Leukemia

B-chronic lymphocytic leukaemia (B-CLL) is a heterogeneous disease characterized by an accumulation of B lymphocytes expressing CD5. To date, the biological significance of this molecule in B-CLL B cells remains to be elucidated. In this study, we have analysed the functional consequences of the binding of an anti-CD5 antibody on B-CLL B cells. To this purpose, we have measured the percentage of viability of B-CLL B cells in the presence or in the absence of anti-CD5 antibodies and also examined some of the biochemical events downstream the CD5-signalling. We demonstrate that anti-CD5 induces phosphorylation of protein tyrosine kinases and protein kinase C (PKC), while no activation of Akt/PKB and MAPKs is detected. This signalling cascade results in viability in a group of patients in which we observe an increase of Mcl-1 levels, whereas the levels of bcl-2, bcl-xL and XIAP do not change. We also report that this pathway leads to IL-10 production, an immunoregulatory cytokine that might act as an autocrine growth factor for leukaemic B cells. Inhibition of PKC prevents the induction of Mcl-1 and IL-10, suggesting that the activation of PKC plays an important role in the CD5-mediated survival signals in B cells from a subset of B-CLL patients.

One hundred seventy adult patients with acute lymphoblastic leukemia (ALL) or acute undifferentiated leukemia (AUL) were entered into a prospective multicenter therapy trial at 25 hospitals. The aim of the trial was to improve remission duration by using a modified form of an intensified induction regimen that was successful in childhood ALL, to define immunologic subtypes of ALL by use of cell-surface markers, and to extract other possible prognostic factors. The overall complete remission rate was 77.8%. The median overall survival time was 26 months, being 4 months for nonresponders and 32 months for responders. The median remission duration for the 126 patients with complete remission was 20 months. Prognostically favorable factors for remission duration were response to chemotherapy within 4 weeks, age less than 35 years, a low initial leukocyte count, and the immunologic subtypes c-ALL with early response to therapy and T-ALL, where 61% and 58%, respectively, are still in comp...

Troxacitabine (Troxatyl; BCH-4556; (-)-2'-deoxy-3'-oxacytidine), a deoxycytidine analogue with an unusual dioxolane structure and nonnatural L-configuration, has potent antitumor activity in animal models and is in clinical trials against human malignancies. The current work ...

Dyskeratosis congenita (DKC) is a paradigmatic telomere disorder characterized by substantial and premature telomere shortening, bone marrow failure, and a dramatically increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). DKC can occur as a late-onset, so-called cryptic form, with first manifestation in adults. Somatic MDS-related mutations are found in up to 35% of patients with acquired aplastic anemia (AA), especially in patients with short telomeres. The aim of our study was to investigate whether cryptic DKC is associated with an increased incidence of MDS-related somatic mutations, thereby linking the accelerated telomere shortening with the increased risk of MDS/AML. Samples from 15 adult patients (median age: 42 years, range: 23-60 years) with molecularly confirmed cryptic DKC were screened using next-generation gene panel sequencing to detect MDS-related somatic variants. Only one of the 15 patients (7%) demonstrated a clinically rele...

The manufacturing of cellular products for immunotherapy, such as chimeric antigen receptor T cells, requires successful collection of mononuclear cells. Collections from children with high-risk leukemia present a challenge, especially because the established COBE Spectra apheresis device is being replaced by the novel Spectra Optia device (Optia) in many institutions. Published experience for mononuclear cell collections in children with Optia is lacking. Our aim was to compare the two collection devices and describe modified settings on the Optia to optimize mononuclear cell collections. As a quality initiative, we retrospectively collected and compared data from mononuclear cell collections on both devices. Collected data included patient's clinical characteristics; collection parameters, including precollection lymphocyte/CD3 counts, total blood volumes processed, runtimes, and side effects (including complete blood count and electrolyte changes); and product characteristics...

Burkitt’s lymphoma (BL) in Turkish children is commonly associated with Epstein–Barr virus (EBV) infection. The C-terminus of the latent membrane protein 1 (LMP-1) of EBV is essential for transformation and the 30-bp deletion detected in this region has been implicated to be associated with a more aggressive malignant phenotype. To understand the molecular mechanisms underlying EBV pathogenesis in BL of

