Publications by authors named "Atsushi Watanabe"

379 Publications

c.14576G>A Is Associated with Intracranial Internal Carotid Artery Saccular Aneurysms.

Genes (Basel) 2021 Sep 23;12(10). Epub 2021 Sep 23.

Department of Neurological Surgery, Nippon Medical School, Bunkyo-ku, Tokyo 1138603, Japan.

A mutation in (c.14576G>A), a gene associated with moyamoya disease (>80%), plays a role in terminal internal carotid artery (ICA) stenosis (>15%) (ICS). Studies on and cerebral aneurysms (AN), which did not focus on the site of origin or morphology, could not elucidate the relationship between the two. However, a report suggested a relationship between and AN in French-Canadians. Here, we investigated the relationship between ICA saccular aneurysm (ICA-AN) and . We analyzed expression in subjects with ICA-AN and atherosclerotic ICS. Cases with a family history of moyamoya disease were excluded. AN smaller than 4 mm were confirmed as AN only by surgical or angiographic findings. was detected in 12.2% of patients with ICA-AN and 13.6% of patients with ICS; patients with ICA-AN and ICS had a similar risk of mutation expression (odds ratio, 0.884; 95% confidence interval, 0.199-3.91; = 0.871). The relationship between ICA-AN and (c.14576G>A) was not correlated with the location of the ICA and bifurcation, presence of rupture, or multiplicity. When the etiology and location of AN were more restricted, the incidence of mutations in ICA-AN was higher than that reported in previous studies. Our results suggest that strict maternal vessel selection and pathological selection of AN morphology may reveal an association between genetic mutations and ICA-AN development. The results of this study may form a basis for further research on systemic vascular diseases, in which the (c.14576G>A) mutation has been implicated.
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http://dx.doi.org/10.3390/genes12101468DOI Listing
September 2021

First report of inherited protein S deficiency caused by paternal mosaicism.

Haematologica 2021 Oct 14. Epub 2021 Oct 14.

Department of Clinical Laboratory Science, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan; Department of Hematology, Kanazawa University Hospital, Kanazawa, Ishikawa.

Not available.
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http://dx.doi.org/10.3324/haematol.2021.278527DOI Listing
October 2021

NUDT15 polymorphism and NT5C2 and PRPS1 mutations influence thiopurine sensitivity in acute lymphoblastic leukaemia cells.

J Cell Mol Med 2021 Oct 12. Epub 2021 Oct 12.

Department of Pediatrics, University of Yamanashi, Yamanashi, Japan.

In chemotherapy for childhood acute lymphoblastic leukaemia (ALL), maintenance therapy consisting of oral daily mercaptopurine and weekly methotrexate is important. NUDT15 variant genotype is reportedly highly associated with severe myelosuppression during maintenance therapy, particularly in Asian and Hispanic populations. It has also been demonstrated that acquired somatic mutations of the NT5C2 and PRPS1 genes, which are involved in thiopurine metabolism, are detectable in a portion of relapsed childhood ALL. To directly confirm the significance of the NUDT15 variant genotype and NT5C2 and PRPS1 mutations in thiopurine sensitivity of leukaemia cells in the intrinsic genes, we investigated 84 B-cell precursor-ALL (BCP-ALL) cell lines. Three and 14 cell lines had homozygous and heterozygous variant diplotypes of the NUDT15 gene, respectively, while 4 and 2 cell lines that were exclusively established from the samples at relapse had the NT5C2 and PRPS1 mutations, respectively. Both NUDT15 variant genotype and NT5C2 and PRPS1 mutations were significantly associated with DNA-incorporated thioguanine levels after exposure to thioguanine at therapeutic concentration. Considering the continuous exposure during the maintenance therapy, we evaluated in vitro mercaptopurine sensitivity after 7-day exposure. Mercaptopurine concentrations lethal to 50% of the leukaemia cells were comparable to therapeutic serum concentration of mercaptopurine. Both NUDT15 variant genotype and NT5C2 and PRPS1 mutations were significantly associated with mercaptopurine sensitivity in 83 BCP-ALL and 23 T-ALL cell lines. The present study provides direct evidence to support the general principle showing that both inherited genotype and somatically acquired mutation are crucially implicated in the drug sensitivity of leukaemia cells.
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http://dx.doi.org/10.1111/jcmm.16981DOI Listing
October 2021

Dysfunction of epithelial permeability barrier induced by HMGB1 in 2.5D cultures of human epithelial cells.

Tissue Barriers 2021 Sep 18:1972760. Epub 2021 Sep 18.

Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.

Airway and intestinal epithelial permeability barriers are crucial in epithelial homeostasis. High mobility group box 1 (HMGB1), increased by various stimuli, is involved in the induction of airway inflammation, as well as the pathogenesis of inflammatory bowel disease. HMGB1 enhances epithelial hyperpermeability. Two-and-a-half dimensional (2.5D) culture assays are experimentally convenient and induce cells to form a more physiological tissue architecture than 2D culture assays for molecular transfer mechanism analysis. In 2.5D culture, treatment with HMGB1 induced permeability of FITC-dextran into the lumen formed by human lung, nasal and intestinal epithelial cells. The tricellular tight junction molecule angulin-1/LSR is responsible for the epithelial permeability barrier at tricellular contacts and contributes to various human airway and intestinal inflammatory diseases. In this review, we indicate the mechanisms including angulin-1/LSR and multiple signaling in dysfunction of the epithelial permeability barrier induced by HMGB1 in 2.5D culture of human airway and intestinal epithelial cells.
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http://dx.doi.org/10.1080/21688370.2021.1972760DOI Listing
September 2021

Association of allele-specific methylation of the ASNS gene with asparaginase sensitivity and prognosis in T-ALL.

