Publications by authors named "Kotaro Matsumoto"

125 Publications

Lenvatinib for poorly differentiated carcinoma of the anterior mediastinum.

Respir Med Case Rep 2021 12;33:101477. Epub 2021 Jul 12.

Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, Japan.

We describe a Case of a 74-year-old Japanese man with poorly differentiated carcinoma of the anterior mediastinum. The patient underwent anterior mediastinal tumor resection through median sternotomy. The tumor, 7.0 × 5.0 cm, had invaded surrounding tissues (pericardium, right lung, right and left brachiocephalic veins, and superior vena cava). Complete resection of the tumor was not performed. One month after the operation, the patient developed multiple pulmonary metastases, right pleural dissemination, and carcinomatous pleurisy. He was treated with lenvatinib, a novel multi-kinase inhibitor, to which the metastasis responded favorably. This case reports for the first time the clinical usefulness of lenvatinib for poorly differentiated carcinoma of the anterior mediastinum. Management of side effects by several methods, including suspending use of medication on weekends (called a weekends-off strategy), is another strong argument to continue lenvatinib administration.
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http://dx.doi.org/10.1016/j.rmcr.2021.101477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349103PMC
July 2021

Iodine containing porous organosilica nanoparticles trigger tumor spheroids destruction upon monochromatic X-ray irradiation: DNA breaks and K-edge energy X-ray.

Sci Rep 2021 Jul 14;11(1):14192. Epub 2021 Jul 14.

Institute for Integrated Cell-Material Sciences, Institute for Advanced Study, Kyoto University, Kyoto, Japan.

X-ray irradiation of high Z elements causes photoelectric effects that include the release of Auger electrons that can induce localized DNA breaks. We have previously established a tumor spheroid-based assay that used gadolinium containing mesoporous silica nanoparticles and synchrotron-generated monochromatic X-rays. In this work, we focused on iodine and synthesized iodine-containing porous organosilica (IPO) nanoparticles. IPO were loaded onto tumor spheroids and the spheroids were irradiated with 33.2 keV monochromatic X-ray. After incubation in CO incubator, destruction of tumor spheroids was observed which was accompanied by apoptosis induction, as determined by the TUNEL assay. By employing the γH2AX assay, we detected double strand DNA cleavages immediately after the irradiation. These results suggest that IPO first generate double strand DNA breaks upon X-ray irradiation followed by apoptosis induction of cancer cells. Use of three different monochromatic X-rays having energy levels of 33.0, 33.2 and 33.4 keV as well as X-rays with 0.1 keV energy intervals showed that the optimum effect of all three events (spheroid destruction, apoptosis induction and generation of double strand DNA breaks) occurred with a 33.2 keV monochromatic X-ray. These results uncover the preferential effect of K-edge energy X-ray for tumor spheroid destruction mediated by iodine containing nanoparticles.
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http://dx.doi.org/10.1038/s41598-021-93429-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280225PMC
July 2021

Interleukin-1 pathway in active large vessel vasculitis patients with a poor prognosis: a longitudinal transcriptome analysis.

Clin Transl Immunology 2021 2;10(7):e1307. Epub 2021 Jul 2.

Division of Rheumatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan.

Objectives: Large vessel vasculitis (LVV) is characterised by a high relapse rate. Because accurate assessment of the LVV disease status can be difficult, an accurate prognostic marker for initial risk stratification is required. We conducted a comprehensive longitudinal investigation of next-generation RNA-sequencing data for patients with LVV to explore useful biomarkers associated with clinical characteristics.

Methods: Key molecular pathways relevant to LVV pathogenesis were identified by examining the whole blood RNA from patients with LVV and healthy controls (HCs). The data were examined by pathway analysis and weighted gene correlation network analysis (WGCNA) to identify functional gene sets that were differentially expressed between LVV patients and HCs, and associated with clinical features. We then compared the expression of the selected genes during week 0, week 6, remission and relapse.

Results: The whole-transcriptome gene expression data for 108 samples obtained from LVV patients ( = 27) and HCs ( = 12) were compared. The pathway analysis and WGCNA revealed that molecular pathway related to interleukin (IL)-1 was significantly upregulated in LVV patients compared with HCs, which correlated with the positron emission tomography vascular activity score, a disease-extent score based on the distribution of affected arteries. Further analysis revealed that the expression levels of genes in the IL-1 signalling pathway remained high after conventional treatment and were associated with disease relapse.

Conclusion: Upregulation of the IL-1 signalling pathway was a characteristic of LVV patients and was associated with the extent of disease and a poor prognosis.
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http://dx.doi.org/10.1002/cti2.1307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251870PMC
July 2021

Chemotherapy with gemcitabine for unresectable intrahepatic cholangiocarcinoma in a patient undergoing maintenance hemodialysis.

Clin J Gastroenterol 2021 Oct 9;14(5):1511-1516. Epub 2021 Jul 9.

Department of Gastroenterology, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan.

A 56-year-old man with chronic renal failure due to diabetic nephropathy had received maintenance dialysis (every 4 h, three times/week). A hypoechoic tumor measuring 67 × 50 mm in the right lobe of the liver was discovered following routine abdominal ultrasonography. Dynamic computed tomography showed a low-density liver tumor, enlarged hilar lymph node, and a small nodule on the dorsal side of the lower lobe of the left lung. Histopathological examination of the liver tumor revealed intrahepatic cholangiocarcinoma. We developed a chemotherapy treatment plan with gemcitabine, which can be performed concurrently with hemodialysis. Gemcitabine (1000 mg/m, three times/cycle) was administered on Friday afternoon, and hemodialysis was performed on Tuesday, Thursday, and Saturday. Anemia and hypotension occurred after gemcitabine administration. Therefore, the dose of darbepoetin alpha was increased, and packed red blood cells were transfused. The patient was treated with gemcitabine for approximately 5 and a half months until computed tomography findings showed progressive disease; the survival time after treatment start was 8 months. Chemotherapy using gemcitabine has not been established in dialysis patients and has little evidence. We report a case of unresectable intrahepatic cholangiocarcinoma that developed during maintenance dialysis and was treated using gemcitabine chemotherapy.
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http://dx.doi.org/10.1007/s12328-021-01478-4DOI Listing
October 2021

Maresin-1 induces cardiomyocyte hypertrophy through IGF-1 paracrine pathway.

