bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Anti-Proliferation of Resveratrol on Human Hematopoietic Progenitor Cells and Leukemic Cells.
Authors: Tsang Kam Sze Kent , Li Karen , Tang Sheung Hang , Wong Angela Pui Yan , Leung Yonna , Ling Margaret Heung 
Published: April 2020

Abstract
Resveratrol is present naturally in a variety of fruits and medicinal plants. It imparts protective benefits to plants against pathogenic attack and environmental stress. In human, it was noted to be able to protect against cardiovascular disease and inhibit platelet aggregation. Its anti-oxidant activities were also suggestive in human cancer chemoprevention and chemotherapy. In this in-vitro study we investigated the anti-proliferative effect of resveratrol on human normal hematopoietic progenitor cells and leukemic cells. Resveratrol of 1 mM to 0.1 μM at 10-fold dilutions were applied to hematopoietic progenitor cultures. Duplicates of 5 x 104 mononuclear cells (n=7) and 5 x 103 CD34+ cells (n=3) derived from 10 umbilical cord blood (UCB) samples were cultured for two weeks in methylcellulose enriched with 100 ng/mL granulocyte-macrophage colony-stimulating factor, 20 ng/mL stem cell factor, 2 IU/mL erythropoietin and various concentration of resveratrol. There was no growth of colony-forming unit (CFU) in cultures supplemented with high-dose resveratrol (10 UCB: 100% in 1 mM, 90% in 100 μM and 10% in 10 μM), exhibiting an inhibitory effect on the proliferation of hematopoietic stem and progenitor cells in a dose-dependent manner. The numbers of CFU-GEMM, CFU-GM and BFU derived from cultures with 10 μM, 1 μM and 0.1 μM resveratrol demonstrated no significant difference as compared to that of control cultures without resveratrol. Ten μM resveratrol were added to 12 human leukemic cell lines (AML: KG-1a, Kasumi-1, HL60, NB4, Meg-01, CHRF 288-11; CML: K562; B-lineage ALL: 697, RS-411, REH; T-lineage ALL: Molt-3, CCRF-CEM) at 5 x 105/mL and cultured for four days in triplicate. Cell counts, trypan blue dye exclusion tests and flow cytometry were conducted daily on cultures to evaluate growth, viability and cell cycle phase distribution, respectively. There was a significant and progressive decrease in the numbers of viable cells in resveratrol-supplemented cultures (median [range]: 26.1% [14.3% – 50.3%] at 24 hours, 43.1% [18.2% – 54.6%] at 48 hours, 45.6% [9.3% – 67.6%] at 72 hours and 32.5% [15.7% – 55.3%] at 96 hours). Cell cycle analysis revealed a remarkably elevated proportion of apoptotic cells at pre-G1 phase in resveratrol-supplemented cultures on day one (with vs. without: 15.9% [2.0% – 41.2%] vs. 7.8% [2.4% – 17.6%]; p=0.011). Besides, a growth arrest of CHRF 288-11 (51.6% vs. 39.8%; p=0.032) and Molt-3 (70.2% vs. 54.2%; p=0.002) was noted in G1 phase, whereas an accumulation of KG-1a (25.8% vs. 19.6%; p=0.019) and CCRF-CEM (26.2% vs. 23.2%; p=0.026) in S phase was observed. Data of this study suggest that 10 μM resveratrol may exert an anti-proliferative effect against human leukemic cells but pose no apparent suppression to normal hematopoiesis.
Functional Analysis of a Cation Transporter OCT6: A Mediator of the Cellular Influx of Adriamycin.
Authors: Okitsu Yoko , Harigae Hideo , Takahashi Shinichiro , Abe Shori , Okabe Mitsunori , Unno Michiaki , Abe Takaaki , Kaku Mitsuo , Sasaki Takeshi 
Published: April 2020

