bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Prognosis of Children and Adolescents with Acute Lymphoblastic Leukemia (ALL) and Very-High Minimal Residual Disease (MRD) and the End of Induction therapy (EOI)? Preliminary Results of the FRALLE 2000 Protocol
Authors: Cayuela Jean-Michel , Beldjord Kheira , Fasola Sylvie , Auclerc Marie-Françoise , Brethon Benoît , Auvrignon Anne , Mechinaud Francoise , Gandemer Virginie , Margueritte Geneviève , Blouin Pascale , Grardel Nathalie , Cavé Hélène , Macintyre Elizabeth , Leverger Leverger , Baruchel Andre 
Published: April 2020

Abstract
MRD at EOI is a powerful prognostic indicator in childhood ALL. Cave et al (N Engl J Med 1998) and van Dongen et al (Lancet 1998) have shown that a very high EOI-MRD (≥ 10−2) is associated to a dismal prognosis (5y EFS: 15–20%). From December 2000 to July 2007 1496 children and adolescents (1–20 years, no Ph+) have been included in the ongoing FRALLE 2000 protocol. EOI-MRD at D35–42 was measured by competitive PCR of Ig/TCR markers and Gene Scan analysis and was decisional for further treatment intensification if ≥ 10−2. 1017 pts are fully evaluable (monitored data, no induction failure, evaluable EOI-MRD, outcome). MFU is 36 months. Three risk-groups have been defined. A (n=620): NCI standard risk BCP-ALL, B (n=265): NCI high risk-ALL, T (n=132): T-cell ALL. Fifty-eight pts (5.7%) have a very high EOI-MRD, 2.6% in group A, 9% in group B, 14% in group T. These pts were more likely than pts with lower MRD (&lt; 10−2) to have a D8 poor prednisone response (PPR) (31% vs 10%, p &lt;.001), a slow marrow response (D21M2 or M3, 24% vs 5%, p &lt;.001) or both (22% vs 1.5%, p &lt;.001). A very high MRD only (no high-risk cytogenetic features, no D8 PPR, no D21 M2/M3 marrow) was found in 33 out the 58 pts (57%), i.e. 3% of all pts. A group pts (n=16) with very high EOI-MRD received a 3 block-consolidation plus a double delayed intensification (DDI) while B or T group pts received a 3 block-consolidation plus DDI (24 pts) or HSCT (18 pts). 5y EFS and OS where 50±10% and 74±7% respectively for the 58 pts. A similar 5 y EFS was found for pts with BCP-ALL or T-cell ALL with very high MRD (50±12% and 48±12%, respectively). There is a trend for a better EFS for pts with very high EOI-MRD only compared to those with other associated high-risk features (60±11% vs 39±11%, p=.10).
Conclusion: these results compare favourably with published results suggesting that intensification of therapy may improve the outcome of pts with bad early response to initial chemotherapy.
Distinct Gene Expression Profiling in AML in Elderly Versus Younger Patients
Authors: de Jonge Henk-Marijn , de Bont Evelina S , Valk Peter , Schuringa Jan Jacob , Kies Marcel P , Woolthuis Carolien M. , Delwel Ruud , Vellenga Edo , Lowenberg B. , Huls Geert A 
Published: April 2020

Abstract
Acute myeloid leukaemia (AML) has a different clinical and biological behaviour in elderly patients. We used Affymetrix HGU133Plus2.0 gene expression data of 525 patients with AML -who were treated on various HOVON/SAKK studies-to ascertain the difference of gene expression profiles in AML samples of older patients compared to AML samples of younger patients. Differentially expressed genes were identified for 175 youngest with a median age of 31-years vs. 175 oldest AML patients with a median age of 59-years using a multivariate permutation test in Biometric Research Branch ArrayTools (BRB ArrayTools). This analysis revealed that 478 probes were up-regulated and 492 probes were down-regulated with increasing age at the significance level of P &lt;1.0×10−5. Biological processes (represented by GO-categories) enriched among the 478 (up) and 492 (down) differentially expressed probes were identified. Processes as regulation of cell proliferation, negative regulation of apoptosis as well as response to stress were up regulated with increasing age, whereas processes as chromatin modification, programmed cell death as well as transcription repressor activity were found to be down regulated with increasing age. It was striking that the tumour suppressor gene p16INK4a was identified as one of the strongest down-regulated genes with age. In contrast, various studies have demonstrated an increasing expression of p16INK4a during physiological ageing. Downregulation of p16INK4a with increasing age was confirmed in an independent cohort of CD34+ cells of 54 AML patients, whereas in CD34+ cells of 23 healthy volunteers p16INK4a was found to be upregulated with increasing age. In conclusion, gene expression profiles of AML samples of young and old patients differ significantly. That these differences in gene expression profiles not simply reflect an ageing phenomenon is illustrated by the down regulation of p16INK4a in samples of elderly AML patients. These data suggest that counteracting the senescence-promoting increase in p16INK4a, which is associated with physiological ageing, plays an important role in the development of AML in elderly patients.
Characterization of Gene p306 Expressed in Monocyte Derived Dendritic Cells
Authors: Bringmann Ani ta , Hilgendorf Ingo , Appel Silke , Held Stefanie , von Schwarzenberg Karin , Grünebach Frank , Brossart Peter 
Published: April 2020

