bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signaling Mechanisms of Anti-Proliferation by Sphingosine 1-Phoshate(S1P) on Acute Promyelocytic Leukemia(APL) Cell Lines.
Authors: Mun Yeung-Chul , Hwang Eui-Soo , Lee Kyoung-Eun , Kwon Jung Mi , Nam Seung-Hyun , Yoo Eun Sun , Bae Yun-Kyung , Lee Seung-Eun , Ahn Jee-Young , Hyun Myung Soo , Kwon Ki Young , Lee Soon Nam , Seong Chu-Myong 
Published: April 2020

Abstract
There is abundant evidence that S1P can function as a second messenger important for regulation of calcium homeostasis, cell growth, and suppression of apoptosis. In many cases, the intracellular level of S1P and ceramide, another important sphingolipid metabolite associated with cell death and cell growth arrest, coordinately determine cell fate. N, N-dimethylsphingosine(DMS) potentiates TNF- and FasL- induced apoptosis in the human acute leukemia jurkat, U937 and HL-60 cell line, which suggests that combining DMS with cytotoxic drugs might be a useful chemotherapeutic approach. In this study, we investigated the role of S1P on proliferation, survival and its signaling mechanisms on the NB4 cell, the human acute promyelocytic leukemia cell line, which has chromosomal abnormality, t(15:17). NB4 cells were exposed to S1P at various concentrations (1, 5, 10 μM) for 48 hours, and then the cell growth was determined by MTT assay. We studied whether NB4 cells have S1P receptors or not. To investigate the signaling mechanisms of S1P on the NB4 cell, we used MAP kinase inhibitors and a PI3K inhibitor including PD98059, U0126 (specific ERK pathway inhibitor), SB203580 (specific p38 pathway inhibitor), and LY294002 (specific PI3K pathway inhibitor). We also examined the effect of pertussis toxin (PTX), a Gi protein inhibitor, on the proliferation of NB4 cells after S1P treatment.
RT-PCR analysis revealed a putative S1P receptor, Edg-3 mRNA expressed in NB4 cells. In the MTT assay, S1P inhibited cell proliferation in a dose-dependent manner. At 10 μM, NB4 cell proliferation was most inhibited. In addition, we found that the inhibitory effect of S1P on the NB4 cell proliferation was inhibited by PD98059, U0126, and PTX. However, SB203580 and LY294002 had not caused an inhibitory effect of S1P on the NB4 cell proliferation.
In contrast to previous knowledge that S1P increases the survival of leukemic cells because apoptosis is prevented by caspase inactivation, our data suggests that S1P inhibits NB4 cell proliferation, through ERK pathway activation, not p38 nor JNK pathways. In addition, the pertussis toxin(PTX)-sensitive GTP-binding protein-coupled receptor, Edg-3, seems to be involved in the antiproliferative signaling of S1P to the NB4 cell.
Understanding the signaling mechanisms of anti-proliferation by S1P can uncover new therapeutic targets for APL and the results of this study warrant further investigation on synergism of S1P with known therapeutic agent, ATRA and Arsenic trioxide on APL cells.
IL-8 and MCP-1 Regulate the Transmigration of Acute Promyelocytic Leukemia toward Alveolar Type II Cells.
