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β-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the β-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of β-Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between β-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting β-Catenin, and that WNK regulates the β-Catenin level. Furthermore, we show that WNK inhibitors induced β-Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of β-Catenin and a therapeutic target of cancer., Sato et al. find that WNK (With No Lysine [K]) acts as a positive regulator of the Wnt signaling pathway by attenuating the interaction between β-Catenin and the Glucose Induce degradation Deficient (GID) complex, and show that a WNK inhibitor also functions as a Wnt inhibitor, suppressing xenograft tumor development in mice. These findings suggest that WNK is a regulator of β-Catenin and a potential therapeutic target

Specimens of lichens collected from southern Myanmar including Tanintharyi and Yangon Regions were examined. As the result of taxonomic examinations, the following 20 species were identified: Astrothelium macrocarpum, Bulbothrix subscortea, Coccocarpia erythroxyli, C. palmicola, Cruentotrema thailandicum, Dirinaria aegialita, D. consimilis, Dyplolabia afzelii, Flakea papillata, Glyphis cicatricosa, Graphis cf. caesiella, G. desquamescens, G. supracola, Malmidea bakeri, Physcia undulata, Pyrenula mamillana, Pyxine dactyloschmidtii, Sarcographa labyrinthica, Trypethelium eluteriae, and Zwackhia prosodea. All of them, except the two species of Coccocarpia, are new records for Myanmar. The ITS rDNA sequences were successfully obtained from 17 samples for 14 species. The BLAST identities for Myanmar collections with the same species in GenBank range from 89 to 100%.

Intravesical bacillus Calmette–Guerin (BCG) is the standard of care for bladder carcinoma in situ (CIS). The response to BCG therapy against CIS is generally assessed by random bladder biopsy (RBB). In this study, we examined the necessity of routine RBB after BCG therapy. We retrospectively identified 102 patients who were initially diagnosed with CIS with or without papillary tumor and received subsequent 6–8-week BCG therapy. Thereafter, all patients underwent voiding cytology analysis, cystoscopy, and RBB to evaluate the effects of BCG therapy. We evaluated the association between clinical parameters (voiding cytology and cystoscopy findings) and the final pathological results by RBB specimens. According to the pathological results of RBB, 30 (29%) patients had BCG-unresponsive disease (remaining urothelial carcinoma was confirmed pathologically) and 20 were diagnosed with CIS. Positive/suspicious voiding cytology and positive cystoscopy findings were well observed in patients who had BCG-unresponsive disease compared with their counterparts (p = 0.116, and p

To clarify the emissions of volatile organic compounds (VOCs) from hen rearing in Japan, we collected air samples from inside a hen shed for the four seasons in 2019 and analyzed 34 VOCs in the air samples by gas chromatography-mass spectrometry and high performance liquid chromatography. The temperature and humidity inside and outside of the shed were monitored simultaneously during each sampling campaign. The average concentrations of VOCs in the shed ranged from 150 to 427 μg m-3, the concentrations being higher in summer and lower in winter. Acetone, dimethyl sulfide, 2-butanone, 2-pentanone, and acetic acid were dominant throughout all the seasons and these five compounds accounted for 70-89% of the total VOCs. The reactivity of each VOC with hydroxyl radical was also calculated and dimethyl sulfide was found to be the most reactive VOC, accounting for 84-94% of the total hydroxyl radical reactivity. The emission rate (ER) for the total VOCs (μg h-1 kg-1) was 602 in winter, 7,900 in spring, 46,500 in summer and 37,600 in autumn, respectively. Acetone, dimethyl sulfide, 2-butanone, 3-pentanone and acetic acid had higher ERs throughout all the seasons, and these five components accounted for 70-90% of the ERs for the total VOCs. The ERs of the VOCs increased exponentially in accord with temperature increases inside the shed, indicating that the ERs of the VOCs depended on the ambient temperature. The annual VOC emission from one hen and from the hen shed was calculated to be 405 g y-1 and 121 kg y-1, respectively.

This study demonstrates the rapid fabrication and utility of 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer film for cell patterning. The film was obtained on a cell culture surface by microcasting MPC polymer ethanol solution into a degassed polydimethylsiloxane mold with a desired pattern. After removal of the mold, 293AD cells were cultured on the surface of the polymer film with the patterned microstructures. Patterned cell adhesion restricted by the film was successfully maintained during at least a 168-h cultivation. The microcast MPC polymer film can be prepared rapidly and used for efficient long-term cell confinement.

To evaluate the oncological feasibility of pure laparoscopic radical nephroureterectomy (p-LRNU) for upper tract urothelial carcinoma (UTUC) compared with conventional LRNU (c-LRNU) using a propensity-adjusted multi-institutional collaboration dataset. Among the 503 UTUC patients who underwent RNU, we identified 219 who underwent c-LRNU (laparoscopic nephrectomy with open bladder cuff resection) and 72 who underwent p-LRNU (dissecting the kidney, ureter, and bladder cuff under complete laparoscopy). We adopted a propensity score (PS) matching method to achieve homogeneity with respect to patient backgrounds. PS matching-adjusted Cox-regression analysis was performed to evaluate the risk factors that influenced oncological outcomes. Sixty-eight p-LRNU and 68 c-LRNU patients were matched. Overall, 51 (37.0%) developed intravesical recurrence (IVR), 21 (15.4%) had disease recurrence, and 20 (14.7%) died. Patients who underwent p-LRNU had a significantly shorter operation time and less blood loss than those who underwent c-LRNU. Although no significant differences in 3-year recurrence-free survival were found between the two methods, atypical recurrence sites were observed in the p-LRNU group, including the brain, sigmoid colon, vagina, and peritoneum. Regarding IVR, the 3-year IVR-free survival rate was 41.8% in the p-LRNU group, which was significantly lower than that in the c-LRNU group (66.6%, p = 0.004). Multivariate analysis demonstrated that a history of bladder cancer, ureteral cancer, and p-LRNU were independent risk factors for subsequent IVR. Although p-LRNU is less invasive, the current technique may increase the incidence of atypical disease recurrence and subsequent IVR due to extravesical and intravesical tumor dissemination.