Abstract
Dendritic cells (DCs) play a significant role in the initiation and maintenance of primary immune responses. The identification of new genes that are involved in DC biology is crucial for a better understanding of the unique DC functions. We approached this issue by generating a substractive cDNA library based on suppression hybridization between monocyte derived DCs (mDCs) cDNA and the reference monocyte cDNA. Among various differentially in mDC expressed genes, we identified the gene p306 with unknown functions. In the following, we characterized the gene p306 and the translated protein splice variants. We confirmed the p306 expression in mDCs on mRNA level by RACE and RT-PCR with subsequent sequencing. Besides the 2 known splice variants, we found a third novel form. Two splice variants were expressed in activated myeloid and plasmacytoid DCs sorted from blood. To characterize the p306 protein forms, we analyzed the hypothetical proteins by various prediction programs. We found that the N-terminus of the protein isoforms is homologue to a DNA-binding protein. Structural features are an oligonucleotide-binding fold with an integrated zinc ribbon. To detect p306 protein expression, we generated a polyclonal antibody and used it in Western blotting experiments. We were able to detect 3 protein bands with sizes of 36 kDa, 84 kDa and about 200 kDa, which differed from the expected sizes of 20 kDa and 111 kDa. We found that the unexpected sizes are in part due to N-glycosylation using the inhibitor tunicamycin. When analyzing cell lysates and nuclear extracts, we found that the 36 kDa protein form is expressed exclusively in the nucleus, while other forms could be detected in nucleus and cytosol. Interestingly, activation of mDCs with Toll like receptor ligands Pam3Cys, Poly I:C, LPS and R848 selectively upregulated the expression of the 84 kDa form in the nucleus. DC treatment with IL-10 or Imatinib, compounds that inhibit DC differentiation and function, abolished the expression of all 3 protein forms. In order to analyze the possible effect of proteases on the post-transcriptional regulation of the protein expression and generation of the identified splice variants, mDCs were treated with several protease inhibitors. DC treatment with cathepsin/subtilisin inhibitor led to the downregulation of all 3 protein variants, indicating that p306 might be involved in the regulation of apoptosis induction. The pan-caspase inhibitor zVAD caused the upregulation of all protein forms. In conclusion, we identified a novel gene p306 that is differentially expressed in mDC, which encodes for at least 3 different splice variants and protein forms with diverse cellular localization. Although the functions of the p306 proteins still have to be determined, the gene p306 is probably involved in binding nucleic acids and in regulating apoptosis induction.
Chemotherapy Alone for Localized Non-Bulky Hodgkin Lymphoma
Authors: Canellos George P. 
Published: April 2020