Am J Physiol Cell Physiol 2021 07 26;321(1):C82-C93. Epub 2021 May 26.

Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

The resolution of inflammation is closely linked with tissue repair. Recent studies have revealed that macrophages suppress inflammatory reactions by producing lipid mediators, called specialized proresolving mediators (SPMs); however, the biological significance of SPMs in tissue repair remains to be fully elucidated in the heart. In this study, we focused on maresin-1 (MaR1) and examined the reparative effects of MaR1 in cardiomyocytes. The treatment with MaR1 increased cell size in cultured neonatal rat cardiomyocytes. Since the expression of fetal cardiac genes was unchanged by MaR1, physiological hypertrophy was induced by MaR1. SR3335, an inhibitor of retinoic acid-related orphan receptor α (RORα), mitigated MaR1-induced cardiomyocyte hypertrophy, consistent with the recent report that RORα is one of MaR1 receptors. Importantly, in response to MaR1, cardiomyocytes produced IGF-1 via RORα. Moreover, MaR1 activated phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and wortmannin, a PI3K inhibitor, or triciribine, an Akt inhibitor, abrogated MaR1-induced cardiomyocyte hypertrophy. Finally, the blockade of IGF-1 receptor by NVP-AEW541 inhibited MaR-1-induced cardiomyocyte hypertrophy as well as the activation of PI3K/Akt pathway. These data indicate that MaR1 induces cardiomyocyte hypertrophy through RORα/IGF-1/PI3K/Akt pathway. Considering that MaR1 is a potent resolving factor, MaR1 could be a key mediator that orchestrates the resolution of inflammation with myocardial repair.
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http://dx.doi.org/10.1152/ajpcell.00568.2020DOI Listing
July 2021

Disseminated Bone Marrow Carcinomatosis Due to Malignant Melanoma of Unknown Primary Origin.

Intern Med 2021 May 22. Epub 2021 May 22.

Department of Gastroenterology, Teikyo University Mizonokuchi Hospital, Japan.

An 80-year-old woman was admitted to our hospital due to appetite loss and vomiting. A blood examination showed liver disorder with disseminated intravascular coagulation. All tumor markers and hepatitis virus markers were negative. Contrast-enhanced computed tomography did not show tumor lesions, bone lesions, lymphadenopathies, or thrombosis. A bone marrow biopsy revealed large, atypical cells with brown pigmentation and positive immunostaining for HMB-45, S100 proteins, and CD79a without myeloid or lymphoid markers. We experienced a case of disseminated carcinomatosis of the bone marrow due to malignant melanoma of unknown primary origin.
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http://dx.doi.org/10.2169/internalmedicine.7274-21DOI Listing
May 2021

Identification of neutrophil β2-integrin LFA-1 as a potential mechanistic biomarker in ANCA-associated vasculitis via microarray and validation analyses.

Arthritis Res Ther 2021 05 6;23(1):136. Epub 2021 May 6.

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.

Background: Leukocyte activation by anti-neutrophil cytoplasmic antibody (ANCA) and the subsequent leukocyte-endothelium interaction play a key role in the development of endothelial damage in ANCA-associated vasculitis (AAV). In contrast to that of leukocyte activation, the exact role of the leukocyte-endothelium interaction via integrin remains unclear. Here, we performed microarray and validation analyses to explore association between the expression levels of lymphocyte function-associated antigen-1 (LFA-1) and the clinical characteristics of patients with AAV.

Methods: We performed gene set enrichment analysis (GSEA) to identify the functional gene sets differentially expressed between patients with AAV and other types of vasculitis and the healthy controls (HCs). Flow cytometry was performed to validate the GSEA results. Treatment-naïve patients were monitored until 24 weeks of treatment. To examine the role of LFA-1 in the neutrophil-endothelium interaction, we performed a leukocyte adhesion and transmigration assay using peripheral blood and human umbilical vein endothelial cells (HUVECs).

Results: GSEA revealed that the molecular pathways involving integrin-related genes were significantly upregulated in patients with AAV compared to that in patients with other types of vasculitis and the HCs. Flow cytometry revealed that the percentage of neutrophils expressing LFA-1 was significantly higher in patients with AAV than in those with large-vessel vasculitis or polyarteritis nodosa and the HCs. LFA-1 levels in the neutrophils were higher in patients with MPO-ANCA-positive expression than in those with a positive PR3-ANCA expression and correlated with the peripheral eosinophil count, serum rheumatoid factor titre, serum C-reactive protein levels, and the vasculitis activity score of systemic and chest components. After 24 weeks of treatment, including prednisolone, cyclophosphamide, rituximab, azathioprine, methotrexate, and/or tacrolimus, neutrophil LFA-1 expression remained high in the non-responder patients, but decreased in the responder patients. The in vitro assay showed that leukocyte migration toward HUVECs was dependent on the interaction between LFA-1 and intercellular adhesion molecule-1 (ICAM1); the migration of leukocytes was inhibited by blocking the adhesion of LFA-1 to ICAM1.

Conclusions: The expression of LFA-1 in neutrophils is increased in patients with AAV. Neutrophil LFA-1 levels correlate with the clinical features of AAV. Inhibiting the adhesion of LFA-1 and ICAM1 impedes the neutrophil-endothelium interaction and may have a therapeutic role in AAV.
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http://dx.doi.org/10.1186/s13075-021-02510-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101175PMC
May 2021

Cardiomyopathy in a dog with multicentric lymphoma following treatment with several anthracyclines.

Open Vet J 2021 Jan-Mar;11(1):6-10. Epub 2021 Jan 7.

Department of Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.

Background: Canine lymphoma is one of the most frequently occurring malignant neoplasms in dogs. Anthracycline-based chemotherapy for the treatment of canine lymphoma is very effective; however, there is not enough evidence for the development of cardiac toxicity using several anthracyclines as chemotherapeutic agents.

