Publications by authors named "Kazuo Kobayashi"

247 Publications

The evaluation of noninferiority for renal composite outcomes between sodium-glucose cotransporter inhibitors in Japan.

Prim Care Diabetes 2021 Sep 4. Epub 2021 Sep 4.

Committee of Hypertension and Kidney Disease, Kanagawa Physicians Association, Yokohama, Japan.

Background: In Japan, six types of sodium-glucose cotransporter inhibitors (SGLT2Is) are currently in use. Here, we evaluated differences in renal composite outcomes between SGLT2Is with or without evidence of cardio vascular outcome trials (CVOTs).

Methods: We retrospectively surveyed 536 Japanese patients with type 2 diabetes mellitus with chronic kidney disease who received SGLT2Is for more than 1 year. Patients were classified as having received empagliflozin, canagliflozin, or dapagliflozin (n = 270, Evidence (+) group) or as having received ipragliflozin, tofogliflozin, or luseogliflozin (n = 266, Evidence (-) group). The propensity score matching method was performed.

Result: On matched cohort model including 205 cases in each group, there were no significant differences in the incidence of renal composite outcomes (n = 28 [14%] in the Evidence (+) group, n = 21 [10%] in the Evidence (-) group for the matched model; p = 0.29) between groups. Cox hazard analyses in the matched cohort model showed that the risk ratio for renal composite outcomes in the Evidence (-) group was 0.73 (95% confidence interval: 0.40-1.32), which was greater than the noninferiority margin of 1.22.

Conclusion: Three SGLT2Is with no CVOT's evidence did not show noninferiority compared with other SGLT2Is with evidences.
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http://dx.doi.org/10.1016/j.pcd.2021.08.012DOI Listing
September 2021

The Combined Use of 5 or More Drugs Is a Factor Related to Lower Adherence to S-1 in S-1 and Oxaliplatin Treatment for Advanced Gastric Cancer.

Biol Pharm Bull 2021 ;44(8):1075-1080

Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research.

S-1 plus oxaliplatin (SOX) is an established treatment for advanced gastric cancer. S-1 adherence is the key to successful SOX treatment. This study focused on S-1 adherence by evaluating real-world adherence to S-1 and investigating factors related to decreased S-1 adherence. This study included cases treated between August 1, 2014 and October 12, 2016 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The S-1 adherence rate per cycle was defined as the number of times a patient took S-1/28. In this study, adherence to S-1 was assessed through pill counts and by asking the patient about the reason for non-adherence at a pharmaceutical outpatient clinic. Univariate and multivariate analyses were performed to investigate factors influencing lower adherence. This analysis included 116 patients evaluated for adherence to S-1 on SOX treatment. The median rate of adherence to S-1 was 92.8% in the first cycle and 90.5% in the seventh cycle. The median relative dose intensity of S-1 was 84.6%. In terms of reasons for nonadherence, patients most commonly cited nausea/vomiting (43.7%), diarrhea (20.8%), missed dose (11.8%), and fever (8.1%). Logistic regression analysis was performed using the most appropriate regression equation, and a significant association was detected with 1 factor, number of combined drugs ≥5 (odds ratio (OR) = 2.50; 95% confidence interval (CI), 1.04-6.03, p = 0.04). Eliminating unnecessary concomitant medications helps maintain proper adherence to S-1 in SOX treatment.
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http://dx.doi.org/10.1248/bpb.b21-00184DOI Listing
January 2021

Diverse LXG toxin and antitoxin systems specifically mediate intraspecies competition in Bacillus subtilis biofilms.

Authors:
Kazuo Kobayashi

PLoS Genet 2021 Jul 19;17(7):e1009682. Epub 2021 Jul 19.

Division of Biological Science, Department of Science and Technology, Nara Institute of Science & Technology, Ikoma, Nara, Japan.

Biofilms are multispecies communities, in which bacteria constantly compete with one another for resources and niches. Bacteria produce many antibiotics and toxins for competition. However, since biofilm cells exhibit increased tolerance to antimicrobials, their roles in biofilms remain controversial. Here, we showed that Bacillus subtilis produces multiple diverse polymorphic toxins, called LXG toxins, that contain N-terminal LXG delivery domains and diverse C-terminal toxin domains. Each B. subtilis strain possesses a distinct set of LXG toxin-antitoxin genes, the number and variation of which is sufficient to distinguish each strain. The B. subtilis strain NCIB3610 possesses six LXG toxin-antitoxin operons on its chromosome, and five of the toxins functioned as DNase. In competition assays, deletion mutants of any of the six LXG toxin-antitoxin operons were outcompeted by the wild-type strain. This phenotype was suppressed when the antitoxins were ectopically expressed in the deletion mutants. The fitness defect of the mutants was only observed in solid media that supported biofilm formation. Biofilm matrix polymers, exopolysaccharides and TasA protein polymers were required for LXG toxin function. These results indicate that LXG toxin-antitoxin systems specifically mediate intercellular competition between B. subtilis strains in biofilms. Mutual antagonism between some LXG toxin producers drove the spatial segregation of two strains in a biofilm, indicating that LXG toxins not only mediate competition in biofilms, but may also help to avoid warfare between strains in biofilms. LXG toxins from strain NCIB3610 were effective against some natural isolates, and thus LXG toxin-antitoxin systems have ecological impact. B. subtilis possesses another polymorphic toxin, WapA. WapA had toxic effects under planktonic growth conditions but not under biofilm conditions because exopolysaccharides and TasA protein polymers inhibited WapA function. These results indicate that B. subtilis uses two types of polymorphic toxins for competition, depending on the growth mode.
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http://dx.doi.org/10.1371/journal.pgen.1009682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321402PMC
July 2021

Comparison of questionnaire responses regarding awareness of Japanese Society of Hypertension guidelines for the management of hypertension between 2014 and 2019 in primary care.

Hypertens Res 2021 Sep 12;44(9):1147-1157. Epub 2021 Jul 12.

Committee of Hypertension and Kidney Disease, Kanagawa Physicians Association, Yokohama, Japan.