Blood Adv 2021 Sep 17. Epub 2021 Sep 17.

University of Yamanashi, School of Medicine, Yamanashi, Japan.

Asparaginase therapy is a key component of chemotherapy for T-cell acute lymphoblastic leukemia (T-ALL) patients. Asparaginase depletes serum asparagine by deamination into aspartic acid. Normal hematopoietic cells can survive due to asparagine synthetase (ASNS) activity, while leukemia cells are supposed to undergo apoptosis due to silencing of the ASNS gene. Since the ASNS gene has a typical CpG island in its promoter, its methylation status in T-ALL cells may be associated with asparaginase sensitivity. Thus, we investigated the significance of ASNS methylation status in asparaginase sensitivity of T-ALL cell lines and prognosis of childhood T-ALL. Sequencing of bisulfite PCR products using next-generation sequencing technology in 22 T-ALL cell lines revealed a stepwise allele-specific methylation of the ASNS gene, in association with an aberrant methylation of a 7q21 imprinted gene cluster. T-ALL cell lines with ASNS hypermethylation status showed significantly higher in vitro l-asparaginase sensitivity in association with insufficient asparaginase-induced upregulation of ASNS gene expression and lower basal ASNS protein expression. A comprehensive analysis of diagnostic samples from childhood T-ALL patients in Japanese cohorts (n = 77) revealed that methylation of the ASNS gene was associated with an aberrant methylation of the 7q21 imprinted gene cluster. In childhood T-ALL patients in Japanese cohorts (n = 75), ASNS hypomethylation status was significantly associated with poor therapeutic outcome, and all cases with poor prognostic SPI1 fusion exclusively showed ASNS hypomethylation status. These observations demonstrate that ASNS hypomethylation status is associated with asparaginase resistance and is a poor prognostic biomarker in childhood T-ALL.
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http://dx.doi.org/10.1182/bloodadvances.2021004271DOI Listing
September 2021

Role of RNF213 polymorphism in defining quasi-moyamoya disease and definitive moyamoya disease.

Neurosurg Focus 2021 09;51(3):E2

1Department of Neurological Surgery, Nippon Medical School, Bunkyo-ku, Tokyo.

Objective: Quasi-moyamoya disease (QMMD) is moyamoya disease (MMD) associated with additional underlying diseases. Although the ring finger protein 213 (RNF213) c.14576G>A mutation is highly correlated with MMD in the Asian population, its relationship to QMMD is unclear. Therefore, in this study the authors sought to investigate the RNF213 c.14576G>A mutation in the genetic diagnosis and classification of QMMD.

Methods: This case-control study was conducted among four core hospitals. A screening system for the RNF213 c.14576G>A mutation based on high-resolution melting curve analysis was designed. The prevalence of RNF213 c.14576G>A was investigated in 76 patients with MMD and 10 patients with QMMD.

Results: There were no significant differences in age, sex, family history, and mode of onset between the two groups. Underlying diseases presenting in patients with QMMD were hyperthyroidism (n = 6), neurofibromatosis type 1 (n = 2), Sjögren's syndrome (n = 1), and meningitis (n =1). The RNF213 c.14576G>A mutation was found in 64 patients (84.2%) with MMD and 8 patients (80%) with QMMD; no significant difference in mutation frequency was observed between cohorts.

Conclusions: There are two forms of QMMD, one in which the vascular abnormality is associated with an underlying disease, and the other in which MMD is coincidentally complicated by an unrelated underlying disease. It has been suggested that the presence or absence of the RNF213 c.14576G>A mutation may be useful in distinguishing between these disease types.
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http://dx.doi.org/10.3171/2021.5.FOCUS21182DOI Listing
September 2021

[Spinal Cord Infarction after Right Upper Lobectomy Combined with Chest Wall Resection].

Kyobu Geka 2021 Sep;74(9):664-667

Department of Thoracic Surgery, Sapporo Medical University, Sapporo, Japan.

A 42-year-old man presented with a one-month history of back pain. Chest computed tomography revealed a mass (7.6×5.7 cm) in the right upper lobe, suspicious of chest wall invasion. We performed right upper lobectomy combined with chest wall resection. Partial dissections of the second to sixth ribs and the third and fourth vertebral bodies were conducted. Postoperatively, motor paralysis of the right lower extremity was observed and a diagnosis of spinal infarction was made. After cerebrospinal fluid drainage and administration of edaravone with early rehabilitation, he was able to walk with a brace and was discharged from the hospital.
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September 2021

Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma.

Cancers (Basel) 2021 Aug 9;13(16). Epub 2021 Aug 9.

Laboratory of Laboratory/Sports Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Ibaraki, Japan.

The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype-phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (, , , , , , and ) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. was the most frequently mutated gene (57, 15.4%), followed by (27, 7.3%), and (18, 4.9%). The incidence of metastatic PPGL was high in carriers (21/57, 36.8%). A few unique recurrent variants ( c.137G>A and c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.
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http://dx.doi.org/10.3390/cancers13164014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394264PMC
August 2021

Nonobese mice with nonalcoholic steatohepatitis fed on a choline-deficient, l-amino acid-defined, high-fat diet exhibit alterations in signaling pathways.

FEBS Open Bio 2021 Aug 14. Epub 2021 Aug 14.

Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture, Setagaya, Japan.

