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Background: The prevalence of Lynch syndrome and the use of universal tumor screening to identify Lynch syndrome among unselected patients with upper urinary tract urothelial carcinoma, which is associated with Lynch syndrome, have not been closely investigated yet., Methods: A total of 166 tumors from 164 upper urinary tract urothelial carcinoma patients were tested for microsatellite instability and expression of mismatch repair proteins (MLH1, MHS2, MSH6 and PMS2) by immunohistochemistry. Genetic testing was performed for patients suspected of having Lynch syndrome. Clinicopathological factors, including familial and personal cancer history associated with mismatch repair deficiency, were evaluated., Results: The frequency of high-level microsatellite instability and loss of at least one mismatch repair protein was 2.4% (4/164); the microsatellite instability and immunohistochemistry results showed complete concordance. Of these four patients, three were genetically proven to have Lynch syndrome, while the remaining one was highly suggestive for Lynch syndrome based on their personal cancer history. Univariate analysis showed that age<70 years (P = 0.04), ureter as the tumor location (P = 0.052), previous history/synchronous diagnosis of colorectal cancer (P < 0.01) and fulfillment of the criteria per the revised Bethesda guideline (P < 0.01) tended to be or were significantly associated with high-level microsatellite instability/mismatch repair loss., Conclusions: The prevalence of Lynch syndrome among unselected upper urinary tract urothelial carcinoma patients was at least 1.8% in our study population. The screening efficacies of the microsatellite instability test and immunohistochemistry appear equivalent. Universal tumor screening may be a valid approach; however, selective screening methods that consider factors associated with mismatch repair loss/high-level microsatellite instability tumors require further investigation., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

A rich line of works focus on designing elegant loss functions under the deep metric learning (DML) paradigm to learn a discriminative embedding space for remote sensing image retrieval (RSIR). Essentially, such embedding space could efficiently distinguish deep feature descriptors. So far, most existing losses used in RSIR are based on triplets, which have disadvantages of local optimization, slow convergence and insufficient use of similarity structure in a mini-batch. In this paper, we present a novel DML method named as global optimal structured loss to deal with the limitation of triplet loss. To be specific, we use a softmax function rather than a hinge function in our novel loss to realize global optimization. In addition, we present a novel optimal structured loss, which globally learn an efficient deep embedding space with mined informative sample pairs to force the positive pairs within a limitation and push the negative ones far away from a given boundary. We have conducted extensive experiments on four public remote sensing datasets and the results show that the proposed global optimal structured loss with pairs mining scheme achieves the state-of-the-art performance compared with the baselines.

Background: Isoetes yunguiensis Q. F. Wang & W. C. Taylor is a lycophyte of an ancient genus, and it is endemic to China. It is a first-class protected plant in China. This living fossil is used in paleoecology and studies on the evolution of Lycophytes in the Yunnan-Guizhou Plateau. In recent years, human activities have caused the disappearance of several wild populations, and the number of plants in the existing populations is low. Study of the genetic structure, distribution pattern, and historical dynamics of I . yunguiensis in all areas of its distribution is of guiding significance for its rational and effective protection., Methods: Expressed sequence tag-simple sequence repeat (EST-SSR) markers were used to study the genetic diversity and structure of I . yunguiensis , and noncoding chloroplast DNA (cpDNA) sequences were used to study the pedigree, population dynamics history, and glacial shelter of I. yunguiensis . A maximum entropy model was used to predict the past, present, and future distribution patterns of I. yunguiensis ., Results: Analysis with EST-SSR markers revealed that I. yunguiensis showed high genetic diversity and that genetic variation was significantly higher within populations than between populations. Based on cpDNA data, it was concluded that there was no significant geographic pedigree in the whole area of I. yunguiensis distribution (NST = 0.344 >  GST = 0.183, p  > 0.05); 21 haplotypes were detected using DnaSP v5. Neutral test and LAMARC simulation showed that I. yunguiensis has experienced rapid expansion in recent years. The maximum entropy model predicted that the potential distribution area of I. yunguiensis in the last glacial maximum period has increased significantly compared with the present distribution area, but the future distribution area did not show substantial changes., Competing Interests: The authors declare there are no competing interests., (©2020 Zheng et al.)

Objectives: To test the reliability of Lateral cephalometric radiographs (LCRs) for use in the assessment of the upper airway, hyoid bone, soft palate, and tongue., Materials and Methods: The records of 57 healthy Chinese children from a nonhospital population (mean age = 12.6 years, SD = 0.5, 28 males and 29 females) who received two consecutive LCRs in the natural head posture were retrospectively analyzed. Fifteen linear, angular, and area measurements were used to describe the airway, hyoid bone, soft palate, and tongue. The reliability between the two LCRs was assessed with the intraclass correlation coefficient (ICC) and F -test. Errors were estimated with the Dahlberg and Bland-Altman method, and intra- and inter-assessor agreements were determined., Results: Measurements of upper airway and hyoid bone had excellent method reliability, intra-assessor reliability, and inter-assessor reliability (ICC > 0.8). However, the method reliability and the inter-assessor reliability for soft palate and tongue was less favorable (ICC from 0.60 to 0.96). Soft palate area and thickness were the most critical parameters. Intra-assessor reliability was greater than both method reliability and inter-assessor reliability (which were similar)., Conclusions: The measurement of upper airway morphology, defined as the intramural space, and of the hyoid bone position were highly reliable on LCRs of children. However, the limited reliability in the assessment of tongue and soft palate area may compromise the diagnostic application of LCRs to these structures.

Background: Platinum-containing regimens are widely used as first-line chemotherapy for unresectable pancreatic neuroendocrine carcinoma (NEC), but second-line chemotherapies have yet to be established., Objectives: We evaluated the safety and efficacy of everolimus in patients with pancreatic NEC refractory or intolerant to platinum-containing chemotherapy., Methods: This study was a prospective, multicenter, phase II trial in patients with pancreatic NEC after platinum-containing chemotherapy. Everolimus treatment was continued until disease progression or intolerable toxicity was observed. The primary endpoint was progression-free survival (PFS)., Results: Participants comprised 25 patients. Median age was 63 years, median PFS was 1.2 months (95% confidence interval [CI] 0.9-3.1 months), median overall survival was 7.5 months (95% CI 3.1-13.5 months), overall response rate was 0%, and disease control rate was 39.1%. Common grade 3/4 adverse events were hyperglycemia (20%), thrombocytopenia (16%), and anemia (16%)., Conclusion: The efficacy of everolimus was limited in patients with unresectable pancreatic NEC., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Introduction: Metabolomics has recently emerged as a tool for understanding comprehensive tumor-associated metabolic dysregulation. However, only limited application of this technology has been introduced into the clinical setting of breast cancer., Objectives: The aim of this study was to determine the feasibility of metabolome analysis using routine CNB/VAB samples from breast cancer patients and to elucidate metabolic signatures using metabolic profiling., Methods: After breast cancer screenings, 20 consecutive patients underwent CNB/VAB, and diagnosed with benign, DCIS and IDC by histology. Metabolome analysis was performed using CE-MS. Differential metabolites were then analyzed and evaluated with MetaboAnalyst 4.0., Results: We measured 116-targeted metabolites involved in energy metabolism. Principal component analysis and unsupervised hierarchical analysis revealed a distinct metabolic signature unique to namely "pure" IDC samples, whereas that of DCIS was similar to benign samples. Pathway analysis unveiled the most affected pathways of the "pure" IDC metabotype, including "pyrimidine," "alanine, aspartate, and glutamate" and "arginine and proline" pathways., Conclusions: Our proof-of-concept study demonstrated that CE-MS-based CNB/VAB metabolome analysis is feasible for implementation in routine clinical settings. The most affected pathways in this study may contribute to improved breast cancer stratification and precision medicine.

