A signaling model of the bank loan market

藤原秀夫教授古稀祝賀記念号Honorable issue in commemoration of Prof. Hideo Fujiwara's 70 years of ageapplication/pdfdepartmental bulletin pape

Prevalence of chromosome 8p11.2 translocations and correlation with myeloid and lymphoid neoplasms associated with FGFR1 abnormalities in a consecutive cohort from nine institutions in Japan

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.Citation: Usuki, K., Kameda, T., Kawano, N. et al. Prevalence of chromosome 8p11.2 translocations and correlation with myeloid and lymphoid neoplasms associated with FGFR1 abnormalities in a consecutive cohort from nine institutions in Japan. Int J Hematol 119, 722–727 (2024). https://doi.org/10.1007/s12185-024-03740-

Effects of mogamulizumab in adult T‐cell leukemia/lymphoma in clinical practice

Objective The efficacy of mogamulizumab in adult T-cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study. Compared with patients in clinical trials, however, most patients in real-life settings have demonstrated worse outcomes. Method We retrospectively analyzed 96 patients with relapsed/refractory ATLL who received mogamulizumab treatment. Results Relapsed/refractory ATLL patients with a median age of 70 years received a median of five courses of mogamulizumab. Hematologic toxicity and skin rash were the most common adverse events, and both were manageable. Of 96 patients, 87 were evaluable for efficacy. The overall response rate was 36%, and the median progression-free survival (PFS) and overall survival (OS) from the start of mogamulizumab therapy were 1.8 and 4.0 months, respectively. Of the original 96 patients, only 25 fulfilled the inclusion criteria of the phase 2 study. Those who met the criteria demonstrated longer median PFS and OS durations of 2.7 and 8.5 months, respectively. The median OS from diagnosis in relapsed/refractory ATLL patients receiving mogamulizumab was 12 months, longer than the 5.8 months in a historical cohort without mogamulizumab. Conclusion In clinical practice, mogamulizumab exhibited antitumor activity in patients with relapsed/refractory ATLL, with an acceptable toxicity profile. Mogamulizumab therapy improved the OS of ATLL patients.Sekine, M, Kubuki, Y, Kameda, T, et al. Effects of mogamulizumab in adult T-cell leukemia/lymphoma in clinical practice. Eur J Haematol. 2017; 98: 501–507. https://doi.org/10.1111/ejh.1286

Effects of tucidinostat in adult T-cell leukemia/lymphoma in clinical practice

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.Citation: Ayako Kamiunten, Takuro Kameda, Masaaki Sekine, Hiroshi Kawano, Takanori Toyama, Keiichi Akizuki, Noriaki Kawano, Kouichi Maeda, Seiichi Sato, Masanori Takeuchi, Junzo Ishizaki, Koshiro Nagamine, Ayuka Kuroki, Ryoma Ikeda, Kengo Matsumoto, Masayoshi Karasawa, Yuki Tahira, Taisuke Uchida, Haruko Shimoda, Tomonori Hidaka, Kiyoshi Yamashita, Hideki Yamaguchi, Yoko Kubuki, Kazuya Shimoda, Kotaro Shide, Effects of tucidinostat in adult T-cell leukemia/lymphoma in clinical practice, International Journal of Hematology, 2025-03-11, https://doi.org/10.1007/s12185-025-03963-

Neoplastic fibrocytes play an essential role in bone marrow fibrosis in Jak2V617F-induced primary myelofibrosis mice

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by clonal myeloproliferation, progressive bone marrow (BM) fibrosis, splenomegaly, and anemia. BM fibrosis was previously thought to be a reactive phenomenon induced by mesenchymal stromal cells that are stimulated by the overproduction of cytokines such as transforming growth factor (TGF)-β1. However, the involvement of neoplastic fibrocytes in BM fibrosis was recently reported. In this study, we showed that the vast majority of collagen- and fibronectin-producing cells in the BM and spleens of Jak2V617F-induced myelofibrosis (MF) mice were fibrocytes derived from neoplastic hematopoietic cells. Neoplastic monocyte depletion eliminated collagen- and fibronectin-producing fibrocytes in BM and spleen, and ameliorated most characteristic MF features in Jak2V617F transgenic mice, including BM fibrosis, anemia, and splenomegaly, while had little effect on the elevated numbers of megakaryocytes and stem cells in BM, and leukothrombocytosis in peripheral blood. TGF-β1, which was produced by hematopoietic cells including fibrocytes, promoted the differentiation of neoplastic monocytes to fibrocytes, and elevated plasma TGF-β1 levels were normalized by monocyte depletion. Collectively, our data suggest that neoplastic fibrocytes are the major contributor to BM fibrosis in PMF, and TGF-β1 is required for their differentiation.Citation: Ozono, Y., Shide, K., Kameda, T., Kamiunten, A., Tahira, Y., Sekine, M., Akizuki, K., Nakamura, K., Iwakiri, H., Sueta, M., Hidaka, T., Kubuki, Y., Yamamoto, S., Hasuike, S., Sawaguchi, A., Nagata, K., & Shimoda, K. (2021). Neoplastic fibrocytes play an essential role in bone marrow fibrosis in Jak2V617F-induced primary myelofibrosis mice. Leukemia, 35(2), 454–467. https://doi.org/10.1038/s41375-020-0880-

TYK2 is essential for the therapeutic effect of IFN-α in Jak2V617F-induced murine myeloproliferative neoplasms

