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  • American Society of Hematology  (15)
  • Evens, Andrew M  (15)
  • 1
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    Inhibition of Autophagy with 3-Methyladenine Synergistically Enhances Cellular Apoptosis Induced by the Histone Deacetylase Inhibitor PCI 24781 in Non-Hodgkin’s Lymphoma Cells
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 3625-3625
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3625-3625
    Abstract: Background: Autophagy represents a potential mechanism of cellular survival in settings of external stressors, such as starvation and exposure to cytotoxic drugs. Driven by the formation of autophagosomes, which digest nonessential cellular components during stress, autogphagy may be pharmacologically inhibited by 3-methyladenine (3-MA), an inhibitor of autophagosome formation. Histone deacetylase inhibitors (HDACI) block cancer cell proliferation by mechanisms that involve epigenetic gene regulation leading to cell growth arrest, differentiation, and apoptosis. Previous investigators have demonstrated synergistic cellular killing by a combination of HDACI and autophagy inhibitors in leukemia cell lines (Carew et al., Blood. 2007). Methods: We investigated whether a similar effect was possible in lymphoma. Specifically, we studied the combination of the pan-HDACI PCI-24781 and 3-MA in three lymphoma cell lines—Ramos (Burkitt’s lymphoma), Jeko, and Granta (both mantle cell lymphoma lines). Cells were cultured in RPMI (Invitrogen) and were incubated for 48 hours with 3-MA (1 mM and 2 mM), PCI-24781 (0.125 uM, 0.25 uM, 0.5 uM) and combinations of both agents. Apoptosis was determined by fluorescence-activated cell sorting (FACS) using AnnexinV-FITC/propidium iodide (AnnexinV+/PI+) staining. Western blots were performed to assess markers of apoptosis—beclin-1 and LC3B isoform I to II conversion. Results: In all three cell lines, treatment with PCI-24781 resulted in a dose-dependent increase in apoptosis. Our previous studies have shown that the IC70 (dose to achieve 70% AnnexinV+/PI+) was 1uM for PCI-24781 in the Ramos cell line. When 3-MA was combined with 0.25 uM PCI-24781, apoptosis increased from 13% to 35%. Similarly, 3-MA increased apoptosis from 8% to 18% and from 30% to 50% when added to PCI 24781 0.125 uM and 0.5 uM, respectively. Similar, albeit less striking, trends were seen in Jeko and Granta cells. Synergy was determined in Ramos cells by the combination index (CI) using isobolograms (CalcuSyn software). Moderate synergy was seen at PCI concentrations of 0.25 and 0.5 uM and a 3-MA concentration of 2 mM, with a CI of approximately 0.7. Immunoblots were analyzed for markers of autophagy—beclin-1 and LC3B isoforms I and II. Combined 3-MA and PCI-24781 reduced Beclin-1 expression as well as the conversion of LC3B isoform I to II in cells treated with the PCI-24781and 3-MA combination, as compared to cells treated with PCI-24781 alone, suggesting that inhibition of autophagy is responsible for the synergistic increase in apoptosis. This reduction was most prominent at 6 hours, indicating that autophagy inhibition is a relatively early event in this model. We conclude that inhibition of autophagy with 3-MA represents a novel approach to synergistically enhance cellular apoptosis induced by HDACI in lymphoma cells. Clinical studies taking advantage of this novel biology are warranted.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.3625.3625
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 2
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    The Novel Organic Arsenical, Darinaparsin (ZIO-101), Induces Apoptosis through AKT and MEK/ERK Pathways In Hodgkin Lymphoma (HL) and T-Cell Lymphoma (TCL) Cell Lines
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2840-2840
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2840-2840
    Abstract: Abstract 2840 Background: The inorganic arsenic, arsenic trioxide (ATO), has a narrow therapeutic index, which has limited its clinical use in most malignancies. Darinaparsin (ZIO-101, S-dimethylarsino-glutathione), synthesized by conjugating dimethylarsenic to glutathione, is a novel organic arsenical that is under investigation as a novel agent for the treatment of cancer. Furthermore, early-phase clinical trials with darinaparsin have demonstrated low toxicity and encouraging clinical efficacy in relapsed/refractory hematologic malignancies. Methods: We treated several TCL cell lines (Jurkat, C10MJ, Hut-78, and MT2) and the resistant HL cell line, L428, with increasing concentrations of darinaparsin (0.5-5μM) +/− the MEK inhibitor, U0126, or ERK siRNA (Qiagen HiPerFect transfection). Cell survival and apoptosis were measured by MTT and Annexin-V/propidium iodide staining, respectively. Further, tumor intracellular darinaparsin and ATO concentrations were assessed