Publications by authors named "Makoto Abe"

104 Publications

Renal Dysfunction as a Predictor of Slow-Flow/No-Reflow Phenomenon and Impaired ST Segment Resolution After Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction With Initial Thrombolysis in Myocardial Infarction Grade 0.

Circ J 2021 Jul 20. Epub 2021 Jul 20.

Department of Cardiology, Fujieda Municipal General Hospital.

Background: The slow-flow/no-reflow phenomenon and impaired ST segment resolution (STR) following primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI) predict unfavorable prognosis and are characterized by obstruction of the coronary microvascular. Several predictors of slow-flow/no-reflow have been revealed, but few studies have investigated predictors of slow-flow/no-reflow and STR exclusively in acute myocardial infarction patients with initial Thrombolysis in Myocardial Infarction (TIMI) Grade 0.Methods and Results:In all, 279 STEMI patients with initial TIMI Grade 0 were enrolled in the study. Slow-flow/no-reflow was defined as TIMI Grade <3 by angiography after PCI, and impaired STR was defined as STR <50% on an electrocardiogram after PCI. Slow-flow/no-reflow was observed in 31 patients. In multivariate analysis, estimated glomerular filtration rate (eGFR; odds ratio [OR] 0.97; P=0.007), a history of cerebrovascular disease (OR 4.65, P=0.007), time to recanalization ≥4 h (OR 2.76, P=0.023), and systolic blood pressure ≤90 mmHg (OR 3.45, P=0.046) were independent predictors of slow-flow/no-reflow. Impaired STR was observed in 102 of 248 patients with TIMI Grade 3. In multivariate analysis, eGFR (OR 0.94, P<0.001) and occlusion of the left anterior descending artery (OR 4.48, P<0.001) were independent predictors of impaired STR; eGFR was the only independent predictor of both slow-flow/no-reflow and impaired STR.

Conclusions: Renal dysfunction may be related to coronary microvascular dysfunction and obstruction.
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http://dx.doi.org/10.1253/circj.CJ-21-0221DOI Listing
July 2021

Assessing the Prognostic Value of Extranodal Extension in Esophageal Cancer from the Pathological Staging Perspective.

J Invest Surg 2021 Jun 6:1-9. Epub 2021 Jun 6.

Department of Surgery, Tochigi Cancer Center Hospital, Utsunomiya, Tochigi, Japan.

Background: Extranodal extension (ENE) is a prognostic factor for several types of malignant tumors, including esophageal cancer. Although the prognostic value of ENE has been investigated in esophageal cancer, its clinical utility warrants further investigation.

Materials And Methods: This retrospective single-center study evaluated 105 patients who underwent esophagectomy and had histologically node-positive metastasis between January 2007 and June 2017. The abilities of ENE to predict overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method and log-rank test, as well as Cox proportional hazard models. Subgroup analyses of ENE's prognostic value were performed according to each pathological tumor-node-metastasis category.

Results: Significant differences according to ENE status were observed in the Kaplan-Meier analyses of OS ( = 0.001) and DFS ( = 0.001), as well as in the Cox proportional hazards models for OS ( = 0.009) and DFS ( = 0.012). Relative to patients without ENE, patients with ENE had significantly poorer OS if they also had pT3 status, pN1 status, or pathological stage III disease. However, no significant differences were observed in the subgroup analyses of pN3 status and pathological stage IV disease.

Conclusions: Among patients with esophageal cancer, ENE status can predict a poor prognosis and may be useful for patient stratification. However, the prognostic value of ENE status may be limited to patients with specific pathological factors.
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http://dx.doi.org/10.1080/08941939.2021.1912221DOI Listing
June 2021

Senescence-accelerated mouse prone 8 (SAMP8) mice exhibit reduced entoconid in the lower second molar.

Arch Oral Biol 2021 Aug 27;128:105172. Epub 2021 May 27.

Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, Yamada-oka 1-8, Suita, Osaka, Japan. Electronic address:

Objective: The position and size of the major cusps in mammalian molars are arranged in a characteristic pattern that depends on taxonomy. In humans, the cusp which locates distally within each molar is smaller than the mesially located cusp, which is referred to as "distal reduction". Although this concept has been well-recognized, it is still unclear how this reduction occurs. Current study examined whether senescence-accelerating mouse prone 8 (SAMP8) mice could be a possible animal model for studying how the mammalian molar cusp size is determined.

Design: SAMP8 mice were compared with parental control (SAMR1) mice. Microcomputed tomography images of young and aged mice were captured to observe molar cusp morphologies. Cusp height from cement-enamel junction and mesio-distal length of molars were measured. The statistical comparison of the measurements was performed by Mann-Whitney U test.

Results: SAMP8 mice showed reduced development of the disto-lingual cusp (entoconid) of lower second molar when compared with SAMR1 mice. The enamel thickness and structure was disturbed at entoconid, and aged SAMP8 mice displayed severe wear of the entoconid in lower second molar. These phenotypes were observed on both sides of the lower second molar.

Conclusions: In addition to the general senescence phenotype observed in SAMP8 mice, this strain may genetically possess molar cusp phenotypes which is determined prenatally. Further, SAMP8 mice would be a potential model strain to study the genetic causes of the distal reduction of molar cusp size.
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http://dx.doi.org/10.1016/j.archoralbio.2021.105172DOI Listing
August 2021

Transoral surgery for superficial head and neck cancer: National Multi-Center Survey in Japan.

Cancer Med 2021 Jun 15;10(12):3848-3861. Epub 2021 May 15.

Department of Gastroenterology, Kobe City Medical Center General Hospital, Kobe, Japan.

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.
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http://dx.doi.org/10.1002/cam4.3927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209601PMC
June 2021

Linked Color Imaging (LCI) Emphasizes the Color Changes in the Gastric Mucosa After Helicobacter pylori Eradication.

Dig Dis Sci 2021 May 12. Epub 2021 May 12.

Department of Gastroenterology and Hepatology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-Ku, Okayama, 700-8558, Japan.

Background: Diffuse redness is a characteristic endoscopic finding that indicates current infection of Helicobacter pylori, which is reduced after successful eradication. Linked color imaging (LCI) has been reported to improve the visibility of diffuse redness compared to white light imaging (WLI); however, quantitative evaluation has not been reported.

