Search

Background: Health systems guidance (HSG) are systematically developed statements that assist with decisions about options for addressing health systems challenges, including related changes in health systems arrangements. However, the development, appraisal, and reporting of HSG poses unique conceptual and methodological challenges related to the varied types of evidence that are relevant, the complexity of health systems, and the pre-eminence of contextual factors. To address this gap, we are conducting a program of research that aims to create a tool to support the appraisal of HSG and further enhance HSG development and reporting. The focus of this paper was to conduct a knowledge synthesis of the published and grey literatures to determine quality criteria (concepts) relevant for this process.Methods: We applied a critical interpretive synthesis (CIS) approach to knowledge synthesis that enabled an iterative, flexible, and dynamic analysis of diverse bodies of literature in order to generate a candidate list of concepts that will constitute the foundational components of the HSG tool. Using our review questions as compasses, we were able to guide the search strategy to look for papers based on their potential relevance to HSG appraisal, development, and reporting. The search strategy included various electronic databases and sources, subject-specific journals, conference abstracts, research reports, book chapters, unpublished data, dissertations, and policy documents. Screening the papers and data extraction was completed independently and in duplicate, and a narrative approach to data synthesis was executed.Results: We identified 43 papers that met eligibility criteria. No existing review was found on this topic, and no HSG appraisal tool was identified. Over one third of the authors implicitly or explicitly identified the need for a high-quality tool aimed to systematically evaluate HSG and contribute to its development/reporting. We identified 30 concepts that may be relevant to the appraisal of HSG and were able to cluster them into three meaningful domains: process principles, content, and context principles.Conclusions: Our study showed the role that the quality criteria play in the development, appraisal, and reporting of HSG and demonstrated the link and resonance within and between the various concepts in the three domains. [ABSTRACT FROM AUTHOR]

Wolbachia and Cardinium are bacterial endosymbionts that are widely distributed amongst arthropods. Both cause reproductive alterations, such as cytoplasmic incompatibility, parthenogenesis and feminization. Here we studied differentially expressed genes in Wolbachia- and Cardinium-infected Bm-aff3 silkworm cells using a silkworm microarray. Wolbachia infection did not alter gene expression or induce or suppress immune responses. In contrast, Cardinium infection induced many immune-related genes, including antimicrobial peptides, pattern recognition receptors and a serine protease. Host immune responses differed, possibly because of the different cell wall structures of Wolbachia and Cardinium because the former lacks genes encoding lipopolysaccharide components and two racemases for peptidoglycan formation. A few possibly non-immune-related genes were differentially expressed, but their involvement in host reproductive alteration was unclear. [ABSTRACT FROM AUTHOR]

Reference materials are used in every laboratory in order to assure the appropriate quality of analytical results. The production of reference materials is not an easy task especially in the case of gaseous, toxic and malodorous compounds. Thermal decomposition of immobilized compounds is a convenient way for the generation of those kinds of mixtures. Temperature is an important variable in this process. In this case, thermoanalytical techniques (thermogravimetry and differential scanning calorimetry (TG-DSC)) and scanning electron microscopy (SEM) were used for checking the temperature range which had been previously determined using thermal desorber-gas chromatograph-flame ionization detector (TD-GC-FID) system. [ABSTRACT FROM AUTHOR]

Abstract: Objective: There is a need to provide an index of muscle contractility in evaluating myopathies especially in the clinical setting. This study was conducted to investigate if the mechanomyogram post-activation potentiation (MMG-PAP) can be used as an index of muscle contractile force potentiation (force-PAP), if it differs between normal and myopathic muscles, and if it can reflect abnormalities in muscle fiber anatomy. Methods: The correlation between MMG-PAP and force-PAP was evaluated in 12 normal subjects after maximum voluntary contraction (MVC) of the biceps brachii muscle. The same method was then applied to study MMG-PAP in 16 patients with myopathies, 16 disease and 25 normal controls. Mean fiber diameters and the proportions of type 1 and 2 fibers in biopsied biceps brachii muscle were determined and compared with MMG-PAP values. Results: There was a significant positive correlation between force-PAP (197±148%) and MMG-PAP (135±68%) immediately after MVC (P<0.05). The mean MMG-PAP in myopathies (66±53%) was significantly lower than those of the disease (128±34%; P<0.005) and normal controls (120±56%; P<0.005). Patients with non-dystrophic myopathies, including those with myositis, had significantly lower MMG-PAP values (38±20%; P<0.005) than those with muscular dystrophy (148±23%). MMG-PAP did not clearly correlate with either type 2 fiber atrophy or type 2 fiber disproportion based on muscle biopsy analysis of myopathic patients. Conclusions: This study shows that MMG-PAP can be used as an index of muscle contractility and that it is significantly lower in non-dystrophic myopathies compared to normal subjects. MMG-PAP does not seem to reflect abnormal muscle fiber anatomy. Significance: MMG-PAP may become a valuable non-invasive tool in augmenting routine clinical electrophysiologic studies especially in evaluating muscle contractility in myopathies. [Copyright &y& Elsevier]

We studied microsatellite frequency and distribution in 21.76-Mb random genomic sequences, 0.67-Mb BAG sequences from the Z chromosome, and 6.3-Mb EST sequences of Bombyx mori. We mined microsatellites of ≥15 bases of mononucleotide repeats and ≥5 repeat units of other classes of repeats. We estimated that microsatellites account for 0.31 % of the genome of B. mori. Microsatellite tracts of A, AT, and ATT were the most abundant whereas their number drastically decreased as the length of the repeat motif increased. In general, tri- and hexanucleotide repeats were overrepresented in the transcribed sequences except TAA, GTA, and TGA, which were in excess in genomic sequences. The Z chromosome sequences contained shorter repeat types than the rest of the chromosomes in addition to a higher abundance of AT-rich repeats. Our results showed that base composition of the flanking sequence has an influence on the origin and evolution of microsatellites. Transitions/transversions were high in microsatellites of ESTs, whereas the genomic sequence had an equal number of substitutions and indels. The average heterozygosity value for 23 polymorphic microsatellite loci surveyed in 13 diverse silkmoth strains having 2–14 alleles was 0.54. Only 36 (18.2%) of 198 microsatellite loci were polymorphic between the two divergent silkworm populations and 10 (5%) loci revealed null alleles. The microsatellite map generated using these polymorphic markers resulted in 8 linkage groups. B. mon microsatellite loci were the most conserved in its immediate ancestor, B. mandarina, followed by the wild saturniid silkmoth, Antheraea assama. [ABSTRACT FROM AUTHOR]

