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Microenvironment lymphoma

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https://www.readbyqxmd.com/read/28088788/dual-syk-jak-inhibition-overcomes-ibrutinib-resistance-in-chronic-lymphocytic-leukemia-cerdulatinib-but-not-ibrutinib-induces-apoptosis-of-tumor-cells-protected-by-the-microenvironment
#1
Ailin Guo, Pin Lu, Greg Coffey, Pamela Conley, Anjali Pandey, Y Lynn Wang
Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28062796/integrated-cellular-and-plasma-proteomics-of-contrasting-b-cell-cancers-reveals-common-unique-and-systemic-signatures
#2
Harvey E Johnston, Matthew J Carter, Kerry L Cox, Melanie Dunscombe, Antigoni Manousopoulou, Paul A Townsend, Spiro D Garbis, Mark S Cragg
Approximately 800,000 leukaemia and lymphoma cases are diagnosed worldwide each year. Burkitt's lymphoma (BL) and chronic lymphocytic leukaemia (CLL), are examples of contrasting B-cell cancers; BL is a highly aggressive lymphoid tumour, frequently affecting children, whilst CLL typically presents as an indolent, slow-progressing leukaemia affecting the elderly. The B-cell-specific over-expression of the myc and tcl1 oncogenes in mice induce spontaneous malignancies modelling BL and CLL, respectively. Quantitative mass spectrometry proteomics and isobaric labelling were employed to examine the biology underpinning contrasting Eμ-myc and Eμ-TCL1 B-cell tumours...
January 4, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28059091/identification-of-distinct-subgroups-of-ebv-positive-post-transplant-diffuse-large-b-cell-lymphoma
#3
Julie Morscio, Julio Finalet Ferreiro, Sara Vander Borght, Emilie Bittoun, Olivier Gheysens, Daan Dierickx, Gregor Verhoef, Iwona Wlodarska, Thomas Tousseyn
Post-transplantation lymphoproliferative disorder is an aggressive complication of transplantation, most frequently of diffuse large B-cell lymphoma morphology and associated with Epstein-Barr virus (EBV) infection/reactivation. In this study the microenvironment of EBV(+) (n=23) and EBV(-) (n=9) post-transplant non-germinal center B-cell diffuse large B-cell lymphoma was characterized. Of EBV(+) cases somatic hypermutation analysis, gene expression profiling, and extensive phenotyping were performed. Our results demonstrated variable cytotoxic T-cell infiltration and significantly increased CD163(+) M2 macrophage infiltration in EBV(+) compared with EBV(-) post-transplant diffuse large B-cell lymphoma...
January 6, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28056186/tampering-with-cancer-chemoresistance-by-targeting-the-tgm2-il6-autophagy-regulatory-network
#4
Han Zhang, Nami McCarty
Macroautophagy/autophagy is a well-established process involved in maintaining cellular homeostasis, but its role in cancer is complex and even controversial. Many studies have reported a correlative relationship between increased autophagy and evolving cancer cells under stress conditions such as nutrient or oxygen deprivation; however, there has been a lack of a plausible mechanistic link to properly target the autophagy process in the context of this microenvironment. We recently unveiled a positive regulatory loop involving TGM2 (transglutaminase 2)-NFKB/NF-κB signaling, IL6 and autophagy in cancer using mantle cell lymphoma (MCL) as a model system...
January 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28055963/emetine-elicits-apoptosis-of-intractable-b-cell-lymphoma-cells-with-myc-rearrangement-through-inhibition-of-glycolytic-metabolism
#5
Tomohiro Aoki, Kazuyuki Shimada, Akihiko Sakamoto, Keiki Sugimoto, Takanobu Morishita, Yuki Kojima, Satoko Shimada, Seiichi Kato, Chisako Iriyama, Shunsuke Kuno, Yasuhiko Harada, Akihiro Tomita, Fumihiko Hayakawa, Hitoshi Kiyoi
Despite improved clinical outcomes of diffuse large B-cell lymphoma, a certain proportion of patients still develop a primary refractory disease. To overcome these lymphomas that are intractable to existing treatment strategies, the tumor microenvironment has been identified as a potential therapeutic target. Here we describe our search for effective drugs for primary refractory lymphoma cells with MYC rearrangement. Through the drug screening of 3,440 known compounds, we identified a unique compound, emetine...