In 2019, the Japanese Society of Hypertension guidelines for the management of hypertension (JSH) were revised. We previously reported the awareness of JSH among general practitioners in 2014, and in the current study, the same questionnaire was administered to determine their awareness of JSH 2019, and their responses were compared. We also sought to identify effective strategies to raise awareness of hypertension. The questionnaires included the same 12 questions as in 2014 and were mailed to members of two professional organizations from October to November 2019. Responses from 256 general practitioners in 2019 and 209 in 2014 were compared using the propensity score matching method to align the responders' backgrounds. Component analysis was performed to classify responders into appropriate clusters. The matched cohort of all 202 responders was analyzed. In both 2014 and 2019, >80% of responders instructed patients to perform home blood pressure monitoring (JSH 2014: 81.7% and JSH 2019: 84.6% in the matched cohort), and >70% instructed patients with hypertension to restrict their salt intake (JSH 2014: 79.7% and JSH 2019: 74.7% in the matched cohort). Regarding the clinical blood pressure measurement method, more responders answered "one time outside the consulting room" in the JSH 2019 group (p = 0.042). Fewer general practitioners responded that differential diagnosis for primary aldosteronism was performed in the JSH 2019 group (p = 0.032); however, the frequency of checking the aldosterone-renin ratio increased in the JSH 2019 group (p = 0.055). We confirmed the change in general practitioners' awareness of hypertension management. The categorized clusters may be useful for the development of effective strategies for higher-quality hypertension management in clinical practice.
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http://dx.doi.org/10.1038/s41440-021-00693-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273028PMC
September 2021

Nationwide questionnaire survey on the management of chronic kidney disease for general practitioners in Japan.

Clin Exp Nephrol 2021 Oct 12;25(10):1093-1102. Epub 2021 Jul 12.

Committee of Kidney and Electrolyte Disease, Japan Physicians Association, Tokyo, Japan.

Background: In 2019, a nationwide questionnaire survey on the management of chronic kidney disease (CKD) was circulated to general practitioners (GPs) throughout Japan by The Japan Physicians Association. The aim was to assess the current state of CKD medical care in the country and evaluate the utilization of CKD-specific guidelines in the treatment by GPs.

Methods: The voluntary survey targeted all members of Japan Physicians Association, a nationwide organization consisting primarily of 15,000 GPs in clinics throughout the country. GPs were divided into groups: 171 GPs using and 414 GPs not using the guidelines. Comparisons between the groups' responses were made using propensity score matching and component cluster analysis.

Results: Overall responses revealed that the estimated glomerular filtration rate's utilization rate was high (95.1%). However, evidence-practice gaps in urine protein quantification and anemia remedy were prominent. There were significantly favorable answers in terms of CKD management in the user group compared with those in the non-user group, except for the questions about a urine check at the first visit, stopping the use of renin-angiotensin system inhibitors, and the target blood pressure for elderly CKD patients. The differences suggest that utilization of the CKD guidelines has improved CKD management practices by GPs.

Conclusions: Further promotion of CKD guidelines utilization (28% in this survey) is considered valid for CKD medical education.
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http://dx.doi.org/10.1007/s10157-021-02084-xDOI Listing
October 2021

Calcium Prevents Biofilm Dispersion in Bacillus subtilis.

J Bacteriol 2021 06 22;203(14):e0011421. Epub 2021 Jun 22.

Division of Bioscience, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan.

Biofilm dispersion is the final stage of biofilm development, during which biofilm cells actively escape from biofilms in response to deteriorating conditions within the biofilm. Biofilm dispersion allows cells to spread to new locations and form new biofilms in better locations. However, dispersal mechanisms have been elucidated only in a limited number of bacteria. Here, we investigated biofilm dispersion in Bacillus subtilis. Biofilm dispersion was clearly observed when B. subtilis was grown under static conditions in modified LB medium containing glycerol and manganese. Biofilm dispersion was synergistically caused by two mechanisms: decreased expression of the operon encoding exopolysaccharide synthetases and the induction of sporulation. Indeed, constitutive expression of the operon in the sporulation-defective Δ mutant prevented biofilm dispersion. The addition of calcium to the medium prevented biofilm dispersion without significantly affecting the expression of the operon and sporulation genes. In synthetic medium, eliminating calcium did not prevent the expression of biofilm matrix genes and, thereby, biofilm formation, but it attenuated biofilm architecture. These results indicate that calcium structurally stabilizes biofilms and causes resistance to biofilm dispersion mechanisms. Sporulation-dependent biofilm dispersion required the operon, encoding dipicolinic acid (DPA) synthase. During sporulation, an enormous amount of DPA is synthesized and stored in spores as a chelate with calcium. We speculate that, during sporulation, calcium bound to biofilm matrix components may be transported to spores as a calcium-DPA complex, which weakens biofilm structure and leads to biofilm dispersion. Bacteria growing as biofilms are notoriously difficult to eradicate and sometimes pose serious threats to public health. Bacteria escape from biofilms by degrading them when biofilm conditions deteriorate. This process, called biofilm dispersion, has been studied as a promising strategy for safely controlling biofilms. However, the regulation and mechanism of biofilm dispersion has been elucidated only in a limited number of bacteria. Here, we identified two biofilm dispersion mechanisms in the Gram-positive, spore-forming bacterium Bacillus subtilis. The addition of calcium to the medium stabilized biofilms and caused resistance to dispersal mechanisms. Our findings provide new insights into biofilm dispersion and biofilm control.
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http://dx.doi.org/10.1128/JB.00114-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223931PMC
June 2021

Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers.

Cancer Chemother Pharmacol 2021 06 26;87(6):767-777. Epub 2021 Feb 26.

Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Purpose: The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (C) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer.

Methods: The C levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5.

Results: We analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the C values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 C levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 C values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035).

Conclusion: This study showed that the C of regorafenib was associated with bilirubin increase, and also clarified for the first time that the C of M5 was significantly correlated with hypertension and severe rash.
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http://dx.doi.org/10.1007/s00280-021-04237-xDOI Listing
June 2021

Functional and structural characterization of a flavoprotein monooxygenase essential for biogenesis of tryptophylquinone cofactor.

Nat Commun 2021 02 10;12(1):933. Epub 2021 Feb 10.

Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.

