bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel, Efficacious Therapeutic Approach to Patients with Acute Promyelocytic Leukemia (APL) Using Differentiating Agent and Metronomic Chemotherapy (CT).
Authors: Banavali Shripad D. , Goyal Lovenish , Nair Reena , Biswas Ghanashyam , Amare-Kadam Pratibha , Baisane Chanda , Mahadik Shashikant , Gujral Sumit , Karanth Narayan , Arora Brijesh , Bhagwat Roshni , Kurkure Purna , Parikh Purvish 
Published: October 2019

Abstract
Background: The prognosis of APL has improved markedly with the use of All-Trans-Retinoic Acid (ATRA), but many patients in developing countries are in the high-risk group at presentation and because of inadequate infrastructure die during aggressive induction therapy due to either sepsis or bleeding and/or ATRA syndrome. There is growing appreciation of pivotal role of angiogenesis in APL (Blood2001; 97: 3919). The objective of our study was to evaluate the efficacy of low-dose oral metronomic CT during induction and maintenance therapy along with ATRA in APL.
Materials and Methods: From 2003, 23 patients (ages 1 yr to 43 yrs; median 24 yrs; 13 females, 10 males; median WBC count 5.09 X 109/L, range 0.5 to 113 X 109 /L; 7 low risk, 7 intermediate risk & 9 high risk) with APL who could not go for standard CT were included. ATRA 45 mg/m2/d was given for 90 days. Oral CT was given with Prednisolone 40 mg/m2/d, Etoposide 50 mg/m2/d and 6-TG 40 mg/m2/d (PET) for 21 days as induction therapy with ATRA. Consolidation was with 3 cycles of single agent Daunorubicin at 45 mg/m2/d on d 1, 2, 3 every 21 days. This was followed by 6 cycles of oral ET/PET. ATRA was continued for 15 days every 3 months for total of 18 months.
Results: The protocol was well tolerated on out-patient basis and after the initial admission at presentation, only 6 patients required readmission. Complete morphological, cytogenetic and molecular remission was achieved in 21 patients (91.3%) at a median of 40 days. There were 2 septic deaths during induction; only 1 patient developed ATRA-syndrome once started on PET. There was 1 remission death because of disseminated chickenpox and 1 patient had CNS relapse. Projected Event Free Survival (EFS) and Overall Survival (OAS) at 24 months is 73% and 84% respectively which is significantly better than our previous results (Am J Hematol1999; 60:87). Interestingly the CR rate and OAS for the 9 high risk patients is 100% so far.
Conclusions: There is a valuable role of single hospital trials in exploring innovative therapies in APL. This pilot study contributes to discussion of 4 more debated issues (1) Is there a role for Ara-C in the treatment of APL. (2) How can one improve the therapy in high risk patients without increasing toxicity, (3) What is the ideal duration of maintenance therapy, and (4) What is the ideal therapy for elderly patients and for those who are known to have appreciable mortality from aggressive chemotherapy.
Meta-Analyses of Randomised Controlled Trials (RCT) of Warfarin and Low Molecular Weight Heparin (LMWH) for the Prevention of Venous Thromboembolism (VTE) and Death in Cancer Patients.
Authors: Wheatley Keith , Gross Laura E. , Hills Robert K. , Young Annie M. 
Published: October 2019

