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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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Expression analysis of zinc-metabolizing enzymes in the saliva as a new method of evaluating zinc content in the body: two case reports and a review of the literature.
Sakata, KI, Hashimoto, A, Kambe, T, Sato, J, Ohga, N, Yamazaki, Y, Koyachi, M, Tatsuki, I, Okada, M, Taro, O, et al
Journal of medical case reports. 2024;(1):198
Abstract
BACKGROUND The activity level of alkaline phosphatase, a zinc-requiring enzyme in the serum, is used to indicate zinc nutritional status; however, it does not correlate with serum zinc levels or subjective symptoms of taste disorder in many cases. Hence, this study focused on the total activity of alkaline phosphatase, a zinc-requiring enzyme. The total alkaline phosphatasa activity level in the saliva was measured before and after zinc supplementation, and the results were compared with serum zinc levels. CASE PRESENTATION This study included patients with hypozincemia, specifically a patient with zinc-deficient taste disorder (patient 1: a 69-year-old Japanese woman) and a patient with glossodynia with zinc deficiency (patient 2: an 82-year-old Japanese woman). Saliva samples were collected, and blood tests were performed before and after zinc supplementation. Subjective symptoms and serum zinc levels were simultaneously evaluated. Zinc supplementation was performed using zinc acetate hydrate or Polaprezinc. CONCLUSIONS Total alkaline phosphatase activity levels were found to be associated with serum zinc levels and subjective symptoms. A further study with a higher number of patients is necessary to confirm whether total alkaline phosphatase activity levels more accurately reflect the amounts of zinc in the body than serum zinc levels.
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Effect of aqueous olanexidine versus alcohol-based chlorhexidine for surgical skin antisepsis on incidence of surgical site infections in gastrointestinal surgery: multicentre randomised controlled clinical trial (OEDO trial) protocol.
Takeuchi, M, Obara, H, Furube, T, Kawakubo, H, Kitago, M, Okabayashi, K, Aoyama, J, Amemiya, R, Fujisaki, H, Sano, J, et al
BMJ open. 2023;(8):e074169
Abstract
INTRODUCTION Surgical site infections (SSIs) are among the most common nosocomial infections in surgery patients. Two types of preparations, povidone-iodine and chlorhexidine-alcohol, are commonly used in preoperative antiseptic procedures worldwide. However, there are inconsistencies among international guideline recommendations concerning skin antiseptics. This trial aimed to evaluate the superiority of olanexidine, which reduced SSI rates more than povidone-iodine in our previous randomised trial, over chlorhexidine-alcohol in clean-contaminated surgery. METHODS AND ANALYSIS This multicentre randomised controlled clinical trial will compare two antiseptics (1.5% olanexidine and 1.0% chlorhexidine-alcohol) to prevent SSI in clean-contaminated gastrointestinal surgeries with surgical wounds. On providing consent, patients aged <18 years will be included. The primary outcome will be the postoperative 30-day overall SSI rate, while the secondary outcomes will be the postoperative 30-day superficial incisional SSI rate, deep incisional SSI rate, organ/space SSI rate, positive bacterial wound culture rate, cultured bacterial strains, rates of intervention-related toxicity and allergic events (eg, erythema, pruritus, dermatitis and other symptoms of allergy around the region disinfected by the antiseptic during surgery), rate of reoperations due to SSI, medical economic effect indicators (based on health insurance claims) and hospital duration. The Mantel-Haenszel method will be used to estimate the adjusted risk ratio and its 95% CI for the primary analysis, which will compare the treatment effects. ETHICS AND DISSEMINATION The protocol was approved by the Institutional Review Board of Keio University School of Medicine and subsequently by the board of each participating site. Participant recruitment began in January 2023. The final results will be published in medical journals after international peer review. TRIAL REGISTRATION NUMBER UMIN000049712.
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Concurrent chemoradiotherapy using proton beams can reduce cardiopulmonary morbidity in esophageal cancer patients: a systematic review.
