Publications by authors named "Kensuke Sasaki"

68 Publications

Klotho deficiency intensifies hypoxia-induced expression of IFN-α/β through upregulation of RIG-I in kidneys.

PLoS One 2021 21;16(10):e0258856. Epub 2021 Oct 21.

Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.

Hypoxia is a common pathway to the progression of end-stage kidney disease. Retinoic acid-inducible gene I (RIG-I) encodes an RNA helicase that recognizes viruses including SARS-CoV2, which is responsible for the production of interferon (IFN)-α/β to prevent the spread of viral infection. Recently, RIG-I activation was found under hypoxic conditions, and klotho deficiency was shown to intensify the activation of RIG-I in mouse brains. However, the roles of these functions in renal inflammation remain elusive. Here, for in vitro study, the expression of RIG-I and IFN-α/β was examined in normal rat kidney (NRK)-52E cells incubated under hypoxic conditions (1% O2). Next, siRNA targeting RIG-I or scramble siRNA was transfected into NRK52E cells to examine the expression of RIG-I and IFN-α/β under hypoxic conditions. We also investigated the expression levels of RIG-I and IFN-α/β in 33 human kidney biopsy samples diagnosed with IgA nephropathy. For in vivo study, we induced renal hypoxia by clamping the renal artery for 10 min in wild-type mice (WT mice) and Klotho-knockout mice (Kl-/- mice). Incubation under hypoxic conditions increased the expression of RIG-I and IFN-α/β in NRK52E cells. Their upregulation was inhibited in NRK52E cells transfected with siRNA targeting RIG-I. In patients with IgA nephropathy, immunohistochemical staining of renal biopsy samples revealed that the expression of RIG-I was correlated with that of IFN-α/β (r = 0.57, P<0.001, and r = 0.81, P<0.001, respectively). The expression levels of RIG-I and IFN-α/β were upregulated in kidneys of hypoxic WT mice and further upregulation was observed in hypoxic Kl-/- mice. These findings suggest that hypoxia induces the expression of IFN-α/β through the upregulation of RIG-I, and that klotho deficiency intensifies this hypoxia-induced expression in kidneys.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258856PLOS
October 2021

A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Kyushu University Hospital, Japan.

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of "unfavorable" molecular signatures.
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http://dx.doi.org/10.1182/bloodadvances.2021004618DOI Listing
October 2021

Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for CRLF2-rearranged Ph-like ALL.

Blood 2021 Sep 29. Epub 2021 Sep 29.

Kyushu University Hospital, Japan.

Acute lymphoblastic leukemia (ALL) harboring the IgH-CRLF2 rearrangement (IgH-CRLF2-r) exhibits poor clinical outcomes and is the most common subtype of Ph-like ALL. While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. To identify molecules/pathways relevant for IgH-CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of Ruxolitinib using two IgH-CRLF2-r ALL lines that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which enabled, for the first time, highly efficient transduction of human B cells. While sgRNAs targeting CRLF2, IL7RA or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B or STAT3 did not, suggesting that STAT signaling is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and Ruxolitinib sensitivity and that CRKL depletion enhances Ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that blocks CRKL phosphorylation, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with Ruxolitinib. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status. Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes.
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http://dx.doi.org/10.1182/blood.2021012976DOI Listing
September 2021

Ustekinumab Improves Active Crohn's Disease by Suppressing the T Helper 17 Pathway.

Digestion 2021 Jul 22:1-10. Epub 2021 Jul 22.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST.

Methods: Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated.

Results: The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action.

Conclusion: In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.
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http://dx.doi.org/10.1159/000518103DOI Listing
July 2021

Targeting leukemia-specific dependence on the de novo purine synthesis pathway.

Leukemia 2021 Aug 3. Epub 2021 Aug 3.

Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, 812-8582, Japan.

Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
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http://dx.doi.org/10.1038/s41375-021-01369-0DOI Listing
August 2021

Chemopreventive effects and anti-tumorigenic mechanisms of 2,6-dimethoxy-1,4-benzoquinone, a constituent of Vitis coignetiae Pulliat (crimson glory vine, known as yamabudo in Japan), toward 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice.

Food Chem Toxicol 2021 Aug 1;154:112319. Epub 2021 Jun 1.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, 700-8530, Japan.