Aims: This study aimed to objectively evaluate the color change of the gastric mucosa after H. pylori eradication.

Methods: Images of the greater curvature of the antrum and corpus were captured, and the sites were biopsied during esophagogastroduodenoscopy (EGD) before and 1 year after eradication. The region of interest (ROI) was set around the biopsied area on the images. The color difference (ΔE) before and after eradication was calculated using the CIE L*a*b* color space. The association between the histological evaluation and the color value of the corresponding ROI was determined.

Results: At the antrum, there was no significant color change with either mode. At the corpus, the a* value, which reflected redness, decreased significantly after eradication with both modes (WLI: 41.2 to 36.0, LCI: 37.5 to 25.5); the b* value, reflecting yellowish, decreased with WLI, but increased significantly with LCI (WLI: 44.6 to 41.6, LCI: 23.9 to 29.2). The ΔE was significantly larger with LCI than with WLI (16.5 vs. 8.6). The a* values at the corpus were generally associated with histological neutrophil infiltration.

Conclusions: Quantitative evaluation revealed that LCI emphasizes the change in color of the gastric mucosa due to the reduction in diffuse redness.
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http://dx.doi.org/10.1007/s10620-021-07030-1DOI Listing
May 2021

Effects of empagliflozin in different phases of diabetes mellitus-related cardiomyopathy: a prospective observational study.

BMC Cardiovasc Disord 2021 Apr 29;21(1):217. Epub 2021 Apr 29.

Department of Cardiology, Fujieda Municipal General Hospital, Surugadai 4-1-11, Fujieda, Shizuoka, 426-8677, Japan.

Background: Diabetes mellitus-related cardiomyopathy (DMCMP), defined as left ventricular (LV) dysfunction caused by hyperglycemia in the absence of coronary artery disease, leads to heart failure (HF). Previous studies have shown that treatment with sodium-glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of exacerbation of HF. The beneficial effects of SGLT2i on HF depend not only on indirect actions such as osmotic diuresis but also on direct actions on the myocardium, leading to improvements in LV function. However, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this observational study was to compare the efficacy of SGLT2i treatment on LV dysfunction between early and advanced DMCMP.

Methods: Thirty-five symptomatic non-ischemic HF patients with LV ejection fraction > 40% and type 2 diabetes mellitus (T2DM) treated with empagliflozin (EMPA group) and 20 controls treated without SGLT2i were enrolled. According to the myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis quantified by cardiac magnetic resonance, the EMPA group was further divided into early DMCMP (n = 16, ECV ≤ 30%) and advanced DMCMP (n = 19, ECV > 30%) groups and followed up prospectively. Echocardiography was performed at baseline and after 12 months. LV function assessed as LV global longitudinal strain (LVGLS) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e') were compared.

Results: ECV was strongly correlated with T2DM duration (r = 0.65, p < 0.001). At baseline, each group had a similar background. After 12 months, the EMPA group, especially the early DMCMP group, showed remarkable improvements in LVGLS (ΔLVGLS: 2.9 ± 3.0% (EMPA) vs. 0.6 ± 2.2% (controls), p = 0.005, and 4.6 ± 1.5% (early DMCMP) vs. 1.6 ± 3.3% (advanced DMCMP), p = 0.003) and E/e' (ΔE/e': - 1.5 ± 4.7 vs. - 0.3 ± 3.0, p = 0.253, and - 3.4 ± 5.5 vs. - 0.1 ± 3.5, p = 0.043).

Conclusions: The positive effects of empagliflozin on LV dysfunction were more remarkable in early than in advanced DMCMP. Early intervention of SGLT2i for DMCMP may be preferable.
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http://dx.doi.org/10.1186/s12872-021-02024-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086321PMC
April 2021

Gastric Adenoma: A High Incidence Rate of Developing Carcinoma and Risk of Metachronous Gastric Cancer according to Long-Term Follow-Up.

Digestion 2021 Apr 9:1-9. Epub 2021 Apr 9.

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.

Introduction: Gastric adenomas are histologically defined as benign epithelial tumors. While some of them remain adenomas for a long time, others progress to carcinomas. However, long-term outcomes of such cases are not entirely clear. Here, we explored the risk factors and incidence of developing carcinoma from gastric adenoma as well as metachronous gastric cancer.

Methods: This study was conducted at a facility that adopted a follow-up strategy for gastric adenoma. Lesions histologically diagnosed as gastric intestinal-type adenomas between January 2004 and December 2016 were analyzed. Clinicopathological data were collected from patients' medical records, and histological changes from adenoma to carcinoma during endoscopic follow-up and risk factors of cancer development were evaluated.

Results: This study involved 409 lesions from 376 patients. The analysis of the development of gastric cancer from adenoma and metachronous gastric cancer was ultimately performed for 282 lesions from 258 patients and 269 lesions from 246 patients, respectively, due to different follow-up periods. The 5-year rate of carcinoma development was 34.0%. Risk factors for carcinoma development upon multivariate analysis were lesion size ≥15 mm and morphological depression. All cases with both factors developed gastric carcinoma, and 50.5% of those with either factor developed carcinoma within 5 years. Gastric adenoma was accompanied by metachronous gastric cancer in 1.5% of the patients annually. The only risk factor for metachronous gastric carcinoma was primary adenoma progressing to carcinoma during the follow-up period.

Discussion/conclusion: Given the high rate of carcinoma development in patients with risk factors, resection of gastric adenoma should be considered during the initial examination. Careful observation and follow-up should also be conducted to detect not only changes in the primary adenoma but also the occurrence of metachronous carcinoma, especially in cases of adenoma progressing to carcinoma.
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http://dx.doi.org/10.1159/000515213DOI Listing
April 2021

Painful Left Bundle Branch Block Syndrome Complicated by Iron-Overload Cardiomyopathy.

Intern Med 2021 Mar 22. Epub 2021 Mar 22.

Department of Cardiology, Fujieda Municipal General Hospital, Japan.

