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Abc lymphoma bortezomib

R Pytlík, M Trněný
BACKGROUND: Diffuse large B -cell lymphoma is a common label for a number of clinico pathological entities, which differ in molecular pathogenesis, clinical presentation and prognosis. Exact correlation between clinico pathological and molecular subtypes of diffuse large B -cell lymphoma was not optimally defined; however, key signal transduction pathways were identified; blockage of these pathways may be therapeutically significant. AIM: The purpose of this review is to show current approach to dia-gnostics of diffuse large B -cell lymphoma on molecular levels, to summarize current firstline treatment options for newly diagnosed diffuse large B -cell lymphoma patients and to introduce new treatment possibilities, which are currently under investigation in clinical trials...
2015: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
Anna-Katharina Zoellner, Stephan Bayerl, Grit Hutter, Yvonne Zimmermann, Wolfgang Hiddemann, Martin Dreyling
Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB=30-66%, ABC=45-57%). Combination treatment with the PI3K-δ inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB=16-38%, ABC=25-50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma...
2015: Leukemia & Lymphoma
Thomas E Witzig, Matthew J Maurer, Mary J Stenson, Cristine Allmer, William Macon, Brian Link, Jerry A Katzmann, Mamta Gupta
The detection of serum free light (FLC) is useful in the diagnosis of several hematological diseases. The role and biological relevance of monoclonal or polyclonal FLC elevations in predicting long-term outcome in diffuse large B-cell lymphoma (DLBCL) is unknown. We determined the relationship of the type of FLC elevations to outcome, tumor genotype, and pattern of serum cytokine elevations in 276 patients with untreated DLBCL. Elevated FLC was an adverse prognostic factor through 6 years of follow-up (monoclonal, Event free survival (EFS) HR = 3...
April 2014: American Journal of Hematology
Rita Coutinho, Andrew James Clear, Andrew Owen, Andrew Wilson, Janet Matthews, Abigail Lee, Rute Alvarez, Maria Gomes da Silva, José Cabeçadas, Maria Calaminici, John G Gribben
PURPOSE: The opportunity to improve therapeutic choices on the basis of molecular features of the tumor cells is on the horizon in diffuse large B-cell lymphoma (DLBCL). Agents such as bortezomib exhibit selective activity against the poor outcome activated B-cell type (ABC) DLBCL. In order for targeted therapies to succeed in this disease, robust strategies that segregate patients into molecular groups with high reliability are needed. Although molecular studies are considered gold standard, several immunohistochemistry (IHC) algorithms have been published that claim to be able to stratify patients according to their cell-of-origin and to be relevant for patient outcome...
December 15, 2013: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Rong Bu, Azhar R Hussain, Khadija A S Al-Obaisi, Maqbool Ahmed, Shahab Uddin, Khawla S Al-Kuraya
Activated B-cell type lymphoma (ABC), a subgroup of diffuse large B-cell lymphoma (DLBCL), has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the anti-apoptotic nuclear factor-κB (NFκB) pathway. The implication of NFκB inhibition in ABC has not yet been fully explored as a potential therapeutic target. Therefore, a panel of ABC cell lines was used to examine the effect of bortezomib, a proteasome inhibitor which blocks degradation of IκBα and consequently inhibits NFκB activity...
February 2014: Leukemia & Lymphoma
Girija Dasmahapatra, Dmitry Lembersky, Minkyeong P Son, Hiral Patel, Derick Peterson, Elisa Attkisson, Richard I Fisher, Jonathan W Friedberg, Paul Dent, Steven Grant
Interactions between the irreversible proteasome inhibitor carfilzomib and the pan-BH3 mimetic obatoclax were examined in germinal center (GC)- and activated B-cell-diffuse large B-cell lymphoma (ABC-DLBCL) cells. Cotreatment with minimally toxic concentrations of carfilzomib (i.e., 2-6 nmol/L) and subtoxic concentrations of obatoclax (0.05-2.0 μmol/L) synergistically increased apoptosis in multiple DLBCL cell lines and increased lethality toward primary human DLBCL but not normal CD34(+) cells. Synergistic interactions were associated with sharp increases in caspase-3 activation, PARP cleavage, p-JNK induction, upregulation of Noxa, and AKT dephosphorylation...