Case Description: An 8-year-old, castrated, mixed-breed dog was diagnosed with multicentric lymphoma and received multi-agent chemotherapy. Complete remission was achieved, but the patient had a relapse of lymphoma. After third-line chemotherapy with epirubicin, the patient was diagnosed with dilated cardiomyopathy. The total cumulative doses of doxorubicin, mitoxantrone, and epirubicin were 125, 8, and 125 mg/m, respectively. Although the patient was treated with cardiac drugs and clinically stabilized, the patient had a relapse of lymphoma and died shortly after the diagnosis of cardiomyopathy.

Conclusion: The patient was suspected to have anthracycline-induced cardiomyopathy. Further studies are required to establish prevention and management strategies for dogs receiving potentially cardiotoxic therapies, such as anthracyclines.
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http://dx.doi.org/10.4314/ovj.v11i1.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057218PMC
January 2021

Analysis of the bone morphogenetic protein 6 gene promoter region in young beef cattle affected by enzootic bovine leukosis.

J Vet Med Sci 2021 Jun 9;83(6):898-904. Epub 2021 Apr 9.

Veterinary Medical Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.

Enzootic bovine leukosis (EBL) is typically observed in cattle over 3 years old. However, some cases of EBL onset in young beef cattle have been reported in Japan. The mechanism for early EBL onset is unclear. In Japan, beef cattle are given large amounts of concentrated feed with low vitamin A. Bone morphogenetic proteins (BMPs) are regulators of cell proliferation, differentiation, and apoptosis, and thought to represent one of the key players in tumor malignancy. The purpose of this study was to evaluate the differences in BMP-6 methylation status between EBL beef cattle under 3 years old and other cattle. We investigated the methylation status of the BMP-6 promoter region in 32 EBL beef cattle under 3 years old. We also compared the methylation status of EBL dairy cattle to that of healthy cattle. Median methylation rate of the BMP-6 promoter region in EBL beef cattle under 3 years old was 8.9%, which was significantly higher than that of other groups. Hypermethylation of the BMP-6 promoter region might contribute to early onset of EBL in beef cattle under 3 years old, and animal feeding management practices specific to beef cattle may affect the methylation status of the BMP-6 promoter region.
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http://dx.doi.org/10.1292/jvms.20-0663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267195PMC
June 2021

A clinical case of acute myelomonocytic leukemia in a Holstein cow.

J Vet Med Sci 2021 May 22;83(5):819-823. Epub 2021 Mar 22.

Veterinary Medical Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.

A 2-year, 3-month-old Holstein cow presented with anorexia and enlarged superficial lymph nodes. Fine needle aspiration cytology of the superficial lymph nodes revealed large blast cells. Hematological examination revealed anemia, neutropenia, and blast cells in peripheral blood. Blast cells were the predominant cell type in bone marrow aspirates. Of the non-erythroid cells, 26%, 58%, and 18% were positive for myeloperoxidase, α-naphthyl acetate esterase, and naphthol AS-D chloroacetate esterase, respectively. Pathological examination revealed the proliferation of neoplastic cells, which were positive for monocytic markers, in the affected lymph nodes. The cow was diagnosed with acute myelomonocytic leukemia based on these findings. This report highlights the importance of performing bone marrow aspiration cytology and cytochemical staining when diagnosing bovine myeloid leukemia.
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http://dx.doi.org/10.1292/jvms.20-0618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182308PMC
May 2021

A case of dropped head syndrome due to focal myositis that worsened with cellulitis and improved only by treatment of cellulitis.

Mod Rheumatol Case Rep 2021 07 31;5(2):431-436. Epub 2021 Mar 31.

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Dropped head syndrome due to focal myositis is extremely rare. Due to the rarity of the disease, its clinical characteristics and prognosis remain unknown. We present a unique case of dropped head syndrome due to focal myositis that exacerbated following cellulitis and was dramatically improved along with the improvement of her cellulitis only treated with antibiotics. We should consider the possibility of preceding trigger event such as infection when we face with the exacerbation of focal myositis before making a decision of strengthening immunosuppressive therapy to avoid unnecessary increase of glucocorticoid.
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http://dx.doi.org/10.1080/24725625.2021.1899381DOI Listing
July 2021

Construction of Boronophenylalanine-Loaded Biodegradable Periodic Mesoporous Organosilica Nanoparticles for BNCT Cancer Therapy.

Int J Mol Sci 2021 Feb 24;22(5). Epub 2021 Feb 24.

Institute for Integrated Cell-Material Sciences, Institute for Advanced Study, Kyoto University, Kyoto 606-8501, Japan.

Biodegradable periodic mesoporous organosilica (BPMO) has recently emerged as a promising type of mesoporous silica-based nanoparticle for biomedical applications. Like mesoporous silica nanoparticles (MSN), BPMO possesses a large surface area where various compounds can be attached. In this work, we attached boronophenylalanine (BPA) to the surface and explored the potential of this nanomaterial for delivering boron-10 for use in boron neutron capture therapy (BNCT). This cancer therapy is based on the principle that the exposure of boron-10 to thermal neutron results in the release of a-particles that kill cancer cells. To attach BPA, the surface of BPMO was modified with diol groups which facilitated the efficient binding of BPA, yielding BPA-loaded BPMO (BPA-BPMO). Surface modification with phosphonate was also carried out to increase the dispersibility of the nanoparticles. To investigate this nanomaterial's potential for BNCT, we first used human cancer cells and found that BPA-BPMO nanoparticles were efficiently taken up into the cancer cells and were localized in perinuclear regions. We then used a chicken egg tumor model, a versatile and convenient tumor model used to characterize nanomaterials. After observing significant tumor accumulation, BPA-BPMO injected chicken eggs were evaluated by irradiating with neutron beams. Dramatic inhibition of the tumor growth was observed. These results suggest the potential of BPA-BPMO as a novel boron agent for BNCT.
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http://dx.doi.org/10.3390/ijms22052251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956258PMC
February 2021

Designing Mesoporous Silica Nanoparticles to Overcome Biological Barriers by Incorporating Targeting and Endosomal Escape.