Painful left bundle branch block (LBBB) syndrome is a rare disease that presents as simultaneous chest pain and transient LBBB without myocardial ischemia. We diagnosed a 72-year-old Japanese man with painful LBBB syndrome complicated by iron-overload cardiomyopathy. Phlebotomy was initially performed to improve myocardial iron deposition and conductive disturbance. Ironically, his chest pain was fully improved by the completion of incessant LBBB and walk-through phenomenon. However, this case demonstrates a clinically significant therapeutic strategy for cardiomyopathy-induced painful LBBB syndrome. Due to the lack of treatment guidelines, individualized treatment is required for each case of painful LBBB.
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http://dx.doi.org/10.2169/internalmedicine.7052-21DOI Listing
March 2021

Tracheobronchial Obstruction Due to Blood Clots in Acute Pulmonary Embolism with Cardiac Arrest Managed with Extracorporeal Membrane Oxygenation.

Intern Med 2021 Mar 15. Epub 2021 Mar 15.

Department of Cardiology, Fujieda Municipal General Hospital, Japan.

A 66-year-old Japanese woman developed pulseless electrical activity following an acute pulmonary embolism and was treated with thrombolytic therapy. She remained hemodynamically unstable and therefore underwent extracorporeal membrane oxygenation (ECMO). While receiving treatment with ECMO, blood clots induced by endobronchial hemorrhage caused tracheobronchial airway obstruction, leading to ventilatory defect. Furthermore, her cardiac function improved, resulting in cerebral hypoxemia progression. Therefore, the blood clots were removed with a Fogarty balloon catheter and endobronchial urokinase administration, resulting in improvement in her respiratory condition. Finally, ECMO was decannulated, and the patient was discharged from our hospital without difficulties in her activities of daily living.
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http://dx.doi.org/10.2169/internalmedicine.6856-20DOI Listing
March 2021

Effect of Empagliflozin as an Add-On Therapy on Decongestion and Renal Function in Patients With Diabetes Hospitalized for Acute Decompensated Heart Failure: A Prospective Randomized Controlled Study.

Circ Heart Fail 2021 03 5;14(3):e007048. Epub 2021 Mar 5.

Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan (S.T., S.S., A.S.).

Background: Empagliflozin reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and cardiovascular disease. We sought to elucidate the effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with type 2 diabetes admitted for acute decompensated heart failure.

Methods: The study was terminated early due to COVID-19 pandemic. We enrolled 59 consecutive patients with type 2 diabetes admitted for acute decompensated heart failure. Patients were randomly assigned to receive either empagliflozin add-on (n=30) or conventional glucose-lowering therapy (n=29). We performed laboratory tests at baseline and 1, 2, 3, and 7 days after randomization. Percent change in plasma volume between admission and subsequent time points was calculated using the Strauss formula.

Results: There were no significant baseline differences in left ventricular ejection fraction and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), hematocrit, or serum creatinine levels between the 2 groups. Seven days after randomization, NT-proBNP level was significantly lower in the empagliflozin group than in the conventional group (=0.040), and hemoconcentration (≥3% absolute increase in hematocrit) was more frequently observed in the empagliflozin group than in the conventional group (=0.020). The decrease in percent change in plasma volume between baseline and subsequent time points was significantly larger in the empagliflozin group than in the conventional group 7 days after randomization (=0.017). The incidence of worsening renal function (an increase in serum creatinine ≥0.3 mg/dL) did not significantly differ between the 2 groups.

Conclusions: In this exploratory analysis, empagliflozin achieved effective decongestion without an increased risk of worsening renal function as an add-on therapy in patients with type 2 diabetes with acute decompensated heart failure. Registration: URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000026315.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007048DOI Listing
March 2021

Rate Versus Rhythm Control in Tachycardia-Induced Cardiomyopathy Patients with Persistent Atrial Flutter.

Int Heart J 2021 ;62(1):119-126

Department of Cardiology, Fujieda Municipal General Hospital.

Tachycardia-induced cardiomyopathy (TIC) is a potentially reversible cardiomyopathy caused by tachyarrhythmia. For atrial flutter (AFL) -induced TIC, a rhythm control strategy, such as catheter ablation, has been recommended. However, the efficacy of rate control has remained unclear due to the difficulty of achieving control using arrhythmic medications.We prospectively assessed 47 symptomatic heart failure (HF) patients with left ventricular ejection fraction (LVEF) < 50% and suspected persistent AFL-induced TIC. Patients were divided into the rhythm control strategy (n = 22; treatment with catheter ablation or electrical cardioversion) and rate control strategy (n = 25; treatment with bisoprolol) groups. The latter was further divided into the strict rate control strategy (average heart rate < 80 bpm) and lenient rate control strategy (average heart rate < 110 bpm) subgroups. The primary outcome was left ventricular (LV) function recovery, which was defined as an increase in LVEF ≥ 20% or to a value of ≥ 55% after 6 months.In the rhythm control strategy group, more patients achieved LV function recovery after 6 months (95.2% versus 60.9%, P = 0.010). The cumulative incidence of worsening HF events was significantly higher in the rate control strategy group than in the rhythm control strategy group (hazard ratio, 4.66; 95% confidence interval, 1.01-21.57). The subgroup study revealed the advantage of the strict rate control strategy for achieving LV function recovery (83.3% versus 36.4%, P = 0.036).The rate control strategy was significantly inferior to the rhythm control strategy for the LV function recovery in TIC patients with persistent AFL. Our findings suggest that the strict rate control strategy should be aimed if the rhythm control strategy cannot be performed.
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http://dx.doi.org/10.1536/ihj.20-266DOI Listing
February 2021

Risk Factors for Gastric Cancer after the Eradication of Helicobacter pylori Evaluated Based on the Background Gastric Mucosa: A Propensity Score-matched Case-control Study.

Intern Med 2021 Apr 9;60(7):969-976. Epub 2020 Nov 9.

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.