Nonaka, T, Kawashiro, S, Ishikawa, H, Ito, Y, Nemoto, K, Ishihara, R, Oyama, T, Oyama, T, Kato, K, Kato, H, et al
Esophagus : official journal of the Japan Esophageal Society. 2023;(4):605-616
Abstract
This systematic review was performed to investigate the superiority of proton beam therapy (PBT) to photon-based radiotherapy (RT) in treating esophageal cancer patients, especially those with poor cardiopulmonary function. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 2000 to August 2020 for studies evaluating one end point at least as follows; overall survival, progression-free survival, grade ≥ 3 cardiopulmonary toxicities, dose-volume histograms, or lymphopenia or absolute lymphocyte counts (ALCs) in esophageal cancer patients treated with PBT or photon-based RT. Of 286 selected studies, 23 including 1 randomized control study, 2 propensity matched analyses, and 20 cohort studies were eligible for qualitative review. Overall survival and progression-free survival were better after PBT than after photon-based RT, but the difference was significant in only one of seven studies. The rate of grade 3 cardiopulmonary toxicities was lower after PBT (0-13%) than after photon-based RT (7.1-30.3%). Dose-volume histograms revealed better results for PBT than photon-based RT. Three of four reports evaluating the ALC demonstrated a significantly higher ALC after PBT than after photon-based RT. Our review found that PBT resulted in a favorable trend in the survival rate and had an excellent dose distribution, contributing to reduced cardiopulmonary toxicities and a maintained number of lymphocytes. These results warrant novel prospective trials to validate the clinical evidence.
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First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50).
Kato, K, Doki, Y, Ogata, T, Motoyama, S, Kawakami, H, Ueno, M, Kojima, T, Shirakawa, Y, Okada, M, Ishihara, R, et al
Esophagus : official journal of the Japan Esophageal Society. 2023;(2):291-301
Abstract
BACKGROUND Programmed cell death 1 (PD-1)-based treatments are approved for several cancers. CheckMate 648, a global, phase 3 trial, showed that first-line nivolumab (anti-PD-1 antibody) plus ipilimumab (NIVO + IPI) or nivolumab plus chemotherapy (NIVO + Chemo) significantly increased survival in advanced esophageal squamous cell carcinoma (ESCC) without new safety signals versus chemotherapy alone (Chemo). METHODS We evaluated the Japanese subpopulation of CheckMate 648 (n = 394/970), randomized to receive first-line NIVO + IPI, NIVO + Chemo, or Chemo. Efficacy endpoints included overall survival (OS) and progression-free survival assessed by blinded independent central review in Japanese patients with tumor-cell programmed death-ligand 1 (PD-L1) expression ≥ 1% and in all randomized Japanese patients. RESULTS In the Japanese population, 131, 126, and 137 patients were treated with NIVO + IPI, NIVO + Chemo, and Chemo, and 66, 62, and 65 patients had tumor-cell PD-L1 ≥ 1%, respectively. In patients with tumor-cell PD-L1 ≥ 1%, median OS was numerically longer with NIVO + IPI (20.2 months; hazard ratio [95% CI], 0.46 [0.30-0.71]) and NIVO + Chemo (17.3 months; 0.53 [0.35-0.82]) versus Chemo (9.0 months). In all randomized patients, median OS was numerically longer with NIVO + IPI (17.6 months; 0.68 [0.51-0.92]) and NIVO + Chemo (15.5 months; 0.73 [0.54-0.99]) versus Chemo (11.0 months). Grade 3-4 treatment-related adverse events were reported in 37%, 49%, and 36% of all patients in the NIVO + IPI, NIVO + Chemo, and Chemo arms, respectively. CONCLUSION Survival benefits with acceptable tolerability observed for NIVO + IPI and NIVO + Chemo treatments strongly support their use as a new standard first-line treatment in Japanese patients with advanced ESCC. GOV ID NCT03143153.
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Pro108Ser mutation of SARS-CoV-2 3CLpro reduces the enzyme activity and ameliorates the clinical severity of COVID-19.