Abstract
VTE is a common clinical problem in cancer patients. Uncertainty remains as to whether prophylactic treatment of oral anticoagulants (mainly warfarin) or LMWHs, given by subcutaneous injection, is beneficial and practice varies widely. It has been proposed that anticoagulant therapy may also improve survival in cancer patients. The largest trial of VTE prophylaxis in cancer patients with central venous catheters (CVCs), WARP, has just been completed and showed no apparent benefit for low dose warfarin - among 811 patients randomised to low dose warfarin versus not, the VTE rate was 5% in both arms (odds ratio [OR]=1.04, 95% confidence interval [CI]=0.56–1.92, p=1.0) and mortality was not reduced (OR=1.02, CI=0.74–1.4, p=0.8) (Young et al., ASCO, 2005, LBA8004). This result needs to be put in the context of other RCTs of prophylaxis with anticoagulants, so we performed a meta-analysis to evaluate the effect of warfarin and LMWH on VTE rates and cancer mortality. Computerized searches for trials were performed, including MedLine, Embase, NCI trials register, ASCO and ASH meeting abstracts. Standard meta-analysis methods were used and the results presented as ORs and CIs, with heterogeneity of treatment effect between trials examined using tests for interaction. In 5 trials (n=1355 patients) of warfarin v. not, there was no clear evidence of a decrease in VTEs (OR=0.68, CI=0.46–1.01, p=0.06). An additional 3 trials (n=2034 for all 8 trials) had survival data and there was no clear evidence of a decrease in mortality (OR=0.88, CI=0.77–1.01, p=0.06). In 5 trials (n=793) of LMWH v. not, VTE rate was reduced (OR=0.53, CI=0.32–0.87, p=0.01). 6 trials (n=1295) contained survival data and mortality was reduced with LMWH (OR=0.79, CI=0.67–0.92, p=0.003). In 3 trials (n=985) of LMWH v. oral anti-coagulation (mainly with warfarin), VTE rates were lower with LMWH (OR=0.46, CI=0.32–0.67, p<0.0001) but no mortality benefit was observed (OR=0.89, CI=0.72–1.1, p=0.3). The results of these preliminary meta-analyses suggest that LMWH is the preferred form of prophylaxis for VTE in cancer patients and that overall, there may be an anti-tumour effect, leading to a survival benefit.
The Bcl-2 Family Protein Inhibitor, ABT-263, Promotes Apoptotic-Like Response in Isolated Platelets.
Authors: Tse Chris , Zhang Haichao , Chen Jun , Fryer Ryan M. , Nelson Richard , Nimmer Paul , Reinhart Glenn A. , Smith Morey L. , Tahir Stephen K. , Rosenberg Saul H. , Elmore Steven W. 
Published: October 2019

Abstract
Platelets are relatively short-lived, anucleated cells derived from megakaryocytes that are essential for proper hemostasis. Although they lack a nucleus, platelets possess a highly organized structure with multiple cellular organelles including mitochondria and a number of specific granules. Upon recruitment to sites of endothelial injury, platelet activation stimulates their adhesion, aggregation and release of granule components leading to coagulation. Many of the cellular changes observed during platelet activation and platelet senescence resemble those observed during apoptosis in nucleated cells, including loss of mitochondrial membrane potential, caspase activation, phosphatidylserine (PS) externalization, cell shrinkage and microparticle formation (analogous to membrane blebbing). ABT-263 is an orally bioavailable Bcl-2 family protein inhibitor currently in clinical development. This compound is a potent antagonist of the anti-apoptotic proteins Bcl-xL, Bcl-2 and Bcl-w and induces apoptosis in cancer cells dependent on these proteins for survival. ABT-263 induces a unique thrombocytopenia in multiple species that is characterized by a rapid clearance of circulating platelets with recovery to normal platelet counts within several days after treatment cessation. To elucidate the mechanisms underlying this thrombocytopenia, a series of in vitro experiments were performed using freshly isolated platelets comparing ABT-263, its enantiomer (which has significantly lower activity against Bcl-2 family proteins) and known platelet activators. ABT-263, but not the enantiomer control, reduced the viability of dog and human platelets and activated key apoptotic processes, including cytochrome c release, caspase 3 activation, and PS externalization. ABT-263 did not induce aggregation of isolated platelets and did not induce surface expression of GPIIb/IIIa that is essential for platelet adhesion to fibrinogen during clot formation. While ABT-263 had no effect on markers of lysosomal- or alpha-granule release, increases in a marker of dense granule release were apparent at high concentrations. Taken together these data suggest that ABT-263 induces an apoptotic-like response in platelets that is distinct from platelet activation. Furthermore, the lack of effect of the enantiomer control compound suggests this effect is mediated through inhibition of antiapoptotic Bcl-2 family members. Loss of membrane asymmetry and PS externalization has been suggested to be the primary signal for the recognition and clearance of senescent platelets by phagocytes of the reticuloendothelial system. Induction of apoptosis in platelets by Bcl-2 family protein inhibitors such as ABT-263 may coopt this process inducing a premature platelet senescence resulting in a novel type of thrombocytopenia, in vivo.
Focal Adhesion Kinase (FAK) Is Required for CXCL12-Induced Dhemotaxis and Adhesion to VCAM-1 in B Lymphocytes and Hematopoietic Stem/Progenitor Cells.
Authors: Silberstein Leslie E. , Dykxhoorn Derek , Le Yi , Honczarenko Marek , Lieberman Judy , Glodek Aleksandra 
Published: October 2019

