Publications by authors named "Akira Sato"

552 Publications

Barthel Index-based functional status as a prognostic factor in young and middle-aged adults with newly diagnosed gastric, colorectal and lung cancer: a multicentre retrospective cohort study.

BMJ Open 2021 Apr 14;11(4):e046681. Epub 2021 Apr 14.

Cancer Control Center, Osaka International Cancer Institute, Osaka, Japan.

Objectives: Functional status assessments of activities of daily living may improve prognostic precision during initial diagnostic evaluations in young and middle-aged adults with cancer. However, the association between pretreatment functional status and survival in these patients is poorly understood. This study aimed to evaluate the prognostic value of functional status in young and middle-aged patients with cancer.

Design: Multicentre retrospective cohort study.

Setting: We used a cancer registry from Osaka Prefecture, Japan. The data were linked to administrative claims data from 35 hospitals in the same prefecture.

Participants: Patients aged 18-69 years who received new diagnoses of gastric, colorectal or lung cancer between 2010 and 2014.

Main Outcome Measure: Cox proportional hazards models of 5-year all-cause mortality were developed to examine the prognostic impact of pretreatment functional status, which was categorised into three levels of functional disability (none, moderate and severe) based on Barthel Index scores. The models controlled for age, sex, comorbidities, cancer stage and tumour histology.

Results: We analysed 12 134 patients. Higher mortality risks were significantly associated with moderate functional disability (adjusted HR 1.44 (95% CI 1.18 to 1.75), 1.35 (95% CI 1.08 to 1.68) and 1.74 (95% CI 1.50 to 2.03) in patients with gastric, colorectal and lung cancer, respectively) and severe functional disability (adjusted HR 3.56 (95% CI 2.81 to 4.51), 2.37 (95% CI 1.89 to 2.95) and 2.34 (95% CI 2.00 to 2.75) in patients with gastric, colorectal and lung cancer, respectively).

Conclusion: Accounting for functional status at cancer diagnosis may improve the prediction of survival time in young and middle-aged adults with cancer. Functional status has potential applications in survival predictions and risk adjustments when analysing outcomes in patients with cancer.
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http://dx.doi.org/10.1136/bmjopen-2020-046681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054075PMC
April 2021

Real-time observation of coronary artery perforation by intravascular ultrasound and optical coherence tomography.

Coron Artery Dis 2021 Mar 16. Epub 2021 Mar 16.

Faculty of Medicine, Department of Cardiology, University of Tsukuba, Tsukuba, Japan.

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http://dx.doi.org/10.1097/MCA.0000000000001036DOI Listing
March 2021

Successful Multivessel Coronary Interventions in a Patient With Single Coronary Artery.

Circ J 2021 Apr 2. Epub 2021 Apr 2.

Department of Cardiology, Faculty of Medicine, University of Tsukuba.

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http://dx.doi.org/10.1253/circj.CJ-21-0128DOI Listing
April 2021

Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells.

Int J Mol Sci 2021 Mar 13;22(6). Epub 2021 Mar 13.

Department of Biochemistry and Molecular Biology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.

5-Fluorouracil (5-FU) is a cornerstone drug used in the treatment of colorectal cancer (CRC). However, the development of resistance to 5-FU and its analogs remain an unsolved problem in CRC treatment. In this study, we investigated the molecular mechanisms and tumor biological aspects of 5-FU resistance in CRC HCT116 cells. We established an acquired 5-FU-resistant cell line, HCT116R. HCT116R cells were cross-resistant to the 5-FU analog, fluorodeoxyuridine. In contrast, HCT116R cells were collaterally sensitive to SN-38 and CDDP compared with the parental HCT16 cells. Whole-exome sequencing revealed that a cluster of genes associated with the 5-FU metabolic pathway were not significantly mutated in HCT116 or HCT116R cells. Interestingly, HCT116R cells were regulated by the function of thymidylate synthase (TS), a 5-FU active metabolite 5-fluorodeoxyuridine monophosphate (FdUMP) inhibiting enzyme. Half of the TS was in an active form, whereas the other half was in an inactive form. This finding indicates that 5-FU-resistant cells exhibited increased TS expression, and the TS enzyme is used to trap FdUMP, resulting in resistance to 5-FU and its analogs.
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http://dx.doi.org/10.3390/ijms22062916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002131PMC
March 2021

Generation of Transgenic Mice that Conditionally Overexpress Tenascin-C.

Front Immunol 2021 8;12:620541. Epub 2021 Mar 8.

Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, Tsu, Japan.

