Publications by authors named "Hirotaka Matsui"

92 Publications

[Molecular mechanisms of myeloid malignancies].

Authors:
Hirotaka Matsui

Rinsho Ketsueki 2021 ;62(8):883-891

Department of Molecular Laboratory Medicine, Kumamoto University.

Almost all genetic abnormalities involved in the occurrence and progression of myelodysplastic syndromes (MDS) and acute myeloid leukemia have been reported within the last decade. The molecular mechanisms of these genetic changes involved in causing dysfunctions in hematopoietic cells have also been clarified in recent years. For MDS, gene mutations of RNA splicing factors and cohesin complex have been shown to trigger not only aberrant RNA splicing or decreased chromatin insulation but also DNA damage response and transcriptional dysregulation through inefficient interaction between promoters and enhancers. Consequently, these newly identified disease-causing mechanisms may be considered potential therapeutic targets.
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http://dx.doi.org/10.11406/rinketsu.62.883DOI Listing
September 2021

HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis.

Elife 2021 08 25;10. Epub 2021 Aug 25.

Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan.

Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism underlying aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their trithorax homology domain 2 (THD2) in various human cell lines. MLL proteins associated with the HBO1 complex through multiple contacts mediated mainly by the ING4/5 and PHF16 subunits in a chromatin-bound context where histone H3 lysine 4 tri-methylation marks were present. Of the many MLL fusions, MLL-ELL particularly depended on the THD2-mediated association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1, and p53. MLL-ELL activated gene expression in murine hematopoietic progenitors by loading an AF4/ENL/P-TEFb (AEP) complex onto the target promoters wherein the HBO1 complex promoted the association with AEP complex over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between the HBO1 complex and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.
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http://dx.doi.org/10.7554/eLife.65872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387021PMC
August 2021

Current Awareness and Status of Venous Ultrasonography in Kumamoto Prefecture - A Report of the Kumamoto Cardiovascular Echocardiography Standardization Project.

Circ Rep 2021 Aug 29;3(8):449-456. Epub 2021 Jun 29.

Department of Laboratory Medicine, Kumamoto University Hospital Kumamoto Japan.

There are few reports on the current awareness and status of venous ultrasonography, including the number of specialists who perform this procedure, in a specific regional area in Japan. This cross-sectional survey study was conducted in Kumamoto Prefecture from October 2018 to March 2019. Of the 366 medical institutions providing cardiology services in Kumamoto Prefecture, 259 (101 general hospitals, 158 small clinics) responded to our questionnaire. In 2017, 21,773 venous ultrasound tests were performed, 21,101 (97%) of which were performed in hospitals and only 672 (3%) were performed in clinics. Both the number of institutions performing venous ultrasounds and the number of tests performed increased over time. Although 317 medical staff in Kumamoto Prefecture were performing transthoracic echocardiography (TTE) when the questionnaires were collected, only 210 performed venous ultrasounds. Although 91% (61/67) of medical institutions could perform TTE within 30 min, only 77% (53/69) performed venous ultrasounds within 30 min. The number of venous ultrasounds per population×100 was largest in the Kumamoto and Kamimashiki areas (1.67) and smallest in the Kamoto area (0.05). This is the first report to reveal the current awareness and status of venous ultrasonography in a specific region in Japan. There are several problems to be overcome, such as a lack of venous ultrasound specialists and the regional disparity in venous ultrasounds in Kumamoto Prefecture.
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http://dx.doi.org/10.1253/circrep.CR-21-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338438PMC
August 2021

HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways.

Elife 2021 07 26;10. Epub 2021 Jul 26.

Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan.

HOXA9 is often highly expressed in leukemias. However, its precise roles in leukemogenesis remain elusive. Here, we show that HOXA9 maintains gene expression for multiple anti-apoptotic pathways to promote leukemogenesis. In MLL fusion-mediated leukemia, MLL fusion directly activates the expression of MYC and HOXA9. Combined expression of MYC and HOXA9 induced leukemia, whereas single gene transduction of either did not, indicating a synergy between MYC and HOXA9. HOXA9 sustained expression of the genes implicated in the hematopoietic precursor identity when expressed in hematopoietic precursors, but did not reactivate it once silenced. Among the HOXA9 target genes, and synergistically induced leukemia with . Not only BCL2, but also SOX4 suppressed apoptosis, indicating that multiple anti-apoptotic pathways underlie cooperative leukemogenesis by HOXA9 and MYC. These results demonstrate that HOXA9 is a crucial transcriptional maintenance factor that promotes MYC-mediated leukemogenesis, potentially explaining why HOXA9 is highly expressed in many leukemias.
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http://dx.doi.org/10.7554/eLife.64148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313233PMC
July 2021

Development of potent antipseudomonal β-lactams by means of polycarboxylation of aminopenicillins.

Microbiol Immunol 2021 Jul 12. Epub 2021 Jul 12.

Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that presents a serious risk to immunosuppressed individuals and other extremely vulnerable patients such as those in intensive care units. The emergence of multidrug-resistant Pseudomonas strains has increased the need for new antipseudomonal agents. In this study, a series of amino group-modified aminopenicillin derivatives was synthesized that have different numbers of carboxyl groups and structurally resemble carboxypenicillin-ureidopenicillin hybrids, and their antipseudomonal activities were evaluated. Among the derivatives synthesized, diethylenetriaminepentaacetic acid (DTPA)-modified amoxicillin (DTPA-Amox) showed potent antipseudomonal activity, not only against the laboratory strain PAO1 but also against clinically isolated Pseudomonas strains that were resistant to piperacillin and carbenicillin. DTPA-Amox had no obvious cytotoxic effects on cultured mammalian cells. In addition, in an in vivo model of leukopenia, DTPA-Amox treatment produced a moderate but statistically significant improvement in the survival of mice with P. aeruginosa strain PAO1 infection. These data suggest that polycarboxylation by DTPA conjugation is an effective approach to enhance antipseudomonal activity of aminopenicillins.
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http://dx.doi.org/10.1111/1348-0421.12930DOI Listing
July 2021

Long-term prognoses of patients with and without re-rupture after arthroscopic rotator cuff repair.