Bioconversion of peptidyl amino acids into enzyme cofactors is an important post-translational modification. Here, we report a flavoprotein, essential for biosynthesis of a protein-derived quinone cofactor, cysteine tryptophylquinone, contained in a widely distributed bacterial enzyme, quinohemoprotein amine dehydrogenase. The purified flavoprotein catalyzes the single-turnover dihydroxylation of the tryptophylquinone-precursor, tryptophan, in the protein substrate containing triple intra-peptidyl crosslinks that are pre-formed by a radical S-adenosylmethionine enzyme within the ternary complex of these proteins. Crystal structure of the peptidyl tryptophan dihydroxylase reveals a large pocket that may dock the protein substrate with the bound flavin adenine dinucleotide situated close to the precursor tryptophan. Based on the enzyme-protein substrate docking model, we propose a chemical reaction mechanism of peptidyl tryptophan dihydroxylation catalyzed by the flavoprotein monooxygenase. The diversity of the tryptophylquinone-generating systems suggests convergent evolution of the peptidyl tryptophan-derived cofactors in different proteins.
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http://dx.doi.org/10.1038/s41467-021-21200-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876137PMC
February 2021

Seasonal shift in epidemics of respiratory syncytial virus infection in Japan.

Epidemiol Infect 2021 02 11;149:e55. Epub 2021 Feb 11.

Department of Public Health, Osaka Institute of Public Health, Osaka, Japan.

In Japan, respiratory syncytial virus (RSV) infection generally has occurred during autumn and winter. However, a possible change in the seasonal trend of RSV infection has been observed recently. The current study was conducted to determine whether the epidemic season of RSV infection in Japan has indeed changed significantly. We used expectation-based Poisson scan statistics to detect periods with high weekly reported RSV cases (epidemic cluster), and the epidemic clusters were detected between September and December in the 2012-2016 seasons while those were detected between July and October in the 2017-2019 seasons. Non-linear and linear ordinary least squares regression models were built to evaluate whether there is a difference in year trend in the epidemic seasonality, and the epidemic season was shifted to earlier in the year in 2017-2019 compared to that in 2012-2016. Although the reason for the shift is unclear, this information may help in clinical practice and public health.
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http://dx.doi.org/10.1017/S0950268821000340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060823PMC
February 2021

Fast autooxidation of a bis-histidyl-ligated globin from the anhydrobiotic tardigrade, Ramazzottius varieornatus, by molecular oxygen.

J Biochem 2021 Sep;169(6):663-673

Graduate School of Pharmaceutical Science, Osaka University, Suita, Japan.

Tardigrades, a phylum of meiofaunal organisms, exhibit extraordinary tolerance to various environmental conditions, including extreme temperatures (-273 to 151°C) and exposure to ionizing radiation. Proteins from anhydrobiotic tardigrades with homology to known proteins from other organisms are new potential targets for structural genomics. Recently, we reported spectroscopic and structural characterization of a hexacoordinated haemoglobin (Kumaglobin [Kgb]) found in an anhydrobiotic tardigrade. In the absence of its exogenous ligand, Kgb displays hexacoordination with distal and proximal histidines. In this work, we analysed binding of the molecular oxygen ligand following reduction of haem in Kgb using a pulse radiolysis technique. Radiolytically generated hydrated electrons (eaq-) reduced the haem iron of Kgb within 20 µs. Subsequently, ferrous haem reacted with O2 to form a ferrous-dioxygen intermediate with a second-order rate constant of 3.0 × 106 M-1 s-1. The intermediate was rapidly (within 0.1 s) autooxidized to the ferric form. Redox potential measurements revealed an E'0 of -400 mV (vs. standard hydrogen electrode) in the ferric/ferrous couple. Our results suggest that Kgb may serve as a physiological generator of O2▪- via redox signalling and/or electron transfer.
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http://dx.doi.org/10.1093/jb/mvab003DOI Listing
September 2021

Sodium-glucose cotransporter 2 inhibitor-induced reduction in the mean arterial pressure improved renal composite outcomes in type 2 diabetes mellitus patients with chronic kidney disease: A propensity score-matched model analysis in Japan.

J Diabetes Investig 2021 Aug 1;12(8):1408-1416. Epub 2021 Feb 1.

Committee of Hypertension and Kidney disease, Kanagawa Physicians Association, Yokohama, Japan.

Aims/introduction: Large-scale clinical trials have reported that, in patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment affords favorable renal outcomes; the underlying mechanisms, however, remain unclear. Thus, this study investigated how SGLT2 inhibitor-induced changes in the mean arterial pressure (MAP; denoted as ΔMAP) are associated with renal outcomes in type 2 diabetes mellitus patients with chronic kidney disease (CKD).

Materials And Methods: We retrospectively assessed the data of 624 Japanese type 2 diabetes mellitus patients with CKD who had been using SGLT2 inhibitors for >1 year. For propensity score matching (1:1 nearest neighbor match, with caliper value = 0.053, no replacement), patients were categorized into two groups based on the ΔMAP (>-4 mmHg [n = 329] and ≤-4.0 mmHg [n = 295]). Composite albuminuria progression or a ≥15% annual reduction in the estimated glomerular filtration rate was regarded as the end-point.

Results: Per group, 173 propensity-matched patients were compared. Patients with ΔMAP ≤-4 mmHg had a significantly lower incidence of composite renal outcomes than those with ΔMAP ≥-4 mmHg (5.8% [n = 10] vs 15.6% [n = 27], P = 0.003). Although the between-group differences in the estimated glomerular filtration rates were non-significant, patients with a ΔMAP ≤-4 mmHg had significantly larger reductions in the logarithmic urine albumin-to-creatinine ratio (P = 0.005).

Conclusions: The degree of blood pressure reduction after SGLT2 inhibitor treatment influenced renal composite outcomes in Japanese type 2 diabetes mellitus patients with CKD, confirming the importance of blood pressure management in type 2 diabetes mellitus patients with CKD, even when they are under SGLT2 inhibitor treatment.
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http://dx.doi.org/10.1111/jdi.13491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354503PMC
August 2021

The influence of long-term administration of SGLT2 inhibitors on blood pressure at the office and at home in patients with type 2 diabetes mellitus and chronic kidney disease.

J Clin Hypertens (Greenwich) 2020 12 21;22(12):2306-2314. Epub 2020 Oct 21.

Committee of Hypertension and Kidney disease, Kanagawa Physicians Association, Yokohama, Japan.

