bluuebunny/crossref_metadata_2025_split huggingface dataset:
Placenta Derived Adherent Cells Modulate the Allogenic Mixed Lymphocyte Reaction Partially via an Indoleamine 2,3-Dioxygenase Mediated Mechanism.
Authors: Liang Bitao , Paludan Casper , Downey Matthew , Lewis Craig , Harbacheuski Ryhor , Rana Hemlata , Lugo Chris , Lu Xiaohua , Lakatos Tara , Wu Wei , Edinger James 
Published: October 2019

Abstract
Placenta Derived Adherent Cells (PDAC) are multipotent progenitor cells derived from human placental tissues. Previously we have reported that PDACs could suppress T-cell proliferation when added to in-vitro mixed lymphocyte reactions (PDAC-MLR) (Paludan C. et al, Blood. (ASH Annual Meeting Abstracts) 2006 108: Abstract 1737). Here we present aspects of the mechanism of this PDAC suppression property. We have found that PDACs modify cytokine production in the PDAC-MLR reaction in comparison to the MLR; TNF-α and IFN-γ are reduced 75% and 30% while TGF-β production is significantly increased. We have used a transwell assay system to investigate the cell-contact-dependency of the effects of PDACs on T-cell proliferation. The assay system comprised combinations of the MLR in the top chamber together with the PDAC-MLR, PDACs plus naive T cells or PDACs alone in the bottom chamber. Maximum inhibition of T cell proliferation of the MLR in the top insert could be achieved by placing the PDAC-MLR co-culture in the bottom chamber. Minimum suppression was obtained when placing PDACs plus naive T cells or PDACs alone in the bottom chamber. PDAC-MLR conditioned media could partially suppress the MLR reaction. Addition of L-tryptophan into the MLR with PDAC conditioned media completely abolished PDAC-induced suppression of T cell proliferation. Likewise, the addition of the 1-methyl tryptophan to the PDAC-MLR reaction could abolish the PDAC-induced suppression. These results suggested that the suppression of the MLR by PDACs was possibly due to the depletion of the essential amino acid L-tryptophan which could be due to up-regulation of indoleamine 2,3-dioxygenase (IDO). Quantitative RT-PCR analysis of IDO gene expression revealed that IDO was up-regulated by about 4000-fold when PDACs were co-cultured with activated T cells, but not when co-cultured with naive T cells. Experiments are ongoing to confirm the causative role of IDO, and other factors, in PDAC-suppression of T-cell proliferation. In summary, we believe that soluble factors including the production of pro-inflammatory cytokines may contribute to PDAC suppression of the MLR, that induction of soluble factors from PDACs is significantly augmented by T-cell activation and that IDO expression by PDACs during the PDAC-MLR reaction plays a significant and direct role in suppression of T cell proliferation by PDACs.
Der(20)idic(20)(p11)del(20)(q11q13) Is Seen Not Only in Myeloid Disorders but Also in Lymphoid Disorders: A Report of Further Seven Cases.
Authors: Li Tianyu , Xue Yongquan , Zhang Jun , Chen Suning , Pan Jinlan , Wu Yafang 
Published: October 2019

Abstract
As a newly identified cytogenetic abnormality, idic(20q−) has been reported in thirteen cases of myelodysplastic syndrome (MDS), one case of chronic myelomonocytic leukemia, and one case of acute myeloid leukemia (AML) since 2004. Here we report additional seven cases consisting of 3 MDS, 2 AML and 2 acute lymphocytic leukemia (ALL). A karyotype analysis using R-banding technique revealed an i(20q−) as a sole anomaly in 5 of them and as a secondary change in other 2 cases: one was a B-cell ALL whose leukemic cells at presentation had a karyotype of 45, XY, dic(9;20)(p11;q11). However, an idic(20q−) was found coexistent with the dic(9;20) as relapse; another was a Ph positive ALL whose leukemic cells simultaneously contained t(9;22)(q34;q11) and idic(20q−). A series of FISH using multiple probes such as the centromeric probes specific for chromosomes 9 and 20, the subtelomeric probe for 20q, the locus-specific probe for 20q12, the whole chromosome paint probes for chromosomes 9 and 22 and the translocation probe for t(9;22) demonstrated the idic(20q−) to be actually a der(20)idic(20)(p11)del(20)(q11q13), confirmed the dic(9;20)(p11;q11) in case 6 and revealed a BCR/ABL fusion gene in case 7. Among them, 2 MDS patients survived and anemic except one lost to follow-up, 2 AML and 2 ALL patients did not obtain complete remission and died with short survivals. Our study brings the total number of cases with idic(20q−) to 22 and suggests that the disease spectrum of idic(20q−) is not restricted to myeloid disorders, and it also includes ALL.
MicroRNA Profiling of EVI1 Deregulated Myeloid Leukemia.
Authors: De Weer An , Poppe Bruce , Mestdagh Pieter , Van Roy Nadine , De Paepe Anne , Verhasselt Bruno , Vandesompele Jo , Speleman Frank 
Published: October 2019