J Phys Ther Sci 2021 Jun 18;33(6):460-465. Epub 2021 Jun 18.

Section of Rehabilitation, Fuchinobe General Hospital, Japan.

[Purpose] We followed-up patients who underwent arthroscopic rotator cuff repair (ARCR) for 2 years to assess the prognosis of rotator cuff tears and compared the outcomes of the patients with and without re-rupture. We also examined the usefulness of Shoulder36, a self-assessment tool, for assessing the long-term prognosis in patients undergoing ARCR. [Participants and Methods] We included 28 patients who received occupational therapy pre- and post-ARCR between April 2012 and August 2015 and categorized them based on the occurrence of re-rupture. We followed-up on their prognoses for 2 years using physical examination and Shoulder36 assessment. [Results] Re-rupture occurred in five patients within 3 months of treatment. During the 2 year follow-up, the control group showed a significant improvement in pain and bi-directional active range of motion during physical assessment and in five out of six domains during Shoulder36 assessment. In contrast, the re-rupture group showed significant differences for only three domains of the Shoulder36 assessment twelve months after surgery. [Conclusion] We confirmed the long-term functional improvement and maintenance in the re-rupture group, suggesting that continued rehabilitation, compensatory movements, and detailed guidance on daily life activities are required for patients after ARCR. Furthermore, Shoulder36 can be useful for assessing the prognosis of patients with and without re-rupture.
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http://dx.doi.org/10.1589/jpts.33.DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219605PMC
June 2021

Successful Cord Blood Transplantation for Idiopathic CD4+ Lymphocytopenia.

Acta Haematol 2021 Jun 1:1-7. Epub 2021 Jun 1.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

Idiopathic CD4+ lymphocytopenia (ICL) is the depletion of CD4+ lymphocytes to <300 cells/mm3 without human immunodeficiency virus infection or other causes of lymphocytopenia. ICL causes fatal infections; its etiology remains unclear and it lacks consensus regarding therapeutic options. We report the first patient with ICL who had a successful clinical course following a cord blood transplant (CBT). A 45-year-old woman was diagnosed with ICL and underwent partial hepatectomy for an abscess caused by the Mycobacterium avium complex. No specific gene alterations were detected through next generation sequencing-based evaluation. Following a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, busulfan, and 4 Gy total body irradiation, a single-unit CBT was performed. Neutrophils were engrafted on day +14. CD4+ lymphocyte counts increased to over 300 cells/mm3 on day +436. After 75 months, she was alive without any sequelae. CBT with an RIC regimen could be a curable treatment option for ICL.
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http://dx.doi.org/10.1159/000516347DOI Listing
June 2021

Colonization of distant organs by tumor cells generating circulating homotypic clusters adaptive to fluid shear stress.

Sci Rep 2021 03 17;11(1):6150. Epub 2021 Mar 17.

Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.

Once disseminated tumor cells (DTCs) arrive at a metastatic organ, they remain there, latent, and become seeds of metastasis. However, the clonal composition of DTCs in a latent state remains unclear. Here, we applied high-resolution DNA barcode tracking to a mouse model that recapitulated the metastatic dormancy of head and neck squamous cell carcinoma (HNSCC). We found that clones abundantly circulated peripheral blood dominated DTCs. Through analyses of multiple barcoded clonal lines, we identified specific subclonal population that preferentially generated homotypic circulating tumor cell (CTC) clusters and dominated DTCs. Despite no notable features under static conditions, this population significantly generated stable cell aggregates that were resistant to anoikis under fluid shear stress (FSS) conditions in an E-cadherin-dependent manner. Our data from various cancer cell lines indicated that the ability of aggregate-constituting cells to regulate cortical actin-myosin dynamics governed the aggregates' stability in FSS. The CTC cluster-originating cells were characterized by the expression of a subset of E-cadherin binding factors enriched with actin cytoskeleton regulators. Furthermore, this expression signature was associated with locoregional and metastatic recurrence in HNSCC patients. These results reveal a biological selection of tumor cells capable of generating FSS-adaptive CTC clusters, which leads to distant colonization.
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http://dx.doi.org/10.1038/s41598-021-85743-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969766PMC
March 2021

Current Awareness and Status of Transthoracic Echocardiography in Kumamoto Prefecture - A Report of the Kumamoto Cardiovascular Echocardiography Standardization Project.

Circ Rep 2020 Apr 21;2(6):297-305. Epub 2020 Apr 21.

Department of Laboratory Medicine, Kumamoto University Hospital Kumamoto Japan.

