Publications by authors named "Takahiro Maeda"

338 Publications

Genotypic and phenotypic features of eye-origin Streptococcus canis isolates from dogs in 2021: relatedness with clonal complex 46 and antimicrobial resistance.

Jpn J Infect Dis 2022 Jul 29. Epub 2022 Jul 29.

Laboratory of Infectious Diseases, Graduate School of Infection Control Sciences & Omura Satoshi Memorial Institute, Kitasato University, Japan.

Eye (including cornea) and ear canal are major sources of Streptococcus canis in companion animal practice. We aimed to clarify genotypic and phenotypic features of the eye-origin isolates in 2021 compared to ear-origin isolates in 2021 and eye-origin isolates in 2017. Of the 102 isolates in 2021, nine eye-origin isolates were enrolled, whereas twenty-one ear-origin isolates in 2021 and thirteen eye-origin isolates in 2017 were included as controls. Genotypic analyses included virulence-associated gene (VAG; inl, sagA, slo, scp, lbp, fbp, gbp, ap1, fp1, and brp) profiling, S. canis M-like protein (SCM) allele typing, multilocus sequence typing, and antimicrobial resistance (AMR) genotyping: phenotypic analyses contained hemolytic activity (HA) measurement and AMR phenotyping. There was only one 2017-eye-origin isolate with high-level HA, while the others showed low-level HA. We observed no association of the 2021-eye-origin population with detection rate of each VAG. There was no association of the 2021-eye-origin population with main SCM allele 2. We found significant association of the 2021-eye-origin population with main clonal complex (CC) 46 containing sequence type (ST) 46/ST2. There was significant association of the 2021-eye-origin population with AMR phenotypes/genotypes. Our observations suggest the unique microbiological features (CC46 having AMR phenotypes/genotypes) among the 2021-eye-origin population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7883/yoken.JJID.2022.137DOI Listing
July 2022

Tooth Loss and Carotid Intima-Media Thickness in Relation to Functional Atherosclerosis: A Cross-Sectional Study.

J Clin Med 2022 Jul 10;11(14). Epub 2022 Jul 10.

Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.

Structural arterial stiffness can be evaluated with carotid intima-media thickness (CIMT). Functional arterial stiffness can be evaluated with cardio-ankle vascular index (CAVI). A positive association between CIMT and tooth loss has been reported, but no studies have evaluated the association between CIMT and tooth loss in relation to functional arterial stiffness (functional atherosclerosis). A cross-sectional study of 1235 Japanese individuals aged 40-89 years was conducted. Tooth loss was defined as being in the lowest tertile for the number of remaining teeth (≤20 in men and ≤19 in women). Functional atherosclerosis was defined as CAVI ≥ 9.0. Independent of known confounding factors, CIMT was positively associated with tooth loss only in participants without functional atherosclerosis. Adjusted odds ratios for tooth loss and a 1 standard deviation increment in CIMT were 1.27 (1.04-1.55) for participants without functional atherosclerosis and 0.99 (0.77-1.26) for participants with functional atherosclerosis. CIMT and functional atherosclerosis had a significant effect on tooth loss; the fully adjusted -value for the interaction on tooth loss was 0.019. Independent of known confounding factors, CIMT is positively associated with tooth loss only in participants without functional atherosclerosis. This finding helps clarify the influence of the progression of arterial stiffness on tooth loss because the progression of structural atherosclerosis might have a beneficial influence on the maintenance of the microcirculation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm11143993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317227PMC
July 2022

Expert Panel Consensus Recommendations on the Use of Circulating Tumor DNA Assays for Patients with Advanced Solid Tumors.

Cancer Sci 2022 Jul 25. Epub 2022 Jul 25.

Translational Research Support Section, National Cancer Center Hospital East.

