The E2F family member of transcription factors includes the atypical member E2F8, which has been little studied in cancer. We report that E2F8 is strongly upregulated in human hepatocellular carcinoma (HCC), where it was evidenced to contribute to oncogenesis and progression. Ectopic overexpression of E2F8 promoted cell proliferation, colony formation, and tumorigenicity, whereas E2F8 knockdown inhibited these phenotypes, as documented in Huh-7, Focus, Hep3B, and YY-8103 HCC cell lines. Mechanistic analyses indicated that E2F8 could bind to regulatory elements of cyclin D1, regulating its transcription and promoting accumulation of S-phase cells. Together, our findings suggest that E2F8 contributes to the oncogenic potential of HCC and may constitute a potential therapeutic target in this disease. Cancer Res; 70(2); 782-91. ©2010 AACR.

The aim of this report was to present a clinical comparison of unrelated cord blood transplantation (CBT) and human leukocyte antigen (HLA)-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) in children with high-risk or advanced acute leukemia. A total of 115 consecutive pediatric patients received unrelated CBT (n = 90) or sibling allo-PBSCT/BMT (n = 25) between 2000 and 2012. Neutrophil and platelet recovery were significantly delayed after CBT compared to allo-PBSCT/BMT. There was no difference in the incidence of acute graft-versus-host disease (GVHD) or chronic GVHD between the two groups. The cumulative incidence of transplant-related mortality (TRM) was higher in the CBT group than in the allo-PBSCT/BMT group (32.5 vs 12.8 %) (p = 0.03). The cumulative incidence of relapse was 13.1 % after CBT, which was significantly lower than that of after allo-PBSCT/BMT (45.3 %) (p = 0.015). The overall survival (OS) and leukemia-free survival (LFS) in the CBT group were similar to those of the allo-PBSCT/BMT group; however, for acute myeloid leukemia (AML) patients, the 5-year LFS in the CBT group was slightly better than the allo-PBSCT/BMT group (55.7 % for CBT and 32.7 % for allo-PBSCT/BMT) (p = 0.08). Our comparisons suggest that for high-risk or advanced childhood acute leukemia, unrelated CBT has a higher TRM and similar long-term survival, but better antileukemia effect than HLA-matched sibling PBSCT/BMT. New strategies and better supportive care are required to decrease the TRM of CBT.

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BackgroundBloodstream infection (BSI) is one of the major causes of morbidity and mortality for patients undergoing hematopoietic stem cell transplantation (HSCT). The unrelated cord blood transplantation (UCBT) can provided opportunities for patients without suitable donors for bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT), while few studies have addressed BSI after UCBT. The aim of this study was to analyse the incidence and risk factors of BSI, causative organisms, microbial resistance, and its impact on the clinical outcomes and survival of patients.MethodsThere are 336 patients, were divided into two groups depending on whether developing BSI. Demographic characteristics, laboratory data, and clinical outcome were compared between different groups. The risk factors of BSI was examined using logistic regression and the survival was examined using the Kaplan-Meier method and log-rank test.ResultsNinety-two patients (27.4%) developed early BSI with 101 pathogenic bacteria isolated, and the median day of developing initial BSI was 4.5 d. Gram-negative bacteria were the most common isolate (60, 59.4%), followed by Gram-positive bacteria (40, 39.6%) and fungi (1, 1.0%). Thirty-seven (36.6%) isolates were documented as having multiple drug resistance (MDR). Myeloid malignancies, conditioning regimens including total body irradiation (TBI), and prolonged neutropenia were identified as the independent risk factors for early BSI. The 3-year OS was 59.9% versus 69.2% in the BSI group and no-BSI group (P = 0.0574), respectively. The 3-year OS of the MDR group was significantly lower than that of the non-BSI group (51.1% versus 69.2%, p = 0.013).ConclusionsOur data indicate that the incidence of early BSI after UCBT was high, especially in patients with myeloid disease and a conditioning regimen including TBI and prolonged neutropenia. Early BSI with MDR after UCBT had a negative impact on long-term survival.