There are few reports on current awareness and status of transthoracic echocardiography (TTE), including the actual performance rate according to echocardiographic guidelines, in a specific area or region. This cross-sectional survey study was conducted in Kumamoto Prefecture from October 2018 to March 2019. There are 366 medical institutions advocating cardiology in Kumamoto Prefecture. Of these, 259 (101 hospitals and 158 clinics) returned questionnaires regarding TTE. In all, 150,570 TTEs were performed in 2017. Of these, 132,771 (88%) were performed in hospitals and 17,799 (12%) were performed in clinics. Physicians performed only 5% of TTEs, whereas sonographers performed 86%. Although the modified Simpson method was performed in 90% of hospitals, 3-dimensional echocardiography was performed in only 2% of hospitals. In addition, the left atrial volume index was not examined in approximately 60% of hospitals, and the mean E/E' ratio was not examined in 80% of hospitals. Multivariable logistic regression analysis revealed that having a Fellow of the Japan Society of Ultrasonic in Medicine was significantly and independently associated with guideline-oriented TTE (odds ratio 9.43; 95% confidence interval 1.22-72.71, P<0.05). The rate of echocardiographic measurements performed according to echocardiographic guidelines is exceptionally low in Kumamoto Prefecture. Sufficient dissemination of echocardiographic guidelines may be important in improving this rate.
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http://dx.doi.org/10.1253/circrep.CR-20-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925316PMC
April 2020

Temporal Change in Longitudinal Strain After Domino Liver Transplantation With Liver Grafts Explanted From Patients With Hereditary Amyloidogenic Transthyretin Amyloidosis.

Circ Rep 2020 Nov 10;2(12):730-738. Epub 2020 Nov 10.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University Kumamoto Japan.

Using transthoracic echocardiography, including 2D speckle tracking imaging (STI), this study examined cardiac function after domino liver transplantation (DLT) with liver grafts explanted from patients with hereditary amyloidogenic transthyretin amyloidosis. In all, 14 patients who underwent DLT at Kumamoto University Hospital and for whom 2D STI information was available were enrolled in the study; time-dependent echocardiographic changes were evaluated in 7. Although left ventricular (LV) systolic and diastolic function did not differ between the pre- and post-DLT periods (mean [±SD] 5.4±1.0 years after DLT), there were significant (P<0.05 for all) increases in the post- vs. pre-DLT period in basal longitudinal strain (LS; -13.4±2.3 vs. -19.3±4.4), relative apical LS index (=apical LS/[basal LS+mid LS]; 0.75±0.20 vs. 0.58±0.08), and LV ejection fraction/global LS (3.91±0.58 vs. 3.06±0.44). Age at the time of DLT was significantly higher in the group with impaired (>-14%) than preserved basal LS (57.2±3.5 vs. 39.6±16.0 years; P<0.05). When control subjects (n=14) were added to the enrolled DLT recipients, multivariable logistic regression analysis revealed that a history of DLT was significantly associated with impaired basal LS (>-14%; odds ratio 28.39, 95% confidence interval 1.89-427.45, P<0.05). LV systolic and diastolic function was preserved in the long term after DLT. However, 2D STI revealed subtle cardiac dysfunction in DLT recipients, which may be an early manifestation of cardiac amyloidosis.
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http://dx.doi.org/10.1253/circrep.CR-20-0106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937528PMC
November 2020

Estimation of the hemoglobin glycation rate constant.

Sci Rep 2021 01 13;11(1):986. Epub 2021 Jan 13.

Department of Internal Medicine, Hakuhokai Central Hospital, Hyogo, 661-0953, Japan.

In a previous study, a method of obtaining mean erythrocyte age ([Formula: see text]) from HbA1c and average plasma glucose (AG) was proposed. However, the true value of the hemoglobin glycation constant ([Formula: see text] dL/mg/day), required for this model has yet to be well characterized. Another study also proposed a method of deriving [Formula: see text] from erythrocyte creatine (EC). Utilizing these formulae, this study aimed to determine a more accurate estimate of [Formula: see text]. One hundred and seven subjects including 31 patients with hemolytic anemia and 76 subjects without anemia were included in this study. EC and HbA1c data were analyzed, and [Formula: see text] using HbA1c, AG and the newly-derived constant, [Formula: see text] were compared to [Formula: see text] using traditional [Formula: see text] in three patients whose data were taken from previous case studies. A value of [Formula: see text] dL/mg/day was determined for [Formula: see text]. [Formula: see text] using HbA1c, AG and [Formula: see text] were found to no be significantly different (paired t-test, [Formula: see text]) to [Formula: see text] using traditional [Formula: see text]. [Formula: see text] enables the estimation of [Formula: see text] from HbA1c and AG.
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http://dx.doi.org/10.1038/s41598-020-80024-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806940PMC
January 2021

Glycosylated ferritin as an improved marker for post-transfusion iron overload.

Int J Hematol 2021 Apr 5;113(4):537-546. Epub 2021 Jan 5.

Department of Clinical Laboratory Medicine, Kumamoto University Hospital, Kumamoto University, Kumamoto, Japan.

Red blood cell (RBC) transfusion is an effective therapy for anemia, but repeated transfusions may cause iron overload-related damage to various organs. Iron chelation therapy, now widely available for patients who have received transfusions, is expected to reduce organ damage even in patients who received many transfusions. Therefore, determining when to start iron chelation therapy is important. In guidelines for iron chelation therapy, the serum ferritin level has been widely accepted as a practical marker for estimating iron overload. However, guidelines recommend multiple measurements of serum ferritin, because levels often fluctuate. Here, we investigated the usefulness of glycosylated ferritin as a marker of iron overload using a cohort consisted of 103 patients who had a total ferritin value over 1000 ng/mL. We found that the volume of RBCs transfused was clearly associated with the glycosylated ferritin level. We also found that acute inflammation, as represented by C-reactive protein values, was associated with increased non-glycosylated ferritin and that patients with hematopoietic diseases had higher glycosylated ferritin levels, possibly because of repeated RBC transfusions. We thus conclude that glycosylated ferritin may be an improved marker for predicting iron overload status.
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http://dx.doi.org/10.1007/s12185-020-03056-9DOI Listing
April 2021

Plasma growth differentiation factor 15: a novel tool to detect early changes of hereditary transthyretin amyloidosis.