Comprehensive genomic profiling is increasingly used to facilitate precision oncology based on molecular stratification. In addition to conventional tissue comprehensive genomic profiling, comprehensive genomic profiling of circulating tumor DNA has become widely utilized in cancer care owing on its advantages, including less invasiveness, rapid turnaround time, and capturing heterogeneity. However, circulating tumor DNA comprehensive genomic profiling has some limitations, mainly false negatives due to low levels of plasma circulating tumor deoxyribonucleic acid and false positives caused by clonal hematopoiesis. Nevertheless, no guidelines and recommendations fully address these issues. Here, an expert panel committee involving representatives from 12 Designated Core Hospitals for Cancer Genomic Medicine in Japan was organized to develop expert consensus recommendations for the use of circulating tumor deoxyribonucleic acid-based comprehensive genomic profiling. The aim was to generate guidelines for clinicians and allied healthcare professionals on the optimal use of the circulating tumor DNA assays in advanced solid tumors and to aid the design of future clinical trials that utilize and develop circulating tumor DNA assays to refine precision oncology. Fourteen clinical questions regarding circulating tumor deoxyribonucleic acid comprehensive genomic profiling including the timing of testing and considerations for interpreting results were established by searching and curating associated literatures, and corresponding recommendations were prepared based on the literature for each clinical question. Final consensus recommendations were developed by voting to determine the level of each recommendation by the committee members.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.15504DOI Listing
July 2022

Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC.

ACS Chem Biol 2022 07 24;17(7):1789-1798. Epub 2022 Jun 24.

Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.

The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and other DcpS-dependent genetic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.2c00145DOI Listing
July 2022

Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model.

Gastric Cancer 2022 Jun 4. Epub 2022 Jun 4.

Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development.

Methods: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO).

Results: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area.

Conclusions: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10120-022-01307-8DOI Listing
June 2022

Draft Genome Sequence of Blood-Origin Pasteurella canis Strain PA42, Isolated from a Dog in Japan.

Microbiol Resour Announc 2022 Jul 31;11(7):e0026022. Epub 2022 May 31.

Laboratory of Infectious Diseases, Graduate School of Infection Control Sciences, Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo, Japan.

We report the draft genome sequence of Pasteurella canis strain PA42, which was isolated from the blood of a diseased dog in Japan in 2021. The 2.151-Mbp genome has a G+C content of 36.6%. Sequences unmapped to the reference genome sequence of NCTC 11621 (GenBank accession number UGTV00000000.1) were characterized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mra.00260-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302189PMC
July 2022

Association between circulating CD34-positive cell count and height loss among older men.

Sci Rep 2022 05 3;12(1):7175. Epub 2022 May 3.

Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Height loss starting in middle age is reportedly significantly associated with death due to cardiovascular disease. Impaired blood flow is the main pathology in cardiovascular disease. Hematopoietic stem cells such as CD34-positive cells play an important role in maintaining the microcirculation and preventing impaired blood flow by activating endothelial repair and angiogenesis. Therefore, circulating CD34-positive cell count could be associated with height loss. To clarify the association between circulating CD34-positive cell count and height loss, we conducted a follow-up study of 363 Japanese men aged 60-69 years over 2 years. Height loss was defined as being in the highest quartile of height decrease per year. Independent of known cardiovascular risk factors, circulating CD34-positive cell count was significantly inversely associated with height loss. The fully adjusted odds ratio (OR) and 95% confidence interval (CI) of height loss for circulating CD34-positive cell count (logarithmic values) was 0.49 (0.32, 0.74). This study suggests that a lower capacity to maintain the microcirculation due to a fewer CD34-positive cells might affect height loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-022-11040-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9064966PMC
May 2022

[NGS-based multi-gene panel testing in hematological malignancies: therapeutic significance].

Authors:
Takahiro Maeda

Rinsho Ketsueki 2022 ;63(4):302-307

Division of Precision Medicine, Kyushu University Graduate School of Medical Sciences.

Next-generation sequencing (NGS)-based multigene panel testing enables assessment of the mutational status of a few hundred genes associated with cancer pathogenesis. Although such tests have been approved by the Pharmaceuticals and Medical Devices Agency for use in patients with treatment-refractory solid tumors,there are no currently available tests for hematologic malignancies. The resultant information from these panel tests is primarily used to identify a potential treatment regimen or targeted therapy for solid tumors. However, genome profiling in hematologic malignancies also guides the clinical management of patients by providing diagnostic and prognostic information. This review summarizes the potential advantage of NGS-based multigene panel tests over conventional tests to determine therapeutic strategies for hematologic malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.63.302DOI Listing
May 2022

Oncological outcomes of dose reductions in cisplatin due to renal dysfunction for patients with metastatic urothelial carcinoma.