Abstract
(Introduction) It is necessary for killing leukemic cells effectively to achieve a sufficient intracellular concentration of anti-cancer drugs. To date, overexpression of efflux pump such as MDR-1 and MRP-1, which leads to a decrease of cellular concentration of drugs, has been shown to attenuate the therapeutic effect of anti-cancer drugs and correlate with low remission rate in acute leukemia. If the expression of genes, which import anti-cancer drugs, can be induced specifically in leukemic cells, it would lead to an increase of intracellular concentration, resulting in an enhancement of the pharmacological effect. In this study, we performed the pharmacological characterization of a cation transporter gene, OCT6, and explore the possibility of its application for anti-cancer therapy.
(Methods) Tissue distribution of OCT6 was examined by Northern blot analysis. Expression in clinical samples that consist of 34 patients; 15 patients with acute lymphoblastic leukemia (ALL), 17 patients with acute myelogenous leukemia (AML), 2 patients with chronic myelogenous leukemia (CML) in blastic crisis, was examined by quantitative RT-PCR. The percentage of blasts in each sample was above 80%. For functional analysis, OCT6 cRNA was injected into Xenopus oocytes and pharmacological analysis was performed. In order to examine the transporting activity in hematopoietic cells, we established subclones of Jurkat, a T lymphocytic leukemia cell line, in which OCT6 gene is constitutively expressed, and the change of the sensitivity for adriamycin was examined.
(Result) By Northernblot analysis, 2.4kb OCT6 mRNA was detected in testis and bone marrow in adult tissues. OCT6 expressed in Xenopus oocytes transported not only tetraethlammonium but also adriamycin in a saturable and dose-dependent manner. The apparent Km value for [14C] adriamycin was 5.2±0.4μM. On the other hand, OCT6 did not transport either of methotrexate (MTX) and 5-fluorouracil (5-FU), which are not organic cations. After the exposure of adrimycin at the therapeutic concentration, the viability of OCT6 overexpressing Jurkat cells was significantly decreased compared to that of control cells. Consistent with this, the percentage of apoptosis cells became higher than that of control cells. When the expression level was examined in clinical samples, the average of the levels of patients was comparable to PBMCs. The level of patients, who achieved with complete remission (CR), was slightly higher than that of patients with non-response (NR), but the difference was not significant. Some patients exhibited the high expression of OCT6, but the distribution did not deviated to either CR or NR group.
(Conclusion) These results suggest that the induction of OCT6 in leukemic cells might be a novel strategy for leukemia treatment.
Cotreatment with Pioglitazone, a Synthetic Ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ), Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis of Human Leukemia Cells.
Authors: Park Joo-In , Han Hoon , Han Ji-Seon , Kwon Hyuk-Chan , Han Jin-Yeong , Jeong Jin-Sook , Bae Yoe-Sik , Kwak Jong-Young 
Published: April 2020

Abstract
Imatinib (STI571, Glivec) is the choice treatment for Bcr/Abl-positive malignancies. Emergence of resistance to Imatinib warrants the exploration of novel well-tolerated anticancer agents. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor family, which mainly associates with the adipocyte differentiation, but also appears to facilitate cell differentiation or apoptosis in certain malignant cells. Previous studies imply that the PPARγ activation pathway may be a possible intervention mode for treatment of leukemia, which is resistant to imatinib (STI571). In this study, we investigated the effects of pioglitazone, a synthetic ligand for PPARg, on the cell growth and TRAIL-induced apoptosis in a novel imatinib (STI571) resistant acute myeloid cell line (SR-1), which we have established from an STI571 resistant blast crisis patient, as well as HL-60 cells. HL-60 and SR-1 cells are relatively resistant to TRAIL-induced apoptosis. Pioglitazone alone inhibited the cell growth of SR-1 and HL-60 cells, but did not induce the apoptosis of these cell lines. However, simultaneous exposure of cells to 100 ng/ml TRAIL with either 25 μM pioglitazone or 50 μM piogliazone resulted in a striking increase in apoptosis. To clarify the mechanism of pioglitazone to sensitize the leukemia cells to TRAIL-induced apoptosis, we investigated the change of the proteins related to cell cycle and apoptosis by western blot. As results, we observed the significant decrease of X-linked inhibitor of apoptosis (XIAP) and the increased expression of p21 by cotreatment of pioglitazone with TRAIL. Taken together, these findings indicate that pioglitazone may have promising activity in augmenting TRAIL-induced apoptosis of human acute leukemia cells including the imatinib (STI571) resistant acute myeloid cell line.
Cytotoxic Chemotherapy-Induced Changes in Plasma Mannan-Binding Lectin in Patients with Cancers.
Authors: Turp Claire , Joyce Hilary , Sivakumaran Muttuswamy 
Published: April 2020

