The emerging emetogenicity of trifluridine/tipiracil (TAS­102) from patient self-reporting: a multicenter, prospective, observational study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001). METHODS: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0. RESULTS: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%. CONCLUSIONS: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment.

[Development of a new method for assessing the availability of low-sodium foods in Japan].

Objectives　Food environment improvement involving salt reduction requires improving access to and labeling low-sodium foods. Assessing the implementation status of these measures is also necessary. However, to date, no established methods exist for assessing the availability of low-sodium foods in communities. In this study, we aimed to devise a survey on the availability of low-sodium foods as a community food environment assessment method in order to establish common assessment methods, criteria, and practical measures, as well as standardization nationwide.Methods　A preliminary survey on the availability of low-sodium foods was conducted in Kitakyushu City in four stores with nationwide representation. Consent for providing information on handled product lists was obtained. The on-site lists collected through direct investigation by surveyors were compared with the handled product lists provided by the stores and analyzed to identify survey challenges and examine feasibility and the potential for accuracy. The definition of low-sodium foods, which emerged as a challenge in the preliminary survey, was confirmed. Preliminary survey data were carefully reviewed to establish classification criteria for low-sodium foods and create a low-sodium food list to serve as a reference for on-site surveys. Forms for recording the results of on-site surveys and a survey manual were developed. Registered dietitians conducted on-site surveys using the manual to confirm its applicability.Results　The preliminary survey results revealed that the on-site lists had fewer omissions and greater feasibility than store-provided lists. After clearly defining low-sodium foods, we established classification criteria (three major categories, seven subcategories, and 37 minor categories) considering the ease of on-site investigations and purchases. Three forms for recording survey results were developed, including a standard input form allowing detailed documentation of the availability of individual low-sodium foods, an aggregation form for a quantitative assessment of low-sodium foods availability, and a display form visualizing the availability of low-sodium foods by store. Furthermore, a survey manual was developed explaining the purpose and approach of the low-sodium foods availability survey, definition and classification criteria for low-sodium foods, and the three forms for recording survey results. Findings indicated that all registered dietitians could conduct on-site surveys using the manual and successfully collect and organize data.Conclusion　On-site surveys using the manual and documentation forms enabled easy and accurate assessments of low-sodium foods availability. Thus, this standardized method to assess the availability of low-sodium foods could be a food environment assessment method for regional salt reduction initiatives.

PRMT1 Sustains De Novo Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast Cancer.

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.

Intraocular Inflammation Secondary to Intravitreal Brolucizumab Injection for Neovascular Age-Related Macular Degeneration in a Patient with Cognitive Impairment.

Background and Objectives: Brolucizumab (IVBr) is a recently introduced anti-vascular endothelial growth factor (anti-VEGF) which has been found to be very effective in treating neovascular age-related macular degeneration (nAMD). We reported our findings in a case of nAMD that developed intraocular inflammation (IOI) after IVBr injections. Materials and Methods: A 79-year-old man was referred to our hospital complaining of reduced vision in both eyes of one-month's duration. His decimal best-corrected visual acuity (BCVA) was 0.9 in the right eye and 1.0 in the left eye. He was diagnosed with nAMD in the left eye and was treated with intravitreal aflibercept (IVA). Despite the three-monthly IVA injections, the serous retinal pigment epithelial detachment (PED) and subretinal fluid (SRF) remained, and the VA gradually decreased to 0.1. Because of the patient being refractory to aflibercept treatment, we switched to 3-monthly IVBr injections. The BCVA gradually improved to 0.3 and optical coherence tomography (OCT) showed an absence of the serous PED and SRF. Three weeks after his third IVBr, he returned to our hospital with a complaint of reduced vision in his left eye that he first noted two weeks earlier. Our examination of the left eye showed signs of IOI mainly in the anterior chamber. The inflammation improved with topical steroids but the treatment of the IOI was delayed for two weeks. The patient was instructed that it was important to begin the treatment as soon as the symptoms of IOI developed. We then performed the Mini-Mental State Examination (MMSE), and his score indicated that he had cognitive impairment. Conclusions: We concluded that before beginning IVBr treatment in nAMD patients, a careful assessment must be made of the cognitive status of the patient.