May 2012: Molecular Cancer Therapeutics
Fernando Cabanillas
During the past decade we have witnessed a number of changes in the field of non-Hodgkin lymphoma (NHL), including new entities added to the classification as well as a better understanding of the biology of diffuse large B-cell lymphoma (DLBCL). An understanding of the epigenetics of NHL is also contributing new agents for the management of this disorder. It has become increasingly clear that DLBCL is a biologically and clinically heterogeneous cell type. Two major categories are now recognized: germinal center B cell and activated B-cell (ABC) types...
June 2011: Clinical Lymphoma, Myeloma & Leukemia
Wyndham H Wilson, Francisco J Hernandez-Ilizaliturri, Kieron Dunleavy, Richard F Little, Owen A O'Connor
Diffuse large B-cell lymphoma (DLBCL) responds well to treatment with CHOP and the R-CHOP regimen, but a subset of patients still fail to achieve complete or durable responses. Recent advances in gene expression profiling have led to the identification of three different subtypes of DLBCL, and confirmed that patients with the activated B-cell (ABC) disease subtype are less likely to respond well to CHOP-based regimens than those with germinal centre B-cell-type (GCB) disease. This discovery could herald the use of gene expression profiling to aid treatment decisions in DLBCL, and help identify the most effective management strategies for patients...
August 2010: Leukemia & Lymphoma
Girija Dasmahapatra, Dmitry Lembersky, Lora Kramer, Richard I Fisher, Jonathan Friedberg, Paul Dent, Steven Grant
Interactions between histone deacetylase inhibitors (HDACIs) and the novel proteasome inhibitor carfilzomib (CFZ) were investigated in GC- and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cells. Coadministration of subtoxic or minimally toxic concentrations of CFZ) with marginally lethal concentrations of HDACIs (vorinostat, SNDX-275, or SBHA) synergistically increased mitochondrial injury, caspase activation, and apoptosis in both GC- and ABC-DLBCL cells. These events were associated with Jun NH2-terminal kinase (JNK) and p38MAPK activation, abrogation of HDACI-mediated nuclear factor-kappaB activation, AKT inactivation, Ku70 acetylation, and induction of gammaH2A...
June 3, 2010: Blood
G Belardo, R Piva, M G Santoro
Nuclear factor-kappaB (NF-kappaB) is involved in multiple aspects of oncogenesis and controls cancer cell survival by promoting anti-apoptotic gene expression. The constitutive activation of NF-kappaB in several types of cancers, including hematological malignancies, has been implicated in the resistance to chemo- and radiation therapy. We have previously reported that cytokine- or virus-induced NF-kappaB activation is inhibited by chemical and physical inducers of the heat shock response (HSR). In this study we show that heat stress inhibits constitutive NF-kappaB DNA-binding activity in different types of B-cell malignancies, including multiple myeloma, activated B-cell-like (ABC) type of diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma presenting aberrant NF-kappaB regulation...
January 2010: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Kieron Dunleavy, Stefania Pittaluga, Myron S Czuczman, Sandeep S Dave, George Wright, Nicole Grant, Margaret Shovlin, Elaine S Jaffe, John E Janik, Louis M Staudt, Wyndham H Wilson
Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed distinct molecular subtypes that include germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. ABC DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor-kappa B (NF-kappaB) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-kappaB might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome...
June 11, 2009: Blood
Girija Dasmahapatra, Dmitry Lembersky, Mohamed Rahmani, Lora Kramer, Jonathan Friedberg, Richard I Fisher, Paul Dent, Steven Grant
Mechanisms underlying interactions between the proteasome inhibitor bortezomib and small molecule Bcl-2 antagonists were examined in GC- and ABC-type human DLBCL (diffuse lymphocytic B-cell lymphoma) cells. Concomitant or sequential exposure to non- or minimally toxic concentrations of bortezomib or other proteasome inhibitors and either HA14-1 or gossypol resulted in a striking increase in Bax/Bak conformational change/translocation, cytochrome c release, caspase activation and synergistic induction of apoptosis in both GC- and ABC-type cells...
May 2009: Cancer Biology & Therapy
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