Publications by authors named "Tetsuya Saito"

94 Publications

Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation.

Bioorg Med Chem 2021 May 30;43:116242. Epub 2021 May 30.

Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0809, USA.

In the face of emerging infectious diseases, there remains an unmet need for vaccine development where adjuvants that enhance immune responses to pathogenic antigens are highly desired. Using high-throughput screens with a cell-based nuclear factor κB (NF-κB) reporter assay, we identified a sulfamoyl benzamidothiazole bearing compound 1 that demonstrated a sustained activation of NF-κB after a primary stimulus with a Toll-like receptor (TLR)-4 agonist, lipopolysaccharide (LPS). Here, we explore systematic structure-activity relationship (SAR) studies on compound 1 that indicated the sites on the scaffold that tolerated modification and yielded more potent compounds compared to 1. The selected analogs enhanced release of immunostimulatory cytokines in the human monocytic cell line THP-1 cells and murine primary dendritic cells. In murine vaccination studies, select compounds were used as co-adjuvants in combination with the Food and Drug Administration approved TLR-4 agonistic adjuvant, monophosphoryl lipid A (MPLA) that showed significant enhancement in antigen-specific antibody titers compared to MPLA alone. Additionally, our SAR studies led to identification of a photoaffinity probe which will aid the target identification and mechanism of action studies in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2021.116242DOI Listing
May 2021

Efficacy of central extracorporeal life support for patients with fulminant myocarditis and cardiogenic shock.

Eur J Cardiothorac Surg 2021 Jun 25. Epub 2021 Jun 25.

Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Objectives: Fulminant myocarditis with cardiogenic shock requires extracorporeal life support (ECLS) and has poor outcomes. To improve outcomes, we have converted patients with severely impaired cardiac and multiorgan function from peripheral to central ECLS. In this study, we reviewed these patients' clinical outcomes and investigated associated factors.

Methods: We retrospectively studied 70 consecutive patients with fulminant myocarditis under peripheral support from 2006 to 2020. Forty-eight patients underwent surgical conversion to central support, and the remaining patients continued peripheral support. The end point was survival and ventricular assist device-free survival.

Results: More severe pulmonary congestion and multiorgan failure were present in patients with central than peripheral support. Weaning from ECLS was achieved in 95% and 62% of patients with peripheral and central support, respectively. Five-year survival was not significantly different between patients with central and peripheral support (71.2% vs 87.5%, respectively; P = 0.15). However, the ventricular assist device-free survival rate was significantly higher in patients with central than peripheral support (82.2% vs 52.0%, respectively; P = 0.017). A peak creatine kinase-MB level of >180 IU/l, rhythm disturbance and aortic valve closure were detrimental to functional recovery in patients with central support.

Conclusions: Conversion to central ECLS is feasible and safe in patients with fulminant myocarditis. Patients with severe myocardial injury as shown by a high creatine kinase-MB level, rhythm disturbance and aortic valve closure should be converted to a durable left ventricular assist device.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ejcts/ezab231DOI Listing
June 2021

Mitochondria-dependent synthetic small-molecule vaccine adjuvants for influenza virus infection.

Proc Natl Acad Sci U S A 2021 Jun;118(23)

Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0809;

Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [-benzyl--(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2025718118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201894PMC
June 2021

Generation and Application of a Reporter Cell Line for the Quantitative Screen of Extracellular Vesicle Release.

Front Pharmacol 2021 16;12:668609. Epub 2021 Apr 16.

Moores Cancer Center, University of California, San Diego, La Jolla, CA, United States.

Extracellular vesicles (EVs) are identified as mediators of intercellular communication and cellular regulation. In the immune system, EVs play a role in antigen presentation as a part of cellular communication. To enable drug discovery and characterization of compounds that affect EV biogenesis, function, and release in immune cells, we developed and characterized a reporter cell line that allows the quantitation of EVs shed into culture media in phenotypic high-throughput screen (HTS) format. Tetraspanins CD63 and CD9 were previously reported to be enriched in EVs; hence, a construct with dual reporters consisting of CD63-Turbo-luciferase (Tluc) and CD9-Emerald green fluorescent protein (EmGFP) was engineered. This construct was transduced into the human monocytic leukemia cell line, THP-1. Cells expressing the highest EmGFP were sorted by flow cytometry as single cell, and clonal pools were expanded under antibiotic selection pressure. After four passages, the green fluorescence dimmed, and EV biogenesis was then tracked by luciferase activity in culture supernatants. The Tluc activities of EVs shed from CD63Tluc-CD9EmGFP reporter cells in the culture supernatant positively correlated with the concentrations of released EVs measured by nanoparticle tracking analysis. To examine the potential for use in HTS, we first miniaturized the assay into a robotic 384-well plate format. A 2210 commercial compound library (Maybridge) was then screened twice on separate days, for the induction of extracellular luciferase activity. The screening data showed high reproducibility on days 1 and 2 (78.6%), a wide signal window, and an excellent Z' factor (average of 2-day screen, 0.54). One hundred eighty-seven compounds showed a response ratio that was 3SD above the negative controls in both day 1 and 2 screens and were considered as hit candidates (approximately 10%). Twenty-two out of 40 re-tested compounds were validated. These results indicate that the performance of CD63Tluc-CD9EmGFP reporter cells is reliable, reproducible, robust, and feasible for HTS of compounds that regulate EV release by the immune cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.668609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085554PMC
April 2021

Small Left Ventricle and Clinical Outcomes After Transcatheter Aortic Valve Replacement.