Abstract
The chemokine CXCL12 (SDF-1) and its receptor CXCR4 play a critical role in hematopoietic progenitor cell migration and positioning within the bone marrow (BM). However, CXCL12/CXCR4-induced signaling pathways in blood cell migration are poorly characterized. Based on previous studies of BM progenitor B cells indicating a strong correlation between FAK signaling and CXCL12 induced adhesion to VCAM-1, we speculated that FAK might be an important signaling component in CXCL12-induced chemotaxis and integrin-mediated adhesion. Here, we used two approaches to reduce FAK expression in (human and mouse) progenitor B cells and mouse Sca-1+, Kit+, Lin− stem/progenitor cells. FAK specific siRNAs reduced FAK expression by 80% and abolished both CXCL12-induced chemotaxis and adhesion to VCAM-1 in the pro-B cell line, REH. FAK knock-down did not change expression levels of CXCR4 and VLA-4 integrin. FAK expression was rescued by transfection with wild type, chicken FAK, which also restored both CXCL12-induced chemotaxis and adhesion. Furthermore, we found that in FAK deficient cells CXCL12-induced activation of the GTP-ase Rap1 was reduced, suggesting the importance of FAK in CXCL12-mediated inside-out integrin activation. CXCL12-mediated chemotaxis was also impaired in primary progenitor B cells and hematopoietic stem/progenitor cells (HSC/P) isolated from FAK floxed mice, in which FAK was deleted by Cre-mediated excision of FAK floxed alleles. Cre-mediated FAK deletion did not affect cell viability or induce apoptosis. These studies suggest that FAK may function as a key intermediary in signaling pathways controlling hematopoietic cell migration and lineage development.
A Screen for Mll-AF9 Cooperating Mutations in Leukemogenesis Using MLV-Based Mutagenesis.
Authors: Bergerson Rachel J.S. , Collier Lara S. , Cox Tony , Hudson Wendy A. , Allaei Raha , Wolff Linda , Kersey John H. , Adams David J. , Largaespada David A. 
Published: October 2019

Abstract
Human translocations involving the MLL gene are associated with a variety of myeloid and lymphoid leukemia. The MLL-AF9 translocation is common in acute myeloid leukemia (AML). C57BL/6 mice with a Mll-AF9 knock-in mimic the phenotype observed in human patients with this translocation: 75% develop AML but only after a preleukemic phase and prolonged latency. A minority of these mice develop acute lymphoblastic leukemia (ALL) (Dobson, et al. EMBO J.1999, 18(13): 3564). This model provides a system for understanding the evolution of AML initiated by a MLL fusion oncoprotein, including the identification of cooperating genetic events required for AML induction. The recombinant retrovirus MOL4070LTR (M4070) induces AML in some strains of mice (Wolff, et al. J Virol.2003, 77(8): 4965). We hypothesized that this virus could cooperate with the MLL-AF9 oncoprotein to accelerate AML by acting as an insertional mutagen, providing second “hits” in leukemia progression. We bred Mll-AF9 heterozygous C57BL/6 males to 129/SvJ wild type (WT) females, and injected the 280 offspring at 3 days of age with either M4070 virus (212) or a control supernatant (68). All mice were genotyped and observed for disease progression. Infected Mll-AF9/+ mice succumb to disease with a significantly reduced latency period when compared to virus treated WT mice (p < .0001) and uninfected Mll-AF9/+ mice (p < .0001), indicating that M4070 infection causes significant leukemia acceleration in these mice. The gross pathology and preliminary analysis of the surface immunophentoype by flow cytometry and Southern blot indicate infected Mll-AF9/+ animals present with primarily myeloid leukemia while infected WT animals present with lymphoid leukemia. To determine what genes, when mutated by M4070 insertion, can cooperate with Mll-AF9, retroviral insertion sites have been cloned from over 140 diseased tissues from our accelerated leukemia animals using a shotgun-based, linker-mediated, cloning protocol. More than 1,000 independent insertions have been isolated and are being analyzed to identify common insertion sites (CIS). So far, we have found several CIS enriched in Mll-AF9/+ AML accelerated by M4070 insertion. We plan to verify nearby genes for cooperation with MLL-AF9 in AML development using human microarray data and mouse modeling.
Analysis of MLL Amplification and 5q Deletions in AML/MDS Cell Lines Identifies Novel Targets.
Authors: Schneider Bjoern , Nagel Stefan , Kaufmann Maren , Quentmeier Hilmar , Matsuo Yoshinobu , Drexler Hans G. , MacLeod Roderick A.F. 
Published: October 2019