Effect of Positive Biopsy Core Rate on Low-dose-rate Brachytherapy Outcomes in Intermediate-risk Prostate Cancer.

BACKGROUND/AIM: Intermediate-risk prostate cancer (PCa) is a highly heterogeneous disease. Although low-dose-rate brachytherapy (LDR-BT) is mainly used for low- to intermediate-risk PCa, limited reports have evaluated the detailed differences in outcomes, including differences between patients with ISUP grade group (GG) 2 and GG3 intermediate-risk PCa. This study aimed to investigate the differences in outcomes between intermediate-risk Japanese patients with GG2 and GG3 PCa who underwent LDR-BT. PATIENTS AND METHODS: This single-center retrospective study included 342 consecutive patients with intermediate-risk PCa; 232 patients with GG2 and 110 with GG3 were treated with LDR-BT at Tokushima University Hospital between July 2004 and December 2019. RESULTS: No significant difference in 5-year biochemical progression-free survival and cancer-specific survival was observed between patients with GG2 and those with GG3 (p=0.649 and p=0.633, respectively). Multivariate analysis showed that radiation doses up to 90% of the prostate volume (D90) and the percentage of positive cores were predictors of recurrence in all patients with intermediate-risk PCa. Group analyses showed that D90 was a predictor for recurrence in patients with GG2. In contrast, a high percentage of positive cores was a significant risk factor for recurrence in patients with GG3. CONCLUSION: Positive core ratios observed on prostate biopsy correlated with higher recurrence rates after LDR-BT. This indicates that the proportion of positive cores in the biopsy may be an important factor in predicting the likelihood of recurrence, especially for patients with GG3 PCa.

Serum Free Fatty Acid Changes Caused by High Expression of Stearoyl-CoA Desaturase 1 in Tumor Tissues Are Early Diagnostic Markers for Ovarian Cancer.

Ovarian cancer has a poor prognosis and is difficult to detect in early stages. Therefore, developing new diagnostic markers for early-stage ovarian cancer is critical. Here, we developed a diagnostic marker for early-stage ovarian cancer on the basis of fatty acid metabolism characteristics of cancer cells. The expression of various fatty acid metabolizing enzymes such as stearoyl-CoA desaturase 1 (SCD1) was altered in early-stage ovarian cancer tissue compared with that in normal ovarian tissue. Changes in the expression of fatty acid metabolizing enzymes, particularly SCD1, in cancer tissues were found to alter concentrations of multiple free fatty acids (FFA) in serum. We were the first to show that fatty acid metabolic characteristics in tissues are related to the FFA composition of serum. Surprisingly, patients with stage I/II ovarian cancer also showed significant changes in serum levels of eight FFAs, which can be early diagnostic markers. Finally, using statistical analysis, an optimal early diagnostic model combining oleic and arachidic acid levels, fatty acids associated with SCD1, was established and confirmed to have higher diagnostic power than CA125, regardless of histology. Thus, our newly developed diagnostic model using serum FFAs may be a powerful tool for the noninvasive early detection of ovarian cancer. SIGNIFICANCE: Measurement of serum FFA levels by changes in the expression of fatty acid metabolizing enzymes in tumor tissue would allow early detection of ovarian cancer. In particular, the SCD1-associated FFAs, oleic and arachidic acid, would be powerful new screening tools for early-stage ovarian cancer.

Prostate-specific Antigen Levels Following Brachytherapy Impact Late Biochemical Recurrence in Japanese Patients With Localized Prostate Cancer.

BACKGROUND/AIM: Evaluation of long-term outcomes is essential for the successful treatment of localized prostate cancer; however, the risk of late recurrence following brachytherapy is still not clear. This study aimed to evaluate the long-term outcomes of low-dose-rate brachytherapy (LDR-BT) for localized prostate cancer in Japanese patients and identify factors associated with late recurrence after treatment. PATIENTS AND METHODS: This single-center, cohort study included patients who underwent LDR-BT at the Tokushima University Hospital in Japan between July 2004 and January 2015; 418 patients, who were followed-up at least 7 years after LDR-BT, were included in the study. Biochemical progression free survival (bPFS) was defined according to the Phoenix definition (nadir PSA+2 ng/ml) and bPFS and cancer specific survival (CSS) were calculated using Kaplan-Meier survival curves. Univariate and multivariate analyses were performed using Cox proportional hazard regression models. RESULTS: Approximately half of the patients with PSA >0.5 ng/ml at 5 years after LDR-BT had a recurrence within the next 2 years. However, only 1.4% of the patients with a PSA ≤0.2 ng/ml at 5 years post-treatment showed tumor recurrence, including those at high risk of treatment failure according to the D'Amico classification. In multivariate analysis, PSA level at 5 years post-treatment was the only predictor of late recurrence after 7 years of treatment. CONCLUSION: PSA levels at 5 years post-treatment were associated with long-term recurrence of localized prostate cancer, which can help alleviate patient anxiety concerning prostate cancer recurrence if PSA levels remain low at 5 years after LDR-BT.