Previously, we isolated and identified anti-mutagenic and anti-inflammatory components from Vitis coignetiae (crimson glory vine, known as yamabudo in Japan) as 2,6-dimethoxy-1,4-benzoquinone (DBQ), fertaric acid and caftaric acid. We also reported that the oral intake of a partially purified fraction from yamabudo juice (yamabudo-fr) or DBQ affords significant protection against two-stage skin carcinogenesis in mice. In this study, we found that oral intake of yamabudo-fr or DBQ affords significant protection against a tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse model of lung tumorigenesis. Furthermore, we investigated the anti-tumorigenic mechanisms of yamabudo juice and DBQ. NNK is known to be a DNA-methylating and alkylating agent; thus, we investigated the anti-tumorigenic mechanisms of yamabudo juice and DBQ in relation to DNA methylation. Pretreatment with yamabudo-fr or DBQ dose-dependently decreased formation of O-methylguanine and N-methylguanine in DNA of the A549 human lung epithelial-like cell line treated with a methylating agent, 1-methyl-3-nitro-1-nitrosoguanidine. Yamabudo juice and DBQ inhibited the mutagenicity of NNK in the Ames test using Salmonella typhimurium TA1535 but not S. typhimurium YG7108, an alkylguanine DNA alkyltransferase-deficient strain (same as TA1535 but Δada::Km, Δogt::Cm). Yamabudo juice and DBQ might accelerate the repair of DNA damage caused by NNK and reduce DNA damage to cells. We also investigated the effects of yamabudo juice and DBQ on signaling pathways in A549 cells. With or without epidermal growth factor stimulation, phosphorylation of Erk1/2, Akt and Stat3 in A549 cells was significantly decreased in the presence of yamabudo juice or DBQ, indicating that yamabudo juice and DBQ suppressed PI3K/AKT, MAPK/ERK and JAK/STAT3 signaling pathways. These results suggest that both initiation and growth/progression steps in carcinogenesis, especially anti-oxidant effects, stimulation of repair of alkyl DNA adducts and suppressed growth signaling pathways are potential anti-tumorigenic targets of yamabudo juice and DBQ in NNK-induced lung tumorigenesis.
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http://dx.doi.org/10.1016/j.fct.2021.112319DOI Listing
August 2021

Dielectric property measurements of corneal tissues for computational dosimetry of the eye in terahertz band and .

Biomed Opt Express 2021 Mar 8;12(3):1295-1307. Epub 2021 Feb 8.

National Institute of Information and Communications Technology, Koganei, Tokyo 184-8795, Japan.

The dielectric constant of the normal corneal tissue of a rabbit eye was obtained in the range from approximately 0.1 to 1 THz, and the drying process on the eye surface exposed to high-power terahertz waves was investigated by reflectance measurement using terahertz time-domain spectroscopy. When the rabbit eye was exposed to terahertz waves at 162 GHz for 6 min with an irradiation power of 360 or 480 mW/cm, the reflectance temporally increased and then decreased with a temperature increase. Based on multiple-reflection calculation using the dielectric constant and anterior segment optical coherence tomography images, those changes in reflectance were attributed to drying of the tear and epithelium of the cornea, respectively. Furthermore, the drying progressed over a temperature increase of around 5°C under our exposure conditions. These findings suggest that the possibility of eye damage increases with the progress of drying and that the setting of the eye surface conditions can be a cause of disagreement between computational and experimental data of absorbed energy under high-level irradiation because reflectance is related to terahertz wave penetration in the eye tissue. The time-domain spectroscopic measurements were useful for the acquisition of the dielectric constant as well as for the real-time monitoring of the eye conditions during exposure measurement.
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http://dx.doi.org/10.1364/BOE.412769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984789PMC
March 2021

Human exposure to radiofrequency energy above 6 GHz: review of computational dosimetry studies.

Phys Med Biol 2021 04 14;66(8). Epub 2021 Apr 14.

University of Pennsylvania, Philadelphia, PA, United States of America.

International guidelines/standards for human protection from electromagnetic fields have been revised recently, especially for frequencies above 6 GHz where new wireless communication systems have been deployed. Above this frequency a new physical quantity 'absorbed/epithelial power density' has been adopted as a dose metric. Then, the permissible level of external field strength/power density is derived for practical assessment. In addition, a new physical quantity, fluence or absorbed energy density, is introduced for protection from brief pulses (especially for shorter than 10 s). These limits were explicitly designed to avoid excessive increases in tissue temperature, based on electromagnetic and thermal modeling studies but supported by experimental data where available. This paper reviews the studies on the computational modeling/dosimetry which are related to the revision of the guidelines/standards. The comparisons with experimental data as well as an analytic solution are also been presented. Future research needs and additional comments on the revision will also be mentioned.
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http://dx.doi.org/10.1088/1361-6560/abf1b7DOI Listing
April 2021

Deletion of Myeloid Interferon Regulatory Factor 4 (Irf4) in Mouse Model Protects against Kidney Fibrosis after Ischemic Injury by Decreased Macrophage Recruitment and Activation.