Abstract
Genomic amplifications of the 11q23 region occur in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) where MLL and a few neighboring genes, notably DDX6, are deemed salient targets. However, the extent to which amp(lified)-MLL and translocated MLL share effector targets remains to be established. Even less is known about the target(s) of deletions affecting the long arm of chromosome 5 (5q-) which reportedly partner amp-MLL. We analyzed three AML/MDS cell lines by cytogenetics (conventional and FISH) in parallel with real time q(uantitative)-PCR at both 11q23 and 5q2 to measure copy number and expression of salient target genes together with putative downstream targets. The cell lines comprised: MOLM-17 (transforming-MDS), SAML-2 (therapy-related AML), and UOC-M1 (AML-M1). All three cell lines exhibited approximately four-fold genomic amplification of 11q23 including MLL and DDX6, while the amplicon extended telomerically to include FLI1 (11q24) and HNT (11q25) in MOLM-17 and UOC-M1 only. Expression, quantified relative to AML/MDS cell lines without MLL rearrangement, revealed that of the genomically amplified genes only MLL was generally overexpressed, namely by 9.5x (MOLM-17), 5.1x (UOC-M1), and 4.6x (SAML-2). In addition to the highest MLL expression, in MOLM-17 FLI1 (3.8x) and DDX6 (2.8x) were significantly upregulated. Expression was also quantified among reputed MLL target genes, and showed that in the three cell lines MEIS1 was upregulated in MOLM-17 only (by 6x), and CDKN2C in all cell lines (by about 2x), while HOXA9 and CDKN1B showed near-normal levels of expression. All three cell lines carried 5q- with a common deleted region at 5q31 extending from 134.2–137.5 Mbp. Of a panel of genes recently identified as 5q- deletion targets (centromere-TIGA1, CAMLG, C5orf15, C5orf14, BRD8, HARS, KIAA0141, CSNK1A1, RBM22-telomere), only C5orf15 (function unknown) and BRD8 (a component of the nua4 histone acetyltransferase complex involved in transcriptional activation) were generally downregulated - to about 0.25x, and about 0.4x normalized expression levels, respectively. Both genes lie within the common deleted region. In summary, we have characterized amp-MLL and 5q- in MOLM-17, the first MDS cell line to be described with these rearrangements, together with two AML cell lines with similar cytogenetic profiles. Our data suggest that MLL is the only clear object of 11q23 amplification hitherto identified and CDKN2C its sole unequivocal target in AML/MDS cell lines. It is possible that MEIS1 is also targeted for activation in specific cell types or disease phases in MDS. These findings also highlight C5orf15 and/or BRD8 as possible leukemogenic accomplices targeted for downregulation in accompanying 5q-. These findings may point to differences in signalling pathways targeted by amp-MLL in AML and MDS.
A CK2-Dependent Mechanism for PML Degradation upon Cellular and Oncogenic Stress.
Authors: Scaglioni Pier P. , Yung Thomas M. , Cai Lu F. , Erdjument-Bromage Hediye , Kaufman Andrew J. , Singh Bhuvanesh , Teruya-Feldstein Julie , Tempst Paul , Pandolfi Pier Paolo 
Published: October 2019

Abstract
The PML tumor suppressor controls key pathways for growth suppression, induction of apoptosis and cellular senescence. PML loss occurs frequently in hematopoietic and solid tumors through unknown post-translational mechanisms. PML loss often correlates with tumor progression. Casein kinase 2 (CK2) is a stress activated serine/threonine protein kinase that is oncogenic and frequently over-expressed in human tumor of multiple histological origins including non Hodgkin’s lymphomas, acute leukemias and multiple myeloma. In addition, CK2 over-expression due to gene amplification has been reported to be a powerful adverse prognostic factor in non-small cell lung cancer. We recently reported that PML undergoes ubiquitin/proteasome mediated degradation in immortalized and tumor derived cell lines (Cell. 2006, 126:269). PML degradation depends on direct CK2 phosphorylation of Ser517 in the PML C-terminal degron. PML mutants that are resistant to CK2 phosphorylation display increased tumor suppressive functions in assays measuring apoptosis, replicative senescence and in xenograft models. Now, we report the identification and characterization of novel cellular and oncogenic stress signaling pathways that control the CK2/PML degradation pathway. This analysis allowed us to determine the signaling cascades upstream of CK2. In addition, we found an inverse correlation between CK2 kinase activity and PML protein levels in cancer-derived cell lines and primary specimens. Significantly, CK2 pharmacological inhibition enhances PML tumor suppressive property in vivo and in vitro. These data identify a key post-translational mechanism that controls PML protein levels and provide therapeutic means toward PML restoration through CK2 inhibition. The implications of these new findings during the physiologic response to cellular stress and in the pathogenesis of hemopoietic malignancies will be discussed at the meeting.
Protein Phosphatase 2A Inactivates Bcl2’s Antiapoptotic Function by Dephosphorylation and Up-Regulation of Bcl2-p53 Binding.
Authors: Deng Xingming , Gao Fengqin , Flagg Tammy , May W. Stratford 
Published: October 2019