J Am Heart Assoc 2021 Apr 20;10(7):e019543. Epub 2021 Mar 20.

Department of Cardiology Keio University School of Medicine Tokyo Japan.

Background In patients undergoing transcatheter aortic valve replacement (TAVR), those with small left ventricle (LV) may have an increased risk of poor outcomes, because small LV is associated with low-flow (LF), left ventricular hypertrophy. However, the impact of small LV on patients undergoing TAVR remains unknown. Methods and Results We examined 2584 patients who underwent TAVR between October 2013 and May 2017 using data from the Japanese multicenter registry. On the basis of the American Society of Echocardiography guidelines, small LV was defined as left ventricular end-diastolic dimension <42.0 mm for men or <37.8 mm for women. The 2-year clinical outcomes were compared between patients with and without small LV using multivariable Cox regression analyses and propensity score matching. Subgroup analyses by LF, left ventricular hypertrophy were performed. Of 2584 patients who underwent TAVR, 466 (18.0%) had small LV. Patients with small LV had smaller body size and less comorbidity, and were more likely to have LF status compared with those without. Small LV was associated with a higher 2-year all-cause (20.8% versus 14.3%; adjusted hazard ratio [HR],1.58 [95% CI, 1.20-2.09]; =0.0013) and cardiovascular mortality (8.8% versus 5.5%; adjusted HR, 1.93 [95% CI, 1.25-2.98]; =0.0028). Propensity score matching analysis showed consistent findings. In subgroup analyses, LF, left ventricular hypertrophy did not interact with small LV. Conclusions Small LV, determined by a simple echocardiographic parameter, was associated with poorer clinical outcomes after TAVR regardless of LF, left ventricular hypertrophy. LV size may be useful for assessing clinical outcomes after TAVR. Registration URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000020423.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.019543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174314PMC
April 2021

Reverse remodelling after aortic valve replacement for chronic aortic regurgitation.

Interact Cardiovasc Thorac Surg 2021 Jun;33(1):10-18

Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Center, Osaka, Japan.

Objectives: This study aimed to assess the long-term outcomes and investigate the factors related to left ventricular (LV) reverse remodelling after aortic valve replacement (AVR) in patients with chronic aortic regurgitation (AR).

Methods: A total of 246 patients who underwent AVR for chronic AR at our institution were included in this retrospective study. Primary end-points included all-cause mortality, cardiac mortality and major adverse cerebral and cardiovascular events. Secondary end-points included cardiac function on echocardiography 1 year after surgery. We explored the predictive factors for reverse remodelling 1 year after surgery.

Results: The 10-year survival rate was 86.0%, with no cardiac deaths in 93.8% and no major adverse cerebral and cardiovascular events in 79.9% of patients. Postoperative LV function and symptoms were significantly improved 1 year after surgery, but 34 patients (13.8%) did not recover normal function and structure. A significant negative correlation was found between the incidence of cardiac death and major adverse cerebral and cardiovascular events and reverse remodelling. Multivariate logistic regression identified preoperative LV ejection fraction (P = 0.001, odds ratio = 1.057) and LV end-systolic dimension index (P = 0.038, odds ratio = 0.912) as significant predictive factors of reverse remodelling 1 year after surgery.

Conclusions: Preoperative LV ejection fraction and LV end-systolic dimension index were predictive factors for reverse remodelling after surgery, which was associated with late outcomes. Earlier surgery may thus help to restore normal LV function and achieve better late outcomes after AVR for AR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/icvts/ivab046DOI Listing
June 2021

Surgical exclusion of an idiopathic saccular aneurysm in the left main trunk of the coronary artery.

Surg Today 2021 Feb 19. Epub 2021 Feb 19.

Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Center, 6-1 Kishibeshimmachi, Suita, Osaka, 564-8565, Japan.

Purpose: A coronary artery aneurysm (CAA) can result in critical cardiac events such as thromboembolic complications or rupture. A saccular CAA located in the left main trunk (LMT) is the most critical form of this pathology and its surgical repair is challenging. We conducted this single-center study to review the surgical outcomes of patients with a saccular CAA in the LMT.