Abstract: Insect metamorphosis is induced by the steroid 20-hydroxyecdysone (20E) in the absence of sesquiterpenoid juvenile hormone (JH). In Drosophila melanogaster, the Broad-Complex (BR-C) transcriptional factor plays critical roles during metamorphosis. We isolated cDNAs encoding BR-C in the silkworm Bombyx mori and examined their mRNA expression. cDNAs for three BR-C isoforms with zinc finger pairs (Z1, Z2 and Z4) and four isoforms lacking them were cloned. Their mRNAs were expressed in multiple tissues at the larval–pupal metamorphosis. In the anterior silk gland, BR-C mRNAs were expressed at the end of the last larval instar but not expressed during the penultimate instar. 20E administration induced BR-C mRNA expression and JH suppressed 20E-induced BR-C expression in this tissue both in vivo and in vitro. Thus, BR-C mRNAs are inducible by 20E only in the absence of JH, a finding that explains their metamorphosis-specific expression. [Copyright &y& Elsevier]

Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory condition of unknown etiology characterized by lymphocytic infiltration, fibrosis, and infiltration of IgG4-positive plasma cells. It affects various organs, including the pancreas and salivary glands. Immunological abnormalities are suspected to play a role in its pathogenesis, and there is an epidemiological link to allergic conditions and type 2 inflammation. This study focused on the expression of thymus and activation-regulated chemokine (TARC)/CCL17, which is involved in the migration of T helper 2 and/or regulatory T cells, in salivary gland tissues of patients with IgG4-RD. We analyzed 60 salivary gland biopsy samples obtained from patients at Sapporo Medical University Hospital between 2015 and 2020. Immunohistochemical analysis revealed TARC/CCL17 positivity in 87.2% of histologically confirmed IgG4-RD cases and negativity in 84.6% of histologically unconfirmed but clinically suspected IgG4-RD cases. There was a significant correlation between histologically confirmed IgG4-RD and TARC/CCL17 expression, suggesting its potential diagnostic utility and possible involvement in the pathogenesis of IgG4-RD.

We aimed to develop an AI model that recognizes and displays loose connective tissue as a dissectable layer in real-time during gastrointestinal surgery and to evaluate its performance, including feasibility for clinical application. Training data were created under the supervision of gastrointestinal surgeons. Test images and videos were randomly sampled and model performance was evaluated visually by 10 external gastrointestinal surgeons. The mean Dice coefficient of the 50 images was 0.46. The AI model could detect at least 75% of the loose connective tissue in 91.8% of the images (459/500 responses). False positives were found for 52.6% of the images, but most were not judged significant enough to affect surgical judgment. When comparing the surgeon's annotation with the AI prediction image, 5 surgeons judged the AI image was closer to their own recognition. When viewing the AI video and raw video side-by-side, surgeons judged that in 99% of the AI videos, visualization was improved and stress levels were acceptable when viewing the AI prediction display. The AI model developed demonstrated performance at a level approaching that of a gastrointestinal surgeon. Such visualization of a safe dissectable layer may help to reduce intraoperative recognition errors and surgical complications., Competing Interests: Declarations. Competing interests: Conflicts of Interest: Y.K. and N.K. are shareholders of Anaut Inc. Y.N. and S.S. are employees of Anaut Inc. T.M. received an honorarium from Anaut Inc. K.K. Y.F., K.M., T.O., H.S. have nothing to disclose. This study was sponsored by Anaut Inc. Ethics approval: This study was approved by the Ethics Committee of the Hyogo College of Medicine (Approval number 3843). This study was conducted in accordance with the 1964 Declaration of Helsinki. All data were provided with the approval of the ethics committees of all institutions participating in the study and were completely anonymized. Informed consents were obtained from all participants in this study., (© 2024. The Author(s).)

Background: A head-to-head comparison between enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) revealed similar survival benefits for castration-resistant prostate cancer (CRPC) in the ENABLE study for PCa. Considering that a dose reduction of ENZ and ABI has demonstrated sufficient inhibitory ability of androgen receptor (AR) signaling, we analyzed the efficacy of modified doses of these agents in the ENABLE study for PCa., Methods: This investigator-initiated, multicenter, randomized controlled trial that was conducted in Japan analyzed the prespecified survival endpoints, prostate-specific antigen (PSA) response rate ( ≥50% decline from baseline), and safety profile in patients treated with modified doses (ENZ ≤ 120 mg/day, ABI ≤ 750 mg/day) compared with those treated with a standard dose (ENZ 160 mg/day, ABI 1000 mg/day) as a starting dose., Results: In total, 92 patients in each arm were treated and analyzed; 16 patients were treated with a modified dose in both the ENZ and ABI arms, respectively. Moreover, 32 patients treated with modified doses showed a significantly better time to PSA progression (TTPP) and overall survival (OS) compared with the 152 patients treated with a standard dose (HR 0.47, 95%CI 0.27-0.83, p = 0.0379, and HR 0.35, 95%CI 0.19-0.63, p = 0.0162). Despite a significantly longer TTPP in the modified ABI group than in the standard ABI group (HR 0.29, 95%CI 0.14-0.62, p = 0.0248), no significant difference was observed in the TTPP between the modified and standard ENZ groups (p = 0.5366). Furthermore, similar adverse event rates and grades were observed in each treatment dose group., Conclusions: The modified doses of ABI showed better TTPP than the standard dose of ABI and may be a potential treatment option for CRPC patients; however, its mechanism is still unclear, although its ability to suppress AR signaling is equivalent to that of a standard dose., (© 2024 Wiley Periodicals LLC.)

Bt has been applied as a gene source for insect-resistant transgenic crops, which represents efficient control of insect pests. In this study, we evaluated the pesticidal specificity of one Bt maize strain, DBN9936, that expresses Cry1Ab protein in Spodoptera litura larvae. The results showed that this Bt maize is active against the younger larvae while causing a sublethal effect on older larvae. To further assess the biological responses of S. litura under sublethal Cry1Ab exposure, the relative concentrations of Cry1Ab in different tissues of fifth instar larvae were investigated, indicating that Cry1Ab is transported along the gut and out of the body via excretion or into the hemocoel and lead to sequestration by molting. Furthermore, the result of ultrastructural observation in sublethal Cry1Ab-treated midgut, namely an increase in lysosome number, with the lysosomal activity activation simultaneously provides a strong indication that lysosome plays an active role in response to sublethal Cry1Ab exposure.

