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1.
PRMT1 Sustains De Novo Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast Cancer.
Yamamoto, T, Hayashida, T, Masugi, Y, Oshikawa, K, Hayakawa, N, Itoh, M, Nishime, C, Suzuki, M, Nagayama, A, Kawai, Y, et al
Cancer research. 2024;(7):1065-1083
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Abstract
UNLABELLED Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1-dependent methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phosphoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied α-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacologic inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, IHC coupled with imaging MS in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC. SIGNIFICANCE PRMT1 promotes chemoresistance in TNBC by methylating metabolic enzymes PFKFB3, PKM2, and PHGDH to augment de novo fatty acid synthesis, indicating that targeting this axis is a potential treatment strategy.
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2.
Gut Frailty: Its Concept and Pathogenesis.
Naito, Y
Digestion. 2024;(1):49-57
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Abstract
BACKGROUND There is still a considerable gap between average life expectancy and healthy life expectancy in Japan. Recent research has revealed that gut frailty may be a worsening factor for various diseases, a cause of chronic inflammation, and a precursor to frailty. SUMMARY Among self-reported symptoms, constipation is particularly significant as one of the key symptoms of gut frailty. Studies have demonstrated that individuals with constipation have significantly lower survival rates and are also at a higher risk of developing various diseases such as chronic kidney disease, cardiovascular diseases, and neurodegenerative disorders like Parkinson's disease. Various molecular mechanisms could contribute to gut frailty, and the decrease in mucus secretion is an extremely early-stage pathology. Dysbiosis of gut microbiota has a major impact on many conditions associated with gut frailty. Prebiotics, probiotics, post-biotics, and fecal microbiota transplantation are under investigation as a treatment option for gut frailty. KEY MESSAGE Although the concept of gut frailty has not yet gained widespread recognition, we hope to propose more practical screening methods, diagnostic approaches, and specific interventions in the future.
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Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors.
Nishida, T, Naito, Y, Takahashi, T, Saito, T, Hisamori, S, Manaka, D, Ogawa, K, Hirota, S, Ichikawa, H
Cancer science. 2024;(3):894-904
Abstract
Approximately 10% of gastrointestinal stromal tumors (GISTs) harbor reportedly no KIT and PDGFRA mutations (wild-type GISTs). The clinicopathological features and oncologic outcomes of wild-type GISTs based on molecular profiles are unknown. We recruited 35 wild-type GIST patients from the two registry studies of high-risk GISTs between 2012 and 2015 and primary GISTs between 2003 and 2014. Molecular profiling of wild-type GISTs was performed by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tumor samples. Among 35 wild-type GISTs, targeted NGS analysis detected NF1, SDH, or BRAF mutation: 16 NF1-GISTs with various NF1 mutations, 12 SDH-GISTs (4 with SDHA mutations, 4 with SDHB mutations, and 4 with SDHB-negative staining), and 5 BRAF-GISTs with the V600E mutation. Two GISTs showed no mutations based on our targeted NGS analysis. Additional gene mutations were infrequent in primary wild-type GISTs and found in TP53, CREBBP, CDKN2A, and CHEK2. Most NF1-GISTs were located in the small intestine (N = 12; 75%) and showed spindle cell features (N = 15; 94%) and multiple tumors (N = 6, 38%) with modest proliferation activities. In contrast, SDH-GISTs were predominantly found in the stomach (N = 11; 92%), exhibiting epithelioid cell (N = 6; 50%) and multiple (N = 6, 50%) features. The overall survival of patients with SDH-GISTs appeared to be better than that of BRAF-GISTs (p = 0.0107) or NF1-GISTs (p = 0.0754), respectively. In conclusion, major molecular changes in wild-type GISTs include NF1, SDH, and BRAF. NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.
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Ultra-High-Molecular-Weight Polyethylene in Hip and Knee Arthroplasties.