BJUI Compass 2021 Sep 9;2(5):322-330. Epub 2021 Mar 9.

Department of Urology Keio University School of Medicine Tokyo Japan.

Objective: To investigate whether dose reductions in cisplatin due to renal dysfunction were associated with worse clinical outcomes in metastatic urothelial carcinoma (UC) patients.

Patients And Methods: One hundred and fifty one metastatic UC patients who received first-line gemcitabine plus cisplatin (GC) salvage chemotherapy without a previous history of peri-surgical chemotherapy were included in this retrospective study. Patients with endogenous creatinine clearance of 60 mL/min or more were treated with a full dose of cisplatin, while those with 45-59 and 30-44 mL/min were treated with 75% and 50% doses, respectively. Patients were divided into three groups based on the average administered dose of cisplatin of 100% (Group A, N = 43), 99%-75% (Group B, N = 59), and less than 75% (Group C, N = 49), and therapeutic responses and the toxicity of GC were compared.

Results: Complete response rates were 9.3%, 13.6%, and 14.3% in groups A, B, and C, respectively. One-year progression-free survival rates were 22.9%, 31.1%, and 36.7% in groups A, B, and C with no significant differences. One-year cancer-specific survival rates were 56.1%, 71.1%, and 68.3% in groups A, B, and C with no significant differences. A multivariate Cox's regression analysis showed that the dose of cisplatin was not an independent prognostic factor for disease progression and cancer death. Furthermore, there were no significant differences in the incidence of severe adverse events.

Conclusions: Dose reductions in cisplatin due to renal dysfunction did not worsen clinical outcomes for metastatic UC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bco2.81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8988766PMC
September 2021

Vascular endothelial growth factor (VEGF) polymorphism rs3025039 and atherosclerosis among older with hypertension.

Sci Rep 2022 04 1;12(1):5564. Epub 2022 Apr 1.

Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Angiogenesis inhibition therapy causes hypertension by increasing peripheral vascular resistance. Vasa vasorum angiogenesis plays a crucial role in the development of atherosclerosis. Since vascular endothelial growth factor (VEGF), which contributes to the progress of angiogenesis, is reported to be inversely associated with the minor allele of polymorphism rs3025039, the minor allele of rs3025039 could be inversely associated with atherosclerosis among individuals with hypertension. A cross-sectional study of 1793 older Japanese adults aged 60-89 years with hypertension who participated in general health check-ups was conducted. Atherosclerosis was defined as carotid intima-media thickness (CIMT) ≥ 1.1 mm. The minor allele of polymorphism rs3025020 was positively associated with VEGF. Therefore, in addition to known cardiovascular risk factors, rs3025020 genotype acted as a confounding factor in the present study. Independent of known confounding factors, the minor allele of rs3025039 was inversely associated with atherosclerosis among older Japanese adults with hypertension. The fully adjusted odds ratio (OR) and 95% confidence interval (CI) for atherosclerosis with the minor allele of rs3025039 was 0.78 (0.64, 0.96). The angiogenesis-related polymorphism rs3025039 was associated with the development of atherosclerosis among older Japanese individuals. This study indicates that the development of atherosclerosis among older individuals might partly indicate a capacity for angiogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-022-09486-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976085PMC
April 2022

Associations among Ratio of Free Triiodothyronine to Free Thyroxine, Chronic Kidney Disease, and Subclinical Hypothyroidism.

J Clin Med 2022 Feb 25;11(5). Epub 2022 Feb 25.

Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.

The ratio of free triiodothyronine (FT3) to free thyroxine (FT4) (FT3/FT4), a maker of peripheral thyroxin deiodination, could indicate activity of thyroid hormone. Since positive association between subclinical hypothyroidism (SCH) and chronic kidney disease (CKD) was reported, clarifying the association among FT3/FT4, SCH, and CKD could be an efficient tool to make a strategy for preventing CKD. A cross-sectional study with 1724 Japanese with normal thyroid hormone was conducted. Significant positive association between SCH and CKD was observed; the adjusted odds ratio (OR) and 95% confidence interval (95% CI) was 2.23 (1.38, 3.59). Even though, FT3/FT4 was found to be inversely associated with CKD whereas positively associated with SCH; the adjusted ORs and 95% CIs for 1 standard deviation (SD) increment of FT3/FT4 were 0.51 (0.35, 0.74) for CKD and 2.40 (1.34, 4.29) for SCH, respectively. FT3/FT4 was also found to be positively associated with SCH without CKD but not those with CKD; 1 SD increment of FT3/FT4 were 3.44 (1.72, 6.91) for SCH without CKD and 1.11 (0.40, 3.06) for SCH with CKD, respectively. Although further investigation is necessary, present study indicates that higher activity of peripheral thyroxin deiodination might have beneficial association on absence of CKD even among SCH which is positively associated with CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm11051269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911058PMC
February 2022