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Although previous studies have demonstrated improved outcomes in umbilical cord blood transplantation (UCBT) by omitting antithymocyte globulin (ATG) in the conditioning regimen, this approach has not been comparatively studied in unrelated peripheral blood stem cell transplantation (UPBSCT). To compare the risks and benefits between UCBT without ATG and UPBSCT in patients with acute leukemia (AL), we conducted a multicenter retrospective study of 79 patients who underwent UCBT (myeloablative conditioning without ATG) and 96 patients who underwent UPBSCT (myeloablative conditioning with ATG). The outcomes were graft failure, neutrophil engraftment, platelet engraftment, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), transplantation-related mortality (TRM), relapse, overall survival (OS), and leukemia-free survival (LFS). Follow-up was censored on October 31, 2016. Engraftment was similar between the 2 groups but granulocyte and platelet recovery were slower in the UCBT group (both P < .001). The incidences of aGVHD, TRM, OS, and LFS were similar between the 2 groups (all P > .05). Without ATG, the UCBT group displayed less cGVHD and less moderate and severe cGVHD (P < .001 and P = .004). The incidences of Epstein-Barr virus viremia and post-transplantation lymphoproliferative disease were significantly lower in the UCBT group (P < .001 and P = .037). UCBT recipients had higher activity Karnofsky performance scores and 3-year GVHD-free/relapse-free survival than the UPBSCT group (P = .03 and P = .04). We observed similar survival when comparing UCBT without ATG and UPBSCT, but we also observed better quality of life in patients undergoing UCBT without ATG. We can therefore conclude that patients with primary AL for whom an appropriate HLA-matched sibling donor is not available could select either UCBT or UPBSCT.

This is a retrospective study to evaluate the efficacy and safety of umbilical cord blood–derived mesenchymal stromal cells (MSCs) for the treatment of pediatric patients with severe BK virus–associated late‐onset hemorrhagic cystitis (BKV‐HC) after unrelated cord blood transplantation (UCBT). Thirteen pediatric patients with severe BKV‐HC from December 2013 to December 2015 were treated with MSCs. The number of MSCs transfused in each session was 1 × 106/kg once a week until the symptoms improved. The median follow‐up time was 1432 (89‐2080) days. The median frequency of MSC infusion was 2 (1‐3), with eight cured cases and five effective cases; the total efficacy rate was 100%. The copy number of urine BKV DNA was 4.43 (0.36‐56.9) ×108/mL before MSC infusion and 2.67 (0‐56.3) ×108/mL after MSC infusion; the difference was not significant (P = .219). There were no significant differences in the overall survival, disease‐free survival, and the incidence of relapse and acute and chronic graft‐versus‐host disease between the MSC infusion group and non‐MSC infusion group. There was also no significant difference in the cytomegalovirus, Epstein‐Barr virus (EBV), and fungal and bacterial infection rates between the two groups. Although umbilical cord blood–derived MSCs do not reduce the number of BKV DNA copies in the urine, the cells have a high efficacy rate and minimal side effects in treating severe BKV‐HC after UCBT among pediatric patients. MSCs do not affect the rates of relapse, long‐term infection, or survival of patients with leukemia.

Our previous studies implicated the involvement of protein kinase-A in the inhibitory effects of isoproterenol and relaxin on oxytocin-stimulated phosphoinositide turnover in rat myometrium. To understand the possible mechanisms involved, the properties and regulation of phospholipase-C (PLC) in purified myometrial plasma membranes from estrogen-primed rats were studied. The PLC activity measured with exogenous [3H]phosphatidylinositol 4,5-bisphosphate as substrate was Ca2+ dependent. The nonhydrolyzable GTP analog guanosine 5'-(3-O-thio)triphosphate stimulated PLC activity with a ED50 of 1.6 microM and shifted the calcium dependence curve to the left. Guanosine 5'-(3-O-thio)triphosphate-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis was inhibited by activation of endogenous and exogenous cAMP-dependent protein kinase (PKA). The effects of endogenous and exogenous PKA were significantly reversed by IP20, a potent synthetic peptide inhibitor of PKA. In the presence of [gamma-32Pi]ATP and exogenous PKA, 32Pi was incorporated in an IP20-sensitive manner into major bands at approximately 17,000, 20,000-24,000, 33,000, 38,000, 40,000-44,000, and other higher mol wt. These data indicate that one or more GTP-binding proteins mediate activation of membrane-bound PLC in rat myometrium. Phosphorylation of one or more membrane-associated proteins by PKA may regulate myometrial PLC activity and play a role in the inhibitory effects of isoproterenol and relaxin.