Abstract
Mannan-binding lectin (MBL) plays an important role in the innate immune responses in primates. The immune function of MBL is mediated by its ability to function as an opsonin and to activate complement through lectin pathway. Recently, there has been an interest in investigating the role of plasma MBL in patients undergoing chemotherapy for leukaemia. Reports indicate that low plasma MBL levels predispose to more severe and frequent infections. There is, however, no clear published data regarding the potential effect of cytotoxic drugs on plasma MBL levels in the absence of any overt sepsis. We conducted a study to obtain this information by carrying out serial measurements of plasma MBL levels during chemotherapy. In addition, we made serial assays of salivary MBL levels to ascertain whether changes in salivary content of this lectin during chemotherapy predispose to mucositis. Ten patients with various non-haematogenous malignancies receiving 3 weekly 5-fluouracil treatment were studied. Blood and saliva samples were collected prior to starting chemotherapy (baseline) and then before subsequent cycles of treatment. ‘Normal range’ of plasma MBL was established by measuring 50 plasma samples obtained from healthy blood donors. Plasma MBL was measured by an ELISA technique using mouse monoclonal antibody IgG1 anti MBL. Salivary MBL level was measured by a modified technique using the same antibody. The results show that there is a marked variation in the plasma MBL levels in healthy individuals (11ng/ml- 9189ng/ml, with a mean of 3057ng/ml). Similarly, the plasma MBL levels of the patient cohort also showed marked variation (10ng/ml- 10896ng/ml with a mean of 3243ng/ml). However, within an individual patient the plasma MBL level rose markedly following first course of chemotherapy. The mean post-first dose rise was 59.2%. Nine out of ten patients exhibited this phenomenon. Interestingly, however, the changes in plasma MBL levels with subsequent treatments were more varied ie in some patients (3/10) the levels continued to rise while in others the levels decreased. Salivary MBL levels in all patients were below detection limit suggesting that polymeric MBL is not present in significant quantities in saliva. Based on the findings of this study we conclude that cytotoxic drugs such as 5-FU may cause significant changes in plasma MBL levels and, therefore, caution should be exercised in interpreting individual measurements following chemotherapy when making any correlation between post chemotherapy plasma MBL levels and infection risk.
Col-6, a Compound Found in Edible Plants, Induces Apoptosis of Human Leukemia Cells and Down-Regulate Bcl-2 Expression.
Authors: Ma Xudong , Beklemisheva A. , Liu Delong , Chiao J.W. 
Published: April 2020

Abstract
Col-6 is a compound found in certain edible plants. Col-6 has been synthesized, and structurely-characterized. This study investigated its effects on the growth of human promyelocytic leukemic cell line, HL-60.
Exposure of HL-60 cells to Col-6 at high concentrations (≥40 μM) resulted in cytolysis in 90% cells within 72 hours. At lower concentrations (&lt;20 μM) the cell density and viability were reduced as compared to untreated cells. A 30% reduction in cell growth rate was seen at 10 μM within 48 hours. A reduction of the proliferating cells in S and G2M phases along with an increase of G1 were detected, indicating a G1 arrest. Multiple assays were used to characterize apoptosis, including DNA strand breaks by TUNEL assay, and the presence of sub-G1 peak by flow cytometry. Col-6 induced apoptosis of HL-60 cells regularly at a concentration as low as 0.1 μM. The degree of apoptosis was proportional to the concentrations and the length of exposure. Mononuclear cells isolated from normal peripheral blood (PBMC) and bone marrow (BMMC) were similarly exposed to Col-6. At a concentration as high as 40 μM, Col-6 did not cause apoptosis of PBMC nor BMMC, suggesting that Col-6 does not have the apoptotic effects on normal non-dividing cells. Apoptosis was further correlated with the increase of caspase 9, and the cleavage of PARP (substrate of caspases), as defined by Western blot analyses. The expression of bcl-2 was markedly decreased in the treated cells.
Conclusion: Col-6, a compound found in edible plants, induced apoptosis of HL-60 cells and down-regulation of bcl-2. Col-6 may be a potential novel anti-leukemia agent. Further in vivo study is indicated.
Decreased Expression of CCAAT/enhancer Binding Protein ζ (C/EBPζ) in Patients with Different Myeloid Diseases.
Authors: Qian Jun , Chen Zi-xing , Lin Jiang , Wang Wei , Cen Jian-nong 
Published: April 2020