The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.

The thermochemical water-splitting iodine–sulfur (IS) process requires corrosion-resistant materials owing to usage of corrosive fluids, such as a mixture of HI–I2–H2O. Fluoropolymers, such as PTFE and PFA, are adaptable as lining materials for protecting plant components. However, there has been a concern: PTFE and PFA have the ability to permeate various permeants. From the viewpoint of corrosion of the base material, the permeation characteristics of HI and I2 should be evaluated to improve the integrity of the IS process. In this study, permeation tests on PTFE and PFA membranes were performed to measure the permeated fluxes of HI and I2, and the effects of the operating conditions on them were investigated. The introduction of a permeability parameter could be successful for normalizing the permeated fluxes for a specific membrane thickness and a vapor pressure. Then, the empirical formula of the permeability was given as an Arrhenius-type equation to use as a plant design. Finally, based on the results, the proper conditions for design of a lining material for the inhibition of HI and I2 permeation are summarized.

In the course of taxonomic studies on Zingiberaceae in Myanmar, a new species of Curcuma assignable to subgenus Ecomatae was discovered in Htamanthi Wildlife Sanctuary, Sagaing Region, northwestern Myanmar. It is described and illustrated here as Curcuma stolonifera. This new species differs from other species in subgenus Ecomatae Skornick. & Sida f. in having a combination of the following characters; long creeping rhizomes, an oblong-lanceolate lamina with reddish midrib, a small number of green bracts, a central inflorescence, pale whitish yellow flowers, and a short slightly L-shaped anther with a curved spur.

An electrochemical membrane Bunsen reaction using a cation exchange membrane (CEM) is a key to achieving iodine-sulfur (IS) thermochemical water splitting for the mass-production of hydrogen. In this study, we prepared a radiation-grafted CEM with a high ion exchange capacity (IEC) and a highly-porous Au-electroplated anode, and then used them for the membrane Bunsen reaction to reduce cell overvoltage. The high ionic content of our CEM led to low resistivity for proton transport, while the high porosity of the electrode led to a large effective surface area for anodic SO2 oxidation. The cell overvoltage for the membrane Bunsen reaction was significantly reduced to 0.21 V at 200 mA/cm2, one-third of that achieved using a commercial CEM and non-porous anode. From the analysis of the current-voltage characteristics, the grafted CEM was demonstrated to play a dominant role in the overvoltage reduction compared to the porous Au anode.

Biochemical recurrence (BCR) after radical prostatectomy (RP) is most commonly diagnosed by detecting an increase in asymptomatic prostate-specific antigen (PSA). We previously reported the “optimal PSA follow-up schedule after RP”. The aim of this study was to confirm the usefulness and safety of that follow-up schedule in another cohort. We retrospectively reviewed the clinicopathological data of 798 consecutive patients who underwent radical prostatectomy between 2009 and 2017. We examined all PSA values measured during follow-up. Furthermore, we estimated the PSA value when we observed the “optimal PSA follow-up schedule” at each timing in the virtual follow-up. BCR was defined as an elevation of PSA to greater than 0.2 ng/ml, and the ideal PSA range for detection of BCR was regarded to be 0.2–0.4 ng/ml. During the mean follow-up period of 5.8 years, BCR occurred in 115 (14.9%) patients and the frequency of virtual follow-up was significantly lower than the actual frequency. However, overlooking of BCR (detecting BCR when PSA exceeded 0.4 ng/ml) was observed in 17 patients, which is higher than the actual frequency of overlooking (12 patients). Therefore, we modified the follow-up schedule, which could achieve the lower follow-up frequency and a limited number of overlooking of BCR (7 patients). This external validation study revealed that the "modified optimal PSA follow-up schedule after RP" can reduce the frequency of PSA measurement with a limited risk of overlooking BCR.

To protect the audiosensory organ from tissue damage from the immune system, the inner ear is separated from the circulating immune system by the blood-labyrinth barrier, which was previously considered an immune-privileged site. Recent studies have shown that macrophages are distributed in the cochlea, especially in the spiral ligament, spiral ganglion, and stria vascularis; however, the direct pathogen defence mechanism used by audiosensory receptor hair cells (HCs) has remained obscure. Here, we show that HCs are protected from pathogens by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker’s organ) cells (GERCs). In isolated murine cochlear sensory epithelium, we established Theiler’s murine encephalomyelitis virus, which infected the SCs and GERCs, but very few HCs. The virus-infected SCs produced interferon (IFN)-α/β, and the viruses efficiently infected the HCs in the IFN-α/β receptor-null sensory epithelium. Interestingly, the virus-infected SCs and GERCs expressed macrophage marker proteins and were eliminated from the cell layer by cell detachment. Moreover, lipopolysaccharide induced phagocytosis of the SCs without cell detachment, and the SCs phagocytosed the bacteria. These results reveal that SCs function as macrophage-like cells, protect adjacent HCs from pathogens, and provide a novel anti-infection inner ear immune system.