Abstract
Chromosomal rearrangements involving the EVI1 gene are a recurrent finding in malignant myeloid disorders. These translocations or inversions contribute to ectopic expression of, or to the formation of fusion genes involving the EVI1 gene. EVI1 transcriptional activation has been reported in up to 10% of acute myeloid leukemia (AML) patients, and is a diagnostic marker which predicts a poor outcome. Recently, microRNA deregulation was identified as a major contributor to cancer initiation and progression. Moreover, miRNA genes were shown to be directly regulated by activated proto-oncogenes. In this study, we investigated which miRNA genes are implicated in the transcriptional pathways governed by the EVI1 oncogene. A total of 384 miRNAs were profiled through automated qRT-PCR using high-throughput quantitative stem-loop RT-PCR (Applied Biosystems). In a first step, differential miRNA expression was determined in 5 EVI1 rearranged/EVI1 overexpressing samples, 5 non-rearranged/EVI1 overexpressing samples and 5 non-rearranged/non-EVI1 overexpressing bone marrow samples. Next, up and down regulated miRNAs were analyzed in the leukemic EVI1 overexpressing cell lines Kasumi-3 and UCSD-AML1 following transient EVI1 RNAi knockdown. We will present the detailed results of these profiling studies as well as the results of data mining for identification of putative EVI1 regulated miRNAs. Further functional studies will be performed in order to select validated miRNA target genes and to asses their contribution to the leukemic phenotype. We anticipate that the discovery of such miRNAs may provide new targets for therapeutic intervention.
ΔNp73 /TAp73 Expression Ratio Is Associated with Ara-C-Induced Apoptosis Resistance in Acute Myeloid Leukemia.
Authors: Araújo Antonio Roberto L. , Panepucci Rodrigo A. , Jacomo Rafael H. , Souza Guilherme A. , Araújo Amélia G. , Lima Ana Silvia G. , Garcia Aglair B. , Falcao Roberto P. , Rego Eduardo M. 
Published: October 2019

Abstract
The p73, a homologue to the tumor suppressor gene p53, is involved in oncogenesis, although its specific role remains unclear. This gene has two distinct promoters which encode for two protein isoforms with opposite transcriptional activities: full-length TAp73 and the ΔNp73, the latter differing by the lack of the N-terminal transactivating domain and, has a dominant-negative function towards p53 and TAp73 activity. In the present study, we have investigated, by Real Time PCR, the gene expression pattern of TAp73 and ΔNp73 in 147 samples from patients with de novo AML and 22 samples of CD34+ hematopoietic progenitor cells isolated from bone marrow of healthy donors. We detected a significantly higher expression of TAp73 and ΔNp73 genes in AML samples compared to normal hematopoietic progenitors. AML samples harboring the chromosomal translocations: PML-RARa, AML1-ETO and CBFβ-MYH11 presented significantly higher levels of the TAp73 than those negative for these rearrangements. In contrast, samples without these gene rearrangements expressed higher levels of the truncated form ΔNp73. No difference was observed among patients with PML-RARa, AML1-ETO and CBFβ-MYH11. In order to determine if the ratio between the relative expression of TAp73 and ΔNp73 genes was associated with differential susceptibility to pro-apoptotic stimuli, we performed an in vitro cytotoxicity assay using Ara-C. Blasts from 20 AML patients were incubated for 24 hours in a medium containing 100μg-ml of Ara-C and evaluated for apoptosis status using Anexin V and Propidium Iodite. The leukemic cells with a higher ΔNp73 / TAp73 ratio were significantly more apoptosis-resistant (Pearson’s R2: −0.607). We also assessed the protein expression by flow cytometry using saturating amounts of specific antibodies for each isoform and analyzing the mean fluorescence channel. Estimated protein expression corroborated the gene expression results. Our results suggest an association between the presence of PML-RARα, AML1-ETO or CBFβ-MYH11 chromosomal translocation and a higher TAp73 gene expression compared to ΔNp73 isoforms expression in AML samples. Moreover, the higher resistence to apoptosis detected in blasts with higher ΔNp73 / TAp73 values suggest that this pathway may contribute to prognosis.
Significant Activity of Dasatinib in CLL Demonstrated by Ex-Vivo Assay.
Authors: Sigal Darren S. , Nieva Jorge , Diver Jonathan , Romeo Elisa , Lee Francis , Saven Alan 
Published: October 2019