Authors: Hsu Hui-Chi , Tsai Wen-Hui , Ho Chi Kuan , Tzeng Cheng-Hwai , Kou Yu Ru 
Published: April 2020

Abstract
All-trans retinoic acid (ATRA) can induces complete remission in patients with acute promyelocytic leukemia (APL), and can also induce retinoic acid (RA) syndrome in upto 30 % of patients. Massive infiltration of APL cells can be found in the alveolar spaces in the patients with RA syndrome, indicating that ATRA-treated APL cells can migrate from blood vessels into the alveolar space and cause a cascade of reactions which results a clinical picture similar to adult respiratory distress syndrome. In this study, we determine the role of IL-8 and monocytes chemotactic protein-1 (MCP-1) in the cross-talk between APL cells and alveolar cells, and their role in the pathophysiology of RA syndrome. In the transmigration assay, ATRA-treated APL cells (NB4 cells) can transmigrate toward alveolar type II cells (A549 cells) in a dose dependent manner (ATRA: 0.01 to 1 mM), which is also in parallel with increased granulocytic differentiation. Chemoattractant activity can be found in the conditioning medium (CM) of A549 cells in the time dependent manner (1-3 days). When exposed to either IL-8 or MCP-1, chemotactic effect can also be found in the ATRA -treated NB4 cells, but not in untreated NB4 cells. We further determined the concentration of IL-8 or MCP-1 in the CM by ELISA. Our data show that the levels of both cytokines were progressively increased in the CM of A549 cells. Synergistic effect was found when A549 cells were co-cultured with NB4 cells. In the presence of ATRA, the levels of IL-8 and MCP-1 were further increased in the CM of co-culture of NB4 cells and A549 cells (p&lt;0.05 & p&lt;0.05; respectively). The chemotactic activity in CM of A549 cells was partially inhibited when the CM was neutralized with anti-IL-8 or anti-MCP-1 antibodies, respectively. In binding assay by flowcytometry, we further demonstrated that both IL-8 and MCP-1 were bound by the ATRA-treated NB4 cells, but not in un-treated NB4 cells. We conclude that both IL-8 and MCP can induce ATRA-treated APL transmigrating toward alveolar space and causing cascade of reactions leading to RA syndrome.
Hsp90 Expression in Acute Myeloid Leukaemia.
Authors: Walsby Elisabeth J. , Gilkes Amanda F. , Walsh Valerie , Mills Kenneth I. , Burnett Alan K. 
Published: April 2020

Abstract
Heat shock protein inhibitors are a potential new class of anti-leukaemic agents with FLT-3 inhibitory activity. 17-allylamino-17-demethoxygeldanamycin (17-AAG) targets Hsp90 which functions as a molecular chaperone protein that promotes folding of nascent and stress denatured proteins helping them to achieve the correct conformation or targeting them for degradation. Hsp90 conformation is altered by binding ATP to a hydrophobic N-terminal pocket leading to hydrolysis which allows the protein to interact with a co-chaperone complex. 17-AAG fills the ATP binding pocket, displacing the nucleotide and inhibiting the function of Hsp90 as a chaperone. 17-AAG may affect signal transduction resulting from client proteins such as p53, c-Raf-1, Akt, Bcr-Abl and FLT-3. The level of expression of Hsp90 in AML is unknown. To examine the expression 252 AML cases and 9 normal samples were assessed by U133A GeneChips with the data analysed by MAS5 and GeneSpring 6.2.1 to give normalised gene expression of Hsp90α and β, a subset of which were then validated by real-time quantitative RT-PCR. The normalised expression range of Hspα was 0.132 to 2.727 with a mean of 0.982 (n=252) which was not significantly different from normal (0.876: n=9). Hsp90α expression was not significantly different in FAB groups, cytogenetic risk group, FLT-3 status overall or within cytogenetic risk groups. The expression of Hsp90β in the AML samples (n=252) (0.959: range 0.171 to 3.397) was not different from normal samples (0.944: range 0.535 to 1.095). However the APL subgroup (M3) (n=31) had a lower expression (0.722) than the other FAB groups (M0, M1, M2, M4, M5, M6, M7) p=0.029. There was no difference within other FAB subgroups. Apart from the influence of the t(15;17) subgroup expression levels did not vary significantly in the cytogenetic risk groups, or with the presence of a FLT-3 mutation overall or within cytogenetic risk groups. Conclusion: Hsp90 isoform expression in AML is variable over a 21 fold range. Expression does not correlate with FAB, cytogenetic risk group or FLT-3 mutation status. The relationship to clinical outcome is currently being analysed.
Impaired Interferon-Gamma Production as a Consequence of Profound STAT4 Deficiency in Lymphocytes of Lymphoma Patients after Autologous Hematopoietic Stem Cell Transplantation.