CONTEXT The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear. OBJECTIVE To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy. DESIGN AND PATIENTS A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM). RESULTS PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P

Background Both pre-supplementary motor area (pre-SMA) and SMA-proper (SMA) must play important roles in visuomotor sequence learning. However, functional differences between the pre-SMA and SMA have not been well studied in humans. Objective To elucidate the functional differences between the pre-SMA and SMA in sequence learning in humans. Methods To induce LTP/LTD, we administered quadripulse transcranial magnetic stimulation (QPS) with an inter-stimulus interval of 5 or 50 ms (QPS-5/50) over the pre-SMA or SMA in healthy volunteers. The sham stimulation was also done as a control. We studied the effects of LTP/LTD in the pre-SMA/SMA on a new sequence learning and the performance of well-learned sequence by using sequence learning task called the “2 × 10 task”. Effects on the simple choice reaction time task were also studied for comparison. Results QPS-5 over the pre-SMA increased the error rate without any changes in movement speed. When administered over the SMA, QPS-5 decreased, and QPS-50 increased the rate of reaction time reduction across trials without changes in the error rate. QPS over neither the pre-SMA nor SMA affected the performances of a well-learned sequence or a simple choice reaction time task. Conclusions Our findings that QPS over the pre-SMA correlated with sequence learning performance and that over the SMA with execution speed are consistent with the previous results in animals and humans. Our results lend further support to the utility of QPS for modulating motor learning in humans.

Mallotus tokiae (Euphorbiaceae), a poorly known species, was described based upon a single fruiting specimen from Surat Thani Province, peninsular Thailand. We found this species with staminate and slightly mature pistillate flowers in Lampi Island, Myanmar. A new locality record, description of flowers, preliminary conservation assessment and DNA barcoding of this species are provided.

BackgroundTo investigate the impact of prostatic shape observed on preoperative magnetic resonance imaging (MRI) on the difficulty of robot-assisted laparoscopic radical prostatectomy (RALP).MethodsWe retrospectively reviewed the operative records of 211 patients who underwent RALP. We excluded patients who received neoadjuvant therapy. All surgeries in this study were performed by two surgeons. Each patient clinicopathological and surgical data were reviewed. Prostate sphericity was evaluated by measuring the roundness of the prostate at the largest axial slice by MRI. The console time was adopted as an objective indicator for assessing surgical difficulty.Results The mean prostate volume was 34 cc (range 14 to 88) and the mean prostate roundness was 0.55 (range 0.24 to 0.90). The mean console time was 194 minutes (range 95 to 296). To assess the relationship between prostate volume and console time, scatter plot analysis was performed. The prostate volume had a weak positive correlation with the console time (r =0.165, p=0.016). Similarly, scatter plot analysis between the prostate roundness and console time demonstrated a weak positive correlation (r =0.167, p=0.015) . Next, we performed subgroup analysis of 56 patients with a large prostate volume (≥ 40 cc), and the positive correlation between the prostate volume and the console time disappeared (r =0.142, p=0.296). On the other hand, the prostate roundness was more strongly correlated with the console time (r =0.439, p=0.001).ConclusionsOur results indicated that the spherical shape of the prostate is associated with the surgical difficulty of RALP, especially in patients with a large prostate volume.

The postoperative course of renal function remains unclear in Cushing syndrome. We examined changes in renal function after adrenalectomy in patients with Cushing syndrome and attempted to identify predictors of renal impairment.The study population comprised 76 patients who underwent adrenalectomy for Cushing and subclinical Cushing syndrome between 2001 and 2018. Renal function and other factors were evaluated pre-operation, at 1 postoperative month, and 1 postoperative year. We defined a ≥10% decrease in the estimated glomerular filtration rate at 1 postoperative year as renal impairment, and predictors associated with this reduction were investigated. The relationship between renal function and steroid replacement after surgery was also examined.Mean pre-operative estimated glomerular filtration rate was 82.2 ml/min/1.73 mThe pre-operative adrenocorticotropic hormone level was a predictor of renal function after adrenalectomy in patients with Cushing or subclinical Cushing syndrome.

To prospectively clarify whether endoscopic contact laser vaporization of the prostate (CVP) can be safely performed even in patients undergoing antithrombotic therapy.Fifty-five patients treated with CVP were enrolled. Patients were assigned to: (i) the antithrombotic therapy group (n = 21, 38%); or (ii) control group without antithrombotic therapy (n = 34, 62%). All patients in the antithrombotic therapy group continued all antithrombotic agents during the perioperative period and thereafter.No difference was noted in patient background between the two groups. In primary endpoints, decreases in the postoperative hemoglobin level were remarkable in the antithrombotic therapy group, while no serious effects were noted in either group. The control and antithrombotic therapy groups did not show a significant difference in the occurrence of catheter obstruction due to blood clots or serious hematuria following catheter removal. During follow-up, transurethral coagulation for hemostasis was needed only in the antithrombotic therapy group, with a frequency of transurethral coagulation of up to 14%. In secondary endpoints, no difference in the occurrence of perioperative or late-onset complications after surgery was noted between the two groups. Finally, no difference was noted in improvements in the International Prostate Symptom Score (IPSS), IPSS quality of life score, overactive bladder symptom score, maximum flow rate, or post-voiding residual urine volume between the two groups throughout the follow-up period.CVP can be performed safely and effectively in patients undergoing continuous antithrombotic therapy. However, the possibility of secondary bleeding after discharge in a subset of patients, such as those undergoing antithrombotic therapy, may be noted.