The decrease in blood pressure is thought to play an important role for the renoprotective effects of sodium-glucose cotransporter 2 inhibitors in patients with diabetes mellitus. However, their influence on blood pressure at home has not been well studied. The aim of this study is to clarify how long-term use of sodium-glucose cotransporter 2 inhibitors influence on blood pressure both at the office and at home, and the kidney function. We retrospectively analyzed 102 patients with type 2 diabetes mellitus and chronic kidney disease to whom sodium-glucose cotransporter 2 inhibitors were administered for more than 1 year, and whose blood pressure were monitored both at the office and at home. The blood pressure at the office and at home significantly decreased, and there was a significant positive correlation between both blood pressure values. Controlled, white-coat, and sustained hypertension were observed in 9.8%, 14.7%, and 55.9% of the patients at the beginning of the treatment, which changed to 16.7%, 15.7%, and 48.0% at the time of the survey, however, the ratio of masked hypertension was not changed (19.6%). The cutoff value of mean arterial pressure at home after treatment for the improvement of urine albumin to creatinine ratio was 92.0 mm Hg, with 54.1% of sensitivity and 60.0% of specificity. Sodium-glucose cotransporter 2 inhibitors can be useful for the strict management of blood pressures both at the office and at home. The decrease in blood pressure at home by this treatment might be related to the improvement of diabetic nephropathy.
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http://dx.doi.org/10.1111/jch.14084DOI Listing
December 2020

Alpha-Fetoprotein-Producing Early Gastric Cancer with Intramucosal Hepatoid and Fetal Enteric Differentiation.

Case Rep Gastroenterol 2020 May-Aug;14(2):426-435. Epub 2020 Aug 26.

Department of Clinical Laboratory Sciences, School of Health Sciences, Shinshu University, Matsumoto, Japan.

Alpha-fetoprotein (AFP)-producing gastric carcinomas (AFPGCs) are relatively rare tumors known to have a poor prognosis and commonly found as advanced lesions. Histologically, AFPGCs have been described as having hepatoid and fetal enteric (enteroblastic) morphology and are associated with conventional adenocarcinomas. Prior studies reported a hepatoid component present only in invasive areas and hypothesized that AFPGCs may develop hepatoid features during the process of tumor invasion. We report three cases of AFP-producing early gastric cancer which had an intramucosal hepatoid component. Immunohistochemistry showed that the hepatoid component was diffusely immunoreactive for SALL4, AFP, arginase-1, and HepPar1, and focally for CDX2 and PDX1. An intramucosal transition between the hepatoid component and conventional intramucosal adenocarcinoma was identified. Two patients also had a coexistent fetal enteric component, which was admixed with a hepatoid component. Although at an early stage one patient subsequently developed liver metastasis and a second patient was suspected of having liver metastasis, these were not biopsy-proven. The latter patient had a previous history of hepatocellular carcinoma (HCC) and SALL4 was used on the HCC to distinguish metastatic/further HCC from a gastric metastatic primary with hepatoid differentiation.
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http://dx.doi.org/10.1159/000508413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506198PMC
August 2020

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma.

In Vivo 2020 Sep-Oct;34(5):2647-2652

Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Background/aim: Immune-related adverse events (irAEs) are associated with the efficacy of immune-checkpoint inhibitors in patients with melanoma and non-small cell lung cancer. We therefore evaluated the relationship between irAEs and nivolumab efficacy against metastatic renal cell carcinoma.

Patients And Methods: The medical records of 53 consecutive patients were reviewed and analyzed.

Results: Median overall survival was significantly better in patients who showed irAEs at any time compared to patients without irAEs (p=0.013). We identified irAEs in 24 of 53 patients (45.3%), including four patients (7.5%) with grade 3 events. Multivariate analysis also revealed that risk factors for the onset of irAEs were positively associated with a platelet-to-lymphocyte ratio <156 before nivolumab treatment (p=0.006).

Conclusion: Development of irAEs was associated with survival outcomes of nivolumab treated patients with metastatic renal cell carcinoma.
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http://dx.doi.org/10.21873/invivo.12083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652517PMC
June 2021

Successful off-pump reimplantation of the anomalous right coronary artery from the pulmonary artery: A case report.

J Cardiol Cases 2020 Aug 6;22(2):68-71. Epub 2020 Jun 6.

Department of Cardiology, Kashiwa Municipal Hospital, Kashiwa, Chiba, Japan.

Anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) is a rare occurrence that requires surgical repair, typically via cardiopulmonary bypass (CPB). In this study, we present the case of a patient with ARCAPA with a high risk of cerebral infarction and left main trunk stenosis. However, because of the high risk of cerebral infarction, CPB was no longer an option during surgical intervention. Instead, we performed off-pump reimplantation of the ARCAPA to the ascending aorta and coronary artery bypass grafting of the left coronary artery. The patient had an uneventful postoperative course. Based on the successful outcomes of this case, we suggest off-pump reimplantation of the ARCAPA to the ascending aorta as a useful alternative for patients who are not eligible to undergo CPB during surgical repair. < Although surgical repair of the anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) usually requires cardiopulmonary bypass (CPB), we present a successful off-pump reimplantation for those who are not eligible to undergo CPB. We performed off-pump reimplantation of the ARCAPA to the ascending aorta and coronary artery bypass grafting of the left coronary artery. Therefore, we found off-pump reimplantation of the ARCAPA to the ascending aorta to be a useful alternative to CPB in high-risk patients.>.
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http://dx.doi.org/10.1016/j.jccase.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403600PMC
August 2020

Retrospective Analysis of the Renoprotective Effects of Long-Term Use of Six Types of Sodium-Glucose Cotransporter 2 Inhibitors in Japanese Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.

Diabetes Technol Ther 2021 02 13;23(2):110-119. Epub 2020 Aug 13.

Committee of Hypertension and Kidney Disease, Kanagawa Physicians Association, Yokohama, Japan.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) provide renal protection in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to elucidate the renal effects of long-term use of six types of SGLT2is in Japanese patients with T2DM and chronic kidney disease (CKD). The Kanagawa Physicians Association maintains a registry of patients who visit their 31 clinics. We retrieved clinical data of patients with T2DM and CKD who were prescribed with SGLT2is for >1 year. A total of 763 patients with a median treatment duration of 33 months were included. The logarithmic value of urine albumin-creatinine ratio (LNACR) decreased significantly from 1.60 ± 0.65 to 1.51 ± 0.67. The multiple linear regression analysis revealed that the LNACR at the initiation of treatment, change in (Δ) diastolic blood pressure, and Δ hemoglobin A1c were independently correlated with ΔLNACR ( < 0.001). The decrease in the LNACR was significantly smaller in the patients with estimated glomerular filtration rate (eGFR) [mL/(min ·1.73 m)] of <60 ( < 0.05). The eGFR decreased from 77.4 ± 22.3 to 72.7 ± 22.5 mL/(min ·1.73 m) ( < 0.001). The multiple linear regression analysis showed that the LNACR at the initiation of treatment, Δbody weight at the previous survey, ΔeGFR at the previous survey, and the eGFR at the initiation of treatment correlated independently with ΔeGFR during the maintenance period ( < 0.001). Greater changes in the eGFR during the maintenance period were observed in the patients with macroalbuminuria or eGFR of <60 ( < 0.01). The study confirmed that the long-term use of six types of SGLT2i improved the albumin-creatinine ratio (ACR), although the eGFR gradually decreased during the treatment. The change in the ACR was significantly smaller in the patients with eGFR of <60 mL/(min ·1.73 m) than in those with eGFR of >60 mL/(min ·1.73 m). However, this was a retrospective observational study; further studies are needed to formulate final conclusions.
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http://dx.doi.org/10.1089/dia.2020.0165DOI Listing
February 2021

Blood pressure after treatment with sodium-glucose cotransporter 2 inhibitors influences renal composite outcome: Analysis using propensity score-matched models.