Most mute people cannot speak due to their vocal cord lesion. Herein, to assist mute people to "speak", we proposed a wearable skinlike ultrasensitive artificial graphene throat (WAGT) that integrated both sound/motion detection and sound emission in single device. In this work, the growth and patterning of graphene can be realized at the same time, and a thin poly(vinyl alcohol) film with laser-scribed graphene was obtained by a water-assisted transferring process. In virtue of the skinlike and low-resistant substrate, the WAGT has a high detection sensitivity (relative resistance changes up to 150% at 133 Ω) and an excellent sound-emitting ability (up to 75 dB at 0.38 W power and 2 mm distance). On the basis of the excellent mechanical-electrical performance of graphene structure, the sound detecting and emitting mechanisms of WAGT are realized and discussed. For sound detection, both the motion of larynx and vibration of vocal cord contribute to throat movements. For sound emission, a thermal acoustic model for WAGT was established to reveal the principle of sound emitting. More importantly, a homemade circuit board was fabricated to build a dual-mode system, combining the detection and emitting systems. Meanwhile, different human motions, such as strong and small throat movements, were also detected and transformed into different sounds like "OK" and "NO". Therefore, the implementation of these sound/motion detection acoustic systems enable graphene to achieve device-level applications to system-level applications, and those graphene acoustic systems are wearable for its miniaturization and light weight.

The purpose of the paper is to study the differences in cell death mechanism of MGC-803 induced by "dextran-magnetic layered double hydroxide-fluorouracil" (DMF) drug delivery system and 5-Fluorouracil (5-Fu), respectively. The inhibitory effect on the proliferation was detected via CCK-8. The morphology of cell death was detected by transmission electron microscopy (TEM). Intracellular ATP, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and Cytosolic Free Ca (Ca 2+ ) level were detected via some methods. The result showed that DMF had more obvious effect in suppressing proliferation compared with 5-Fu, and changed cell death pattern of 5-Fu from apoptosis to oncosis. The ATP decrease, MMP loss, Ca 2+ increase, the activation of uncoupling protein-2 (UCP-2) and calpain-1 were significant after DMF exposure. However, DMF did not result in ROS accumulation. DMF could involve in activation of porimin, and the cascade reaction of caspases-3, -7, -9, and -12 and poly ADP-ribose polymerase (PARP) through Western blot. DMF showed a stronger injury on nuclear membrane in the cascade reaction of caspases-6, -8 and lamin-A. DMF triggered rapid depletion of ATP, which was consistent with the phenotype of oncosis. Endogenous mitochondrial apoptosis might not be the main cause of cell swelling. DMF could induce strong endoplasmic reticulum stress (ERS) effect, there might be some signaling pathways related with ERS during the process of oncosis. The calpain system might not be a key factor for structural damage in oncosis induced by DMF. DMF could induce the caspases cascade reactions similar to apoptosis, but inflicted a more strong damage on nuclear membrane and PARP.

Background and Aims: Chronic pain is a significant health care problem which is often encountered in medical institute out-patient clinics . In previous studies we have reported on the benefits of low level laser therapy (LLLT) for chronic musculoskeletal pain patients. The present study is a report on the effects of LLLT in patients with pain in major muscles which govern the motion of two joints (2-joint muscles)., Materials and Methods: Over the past 5 years, 19 subjects visited our out-patient clinic with complaints of pain in 2-joint muscles (biceps brachii muscle or gastrocnemius muscle). They were treated with LLLT using a 1000 mW semi-conductor laser device delivering 20.1 J/cm 2 per point at 830 nm in continuous wave. Four shots were given per session (1 treatment) twice a week for 2 months (total of 16 treatments)., Results: A treatment approach modified from the methods of Shiroto and Ohshiro, was used, and the efficacy of LLLT for pain attenuation in the affected muscle was determined. After the end of the treatment regimen, excellent and good improvement was observed in 16 patients out of 19. Discussions with the patients revealed that it was important for them to learn how to modify their everyday life to avoid posture and activities of daily life that could cause them pain in the 2-joint muscles, in order to enjoy continuous benefits from the treatment., Conclusion: The present study demonstrated that LLLT was an effective form of treatment for pain in the biceps brachii and gastrocnemius muscles. To maximize and prolong treatment efficacy, advice should be given to patients to avoid adopting any posture and activities of daily living which would cause pain in these specific muscles., (2019, Japan Medical Laser Laboratory.)

Materials that demonstrate near-infrared (NIR) absorption and can simultaneously convert the electromagnetic irradiation into heat are promising for photothermal therapy. Traditionally, such a material is either pure inorganic, such as CuS, Ag 2 S, and carbon nanotube, or pure organic, such as polyaniline, polypyrrole, and conjugated polymers. Here we show that strong NIR photothermal effect can also be achieved in inorganic-organic hybrid coordination polymers (CPs) or metal-organic frameworks (MOFs). Our strategy is to construct CPs with inorganic Ag-S components that are interlinked by the organic ligands into a higher-dimensional hybrid network. Interestingly, the two resulting CPs, [Ag(Py-4-CSS)] n 1 and [Ag 2 (Py-4-CSS)(Py-4-CSSS)] n 2 (Py-4-CSS = pyridine-4-dithiocarboxylate; Py-4-CSSS = pyridine-4-perthiocarboxylate), show disparate structures due to the varied coordination mode of the pyridine group. For 1, the N atom coordinates to the Ag + center and forms a two-dimensional square framework, while for 2, such a Ag-N bond is disconnected and forms only a one-dimensional structure. Interestingly, this difference leads to the distinct absorption properties in the NIR region. Under 800 nm radiation, the temperature of 1 can rise up to 24.5 °C in 3 min with photothermal conversion efficiency of 22.1%, which is about 2× that of pure inorganic Ag 2 S material and among the highest compared to various known inorganic materials, for example, Au nanoshells (13%), nanorods (21%), and Cu 2- x Se nanocrystals (22%) irradiated with 800 nm light, while for 2, the NIR absorption is absent. This result first demonstrates that the inorganic-organic hybrid approach can be applied to construct superior NIR photothermal materials, but the control of the structure is vital. Here the coordinating nitrogen atoms in 1 are conceived to be critical in promoting the charge transfer between the dithiocarboxylate ligands. To elucidate the response to NIR irradiation of 1, we measured the heat capacity and dielectric constant of 1 and also performed density functional theory calculations. Significantly, the large dielectric constant and flat energy bands indicates 1 is much easier to be polarized and has a high electron effective mass. Thus, unlike the pure inorganic material, such as Ag 2 S, in which electron and hole can quantum mechanically combine to give off light, the joint-force of organic ligands in 1 effectively enhances polaronic recombination into heat.