Tenascin-C (TNC) is an extracellular matrix glycoprotein that is expressed during embryogenesis. It is not expressed in normal adults, but is up-regulated under pathological conditions. Although TNC knockout mice do not show a distinct phenotype, analyses of disease models using TNC knockout mice combined with experiments revealed the diverse functions of TNC. Since high TNC levels often predict a poor prognosis in various clinical settings, we developed a transgenic mouse that overexpresses TNC through Cre recombinase-mediated activation. Genomic walking showed that the transgene was integrated into and truncated the gene. While homozygous transgenic mice showed a severe neurological phenotype, heterozygous mice were viable, fertile, and did not exhibit any distinct abnormalities. Breeding hemizygous mice with Nkx2.5 promoter-Cre or α-myosin heavy chain promoter Cre mice induced the heart-specific overexpression of TNC in embryos and adults. TNC-overexpressing mouse hearts did not have distinct histological or functional abnormalities. However, the expression of proinflammatory cytokines/chemokines was significantly up-regulated and mortality rates during the acute stage after myocardial infarction were significantly higher than those of the controls. Our novel transgenic mouse may be applied to investigations on the role of TNC overexpression in various tissue/organ pathologies using different Cre donors.
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http://dx.doi.org/10.3389/fimmu.2021.620541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982461PMC
March 2021

Stomatin-mediated inhibition of the Akt signaling axis suppresses tumor growth.

Cancer Res 2021 Mar 23. Epub 2021 Mar 23.

Department of Biochemistry and Molecular Biology, Shiga University of Medical Science

The growth and progression of cancers are crucially regulated by the tumor microenvironment where tumor cells and stromal cells are mutually associated. In this study, we found that stomatin expression was markedly upregulated by the interaction between prostate cancer cells and stromal cells. Stomatin suppressed cancer cell proliferation and enhanced apoptosis in vitro and inhibited xenograft tumor growth in vivo. Stomatin inhibited Akt activation, which is mediated by phosphoinositide-dependent protein kinase 1 (PDPK1). PDPK1 protein stability was maintained by its binding to heat shock protein 90 (HSP90). Stomatin interacted with PDPK1 and interfered with the PDPK1-HSP90 complex formation, resulting in decreased PDPK1 expression. Knockdown of stomatin in cancer cells elevated Akt activation and promoted cell increase by promoting the interaction between PDPK1 and HSP90. Clinically, stomatin expression levels were significantly decreased in human prostate cancer samples with high Gleason scores, and lower expression of stomatin was associated with higher recurrence of prostate cancer after the operation. Collectively, these findings demonstrate the tumor-suppressive effect of stromal-induced stomatin on cancer cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2331DOI Listing
March 2021

Differences Between Patients with and without Atherosclerosis in Expression Levels of Inflammatory Mediators in the Adipose Tissue Around the Coronary Artery.

Int Heart J 2021 Mar 17;62(2):390-395. Epub 2021 Mar 17.

Division of Cardiovascular Surgery, Shiga University of Medical Science.

Perivascular adipose tissue (PVAT) secretes large amounts of inflammatory mediators and plays a certain role in atherosclerosis formation from the exterior of the vessel. In the present study, we examined the expression level of inflammation-related mediators using adipose tissue samples harvested from patients with and without coronary artery disease (CAD). The subjects were 23 patients who underwent elective coronary bypass surgery (CAD group) and 17 patients who underwent elective mitral valve surgery (non-CAD group) between January 2017 and March 2018. The adipose tissue was harvested from three sites: the ascending aorta (AO), subcutaneous fat (SC), and pericoronary artery (CO) for the measurement of the expression levels of interleukin (IL) -1β, IL-6, IL-10, tumor necrosis factor (TNF) -α, interferon (INF) -γ, and arginase (Arg) -1. In both the non-CAD and CAD groups, the expression levels of all mediators, except Agr-1, which showed a tendency to have higher levels in the SC than in the AO and CO, tended to upregulate in the AO than in the SC and CO. The CAD group had higher values of almost all mediators, except Arg-1. Most importantly, the expression levels of IL-1β, IL-6, and IL-10 in the coronary artery were significantly higher in the CAD group. The expression levels of inflammatory mediators in the pericoronary adipose tissue were significantly higher in the CAD than in the non-CAD group. The adipose tissue appears to influence atherosclerosis formation from the exterior of the coronary artery.
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http://dx.doi.org/10.1536/ihj.20-585DOI Listing
March 2021

Impact of diagnosis-to-ablation time on non-pulmonary vein triggers and ablation outcomes in persistent atrial fibrillation.

J Cardiovasc Electrophysiol 2021 Mar 13. Epub 2021 Mar 13.

Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Introduction: Non-pulmonary vein (PV) triggers are a major cause of atrial tachyarrhythmia (ATA) recurrence after catheter ablation. However, the effect of the diagnosis-to-ablation time (DAT) on non-PV triggers in persistent atrial fibrillation is unknown.

Methods And Results: This observational study evaluated 502 consecutive persistent AF patients who underwent initial ablation. We compared 408 patients whose DAT was <3 years with 94 patients whose DAT was ≥3 years. Following PV and posterior wall isolation, 193 non-PV triggers, including 50 AFs, 30 atrial tachycardias (ATs), and 113 repetitive atrial premature beats, were elicited and ablated in 137 (27%) patients. Specifically, 80 non-PV AF/AT triggers were provoked in 64 (13%) patients, being identified more frequently in the DAT ≥ 3 years group than in the DAT < 3 years group (20% vs. 11%, p = .025) especially with a higher prevalence of coronary sinus/inferior left atrial triggers. During a median follow-up of 770 days, the ATA recurrence-free rate was higher in the DAT < 3 years group than the DAT ≥ 3 years group (79% vs. 53% at 2 years, p < .001). In a multivariate analysis, female sex (odds ratio: 2.70, p = .002) and a longer DAT (odds ratio: 1.13/year, p = .008) were predictors of non-PV AF/AT triggers, and a longer DAT (hazard ratio: 1.12/year, p < .001) and non-PV AT/AF triggers (hazard ratio: 1.79, p = .009) were associated with ATA recurrence.

