Ablation of Fbxw7 Eliminates Leukemia-Initiating Cells by Preventing Quiescence

SummaryImatinib eradicates dividing progenitor cells of chronic myeloid leukemia (CML) but does not effectively target nondividing leukemia-initiating cells (LICs); thus, the disease often relapse after its discontinuation. We now show that Fbxw7 plays a pivotal role in maintenance of quiescence in LICs of CML by reducing the level of c-Myc. Abrogation of quiescence in LICs by Fbxw7 ablation increased their sensitivity to imatinib, and the combination of Fbxw7 ablation with imatinib treatment resulted in a greater depletion of LICs than of normal hematopoietic stem cells in mice. Purging of LICs by targeting Fbxw7 to interrupt their quiescence and subsequent treatment with imatinib may thus provide the basis for a promising therapeutic approach to CML

Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis

Cell proliferation is strictly controlled during differentiation. In T cell development, the cell cycle is normally arrested at the CD4+CD8+ stage, but the mechanism underlying such differentiation-specific exit from the cell cycle has been unclear. Fbxw7 (also known as Fbw7, Sel-10, hCdc4, or hAgo), an F-box protein subunit of an SCF-type ubiquitin ligase complex, induces the degradation of positive regulators of the cell cycle, such as c-Myc, c-Jun, cyclin E, and Notch. FBXW7 is often mutated in a subset of human cancers. We have now achieved conditional inactivation of Fbxw7 in the T cell lineage of mice and found that the cell cycle is not arrested at the CD4+CD8+ stage in the homozygous mutant animals. The mutant mice manifested thymic hyperplasia as a result of c-Myc accumulation and eventually developed thymic lymphoma. In contrast, mature T cells of the mutant mice failed to proliferate in response to mitogenic stimulation and underwent apoptosis in association with accumulation of c-Myc and p53. These latter abnormalities were corrected by deletion of p53. Our results suggest that Fbxw7 regulates the cell cycle in a differentiation-dependent manner, with its loss resulting in c-Myc accumulation that leads to hyperproliferation in immature T cells but to p53-dependent cell-cycle arrest and apoptosis in mature T cells

Role of the UBL-UBA Protein KPC2 in Degradation of p27 at G(1) Phase of the Cell Cycle

KPC2 (Kip1 ubiquitylation-promoting complex 2) together with KPC1 forms the ubiquitin ligase KPC, which regulates degradation of the cyclin-dependent kinase inhibitor p27 at the G(1) phase of the cell cycle. KPC2 contains a ubiquitin-like (UBL) domain, two ubiquitin-associated (UBA) domains, and a heat shock chaperonin-binding (STI1) domain. We now show that KPC2 interacts with KPC1 through its UBL domain, with the 26S proteasome through its UBL and NH(2)-terminal UBA domains, and with polyubiquitylated proteins through its UBA domains. The association of KPC2 with KPC1 was found to stabilize KPC1 in a manner dependent on the STI1 domain of KPC2. KPC2 mutants that lacked either the NH(2)-terminal or the COOH-terminal UBA domain supported the polyubiquitylation of p27 in vitro, whereas a KPC2 derivative lacking the STI1 domain was greatly impaired in this regard. Depletion of KPC2 by RNA interference resulted in inhibition of p27 degradation at the G(1) phase, and introduction of KPC2 derivatives into the KPC2-depleted cells revealed that the NH(2)-terminal UBA domain of KPC2 is essential for p27 degradation. These observations suggest that KPC2 cooperatively regulates p27 degradation with KPC1 and that the STI1 domain as well as the UBL and UBA domains of KPC2 are indispensable for its function

Secondary Adrenal Insufficiency Due to Isolated ACTH Deficiency Induced by Pembrolizumab: A Report of Two Cases of Uterine Endometrial Cancer