Abstract
Combined modality therapy with radiation and chemotherapy has been the standard treatment for limited-stage HL. Long-term toxicities, including cardiac and disease and secondary cancers, s have been reported in multiple series with long follow-up. Lower doses and smaller fields may be less toxic, but mediastinal/cardiac radiation is unavoidable in most cases. The Dana-Farber Cancer Institute and Massachusetts General Hospital lymphoma teams have now treated 74 patients with localized, non-bulky classical HL with chemotherapy as the only therapy. The median age of the series was 29 years (17–42). The M/F ratio was 33/41. The clinical stages were IA (10), IIA (56), IIB (9). The treatment consisted of ABVD × 6 cycles (70 pts), ABVD × 4 cycles (3 pts), and variants of ABVD (2 pts). The median F/U is 48+ months (4+–174+). One patient had primary refractory disease. Seven patients (median age 30, range 20–38) have relapsed (6, 10, 10, 11, 14, 20 and 63 months) whose original stage was IA (1), IIA (3), IIB (3). The progression-free survival at 4 years is 91%. All patients are alive. Six of seven patients received salvage RT and autologous stem cell transplantation, and only one has relapsed to date. In retrospect, all seven patients who relapsed from CR or CRu were FDG-PET negative at mid-cycle. Thus far, there has been no long-term, chemotherapy-related toxicity in the patients who remain in remission. 94% (62/66) asymptomatic patients remain in remission compared to 6/9 (67%) IIB patients.
Conclusion: In young adults with non-bulky, localized HL chemotherapy alone with ABVD can achieve excellent progression-free and overall survival, especially those asymptomatic at diagnosis. These data and previously published results indicate an equivalent long-term outcome when compared to combined modality trials but without the long-term risks of radiation therapy. Avoidance of radiation therapy may be even more important in the pediatric age group.
Direct Inhibitory Effects of Lenalidomide on the Proliferation and VEGF Production of Non-Hodgkin Lymphoma Cells Are Associated with Increased SPARC Expression
Authors: Zhang Ling-Hua , Schafer Peter H , Muller George , Stirling David , Bartlett Blake 
Published: April 2020

Abstract
Lenalidomide is an oral anti-angiogenic, anti-proliferative and immunomodulatory drug approved for the treatment of Low- or Intermediate-risk myelodysplastic syndrome associated with a del(5q) cytogenetic abnormality, and in combination with dexamethasone for previously treated multiple myeloma. Early clinical results suggest potential clinical efficacy in B-cell non-Hodgkin lymphoma (NHL). In this study, we investigated lenalidomide-mediated inhibition of cell proliferation and angiogenic factors in the following NHL subtypes: mantle cell lymphoma (MCL), diffuse large-B-cell lymphoma, and follicular lymphoma (FL). The effect of lenalidomide on these tumor cells was determined after 1–3 days of treatment by 3H-thymidine incorporation, Luminex-based microbead array, and real-time qRT-PCR. We also assessed the expression of tumor suppressor genes such as p21cip1 and secreted protein acidic and rich in cysteine (SPARC). We found that lenalidomide induced direct anti-proliferative effects on each NHL subtype, with MCL cells being the most sensitive. Pro-angiogenic factors such as vascular endothelial growth factor (VEGF) were expressed at a high level in all lymphoma cell lines. Lenalidomide inhibited VEGF production at much lower concentrations than required for anti-proliferative effects, particularly in MCL and FL cell lines. Addition of recombinant human VEGF or neutralizing anti-VEGF antibody had no effect on MCL cell proliferation, suggesting that these effects are independent. Mechanistic studies indicated that lenalidomide strongly increased the gene expression of the tumor suppressor genes p21cip1 and SPARC to varying degrees. Elevation of SPARC mRNA significantly correlated with both the anti-proliferative and the VEGF-suppressive effects of lenalidomide on MCL cells (p &lt; 0.05). Transfection of tumor cells with SPARC siRNA led to significant resistance to lenalidomide suggesting that this effect is mediated at least in part through the up-regulation of SPARC. In conclusion, lenalidomide demonstrates anti-proliferative activity against multiple NHL cell subtypes with greatest potency against MCL. The potent anti-VEGF activity of lenalidomide supports the anti-angiogenic potential of the drug. Thus, lenalidomide-induced up-regulation of SPARC mRNA correlates with MCL sensitivity and may have biomarker potential.
Phosphoproteomic Analysis of Primary Acute Myeloid Leukemia Cells Reveals Redundant Roles for Src Family Kinases in AML Survival
Authors: Dierov Jamil K. , Kim Tae Kon , Yang Xiaowei , Perl Alexander , Burke Beth A , Wang Zhu , Gu Ting-Lei , Gewirtz Alan M. , Corey Seth J. , Polakiewicz Roberto , Carroll Martin 
Published: April 2020