Conclusion: Early ablation after the first diagnosis of persistent AF may reduce emerging non-PV AF/AT triggers and ATA recurrence.
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http://dx.doi.org/10.1111/jce.15002DOI Listing
March 2021

A novel challenge of nondestructive analysis on OGATA Koan's sealed medicine by muonic X-ray analysis.

J Nat Med 2021 Mar 13. Epub 2021 Mar 13.

The Museum of Osaka University, 1-13, Machikaneyama-cho, Toyonaka, Osaka, 560-0043, Japan.

OGATA Koan (1810-63) was a physician and the director of Tekijuku, and he contributed to Western medicine in the late Edo period. Osaka University preserves two of his medicine chests. One of the chests, which was used in his last years (the second chest) contained 22 glass bottles and 6 wooden cylinders. These bottles and cylinders contained formulated medicines; however, about half cannot be opened because of the long-term storage. It is necessary to comprehend the physical property of both the containers and their contents for investigation of this adequate preservation method; however, destructive analysis is not allowed. To analyze the medicines sealed in the glass bottles, we focused on muonic X-ray analysis, which has high transmittance. First, we certified the analytical methods using a historical medicinal specimen preserved in Osaka University. Thereafter, we applied the method on the bottles stored in the second chest. X-ray fluorescence identified the glass of those bottles to be lead potash glass. Among these bottles, we chose the bottle with the label "," which contains white powdered medication, for muonic X-ray analysis. We identified the contents of the medication in the glass to be HgCl. Through this study, we first applied muonic X-ray analysis on the medical inheritances and succeeded to detect the elements contained both in the container and in the contents of the sealed bottle. This would be a new method for nondestructive analysis of such cultural properties.
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http://dx.doi.org/10.1007/s11418-021-01487-0DOI Listing
March 2021

Increasing trends in the prevalence of prior cancer in newly diagnosed lung, stomach, colorectal, breast, cervical, and corpus uterine cancer patients: a population-based study.

BMC Cancer 2021 Mar 10;21(1):264. Epub 2021 Mar 10.

Department of Cancer Strategy, Cancer Control Center, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, Japan.

Background: Cancer survivors are frequently excluded from clinical research, resulting in their omission from the development of many cancer treatment strategies. Quantifying the prevalence of prior cancer in newly diagnosed cancer patients can inform research and clinical practice. This study aimed to describe the prevalence, characteristics, and trends of prior cancer in newly diagnosed cancer patients in Japan.

Methods: Using Osaka Cancer Registry data, we examined the prevalence, characteristics, and temporal trends of prior cancer in patients who received new diagnoses of lung, stomach, colorectal, female breast, cervical, and corpus uterine cancer between 2004 and 2015. Site-specific prior cancers were examined for a maximum of 15 years before the new cancer was diagnosed. Temporal trends were evaluated using the Cochran-Armitage trend test.

Results: Among 275,720 newly diagnosed cancer patients, 21,784 (7.9%) had prior cancer. The prevalence of prior cancer ranged from 3.3% (breast cancer) to 11.1% (lung cancer). In both sexes, the age-adjusted prevalence of prior cancer had increased in recent years (P values for trend < 0.001), especially in newly diagnosed lung cancer patients. The proportion of smoking-related prior cancers exceeded 50% in patients with newly diagnosed lung, stomach, colorectal, breast, and cervical cancer.

Conclusions: The prevalence of prior cancer in newly diagnosed cancer patients is relatively high, and has increased in recent years. Our findings suggest that a deeper understanding of the prevalence and characteristics of prior cancer in cancer patients is needed to promote more inclusive clinical research and support the expansion of treatment options.
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http://dx.doi.org/10.1186/s12885-021-08011-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948331PMC
March 2021

Interaction of Native- and Oxidized-Low-Density Lipoprotein with Human Estrogen Sulfotransferase.

Protein J 2021 Apr 4;40(2):192-204. Epub 2021 Mar 4.

Department of Pharmaceutical Health Science, Faculty of Pharmacy, Iryo Sosei University, 5-5-1, Chuodai-Iino, Iwaki, Fukushima, 970-8551, Japan.