BackgroundThe aims of this study were (1) to clarify the impact of tertiary lymphoid structure (TLS) status on the outcome and immunogenomic profile of human clear cell renal cell carcinoma (ccRCC) and (2) to determine phenotypic differences in TLSs between different types of genitourinary cancer, that is, urinary ccRCC and bladder cancer.MethodsWe performed a quantitative immunohistological analysis of ccRCC tissue microarrays and conducted integrated genome mutation analysis by next-generation sequencing and methylation array analysis. Since the tumor immune microenvironment of ccRCC often differs from that of other cancer types, we analyzed the phenotypic differences in TLSs between ccRCC and in-house bladder cancer specimens.ResultsVarying distribution patterns of TLSs were observed throughout ccRCC tumors, revealing that the presence of TLSs was related to poor prognosis. An analysis of genomic alterations based on TLS status in ccRCC revealed that alterations in the PI3K-mTOR pathway were highly prevalent in TLS-positive tumors. DNA methylation profiling also revealed distinct differences in methylation signatures among ccRCC samples with different TLS statuses. However, the TLS characteristics of ccRCC and bladder cancer markedly differed: TLSs had the exact opposite prognostic impact on bladder cancer as on ccRCC. The maturity and spatial distribution of TLSs were significantly different between the two cancer types; TLSs were more mature with follicle-like germinal center organization and likely to be observed inside the tumor in bladder cancer. Labeling for CD8, FOXP3, PD-1, and PD-L1 showed marked differences in the diversity of the immune microenvironment surrounding TLSs. The proportions of CD8-, FOXP3-, and PD-L1-positive cells were significantly higher in TLSs in bladder cancer than in TLSs in ccRCC; rather the proportion of PD-1-positive cells was significantly higher in TLSs in ccRCC than in TLSs in bladder cancer.ConclusionThe immunobiology of ccRCC is unique, and various cancerous phenomena conflict with that seen in other cancer types; therefore, comparing the TLS characteristics between ccRCC and bladder cancer may help reveal differences in the prognostic impact, maturity and spatial distribution of TLSs and in the immune environment surrounding TLSs between the two cancers.

Climate change has the potential to cause forest range shifts at a broad scale and consequently can alter crucial forest functions, including carbon sequestration. However, global-scale projections of future forest range shifts remain challenging because our knowledge of the physiological responses of plants to climatic stress is limited to particular species and is insufficient for wide-range projections, in addition to the uncertainties in the impacts of non-climatic factors, such as wildfire, wind, and insect outbreaks. To evaluate the vulnerability and resilience of forests to climate change, we developed a new empirical approach using climatic indices reflecting physiological stressors on plants. We calculated the global distributions of seven indices based on primary climatic stressors (drought, solar radiation, and temperature) at high resolution. We then modeled the relationship between the seven indices and global forest extent. We found two key stressors driving climate-induced forest range shifts on a global scale: low temperature under high radiation and drought. At high latitudes of the Northern Hemisphere, forest establishment became difficult when the mean temperature was less than approximately 7.2 °C in the highest radiation quarter. Forest sensitivity to drought was more pronounced at mid-latitudes. In areas where the humidity index (ratio of precipitation to potential evapotranspiration) was below 0.45, shrubland and grassland became more dominant than forests. Our results also suggested that the impacts of climate change on global forest range shifts will be geographically biased depending on the areas affected by the key climatic stressors. Potential forest gain was remarkable in boreal regions due to increasing temperature. Potential forest loss was remarkable in current tropical grassland and temperate forest/grassland ecoregions due to increasing drought. Our approach using stress-reflecting indices could improve our ability to detect the roles of climatic stressors on climate-induced forest range shifts.

Simple Summary Triple-negative breast cancer is a subset of breast cancer that occurs frequently in young women and tends to exhibit aggressive, metastatic behavior. The therapeutic molecular targets found in other types of breast cancer are absent; therefore, this type of cancer has a poorer prognosis. To search for effective treatments for this type of cancer, we analyzed the effect of the DNA-demethylating agent, decitabine, which is commonly used in patients with myelodysplastic syndrome. We found that in triple-negative breast cancer cell subtypes, inhibition of cell death and cell growth in response to cisplatin, which is used to treat metastatic breast cancer, is enhanced when used in combination with decitabine. We also found that in decitabine-refractory cell subtypes, cisplatin alone is effective at inducing cell death. These results indicate the possibility of effective new combination therapies in triple-negative breast cancers. Abstract Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC.