Methods: Between May, 2012 and June, 2020, five patients with a saccular CAA in the LMT underwent surgery at our center. The median age at operation was 66.5 (59.7-69) years and the median diameter of the CAA was 13.0 mm (IQR 11-14 mm).

Results: The CAA was fully excluded by patch closure of the LMT orifice and direct closure of the distal LMT, supplemented by coronary artery bypass grafting with the exclusive use of arterial conduits. There was no in-hospital mortality, although one patient suffered graft spasm-related myocardial infarction with complete recovery. Post-operative angiography showed a fully excluded LMT in all patients. There was no mortality or adverse cardiac events during follow-up.

Conclusions: Our surgical policy for CAA in the LMT is feasible and safe; however, coronary blood flow is dependent on reliable bypasses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00595-021-02246-0DOI Listing
February 2021

Novel risk score for predicting recurrence of atrial fibrillation after the Cryo-Maze procedure.

Eur J Cardiothorac Surg 2021 06;59(6):1218-1225

Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Research Center, Suita, Osaka, Japan.

Objectives: This study aimed to develop a novel risk score model for quantitative prediction of the rate of atrial fibrillation (AF) recurrence after the Cryo-Maze procedure in patients with persistent AF.

Methods: We enrolled 450 consecutive patients who underwent the Cryo-Maze procedure for persistent AF concomitant with other cardiac procedures in our institute between 2001 and 2019. We randomly divided the cohort into two groups. We derived a model in a 'development cohort' (270 patients; 60%) and validated it in a 'test cohort' (180 patients; 40%) by receiver operating characteristic curve analysis.

Results: The median follow-up was 5.2 (interquartile range: 2.0-9.9) years. The 1-, 5-, 10- and 15-year rates of freedom from AF recurrence in the entire cohort were 91.4%, 83.5%, 76.2% and 57.1%, respectively. Risk factors for AF recurrence examined by logistic regression analysis included F-wave voltage in V1 < 0.2 mV, preoperative AF duration >5 years and left atrial volume index >100 ml/m2. Points were assigned to each risk factor according to its odds ratio. A novel risk score model was developed using these three variables and age, with a range up to 10 points. High score (>7) predicted high rates of AF recurrence after the Cryo-Maze procedure. The area under the receiver operating characteristic curve of the novel risk model score was 0.78 (95% confidence interval: 0.65-0.91) in the test cohort.

Conclusions: Use of the Cryo-Maze procedure should be carefully considered in patients with a higher model score because of a higher risk of AF recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ejcts/ezaa468DOI Listing
June 2021

Comparison of safety and haemodynamic performance between the Avalus™ stented aortic valve bioprosthesis and Magna™ valve in Japanese patients.

Gen Thorac Cardiovasc Surg 2021 Jul 5;69(7):1060-1069. Epub 2021 Jan 5.

Department of Cardiovascular Surgery, National Cerebral and Cardiovascular Center, 6-1 Kishibeshimmachi, Suita, Osaka, 564-8565, Japan.

Objectives: A new stented bovine pericardial valve (Avalus™) has been proven safe and effective with good hemodynamic performance in Western populations. However, its use in Japanese patients is poorly understood. We retrospectively compared the feasibility, safety, and valve haemodynamics between the Avalus™ and Magna™ valves in patients who underwent surgical aortic valve replacement (SAVR).

Methods: This study included 87 patients receiving an Avalus™ valve and 387 receiving a Magna™ valve. We evaluated adverse events, outcomes, and valve haemodynamics within 1 year postoperatively. There were no significant differences in any surgical risk scores.

Results: No in-hospital mortality occurred in the Avalus™ group, but two mortality events occurred in the Magna™ group. No pacemaker implantation for complete atrioventricular block was required in the Avalus™ group. There was no significant difference in in-hospital or clinical outcomes between the two groups until 1 year postoperatively. Left ventricular mass index reduction appeared to predominate in the Avalus™ over Magna™ group. There was no significant difference in the mean pressure gradient or effective orifice area of each valve size at 1 week or 1 year between the two groups, apart from the mean pressure gradient of the 23-mm valve at 1 week. Three patients (3.4%) in the Avalus™ group and 39 (10.8%) in the Magna™ group (p = 0.12) had severe patient-prosthesis mismatch at 1 week postoperatively.

Conclusions: The new Avalus™ stented aortic valve bioprosthesis was associated with good in-hospital outcomes and good valve functionality post-SAVR in Japanese patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11748-020-01566-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203521PMC
July 2021

Successful surgical resection and reconstruction for a huge primary cardiac lymphoma filling the right heart.

J Card Surg 2021 Jan 30;36(1):342-344. Epub 2020 Oct 30.