The proband was a 62-year-old man with ureter cancer. He had a history of metachronous colorectal and gastric cancer. Immunohistochemical staining showed the absence of both MSH2 and MSH6 proteins in the ureter cancer and other available cancer tissue specimens. Genetic testing was conducted to identify the causative genes of hereditary gastrointestinal cancer syndromes including mismatch repair genes. We detected a germline variant, c.2635-3delC, within the splice acceptor site of exon 16, in the MSH2 gene. To investigate whether this variant affected splicing of the gene, RNA sequencing was performed using blood samples. We observed a substantial amount of the transcripts that lacked proper splicing of intron 15 in the indexed case, whereas, a very low amount of such aberrant transcripts was detected in the controls, strongly indicating an association between the variant and splicing defect. These results indicate that MSH2 c.2635-3delC affects normal splicing and might be a cause of Lynch syndrome., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: DKC1 (dyskerin pseudouridine synthase 1) is a causative gene for X-linked dyskeratosis congenita. Approximately 8% of patients with dyskeratosis congenita have malignancy, but information about the development of malignancy in patients with dyskeratosis congenita is limited., Case Presentation: A young Japanese patient with bone marrow failure developed metachronous rectal adenocarcinomas at the ages of 16 and 18 years. He had no family history of cancer. Microsatellite instability testing with rectal tumor tissue demonstrated low-level microsatellite instability. To clarify whether any cancer susceptibility genes were involved in the development of rectal cancer, RNA sequencing was performed. Cancer-related genes were assessed, and a c.361A>G (p.Ser121Gly) germline variant was detected in DKC1. The same missense variant was previously reported in two patients with dyskeratosis congenita as a pathogenic variant, but those patients did not develop malignancies., Conclusions: Our patient developed rectal cancer at an early age of onset compared with the previously reported typical onset age of patients with dyskeratosis congenita. DKC1 might be involved in predisposition to colorectal cancer in young adulthood; therefore, appropriate surveillance may be considered.

Background: Hepatocellular carcinoma (HCC) is one of the leading cause of cancer associated deaths worldwide. Independent studies have proposed altered DNA methylation pattern and aberrant microRNA (miRNA) levels leading to abnormal expression of different genes as important regulators of disease onset and progression in HCC. Here, using systems biology approaches, we aimed to integrate methylation, miRNA profiling and gene expression data into a regulatory methylation-miRNA-mRNA (meth-miRNA-mRNA) network to better understand the onset and progression of the disease., Methods: Patients' gene methylation, miRNA expression and gene expression data were retrieved from the NCBI GEO and TCGA databases. Differentially methylated genes, and differentially expressed miRNAs and genes were identified by comparing respective patients' data using two tailed Student's t-test. Functional annotation and pathway enrichment, miRNA-mRNA inverse pairing and gene set enrichment analyses (GSEA) were performed using DAVID, miRDIP v4.1 and GSEA tools respectively. meth-miRNA-mRNA network was constructed using Cytoscape v3.5.1. Kaplan-Meier survival analyses were performed using R script and significance was calculated by Log-rank (Mantel-Cox) test., Results: We identified differentially expressed mRNAs, miRNAs, and differentially methylated genes in HCC as compared to normal adjacent tissues by analyzing gene expression, miRNA expression, and methylation profiling data of HCC patients and integrated top miRNAs along with their mRNA targets and their methylation profile into a regulatory meth-miRNA-mRNA network using systems biology approach. Pathway enrichment analyses of identified genes revealed suppressed metabolic pathways and hyperactive cell cycle signaling as key features of HCC onset and progression which we validated in 10 different HCC patients' datasets. Next, we confirmed the inverse correlation between gene methylation and its expression, and between miRNA and its targets' expression in various datasets. Furthermore, we validated the clinical significance of identified methylation, miRNA and mRNA signatures by checking their association with clinical features and survival of HCC patients., Conclusions: Overall, we suggest that simultaneous (1) reversal of hyper-methylation and/or oncogenic miRNA driven suppression of genes involved in metabolic pathways, and (2) induction of hyper-methylation and/or tumor suppressor miRNA driven suppression of genes involved in cell cycle signaling have potential of inhibiting disease aggressiveness, and predicting good survival in HCC., Competing Interests: The authors declare that they have no competing interests.

Homologous recombination (HR) contributes to the repair of DNA double-strand breaks (DSBs) and inter-strand crosslinks. The HR activity in cancer cells can be used to predict their sensitivity to DNA-damaging agents that cause these damages. To evaluate HR activity, we developed a system called Assay for Site-specific HR Activity (ASHRA), in which cells are transiently transfected with an expression vector for CRISPR/Cas9 and a HR donor sequence containing a marker gene. DSBs are created by Cas9 and then repaired by HR using donor vector sequences homologous to the target gene. The level of genomic integration of the marker gene is quantified by Western blotting, flowcytometry, or quantitative PCR (qPCR). ASHRA detected HR deficiency caused by BRCA1, BARD1, or RAD51 knockdown or introduction of BRCA1 variants. The influence of BRCA1 variants on HR, as determined by qPCR, was consistent with the chemosensitivities of the transfected cells. The qPCR format of ASHRA could measure HR activity in both transcribed and un-transcribed regions. Knockdown of BRCA1 nor BARD1 did not affect HR activity in a transcriptionally inactive site. ASHRA can evaluate HR activity and will be useful for predicting sensitivity to chemotherapy, screening drugs that affect HR, and investigating the mechanisms of HR.

Background: Pazopanib is an effective treatment option for renal cell carcinoma (RCC). However, the therapy is often limited by the appearance of adverse events (AEs), including nausea/vomiting, hepatic impairment, hand-foot syndrome, diarrhea, hypertension and oral mucositis. Early management of AEs is, therefore, extremely important in order to maximize treatment outcomes., Patients and Methods: This non-randomized controlled before-and-after study was carried out to evaluate the effectiveness of our comprehensive pharmaceutical interventions in 37 outpatients receiving pazopanib for RCC (experimental group). Data were compared with those obtained from 13 patients before the start of pharmaceutical intervention (control group)., Results: The incidence rates of grade 2 or more nausea and anorexia were significantly lower in the experimental, than in the control group (3% versus 38% for nausea, respectively, p=0.003; 8% versus 46% for anorexia, respectively, p=0.005). Importantly, non-adherence based on patient self-assessment was not observed with intervention (0% versus 38%, p<0.001). Consequently, the median total dose of pazopanib was increased by the intervention (72,600 versus 18,200 mg, p=0.002). Moreover, the median time to treatment failure was significantly longer with intervention than before (10.2 versus 1.7 months, HR=0.23, 95% CI=0.110-0.499, p<0.001). These findings suggest that our interventions are highly effective for enhancing treatment outcomes., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Colorectal cancer (CRC), also known as colon cancer, is the third most common form of cancer worldwide in men and the second in women and is characterized by several genetic alterations, among them the expression of several genes. 1,2-dimethylhydrazine (DMH) and its metabolite azoxymethane (AOM) are procarcinogens commonly used to induce colon cancer in rats (DMH/AOM rat model). This rat model has been used to study changes in mRNA expression in genes involved in this pathological condition. However, a lack of proper detailed PCR primer design in the literature limits the reproducibility of the published data. The present study aims to design, optimize and validate the qPCR, in accordance with the MIQE (Minimum Information for Publication of Quantitative Real-Time PCR Experiments) guidelines, for seventeen genes commonly used in the DMH/AOM rat model of CRC ( Apc, Aurka, Bax, Bcl2, β -catenin, Ccnd1, Cdkn1a, Cox2, Gsk3beta, IL-33, iNOs, Nrf2, p53, RelA, Smad4, Tnfα and Vegfa ) and two reference genes ( Actb or β - actin and B2m ). The specificity of all primer pairs was empirically validated on agarose gel, and furthermore, the melting curve inspection was checked as was their efficiency (%) ranging from 90 to 110 with a correlation coefficient of r 2  > 0.980. Finally, a pilot study was performed to compare the robustness of two candidate reference genes., Competing Interests: The authors declare there are no competing interests.