Cytosolic estrogen sulfotransferase (SULT1E) mainly catalyzes the sulfate conjugation of estrogens, which decrease atherosclerosis progression. Recently we reported that a YKEG sequence in human SULT1E1 (hSULT1E1) corresponding to residues 61-64 can bind specifically to oxidized low-density lipoprotein (Ox-LDL), which plays a major role in the pathogenesis of atherosclerosis; its major oxidative lipid component lysophosphatidylcholine (LPC), and its structurally similar lipid, platelet-activating factor (PAF). In this study, we investigated the effect of Ox-LDL on the sulfating activity of hSULT1E1. In vivo experiments using a mouse model of atherosclerosis showed that the protein expression of SULT1E1 was higher in the aorta of mice with atherosclerosis compared with that in control animals. Results from a sulfating activity assay of hSULT1E1 using 1-hydroxypyrene as the substrate demonstrated that Ox-LDL, LPC, and PAF markedly decreased the sulfating activity of hSULT1E1, whereas native LDL and 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) as one of the oxidized phosphatidylcholines showed the opposite effect. The sulfating activity greatly changed in the presence of LPC, PAF, and POVPC in their concentration-dependen manner (especially above their critical micelle concentrations). Moreover, Ox-LDL specifically recognized dimeric hSULT1E1. These results suggest that the effects of Ox-LDL and native LDL on the sulfating activity of hSULT1E1 might be helpful in elucidating the novel mechanism underlying the pathogenesis of atherosclerosis, involving the relationship between estrogen metabolism, LDL, and Ox-LDL.
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http://dx.doi.org/10.1007/s10930-021-09971-yDOI Listing
April 2021

Catheter ablation for atrial fibrillation in patients with congestive heart failure.

Int J Cardiol 2021 Feb 27. Epub 2021 Feb 27.

Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

Background: We evaluated the 1-year success rate of maintaining sinus rhythm after catheter ablation (CA) for atrial fibrillation (AF) in patients with or without congestive heart failure (CHF).

Methods: In this single-centre retrospective matched-pair cohort study of 3,018 AF patients who underwent initial CA between January 2012 and June 2018, 227 pairs with (CHF group) or without CHF (control group) were matched using propensity scores. In the CHF group, 108 patients were assigned to the arrhythmia-induced cardiomyopathy (AIC) group whose left ventricular systolic dysfunction was explained only by lasting AF or atrial tachycardia; the remaining 119 had organic heart diseases (non-AIC group). We evaluated the 1-year AF-free survival and changes in clinical findings before and after CA.

Results: The CHF and control groups showed similar AF-free survival; however, AIC patients had significantly better survival than non-AIC patients. AF recurrence was significantly related to CHF re-hospitalisation, which was significantly more frequent in the non-AIC group than in the AIC group. The clinical outcomes of left atrial dilation, brain natriuretic peptide level, and left ventricular ejection function improved significantly before and after CA in both groups. The degree of improvement was significantly better in the AIC group than in the non-AIC group.

Conclusions: The 1-year success rate was not significantly different between the CHF and control groups. The 1-year success rate in the AIC group was similar to that in the AIC-control group and was better than that in the non-AIC group. CHF clinical outcomes were improved significantly.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.060DOI Listing
February 2021

Presence of non-pulmonary vein foci in patients with atrial fibrillation undergoing standard ablation of pulmonary vein isolation: Clinical characteristics and long-term ablation outcome.

Int J Cardiol Heart Vasc 2021 Feb 21;32:100717. Epub 2021 Jan 21.

Department of Cardiology, Tokyo Medical and Dental University, Tokyo, Japan.

Background: The clinical characteristics of atrial fibrillation (AF) resulting from non-pulmonary vein (PV) triggers remain unknown. This study aimed to evaluate the clinical characteristics of patients with AF caused by non-PV triggers, localization of non-PV foci, clinical differences, and clinical outcomes after catheter ablation in each AF focus.

Methods: A total of 2967 patients who underwent initial catheter ablation for paroxysmal or persistent AF were examined. After PV isolation, all patients underwent high-dose isoproterenol infusion to assess the existence of non-PV foci.

Results: Non-PV foci were identified in 564 patients (19.2%). The localization of successfully ablated non-PV foci in 514 patients were the superior vena cava (SVC: 213 cases), interatrial septum (IAS: 125 cases), coronary sinus (CS: 98 cases), right atrium (RA: 125 cases), left atrium (LA: 114 cases), and unmappable (50 cases). Multivariate analysis revealed that female gender, low body mass index (BMI), non-paroxysmal AF (PAF), and sick sinus syndrome were independent and significant indicators of non-PV foci. In the multivariate analysis of each AF focus, female gender, low BMI, and non-PAF were significant predictors of IAS and CS foci, RA and IAS foci, and CS foci, respectively. In addition, dilatation of the LA was significantly associated with LA foci, whereas RA, LA, IAS, and CS foci were associated with AF recurrence.

Conclusion: These findings could help to identify patients at a higher risk of AF caused by non-PV triggers and clarify the clinical difference according to the localization of non-PV foci.
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http://dx.doi.org/10.1016/j.ijcha.2021.100717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822950PMC
February 2021

Enhancement of Photosynthetic Iron-Use Efficiency Is an Important Trait of for Adaptation of Photosystems to Iron Deficiency.

Plants (Basel) 2021 Jan 25;10(2). Epub 2021 Jan 25.

Laboratory of Biochemistry in Plant Productivity, Department of Agricultural Chemistry, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, Japan.