J Am Soc Nephrol 2021 05 22;32(5):1037-1052. Epub 2021 Feb 22.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

Background: AKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear.

Methods: We used mice with myeloid or macrophage cell-specific deletion of (MΦ ) to evaluate Irf4's role in renal macrophage polarization and development of fibrosis after severe AKI.

Results: Surprisingly, although macrophage deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow-derived monocytes (BMDMs) from MΦ mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in MΦ mice or in wild-type mice with inhibition of AKT activity.

Conclusions: Deletion of from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.
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http://dx.doi.org/10.1681/ASN.2020071010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259665PMC
May 2021

Activation of hypoxia-sensing pathways promotes renal ischemic preconditioning following myocardial infarction.

Am J Physiol Renal Physiol 2021 04 1;320(4):F569-F577. Epub 2021 Feb 1.

Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Ischemic heart disease is the leading cause of death worldwide and is frequently comorbid with chronic kidney disease. Physiological communication is known to occur between the heart and the kidney. Although primary dysfunction in either organ can induce dysfunction in the other, a clinical entity known as cardiorenal syndrome, mechanistic details are lacking. Here, we used a model of experimental myocardial infarction (MI) to test effects of chronic cardiac ischemia on acute and chronic kidney injury. Surprisingly, chronic cardiac damage protected animals from subsequent acute ischemic renal injury, an effect that was accompanied by evidence of chronic kidney hypoxia. The protection observed post-MI was similar to protection observed in a separate group of healthy animals housed in ambient hypoxic conditions prior to kidney injury, suggesting a common mechanism. There was evidence that chronic cardiac injury activates renal hypoxia-sensing pathways. Increased renal abundance of several glycolytic enzymes following MI suggested that a shift toward glycolysis may confer renal ischemic preconditioning. In contrast, effects on chronic renal injury followed a different pattern, with post-MI animals displaying worsened chronic renal injury and fibrosis. These data show that although chronic cardiac injury following MI protected against acute kidney injury via activation of hypoxia-sensing pathways, it worsened chronic kidney injury. The results further our understanding of cardiorenal signaling mechanisms and have implications for the treatment of heart failure patients with associated renal disease. Experimental myocardial infarction (MI) protects from subsequent ischemic acute kidney injury but worsens chronic kidney injury. Observed protection from ischemic acute kidney injury after MI was accompanied by chronic kidney hypoxia and increased renal abundance of hypoxia-inducible transcripts. These data support the idea that MI confers protection from renal ischemic injury via chronic renal hypoxia and activation of downstream hypoxia-inducible signaling pathways.
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http://dx.doi.org/10.1152/ajprenal.00476.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083970PMC
April 2021

Podocyte EGFR Inhibits Autophagy Through Upregulation of Rubicon in Type 2 Diabetic Nephropathy.

Diabetes 2021 02 25;70(2):562-576. Epub 2020 Nov 25.

Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN

Renal epidermal growth factor receptor (EGFR) signaling is activated in models of diabetic nephropathy (DN), and inhibition of the EGFR signaling pathway protects against the development of DN. We have now determined that in cultured podocytes, high glucose led to increases in activation of EGFR signaling but decreases in autophagy activity as indicated by decreased beclin-1 and inhibition of LC3B autophagosome formation as well as increased rubicon (an autophagy inhibitor) and SQSTM1 (autophagy substrate). Either genetic (small interfering [si]EGFR) or pharmacologic (AG1478) inhibition of EGFR signaling attenuated the decreased autophagy activity. In addition, rubicon siRNA knockdown prevented high glucose-induced inhibition of autophagy in podocytes. We further examined whether selective EGFR deletion in podocytes affected the progression of DN in type 2 diabetes. Selective podocyte EGFR deletion had no effect on body weight or fasting blood sugars in either mice or ; mice, a model of accelerated type 2 DN. However selective podocyte EGFR deletion led to relative podocyte preservation and marked reduction in albuminuria and glomerulosclerosis, renal proinflammatory cytokine/chemokine expression, and decreased profibrotic and fibrotic components in ; mice. Podocyte EGFR deletion led to decreased podocyte expression of rubicon, in association with increased podocyte autophagy activity. Therefore, activation of EGFR signaling in podocytes contributes to progression of DN at least in part by increasing rubicon expression, leading to subsequent autophagy inhibition and podocyte injury.
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http://dx.doi.org/10.2337/db20-0660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881855PMC
February 2021

Clinical characteristics of inflammatory bowel disease patients with immunoglobulin A nephropathy.