Abstract
DNA damage-induced p53/Bcl2 interaction at the outer mitochondrial membranes results in a Bcl2 conformational change and loss of its antiapoptotic function. Our data now indicate that either treatment of cells with the protein phosphatase 2A (PP2A) inhibitor, okadaic acid (10 nM), or specific disruption of PP2A activity by the expression of SV40 small tumor antigen enhances Bcl2 phosphorylation and suppresses the cisplatin-stimulated Bcl2-p53 interaction in association with prolonged cell survival. By contrast, C2-ceramide, a potent PP2A activator, reduces Bcl2 phosphorylation and increases Bcl2-p53 binding and promotes apoptotic cell death, suggesting that PP2A may function as a physiological regulator of Bcl2 by, at least in part, affecting its association with p53. Overexpression of the PP2A catalytic subunit (PP2A/C) suppresses Bcl2 phosphorylation in association with increased p53-Bcl2 binding and apoptotic cell death. By contrast, specific depletion of PP2A/C by RNA interference enhances Bcl2 phosphorylation, suppresses p53-Bcl2 interaction and prolongs cell survival. Purified PP2A can directly enhance the formation of the p53-Bcl2 complex in vitro in an okadaic acid-sensitive manner, supporting a direct mechanism. Importantly, PP2A directly interacts with Bcl2 at its BH4 domain which may function as the PP2A ‘docking site’ to potentially ‘bridge’ PP2A to the flexible loop domain which contains the physiological serine 70 phosphorylation site. Thus, PP2A may provide a double whammy to Bcl2’s survival function by both dephosphorylating and enhancing p53-Bcl2 binding. Therapeutically stimulating Bcl2 dephosphorylation and/or increasing Bcl2/p53 binding by activating PP2A may represent an efficient and novel antineoplastic approach.
JAZ Is Required for Interlukin-3 Withdrawal-Induced Apoptosis by Directly Activating p53.
Authors: Yang Mingli , Qiu Jingxin , Li Ying , Jia Jinghua , May W. Stratford 
Published: October 2019

Abstract
By screening a murine interleukin-3 (IL-3)-dependent myeloid cell cDNA library, we previously identified JAZ (Just Another Zinc Finger Protein), a novel zinc finger (ZF) protein that localizes in the nucleus and preferentially binds dsRNA rather than DNA. Forced overexpression of JAZ induces apoptosis but the mechanism was not known. JAZ is differentially expressed in CD34+ primary human and mouse bone marrow cells including mononuclear myeloid and lymphoid cells but not in multinuclear megakaryocytes, indicating that JAZ may function in hematopoietic progenitor cells. Since IL-3 withdrawal induces apoptosis in factor-dependent myeloid and lymphoid cells, we tested whether endogenous JAZ is involved. Hematopoietic cell lines including murine NFS/N1.H7, 32D myeloid and BaF3 lymphoid cells were deprived of IL-3 for 0, 0.5, 1, 2, 4, 6, 8, 12, 24 and/or 48 hr. Results reveal that JAZ expression is upregulated prior to induction of cell death. While a role for p53 in hematopoietic progenitor cell response to apoptosis-inducing stress has been postulated, the mechanism is not clear. Therefore, we assessed whether p53 expression or activation can be affected by JAZ. Results reveal that in association with JAZ upregulation, IL-3 withdrawal also induces p53 expression and importantly, up-regulates its transcriptional activity as assessed by increased BAX expression. To verify p53 dependency, p53-deficient murine M1 and human K562 leukemic cells were also tested. These p53-deficient cells are highly insensitive to serum withdrawal-induced cell death. Importantly, siRNA-mediated ‘knock-down’ of endogenous JAZ (by 70–80%) attenuates stress-induced cell death in NFS/N1.H7 but not M1 cells. These data point to a necessary role for JAZ in IL-3 or growth factor withdrawal-induced hematopoietic cell death in a p53-dependent manner. Further analysis using co-immunoprecipitation studies indicates that endogenous JAZ and p53 associate upon IL-3 withdrawal. Furthermore, using p53+/+ and p53−/− isogenic murine embryonic fibroblasts (MEFs), we clearly show that JAZ not only directly interacts with p53 but also stimulates its transcriptional activity, resulting in mediation/acceleration of stress-activated, p53-dependent apoptosis. Therefore, we propose that the nuclear factor JAZ may be a novel regulator of p53 in the hematopoietic cell response to stress leading to apoptosis. Since only about 15% of hematologic-malignancies express mutant (transcriptionally inactive) p53, it may be possible to therapeutically target wild-type p53 through a mechanism involving JAZ.