Immune checkpoint inhibitor (ICI) therapy has caused a paradigm shift in cancer therapeutic strategy. However, this therapy only benefits a subset of patients. The difference in responses to ICIs is believed to be dependent on cancer type and its tumor microenvironment (TME). The TME is favorable for cancer progression and metastasis and can also help cancer cells to evade immune attacks. To improve the response to ICIs, it is crucial to understand the mechanism of how the TME is maintained. Protein arginine methyltransferase 5 (PRMT5) di-methylates arginine residues in its substrates and has essential roles in the epigenetic regulation of gene expression, signal transduction, and the fidelity of mRNA splicing. Through these functions, PRMT5 can support cancer cell immune evasion. PRMT5 is necessary for regulatory T cell (Treg) functions and promotes cancer stemness and the epithelial–mesenchymal transition. Specific factors in the TME can help recruit Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells into tumors. In addition, PRMT5 suppresses antigen presentation and the production of interferon and chemokines, which are necessary to recruit T cells into tumors. Overall, PRMT5 supports an immunosuppressive TME. Therefore, PRMT5 inhibition would help recover the immune cycle and enable the immune system-mediated elimination of cancer cells.

213 Background: Preclinical and clinical data from various types of cancer show that the gut microbiome can affect the outcome of treatments with immune checkpoint inhibitors or cytotoxic chemotherapies. However, the relationship between the microbiome and treatment outcomes in prostate cancer has remained unclear. Here, we present a comprehensive analysis of the relationship between the gut microbiome and treatment outcomes from a nationwide genome screening project (MONSTAR-SCREEN 1) in patients with metastatic castration-sensitive and -resistant prostate cancer (mCSPC and mCRPC). Methods: We performed 16S rRNA gene sequencing of fecal DNA from 73 mCSPC and 83 mCRPC patients before treatment. The microbiome data were compared using the Wilcoxon-Mann-Whitney test or Fisher’s exact test. Survival status and therapeutic efficacy of ADT based treatment were prospectively collected and estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival in different strata. Results: Fecal samples from mCRPC had more Klebsiella and Enterobacteriaceae than those from mCSPC, whereas mCSPC had more Akkermansia and Bifidobacterium compared to mCRPC. Prior and concurrent usage of anti-biotics did not affect diversity of the amplicon sequence variants (ASVs), KEGG orthology and metabolism pathway representation. Anti-biotics also did not influence time to treatment failure (TTF) in mCRPC (HR:0.81, 95%CI:0.36–1.78) and mCSPC (HR:1.35, 95%CI:0.55–3.34). mCRPC had more diverse KEGG orthology compared to mCSPC ( p=0.0009), however, no statistical differences were observed in the ASV ( p=0.77) and metabolism pathway representation ( p=0.35) between mCRPC and mCSPC. High ASV tended to be associated with longer TTF rather than low ASV in both mCRPC (Adjusted HR:0.63, 95%CI:0.34–1.10) and mCSPC (Adjusted HR:0.66, 95%CI:0.31–1.40). mCRPC patients with high AVS also showed significant longer PSA-progression free survival than patients with low ASV (HR:053, 95%CI:0.28–0.99). Conclusions: This investigation revealed significant differences in the microbiome status of mCRPC compared to mCSPC. These differences and diversity might influence the outcomes of ADT based treatment in prostate cancer.

680 Background: With the induction of targeted agents and immune checkpoint inhibitors, treatment strategies for systemic treatment of metastatic renal cell carcinoma (mRCC) have been changed with improved survival. However, those agents were approved based on phase 3 study results designed for clear cell mRCC. For patients with non-clear cell mRCC, those drugs designed for clear cell mRCC have also been used because no validated systemic therapy exists. This retrospective study aimed to identify patients with non-clear cell mRCC who benefit from systemic therapy. Methods: A total of 255 patients with mRCC were reviewed (Institutional review board approval No 2013-0425). Among them, 41 patients who pathologically diagnosed as non-clear cell mRCC and received systemic therapy were retrospectively analyzed. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each variable on progression free survival (PFS) and overall survival (OS) were investigated. OS for patients with non-clear cell mRCC was further investigated with univariate and multivariate Cox’s proportional hazards regression models. Results: After a median follow-up of 33.9 months after first line treatment initiation, the median PFS was 3.3 and 19.7 months for non-clear cell and clear cell RCC, respectively (p

Trochodendron aralioides Siebold & Zucc. is a relic tree that is discontinuously scattered across the mountainous areas of Japan, Taiwan, and South Korea, but the origin of T. aralioides in South Korea is still unclear and debated. To confirm its distribution and explore its origins, we constructed a streamlined framework to examine potential species distribution using multiple open access data and free and open-source software, as well as employing maximum entropy principles to predict the potential distribution of T. aralioides. The results showed reasonably good discrimination and were used to examine and discuss the explicit distribution of T. aralioides. The potential distribution of T. aralioides in Japan extended from Iriomote Island to approximately 37° N in Honshu on the Pacific Ocean side. In Taiwan, the potential distribution of T. aralioides was more common than in Japan. It occurred at 1500–3000 m a.s.l. across the Central Mountain Range and decreased toward the northern and southern tips, correlating to the descending pattern of the cloud belt. Thermal and moisture conditions were important factors to determine the distribution of T. aralioides. The potential distribution indicated that Jeju island had high potential as a habitat for T. aralioides, and that may indirectly imply its existence and origins in South Korea, as some researchers have noted.

