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https://www.readbyqxmd.com/read/28100580/venetoclax-in-patients-with-previously-treated-chronic-lymphocytic-leukemia
#1
Andrew W Roberts, Stephan Stilgenbauer, John F Seymour, David C S Huang
Venetoclax is the first BCL2 inhibitor to enter routine clinical practice. It is an orally bioavailable small molecule that binds BCL2 very specifically. Acting as a pharmacological mimic of the proteins that initiate apoptosis (a so-called BH3-mimetic), venetoclax rapidly induces apoptosis in chronic lymphocytic leukemia (CLL) cells which express high levels of BCL2 and rely on it to maintain their survival. As a single agent, daily venetoclax treatment induced durable responses in 79% of patients with relapsed or refractory CLL or small lymphocytic lymphoma in a Phase 1 study, including complete remissions in 20% of patients...
January 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28095352/the-relationship-of-rel-proto-oncogene-to-pathobiology-and-chemoresistance-in-follicular-and-transformed-follicular-lymphoma
#2
Xiaozhou Hu, Esra Baytak, Jinnan Li, Burcu Akman, Kaan Okay, Genfu Hu, Anna Scuto, Wenyan Zhang, Can Küçük
Follicular lymphoma (FL) is a common type of indolent lymphoma that occasionally transforms to more aggressive B-cell lymphomas. These transformed follicular lymphomas (tFL) are often associated with chemoresistance whose mechanisms are currently unknown. REL, a proto-oncogene located on frequently amplified 2p16.1-p15 locus, promotes tumorigenesis in many cancer types through deregulation of the NF-κB pathway; however, its role in FL pathobiology or chemoresistance has not been addressed. Here, we evaluated REL gene copy number by q-PCR on FFPE FL tumor samples, and observed REL amplification in 30...
January 9, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28089635/venetoclax-plus-rituximab-in-relapsed-or-refractory-chronic-lymphocytic-leukaemia-a-phase-1b-study
#3
John F Seymour, Shuo Ma, Danielle M Brander, Michael Y Choi, Jacqueline Barrientos, Matthew S Davids, Mary Ann Anderson, Anne W Beaven, Steven T Rosen, Constantine S Tam, Betty Prine, Suresh K Agarwal, Wijith Munasinghe, Ming Zhu, L Leanne Lash, Monali Desai, Elisa Cerri, Maria Verdugo, Su Young Kim, Rod A Humerickhouse, Gary B Gordon, Thomas J Kipps, Andrew W Roberts
BACKGROUND: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. METHODS: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial...
January 12, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28069569/the-crebbp-acetyltransferase-is-a-haploinsufficient-tumor-suppressor-in-b-cell-lymphoma
#4
Jiyuan Zhang, Sofija Vlasevska, Victoria A Wells, Sarah Nataraj, Antony B Holmes, Romain Duval, Stefanie N Meyer, Tongwei Mo, Katia Basso, Paul K Brindle, Shafinaz Hussein, Riccardo Dalla-Favera, Laura Pasqualucci
Inactivating mutations of the CREBBP acetyltransferase are highly frequent in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common germinal-center (GC) derived cancers. However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Here we show that CREBBP regulates enhancer/super-enhancer networks with central roles in GC/post-GC cell fate decisions, including genes involved in signal transduction by the B-cell receptor and CD40 receptor, transcriptional control of GC and plasma cell development, and antigen presentation...
January 9, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28061782/double-hit-lymphomas-clinical-morphological-immunohistochemical-and-cytogenetic-study-in-a-series-of-brazilian-patients-with-high-grade-non-hodgkin-lymphoma
#5
Cristiano Claudino Oliveira, Helena Maciel-Guerra, Luan Kucko, Eric Jun Hirama, Américo Delgado Brilhante, Francisco Carlos Quevedo, Isabela Werneck da Cunha, Fernando Augusto Soares, Ligia Niero-Melo, Patrícia Pintor Dos Reis, Maria Aparecida Custodio Domingues
BACKGROUND: Double-hit lymphomas (DHL) are rare high-grade neoplasms characterized by two translocations: one involving the gene MYC and another involving genes BCL2 or BCL6, whose diagnosis depends on cytogenetic examination. This research studied DHL and morphological and/or immunophenotypic factors associated with the detection of these translocations in a group of high-grade non-Hodgkin lymphoma cases. METHOD: Clinical and morphological reviews of 120 cases diagnosed with diffuse large B-cell lymphoma and Burkitt lymphoma were conducted...