Nonalcoholic steatohepatitis (NASH) is often associated with obesity, but some patients develop NASH without obesity. The physiological processes by which nonobese patients develop NASH and cirrhosis have not yet been determined. Here, we analyzed the effects of dietary methionine content on NASH induced in mice fed on a choline-deficient, methionine-lowered, l-amino acid-defined high-fat diet (CDAHFD). CDAHFD with insufficient methionine induced insulin sensitivity and enhanced NASH pathology, but without obesity. In contrast, CDAHFD with sufficient methionine induced steatosis, and unlike CDAHFD with insufficient methionine, also induced obesity and insulin resistance. Gene profile analysis revealed that the disease severity in CDAHFD may partially be due to upregulation of the Rho family GTPases pathway and mitochondrial and nuclear receptor signal dysfunction. The signaling factors/pathways detected in this study may assist in future study of NASH regulation, especially its 'nonobese' subtype.
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http://dx.doi.org/10.1002/2211-5463.13272DOI Listing
August 2021

Vessel sealing system for video-assisted lung resection for cancer reduces chylothorax and bleeding.

J Thorac Dis 2021 Jun;13(6):3458-3466

Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Hokkaido, Japan.

Background: The objective of this study was to analyze the efficacy of the LigaSure vessel sealing system for lung cancer resection with node dissection, as this has not been sufficiently evaluated.

Methods: From 2004 to 2018, 948 patients underwent anatomical pulmonary resection with node dissection for non-small cell lung carcinoma (NSCLC) via the video-assisted thoracoscopic surgery (VATS) approach. Medical records of these patients were reviewed retrospectively. Univariate and multivariate analyses were conducted to determine the risk factors for chylothorax and blood loss.

Results: Of the 948 patients, 318 (33.5%) who underwent anatomical lung resection with node dissection by conventional methods without vessel sealing system and 630 (66.5%) who underwent lung resection with node dissection with the vessel sealing system were included. The median intraoperative blood loss was 100 mL. Postoperative chylothorax occurred in 9 (2.8%) patients in the conventional method group with 2 (0.3%) patients in the vessel sealing system group (P=0.001). Patients in the vessel sealing group who developed chylothorax were cured by conservative treatment. Univariate and multivariate analyses identified male sex [odds ratio (OR) 2.053; 95% confidence interval (CI): 1.494-2.820; P<0.001] and the use of vessel sealing system (OR 0.342; 95% CI: 0.256-0.457; P<0.001) as independent predictors of intraoperative blood loss. The univariate and multivariate analyses identified the use of the vessel sealing system (OR 0.108; 95% CI: 0.023-0.504; P=0.005) as an independent predictor of chylothorax incidence.

Conclusions: Vessel sealing system for lung cancer resection could decrease chest tube duration, amount of intraoperative bleeding, and incidence of chylothorax in patients who undergo lung resection with node dissection.
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http://dx.doi.org/10.21037/jtd-21-169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264714PMC
June 2021

Epigenetic Modification of Death Receptor Genes for TRAIL and TRAIL Resistance in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia.

Genes (Basel) 2021 06 5;12(6). Epub 2021 Jun 5.

Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.

Immunotherapies specific for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), such as anti-CD19 chimeric antigen receptor (CAR) T-cells and blinatumomab, have dramatically improved the therapeutic outcome in refractory cases. In the anti-leukemic activity of those immunotherapies, TNF-related apoptosis-inducing ligand (TRAIL) on cytotoxic T-cells plays an essential role by inducing apoptosis of the target leukemia cells through its death receptors (DR4 and DR5). Since there are CpG islands in the promoter regions, hypermethylation of the and genes may be involved in resistance of leukemia cells to immunotherapies due to TRAIL-resistance. We analyzed the and methylation status in 32 BCP-ALL cell lines by sequencing their bisulfite PCR products with a next-generation sequencer. The and methylation status was significantly associated with the gene and cell-surface expression levels and the TRAIL-sensitivities. In the clinical samples at diagnosis (459 cases in the NOPHO study), both and genes were unmethylated in the majority of cases, whereas methylated in several cases with dic(9;20), -rearrangement, and hypodiploidy, suggesting that evaluation of methylation status of the and genes might be clinically informative to predict efficacy of immunotherapy in certain cases with such unfavorable karyotypes. These observations provide an epigenetic rational for clinical efficacy of immunotherapy in the vast majority of BCP-ALL cases.
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http://dx.doi.org/10.3390/genes12060864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229974PMC
June 2021

Two cases of left recurrent laryngeal nerve paralysis after right superior mediastinal node dissection.

Surg Case Rep 2021 Jun 28;7(1):151. Epub 2021 Jun 28.

Department of Thoracic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.

Background: Ipsilateral recurrent laryngeal nerve paralysis is one of the rare complications during the superior mediastinal node dissection for lung cancer. However, very few reports of contralateral recurrent laryngeal nerve paralysis during the procedure are available.

Case Presentation: Two women aged 74 and 80 years developed hoarseness after undergoing right upper lobectomy and right superior mediastinal node dissection for primary lung cancer. Postoperative laryngoscopy in the two patients confirmed left vocal cord paralysis.

Conclusion: Node dissection is performed in the standard procedure for right upper lobe lung cancer. At this time, care must be taken not to cause damage not only to the recurrent laryngeal nerve on the ipsilateral side but also to the recurrent laryngeal nerve on the contralateral side.
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http://dx.doi.org/10.1186/s40792-021-01236-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239095PMC
June 2021

Subcarinal lymph node dissection in solo robot-assisted thoracic surgery.

Ann Thorac Surg 2021 Jun 5. Epub 2021 Jun 5.

