Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2.

細胞老化から癌化への変換のカギとなる解糖系制御機構解明に成功 -代謝を標的とした新しい抗がん剤開発に期待-. 京都大学プレスリリース. 2014-02-24.Despite the well-documented clinical significance of the Warburg effect, it remains unclear how the aggressive glycolytic rates of tumor cells might contribute to other hallmarks of cancer, such as bypass of senescence. Here, we report that, during oncogene- or DNA damage-induced senescence, Pak1-mediated phosphorylation of phosphoglycerate mutase (PGAM) predisposes the glycolytic enzyme to ubiquitin-mediated degradation. We identify Mdm2 as a direct binding partner and ubiquitin ligase for PGAM in cultured cells and in vitro. Mutations in PGAM and Mdm2 that abrogate ubiquitination of PGAM restored the proliferative potential of primary cells under stress conditions and promoted neoplastic transformation. We propose that Mdm2, a downstream effector of p53, attenuates the Warburg effect via ubiquitination and degradation of PGAM

Production and nonclinical evaluation of an autologous iPSC-derived platelet product for the iPLAT1 clinical trial

血小板減少症に対するiPS細胞由来血小板の自己輸血に関する臨床研究」の成果公表（論文発表）について. 京都大学プレスリリース. 2022-09-30.Donor-derived platelets are used to treat or prevent hemorrhage in patients with thrombocytopenia. However, ∼5% or more of these patients are complicated with alloimmune platelet transfusion refractoriness (allo-PTR) due to alloantibodies against HLA-I or human platelet antigens (HPA). In these cases, platelets from compatible donors are necessary, but it is difficult to find such donors for patients with rare HLA-I or HPA. To produce platelet products for patients with aplastic anemia with allo-PTR due to rare HPA-1 mismatch in Japan, we developed an ex vivo good manufacturing process (GMP)–based production system for an induced pluripotent stem cell–derived platelet product (iPSC-PLTs). Immortalized megakaryocyte progenitor cell lines (imMKCLs) were established from patient iPSCs, and a competent imMKCL clone was selected for the master cell bank (MCB) and confirmed for safety, including negativity of pathogens. From this MCB, iPSC-PLTs were produced using turbulent flow bioreactors and new drugs. In extensive nonclinical studies, iPSC-PLTs were confirmed for quality, safety, and efficacy, including hemostasis in a rabbit model. This report presents a complete system for the GMP-based production of iPSC-PLTs and the required nonclinical studies and thus supports the iPLAT1 study, the first-in-human clinical trial of iPSC-PLTs in a patient with allo-PTR and no compatible donor using the autologous product. It also serves as a comprehensive reference for the development of widely applicable allogeneic iPSC-PLTs and other cell products that use iPSC-derived progenitor cells as MCB

Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma

成人T細胞白血病リンパ腫（ATL）におけるゲノム情報と臨床情報を統合したリスクモデルを確立 --ATLの個別化医療を推進--. 京都大学プレスリリース. 2023-04-10.The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment. To identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and high-risk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] 5.46, p < 0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR 2.33, p = 0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATL-PI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (−4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (−2), and GATA3 (−3)

近位尿細管障害の強さや頻度が腎予後を決定する

京都大学0048新制・課程博士博士(医学)甲第21008号医博第4354号新制||医||1028(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 長船 健二, 教授 小川 修, 教授 横出 正之学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Long-Term Prognosis of Hyperferritinemia Induced by Intravenous Iron Therapy in Patients Undergoing Maintenance Hemodialysis: A 10-Year, Single-Center Study

Optimal ferritin level in hemodialysis patients between Japan and other countries is controversial. Long-term side effects of iron supplementation in these patients remain unclear. We aimed to elucidate whether past hyperferritinemia in hemodialysis patients was associated with high risk of death and cerebrovascular and cardiovascular diseases (CCVDs). This small retrospective cohort study included approximately 44 patients unintentionally supplemented with excessive intravenous iron. A significantly higher risk of CCVDs was observed in patients with initial serum ferritin levels ≥1000 ng/mL than in the remaining patients. High ferritin levels slowly decreased to <300 ng/mL in a median of 24.2 (10.5–46.5) months without treatment. However, compared with the remaining patients, only patients whose ferritin levels did not decrease to <300 ng/mL steadily had a significantly higher risk of all-cause death (hazard ratio, 9.6). Long-term hyperferritinemia due to intravenous iron therapy is a risk factor for death in maintenance hemodialysis patients. For a prolonged better prognosis, intravenous iron should be carefully administered so as to avoid hyperferritinemia in patients with hemodialysis