Leaf iron (Fe) contents in Fe-deficiency-tolerant plants are not necessarily higher than that in Fe-deficiency-susceptible ones, suggesting an unknown mechanism involved in saving and allowing the efficient use of minimal Fe. To quantitatively evaluate the difference in Fe economy for photosynthesis, we compared the ratio of CO assimilation rate to Fe content in newly developed leaves as a novel index of photosynthetic iron-use efficiency (PIUE) among 23 different barley ( L.) varieties. Notably, varieties originating from areas with alkaline soil increased PIUE in response to Fe-deficiency, suggesting that PIUE enhancement is a crucial and genetically inherent trait for acclimation to Fe-deficient environments. Multivariate analyses revealed that the ability to increase PIUE was correlated with photochemical quenching (qP), which is a coefficient of light energy used in photosynthesis. Nevertheless, the maximal quantum yield of photosystem II (PSII) photochemistry, non-photochemical quenching, and quantum yield of carbon assimilation showed a relatively low correlation with PIUE. This result suggests that the ability of Fe-deficiency-tolerant varieties of barley to increase PIUE is related to optimizing the electron flow downstream of PSII, including cytochrome and photosystem I.
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http://dx.doi.org/10.3390/plants10020234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911540PMC
January 2021

Tenascin-C: an emerging prognostic biomarker in diabetes.

Ann Transl Med 2020 Dec;8(24):1699

Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

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http://dx.doi.org/10.21037/atm-2020-116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812241PMC
December 2020

Trends in survival of leukemia among children, adolescents, and young adults: A population-based study in Osaka, Japan.

Cancer Sci 2021 Mar 3;112(3):1150-1160. Epub 2021 Feb 3.

Cancer Control Center, Osaka International Cancer Institute, Osaka, Japan.

This study focused on children as well as adolescents and young adults (AYAs) and aimed to examine trends in survival of leukemia over time using population-based cancer registry data from Osaka, Japan. The study subjects comprised 2254 children (0-14 years) and 2,905 AYAs (15-39 years) who were diagnosed with leukemia during 1975-2011. Leukemia was divided into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and other leukemias. We analyzed 5-year overall survival probability (5y-OS), using the Kaplan-Meier method and expressed time trends using the joinpoint regression model. For recently diagnosed (2006-2011) patients, a Cox proportional hazards model was applied to determine predictors of 5y-OS, using age group, gender, and treatment hospital as covariates. Over the 37-year period, 5y-OS greatly improved among both children and AYAs, for each leukemia type. Among AYAs, 5y-OS of ALL improved, especially after 2000 (65% in 2006-2011), when the pediatric regimen was introduced but was still lower than that among children (87% in 2006-2011, P < .001). Survival improvement was most remarkable in CML, and its 5y-OS was over 90% among both children and AYAs after the introduction of molecularly targeted therapy with tyrosine kinase inhibitors. Among patients with recently diagnosed AML, the risk of death was significantly higher for patients treated at nondesignated hospitals than those treated at designated cancer care hospitals. The changes in survival improvement coincided with the introduction of treatment regimens or molecularly targeted therapies. Patient centralization might be one option which would improve survival.
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http://dx.doi.org/10.1111/cas.14808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935797PMC
March 2021

Occurrence of Methicillin-Resistant spp. on Brazilian Dairy Farms that Produce Unpasteurized Cheese.

Toxins (Basel) 2020 12 8;12(12). Epub 2020 Dec 8.

Faculdade de Ciências Agrárias e Veterinárias, UNESP-Universidade Estadual Paulista, Via de Acesso Paulo Castellane, s/n, Jaboticabal CEP 14884-900, Brazil.

Methicillin-resistant spp. (MRS) have been identified in several foods, including dairy products. Studies are needed about their occurrence and genetic diversity in the dairy production chain in order to gain a better understanding of their epidemiology and control. This study therefore focuses on isolating and characterizing MRS strains detected in milk used in the production of Brazilian artisanal unpasteurized cheeses. To this end, samples were collected from bovine feces, the hands of milkmen, milking buckets, sieves, unpasteurized milk, whey, water, artisanal unpasteurized cheeses, cheese processing surfaces, cheese handlers, cheese trays, cheese molds, and skimmers at five dairy farms located in the state of São Paulo, Brazil. Colonies suggestive of spp. were subjected to multiplex PCR to confirm the presence of and to detect the gene. Sixteen isolates containing gene were detected in samples from unpasteurized cheese and from cheese handlers. None of these isolates were positive to enterotoxin genes. These 16 isolates were subjected to antimicrobial susceptibility tests, which revealed they were resistant to oxacillin, penicillin, and cefepime. Using gene sequencing, the MRS isolates were identified as , and . Furthermore, isolates from cheese handlers' hands and artisanal unpasteurized cheese presented high genetic similarity by random amplified polymorphic DNA (RAPD-PCR) analysis, which indicates cross contamination during cheese production. Thus, we found that people directly involved in milking and cheese processing activities at small dairy farms are a potential source of contamination of MRS strains in unpasteurized milk and cheese, representing a risk to public health.
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http://dx.doi.org/10.3390/toxins12120779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762534PMC
December 2020

In vivo evaluation of coronary arteritis by serial optical coherence tomography in large vessel vasculitis.