Department of Thoracic Surgery, Sapporo Medical University School of Medicine and Hospital, Sapporo, Japan. Electronic address:

The surgical instruments used in robot-assisted thoracic surgery are flexible to enable the surgeon to approach the surgical field from any direction. However, even in robot-assisted thoracic surgery, subcarinal lymph node dissection requires a precise technique suitable for a small area surrounded by important organs. We present a method of subcarinal node dissection with solo robot-assisted thoracic surgery using bronchial traction method and a metal basket suction device, the Dobon®.
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http://dx.doi.org/10.1016/j.athoracsur.2021.05.038DOI Listing
June 2021

Efficacy and safety of nintedanib for pulmonary fibrosis in severe pneumonia induced by COVID-19: An interventional study.

Int J Infect Dis 2021 Jul 25;108:454-460. Epub 2021 May 25.

Division of Trauma and Surgical Critical Care, Osaka General Medical Center, Osaka, Japan. Electronic address:

Objectives: One of the most significant features of poor prognosis in COVID-19 is pulmonary fibrosis. Nintedanib is a new antifibrotic agent that interferes with processes of pulmonary fibrosis. This study aimed to investigate the efficacy and safety of nintedanib in COVID-19.

Methods: This was an interventional study in which adult patients with COVID-19 requiring mechanical ventilation were consecutively enrolled. The primary endpoint was 28-day mortality after the initiation of mechanical ventilation. The secondary endpoints were length of mechanical ventilation, volume of lung injury, and the incidence of gastrointestinal adverse events and acute liver failure.

Results: Thirty patients with COVID-19 underwent nintedanib therapy. We included 30 patients not receiving nintedanib as the historical control group. There were no significant differences in 28-day mortality between the groups (23.3% vs 20%, P = 0.834). Lengths of mechanical ventilation were significantly shorter in the nintedanib group (P = 0.046). Computed tomography volumetry showed that the percentages of high-attenuation areas were significantly lower in the nintedanib group at liberation from mechanical ventilation (38.7% vs 25.7%, P = 0.027). There were no significant differences in the adverse events.

Conclusions: The administration of nintedanib may offer potential benefits for minimizing lung injury in COVID-19.
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http://dx.doi.org/10.1016/j.ijid.2021.05.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146615PMC
July 2021

Potential local adaptation of corals at acidified and warmed Nikko Bay, Palau.

Sci Rep 2021 05 27;11(1):11192. Epub 2021 May 27.

Palau International Coral Reef Center, 1 M-Dock Road, PO Box 7086, Koror, 96940, Republic of Palau.

Ocean warming and acidification caused by increases of atmospheric carbon dioxide are now thought to be major threats to coral reefs on a global scale. Here we evaluated the environmental conditions and benthic community structures in semi-closed Nikko Bay at the inner reef area in Palau, which has high pCO and seawater temperature conditions with high zooxanthellate coral coverage. Nikko Bay is a highly sheltered system with organisms showing low connectivity with surrounding environments, making this bay a unique site for evaluating adaptation and acclimatization responses of organisms to warmed and acidified environments. Seawater pCO/Ω showed strong gradation ranging from 380 to 982 µatm (Ω: 1.79-3.66), and benthic coverage, including soft corals and turf algae, changed along with Ω while hard coral coverage did not change. In contrast to previous studies, net calcification was maintained in Nikko Bay even under very low mean Ω (2.44). Reciprocal transplantation of the dominant coral Porites cylindrica showed that the calcification rate of corals from Nikko Bay did not change when transplanted to a reference site, while calcification of reference site corals decreased when transplanted to Nikko Bay. Corals transplanted out of their origin sites also showed the highest interactive respiration (R) and lower gross photosynthesis (Pg) to respiration (Pg:R), indicating higher energy acquirement of corals at their origin site. The results of this study give important insights about the potential local acclimatization and adaptation capacity of corals to different environmental conditions including pCO and temperature.
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http://dx.doi.org/10.1038/s41598-021-90614-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159998PMC
May 2021

[Probable Immunoglobulin G4 (IgG4)-related Periaortitis Requiring Differentiation from Mediastinal Tumor].

Kyobu Geka 2021 Feb;74(2):108-111

Department of Thoracic Surgery, Sapporo Medical University, Sapporo, Japan.

A 42-year-old man with a history of suspected of Behcet's disease underwent oral steroid treatment. During follow-up, chest X-ray revealed an abnormal shadow of the mediastinum. Chest computed tomography(CT) showed a circumferential tumor around the descending thoracic aorta. Enhanced CT showed a lowly and uniformly enhanced tumor at delay phase. A mediastinal tumor was suspected, which prompted a biopsy of the periaortic tumor by video-assisted thoracic surgery (VATS). Histopathological diagnosis showed numerous immunogloblin G4 (IgG4)-positive plasma cells suggesting the possibility of IgG4-related periaortitis. However, based on the diagnostic criteria, the case was comprehensively diagnosed as probable IgG4-related periaortitis, steroid treatment may have affected blood IgG4-positive cells and tissues.
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February 2021

Effects of histone deacetylase inhibitors Tricostatin A and Quisinostat on tight junction proteins of human lung adenocarcinoma A549 cells and normal lung epithelial cells.

Histochem Cell Biol 2021 Jun 11;155(6):637-653. Epub 2021 May 11.

Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan.

