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The suppression of androgen receptor (AR) expression exacerbates the migration potential of prostate cancer. This study identified a previously unrecognized regulation of the AR-controlled pathway that promotes migration potential in prostate cancer cells. Prostate cancer cells that pass through a transwell membrane (mig cells) have a higher migration potential with a decreased AR expression than parental cells. In this study, we aimed to elucidate the mechanism of migration enhancement associated with the suppression of AR signaling. Expression of C-C motif ligand 20 (CCL20) is upregulated in mig cells, unlike in the parental cells. Knockdown of AR with small interfering RNA (siAR) in LNCaP and C4-2B cells increased CCL20 secretion and enhanced the migration of cancer cells. Mig cells, CCL20-treated cells, and siAR cells promoted cell migration with an enhancement of AKT phosphorylation and Snail expression, while the addition of a C-C chemokine receptor 6 (CCR6, the specific receptor of CCL20) inhibitor, anti-CCL20 antibody, and AKT inhibitor suppressed the activation of AKT and Snail. With 59 samples of prostate cancer tissue, CCL20 secretion was profuse in metastatic cases despite low AR expression levels. Snail expression was associated with the expression of CCL20 and CCR6. A xenograft study showed that the anti-CCL20 antibody significantly inhibited Snail expression, thereby suggesting a new therapeutic approach for castration-resistant prostate cancer with the inhibition of the axis between CCL20 and CCR6.

Background: The percentage of positive cores (PPC) is increasingly recognized as a prognostic factor in prostate cancer. However, the usefulness of PPC for patients undergoing androgen deprivation therapy (ADT) and high-risk group has not been adequately studied. Methods: A retrospective analysis was conducted of 255 patients who underwent prostate biopsy (all-case group). We examined the efficacy of PPC as a prognostic biomarker. Results: Eighty-nine patients were treated with ADT alone (ADT group), and 107 patients were classified as high-risk (high-risk group). The median duration of follow-up was 112.4 months, 85.3 months, and 110.0 months for the all-case group, ADT group, and high-risk group, respectively. Patients with PPC >60% had significantly shorter prostate cancer-specific survival (CSS) and castration-resistant prostate cancer-free survival (CFS) in the all-case group and ADT group. In high-risk group, patients with PPC >60% had shorter CFS but no difference in CSS. Multivariate analysis showed that significant independent predictors of prostate CSS were the presence of metastasis at diagnosis and PPC >60% in the all-case group and ADT group. Conclusions: This study demonstrates that PPC may be a prognostic factor in ADT treatment and high-risk patients.

BACKGROUND/AIM To investigate the blood markers for predicting pembrolizumab efficacy in advanced urothelial carcinoma (UC). PATIENTS AND METHODS This study included 91 advanced UC patients. The relationship between prognosis and markers from peripheral blood cell counts, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic inflammation response index (SIRI=monocytes × neutrophils/lymphocytes), was evaluated. RESULTS Multivariate analysis indicated that pretreatment NLR and the 1-month-change NLR were both significantly associated with overall survival (OS) after pembrolizumab initiation. When the patients were divided into four groups according to calculated cutoffs using Cox proportional hazard model, the pretreatment NLR

Objective Prostate-specific antigen is considered the most useful biomarker for prostate cancer, but not in all cases. In a previous study, we have shown that a risk classification combining prostate-specific antigen ≥100 ng/mL and chemokine (CC motif) ligand 2 ≥ 320 pg/mL can predict survivals. We investigated the long-term usefulness of serum chemokine (CC motif) ligand 2 as a complementary biomarker to prostate-specific antigen and developed a novel risk classification system. Methods Serum samples were collected from 379 patients who underwent prostate biopsy at Kanazawa University Hospital between 2007 and 2013, and 255 patients with histologically diagnosed prostate cancer were included in this study. We retrospectively examined the efficacy of serum chemokine (CC motif) ligand 2 as a prognostic biomarker. Results Patients with chemokine (CC motif) ligand 2 ≥ 320 pg/mL exhibited a significantly shorter overall survival, prostate cancer-specific survival and castration-resistant prostate cancer-free survival than those with chemokine (CC motif) ligand 2 Conclusions This study demonstrated the utility of serum chemokine (CC motif) ligand 2 level as a predictive biomarker of long-term overall survival in prostate cancer. A novel risk classification system that predicts long-term overall survival based on the combined indications of chemokine (CC motif) ligand 2 level, prostate-specific antigen level and Gleason score may be a useful prognostic tool for prostate cancer.