Purpose: In laparoscopic inguinal hernia surgery, proper recognition of loose connective tissue, nerves, vas deferens, and microvessels is important to prevent postoperative complications, such as recurrence, pain, sexual dysfunction, and bleeding. EUREKA (Anaut Inc., Tokyo, Japan) is a system that uses artificial intelligence (AI) for anatomical recognition. This system can intraoperatively confirm the aforementioned anatomical landmarks. In this study, we validated the accuracy of EUREKA in recognizing dissection layers, nerves, vas deferens, and microvessels during transabdominal preperitoneal inguinal hernia repair (TAPP)., Methods: We used TAPP videos to compare EUREKA's recognition of loose connective tissue, nerves, vas deferens, and microvessels with the original surgical video and examined whether EUREKA accurately identified these structures. Intersection over Union (IoU) and F1/Dice scores were calculated to quantitively evaluate AI predictive images., Results: The mean IoU and F1/Dice scores were 0.33 and 0.50 for connective tissue, 0.24 and 0.38 for nerves, 0.50 and 0.66 for the vas deferens, and 0.30 and 0.45 for microvessels, respectively. Compared with the images without EUREKA visualization, dissection layers were very clearly recognized and displayed when appropriate tension was applied., Competing Interests: Declarations. Conflict of interest: The authors report no conflicts of interest. Ethical approval: The study was approved by the Institutional Ethical Board of Tsudanuma Central General Hospital. Human and animal rights: All procedures performed in studies involving human participants were performed according to the ethical standards of the Institutional and/or National Research Committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s).)

Genome sequences contain the fundamental genetic information that largely determines the biology of a species. Over the past 20 years, advancements in high-throughput sequencing technologies and bioinformatics tools have matured, facilitating genome assembly and ushering in the telomere-to-telomere (T2T) era. Bombyx mori is renowned as a silk-producing insect and serves as an important model organism extensively studied across various fields of biology. In this study, we present the first assembled T2T genome by integrating HiFi, ultra-long ONT, NGS, and Hi-C data. This assembly comprises 450,267,439 base pairs from 28 chromosomes and includes annotations for a total of 18,253 protein-coding genes. A completeness evaluation revealed that 99.1% of conserved single-copy genes were included, as determined by a BUSCO analysis. Furthermore, the consensus quality (QV) assessed through Merqury was recorded at 59.88. The proportion of repeat sequence achieved 60.77%, marking it as the highest reported value for B. mori to date. In comparison to previously published genomes, our assembly offers a more complete and higher quality representation, particularly concerning highly homologous tandem regions such as telomeres, rDNA clusters, and Gr family regions. Furthermore, our extensive experience in genome assembly, including sample preparation experience and assembly strategies to reduce complexity, will provide valuable references for other species aiming to achieve their own T2T genome assemblies.

Waldiomycin is an inhibitor of histidine kinases (HKs). Although most HK inhibitors target the ATP-binding region, waldiomycin binds to the intracellular dimerization domain (DHp domain) with its naphthoquinone moiety presumed to interact with the conserved H-box region. To further develop inhibitors targeting the H-box, various 2-aminonaphthoquinones with cyclic, aliphatic, or aromatic amino groups and naphtho [2,3-d] isoxazole-4,9-diones were synthesized. These compounds were tested for their inhibitory activity (IC 50 ) against WalK, an essential HK for Bacillus subtilis growth, and their minimum inhibitory concentrations (MIC) against B. subtilis. As a result, 11 novel HK inhibitors were obtained as naphthoquinone derivatives (IC 50 : 12.6-305 µM, MIC: 0.5-128 µg ml -1 ). The effect of representative compounds on the expression of WalK/WalR regulated genes in B. subtilis was investigated. Four naphthoquinone derivatives induced the expression of iseA (formerly yoeB), whose expression is negatively regulated by the WalK/WalR system. This suggests that these compounds inhibit WalK in B. subtilis cells, resulting in antibacterial activity. Affinity selection/mass spectrometry analysis was performed to identify whether these naphthoquinone derivatives interact with WalK in a manner similar to waldiomycin. Three compounds were found to competitively inhibit the binding of waldiomycin to WalK, suggesting that they bind to the H-box region conserved in HKs and inhibit HK activity., (© 2024. The Author(s).)