Histone deacetylase (HDAC) inhibitors have a potential therapeutic role for non-small cell lung cancer (NSCLC). However, more preclinical studies of HDAC inhibitors in NSCLC and normal lung epithelial cells are required to evaluate their antitumor activities and mechanisms. The bicellular tight junction molecule claudin-2 (CLDN-2) is highly expressed in lung adenocarcinoma tissues and increase the proliferation of adenocarcinoma cells. Downregulation of the tricellular tight junction molecule angulin-1/LSR induces malignancy via EGF-dependent CLDN-2 and TGF-β-dependent cellular metabolism in human lung adenocarcinoma cells. In the present study, to investigate the detailed mechanisms of the antitumor activities of HDAC inhibitors in lung adenocarcinoma, human lung adenocarcinoma A549 cells and normal lung epithelial cells were treated with the HDAC inibitors Trichostatin A (TSA) and Quisinostat (JNJ-2648158) with or without TGF-β. Both HDAC inhibitors increased anguin-1/LSR, decrease CLDN-2, promoted G1 arrest and prevented the migration of A549 cells. Furthermore, TSA but not Quisinostat with or without TGF-β induced cellular metabolism indicated as the mitochondrial respiration measured using the oxygen consumption rate. In normal human lung epithelial cells, treatment with TSA and Quisinostat increased expression of LSR and CLDN-2 and decreased that of CLDN-1 with or without TGF-β in 2D culture. Quisinostat but not TSA with TGF-β increased CLDN-7 expression in 2D culture. Both HDAC inhibitors prevented disruption of the epithelial barrier measured as the permeability of FD-4 induced by TGF-β in 2.5D culture. TSA and Quisinostat have potential for use in therapy for lung adenocarcinoma via changes in the expression of angulin-1/LSR and CLDN-2.
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http://dx.doi.org/10.1007/s00418-021-01966-1DOI Listing
June 2021

Institutional and Social Issues Surrounding Genetic Counselors in Japan: Current Challenges and Implications for the Global Community.

Front Genet 2021 13;12:646177. Epub 2021 Apr 13.

Department of Biomedical Ethics and Public Policy, Graduate School of Medicine, Osaka University, Suita, Japan.

In recent years, genetic counseling has started playing a major role in the field of genomic medicine. There are currently about 7,000 genetic counselors in more than 28 countries, with 267 certified genetic counselors in Japan alone (about 2 per million population, as of April 2020). While the rapid advancement of genomic medicine has expanded this field, the challenges genetic counselors face are also evolving. This article aims to provide an overview of the institutional and social issues surrounding genetic counselors in Japan and discuss implications for the global community. In Japan, with the rapid changes in genomic medicine and the establishment of a delivery mechanism within the healthcare system, several issues need to be discussed. First, many genetic testing, counseling, and preventive healthcare programs are not covered by public health insurance. Second, reducing human resource shortages for genetic counseling is an urgent issue. Third, the lack of a national qualification in the profession is critically important issue in the field. Fourth, research on the role and value of genetic counselors is still limited. To address these issues, discussions among relevant stakeholders, including genetic counselors, professionals in genomic medicine, and lawmakers, are necessary. Additionally, we believe that research by genetic counselors to evaluate and improve their practice and examine institutional and social issues is crucial for developing their profession's activities and delivering high-quality healthcare to many people. To establish the position and role of the relatively new profession of genetic counselor, sharing information and collaborating on institutional and social challenges faced by genetic counselors globally will be beneficial.
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http://dx.doi.org/10.3389/fgene.2021.646177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076856PMC
April 2021

Quantification of tire wear particles in road dust from industrial and residential areas in Seoul, Korea.

Sci Total Environ 2021 Aug 18;784:147177. Epub 2021 Apr 18.

Department of Environmental Engineering, Inha University, Incheon 22212, Republic of Korea; Program in Environmental and Polymer Engineering, Inha University, Incheon 22212, Republic of Korea. Electronic address:

In this study, we examined tire and road wear microparticles (TRWMPs) in road dust along the Seoul metropolitan area, from industrial and residential areas. The road dust samples were collected via vacuum sweep methods and then filtered to obtain particles with diameters less than 75 μm. To quantify the TRWMPs in road dust, we used the raw materials of tire components, natural rubber (NR), and styrene-butadiene rubber (SBR), as standard materials. We evaluated the usability of the pyrolyzer-gas chromatography/mass spectrometry py-GC/MS method introduced in ISO/TS 20593 by confirming the decomposition temperatures of the NR and SBR by thermogravimetric (TG) and evolved gas analysis (EGA)-MS. The average of TRWMPs in industrial and residential area road dust were 22,581 and 9818 μg/g, respectively, indicating that the industrial area has 2.5 times higher TRWMPs concentration. Further, the NR, the main component of truck bus radial, to SBR, the main component of passenger car radial, ratio was slightly higher in the industrial area than in the residential area. This presumably means that the high traffic volume, including heavy duty vehicles in industrial areas, affected the higher concentration of TRWMPs. This study reveals the growing evidence of the importance of TRWMPs in road dust and how TRWMPs quantity can impact the air quality of the Seoul metropolitan area.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147177DOI Listing
August 2021

Easy Suction Technique During Robotic-Assisted Thoracoscopic Lobectomy.

Ann Thorac Surg 2021 Nov 18;112(5):e381-e382. Epub 2021 Mar 18.

Department of Thoracic Surgery, Sapporo Medical University School of Medicine and Hospital, Sapporo, Japan. Electronic address:

In robotic-assisted thoracoscopic surgery, surgeons may encounter bleeding issues requiring compression techniques and time to achieve hemostasis. During this time, surgeons cannot use the robot arm and may require an assistant to perform suction, thus increasing the cost of the procedure. This report describes an alternative suction device, Dobon (Senko Medical Instrument Mfg, Tokyo, Japan), which is usually used for pediatric cardiac surgery, for use in robotic-assisted thoracoscopic surgery. The report presents the technique for using this device and comments on the advantages, including decreased cost and an improved surgical visual field.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.019DOI Listing
November 2021

Treatment of air leakage using the VIO soft coagulation system: a mouse pulmonary air leak model.

Surg Today 2021 Sep 20;51(9):1521-1529. Epub 2021 Mar 20.