Objective The eradication of Helicobacter pylori (H. pylori) reduces the risk for gastric cancer (GC) development, but it cannot prevent GC completely. We investigated the risk factors of early GC development after the eradication of H. pylori, based on the histological characteristics of gastric mucosa. Methods Sixty-one patients who underwent endoscopic submucosal dissection for early GC after successful H. pylori eradication (Group A) and 122 patients without developing a gastric neoplasm over 3 years after successful H. pylori eradication (Group B) were analyzed. We compared the histological findings of the patients enrolled in Group A and Group B before and after the propensity score-matching. Results Comparing the characteristics of two the groups, Group A consisted predominantly of males, had significantly more elderly patients, and the years after successful eradication tended to be longer. We performed score matching for these three factors to reduce the influence of any confounding factors. After matching, the scores of inflammation for Group A (n=54) was significantly higher than those of Group B (n=54) at the greater curvature of the antrum, the lesser curvature of the corpus, and the greater curvature of the corpus. According to a multivariate analysis, inflammation of the greater curvature of the antrum and lesser curvature of the corpus were found to be independent risk factors. The risk ratio and 95% CI were 5.92 (2.11-16.6) (p<0.01), and 3.56 (1.05-13.2) (p=0.04), respectively. Conclusion A continuous high level of inflammation of the background gastric mucosa may be a risk factor for gastric cancer onset after H. pylori eradication.
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http://dx.doi.org/10.2169/internalmedicine.5486-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079910PMC
April 2021

An autopsy case report of extensive intramyocardial hemorrhage complicated with acute myocardial infarction.

J Cardiol Cases 2020 Sep 24;22(3):121-124. Epub 2020 Jun 24.

Department of Cardiology, Fujieda Municipal General Hospital, Japan.

Hemorrhagic myocardial infarction (HMI) is a complication associated with percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). We carried out a successful PCI for a 59-year old Japanese man presenting with chest pain due to AMI over 5 h. The onset to balloon time was 363 min. The next morning, he suffered cardiogenic shock, even with an auxiliary circulating device, which eventually resulted in death. An autopsy revealed extensive HMI. The necrotic myocardium showed not only coagulation necrosis but also contraction band necrosis which suggests myocardial injury due to late reperfusion. Although the intramyocardial hemorrhage was confined to the necrotic area, it was beyond the perfusion area of the culprit artery. Here, we describe a case of death with severe HMI. HMI can be a serious complication and worsen prognosis. < The aim of primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) is to recanalize the infarct related artery and salvage the ischemic myocardium. However, late reperfusion sometimes leads to hemorrhagic myocardial infarction (HMI) as a result of myocardial injury. To avoid extensive HMI in AMI patients, primary PCI should be performed as soon as possible.>.
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http://dx.doi.org/10.1016/j.jccase.2020.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452321PMC
September 2020

Kruppel-like factor 4 upregulates matrix metalloproteinase 13 expression in chondrocytes via mRNA stabilization.

Cell Tissue Res 2020 Nov 15;382(2):307-319. Epub 2020 Jun 15.

Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Matrix metalloproteinase 13 (MMP13) is indispensable for normal skeletal development and is also a principal proteinase responsible for articular joint pathologies. MMP13 mRNA level needs to be tightly regulated in both positive and negative manners to achieve normal development and also to prevent joint destruction. We showed previously that Kruppel-like factor 4 (KLF4) strongly induces the expression of members of the MMP family of genes including that for MMP13 in cultured chondrocytes. Through expression-based screening of approximately 400 compounds, we identified several that efficiently downregulated MMP13 gene expression induced by KLF4. Compounds grouped as topoisomerase inhibitors (transcriptional inhibitors) downregulated MMP13 expression levels, which proved the validity of our screening method. In this screening, trichostatin A (TSA) was identified as one of the most potent repressors. Mechanistically, increased MMP13 mRNA levels induced by KLF4 were not mainly caused by increased rates of RNA polymerase II-mediated MMP13 transcription, but arose from escaping mRNA decay. TSA treatment almost completely blunted the effect of KLF4. Importantly, KLF4 was detected in chondrocytes at the joint destruction sites in a rodent model of osteoarthritis. Our results partially explain how KLF4 regulates numerous proteinase gene expressions simultaneously in chondrocytes. Also, these observations suggest that modulation of KLF4 activity or expression could be a novel therapeutic target for osteoarthritis.
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http://dx.doi.org/10.1007/s00441-020-03228-3DOI Listing
November 2020

Prospective Comparison of Intraoperative Touch Imprint Cytology and Frozen Section Histology on Axillary Sentinel Lymph Nodes in Early Breast Cancer Patients.

Acta Cytol 2020 25;64(5):492-497. Epub 2020 May 25.

Department of Pathology, Tajimi City Hospital, Tajimi, Japan.

Introduction: Since the late 1970s, sentinel lymph node biopsy (SLNB) has been used for several solid malignancies to identify lymph node metastases. This procedure is associated with less surgical morbidity than complete lymphadenectomy. Recent evidence suggests that axillary lymphadenectomy is not required for breast sentinel nodes with micrometastases (≤2 mm). Current clinical management of sentinel nodes indicates that only macrometastases (>2 mm) should be detected intraoperatively. In Japan, an intraoperative histopathological frozen section (FS) method is used to identify lymph node metastases, but this method takes more than 30 min and requires complex techniques and expensive equipment. Touch imprint cytology (TIC) is an easier, less expensive, and faster method, but its sensitivity has been shown to be low.

Objective: The purpose of this study was to determine if TIC is more useful than FS in identifying macrometastases in sentinel lymph nodes in preoperative node-negative breast cancer operations.

Methods: A prospective review of 49 consecutive patients with node-negative breast cancer treated with SLNB and intraoperative TIC and FS between November 2017 and June 2019 was performed. TIC samples were stained using Papanicolaou and Diff-Quick stains. Results were compared with routine postoperative paraffin sections.

Results: With TIC, the Papanicolaou stain took a mean of 12 min, and the Diff-Quick stain took a mean of 10 min. Results of both TIC stain methods were the same. In contrast, the FS method took a mean of 80 min (including the transfer of specimens to a different hospital with the necessary equipment). TIC confirmed macrometastases in 5 cases. All macrometastases were diagnosed equally by the 2 techniques. Both the sensitivity and specificity of TIC were 100% for detection of macrometastases.

Conclusion: TIC of SLNB for breast cancer is an easy and useful method for the detection of macrometastases of breast sentinel nodes.
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http://dx.doi.org/10.1159/000508016DOI Listing
September 2020

Impact of adjunctive tolvaptan on sympathetic activity in acute heart failure with preserved ejection fraction.

ESC Heart Fail 2020 06 3;7(3):933-937. Epub 2020 Apr 3.

Division of Cardiology, Osaka General Medical Center, Osaka, Japan.