Glutamate receptors are divided in two unrelated families: ionotropic (iGluR), driving synaptic transmission, and metabotropic (mGluR), which modulate synaptic strength. The present classification of GluRs is based on vertebrate proteins and has remained unchanged for over two decades. Here we report an exhaustive phylogenetic study of GluRs in metazoans. Importantly, we demonstrate that GluRs have followed different evolutionary histories in separated animal lineages. Our analysis reveals that the present organization of iGluRs into six classes does not capture the full complexity of their evolution. Instead, we propose an organization into four subfamilies and ten classes, four of which have never been previously described. Furthermore, we report a sister class to mGluR classes I-III, class IV. We show that many unreported proteins are expressed in the nervous system, and that new Epsilon receptors form functional ligand-gated ion channels. We propose an updated classification of glutamate receptors that includes our findings., Competing Interests: DR, JJ, EG, GG, RR, JL, DB, EN, JG, PF, HE, NR, DS, ÀB No competing interests declared, (© 2018, Ramos-Vicente et al.)

Multicomponent formulations have attracted increasing attention because of their favourable patient compliance and greater therapeutic effect. The aim of this study was to develop a multicomponent nanosuspension formulation of bufadienolides, the antitumor components of a traditional Chinese medicine, toad venom, using a wet-milling technique to improve its dissolution behaviour. Croscarmellose sodium (CCS) and sodium lauryl sulfate (SLS) were chosen as the combined stabilizers of the nanosuspension. A Taguchi orthogonal array design was used for this study to optimize the formulation and process parameters. The optimized nanosuspension was characterized by its particle size distribution, zeta potential, morphology, crystallinity, molecular interactions, stability and dissolution. The results showed that the nanosuspension was a homogeneous amorphous system with average particle sizes of <100 nm and significantly improved dissolution behaviour. It was also physically stable for at least 2 months; steric and kinetic stabilization were its main stability mechanisms. These findings suggested that the use of wet milling to fabricate nanosuspensions is a promising method for achieving the fast and synchronized dissolution of multicomponent formulations, presumably increasing the bioavailability of poorly water-soluble drugs.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Study Design: A retrospective study., Objective: The aim of this study was to determine the publication rate and impact factors (IFs) among all abstracts presented at the 2010 and 2012 meetings of the International Society for the Study of Lumbar Spine (ISSLS)., Summary of Background Data: The publication rate of abstracts presented at overseas meetings was reported to be around 50%. However, the publication rate and IFs of oral and poster presentations made at ISSLS meetings were unclear. Moreover, whether the publication rates and IFs differed for papers associated with oral or poster presentations at ISSLS meetings was unknown., Methods: We investigated all 1126 abstracts (oral, special posters, general posters) presented at ISSLS meetings held between 2010 and 2012. PubMed was searched to identify publications and IFs were determined using journal citation reports. We also compared the publication rates and IFs between oral and poster presentations., Results: The overall publication rate was 50.1% for three ISSLS meetings (564 publications/1126 abstracts). The overall publication rate for oral presentations, special posters, and general posters given in the 2010 to 2012 meetings was 62.0%, 48.3, and 46.6%, respectively. Overall, papers related to oral presentations had significantly higher publication rates than those of special and general posters (P = 0.0002). The average IFs of publications associated with abstracts presented at three ISSLS meetings was 2.802 for oral presentations, 2.593 for special posters, and 2.589 for general posters. There were no significant differences in average IFs between oral and poster presentations (P > 0.05)., Conclusion: The publication rate for abstracts presented at ISSLS meetings was high and similar to publication rates for abstracts presented at other meetings concerning orthopedic and spine research. However, there was no significant difference in IFs between oral and poster presentations, suggesting that abstract evaluations cannot predict IFs of the eventual publication., Level of Evidence: 4.

Purpose: Streptozocin (STZ) is a key agent for treating advanced pancreatic neuroendocrine tumors (pNET). Most STZ regimens for pNET are daily and also include 5-fluorouracil (5FU), whereas STZ monotherapy and weekly regimens have also been applied in daily practice in Japan. The present study aimed to evaluate responses to weekly regimens and to STZ monotherapy, and to identify a predictive marker of a response to STZ., Methods: Clinical data regarding STZ-based chemotherapy for pNET were collected between 2015 and 2017 at 25 facilities. We analyzed the effects, safety, progression-free survival (PFS), and factors that correlate with responses to STZ., Results: The overall objective response rate (ORR) of 110 patients who underwent STZ-based chemotherapy (monotherapy, 81.8%; weekly regimen 46.4%) was 21.8%, and PFS was 9.8 months. The ORR of weekly vs. daily regimens was 21.6 vs. 22.0% (P = 1.000), and that of monotherapy vs. combination therapy was 21.1 vs. 25.0% (P = 0.766). A Ki67 proliferation index (Ki67) of > 5% was a predictive marker of a response to STZ (P = 0.017), whereas regimen type, mono- or combination therapy, treatment line and liver tumor burden were not associated with responses. The frequencies of Grade ≥ 3 nausea and hematological adverse events were significantly lower for monotherapy than combination therapy (P = 0.032)., Conclusions: The effects of weekly STZ monotherapy on pNET are comparable to those previously reported and the toxicity profile was acceptable. Ki67 > 5% was the sole predictive marker of an objective response.

Hydration of the subducting oceanic plate determines the amount of water transported from Earth's surface into its interior, and plate bending-related faulting (bend faulting) just prior to subduction is considered to promote hydration. Bend faulting shows significant spatial variation, but its contribution to hydration is still poorly understood. Here we present the results of controlled-source seismic surveys around the junction of the Japan and Kuril trenches. We found structural changes caused by bend faulting before subduction differed distinctly between both trenches and were well correlated with plate hydration after subduction, suggesting the bend faulting controls spatial variations in plate hydration. Differences in bend faulting are closely related to the angle between the current trench and the ancient spreading ridge, and the hydration is more extensive where this trench-ridge angle is oblique in the study area. Thus, we propose this angle is a major factor controlling plate hydration.

Purpose: To evaluate the diagnostic performance of combining non-enhanced magnetic resonance imaging (MRI) and non-enhanced endoscopic ultrasonography (EUS) for assessing the malignant potential of lesions in patients with intraductal papillary mucinous neoplasms of the pancreas (IPMNs)., Material and Methods: Data from 38 patients histopathologically diagnosed with IPMN adenomas or IPMN adenocarcinomas were retrospectively analysed. Preliminary univariate and multivariate analyses were conducted to identify statistically significant associations. Three blinded radiologists evaluated the image sets to assess the diagnostic performance of combined use of non-enhanced MRI and EUS as opposed to non-enhanced MRI alone in distinguishing malignant from benign lesions. Observer performance and interobserver variability were determined using receiver-operating-characteristic curve analysis and weighted κ statistics., Results: Multivariate analyses identified a significant difference between the abrupt change in the main pancreatic duct (MPD) calibre with distal pancreatic atrophy and the signal intensity of lesion-to-spinal cord ratio on MRI; a significant difference was observed in MPD size on EUS. Diagnostic performance assessments of the image sets did not differ significantly between the blinded radiologists., Conclusions: The clinical utility of non-enhanced EUS may be attributive in evaluating IPMN that has already been evaluated by non-enhanced MRI., Competing Interests: The authors report no conflict of interest.

