論文 - 下田 和哉
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Fauzi Y.R., Nakahata S., Shimoda K., Matsuura T., Hagiwara S., Inoue K., Moritake H., Morishita K.
Biochemical and Biophysical Research Communications 756 151564 2025年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
Previously, we developed a complete human IgG TFR1 antibody (JST-TFR09/PPMX-T003) that showed a potentially practical therapeutic effect against adult T-cell leukemia/lymphoma (ATLL) in vitro and in vivo. In the present study, to elucidate the molecular mechanism underlying ATLL cell death induced by anti-TFR1 antibodies, we performed comprehensive gene expression analysis and mass spectrometry on ATLL cells treated with PPMX-T003 antibody. These results suggest that PPMX-T003 antibody treatment of ATLL cell lines induces ferroptosis mediated by ferritin degradation. PPMX-T003 antibody-treated ATLL cell lines showed a decrease in ferritin proteins, an increase in ferrous iron (Fe2+), reactive oxygen species (ROS) generation, and malondialdehyde as induction of lipid peroxidation. Moreover, treatment with a ferroptosis inhibitor (ferroportin-1) inhibited the cell death induced by PPMX-T003 antibody in ATLL cells. Furthermore, NCO4A and LC3-II were induced following antibody treatment, and ferritin degradation was inhibited by lysosomal inhibitors, suggesting that ferritin degradation depends on autolysosomal system activation. Here, we introduce ferroptosis as one of the potential mechanisms of PPMX-T003 antibody, which is promising for future therapeutic antibodies targeting a wide range of leukemia and cancers, including ATLL.
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Effects of tucidinostat in adult T-cell leukemia/lymphoma in clinical practice 査読あり
Kamiunten A., Kameda T., Sekine M., Kawano H., Toyama T., Akizuki K., Kawano N., Maeda K., Sato S., Takeuchi M., Ishizaki J., Nagamine K., Kuroki A., Ikeda R., Matsumoto K., Karasawa M., Tahira Y., Uchida T., Shimoda H., Hidaka T., Yamashita K., Yamaguchi H., Kubuki Y., Shimoda K., Shide K.
International Journal of Hematology 2025年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Hematology
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy with a poor prognosis. We conducted a retrospective study across six institutions in Miyazaki Prefecture, Japan, to assess the efficacy of tucidinostat in patients with relapsed/refractory ATL who had not undergone transplantation. Between October 2021 and July 2023, 24 patients aged 41 to 88 years (median, 73.4 years) who had undergone prior therapies, including intensive chemotherapy (79.2%) and mogamulizumab immunotherapy (79.2%), received tucidinostat. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated as key outcomes. ORR and DCR reached 54.2% and 91.7%, respectively. The median PFS was 3.95 months, and OS was 8.04 months, which were not inferior to the results of a phase IIb study. The influential factors for PFS were age ≥ 75 years and high soluble IL-2 receptor (sIL-2R) levels above 5000 U/mL at the start of treatment. Favorable patients without these factors achieved a PFS of 11.4 months. Treatment-related adverse events were mainly hematologic but were managed over the course of treatment. Our findings indicate that tucidinostat provides survival benefits in patients with relapsed/refractory ATL in clinical practice and highlight key clinical factors for better outcomes.
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Takahashi N., Takenaka K., Iriyama N., Kirito K., Kawaguchi T., Kimura S., Shimoda K.
International Journal of Hematology 121 ( 1 ) 5 - 38 2025年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Hematology
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Yoshikawa N., Ehara Y., Yamada Y., Matsusaki Y., Shimoda K., Ikeda R.
Scientific Reports 15 ( 1 ) 3364 2025年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Intra-patient variability in immunosuppressive blood drug concentrations is a potential biomarker in managing organ transplant patients. However, the association between the time in therapeutic range of tacrolimus blood concentrations and its efficacy in preventing graft-versus-host disease remains unknown. In this study, we analyzed the relationship between the time in therapeutic range of tacrolimus blood concentrations and its efficacy in acute graft-versus-host disease prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation. Eligible patients administered tacrolimus were categorized into two groups based on the grade of acute graft-versus-host disease, and propensity score matching was performed using graft-versus-host disease prophylaxis protocols and days to the disease onset to compare time in therapeutic range. In patients with tacrolimus blood concentration therapeutic range ≥ 10 ng/mL, time in therapeutic range during the first 4 weeks post-transplantation was significantly lower in the Grade II–III than in the Grade 0–I group. Among propensity score matching-extracted patients, the Grade II–III group had significantly lower time in therapeutic range during the first 2 and 4 weeks post-transplantation. Our results suggest that high time in therapeutic range early post-transplantation, particularly within 4 weeks, may avert the severity of acute graft-versus-host disease.