Intest Res 2020 Nov 9. Epub 2020 Nov 9.

Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan.

Background/aims: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract. Some patients with this condition have been reported to present with immunoglobulin A nephropathy (IgAN), a renal complication that can cause end-stage renal failure, but the frequency of this comorbidity has not been described. Thus, the aim of this study was to investigate the frequency of IgAN in patients with IBD.

Methods: This study included 620 patients with IBD (338 with ulcerative colitis [UC] and 282 with Crohn's disease [CD]) from the Hiroshima University Hospital outpatient department. IgAN cases were identified from medical interviews, blood examinations (serum immunoglobulin A), and urinalyses (occult blood, proteinuria). Definitive IgAN cases were diagnosed by renal biopsies, while those detected through the clinical course and test results, but not clinically recommended for renal biopsy, were defined as suspected IgAN.

Results: We analyzed 427 cases meeting the inclusion criteria (220 with UC and 207 with CD). The incidence of IgAN across all patients with IBD was 3.0%. The frequency of IgAN was significantly higher in patients with CD (11/207, 5.3%) than in those with UC (2/220, 0.9%) (P< 0.01). Moreover, a significant correlation was found between CD patients with ileostomy or colostomy and a diagnosis of IgAN.

Conclusions: Patients with IBD present a high incidence of IgAN, especially those with CD who have undergone ileostomy or colostomy.
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http://dx.doi.org/10.5217/ir.2020.00067DOI Listing
November 2020

Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study.

Ann Hematol 2021 Jan 5;100(1):197-208. Epub 2020 Nov 5.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.
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http://dx.doi.org/10.1007/s00277-020-04310-0DOI Listing
January 2021

Beneficial tyrosine kinase inhibitor therapy in a patient with relapsed BCR-ABL1-like acute lymphoblastic leukemia with CCDC88C-PDGFRB fusion.

Int J Hematol 2021 Feb 19;113(2):285-289. Epub 2020 Sep 19.

Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.

BCR-ABL1-like acute lymphoblastic leukemia (ALL) is a neoplasm of lymphoblasts committed to the B-cell lineage that lack the BCR-ABL1 translocation but show a pattern of gene expression very similar to that seen in ALL with BCR-ABL1 with poor prognosis. A 22-year-old female was diagnosed with common-B-cell-ALL positive for CD10, CD19, CD22, CD79a, CD34, HLA-DR, and TdT in January 2017, and achieved complete remission (CR) with induction therapy, followed by consolidation therapy and maintenance therapy. In March 2020, 6 months after the completion of maintenance therapy, she relapsed. Inotuzumab ozogamicin (IO) was administered, and on day 28, bone marrow evaluation showed a morphologic CR. She had an HLA-identical sibling, and transplantation in her 2nd CR was planned. Because her ALL had been identified as BCR-ABL1-like ALL with CCDC88C-PDGFRB fusion, she was treated with imatinib for 2 months accompanied by 2 intrathecal methotrexate therapies, and 1 course of L-asparaginase, vincristine, and prednisolone in an outpatient setting. MRD analysis revealed potent efficacy of 2 months imatinib therapy; IgH MRD decreased from 1 × 10 to 1 × 10, and CCDC88C-PDGFRB/10ABL from 37.3 to 0. It is earnestly desired that well-designed clinical trials of TKI in ABL class-mutant BCR-ABL1-like ALL be conducted in Japan.
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http://dx.doi.org/10.1007/s12185-020-03006-5DOI Listing
February 2021

Plasmablastic lymphoma occurring in the vicinity of enterocutaneous fistula in Crohn's disease.

J Dermatol 2020 Dec 4;47(12):e442-e443. Epub 2020 Sep 4.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1111/1346-8138.15600DOI Listing
December 2020

Management of Recurrent Pterygium with Severe Symblepharon Using Mitomycin C, Double Amniotic Membrane Transplantation, Cryopreserved Limbal Allograft, and a Conjunctival Flap.

Int Med Case Rep J 2020 21;13:201-209. Epub 2020 May 21.

Department of Ophthalmology, Kurume University School of Medicine, Fukuoka, Japan.