Hands-on seminar for image-guided adaptive brachytherapy and intracavitary/interstitial brachytherapy for uterine cervical cancer.

OBJECTIVE: Compared with the implementation speed of image-guided adaptive brachytherapy for uterine cervical cancer, that of intracavitary and interstitial brachytherapy is slow, possible because it requires more invasive procedure of inserting needles directly into tumours. To accelerate the implementation speed of intracavitary and interstitial brachytherapy, a first hands-on seminar for image-guided adaptive brachytherapy and intracavitary and interstitial brachytherapy for uterine cervical cancer was held on 26 November 2022, supported by Japanese Society for Radiology and Oncology. This article deals with this hands-on seminar and difference of degree of confidence of participants in starting intracavitary and interstitial brachytherapy before and after the seminar. METHODS: The seminar consisted of lectures regarding intracavitary and interstitial brachytherapy in the morning and hands-on practice of needle insertion and contouring, as well as dose calculation practice using the radiation treatment system in the evening. Prior to and following the seminar, participants completed a questionnaire asking about their level of confidence in performing intracavitary and interstitial brachytherapy, expressed between 0 and 10 (the higher the number, the stronger the confidence). RESULTS: A total of 15 physicians, six medical physicists and eight radiation technologists from 11 institutions attended the meeting. The median level of confidence before and after the seminar was 3 (range, 0-6) and 5.5 (range, 3-7), respectively, and a statistically significant improvement was observed (P<0.001). CONCLUSION: It was suggested that the hands-on seminar on intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer improved the level of confidence of the attendees and propelled their motivation, through which it is expected that the implementation of intracavitary and interstitial brachytherapy will be accelerated.

Polysulfide Serves as a Hallmark of Desmoplastic Reaction to Differentially Diagnose Ductal Carcinoma In Situ and Invasive Breast Cancer by SERS Imaging.

Pathological examination of formalin-fixed paraffin-embedded (FFPE) needle-biopsied samples by certified pathologists represents the gold standard for differential diagnosis between ductal carcinoma in situ (DCIS) and invasive breast cancers (IBC), while information of marker metabolites in the samples is lost in the samples. Infrared laser-scanning large-area surface-enhanced Raman spectroscopy (SERS) equipped with gold-nanoparticle-based SERS substrate enables us to visualize metabolites in fresh-frozen needle-biopsied samples with spatial matching between SERS and HE staining images with pathological annotations. DCIS (n = 14) and IBC (n = 32) samples generated many different SERS peaks in finger-print regions of SERS spectra among pathologically annotated lesions including cancer cell nests and the surrounding stroma. The results showed that SERS peaks in IBC stroma exhibit significantly increased polysulfide that coincides with decreased hypotaurine as compared with DCIS, suggesting that alterations of these redox metabolites account for fingerprints of desmoplastic reactions to distinguish IBC from DCIS. Furthermore, the application of supervised machine learning to the stroma-specific multiple SERS signals enables us to support automated differential diagnosis with high accuracy. The results suggest that SERS-derived biochemical fingerprints derived from redox metabolites account for a hallmark of desmoplastic reaction of IBC that is absent in DCIS, and thus, they serve as a useful method for precision diagnosis in breast cancer.

Differences between professionals in treatment planning for patients with stage III lung cancer using treatment-planning QA software.