Abstract
Recent results have demonstrated that multiple signal transduction pathways are activated in acute myeloid leukemia (AML) cells, however, the tyrosine kinase(s) that phosphorylates these signaling proteins is not identified. We have analyzed AML cells using a phosphoproteomics screen and demonstrate that the Src family kinases, Lyn, Lck and Fgr, are phosphorylated on their activation sites in AML samples. Expression and activation of Lyn has been previously confirmed. Evaluation of Lck demonstrated that Lck is expressed to a variable degree but consistently in AML samples (n=20). Lck kinase assays show activation of Lck in 17/20 samples tested at levels above the level of activation detectable in normal CD34+ progenitor cells. Lyn and Lck both contribute to AML cell growth as siRNA depletion of either kinase leads to decreased leukemia colony forming activity. Interestingly, both Lyn and Lck contribute to phosphorylation of STAT5 as STAT5 phosphorylation is decreased but not abrogated by siRNA modification of either kinase alone. Consistent with the necessity for this signaling pathway for optimal AML cell growth, siRNA knockdown of STAT5 leads to decreased expression of both STAT5A and STAT5B, decreased expression of the STAT5 target protein, Bclxl and decreased AML colony forming ability. Based on this data, we have studied the FDA approved compound, Dasatinib, and demonstrate that Dasatinib decreases AML colony formation in 4 out of 5 samples tested. Overall, these results demonstrate that SFK’s act redundantly to regulate STAT5 phosphorylation and AML cell growth in primary cells and that phosphoprotein analysis is a robust approach to identify new targets for therapy of malignancy. Src family kinase inhibitors may be valuable in the therapy of AML.
Characterization of the Effects of Pim Kinase Inhibition on Multiple Oncogene-Driven Cell Lines
Authors: Gross Stefan David , Robinson John E , Allen Shelley , Cox April , DeWolf Walt E , Galbraith Sarah , Lee Patrice , Lemieux Christine , Lyssikatos Joseph P , Marmsater Fredrik , Martinson Matthew , Munson Mark C , Wallace Ross D , Woessner Rich , Zuzack John , Winkler James , Koch Kevin 
Published: April 2020

Abstract
We report here the biological effects of inhibiting Pim-1, -2 and -3 serine/threonine protein kinases in cells and in vivo using a novel, potent and selective small molecule inhibitor directed against these kinases. In vitro enzyme assays revealed potent inhibition of all three Pim kinase isoforms while maintaining selectivity against more than 220 other protein kinases. In cells, compound treatment produced biological effects consistent with Pim inhibition, including a reduction in BAD protein phosphorylation. Moreover, this biological activity corresponds well with the compound’s anti-proliferative and pro-apoptotic activity in the IL-3 dependent mouse pro-B cell line Ba/F3 and in factor-indpendent Ba/F3 cell lines dependent upon the expression of BCR-Abl or TEL-JAK2 for growth and survival. Importantly, compared to the BCR-Abl driven Ba/F3 cell line, this compound was equally effective at blocking the growth of an Imatinib-resistant BCR-Abl[ T315I]-driven Ba/F3 cell line. Finally, this compound possesses pharmacokinetic properties that predict the potential for in vivo activity. Therefore, we assessed the effect of Pim kinase inhibition on tumor growth in a mouse subcutaneous tumor xenograft model employing a cell line driven by the TEL-JAK2 oncogene. Results demonstrated that the compound significantly inhibited tumor growth in a dose-dependent manner. In terms of potential clinical utility, these data show that Pim kinase inhibition could be an effective therapeutic strategy for numerous hematologic malignancies including chronic and acute myelogenous leukemias, particularly in those patients that have become resistant to existing therapies such as Imatinib.
Modulation of Cancer Cell-Associated Procoagulant Activity (PCA) by a Novel, Small Molecule, Orally Active Inhibitor of Oxidative Stress Pathways
Authors: Mousa Shaymaa S. , Patil Ghanshyam , Lansing Lawrence , Dier Emmy , Kannanayakal Theresa , Rickles Frederick , Mousa Shaker S 
Published: April 2020