Effect of Subclinical Hypothyroidism on the Association between Hemoglobin A1c and Reduced Renal Function: A Prospective Study.

Diagnostics (Basel) 2022 Feb 11;12(2). Epub 2022 Feb 11.

Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.

Subclinical hypothyroidism (SCH) was reported to be associated with accelerating endothelial dysfunction, which is recognized as one of the upstream mechanisms that leads to glomerular injury (lower glomerular filtration rate (GFR)). SCH was also reported to be associated with hyperglycemia, which is associated with higher hemoglobin A1c (HbA1c) levels and induces endothelial dysfunction. Therefore, SCH status could influence the association between HbA1c and reduced eGFR. To clarify those associations, we conducted a prospective study of 1580 Japanese individuals who participated in an annual health check-up in 2014 with 2.8 years of follow-up. All participants had free triiodothyronine (T3) and free thyroxine (T4) levels in the normal range. Among study participants, 88 were diagnosed as having SCH. Even though no significant correlation was observed between HbA1c and annual change in estimated GFR among participants without SCH (multi-adjusted standardized parameter estimate (β) = 0.03, = 0.250), a significant inverse association was observed among participants with SCH (β = -0.26, = 0.014). When those analyses were performed among participants who were not taking glucose lowering medication, the observed associations were essentially the same: β = 0.03, = 0.266 for participants without SCH and β = -0.32, = 0.006 for participants with SCH, respectively. Therefore, SCH status could influence the association between HbA1c and renal function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/diagnostics12020462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8871099PMC
February 2022

Comparing Genomic Characteristics of Associated with Invasiveness over a 20-year Period in Korea.

Ann Lab Med 2022 Jul;42(4):438-446

Department of Laboratory Medicine, Gyeongsang National University Changwon Hospital, Changwon, Korea.

Background: Few studies have investigated the invasiveness of based on whole-genome sequencing (WGS). Using WGS, we determined the genomic features associated with invasiveness of strains in Korea.

Methods: Forty-five strains from 1997, 2006, and 2017, including common emm types, were selected from the repository at Gyeongsang National University Hospital in Korea. In addition, 48 strains were randomly selected depending on their invasiveness between 1997 and 2017 to evaluate the genetic evolution and the associations between invasiveness and genetic profiles. Using WGS datasets, we conducted virulence-associated DNA sequence determination, genotyping, multi-locus sequence typing (MLST), and superantigen gene profiling.

Results: In total, 87 strains were included in this study. There were no significant differences in the genomic features throughout the study periods. Four genes, , , , and , were detected only in invasive strains. There was a significant association between invasiveness and cluster type A-C3, including, 1.0, 1.18, 1.3, and 1.76 (<0.05). The predominant 1 lineage belonged to ST28. There were no associations between invasiveness and superantigen gene profiles.

Conclusions: This is the first study using WGS datasets of strains collected between 1997 and 2017 in Korea. Streptococcal invasiveness is associated with the presence of , , , and . The 1 lineage and ST28 clone are explicitly associated with invasiveness, whereas genomic features remained stable over the 20-year period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3343/alm.2022.42.4.438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859563PMC
July 2022

Normal Anti-Thyroid Peroxidase Antibody (TPO-Ab) Titers and Active Arterial Wall Thickening among Euthyroid Individuals: A Prospective Study.

J Clin Med 2022 Jan 20;11(3). Epub 2022 Jan 20.

Department of General Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.