Authors: Robertson Michael J. , Chang Hua-Chen , Pelloso David , Kaplan Mark H. 
Published: April 2020

Abstract
Production of IFN-gamma has been found to be critical for optimal antitumor immunotherapy in several preclinical animal models. IL-12-induced IFN-gamma production is markedly defective in patients with lymphoma who have undergone autologous hematopoietic stem cell transplantation (AHSCT). We have investigated the mechanism of defective IFN-gamma production after AHSCT. Increasing the number of CD4 T cells in IFN-gamma assays did not substantially improve IFN-gamma production by post-transplant patient peripheral blood mononuclear cells (PBMCs). Thus, the quantitative deficiency in CD4 T cells observed for up to a year after AHSCT was not the primary mechanism of defective IFN-gamma production. Post-transplant patient T cells and NK cells expressed the IL-12 receptor beta1 subunit at significantly higher levels than did control PBMCs. Moreover, IL-12 receptor beta2 was expressed by a higher proportion of NK cells from post-transplant patients as compared to control subjects. Thus, down-regulation of IL-12 receptor subunits did not account for defective IFN-gamma production by post-transplant patient PBMCs. Levels of Jak2 and Tyk2 were comparable in control and post-transplant patient PBMCs. In contrast, IL-12-induced tyrosine phosphorylation of STAT4 was undetectable or barely detectable in post-transplant patient PBMCs, whereas it was readily detectable in control PBMCs. The total levels of STAT4 protein were also markedly decreased (P&lt;0.027) in post-transplant patient PBMCs (3275+/−1692; mean+/−SE by densitometric analysis) as compared to control PBMCs (8644+/−732). This profound STAT4 deficiency persists for at least 6 months following AHSCT. Incubation of post-transplant patient PBMCs with IL-12 and IL-18 in combination partially reversed the defective IFN-gamma production seen after stimulation with IL-12 alone. IFN-gamma production in response to IL-12 plus IL-18 was not associated with increased expression of STAT4 but was dependent on the activity of p38 MAP kinase. These results indicate that defective IFN-gamma production is due to an intrinsic deficiency in STAT4 expression by post-transplant patient lymphocytes and suggest strategies for circumventing this deficiency in post-transplant cancer immunotherapy.
Interleukin 12 in Combination with Tumor Cell Vaccines Elicits Anti-Leukemic Immune Responses in a Murine Model of Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia.
Authors: Gruber Tanja A. , Skelton Dianne C. , Kohn Donald B. 
Published: April 2020

Abstract
Current intensive chemotherapy regimens have dramatically increased survival in acute lymphoblastic leukemia (ALL) patients compared to the 1950s when single agent chemotherapy was used. Despite this success certain subsets of patients have a high rate of relapse such as those with the Philadelphia chromosome (Ph+). Because the Bcr-Abl oncogene is a novel protein product and uniquely expressed in the leukemia clone, it has the potential to generate anti-leukemic immune responses. Our lab has been studying immunotheraputic approaches for Ph+ ALL using a murine model. Previous data have demonstrated that transduction of leukemia cells with the immunomodulators CD40Ligand, CD80, and GM-CSF generate T and NK cell immune responses. When irradiated and given as a vaccine these gene-modified cells are able to protect a portion of mice from an otherwise lethal dose of leukemia. We looked at the ability to systemic IL-12 treatments to potentiate this immune response and found that IL-12 alone was able to eliminate pre-existing disease in mice. IL-12 treatments, however, did not establish immunologic memory and did not protect mice from subsequent re-challenge with a lethal dose of leukemia. IL-12 protection was primarily mediated by CD4 and CD8 T cells as demonstrated by a decrease in survival in nude mice. When CD4 or CD8 T cells were depleted individually, however, protection was maintained indicating that one cell type can compensate for the other in its absence. Depletion of NK cells from Nude mice further decreased survival indicating a role for these cells in the protection. Thus protection was mediated in part by CD4 T lymphocytes, CD8 T lymphocytes, and Natural Killer cells. The ability of IL-12 to activate three different cell types may explain the efficacy seen in this model, where other cytokines alone have failed. In combination, IL-12 and our leukemia cell vaccine are effective in eliminating pre-established aggressive Philadelphia chromosome positive leukemia and establishing long lasting immunity from subsequent lethal doses of wild type leukemia. As expected, the immunologic memory generated by vaccination with gene modified leukemia cells was mediated by CD4 T cells as indicated by depletion studies. These studies demonstrate the feasibility of immunotheraputic approaches in the treatment of Ph+ ALL.