Department of Thoracic Surgery, School of Medicine and Hospital, Sapporo Medical University, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.

Purpose: We aimed to compare the efficacy of the VIO soft coagulation system (VSCS) for the treatment of air leaks by sealing with fibrin glue, and also assess the histological alterations that occur after soft coagulation.

Methods: A mouse pulmonary air leak model was designed. The pulmonary fistula was subsequently coagulated with the VSCS or sealed with fibrin glue with polyglycolic acid (PGA) sheets. The burst pressure at air leak recurrence was measured in each group, and the results were compared. We also evaluated the histological alterations in the mouse pulmonary air leak model after soft coagulation with the VSCS.

Results: The burst pressure in the soft coagulation group (80 W/Effect 5) (median 42.8; range 35.4-53.8 cmHO) was similar to that in the fibrin glue group (median 41.5; range 34.6-43.9 cmHO) (p = 0.21). Histological examinations revealed that the visceral pleura remained torn, the structure of the pulmonary alveolus was maintained, and the coagulated fistula was covered with a fibrin membrane in the soft coagulation group.

Conclusions: The pressure resistance following soft coagulation was equivalent to that after sealing using fibrin glue with PGA sheets. The air leaks were likely controlled by covering the fistula with a fibrin membrane after soft coagulation with the VSCS.
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http://dx.doi.org/10.1007/s00595-021-02251-3DOI Listing
September 2021

Association of relapse-linked ARID5B single nucleotide polymorphisms with drug resistance in B-cell precursor acute lymphoblastic leukemia cell lines.

Cancer Cell Int 2020 Sep 4;20(1):434. Epub 2020 Sep 4.

Department of Pediatrics, School of Medicine, University of Yamanashi, Shimokato, Chuo, Yamanashi, 1110, Japan.

Background: The genetic variants of the ARID5B gene have recently been reported to be associated with disease susceptibility and treatment outcome in childhood acute lymphoblastic leukemia (ALL). However, few studies have explored the association of ARID5B with sensitivities to chemotherapeutic agents.

Methods: We genotyped susceptibility-linked rs7923074 and rs10821936 as well as relapse-linked rs4948488, rs2893881, and rs6479778 of ARDI5B by direct sequencing of polymerase chain reaction (PCR) products in 72 B-cell precursor-ALL (BCP-ALL) cell lines established from Japanese patients. We also quantified their ARID5B expression levels by real-time reverse transcription PCR, and determined their 50% inhibitory concentration (IC50) values by alamarBlue assays in nine representative chemotherapeutic agents used for ALL treatment.

Results: No significant associations were observed in genotypes of the susceptibility-linked single nucleotide polymorphisms (SNPs) and the relapsed-linked SNPs with ARID5B gene expression levels. Of note, IC50 values of vincristine (VCR) (median IC50: 39.6 ng/ml) in 12 cell lines with homozygous genotype of risk allele (C) in the relapse-linked rs4948488 were significantly higher (p = 0.031 in Mann-Whitney U test) than those (1.04 ng/ml) in 60 cell lines with heterozygous or homozygous genotypes of the non-risk allele (T). Furthermore, the IC50 values of mafosfamide [Maf; active metabolite of cyclophosphamide (CY)] and cytarabine (AraC) tended to be associated with the genotype of rs4948488. Similar associations were observed in genotypes of the relapse-linked rs2893881 and rs6479778, but not in those of the susceptibility-linked rs7923074 and rs10821936. In addition, the IC50 values of methotrexate (MTX) were significantly higher (p = 0.023) in 36 cell lines with lower ARID5B gene expression (median IC50: 37.1 ng/ml) than those in the other 36 cell lines with higher expression (16.9 ng/ml).

Conclusion: These observations in 72 BCP-ALL cell lines suggested that the risk allele of the relapse-linked SNPs of ARID5B may be involved in a higher relapse rate because of resistance to chemotherapeutic agents such as VCR, CY, and AraC. In addition, lower ARID5B gene expression may be associated with MTX resistance.
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http://dx.doi.org/10.1186/s12935-020-01524-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839197PMC
September 2020

Adverse effects of LPS on membrane proteins in lactating bovine mammary epithelial cells.

Cell Tissue Res 2021 May 12;384(2):435-448. Epub 2021 Jan 12.

Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Hokkaido University, North 9, West 9, Sapporo, Hokkaido, 060-8589, Japan.

Mastitis causes a decrease in milk yield and abnormalities in milk components from dairy cows. Escherichia coli and the E. coli lipopolysaccharide (LPS) cell wall component directly downregulate milk production in bovine mammary epithelial cells (BMECs). However, the detailed mechanism by which this occurs in BMECs remains unclear. Various membrane proteins, such as immune sensors (Toll-like receptors, TLR), nutrient transporters (glucose transporter and aquaporin), and tight junction proteins (claudin and occludin) are involved in the onset of mastitis or milk production in BMECs. In this study, we investigated the influence of LPS on membrane proteins using an in vitro culture model. This mastitis model demonstrated a loss of glucose transporter-1 and aquaporin-3 at lateral membranes and a decrease in milk production in response to LPS treatment. LPS disrupted the tight junction barrier and caused compositional changes in localization of claudin-3 and claudin-4, although tight junctions were maintained to separate the apical membrane domains and the basolateral membrane domains. LPS did not significantly affect the expression level and subcellular localization of epidermal growth factor receptor in lactating BMECs with no detectable changes in MEK1/2-ERK1/2 signaling. In contrast, NFκB was concurrently activated with temporal translocation of TLR-4 in the apical membranes, whereas TLR-2 was not significantly influenced by LPS treatment. These findings indicate the importance of investigating the subcellular localization of membrane proteins to understand the molecular mechanism of LPS in milk production in mastitis.
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http://dx.doi.org/10.1007/s00441-020-03344-0DOI Listing
May 2021

A trans fatty acid substitute enhanced development of liver proliferative lesions induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet.