Background: Synaptic Ras-GTPase-activating protein 1 (SYNGAP1) is an abundant brain-specific protein localized at the postsynaptic density of mammalian excitatory synapses. SYNGAP1 functions as a crucial regulator of downstream intracellular signaling triggered by N-methyl-d-aspartate receptor activation. One of the most important signaling pathways regulated by SYNGAP1 is the Ras-Raf-MEK-ERK pathway. SYNGAP1 deficiency is associated with hyperphosphorylation of MEK and ERK kinases and with altered synaptic function in Syngap1 +/- mice. Loss-of-function mutations in the SYNGAP1 gene have been documented in many human cognitive and neurological disorders. However, there are currently no approaches that reverse the phenotypes of SYNGAP1 deficiency., Methods: Using electrophysiological recordings of field responses in hippocampal slices, we examined if disturbances of synaptic physiology in the hippocampus of 7-8-month old Syngap1 +/- mice were sensitive to the effect of the MEK inhibitor PD-0325901 given orally for 6days., Results: We found that in hippocampal slices from vehicle-treated Syngap1 +/- mice, basal synaptic responses were higher and their long-term potentiation (LTP) was lower than in slices from wild-type littermates. Chronic administration of PD-0325901 normalized basal synaptic responses, but did not reverse LTP deficit., Conclusions: The differential sensitivity of basal synaptic transmission and LTP to MEK inhibition indicates that the effects of SYNGAP1 deficiency on these synaptic parameters are mediated by distinct pathways. Our findings also suggest that at least some physiological phenotypes of the germline Syngap1 mutation can be ameliorated by pharmacological treatment of adult animals., (Copyright © 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Background: Although patients with EGFR-mutant non-small-cell lung cancer (NSCLC) benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs), outcomes are limited by the eventual development of acquired resistance. We conducted a retrospective study to evaluate the efficacy and feasibility of EGFR-TKI therapy beyond focal progression, associated with microwave ablation., Methods: Patients with metastatic EGFR-mutant NSCLC treated with EGFR-TKIs at our institutions from May 2012 to December 2017 were identified. Patients with single lesion progression, treated with MWA, and continually administered EGFR-TKI therapy until further progression, were included in the study. Initial response to target therapy, median progression-free survival (PFS1), and first progression site were recorded. The median time to progression after local therapy (PFS2) was also assessed. Overall survival was calculated from the initiation of EGFR-TKIs to the date of final follow-up or death., Results: Fifteen out of 205 patients (10%) satisfied the inclusion criteria. Local therapy was well tolerated, and complete ablation was performed in 11 (73.3%) patients. The median PFS1 was 9.5 months (range 6-41), and the median PFS2 was 8 months (range 3-24). The corresponding 6 and 12 month PFS rates were 73.3% and 26.7%, respectively. Median overall survival was 23 months (range 15-64)., Conclusion: The longer disease control observed in our patients suggests that continuation of EGFR-TKI beyond focal progression associated to microwave ablation is an efficacious therapeutic strategy., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

In this paper, we propose a learning-based supervised discrete hashing method. Binary hashing is widely used for large-scale image retrieval as well as video and document searches because the compact binary code representation is essential for data storage and reasonable for query searches using bit-operations. The recently proposed supervised discrete hashing (SDH) method efficiently solves mixed-integer programming problems by alternating optimization and the discrete cyclic coordinate descent (DCC) method. Based on some preliminary experiments, we show that the SDH method can be simplified without performance degradation. We analyze the simplified model and provide a mathematically exact solution thereof; we reveal that the exact binary code is provided by a "Hadamard matrix." Therefore, we named our method Hadamard codedsupervised discrete hashing (HC-SDH). In contrast to SDH, our model does not require an alternating optimization algorithm and does not depend on initial values. HC-SDH is also easier to implement than iterative quantization (ITQ). Experimental results involving a large-scale database show that Hadamard coding outperforms conventional SDH in terms of precision, recall, and computational time. On the large datasets SUN-397 and ImageNet, HC-SDH provides a superior mean average of precision (mAP) and top-accuracy compared to the conventional SDH methods with the same code length and FastHash. The training time of HC-SDH is 170 times faster than conventional SDH and the testing time including the encoding time is seven times faster than FastHash which encodes using a binary-tree.

Objective: The diagnostic performance of endoscopic retrograde cholangiography (ERC) with radiography is imperfect. We assessed the value of adding tomosynthesis to ERC with radiography for the detection of choledocholithiasis., Methods: This study included 102 consecutive patients (choledocholithiasis/non-choledocholithiasis, n = 57/45), who underwent both radiography and tomosynthesis for ERC in the same examination and were not diagnosed with malignancy. The reference standard for the existence of choledocholithiasis was confirmed by endoscopic stone extraction during ERC, intraoperative cholangiography, or follow up with magnetic resonance cholangiopancreatography (n = 78, 11, and 13, respectively). A gastroenterologist and a radiologist independently evaluated the radiographs and the combination of tomosynthesis and radiographic images in a blinded and randomised manner. Receiver operating characteristic analysis was used for statistical analysis., Results: The areas under the receiver operating characteristic curve for combined tomosynthesis and radiography were significantly higher than those for radiography alone for both readers: Reader 1/Reader 2, 0.929/0.956 [95% confidence interval (CI), 0.861-0.965/0.890-0.983) vs 0.803/0.769 (95% confidence interval, 0.707-0.873/0.668-0.846), respectively (p = 0.0047/< 0.0001)., Conclusion: Adding tomosynthesis to radiography improved the diagnostic performance of ERC for detection of choledocholithiasis. Advances in knowledge: Adding tomosynthesis to radiography improves detection of choledocholithiasis and tomosynthesis images can be obtained easily after radiographs and repeated immediately.

Silicosis is the most common occupational lung disease in China, and is associated with a variety of complications, many of which are poorly understood. For example, recent data indicate that silicosis associates with the development of osteopenia, and in some cases this bone loss is severe, meeting criteria for osteoporosis. Although many factors are likely to contribute to this relationship, including a sedentary lifestyle in patients with advanced silicotic lung disease, we hypothesized that silica might directly reduce bone mineral density. In the present study, six Wistar rats were exposed to silica for 24 weeks in order to induce pulmonary silicosis and examine the relationship to bone mineral density. As expected, all rats exposed to silica developed severe pulmonary fibrosis, as manifested by the formation of innumerable silicotic nodules and the deposition of large amounts of interstitial collagen. Moreover, micro-CT results showed that bone mineral density (BMD) was also significantly reduced in rats exposed to silica when compared control animals and this associated with a modest reduction in serum calcium and 25-hydroxyvitamin D levels. In addition, we found that decreased BMD was also linked to increased osteoclast activity as well as fibrosis-like changes, and to the deposition of silica within bone marrow. In summary, our findings support the hypothesis that silicosis reduces bone mineral density and provide support for ongoing investigations into the mechanisms causing osteopenia in silicosis patients., (Copyright © 2018. Published by Elsevier Inc.)