Treatment of Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) with Concurrent Chemotherapy and Imatinib Mesylate.
Authors: Ribera Josep-Maria , Oriol Albert , Gonzalez Marcos , Vidriales Maria-Belen , Xicoy Blanca , Grau Javier , Esteve Jordi , Brunet Salut , Potro Eloy Del , Moreno Maria-Jose , Tormo Mar , Martin-Reina Maria-Victoria , Deben Guillermo , Parody Ricardo , Lahuerta Juan-Jose , Miguel Jesus-Fernando San 
Published: April 2020

Abstract
Imatinib mesylate as a single agent has modest activity in refractory/relapsed Ph-positive ALL. Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL was explored. Nineteen patients (pts) with de novo Ph-positive ALL were included in a prospective trial. Induction chemotherapy consisted of imatinib mesylate (400 mg/d, p.o.) and VCR (1.5mg/m2/wk), DNR (60 mg/m2/wk) and PDN (60mg/m2/d) for 4 weeks if adequate bone marrow response (&lt;5% blast cells) at day +14 was observed. If not mitoxantrone (12 mg/m2, d15, 16, 17) and HD-ARAC (1,000mg/m2/12h d 18, 19) were administered. Consolidation chemotherapy (C1) included imatinib mesylate and MP, HD-MTX (1.5 g/m2), VM-26 and ARA-C. Pts with a HLA-identical family or MUD donor were submitted to SCT. IF no MUD donor was found a second consolidation cycle (C2) with imatinib mesylate, VCR, DNR, DXM and CPM was administered. Pts without family donor or with no MUD donor after 6 mo. of active search were submitted to autologous SCT. After SCT imatinib mesylate was administered from the sustained hematological recovery to the eventual relapse or at least up to 1 yr. of continuous molecular remission. Sequential MRD study was performed by cytofluorometry and quantitative RT-PCR. Up to July 2004, 19 pts (10 males, mean [SD] age 43[12] yr., range 17–62, p190bcr-abl in 75% of the cases) were included. One pt is still on treatment, 1 died in induction because of infection, 1 was refractory and the remaining 16 (89%) attained CR. Slow bone marrow response was observed in 4 out of 14 evaluable pts. Three patients have relapsed before SCT, 8 are on consolidation therapy and SCT was performed in 5 (3 from family donor and 2 MUD). 1 pt died after SCT and no relapses after SCT have been observed to date (range 1–6 months from SCT). With a median follow-up of 5 (0.2–14) mo., 3 pts have died, 2 are alive in second CR and 13 are in first CR, with a median DFS of 8 mo. and an OS probability of 66±30%. Levels of BCR-ABL/GUS x100 less than 0.05 were observed in 6/12 (50%) pts at the end of induction therapy. There was a further 1–2 log median reduction of BCR/ABL transcripts at the end of C1, (BCR-ABL/GUS x100 less than 0.05 in 5/6 cases). No additional reduction of transcripts was observed between C1 and SCT. A good correlation between molecular and cytofluorometric MRD data was observed. Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL pts is feasible and the preliminary data are promising in terms of high rate of clinical and molecular CR. Continued accrual and longer follow-up of the current cohort is needed.
Effective Treatment of Elderly Acute Myeloid Leukaemia (AML) with Continuous Combined Granulocyte Colony Stimulating Factor (G-CSF) and Single Oral Chemotherapeutic Agents.