We report here a case of postoperative recurrent adenosquamous carcinoma (ASC) of the esophagogastric junction (EGJ) treated with S-1 therapy. A 79-year-old woman was diagnosed with carcinoma of the EGJ. Thoracoscopic subtotal esophagectomy was performed, and pathological examination revealed advanced ASC with lymph node metastasis. Five months after surgery, multiple lung metastases and multiple lymph node metastases were observed, and the patient was treated with S-1 monotherapy, which showed partial response and may be effective for advanced ASC of the EGJ. On the other hand, immunohistological analysis of the tumors showed a relatively wide range of areas that could differentiate into both adenocarcinoma and squamous cell carcinoma, suggesting that tumor cells with multidifferentiation potential, or at least the ability to differentiate into both adeno-epithelial and squamous epithelial cells, were the likely source of the tumors., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Introduction: Antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using the national surveillance data, comprising 793 bacterial strains from eight clinically relevant species., Materials and Methods: Data were collected for the fourth national surveillance project from July 2020 to December 2021 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was supervised with the cooperation of 43 medical institutions throughout Japan., Results: Fluoroquinolone required a minimum inhibitory concentration (MIC) of 2-64 mg/L to inhibit the 330 tested Escherichia coli strains. The proportion of levofloxacin-resistant E. coli strains increased from 28.6% in 2008 to 29.6% in 2011, 38.5% in 2015, and 44.5% in 2021. The proportion of levofloxacin-resistant strains of Pseudomonas aeruginosa also increased from previous survey results, showing a continuing downward trend. Conversely, the proportion of levofloxacin-resistant strains of Enterococcus faecalis decreased relative to previous reports. Neither multidrug-resistant P. aeruginosa nor carbapenem-resistant Enterobacteriaceae were detected. For methicillin-resistant Staphylococcus aureus (MRSA), the proportion of vancomycin-susceptible strains (MIC of 2 μg/mL) decreased from 14.7% to 7.7%., Discussion: Bacterial strains that produced extended-spectrum β-lactamase included E. coli (82/330 strains, 24.8%), Klebsiella pneumoniae (11/68 strains, 16.2%), and Proteus mirabilis (4/26 strains, 15.4%). As compared to previous surveillance reports, these strains showed an increase in proportion over the years., Competing Interests: Declaration of competing interest Satoshi Takahashi received speaker honoraria from Fujirebio Inc. and research funding from Shino-Test Corporation, Roche Diagnostic K. K., Fujirebio Inc., and Abbott Japan Co., Ltd. Koichiro Wada received speaker honoraria from Janssen Pharmaceutical K.K., and MSD K.K. Shingo Yamamoto received speaker honoraria from MSD K.K., Fuso Pharmaceutical Industries, Ltd., Daiichi Sankyo Co., Ltd. and scholarship donations from Takeda Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd. and research funding from Takeda Pharmaceutical Co., Ltd. Tetsuya Matsumoto received speaker honoraria from MSD K.K., Pfizer Japan Inc., and Kyorin Pharmaceutical Co., Ltd., and research funding from Kewpie Corporation., Biofermin Pharmaceutical Co., Ltd. Kazumasa Matsumoto received research funding from Sysmex Corporation. Tohru Nakagawa received speaker honoraria from Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., and Janssen Pharmaceutical K.K., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Cry1Ab has emerged as a bio-insecticide to control Spodoptera litura (Lepidoptera: Noctuidae). However, the sublethal effects of Cry1Ab on the physiological changes and molecular level of S. litura have not been well documented. Our aims in this study were to assess the sublethal effect of Cry1Ab on S. litura, including midgut and Malpighian tubules as targets., Results: After sublethal Cry1Ab exposure, distinct histological alterations were mainly observed in the midgut. Furthermore, the results of comparative RNA sequencing and tandem mass tag-based proteomics showed that, in the midgut, most differential expression genes (DEGs) were up-regulated and significantly enriched in the serine protease activity pathway, and up-regulated differential expression proteins (DEPs) were mainly associated with the oxidative phosphorylation pathway, whereas the down-regulated involved in the ribosome pathways. In the Malpighian tubules, DEGs and DEPs were significantly enriched in the ribosome pathway. We proposed that ribosome may act as a universal target in energy metabolism with other pathways via the results of protein-protein interaction analysis. Further, by verification of the mRNA expression of some Cry protein receptor and detoxification genes after Cry1Ab treatment, it was suggested that the ribosomal proteins (RPs) possibly participate in influencing the Bt-resistance of S. litura larvae under sublethal Cry1Ab exposure., Conclusion: Under sublethal Cry1Ab exposure, the midgut of S. litura was damaged, and the proteotranscriptomic analysis elucidated that Cry1Ab disrupted the energy homeostasis of larvae. Furthermore, we emphasized the potential role of ribosomes in sublethal Cry1Ab exposure. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Aim: This study aimed to evaluate the risk classification system using the detailed positive surgical margin (PSM) status to predict biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP)., Methods: We retrospectively analyzed 427 patients who underwent RARP between January 2016 and March 2020. We investigated risk factors for BCR using univariate and multivariate Cox proportional hazard regression models. The biochemical recurrence-free survival (BRFS) rate was assessed using the Kaplan-Meier method., Results: The median follow-up period was 43.4 months and 99 patients developed BCR. In the multivariate analysis, maximum PSM length > 5.0 mm and the International Society of Urological Pathology grade group (ISUP GG) at the PSM ≥3 were predictive factors for BCR in patients with a PSM. In the multivariate analysis, these factors were also independent predictive factors in the overall study population, including patients without a PSM. We classified the patients into four groups using these factors and found that the 1-year BRFS rates in the negative surgical margin (NSM) group, low-risk group (PSM and neither factor), intermediate-risk group (either factor), and high-risk group (both factors) were 94.9%, 94.5%, 83.1%, and 52.9%, respectively. The low-risk group showed similar BRFS to the NSM group (p = 0.985), while the high-risk group had significantly worse BRFS than the other groups (p < 0.001)., Conclusion: Maximum PSM length > 5.0 mm and ISUP GG at the PSM ≥3 were independent predictive factors for BCR after RARP. Risk classification for BCR using these factors is considered to be useful and might help urologists decide on additional treatment after RARP., (© 2024 John Wiley & Sons Australia, Ltd.)

Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) can improve the survival of patients with castration-resistant prostate cancer (CRPC). However, the agent that is more effective against nonmetastatic CRPC remains unclear. To evaluate the agent that can be used as the first-line treatment for CRPC, an investigator-initiated, multicenter, randomized controlled trial (ENABLE Study for PCa) including both metastatic and nonmetastatic CRPC was conducted in Japan. The prostate-specific antigen (PSA) response rate, overall survival, some essential survival endpoints, and safety of patients with nonmetastatic CRPC were also analyzed. In this subanalysis, 15 and 26 patients in the ENZ and ABI arms, respectively, presented with nonmetastatic CRPC. There was no significant difference in terms of the PSA response rate between the ENZ and ABI arms (80% and 64%, respectively; p = 0.3048). The overall survival did not significantly differ between the two arms (HR: 0.68; 95% CI: 0.22-2.14, p = 0.5260). No significant differences were observed in terms of radiographic progression-free survival and cancer-specific survival between the ENZ and ABI arms (HR: 0.81; 95% CI: 0.35-1.84; p = 0.6056 and HR: 0.72; 95% CI: 0.19-2.73; p = 0.6443, respectively). Only four and six patients in the ENZ and ABI arms, respectively, had ≥grade 3 adverse events. ABI and ENZ had similar efficacy and safety profiles in patients with nonmetastatic CRPC.

Background: This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients., Methods: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs])., Results: We included 222 patients. The median age was 69 years (interquartile range 62-74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS., Conclusion: The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy., (© 2023 The Japanese Urological Association.)

We have performed a powder neutron diffraction study on CsO 2 , where the unpaired electron withs=1/2in theπ∗orbital of the O2-ion is responsible for the magnetism. The magnetic reflections 0120 and 0121 were observed below the Néel temperature of about 10 K. An antiferromagnetic structure with a propagation vector of (0,12, 0) and magnetic moments parallel to the a -axis is the most plausible. The magnitude of the ordered moment is about 0.2  µ B , which is considered to be strongly reduced due to the one-dimensionality of the system. We propose a possibleπ∗orbital order that can explain the obtained magnetic structure, and discuss its relation to the one-dimensionality., (© 2023 IOP Publishing Ltd.)

A 79-year-old man was diagnosed with esophagogastric junction adenocarcinoma, cT3N3M0, cStage Ⅲ, including enlarged lymph node metastases(Bulky N)in the middle mediastinum and intraperitoneal. A total of 2 cycles of S-1 plus oxaliplatin(SOX)was administered. After neoadjuvant chemotherapy, the primary tumor and enlarged lymph nodes had greatly decreased in size. Subsequently, thoracoscopic subtotal esophagectomy and reconstruction with a gastric tube were performed. Histopathological examinations showed no residual cancer cells in the primary lesion and dissected lymph nodes (pathological complete response). Preoperative chemotherapy containing SOX could be a useful treatment strategy for patients with esophagogastric junction adenocarcinoma with enlarged lymph node metastasis.