ACS Appl Mater Interfaces 2021 Mar 17;13(8):9656-9666. Epub 2021 Feb 17.

Chemistry in Pharmaceutical Sciences, School of Pharmacy, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Pz/Ramón y Cajal s/n, Madrid 28040, Spain.

The several biological barriers that nanoparticles might encounter when administered to a patient constitute the major bottleneck of nanoparticle-mediated tumor drug delivery, preventing their successful translation into the clinic and reducing their therapeutic profile. In this work, mesoporous silica nanoparticles have been employed as a platform to engineer a versatile nanomedicine able to address such barriers, achieving (a) excessive premature drug release control, (b) accumulation in tumor tissues, (c) selective internalization in tumoral cells, and (d) endosomal escape. The nanoparticles have been decorated with a self-immolative redox-responsive linker to prevent excessive premature release, to which a versatile and polyvalent peptide that is able to recognize tumoral cells and induce the delivery of the nanoparticles to the cytoplasm via endosomal escape has been grafted. The excellent biological performance of the carrier has been demonstrated using 2D and 3D cell cultures and a tumor-bearing chicken embryo model, demonstrating in all cases high biocompatibility and cytotoxic effect, efficient endosomal escape and tumor penetration, and accumulation in tumors grown on the chorioallantoic membrane of chicken embryos.
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http://dx.doi.org/10.1021/acsami.0c21507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944478PMC
March 2021

Immunohistochemical detection of procalcitonin in fibrolamellar hepatocellular carcinoma.

Clin J Gastroenterol 2021 Jun 10;14(3):827-830. Epub 2021 Feb 10.

Department of Gastroenterology, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan.

A 25-year-old woman with fever and epigastric pain was referred to our hospital. Blood examination showed significant liver dysfunction, markedly high C-reactive protein (CRP 19.1 mg/dL) and procalcitonin (48.3 ng/mL) levels. Dynamic computed tomography showed a tumor approximately 120 mm in size in the right lobe of the liver, but with no abscess formation. The patient was hospitalized and started on antibiotics; her CRP level improved, but the procalcitonin level did not decrease. Histopathological examination of the liver tumor biopsy revealed fibrolamellar hepatocellular carcinoma (FLC). Positive staining of the FLC with an anti-procalcitonin antibody suggested the production of procalcitonin.
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http://dx.doi.org/10.1007/s12328-021-01354-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154767PMC
June 2021

Platelet CXCL4 mediates neutrophil extracellular traps formation in ANCA-associated vasculitis.

Sci Rep 2021 01 8;11(1):222. Epub 2021 Jan 8.

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Neutrophils form neutrophil extracellular traps (NETs), which are involved in the pathogenesis of ANCA-associated vasculitis (AAV). Recent reports suggest that platelets stimulated via toll-like receptor (TLR) pathways can induce NETs formation. However, the mechanism underlying the involvement of platelets in NETs formation in AAV is unknown. We investigated the role of platelets in the pathogenesis of AAV. Platelets from AAV patients and healthy controls (HCs) were co-cultured with peripheral neutrophils, and NETs formation was visualized and quantified. The expression levels of TLRs on platelets were examined by flow cytometry. Platelets were treated with a TLR agonist, platelet-derived humoral factor, CXCL4 (platelet factor 4: PF4), and/or anti-CXCL4 antibody to investigate the effects of TLR-CXCL4 signaling on NETs formation. Platelets from AAV significantly upregulated NETs formation in vitro. Flow cytometric analysis revealed that the proportion of TLR9 positive platelets was significantly higher in AAV than HCs. CXCL4 released from TLR9 agonist-stimulated platelets was significantly enhanced in AAV, which subsequently increased NETs formation. Further, neutralizing anti-CXCL4 antibody significantly inhibited NETs formation enhanced by platelets from AAV. TLR9 signaling and CXCL4 release underlie the key role that platelets play in NETs formation in the pathogenesis of AAV.
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http://dx.doi.org/10.1038/s41598-020-80685-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794527PMC
January 2021

Transcription factor old astrocyte specifically induced substance is a novel regulator of kidney fibrosis.

FASEB J 2021 02 5;35(2):e21158. Epub 2020 Nov 5.

Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Prevention of kidney fibrosis is an essential requisite for effective therapy in preventing chronic kidney disease (CKD). Here, we identify Old astrocyte specifically induced substance (OASIS)/cAMP responsive element-binding protein 3-like 1 (CREB3l1), a CREB/ATF family transcription factor, as a candidate profibrotic gene that drives the final common pathological step along the fibrotic pathway in CKD. Although microarray data from diseased patient kidneys and fibrotic mouse model kidneys both exhibit OASIS/Creb3l1 upregulation, the pathophysiological roles of OASIS in CKD remains unknown. Immunohistochemistry revealed that OASIS protein was overexpressed in human fibrotic kidney compared with normal kidney. Moreover, OASIS was upregulated in murine fibrotic kidneys, following unilateral ureteral obstruction (UUO), resulting in an increase in the number of OASIS-expressing pathological myofibroblasts. In vitro assays revealed exogenous TGF-β1 increased OASIS expression coincident with fibroblast-to-myofibroblast transition and OASIS contributed to TGF-β1-mediated myofibroblast migration and increased proliferation. Significantly, in vivo kidney fibrosis induced via UUO or ischemia/reperfusion injury was ameliorated by systemic genetic knockout of OASIS, accompanied by reduced myofibroblast proliferation. Microarrays revealed that the transmembrane glycoprotein Bone marrow stromal antigen 2 (Bst2) expression was reduced in OASIS knockout myofibroblasts. Interestingly, a systemic anti-Bst2 blocking antibody approach attenuated kidney fibrosis in normal mice but not in OASIS knockout mice after UUO, signifying Bst2 functions downstream of OASIS. Finally, myofibroblast-restricted OASIS conditional knockouts resulted in resistance to kidney fibrosis. Taken together, OASIS in myofibroblasts promotes kidney fibrosis, at least in part, via increased Bst2 expression. Thus, we have identified and demonstrated that OASIS signaling is a novel regulator of kidney fibrosis.
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http://dx.doi.org/10.1096/fj.202001820RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821213PMC
February 2021

Clinical Features and Liver Injury in Patients with COVID-19 in the Japanese Population.