Abstract
CCAAT/enhancer binding proteins (C/EBPs) are a family of transcription factors that have been implicated in diverse cellular functions such as cellular differentiation and proliferation, and inflammatory processes. C/EBPζ, also known as GADD153, CHOP10, DDIT3, has been found associated with the development of myxoid liposarcoma and with the progression of melanoma. Based on the results of gene expression profiling on MDS patients in our laboratory, the down-regulated C/EBPζ (DDIT3) gene was selected to be one of the “candidate genes” with most remarkable differential expression pattern in MDS patients in comparison with the normal control. To further investigate the correlation of C/EBPζ transcript levels with the development of leukaemia, samples from 187 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myeloid leukaemia (CML) were detected for C/EBPζ mRNA using real-time quantitative PCR (RQ-PCR). RQ-PCR analysis demonstrated that the median levels of C/EBPζ were significantly decreased in MDS, AML, and CML patients compared to normal controls (1.40, 0.96, 2.60 versus 12.20, P&lt;0.0001). Significant differences were also observed between patients with CML and with AML or MDS. These results suggest that the insufficient dosage of C/EBPζ might be involved in the development of acute leukemia.
Autologous Tumor Combined with a GM-CSF-Secreting Cell Line Vaccine (GVAX®) Following Autologous Stem Cell Transplant (ASCT) in Multiple Myeloma.
Authors: Borrello Ivan , Biedrzycki Barbara , Sheets Nicole , George Beena , Racke Frederick , Loper Kathy , Noonan Kimberly , Donnelly Amy , Hege Kristen , Levitski Hyam 
Published: April 2020

Abstract
Background: Preclinical models have demonstrated enhanced cancer vaccine efficacy when administered early following ASCT and accompanied by vaccine-primed lymphocyte infusion.
Methods: Patients with untreated myeloma were enrolled and underwent a bone marrow harvest to obtain tumor cells for vaccine processing. Patients eligible for ASCT following induction chemotherapy received a pre-transplant vaccination followed by leukapheresis to collect “primed” lymphocytes that were reinfused with the stem cell graft. Eight post-transplant vaccinations were administered at 3-week intervals starting 6 weeks posttransplant. The vaccine formulation consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting K562 cells (CG9962) at a ratio of 5:2, respectively. Three dose levels were assigned (1, 4, and 10 x107 tumor cells/vaccination) based on tumor cell yield from the bone marrow harvest.
Results: 22 patients underwent tumor harvest, 18 completed induction chemotherapy, and 16 proceeded to vaccination (1 at 1 x 107,4 at 4x107, and 13 at 10x107) and ASCT. At baseline, the median b2 microglobulin was 4 (2–14) and 35% had an IgA subtype. No grade 3/4 vaccine-related toxicities were observed. Median time to neutrophil engraftment (&gt;500) and platelet engraftment (&gt;50K) was 10 days. Local vaccine injection site reactions were observed in all patients. Delayed-type hypersensitivity (DTH) reactions to injections of irradiated autologous tumor cells were induced in only 1/15 patients after 4 post-transplant vaccines, but 4/10 were positive at one year post transplant. Induction of autologous tumor-reactive antibodies as well as antibodies reactive against CG9962 cells was observed. In vitro studies have demonstrated the induction and adoptive transfer of tumor-specific cellular immune responses that can be followed throughout the post-transplant period. Reproducible serum GM-CSF levels were achieved with repeated vaccinations suggesting no increased clearance of CG9962 cells due to induction of an allogeneic immune response. Of the 16 patients that have completed the ASCT, there were 6 complete and 5 partial remissions, for an overall response rate of 69%. Three patients with rising paraprotein levels early post-transplant have demonstrated paraprotein declines following initiation of post-transplant vaccines, suggesting a possible vaccine-mediated effect.
Conclusions: These data demonstrate the feasibility of this vaccine approach and show the therapeutic potential of K562 GVAX® vaccination in the ASCT setting in multiple myeloma.
Imatinib Mesylate for Refractory Acute Myeloblastic Leukemia Harboring inv(16) and C-KIT Exon 8 Mutation.
Authors: Matsuno Naofumi , Nanri Tomoko , Kawakita Toshiro , Mitsuya Hiroaki , Asou Norio 
Published: April 2020