Background: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC., Methods: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade  ≥ 3 adverse events (AEs) were evaluated., Results: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment., Conclusion: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate the significance of both low and high body mass index (BMI) as a biomarker in first-line tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC)., Methods: The oncological outcome of 235 patients with mRCC treated with TKI from 2007 to 2018 was reviewed retrospectively. All patients received first-line TKI as therapy. We analyzed the relationship between BMI (low and high) and disease control rate. The primary outcome was progression free survival and overall survival, and the association between BMI and survival prognosis was evaluated., Results: The median BMI was 22.5 kg/m 2 , and 25 patients (10.7%) had a low BMI (<18.5 kg/m 2 ), 158 patients (67.2%) had a normal BMI (18.5-25 kg/m 2 ), and 52 patients (22.1%) had a high BMI (≥ 25 kg/m 2 ). Patients in the low BMI group had a significantly lower disease control rate, whereas patients in the high BMI group had a significantly higher disease control rate (p = 0.002 and p = 0.030, respectively). A log-rank test showed prognosis to be significantly poorer in the low BMI group and to be significantly better in the high BMI group than that in the normal BMI group. Multivariable Cox regression analysis showed that low BMI was an independent indicator of poor prognosis, whereas high BMI was an independent indicator of favorable prognosis., Conclusion: We showed the impact of both low and high BMI on predicting therapeutic efficacy and prognosis in mRCC patients treated with TKI., (© 2022 The Japanese Urological Association.)

Objectives: This study aimed to clarify the significance of therapeutic timing on the effectiveness of nivolumab for treating metastatic renal cell carcinoma., Marterials and Methods: Fifty-eight patients with metastatic renal cell carcinoma treated with nivolumab monotherapy were retrospectively studied. Patients who were treated with nivolumab as second-line therapy were included in the second-line group, while the others were included in the later-line group. The clinicopathological characteristics, effects of nivolumab, and prognoses of these groups were compared., Results: Twenty and thirty-eight patients were included in the second-line and later-line groups, respectively. There were no significant differences in the distribution of International Metastatic Renal Cell Carcinoma Database Consotium risk and other clinicopathological characteristics between the 2 groups. The proportion of patients whose objective best response was progressive disease in the second-line group was significantly lower than that in the later-line group (15% vs. 50%, p = 0.0090). The 50% progression-free survival with nivolumab in the second-line group was significantly better than that in the later-line group (not reached and 5 months, p = 0.0018). Multivariate analysis showed that the second-line setting was an independent predictive factor for better progression-free survival ( p = 0.0028, hazard ratio = 0.108). The 50% overall survival after starting nivolumab in the second-line and later-line groups was not reached and 27.8 months, respectively ( p = 0.2652)., Conclusions: The therapeutic efficacy of nivolumab as second-line therapy is expected to be better than that of later therapy., Competing Interests: Jun Teishima has received lecture fees from Pfizer Inc. and Novartis Pharma Inc., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

Introduction and Objectives: Intermediate risk group of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria is thought to consist of patients with different prognoses. This study investigated the impact of a pretreated modified Glasgow prognostic score (mGPS), which is defined on the basis of the pretreated serum albumin and C-reactive protein level, on predicting the prognosis of patients with metastatic renal cell carcinoma (mRCC) and its usefulness for the re-stratification of patients into a more improved risk model., Materials and Methods: One hundred ninety-six mRCC patients treated with first-line tyrosine kinase inhibitor (TKI) were retrospectively investigated. All patients were classified into either a high-mGPS or a low-mGPS group on the basis of mGPS score upon starting systemic therapy, the overall survival (OS) and cancer specific survival (CSS) rates in each group were compared. We use decision curve analysis and calculate C-index based on OS and CSS to compare IMDC+mGPS model and IMDC model., Results: The categories of favorable, intermediate, and poor risk groups in the IMDC model were assessed in 32, 113, and 51 cases, respectively. The low- and high-mGPS groups consisted of 149 and 47 cases. The median OS in the high- and low-mGPS groups were 38.4 months and 5.6 months, and their median CSSs were 41.0 months and 5.6 months, respectively (P < 0.0001). Multivariate analysis showed that a high mGPS, multiple metastatic organs, and hypercalcemia were independent predictive factors for a worse OS (P = 0.0260). Next, we divided the intermediate risk group into two subgroups using the mGPS score. The OS and CSS for the high-mGPS subgroup were significantly worse than those for the low-mGPS one (P = 0.0024, median OS: 21.0 months and 33.7 months, P = 0.0007, median CSS: 21.0 months and 39.8 months), and there was no significant difference in OS between the high-mGPS subgroup in the intermediate risk group and poor risk group (P = 0.2250). The value of C-index based on OS at IMDC and IMDC+mGPS model were 0.6771 and 0.6967, and those based on CSS were 0.6850 and 0.7080, respectively. In decision curve analysis to evaluate the clinical net benefit using the IMDC+mGPS model compared to the IMDC model, there was no significant difference between the two groups., Conclusion: mGPS is useful for establishing a more improved prognostic model that is able to stratify mRCC patients treated with first-line TKI., Competing Interests: Conflict of interest Jun Teishima has received lecture fees from Pfizer Inc. and Merck Biopharma Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Vaccination is an essential strategy to prevent infection in the SARS-CoV-2 pandemic. However, there are concerns about vaccine efficacy and the impact of vaccination on cancer treatment. Additionally, the emergence of novel variants may affect vaccination efficacy. This multi-center, prospective, observational study investigated the efficacy and impact of vaccination against SARS-CoV-2 variants on treatment among breast cancer patients in Japan., Methods: Patients with breast cancer scheduled to be vaccinated with the SARS-CoV-2 vaccine from May to November 2021 were prospectively enrolled (UMIN000045527). They were stratified into five groups according to their cancer treatment: no treatment, hormone therapy, anti-human epidermal growth factor receptor (HER)2 therapy, chemotherapy, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Serum samples for assessing serological responses were collected before the first vaccination and after the second vaccination., Results: Eighty-five breast cancer patients were included. The overall seroconversion rate after second vaccination was 95.3% and the lowest seroconversion rate was 81.8% in the patients under chemotherapy. The overall positivity rate of neutralizing antibodies against the wild-type, α, Δ, κ, and omicron variants were 90.2%, 81.7%, 96.3%, 84.1%, and 8.5%, respectively. Among the patients under chemotherapy or CDK4/6 inhibitors, various degrees of decreased neutralizing antibody titers against SARS-CoV-2 variants were observed. Withdrawal or reduction of systemic therapy because of vaccination was observed in only one patient., Conclusion: Our data support SARS-CoV-2 vaccination for breast cancer patients. However, a reduction in neutralizing antibody titers was suggested during chemotherapy and CDK4/6 inhibitors, raising concerns about the impact on long-term infection prevention., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The repeated-dose liver micronucleus (RDLMN) assay has been well-developed and applied because of its simplicity and the ease of integration into general toxicity studies which is the preferred method from the 3R's point of view. In this assay, we observed micronucleated hepatocytes which accumulated during a rather long-term dosing period. When considering integration into general toxicity studies, the effects of age of the animals used in the micronucleus assay becomes a major issue. The effect of age on the micronucleus induction rate has been reported in bone marrow micronucleus assays, and it is considered that the decrease in cell proliferation rate due to aging is the cause of the decrease in sensitivity. A decrease in sensitivity due to aging was also reported in a liver micronucleus assay using clofibrate and the cause is considered to be a decrease in hepatocyte proliferation activity due to aging. However, no actual decrease in hepatocyte proliferation rate due to aging has been reported. In addition, there are no reports, so far, on whether similar effects of aging appear when other substances were administered. To investigate the effects of aging in the RDLMN assay, this study focused on the effects of 14-day repeated administration of DEN, a well-known genotoxic hepatocarcinogen with the hepatocyte toxicity which should cause an elevation of cell proliferation rate as a reflective regeneration., Results: The liver micronuclei induced by DEN were equivalent between the two age groups (i.e., six and eight weeks of age at the start of dosing). In the histopathological examination for the liver, single cell necrosis, karyomegaly, and increased mitosis were observed in the hepatocytes, and the frequency and severity were increased dose-dependently. Ki-67 immunohistochemical analysis which can detect all cells in the cell cycle other than those in the G0 phase revealed dose-dependent increase of cell proliferation activity, and the difference between ages was not observed., Conclusion: The effect of aging on the RDLMN assay could not be recognized when DEN was administered for 14 days in rats. Meanwhile, it was supported by the histopathological examination and Ki-67 immunohistochemical analysis that such an effect of aging was masked by the compensatory hepatocyte proliferation which was induced by the hepatocyte toxicity of DEN., (© 2022. The Author(s).)