with mass spectrometry, while transcription pathway intermediates were analyzed by Western blotting. Results: Darinaparsin inhibited cell growth and induced apoptosis in all cell lines at 1–3μM. At 2μm (48 hours), darinaparsin induced approximately 80% apoptosis in each of the four TCL lines, while 3μM resulted in 65% apoptosis in L428 cells. By comparison, 〉 10μM of ATO (48 hours) was required to induce 40% apoptosis in TCL and 25% apoptosis in L428. At 1–3μM, darinaparsin induced significant increases in caspase 3 and PARP activation in TCL, while interestingly, minimal caspase or PARP was observed in L428. Notably, in L428 cells at 1 hour, mass spectrometry showed that intracellular accumulation of darinaparsin was 〉 10-fold higher as compared with equivalent ATO concentrations (p 〈 0.01). We also treated L428 cells with U0126 (5μM) or ERK2 siRNA, both combined with darinaparsin. Pre-incubation with U0126 or siRNA knock down of ERK2, followed by treatment with darinaparsin, significantly enhanced darinaparsin-induced apoptosis (p 〈 0.05). To further investigate darinaparsin-induced signaling pathways, we analyzed phospho-AKT (p-AKT), and phospho-ERK (p-ERK) in Jurkat and L428. We found down-regulation of p-AKT in Jurkat as well as L428 cells, while total AKT remained unchanged. Additionally, an increase in p-ERK was observed in L428 cells with 2–3μM darinaparsin, while p-ERK was down-regulated in Jurkat cells. Conclusions: Darninaparsin induces significant cell death in HL and TCL cell lines that is mediated through AKT and MEK/ERK-based pathways. Additionally, markedly higher intracellular darinaparsin levels are achieved in lymphoma cells compared with equivalent concentrations of ATO. Continued pre-clinical and clinical trial investigation of darinaparsin in HL and TCL is warranted. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2840.2840
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    Pancreatitis In Patients Treated With Brentuximab Vedotin: A Previously Unrecognized Serious Adverse Event
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4380-4380
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4380-4380
    Abstract: Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial (NCT01476410), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in Table 1. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens:Seattle Genetics : Consultancy, Honoraria. Fenske:Seattle Genetics: Consultancy. Hamlin:Seattle Genetics : Consultancy, Honoraria. Coiffier:Millennium Pharmaceuticals : Consultancy. Engert:Millennium Pharmaceuticals : Consultancy. Moskowitz:Seattle Genetics : Research Funding. Ghosh:Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich:Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon:Seattle Genetics : Research Funding. Winter:Seattle Genetics : Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4380.4380
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 4
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    Bortezomib May Be Safely Combined with Y-90 Ibritumomab Tiuxetan In Patients with Relapsed/Refractory Follicular or Transformed Non-Hodgkin Lymphoma: A Phase I Trial of Combined Induction Therapy and Bortezomib Consolidation
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1749-1749
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1749-1749
    Abstract: Abstract 1749 Background: Preclinical studies suggest that bortezomib, through inhibition of NF-kB activation, may act as a radiosensitizer and enhance the effects of radioimmunotherapy. Methods: This phase I trial was designed to determine the maximum tolerated dose (MTD) of weekly bortezomib induction combined with Y-90-ibritumomab tiuxetan in patients 18 years or older with relapsed/refractory follicular or transformed non-Hodgkin lymphoma. In addition, we assessed the tolerability of weekly bortezomib consolidation following induction therapy. Cohorts consisting of three patients each were treated with bortezomib induction at doses of 1.0, 1.3, or 1.6 mg/m2 on days 1, 8, 15, and 22, rituximab 250 mg/m2 on days 8 and 15, and Y-90 ibritumomab tiuxetan 0.4 mCi/kg on day 15. Consolidation, consisting of bortezomib 1.6 mg/m2 weekly on days 1, 8, and 15 of three 28 day cycles, was initiated on day 71 after recovery of the platelet count to 100,000/uL and ANC 〉 1,000/uL. At least three patients per cohort were followed for 7 weeks or had recovery of blood counts without dose-limiting toxicities (DLTs) before dose escalation was allowed. MTD was defined as the dose previous to that in which two patients had DLTs. To be evaluable, patients were required to have received at least two doses of bortezomib and the Y-90-ibritumomab tiuxetan therapeutic dose. Response was assessed by CT scanning following induction therapy and PET/CT and diagnostic CT scans after completion of consolidation. Results: Nine