Background: The quality of treatment planning for stage III non-small cell lung cancer varies within and between facilities due to the different professions involved in planning. Dose estimation parameters were calculated using a feasibility dose-volume histogram (FDVH) implemented in the treatment planning quality assurance software PlanIQ. This study aimed to evaluate differences in treatment planning between occupations using manual FDVH-referenced treatment planning to identify their characteristics. Materials and methods: The study included ten patients with stage III non-small cell lung cancer, and volumetric-modulated arc therapy was used as the treatment planning technique. Fifteen planners, comprising five radiation oncologists, five medical physicists, and five radiological technologists, developed treatment strategies after referring to the FDVH. Results: Medical physicists had a higher mean dose at D98% of the planning target volume (PTV) and a lower mean dose at D2% of the PTV than those in other occupations. Medical physicists had the lowest irradiation lung volumes (V5 Gy and V13 Gy) compared to other professions, and radiation oncologists had the lowest V20 Gy and mean lung dose. Radiological technologists had the highest irradiation volumes for dose constraints at all indexes on the normal lung volume. Conclusions: The quality of the treatment plans developed in this study differed between occupations due to their background expertise, even when an FDVH was used as a reference. Therefore, discussing and sharing knowledge and treatment planning techniques among professionals is essential to determine the optimal treatment plan for each facility and patient.

Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating ß-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody.

BACKGROUND: Understanding the mechanisms of non-T cell inflamed tumor microenvironment (TME) and their modulation are important to improve cancer immunotherapies such as immune checkpoint inhibitors. The involvement of various immunometabolisms has recently been indicated in the formation of immunosuppressive TME. In this study, we investigated the immunological roles of stearoyl-CoA desaturase 1 (SCD1), which is essential for fatty acid metabolism, in the cancer immune response. METHODS: We investigated the roles of SCD1 by inhibition with the chemical inhibitor or genetic manipulation in antitumor T cell responses and the therapeutic effect of anti-programmed cell death protein 1 (anti-PD-1) antibody using various mouse tumor models, and their cellular and molecular mechanisms. The roles of SCD1 in human cancers were also investigated by gene expression analyses of colon cancer tissues and by evaluating the related free fatty acids in sera obtained from patients with non-small cell lung cancer who were treated with anti-PD-1 antibody. RESULTS: Systemic administration of a SCD1 inhibitor in mouse tumor models enhanced production of CCL4 by cancer cells through reduction of Wnt/ß-catenin signaling and by CD8+ effector T cells through reduction of endoplasmic reticulum stress. It in turn promoted recruitment of dendritic cells (DCs) into the tumors and enhanced the subsequent induction and tumor accumulation of antitumor CD8+ T cells. SCD1 inhibitor was also found to directly stimulate DCs and CD8+ T cells. Administration of SCD1 inhibitor or SCD1 knockout in mice synergized with an anti-PD-1 antibody for its antitumor effects in mouse tumor models. High SCD1 expression was observed in one of the non-T cell-inflamed subtypes in human colon cancer, and serum SCD1 related fatty acids were correlated with response rates and prognosis of patients with non-small lung cancer following anti-PD-1 antibody treatment. CONCLUSIONS: SCD1 expressed in cancer cells and immune cells causes immunoresistant conditions, and its inhibition augments antitumor T cells and therapeutic effects of anti-PD-1 antibody. Therefore, SCD1 is an attractive target for the development of new diagnostic and therapeutic strategies to improve current cancer immunotherapies including immune checkpoint inhibitors.

Posterior scleritis with choroidal detachments and periaortitis associated with IgG4-related disease: A case report.