Introduction and Objectives: The aim of this study was to investigate prognostic factors and to establish a prognostic model using them for upfront cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitor (ICI) and/or tyrosine kinase inhibitor (TKI)., Materials and Methods: Two hundred eleven patients who were diagnosed as mRCC at initial diagnosis and were treated with TKI and/or ICI were classified into 2 groups: those undergoing CN (upfront CN group, 117 cases) and those who initially underwent systemic therapy (non-upfront CN group, 94 cases). In the upfront CN group, the patients' background and overall survival (OS) were compared with those in the other two groups, and prognostic factors were analyzed. A prognostic model of the upfront CN group was established., Results: The median of the observation period for the upfront CN group was 25 months. The rates of patients with clear cell histology, with a Karnofsky performance status (KPS) of ≥ 80%, with a single metastatic organ, with a normal pretreated C-reactive protein level, and with an intermediate risk according to the International mRCC Database Consortium (IMDC) model were significantly higher than those in the non-upfront CN group (87.2% and 30.9%, p < 0.0001; 92.3% and 77.7%, p = 0.0025; 41.9% and 24.5%, p = 0.0080; 47.9% and 13.8%, p < 0.0001; 66.7% and 45.7%, p = 0.0023, respectively). The 50% OS in the upfront CN group was 33.1 months, significantly better than that in the non-upfront CN group (11.1 months, p < 0.0001), and these results were consistent regardless of their prognostic risk level. Multivariate analysis showed that multiple metastatic organs and a KPS of < 80% were independent predictive factors for OS (hazard ratio: 1.653 and 2.995, p = 0.0339 and 0.0054, respectively). Using these two parameters to stratify the upfront CN group, the 50% OSs in cases with no risk factors, in those with one factor, and in those with two factors were 43.4 months, 29.1 months, and 7.7 months, respectively (p < 0.0001)., Conclusion: The upfront CN group was able to be stratified by our prognostic model into three subgroups with different prognoses. This model can provide useful information for making decisions in consideration of upfront CN in patients with mRCC., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) improve survival in castration-resistant prostate cancer (CRPC). However, which agent is better for patients with CRPC remains unclear., Objective: To evaluate whether ENZ or ABI is better as first-line treatment for CRPC., Design Setting and Participants: An investigator-initiated, multicenter, randomized controlled trial was conducted in Japan. The study enrolled 203 patients with CRPC before chemotherapy between February 20, 2015, and July 31, 2019. Patients were randomly assigned 1:1 to the ENZ or ABI arm., Outcome Measurements and Statistical Analysis: The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included the PSA response rate (≥50% decline from baseline), overall survival, and safety. A log-rank test was used for comparison of survival analyses between arms., Results and Limitations: After randomization, 92 patients in each arm were treated and analyzed. Time to PSA progression did not significantly differ between the arms (median 21.2 mo for ENZ and 11.9 mo for ABI; hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.51-1.27; p = 0.1732). There was a significant difference in the PSA response rate between the arms (72% for ENZ and 57% for ABI; p = 0.0425). There was no significant difference in overall survival (median 32.9 mo for ENZA and 35.5 mo for ABI; HR 1.17, 95% CI 0.72-1.88; p = 0.5290). Grade ≥3 adverse events were observed in 11% of patients in the ENZA arm and 21% in the ABI arm ( p = 0.1044)., Conclusions: ENZ did not show any survival benefit in comparison to ABI, but showed a better PSA response rate with a low rate of severe adverse events in CRPC., Patient Summary: Results from our study suggest that use of enzalutamide before abiraterone may have potential clinical benefits for patients with castration-resistant prostate cancer., (© 2022 The Author(s).)