Department of Cardiac Surgery, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Primary cardiac lymphoma (PCL) is rare, with a frequency of 1.0%-1.6% among cardiac malignant tumors. Chemotherapy is often selected as a first-line treatment for PCL. However, when the tumor causes heart failure or life-threatening hemodynamic collapse, antecedent urgent surgery is required. We herein report a successful case of complete tumor resection and reconstruction of the right atrium and right ventricle using a bovine pericardial patch combined with tricuspid valve replacement in a patient with a huge PCL filling the right heart that manifested as tricuspid valve stenosis and subsequent heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jocs.15152DOI Listing
January 2021

Splenic sarcoid reaction mimicking metachronous metastasis in patients after distal gastrectomy for gastric cancer: a case report and literature review.

Surg Case Rep 2020 Jul 29;6(1):185. Epub 2020 Jul 29.

Department of Surgery, Saiseikai Kawaguchi General Hospital, 5-11-5 Nisikawaguchi, Kawaguchi, Saitama, 332-8558, Japan.

Background: The occurrence of sarcoid reactions has been recognized in various cancers. The common location for observing these granulomas is mainly the lymph nodes, but a rare occurrence in the spleen has been reported. Almost all splenic sarcoid reactions associated with gastric cancer have been resected synchronously and diagnosed accidentally, and a rare metachronous occurrence of a sarcoid reaction in the spleen after distal gastrectomy can mimic cancer metastasis. We describe a rare case of a splenic sarcoid reaction recognized in a patient with gastric cancer 6 months after distal gastrectomy.

Case Presentation: An 82-year-old man underwent laparoscopic distal gastrectomy for gastric cancer (T3N0M0, stage IIA). Six months after gastrectomy, CT and 18F-fluorodeoxyglucose (FDG)-PET/CT showed the appearance of a splenic mass. We diagnosed solitary splenic metastasis from gastric cancer and performed laparoscopic-assisted splenectomy. His splenic tumor was diagnosed as a sarcoid reaction by histopathological examination.

Conclusion: To our knowledge, this is the first report of a splenic sarcoid reaction recognized 6 months after distal gastrectomy for gastric cancer without any chemotherapy. The splenic sarcoid reaction and cancer metastasis to the spleen were undistinguishable from the CT and FDG-PET/CT findings. The present case and literature review showed that cases of splenic sarcoid reactions associated with gastric cancer can also be accompanied by the occurrence of these granulomas in lymph nodes. When the appearance of a solitary mass is observed in the spleen after resection of primary cancer, it is necessary to consider not only cancer metastasis but also sarcoid reactions. Retrospective histopathological confirmation of the existence of sarcoid reactions in lymph nodes from resected specimens might possibly avoid incorrect diagnosis and intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40792-020-00955-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391455PMC
July 2020

Impact of beta blockers on patients undergoing transcatheter aortic valve replacement: the OCEAN-TAVI registry.

Open Heart 2020 07;7(2)

Cardiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

Objective: There is paucity of data on optimal medical treatment, including use of beta blockers for patients undergoing transcatheter aortic valve replacement (TAVR). The study aimed to investigate the association of beta blockers and clinical outcomes following TAVR.

Methods: We examined data of 2563 patients who underwent TAVR between October 2013 and May 2017 obtained from a prospective multicentre cohort registry, the optimised catheter valvular intervention-TAVI registry. We compared the 2-year cardiovascular and non-cardiovascular mortality and in-hospital outcomes between patients with and without preprocedural beta-blocker administration by propensity score matching (PSM).

Results: Preprocedural beta blockers were prescribed in 867 patients (33.8%). After PSM, the incidence of in-hospital congestive heart failure was significantly lower in patients with preprocedural beta blocker (p=0.046). No differences were found in 2-year cardiovascular and non-cardiovascular mortality. In the subgroup analyses, beta-blocker administration was associated with a lower cardiovascular mortality within 2 years in patients with a history of coronary artery bypass grafting (CABG; log-rank p=0.017), presence of peripheral artery disease (PAD; log-rank p=0.003) and brain natriuretic peptide (BNP) ≥400 pg/mL (log-rank p=0.003). When stratified by postprocedural left ventricular ejection fraction (post-LVEF), beta-blocker administration was associated with a lower cardiovascular mortality among patients with post-LVEF <50% (log-rank p=0.024).

Conclusions: Preprocedural beta-blocker administration was not associated with 2-year cardiovascular and non-cardiovascular mortality in overall, but was associated with a lower 2-year cardiovascular mortality in patients with a history of CABG, presence of PAD, BNP ≥400 pg/mL and post-LVEF <50%. The findings must be validated using randomised trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/openhrt-2020-001269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342827PMC
July 2020

Loss of autophagy impairs physiological steatosis by accumulation of NCoR1.

Life Sci Alliance 2020 01 26;3(1). Epub 2019 Dec 26.