Despite an old history behind the identification of the leading role of c-Myc in leukemogenesis, the road to constructing a therapeutic perspective for this molecule in acute lymphoblastic leukemia (ALL) is yet mesmerizing. This study was designed to provide a better outlook for the anticancer property of 10058-F4, an appealing inhibitor of c-Myc, in pre-B ALL cell lines either in the context of monotherapy or in combination with chemotherapeutic drugs. Our results declared that abrogation of c-Myc decreased the proliferative capacity of pre-B ALL-derived cells through halting the transition of the cells from G1 phase, and reducing the replicative potential of both REH and Nalm-6 cells, at least partly, through c-Myc-mediated suppression of human telomerase reverse transcrip-tase. Moreover, 10058-F4 potently induced a caspase-3-dependent apoptosis in pre-B ALL cells via shifting the balance between pro-and anti-apoptotic target genes. Although the inhibition of PI3Kδ using Idelalisib upregulated the messenger RNA expression of autophagy-related genes in 10058-F4-treated cells, treatment with autophagy inhibitor chloroquine decreased viability of the cells, either as a single agent or in combination with Idelalisib and/or 10058-F4; suggesting that the activation of autophagy in pre-B ALL cells could blunt apoptotic events and attenuate anticancer effect of both c-Myc and PI3K inhibitors. Finally, the results of our synergistic experiments delineated that 10058-F4 produced a synergistic effect with vincristine and provided an enhanced therapeutic efficacy in ALL cells, highlighting that c-Myc oncoprotein could be a bona fide target for the treatment of ALL. K E Y W O R D S acute lymphoblastic leukemia, autophagy, c-Myc, PI3K signaling pathway, 10058-F4

Stressful events that disrupt the assumptive world can force people to make cognitive changes to accommodate these highly stressful experiences. As fundamental assumptions are reestablished, many people report changes and experiences that reflect posttraumatic growth (PTG). The present research describes the development of the Core Beliefs Inventory (CBI), a brief measure of disruption of the assumptive world developed for use in applied research and clinical settings. Three studies, two using college samples (Study 1, n=181 and Study 2, n=297 time 1; 85 time 2) and the third using leukemia patients (Study 3, n=70 time 1; 43 time 2), assessed the utility of the CBI to predict PTG in both cross-sectional and longitudinal designs. Relationships between the CBI and measures of self-reported PTG and well-being indicate that the CBI has construct validity, acceptable test-retest reliability, and very good internal consistency. The CBI may be a useful tool in investigating predictions about the effects of stressful experiences on an individual's assumptive world, PTG, and successful adaptation.

Background In 2002, a poster alerted the French health authorities to the possibility that the risk of childhood leukaemia might be increased by hepatitis B vaccination. Elucidating the role of vaccination in the aetiology of childhood acute leukaemia (AL) was therefore included in the objectives of an ongoing national study. Methods The ESCALE study was a French national population-based case-control

Cord-blood banks have increased the use of cord-blood transplantation in patients with hematologic disorders. We have established a registry containing information on the outcome of cord-blood transplantation. We sent questionnaires to 45 transplantation centers for information on patients receiving cord-blood transplants from 1988 to 1996. Reports on 143 transplantations, performed at 45 centers, were studied, and the responses were analyzed separately according to whether the donor was related or unrelated to the recipient. Among 78 recipients of cord blood from related donors, the Kaplan-Meier estimate of survival at one year was 63 percent. Younger age, lower weight, transplants from HLA-identical donors, and cytomegalovirus-negative serologic results in the recipient were favorable prognostic factors. Graft-versus-host-disease of at least grade II occurred at estimated rates of 9 percent in 60 recipients of HLA-matched cord blood and 50 percent in 18 recipients of HLA-mismatched cord blood. Neutrophil engraftment was associated with an age of less than six years (P = 0.02) and a weight of less than 20 kg (P = 0.02), and it occurred in 85 percent of patients receiving 37 million or more nucleated cells per kilogram of body weight. Among 65 patients who received cord blood from unrelated donors, the Kaplan-Meier estimate of survival at one year was 29 percent. Cytomegalovirus-negative serologic status in these recipients was associated with improved survival (P = 0.03) and was the most important predictor of graft-versus-host disease (P = 0.04). Neutrophil recovery occurred in 94 percent of the patients who received 37 million or more nucleated cells per kilogram from unrelated donors. Cord blood is a feasible alternative source of hematopoietic stem cells for pediatric and some adult patients with major hematologic disorders, particularly if the donor and the recipient are related.

We have utilized 2 recombinant DNA strategies for immunization against FeLV in cats: (a) modified live virus was attenuated by mutation and recombination, and (b) an immunogen, consisting of subunit envelope protein, was prepared in genetically engineered yeast. Results indicated that the genetically manipulated live virus preparations were not protective against FeLV challenge because they were either not attenuated in virulence or were not sufficiently antigenic. Immunization with yeast-synthesized FeLV envelope protein followed by the modified live virus gave protective immunity in cats under experimental conditions. Future immunization attempts will concentrate on enhancing the immunogenic potency of the yeast- synthesized FeLV envelope protein.