BACKGROUND: IgG4-related diseases (IgG4-RDs) are known to disrupt the functioning of multiple organs and are usually associated with mass lesions. Periaortitis, an inflammation of the adventitia and tissues surrounding the aorta, is an example of an IgG4-RD. In ophthalmology, an enlargement of the lacrimal gland is a well-known IgG4-RD, and scleritis has also been reported to be an IgG4-RD although it is rare. We report our findings in a case with periaortitis and posterior scleritis that were present at the same time, and they responded well to systemic steroid therapy. PATIENTS CONCERNS: A 79-year-old man with dementia and Lewy bodies was referred to our hospital because of uveitis in both eyes that did not respond to topical steroid therapy. DIAGNOSIS: We found anterior scleritis in the right eye and uveitis with shallow anterior chambers in both eyes. B-mode echography showed choroidal detachments (CDs) and a T sign in the right eye. The CDs were assumed to have progressed to the posterior scleritis which then caused the severe vision reduction. The patient was referred to the Internal Medicine Department because the systemic inflammatory disease was suspected due to the high levels of C-reactive protein (CRP) and the fast erythrocyte sedimentation rate. Systemic CT scans showed periaortitis only at the lumbar region. Because of the high levels of IgG4, the patient was diagnosed with IgG4-RD. INTERVENTIONS: The patient received intravenous and oral steroid therapy. The first 125 mg of methylprednisolone (mPSL) for 3 days was intravenous, after which it was switched to oral prednisolone (PSL) therapy and the dosage was gradually reduced. OUTCOMES: The posterior scleritis and periaortitis responded well to the systemic steroid therapy. One year and a half after the onset of the disease, the patient is still taking 5 mg of PSL. CONCLUSIONS: Scleritis with multiple CDs and periaortitis were strongly suspected to be due to IgG4-RD although no definitive diagnosis was made by biopsy of the lesions. Clinicians should be aware that IgG4-RD should be considered as one of the causes of posterior scleritis.

Extreme leanness, lower skeletal muscle quality, and loss of muscle mass during treatment are predictors of poor prognosis in cervical cancer treated with concurrent chemoradiation therapy.

BACKGROUND: Human papillomavirus vaccination is not widespread in Japan, and the low screening rates result in many cases of locally advanced cervical cancer. We investigated the prognostic significance of sarcopenia in patients with cervical cancer to guide healthcare policies to improve treatment outcomes. METHODS: This retrospective study included 83 patients with cervical cancer without distant metastasis who underwent primary concurrent chemoradiotherapy between 2013 and 2018. We analyzed the indicators of physical condition and muscle quantity using the SYNAPSE VINCENT software. Muscle mass and the relationship between treatment toxicity and prognosis were evaluated. RESULTS: The patients' median age was 60 (range 33‒80) years. Cancer stage distribution was as follows: cT2b or higher, 84.3%; N1, 65.1%; and MA, 27.7%. The overall sarcopenia (skeletal muscle index [SMI] < 38.5) rate was 30.1%, and the rate was 33.9 and 22.2% in patients aged < 64 and ≥ 65 years, respectively. No correlation was observed between clinical stage and musculoskeletal indices. Treatment resulted in decreased body weight and SMI; after treatment, the sarcopenia rate increased to 37.3%. A higher intramuscular adipose tissue content (IMAC) reduced the number of chemotherapy cycles needed. Treatment-associated SMI decreases of ≥ 7% indicated poor prognosis, with significant differences in progression-free survival and overall survival (p = 0.013 and p = 0.012, respectively). Patients who were very lean (body mass index < 18.5 kg/m2) before treatment had a poor prognosis (p = 0.016 and p < 0.001). CONCLUSIONS: Our findings emphasize the importance of assessing original nutritional status and maintaining muscle mass and quality during the treatment of patients with cervical cancer.

Changes in fine structure of amylopectin and internal structures of starch granules in developing endosperms and culms caused by starch branching enzyme mutations of japonica rice.

KEY MESSAGE: BEIIb plays a specific role in determining the structure of amylopectin in rice endosperm, whereas BEIIa plays the similar role in the culm where BEIIb is absent. Cereals have three types of starch branching enzymes (BEs), BEI, BEIIa, and BEIIb. It is widely known that BEIIb is specifically expressed in the endosperm and plays a distinct role in the structure of amylopectin because in its absence the amylopectin type changes to the amylose-extender-type (ae-type) or B-type from the wild-type or A-type and this causes the starch crystalline allomorph to the B-type from the wild-type A-type. This study aimed to clarify the role of BEIIa in the culm where BEIIb is not expressed, by using a be2a mutant in comparison with results with be2b and be1 mutants. The results showed that the amylopectin structure exhibited the B-type in the be2a culm compared with the A-type in the wild-type culm. The starch granules from the be2a culm also showed the B-type like allomorph when examined by X-ray diffraction analysis and optical sum frequency generation spectroscopy. Both amylopectin chain-length profile and starch crystalline properties were found to be the A-type at the very early stage of endosperm development at 4-6 days after pollination (DAP) even in the be2b mutant. All these results support a view that in the culm as well as in the endosperm at 4-6 DAP, BEIIa can play the role of BEIIb which has been well documented in maturing endosperm. The possible mechanism as to how BEIIa can play its role is discussed.