BRCA-related breast carcinoma can be prevented through prophylactic surgery and an intensive follow-up regimen. However, BRCA genetic tests cannot be routinely performed, and some BRCA mutations could not be defined as deleterious mutations or normal variants. Therefore, an easy functional assay of BRCA will be useful to evaluate BRCA status. As it has been reported that BRCA functions in the regulation of centrosome number, we focused on centrosome number in cancer tissues. Here, 70 breast cancer specimens with known BRCA status were analyzed using immunofluorescence of γ-tubulin (a marker of centrosome) foci. The number of foci per cell was higher in cases with BRCA mutation compared to wild-type cases, that is, 1.9 (95% confidence interval [CI], 1.5-2.3) vs 0.5 (95% CI, 0.2-0.8) (P < .001). Specifically, foci numbers per cell in BRCA1 and BRCA2 mutation cases were 1.2 (95% CI, 0.6-1.8) and 2.2 (95% CI, 1.7-2.6), respectively, both higher than those in wild-type cases (P = .042 and P < .0001, respectively). The predictive value of γ-tubulin foci as determined by area under the curve (AUC = 0.86) for BRCA status was superior to BRCAPRO (AUC = 0.69), Myriad Table (AUC = 0.61), and KOHBRA BRCA risk calculator (AUC = 0.65) pretest values. The use of γ-tubulin foci to predict BRCA status had sensitivity = 83% (19/23), specificity = 89% (42/47), and positive predictive value = 77% (20/26). Thus, γ-tubulin immunofluorescence, a functional assessment of BRCA, can be used as a new prospective test of BRCA status., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Genome editing using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) predominantly induces non-homologous end joining (NHEJ), which generates random insertions or deletions, whereas homology-directed repair (HDR), which generates precise recombination products, is useful for wider applications. However, the factors that determine the ratio of HDR to NHEJ products after CRISPR/Cas9 editing remain unclear, and methods by which the proportion of HDR products can be increased have not yet been fully established. We systematically analyzed the HDR and NHEJ products after genome editing using various modified guide RNAs (gRNAs) and Cas9 variants with an enhanced conformational checkpoint to improve the fidelity at endogenous gene loci in HEK293T cells and HeLa cells. We found that these modified gRNAs and Cas9 variants were able to enhance HDR in both single-nucleotide substitutions and a multi-kb DNA fragment insertion. Our results suggest that the original CRISPR/Cas9 system from the bacterial immune system is not necessarily the best option for the induction of HDR in genome editing and indicate that the modulation of the kinetics of conformational checkpoints of Cas9 can optimize the HDR/NHEJ ratio.

Objectives: We aimed to determine whether high-resolution specimen-positron emission mammography (PEM) using fluorodeoxyglucose ( 18 F-FDG) can reveal extension of breast cancer in breast-conserving surgery (BCS), and assess the safety of radiation exposure to medical staff., Methods: Sixteen patients underwent positron emission tomography, and then BCS with intraoperative frozen section analysis on the same day. Resected specimens with remaining 18 F-FDG accumulation were scanned by high-resolution PEM. At least 1 day after surgery, tumour extension was evaluated by three independent experienced readers and by binarized images from the specimen-PEM data. Intraoperative exposure of medical staff to 18 F-FDG was measured., Results: Specimen-PEM evaluations of binarized images and the three investigators detected all (100 %, 12/12) invasive lesions and 94.4 % (17/18) of in situ lesions using both methods. The positive predictive value of the accumulated lesions was 74.4 % (29/39) for the binarized images and 82.9 % (29/35) for the three investigators. Analysis of intraoperative frozen sections detected 100 % (2/2) of the margin-positive cases, also detected by both specimen-PEM evaluation methods with no false-positive margin cases. The mean exposure of the medical staff to 18 F was 18 μSv., Conclusions: Specimen-PEM detected invasive and in situ lesions with high accuracy and allowable radiation exposure., Key Points: • Specimen-PEM detected invasive and in situ lesions with high accuracy. • Specimen-PEM predicted complete resection with the same accuracy as frozen section analysis. • Breast-conserving surgery after fluorodeoxyglucose injection was performed with low medical staff exposure.

Cross-talk between competitive endogenous RNAs (ceRNAs) may play a critical role in revealing potential mechanisms of tumor development and physiology. Glioblastoma is the most common type of malignant primary brain tumor, and the mechanisms of tumor genesis and development in glioblastoma are unclear. Here, to investigate the role of non-coding RNAs and the ceRNA network in glioblastoma, we performed paired-end RNA sequencing and microarray analyses to obtain the expression profiles of mRNAs, lncRNAs, circRNAs and miRNAs. We identified that the expression of 501 lncRNAs, 1999 mRNAs, 2038 circRNAs and 143 miRNAs were often altered between glioblastoma and matched normal brain tissue. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed on these differentially expressed mRNAs and miRNA-mediated target genes of lncRNAs and circRNAs. Furthermore, we used a multi-step computational framework and several bioinformatics methods to construct a ceRNA network combining mRNAs, miRNAs, lncRNAs and circRNA, based on co-expression analysis between the differentially expressed RNAs. We identified that plenty of lncRNAs, CircRNAs and their downstream target genes in the ceRNA network are related to glutamatergic synapse, suggesting that glutamate metabolism is involved in glioma biological functions. Our results will accelerate the understanding of tumorigenesis, cancer progression and even therapeutic targeting in glioblastoma.

Migration and homing of dendritic cells (DCs) to lymphoid organs are quite crucial for T cell-induced immune response against tumor. However, tumor microenvironment can make some tumor cells escape immune response by impairing DC migration. Prostaglandin E 2 (PGE 2 ) plays important roles in initiating and terminating inflammatory responses. In this study, we investigated whether PGE 2 could inhibit murine prostate cancer progression by countervailing tumor microenvironment-induced impairment of dendritic cell migration. We found that murine prostate cancer cell line RM-1-conditioned medium impaired chemotactic movement of marrow-derived DCs and splenic cDCs toward CC chemokine receptor-7 (CCR7) ligand CCL19 in vitro and migration to draining lymph gland in vivo. Meanwhile, it also induced LXR α activation and CCR7 inhibition on maturing DCs. However, the treatment of PGE 2 rescued this impairment of DC migration with upregulation of CCR7 and inhibition of LXR α . Further, it was observed that PGE 2 also increased MMP9 expression and activated Notch1 signaling on DCs. In RM-1-bearing mouse model, PGE 2 treatment was identified to inhibit tumor growth and induce more tumor-infiltrating T cells and CD11c dendritic cells in tumor sites. Therefore, our findings may demonstrate a new perspective for therapeutic interventions on prostate cancer immunoescape.

Introduction: Osteoporosis and sarcopenia are said to be similar disorders. However, few reports have described the effects of anti-osteoporosis drugs on muscle mass in clinical practice., Methods: We selected 150 postmenopausal women with osteoporosis treated by minodronate (osteoporosis medication [OM] group) and 50 postmenopausal women without osteoporosis who did not receive treatment (no osteoporosis [NO] group). The OM group was further divided into two treatment subgroups: a combination of monthly minodronate and daily activated vitamin D vs. monthly minodronate alone. We measured lumbar spine and femoral neck bone mineral density (BMD) with dual-energy X-ray absorptiometry and muscle mass of the upper limbs, lower limbs, and trunk with bioelectrical impedance analysis at baseline and after 6 months., Results: The OM and NO groups contained 130 and 37 patients, respectively (mean age: 73.9 ± 8.3 and 74.1 ± 10.0 years, respectively). In the OM group, lumbar spine BMD significantly increased after 6 months, while lower limb muscle mass significantly decreased. In the NO group, lumbar spine BMD and lower limb muscle mass did not significantly change after 6 months. In the OM group, BMD of the lumbar spine significantly increased but the lower limb muscle mass significantly decreased after 6 months relative to the NO group. In the combination therapy subgroup of the OM group muscle mass decreased significantly less than in the minodronate-alone subgroup., Conclusions: In postmenopausal women with osteoporosis, minodronate can increase BMD but cannot increase muscle mass. However, simultaneous use of activated vitamin D can suppress muscle mass decrease. The combination of activated vitamin D and minodronate may be useful for treating osteoporosis in postmenopausal women., Competing Interests: Conflicts of Interest: The authors declare that there are no conflicts of interest.