Authors: Curnow Jennifer L. , Piccolo Francesco , Ward Christopher M. , Coyle Luke , Fay Keith , Mackinlay Naomi , Ramanathan Sundra , Arthur Christopher 
Published: April 2020

Abstract
Advanced age is a poor prognostic factor in acute myeloid leukaemia (AML). There is evidence that continuous low-dose chemotherapy with oral agents can achieve partial remission in AML and may be suitable as palliative therapy in elderly patients. Such low-dose treatment is usually complicated by drug-related neutropenia and thrombocytopenia. Granulocyte colony stimulating factor (G-CSF) may lessen the associated neutropenia and some anecdotal reports suggest G-CSF alone may be able to induce remission in AML. The study aim was to assess the benefits of combining an oral chemotherapeutic agent with continuous G-CSF. We describe a retrospective audit of 12 elderly patients with AML, diagnosed between 2000 and 2002, who were deemed to be either unfit for induction chemotherapy or who had failed to respond to intravenous chemotherapy. Patients were treated with continuous oral mercaptopurine, thioguanine, or hydroxyurea with concomitant G-CSF on three to seven days/week. The median age at diagnosis was 80 years (range 70–89 years). Eight (67%) had a preceding myelodysplastic syndrome. Eleven of the twelve patients died within the study period described, with a median survival of 9 months (95%CI 4.32–13.75). Eleven patients (92%) had a response to treatment, with blast disappearance obtained within 14 days of starting treatment. All patients achieved an increase in neutrophil count &gt;0.5x109/L. Neutrophil recovery was attained within a mean of 13 days of treatment. From the onset of treatment, patients had neutrophils greater than 0.5 x109/L for 71% of the time, despite being on continuous cytotoxic treatment. Five patients (42%) had a platelet response with a rise in count above 100x109/L. A total of nine (75%) patients experienced a period of platelet transfusion independence and four (33%) patients became red cell transfusion independent for a mean of 4.6 and 4.8 months respectively. The analysis of this small cohort suggests that G-CSF administered in combination with one of the above oral chemotherapeutic agents, may be a novel way of providing treatment to elderly patients with AML which is both tolerable and of potential survival benefit.
Comparison of FDG-PET and Ga-67 Scintigraphy in the Evaluation of Lymphoma and Its Relationship to the Pathologic Diagnosis Using WHO Classification System.
Authors: Tsukamoto Norifumi , Hideki Uchiumi , Matsushima Takafumi , Karasawa Masamitsu , Murakami Hirokazu , Kojima Masaru , Nojima Yoshihisa 
Published: April 2020

Abstract
In the management of lymphoma patients, 18fluoro-2-deoxyglucose positron emission tomography (FDG-PET) has emerged as an important tool. However there are conflicting results that have been reported concerning its usefulness in different histological subtypes, especially in indolent lymphomas. The aim of this study was to retrospectively assess and compare the sensitivity of FDG-PET with gallium-67 citrate scintigraphy (Ga-67) with regard to the capacity for identification of disease involvement in patients with malignant lymphoma, and to investigate the relationship with the World Health Organization’s (WHO) classification system for pathological diagnosis of such cases.
We contemporaneously performed 100 cases of FDG-PET and Ga-67 in addition to CT scans and/or MRIs prior to the treatment. Histological diagnoses included diffuse large B-cell lymphoma (DLBCL; n=38), MALT lymphoma (MALT; n=29), follicular lymphoma (FL; n=14), Hodgkin lymphoma (HL; n=8), NK lymphoma (NK; n=2), mantle cell lymphoma (MCL; n=2), Burkitt lymphoma (Burkitt; n=2), splenic marginal zone lymphoma (SMZL; n=2), and one case each with anaplastic large cell lymphoma (ALCL), peripheral T cell lymphoma (PTCL) and small lymphocytic lymphoma (SLL).