ESC Heart Fail 2021 04 30;8(2):1178-1185. Epub 2020 Dec 30.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan.

Aims: Hereditary transthyretin (ATTRv) amyloidosis is the most frequent and representative form of autosomal dominant hereditary systemic amyloidosis. Disease-modifying treatments of the disease are more effective during the early stages, and we require biomarkers to detect early pathological changes for prompt diagnosis. This study aimed to investigate whether plasma growth differentiation factor 15 (GDF-15) levels could aid detection of early pathological changes in ATTRv amyloidosis.

Methods And Results: We retrospectively studied 32 patients with ATTRv amyloidosis, eight asymptomatic TTR mutation carriers, and eight healthy volunteers. We evaluated plasma GDF-15 levels in these subjects as related to levels of brain natriuretic peptide and high-sensitivity troponin T, echocardiographic features, Tc-pyrophosphate (PYP) scans, and cardiac magnetic resonance imaging findings. Plasma GDF-15 levels significantly increased even in asymptomatic TTR mutation carriers compared with healthy volunteers (P < 0.01). Plasma GDF-15 levels were significantly correlated with plasma brain natriuretic peptide values (P < 0.01), serum high-sensitivity troponin T values (P < 0.05), and interventricular septal thickness at end-diastole (P < 0.01) in patients with ATTRv amyloidosis. Plasma GDF-15 levels in patients with PYP-positive ATTRv amyloidosis were significantly higher than those in patients with PYP-negative ATTRv amyloidosis (P < 0.01). Plasma GDF-15 levels in patients with late gadolinium enhancement-positive ATTRv amyloidosis were significantly higher than those in patients with late gadolinium enhancement-negative ATTRv amyloidosis (P < 0.01). Groups of patients with different TTR genotypes manifested different plasma GDF-15 levels.

Conclusions: Growth differentiation factor 15 may reflect early pathological changes of ATTRv amyloidosis.
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http://dx.doi.org/10.1002/ehf2.13176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006664PMC
April 2021

Multiorgan failure with abnormal receptor metabolism in mice mimicking Samd9/9L syndromes.

J Clin Invest 2021 02;131(4)

Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Autosomal dominant sterile α motif domain containing 9 (Samd9) and Samd9L (Samd9/9L) syndromes are a large subgroup of currently established inherited bone marrow failure syndromes that includes myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE), ataxia pancytopenia, and familial monosomy 7 syndromes. Samd9/9L genes are located in tandem on chromosome 7 and have been known to be the genes responsible for myeloid malignancies associated with monosomy 7. Additionally, as IFN-inducible genes, Samd9/9L are crucial for protection against viruses. Samd9/9L syndromes are caused by gain-of-function mutations and develop into infantile myelodysplastic syndromes associated with monosomy 7 (MDS/-7) at extraordinarily high frequencies. We generated mice expressing Samd9LD764N, which mimic MIRAGE syndrome, presenting with growth retardation, a short life, bone marrow failure, and multiorgan degeneration. In hematopoietic cells, Samd9LD764N downregulates the endocytosis of transferrin and c-Kit, resulting in a rare cause of anemia and a low bone marrow reconstitutive potential that ultimately causes MDS/-7. In contrast, in nonhematopoietic cells we tested, Samd9LD764N upregulated the endocytosis of EGFR by Ship2 phosphatase translocation to the cytomembrane and activated lysosomes, resulting in the reduced expression of surface receptors and signaling. Thus, Samd9/9L is a downstream regulator of IFN that controls receptor metabolism, with constitutive activation leading to multiorgan dysfunction.
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http://dx.doi.org/10.1172/JCI140147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880413PMC
February 2021

Elevated C-reactive protein is significantly associated with left ventricular dysfunction in patients with aortic regurgitation and concomitant collagen disease.

Int J Cardiol 2021 04 24;328:152-157. Epub 2020 Dec 24.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Center of Metabolic Regulation of Healthy Aging, Kumamoto University Faculty of Life Sciences, Kumamoto, Japan.

Background: Collagen disease is an important cause of aortic regurgitation (AR). Although aortic valve surgery is recommended for patients with AR and depressed left ventricular (LV) function, there have been few reports about risk factors for LV dysfunction in patients with AR concomitant with collagen disease.

Methods And Results: We conducted this study at Kumamoto University Hospital in Japan. A total of 41 patients who had moderate to severe AR and concomitant collagen disease between January 2014 and December 2019 were enrolled. With regard to baseline characteristics, there were no significant differences in the type of collagen disease or El Khoury class between patients with preserved LV function and those with reduced LV function. B-type natriuretic peptide (375.2 [257.9-3852.6]pg/ml vs. 64.0 [33.3-133.6]pg/ml, p < 0.01), C-reactive protein (CRP) levels (2.00 [1.24-9.14]mg/dl vs. 0.19 [0.06-0.52]mg/dl, p < 0.01) and neutrophil-to-lymphocyte ratio (7.94 [3.30-9.98] vs. 3.94 [1.83-5.58], p < 0.05) were significantly higher, and hemoglobin level (10.7 ± 1.6 g/dl vs. 12.2 ± 1.8 g/dl, p < 0.05) was significantly lower in patients with reduced LV function than in those with preserved LV function. There were no significant differences in any variables associated with severity and features of AR. Multivariable logistic regression analysis showed that high CRP levels (≥1.0 mg/dl) were independently and significantly associated with LV dysfunction in patients with AR and collagen disease, even after adjusting for the severity of AR (odds ratio: 95.7; 95% confidence interval: 4.6-1990.4, p < 0.01).