Department of Physiology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan

Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, such as after a meal. LDs serve as an energy reservoir during fasting and have a buffering capacity that prevents lipotoxicity. Autophagy and the autophagic machinery have been proposed to play a role in LD biogenesis, but the underlying molecular mechanism remains unclear. Here, we show that when nuclear receptor co-repressor 1 (NCoR1), which inhibits the transactivation of nuclear receptors, accumulates because of autophagy suppression, LDs decrease in size and number. Ablation of , a gene essential for autophagy, suppressed the expression of gene targets of liver X receptor α, a nuclear receptor responsible for fatty acid and triglyceride synthesis in an NCoR1-dependent manner. LD accumulation in response to fasting and after hepatectomy was hampered by the suppression of autophagy. These results suggest that autophagy controls physiological hepatosteatosis by fine-tuning NCoR1 protein levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.26508/lsa.201900513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932742PMC
January 2020

Laparoscopic treatment in a patient with median arcuate ligament syndrome identified at the onset of superior mesenteric artery dissection: a case report.

Surg Case Rep 2019 Dec 11;5(1):197. Epub 2019 Dec 11.

Department of Surgery, Saiseikai Kawaguchi General Hospital, 5-11-5 Nisikawaguchi, Kawaguchi, Saitama, 332-8558, Japan.

Background: Median arcuate ligament syndrome (MALS) is a rare clinical entity caused mainly by extrinsic compression of the celiac axis by the median arcuate ligament (MAL). Severe celiac artery stenosis can lead to the development of collateral circulation, aneurysms, and, rarely, superior mesenteric artery (SMA) dissection. The treatment of MALS involves the surgical release of the MAL. However, a standard procedure with the use of laparoscopy has not been established, and intraoperative complications can lead to severe vascular injury.

Case Presentation: The patient was a 43-year-old man with MALS identified at the onset of SMA dissection. After treatment for the SMA dissection, he underwent laparoscopic MAL release. Using the technique of laparoscopic gastrectomy within the surgical field, we performed laparoscopic MAL release and ganglionectomy safely with a good view. Immediate symptomatic improvement was acquired, and no recurrence was observed at the 20-month follow-up.

Conclusion: We reported a rare case of MALS and SMA dissection. A horizontal 3D laparoscopic approach of the celiac axis allows for safe, meticulous, and radical MAL release and ganglionectomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40792-019-0758-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906274PMC
December 2019

Physical Meanings of Fractal Behaviors of Water in Aqueous and Biological Systems with Open-Ended Coaxial Electrodes.

Sensors (Basel) 2019 Jun 8;19(11). Epub 2019 Jun 8.

A Graduate School of Science, Kyushu University, 744, Motooka, Nishi-ku, Fukuoka 819-0395, Japan.

The dynamics of a hydrogen bonding network (HBN) relating to macroscopic properties of hydrogen bonding liquids were observed as a significant relaxation process by dielectric spectroscopy measurements. In the cases of water and water rich mixtures including biological systems, a GHz frequency relaxation process appearing at around 20 GHz with the relaxation time of 8.2 ps is generally observed at 25 °C. The GHz frequency process can be explained as a rate process of exchanges in hydrogen bond (HB) and the rate becomes higher with increasing HB density. In the present work, this study analyzed the GHz frequency process observed by suitable open-ended coaxial electrodes, and physical meanings of the fractal nature of water structures were clarified in various aqueous systems. Dynamic behaviors of HBN were characterized by a combination of the average relaxation time and the distribution of the relaxation time. This fractal analysis offered an available approach to both solution and dispersion systems with characterization of the aggregation or dispersion state of water molecules. In the case of polymer-water mixtures, the HBN and polymer networks penetrate each other, however, the HBN were segmented and isolated more by dispersed and aggregated particles in the case of dispersion systems. These HBN fragments were characterized by smaller values of the fractal dimension obtained from the fractal analysis. Some examples of actual usages suggest that the fractal analysis is now one of the most effective tools to understand the molecular mechanism of HBN in aqueous complex materials including biological systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/s19112606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604069PMC
June 2019

Autophagy regulates lipid metabolism through selective turnover of NCoR1.

Nat Commun 2019 04 5;10(1):1567. Epub 2019 Apr 5.

Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, 951-8510, Japan.

Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-08829-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450892PMC
April 2019

Trans-radial percutaneous coronary intervention for patients with severe chronic renal insufficiency and/or on dialysis.

Heart Vessels 2019 Sep 22;34(9):1412-1419. Epub 2019 Mar 22.

Department of Cardiology, Japanese Red Cross Ashikaga Hospital, Ashikaga, Japan.