Purpose: The aim of this study was to evaluate the clinical outcomes of management of recurrent pterygium with severe symblepharon using mitomycin C, double amniotic membrane transplantation, cryopreserved limbal allograft, and a conjunctival flap.

Patients And Methods: This retrospective case series included 10 eyes of 10 patients with recurrent pterygium with severe symblepharon. Eight patients have diplopia in primary gaze. All patients underwent pterygium excision, application of mitomycin C (MMC), double amniotic membrane transplantation (AMT), cryopreserved limbal allograft (CLA) transplantation, and placement of a conjunctival flap. Outcome measures were visual acuity, astigmatism, and recurrence. Recurrence was defined as the presence of fibrovascular proliferative tissue crossing the limbus.

Results: The patients' mean age was 73.8 years. The mean follow-up period was 3.0 years. The mean preoperative and postoperative best-corrected visual acuities (logMAR conversion) were 0.43 and 0.30, respectively. The mean preoperative and postoperative astigmatism were -3.89 diopters and -1.54 diopters, respectively, and there was a significant difference. No recurrence occurred in any of the eyes. Symblepharon was released in all eyes. Diplopia in primary gaze was resolved in all eyes.

Conclusion: Management of recurrent pterygium with severe symblepharon using MMC, double AMT, CLA, and a conjunctival flap was an effective treatment.
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http://dx.doi.org/10.2147/IMCRJ.S245256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247734PMC
May 2020

Multiple retinal vein thromboses after intravitreal aflibercept injections for age-related macular degeneration.

Acta Ophthalmol 2020 Jun 13;98(4):e527-e528. Epub 2020 Jan 13.

Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan.

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http://dx.doi.org/10.1111/aos.14345DOI Listing
June 2020

Rho Guanine Nucleotide Exchange Factors Regulate Horizontal Axon Branching of Cortical Upper Layer Neurons.

Cereb Cortex 2020 04;30(4):2506-2518

Cellular and Molecular Neurobiology Group, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.

Axon branching is a crucial process for cortical circuit formation. However, how the cytoskeletal changes in axon branching are regulated is not fully understood. In the present study, we investigated the role of RhoA guanine nucleotide exchange factors (RhoA-GEFs) in branch formation of horizontally elongating axons (horizontal axons) in the mammalian cortex. In situ hybridization showed that more than half of all known RhoA-GEFs were expressed in the developing rat cortex. These RhoA-GEFs were mostly expressed in the macaque cortex as well. An overexpression study using organotypic cortical slice cultures demonstrated that several RhoA-GEFs strongly promoted horizontal axon branching. Moreover, branching patterns were different between overexpressed RhoA-GEFs. In particular, ARHGEF18 markedly increased terminal arbors, whereas active breakpoint cluster region-related protein (ABR) increased short branches in both distal and proximal regions of horizontal axons. Rho kinase inhibitor treatment completely suppressed the branch-promoting effect of ARHGEF18 overexpression, but only partially affected that of ABR, suggesting that these RhoA-GEFs employ distinct downstream pathways. Furthermore, knockdown of either ARHGEF18 or ABR considerably suppressed axon branching. Taken together, the present study revealed that subsets of RhoA-GEFs differentially promote axon branching of mammalian cortical neurons.
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http://dx.doi.org/10.1093/cercor/bhz256DOI Listing
April 2020

Inhibition of the H3K4 methyltransferase MLL1/WDR5 complex attenuates renal senescence in ischemia reperfusion mice by reduction of p16.

Kidney Int 2019 11 1;96(5):1162-1175. Epub 2019 Aug 1.

Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan. Electronic address:

Renal function declines with aging and is pathologically characterized by chronic inflammation and fibrosis. Renal senescence is induced not only by aging but also by various stimuli, including ischemia reperfusion injury. Recently, the accumulation of p16-positive cells in the kidney has been considered a molecular feature of renal senescence, with the p16 gene reportedly regulated by mixed-lineage leukemia 1 (MLL1)/WD-40 repeat protein 5 (WDR5)-mediated histone 3 lysine 4 trimethylation (H3K4me3). Here, we determined whether inhibition of MLL1/WDR5 activity attenuates renal senescence, inflammation, and fibrosis in mice with ischemia reperfusion injury and in cultured rat renal fibroblasts. MM-102 or OICR-9429, both MLL1/WDR5 protein-protein interaction inhibitors, and small interfering RNA (siRNA) for MLL1 or WDR5 suppressed the expression of p16 in mice with ischemia reperfusion injury, accompanied by downregulation of H3K4me3 expression. MM-102 attenuated renal fibrosis and inflammation in the kidney of mice with ischemia reperfusion injury. Moreover, in vitro study showed that transforming growth factor-β1 induced the expression of MLL1, WDR5, H3K4me3, and p16. Finally, chromatin immunoprecipitation identified the p16 promoter at an H3K4me3 site in renal fibroblasts. Thus, our findings show that H3K4me3 inhibition ameliorates ischemia reperfusion-induced renal senescence along with fibrosis and inflammation.
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http://dx.doi.org/10.1016/j.kint.2019.06.021DOI Listing
November 2019

Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice.