Abstract
Introduction: Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by the accumulation of mature monoclonal B-lymphocytes. Combination therapies produce high response rates, including complete responses, but all patients will eventually relapse. Novel therapies are needed. Ex-vivo chemosensitivity assays offer two distinct advantages for identifying new CLL therapies. First, agents can be screened without exposing patients to unnecessary risk. Second, no CLL clonogenic cell lines exist, requiring that patient samples be analyzed in an ex-vivo manner. Dasatinib is a potent inhibitor of Src, Abl, and several other tyrosine kinases. B-CLL has been characterized as having anomalous signaling through Lyn kinase, a member of the Src family. We sought to determine the single agent and combination ex-vivo activity of dasatinib in CLL samples.
Methods: We used an ATP-luminescent chemosensitivity assay (ViaLight, Lonza, Basel, Switzerland) to assess the activity of single agent dasatinib (0.01 nM to 1 μM), and dasatinib (1, 10, 100 nM) in combination with fludarabine (0.06 to 64 μg/ml), chlorambucil (0.2 to 102.4 μg/ml), or methylprednisolone (0.02 to 2,000 μg/ml) in CLL patient peripheral blood samples. Patients had a diagnosis of B-CLL, WBC count greater than 20 x 109/L, no chemotherapy within 14 days, and no antibody therapy within 28 days.
Results: Five patient samples were obtained; 4 from untreated patients and 1 from a patient being treated with fludarabine. Rai stages ranged from 0 to IV. Single agent dasatinib induced apoptosis in 3 of 5 CLL samples tested. The two samples without apoptosis were from untreated patients. IC50 values were >1 (no apoptosis), >1 (no apoptosis), 0.2, 0.2, and 0.04 (fludarabine treated patient) μM. The IC50 values of single agent fludarabine were 1.3, 0.18, 1, 0.22, and 3 (fludarabine treated patient) μg/ml, respectively. The IC50 values of fludarabine in combination with 100 nM dasatinib were 0.41, <0.06, 0.45, <0.06, and <0.06 (fludarabine treated patient) μg/ml, respectively.
Conclusions: In this ex-vivo CLL model, dasatinib has significant single agent activity and may be synergistic in combination regimens. All responses were achieved with clinically attainable concentrations of dasatinib. These ATP-luminescent chemosensitivity results provide the pre-clinical rationale for clinical studies of dasatinib in patients with CLL. Currently, two single agent dasatinib phase II studies are accruing patients and plans exist for a combination dasatinib study in CLL patients next year.
The Histone Deacetylase Inhibitor, Sodium Butyrate, Augments Chlorambucil Cytotoxicity in the Promyelocytic Leukaemia Cell Line, HL-60.
Authors: Kwa Faith , Kapuscinski Miroslav , Cole-Sinclair Merrole 
Published: October 2019

Abstract
Treatment of various haematological malignancies such as chronic lymphocytic leukaemia (CLL) with alkylating drugs (e.g. chlorambucil, CLB) fails to extinguish the leukaemic clone and often results in chemo-resistance. A possible mechanism of drug resistance in CLL B cells is p53 inactivation. The resistance of cells to standard chemotherapy may be ameliorated by agents that alter the chromatin remodelling processes, DNA methylation and histone acetylation (e.g. sodium butyrate, NaBu). We used the HL-60 cell line (which carries a non-functional p53 protein) as a cell model for resistant CLL B cells and determined the sensitivity of HL-60 cells to a range of concentrations of CLB (5μM,10μM and 20μM) and NaBu (0.5mM, 1mM and 2mM) by tetrazolium salt-based proliferation assays of cells incubated with the drugs over 4 days (days 0, 1, 2 and 3). Cells were resistant to 5μM CLB until day 3 where 56% of cells were killed. 10μM and 20μM CLB had very similar effects (p>0.05) with both treatments killing 83.2% and 87.3% respectively of cells by the end of the incubation. The cell death induced by NaBu was both time- and dose-dependent, with 2mM NaBu being the most effective treatment, while 0.5mM NaBu did not result in significant cell death (p>0.05). To investigate if the treatment of HL-60 cells with both drugs would enhance or have an additive killing effect on the cells, we tested combined treatment involving a series of lower drug concentrations of each of the two drugs (5μM/10μM CLB ± 0.2mM/0.5mM/1mM). All combined treatments using 5μM CLB were more effective in cell killing than when the cells were treated singly with CLB or NaBu (p<0.001). The most effective combined treatment was 5μMCLB+0.2mM NaBu (62% cell death) compared to only 10% and 40% cell killing caused by CLB and NaBu alone, respectively. In contrast, the effect of 10μM CLB was not augmented by NaBu in concentrations ranging between 0.2mM and 1mM (p>0.05). In conclusion, combined treatment involving NaBu increased the cytotoxic effect of low concentrations of CLB in p53-inactivated cells, implying the potential benefit of chromatin modifying agents in cytotoxic therapy. Further studies including the use of a wider range of concentrations of CLB with NaBu or other chromatin modifying agents are underway to investigate possible synergism in the killing of HL-60 cells by these agents.
Suppression of Angiogenesis and Resistance to Doxorubicin by the Thyroid Hormone Tetraiodothyroacetic Acid.
Authors: Mousa Shaker A. , O’Connor Laura , Aljada Ahmad , Davis Paul , Rebbaa Abdelhadi 
Published: October 2019