Abstract
Background: The association between malignancy and venous thromboembolism (VTE) is well-recognized. VTE is associated with a systemic hypercoagulable state that is secondary to cancer, cancer-associated therapy and the host inflammatory response. We have tested the ability of OT-304, which is a dual inhibitor of reactive oxygen species (ROS)-mediated activation of both the EGR-1 and NF-κB pathways, to inhibit the PCA of tumor cells.
Methods: Molecular measurements of NF-kB (p50/p65), IkBa, TNF-a, EGR1 and tissue factor (TF) were performed on the human monocytic cell line THP-1, and human umbilical vein endothelial cells (HUVECs) using Affymetrix micro-array, RTPCR, Western blot, ELISA and gel shift assays. The cell-based, anticoagulant efficacy of OT-304 at 1–30 mM was determined in in vitro models of both pro-inflammatory and cancer cell-associated hypercoagulable states, using thrombelastography (TEG) in human blood and in a rabbit model of cell-based coagulation activation.
Results: OT-304 effectively inhibited LPS-mediated TNF-α production in human blood and in THP-1 cells, with an IC50 of 6.7 mM. Similarly, in mice, in a dose-dependent manner, OT-304 at 0.1–50mg/kg IP or 1.0–150 mg/kg oral, inhibited LPS-induced NF-κB activation-associated up-regulation of various chemokines and cytokines. At the molecular level, OT-304 demonstrated effective inhibition of LPS-induced NF-κB activation, nuclear translocation of p50/p65, degradation of IKBa, without any effect on nuclear p50/p65 DNA binding. OT-304 appeared to induce modest down-regulation of the key procoagulant mediator TF, presumably via the inhibition of EGR1. In human whole blood subjected to TEG, OT-304 inhibited the procoagulant effect induced by LPS, lipid hydroperoxide, and ceramide, without directly affecting factor Xa, factor IIa or other coagulation factors. Additionally, OT-304 at 0.1–10 mM inhibited the PCA of glioma, lung, and pancreatic cancer cells. In comparison to the low-molecular-weight heparin, enoxaparin, OT-304 (1–30 ug/ml) was without any significant effect on soluble blood coagulation, as measured by the activated partial thromboplastin time. Repeated administration of OT-304 to mice (10 mg/kg, IP daily for up to 14 days), was without any hemorrhagic toxicity as compared to enoxaparin administered at the same dose. In a mouse xenograft model of human glioma, OT-304 (30 mg/kg, IP, daily for 15 days) resulted in significant inhibition of tumor growth, tumor angiogenesis, and glioma-associated elevation of plasma D-dimer. In rabbits, OT-304 (10 mg/kg IP) resulted in significant inhibition of LPS-induced PCA.
Conclusions: OT-304, by virtue of its ability to target and modulate more than one pathway, may represent a promising anti-cancer therapy, capable of inhibiting tumor growth, inflammation and cancer-associated thrombosis without compromising hemostasis.
Accelerated Cellular Senescence in Myelodysplastic Syndrome
Authors: Wang Yuanyuan , Chen Zixing , Cen Jiannong , Shen Hongjie , Qi Xiaofei , He Jun , Liu Dandan , Yao Li 
Published: April 2020

Abstract
Myelodysplastic syndrome (MDS) is a group of hematopoietic stem/progenitor cell clonal disorders characterized by dysplastic morphology of at least one cell lineage and high risk of evolution to acute myeloid leukemia (AML). Thus, it could be viewed as a preneoplastic stage prior to development of overt acute myeloid leukemia (AML). A number of studies indicated that oncogene-induced senescence as a crucial cellular response at premalignant stage can protect cells from tumor formation. Senescent cells emerged in premalignant cell population but not in malignant ones. p16INK4a have been identified as a cellular senescence-associated molecular marker. In present study, we have determined and compared the expression level of p16INK4a by quantitative RT-PCR and western blot in BM mononuclear cells (BMMNCs)/CD34+ cells among 53 patients of MDS and 12 of AML as well as 11 healthy controls. A significantly upregulated expression level of p16INK4a in MDS, while an significantly lower p16INK4a expression level in AML had been detected in comparison with that in healthy controls(&lt;0.05). The IPSS score of these MDS patients negatively correlated with the p16INK4a expression level. To further confirm the senescent status, the cells of MDS, AML patients and healthy controls were examined by histochemical assays for the activity of senescence-associated beta galactosidase (SA-β-Gal). A weak blue stain reflecting the SA-β-Gal activity could be found in less than 10% cells from healthy controls after four days’ culture. On the contrary, a much stronger blue stain for SA-β-Gal had been detected in about 30–40% cells from MDS, and a little-to-no blue stain in AML cells. The semi-quantitative RT-PCR had demonstrated a similar pattern of SA-β-Gal expression among these three groups. Our preliminary results raise the question whether an accelerated cellular senescence in addition to apoptosis may contribute to the hematopoietic ineffectiveness and dysplastic morphology of cells in MDS, and if it could be of any implications for the progression of the disease.