diffuse alveolar hemorrhage (DAH), n = 4; fungal infection, n = 3; tuberculosis, n = 2 and pulmonary edema, n = 2. Two chest radiologists retrospectively evaluated the CT criteria, which consisted of 12 findings. Results The nodule (p = 0.015), the bronchovascular bundle (BVB) thickening (p = 0.001), and the interlobular septum (ILS) thickening (p = 0.002) were significantly infrequent in PCP. The ILS thickening was significantly frequent in drug-induced pneumonia (p p = 0.005). The nodule was significantly frequent in DAH (p = 0.049). Conclusion Nodules, BVB thickening, and ILS thickening could be useful HRCT findings for the differential diagnosis of pulmonary complications in immunocompromised patients with extensive GGA.

Background Routine use of neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP) is not recommended, but it is sometimes performed to reduce the prostate size and tumor volume or to prevent tumor progression during the wait times for surgery in clinical practice. On the other hand, the impact of NHT on the pattern of biochemical recurrence (BCR) is unknown. Methods We retrospectively examined 1749 consecutive patients who underwent RP between 1996 and 2017. Among the patients who met the inclusion criteria, BCR developed in 240 of non-NHT patients and in 120 of NHT patients during the mean follow-up period of 6.9 years. We examined the impact of NHT on the PSA-doubling time (DT) following BCR at different times after RP. Results The median PSA-DTs in non-NHT patients who experienced BCR in the first year after surgery, between 1 and 2 years, between 2 and 3 years, between 3 and 4 years, between 4 and 5 years, and at > 5 years were 5.5, 8.8, 11.3, 17.7, 18.2, and 18.4 months, respectively. On the other hand, those in NHT patients were 1.4, 4.1, 9.1, 13.4, 27.2, and 19.3 months, respectively. The differences of PSA-DTs in the first year after surgery (p

Background Alzheimer’s disease (AD) is assessed by carefully examining a patient’s cognitive impairment. However, previous studies reported inadequate diagnostic accuracy for dementia in primary care settings. Many hospitals use the automated quantitative evaluation method known as the Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD), wherein brain MRI data are used to evaluate brain morphological abnormalities associated with AD. Similarly, an automated quantitative evaluation application called the easy Z-score imaging system (eZIS), which uses brain SPECT data to detect regional cerebral blood flow decreases associated with AD, is widely used. These applications have several indicators, each of which is known to correlate with the degree of AD. However, it is not completely known whether these indicators work better when used in combination in real-world clinical practice. Methods We included 112 participants with mild cognitive impairment (MCI) and 128 participants with early AD in this study. All participants underwent MRI, SPECT, and the Mini-Mental State Examination (MMSE). Demographic and clinical characteristics were assessed by univariate analysis, and logistic regression analysis with a combination of MMSE, VSRAD and eZIS indicators was performed to verify whether the diagnostic accuracy in discriminating between MCI and early AD was improved. Results The area under the receiver operating characteristic curve (AUC) for the MMSE score alone was 0.835. The AUC was significantly improved to 0.870 by combining the MMSE score with two quantitative indicators from the VSRAD and eZIS that assessed the extent of brain abnormalities. Conclusion Compared with the MMSE score alone, the combination of the MMSE score with the VSRAD and eZIS indicators significantly improves the accuracy of discrimination between patients with MCI and early AD. Implementing VSRAD and eZIS does not require professional clinical experience in the treatment of dementia. Therefore, the accuracy of dementia diagnosis by physicians may easily be improved in real-world primary care settings.

High temperature gas-cooled reactor (HTGR) can be used in various ways such as hydrogen production and process heat supply as well as power generation. For the commercial HTGR, R&D on the system, and safety designs, key components for heat application and advanced fuel have been carried out by JAEA as shown in the following items: system design for power generation, system design for cogeneration, system design for steelmaking, safety design for connection of HTGR and heat application system, gas turbine technology for power generation, iodine–sulfur process technology for hydrogen production, system integration technology for connection of heat application system and HTGR, prevention technology for air ingress during depressurization accident, advanced fuel technology for high burnup, advanced fuel technology for plutonium burner, and advanced fuel technology for reduction of high-level radioactive waste. The final chapter explained research and development on the system and safety designs, key components for heat application and advanced fuel.