Cancer stem cells (CSCs) have tumour initiation, self-renewal, and long-term tumour repopulation properties, and it is postulated that differentiated somatic cells can be reprogrammed to CSCs by oncogenic signals. We previously showed that oncogenic HRASV12 conferred tumour initiation capacity in tumour suppressor p53-deficient (p53−/−) primary mouse embryonic fibroblasts (MEFs) through transcription factor NF-κB-mediated enhancement of glucose uptake; however, the underlying mechanisms of RAS oncogene-induced CSC reprogramming have not been elucidated. Here, we found that the expression of the reprogramming factor SOX2 was induced by HRASV12 in p53−/− MEFs. Moreover, gene knockout studies revealed that SOX2 is an essential factor for the generation of CSCs by HRASV12 in mouse and human fibroblasts. We demonstrated that HRASV12-induced cyclin-dependent kinase 1 (CDK1) activity and subsequent enhancement of protein O-GlcNAcylation were required for SOX2 induction and CSC generation in these fibroblasts and cancer cell lines containing RAS mutations. Moreover, the CDK inhibitor dinaciclib and O-GlcNAcylation inhibitor OSMI1 reduced the number of CSCs derived from these cells. Taken together, our results reveal a signalling pathway and mechanism for CSC generation by oncogenic RAS and suggest the possibility that this signalling pathway is a therapeutic target for CSCs.

Although sensorineural hearing loss (SHL) is relatively common, its cause has not been identified in most cases. Previous studies have suggested that viral infection is a major cause of SHL, especially sudden SHL, but the system that protects against pathogens in the inner ear, which is isolated by the blood-labyrinthine barrier, remains poorly understood. We recently showed that, as audiosensory receptor cells, cochlear hair cells (HCs) are protected by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker’s organ) cells (GERCs) against viral infections. Here, we found that virus-infected SCs and GERCs induce HC death via production of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Notably, the HCs expressed the TRAIL death receptors (DR) DR4 and DR5, and virus-induced HC death was suppressed by TRAIL-neutralizing antibodies. TRAIL-induced HC death was not caused by apoptosis, and was inhibited by necroptosis inhibitors. Moreover, corticosteroids, the only effective drug for SHL, inhibited the virus-induced transformation of SCs and GERCs into macrophage-like cells and HC death, while macrophage depletion also inhibited virus-induced HC death. These results reveal a novel mechanism underlying virus-induced HC death in the cochlear sensory epithelium and suggest a possible target for preventing virus-induced SHL.

Background Cabozantinib is an oral tyrosine kinase inhibitor in renal cell carcinoma (RCC), whose targets include oncogenic AXL and unique ligand GAS6. Critical gaps in basic knowledge need to be addressed to devise an exclusive biomarker and candidate when targeting the AXL/GAS6 axis. Methods To clarify the effects of the AXL/GAS6 axis on RCC, we herein performed a large-scale immunogenomic analysis and single-cell counts including various metastatic organs and histological subtypes of RCC. We further applied genome-wide mutation analyses and methylation arrays. Results Varying patterns of AXL and GAS6 expression were observed throughout primary RCC tumours and metastases. Scoring individual AXL/GAS6 levels in the tumour centre and invasive margin, namely, the AXL/GAS6 score, showed a good ability to predict the prognosis of clear cell RCC. Metastasis- and histological subtype-specific differences in the AXL/GAS6 score existed since lung metastasis and the papillary subtype were weakly related to the AXL/GAS6 axis. Cell-by-cell immunohistological assessments clarified an immunosuppressive environment in tumours with high AXL/GAS6 scores. Genomic alterations in the PI3K-mTOR pathway and DNA methylation profiling revealed distinct differences with the AXL/GAS6 score in ccRCC. Conclusion The AXL/GAS6 scoring system could predict the outcome of prognosis and work as a robust biomarker for the immunogenomic state in RCC.

Kawasaki disease (KD) is an acute inflammatory syndrome of unknown etiology that is complicated by cardiovascular sequelae. Chronic inflammation (vasculitis) due to KD might cause vascular cellular senescence and vascular endothelial cell damage, and is a potential cause of atherosclerosis in young adults. This study examined the effect of KD and HMG-CoA inhibitors (statins) on vascular cellular senescence and vascular endothelial cells. Candida albicans water-soluble fraction (CAWS) was administered intraperitoneally to 5-week-old male apolipoprotein E-deficient (ApoE−) mice to induce KD-like vasculitis. The mice were then divided into three groups: control, CAWS, and CAWS+statin groups. Ten weeks after injection, the mice were sacrificed and whole aortic tissue specimens were collected. Endothelial nitric oxide synthase (eNOS) expression in the ascending aortic intima epithelium was evaluated using immunostaining. In addition, eNOS expression and levels of cellular senescence markers were measured in RNA and proteins extracted from whole aortic tissue. KD-like vasculitis impaired vascular endothelial cells that produce eNOS, which maintains vascular homeostasis, and promoted macrophage infiltration into the tissue. Statins also restored vascular endothelial cell function by promoting eNOS expression. Statins may be used to prevent secondary cardiovascular events during the chronic phase of KD.

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 immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs., Targeting the inhibitory receptors (IRs) LAG-3, TIM-3 and TIGIT is a promising immune-oncology approach and the identification of biomarkers of response is crucial. Here, the authors apply automated single-cell count for these IRs in human renal cell carcinoma and investigate the immunogenomic landscape of the disease.