Eur Heart J 2020 Dec 9. Epub 2020 Dec 9.

Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.

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http://dx.doi.org/10.1093/eurheartj/ehaa991DOI Listing
December 2020

What is this Image? 2020: Image 3 Result Pure septal myocardial infarction.

J Nucl Cardiol 2020 12;27(6):1915-1918

Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.

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http://dx.doi.org/10.1007/s12350-020-02416-6DOI Listing
December 2020

Association between the locations of non-pulmonary vein triggers and ablation outcomes in repeat procedures after cryoballoon ablation of paroxysmal atrial fibrillation.

J Interv Card Electrophysiol 2020 Nov 6. Epub 2020 Nov 6.

Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Purpose: We examined the characteristics of non-pulmonary vein (PV) triggers in repeat ablation after cryoballoon ablation for paroxysmal atrial fibrillation (PAF).

Methods: This study evaluated 119 patients undergoing a second ablation procedure for recurrent atrial tachyarrhythmia (ATA) after cryoballoon PV isolation (CB-PVI) for PAF.

Results: Fifty-three of 119 (45%) patients had PV reconnection. All reconnected PVs were isolated. No non-PV triggers were elicited in 42/119 (35%) patients (NNPV group). In 77/119 (65%) patients, 139 isoproterenol-induced non-PV triggers, including 45 triggers that initiated AF, were identified. Non-PV triggers initiating AF were observed at the superior vena cava (SVC), left atrial posterior wall (LAPW) including the PV antra, interatrial septum, right atrium, left atrial appendage/mitral anulus, and coronary sinus in 14 (12%), 10 (8%), 8 (7%), 7 (6%), 4 (3%), and 2 (2%) patients, respectively. Non-PV triggers originated from only the SVC and/or LAPW including the PV antra, and the SVC and/or LAPW was isolated in 18/119 (15%) patients (SVC/LAPW group). Non-PV triggers originating from other sites were focally ablated in 59/119 (50%) patients (OS group). During a median 461 days of follow-up, 39/42 (93%), 17/18 (94%), and 38/59 (64%) patients in the NNPV, SVC/LAPW, and OS groups, respectively, remained ATA recurrence-free. The recurrence rate was higher in the OS group than in the NNPV (P = 0.005) or SVC/LAPW groups (P = 0.042).

Conclusions: Over half of patients had non-PV triggers at subsequent ablation after CB-PVI. Non-PV triggers from the SVC/LAPW can be eliminated more successfully than triggers from other sites.
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http://dx.doi.org/10.1007/s10840-020-00913-9DOI Listing
November 2020

The impact of left atrium size on selection of the pulmonary vein isolation method for atrial fibrillation: Cryoballoon or radiofrequency catheter ablation.

Am Heart J 2021 01 22;231:82-92. Epub 2020 Oct 22.

Department of Cardiology, Sakakibara Heart Institute, 3-16-1 Asahicho, Fuchu-shi, Tokyo, Japan.

Background: Pulmonary vein isolation (PVI) is the cornerstone of ablation strategies for atrial fibrillation (AF), and noninferiority of cryoballoon (CB) over radiofrequency (RF) ablation has been previously reported. One of the risk factors of recurrence is left atrium (LA) enlargement. This study aimed to analyze the impact of LA enlargement on the selection of CB or RF ablation for AF patients.

Methods: A total of 2,224 AF patients (64.4 ± 10.7 years, 65.5% male) who underwent PVI were analyzed retrospectively. Left atrial diameter (LAD) and volume (LAV) were measured using echocardiography before the procedures. LA enlargement was defined as LAD ≥40 mm and LAV index (LAVI) ≥35 mL/m. Patients undergoing CB and RF ablation were propensity score matched, and 376 matched pairs were evaluated.

Results: Cox proportional hazard analysis revealed that LAD (95% CI, 1.01-1.05), LAV (95% CI, 1.01-1.02), and LAVI (95% CI, 1.01-1.03) were independent predictors of recurrence. CB showed equivalent clinical outcomes to those of RF with shorter procedure time required for patients without LA enlargement. CB was inferior to RF in patients with LA enlargement (LAD, 74.5% vs 84.6%, P = .028; LAVI, 74.7% vs 83.4%, P = .015), and large LAVI was associated with a higher prevalence of non-PV foci (35% vs 29%, P = .008).

Conclusions: CB ablation may be recommended for patients without enlarged LA based on the short procedure time and efficacy, whereas RF would be more appropriate in large LAs. LAVI may be a valuable reference to predict PVI outcomes and in selecting the ablation method.
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http://dx.doi.org/10.1016/j.ahj.2020.10.061DOI Listing
January 2021

Efficacy of Excimer Laser Coronary Angioplasty for Repeated In-Stent Restenosis With Neointimal Hyperplasia and Underexpanded Stent.

Circ J 2020 Nov 15;84(12):2322. Epub 2020 Oct 15.

Department of Cardiology, Faculty of Medicine, University of Tsukuba.