Pembrolizumab is currently considered the standard second-line treatment for advanced urothelial carcinoma (UC). This study aimed to investigate the efficacy and safety of pembrolizumab in patients with advanced UC in real-world data, which is not well-reported.The study included 97 patients with advanced UC whose lesions were classified according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median age was 73 years. Nineteen patients (20%) with performance status (PS) 2-4 were included. The percentages of liver, lung, bone, and lymph node metastasis were 18%, 27%, 19%, and 76%, respectively. The efficacy, safety, and risk factors for prognosis were evaluated for patients with and without measurable lesions.The best response was complete response in nine patients (9%) and partial response in 16 patients (17%). The median progression-free survival and overall survival were 3.7 months (95% confidence interval [CI]: 2.8-4.7) and 11.8 months (95% CI: 6.7-17.0), respectively. Twenty-one (22%) patients had no measurable lesions per RECIST. In univariate and multivariate analysis, PS 2-4 and lesions by RECIST were identified as factors associated with short overall survival (OS). The median OS of 18.3 months in patients without lesions by RECIST was significantly longer than the median OS of 6.7 months in patients with lesions by RECIST (p = .012).We demonstrated that good PS 0-1 and no measurable lesions, especially small lesions, by RECIST were favorable prognostic factors in patients with advanced UC treated by pembrolizumab.

Autophagy has been reported to play a crucial role in the maintenance of intracellular homeostasis, including in pancreatic beta cells. Rubicon, which interacts with the phosphoinositide 3-kinase (PI3K) complex, through autophagy-related 14 (ATG14), is among the few autophagy regulators that have been reported to inhibit autophagic flux to date and the deletion of Rubicon has been shown to increase autophagic flux. Based on previous results showing a causal relationship between autophagic dysfunction and pancreatic beta-cell impairment, we hypothesized that the deletion of Rubicon in pancreatic beta cells would improve cell integrity and confer protective effects. To test this hypothesis, we first confirmed that Rubicon knockdown (KD) promoted autophagic flux in βTC3 pancreatic beta-cell line. Next, we generated pancreatic beta-cell-specific Rubicon knockout (βKO) mice, by administering tamoxifen to Rubiconflox/flox:MIP-Cre-ERT mice, which showed normal glucose tolerance and insulin secretion under a normal chow diet, despite successful gene recombination. We also attempted to increase insulin resistance by feeding the mice with a high-fat diet for an additional 2 months to find little differences among the parameters evaluated for glucose metabolism. Finally, severe insulin resistance was induced with insulin receptor antagonist treatment, which resulted in comparable glucose homeostasis measurements between Rubicon βKO and control mice. In summary, these results suggest that in pancreatic beta cells, Rubicon plays a limited role in the maintenance of systemic glucose homeostasis.

This study evaluated the effects of three types of hybrid iterative reconstruction (IR) on image quality of pediatric body computed tomography images. The image quality components evaluated were noise power spectrum (NPS), task-based modulation transfer function (TTF), and system performance function (SPF). As the IR strength was increased while reducing the radiation dose, the NPS increased in a low-frequency range and the TTF decreased in low-contrast regions. In the low-contrast regions, the calculated SPF decreased over the entire frequency range. Alternatively, in the high-contrast regions, the SPF decreased in the low-frequency regions and increased in the high-frequency regions. The radiation dose reduction using the hybrid IR resulted in the deterioration of the image quality in the low-contrast regions and changes in the spatial frequency characteristics in the high-contrast regions.

N-Nitrosoproline (NPRO) is known to form endogenously from sodium nitrite and the amino acid proline, and is thought to be non-mutagenic and non-carcinogenic. However, earlier studies in our laboratory showed that irradiated NPRO can be converted directly to a mutagenic compound upon UVA irradiation. We previously investigated the mutagenic spectrum of NPRO on M13mp2 DNA with UVA irradiation, and found a hot spot comprising AT to GC, where there might be a particular photoreaction of adenine residues with NPRO. In the present study, we investigated the reaction of NPRO with 2'-deoxyadenosine (dA) under UVA irradiation, and identified the chemical structures of the photoproducts. Photoproducts from NPRO and dA were isolated and analyzed with HPLC, MS and NMR. (R)-, (S)-2-(2-pyrrolidyl)-2’-deoxyadenosine (P1, P2) and deoxyinosine (dI) were identified from the mixture of dA and NPRO irradiated with UVA. Results suggest that UVA-activated NPRO produces pyrrolidyl cations which react with dA to generate pyrrolidyl-dA adducts. Production of P1 and P2 from irradiated NPRO with dA increased under N2 saturation compared to those under air saturation, while production of P1 and P2 from irradiated solution under O2 saturation was lower compared to that under air. These results suggest that a Type-I mechanism is involved in the photoproduction of P1 and P2. Furthermore, reactive oxygen species generated during photo-reaction in the presence of O2 may act to destroy the activated form of irradiated NPRO to reduce the formation of P1 and P2. The formation of dI in the irradiated mixture of NPRO with dA might mediate NO release from irradiated NPRO.