J Diabetes Investig 2021 Jan 10;12(1):74-81. Epub 2020 Jul 10.

Committee of Hypertension and Kidney Disease, Kanagawa Physicians Association, Yokohama, Japan.

Aims/introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcome in patients with type 2 diabetes mellitus, but the mechanism is not fully understood. The aim of this retrospective study was to assess the association of achieved blood pressure with renal outcomes in Japanese type 2 diabetes mellitus patients with chronic kidney disease.

Materials And Methods: We assessed 624 Japanese type 2 diabetes mellitus patients with chronic kidney disease taking SGLT2i for >1 year. The patients were classified as those with post-treatment mean arterial pressure (MAP) of ≥92 mmHg (n = 344) and those with MAP of <92 mmHg (n = 280) for propensity score matching (1:1 nearest neighbor match with 0.04 of caliper value and no replacement). The end-point was a composite of progression of albuminuria or a decrease in the estimated glomerular filtration rate by ≥15% per year.

Results: By propensity score matching, a matched cohort model was constructed, including 201 patients in each group. The incidence of renal composite outcome was significantly lower among patients with MAP of <92 mmHg than among patients with MAP of ≥92 mmHg (n = 11 [6%] vs n = 26 [13%], respectively, P = 0.001). The change in estimated glomerular filtration rate was similar in the two groups; however, the change in the albumin-to-creatinine ratio was significantly larger in patients with MAP of <92 mmHg.

Conclusions: In Japanese type 2 diabetes mellitus patients with chronic kidney disease, blood pressure after SGLT2i administration influences the renal composite outcome. Blood pressure management is important, even during treatment with SGLT2i.
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http://dx.doi.org/10.1111/jdi.13318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779270PMC
January 2021

Role of Glutamate Synthase in Biofilm Formation by Bacillus subtilis.

J Bacteriol 2020 06 25;202(14). Epub 2020 Jun 25.

Division of Biological Science, Nara Institute of Science & Technology, Ikoma, Nara, Japan

forms robust biofilms in the presence of large amounts of carbon sources, such as glycerol. However, little is known about the importance of the metabolic systems, or the relationship between metabolic systems and regulatory systems, involved in biofilm formation. Glutamate synthase, encoded by , is an enzyme that converts 2-ketoglutarate (a tricarboxylic acid [TCA] cycle intermediate) and glutamine into glutamate, which is a general amino group donor in metabolism. Here, we show that a Δ mutant exhibited early arrest of biofilm formation in complex medium containing glycerol. This phenotype was not due to glutamate auxotrophy. Consistent with its biofilm formation phenotype, the Δ mutant exhibited an early decrease in expression of the and operons, which are responsible for production of biofilm matrix polymers. This resulted from decreased activity of their regulator, Spo0A, as evidenced by reduced expression of other Spo0A-regulated genes in the Δ mutant. The Δ mutation prevented biofilm formation only in the presence of large amounts of glycerol. Moreover, limited expression of citrate synthase (but not other TCA enzymes) restored biofilm-forming ability to the Δ mutant. These results indicate that the Δ mutant accumulates an inhibitory intermediate (citrate) in the TCA cycle in the presence of large amounts of glycerol. The Δ mutant formed biofilms when excess iron was added to the medium. Taken together, the data suggest that accumulation of citrate ions by the Δ mutant causes iron shortage due to chelation, which prevents activation of Spo0A and causes defective biofilm formation. , a model organism for bacterial biofilm formation, forms robust biofilms in a medium-dependent manner. Although the regulatory network that controls biofilm formation has been well studied, the importance of the underlying metabolic systems remains to be elucidated. The present study demonstrates that a metabolic disorder in a well-conserved metabolic system causes accumulation of an inhibitory metabolic intermediate that prevents activation of the system that regulates biofilm formation. These findings increase our understanding of the coordination between cellular metabolic status and the regulatory networks governing biofilm formation.
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http://dx.doi.org/10.1128/JB.00120-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317036PMC
June 2020

Impact of Primary Pegfilgrastim Prophylaxis on Relative Dose Intensity in Neoadjuvant/Adjuvant FEC-100 Chemotherapy.

Anticancer Res 2020 Feb;40(2):915-921

Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Background/aim: This study aimed was to clarify the impact of pegfilgrastim (PEG) 3.6 mg primary prophylaxis of febrile neutropenia (FN) on the average relative dose intensity (ARDI) of neoadjuvant/adjuvant FEC-100 for breast cancer.

Materials And Methods: This retrospective, single-centre cohort study including 296 patients who received FEC-100 compared PEG and non-PEG groups. The PEG group received PEG 3.6 mg as a single subcutaneous injection in each study cycle. The primary endpoint was the ARDI of FEC-100. The secondary endpoints were patient percentage of ARDI≥85%, factors associated with ARDI≥85%, and reasons for reduced ARDI.

Results: The PEG group showed significantly higher mean ARDI (95.6% versus 90.7%, p<0.001) and patient percentage of ARDI≥85% (93.0% versus 79.9%, p=0.001). PEG was significantly associated with ARDI≥85% (p=0.009). Neutropenia and FN, the main reasons for reduced ARDI, were significantly lower in the PEG group (p<0.05).

Conclusion: Primary PEG 3.6 mg prophylaxis increased the ARDI of FEC-100.
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http://dx.doi.org/10.21873/anticanres.14024DOI Listing
February 2020

Comparison of cisplatin-induced nephrotoxicity when using conventional versus short hydration in gastric cancer-a retrospective study.