This study aimed to clarify how composition and water immersion of home reliners affect the attenuation of the transmitted load. To conduct a transmitted load measurement, we used three different home reliners (Tafugurippu Pink A, Liodent Pink, and Cushion Correct), which were combined acrylic resin disks. They were immersed in distilled water and then placed on a silicone quasi-mucosa (φ20×1.5 mm), which was set on a pressure sensor (φ8×0.35 mm), followed by the application of static load. Subsequently, gel permeation chromatography (GPC) and gas chromatography (GC) were used to clarify the composition of each home reliner. The attenuation of the transmitted load began 3 h after immersion. Moreover, both GPC and GC revealed a difference in composition among the three products. Further, the difference in the vinyl acetate molecular weight distribution and ethyl alcohol content affected the attenuation of the transmitted load of home reliners after water absorption.

The Foxe3 rct mutation, which causes early-onset cataracts, is a recessive mutation found in SJL/J mice. A previous study reported that cataract phenotypes are modified by the genetic background of mouse inbred strains and that the Pde6b rd1 mutation, which induced degeneration of the photoreceptor cells, is a strong candidate genetic modifier to accelerate the severity of cataractogenesis of Foxe3 rct mice. We created congenic mice by transferring a genomic region including the Foxe3 rct mutation to the B6 genetic background, which does not carry the Pde6b rd1 mutation. In the congenic mice, the cataract phenotypes became remarkably mild, and the development of cataracts was suppressed for a long time. Moreover, we created transgenic mice by injecting BAC clones including the wild-type Pde6b gene into the eggs of SJL-Foxe3 rct mice. Although the resistant effect for cataract phenotypes in transgenic mice was less than that in congenic mice, the severity and onset time of cataract phenotypes were clearly improved and delayed, respectively, compared with the phenotypes of the original SJL-Foxe3 rct mice. These results clearly show that the development of early-onset cataracts requires at least two mutant alleles of Foxe3 rct and Pde6b rd1 , and another modifier associated with the severity of cataract phenotypes in Foxe3 rct mice underlies the genetic backgrounds in mice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The taste of umami peptide H-Lys-Gly-Asp-Glu-Glu-Ser-Leu-Ala-OH (LGAGGSLA) is controversial. One possible reason for this controversy is the use of chemically synthesized LGAGGSLA to confirm its taste. To explore other ways to further confirm the flavor of LGAGGSLA, we developed a new strategy to prepare a bio-source peptide by adopting a gene engineering method to express LGAGGSLA in recombinant Escherichia coli. In our previous work, we structured the LGAGGSLA recombinant expression system and optimized the culturing conditions for preparing a fusion protein. However, the fusion protein was not cleaved by enterokinase to obtain LGAGGSLA. Because the cleavage conditions of commercial enterokinase were not specific and recombinant engineered bacteria had the potential to be used in industrial processes, in this addendum, we calculated the mass and volume yields of key processing steps in the preparation of LGAGGSLA, and established a model of cleavage conditions with the cleavage ratio of LGAGGSLA. When the LGAGGSLA was confirmed to show umami taste, it is considered as a new umami or umami enhancer. The gene information of LGAGGSLA should have a great potential in the development of new flavor product and food product containing high umami flavor.

Objectives: To clarify the effects of dutasteride on serum hormone levels and aging male symptoms in patients with benign prostatic enlargement., Methods: The present prospective study was carried out in 110 symptomatic benign prostatic enlargement patients treated with daily administration of 0.5 mg dutasteride. We analyzed serum hormonal levels and aging related symptoms using a validated Aging Male Symptom questionnaire at baseline and after 3 months of dutasteride treatment., Results: The mean total testosterone, free testosterone and luteinizing hormone levels after dutasteride treatment were approximately 20% higher than those at baseline. The percentage increases in total and free testosterone levels were negatively correlated with these baseline levels. Baseline age, levels of total testosterone and free testosterone, and the changes in the rate of luteinizing hormone after dutasteride treatment tended to be correlated with an increase in the rate of total testosterone and free testosterone after dutasteride treatment. In a subgroup of 26 patients with moderate-to-severe aging male symptoms, poor morning erection and free testosterone levels <8.5 pg/mL, total aging male symptoms, and somatic symptoms scores significantly decreased after dutasteride treatment with an increase of total and free testosterone., Conclusions: The increase of endogenous free testosterone and total testosterone by dutasteride might bring additional benefits of improvement of aging male-related symptoms, especially in patients with lower free testosterone baseline levels and moderate-to-poor aging-related symptoms., (© 2017 The Japanese Urological Association.)

The interactions of the lithospheric plates that form the Earth's outer shell provide much of the evidentiary basis for modern plate tectonic theory. Seismic discontinuities in the lithosphere arising from mantle convection and plate motion provide constraints on the physical and chemical properties of the mantle that contribute to the processes of formation and evolution of tectonic plates. Seismological studies during the past two decades have detected seismic discontinuities within the oceanic lithosphere in addition to that at the lithosphere-asthenosphere boundary (LAB). However, the depth, distribution, and physical properties of these discontinuities are not well constrained, which makes it difficult to use seismological data to examine their origin. Here we present new active-source seismic data acquired along a 1,130 km profile across an old Pacific plate (148-128 Ma) that show oceanic mid-lithosphere discontinuities (oceanic MLDs) distributed 37-59 km below the seafloor. The presence of the oceanic MLDs suggests that frozen melts that accumulated at past LABs have been preserved as low-velocity layers within the current mature lithosphere. These observations show that long-offset, high-frequency, active-source seismic data can be used to image mid-lithospheric structure, which is fundamental to understanding the formation and evolution of tectonic plates.

Although the clinical utility of a frozen section analysis (FSA) at the time of radical cystectomy (RC) has already been established, its significance and utility in bladder cancer patients receiving neoadjuvant chemotherapy (NAC) have not yet been fully evaluated. We identified 458 patients (937 ureters) who underwent open RC for bladder cancer at our 7 Japanese institutions between 2004 and 2015. Among these patients, 139 (284 ureters) received NAC before RC (NAC group), while 319 (653 ureters) underwent RC alone (non-NAC group). FSA was performed on 356 out of 937 (38.0%) ureters and 179 out of 458 (39.1%) patients. FSA was positive in 30 out of 356 (8.4%) ureters and its sensitivity, specificity, and accuracy were 89.3, 98.5, and 97.8%, respectively. In the NAC group, FSA was performed on 138 out of 284 (48.6%) ureters and 68 out of 139 (48.9%) patients. FSA was positive in 8 out of 138 ureters (5.8%), and its sensitivity, specificity, and accuracy were 77.8, 99.2, and 97.8%, respectively. In the non-NAC group, FSA was performed on 218 out of 653 (33.4%) ureters and 111 out of 319 (34.8%) patients. FSA was positive in 22 out of 218 (10.1%) ureters, and its sensitivity, specificity, and accuracy were 94.7, 98.0, and 97.7%, respectively. No correlation was observed between preoperative clinical factors and FSA positivity in the NAC group; however, in the non-NAC group, the incidence of FSA positivity in the ureters of patients with concomitant CIS in TUR-BT specimens was 8/41 (19.5%), which was significantly higher than that in their counterpart (14/177, 7.9%, p = 0.033). Even in the era of NAC in the management of bladder cancer patients, the performance of FSA does not change and FSA at the time of RC may provide useful diagnostic information.