Int J Mol Sci 2019 Sep 21;20(19). Epub 2019 Sep 21.

Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose City, Tokyo 204-8588, Japan.

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 μg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1β, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration.
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http://dx.doi.org/10.3390/ijms20194680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801943PMC
September 2019

Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice.

Diabetol Metab Syndr 2019 22;11:57. Epub 2019 Jul 22.

1Department of Medical Science, Graduate School of Medicine, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551 Japan.

Background: Recently, clinical studies have shown the protective effects of sodium glucose co-transporter2 (SGLT2) inhibitors against progression of diabetic nephropathy, but the underlying molecular mechanisms remain unclear.

Methods: Diabetic mice were prepared by injecting nicotinamide and streptozotocin, followed by high-sucrose diet feeding (NA/STZ/Suc mice). The SGLT2 inhibitor canagliflozin was administered as a 0.03% (w/w) mixture in the diet for 4 weeks. Then, various parameters and effects of canagliflozin on diabetic nephropathy were investigated.

Results: Canagliflozin administration to NA/STZ/Suc mice normalized hyperglycemia as well as elevated renal mRNA of collagen 1a1, 1a2, CTGF, TNFα and MCP-1. Microscopic observation revealed reduced fibrotic deposition in the kidneys of canagliflozin-treated NA/STZ/Suc mice. Interestingly, the protein level of Pin1, reportedly involved in the inflammation and fibrosis affecting several tissues, was markedly increased in the NA/STZ/Suc mouse kidney, but this was normalized with canagliflozin treatment. The cells showing increased Pin1 expression in the kidney were mainly mesangial cells, along with podocytes, based on immunohistochemical analysis. Furthermore, it was revealed that canagliflozin induced AMP-activated kinase (AMPK) activation concentration-dependently in CRL1927 mesangial as well as THP-1 macrophage cell lines. AMPK activation was speculated to suppress mesangial cell proliferation and exert anti-inflammatory effects in hematopoietic cells.

Conclusion: Therefore, we can reasonably suggest that normalized Pin1 expression and AMPK activation contribute to the molecular mechanisms underlying SGLT2 inhibitor-induced suppression of diabetic nephropathy, possibly at least in part by reducing inflammation and fibrotic change.
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http://dx.doi.org/10.1186/s13098-019-0454-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647324PMC
July 2019

The Role of the EGF Receptor in Sex Differences in Kidney Injury.

J Am Soc Nephrol 2019 09 10;30(9):1659-1673. Epub 2019 Jul 10.

Division of Nephrology and Hypertension, Department of Medicine,

Background: Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury.

Methods: To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines.

Results: In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells.

Conclusions: These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.
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http://dx.doi.org/10.1681/ASN.2018121244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727256PMC
September 2019

microRNA-200c regulates KLOTHO expression in human kidney cells under oxidative stress.

PLoS One 2019 14;14(6):e0218468. Epub 2019 Jun 14.

Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.

KLOTHO deficiency is associated with the progression of kidney dysfunction, whereas its overexpression exerts renoprotective effects. Oxidative stress suppresses KLOTHO expression in renal epithelial cells but upregulates microRNA-200c (miR-200c) in human umbilical vein endothelial cells. In this study, we investigated whether oxidative stress-induced miR-200c is implicated in KLOTHO downregulation in human renal tubular epithelium (HK-2) cells. HK-2 cells were stimulated with hydrogen peroxide (H2O2) to examine the effect of oxidative stress. A luciferase reporter containing the KLOTHO 3'-UTR was used to investigate the effect of miR-200c on KLOTHO mRNA metabolism. The expressions of KLOTHO, oxidative stress markers, and miR-200c were determined in human kidney biopsy specimens. H2O2 suppressed KLOTHO expression without a reduction in KLOTHO mRNA levels but upregulated miR-200c expression. Similarly, transfection of a miR-200c mimic reduced KLOTHO levels and luciferase activity without a reduction in KLOTHO mRNA levels. In contrast, transfection of a miR-200c inhibitor maintained KLOTHO expression. Immunofluorescent assay revealed KLOTHO was present in the cytosol and nuclei of HK-2 cells. In human kidney biopsies, KLOTHO expression was inversely correlated with levels of oxidative stress markers (8-hydroxy-2'-deoxyguanosine: ρ = -0.38, P = 0.026; 4-hydroxy-2-hexenal: ρ = -0.35, P = 0.038) and miR-200c (ρ = -0.34, P = 0.043). Oxidative stress-induced miR-200c binds to the KLOTHO mRNA 3'-UTR, resulting in reduced KLOTHO expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218468PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568409PMC
February 2020