Aims: Acute decompensated heart failure (ADHF) is generally treated by decongestion using diuretic therapy. However, the use of loop diuretics is associated with increased cardiac sympathetic nerve activity (CSNA). We aimed to evaluate the effect of adjunctive tolvaptan therapy on CSNA in ADHF patients with preserved left ventricular ejection fraction (LVEF).

Methods And Results: We enrolled 51 consecutive ADHF patients with LVEF ≥45%. Patients were randomly assigned to receive either tolvaptan add-on (n = 25) or conventional diuretic therapy (n = 26). Cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging was performed after stabilisation of heart failure symptoms, and the cardiac MIBG heart-to-mediastinum ratio (HMR) and washout rate (WR) were calculated. There were no significant differences in the body weight change and total urine volume during 2 days after randomisation or in the HMR on delayed image (HMR(d)) and WR between the tolvaptan and conventional groups. After stratification based on the median change in body weight, the patients with higher weight reduction had a significantly lower HMR(d) (P = 0.0128) and tended to have a higher WR (P = 0.0786) in the conventional group, whereas the cardiac MIBG imaging results were not influenced by body weight reduction in the tolvaptan group.

Conclusions: Adjunctive tolvaptan therapy may provide rapid decongestion without a harmful effect on CSNA in ADHF patients with preserved LVEF.
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http://dx.doi.org/10.1002/ehf2.12690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261536PMC
June 2020

The plasma supply in Japan.

Transfus Apher Sci 2020 Apr 28;59(2):102749. Epub 2020 Feb 28.

Akita Red Cross Blood Center, Japan.

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http://dx.doi.org/10.1016/j.transci.2020.102749DOI Listing
April 2020

Prognostic significance of cardiac I-123-metaiodobenzylguanidine imaging in patients with reduced, mid-range, and preserved left ventricular ejection fraction admitted for acute decompensated heart failure: a prospective study in Osaka Prefectural Acute Heart Failure Registry (OPAR).

Eur Heart J Cardiovasc Imaging 2021 01;22(1):58-66

Division of Cardiology, Osaka General Medical Center, 3-1-56, Mandai-Higashi, Sumiyoshi-ku, Osaka 558-8558, Japan.

Aims: Cardiac 123I-metaiodobenzylguanidine (123I-MIBG) imaging provides prognostic information in patients with chronic heart failure (HF). However, there is little information available on the prognostic role of cardiac 123I-MIBG imaging in patients admitted for acute decompensated heart failure (ADHF), especially relating to reduced ejection fraction [HFrEF; left ventricular ejection fraction (LVEF) < 40%], mid-range ejection fraction (HFmrEF; 40% ≤ LVEF < 50%) and preserved ejection fraction (HFpEF; LVEF ≥ 50%).

Methods And Results: We studied 349 patients admitted for ADHF and discharged with survival. Cardiac 123I-MIBG imaging, echocardiography, and venous blood sampling were performed just before discharge. The cardiac 123I-MIBG heart-to-mediastinum ratio (late H/M) was measured on the chest anterior view images obtained at 200 min after the isotope injection. The endpoint was cardiac events defined as unplanned HF hospitalization and cardiac death. During a follow-up period of 2.1 ± 1.4 years, 128 patients had cardiac events (45/127 in HFrEF, 28/78 in HFmrEF, and 55/144 in HFpEF). On multivariable Cox analysis, late H/M was significantly associated with cardiac events in overall cohort (P = 0.0038), and in subgroup analysis of each LVEF subgroup (P = 0.0235 in HFrEF, P = 0.0119 in HFmEF and P = 0.0311 in HFpEF). Kaplan-Meier analysis showed that patients with low late H/M (defined by median) had significantly greater risk of cardiac events in overall cohort (49% vs. 25% P < 0.0001) and in each LVEF subgroup (HFrEF: 48% vs. 23% P = 0.0061, HFmrEF: 51% vs. 21% P = 0.0068 and HFpEF: 50% vs. 26% P = 0.0026).

Conclusion: Cardiac sympathetic nerve dysfunction was associated with poor outcome in ADHF patients irrespective of HFrEF, HFmrEF, or HFpEF.
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http://dx.doi.org/10.1093/ehjci/jeaa025DOI Listing
January 2021

Tolerability and efficacy of the concentration of iodine solution during esophageal chromoendoscopy: a double-blind randomized controlled trial.

Gastrointest Endosc 2020 04 25;91(4):763-770. Epub 2019 Oct 25.

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Department of Endoscopy, Okayama University Hospital, Okayama, Japan.

Background And Aims: Esophageal chromoendoscopy with iodine solution is an important diagnostic method for the detection of superficial esophageal cancer. However, the concentration of iodine solution has differed among reports. This study aimed to evaluate patient discomfort with different iodine concentrations.

Methods: We performed a prospective, double-blind, randomized study. We prospectively enrolled and analyzed 77 patients who were at high risk for esophageal carcinoma and scheduled to undergo EGD from March 2018 to January 2019. All patients were divided into 2 groups before the procedure to compare pain measurements: a 1% iodine solution group (group A) and a 2% iodine solution group (group B). The primary endpoint of this study was the difference in pain measurement between 1% and 2% iodine solution chromoendoscopy. Secondary endpoints were safety, detection yield, and color evaluation based on both the endoscopist's survey and color values, as determined using the Commission Internationale de l'Eclairage (CIELAB, Vienna, Austria) color evaluation system, in the iodine-faded and iodine-stained area of each group.

Results: Heartburn and retrosternal pain in group A were significantly lower than those in group B (P = .02). Eleven patients reported heartburn and retrosternal pain (group A, 2; group B, 9). Four patients reported pain above the sternal angle and 7 below the sternal angle. There was no significant difference between the 2 groups with regard to detection yield, color evaluation by the endoscopist's assessment, or color values. No patients had any adverse events, and all safely completed this study.

Conclusions: The 2% iodine solution resulted in significantly greater pain than the 1% iodine solution, and the color of the stained esophageal images of each group was the same from this study. Therefore, the 1% iodine solution is recommended for esophageal chromoendoscopy. (Clinical trial registration number: UMIN 000029796.).
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http://dx.doi.org/10.1016/j.gie.2019.10.022DOI Listing
April 2020

Evaluation of the Usefulness and Convenience of the Kyoto Classification of Gastritis in the Endoscopic Diagnosis of the Helicobacter pylori Infection Status.