Attitudes toward using "Simple simulator for calculating nutritional food stocks in preparation for large-scale disasters" among local governmental personnel and public health dietitians in Japan: An explanatory mixed methods study.

The Japanese Ministry of Health, Labour and Welfare compiled an Excel sheet - "Simple simulator for calculating nutritional food stocks in preparation for large-scale disasters" (Simulator). We examined the level of recognition and use of the Simulator by local governments and identified the points for its improvement. In stage 1, we surveyed local government personnel who participated in the "Workshop for nutrition assistance during large-scale disasters" held in November 2020 (n = 458; 313 responded) with an online questionnaire on the use of the Simulator and associated issues. Stage 2 involved group interviews with 15 public health dietitians who had been involved in food assistance during past natural disasters to identify points for improving the Simulator and the problems with food assistance during natural disasters. In stage 1, 233 responders (74.4%) confirmed their awareness of the existence of the Simulator. While 85 individuals (36.6%) used the Simulator, 63 individuals (74.1%) confirmed that they would use it in the future to plan and evaluate local government stocks. In stage 2, multiple comments regarding the Simulator's applicability and improvement in a realistic situation were collected. In order for the administrative staff in charge of disaster management to understand the nutritional importance of stockpiling main/side dishes, it was suggested that specific combinations of foods that meet the required amounts should be shown and that visualization using food products and the number of people covered by stockpiled foods may be easier to understand than pure nutritional values.

DNA repair factor KAT5 prevents ischemic acute kidney injury through glomerular filtration regulation.

The "preconditioning effect" in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.

Pathway engineering for high-yield production of lutein in Escherichia coli.

Lutein is an industrially important carotenoid pigment, which is essential for photoprotection and photosynthesis in plants. Lutein is crucial for maintaining human health due to its protective ability from ocular diseases. However, its pathway engineering research has scarcely been performed for microbial production using heterologous hosts, such as Escherichia coli, since the engineering of multiple genes is required. These genes, which include tricky key carotenoid biosynthesis genes typically derived from plants, encode two sorts of cyclases (lycopene ε- and ß-cyclase) and cytochrome P450 CYP97C. In this study, upstream genes effective for the increase in carotenoid amounts, such as isopentenyl diphosphate isomerase (IDI) gene, were integrated into the E. coli JM101 (DE3) genome. The most efficient set of the key genes (MpLCYe, MpLCYb and MpCYP97C) was selected from among the corresponding genes derived from various plant (or bacterial) species using E. coli that had accumulated carotenoid substrates. Furthermore, to optimize the production of lutein in E. coli, we introduced several sorts of plasmids that contained some of the multiple genes into the genome-inserted strain and compared lutein productivity. Finally, we achieved 11 mg/l as lutein yield using a mini jar. Here, the high-yield production of lutein was successfully performed using E. coli through approaches of pathway engineering. The findings obtained here should be a base reference for substantial lutein production with microorganisms in the future.

Capsanthin Production in Escherichia coli by Overexpression of Capsanthin/Capsorubin Synthase from Capsicum annuum.

Capsanthin, a characteristic red carotenoid found in the fruits of red pepper (Capsicum annuum), is widely consumed as a food and a functional coloring additive. An enzyme catalyzing capsanthin synthesis was identified as capsanthin/capsorubin synthase (CCS) in the 1990s, but no microbial production of capsanthin has been reported. We report here the first successful attempt to biosynthesize capsanthin in Escherichia coli by carotenoid-pathway engineering. Our initial attempt to coexpress eight enzyme genes required for capsanthin biosynthesis did not detect the desired product. The dual activity of CCS as a lycopene ß-cyclase as well as a capsanthin/capsorubin synthase likely complicated the task. We demonstrated that a particularly high expression level of the CCS gene and the minimization of byproducts by regulating the seven upstream carotenogenic genes were crucial for capsanthin formation in E. coli. Our results provide a platform for further study of CCS activity and capsanthin production in microorganisms.