Conclusions: Uncontrolled inflammation, represented as high CRP levels, is an important marker for LV dysfunction in patients with AR and collagen disease.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.053DOI Listing
April 2021

Mesh exposure after transvaginal mesh prolapse surgery: Out of permissible range?

Int J Urol 2021 02 10;28(2):202-207. Epub 2020 Nov 10.

Department of, Urology, Japanese Red Cross Nagoya First Hospital, Nagoya, Aichi, Japan.

Objectives: To investigate the prevalence of postoperative complications after transvaginal mesh prolapse surgery, and whether modified transvaginal mesh prolapse surgery (without transobturator arms or posterior mesh) has less prevalence of mesh exposure compared with conventional transvaginal mesh prolapse surgery.

Methods: Medical charts were retrospectively examined for 2648 patients who underwent transvaginal mesh prolapse surgery in a general hospital (2006-2017). Conventional transvaginal mesh prolapse surgery (Prolift-type, n = 2258) was used, with a shift from 2015 to modified transvaginal mesh prolapse surgery (Uphold-type, n = 330). Patients were instructed to have >2 years of follow up and to report if they had problems regarding the operation.

Results: The prevalence of mesh exposure was 34 out of 2648 (1.28%); 18 vagina (0.68%), 10 bladder (0.38%), two ureter (0.08%) and four rectum (0.15%). The modified transvaginal mesh prolapse surgery group had only one case with vaginal exposure. Vaginal exposure was managed transvaginally or followed by observation. Rectal exposure was managed transvaginally without colostomy. Bladder exposure was managed by transurethral resection with saline. Open ureterocystostomy was carried out to treat ureteral exposure. In the conventional transvaginal mesh prolapse surgery group, three cases of ureteral stenosis and one case with vaginal evisceration of the small intestine were managed transvaginally. The prevalence of postoperative chronic pain was 13 out of 2648 (0.49%; with one patient in the modified transvaginal mesh prolapse surgery group). The patients underwent pharmacotherapy, and one patient underwent additional surgical treatment.

Conclusions: The reoperation rate as a result of complications after transvaginal mesh prolapse surgery seems to be low. The reoperation rate as a result of prolapse recurrence is also low. A shift from conventional transvaginal mesh prolapse surgery to modified transvaginal mesh prolapse surgery might contribute to a further decrease in the risk of complications.
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http://dx.doi.org/10.1111/iju.14425DOI Listing
February 2021

Usefulness of relative apical longitudinal strain index to predict positive Tc-labeled pyrophosphate scintigraphy findings in advanced-age patients with suspected transthyretin amyloid cardiomyopathy.

Echocardiography 2020 11 4;37(11):1774-1783. Epub 2020 Nov 4.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Background: We previously reported that a high score (2 or 3 points) according to the Kumamoto criteria, a combination of high-sensitivity cardiac troponin T (hs-cTnT) ≥0.308 ng/mL, the length of QRS ≥ 120 ms in electrocardiogram, and left ventricular (LV) posterior wall thickness ≥ 13.6 mm, increases the pretest probability of Tc-labeled pyrophosphate ( Tc-PYP) scintigraphy in patients with suspected transthyretin amyloid cardiomyopathy (ATTR-CM). However, some patients with a low score (0 or 1 point) show positive findings on Tc-PYP scintigraphy. Therefore, we evaluated the usefulness of additional examinations, including echocardiographic assessment of myocardial strain, to raise the pretest probability of Tc-PYP scintigraphy for these patients.

Methods And Results: We examined 109 consecutive patients aged ≥70 years with low scores according to the Kumamoto criteria who underwent Tc-PYP scintigraphy. Nineteen patients (17%) had positive Tc-PYP scintigraphy findings. The relative apical longitudinal strain (LS) index (apical LS/ basal LS + mid LS) (RapLSI) was significantly higher in patients with positive than negative Tc-PYP scintigraphy findings (1.04 ± 0.37 vs 0.70 ± 0.28, P < .01). Multivariable logistic regression analysis revealed that a high RapLSI (≥1.04) was significantly associated with Tc-PYP positivity (odds ratio, 14.14; 95% confidence interval, 3.36-59.47; P < .01). The sensitivity, specificity, and accuracy of the diagnostic model using the RapLSI for identification of Tc-PYP positivity were 53%, 94%, and 87%, respectively.

Conclusions: A high RapLSI can raise the pretest probability of Tc-PYP scintigraphy in patients with a low score according to the Kumamoto criteria. The RapLSI can assist clinicians in determining strategies for these patients.
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http://dx.doi.org/10.1111/echo.14892DOI Listing
November 2020

Activation of CpG-Rich Promoters Mediated by MLL Drives MOZ-Rearranged Leukemia.

Cell Rep 2020 09;32(13):108200

Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan; Division of Hematological Malignancy, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. Electronic address:

Uncontrolled self-renewal of hematopoietic progenitors induces leukemia. To self-renew, leukemia cells must continuously activate genes that were previously active in their mother cells. Here, we describe the circuitry of a transactivation system responsible for oncogenic self-renewal. MLL recruits RNA polymerase II (RNAP2) to unmethylated CpG-rich promoters by its CXXC domain and activates transcription by transcriptional regulators, including the AF4 family/ENL family/P-TEFb complex, DOT1L, and p300/CBP histone acetyl transferases. MOZ also targets a broad range of CpG-rich promoters through association with RNAP2 and MLL. Leukemic fusion proteins such as MOZ-TIF2 and MLL-AFX constitutively activate CpG-rich promoters by aberrantly recruiting p300/CBP. Pharmacological inhibition of MLL or DOT1L induces differentiation of MOZ-TIF2-transformed cells. These results reveal that activation of unmethylated CpG-rich promoters mediated by MLL is the central mechanism of oncogenic self-renewal in MOZ-rearranged leukemia and indicate that the molecularly targeted therapies intended for MLL-rearranged leukemia can be applied for MOZ-rearranged leukemia.
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http://dx.doi.org/10.1016/j.celrep.2020.108200DOI Listing
September 2020

Novel dot-blot assay for detection of vascular Notch3 aggregates in patients with CADASIL.