Background: Pembrolizumab is currently considered the standard second-line treatment for advanced urothelial carcinoma (UC). This study aimed to investigate the efficacy and safety of pembrolizumab in patients with advanced UC in real-world data, which is not well-reported.Methods: The study included 98 patients with advanced UC who were treated with pembrolizumab after platinum-based chemotherapy at eight hospitals. The efficacy, safety, and risk factors for prognosis were evaluated. Results: The median age was 73 years. Nineteen patients (19%) with performance status (PS) 2-4 were included. The percentages of liver, lung, bone, and lymph node metastasis were 18%, 27%, 19%, and 76%, respectively. The best response was complete response in nine patients (9%) and partial response in 16 patients (17%). The median progression-free survival and overall survival were 3.7 months (95% confidence interval [CI]: 2.8–4.7) and 11.8 months (95% CI: 6.7–17.0), respectively. Poor PS, liver metastasis, and higher C-reactive protein were poor prognostic factors. Hyperprogression was observed in nine patients (9%), who were mostly of poor PS and had high-volume lesions. Severe adverse events (AEs) were observed in 18 patients (19%), and five patients died because of AEs (5%). Atypical AEs, such as pneumocystis pneumonia and acute myeloid leukemia, were observed in our cohort. Conclusion: The efficacy of pembrolizumab for advanced UC in our cohort was better than a previous phase III trial (KEYNOTE-045), possibly owing to lower cancer volume and fewer visceral metastases in our patients.

Computed tomography (CT) is commonly used to assess for cerebral hemorrhage and acute ischemic stroke. We investigated the accuracy of CT using a low tube voltage technique in acute ischemic stroke. We compared the standard deviation (SD), contrast between gray and white matter, and contrast-to-noise ratio (CNR) between three groups (120 kV 500 mAs, 100 kV 850 mAs, and 100 kV 750 mAs using hybrid iterative reconstruction) in 50 patients without lesions, and visual evaluation using the normalized rank approach was also performed. The mean value of SD was 4.02, 4.22, and 4.04, respectively, and the contrast between gray and white matter was 7.08, 8.66, and 8.68 HU, respectively; in addition, the CNR was 1.77, 2.06, and 2.15, respectively. The difference between the 100 kV and 120 kV groups was significant (p < 0.01). Visual evaluation showed a significant difference between the 100 and 120 kV groups (p < 0.05).

A 36-year-old male was referred to our hospital with left scrotal swelling. Computed tomography revealed a massive tumor in his left scrotum. The tumor extended along the gonadal vein extraperitoneally forming a massive tumor. Pathological examination showed a mixed-type germ cell tumor. Despite several chemotherapeutic treatments, the tumor continued to grow, and the patient died 28 months later after his first presentation at our institution. Autopsy revealed that the tumor comprised rhabdomyosarcoma and mature teratoma. We could not find useful tumor markers to facilitate the diagnosis of rhabdomyosarcoma. However, we recommend rebiopsy or palliative operation as options for re-diagnosis in case of resistant germ cell tumor. Here, we present a case of testicular tumor that exhibited different pathological examination results before and after treatment.

Autophagy is a bulk degradation system which plays an important role to maintain cell homeostasis. We have shown that deficiency of autophagy in pancreatic β cells leads to their failure and deterioration of glucose tolerance. On the other hand, there has been controversy over induction of autophagic flux in β cells following different physiological contexts, as it has been difficult to estimate autophagy flux by using conventional methods such as estimation of LC3-lipidation. Recently, application of a novel autophagy flux, GFP-LC3-RFP-LC3ΔG, is reported, which enables us to evaluate autophagy flux by calculating ratio between the fluorescence of GFP and RFP, as GFP-LC3 is degraded specifically in autolysosomes, whereas RFP-LC3ΔG remains intact in cytosol as an internal control. To improve its usefulness, we modified it to construct pHluorin-LC3-mCherry. First, we expressed this probe in MIN6 cells and confirmed decrease of pHluorin/mCherry ratio following induction of autophagic flux in starvation or administration of specific mTOR inhibitor, Torin-1. Next, we generated knock-in mouse in which the probe is expressed under the control of CAG promotor in ROSA26 locus. Its expression was confirmed based on Western blot and fluorescent microscopy in almost all the tissues that we examined. Then we stimulated the mice with starvation and detected that pHluorin/mCherry ratio decreases after starvation in several organs, including liver and muscle which are deeply involved in glucose homeostasis. Finally, we investigated whether autophagic flux is changed after starvation in pancreatic beta cells and successfully demonstrated that the flux is increased following prolonged starvation. In addition, we also illustrated upregulation of autophagic flux in isolated islets after glucose and amino acid starvation. These results show dynamic change of autophagic flux after starvation in many tissues related to glucose homeostasis including βcells. Disclosure S. Aoyama: None. Y. Nishida: None. R. Yazawa: None. I. Tanida: None. T. Miyatsuka: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited.