January 7, 2017: Diagnostic Pathology
https://www.readbyqxmd.com/read/28057912/mir-340-inhibits-proliferation-and-induces-apoptosis-in-gastric-cancer-cell-line-sgc-7901-possibly-via-the-akt-pathway
#6
Jinzhong Yu, Ruijie Wang, Jianshe Chen, Jinfeng Wu, Zhongqin Dang, Qinsheng Zhang, Bo Li
BACKGROUND Gastric cancer is among the most common types of cancer, with high morbidity and mortality. MicroRNAs (miRNAs) play vital roles in the tumorigenesis and biology of gastric cancer. This study aimed to reveal the role of miR-340 in gastric cancer cell proliferation and apoptosis and to elucidate the potential mechanisms. MATERIAL AND METHODS Human gastric cancer cells SGC-7901 were used in this study for cell transfection with miR-340 mimic or inhibitor. After transfection, cell viability, proliferation, and apoptosis were examined by MTT, BrdU, and flow cytometry assays, respectively...
January 6, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28057804/cell-cycle-progression-dictates-the-requirement-for-bcl2-in-natural-killer-cell-survival
#7
Charlotte Viant, Sophie Guia, Robert J Hennessy, Jai Rautela, Kim Pham, Claire Bernat, Wilford Goh, Yuhao Jiao, Rebecca Delconte, Michael Roger, Vanina Simon, Fernando Souza-Fonseca-Guimaraes, Stephanie Grabow, Gabrielle T Belz, Benjamin T Kile, Andreas Strasser, Daniel Gray, Phillip D Hodgkin, Bruce Beutler, Eric Vivier, Sophie Ugolini, Nicholas D Huntington
Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells...
January 5, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28039906/prognostic-impact-of-cd5-expression-in-diffuse-large-b-cell-lymphoma-in-patients-treated-with-rituximab-epoch
#8
Beenu Thakral, L Jeffrey Medeiros, Parth Desai, Pei Lin, C Cameron Yin, Guilin Tang, Joseph D Khoury, Shimin Hu, Jie Xu, Sanam Loghavi, Bei Hu, Yasuhiro Oki, Shaoying Li
OBJECTIVES: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) represents 5-10% of all DLBCL cases, which has been associated with a poorer prognosis in patients treated with R-CHOP. Prognostic impact of CD5 expression in DLBCL patients treated with R-EPOCH has not been evaluated. METHODS: We studied 130 patients with de novo DLBCL who received frontline R-EPOCH therapy. The clinicopathologic features and overall survival (OS) were compared between the CD5+ and CD5-negative DLBCL patients...
December 31, 2016: European Journal of Haematology
https://www.readbyqxmd.com/read/28038709/signet-ring-cell-lymphoma-clinicopathologic-immunohistochemical-and-fluorescence-in-situ-hybridization-studies-of-7-cases
#9
Shanxiang Zhang, Jihong Sun, Yanan Fang, Mehdi Nassiri, Lanting Liu, Jiehao Zhou, Ryan Stohler, Haki Choi, Gail H Vance
CONTEXT: Signet-ring cell lymphoma (SRCL) is a rare morphologic variant of non-Hodgkin lymphoma. Although it was initially reported as a rare morphologic variant of follicular lymphoma (FL), SRCL has to date been described in most types of non-Hodgkin lymphoma, mostly as single-case reports. OBJECTIVE: To study SRCL systematically by immunohistochemical stains and fluorescent in situ hybridization analyses. DESIGN: Seven SRCL cases were stained for CD3, CD5, CD20, PAX-5, CD10, CD21, CD23, cyclin D1, BCL2, BCL6, Ki-67, and MUM-1, and were analyzed by fluorescent in situ hybridization for BCL2, BCL6, MYC, and MALT1 rearrangements...
February 2017: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/28035374/activation-of-oncogenic-pathways-in-classical-hodgkin-lymphoma-by-decitabine-a-rationale-for-combination-with-small-molecular-weight-inhibitors
#10
Tatjana Maria Swerev, Thomas Wirth, Alexey Ushmorov
DNA methylation is an epigenetic control mechanism that contributes to the specific phenotype and to the oncogenic program of virtually all tumor entities. Although efficacy of demethylating agents in classical Hodgkin lymphoma (cHL) was not specifically tested, a case of regression of relapsed metastatic cHL was described as a fortunate side‑effect of the demethylating agent 5‑azacytidine in a patient with myelodysplastic syndrome. We investigated molecular mechanisms of decitabine (5‑Aza‑dC) antitumor activity in cHL using gene expression profiling followed by gene set enrichment analysis...