Immune checkpoint inhibitors (ICIs) enhance antitumoral immune mechanisms and are used to treat various types of solid tumors including those that are microsatellite instability (MSI)-high. Uterine endometrial cancer is one of the most frequent tumor types that shows MSI-high, and, consequently, opportunities to use ICIs for endometrial cancer treatment are increasing. While using ICIs, it is important to monitor and manage various immune-related adverse events (irAEs). Here, we report two cases of secondary adrenal insufficiency during treatment of endometrial cancer with pembrolizumab. Both cases showed appetite loss and general fatigue after the 6th or 12th cycle of pembrolizumab. They were admitted to our hospital because of remarkable hyponatremia. Both cases showed no adrenocorticotropic hormone (ACTH) or cortisol response to CRH loading tests. Other pituitary hormone levels were normal, and MRI revealed no sign of hypophysitis in either patient. They were diagnosed with secondary adrenal insufficiency due to isolated ACTH deficiency and recovered soon after the administration of hydrocortisone and hydration. Thus, we should be aware of irAEs with the use of ICIs. In particular, adrenocortical insufficiency is sometimes lethal without appropriate treatment. Because the clinical symptoms are fatigue, appetite loss, and nausea, patients might be misjudged to have symptoms related to cancer. Checking serum morning cortisol before ICIs use and monitoring serum sodium levels could provide clues to diagnose secondary adrenal insufficiency

Can We Predict the Premature Labor in Patients with Placenta Previa? ; A Retrospective Study on Maternal Symptoms during Pregnancy

Objectives : This study aimed to predict the gestational weeks by characterizing maternal genital bleeding and uterine contraction during pregnancy in patients with placenta previa. Methods : Included in this study were 87 patients with placenta previa, diagnosed at the time of delivery at our institution. Genital bleeding and uterine contraction characteristics and clinical data from mothers who delivered at < 37 weeks were compared to that of mothers who delivered at ≧ 37 weeks. Results : There were 37 deliveries (42.5%) at < 37 gestational weeks and 50 deliveries (57.4%) at ≧ 37 gestational weeks. In 69 of 87 cases (79.3%), genital bleeding wasrecognized during pregnancy, and in 63 cases (72.4%) genital bleeding was the first symptom to occur during pregnancy. Uterine contraction during pregnancy was recognized in 48 cases (55.2%), including 36 (41.4%) that occurred as the first symptom of pregnancy. Logistic regression analysis revealed that when genital bleeding occurred at < 29 and < 31 weeks, patients were at high risk for delivery at < 34 and < 37 weeks, respectively, and when first uterine contraction occurred at < 29 weeks, they were at high risk for delivery at < 34 weeks. Conclusion : In patients with placenta previa, the number of gestational weeks to the occurrence of the first genital bleeding can be used as a predictor of the number of weeks to term.前置胎盤は妊娠後半期における産科救急の代表的な疾患で, 母体出血および早産の点から, 母児双方に関してハイリスクな妊娠である. 経膣超音波断層法の普及を背景として, 本症の診断は容易かつ確実になされるようになった. しかしながら, 本症において安静入院時期の決定および早産予防の視点から分娩時期を予測する検討はなされていない. 本検討では, 妊娠経過中に母体に起きる性器出血および子宮収縮の2つの主症状に着目した. これらの症状の出現時期とその特徴から分娩時期を予測することを目的とし, 九州大学医学部附属病院周産母子センターにおいて過去10年間に経験した前置胎盤症例について後方視的に検討を行った