Creation of a seabed map is a significant task for various activities including safe navigation of vessels, commercial fishing and securing sea-mined resources. Conventionally, search machines including autonomous underwater vehicles or sonar systems have been used for this purpose. Here, we propose a completely different approach to improve the seabed map by using benthic (sting and electric) rays as agents which may explore the seabed by their autonomous behavior without precise control and possibly add extra information such as biota. For the first step to realize this concept, the detail behavior of the benthic rays must be analyzed. In this study, we used a system with a large water tank (10 m × 5 m × 6 m height) to measure the movement patterns of the benthic rays. We confirmed that it was feasible to optically trace the 2D and 3D movement of a sting and an electric ray and that the speed of the rays indicated whether they were skimming slowly over the bottom surface or swimming. Then, we investigated feasibility for measuring the sea bottom features using two electric rays equipped with small pingers (acoustic transmitters) and receivers on a boat. We confirmed tracing of the movements of the rays over the sea bottom for more than 90 min at 1 s time resolution. Since we can know whether rays are skimming slowly over the bottom surface or swimming in water from the speed, this would be applicable to mapping the sea bottom depth. This is the first step to investigate the feasibility of mapping the seabed using a benthic creature.

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle‐invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa‐4N0‐2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2‐4N0‐2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer‐specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non‐MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC., We conducted a multicenter cohort study describing the clinicopathological characteristics of muscle‐invasive bladder recurrence developed after surgical management of upper tract urothelial carcinoma.

Contactless particle manipulation based on a thermal field has shown great potential for biological, medical, and materials science applications. However, thermal diffusion from a high-temperature area causes thermal damage to bio-samples. Besides, the permanent bonding of a sample chamber onto microheater substrates requires that the thermal field devices be non-disposable. These limitations impede use of the thermal manipulation approach. Here, a novel manipulation platform is proposed that combines microheaters and an area cooling system to produce enough force to steer sedimentary particles or cells and to limit the thermal diffusion. It uses the one-time fabricated motherboard and an exchangeable sample chamber that provides disposable use. Sedimentary objects can be steered to the bottom center of the thermal field by combined thermal convection and thermophoresis. Single particle or cell manipulation is realized by applying multiple microheaters in the platform. Results of a cell viability test confirmed the method's compatibility in biology fields. With its advantages of biocompatibility for live cells, operability for different sizes of particles and flexibility of platform fabrication, this novel manipulation platform has a high potential to become a powerful tool for biology research.

A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabeled LAG-3, TIM-3, and TIGIT, we revealed that individual IR levels with exclusive domination in each tumour can be valid biomarkers for profiling human renal cell carcinoma (RCC). We uncovered the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validated our results and devised a workflow with optimal biomarker cut-offs for discriminating the tumour profiles of LAG-3, TIM-3, and TIGIT. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations on immunotherapy responses after targeting a new series of IRs.

A new cynipid species, Lithosaphonecrus mindatus Ide, Aung & Tanaka, sp. nov., is described from Chin State, northwestern Myanmar. This is the first record of Cynipidae from this country. The new species emerged from a bud gall of Lithocarpus thomsonii. The new species’ morphological features closely resemble L. arcoverticus Liu, Zhu & Pang, but differ from the latter due to the presence of a broad foveal septum on the mesoscutellum and short triangular median mesoscutal impression and absence of the anteroadmedian signum on the mesoscutum. Partial sequences of cytochrome c oxidase subunit I region (614 bp) show a 14–15% difference between the new species and other congeners.