Hasegawa, M, Tone, S, Naito, Y, Sudo, A
Materials (Basel, Switzerland). 2023;(6)
Abstract
Ultra-high-molecular-weight polyethylene (UHMWPE) wear and particle-induced osteolysis contribute to the failure of total hip arthroplasty (THA) and total knee arthroplasty (TKA). Highly crosslinked polyethylene (HXLPE) was developed in the late 1990s to reduce wear and has shown lower wear rates and loosening than conventional UHMWPE in THA. The irradiation dose for crosslinking is up to 100 kGy. However, during crosslinking, free radical formation induces oxidation. Using HXLPE in THA, the cumulative revision rate was determined to be significantly lower (6.2%) than that with conventional UHMWPE (11.7%) at a mean follow-up of 16 years, according to the Australian Orthopaedic Association National Joint Replacement Registry. However, HXLPE does not confer to TKA the same advantages it confers to THA. Several alternatives have been developed to prevent the release of free radicals and improve polymer mechanical properties, such as thermal treatment, phospholipid polymer 2-methacryloyloxyethyl phosphorylcholine grafting, remelting, and vitamin E addition. Among these options, vitamin E addition has reported good clinical results and wear resistance similar to that of HXLPE without vitamin E, as shown by short-term clinical studies of THA and TKA. This review aims to provide a comprehensive overview of the development and performance of UHMWPE in THA and TKA.
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Evaluation of the initial timing of infection control pharmacist-driven audit and monitoring of vancomycin therapy in patients with infectious diseases: A retrospective observational study.
Sugita, H, Okada, N, Okamoto, M, Abe, M, Sekido, M, Tanaka, M, Tamatukuri, T, Naito, Y, Yoshikawa, M, Inoue, E, et al
PloS one. 2023;(8):e0291096
Abstract
BACKGROUND Early monitoring and feedback on the treatment of infectious diseases are some of the methods for optimising antimicrobial treatment throughout the treatment period. Prospective audits and feedback interventions have also been shown to improve antimicrobial use and reduce antimicrobial resistance. We examined the appropriate use of antimicrobials by focusing on the initial timing for audits and feedback intervention of antimicrobial prescription by Infection Control Team pharmacists. METHODS We conducted a retrospective observational study in a university hospital in Tokyo, Japan from 1 January 2019 to 31 May 2021. We retrospectively enrolled patients with infections and those patients suspected of having an infection, who were administered vancomycin and assessed at our hospital. The definition of primary outcome was the maintenance of target vancomycin trough blood concentrations of 10-20 μg/ml during treatment. Multivariable logistic regression and multivariate linear regression analyses were performed to test the effectiveness of the initial timing of the intervention by Infection Control Team pharmacists as the explanatory variable. RESULTS A total of 638 patients were included in this study, with a median age of 69 years (interquartile range: 54-78 years). Multivariable logistic regression revealed that the maintenance of target vancomycin trough concentrations was not associated with the timing of the audit and the initiation of monitoring by Infection Control Team pharmacists (adjusted odds ratio: 0.99, 95% confidence interval: 0.99-1.00, p = 0.990). Multivariate linear regression revealed that the duration of vancomycin administration was significantly correlated with the timing of initiation of monitoring by Infection Control Team pharmacists (adjusted estimate: 0.0227, standard error: 0.0051, p = 0.012). CONCLUSIONS Our study showed that early initiation of a comprehensive audit and monitoring by Infection Control Team pharmacists did not affect the maintenance of the target vancomycin trough blood concentration. However, it reduced the duration of vancomycin administration.
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Quality of life in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer.