J Chemother 2020 May 21;32(3):144-150. Epub 2020 Jan 21.

Department of Pharmacy, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Although a short hydration protocol for cisplatin has been recently developed for use in lung cancer, this has yet to be established for gastric cancer. This study reviewed medical records of patients with gastric cancer who received XPT(capecitabine/cisplatin/trastuzumab) therapy containing cisplatin. Patients received either the conventional or short hydration regimen. Nephrotoxicity was compared between these two regimens by monitoring the serum creatinine. Out of the 26 total patients, 19 received the conventional regimen while 7 received the short hydration regimen. There was a higher nephrotoxicity was observed in the group receiving the conventional regimen (42.1%, 8/19) as compared to the short hydration regimen (0%, 0/7). There was a statistically significant difference in nephrotoxicity between the regimens ( = 0.039). Study results suggest that short hydration may be a feasible regimen for XPT therapy in gastric cancer patients.
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http://dx.doi.org/10.1080/1120009X.2020.1713507DOI Listing
May 2020

Association of Immune-Related Adverse Events with Pembrolizumab Efficacy in the Treatment of Advanced Urothelial Carcinoma.

Oncology 2020 14;98(4):237-242. Epub 2020 Jan 14.

Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Purpose: Immune-related adverse events (irAEs) have been associated with the efficacy of programmed cell death protein 1 (PD-1) inhibitors in patients with urothelial cancer. We therefore evaluated the relationship between irAEs and pembrolizumab efficacy in urothelial cancer patients.

Methods: Patients with urothelial cancer who were treated with pembrolizumab in a second-line setting or later between January 2018 and December 2018 were identified by reviewing their medical records from the Cancer Institute Hospital, Japanese Foundation for Cancer Research. Data were updated as of December 31, 2018. Kaplan-Meier curves for overall survival (OS) and time to treatment failure (TTF) according to irAE grade were evaluated using the log-rank test. Risk factors for exacerbation of irAEs were also evaluated with multivariate analysis.

Results: In this retrospective study, 43 patients received pembrolizumab. We identified irAEs in 22 of the 43 patients (51.2%), including 11 patients (25.6%) with grade 2 or 3 events. In patients with irAE grade 0 or 1, median TTF was 127 days, and median OS was 160 days according to the Kaplan-Meier method. On the other hand, in patients with irAE grade ≥2, median TTF and OS were not reached. Multivariate analysis also revealed that risk factors for exacerbation of irAEs (to grade ≥2) were positively associated with lymphocyte count at baseline (>2,000/µL) before pembrolizumab treatment (p = 0.021).

Conclusions: Development of irAEs was associated with survival outcome of pembrolizumab treatment in patients with advanced urothelial cancer.
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http://dx.doi.org/10.1159/000505340DOI Listing
April 2020

Relation between Blood Pressure Management and Renal Effects of Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Patients with Chronic Kidney Disease.

J Diabetes Res 2019 3;2019:9415313. Epub 2019 Nov 3.

Committee of Hypertension and Kidney Disease, Kanagawa Physicians Association, Yokohama, Kanagawa Prefecture, Japan.

Aim: The renoprotective effect of sodium-glucose cotransporter 2 inhibitors is thought to be due, at least in part, to a decrease in blood pressure. The aim of this study was to determine the renal effects of these inhibitors in low blood pressure patients and the dependence of such effect on blood pressure management status.

Methods: The subjects of this retrospective study were 740 patients with type 2 diabetes mellitus and chronic kidney disease who had been managed at the clinical facilities of the Kanagawa Physicians Association. Data on blood pressure management status and urinary albumin-creatinine ratio were analyzed before and after treatment.

Results: Changes in the logarithmic value of urinary albumin-creatinine ratio in 327 patients with blood pressure < 130/80 mmHg at the initiation of treatment and in 413 patients with BP above 130/80 mmHg were -0.13 ± 1.05 and -0.24 ± 0.97, respectively. However, there was no significant difference between the two groups by analysis of covariance models after adjustment of the logarithmic value of urinary albumin-creatinine ratio at initiation of treatment. Changes in the logarithmic value of urinary albumin-creatinine ratio in patients with mean blood pressure of <102 mmHg ( = 537) and those with ≥102 mmHg ( = 203) at the time of the survey were -0.25 ± 1.02 and -0.03 ± 0.97, respectively, and the difference was significant in analysis of covariance models even after adjustment for the logarithmic value of urinary albumin-creatinine ratio at initiation of treatment ( < 0.001).

Conclusion: Our results confirmed that blood pressure management status after treatment with SGLT2 inhibitors influences the extent of change in urinary albumin-creatinine ratio. Stricter blood pressure management is needed to allow the renoprotective effects of sodium-glucose cotransporter 2 inhibitors.
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http://dx.doi.org/10.1155/2019/9415313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875192PMC
April 2020

Immune-Focusing Properties of Virus-like Particles Improve Protective IgA Responses.

J Immunol 2019 12 8;203(12):3282-3292. Epub 2019 Nov 8.

Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;

Virus-like particles (VLPs) provide a well-established vaccine platform; however, the immunogenic properties acquired by VLP structure remain poorly understood. In this study, we showed that systemic vaccination with norovirus VLP recalls human IgA responses at higher magnitudes than IgG responses under a humanized mouse model that was established by introducing human PBMCs in severely immunodeficient mice. The recall responses elicited by VLP vaccines depended on VLP structure and the disruption of VLP attenuated recall responses, with a more profound reduction being observed in IgA responses. The IgA-focusing property was also conserved in a murine norovirus-primed model under which murine IgA responses were recalled in a manner dependent on VLP structure. Importantly, the VLP-driven IgA response preferentially targeted virus-neutralizing epitopes located in the receptor-binding domain. Consequently, VLP-driven IgA responses were qualitatively superior to IgG responses in terms of the virus-neutralizing activity in vitro. Furthermore, the IgA in mucosa obtained remarkable protective function toward orally administrated virus in vivo. Thus, our results indicate the immune-focusing properties of the VLP vaccine that improve the quality/quantity of mucosal IgA responses, a finding with important implications for developing mucosal vaccines.
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http://dx.doi.org/10.4049/jimmunol.1900481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900486PMC
December 2019

Factors Associated With Regorafenib Adherence With Metastatic Colorectal Cancer.

Patient Prefer Adherence 2019 15;13:1745-1750. Epub 2019 Oct 15.

Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-Ku, Tokyo 135-8550, Japan.