N-nitrosoproline (NPRO) is formed from nitrosation of proline and has been reported to be non-carcinogenic and non-mutagenic. However, earlier studies in our laboratory showed that pre-irradiated NPRO can be converted to a mutagenic form. We previously investigated the reaction of NPRO with dA or dG under UVA irradiation and identified the formation of 2-pyrrolidyl-dA adducts (P1 & P2) and 8-pyrrolidyl-dG adducts (G1 & G2) as well as four known modified nucleosides, although several peaks found in the HPLC profiles of UVA-irradiated mixtures of dA and NPRO remain unidentified. In the present study we isolated new photoproducts from irradiated mixtures of dA and NPRO and identified (R)- and (S)-8-(2-pyrrolidyl)-2′-deoxyadenosine (A1 and A2) as products by MS and NMR. We also investigated the photoadducts formed in DNA treated with NPRO under UVA irradiation, and detected A1 and/or A2 (probably both), P1, P2, G1 and/or G2, and 8-oxodG as products. Under anaerobic conditions, formation of A1 and A2 was greater than that under aerobic conditions, suggesting that photo-reactions comprising pyrrolidyl radical with dA may increase under anaerobic conditions given reduced competition with oxidative photo-reactions which may decompose pyrrolidyl-dA adducts.

To explore possible genotoxicity of N-nitrosoproline (NPRO), we investigated near-ultraviolet radiation (UVA)-mediated chemical reaction of NPRO with 2′-deoxyguanosine (dG). An acidic solution containing NPRO and dG was irradiated with UVA and products were analyzed by HPLC. In addition to the three known modified guanine nucleosides, i.e., 2′-deoxyxanthosine, 8-oxo-7,8-dihydro-2′-deoxyguanosine and 2′-deoxyoxanosine, we found two products. These new products were isolated and identified as (R)- and (S)-8-(2-pyrrolidyl)-2′-deoxyguanosine (G1 and G2, respectively). Experiments using monochromatic UVA in the range 300–400 nm were performed to determine the relation between products-yield and wavelength, and the highest yields of both G1 and G2 were found to occur at 340 nm. This wavelength coincided with the absorption maximum of NPRO. We propose that the NO radical produced from NPRO by photolysis triggers the formation of these products. Further investigation using calf thymus DNA showed that G1 and/or G2, probably both, could be produced by UVA irradiation of DNA + NPRO as well.

When decommissioning a nuclear power plant, it is difficult to make an appropriate plan to ensure sufficient space for temporary placement and conveyance operations of dismantling targets. This paper describes a system to support temporary placement and conveyance operations using augmented reality (AR). The system employs a laser range scanner to measure the three-dimensional (3D) information of the environment and a dismantling target to produce 3D surface polygon models. Then, the operator simulates temporary placement and conveyance operations using the system by manipulating the obtained 3D model of the dismantling target in the work field. Referring to the obtained 3D model of the environment, a possible collision between the dismantling target and the environment is detectable. Using AR, the collision position is presented intuitively. After field workers evaluated this system, the authors concluded that the system is feasible and acceptable to verify whether spaces for passage and temporary storage are sufficient for temporary placement and conveyance operations. For practical use in the future, some new functions must be added to improve the system. For example, it must be possible for multiple workers to use the system simultaneously by sharing the view of dismantling work.

We propose the formation of silica glass with improved optical transport properties by compressing its melted phase with a hot isostatic pressure machine at high pressure and temperature. The lowest Rayleigh scattering loss was obtained for the glass held at 200 MPa and 2073 K for 4 h. The observed loss corresponds to 0.07 dB/Km at 1.55 μm, which is about half of the loss in conventional silica glass fiber. The decrease in the loss was well explained in terms of the decrease in the size of the sub-nanometer-sized structural voids observed by positron annihilation lifetime spectroscopy in silica glass. The achievement of high transparency and strong confinement of light represents a promising result for the development of future fiber-core media.

Formation-flight, which involves multiple spacecraft, is a key technology to conduct future space applications. The formation flight of multiple spacecraft using virtual structure approach and backstepping method is proposed. Decentralized scheme is used for information communication, and two simple anti-windup methods are studied to avoid the controller saturation tuning of backstepping controller gains, and tuning of virtual structure controller gains. Numerical simulations show that the proposed controller, which combines the virtual structure approach with backstepping method, can achieve formation flight effectively.