February 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28034071/relapsed-or-refractory-double-expressor-and-double-hit-lymphomas-have-inferior-progression-free-survival-after-autologous-stem-cell-transplantation
#11
Alex F Herrera, Matthew Mei, Lawrence Low, Haesook T Kim, Gabriel K Griffin, Joo Y Song, Reid W Merryman, Victoria Bedell, Christine Pak, Heather Sun, Tanya Paris, Tracey Stiller, Jennifer R Brown, Lihua E Budde, Wing C Chan, Robert Chen, Matthew S Davids, Arnold S Freedman, David C Fisher, Eric D Jacobsen, Caron A Jacobson, Ann S LaCasce, Joyce Murata-Collins, Auayporn P Nademanee, Joycelynne M Palmer, German A Pihan, Raju Pillai, Leslie Popplewell, Tanya Siddiqi, Aliyah R Sohani, Jasmine Zain, Steven T Rosen, Larry W Kwak, David M Weinstock, Stephen J Forman, Dennis D Weisenburger, Young Kim, Scott J Rodig, Amrita Krishnan, Philippe Armand
Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled...
January 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28018176/activated-microglia-induce-bone-marrow-mesenchymal-stem-cells-to-produce-glial-cell-derived-neurotrophic-factor-and-protect-neurons-against-oxygen-glucose-deprivation-injury
#12
Bingke Lv, Feng Li, Jie Fang, Limin Xu, Chengmei Sun, Jianbang Han, Tian Hua, Zhongfei Zhang, Zhiming Feng, Qinghua Wang, Xiaodan Jiang
In this study, we investigated interactions among microglia (MG), bone marrow mesenchymal stem cells (BMSCs) and neurons in cerebral ischemia and the potential mechanisms using an in vitro oxygen-glucose deprivation (OGD) model. Rat BMSCs were incubated with conditioned medium (CM) from in vitro cultures of OGD-activated rat MG and murine BV2 MG cells. Effects of glial cell-derived neurotrophic factor (GDNF) on rat neuron viability, apoptosis, lactate dehydrogenase (LDH) leakage and mitochondrial membrane potential (MMP) were analyzed in this model...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28017967/duvelisib-treatment-is-associated-with-altered-expression-of-apoptotic-regulators-that-helps-in-sensitization-of-chronic-lymphocytic-leukemia-cells-to-venetoclax-abt-199
#13
V M Patel, K Balakrishnan, M Douglas, T Tibbitts, E Y Xu, J L Kutok, M Ayers, A Sarkar, R Guerrieri, W G Wierda, S O'Brien, N Jain, H M Stern, V Gandhi
Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma (iNHL). In CLL, duvelisib monotherapy is associated with high iwCLL and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene-expression studies (RNA seq, Nanostring, Affymetrix array, and real time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes...
December 26, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28011484/potential-prognostic-molecular-signatures-in-a-preclinical-model-of-melanoma
#14
Sotirios P Fortis, Eleftheria A Anastasopoulou, Ioannis F Voutsas, Constantin N Baxevanis, Sonia A Perez, Louisa G Mahaira
Numerous studies have revealed a variety of pathways involved in the development of melanoma, however, the molecular and genetic divergence of underlying mechanisms remain vague. In a mouse model, we studied the expression pattern of insulin-like growth factor 2 mRNA-binding protein 1 (Igf2bp1) and target genes microphthalmia-associated transcription factor (Mitf), v-myc avian myelocytomatosis viral oncogene homolog (Myc), B-cell lymphoma 2 (Bcl2), prothymosin alpha (Ptma) and melan-A (Mlana) in relation to tumor-growth characteristics...
January 2017: Anticancer Research
https://www.readbyqxmd.com/read/28007011/mimicking-the-acute-myeloid-leukemia-niche-for-molecular-study-and-drug-screening
#15
Mohammad Houshmand, Masoud Soleimani, Amir Atashi, Giuseppe Saglio, Mohammad Abdollahi, Mahin Nikougoftar Zarif
Bone marrow niche is a major contributing factor in leukemia development and drug resistance in acute myeloid leukemia (AML) patients. Although mimicking leukemic bone marrow niche relies on two-dimensional (2D) culture conditions, it cannot recapitulate complex bone marrow structure that causes introduction of different three-dimensional (3D) scaffolds. Simultaneously, microfluidic platform by perfusing medium culture mimic interstitial fluid flow, along with 3D scaffold would help for mimicking bone marrow microenvironment...