Intern Med 2020 1;59(19):2353-2358. Epub 2020 Oct 1.

Department of Medicine, Teikyo University School of Medicine, Japan.

Objective Liver injury is a notable complication of coronavirus disease 2019 (COVID-19). This study aimed to clarify the clinical features and liver injury in Japanese patients with COVID-19. Methods We conducted a multicenter retrospective cohort study. All consecutive patients with COVID-19 who visited or were admitted to our hospital before May 12, 2020, were enrolled. Their demographics, symptoms, laboratory findings, comorbidities, concomitant drugs, treatment, and clinical course were reviewed. We defined liver injury as alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) levels over the upper limit of normal. Results Twenty-two patients with COVID-19 (median age, 47 years old; men/women, 13/9) were enrolled. Two patients had underlying liver diseases, and two were diagnosed as having COVID-19 without any symptoms. Elevated ALT and GGT levels were found in 12 and 12 patients, respectively, and liver injury was observed in 15 patients (68.2%). Compared with the patients without liver injury, those with liver injury had a significantly higher fever during the clinical course (median, 37.5°C vs. 38.8°C, p=0.006). A significant correlation was found between the highest serum liver values and the highest body temperature in each patient. Among the 22 patients, 4 required artificial respiratory support, and 2 died thereafter. Liver injury was not associated with the severity or mortality of COVID-19. Conclusion Elevated levels of liver enzymes in the Japanese patients with COVID-19 were associated with the highest body temperature during the clinical course but not with the severity or mortality of COVID-19.
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http://dx.doi.org/10.2169/internalmedicine.5777-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644502PMC
October 2020

Distinct features between HLA-DR+ and HLA-DR- PD-1hi CXCR5- T peripheral helper cells in seropositive rheumatoid arthritis.

Rheumatology (Oxford) 2021 01;60(1):451-460

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo.

Objectives: PD-1hi CXCR5- T peripheral helper (Tph) cells are newly identified pathogenic CD4 helper T cells in RA. We evaluated the usefulness of Tph cell subsets as biomarkers of RA.

Methods: RA patients who visited our rheumatology department between May 2015 and September 2017 and met the 2010 ACR/EULAR classification criteria were included. We compared the correlation of DAS28-ESR between Tph cell subsets and 40 immune cell subsets. We also explored which subsets reflected the chronological changes in the disease activity after treatment.

Results: Thirty-four seropositive RA patients, 11 seronegative RA patients and 34 healthy controls were included. Tph cell subsets that correlated with the DAS28-ESR were HLA-DR+ Tph cells (rs = 0.50, P = 0.002), HLA-DR- Tph cells (rs = 0.39, P = 0.03) and Tph1 cells (rs = 0.41, P = 0.02). Among the other 40 immune cell subsets, HLA-DR+ Th1-17 cells (rs = 0.38, P = 0.03), activated B cells (rs = -0.35, P = 0.04), plasma cells (rs = 0.43, P = 0.01) and CD14++ CD16+ monocytes (rs = 0.36, P = 0.04) correlated, but not strongly as HLA-DR+ Tph cells. However, MTX treatment reduced the proportion of HLA-DR+ Tph cells independently of the disease activity. In contrast, HLA-DR- Tph cells accurately reflected the change in the DAS28-ESR during MTX treatment.

Conclusion: HLA-DR+ Tph cells were decreased with MTX treatment, independent of the disease activity, while HLA-DR- Tph cells reflected the disease activity accurately during the treatment.
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http://dx.doi.org/10.1093/rheumatology/keaa417DOI Listing
January 2021

Studies on the Exposure of Gadolinium Containing Nanoparticles with Monochromatic X-rays Drive Advances in Radiation Therapy.

Nanomaterials (Basel) 2020 Jul 9;10(7). Epub 2020 Jul 9.

Kansai Photon Science Institute, Quantum Beam Science Research Directorate, National Institutes for Quantum and Radiological Science and Technology, Hyogo 679-0198, Japan.

While conventional radiation therapy uses white X-rays that consist of a mixture of X-ray waves with various energy levels, a monochromatic X-ray (monoenergetic X-ray) has a single energy level. Irradiation of high-Z elements such as gold, silver or gadolinium with a synchrotron-generated monochromatic X-rays with the energy at or higher than their K-edge energy causes a photoelectric effect that includes release of the Auger electrons that induce DNA damage-leading to cell killing. Delivery of high-Z elements into cancer cells and tumor mass can be facilitated by the use of nanoparticles. Various types of nanoparticles containing high-Z elements have been developed. A recent addition to this growing list of nanoparticles is mesoporous silica-based nanoparticles (MSNs) containing gadolinium (Gd-MSN). The ability of Gd-MSN to inhibit tumor growth was demonstrated by evaluating effects of irradiating tumor spheroids with a precisely tuned monochromatic X-ray.
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http://dx.doi.org/10.3390/nano10071341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408070PMC
July 2020

Longitudinal immune cell monitoring identified CD14 CD16 intermediate monocyte as a marker of relapse in patients with ANCA-associated vasculitis.

Arthritis Res Ther 2020 06 16;22(1):145. Epub 2020 Jun 16.

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease that affects small- to medium-sized blood vessels. Despite treatments having been improved, patients often experience disease relapses. It remains unclear how the immune cells involve in the development of vasculitis and how they fluctuate over the course of treatment. In this study, we aimed to identify the immune subsets and serum cytokines associated with disease relapse by comprehensive immuno-phenotyping in AAV patients.

Methods: We reviewed consecutive patients (n = 29) from Keio University Hospital who had been newly diagnosed with AAV from January 2015 to February 2019 and chronologically followed until 52 weeks. Numbers of circulating T cells, B cells, monocytes, and granulocytes were analyzed by flow cytometry (FACS). Serum levels of cytokines were measured by electrochemiluminescence enzyme immunoassay. Clinical information was obtained from patients' records and association with time-course changes in immuno-phenotypes and serum levels of cytokines were assessed.