J Neurol Sci 2020 08 21;415:116931. Epub 2020 May 21.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; Department of Amyloidosis Research, Nagasaki International University, Sasebo 859-3298, Japan.

To detect vascular Notch3 extracellular domain aggregates in CADASIL, we developed a novel dot-blot assay with both autopsy and biopsy skin samples. We obtained samples from 11 patients with CADASIL and 12 control patients, and we performed dot-blot analyses by using sequential biochemical tissue extractions with three different antibodies against specific regions of the Notch3 extracellular domain. We also analyzed clinical features and vascular accumulations of Notch3 by immunohistochemistry. Via the dot-blot assay with the antibody against the C-terminal region of the Notch3 extracellular domain, we successfully detected Notch3 extracellular domain aggregates in skin tissue homogenates obtained from patients with CADASIL. Our novel method may therefore aid the diagnosis of CADASIL.
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http://dx.doi.org/10.1016/j.jns.2020.116931DOI Listing
August 2020

Identification of novel methylation markers in HPV-associated oropharyngeal cancer: genome-wide discovery, tissue verification and validation testing in ctDNA.

Oncogene 2020 06 15;39(24):4741-4755. Epub 2020 May 15.

Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan.

Human papilloma virus (HPV)-associated oropharyngeal cancer (OPC) is an independent tumour type with regard to cellular, biological, and clinical features. The use of non-invasive biomarkers such as circulating tumour DNA (ctDNA) may be relevant in early diagnosis and eventually improve the outcomes of patients with head and neck squamous cell carcinoma (HNSCC). Genome-wide discovery using RNA sequencing and reduced representation bisulfite sequencing yielded 21 candidates for methylation-targeted genes. A verification study (252 HNSCC patients) using quantitative methylation-specific PCR (Q-MSP) identified 10 genes (ATP2A1, CALML5, DNAJC5G, GNMT, GPT, LY6D, LYNX1, MAL, MGC16275, and MRGPRF) that showed a significant increase recurrence in methylation groups with OPC. Further study on ctDNA using Q-MSP in HPV-associated OPC showed that three genes (CALML5, DNAJC5G, and LY6D) had a high predictive ability as emerging biomarkers for a validation set, each capable of discriminating between the plasma of the patients from healthy individuals. Among the 42 ctDNA samples, methylated CALML5, DNAJC5G, and LY6D were observed in 31 (73.8%), 19 (45.2%), and 19 (45.2%) samples, respectively. Among pre-treatment ctDNA samples, methylated CALML5, DNAJC5G, and LY6D were observed in 8/8 (100%), 7/8 (87.5%), and 7/8 (87.5%) samples, respectively. Methylated CALML5, DNAJC5G, and LY6D were found in 2/8 (25.0%), 0/8 (0%), and 1/8 (12.5%) of the final samples in the series, respectively. Here, we present the relationship between the methylation status of three specific genes and cancer recurrence for risk classification of HPV-associated OPC cases. In conclusion, ctDNA analysis has the potential to aid in determining patient prognosis and real-time surveillance for disease recurrences and serves as an alternative method of screening for HPV-associated OPC.
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http://dx.doi.org/10.1038/s41388-020-1327-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286817PMC
June 2020

Molecular pathogenesis of progression to myeloid leukemia from TET-insufficient status.

Blood Adv 2020 03;4(5):845-854

Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Loss-of-function mutations in ten-eleven translocation-2 (TET2) are recurrent events in acute myeloid leukemia (AML) as well as in preleukemic hematopoietic stem cells (HSCs) of age-related clonal hematopoiesis. TET3 mutations are infrequent in AML, but the level of TET3 expression in HSCs has been found to decline with age. We examined the impact of gradual decrease of TET function in AML development by generating mice with Tet deficiency at various degrees. Tet2f/f and Tet3f/f mice were crossed with mice expressing Mx1-Cre to generate Tet2f/wtTet3f/fMx-Cre+ (T2ΔT3), Tet2f/fTet3f/wtMx-Cre+ (ΔT2T3), and Tet2f/fTet3f/fMx-Cre+ (ΔT2ΔT3) mice. All ΔT2ΔT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2ΔT3 and ΔT2T3 mice developed AML at longer latencies, with a median survival of ∼27 weeks. Remarkably, all 9 T2ΔT3 and 8 ΔT2T3 mice with AML showed inactivation of the remaining nontargeted Tet2 or Tet3 allele, respectively, owing to exonic loss in either gene or stop-gain mutations in Tet3. Recurrent mutations other than Tet3 were not noted in any mice by whole-exome sequencing. Spontaneous inactivation of residual Tet2 or Tet3 alleles is a recurrent genetic event during the development of AML with Tet insufficiency.
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http://dx.doi.org/10.1182/bloodadvances.2019001324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065477PMC
March 2020

[A CASE OF RENAL UNDIFFERENTIATED/UNCLASSIFIED SARCOMA WITH LONG-TERM SURVIVAL AFTER PRIMARY AND METASTATIC LESIONS].

Nihon Hinyokika Gakkai Zasshi 2019 ;110(1):18-21

Department of Urology, Japanese Red Cross Nagoya First Hospital.