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C-Mannosyl tryptophan is a novel biomarker for thrombocytosis of myeloproliferative neoplasms 査読あり
Tabata S., Yamashita Y., Inai Y., Morita S., Kosako H., Takagi T., Shide K., Manabe S., Matsuoka T.A., Shimoda K., Sonoki T., Ihara Y., Tamura S.
Scientific Reports 14 ( 1 ) 18858 2024年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
C-Mannosyl tryptophan (CMW), a unique glycosylated amino acid, is considered to be produced by degradation of C-mannosylated proteins in living organism. Although protein C-mannosylation is involved in the folding and secretion of substrate proteins, the pathophysiological function in the hematological system is still unclear. This study aimed to assess CMW in the human hematological disorders. The serum CMW levels of 94 healthy Japanese workers were quantified using hydrophilic interaction liquid chromatography. Platelet count was positively correlated with serum CMW levels. The clinical significance of CMW in thrombocytosis of myeloproliferative neoplasms (T-MPN) including essential thrombocythemia (ET) were investigated. The serum CMW levels of the 34 patients with T-MPN who presented with thrombocytosis were significantly higher than those of the 52 patients with control who had other hematological disorders. In patients with T-MPN, serum CMW levels were inversely correlated with anemia, which was related to myelofibrosis (MF). Bone marrow biopsy samples were obtained from 18 patients with ET, and serum CMW levels were simultaneously measured. Twelve patients with bone marrow fibrosis had significantly higher CMW levels than 6 patients without bone marrow fibrosis. Collectively, these results suggested that CMW could be a novel biomarker to predict MF progression in T-MPN.
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Long-term safety and efficacy of ropeginterferon alfa-2b in Japanese patients with polycythemia vera 査読あり
Kirito K., Sugimoto Y., Gotoh A., Takenaka K., Ichii M., Inano T., Shirane S., Ito M., Zagrijtschuk O., Qin A., Kawase H., Sato T., Komatsu N., Shimoda K.
International Journal of Hematology 120 ( 6 ) 675 - 683 2024年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Hematology
Ropeginterferon alfa-2b (ropegIFN), a new-generation interferon-based agent, has been approved in Japan for patients with polycythemia vera (PV) who are ineligible for or respond inadequately to conventional treatment. However, long-term outcomes with ropegIFN in Japanese patients have not been reported. This extension of a phase 2 study of ropegIFN in Japanese patients with PV aimed to determine its long-term safety/efficacy, and changes over time in JAK2 V617F allele burden. Here, we report data from the phase 2 study and subsequent extension over a period of 36 months. The primary endpoint was the complete hematologic response (CHR) maintenance rate without phlebotomy (hematocrit value < 45% without phlebotomy during the previous 12 weeks, platelet count ≤ 400 × 109/L, and white blood cell count ≤ 10 × 109/L). The CHR maintenance rates were 8/27 (29.6%), 18/27 (66.7%), and 22/27 (81.5%) at 12, 24, and 36 months, respectively. No thrombotic or hemorrhagic events occurred. The median allele burden change from baseline was − 74.8% at 36 months. All patients experienced adverse events; 25/27 (92.6%) experienced adverse drug reactions (ADRs), but no serious ADRs or deaths occurred. This interim analysis demonstrated the safety and efficacy of ropegIFN over 36 months in Japanese patients with PV.
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Kitamura A., Yanagi S., Shide K., Sato Y., Kamiunten A., Yamanari Y., Kitamura A., Sumiyoshi M., Oda Y., Tsubouchi H., Shimoda K., Miyazaki T.