Relationship between power density and surface temperature elevation for human skin exposure to electromagnetic waves with oblique incidence angle from 6 GHz to 1 THz.

Phys Med Biol 2019 03 14;64(6):065016. Epub 2019 Mar 14.

National Institute of Information and Communications Technology, 4-2-1 Koganei, Tokyo 184-8795, Japan.

This study presents an investigation of human skin exposure to obliquely incident electromagnetic waves at frequencies from 6 GHz to 1 THz. We aim to clarify the relationship between the power density and the skin surface temperature elevation under various exposure conditions. A Monte Carlo simulation was conducted to assess the transmittance and surface temperature elevation considering the variation of skin tissue thickness. For the case of TM wave injection, transmittance increases with increasing incidence angle from the normal incidence because of the Brewster effect. The normal incidence is confirmed as the worst-case exposure condition when the incident power density is defined in an area normal to the propagation direction. In addition, we investigated the power density required to obtain the equivalent temperature elevation over the skin surface. The analysis shows that the incident power density defined in the direction normal to the skin surface may underestimate the temperature elevation when TM waves are incident over the normal incidence up to the maximum transmittance angle. Our results also show that the power density inside the skin surface strongly correlates with the surface temperature elevation but less dependent on the frequency and independent of the oblique incidence angle and polarization. The findings of this study are expected to be valuable for discussing how to use the different definitions of power density based on dosimetric characteristics as measures in safety guidelines to protect humans from excessive temperature elevation by millimeter and submillimeter-wave exposure.
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http://dx.doi.org/10.1088/1361-6560/ab057aDOI Listing
March 2019

The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model.

Int J Mol Sci 2018 Dec 10;19(12). Epub 2018 Dec 10.

Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, Chuo-ku, Tokyo 103-0002, Japan.

Recent clinical studies have demonstrated the protective effect of xanthine oxidase (XO) inhibitors against chronic kidney diseases, although the underlying molecular mechanisms remain unclear. However, to date, neither clinical nor basic research has been carried out to elucidate the efficacy of XO inhibitor administration for IgA nephropathy. We thus investigated whether febuxostat, an XO inhibitor, exerts a protective effect against the development of IgA nephropathy, using gddY mice as an IgA nephropathy rodent model. Eight-week-old gddY mice were provided drinking water with (15 μg/mL) or without febuxostat for nine weeks and then subjected to experimentation. Elevated serum creatinine and degrees of glomerular sclerosis and fibrosis, judged by microscopic observations, were significantly milder in the febuxostat-treated than in the untreated gddY mice, while body weights and serum IgA concentrations did not differ between the two groups. In addition, elevated mRNA levels of inflammatory cytokines such as TNFα, MCP-1, IL-1β, and IL-6, collagen isoforms and chemokines in the gddY mouse kidneys were clearly normalized by the administration of febuxostat. These data suggest a protective effect of XO inhibitors against the development of IgA nephropathy, possibly via suppression of inflammation and its resultant fibrotic changes, without affecting the serum IgA concentration.
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http://dx.doi.org/10.3390/ijms19123967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320819PMC
December 2018

TGF-β promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration.

JCI Insight 2018 11 2;3(21). Epub 2018 Nov 2.

Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

TGF-β signals through a receptor complex composed of 2 type I and 2 type II (TGF-βRII) subunits. We investigated the role of macrophage TGF-β signaling in fibrosis after AKI in mice with selective monocyte/macrophage TGF-βRII deletion (macrophage TGF-βRII-/- mice). Four weeks after injury, renal TGF-β1 expression and fibrosis were higher in WT mice than macrophage TGF-βRII-/- mice, which had decreased renal macrophages. The in vitro chemotactic response to f-Met-Leu-Phe was comparable between bone marrow-derived monocytes (BMMs) from WT and macrophage TGF-βRII-/- mice, but TGF-βRII-/- BMMs did not respond to TGF-β. We then implanted Matrigel plugs suffused with either f-Met-Leu-Phe or TGF-β1 into WT or macrophage TGF-βRII-/- mice. After 6 days, f-Met-Leu-Phe induced similar macrophage infiltration into the Matrigel plugs of WT and macrophage TGF-βRII-/- mice, but TGF-β induced infiltration only in WT mice. We further determined the number of labeled WT or TGF-βRII-/- BMMs infiltrating into WT kidneys 20 days after ischemic injury. There were more labeled WT BMMs than TGF-βRII-/- BMMs. Therefore, macrophage TGF-βRII deletion protects against the development of tubulointerstitial fibrosis following severe ischemic renal injury. Chemoattraction of macrophages to the injured kidney through a TGF-β/TGF-βRII axis is a heretofore undescribed mechanism by which TGF-β can mediate renal fibrosis during progressive renal injury.
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http://dx.doi.org/10.1172/jci.insight.123563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238749PMC
November 2018

TGF-β1 promotes expression of fibrosis-related genes through the induction of histone variant H3.3 and histone chaperone HIRA.

Sci Rep 2018 09 19;8(1):14060. Epub 2018 Sep 19.

Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.

Renal fibrosis is a histological manifestation that occurs in almost every type of chronic kidney disease. Histone variant H3.3 and its chaperone, histone cell cycle regulation defective homolog A (HIRA), serve as epigenetic marks that regulate transcriptional activity. In this study, we assessed the roles of histone H3.3 and HIRA in unilateral ureteral-obstruction (UUO) mice. In UUO mice, the levels of histone H3.3 and HIRA were significantly upregulated in the kidneys. These upregulated levels were decreased by a TGF-β1 neutralizing antibody. TGF-β1 induced histone H3.3 and HIRA expression in vitro via a Smad3-dependent pathway in normal rat kidney (NRK)-52E cells. Additionally, knockdown of HIRA expression decreased histone H3.3 expression and fibrogenesis in NRK-52E cells after TGF-β1 stimulation. Chromatin immunoprecipitation analysis revealed that promoters of fibrosis-related genes were immunoprecipitated with both histone H3.3 and HIRA in NRK-52E cells. Lastly, in human kidney biopsies from patients diagnosed with IgA nephropathy, histone H3.3 and HIRA immunostaining correlated positively with areas of fibrosis and estimated glomerular filtration rate. In conclusion, TGF-β1 induces expression of histone H3.3 and HIRA, which regulates expression of fibrosis-related genes.
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http://dx.doi.org/10.1038/s41598-018-32518-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145928PMC
September 2018

Intercomparison of methods for measurement of dielectric properties of biological tissues with a coaxial sensor at millimeter-wave frequencies.

Phys Med Biol 2018 10 16;63(20):205008. Epub 2018 Oct 16.

National Institute of Information and Communications Technology, Koganei, Tokyo, 184-8795, Japan.

Coaxial sensors are effective for measurement of dielectric properties of biological tissues. Several measurement methods used to derive dielectric properties have been investigated for the measurement with a coaxial sensor at microwave frequencies. While the measurement accuracy depends on the method used, there has been insufficient intercomparison of these methods and their model approximation errors. On the other hand, we have developed a coaxial sensor for the measurement of complex permittivity at millimeter-wave (MMW) frequencies of up to 100 GHz. However, the scarcity of reference data at MMW frequencies makes the validation of the measurement system difficult. Thus, it is essential to clarify the model approximation error of the method used in the measurement system, particularly at MMW frequencies. This study aims to clarify the model approximation errors of methods for dielectric property measurement using a coaxial sensor at MMW frequencies. The model approximation errors were assessed by comparing results obtained by the methods with those based on the theoretical formula of the full-wave modal expression of Maxwell's equations. The measurement uncertainty for the theoretical formula was estimated for a standard liquid sample to clarify the contribution of the model approximation errors to the uncertainty. Furthermore, the methods were applied to the measurement of porcine tissues at body temperature, and the measurement accuracy and usability for measurement at MMW frequencies are discussed.
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http://dx.doi.org/10.1088/1361-6560/aae0e5DOI Listing
October 2018

Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS.

Blood Adv 2018 09;2(17):2242-2252

Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.
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http://dx.doi.org/10.1182/bloodadvances.2018018754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134219PMC
September 2018
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