INTRODUCTION The goal of partial nephrectomy for renal tumors is complete tumor removal with the preservation of renal function and no complications. Trifecta (total ischemia time

Reduced cortical plasticity has been previously reported in older adult as compared with young adults. However, the effects of dopamine on this plasticity reduction remain unknown. Here, we assessed the effects of high-dose (200 mg) and medium-dose (100 mg) L-3,4-dihydroxyphenylalanine (L-DOPA) intake on the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS) in older adults (aged ∼65 years). The subjects were 32 (200 mg) and 20 (100 mg) healthy older adult volunteers. This study was designed as a double-blind, crossover and placebo-controlled trial on one dose of L-dopa. Two hours after taking L-DOPA or placebo-drug, QPS was applied over the motor cortex. Motor evoked potentials were recorded to evaluate the motor cortical excitability changes. We found that both doses of L-DOPA enhanced LTP after QPS in older adults as one group. We classified subjects into QPS responders and QPS nonresponders. Both L-DOPA doses produced significant LTP enhancement in QPS nonresponders, whereas either of doses did not produce significant LTP enhancement in QPS responders. Collectively, our findings suggest that the neural plasticity reductions observed in older adults could be partly improved by dopamine.

The earliest colonisation of oceanic islands by Homo sapiens occurred ~50 000–30 000 years ago in the Western Pacific, yet how this was achieved remains a matter of debate. With a focus on East Asia, the research presented here tests the hypothesis that bamboo rafts were used for these early maritime migrations. The authors review the evidence for Palaeolithic seafaring in East Asia as the context for an experimental archaeology project to build two bamboo watercraft. Sea trials demonstrate the unsuitability of bamboo, at least in East Asia, indicating that more sophisticated and durable vessels would have been required to traverse the Kuroshio Current.

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.

In this study, the catalytic decomposition of hydrogen iodide was theoretically and experimentally investigated in a silica-based ceramic membrane reactor to assess the reactor's suitability for thermochemical hydrogen production. The silica membranes were fabricated by depositing a thin silica layer onto the surface of porous alumina ceramic support tubes via counter-diffusion chemical vapor deposition of hexyltrimethoxysilane. The performance of the silica-based ceramic membrane reactor was evaluated by exploring important operating parameters such as the flow rates of the hydrogen iodide feed and the nitrogen sweep gas. The influence of the flow rates on the hydrogen iodide decomposition conversion was investigated in the lower range of the investigated feed flow rates and in the higher range of the sweep-gas flow rates. The experimental data agreed with the simulation results reasonably well, and both highlighted the possibility of achieving a conversion greater than 0.70 at decomposition temperature of 400 °C. Therefore, the developed silica-based ceramic membrane reactor could enhance the total thermal efficiency of the thermochemical process.

To clarify the nature and characteristics of volatile organic compounds (VOCs) emitted from dairy cattle within a cattle shed located in Chiba, Japan, air samples were collected and analyzed for the four seasons in 2017-2018. Thirty-four VOCs were determined by gas chromatography-mass spectrometry and high performance liquid chromatography. In addition, air temperature and relative humidity inside and outside of the shed were monitored during each sampling campaign to estimate the ventilation rate of the shed. The average concentrations of total VOCs (μg m-3) in the shed in each season were 50.5 (spring), 128.4 (summer), 168.8 (autumn), and 199.5 (winter). Ketones were always the most dominant components followed by alcohols and volatile fatty acids (VFAs). The sum of ketones, alcohols, and VFAs accounted for more than 80% of the total VOCs in all seasons. Acetone, 3-pentanone, 1-butanol, and acetic acid were the major components regardless of the season, accounting for more than 60% of the total VOCs. The average emission rates of total VOCs from the shed (μg h-1 kg-1) were calculated to be 623 (spring), 1520 (summer), 585 (autumn) and 469 (winter). The emission rates of almost all the VOCs except alcohols increased exponentially with increase of air temperature in the shed. The ranges of the emission rates for each class of chemical (μg h-1 kg-1) were 39-170 (VFAs), 247-913 (ketones), 65-134 (alcohols), 40-122 (phenols), 10-122 (aldehydes), 4.17-22.3 (sulfur compounds), and 0.0067-0.74 (indoles). Furthermore, the annual emissions of VOCs for a single dairy cattle and for the cattle shed were estimated to be 5.5 kg and 44 kg, respectively

To examine the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation.The study population consisted of 431 patients, all of whom underwent radical prostatectomy and developed BCR (PSA 0.2 ng/mL). According to the two risk factors [Gleason score ≥ 8 and PSA-doubling time (DT) 6 months], we divided the patients into two groups. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group. We set the starting point at the timing of BCR, and the endpoints were development to castration-resistant prostate cancer (CRPC) and cancer-specific death.During the mean follow-up period of 8.3 years after BCR, CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. We first divided the 191 high/intermediate-risk patients according to the PSA level (PSA 1.0 ng/mL, PSA 1.0-4.0, and PSA 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. We found that delayed (PSA 4.0 ng/mL) or no salvage therapy was significantly associated with CRPC and cancer-specific death. In the 240 low-risk patients, Kaplan-Meier curves demonstrated no significant difference in CRPC-free survival or cancer-specific survival within 10 years from the timing of BCR.Observation after BCR without salvage therapy or delayed administration may be an option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months when their life expectancy is within 10 years.