American Journal of Case Reports 25 e945804 2024年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Case Reports
Patient: Male, 32-year-old Final Diagnosis: B-acute lymphoblastic leukemia Symptoms: Dyspnea • face swelling Clinical Procedure: — Specialty: Oncology Objective: Unknown etiology Background: Fibrosing mediastinitis (FM) is a rare, fibroproliferative disorder within the mediastinum. It is extremely rare for hematologic malignancies to develop as FM. Case Report: A 32-year-old Japanese man with a 1-month history of headache and 2-week history of facial swelling underwent chest computed tomography (CT); a diffuse mass-like lesion was revealed in the anterior mediastinum with severe stenosis of vital mediastinal organs. After a surgical biopsy, an initial diagnosis of idiopathic FM was made. The FM lesions responded mildly to corticosteroids but recurred repeatedly. Sixteen months after the treatment initiation, blasts appeared in the peripheral blood (PB), and the patient was diagnosed with B-acute lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL/LBL). Chemotherapy led to complete remission of the B-ALL/LBL and almost complete disappearance of FM-like lesions. Immunohistochemistry of the mediastinal biopsy specimen taken before the blasts’ appearance in PB demonstrated a CD34/CD7/terminal deoxynucleotidyl transferase-positive population, an identical pattern of expression common to the blasts in the patient’s PB and bone marrow. Conclusions: This is the first case report of B-ALL/LBL presenting as FM. This case underscores the importance of considering the possibility of latent hematologic malignancy even in the absence of new symptoms other than those caused by FM lesions for a long period of time. This is the first demonstration that leukemia cells may be present in the FM lesions from the initial stage of disease onset. Even if a diagnosis of idiopathic FM is confirmed, continued suspicion of the presence of hematologic malignancy is vital for improving patient outcomes.
DOI： 10.12659/AJCR.945804
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Chiba N., Suzuki S., Enriquez-Vera D., Utsunomiya A., Kubuki Y., Hidaka T., Shimoda K., Nakahata S., Yamada T., Morishita K.
Heliyon 10 ( 20 ) e38507 2024年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Heliyon
Adult T-cell leukemia/lymphoma (ATLL) is a refractory blood cancer with severe immunodeficiency resulting from retroviral infection. ATLL develops in only 5 % of HTLV-1-infected individuals, but the entire mechanism of ATLL progression remains unknown. Since recent studies have reported that the gut microbiome influences the progression of various diseases, we hypothesized that ATLL is also related to the gut microbiome and aimed to investigate this relationship. We analyzed the taxonomic and functional profiles of the gut microbiota of ATLL patients (n = 28) and HTLV-1-infected individuals (n = 37). We found that the succinic semialdehyde (SSA) synthesis pathway was significantly enriched in the gut microbiome of ATLL patients (P = 0.000682), and Klebsiella, whose abundance was significantly greater in ATLL patients and high-risk HTLV-1-infected individuals (P = 0.0326), was the main contributor to this pathway. Administration of SSAs to ATLL cell lines resulted in significant cell proliferation. Herein, we propose that the gut microbiome can regulate ATLL progression via metabolites.
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Sugimoto Y, Nagaharu K, Ohya E, Ohishi K, Tawara I, Ito T, Gotoh A, Nakamae M, Kimura F, Koike M, Kirito K, Wada H, Usuki K, Tanaka T, Mori T, Wakita S, Saito TI, Saito AM, Shimoda K, Kurokawa T, Tomita A, Edahiro Y, Hashimoto Y, Kiyoi H, Akashi K, Matsumura I, Takenaka K, Komatsu N
International journal of hematology 120 ( 6 ) 684 - 693 2024年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Hematology
We report the first large-scale retrospective cohort study on adolescent and young adult (AYA) polycythemia vera (PV) and essential thrombocythemia (ET) in Japan, a subgroup analysis using Japanese multicenter registry data (JSH-MPN-R18). This study included patients with PV (n = 31) or ET (n = 141) aged 20 to 39 years at the initial visit. Hemorrhage-free survival (HFS) was better in AYA ET than in non-AYA ET (5-year HFS: 100% vs. 88.6%, p < 0.01), which might be attributed to differences in antithrombotic treatment rates between AYA and non-AYA patients. Although thrombosis-free survival did not differ statistically, the percentage of venous thrombotic events (TEs) among total TEs was higher in AYA compared to non-AYA PV and ET in Japan (26.0% vs. 6.0%, p < 0.01), but much lower than figures reported in European or US cohorts. Cytoreductive therapy (CRT) was administered to 25.8% of AYA patients with PV and 43.3% of AYA patients with ET, and the reason was usually unrelated to high risk of thrombosis. These results could be used to develop a more appropriate strategy for managing PV and ET in the Japanese AYA population.