Digestion 2020 19;101(6):771-778. Epub 2019 Sep 19.

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background/aims: The Kyoto Classification of Gastritis was published in 2014. Although this classification is now widely used in Japan, its usefulness and convenience have not been sufficiently evaluated. This study aimed to evaluate the usefulness and convenience of this classification in the endoscopic diagnosis of Helicobacter pylori infection.

Methods: We made a test for the endoscopic diagnosis of H. pylori infection comprising 30 cases who had representative endoscopic features of non-, active, or inactive gastritis. Thirty-eight participants took the test before and after a brief mini-lecture on the Kyoto Classification of Gastritis. Eighteen participants took the test again 3 months later. We investigated the accuracy before, just after, and 3 months after the mini-lecture.

Results: The accuracy of endoscopists after the lecture was significantly improved in comparison to before the lecture (77.6 vs. 83.3%). Medical students also showed significantly improved accuracy after the lecture (56.7 vs. 71.7%). Among endoscopists, this improvement was maintained after 3 months. Before the lecture, the accuracy of diagnosing non-gastritis was 90.3%; it tended to be further improved 3 months later (96.5%). A >10% point increase was observed in diagnosing active (72.7-83.3%) and inactive gastritis (73.2-84.3%) at 3 months after the lecture in comparison to before the lecture.

Conclusion: A brief mini-lecture on the Kyoto Classification of Gastritis improved the accuracy in the endoscopic diagnosis of gastritis, indicating that understanding this classification is useful for the prompt diagnosis of H. pylori infection during esophagogastroduodenoscopy.
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http://dx.doi.org/10.1159/000502573DOI Listing
September 2019

Prognostic Value of Calculated Plasma Volume Status in Patients Admitted for Acute Decompensated Heart Failure - A Prospective Comparative Study With Other Indices of Plasma Volume.

Circ Rep 2019 Aug 24;1(9):361-371. Epub 2019 Aug 24.

Division of Cardiology, Osaka General Medical Center Osaka Japan.

Congestion is one of the main predictors of poor outcome in patients with heart failure (HF); thus, a simple tool to evaluate plasma volume (PV), which can be used for risk stratification of HF patients, is necessary. We sought to compare the prognostic values of commonly used formulas for the estimation of PV and relative PV status (PVS) in patients admitted with acute decompensated HF (ADHF). We analyzed 384 consecutive ADHF patients who survived to discharge. The PV was calculated by 3 commonly used formulas (Strauss, Kaplan, and Hakim), and the relative PVS was calculated using the Hakim formula at both admission and discharge. The primary endpoint was a composite of all-cause mortality and hospitalization for worsening HF. The secondary endpoints were pump failure death (PFD) and sudden cardiac death (SCD). During a median follow-up of 743 days, 175 patients reached the primary endpoint, 28 patients had PFD, and 20 patients had SCD. Multivariate Cox analysis revealed that among the PV indices, only the PVS values at admission and discharge were independent predictors of the primary endpoint. In addition, the PVS values at admission and discharge were independent predictors of PFD and SCD in the multivariate analysis. Among the indices of PV, the calculated PVS may be the most useful for predicting prognosis in ADHF patients.
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http://dx.doi.org/10.1253/circrep.CR-19-0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892481PMC
August 2019

Prognostic significance of serum cholinesterase in patients with acute decompensated heart failure: a prospective comparative study with other nutritional indices.

Am J Clin Nutr 2019 08;110(2):330-339

Division of Cardiology, Osaka General Medical Center, Osaka, Japan.

Background: Nutritional status is associated with poor outcomes in patients with heart failure. Serum cholinesterase (CHE) concentration, a marker of malnutrition, was reported to be a prognostic factor in patients with chronic heart failure. The geriatric nutritional risk index (GNRI), the controlling nutritional status (CONUT) score, and the prognostic nutritional index (PNI) are established objective nutritional indices.

Objective: The aim of this study was to clarify the prognostic significance of CHE concentration and to compare it with other well-established objective nutritional indices in patients with acute decompensated heart failure (ADHF).

Methods: We prospectively enrolled 371 consecutive patients admitted for ADHF with survival discharge. Laboratory data including CHE and the objective nutritional indices were obtained at discharge. The primary endpoint of this study was all-cause mortality.

Results: During a mean ± SD follow-up period of 2.5 ± 1.4 y, 112 patients died. CHE concentration was significantly associated with all-cause mortality independently of GNRI, CONUT score, or PNI, after adjustment for major confounders including other nutritional indices, such as age, sex, systolic blood pressure, BMI, left ventricular ejection fraction, history of hypertension, diabetes mellitus, dyslipidemia, prior heart failure hospitalization, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, β-blocker use, statin use, hemoglobin, sodium, blood urea nitrogen, albumin, C-reactive protein, and brain natriuretic peptide concentrations via multivariable Cox analysis. Kaplan-Meier analysis revealed that the risk of all-cause mortality significantly increased in accordance with CHE stratum [lowest tertile: 53%, adjusted HR: 6.92; 95% CI: 3.87, 12.36, compared with middle tertile: 28%, adjusted HR: 2.72; 95% CI: 1.45, 5.11, compared with highest tertile: 11%, adjusted HR: 1.0 (reference), P < 0.0001]. CHE showed the best area under the curve value (0.745) for the prediction of all-cause mortality compared with the other objective nutritional indices. Net reclassification improvement afforded by adding CHE to the fully adjusted multivariable model was statistically significant for all-cause mortality (0.330; 95% CI: 0.112, 0.549, P = 0.0030).

Conclusion: CHE is a simple, strong prognostic marker for the prediction of all-cause mortality in patients with ADHF.
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http://dx.doi.org/10.1093/ajcn/nqz103DOI Listing
August 2019

Clinicopathological Features and Outcomes of Endoscopic Submucosal Dissection for Superficial Cancer of the Pharynx.