Abstract
While approximately 50% of acute myeloblastic leukemia (AML) patients carrying favorable karyotypes show long-term survival, treatment outcome is not universally favorable in such patients. Recently, mutations in the C-KIT and FLT3 genes were frequently found in patients with inv(16) AML. Of 15 patients we examined, 2 had the FLT3-D835 mutations, 1 had a mutation in the second tyrosine kinase domain, 1 in the juxtamembrane domain, and 1 in the exon 8 of the C-KIT gene. These mutations are potential therapeutic targets for specific tyrosine kinase inhibitors. In this study, we present a case of inv(16) AML harboring C-KIT exon 8 mutation that was successfully treated with imatinib mesylate. After treatment with low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG) plus vincristine and prednisone (VP), a 58-year-old man with AML M4Eo showed second relapse with left inguinal lymph nodes involvement. The patient was treated with high-dose cytarabine and mitoxantrone only unsuccessfully. However, the following treatment with 400 mg of imatinib mesylate for 2 weeks in combination with CAG plus VP brought about complete hematological remission. This treatment was well tolerated, and no severe adverse events occurred. This observation suggests that imatinib mesylate can be an alternative treatment modality for AML with the mutation in exon 8 of the C-KIT gene, although further studies are required to confirm the efficacy of this approach for refractory AML.
Prognostic Value of Early Treatment Response in Children with Acute Lymphoblastic Leukemia: A Single Institution Experience in Shanghai, China.
Authors: Tie Li-Jun , Gu Long-Jun , Song De-Lian , Jiang Li-Ming , Xue Hui-Liang , Tang JingYan , Dong Lu , Pan Ci , Chen Jing , Wang Yao-Ping , Chen Jing 
Published: April 2020

Abstract
Early response to therapy is one of the most important prognostic factors in childhood ALL. In the early 1980s, assessment of early treatment response to therapy relied mainly on morphological examination of peripheral blood or bone marrow after single-agent or multi-agent remission induction therapy. More recently, measurement of minimal residual disease (MRD) by flow cytometric detection of aberrant immunophenotype or by polymerase chain reaction of clonal T-cell receptor or immunoglobulin gene rearrangement emerged as a more reliable prognostic indicator. We evaluated the prognostic significance of early treatment response in our recent clinical trial. Among the children with ALL who entered protocol of ALL-XH-99 from January 1998 to May 2003, 193 patients with newly diagnosed ALL comprise the basis for this report. We examined blast cell count in the bone marrow on day 19 of remission induction and at the end of 35 days of remission induction. Minimal residual disease was measured with the use of flow cytometry. Probability of event-free survival was estimated by Kaplan-Meier analysis and the distributions of pEFS were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors. Univariate analysis indicated the probability of 4-year event-free survival (pEFS) was significantly worse for patients with ≥ 5% lymphoblasts in the bone marrow on day 19 as compared to those with less than 5% lymphoblasts on that date (42.59%±14.28% vs 74.24%±6.67%, P=0.0006). The probability of 4-year event-free survival (pEFS) was significantly worse for patients with any amount of lymphoblasts in the bone marrow on the remission date as compared to that of other patients with no morphologically identifiable blasts (63.47%±9.23% vs 76.41%±6.09%, P=0.0130). Patients who achieved a minimal residual level &lt; 0.01%, fared significantly better than those with a higher level. (23.81%±20.26% vs 94.44%±5.4%, P=0.001). Early treatment response as assessed by morphologic examination or minimal residual leukemia determination by flow cytometry has important prognostic significance, and can be performed in a resource-poor patient population.