The double perovskite CaMnTi 2 O 6 , is a rare A-site ordered perovskite oxide that exhibits a sizable ferroelectric polarization and relatively high Curie temperature. Using first-principles calculations combined with detailed symmetry analyses, we identify the origin of the ferroelectricity in CaMnTi 2 O 6 . We further explore the material properties of CaMnTi 2 O 6 , including its ferroelectric polarization, dielectric and piezoelectric responses, magnetic order, electronic structure, and optical absorption coefficient. It is found that CaMnTi 2 O 6 exhibits room-temperature-stable ferroelectricity and moderate piezoelectric responses. Moreover, CaMnTi 2 O 6 is predicted to have a semiconducting energy band gap similar to that of BiFeO 3 , and its band gap can further be tuned via distortions of the planar Mn-O bond lengths. CaMnTi 2 O 6 exemplifies a new class of single-phase semiconducting ferroelectric perovskites for potential applications in ferroelectric photovoltaic solar cells.

An efficient and sensitive chiral analytical method was established for the determination of the chiral fungicide prothioconazole and its major chiral metabolite prothioconazole-desthio in agricultural and environmental samples using ultraperformance liquid chromatography-tandem mass spectrometry. The optical rotation and absolute configuration of enantiomers were identified by optical rotation detector and electronic circular dichroism spectra. The elution order of prothioconazole and its chiral metabolite enantiomers was R-(+)-prothioconazole-desthio, S-(-)-prothioconazole-desthio, R-(-)-prothioconazole, and S-(+)-prothioconazole. The mean recoveries from the samples was 71.8-102.0% with intraday relative standard deviations (RSDs) of 0.3-11.9% and interday RSDs of 0.9-10.6%. The formation of prothioconazole-desthio was studied in soil under field conditions and enantioselective degradation was observed for chiral prothioconazole. Remarkable enantioselective degradation was observed: R-prothioconazole degraded preferentially with EF values from 0.48 to 0.37. Although prothioconazole-desthio is the most remarkably bioactive metabolite, no obvious enantioselective behavior was observed in soil. These results may help to systematically evaluate prothioconazole and its metabolites in food and environmental safety.

Luminescent semiconductor nanocrystals, also known as quantum dots (QDs), have rich surface chemistry and unique optical properties that make them useful as probes or carriers for molecular diagnostics and therapeutics. However, their potential toxicity and instability in biological environments have puzzled scientific researchers. Much research effort has been devoted to encapsulation of QDs with liposomal hybrids to make them versatile nanocarriers for simultaneous therapeutics and diagnostics (theranostics) and considerable progress has been made over recent years. We provide an overview of the use of QD-liposome complexes (QLCs) for imaging applications, in particular applications in theranostics. More specifically, the design considerations, intracellular uptake and tissue-specific targeting of QLCs are highlighted. Current findings of QLCs for theranostics are discussed. We also discuss the challenges and highlight future directions for applications of liposome-QD hybrid nanocarriers in the biomedical arena.

Background: Hyperfibrinolysis is a critical complication in severe trauma. Hyperfibrinolysis is traditionally diagnosed via elevated D-dimer or fibrin/fibrinogen degradation product levels, and recently, using thromboelastometry. Although hyperfibrinolysis is observed in patients with severe isolated traumatic brain injury (TBI) on arrival at the emergency department (ED), it is unclear which factors induce hyperfibrinolysis. The present study aimed to investigate the factors associated with hyperfibrinolysis in patients with isolated severe TBI., Methods: We conducted a multicentre retrospective review of data for adult trauma patients with an injury severity score ≥ 16, and selected patients with isolated TBI (TBI group) and extra-cranial trauma (non-TBI group). The TBI group included patients with an abbreviated injury score (AIS) for the head ≥ 4 and an extra-cranial AIS < 2. The non-TBI group included patients with an extra-cranial AIS ≥ 3 and head AIS < 2. Hyperfibrinolysis was defined as a D-dimer level ≥ 38 mg/L on arrival at the ED. We evaluated the relationships between hyperfibrinolysis and injury severity/tissue injury/tissue perfusion in TBI patients by comparing them with non-TBI patients., Results: We enrolled 111 patients in the TBI group and 126 in the non-TBI group. In both groups, patients with hyperfibrinolysis had more severe injuries and received transfusion more frequently than patients without hyperfibrinolysis. Tissue injury, evaluated on the basis of lactate dehydrogenase and creatine kinase levels, was associated with hyperfibrinolysis in both groups. Among patients with TBI, the mortality rate was higher in those with hyperfibrinolysis than in those without hyperfibrinolysis. Tissue hypoperfusion, evaluated on the basis of lactate level, was associated with hyperfibrinolysis in only the non-TBI group. Although the increase in lactate level was correlated with the deterioration of coagulofibrinolytic variables (prolonged prothrombin time and activated partial thromboplastin time, decreased fibrinogen levels, and increased D-dimer levels) in the non-TBI group, no such correlation was observed in the TBI group., Conclusions: Hyperfibrinolysis is associated with tissue injury and trauma severity in TBI and non-TBI patients. However, tissue hypoperfusion is associated with hyperfibrinolysis in non-TBI patients, but not in TBI patients. Tissue hypoperfusion may not be a prerequisite for the occurrence of hyperfibrinolysis in patients with isolated TBI.

Major intrinsic protein of lens fiber (MIP) is one of the proteins essential for maintaining lens transparency while also contributing to dominant cataracts in humans. The Nodai cataract (Nat) mice harbor a spontaneous mutation in Mip and develop early-onset nuclear cataracts. The Nat mutation is a c.631G>A mutation (Mip Nat ), resulting in a glycine-to-arginine substitution (p.Gly211Arg) in the sixth transmembrane domain. The Mip Nat/Nat homozygotes exhibit congenital cataracts caused by the degeneration of lens fiber cells. MIP normally localizes to the lens fiber cell membranes. However, the Mip Nat/Nat mice were found to lack an organelle-free zone, and the MIP was mislocalized to the nuclear membrane and perinuclear region. Furthermore, the Mip Nat/+ mice exhibited milder cataracts than Mip Nat/Nat mice due to the slight degeneration of the lens fiber cells. Although there were no differences in the localization of MIP to the membranes of lens fiber cells in Mip Nat/+ mice compared to that in wild-type mice, the protein levels of MIP were significantly reduced in the eyes. These findings suggest that cataractogenesis in Mip Nat mutants are caused by defects in MIP expression. Overall, the Mip Nat mice offer a novel model to better understand the phenotypes and mechanisms for the development of cataracts in patients that carry missense mutations in MIP.