Acta Med Okayama 2019 Apr;73(2):109-115

Department of Gastroenterology and Hepatology,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558,

The efficacy and safety of endoscopic submucosal dissection (ESD) for superficial cancer of the pharynx are still unclear. To identify clinicopathological features of superficial pharyngeal cancer, and the efficacy and safety of ESD, we retrospectively assessed 70 pharyngeal cancers in 59 patients who underwent ESD. Of these patients, 61.0% and 50.8% had a history of esophageal cancer and head and neck cancer, respectively. The median tumor size was 15 mm, and 75.7% of the lesions were located at the piriform sinus. The en bloc resection rate was 94.9%. Treatment-related adverse events occurred in 8 cases, but there was no treatment-related death. The lateral margin was positive for neoplasm in 3 lesions (4.3%) and inconclusive in 27 lesions (38.6%), but no local recurrence was observed. Cervical lymph node metastasis was observed in 6 patients, and was successfully treated by cervical lymph node dissection. The three-year overall survival rate was 91.5% (95%CI: 76.6-97.3%) and the cause-specific survival rate was 97.6% (95%CI: 84.9-99.7%). In conclusion, ESD for superficial pharyngeal cancer was safe and effective. "Resect and watch" is probably a feasible and rational strategy for treatment of patients with superficial pharyngeal cancer.
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http://dx.doi.org/10.18926/AMO/56646DOI Listing
April 2019

Prediction of sudden cardiac death in chronic heart failure patients with reduced ejection fraction by ADMIRE-HF risk score and early repolarization pattern.

J Nucl Cardiol 2020 06 13;27(3):992-1001. Epub 2019 Feb 13.

Division of Cardiology, Osaka General Medical Center, 3-1-56, Mandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558, Japan.

Background: AdreView myocardial imaging for risk evaluation in heart failure (ADMIRE-HF) risk score is a novel risk score to predict serious arrhythmic risk in chronic heart failure patients with reduced ejection fraction (HFrEF). Moreover, early repolarization pattern (ERP) has been shown to be associated with an increased risk of sudden cardiac death (SCD) in HFrEF patients. We sought to investigate the prognostic value of combining ADMIRE-HF risk score and ERP to predict SCD in HFrEF patients.

Methods: We studied 90 HFrEF outpatients with LVEF< 40% in our prospective cohort study. In cardiac MIBG imaging, the heart-to-mediastinum (H/M) ratio was measured on the delayed planar image. ADMIRE-HF risk score was derived from the sum of the point values of LVEF, H/M ratio, and systolic blood pressure. We also assessed ERP on the standard electrocardiogram.

Results: During a median follow-up of 7.5(4.5-12.0) years, 22 patients had SCD. At multivariate Cox analysis, ADMIRE-HF risk score and ERP were independently associated with SCD. Patients with both intermediate/high ADMIRE-HF score and ERP had a higher SCD risk than those with either and none of them.

Conclusion: The combination of ADMIRE-HF risk score and ERP would provide the incremental prognostic information for predicting SCD in HFrEF patients.
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http://dx.doi.org/10.1007/s12350-019-01639-6DOI Listing
June 2020

Kruppel-Like Factor 4 represses osteoblast differentiation via ciliary Hedgehog signaling.

Exp Cell Res 2018 10 5;371(2):417-425. Epub 2018 Sep 5.

Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, Osaka, Japan. Electronic address:

Primary cilia are appendages observed in most types of cells, and serve as cellular antennae for sensing environmental signals. Evidence is accumulating that correct ciliogenesis and ciliary functions are indispensable for normal skeletal development by regulating signaling pathways important for bone development. However, whether ciliogenesis is regulated by bone-related factors in osteoblasts is largely unknown. Here we show that Kruppel-Like Factor 4 (KLF4), which is known to repress osteoblast differentiation, supports the formation and maintenance of cilia in cultured osteoblasts; however, the length of the cilia observed in KLF4-induced cells were significantly shorter compared to the control cells. Basal Hedgehog signaling was repressed by KLF4. Significantly, activating Hedgehog signaling using a Smoothened agonist significantly rescued osteoblast mineralization and osteoblastic gene expressions. Global gene expression analysis showed that KLF4 induced number of genes including the nuclear receptor, Pregnane X receptor (PXR), and PXR repressed calvarial osteoblast mineralization and repressed Gli1 expression similar as the effect observed by inducing KLF4. Our results implicate that KLF4 plays important roles for maintaining osteoblasts in an immature state by repressing basal activation of the Hedgehog signaling.
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http://dx.doi.org/10.1016/j.yexcr.2018.09.002DOI Listing
October 2018

Serial Change in Serum Chloride During Hospitalization Could Predict Heart Failure Death in Acute Decompensated Heart Failure Patients.

Circ J 2018 03 22;82(4):1041-1050. Epub 2018 Feb 22.

Division of Cardiology, Osaka General Medical Center.

Background: Although hyponatremia predicts morbidity and mortality in acute decompensated heart failure (ADHF), hypochloremia is also independently associated with poor prognosis in ADHF. Little is known, however, about the prognostic value of serial change in serum chloride during hospitalization in ADHF patients.Methods and Results:We prospectively studied 208 ADHF survivors after discharge and divided them into 4 groups according to serum chloride on admission and at discharge: (1) persistent hypochloremia group (n=12), hypochloremia both on admission and at discharge; (2) progressive hypochloremia group (n=42), development of hypochloremia after admission; (3) improved hypochloremia group (n=14), hypochloremia only on admission; and (4) no hypochloremia group, no hypochloremia during hospitalization (n=140). During a mean follow-up period of 1.86±0.76 years, 20 of 208 patients had heart failure death (HFD). In a model adjusted for hyponatremia, hypochloremia both on admission and at discharge was still significantly associated with HFD. Hyponatremia, however, was not significantly associated with HFD after adjustment for hypochloremia. Patients with persistent hypochloremia (HR, 9.13; 95% CI: 2.56-32.55) and with progressive hypochloremia (HR, 4.65; 95% CI: 1.61-13.4) had a significantly greater risk of HFD than those without hypochloremia during hospitalization.

Conclusions: Both persistent hypochloremia and progressive hypochloremia during hospitalization are associated with HFD in ADHF patients.
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http://dx.doi.org/10.1253/circj.CJ-17-0938DOI Listing
March 2018

Clinical outcome of patients with obscure gastrointestinal bleeding during antithrombotic drug therapy.

Therap Adv Gastroenterol 2018 14;11:1756283X17746930. Epub 2018 Jan 14.