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Nagaharu K., Ohya E., Edahiro Y., Hashimoto Y., Ito T., Gotoh A., Nakamae M., Kimura F., Koike M., Kirito K., Wada H., Usuki K., Tanaka T., Mori T., Wakita S., Saito T.I., Saito A.M., Shimoda K., Kurokawa T., Tomita A., Kiyoi H., Akashi K., Matsumura I., Takenaka K., Komatsu N., Ohishi K., Tawara I., Sugimoto Y.
Annals of Hematology 103 ( 10 ) 4349 - 4350 2024年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Annals of Hematology
In the published paper, it was observed that a portion of Supplementary Figure 1 is highlighted in red and Supplementary Figure 2 lacks the figures. The original article has been corrected.
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Abu-Zeinah G., Qin A., Gill H., Komatsu N., Mascarenhas J., Shih W.J., Zagrijtschuk O., Sato T., Shimoda K., Silver R.T., Mesa R.
Annals of Hematology 103 ( 9 ) 3573 - 3583 2024年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Annals of Hematology
Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with “early/lower-risk PMF”, defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.
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Nagaharu K., Ohya E., Edahiro Y., Hashimoto Y., Ito T., Gotoh A., Nakamae M., Kimura F., Koike M., Kirito K., Wada H., Usuki K., Tanaka T., Mori T., Wakita S., Saito T.I., Saito A.M., Shimoda K., Kurokawa T., Tomita A., Kiyoi H., Akashi K., Matsumura I., Takenaka K., Komatsu N., Ohishi K., Tawara I., Sugimoto Y.
Annals of Hematology 103 ( 9 ) 3535 - 3541 2024年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Annals of Hematology
Thrombosis in myeloproliferative neoplasms (MPNs) is an important clinical problem, and risk-stratified management is essential. To identify the clinical characteristics of thrombosis in patients with MPNs, a nationwide multi-institutional retrospective analysis (JSH-MPN-R18) was conducted. The aim of the present study was to perform a sub-analysis of JSH-MPN-R18 findings to clarify the predictive parameters for thrombosis among complete blood count (CBC) results. Among the patients enrolled in JSH-MPN-R18, those with essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456) were investigated. We analyzed and compared CBC parameters between patients with and those without any thrombotic events using Welch’s T-test. Statistical analyses were performed using the R statistical software. Thrombotic events were observed in 74 patients with ET. In multivariate analysis, only the neutrophil ratio was slightly but significantly higher for ET patients with thrombosis than for those without (p < 0.05). Of note, the absolute neutrophil count (aNeu) was considered a useful predictive tool for thrombosis among patients classified as low-risk according to the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia. Among PV patients, those with thrombosis showed significantly higher hematocrit and aNeu than did those without thrombosis. As a thrombosis-associated factor, the neutrophil ratio was slightly but significantly elevated in patients with ET. This myeloid skew might reflect a higher value of JAK2 V617F allelic frequency in patients with ET with thrombosis; this was not clarified in JSH-MPN-R18. Further accumulation of evidence, including genetic information for JAK2 and other passenger mutations, is warranted.
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Shimoda K., Komatsu N., Matsumura I., Ikeda K., Hino M., Hidaka M., Maeda Y., Kondo T., Fujisaki T., Shoshi K., Azuma K., Fukushima R., Kawashima J., Kosugi H.