Purpose: The objective of this study was to compare perioperative outcomes and total and split renal function between laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RAPN). Predictive risk factors of preservation of operated renal function were also assessed., Methods: We retrospectively analyzed 173 patients who underwent LPN (n = 84) or RAPN (n = 89) between 2010 and 2020. After propensity score matching (1:1), perioperative outcomes and total and split renal function were assessed. Logistic regression analysis was used to evaluate predictive risk factors of preservation of operated renal function. Trifecta criteria were defined as negative surgical margins, warm ischemia time (WIT) < 25 min, and no complications more than Clavien-Dindo grade II within 4 weeks after surgery. Split renal function was evaluated by mercaptoacetyltriglycine renal scan., Results: After propensity score matching, 42 patients were allocated to each group. RAPN was associated with significantly shorter WIT (RAPN vs LPN: 12 vs 22 min; p < 0.0001) and higher trifecta achievement rate (93.3 vs 64.2%; p < 0.0001). Other perioperative outcomes and total and split renal function were not significantly different between LPN and RAPN. The R.E.N.A.L. nephrometry score (RNS) was a predictive risk factor of preservation of operated renal function in the multivariable logistic regression analysis (odds ratio 1.68, 95% confidence interval 1.29-2.20, p < 0.0001)., Conclusions: RAPN improved WIT and trifecta achievement rate, but it did not improve the preservation of operated renal function, for which RNS was found to be a strong predictive risk factor., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: There are various alternative first-line therapeutic options besides tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC). To inform therapeutic decision-making for such patients, this study aimed to identify predictive factors for resistance to TKI., Materials and Methods: A total of 239 cases of mRCC patients who received first-line TKI therapy were retrospectively studied. Patients with a radiologic diagnosis of progressive disease within 3 months after initiating therapy were classified as primary refractory cases; the others were classified as non-primary refractory cases. The association between primary refractory cases and age, gender, pathology findings, serum c-reactive protein (CRP) level, metastatic organ status, and 6 parameters defined by the International Metastatic Renal Cell Carcinoma Database Consortium were analyzed., Results: Of 239 cases, 32 (13.3%) received a radiologic diagnosis of progressive disease within 3 months after initiating therapy. The rates of sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, presence of liver metastasis, anemia, and time from diagnosis to treatment interval of less than a year were significantly higher in the primary refractory group. Multivariate analysis showed that sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, and liver metastasis were independently associated with primary refractory disease. A risk-stratified model based upon the number of patients with these factors indicated rates of primary refractory disease of 4.0%, 10.1%, and 45.0% for patients with 0, 1, and 2 or more factors, respectively., Conclusions: Sarcomatoid differentiation, hypercalcemia, an elevated serum CRP level, and presence of liver metastasis were associated with primary refractory disease in mRCC patients receiving first-line TKI therapy. These results provide clinicians with useful information when selecting a first-line therapeutic option for mRCC patients., Competing Interests: Jun Teishima has received lecture fees from Pfizer Inc. and Novartis Pharma Inc., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc.)

Background/aim: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study aimed to examine the role of CD44 in sunitinib resistance and as a predictive marker in mRCC., Materials and Methods: We analyzed the effect of CD44 knockdown on sunitinib resistance in RCC cell lines using WST-1 assays. CD44 expression in mRCC patients treated with first-line sunitinib was determined by immunohistochemistry. We validated the findings of this study by in silico analysis., Results: CD44 knockdown increased sensitivity to sunitinib. Immunohistochemical analysis revealed that 19 (34.5%) of 55 mRCC cases were positive for CD44. CD44-positive cases were associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, high CD44 expression was significantly associated with poor PFS after sunitinib but not after avelumab + axitinib therapy., Conclusion: CD44 is involved in sunitinib resistance and may be a promising marker for sunitinib treatment in mRCC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study examined the potential role of p53 in sunitinib resistance and as a predictive marker in mRCC., Materials and Methods: We analysed the effects of p53 knockout on sunitinib resistance. p53 expression in 53 mRCC patients receiving first-line sunitinib was determined immunohistochemically. We performed in silico analysis to examine the predictive value of p53 in mRCC., Results: WST-1 assays showed that p53 knockout decreased sensitivity to sunitinib. Sunitinib and nutlin-3 together suppressed cell growth. Immunohistochemistry revealed 11 p53-positive cases among 53 patients with mRCC. Kaplan-Meier analysis showed that p53-positive cases tended to be associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, TP53 mutation was significantly associated with poor PFS after sunitinib treatment., Conclusion: p53 may be involved in sunitinib resistance and represent a valuable marker for sunitinib treatment in mRCC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Continuous social isolation (SI) from an early developmental stage may have different effects in youth and adulthood. Moreover, SI is reported to impair neuronal plasticity. In this study, we used post-weaning rats to compare the impact of continuous SI on depressive-like, anxiety-related, and fear-related behaviors and neuronal plasticity in puberty and adulthood. Furthermore, we assessed the effect of lithium on behavioral changes and neuronal plasticity. Continuous SI after weaning induced depressive-like behaviors in puberty; however, in adulthood, depressive-like and anxiety-related behaviors did not increase, but-paradoxically-decreased in comparison with the controls. The decreased expression of neuronal plasticity-related proteins in the hippocampus in puberty was more prominent in the prefrontal cortex and hippocampus in adulthood. In contrast, SI after weaning tended to decrease fear-related behaviors in puberty, a decrease which was more prominent in adulthood with increased neuronal plasticity-related protein expression in the amygdala. Lithium administration over the last 14 days of the SI-induced period removed the behavioral and expression changes of neuronal plasticity-related proteins observed in puberty and adulthood. Our findings suggest that the extension of the duration of SI from an early developmental stage does not simply worsen depressive-like behaviors; rather, it induces a behavior linked to neuronal plasticity damage. Lithium may improve behavioral changes in puberty and adulthood by reversing damage to neuronal plasticity. The mechanisms underlying the depressive-like and anxiety-related behaviors may differ from those underlying fear-related behaviors., (© 2021. The Author(s).)

Scales are symbolic characteristic of Lepidoptera; however, nothing is known about the contribution of cuticular proteins (CPs) to the complex patterning of lepidopteran scales. This is because scales are resistant to solubilization, thus hindering molecular studies. Here we succeeded in dissolving developing wing scales from Bombyx mori, allowing analysis of their protein composition. We identified a distinctive class of histidine rich (His-rich) CPs (6%-45%) from developing lepidopteran scales by LC-MS/MS. Functional studies using RNAi revealed CPs with different histidine content play distinct and critical roles in constructing the microstructure of the scale surface. Moreover, we successfully synthesized films in vitro by crosslinking a 45% His-rich CP (BmorCPR152) with laccase2 using N-acetyl- dopamine or N-β-alanyl-dopamine as the substrate. This molecular study of scales provides fundamental information about how such a fine microstructure is constructed and insights into the potential application of CPs as new biomaterials.