Abe, K, Kabe, Y, Uchiyama, S, Iwasaki, YW, Ishizu, H, Uwamino, Y, Takenouchi, T, Uno, S, Ishii, M, Maruno, T, et al
Scientific reports. 2022;(1):1299
Abstract
Recently, an international randomized controlled clinical trial showed that patients with SARS-CoV-2 infection treated orally with the 3-chymotrypsin-like protease (3CLpro) inhibitor PF-07321332 within three days of symptom onset showed an 89% lower risk of COVID-19-related hospital admission/ death from any cause as compared with the patients who received placebo. Lending support to this critically important result of the aforementioned trial, we demonstrated in our study that patients infected with a SARS-Cov-2 sub-lineage (B.1.1.284) carrying the Pro108Ser mutation in 3CLpro tended to have a comparatively milder clinical course (i.e., a smaller proportion of patients required oxygen supplementation during the clinical course) than patients infected with the same sub-lineage of virus not carrying the mutation. Characterization of the mutant 3CLpro revealed that the Kcat/Km of the 3CLpro enzyme containing Ser108 was 58% lower than that of Pro108 3CLpro. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) revealed that the reduced activity was associated with structural perturbation surrounding the substrate-binding region of the enzyme, which is positioned behind and distant from the 108th amino acid residue. Our findings of the attenuated clinical course of COVID-19 in patients infected with SARS-CoV-2 strains with reduced 3CLpro enzymatic activity greatly endorses the promising result of the aforementioned clinical trial of the 3CLpro inhibitor.
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Fruit and vegetable consumption and risk of esophageal cancer in the Asian region: a systematic review and meta-analysis.
Sakai, M, Kitagawa, Y, Saeki, H, Miyazaki, T, Yamaji, T, Nemoto, K, Oyama, T, Muto, M, Takeuchi, H, Toh, Y, et al
Esophagus : official journal of the Japan Esophageal Society. 2022;(1):27-38
Abstract
The consumption of fruit and vegetables was reported to be associated with a reduced risk of esophageal cancer (EC) in many studies of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) from different regions worldwide. Therefore, to provide precise information to reduce the risk of EC in Asia, we performed a systematic review and meta-analysis of studies conducted in the Asian region about fruit and vegetable consumption and the risk of EC. We searched the MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases from January 2010 to December 2020. The summary relative risk (SRR) and 95% CI were calculated using a random-effects model. In addition, I2 statistics were used to detect heterogeneity. Twenty-two studies were eligible for meta-analysis (16 case-control studies and 6 cohort studies). The SRR for the lowest versus highest fruit consumption was 0.64 (95% CI 0.53-0.77, I2 = 82%). That for the lowest versus highest vegetable consumption was 0.61 (95% CI 0.50-0.74, I2 = 81%). Based on subgroup analysis, a validated Food Frequency Questionnaire (FFQ) was significantly associated (SRR for fruit: 0.54; 95% CI 0.40-0.74, SRR for vegetable: 0.60; 95% CI 0.48-0.76) with low heterogeneity (I2 = 48% for fruit, I2 = 0% for vegetables). Egger's funnel plot asymmetry test demonstrated publication bias (P < 0.001 for fruit, P = 0.009 for vegetables). Fruit and vegetable consumption might be associated with a lower risk of EC in the Asian region. However, further substantial prospective studies with a validated FFQ and well-controlled important confounding factors are required to confirm the association.
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Peritoneal dissemination of pancreatic cancer caused by endoscopic ultrasound-guided fine needle aspiration: A case report and literature review.
Kojima, H, Kitago, M, Iwasaki, E, Masugi, Y, Matsusaka, Y, Yagi, H, Abe, Y, Hasegawa, Y, Hori, S, Tanaka, M, et al
World journal of gastroenterology. 2021;(3):294-304
Abstract
BACKGROUND Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a biopsy technique widely used to diagnose pancreatic tumors because of its high sensitivity and specificity. Although needle-tract seeding caused by EUS-FNA has been recently reported, dissemination of pancreatic cancer cells is generally considered to be a rare complication that does not affect patient prognosis. However, the frequency of dissemination and needle-tract seeding appears to have been underestimated. We present a case of peritoneal dissemination of pancreatic cancer due to preoperative EUS-FNA. CASE SUMMARY An 81-year-old man was referred to the Department of Surgery of our hospital in Japan owing to the detection of a pancreatic mass on computed tomography during medical screening. Trans-gastric EUS-FNA revealed that the mass was an adenocarcinoma; hence laparoscopic distal pancreatectomy with lympha-denectomy was performed. No intraoperative peritoneal dissemination and liver metastasis were visually detected, and pelvic lavage cytology was negative for carcinoma cells. The postoperative surgical specimen was negative for carcinoma cells at the dissected margin and the cut end margin; however, pathological findings revealed adenocarcinoma cells on the peritoneal surface proximal to the needle puncture site, and the cells were suspected to be disseminated via EUS- FNA. Hence, the patient received adjuvant therapy with S-1 (tegafur, gimeracil, and oteracil potassium); however, computed tomography performed 5 mo after surgery revealed liver metastasis and cancerous peritonitis. The patient received palliative therapy and died 8 mo after the operation. CONCLUSION The indications of EUS-FNA should be carefully considered to avoid iatrogenic dissemination, especially for cancers in the pancreatic body or tail.