International Journal of Hematology 120 ( 3 ) 314 - 324 2024年9月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Hematology
Momelotinib, an oral Janus kinase (JAK) 1/2 and activin A receptor type 1 inhibitor, improved symptoms, splenomegaly, and anemia in patients with myelofibrosis (MF). This sub-analysis of SIMPLIFY-1 evaluated the efficacy and safety of momelotinib versus ruxolitinib in Japanese patients with JAK inhibitor (JAKi)-naïve MF. Patients were randomized 1:1 to receive momelotinib 200 mg once daily or ruxolitinib 20 mg twice daily (or modified based on label) for 24 weeks, after which patients could receive open-label momelotinib. The primary endpoint was splenic response rate (SRR; ≥ 35% reduction in spleen volume) at 24 weeks; main secondary endpoints were total symptom score (TSS) response (≥ 50% reduction) and transfusion independence (TI) rates. Fifteen Japanese patients (momelotinib, n = 6; ruxolitinib, n = 9) were enrolled; all completed treatment. At Week 24, SRR was 50.0% with momelotinib and 44.4% with ruxolitinib. TSS response rates were 33.3% and 0%, and TI rates were 83.3% and 44.4%. Any-grade treatment-related adverse event (TRAE) rates were 83.3% with momelotinib and 88.9% with ruxolitinib. Grade 3/4 TRAE rates were 0% and 55.6%, with specific events being anemia (55.6%) and vertigo (11.1%) with ruxolitinib. Momelotinib was well tolerated, improved spleen and symptom responses, and reduced transfusion requirements in Japanese patients with JAKi-naïve MF.
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Watanuki S., Kobayashi H., Sugiura Y., Yamamoto M., Karigane D., Shiroshita K., Sorimachi Y., Morikawa T., Fujita S., Shide K., Haraguchi M., Tamaki S., Mikawa T., Kondoh H., Nakano H., Sumiyama K., Nagamatsu G., Goda N., Okamoto S., Nakamura-Ishizu A., Shimoda K., Suematsu M., Suda T., Takubo K.
Cell Stem Cell 31 ( 8 ) 1145 - 1161.e15 2024年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Cell Stem Cell
Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.
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Shimoda K., Qin A., Komatsu N., Kirito K.
International Journal of Hematology 120 ( 2 ) 151 - 156 2024年8月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Hematology
Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by clonal erythrocytosis. A phase 2 study reported that ropeginterferon alfa-2b is a well-tolerated and effective treatment for PV in Japanese patients. This post hoc analysis of the phase 2 data further evaluated outcomes in patients at low risk of thrombosis (low-risk PV). Among 20 patients with low-risk PV, 60.0% (12/20) and 85.0% (17/20) achieved < 45% hematocrit by weeks 24 and 52, respectively. The proportion of responders with complete hematologic response (CHR) was 60.0% (12/20) at week 52, and the median time to response was 11.9 months. The mean JAK2 V617F allele burden decreased from 75.8% at baseline to 53.7% at week 52. No patient experienced thrombosis or bleeding episodes. All patients experienced treatment-emergent adverse events (TEAEs) related to ropeginterferon alfa-2b, but no grade ≥ 3 TEAEs or deaths related to ropeginterferon alfa-2b occurred, and no new safety concerns arose. This analysis indicated that ropeginterferon alfa-2b may be an effective treatment option for Japanese patients with low-risk PV.
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Ropeginterferon alfa-2b shows anti-polycythaemia vera activity without causing clinically significant anaemia. 査読あり
Kirito K, Qin A, Suo S, Fu R, Wu D, Sato T, Zagrijtschuk O, Shimoda K, Komatsu N, Jin J
BJC reports 2 ( 1 ) 51 2024年7月
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Uchida T., Ueno H., Sekishima A., Sekishima H., Konagata A., Nakamura T., Kogo F., Nabekura H., Tanaka Y., Shimizu K., Yamaguchi H., Shimoda K.