Lipids Health Dis 2020 Dec 14;19(1):251. Epub 2020 Dec 14.

Department of Nutritional Science and Food Safety, Faculty of Applied Bioscience, Tokyo University of Agriculture , 1-1-1, Sakuragaoka, Setagaya, Tokyo, 156-8502, Japan.

Background: Nonalcoholic steatohepatitis (NASH) is a form of liver disease characterized by steatosis, necroinflammation, and fibrosis, resulting in cirrhosis and cancer. Efforts have focused on reducing the intake of trans fatty acids (TFAs) because of potential hazards to human health and the increased risk for NASH. However, the health benefits of reducing dietary TFAs have not been fully elucidated. Here, the effects of TFAs vs. a substitute on NASH induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet (CDAA-HF) were investigated.

Methods: Mice were fed CDAA-HF containing shortening with TFAs (CDAA-HF-T(+)), CDAA-HF containing shortening without TFAs (CDAA-HF-T(-)), or a control chow for 13 or 26 weeks.

Results: At week 13, NASH was induced in mice by feeding CDAA-HF-T(+) containing TFAs or CDAA-HF-T(-) containing no TFAs, but rather mostly saturated fatty acids (FAs), as evidenced by elevated serum transaminase activity and liver changes, including steatosis, inflammation, and fibrosis. CDAA-HF-T(-) induced a greater extent of hepatocellular apoptosis at week 13. At week 26, proliferative (preneoplastic and non-neoplastic) nodular lesions were more pronounced in mice fed CDAA-HF-T(-) than CDAA-HF-T(+).

Conclusions: Replacement of dietary TFAs with a substitute promoted the development of proliferation lesions in the liver of a mouse NASH model, at least under the present conditions. Attention should be paid regarding use of TFA substitutes in foods for human consumption, and a balance of FAs is likely more important than the particular types of FAs.
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http://dx.doi.org/10.1186/s12944-020-01423-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737357PMC
December 2020

The left main bronchus transected incorrectly during video-assisted thoracoscopic lobectomy: a case report.

Surg Case Rep 2020 Nov 19;6(1):291. Epub 2020 Nov 19.

Department of Thoracic Surgery, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.

Background: Several severe intraoperative complications of lung cancer surgery have been reported, but the incorrect transection of the main bronchus is a very rare and serious complication. We report a surgical case of a patient with left lower lobe lung cancer invading the inferior segment of the lingula, with fused interlobar fissure and dense pleural adhesion, in which the left main bronchus was mistaken for the left lower lobe bronchus and was transected.

Case Presentation: A 64-year-old woman with lung adenocarcinoma was referred to our hospital for surgical treatment. Chest computed tomography (CT) scan showed a 30-mm nodule with a clear border and irregular margins in the center of the anterior (S8) segment of the lower lobe of the left lung and another similar 30-mm nodule in the lateral (S9) segment of the same lobe. Metastasis within the same lobe was suspected. A thoracoscopic left lower lobectomy was scheduled for the patient. As the patient had a moderately, fused fissure, dense pleural adhesion, and suspicious tumor invasion from the left S8 segment to the left S5 segment, and the interlobar node tightly adhered to the main PA at the site of basilar artery origin of the LLL, we performed left lower lobectomy and a left S5 segmentectomy using the fissureless fissure-last technique. During surgery, the left main bronchus was mistaken for the left lower lobe bronchus and was transected. After transecting the left main bronchus, we performed a sleeve bronchoplasty to prevent pneumonectomy.

Conclusions: We experienced the rare and serious intraoperative complication of the incorrect transection of the main bronchus. There are few reports of this intraoperative complication, and it should not be overlooked by surgeons.
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http://dx.doi.org/10.1186/s40792-020-01073-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677413PMC
November 2020

Assessment of MGMT methylation status using high-performance liquid chromatography in newly diagnosed glioblastoma.

Clin Epigenetics 2020 11 17;12(1):174. Epub 2020 Nov 17.

Departments of Neurosurgery, University of Yamanashi, Chuo, Yamanashi, Japan.

Background: The utility of O-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation status as a prognostic marker in patients with glioblastoma (GBM) has been established. However, the number of CpG sites that must be methylated to cause transcriptional silencing remains unclear, and no significant consensus exists on the optimal method of assessing MGMT methylation. We developed a new high-performance liquid chromatography (HPLC) method that enables accurate analysis of DNA methylation levels using long PCR products. In the present study, we analyzed the MGMT methylation status of 28 isocitrate dehydrogenase-wild-type GBMs treated with temozolomide using ion-exchange HPLC and set the optimal cutoff values.

Results: We designed three primers for separate regions (regions 1-3) that had 21 to 38 CpGs for PCR and validated the MGMT promoter methylation status using frozen samples. There was a strong correlation between HPLC and bisulfite sequencing results (R = 0.794). The optimal cutoff values for MGMT methylation in HPLC were determined to allow differentiation of patient prognosis by receiver operating characteristic curve analysis. The cutoff values were 34.15% for region 1, 8.84% for region 2, and 36.72% for region 3. Kaplan-Meyer curve analysis estimated that the most differentiated prognosis was enabled in the setting of 8.84% methylation of MGMT in region 2. Progression-free survival and overall survival were significantly longer for patients in this setting of region 2 methylation (p = 0.00365 and p = 0.00258, respectively).