(Case) A 56-year-old woman who complained of urinary frequency and macrohematuria. Abdominal US, enhanced CT and MRI revealed a left renal tumor. A left radical nephrectomy was performed in May 1997, and the pathological diagnosis was renal fibrosarcoma. Follow-up computed CT was performed routinely. A metastatic lesion in the right lung revealed 19 months after the nephrectomy.She underwent partial pneumonectomy in January 1999, and the pathological diagnosis was also fibrosarcoma. She was followed up until 2009 without recurrence.In 2015, she was admitted in the Department of Orthopedics due to femoral neck fracture in 2015, thus we could find out she was alive, tumor-free 18 years after the nephrectomy. We added the immunohistochemistical study to her specimen of kidney and lung, and the diagnosis was changed to undifferentiated/unclassified sarcoma. (Conclusion) Metastatic renal sarcoma has a poor prognosis in general. We experienced a long-term survival case of undifferentiated/unclassified renal sarcoma with lung metastasis, and report it with some literature review.
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http://dx.doi.org/10.5980/jpnjurol.110.18DOI Listing
July 2020

De novo p.G696S mutation in COL4A1 causes intracranial calcification and late-onset cerebral hemorrhage: A case report and review of the literature.

Eur J Med Genet 2020 Apr 16;63(4):103825. Epub 2019 Dec 16.

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

Background: The collagen type IV alpha 1 chain (COL4A1) is an essential component of the basement membrane in small vessels. Pathogenic variants in COL4A1 cause perinatal cerebral hemorrhages in an autosomal-dominant fashion. However, little is known about the long-term outcomes of patients with mildly affecting COL4A1 mutations.

Case Report: We report a 17-year-old boy, who presented with recurrent intracranial hemorrhages in the periventricular white matter. He had been followed-up as a child with cerebral palsy bearing intracranial calcifications, developmental delay and epilepsy. Screening tests in infancy provided negative results for intrauterine infections. Severe motor and cognitive deficits persisted after admission. Carbazochrome was introduced on day 19 of admission, which appeared to prevent extension and reactivation of cerebral hemorrhages for over 6 months after discharge.

Results: Targeted sequencing of NOTCH3 and TREX1 excluded causal mutations in these genes. The whole-exome sequencing revealed that he carried a de novo mutation in COL4A1 (p.Gly696Ser). An overview of the literature for 345 cases with COL4A1 mutations supported evidence that p.Gly696Ser is associated with the unique phenotype of late-onset hemorrhage among patients with COL4A1-associated cerebral angiopathy.

Conclusions: This case first demonstrates that infants with COL4A1-associated leukoencephalopathy and calcifications have a risk for developing the rupture of small vessels in the cerebral white matter after 10 years of age.
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http://dx.doi.org/10.1016/j.ejmg.2019.103825DOI Listing
April 2020

Razor-type dermatomes enable quick and thin vaginal dissection with less bleeding in colpocleisis.

Int Urogynecol J 2020 09 27;31(9):1959-1964. Epub 2019 Nov 27.

Department of Urology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.

Introduction And Hypothesis: Although colpocleisis is a low-invasive surgical option to treat pelvic organ prolapse, it sometimes involves a long operative time with substantial bleeding. To streamline the vaginal dissection process in colpoclesis, we introduced the usage of dermatomes.

Methods: All patients were sexually inactive women with post-hysterectomy prolapse. Data of the dermatome group were retrospectively compared with those of the historical control group based on operative features, perioperative complications and pathology of dissected tissue. In the dermatome group, 34 women underwent total colpocleisis with vaginal dissection using dermatomes; 4 were done mainly with electric dermatomes, and 30 were done with razor-type dermatomes. In the control group, 20 women underwent total colpocleisis with vaginal dissection using Metzenbaum scissors.

Results: Using dermatomes in vaginal dissection was helpful to shorten total operative time (including perineoplasty) by one third from 76 to 51 min, to shorten the time of colpocleisis by half, from 62 to 32 min, and to reduce intraoperative bleeding by 76%, from 62 to 15 ml. In addition, none in the dermatome group and 2/20 patients in the control group had unintended peritoneal opening. Dissection with scissors removed not only the epithelium and submucosal layer but also the muscle layer. This was minimized with razor-type dermatomes and never occurred with electric dermatomes. Whereas electric dermatomes are difficult to get accustomed to and are expensive, razor-type dermatomes enable thinner dissection compared with scissors, are easy to handle and are inexpensive.

Conclusions: Razor-type dermatomes enable quick and thin vaginal dissection with less bleeding. Therefore, they can be recommended as a practical tool for colpocleisis, a prolapse operation mainly for frail elderly patients.
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http://dx.doi.org/10.1007/s00192-019-04162-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427706PMC
September 2020

HbA1c adjusted by erythrocyte creatine is a useful glycemic control indicator in patients with hemolysis.

Clin Biochem 2019 Nov 3;73:77-81. Epub 2019 Aug 3.

Department of Biomedical Laboratory Sciences, Faculty of Health Sciences, Kumamoto University, Kumamoto, Japan.

Objectives: HbA1c shows low in patients with hemolysis, whereas glycated albumin (GA) is not affected by hemolysis. Therefore, the GA/HbA1c ratio reflects hemolysis in diabetic patients with hemolysis. Erythrocyte creatine (EC) is an indicator of hemolysis that reflects the mean erythrocyte age. The aim of this study was to examine whether HbA1c adjusted by EC accurately reflected glycemic control in patients with hemolysis.