Diabetology International 15 ( 3 ) 439 - 446 2024年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Diabetology International
Aim: Education on insulin self-injection techniques is important for good glycemic control, but its effectiveness in some elderly patients is limited due to loss of cognitive function and impaired activities of daily living. We hypothesized that classification using the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) would help identify elderly patients with diabetes who effectively learn self-injection techniques. Methods: Diabetes patients aged ≥ 65 years who used a self-injection insulin pen were administered the DASC-8 and a questionnaire to evaluate insulin self-injection techniques, and then received technical education. The questionnaire was administered again 4 months later, and patients were classified into the education-effective and education-ineffective groups. The achievement of HbA1c targets defined for each patient according to guidelines based on DASC-8 category was examined over 12 months. Results: 76 Japanese patients (median age 72.0 years and 53.9% female) with DASC-8 categories I (n = 55), II (n = 13), and III (n = 8) were enrolled. In the education-effective group, the percentage of patients in category I was significantly higher than that of patients in category II or III (92.0% to 23.8%, P < 0.001). Category I was independently associated with education effectiveness (odds ratio 14.50, 95% confidence interval: 2.110–100.0, P = 0.007). Category I patients in the education-effective group showed significantly improved achievement of target HbA1c from baseline to the 12th month (from 27.6% to 62.1%, P = 0.008). Conclusions: The DASC-8 was a useful indicator for identifying elderly patients who would benefit from education on self-injection techniques.
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Usuki K., Kameda T., Kawano N., Ito T., Hashimoto Y., Shide K., Kawano H., Sekine M., Toyama T., Iizuka H., Sato S., Takeuchi M., Ishizaki J., Maeda K., Nakai M., Yamashita K., Kubuki Y., Shimoda K.
International Journal of Hematology 119 ( 6 ) 722 - 727 2024年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Hematology
Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities (MLN-FGFR1 abnormalities) are rare hematologic malignancies associated with chromosome 8p11.2 abnormalities. Translocations of 8p11.2 were detected in 10 of 17,039 (0.06%) unique patient cytogenetic studies performed at nine institutions in Japan. No inversions or insertions of 8p11.2 were detected. Among the 10 patients with 8p11.2 translocations, three patients were diagnosed with MLN-FGFR1 abnormalities, which were confirmed by FISH analysis. Peripheral blood eosinophilia was observed in all three patients, and all progressed to AML or T-lymphoblastic lymphoma/leukemia. The prevalence of 8p11.2 translocations in clinical practice and the proportion of MLN-FGFR1 abnormalities in patients with 8p11.2 translocations in Japan were consistent with those in previous reports from Western countries.
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Ichikawa T., Suekane A., Nakahata S., Iha H., Shimoda K., Murakami T., Morishita K.
International Journal of Molecular Sciences 25 ( 5 ) 2842 2024年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Molecular Sciences
N-myc downstream-regulated gene 2 (NDRG2), which is a tumour suppressor, is frequently lost in many types of tumours, including adult T-cell leukaemia/lymphoma (ATL). The downregulation of NDRG2 expression is involved in tumour progression through the aberrant phosphorylation of several important signalling molecules. We observed that the downregulation of NDRG2 induced the translocation of protein arginine methyltransferase 5 (PRMT5) from the nucleus to the cytoplasm via the increased phosphorylation of PRMT5 at Serine 335. In NDRG2low ATL, cytoplasmic PRMT5 enhanced HSP90A chaperone activity via arginine methylation, leading to tumour progression and the maintenance of oncogenic client proteins. Therefore, we examined whether the inhibition of PRMT5 activity is a drug target in NDRG2low tumours. The knockdown of PRMT5 and binding partner methylsome protein 50 (MEP50) expression significantly demonstrated the suppression of cell proliferation via the degradation of AKT and NEMO in NDRG2low ATL cells, whereas NDRG2-expressing cells did not impair the stability of client proteins. We suggest that the relationship between PRMT5/MEP50 and the downregulation of NDRG2 may exhibit a novel vulnerability and a therapeutic target. Treatment with the PRMT5-specific inhibitors CMP5 and HLCL61 was more sensitive in NDRG2low cancer cells than in NDRG2-expressing cells via the inhibition of HSP90 arginine methylation, along with the degradation of client proteins. Thus, interference with PRMT5 activity has become a feasible and effective strategy for promoting cancer vulnerability in NDRG2low ATL.
DOI： 10.3390/ijms25052842
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Mine K., Nagafuchi S., Akazawa S., Abiru N., Mori H., Kurisaki H., Shimoda K., Yoshikai Y., Takahashi H., Anzai K.
Nature Communications 15 ( 1 ) 1337 2024年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Nature Communications
Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8+ T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8+ T-BET+ cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8+ T cells and the CD8+ resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in β-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET+ CTLs, inflammation in β-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.