前置胎盤症例における症状とその初発時期からみた分娩時期の後方視的検討

Objectives : This study aimed to predict the gestational weeks by characterizing maternal genital bleeding and uterine contraction during pregnancy in patients with placenta previa. Methods : Included in this study were 87 patients with placenta previa, diagnosed at the time of delivery at our institution. Genital bleeding and uterine contraction characteristics and clinical data from mothers who delivered at < 37 weeks were compared to that of mothers who delivered at ≧ 37 weeks. Results : There were 37 deliveries (42.5%) at < 37 gestational weeks and 50 deliveries (57.4%) at ≧ 37 gestational weeks. In 69 of 87 cases (79.3%), genital bleeding wasrecognized during pregnancy, and in 63 cases (72.4%) genital bleeding was the first symptom to occur during pregnancy. Uterine contraction during pregnancy was recognized in 48 cases (55.2%), including 36 (41.4%) that occurred as the first symptom of pregnancy. Logistic regression analysis revealed that when genital bleeding occurred at < 29 and < 31 weeks, patients were at high risk for delivery at < 34 and < 37 weeks, respectively, and when first uterine contraction occurred at < 29 weeks, they were at high risk for delivery at < 34 weeks. Conclusion : In patients with placenta previa, the number of gestational weeks to the occurrence of the first genital bleeding can be used as a predictor of the number of weeks to term.前置胎盤は妊娠後半期における産科救急の代表的な疾患で, 母体出血および早産の点から, 母児双方に関してハイリスクな妊娠である. 経膣超音波断層法の普及を背景として, 本症の診断は容易かつ確実になされるようになった. しかしながら, 本症において安静入院時期の決定および早産予防の視点から分娩時期を予測する検討はなされていない. 本検討では, 妊娠経過中に母体に起きる性器出血および子宮収縮の2つの主症状に着目した. これらの症状の出現時期とその特徴から分娩時期を予測することを目的とし, 九州大学医学部附属病院周産母子センターにおいて過去10年間に経験した前置胎盤症例について後方視的に検討を行った

Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver

E3 ubiquitin ligase complexes of the SCF type consist of ring-box 1 (Rbx1), cullin 1 (Cul1), S-phase kinase-associated protein 1 (Skp1), and a member of the F-box family of proteins. The identity of the F-box protein determines the substrate specificity of the complex. The F-box family member F-box– and WD repeat domain–containing 7 (Fbxw7; also known as Fbw7, SEL-10, hCdc4, and hAgo) targets for degradation proteins with wide-ranging functions, and uncovering its in vivo role has been difficult, because Fbxw7–/– embryos die in utero. Using two different Cre-loxP systems (Mx1-Cre and Alb-Cre), we generated mice with liver-specific null mutations of Fbxw7. Hepatic ablation of Fbxw7 resulted in hepatomegaly and steatohepatitis, with massive deposition of triglyceride, a phenotype similar to that observed in humans with nonalcoholic steatohepatitis. Both cell proliferation and the abundance of Fbxw7 substrates were increased in the Fbxw7-deficient liver. Long-term Fbxw7 deficiency resulted in marked proliferation of the biliary system and the development of hamartomas. Fbxw7 deficiency also skewed the differentiation of liver stem cells toward the cholangiocyte lineage rather than the hepatocyte lineage in vitro. This bias was corrected by additional loss of the Notch cofactor RBP-J, suggesting that Notch accumulation triggered the abnormal proliferation of the biliary system. Together, our results suggest that Fbxw7 plays key roles, regulating lipogenesis and cell proliferation and differentiation in the liver

Prognostic Factors for Severe-to-Fatal Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Multicenter Prospective Cohort Study

The prognostic factors associated with severe-to-fatal post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remain unclear despite the extensive number of studies on PEP. In total, 3739 ERCP patients with biliary disease with an intact papilla and indicated for ERCP were prospectively enrolled at 36 centers from April 2017 to March 2018. Those with acute pancreatitis diagnosed before ERCP, altered gastrointestinal anatomy, and an American Society of Anesthesiologists (ASA) physical status > 4 were excluded. Univariate and multivariate logistic regression analyses were performed on patient-related factors, operator-related factors, procedure-related factors, and preventive measures to identify potential prognostic factors for severe-to-fatal PEP. Multivariate analyses revealed pancreatic guidewire-assisted biliary cannulation (OR 13.59, 95% CI 4.21–43.83, p p p = 0.015) as significant risk factors for severe-to-fatal PEP. Preventive measures included endoscopic biliary sphincterotomy (EST; OR 0.29, 95% CI, 0.11–0.79, p = 0.015) and prophylactic pancreatic stents (PPSs; OR 0.11, 95% CI, 0.01–0.87, p = 0.036). In biliary ERCP, pancreatic guidewire-assisted biliary cannulation, NSAID administration after ERCP, and previous pancreatitis were risk factors for severe-to-fatal PEP, whereas EST and PPS were significant preventive measures for severe-to-fatal PEP