Periprocedural bleeding is associated with an increased risk of mortality during percutaneous coronary intervention (PCI), especially in patients with severe chronic renal insufficiency. Therefore, trans-radial intervention (TRI) should be considered in these patients; however, PCI operators usually avoid this approach because of the risk of radial artery occlusion. We aimed to investigate the associations of TRI and in-hospital complications in these patients. This study included 306 consecutive patients with severe chronic renal insufficiency and/or on dialysis who underwent PCI. Patients were prospectively enrolled and divided according to the access site into TRI group and trans-femoral intervention group. Severe renal insufficiency was defined as estimated glomerular filtration rate < 30 mL/min/1.73 m. Radial access was limited to the opposite side of the arteriovenous fistula in patients on hemodialysis. The primary study endpoint was the composite of in-hospital bleeding complications and death. TRI benefit was evaluated by inverse probability treatment weighted analysis. TRI was performed in 112 (37.3%) patients. TRI group included older patients with significantly lower rates of diabetes mellitus, dialysis, and three-vessel disease. Crossover to the other approach occurred only in TRI group (2.6%). The primary endpoint was significantly lower in TRI group (11.5% vs. 2.6%, P = 0.006). After an inverse probability treatment weighted analysis, TRI was an independent prognostic factor for a decrease in the primary endpoint (OR 0.19; 95% CI 0.051-0.73; P = 0.015). Radial artery occlusion occurred in three patients on dialysis (9.1%). TRI may determine better in-hospital outcomes in patients with severe chronic renal insufficiency and/or on dialysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00380-019-01387-0DOI Listing
September 2019

Novel Insights of Jailed Balloon and Jailed Corsair Technique for Percutaneous Coronary Intervention of Bifurcation Lesions.

Cardiovasc Revasc Med 2019 Dec 2;20(12):1065-1072. Epub 2019 Feb 2.

Department of Cardiology, Japanese Red Cross Ashikaga Hospital, Ashikaga, Japan.

Background: The optimal technique for percutaneous coronary intervention (PCI) of a bifurcation lesion remains uncertain. JBT/JCT techniques are now emerging for protection of the side branch (SB). We aimed to compare jailed balloon (JBT) and jailed Corsair (JCT) techniques to the conventional jailed wire technique.

Methods: We analyzed 850 consecutive patients (995 bifurcation lesions), who underwent PCI. The bifurcation lesions were classified as jailed wire (-), jailed wire (+), JBT, and JCT. We assessed temporary thrombolysis in myocardial infarction (TIMI) flow grade ≤2, permanent TIMI flow grade ≤2 in the SB, and SB occlusion related myocardial infarction and compared these endpoints with inverse probability treatment weighted analysis.

Results: The percentage of each group is as follows: jailed wire (-); 44.7%; jailed wire (+) 50.9%; JBT 1.7%; JCT 2.7%. The Corsair could not be delivered with a stent because of severe calcifications (3.7%) and a jailed balloon was entrapped with the stent after dilatation (5.9%). Compared to the jailed wire (+), JBT/JCT had a higher percentage of true bifurcations, arterial sheath size ≥7 Fr, and a lower proportion of wire recrossing (all, P < 0.05). After adjustment, temporary and permanent TIMI flow grade ≤2 in the SB, and SB occlusion related myocardial infarction were not significantly different (OR: 1.08, CI: 0.32-3.71, P = 0.90; OR: 0.88, CI: 0.11-6.91, P = 0.91; OR: 1.94, CI: 0.23-16.5, P = 0.55 respectively).

Conclusions: Our data could not prove the efficacy of JBT/JCT, but revealed novel insights about these techniques. A larger study is necessary to prove the efficacy of JBT/JCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carrev.2019.01.033DOI Listing
December 2019

p62/SQSTM1: 'Jack of all trades' in health and cancer.

FEBS J 2019 01 18;286(1):8-23. Epub 2018 Dec 18.

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

p62 is a stress-inducible protein able to change among binding partners, cellular localizations and form liquid droplet structures in a context-dependent manner. This protein is mainly defined as a cargo receptor for selective autophagy, a process that allows the degradation of detrimental and unnecessary components through the lysosome. Besides this role, its ability to interact with multiple binding partners allows p62 to act as a main regulator of the activation of the Nrf2, mTORC1, and NF-κB signaling pathways, linking p62 to the oxidative defense system, nutrient sensing, and inflammation, respectively. In the present review, we will present the molecular mechanisms behind the control p62 exerts over these pathways, their interconnection and how their deregulation contributes to cancer progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/febs.14712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379270PMC
January 2019

Effect of Continuous-Flow Mechanical Circulatory Support on Microvasculature Remodeling in the Failing Heart.

Artif Organs 2019 Apr 4;43(4):350-362. Epub 2018 Nov 4.

Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Left ventricle (LV) unloading caused by a left ventricular assist device (LVAD) has been shown to enhance reverse LV remodeling in end-stage cardiomyopathy. Several reports consistently suggest that a pulsatile-flow LVAD has more profound effects compared to continuous-flow LVAD, though the responsible mechanisms are not fully understood. We hypothesized that arterial pulsatility, being affected by the type of LVAD, may affect microvasculature and functional/pathological LV remodeling in end-stage cardiomyopathy. The study included 18 patients with chronic heart failure who underwent LVAD implantation. Eight patients were implanted with pulsatile-flow LVAD, and 10 patients were implanted with continuous-flow LVAD. The results of serial echocardiograms and histopathological assessment of transmural LV tissues, which were collected during the implantation and removal of LVADs, were compared between the groups. The results of echocardiography showed that LV systolic dimension and LV ejection fraction improved greatly in the pulsatile-flow LVAD group compared to the continuous-flow LVAD group. Histological analysis showed that in both groups, increased microvasculature density and decreased cardiomyocyte size during LVAD support had no significant difference. In contrast, only the patients with continuous-flow LVADs had presented with significant increase in α-smooth muscle actin (α-SMA)-positive layer thickness and the number of proliferating cell nuclear antigen (PCNA)-positive cells of myocardial arterioles. We concluded that the use of long-term continuous-flow LVAD support, having less pulsatility, had induced more thickening to the medial layer of myocardial arterioles compared to the use of pulsatile-flow LVADs. Our findings suggest that the pathological impairment of myocardial microvascular structure during continuous-flow LVAD support may be a novel mechanism which accounts for the difference in LV remodeling depending on the type of LVAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/aor.13348DOI Listing
April 2019

The Adaptive Remodeling of the Anterior Mitral Leaflet and Chordae Tendineae Is Associated with Mitral Valve Function in Advanced Ischemic and Nonischemic Dilated Cardiomyopathy.

Int Heart J 2018 Sep 11;59(5):959-967. Epub 2018 Aug 11.

Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine.

The degree or nature of functional mitral regurgitation (MR) is not necessarily correlated with the size or function of the left ventricle (LV). We hypothesized that the anatomical structure of the mitral valve (MV) complex might play a role in functional MR in ischemic or nonischemic dilated cardiomyopathy (DCM).The structure of the LV and MV complex in DCM patients (n = 29) was assessed using electrocardiogram-gated 320-slice computed tomography and was compared with that in healthy patients (n = 12). Twenty-five DCM patients with mild or low MR (DCM-lowMR) had markedly greater length, diameter, and sphericity index of the LV and a larger tenting area than the controls. The distance between the papillary muscle (PM) tip and the mitral annular plane was not different between DCM-lowMR and normal hearts despite the greater LV length observed in DCM-lowMR. Furthermore, DCM-lowMR had markedly longer chordae tendineae (DCM-lowMR: 24 [20-26] mm; controls: 14 [13-16] mm; P < 0.01) and larger anterior leaflets (DCM-lowMR: 30 [27-31] mm; controls: 22 [20-24] mm; P < 0.01), thus suggesting the adaptive remodeling of the MV complex. Four DCM patients with moderate-severe MR had unbalanced remodeling, such as excessive LV dilatation, short anterior mitral leaflets, and short chordae tendineae.The development of functional MR might be associated with the remodeling of LV and MV components, such as the PMs, chordae tendineae, or anterior MV leaflets. Detailed anatomical assessments of the LV and MV complex would contribute to the adequate staging of ischemic or nonischemic DCM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1536/ihj.17-465DOI Listing
September 2018

Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions.

Oncogenesis 2018 Jan 23;7(1). Epub 2018 Jan 23.

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

We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41389-017-0018-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833787PMC
January 2018

Negative Regulation of the Keap1-Nrf2 Pathway by a p62/Sqstm1 Splicing Variant.

Mol Cell Biol 2018 04 15;38(7). Epub 2018 Mar 15.

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

A key antioxidant pathway, the Keap1-Nrf2 system, is regulated by p62/Sqstm1 via multiple mechanisms, including gene expression, posttranslational modifications (such as ubiquitination and phosphorylation), and autophagic degradation of p62/Sqstm1 and Keap1. Here we demonstrate a novel mode of regulation of the Keap1-Nrf2 system, mediated by a splicing variant of p62/Sqstm1 pre-mRNA. Ensembl database searches and subsequent biochemical analyses of mice revealed the presence of an mRNA that encodes a p62/Sqstm1 protein lacking the Keap1-interacting region (KIR), which is essential for the interaction with Keap1. Like full-length p62, the variant was induced under conditions in which Nrf2 was activated (e.g., impairment of autophagy), formed oligomers with itself and/or the full-length protein, and was degraded by autophagy. However, the variant failed to interact with Keap1 and sequester it in variant-positive aggregates. Remarkably, while full-length p62 stabilized Nrf2 and induced the gene expression of Nrf2 targets, the variant increased the amount of Keap1 and enhanced ubiquitination of Nrf2, thereby suppressing the induction of Nrf2 targets. Hepatocytes isolated from genetically modified mice that express full-length p62, but not the variant, were susceptible to activation of Nrf2 in response to stress. Collectively, our results suggest that splicing of p62/Sqstm1 pre-mRNA negatively regulates the Keap1-Nrf2 pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/MCB.00642-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854834PMC
April 2018

A Transradial Approach of Cardiac Catheterization for Patients on Dialysis.