Among euthyroid individuals, having an anti-thyroid peroxidase antibody (TPO-Ab) titer in the normal range (negative) is positively associated with atherosclerosis as evaluated based on carotid intima-media thickness (CIMT). Atherosclerosis is an established risk factor for cardiovascular disease, but no significant association between yearly progression in CIMT and cardiovascular disease has been reported. Therefore, clarifying the association between having a TPO-Ab titer in the normal range and yearly progression in CIMT (i.e., active arterial wall thickening) among euthyroid individuals could help inform strategies for preventing cardiovascular disease. We conducted a prospective study of 1069 Japanese subjects with free triiodothyronine and free thyroxine levels within the normal range. Having a TPO-Ab titer in the normal range was significantly positively associated with baseline atherosclerosis and significantly inversely associated with active arterial wall thickening. After adjusting for known confounding factors, the adjusted odds ratio (OR) and 95% confidence interval (CI) of log (TPO-Ab titer) for baseline atherosclerosis and active arterial wall thickening was 2.16 (1.07, 4.35) and 0.59 (0.37, 0.93), respectively. Since progression in CIMT is a process of aggressive endothelial repair, deficient endothelial repair inhibits active arterial wall thickening. Therefore, high-normal TPO-Ab titers might induce a deficiency in endothelial repair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm11030521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836412PMC
January 2022

Hinge fractures reaching the tibial plateau can be caused by forcible opening of insufficient posterior osteotomy during open-wedge high tibial osteotomy.

Knee Surg Sports Traumatol Arthrosc 2022 Jan 4. Epub 2022 Jan 4.

Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Purpose: The purpose of this study was to use the finite element method (FEM) to reproduce fracture lines that reach the lateral tibial plateau during open-wedge high tibial osteotomy (OWHTO) in patients with Type III lateral hinge fracture (LHF). It was hypothesized that the FEM could clarify biomechanical causes of Type III LHF, enabling prevention of adverse complications.

Methods: This study used the nonlinear FEM to analyze the data of eight knees in eight patients (two males and six females) with Type III LHF among 82 patients who underwent OWHTO, as well as the data of eight individuals with no LHF. To predict the onset of Type III LHF, simulation models were also developed in which posterior osteotomy sufficiency varied from 50% to perfect, the latter defined as osteotomy reaching the hinge point.

Results: Real-life instances of Type III LHF caused by insufficient posterior osteotomy were reproduced in all patient-specific FEM models, and these models accurately predicted fracture types and locations. During opening of the osteotomy gap, the fracture line reached the lateral tibial plateau, and extended vertically from the end of the insufficient posterior osteotomy, avoiding the rigid proximal tibiofibular joint. In contrast, sufficient posterior osteotomy resulted in a lack of LHF. Posterior osteotomy extension ≥ 70% of the width of the osteotomy plane was the cut-off value to prevent Type III LHF.

Conclusion: Forced opening of insufficient posterior osteotomy was found to be a biomechanical cause of Type III LHF that extended perpendicularly to the lateral tibial plateau, avoiding the proximal tibiofibular joint. The clinical significance of this study is that sufficient posterior osteotomy during OWHTO, defined as at least 70% of the width of the osteotomy plane, can prevent Type III LHF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00167-021-06816-0DOI Listing
January 2022

Dog/cat-origin quinolone-resistant Streptococcus agalactiae isolates with point mutations in quinolone resistance-determining regions: Relatedness with clonal complex 10.

J Infect Chemother 2022 Mar 27;28(3):389-395. Epub 2021 Nov 27.

Laboratory of Infectious Diseases, Graduate School of Infection Control Sciences & Ōmura Satoshi Memorial Institute, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. Electronic address:

Objective: We aimed to investigate dog/cat-origin quinolone-resistant Streptococcus agalactiae isolates with point mutations in quinolone resistance-determining regions (QRDRs) and to define the relatedness between quinolone-resistant isolates and their microbiological features of capsular genotype, sequence type (ST)/clonal complex (CC), and antimicrobial resistance (AMR) gene.

Methods: With dog/cat-origin 22 isolates, type strain, and human-origin 6 isolates, we performed antimicrobial susceptibility testing by agar plate dilution method using levofloxacin, ciprofloxacin, and moxifloxacin. We also determined amino acid sequences in QRDRs of gyrA/gyrB/parC/parE genes and their point mutations. We conducted capsular genotyping, multilocus sequence typing, and AMR genotyping in our previous investigations. Correlations between quinolone-resistant population and their microbiological features were examined.