Taira, N, Kashiwabara, K, Tsurutani, J, Kitada, M, Takahashi, M, Kato, H, Kikawa, Y, Sakata, E, Naito, Y, Hasegawa, Y, et al
Breast cancer (Tokyo, Japan). 2022;(1):131-143
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Abstract
BACKGROUND To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). METHODS Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/m2 vs. MD: 220 mg/m2 vs. LD 180 mg/m2). QoL was assessed at baseline and during the second, fourth and sixth courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM). RESULTS A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P < 0.001, LD vs. SD P < 0.001). Differences from baseline for FACT-Taxane total, physical and emotional well-being, and taxane subscale scores at MD and LD were also higher than at SD. The difference from baseline for the CFS score at LD was lower than at SD (P = 0.013) and those for EQ-5D utility scores at MD and LD were higher than at SD (MD vs. SD P = 0.011, LD vs. SD P < 0.001). CONCLUSION QoL of patients treated with 220 or 180 mg/m2 of q3w nab-PTX was significantly better than that of patients treated with 260 mg/m2. TRIAL REGISTRATION The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN000015516), on 01/11/2014. Details are available at the following address: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017916.
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Mucosal interleukin-8 expression as a predictor of subsequent relapse in ulcerative colitis patients with Mayo endoscopic subscore 0.
Uchiyama, K, Takagi, T, Mizushima, K, Asaeda, K, Kajiwara, M, Kashiwagi, S, Toyokawa, Y, Hotta, Y, Tanaka, M, Inoue, K, et al
Journal of gastroenterology and hepatology. 2022;(6):1034-1042
Abstract
BACKGROUND AND AIM Complete endoscopic mucosal healing is defined as a Mayo endoscopic subscore of 0. Some patients diagnosed with a Mayo endoscopic subscore 0 may present with subsequent clinical relapse. Here, we aimed to demonstrate mucosal cytokine profile as a predictor of clinical relapse in ulcerative colitis patients with a Mayo endoscopic subscore of 0 as a marker of mucosal healing. METHODS We conducted prospective observational pilot study to examine the relationship between mucosal cytokine expression and subsequent relapse of UC patients diagnosed with a Mayo endoscopic subscore of 0. We enrolled 55 patients, and expression of cytokines tumor necrosis factor-α, interferon γ, interleukin-1β, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-9, interleukin-10, interleukin-12, interleukin-13, interleukin-15, interleukin-17A, interleukin-17F, interleukin-18, interleukin-21, interleukin-22, interleukin-23, interleukin-27, and interleukin-33 was measured by quantitative real-time PCR using rectal mucosa biopsy materials. Cytokine expression levels were compared between patients who relapsed between March 1, 2016, and March 30, 2020, of the study period and those who remained in remission. RESULTS Ten cytokines, including interleukin-2, interleukin-4, interleukin-8, interleukin-10, interleukin-12, interleukin-15, interleukin-17A, interleukin-21, interleukin-23, and interleukin-33, were significantly elevated in patients with subsequent relapse compared with those who remained in remission. Interleukin-8 expression was the most useful predictor. CONCLUSIONS In the rectal mucosa of ulcerative colitis patients with Mayo endoscopic subscore 0, levels of several cytokines were elevated in cases of subsequent relapse. Among these, interleukin-8 expression was the most useful for predicting relapse.
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Effects of calcium hydroxide intracanal medicament on push-out bond strength of endodontic sealers: A systematic review and meta-analysis.