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background: The clinical outcome of patients with obscure gastrointestinal bleeding (OGIB) during antithrombotic drug therapy has not been fully investigated.

Methods: Patients who underwent video capsule endoscopy (VCE) for the investigation of OGIB at Okayama University Hospital from January 2009 to March 2016 were enrolled. We evaluated the VCE findings, the patterns of OGIB, and the rate of rebleeding within 1 year in antithrombotic drug users and antithrombotic drug nonusers.

Results: A total of 181 patients were enrolled. Among the antithrombotic drug users, the rate of VCE positivity in the patients with overt OGIB was significantly higher in comparison with patients with occult OGIB (45% 16%, = 0.014), whereas there was no significant difference among the antithrombotic drug nonusers (27% 26%, = 1.0). Among the antithrombotic drug users, the rate of rebleeding among the VCE-positive patients was significantly higher in comparison with the VCE-negative patients (50% 5.9%, = 0.011). Moreover, among antithrombotic drug users who did not receive therapeutic intervention, the rate of rebleeding among the VCE-positive patients was significantly higher in comparison with the VCE-negative patients (75% 6.3%, = 0.001). However, among the antithrombotic drug nonusers who did not receive therapeutic intervention, the rebleeding rate of the VCE-positive patients was not significantly different from that of the VCE-negative patients (20% 9.4%, = 0.43).

Conclusion: Therapeutic intervention should be considered for patients with overt OGIB who are VCE positive and who use antithrombotic drugs due to the high risk of rebleeding.
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http://dx.doi.org/10.1177/1756283X17746930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788140PMC
January 2018

HipOP mesenchymal population has high potential for repairing injured peripheral nerves.

J Cell Biochem 2018 06 1;119(6):4836-4844. Epub 2018 Mar 1.

Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, Osaka, Japan.

Bone marrow stromal cells (BMSCs) are reportedly a heterogeneous population of mesenchymal stem cells (MSCs). Recently, we developed a simple strategy for the enrichment of MSCs with the capacity to differentiate into osteoblasts, chondrocytes, and adipocytes. On transplantation, the progenitor-enriched fractions can regenerate the bone with multiple lineages of donor origin and are thus called "highly purified osteoprogenitors" (HipOPs). Although our previous studies have demonstrated that HipOPs are enriched with MSCs and exhibit a higher potential to differentiate into osteoblasts, adipocytes, and chondrocytes than BMSCs, their potential to differentiate into neural cells has not been clarified. In this study, we evaluated the efficacy of HipOPs as a resource of neural stem cells. The neurosphere assay showed that neurospheres formed by HipOPs exhibited self-renewal ability and their size was generally larger than that of neurospheres formed by BMSCs. A limiting dilution assay was used to evaluate the frequency of neural progenitors in BMSCs and HipOPs. The results demonstrated that the frequency of neural progenitors in HipOPs was 120-fold higher than that in BMSCs. Furthermore, to investigate the in vivo regenerative potential of the peripheral nerve, we modified a murine peripheral nerve injury experimental model and demonstrated that HipOPs exhibit a higher efficacy in repairing injured peripheral nerves. These findings suggest that HipOPs are a useful cell resource for regenerative therapies such as that in case of peripheral nerve injury.
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http://dx.doi.org/10.1002/jcb.26684DOI Listing
June 2018

Worsened outcome in patients with pancreatic ductal carcinoma on long-term diabetes: association with E-cadherin1 (CDH1) promoter methylation.

Sci Rep 2017 12 22;7(1):18056. Epub 2017 Dec 22.

Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.

Prevalence of pancreatic ductal carcinoma (PDC) is nearly twice in patients with diabetes mellitus, but the reason for this close association remains obscure. Recently promoter methylation of E-cadherin1 (CDH1) and CDKN2A genes, encoding E-cadherin and P16 respectively, are invoked in development of PDC. It is still unclear whether diabetes affects such epigenetic changes and malignant behavior in PDC. In this study, we studied whether diabetes influences the clinico-pathological profile and methylation status of CDH1 and CDKN2A genes in patients with PDC. PDC subjects were divided into 3 groups; 59 cases without diabetes (non-DM), 17 cases with short-term diabetes (short-DM)(diabetes duration 3 yrs>) and 33 cases with long-term diabetes (long-DM)(≧3 yrs). Compared to non-DM or short-DM, long-DM was associated with a higher histological grade of malignancy and a higher tumor stage. Promoter methylation of both CDH1 and CDKN2A was encountered more frequently in PDC patients with long-DM than non-DM or short DM. Cases with CDH1 promoter methylation showed reduced E-cadherin expression and worsened survival. We consider that the presence of long-DM has a negative impact on the prognosis of PDC patients which may be relevant to a high frequency of promoter methylation of CDH1.
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http://dx.doi.org/10.1038/s41598-017-18438-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741711PMC
December 2017

Correlation between c-Met and ALDH1 contributes to the survival and tumor-sphere formation of ALDH1 positive breast cancer stem cells and predicts poor clinical outcome in breast cancer.

Genes Cancer 2017 Jul;8(7-8):628-639

Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.

c-Met is a receptor-type tyrosine kinase, which is involved in a wide range of cellular responses such as proliferation, motility, migration and invasion. It has been reported to be overexpressed in various cancers. However, the role of c-Met in breast cancer stem cells (CSCs) still remains unclear. We herein, show that expression is significantly elevated in Basal-like type of breast cancer in comparison with other subtypes. High expression of strongly correlated with the expression of two CSC markers, and in breast cancers. In addition, breast cancers at tumor stage III-IV expressing both and had poor prognosis. Furthermore, treatment with c-Met inhibitors (Crizotinib, Foretinib, PHA-665752 and Tivantinib) in MDA-MB157 cells with high c-Met protein expression resulted in significant suppression in cell viability, contrary to MDA-MB468 cells with low c-Met protein expression. These c-Met inhibitors also suppressed cell viability and tumor-sphere formation of ALDH1 breast cancer cells with high c-Met expression. These results suggest that c-Met in ALDH1 positive CSCs seems to play an important role in breast cancer repopulation. Therefore, we conclude that c-Met is a potential therapeutic target in ALDH1 positive breast CSCs.
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http://dx.doi.org/10.18632/genesandcancer.148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620008PMC
July 2017
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