Invasive alien tree species can exert severe impacts, especially in insular biodiversity hotspots, but have been inadequately studied. Knowledge of the life history and population trends of an invasive alien tree species is essential for appropriate ecosystem management. The invasive tree Bischofia javanica has overwhelmed native trees on Haha-jima Island in the Ogasawara Islands, Japan. We explored forest community dynamics 2 years after a typhoon damaged the Sekimon primary forests on Haha-jima Island, and predicted the rate of population increase of B. javanica using a logistic model from forest dynamics data for 19 years. During the 2 years after the typhoon, only B. javanica increased in population size, whereas populations of native tree species decreased. Stem diameter growth of B. javanica was more rapid than that of other tree species, including native pioneer trees. Among the understory stems below canopy trees of other species, B. javanica grew most rapidly and B. javanica canopy trees decreased growth of the dominant native Ardisia sieboldii. These competitive advantages were indicated to be the main mechanism by which B. javanica replaces native trees. The logistic model predicted that B. javanica would reach 30% of the total basal area between 2017 (in the eastern plot adjacent to a former B. javanica plantation) and 2057 (in the western plot distant from the plantation site), which is a maximum percentage allowing to eradicate under the present guideline of the National Forest. The results suggest immediate removal of B. javanica is required to preserve native biodiversity in these forests.

Patterned cell culturing is one of the most useful techniques for understanding the interaction between geometric conditions surrounding cells and their behaviors. The authors previously proposed a simple method for cell patterning with an agarose gel microstructure fabricated by microcasting with a degassed polydimethylsiloxane (PDMS) mold. Although the vacuum pressure produced from the degassed PDMS can drive a highly viscous agarose solution, the influence of solution viscosity on the casting process is unknown. This study investigated the influences of micro-channel dimensions or solution viscosity on the flow of the solution in a micro-channel of a PDMS mold by both experiments and numerical simulation. It was found experimentally that the degassed PDMS mold was able to drive a solution with a viscosity under 575 mPa·s. A simulation model was developed which can well estimate the flow rate in various dimensions of micro-channels. Cross-linked albumin has low viscosity (1 mPa·s) in aqueous solution and can undergo a one-way dehydration process from solution to solid that produces cellular repellency after dehydration. A microstructure of cross-linked albumin was fabricated on a cell culture dish by the microcasting method. After cells were seeded and cultivated on the cell culture dish with the microstructure for 7 days, the cellular pattern of mouse skeletal myoblast cell line C2C12 was observed. The microcasting with cross-linked albumin solution enables preparation of patterned cell culture systems more quickly in comparison with the previous agarose gel casting, which requires a gelation process before the dehydration process.

2-Methacryloyloxyethyl phosphorylcholine (MPC) polymers including hydrophobic units such as poly(MPC-co-butyl methacrylate) (PMB) and poly(MPC-co-dodecyl methacrylate) (PMD) are used as coating agents for medical devices because of their antifouling effects. In this study, the whole hydration process of MPC polymer-coated surfaces was investigated using air-injection-mediated liquid exclusion (AILE) methods in which the liquid exclusion diameter during air injection was correlated to the water-repelling property. The prejetted and standard AILE methods showed the initial change from a dry to a wet state and the swelling behaviors of the MPC polymers, respectively. The liquid exclusion diameter of the MPC polymer-coated surfaces increased with an increase in the immersion time in various aqueous solutions such as deionized water, phosphate-buffered saline (PBS), and cell culture media. Moreover, the liquid exclusion diameter of the PMD-coated surface was larger than that of the PMB-coated one. Ellipsometry directly indicated the polymer layers swollen in water. Scanning probe microscopy (SPM) revealed that nanosized protuberances were formed in water, especially at the PMD-coated surface. The different swelling behaviors of these MPC polymer-coated surfaces affected the liquid exclusion diameters. Thus, the AILE methods are a powerful tool to elucidate the hydration process in various liquid media.