Results: Comprehensive immuno-phenotyping data from 161 samples from 29 AAV patients at diagnosis; at weeks 4, 12, 24, and 52 of treatment; and at time of major relapse were examined. FACS analysis from patients with relapse revealed that CD14 CD16 intermediate monocytes and plasma cells concomitantly changed associated with disease relapse, which were independent from treatment regimen, ANCA status, or disease phenotype. In particular, the number of CD14 CD16 intermediate monocytes at relapse was significantly higher than that in remission or in healthy controls. Serum cytokine measurement revealed that changes of monocyte-derived proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α were associated with disease status.

Conclusions: Chronological changes in CD14 CD16 intermediate monocyte counts can be a marker of disease relapse in AAV patients.
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http://dx.doi.org/10.1186/s13075-020-02234-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298936PMC
June 2020

Acute monoblastic leukemia in a feline leukemia virus-negative cat.

J Vet Med Sci 2020 Jul 22;82(7):1000-1005. Epub 2020 May 22.

Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan.

A 12-year-old female domestic short-haired cat was presented due to weight loss, anorexia, and tachypnea. Complete blood count revealed severe anemia, leukocytosis with massive undifferentiated blast cells, and thrombocytopenia. Bone marrow aspiration showed acute myeloid leukemia, subclassified as monoblastic leukemia (M5a) based on the outcomes of the cytochemistry examinations. The SNAP feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) test using whole blood was negative. In addition, FeLV/FIV proviral polymerase chain reaction test using bone marrow aspirate was also negative. Although the cat was treated with doxorubicin, cytosine arabinoside, and prednisolone, anemia did not improve without blood transfusion. The owner declined further treatment after 2 months, and the cat died a few days later.
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http://dx.doi.org/10.1292/jvms.20-0157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399316PMC
July 2020

β2-adrenergic stimulation induces interleukin-6 by increasing Arid5a, a stabilizer of mRNA, through cAMP/PKA/CREB pathway in cardiac fibroblasts.

Pharmacol Res Perspect 2020 04;8(2):e00590

Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.

Background And Purpose: In cardiovascular diseases, cardiac fibroblasts (CFs) participate in the myocardial inflammation by producing pro-inflammatory cytokines, worsening the prognosis. β2-adrenergic receptor (AR) and β3AR are expressed in CFs, and β-adrenergic stimulation promotes CFs to produce pro-inflammatory cytokines. However, the mechanism of the expression of pro-inflammatory cytokines in response to β-adrenergic stimulation remains to be fully elucidated.

Experimental Approach: CFs were isolated from adult wild-type or AT-rich interactive domain-containing protein 5A (Arid5a) knockout mice. The expression of mRNA was measured by real-time RT-PCR. Interleukin (IL)-6 protein was measured by ELISA. The activity of nuclear factor-κB (NF-κB) and cyclic AMP (cAMP) response element binding protein (CREB) was assessed by ELISA-like assay or Western blotting.

Key Results: The β-adrenergic stimulation remarkably induced IL-6 mRNA and protein through β2AR in CFs. The activation of adenylate cyclase and the enhancement of intracellular cAMP resulted in the upregulation of IL-6 mRNA expression. The induction of IL-6 transcript by β2AR signaling was independent of NF-κB. Concomitant with IL-6, the expression of Arid5a, an IL-6 mRNA stabilizing factor, was enhanced by β2-adrenergic stimulation and by cAMP increase. Importantly, β2AR signaling-mediated IL-6 induction was suppressed in Arid5a knockout CFs. Finally, β2AR stimulation phosphorylated CREB via PKA pathway, and the activation of CREB was essential for the induction of Arid5a and IL-6 mRNA.

Conclusion And Implications: β2-adrenergic stimulation post-transcriptionally upregulates the expression of IL-6 by the induction of Arid5a through cAMP/PKA/CREB pathway in adult CFs. β2AR/Arid5a/IL-6 axis could be a therapeutic target against cardiac inflammation.
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http://dx.doi.org/10.1002/prp2.590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164407PMC
April 2020

Distinguishing coagulase-negative Staphylococcus bacteremia from contamination using blood-culture positive bottle detection pattern and time to positivity.

J Infect Chemother 2020 Jul 2;26(7):672-675. Epub 2020 Mar 2.

Central Laboratory, Teikyo University Mizonokuchi Hospital, Kanagawa, Japan; Fourth Department of Internal Medicine, Teikyo University Mizonokuchi Hospital, Kanagawa, Japan.

Aim: Detection of coagulase-negative Staphylococcus in blood culture may be a result of either bacteremia or contamination. This often leads to diagnostic uncertainly. Our objective was to develop a method for differentiating whether a coagulase-negative Staphylococcus sp. positive blood culture represents bacteremia or contamination based on positive bottle detection pattern and time to positivity (TTP).

Methods: This study included 155 and 51 adults with positive blood cultures for Staphylococcus epidermidis and Staphylococcus hominis, respectively, over a three-year period from 2016 to 2018. Positive blood culture cases were categorized as either bacteremia or contamination based on the clinically available information, and the detection pattern and TTP in each category were investigated.

Results: A total of 57, 92, and 6 S. epidermidis positive blood cultures were categorized as bacteremia, contamination, and undetermined, respectively, whereas 15 and 36 S. hominis positive blood cultures were categorized as bacteremia and contamination, respectively. For positive blood cultures categorized as bacteremia, all four bottles in two sets of blood cultures were positive in 47/47 S. epidermidis and 14/14 S. hominis, respectively, whereas either one bottle in each of two sets or three bottles in two sets were positive in 10/19 S. epidermidis and 1/4 S. hominis, respectively; most of those TTPs were <48 h. Among them, the TTP in catheter-related blood stream infection was <24 h.