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http://dx.doi.org/10.1253/circj.CJ-20-0690DOI Listing
November 2020

In Vivo Evaluation of Tissue Protrusion by Using Optical Coherence Tomography and Coronary Angioscopy Immediately After Stent Implantation.

Circ J 2020 Nov 13;84(12):2235-2243. Epub 2020 Oct 13.

Department of Cardiology, Faculty of Medicine, University of Tsukuba.

Background: The relationship between the characteristics of tissue protrusion detected by using optical coherence tomography (OCT) and the findings of coronary angioscopy (CAS) immediately after stent implantation were evaluated.Methods and Results:A total of 186 patients (192 stents) underwent OCT before and after stenting and were observed by using CAS immediately after stenting and at the chronic phase. Patients were assigned to irregular protrusion, smooth protrusion, and disrupted fibrous tissue protrusion groups according to OCT findings. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured before and after stent implantation. The grade of yellow color (YC) and neointimal coverage (NC), and incidence of thrombus in the stented segment were evaluated by using CAS. After stent implantation, maximum YC grade (smooth, 0.64±0.80; disrupted fibrous tissue, 0.50±0.77; irregular, 1.50±1.09; P<0.0001), a prevalence of Max-YC grade of 2 or 3 (smooth, 17%; disrupted fibrous tissue, 17%; irregular, 50%; P<0.0001) and thrombus (smooth, 15%; disrupted fibrous tissue, 10%; irregular, 69%; P=0.0005), and elevated hs-CRP levels (smooth, 0.22±0.89; disrupted fibrous tissue, -0.05±0.29; irregular, 0.75±1.41; P=0.023) were significantly higher in irregular protrusion than in the other 2 groups. In the chronic phase, maximum- and minimum-NC grade and heterogeneity index, and thrombus did not differ significantly among the 3 groups.

Conclusions: Irregular protrusion was associated with atherosclerotic yellow plaque, incidence of thrombus, and vascular inflammation. The angioscopic findings in the chronic phase may endorse the clinical efficacy of second- and third-drug eluting stents, regardless of the tissue protrusion type.
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http://dx.doi.org/10.1253/circj.CJ-20-0306DOI Listing
November 2020

Trimebutine attenuates high mobility group box 1-receptor for advanced glycation end-products inflammatory signaling pathways.

Biochem Biophys Res Commun 2020 12 8;533(4):1155-1161. Epub 2020 Oct 8.

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan. Electronic address:

We previously identified papaverine as an inhibitor of receptor for advanced glycation end-products (RAGE) and showed its suppressive effect on high mobility group box 1 (HMGB1)-mediated responses to inflammation. Here, we found trimebutine to be a 3D pharmacophore mimetics of papaverine. Trimebutine was revealed to have more potent suppressive effects on HMGB1-induced production of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α in macrophage-like RAW264.7 cells and mouse bone marrow primarily differentiated macrophages than did papaverine. However, the inhibitory effect of trimebutine on the interaction of HMGB1 and RAGE was weaker than that of papaverine. Importantly, mechanism-of-action analyses revealed that trimebutine strongly inhibited the activation of RAGE downstream inflammatory signaling pathways, especially the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are mediator/effector kinases recruited to the intracellular domain of RAGE. Consequently, the activation of Jun amino terminal kinase, which is an important effector kinase for the up-regulation of pro-inflammatory cytokines, was inhibited. Taken together, these results suggest that trimebutine may exert its suppressive effect on the HMGB1-RAGE inflammatory signal pathways by strongly blocking the recruitment of ERK1/2 to the intracellular tail domain of RAGE in addition to its weak inhibition of the extracellular interaction of HMGB1 with RAGE. Thus, trimebutine may provide a unique scaffold for the development of novel dual inhibitors of RAGE for inflammatory diseases.
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http://dx.doi.org/10.1016/j.bbrc.2020.09.126DOI Listing
December 2020

Intracellular microRNA expression patterns influence cell death fates for both necrosis and apoptosis.

FEBS Open Bio 2020 Nov 22;10(11):2417-2426. Epub 2020 Oct 22.

Division of International Infectious Disease Control, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan.

MicroRNAs (miRNAs) are small noncoding RNA molecules that interact with target mRNAs at specific sites to induce cleavage of the mRNA or inhibit translation. Such miRNAs play a vital role in gene expression and in several other biological processes, including cell death. We have studied the mechanisms regulating cell death (necrosis in original F28-7 cells and apoptosis in their variant F28-7-A cells) in the mouse mammary tumor cell line FM3A using the anticancer agent floxuridine (FUdR). We previously reported that inhibition of heat-shock protein 90 by the specific inhibitor geldanamycin (GA) in F28-7 cells causes a shift from necrosis to apoptosis. In this study, we investigated the intracellular miRNA expression profiles of FUdR-treated F28-7 cells (necrotic condition), GA plus FUdR-treated F28-7 cells (apoptotic condition), and FUdR-treated F28-7-A cells (apoptotic condition) through miRNA microarray analysis. In addition, we knocked down Dicer, a key molecule for the expression of mature miRNAs, in F28-7 cells to examine whether it modulates FUdR-induced cell death. Our analysis revealed that the miRNA expression patterns differ significantly between these cell death conditions. Furthermore, we identified miRNA candidates that regulate cell death. Knockdown of Dicer in FUdR-treated necrosis-fated cells caused a partial shift from necrosis to apoptosis. These findings suggest that modulation of miRNA expression patterns influences the decision of cell death fate toward necrosis or apoptosis. Our findings may serve as a basis for further study of the functions of miRNAs in cell death mechanisms.
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http://dx.doi.org/10.1002/2211-5463.12995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609763PMC
November 2020