J Invasive Cardiol 2018 Jun 15;30(6):212-217. Epub 2018 Jan 15.

Department of Cardiology, Japanese Red Cross Ashikaga Hospital, 284-1 Yobe-cho, Ashikaga, Japan.

Background: Periprocedural bleeding is associated with increased risk of early mortality during percutaneous coronary intervention (PCI), especially in patients on dialysis. A transradial approach (TRA) should be considered for these patients; however, PCI operators avoid this approach because of the risk of radial artery occlusion (RAO). The aim of this study is to construct a TRA system and clarify its safety in patients on dialysis.

Methods: Eighty-eight consecutive patients on dialysis who underwent cardiac catheterization were prospectively included in this study and divided according to the access site into either the TRA group or the transfemoral approach (TFA) group. Radial access was limited in the opposite side of arteriovenous fistula. The study endpoints were in-hospital and 30-day mortality rates, puncture-site related bleeding complications, and other complications. The study safety endpoints were procedure success rate and RAO rate in the TRA group.

Results: Mean patient age was 70.4 ± 8.5 years. PCI was performed in 43 patients (48.9%). The TRA and TFA groups included 62 patients (70.5%) and 26 patients (29.5%), respectively. In-hospital and 30-day mortality rates were 0.0% in both groups. Puncture-site bleeding rates were 3.8% in the TFA group and 0.0% in the TRA group (P=.12). Procedural success rate in the TRA group was 98.4%. Crossover to TFA was necessary in 1 patient due to radial artery spasm. RAO occurred in 4 patients (6.5%).

Conclusions: Constructed TRA can be safely used in patients on dialysis. Our study could lead to an increase in TRA in these patients, which would lead to better prognosis and patient comfort.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2018

Hemophagocytic Syndrome Complicated with Dermatomyositis Controlled Successfully with Infliximab and Conventional Therapies.

Intern Med 2017 1;56(23):3237-3241. Epub 2017 Dec 1.

Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Japan.

A 57-year-old woman was admitted to our hospital because of a high fever, anemia, and hyperferritinemia. Since a bone marrow examination revealed hemophagocytosis, she was diagnosed with hemophagocytic syndrome (HPS). During treatment of HPS, a heliotrope rash and Gottron's sign appeared with elevated levels of serum aldolase. She also developed heart failure. She was diagnosed with dermatomyositis (DM) and associated myocarditis. Although the administration of glucocorticoids, calcineurin inhibitors, intravenous immunoglobulins, and etoposide ameliorated the clinical findings of DM and cytopenia, the fever and hyperferritinemia remained. The addition of infliximab to glucocorticoids and tacrolimus improved the fever and hyperferritinemia and enabled a reduction in the dose of prednisolone without relapse of the diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.7966-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742400PMC
June 2018

Recent Inferior Myocardial Infarction Complicated with a Right Ventricular Thrombus Detected by Three Cardiac Imaging Modalities.

Intern Med 2018 Mar 20;57(5):693-695. Epub 2017 Nov 20.

Department of Cardiology, Japanese Red Cross Ashikaga Hospital, Japan.

We report the case of a 71-year-old woman diagnosed with recent inferior myocardial infarction complicated with right ventricular infarction and a right ventricular thrombus. Three-dimensional transthoracic echocardiography, contrast-enhanced computed tomography, and cardiac magnetic resonance imaging clearly detected a thrombus. We consider cases with a recent right ventricular infarction to require assessment for thrombus formations in the right ventricle. Fortunately, vigorous anticoagulation therapy resolved the thrombi in both the right ventricle and right coronary artery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.9431-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874341PMC
March 2018

Origins of fibroblasts in rheumatoid synovial tissues: Implications from organ fibrotic models.

Mod Rheumatol 2018 Jul 25;28(4):579-582. Epub 2017 Oct 25.

a Department of Rheumatology, Graduate School of Medical and Dental Sciences , Tokyo Medical and Dental University (TMDU) , Tokyo , Japan.

Fibroblasts play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Accumulation of fibroblasts in the synovial tissues characterizes the pathology of RA. Understanding how fibroblasts accumulate could lead to discovery of new therapeutic targets in RA treatment, while current antirheumatic therapies still have problems in efficacy and safety. In this regard, several studies have revealed cellular origins of fibroblasts in fibrotic tissues in murine models of organ fibrosis. Some studies employed lineage tracing, which bring generally convincing results, using transgenic mice. They demonstrated that resident fibroblasts, pericytes, mesenchymal stem cells, epithelial cells, endothelial cells and bone-marrow-derived and circulating cells can be cellular origins of fibroblasts in organ fibrotic tissues. In this review, we summarize and discuss available evidence for the origins of fibroblasts accumulating in the arthritic synovial tissues and organ fibrotic tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14397595.2017.1386837DOI Listing
July 2018