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Effects of an elemental diet to reduce adverse events in patients with esophageal cancer receiving docetaxel/cisplatin/5-fluorouracil: a phase III randomized controlled trial-EPOC 2 (JFMC49-1601-C5).
Tanaka, Y, Takeuchi, H, Nakashima, Y, Nagano, H, Ueno, T, Tomizuka, K, Morita, S, Emi, Y, Hamai, Y, Hihara, J, et al
ESMO open. 2021;(5):100277
Abstract
BACKGROUND Oral mucositis (OM) is an unpleasant adverse event in patients receiving chemotherapy. A prospective feasibility study showed that elemental diet (ED), an oral supplement that does not require digestion, may prevent OM. Based on this, we established a central review system for oral cavity assessment by dental oncology specialists blinded to background data. We used this system to elucidate the preventive effect of an ED against OM in patients with esophageal cancer receiving docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy. PATIENTS AND METHODS In this phase III, multicenter, parallel-group, controlled trial, patients consuming a normal diet orally were randomly assigned (1 : 1) to receive two cycles of DCF with (group A) or without (group B) an ED (Elental® 160 g/day). We assessed the incidence of grade ≥2 OM evaluated by two reviewers, changes in body weight, prealbumin, C-reactive protein, and DCF completion rate based on ED compliance. RESULTS Of the 117 patients randomly assigned to treatment, four failed to start treatment and were excluded from the primary analysis; thus, groups A and B comprised 55 and 58 patients, respectively. There were no significant differences in background characteristics. Grade ≥2 OM was observed in eight (15%) and 20 (34%) patients in groups A and B, respectively (P = 0.0141). Changes in body weight and prealbumin during the two DCF cycles were significantly higher in group A than B (P = 0.0022 and 0.0203, respectively). During the first cycle, changes in C-reactive protein were significantly lower in group A than B (P = 0.0338). In group A (receiving ED), the DCF completion rate was 100% in patients with 100% ED compliance and 70% in patients failing ED completion (P = 0.0046). CONCLUSIONS The study findings demonstrate that an ED can prevent OM in patients with esophageal cancer receiving chemotherapy.
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10.
Late-onset acute liver failure due to Wilson's disease managed by plasmapheresis and hemodiafiltration successfully serving as a bridge for deceased donor liver transplantation: a case report and literature review.
Sukezaki, A, Chu, PS, Shinoda, M, Hibi, T, Taniki, N, Yoshida, A, Kawaida, M, Hori, S, Morikawa, R, Kurokouchi, A, et al
Clinical journal of gastroenterology. 2020;(6):1239-1246
Abstract
Late-onset acute liver failure due to Wilson's disease (WD-ALF) is rare. A 44-year-old female patient presenting acute hepatic decompensation with extreme coagulopathy was transferred to our hospital for evaluation for liver transplantation (LT). Alveolar hemorrhage and Coombs-negative acute hemolysis occurred during workup. Mechanical ventilation, plasmapheresis, and hemodiafiltration with zinc and chelation were started immediately before placing the patient on the waitlist for deceased donor LT (DDLT), with a tentative diagnosis of WD-ALF using the Leipzig score and quick diagnostic criteria suggested by the Acute Liver Failure Study Group Registry. The peak MELD score was 40, and the revised version of King's score for WD was 13. Serum free copper levels and the patient's overall general condition were stabilized with artificial support systems, although triphasic wave on electroencephalogram and liver atrophy were noted. She successfully underwent emergent DDLT approximately 2 weeks after suffering from acute hemolysis and survived. The genetic tests confirmed mutations at 2 loci in the ATP7B gene and, therefore, the diagnosis of WD. This is the first and oldest patient reported in Japan to present late-onset WD-ALF that was successfully treated with emergent DDLT.