Materials And Methods: A total of 238 individuals, consisting of 131 diabetic patients and 107 non-diabetic subjects, and consisting of 42 patients with hemolysis, and 196 subjects without hemolysis were selected for the study. HbA1c expressed in the IFCC units (iA1c) as well as in the NGSP units (A1C) were used. From the fact that EC and the GA/iA1c ratio showed a significant positive correlation, a formula for iA1c adjusted by EC (ECadj-iA1c) was created from a regression equation between EC and the GA/iA1c ratio.

Results: Significant correlations were observed between the GA/iA1c ratio and various hemolytic indicators but not between the GA/ECadj-iA1c ratio and those hemolytic indicators. The GA/iA1c ratio in individuals with hemolysis was significantly higher than in individuals without hemolysis, while no significant differences were observed in the GA/ECadj-iA1c ratio between the groups. Further, iA1c concentrations in non-diabetic patients with hemolysis were significantly lower than in the non-diabetic subjects without hemolysis, whereas ECadj-iA1c and GA concentrations showed no significant difference between the two groups.

Conclusions: These results suggested that ECadj-iA1c accurately reflected glycemic control in patients with hemolysis.
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http://dx.doi.org/10.1016/j.clinbiochem.2019.08.004DOI Listing
November 2019

Hemolysis causes a decrease in HbA1c level but not in glycated albumin or 1,5-anhydroglucitol level.

Scand J Clin Lab Invest 2019 Oct 17;79(6):377-380. Epub 2019 Jun 17.

Department of Internal Medicine, Hakuhokai Central Hospital , Hyogo , Japan.

HbA1c has been widely used as a glycemic control indicator or as a diagnostic indicator for diabetes mellitus. However, HbA1c is affected by the erythrocyte life span and, therefore, shows falsely low values in hemolytic patients. Erythrocyte creatine (EC) is a sensitive hemolytic marker that reflects the mean erythrocyte age. In the present study, the relationships of HbA1c, glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG) with different hemolytic markers, including EC, were investigated in non-diabetic individuals. A total of 43 non-diabetic individuals whose complete blood count and reticulocytes were measured via medical examinations were included in this study (28 individuals with hemolysis and 15 individuals without hemolysis). Those with suspected diabetes mellitus based on medical history, low 1,5-AG values, or had comorbid liver and renal diseases were excluded from this study. HbA1c, GA, 1,5-AG, and various hemolytic markers were measured to examine the correlation of the glycemic control indicators with the various hemolytic markers. A significant correlation was observed between GA and 1,5-AG but not between HbA1c and GA or 1,5-AG. Significant correlations were observed between HbA1c values and various hemolytic markers (reticulocytes, haptoglobin, and EC) but not between GA or 1,5-AG values and those hemolytic markers. HbA1c, but not with GA and 1,5-AG, showed significant correlations with the hemolytic markers. These results suggested that HbA1c does not reflect the glycemic control accurately in hemolytic patients, while GA and 1,5-AG values are not affected by mean erythrocyte age and, therefore, accurately reflect the glycemic control.
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http://dx.doi.org/10.1080/00365513.2019.1627577DOI Listing
October 2019

Development of caseous calcification of mitral annulus after initiation of hemodialysis therapy.

J Cardiol Cases 2019 Jun 8;19(6):190-193. Epub 2019 Mar 8.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

We here present a 59-year-old man who had undergone peritoneal dialysis (PD) for 7 years and hemodialysis for the following 6 years in the Japanese Red Cross Kumamoto Hospital. Six years after commencing PD, transthoracic echocardiography showed a highly echoic mass with a transverse diameter of almost 15 mm in the posterior mitral leaflet. Because the mass increased from 2 years after initiation of hemodialysis, reaching over 25 mm by 6 years after commencing hemodialysis, tumor resection and mitral valve replacement were performed. When the surface of the mass was incised, white opalescent liquid drained out of the mass and histological examination showed multiple calcified nodules and granulation tissue, resulting in diagnosis of a caseous calcification of mitral annulus. < Caseous calcification of mitral annulus (CCMA) is usually associated with end-stage renal disease. In the present case, a 59-year-old man had undergone peritoneal dialysis for 7 years, after which he had undergone hemodialysis for 6 years. The development of CCMA was seen after initiation of hemodialysis therapy. Routine echocardiography is useful for early diagnosis of CCMA, especially in patients whose type of dialysis changed from PD to hemodialysis.>.
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http://dx.doi.org/10.1016/j.jccase.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546639PMC
June 2019

Hereditary ATTR Amyloidosis with Cardiomyopathy Caused by the Novel Variant Transthyretin Y114S (p.Y134S).

Intern Med 2019 Sep 7;58(18):2695-2698. Epub 2019 Jun 7.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan.

We report the clinical features of a patient with hereditary transthyretin (ATTR) amyloidosis associated with a novel mutation (Y114S, p.Y134S). A 65-year-old Japanese man was admitted to our hospital after a 3-year history of progressive dyspnea on exertion. Five years previously, he presented dysesthesia in both hands caused by carpal tunnel syndrome. A genetic analysis revealed a base pair substitution of adenine to cytosine in the second codon of exon 4, residue 114, in the TTR gene (c.401A>C). The clinical characteristics were progressive cardiomyopathy with a poor vital prognosis, late onset, sporadic case, bilateral carpal tunnel syndrome, hypothyroidism, and small fiber neuropathy.
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http://dx.doi.org/10.2169/internalmedicine.2456-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794161PMC
September 2019

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH.

J Biol Chem 2019 07 5;294(29):11259-11275. Epub 2019 Jun 5.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81-127, is highly amyloidogenic , even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81-127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils , and pyrvinium pamoate also stabilized the tetrameric structure of TTR in patient plasma. We conclude that our TTR81-127-based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis.
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http://dx.doi.org/10.1074/jbc.RA119.007851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643022PMC
July 2019
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