Introduction: Regorafenib is an oral multikinase inhibitor for the treatment of metastatic colorectal cancer (mCRC). The clinical factors that may affect adherence to regorafenib remain unclear. The aim of this study was to evaluate adherence to regorafenib with mCRC and to identify factors that might affect adherence to regorafenib.

Methods: A total of 108 consecutively enrolled Japanese patients with mCRC received regorafenib. Adherence was measured by pharmacists using pill counts and a self-reported treatment diary for patients at a pharmaceutical outpatient clinic. The median relative dose intensities of regorafenib and the factors adversely affecting adherence were retrospectively surveyed. Logistic regression analysis was then performed using patient socio-demographic factors and clinical factors.

Results: A total of 96 patients were included in the analysis. The median adherence rate was 61.7% in the first cycle. The median relative dose intensity was 57.1%. The most common reason for non-adherence was a hand-foot-skin reaction (35.6%). On multivariate analysis, increased non-adherence to regorafenib was significantly associated with sex (female) [odds ratio (OR) = 4.36; 95% confidence interval (CI): 1.43-13.22, = 0.01].

Discussion: Hand-foot-skin reactions and female sex were associated with lower adherence to regorafenib. Since these factors could be associated with lower adherence to regorafenib, it would be useful to consider these factors when assessing adherence.
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http://dx.doi.org/10.2147/PPA.S217835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800560PMC
October 2019

Biofilm-associated toxin and extracellular protease cooperatively suppress competitors in Bacillus subtilis biofilms.

PLoS Genet 2019 10 17;15(10):e1008232. Epub 2019 Oct 17.

Division of Biological Science, Nara Institute of Science & Technology, Ikoma, Nara, Japan.

In nature, most bacteria live in biofilms where they compete with their siblings and other species for space and nutrients. Some bacteria produce antibiotics in biofilms; however, since the diffusion of antibiotics is generally hindered in biofilms by extracellular polymeric substances, i.e., the biofilm matrix, their function remains unclear. The Bacillus subtilis yitPOM operon is a paralog of the sdpABC operon, which produces the secreted peptide toxin SDP. Unlike sdpABC, yitPOM is induced in biofilms by the DegS-DegU two-component regulatory system. High yitPOM expression leads to the production of a secreted toxin called YIT. Expression of yitQ, which lies upstream of yitPOM, confers resistance to the YIT toxin, suggesting that YitQ is an anti-toxin protein for the YIT toxin. The alternative sigma factor SigW also contributes to YIT toxin resistance. In a mutant lacking yitQ and sigW, the YIT toxin specifically inhibits biofilm formation, and the extracellular neutral protease NprB is required for this inhibition. The requirement for NprB is eliminated by Δeps and ΔbslA mutations, either of which impairs production of biofilm matrix polymers. Overexpression of biofilm matrix polymers prevents the action of the SDP toxin but not the YIT toxin. These results indicate that, unlike the SDP toxin and many conventional antibiotics, the YIT toxin can pass through layers of biofilm matrix polymers to attack cells within biofilms with assistance from NprB. When the wild-type strain and the YIT-sensitive mutant were grown together on a solid medium, the wild-type strain formed biofilms that excluded the YIT-sensitive mutant. This observation suggests that the YIT toxin protects B. subtilis biofilms against competitors. Several bacteria are known to produce antibiotics in biofilms. We propose that some bacteria including B. subtilis may have evolved specialized antibiotics that can function within biofilms.
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http://dx.doi.org/10.1371/journal.pgen.1008232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818787PMC
October 2019

Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection.

Int Immunol 2019 11;31(12):781-793

Department of Bacteriology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan.

Macrophages are major components of tuberculosis (TB) granulomas and are responsible for host defenses against the intracellular pathogen, Mycobacterium tuberculosis. We herein showed the strong expression of hypoxia-inducible factor-1α (HIF-1α) in TB granulomas and more rapid death of HIF-1α-conditional knockout mice than wild-type (WT) mice after M. tuberculosis infection. Although interferon-γ (IFN-γ) is a critical host-protective cytokine against intracellular pathogens, HIF-1-deficient macrophages permitted M. tuberculosis growth even after activation with IFN-γ. These results prompted us to investigate the role of HIF-1α in host defenses against infection. We found that the expression of lactate dehydrogenase-A (LDH-A) was controlled by HIF-1α in M. tuberculosis-infected macrophages IFN-γ independently. LDH-A is an enzyme that converts pyruvate to lactate and we found that the intracellular level of pyruvate in HIF-1α-deficient bone marrow-derived macrophages (BMDMs) was significantly higher than in WT BMDMs. Intracellular bacillus replication was enhanced by an increase in intracellular pyruvate concentrations, which were decreased by LDH-A. Mycobacteria in phagosomes took up exogenous pyruvate more efficiently than glucose, and used it as the feasible carbon source for intracellular growth. These results demonstrate that HIF-1α prevents the hijacking of pyruvate in macrophages, making it a fundamental host-protective mechanism against M. tuberculosis.
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http://dx.doi.org/10.1093/intimm/dxz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839748PMC
November 2019

Sequential Sensing by TLR2 and Mincle Directs Immature Myeloid Cells to Protect against Invasive Group A Streptococcal Infection in Mice.

Cell Rep 2019 04;27(2):561-571.e6

Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, 4-2-1 Aoba-cho, Higashimurayama-shi, Tokyo 189-0002, Japan.

Severe invasive group A Streptococcus (GAS) infection evades anti-bacterial immunity by attenuating the cellular components of innate immune responses. However, this loss of protection is compensated for by interferon (IFN)-γ-producing immature myeloid cells (γIMCs), which are selectively recruited upon severe invasive GAS infection in mice. Here, we demonstrate that γIMCs provide this IFN-γ-mediated protection by sequentially sensing GAS through two distinct pattern recognition receptors. In a mouse model, GAS is initially recognized by Toll-like receptor 2 (TLR2), which promptly induces interleukin (IL)-6 production in γIMCs. γIMC-derived IL-6 promotes the upregulation of a recently identified GAS-sensing receptor, macrophage-inducible C-type lectin (Mincle), in an autocrine or paracrine manner. Notably, blockade of γIMC-derived IL-6 abrogates Mincle expression, downstream IFN-γ production, and γIMC-mediated protection against severe invasive GAS infection. Thus, γIMCs regulate host protective immunity against severe invasive GAS infection via a TLR2-IL-6-Mincle axis.
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http://dx.doi.org/10.1016/j.celrep.2019.03.056DOI Listing
April 2019

Proton Transfer Accompanied by the Oxidation of Adenosine.