patients with a median age of 55 (range: 29–71) were treated with bortezomib combined with Y-90-ibritumomab tiuxetan. Eight patients had FL and one had evidence of a transformation to diffuse, large B-cell lymphoma. All had a performance status of 0 or 1, and all had been previously treated with rituximab either as a single agent or in combination with chemotherapy. All but one had received prior chemotherapy [R-CHOP (n=7), chlorambucil (n=1), or R-CVP (n=2)], and three had received radiotherapy. Only one had bone marrow involvement. The median number of prior therapies was one (range: 1–3). Grade 3 or 4 toxicities were observed in all but one of the patients and as expected, all but one of these toxicities were hematologic (leukopenia, lymphopenia, neutropenia, and/or thrombocytopenia). One patient had grade 3 cardiotoxicity cha racterized by palpitations and shortness of breath on day 15 of her first consolidation, with PVC's noted on subsequent EKG. Though uncommon, cardiotoxicity has been reported in association with bortezomib in the form of systolic heart failure, arrhythmias, and angina. It should be noted that this patient was previously treated with an anthracycline as have the majority of patients reported to have experienced cardiotoxicity in association with bortezomib. A DLT of grade 4 thrombocytopenia lasting more than ten days was observed in two of three patients treated with bortezomib at 1.6 mg/m2. One of these two patients was the only one to receive .3 mCi/kg rather than .4 mCi/kg of the radioisotope because of thrombocytopenia on the day of treatment. Thus, the MTD of bortezomib was 1.3 mg/m2. All patients are alive, and the median followup for those patients who have not progressed is 6.5 months (range: 3 – 15 mo.). All but one patient responded to therapy (4 CR/CRu, 4PR, 1 SD). The four complete responders remain in remission at 3.0, 5.0, 5.0 and 15.0 months. All of the partial responders have progressed (3.5, 3.5, 11.5, and 17.5 months), as has the patient with stable disease (5.0 months). Conclusions: The MTD for weekly bortezomib combined with Y-90 ibritumomab tiuxetan induction therapy is 1.3 mg/m2. Consolidation with bortezomib at 1.6 mg/m2 was well tolerated in this group of relapsed/refractory follicular and transformed non-Hodgkin lymphoma patients. Nearly all patients responded. A phase II trial at the MTD is underway to better define the toxicity and effectiveness of this regimen in patients with relapsed/refractory FL. Disclosures: Evens: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrm: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ziopharm: Membership on an entity's Board of Directors or advisory committees; Lilly: Research Funding; Ortho- Biotec: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Gordon:Cure Tech, Ltd: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Inc: Research Funding; Genentech: Speakers Bureau; Millenium: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees. Winter:Millenium: Consultancy, Research Funding; Pfizer/Wyeth: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Spectrum: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1749.1749
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 5
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    Whole Genome and Exome Sequencing Defines The Genetic Landscape Of Hepatosplenic T-Cell Lymphoma
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 842-842
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 842-842
    Abstract: Hepatosplenic T-cell lymphoma (HSTL) is a rare form of lymphoma, comprising less than 1% of the cases. However, HSTL extracts a highly disproportionate toll on patients with a median age of diagnosis of 35 years and an expected median survival of less than two years. The vast majority of HSTL patients eventually succumb to their disease. The genetic basis of the disease is largely unknown. Although abnormalities of chromosome 7, including isochromosome 7q occur commonly in the disease, the role of specific genes and genetic mutations to the disease remains essentially unknown. Methods In this study, we sought to define the genetic features of HSTL through the whole genome sequencing and exome sequencing of 32 HSTL tumors and germline DNA (where available) from the same patients. Exome enrichment of DNA was carried out using the Agilent solution-based system of exon capture, which uses RNA baits to target all protein coding genes as well as ∼700 human microRNAs. Both whole genome and exome sequencing were performed using the Illumina platform. Results We identified 28 candidate cancer genes that were recurrently mutated in HSTL. Commonly implicated biological processes comprising these genes included signal transduction (e.g. PIK3CD, KRAS) and chromatin modification (e.g. TET1, SETD2 and MLL3), accounting for 16% and 23% of the total genetic events, respectively. Nearly all of these genes have been implicated in HSTL for the first time and provide new insights into the pathogenesis of the disease and potential targets for therapy. Whole genome sequencing confirmed isochromosome 7q as the most common recurrent chromosomal abnormality in HSTL and additional structural genetic alterations in chromosome 7. Conclusion Our study provides the most comprehensive genetic portrait of HSTL to date, and is a significant step in defining the genetic causes of this disease. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.842.842