Conclusions: The combination of our HPLC method and the original primer setting provides a new standard method for determination of MGMT methylation status in patients with GBM and is useful for refining MGMT-based drug selection.
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http://dx.doi.org/10.1186/s13148-020-00968-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672949PMC
November 2020

Hybrid emergency room shows maximum effect on trauma resuscitation when used in patients with higher severity.

J Trauma Acute Care Surg 2021 02;90(2):232-239

From the Division of Trauma and Surgical Critical Care (Y.U., A.W., N.M., S.F.), Osaka General Medical Center, Osaka; Department of Traumatology and Acute Critical Medicine (T.K.), Graduate School of Medicine, Osaka University, Suita; and Department of Emergency Medicine (K.Y.), Osaka Medical College, Osaka, Japan.

Background: The hybrid emergency room (ER) system is a novel trauma workflow that uses angio-computed tomography equipment in a trauma resuscitation room. Although the hybrid ER system decreases time to start surgery and endovascular treatments and improves mortality, the optimal target benefitting from this system remained unclear. We aimed to identify a subset of trauma patients likely to receive the greatest benefits from the hybrid ER.

Methods: This retrospective cohort study was conducted in a tertiary hospital in Japan from August 2007 to January 2020. We consecutively included severe adult blunt trauma patients (Injury Severity Score [ISS], ≥16) and divided them into two groups: conventional group (August 2007 to July 2011) and hybrid ER (August 2011 to January 2020) group. We evaluated the association between the hybrid ER group and 28-day mortality using multivariable logistic regression analysis. The 28-day mortality trend during the study period was evaluated with restricted cubic spline analysis. To evaluate heterogeneity of effects within various patient severities, we evaluated whether the patients' ISS modified the effect of the hybrid ER on survival.

Results: Among 1,050 trauma patients, the conventional group comprised 360 patients and the hybrid ER group comprised 690 patients. Injury Severity Score and probability of survival (Ps) were not significantly different between the groups. Twenty-eight-day mortality was significantly lower in the hybrid ER group (Ps-adjusted odds ratio, 0.48; 95% confidence interval, 0.32-0.71; p < 0.001). Restricted cubic spline analysis revealed that Ps-adjusted 28-day mortality sharply decreased approximately 200 days after installation of the hybrid ER. Increase of survival probabilities according to the increase of ISS was significantly improved in hybrid ER group (p = 0.014). Because ISS increased to >25, survival probabilities in the hybrid ER group were higher compared with those in the conventional group.

Conclusion: The hybrid ER may improve posttraumatic mortality, especially in patients with higher baseline severity.

Level Of Evidence: Therapeutic/care management, level IV.
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http://dx.doi.org/10.1097/TA.0000000000003020DOI Listing
February 2021

Inherited genetic variants associated with glucocorticoid sensitivity in leukaemia cells.

J Cell Mol Med 2020 11 1;24(22):12920-12932. Epub 2020 Oct 1.

Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan.

Identification of genetic variants associated with glucocorticoids (GC) sensitivity of leukaemia cells may provide insight into potential drug targets and tailored therapy. In the present study, within 72 leukaemic cell lines derived from Japanese patients with B-cell precursor acute lymphoblastic leukaemia (ALL), we conducted genome-wide genotyping of single nucleotide polymorphisms (SNP) and attempted to identify genetic variants associated with GC sensitivity and NR3C1 (GC receptor) gene expression. IC50 measures for prednisolone (Pred) and dexamethasone (Dex) were available using an alamarBlue cell viability assay. IC50 values of Pred showed the strongest association with rs904419 (P = 4.34 × 10 ), located between the FRMD4B and MITF genes. The median IC50 values of prednisolone for cell lines with rs904419 AA (n = 13), AG (n = 31) and GG (n = 28) genotypes were 0.089, 0.139 and 297 µmol/L, respectively. For dexamethasone sensitivity, suggestive association was observed for SNP rs2306888 (P = 1.43 × 10 ), a synonymous SNP of the TGFBR3 gene. For NR3C1 gene expression, suggestive association was observed for SNP rs11982167 (P = 6.44 × 10 ), located in the PLEKHA8 gene. These genetic variants may affect GC sensitivity of ALL cells and may give rise to opportunities in personalized medicine for effective and safe chemotherapy in ALL patients.
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http://dx.doi.org/10.1111/jcmm.15882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701530PMC
November 2020

Marked motor function improvement in a 32-year-old woman with childhood-onset hypophosphatasia by asfotase alfa therapy: Evaluation based on standardized testing batteries used in Duchenne muscular dystrophy clinical trials.

Mol Genet Metab Rep 2020 Dec 9;25:100643. Epub 2020 Sep 9.

Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan.

Hypophosphatasia (HPP) is a rare disorder resulting from biallelic loss-of-function variants or monoallelic dominant negative variants in the gene. We herein describe the clinical outcome of a 32-year-old woman with childhood-onset HPP caused by compound heterozygous variants in . Her chief complaints were severe musculoskeletal pain, muscle weakness, and impaired daily activities necessitating assistance in housework and child-rearing in addition to a history of early tooth loss and mildly short stature. Asfotase alfa therapy produced a remarkable increase in muscle strength and daily activities and markedly reduced musculoskeletal pain. Drug efficacy was clearly demonstrated through multiple test batteries (muscle strength test using microFET®2, six-minute walking test, Stair Climb Test, rising-from-floor-time test, and number-of-steps test using Actigraph®) currently adopted as standardized evaluations in Duchenne muscular dystrophy clinical trials since no test batteries for HPP have been established to date. These tests may also be promising for the assessment of HPP.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494508PMC
December 2020
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