Background The Rock Ptarmigan Lagopus muta japonica lives in the alpine zones of central Japan, which is the southern limit of the global distribution for this species. This species is highly dependent on alpine habitats, which are considered vulnerable to rapid climate change. This study aimed to assess the impact of climate change on potential L. muta japonica habitat based on predicted changes to alpine vegetation, to identify population vulnerability under future climatic conditions for conservation planning. We developed species distribution models, which considered the structure of the alpine ecosystem by incorporating spatial hierarchy on specific environmental factors to assess the potential habitats for L. muta japonica under current and future climates. We used 24 general circulation models (GCMs) for 2081–2100 as future climate conditions. Results The predicted potential habitat for L. muta japonica was similar to the actual distribution of the territories in the study area of Japan’s northern Alps (36.25–36.5°N, 137.5–137.7°E). Future potential habitat for L. muta japonica was projected to decrease to 0.4% of the current potential habitat in the median of occurrence probabilities under 24 GCMs, due to a decrease in alpine vegetation communities. Some potential habitats in the central and northwestern part of the study area were predicted to be sustained in the future, depending on the GCMs. Conclusions Our model results predicted that the potential habitats for L. muta japonica in Japan’s northern Alps, which provides core habitat for this subspecies, would be vulnerable by 2081–2100. Small sustainable habitats may serve as refugia, facilitating the survival of L. muta japonica populations under future climatic conditions. Impact assessment studies of the effect of climate change on L. muta japonica habitats at a nationwide scale are urgently required to establish effective conservation planning for this species, which includes identifying candidate areas for assisted migration as an adaptive strategy. Electronic supplementary material The online version of this article (10.1186/s12898-019-0238-8) contains supplementary material, which is available to authorized users.

Thermochemical hydrogen production has attracted considerable interest as a clean energy solution to address the challenges of climate change and environmental sustainability. The thermochemical water-splitting iodine-sulfur (IS) process uses heat from nuclear or solar power and thus is a promising next-generation thermochemical hydrogen production method that is independent of fossil fuels and can provide energy security. This paper presents the current state of research and development (R&D) of the IS process based on membrane techniques using solar energy at a medium temperature of 600 °C. Membrane design strategies have the most potential for making the IS process using solar energy highly efficient and economical and are illustrated here in detail. Three aspects of membrane design proposed herein for the IS process have led to a considerable improvement of the total thermal efficiency of the process: membrane reactors, membranes, and reaction catalysts. Experimental studies in the applications of these membrane design techniques to the Bunsen reaction, sulfuric acid decomposition, and hydrogen iodide decomposition are discussed.

Background International Metastatic Renal Cell Carcinoma Database Consortium model predicts the outcomes of metastatic renal cell carcinoma stratified into favorable, intermediate, and poor risk groups (FG, IG, and PG, respectively), with approximately 50% of patients being classified as IG. We aimed to generate better risk model based on the sub-classification of IG. Methods We analyzed records of 213 consecutive patients receiving molecular targeted therapy. Age, gender, histology, type of initial molecular targeted therapy, serum laboratory data, previous nephrectomy and immunotherapy, and metastatic sites were used for IG sub-stratification. Modified and original models were compared using a concordance correlation coefficient analysis. Results Median follow-up was 17.8 months. Serum albumin, serum C-reactive protein, and bone metastases were independent predictors of overall survival (OS) in IG. IG was sub-classified into low-, middle-, and high-risk IG according to the number of predictors. The following modified model was developed: modified FG (FG & low-risk IG), modified IG (middle-risk IG), and modified PG (PG & high-risk IG). Concordance indices for original and modified models were 0.68 and 0.73, respectively (P < 0.001). OS was significantly longer in modified PG treated with mammalian target of rapamycin inhibitors as second-line therapy than with tyrosine kinase inhibitors, whereas this was not observed in the original model. Conclusions We successfully developed modified IMDC model using a two-step process: the original IMDC plus an IG sub-stratification, and demonstrated that it predicts outcomes more accurately than original model.

The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. We retrospectively reviewed 82 consequent intermediate-risk mRCC patients who received second-line molecular targeted therapy. We classified patients who had serum CRP higher than 0.5 mg/dl in elevated CRP group because the median baseline serum CRP level before second-line treatment was 0.51 mg/dl. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS). Thirty-three out of 82 (40%) patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group was 11.5 (95% CI 5.4–17.5) and 29.4 (95% CI 25.5–33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5, 95% CI 1.4–4.2, p = 0.001). The serum CRP levels after first-line treatment termination could divide intermediate risk group mRCC patients into two prognostic subgroups in second-line targeted treatment setting.

The aims of this study were to compare the high-resolution computed tomography (HRCT) findings of pulmonary infections in immunocompromised patients and to assess the usefulness of HRCT in the differential diagnosis of these infections. A total of 345 immunocompromised patients with pulmonary infections were included in this study. The diagnoses of the patients consisted of bacterial pneumonia (123 cases), pneumocystis pneumonia (PCP) (105 cases), fungal pneumonia (80 cases), tuberculosis (15 cases), cytomegalovirus pneumonia (11 cases), and septic embolism (11 cases). Two chest radiologists retrospectively evaluated the computed tomography (CT) images, which consisted of 22 findings including ground-glass attenuation, consolidation, nodules, and thickening of the bronchial wall and interlobular septum. Associations between the CT criteria and infections were investigated using χ2 test; multiple logistic regression analyses were conducted to identify the significant indicator for each infection. The area under the curve (AUC) of each model was calculated. Bronchial wall thickening was a significant indicator for bacterial pneumonia (p = 0.002; odds ratio [OR], 2.341; 95% confidence interval [CI], 1.378–3.978). The presence of a mosaic pattern and the absence of nodules were significant indicators for PCP (p