Conclusion: Although clinical assessment is crucial to differentiate between bacteremia and contamination, a combination of positive bottle detection pattern and TTP is a valuable diagnostic auxiliary tool.
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http://dx.doi.org/10.1016/j.jiac.2020.02.004DOI Listing
July 2020

Fructo-oligosaccharides ameliorate steatohepatitis, visceral adiposity, and associated chronic inflammation via increased production of short-chain fatty acids in a mouse model of non-alcoholic steatohepatitis.

BMC Gastroenterol 2020 Feb 27;20(1):46. Epub 2020 Feb 27.

Fourth Department of Internal Medicine, Teikyo University Mizonokuchi Hospital, 5-1-1 Futako, Takatsu-ku, Kawasaki-shi, Kanagawa, 213-8507, Japan.

Background: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Within the spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) in combination with hepatic inflammation and fibrosis can lead to liver cirrhosis and hepatocellular carcinoma. Dysbiosis was reported to contribute to NASH pathogenesis. This study aimed to determine the effects of fructo-oligosaccharides (FOS) on steatohepatitis and visceral adiposity in an obese mouse model of NASH.

Methods: Twelve newborn C57BL/6 J male mice were subcutaneously injected with monosodium glutamate (MSG) to induce obesity on a conventional diet. Six mice were also administered 5% FOS via drinking water from 10 weeks of age. At 18 weeks, histological characteristics of the liver and epididymal fat were compared between the groups. Hepatic mRNA expression of lipid metabolism enzymes and SCFA in feces and sera were measured.

Results: Hepatic steatosis, inflammatory cell infiltration, and hepatocyte ballooning in the liver and increased hepatic mRNA expression of fatty acid synthase and glycerol-3-phosphate acyltransferase were observed in the MSG-treated mice. FOS treatment improved the liver pathology and blunted the increases in the mRNA expression levels of lipid metabolism enzymes. In addition, FOS inhibited adipocyte enlargement and formation of crown-like structures and reduced the M1 macrophage frequency in the epididymal fat of the MSG mice (39.4% ± 3.0% vs. 22.8% ± 0.7%; P = 0.001). FOS increased not only the fecal concentrations of n-butyric acid (0.04 ± 0.01 vs. 0.38 ± 0.14 mg/g, P = 0.02), propionic acid (0.09 ± 0.03 vs. 0.42 ± 0.16 mg/g, P = 0.02), and acetic acid (0.65 ± 0.16 vs. 1.48 ± 0.29 mg/g, P = 0.03) but also the serum concentration of propionic acid (3.9 ± 0.5 vs. 8.2 ± 0.5 μmol/L, P = 0.001).

Conclusions: FOS ameliorates steatohepatitis, visceral adiposity, and chronic inflammation by increasing SCFA production.
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http://dx.doi.org/10.1186/s12876-020-01194-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045471PMC
February 2020

Biodegradable Periodic Mesoporous Organosilica (BPMO) Loaded with Daunorubicin: A Promising Nanoparticle-Based Anticancer Drug.

ChemMedChem 2020 04 11;15(7):593-599. Epub 2020 Feb 11.

Institute for Integrated Cell-Material Sciences (ICeMS), Institute for Advanced Study Kyoto University, Kyoto, 606 8501, Japan.

Biodegradable periodic mesoporous organosilica (BPMO) nanoparticles have emerged as a promising type of nanocarrier for drug delivery, given the biodegradable feature is advantageous for clinical translation. In this paper, we report synthesis and characterization of daunorubicin (DNR) loaded BPMO. DNR was loaded onto rhodamine B-labeled BPMO that contain tetrasulfide bonds. Tumor spheroids and chicken egg tumor models were used to characterize the activity in biological settings. In the first experiment we examined the uptake of BPMO into tumor spheroids prepared from ovarian cancer cells. BPMO were efficiently taken up into tumor spheroids and inhibited their growth. In the chicken egg tumor model, intravenous injection of DNR-loaded BPMO led to the elimination of ovarian tumor. Lack of adverse effect on organs such as lung appears to be due to excellent tumor accumulation of BPMO. Thus, DNR-loaded BPMO represents a promising nanodrug compared with free DNR currently used in cancer therapy. OK.
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http://dx.doi.org/10.1002/cmdc.201900595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187469PMC
April 2020

Significant association between clinical characteristics and changes in peripheral immuno-phenotype in large vessel vasculitis.

Arthritis Res Ther 2019 12 30;21(1):304. Epub 2019 Dec 30.

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.

Background: Large vessel vasculitis (LVV) is a type of vasculitis characterized by granulomatous inflammation of medium- and large-sized arteries. Clinical assessment of acute phase reactants has been conventionally used to diagnose and monitor diseases; however, accurate assessment of vascular disease activity status can be difficult. In this study, we investigated comprehensive immuno-phenotyping to explore useful biomarkers associated with clinical characteristics.

Methods: Consecutive patients with newly diagnosed LVV who visited our institution between May 2016 and May 2019 were enrolled. The number of circulating T cells, B cells, natural killer cells, dendritic cells, monocytes, and granulocytes was examined and chronologically followed. Baseline and time-course changes in immuno-phenotyping associated with disease activity were assessed.

Results: Comprehensive immuno-phenotyping data from 90 samples from each of 20 patients with LVV were compared with those from healthy controls (HCs). The number of helper T (Th), follicular helper T (Tfh), CD8 T, CD14 CD16 monocytes, and neutrophils were higher in patients with giant cell arteritis (GCA) and/or Takayasu arteritis (TAK) than in HCs. Among them, the number of CD8 T and CD8 Tem were higher in patients with TAK than in GCA. Notably, memory CD4 and CD8 T cells in patients with TAK remained high even in the remission phase. Further analysis revealed that the number of Th1, Th17, and Tfh cells was associated with disease relapse in GCA and TAK and that the number of CD8 T cells was associated with relapse in TAK. Th1, Th17, and Tfh cells decreased after treatment with biologic agents, while CD8 T cells did not.