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 6
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    PX-478, a Novel Small Molecule Inhibitor of Hypoxia Inducible Factor-1 (HIF-1) Downregulates HIF and Induces Cytotoxicity in Diffuse Large B Cell Lymphoma Cells.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2713-2713
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2713-2713
    Abstract: Abstract 2713 Poster Board II-689 Introduction: HIF-1 is a transcription factor that serves as a master regulator of cellular responses to hypoxia and regulates genes required for adaptation to hypoxia. Although the expression of HIF-1α subunit is constitutive, HIF-1α protein levels are regulated in response to oxygen tension. Under normoxic conditions, HIF-1α is degraded by the proteasome, and HIF-1 remains inactive. In hypoxia, HIF-1α is stabilized and forms a complex with HIF-1β that allows HIF-1 to function as a transcription factor. Thus, HIF-1α is activated only during hypoxia under normal physiologic conditions. By contrast, HIF-1α is frequently activated in cancer cells, including under normoxic conditions by oncogene products or impaired activity of tumor suppressor genes. We previously reported that there is constitutive stabilization of HIF-1α in many non-Hodgkin lymphoma (NHL) cell lines as well as among a significant fraction of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma patients (Evens et al, BJH, 2008), implicating a potential role of dysregulated HIF activation in NHL. Constitutive expression of HIF-1α enhances vascularization, increases glucose metabolism, and induces the expression of anti-apoptotic proteins in cancer tissues. HIF-1α is thought to be one of the most important molecular targets in the treatment of cancer. PX-478 is a novel small molecule inhibitor of HIF-1α being developed for the treatment of cancer. Methods: We treated several DLBCL cell lines (SUDHL4, SUDHL6, and SUDHL10) with increasing concentrations (2–25μM) of PX-478 for 4 hours followed by 20-hour incubation under normoxic (5% oxygen) or hypoxic (1.5% oxygen) conditions. Cell viability was assessed by MTT assay. Expression of HIF-1α and HIF-2α were measured by Western blotting after pre-incubation of cells with 5–25μM PX-478 followed by 20-hour incubation under normoxia or hypoxia. Results: Under hypoxic conditions, dose-dependent downregulation of HIF-1α protein levels were noted with complete absence of HIF-1α by 20μM. Interestingly, lower concentrations of PX-478 were needed for effective HIF-1α downregulation in normoxia. Of note, there was no change in HIF-2α protein levels observed in either normoxic or hypoxic conditions. In cell viability studies, time- and dose-dependent cell death of PX-478 was documented in all cell lines with an associated IC50 of 15–20μM (figure below). Conclusion: Our observations suggest that the novel small molecule HIF-1α inhibitor, PX-478, effectively downregulates HIF-1α protein at low concentrations and induces cell death in DLBCL cells. Further studies to elucidate the mechanisms of HIF-1α dependent cell death in lymphoma and the associated novel therapeutics to target this pathway are warranted. Disclosures: Gordon: Cure Tech: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2713.2713
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 7
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    MicroRNAs Distinguish Burkitt Lymphoma from the Molecular Subsets of Diffuse Large B Cell Lymphoma.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 3353-3353
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3353-3353