Abstract
Thyroid hormone has been recently shown to induce tumor growth and angiogenesis. These angiogenesis modulating activities are initiated at endothelial cell plasma membrane receptor via the integrin αVβ3, at or near the Arg-Gly-Asp (RGD) recognition site on the integrin. In the present study, we have investigated the effect of tetraiodothyroacetic acid (tetrac), a deaminated thyroid hormone analog that inhibits thyroid hormone-binding to the cell surface integrin, on angiogenesis and cancer cell resistance to doxorubicin both in vitro and in vivo. Two angiogenesis models were studied in which vascular endothelial growth factor, VEGF165 or basic fibroblast growth factor, FGF2 (1–2 μg/ml) or thyroid hormone, thyroxin (L-T4 or T3) were used either to induce tube formation in the human dermal micro-vascular endothelial cells (HDMEC), or to stimulate new blood vessel branch formation in the chick chorioallantoic membrane (CAM) models. In both models, Tetrac (0.1–10 μM) inhibited the pro-angiogenesis activity of VEGF, FGF2, L-T4 or T3 by more than 50% at 1.0 uM RT-PCR revealed that tetrac (1–3 μM) decreased abundance of angiopoietin-2 mRNA but did not affect the mRNA levels of angiopoietin-1, in VEGF-exposed endothelial cells, suggesting that specific angiogenic pathways are targeted by this compound. Additionally, microarray was used to examine changes in expression of Matrix Metalloproteinases (MMP) and Tissue Inhibitor of Metalloproteinases (TIMP) following VEGF treatment with and without tetrac. HDMEC cells treated with VEGF exhibited 3–5-fold increase in MMP-15 and MMP-19 expression and tetrac (3μM), inhibited expression of MMP-15 and MMP-19 by 3–9-fold, respectively. Expression of TIMP-3 was increased 5.4-fold following VEGF and tetrac treatment when compared to treatment with VEGF alone. This finding suggests that part of the mechanism by which tetrac inhibits VEGF-stimulated angiogenesis involves inhibition of certain MMPs and increase in TIMP expression. Investigation of the anti-proliferative function of tetrac was carried out using the αVβ3 expressing breast cancer cells MC7 and their drug resistant counterparts. Interestingly, proliferation of both cell lines was inhibited similarly by tetrac suggesting that this analog may circumvent drug resistance. In fact, tetrac was able to reverse resistance to doxorubicin in vitro and to suppress growth of doxorubicin resistant tumors in nude mice. Inhibition of the drug transporter p-glycoprotein was found to play a key role in mediating the action of tetrac. Taken together, findings presented in this study provide evidence that the anticancer function of tetrac can be attributed to its anti-angiogenic and drug resistance reversal activities.
Novel Deuterated Gemini-Vitamin D3 Analogs Have Potent Antitumor Activity.
Authors: Okamoto Ryoko , Saito Tsuyako , Haritunians Talin , O’Kelly James , Uskokovic Milan , Koeffler H. Phillip 
Published: October 2019