Alhajj, MN, Daud, F, Al-Maweri, SA, Johari, Y, Ab-Ghani, Z, Jaafar, M, Naito, Y, Prananingrum, W, Ariffin, Z
Journal of esthetic and restorative dentistry : official publication of the American Academy of Esthetic Dentistry ... [et al.]. 2022;(8):1166-1178
Abstract
OBJECTIVE To investigate the effect of calcium hydroxide intracanal medicament on the push-out bond strength of resin-based and calcium silicate-based endodontic sealers. METHODS A comprehensive search of was conducted for all relevant in-vitro studies. All randomized controlled in-vitro studies that evaluated the effect of calcium hydroxide on the push-out bond strength of resin-based or calcium silicate-based endodontic sealers were assessed. The variables of interest were extracted, and the risk of the included studies was evaluated. The standardized mean difference was calculated and the significance level was set at p value <0.05. RESULTS A total of 26 studies were eligible for analysis. There were 45 independent comparison groups and 1009 recruited teeth. The pooled data showed no significant difference in push-out bond strength between calcium hydroxide and control group in the resin-based group (SMD = 0.03; 95% CI = -0.55, 0.60; p = 0.93), and calcium silicate-based group (SMD = 0.02; 95% CI = -0.31, 0.35; p = 0.90). Most of the studies (21 out of 26) were at medium risk of bias and five studies showed a low risk of bias. CONCLUSION The available evidence suggests that calcium hydroxide used as intracanal medication does not influence the push-out bond strength of the resin- and calcium silicate-based endodontic sealers. CLINICAL SIGNIFICANCE The results of this meta-analysis suggest that calcium hydroxide used as intracanal medication does not influence the push-out bond strength of resin-based and calcium silicate-based endodontic sealers.
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Advanced endoscopy for the management of inflammatory digestive diseases: Review of the Japan Gastroenterological Endoscopy Society core session.
Matsuura, M, Matsumoto, T, Naito, Y, Saitoh, Y, Kanai, T, Suzuki, Y, Tanaka, S, Ogata, H, Hisamatsu, T
Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society. 2022;(4):729-735
Abstract
A series of workshops entitled "Advanced endoscopy in the management of inflammatory digestive disease" was held at the 97th to 100th biannual meeting of the Japan Gastroenterological Endoscopy Society. During these core sessions, research findings concerning various endoscopic practices in the field of inflammatory bowel disease (IBD) were presented, and meaningful discussions were shared on the evolving role and future challenges of endoscopy in IBD. This article reviews these core sessions and discusses current topics on the role of endoscopy, focusing on the diagnosis, disease monitoring, mucosal healing assessments, cancer surveillance, and therapeutic interventions in IBD.
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Merestinib monotherapy or in combination for japanese patients with advanced and/or metastatic cancer: A phase 1 study.
Doi, T, Yamamoto, N, Naito, Y, Kuboki, Y, Koyama, T, Piao, Y, Tsujimoto, N, Asou, H, Inoue, K, Kondo, S
Cancer medicine. 2021;(19):6579-6589
Abstract
This phase 1, multi-center, nonrandomized, open-label, dose-escalation study consisted of Part A wherein merestinib 80 or 120 mg (40-mg tablets) was administered orally QD during a 28-day cycle to patients diagnosed with solid tumors and Part B wherein merestinib 80 mg (40-mg tablets) was administered orally QD, and cisplatin 25 mg/m2 + gemcitabine 1000 mg/m2 administered IV on Day 1 and Day 8 of a 21-day cycle (for a maximum of eight cycles) to patients diagnosed with biliary tract carcinoma (BTC). Nineteen patients were screened and 18 patients were (Part A, n = 10; Part B, n = 8) enrolled in the trial and received treatment. All patients in Parts A and B were from Japan and were within an age range of 43-73 years, with an ECOG PS of 0.1. No dose-limiting toxicity or deaths were experienced in the study. Dose-limiting toxicity equivalent toxicity of Grade 4 platelet count decreased (n = 1) and was observed in Part B. In Part A, treatment-related Grade ≥3 TEAEs were reported in one patient (PT: ALT increased and AST increased), while in Part B, five patients reported treatment-related Grade ≥3 TEAEs with four of the five patients reporting an event of neutrophil count decreased. No complete response was reported in either Part. One patient in Part B reported partial response while four patients in each part reported stable disease. Merestinib monotherapy was concluded to be tolerable in Japanese patients, and its combination with cisplatin and gemcitabine is a tolerable regimen for Japanese patients with BTC. Trial registration: NCT03027284 (ClinicalTrials.gov) registered on 23 January 2017.