Results: We found dog/cat-origin seven (31.8%) quinolone-resistant isolates harboring minimum inhibitory concentrations (MICs) of levofloxacin 16-32 μg/mL, ciprofloxacin 32 μg/mL, and moxifloxacin 2-4 μg/mL: human three isolates indicated MICs of levofloxacin 16-64 μg/mL, ciprofloxacin 32 μg/mL, and moxifloxacin 2-16 μg/mL. Point mutations Ser81Leu in gyrA and Ser79Phe/Ser79Tyr/Asp83Asn/Gly128Asp in parC were observed among these resistant isolates: mutations Leu495Ile/Val503Ile in parE was found among quinolone-nonresistant isolates. There was a significant correlation between dog/cat-origin quinolone-resistant population and ST10 (p = 0.023)/CC10 (p = 0.021).

Conclusion: To our best knowledge, this is the first report assessing dog/cat-origin quinolone-resistant S. agalactiae. Our observations could be applied in future, by veterinarians while treating dogs and cats with clinical symptoms/signs suggestive of streptococcal infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jiac.2021.11.015DOI Listing
March 2022

EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma.

Sci Rep 2021 11 1;11(1):21396. Epub 2021 Nov 1.

Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2H3K27me3 cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-00889-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560765PMC
November 2021

Posttreatment after Lenvatinib in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2021 Sep 20;10(5):473-484. Epub 2021 Apr 20.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy.

Methods: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions.

Results: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively.

Conclusion: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000515552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527907PMC
September 2021

The use of information and communication technology in Japanese rural clinics.

J Rural Med 2021 Oct 1;16(4):298-300. Epub 2021 Oct 1.

Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Japan.

High-speed information and communication technology (ICT) networks stretch all over Japan. However, their utility in facilitating rural healthcare remains uncharacterized. A nationwide questionnaire survey was sent by mail to 1,018 rural clinics constructed in a public manner in municipalities throughout Japan. ICT use was classified by type, including a doctor-to-doctor manner. Only 19% of the 303 clinics surveyed (with a response rate of 30%) used ICT. Specifically, 50% used it in a doctor-to-doctor manner, while 35% used it to obtain electronic medical records. Differences in proficiency levels among ICT users were cited by 21% of the respondents as a major problem associated with ICT use. In Japan, the prevalence of ICT use for rural healthcare appeared low. We suggest a policy reform to facilitate ICT use in rural healthcare.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2185/jrm.2021-026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527613PMC
October 2021

Granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α in combination is a useful diagnostic biomarker to distinguish familial Mediterranean fever from sepsis.

Arthritis Res Ther 2021 10 15;23(1):260. Epub 2021 Oct 15.

Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Objective: To identify potential biomarkers to distinguish familial Mediterranean fever (FMF) from sepsis.

Method: We recruited 28 patients diagnosed with typical FMF (according to the Tel Hashomer criteria), 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the FMF and sepsis groups in order to identify specific molecular networks. Multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by importance and determine specific biomarkers for distinguishing FMF from sepsis.

Results: Fifteen of the 40 cytokines were found to be suitable for further analysis. Levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor 2, vascular endothelial growth factor, macrophage inflammatory protein-1b, and interleukin-17 were significantly elevated, whereas tumor necrosis factor-α (TNF-α) was significantly lower in patients with FMF compared with those with sepsis. Cytokine clustering patterns differed between the two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both GM-CSF and TNF-α could distinguish FMF from sepsis with high accuracy (cut-off values for GM-CSF = 8.3 pg/mL; TNF-α = 16.3 pg/mL; sensitivity, 92.9%; specificity, 94.4%; accuracy, 93.4%).

Conclusion: Determination of GM-CSF and TNF-α levels in combination may represent a biomarker for the differential diagnosis of FMF from sepsis, based on measurement of multiple cytokines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13075-021-02644-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518289PMC
October 2021

A germinal center-associated microenvironmental signature reflects malignant phenotype and outcome of DLBCL.

Blood Adv 2022 04;6(7):2388-2402

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, 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 (COO), 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006269PMC
April 2022

Association between thyroid-stimulating hormone (TSH) and proteinuria in relation to thyroid cyst in a euthyroid general population.

J Physiol Anthropol 2021 Oct 9;40(1):15. Epub 2021 Oct 9.