Abstract
The active form of vitamin D3, 1,25(OH)2D3, is an important regulator of calcium and bone metabolism. Also, it inhibits proliferation and induces differentiation of a variety of malignant cells. Here, we synthesized a new class of vitamin D3 analogs, which have a C-20 methyl group and a deuterium substituted basic side chain [Deuterated Gemini (DG)]. Six DG analogs were evaluated for their ability to inhibit growth of myeloid leukemia (HL-60), prostate (LNCaP and PC-3), lung (H520) and breast (MCF-7) cancer cell lines. All 6 DG analogs inhibited growth in a dose-dependent manner and had very similar potency. Most effective DG, BXL-01-0120, was over 70-fold more potent than 1,25(OH)2D3 in inhibiting 50% clonal growth (ED50) of HL-60, LNCaP, PC-3, H520 and MCF-7 cells with ED50s ranging from 10−11 M to 10−13 M. Focusing on this analog for further analyses, pulse-exposure, wash and culture experiments showed that 48 hours exposure of HL-60 cells to BXL-01-0120 (10−9 M) had potent anti-proliferative activity (82% growth inhibition compared to diluent control cells). Cell cycle assays found that BXL-01-0120 (10−10 M, 4 days) increased the percent of cells in the G0/G1-phase (61%, diluent control 47%) associated with a decrease S-phase (18%, diluent control 42%). BXL-01-0120 (10−10 M, 4 days) caused apoptosis in approximately 15% of cells. 1,25(OH)2D3 at the same concentration and duration changed neither the cell cycle nor number of cells undergoing apoptosis compared to control HL-60 cells. BXL-01-0120 (10−10 M, 4 days) strongly induced expression of the CD11b and CD14 (monocyte / macrophage differentiation markers) on HL-60 cells (87%); in contrast, 1,25(OH)2D3(10−10 M) stimulated a mean 43% of the cells to express these cell surface proteins. In summary, DGs strongly inhibited clonal proliferation, induced differentiation and cell cycle arrest in several types of cancer cells, especially HL-60 cells, suggesting that further preclinical and clinical studies to explore their anticancer potential are warranted.
Selenium Enhances the Anti-Angiogenic Effects of Bevacuzimab (Anti-VEGF Antibody) in Human Acute Myeloid Leukemia Xenograft Models.
Authors: Doro Nathaniel C. , Lal Deepika , Rustum Youcef , Wang Eunice S. 
Published: October 2019

Abstract
Selenium, a known antioxidant used in chemoprevention, has recently been shown to improve the efficacy of chemotherapy agents and mediate anti-angiogenic effects in preclinical solid tumor models. Prior data has also shown that sodium selenite can induce apoptosis of human acute myeloid leukemia (AML) cells in vitro. While the use of high non-toxic doses of selenium has been demonstrated to effectively enhance the therapeutic efficacy and selectivity of various anti-cancer drugs in multiple solid tumor xenograft models (Cao et al, Clin Canc Res10: 2561–2569, 2004), the in vivo effects of selenium compounds in hematological malignancies have not been extensively explored. Our laboratory has previously demonstrated the preclinical efficacy of VEGF inhibitors in human leukemia xenograft models. Here we investigated the in vitro and in vivo effects of seleno-L-methionine (SLM), alone and in combination with chemotherapy and anti-VEGF antibody, in human AML. The mechanism of action, dosage, and time course of SLM effects on AML cells (ML-2 and HL60) in vitro were determined using colorimetric (CCK-8) viability, tritiated thymidine proliferation, and Annexin-V flow cytometric assays. SLM therapy resulted in dose dependent inhibition of AML proliferation with marked induction of apoptosis and a 67–92% reduction in viable cells at 400–500 μM. Ten million AML cells (ML-2 and HL60-luciferase) were then subcutaneously engrafted into immunodeficient (SCID/SCID) mice. ML-2 tumor bearing mice were treated with PBS (vehicle), SLM (200 mcg p.o. daily), cytarabine (Ara-C 2 mg i.p. for 3 days), or combination SLM + Ara-C therapy for over two weeks. SLM showed no effective modulation of therapeutic efficacy and toxicity in AML tumor models, when combined with Ara-C. Neither SLM nor Ara-C alone or in combination resulted in significant reduction of AML growth. ML-2 and HL60-luciferase tumor bearing mice were then treated with PBS, SLM (200 mcg p.o. daily), anti-VEGF antibody bevacuzimab (BV 100mcg i.p. twice weekly), or SLM + BV for three weeks. Disease progression was monitored by tumor volume, end tumor weight, and bioluminescent imaging. Although SLM alone was ineffective in reducing HL60 leukemia growth, SLM + BV combination therapy effectively induced a 75% reduction in mean tumor volume after 21 days of treatment which was statistically greater than BV therapy alone (62% reduction). Synergistic effects of SLM+BV therapy was also confirmed by differences in mean tumor weights and bioluminescent imaging as compared with single agent BV and SLM treated mice. Similar results were seen in the ML-2 AML xenograft model.
Conclusions: SLM improved the anti-angiogenic and anti-tumor effects of anti-VEGF therapy with bevacizumab in human AML xenograft models. Additional studies investigating the mechanisms of action of these synergistic effects will be presented.