Conclusions: Our results from peripheral immuno-phenotyping analysis indicate that the numbers of Th and Tfh cells changed along with the disease condition in both GCA and TAK, while that of CD8 T cells did not, especially in TAK. Treatment with biologic agents decreased the proportion of Th and Tfh cells, but not CD8 T cells, in the patients. Chronological immuno-phenotyping data explained the difference in therapeutic response, such as reactivities against biologics, between GCA and TAK.
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http://dx.doi.org/10.1186/s13075-019-2068-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937853PMC
December 2019

Molecular diagnosis of bovine B-cell lymphoma using polymerase chain reaction for immunoglobulin heavy chain gene.

J Vet Med Sci 2020 Jan 4;82(1):61-63. Epub 2019 Dec 4.

United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan.

We performed a clonality analysis using polymerase chain reaction (PCR) for immunoglobulin heavy chain (IgH) gene rearrangement, specifically with regard to its utility as a method to diagnose bovine B-cell lymphoma. PCR for IgH gene rearrangement indicated monoclonal proliferation of B-cells in 24 of 35 cattle with B-cell lymphoma. In contrast, PCR for IgH gene rearrangement in lymph nodes and tumor tissues from 65 cattle diagnosed with tumors other than B-cell lymphoma and non-tumors revealed polyclonal population of B-cells. Sensitivity, specificity, positive predictive value, and negative predictive value for PCR for IgH gene rearrangement for bovine B-cell lymphoma were 68.6%, 100%, 100%, and 85.5%, respectively. Clonality analysis using PCR for IgH gene rearrangement may be useful for adjunctive diagnosis of bovine B-cell lymphoma.
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http://dx.doi.org/10.1292/jvms.19-0418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983668PMC
January 2020

Various CAM tumor models.

Enzymes 2019 31;46:37-57. Epub 2019 Oct 31.

Institute for Integrated Cell-Material Sciences, Institute for Advanced Study, Kyoto University, Kyoto, Japan. Electronic address:

Many types of in vivo animal tumor models have been established. Among these, the chicken chorioallantoic membrane (CAM) model has proven to be particularly useful for transplanting various types of cancer cell lines or tumor tissues to study tumor formation, angiogenesis and metastasis. The CAM model is useful as an animal tumor model, as tumor could be rapidly formed. The tumor formation occurs in 3-4 days, much faster than in mouse models. In addition, the CAM model can be used for drug screening for cancer therapy. This chapter provides an overview of various types of CAM tumor models.
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http://dx.doi.org/10.1016/bs.enz.2019.10.001DOI Listing
November 2019

Destruction of tumor mass by gadolinium-loaded nanoparticles irradiated with monochromatic X-rays: Implications for the Auger therapy.

Sci Rep 2019 09 30;9(1):13275. Epub 2019 Sep 30.

Institute for Integrated Cell-Material Sciences, Institute for Advanced Study, Kyoto University, Kyoto, Japan.

Synchrotron generated monochromatic X-rays can be precisely tuned to the K-shell energy of high Z materials resulting in the release of the Auger electrons. In this work, we have employed this mechanism to destruct tumor spheroids. We first loaded gadolinium onto the surface of mesoporous silica nanoparticles (MSNs) producing gadolinium-loaded MSN (Gd-MSN). When Gd-MSN was added to the tumor spheroids, we observed efficient uptake and uniform distribution of Gd-MSN. Gd-MSN also can be taken up into cancer cells and localize to a site just outside of the cell nucleus. Exposure of the Gd-MSN containing tumor spheroids to monochromatic X-ray beams resulted in almost complete destruction. Importantly, this effect was observed at an energy level of 50.25 keV, but not with 50.0 keV. These results suggest that it is possible to use precisely tuned monochromatic X-rays to destruct tumor mass loaded with high Z materials, while sparing other cells. Our experiments point to the importance of nanoparticles to facilitate loading of gadolinium to tumor spheroids and to localize at a site close to the nucleus. Because the nanoparticles can target to tumor, our study opens up the possibility of developing a new type of radiation therapy for cancer.
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http://dx.doi.org/10.1038/s41598-019-49978-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768997PMC
September 2019

Pilot study on serum C-reactive protein in pet rabbits: clinical usefulness.

Vet Rec Open 2019 13;6(1):e000272. Epub 2019 Sep 13.

Clinical Veterinary Science, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.

Objectives: The present study was performed to evaluate the usefulness of serum C-reactive protein (CRP) as an acute phase reactive protein in pet rabbits in clinical practice.

Methods: The CRP level using a rabbit CRP ELISA and white blood cell (WBC) count in pet rabbits (30 healthy controls and 62 with various diseases) were measured in the clinical practice setting. The CRP level and WBC count were measured before and after ovariohysterectomy of a healthy rabbit and a rabbit with uterine adenocarcinoma. The association between the CRP level and mortality in rabbits with various diseases was assessed.

Results: The CRP level in healthy controls was 0.52±0.82 mg/dl (mean±SD). No age and sex-related differences in neither the CRP level nor WBC count were observed in the healthy control rabbits. The CRP levels in rabbits with gastrointestinal disease (n=22, 11.74±22.89 mg/dl), reproductive and urinary system disease (n=20, 21.19±49.68 mg/dl), dental disease (n=6, 4.87±5.47 mg/dl) and musculoskeletal disease (n=4, 85.66±107.28 mg/dl) were significantly higher than those in healthy controls. The CRP levels in rabbits with neurological disease (n=7, 2.55±1.79 mg/dl) and dermatological disease (n=3, 8.84±7.71 mg/dl) were higher than those in healthy controls, but no significant difference was observed. The WBC counts were not significantly different between rabbits with diseases and healthy controls. Serum samples were collected from two rabbits before and after ovariohysterectomy. In both rabbits, the CRP peaked on postoperative day 1, but no obvious WBC peak was observed. The mortality rate increased as the CRP level increased; the mortality rate was significantly higher in rabbits with a CRP level of ≥100 mg/dl than of <10 mg/dl.

Conclusions: This study indicates that the serum CRP level is useful to determine the disease status, monitor the treatment course and evaluate the prognosis in pet rabbits in clinical practice.
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http://dx.doi.org/10.1136/vetreco-2017-000272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746537PMC
September 2019
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