Division of Promotion of Collaborative Research on Radiation and Environment Health Effects, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

Background: High normal levels of thyroid-stimulating hormone (TSH) have been reported to be associated with chronic kidney disease (CKD) among euthyroid individuals. However, there has been only limited research on the association between TSH and proteinuria, a major risk factor for the progression of renal disease.

Methods: A cross-sectional study of 1595 euthyroid individuals was conducted. All participants were within the normal range for free triiodothyronine (T3), free thyroxine (T4), and TSH. Analyses were stratified by thyroid cyst status to test the hypothesis that the absence of thyroid cysts, an indicator of latent thyroid damage, is associated with declining ability to synthesis thyroid hormone.

Results: For participants with thyroid cysts, a significant inverse association between TSH and proteinuria was observed (adjusted odds ratio (95% confidence intervals) of log-transformed TSH for proteinuria 0.40 (0.18, 0.89)). In participants without thyroid cysts, a significant positive association between those two factors was observed (2.06 (1.09, 3.90)).

Conclusions: Among euthyroid individuals in the general population, being in the normal range of TSH was found to have an ambivalent association with proteinuria. Thyroid cyst status could be an effect modifier for those associations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40101-021-00264-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502342PMC
October 2021

Atypical Cogan's Syndrome Mimicking Giant Cell Arteritis Successfully Treated with Early Administration of Tocilizumab.

Intern Med 2022 Apr 5;61(8):1265-1270. Epub 2021 Oct 5.

Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Japan.

A 49-year-old Japanese man with a 2-month history of a fever, headache, and bilateral conjunctival hyperemia was admitted. His condition fulfilled the giant cell arteritis classification criteria (new headache, temporal artery tenderness, elevated ESR) and atypical Cogan's syndrome (CS) with scleritis and sensorineural hearing loss (SNHL). The interleukin (IL)-6 serum level was extremely high. Two weeks after his insufficient response of SNHL and scleritis to oral prednisolone, we administered tocilizumab (TCZ); rapid improvements in scleritis and SNHL occurred. Early IL-6 target therapy can help prevent irreversible CS-induced sensory organ damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.7674-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9107983PMC
April 2022

Ribosomal stress induces 2-cell embryo-like state transition of the mouse ESCs through p53 activation.

Biochem Biophys Res Commun 2021 11 27;579:175-180. Epub 2021 Sep 27.

Medical School, Osaka University, Yamada-oka 2-2, Suita, Osaka, 565-0871, Japan. Electronic address:

Embryonic stem cells (ESCs) maintain a pluripotent state and genome integrity in long-term culture. A rare population of ESCs showing 2-cell embryo-specific gene expression is believed to play critical roles in sustainable pluripotency and genome stability. However, the molecular mechanism controlling this transition to a 2-cell embryo-like (2CL) state remains unclear. We carried out screening to search for the factors involved in 2CL state induction and found a ribosomal RNA processing factor, Pum3 to be a candidate. Increased 2CL state population accompanied with an accumulation of pre-ribosomal RNA and activated p53 in the Pum3-KO ESC. Furthermore, the increase of 2CL state cells in the Pum3-KO ESCs was completely abrogated by the deletion of p53. The DNA damage induced by the Ultraviolet light (UV) irradiation and Zeocin promoted the transition to a 2CL state in a p53-dependent manner. Thus, our study provides new insights into a 2CL state transition mechanism through stress-dependent p53 activation of ESCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2021.09.068DOI Listing
November 2021

CAL-1 as Cellular Model System to Study CCR7-Guided Human Dendritic Cell Migration.

Front Immunol 2021 16;12:702453. Epub 2021 Sep 16.

Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland.