    Abstract: Background: Burkitt lymphoma (BL) is a highly aggressive lymphoma that can be cured in up to 80% of patients when treated with intensive multi-agent chemotherapy. The distinction between BL and diffuse large B-cell lymphoma (DLBCL) is critical because there are important differences in their clinical management. However, the distinction can be difficult because of an overlap between DLBCL and BL in morphology, immunophenotype and cytogenetics. Previous work has shown that gene expression profiling can distinguish these entities with a high degree of certainty. Our previous work has demonstrated that microRNAs play a direct role in regulating key transcription factors in normal and malignant B cells. We investigated whether microRNA expression could be used to reliably distinguish BL from DLBCL. Methods: Biopsy samples were collected from 104 patients with a diagnosis of either sporadic BL (N=25) or DLBCL (N=79). All cases were reviewed for pathology diagnosis and profiled for microRNA expression using microarrays. Using the 30 most highly differentially expressed microRNAs with the highest t-statistic, we applied singular value decomposition to identify the 10 most predictive microRNAs. Using those 10 microRNAs, we constructed a Bayesian predictor to distinguish BL from DLBCL. The predictor performance was tested using leave-one-out cross-validation. We further applied gene expression profiling to 52 cases of DLBCL to identify the molecular subsets of DLBCL: activated B cell type and germinal center B cell type DLBCL. We constructed a Bayesian predictor to distinguish these molecular subsets based upon their gene expression. A separate predictor was created from the microRNA profiles of these DLBCL subsets and tested using leave-one-out cross-validation. In order to understand the effects of lineage-specific microRNAs in B cell lymphomas, we applied FACS-sorting to isolate mature B cell subsets including naïve B cells, germinal center B cells, plasma cells and memory cells. We compared the microRNAs involved in germinal center differentiation to those expressed highly in Burkitt lymphoma. Results: The predictor constructed based on microRNA expression was 90% accurate in distinguishing Burkitt lymphoma from DLBCL, using pathology diagnosis as the standard. The microRNA-based predictor was also over 90% accurate in the distinction of the molecular subsets of DLBCL, compared to the gold standard of gene expression-profiling. Further, we found that the Burkitt lymphoma cases consistently expressed microRNAs related to normal germinal center B cell differentiation, suggesting that they also maintain expression of B cell stage-specific microRNAs. Conclusion: This study demonstrates that the microRNA expression profiles can be used to accurately distinguish Burkitt lymphoma from DLBCL. The ability of the predictor to identify the molecular subsets of patients with DLBCL and those with BL suggests that it will be useful in the diagnosis and management of patients with Burkitt lymphoma. Further, the patterns of microRNA expression and their target genes suggests a role for microRNAs in the pathophysiology of these tumors.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.3353.3353
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
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  • 8
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    Mitochondrial-Mediated Apoptosis in Lymphoma by the Diterpenoid Lactone Andrographolide (Andro), the Active Component of Andrographolis Paniculata.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2710-2710
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2710-2710
    Abstract: Abstract 2710 Poster Board II-686 Introduction/Background: Andrographolide is a diterpenoid lactone isolated from Andrographis paniculata (King of Bitters), an important herbal medicine used in China and other Asian countries to treat a range of diseases, such as respiratory infection, fever, bacterial dysentery and diarrhea. The major bioactive component extracted from Andrographis paniculata is andrographolide. The three hydroxyls at C-3, C-19 and C-14 are responsible for its biological activities. Recently, the anti-cancer properties of andrographolide have been recognized, and it has been tested in human patients. We hypothesized that the mechanism of cell death may depend on caspase activation and mitochondrial mediated cell death pathways. Methods: Using cells lines Ramos (p53 mutated Burkitts lymphoma (BL)), HF-1 (follicular lymphoma (FL)), SUDHL-4 (diffuse large B-cell lymphoma (DLBCL)) and Granta (mantle cell lymphoma (MCL)) we measured cellular cytotoxicity by MTT and apoptosis and quantified by Annexin V-FITC and PI with flow cytometry using FACS. Reactive oxygen species (ROS) production was determined by oxidation of H2DCFDA to dichlorofluorescein (DCF) and quantified by fluorescence intensity and read by flow cytometry. We investigated the mechanism of apoptosis in lymphoma cell lines and patient samples by measuring caspase activation and PARP cleavage by Western blot and Bax conformational change by immunoflourescence. Further, we dissected the influence of the Bax/Bak pathway by using Bax−/−/Bak−/− mouse endothelial fibroblasts (MEFS). Results: We found that andrographolide inhibited survival in all cell lines and was dose and time dependent (IC50 from 15-40uM in cell lines), and was accompanied by ROS production. Cell death was a result of apoptosis and was also dose and time dependent and inhibited by the anti- oxidant N-acetyl-L-cysteine (NAC) and by the pan-caspase inhibitor Z-VAD-FMK and enhanced by the glutathione (GSH) depleting agent buthionine sulfoximine (BSO) and accompanied by PARP cleavage. Similar data were extant in fresh samples from patients with FL, DLBCL, and MCL and there was activation of caspases 3, 8 and 9 in all cell lines and in all patient samples. In order to determine if mitochondrial pathways are involved in cell death, we studied Bax conformational change with the 6A7 monoclonal antibody, which specifically binds Bax protein with conformational change. We found that andrographolide induced Bax conformational change in SUDHL4 and HF1 and similarly in diffuse large B-cell lymphoma and follicular lymphoma pt samples and that this was accompanied by translocation of Bax to the mitochondria in SUDHL-4 (Figure bottom left) and HF-1 (Figure bottom right). Next, using mouse endothelial fibroblast (MEFs) Bax/Bak knockouts (MEFBAX−/−/BAK−/−), we found that andrographolide-induced apoptosis (Figure top left) and change in mitochondrial membrane potential (Figure top right) was mediated through Bax/Bak. Conclusion: This is the first demonstration that andrographolide causes ROS-dependent apoptosis in lymphoma cell lines and in primary tumor samples, and the mechanism appears to proceed through intrinsic and extrinsic caspase pathways and is associated with Bax/Bak mitochondrial translocation. Further studies of diterpenoid lactones in lymphoma are warranted. Disclosures: Gordon: Cure Tech: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2710.2710
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 9
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    Ethnicity Significantly Influences Incidence Patterns and Predicts Mortality: Adult Hodgkin Lymphoma (HL) In the United States (US)
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2683-2683
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2683-2683
    Abstract: Abstract 2683 Background: Pediatric HL studies have suggested survival differences based on ethnicity. However, little data is available regarding the impact, if any, of ethnicity on incidence patterns, disease histology, and/or survival among adult HL. Methods: We examined data for 13 US SEER areas, several of which contain large Hispanic and Black populations. Case information was obtained from the 11/2009 SEER data submission released April 2010. We analyzed incidence, HL histology, and mortality rates according to ethnicity, age, and gender. We also examined incidence patterns across the past four decades. All analyses used SEER*Stat. Results: A total of 16,783 HL cases were diagnosed among residents in the 13 SEER registry areas during 1992–2007, with non-Hispanic Whites contributing the largest number (n=11,890), followed by Hispanics (n=2,190), and Blacks (n=1,724). Consistent with SEER 9 results (1973 data), Whites show a continued bimodal age-incidence curve (6.0/100,000 ages 25–29, 2.5/100,000 ages 50–54, and 4.5/100,000 age 75–79). However, Blacks have a much less apparent bimodal pattern (4.5/100,000 ages 25–29, 2.6/100,000 ages 50–54, and 3.0/100,000 ages 75–79), while Hispanics are distinctly not bimodal with a small increase at 20–24 (2.4/100,000) followed by an exponential-like increase with peak HL incidence at ages 80–84 (7.0/100,000). Moreover, among persons 〉 65 years, HL is currently significantly more common in Hispanics than Whites (4.7-7.0/100,000 vs 3.9–4.5/100,000, respectively, p 〈 0.05). With gender, HL is more common in males than females, regardless of ethnicity. Interestingly, the male excess, however, does not occur until ages 30–34 (all ethnicities). Furthermore, from 1975–2007, HL incidence increased in Black females (annual percent change (APC) = 2.5; p 〈 0.05) and White females (APC = 0.4; p 〈 0.05). According to histology, both nodular sclerosis and mixed cellularity are more common in Whites followed by Blacks and Hispanics, while in persons age 60–84, both histologies are significantly more common in Hispanics compared with Whites and Blacks. Over the past 20 years, mortality has declined within each race by 10.3%–13.7% (p 〈 0.05). However, age-specific ethnic survival disparities are apparent (Figure 1). For ages 65–84, Hispanics have a significantly increased mortality rate compared with Whites/Blacks (p 〈 0.05). Conversely, among ages 20–44, Hispanics have a lower mortality rate versus Whites and Blacks. Conclusions: Multiple important epidemiologic and mortality differences are evident across and within ethnicities in adult HL. *Both sexes (1992-2007). Rates are per 100,000. Mortality source: US Mortality Files, National Center for Health Statistics, CDC. Accessed August 12th, 2010. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2683.2683
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 10