Interferon-α (IFN-α) exhibits antiviral and antiproliferative effects on normal and neoplastic cells. Intracellular signaling of IFN-α is mediated by tyrosine kinase 2 (TYK2) and janus kinase 1 (JAK1), followed by signal transducers and activators of transcription (STATs). TYK2 is redundant for the antiviral effect of IFN-α; however, the requirements for antiproliferative effects are unknown. We assessed the role of TYK2 in the effects of IFN-α in myeloproliferative neoplasm (MPN) model mice. Jak2V617F transgenic mice develop MPNs resembling human primary myelofibrosis, and ropeginterferon-α-2b ameliorated their features. However, these IFN-α effects were absent in Jak2V617F;Tyk2−/− mice. In mixed wild-type (WT)/Jak2V617F chimeric mice, IFN-α treatment induces Jak2V617F hematopoietic stem cells (HSCs) to enter the cell cycle and skew their differentiation into the megakaryocyte lineage, decreasing the number of Jak2V617F HSCs. The effects of IFN-α on Jak2V617F HSCs were not observed in mixed WT/Jak2V617F;Tyk2−/− mice, indicating that TYK2 is essential for the effects of IFN-α on both Jak2V617F progenitors and HSCs. The mechanism of IFN-α in Jak2V617F HSCs and progenitors differed: genes regulating the cell cycle were enriched in IFN-α–stimulated Jak2V617F HSCs, but not in Jak2V617F progenitors; genes regulating antiproliferation were enriched in IFN-α–stimulated Jak2V617F progenitors but not in Jak2V617F HSCs. The major IFN-α signaling molecule activated by JAKs is STAT1, which is essential for the antiviral effect. Most effects of IFN-α on Jak2V617F cells were preserved in Jak2V617F;Stat1−/− mice but to a moderate degree compared with Jak2V617F mice. Our study reveals essential roles of TYK2 for the preferential suppressive effect of IFN-α on Jak2V617F progenitors and HSCs

Impaired humoral immunity following COVID-19 vaccination in HTLV-1 carriers

Background Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown. Methods To investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors. Results We analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers. Conclusions The humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them.Citation: Takuro Kameda, Atae Utsunomiya, Nobuaki Otsuka, Yoko Kubuki, Taisuke Uchida, Kotaro Shide, Ayako Kamiunten, Nobuaki Nakano, Masahito Tokunaga, Takayoshi Miyazono, Yoshikiyo Ito, Kentaro Yonekura, Toshiro Kawakita, Keiichi Akizuki, Yuki Tahira, Masayoshi Karasawa, Tomonori Hidaka, Ayaka Konagata, Norifumi Taniguchi, Yuma Nagatomo, Fumiko Kogo, Koichiro Shimizu, Hiroaki Ueno, Junzo Ishizaki, Naoya Takahashi, Yoshihiko Ikei, Michihiro Hidaka, Hideki Yamaguchi, Kazuya Shimoda, Impaired humoral immunity following COVID-19 vaccination in HTLV-1 carriers. BMC Infectious Diseases. 2024-01-17, 24(1), https://doi.org/10.1186/s12879-024-09001-

サポーティング・サービスを伴う耐久財独占と過剰なモデル・チェンジ

2004-06-30This paper considers the products which are composed of hardware and software. Hardware is durable and supplied by the monopolist, whereas software is non-durable and supplied by monopolistic competitive firms. The monopolist may introduce hardware of new model into the market in order to make the consumers renew their old one. But this may be undesirable from the social viewpoint, because new hardware needs development of new software and this development cost may be socially wasteful. Such wastefulness will be much strengthen when old software doesn’t work in new hardware, that is, incompatible. The purpose of this paper is to indicate the condition in which the excessive model change can occur, especially by explaining with the development cost and the degree of product differentiation of software.departmental bulletin pape

p16 positively controls p21 expression in epithelial cells.

<p>MCF-10A cells were transfected with a plasmid bearing the <i>CDKN2A</i>-ORF or a control plasmid. (A) 2x10⁴ cells were plated in E-16 plate for 48 hrs and cell proliferation was monitored using the RTCA-DP system. Cell index (CI) represents cell impedance measurement, which represents quantitative information about cell number. (B) p16 and Ki-67 immunostaining. Upper panel: phase contrast microscopy, lower panel: Labeling Index for Ki-67 and p16 staining was determined for at least 500 cells per data point and expressed as mean ± S.D of triplicate determinations. (C) Whole cell lysates were prepared from the indicated cells and were used for immunoblotting utilizing antibodies against the indicated proteins. (D) Total RNA was purified and used for qRT-PCR amplification using specific primers for the indicated genes.</p

p16 controls the transcription of the <i>CDKN1A</i> mRNA through AUF1.

<p>(A) Cell lysates were prepared from <i>CDKN2A</i>-shRNA expressing cells and their control counterparts and AUF1 mouse monoclonal antibody and mouse IgG (used as control) were utilized for immunoprecipitation. Co-precipitated RNA was purified and used for quantitative RT-PCR reactions. (B) Total RNA was purified from p16 proficient (HFSN1 and EH1) and p16-deficient (U2OS and HFSN1 expressing <i>CDKN2A</i>-shRNA) cells, expressing either AUF1-siRNA or control-siRNA. Transcripts for the indicated genes were amplified by quantitative RT-PCR. (C) U2OS cells were transfected with EGFP reporter containing either the wild-type (WT) or the mutated (Mut) <i>CDKN1A</i> ARE, while U2OS containing AUF1-siRNA as well as EH1 cells were transfected with the <i>CDKN1A</i>-WT-ARE construct. GFP fluorescence was measured 24 hrs post-transfection. Error bars represent means ± S.D. *: <i>p</i>-value < 0.05.</p