The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5.We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC).The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4+5 and 29 patients with GS 5+4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4+5, and GS 5+4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4+5 than in GS 5+4 or higher (P .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4+5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5+4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P .001) greatly affected BCR.Our follow-up study revealed that men with GS 4+5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4+5 and GS 5+4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients.

INTRODUCTION AND OBJECTIVE:Because CBZ-resistant CRPC has an extremely poor prognosis, establishment of a novel treatment for CBZ-resistant CRPC is greatly needed. The aim of this study was to expl...

INTRODUCTION AND OBJECTIVE:Biochemical recurrence (BCR) after radical prostatectomy (RP) is most commonly diagnosed by detecting an asymptomatic prostate specific antigen (PSA) increase. PSA monito...

INTRODUCTION AND OBJECTIVE:Cabazitaxel (CBZ) has been identified as the most effective cytotoxic agent for improving survival in men with docetaxel-refractory castration-resistant prostate cancer (...

INTRODUCTIONAND OBJECTIVE: The relationship between malignant neoplasms and long non-coding RNA (lncRNA) have been emerging. Yet, little is known about cancerous lncRNA profiles due to lack of appr...

INTRODUCTION AND OBJECTIVE:Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for patients with locally advanced or metastatic urothelial carcinoma (UC). However, the phenotypic hal...

INTRODUCTION AND OBJECTIVE:Robot-assisted laparoscopic radical prostatectomy (RALP) is a valuable treatment option for clinically localized prostate cancer . However, RALP for larger prostates is a...

INTRODUCTION AND OBJECTIVE:AXL is the TAM family of receptor tyrosine kinases targeted by a new approved Cabozantinib in renal cell carcinoma (RCC). A growing body of evidence suggests a relationsh...

INTRODUCTION AND OBJECTIVE:Liposarcoma is one of the most common subtypes of soft tissue sarcoma. The tumor often develops in the lower extremities and the retroperitoneal or paratesticular region....

INTRODUCTION AND OBJECTIVE:Although Vesical Imaging-Reporting and Data System (VI-RADS) has introduced for additional diagnostic modality for bladder cancer (Bca) patients, the diagnostic accuracy ...

INTRODUCTION AND OBJECTIVE:The number of chronic renal failure has been rapidly growing. Further, not only in advanced nations, the number of dialysis patients continues to increase explosively eve...

The extracellular matrix (ECM) surrounding cancer cells becomes stiffer during tumor progression, which influences cancer cell behaviors such as invasion and proliferation through modulation of gene expression as well as remodeling of the actin cytoskeleton. In this study, we show that MMP24 encoding matrix metalloproteinase (MMP)-24 is a novel target gene of Yes-associated protein (YAP), a transcription coactivator known as a mechanotransducer. We first examined the effect of substrate stiffness on MMP24 expression in MCF-7 human breast cancer cells and showed that the expression of MMP24 was significantly higher in cells grown on stiff substrates than that on soft substrates. The MMP24 expression was significantly reduced by knockdown of YAP. In contrast, the expression of constitutively active YAP increased MMP24 promoter activity. In addition, binding of YAP to the MMP24 promoter was confirmed by the chromatin immunoprecipitation (ChIP) assay. These results show that ECM stiffening promotes YAP activation, thereby inducing MMP24 expression. Based on the Human Protein Atlas database, breast cancer patients with lower MMP24 expression exhibit the worse survival rates overall. Thus, MMP24 may negatively regulate the aggressiveness of cancer cells under the stiff ECM environment during tumor progression.