Antinociceptive activity of the novel RAGE inhibitor, papaverine, in a mouse model of chronic inflammatory pain.

Synapse 2021 Mar 2;75(3):e22188. Epub 2020 Oct 2.

Laboratory of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Japan.

Extracellular high-mobility group box 1 (HMGB1) is known to mediate the inflammatory response through pattern recognition receptors, including the receptor for advanced glycation end products (RAGE) or the toll-like receptors (TLRs). The aim of the present study was to investigate whether papaverine, a novel RAGE inhibitor, could suppress inflammatory pain in mice after several time points, which was induced by the injection of complete Freund's adjuvant (CFA). We also investigated the influence of redox modulation during a state of chronic inflammatory pain. Although papaverine did not suppress CFA-induced mechanical allodynia on Day 7, papaverine significantly suppressed CFA-induced mechanical allodynia on Days 14 and 28. In contrast, the radical scavenger N-tert-Butyl-α-phenylnitrone (PBN) suppressed mechanical allodynia in mice on Days 7 and 14, but not on Day 28. We demonstrated that the RAGE inhibitor improves mechanical allodynia in chronic inflammatory conditions. Moreover, we also found that high levels of reactive oxygen species (ROS) contributed to the early phase of CFA-induced mechanical allodynia. Precisely, lower ROS levels contributed to the inflammatory pain response via the all-thiol HMGB1/RAGE signaling pathway during the chronic state. These findings led us to propose that ROS levels modulate RAGE and/or TLR4-mediated inflammatory allodynia by regulating the concentrations of disulfide HMGB1 or all-thiol HMGB1.
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http://dx.doi.org/10.1002/syn.22188DOI Listing
March 2021

Potential risk of perioperative thromboembolism in patients with antiphospholipid syndrome who undergo transcatheter aortic valve implantation: A case series.

Catheter Cardiovasc Interv 2020 Sep 25. Epub 2020 Sep 25.

Faculty of Medicine, Department of Cardiology, University of Tsukuba, Tsukuba, Japan.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by a positive serum antiphospholipid antibody status. Patients with APS usually have an underlying hypercoagulable state, which can increase the risk of perioperative thromboembolism. We describe three patients with APS who underwent transcatheter aortic valve implantation for symptomatic severe aortic stenosis. Of them, two had complicated cerebrovascular events, and the other had no complications. Careful antithrombotic management is essential to minimize the risk of thromboembolism and bleeding in patients with APS.
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http://dx.doi.org/10.1002/ccd.29300DOI Listing
September 2020

Incidental Myocardial Reduction for Hypertrophic Obstructive Cardiomyopathy With Acute Myocardial Infarction.

JACC Cardiovasc Interv 2020 10 26;13(20):2440-2443. Epub 2020 Aug 26.

Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

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http://dx.doi.org/10.1016/j.jcin.2020.06.051DOI Listing
October 2020

Anticancer Strategy Targeting Cell Death Regulators: Switching the Mechanism of Anticancer Floxuridine-Induced Cell Death from Necrosis to Apoptosis.

Int J Mol Sci 2020 Aug 16;21(16). Epub 2020 Aug 16.

Division of International Infectious Disease Control, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.

Cell death can be broadly characterized as either necrosis or apoptosis, depending on the morphological and biochemical features of the cell itself. We have previously reported that the treatment of mouse mammary carcinoma FM3A cells with the anticancer drug floxuridine (FUdR) induces necrosis in the original clone F28-7 but apoptosis in the variant F28-7-A. We have identified regulators, including heat shock protein 90, lamin-B1, cytokeratin-19, and activating transcription factor 3, of cell death mechanisms by using comprehensive gene and protein expression analyses and a phenotype-screening approach. We also observed that the individual inhibition or knockdown of the identified regulators in F28-7 results in a shift from necrotic to apoptotic morphology. Furthermore, we investigated microRNA (miRNA, miR) expression profiles in sister cell strains F28-7 and F28-7-A using miRNA microarray analyses. We found that several unique miRNAs, miR-351-5p and miR-743a-3p, were expressed at higher levels in F28-7-A than in F28-7. Higher expression of these miRNAs in F28-7 induced by transfecting miR mimics resulted in a switch in the mode of cell death from necrosis to apoptosis. Our findings suggest that the identified cell death regulators may play key roles in the decision of cell death mechanism: necrosis or apoptosis.
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http://dx.doi.org/10.3390/ijms21165876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461588PMC
August 2020