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    All Trans Retinoic Acid Nanodisks Enhance Retinoic Acid Receptor-Mediated Apoptosis and Cell Cycle Arrest in Mantle Cell Lymphoma.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3722-3722
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3722-3722
    Abstract: Abstract 3722 Poster Board III-658 Background Mantle cell lymphoma (MCL) is characterized by the translocation t (11; 14)(q13; q32), aggressive clinical behavior, and poor patient outcomes following conventional chemotherapy. New treatment approaches are needed that target novel pathways. All-trans retinoic acid (ATRA) is a key retinoid that acts through nuclear receptors that function as ligand-inducible transcription factors. We hypothesized that since MCL cells express retinoid receptors, ATRA will exert anti-proliferative effects and thus may have a role in treatment. In the present study, we pursued a novel approach to deliver an ATRA payload to MCL cells in culture. This water insoluble bioactive lipid was stably incorporated into nanoscale lipid particles, termed nanodisks (ND). ND are comprised of a disk-shaped phospholipid bilayer whose periphery is stabilized by amphipathic apolipoproteins. It was hypothesized that following cellular uptake and/or liberation of ATRA from ND, this retinoid will interact with intracellular binding proteins and, ultimately, nuclear hormone receptors, leading to target gene transactivation, cell growth arrest and/or apoptosis. Methods We studied the mantle cell lymphoma cell lines Granta, NCEB and JEKO. ATRA-ND were prepared using recombinant human apolipoprotein A-I as the scaffold protein. Empty ND, lacking ATRA, were prepared in the same manner except that ATRA was omitted from the formulation contents. In various experiments ATRA was presented to cells using dimethylsulfoxide (DMSO) as vehicle (naked ATRA). Reactive oxygen species (ROS) were measured by oxidation of 2'7'dichlorofluorescein diacetate (H2DCFDA) to dichlorofluorescein (DCF) and quantified by fluorescence intensity using FACS. Apoptosis was quantified by Annexin V-FITC and PI using flow cytometry and FACS. Cell cycle analysis was measured by flow cytometry using FACS. PARP cleavage, caspase activation and analysis of cell cycle regulator proteins was measured by Western blotting, and retinoic acid receptor activity was measured by RT-PCR. Results We found that ATRA-ND induced significantly more cell death than naked ATRA (in dimethylsulfoxide) or empty ND. In all three cell lines, ATRA-ND induced reactive oxygen species (ROS) generation to a greater extent than naked ATRA. Incubation of cells with the antioxidant, N-acetylcysteine, inhibited ATRA-ND-induced apoptosis. Compared to naked ATRA, ATRA-ND enhanced G1 cell cycle arrest. Cyclin dependent kinases (CDK) regulate checkpoints that integrate mitogenic and growth inhibitory signals during cell cycle transitions. CDK inhibitors bind to CDK and inhibit kinase activity, leading to cell cycle arrest. P21 and p27 negatively regulate CDKs, and since p21 is induced by the tumor suppressor p53 in response to DNA damage, the expression level of these proteins was examined in Granta cells as a function of ATRA exposure. Compared to untreated control cells, no changes in the level of these proteins were seen following incubation with empty-ND. Whereas naked ATRA induced a modest increase in p21, p27 and p53, much larger increases were induced by ATRA-ND. Further ATRA-ND resulted in striking decrease in cyclin-D1. At ATRA concentrations that induce apoptosis, expression levels of the retinoic acid receptor- α (RAR α) and retinoid X receptor- γ (RXR γ) were increased. Furthermore, the RAR antagonist, Ro41-5253, inhibited ATRA-ND-induced ROS generation and abrogated ATRA-ND-induced cell growth arrest and apoptosis. Taken together, we found that ATRA-ND-induced apoptosis is dependent on ROS generation and RAR activation. We do not know if ATRA in ND is more stable or resists degradation during the course of cell incubations or whether ATRA-ND are taken up by the cells via receptor mediated endocytosis. Further work is required to elucidate the molecular basis of the enhanced biological activity of ATRA when presented to cells as a component of ND. Conclusion ATRA-ND greatly enhanced apoptosis and cell cycle arrest in MCL cell lines, and resulted in increase in p21, p27 and p53 with a decrease in cyclin D1. It is conceivable that solubilization of ATRA in the ND hydrophobic milieu effectively concentrates this bioactive lipid and provides a means for more efficient delivery to target cells. Nonetheless, results obtained in this study suggest ATRA-ND represent a potentially effective approach to the treatment of MCL and should be explored further. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3722.3722
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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