January 13, 2017: Tissue Engineering. Part C, Methods
https://www.readbyqxmd.com/read/27995457/detection-of-chromosomal-abnormalities-by-g-banding-and-prognostic-impact-in-follicular-lymphoma-in-the-rituximab-era
#16
Taku Tsukamoto, Miki Kiyota, Eri Kawata, Nobuhiko Uoshima, Shotaro Tatekawa, Yoshiaki Chinen, Hisao Nagoshi, Shinsuke Mizutani, Yuji Shimura, Mio Yamamoto-Sugitani, Tsutomu Kobayashi, Shigeo Horiike, Satoru Yasukawa, Akio Yanagisawa, Masafumi Taniwaki, Junya Kuroda
Disease-specific cytogenetic abnormalities involving BCL2 gene rearrangement frequently co-exist with other cytogenetic abnormalities, contributing to disease progression in follicular lymphoma (FL). In the present study, we retrospectively investigated the prognostic impact of BCL2-unrelated cytogenetic abnormalities in FL. Of 139 consecutively diagnosed patients with FL at two independent institutes, metaphase spreads of tumor cells were obtained for use in G-banding analysis in 77 patients. The recurrent additional cytogenetic abnormalities included chromosome gains +5 (n = 8), +7 (n = 16), +12 (n = 10), and +X (n = 12), and losses -8 (n = 7), -13 (n = 12) -15 (n = 7), and 6q- (n = 7)...
December 19, 2016: International Journal of Hematology
https://www.readbyqxmd.com/read/27993575/b-cell-post-transplant-lymphoproliferative-disorder-isolated-to-the-central-nervous-system-is-ebv-positive-and-lacks-p53-and-myc-expression-by-immunohistochemistry
#17
Andrew Sundin, Bartosz J Grzywacz, Sophia Yohe, Michael A Linden, Elizabeth L Courville
In this retrospective study from one institution, we performed a clinicopathologic study of a cohort of patients with post-transplant lymphoproliferative disorder (PTLD) confined to the central nervous system. We also identified a comparison cohort of patients with de novo primary diffuse large B-cell lymphoma of the central nervous system. We performed a detailed morphologic review, evaluated Epstein-Barr Virus (EBV) by in-situ hybridization, and interpreted a panel of immunohistochemical stains in a subset of cases including Hans classification markers (CD10, BCL6, MUM1), p53, CD30, myc, and BCL2...
December 16, 2016: Human Pathology
https://www.readbyqxmd.com/read/27990281/mitochondrial-apoptosis-and-bh3-mimetics
#18
REVIEW
Haiming Dai, X Wei Meng, Scott H Kaufmann
The BCL2-selective BH3 mimetic venetoclax was recently approved for the treatment of relapsed, chromosome 17p-deleted chronic lymphocytic leukemia (CLL) and is undergoing extensive testing, alone and in combination, in lymphomas, acute leukemias, and solid tumors. Here we summarize recent advances in understanding of the biology of BCL2 family members that shed light on the action of BH3 mimetics, review preclinical and clinical studies leading to the regulatory approval of venetoclax, and discuss future investigation of this new class of antineoplastic agent...
2016: F1000Research
https://www.readbyqxmd.com/read/27986884/beyond-rchop-a-blueprint-for-diffuse-large-b-cell-lymphoma-research
#19
REVIEW
Grzegorz S Nowakowski, Kristie A Blum, Brad S Kahl, Jonathan W Friedberg, Lawrence Baizer, Richard F Little, David G Maloney, Laurie H Sehn, Michael E Williams, Wyndham H Wilson, John P Leonard, Sonali M Smith
Diffuse large B cell lymphoma (DLBCL) comprises multiple molecular and biological subtypes, resulting in a broad range of clinical outcomes. With standard chemoimmunotherapy, there remains an unacceptably high treatment failure rate in certain DLBCL subsets: activated B cell (ABC) DLBCL, double-hit lymphoma defined by the dual translocation of MYC and BCL2, dual protein-expressing lymphomas defined by the overexpression of MYC and BCL2, and older patients and those with central nervous system involvement. The main research challenges for DLBCL are to accurately identify molecular subsets and to determine if specific chemotherapy platforms and targeted agents offer differential benefit...
December 2016: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27973535/the-influence-of-programmed-cell-death-in-myeloid-cells-on-host-resilience-to-infection-with-legionella-pneumophila-or-streptococcus-pyogenes
#20
Pia Gamradt, Yun Xu, Nina Gratz, Kellyanne Duncan, Lester Kobzik, Sandra Högler, Pavel Kovarik, Thomas Decker, Amanda M Jamieson
Pathogen clearance and host resilience/tolerance to infection are both important factors in surviving an infection. Cells of the myeloid lineage play important roles in both of these processes. Neutrophils, monocytes, macrophages, and dendritic cells all have important roles in initiation of the immune response and clearance of bacterial pathogens. If these cells are not properly regulated they can result in excessive inflammation and immunopathology leading to decreased host resilience. Programmed cell death (PCD) is one possible mechanism that myeloid cells may use to prevent excessive inflammation...
December 2016: PLoS Pathogens
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