Objective The indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (RNU) or upfront RNU followed by adjuvant chemotherapy (AC). Materials and methods Among 966 UTUC patients, we identified 89 with clinical nodal involvement who received either NAC before RNU nor AC after upfront RNU. Cox proportional hazard models were employed to evaluate the impact of chemotherapy modality on the oncological outcomes. Results Of the patient cohort, 36 (40.4%) received NAC followed by RNU, whereas 53 (59.6%) underwent RNU followed by AC. Multivariate analysis revealed that tumor size ≥3 cm, clinical T4, and gemcitabine and cisplatin regimen were independent risk factors for disease recurrence, whereas NAC followed by RNU was an independent factor for favorable RFS. Furthermore, regarding cancer-specific survival (CSS), NAC followed by RNU remained an independent factor for favorable CSS. According to Kaplan-Meier analysis, the 1-year and 2-year RFS were 67.9% and 47.0%, respectively, in the NAC+RNU group, which were significantly higher than those in the RNU+AC group (43.9% and 24.6%, respectively, P = 0.006). Moreover, the 1-year and 2-year CSS were 80.5% and 64.2%, respectively, in the NAC+RNU group, which were higher than those in the RNU+AC group (68.6% and 48.2%, respectively, P = 0.016). Conclusion For node-positive UTUC patients, NAC followed by RNU was more clinically beneficial than RNU followed by AC.

Bacillus Calmette-Guerin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.

HER3, a member of the receptor tyrosine kinase super family, is overexpressed in a number of cancers, and is associated with malignant phenotypes. Control of the protein stability of the membrane, as well as nuclear receptors, has been known to be an important process affecting tumor cells; however, their relationships have yet to be elucidated. In this study, we demonstrate that estradiol promotes rapid degradation of HER3 via the proteasome pathway in ER-positive breast cancer, MCF-7. ER prevented HER3 degradation, and knockdown of ER expression by si-RNA promoted rapid degradation of HER3. Breakdown of HER3 and ER were regulated by a ubiquitin ligase Nedd4-1 in the presence of estradiol stimulation. We speculate that estradiol quickly degrades ER, making HER3 accessible by Nedd4-1, and leads to the rapid degradation of HER3. In addition, knockdown of ubiquitin ligase Nedd4-1 enhances estradiol induced cell proliferation. These results indicate that HER3 and Nedd4-1 in ER-positive breast cancers might be an important therapeutic target., Highlights • First time we found that estradiol promotes rapid degradation of HER3 in ER-positive breast cancer MCF-7 cells. • Knockdown of ubiquitin ligase Nedd4-1 decreased the degradation efficiency of HER3 in the presence of estradiol. • Knockdown of Nedd4-1 enhanced estradiol induced tumor cell proliferation.

Cancers acquire resistance to systemic treatment with platinum‐based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single‐cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA‐seq, we uncovered a novel gene, COX7B, associated with platinum‐resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA‐seq data from platinum‐naïve cancer cells demonstrated a low‐COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low‐COX7B subclone behaved as cells with acquired platinum‐resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum‐resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.

Interleukin-8 (IL-8) is a pro-inflammatory chemokine that is associated with induction of chemotaxis and degranulation of neutrophils. IL-8 is overexpressed in many tumors, including colon and lung cancer, and recent studies demonstrated essential roles for IL-8 in tumor progression within the tumor microenvironment. However, the molecular mechanism underlying the functions of IL-8 in tumor progression is unclear. In this study, we found that IL-8 is overexpressed in colon and lung cancer cells with cancer stem cell (CSC)-like characteristics and is required for CSC properties, including tumor-initiating abilities. These findings suggest that IL-8 plays an essential role in the development of CSCs. We also showed that IL-8 stimulation of colon and lung cancer cells-induced glucose uptake and expressions of glucose transporter 3 (GLUT3) and glucosamine fructose-6-phosphate aminotransferase (GFAT), a regulator of glucose flux to the hexosamine biosynthetic pathway, resulting in enhancement of protein O-GlcNAcylation. We demonstrated that these events are required for the generation and maintenance CSC-like characteristics of colon and lung cancer cells. Moreover, an O-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced O-GlcNAcylation is required for generation and maintenance of CSCs of colon and lung cancer cells and suggests this regulatory pathway as a candidate therapeutic target of CSCs.

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.