Ion selectivity of the potassium channel is crucial for regulating electrical activity in living cells; however, the mechanism underlying the potassium channel selectivity that favors large K + over small Na + remains unclear. Generally, Na + is not completely excluded from permeation through potassium channels. Herein, the distinct nature of Na + conduction through the prototypical KcsA potassium channel was examined. Single-channel current recordings revealed that, at a high Na + concentration (200 mM), the channel was blocked by Na + , and this blocking was relieved at high membrane potentials, suggesting the passage of Na + across the channel. At a 2,000 mM Na + concentration, single-channel Na + conductance was measured as one-eightieth of the K + conductance, indicating that the selectivity filter allows substantial conduit of Na + Molecular dynamics simulations revealed unprecedented atomic trajectories of Na + permeation. In the selectivity filter having a series of carbonyl oxygen rings, a smaller Na + was distributed off-center in eight carbonyl oxygen-coordinated sites as well as on-center in four carbonyl oxygen-coordinated sites. This amphipathic nature of Na + coordination yielded a continuous but tortuous path along the filter. Trapping of Na + in many deep free energy wells in the filter caused slow elution. Conversely, K + is conducted via a straight path, and as the number of occupied K + ions increased to three, the concerted conduction was accelerated dramatically, generating the conductance selectivity ratio of up to 80. The selectivity filter allows accommodation of different ion species, but the ion coordination and interactions between ions render contrast conduction rates, constituting the potassium channel conductance selectivity., Competing Interests: The authors declare no competing interest.

Voracious feeding, trans-continental migration and insecticide resistance make Spodoptera litura among the most difficult Asian agricultural pests to control. Larvae exhibit strong circadian behavior, feeding actively at night and hiding in soil during daytime. The daily pattern of larval metabolism was reversed, with higher transcription levels of genes for digestion (amylase, protease, lipase) and detoxification (CYP450s, GSTs, COEs) in daytime than at night. To investigate the control of these processes, we annotated nine essential clock genes and analyzed their transcription patterns, followed by functional analysis of their coupling using siRNA knockdown of interlocked negative feedback system core and repressor genes (SlituClk, SlituBmal1 and SlituCwo). Based on phase relationships and overexpression in cultured cells the controlling mechanism seems to involve direct coupling of the circadian processes to E-boxes in responding promoters. Additional manipulations involving exposure to the neonicotinoid imidacloprid suggested that insecticide application must be based on chronotoxicological considerations for optimal effectiveness.

We retrospectivelyevaluated postoperative inguinal hernias (PIHs) after robot-assisted radical prostatectomy(RARP) with a technique for preventing hernias byspermatic cord isolation. Among the RARPs performed from 2016 to 2018, 191 cases were evaluated 12 or more months after surgery. In all the cases, the peritoneum was isolated from the spermatic cord by5 cm or more as a hernia prevention technique during RARP. We compared the background factors between PIH-positive and PIH-negative groups. The PIH-positive group had a significantlylower bodymass index (BMI) than the PIH-negative group (20.6 kg/m2 vs 23.8 kg/m2, p＝0.0079), but there were no significant differences in other background factors. When patients were classified into three groups byBMI, low (＜21.9 kg/m2), intermediate (21.9 to 25.5 kg/m2), and high (＞25.5 kg/m2), the rate of PIH was 8.5% for the low group, 2.1% for the intermediate group, and 0% for the high group. Our findings suggest that incidences of inguinal hernias after the preventive technique of spermatic cord isolation in RARP, and the BMIs tended to be low in the hernia cases.

(Objective) We compared the perioperative parameters of robot-assisted radical cystectomy (RARC) and laparoscopic radical cystectomy (LRC) to evaluate the utility of RARC. (Patients and methods) At Hiroshima City Asa Hospital, 25 patients underwent RARC from July 2018 to May 2020 (R group) and 79 patients underwent LRC from July 2012 to June 2018 (L group). We retrospectively compared the patient characteristics, perioperative outcomes, and pathological outcomes between the R group and the L group. (Results) Regarding the patient characteristics, the R group had significantly more neo-adjuvant chemotherapy than the L group (64.0% vs. 32.9%, P=0.009), but the other characteristics did not differ. Between the R group and the L group, there were no significant differences in the total operating time (R group = 400 minutes vs. L group = 421 minutes), estimated blood loss (R group = 228 ml vs. L group = 318 ml), or pathological outcomes. However, there were significantly less postoperative complications in the R group than in the L group (24.0% vs. 52.6%, P=0.020). (Conclusion) This study showed that there might be benefits to introducing RARC into medical centers that perform LRC.

The local conformation of polystyrene (PS) at the phase-separated lamellar interface with poly(methyl methacrylate) (PMMA) in their diblock copolymer (BCP) was examined by sum-frequency generation spectroscopy in conjunction with a full-atomistic molecular dynamics simulation. While PS phenyl groups of BCP were oriented in the interfacial region, they were random in the bulk. Such an interfacial orientation of phenyl groups was not clear for the corresponding blend of PS and PMMA. The PS backbone of BCP was in-plane oriented and folded near to the chemical junction point located in the interfacial region and the orientation became random at several nanometers distant. No evidence for the chain folding at the interface was found for the blend system.

Introduction: International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria are the most representative risk model for patients with metastatic renal cell carcinoma (mRCC). However, the intermediate-risk group of IMDC criteria is thought to include patients with different prognoses because many of the patients are classified into the intermediate-risk group. In this study, we investigated the impact of systemic immune-inflammation index (SII), which is calculated based on neutrophil count, platelet count, and lymphocyte count, on predicting the prognosis in patients with mRCC, and its usefulness for re-classification of patients with a more sophisticated risk model., Methods: From January 2008 to January 2018, 179 mRCC patients with a pretreatment and SII were retrospectively investigated. All patients were classified into either a high-SII group or a low-SII group based on the cutoff value of a SII at 730, as reported in previous studies; the overall survival (OS) rates in each group were compared., Results: The median age was 65 years old. Males and females comprised 145 and 34 cases, respectively. The categories of favorable-, intermediate-, and poor-risk groups in the IMDC model were assessed in 39, 102, and 38 cases, respectively. The median observation period was 24 months. The low-SII and high-SII groups consisted of 73 and 106 cases, respectively. The 50% OS in the high-SII group was 21.4 months, which was significantly worse than that in the low-SII group (49.7 months; p<0.0001). Multivariate analysis showed that a high SII was an independent predictive factor for a worse OS. Next, we constructed a modified IMDC risk model that included the SII instead of a neutrophil count and a platelet count. By using this modified IMDC model, all cases were re-classified into four groups of 33, 52, 81, and 13 cases with 50% OS of 88.8, 45.9, 29.4, and 4.8 months, respectively., Conclusions: The SII is useful for establishing a more sophisticated prognostic model that can stratify mRCC patients into four groups with different prognoses.