Chemistry 2019 Jun 13;25(32):7711-7718. Epub 2019 May 13.

The Institute of Scientific and Industrial Research (SANKEN), Osaka University, Mihogaoka 8-1, Ibaraki, Osaka, 567-0047, Japan.

Despite numerous experimental and theoretical studies, the proton transfer accompanying the oxidation of 2'-deoxyadenosine 5'-monophosphate 2'-deoxyadenosine 5'-monophosphate (5'-dAMP, A) is still under debate. To address this issue, we have investigated the oxidation of A in acidic and neutral solutions by using transient absorption (TA) and time-resolved resonance Raman (TR ) spectroscopic methods in combination with pulse radiolysis. The steady-state Raman signal of A was significantly affected by the solution pH, but not by the concentration of adenosine (2-50 mm). More specifically, the A in acidic and neutral solutions exists in its protonated (AH (N1+H )) and neutral (A) forms, respectively. On the one hand, the TA spectral changes observed at neutral pH revealed that the radical cation (A ) generated by pulse radiolysis is rapidly converted into A (N6-H) through the loss of an imino proton from N6. In contrast, at acidic pH (<4), AH (N1+H ) generated by pulse radiolysis of AH (N1+H ) does not undergo the deprotonation process owing to the pK value of AH (N1+H ), which is higher than the solution pH. Furthermore, the results presented in this study have demonstrated that A, AH (N1+H ), and their radical species exist as monomers in the concentration range of 2-50 mm. Compared with the Raman bands of AH (N1+H ), the TR bands of AH (N1+H ) are significantly down-shifted, indicating a decrease in the bond order of the pyrimidine and imidazole rings due to the resonance structure of AH (N1+H ). Meanwhile, A (N6-H) does not show a Raman band corresponding to the pyrimidine+NH scissoring vibration due to diprotonation at the N6 position. These results support the final products generated by the oxidation of adenosine in acidic and neutral solutions being AH (N1+H ) and A (N6-H), respectively.
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http://dx.doi.org/10.1002/chem.201900732DOI Listing
June 2019

Association of Hand-Foot Skin Reaction with Regorafenib Efficacy in the Treatment of Metastatic Colorectal Cancer.

Oncology 2019 14;96(4):200-206. Epub 2019 Feb 14.

Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Purpose: Hand-foot skin reaction (HFSR) can deteriorate quality of life in patients receiving regorafenib. Cutaneous toxicity is a main adverse effect of multikinase inhibitors and has also been associated with clinical outcome. This study assessed the association between the antitumor efficacy of regorafenib and HFSR in patients with metastatic colorectal cancer (mCRC).

Methods: Patients who received regorafenib at 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they developed HFSR between May 2013 and October 2015. Estimates of overall survival and progression-free survival were calculated using the Kaplan-Meier method.

Results: Ninety-seven patients received at least one dose of regorafenib in this retrospective study. Of these patients, 81.4% (n = 79) experienced HFSR of any grade, and 34.0% (n = 33) had grade 3 HFSR. Among those patients with HFSR at any time during the study, 68.0% (n = 66) underwent the first HFSR event (any grade) during cycle 1. Both overall survival and progression-free survival were improved in patients who had HFSR grade ≥2 at any time compared with those who had HFSR grade ≤1. Multivariate logistic regression analysis revealed a history of HFSR grade ≥2 induced by capecitabine as a significant risk factor for severe HFSR (grade ≥2).

Conclusions: Patients with mCRC treated using regorafenib who experienced severe HFSR showed better overall survival than patients without severe HFSR. Severe HFSR may offer an early surrogate marker for the efficacy of regorafenib in patients with mCRC.
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http://dx.doi.org/10.1159/000495989DOI Listing
May 2019

Pulse Radiolysis Studies for Mechanism in Biochemical Redox Reactions.

Authors:
Kazuo Kobayashi

Chem Rev 2019 03 11;119(6):4413-4462. Epub 2019 Feb 11.

The Institute of Scientific and Industrial Research , Osaka University , Mihogaoka 8-1 , Ibaraki , Osaka 567-0047 , Japan.

Pulse radiolysis is a powerful method for generating highly reduced or oxidized species and free radicals. Combined with fast time-resolved spectroscopic measurement, we can monitor the reactions of intermediate species on time scales ranging from picoseconds to seconds. The application of pulse radiolysis to water generates hydrated electrons (e) and specific radicals, rendering this technique useful for investigating a number of biological redox processes. The first pulse radiolysis redox investigations explored in this review involved intramolecular electron transfer processes in protein with multiple electron-accepting sites. Pulse radiolysis enabled direct monitoring of the internal electron transfer rates and the distribution of electrons within proteins. Structural information from X-ray data has allowed analysis of the rate constants and their activation parameters in relation to the mechanisms with current theoretical treatments. The second set of pulse radiolysis redox investigations explored here concerned the intermediates of enzyme reactions after redox reactions. Pulse radiolysis allowed the extremely rapid donation of electrons to a redox center in a protein. It makes it possible to observe the unstable intermediates after the reduction and the following subsequent steps. For example, the intermediates generated through the one-electron reduction of oxygenated hemoproteins, such as cytochrome P450 and nitric oxide synthase, were characterized. Interestingly, ligand exchange can occur upon the reduction of heme iron, in which different amino acid residues bind to heme in the ferrous and ferric states, respectively. We directly observed the ligand-switching intermediates of bacterial CooA, a CO sensor, and bacterial iron response regulator protein. These ligand exchange processes are physiologically important for regulating the electrode potential and effective formation of superoxide anion or HO. The third set of pulse radiolysis redox investigations explored in this review concerns free-radical processes in biological systems. Free radicals are produced in cells and organisms in a variety of processes. The cell has developed special and very effective machinery for controlling and detoxifying reactive radicals. Radiation-generated radicals allow studies of the reactions between specific radicals and solutes, often revealing the mechanisms underlying the initial and subsequent reactions. The crucial contribution was made using pulse radiolysis techniques and knowledge of the identities, properties, and reactions of radicals. These radicals include superoxide (O), nitric monoxide (NO), ascorbate, urate, and protein radicals. This review focuses on the reactions of these radicals and their physiological functions.
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http://dx.doi.org/10.1021/acs.chemrev.8b00405DOI Listing
March 2019
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