In the 100 lymphoma cases, FDG-PET was unable to detect at least one of the disease involvement sites for 2/38 in DLBCL, 3/14 in FL, 1/8 in HD, 11/29 in MALT, 2/2 in SMZL, and 1/1 in SLL. FDG-PET detected more involvement sites than Ga-67 with 11/38 in DLBCL, 6/14 in FL, 4/8 in HL, 7/29 in MALT, 2/2 in MCL, and 1/2 in NK. In contrast, Ga-67 was more informative in two cases of MALT and in one case of SMZL, in which the regions included the eyelid, pleura and spleen.
During the lymphoma imaging that was done before therapy, FDG-PET was highly sensitive in aggressive and high-grade lymphoma patients as compared to seen for Ga-67. In contrast, FDG-PET seemed to be more informative in FL with regard to indolent lymphomas, but was especially less reliable in MALT and SMZL. Anatomical imaging from CT scans and MRIs were useful in that they provided additional helpful information for the FDG-PET results in the lymphoma subgroups.
Result of FDG-PET and Ga scintigraphy
CT positive CT positive Histology No. of cases PET negative Ga negative ALCL 1 0 0 Burkitt 2 0 1 DLBCL 38 2 13 FL 14 3 8 HL 8 1 5 MALT 29 11 14 MCL 2 0 2 NK 2 0 1 peripheral T 1 0 0 SLL 1 1 1 SMZL 2 2 1
Prognostic Value of ZAP-70 Expression Detected by Immunohistochemistry on Bone Marrow Biopsies in Early Phase Chronic Lymphocytic Leukaemia.
Authors: Ambrosetti Achille , Zanotti Roberta , Chilosi Marco , Zanetti Flavia , Lestani Maurizio , Pattaro Cristian , Remo Andrea , Perbellini Omar , Pizzolo Giovanni 
Published: April 2020

Abstract
New biological prognostic factors have been developed over the last years with the aim of predicting at presentation the heterogeneous clinical course of B chronic lymphocytic leukaemia (B-CLL) and of planning a risk-adapted treatment strategy. Among them ZAP-70 expression on leukemic cells as evaluated by molecular analysis or flow cytometry, initially proposed as surrogate of IgVH mutational status, appears a strong prognostic marker in B-CLL. However the optimal methodological approach to immunophenotipical demonstration of ZAP-70 expression as still matter of debate. We evaluated the cytoplasmic expression of ZAP-70 protein in leukemic cells by immunohistochemical method on bone marrow trephine biopsies taken at diagnosis of 84 patients with B-CLL. We used a mouse anti-human monoclonal antibody to ZAP-70 (clone 2F3.2, 1/200, Upstate, Lake Placid NY) with a polymeric labelling two-step method (Dako cytomation EnVision+, HRP). The results were correlated with age, sex, Binet stage, pattern of bone marrow infiltration, survival and clinical outcome. They were 54 males (64%), aged 34 to 80 years (median 62.5). At presentation 69 (82%) were Binet stage A, 9 (11%) stage B and 6 (7%) stage C. Among the 60 survivors, the median follow-up period from diagnosis was 78.5 months (range 22 – 236 months) Thirty-nine cases (46%) of B-CLL patients had cytoplasmic expression of ZAP-70. This group of patients presented higher percentage of advanced Binet stage (B–C) (p= 0.001). The ZAP-70 positivity was significantly related to inferior OS (55% vs 90% at 7 years)(HR 4.67 CI 1.95–11.14) and PFS (15% vs 57% at 7 years) (HR 5.52 CI 2.57–11.86), confirmed in multivariate analysis. ZAP-70 expression was correlated to poorer outcome also when we evaluated only the 69 stage A patients and the 56 cases with non-diffuse bone marrow infiltration, whereas in patients with diffuse pattern ZAP-70 expression had no prognostic significance. In conclusion, immunohistological detection of ZAP-70 on bone marrow samples at diagnosis appears a useful methodological approach to identify patients with different prognosis in B-CLL.