Dendritic cells (DCs) are potent and versatile professional antigen-presenting cells and central for the induction of adaptive immunity. The ability to migrate and transport peripherally acquired antigens to draining lymph nodes for subsequent cognate T cell priming is a key feature of DCs. Consequently, DC-based immunotherapies are used to elicit tumor-antigen specific T cell responses in cancer patients. Understanding chemokine-guided DC migration is critical to explore DCs as cellular vaccines for immunotherapeutic approaches. Currently, research is hampered by the lack of appropriate human cellular model systems to effectively study spatio-temporal signaling and CCR7-driven migration of human DCs. Here, we report that the previously established human neoplastic cell line CAL-1 expresses the human DC surface antigens CD11c and HLA-DR together with co-stimulatory molecules. Importantly, if exposed for three days to GM-CSF, CAL-1 cells induce the endogenous expression of the chemokine receptor CCR7 upon encountering the clinically approved TLR7/8 agonist Resiquimod R848 and readily migrate along chemokine gradients. Further, we demonstrate that CAL-1 cells can be genetically modified to express fluorescent (GFP)-tagged reporter proteins to study and visualize signaling or can be gene-edited using CRISPR/Cas9. Hence, we herein present the human CAL-1 cell line as versatile and valuable cellular model system to effectively study human DC migration and signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.702453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482423PMC
December 2021

Intravenous cyclophosphamide treatment for systemic lupus erythematosus with severe autonomic disorders confirmed by head-up tilt table test: A case series.

Mod Rheumatol Case Rep 2022 Jan;6(1):47-51

Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Autonomic disorders are common in patients with systemic lupus erythematosus (SLE), but the therapeutic strategy and methods for evaluating the effects of therapy have not been established. We describe the three cases of SLE patients who developed severe autonomic disorders as demonstrated by the head-up tilt table test (HUT). All three patients were treated by intensive immunosuppressive treatments including intravenous cyclophosphamide (IVCY); their HUT results all became negative. Our cases suggest that IVCY treatment can be a good therapeutic option for severe autonomic disorders in SLE patients. The HUT is a useful objective method for the diagnosis of and the evaluation of longitudinal therapeutic effects on autonomic disorders in SLE patients with orthostatic intolerance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/mrcr/rxab027DOI Listing
January 2022

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

Blood 2022 02;139(5):748-760

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

Acute lymphoblastic leukemia (ALL) harboring the IgH-CRLF2 rearrangement (IgH-CRLF2-r) exhibits poor clinical outcomes and is the most common subtype of Philadelphia chromosome-like acute lymphoblastic leukemia (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 2 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 single-guide RNAs (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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021012976DOI Listing
February 2022

Long-term effects of endoscopic papillary large balloon dilation in patients with challenging bile duct calculi: A retrospective observational study.

Medicine (Baltimore) 2021 Sep;100(36):e27227

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Abstract: Endoscopic papillary large balloon dilation (EPLBD) can be used to treat challenging common bile duct stones. No previous studies have reported intractable cases treated either by EPLBD or mechanical lithotripter use. We aimed to evaluate and compare the long-term effects of EPLBD with mechanical lithotripter use.This retrospective cohort study reviewed data from 153 patients admitted to the Eastern Chiba Medical Center from April 2014 to March 2020, presenting with common bile duct calculi that could not be removed using a basket or balloon catheter. Patients were divided into groups depending on whether the treatment was performed using a mechanical lithotripter or EPLBD. The primary outcome was the recurrence rate of common bile duct calculi, and the secondary outcome was the rate of postoperative adverse events. The Wilcoxon test was used to compare the 2 groups. Statistical significance was set at P < .05.The median age of patients included in the lithotripter and EPLBD groups were 73 years and 83 years, respectively (P = .006), while the sex ratio (male:female) in the groups was 18:13 and 55:67, respectively. The EPLBD group showed a statistically larger median bile duct diameter (13 mm [range: 8-24 mm] vs 11 mm [range: 5-16 mm]; P < .001), larger maximal calculus diameter (median, 13.5 mm [range: 8-25 mm] vs 11 mm [range: 7-16 mm]; P < .001), and shorter median cumulative treatment time after reaching the duodenal papilla (35.5 minutes [range: 10-176 minutes] vs 47 minutes [range: 22-321 minutes]; P = .026) in comparison to the lithotripter group. There was no significant difference in the rate of adverse events between the EPLBD and the mechanical lithotripter groups. The recurrence rate was significantly lower (P = .014) in the EPLBD group.EPLBD increases therapeutic efficacy and reduces treatment duration for patients in whom calculus removal is difficult, without increasing the frequency of adverse events. No serious adverse events were observed. Additionally, EPLBD appears to reduce the risk of long-term recurrence. Future studies are needed to evaluate long-term outcomes in younger patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000027227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428757PMC
September 2021
-->