December 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/28054086/3d-microvascular-model-recapitulates-the-diffuse-large-b-cell-lymphoma-tumor-microenvironment-in-vitro
#6
Robert G Mannino, Adriana N Santiago-Miranda, Pallab Pradhan, Yongzhi Qiu, Joscelyn C Mejias, Sattva S Neelapu, Krishnendu Roy, Wilbur A Lam
Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer that affects ∼22 000 people in the United States yearly. Understanding the complex cellular interactions of the tumor microenvironment is critical to the success and development of DLBCL treatment strategies. In vitro platforms that successfully model the complex tumor microenvironment without introducing the variability of in vivo systems are vital for understanding these interactions. To date, no such in vitro model exists that can accurately recapitulate the interactions that occur between immune cells, cancer cells, and endothelial cells in the tumor microenvironment of DLBCL...
January 5, 2017: Lab on a Chip
https://www.readbyqxmd.com/read/28038319/recruitment-of-tiam1-to-semaphorin-4d-activates-rac-and-enhances-proliferation-invasion-and-metastasis-in-oral-squamous-cell-carcinoma
#7
Hua Zhou, Maricel G Kann, Emily K Mallory, Ying-Hua Yang, Amr Bugshan, Nada O Binmadi, John R Basile
The semaphorins and the plexins are a family of large, cysteine-rich proteins originally identified as regulators of axon growth and lymphocyte activation that are now known to provide motility and positional information for a number of cell and tissue types. For example, our group and others have shown that some malignancies over express Semaphorin 4D (S4D), which acts through its receptor Plexin-B1 (PB1) on endothelial cells to attract blood vessels from the surrounding stroma for the purpose of supporting tumor growth...
December 27, 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28018857/murine-models-of-splenic-marginal-zone-lymphoma-a-role-for-cav1
#8
REVIEW
Chelsey L Patten, Christine E Cutucache
Dozens of murine models of indolent and aggressive B-cell lymphomas have been generated to date. These include those manifesting chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), as well as xenografts of mantle cell lymphoma (MCL). These models have led to an improved understanding of disease etiology, B-cell biology, immunomodulation, and the importance of the tumor microenvironment. Despite these efforts in CLL, DLBCL, and MCL, considerably little progress toward a model of splenic marginal zone lymphoma (SMZL) has been accomplished...
2016: Frontiers in Oncology
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
#9
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/28007011/mimicking-the-acute-myeloid-leukemia-niche-for-molecular-study-and-drug-screening
#10
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/28000533/prospects-to-improve-chimeric-antigen-receptor-t-cell-therapy-for-solid-tumors
#11
Chuan Jin, Di Yu, Magnus Essand
Adoptive transfer of patient-derived T-cells engineered with a chimeric antigen receptor (CAR) targeting the pan-B-cell marker CD19 has led to complete remission in patients with B-cell leukemias while response rates are more modest for B-cell lymphomas. This can be attributed to the fact that the semi-solid structure of lymphomas impedes T-cell infiltration and that the immune suppressive microenvironment within these tumors dampens the effect of CAR T-cells. These obstacles are even more pronounced for solid tumors where dense and often highly immunosuppressive structures are found...
December 2016: Immunotherapy
https://www.readbyqxmd.com/read/27999289/characterization-of-the-microenvironment-of-nodular-lymphocyte-predominant-hodgkin-lymphoma
#12
Lydia Visser, Rui Wu, Bea Rutgers, Arjan Diepstra, Anke van den Berg
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is characterized by a low percentage of neoplastic lymphocyte predominant (LP) cells in a background of lymphocytes. The goal of this study is to characterize the microenvironment in NLPHL. Ten NLPHL cases and seven reactive lymph nodes (RLN) were analyzed by flow cytometry for the main immune cells and multiple specific subpopulations. To discriminate between cells in or outside the tumor cell area, we used CD26. We observed significantly lower levels of CD20+ B-cells and CD56+ NK cells and higher levels of CD4+ T-cells in NLPHL in comparison to RLN...
December 16, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27993085/vaccine-strategies-for-the-treatment-of-lymphoma-preclinical-progress-and-clinical-trial-update
#13
Thomas U Marron, Lukas Ronner, Peter E Martin, Christopher R Flowers, Joshua D Brody
The clonal B-cell immunoglobulin idiotype found on the surface of lymphomas was the first targeted tumor-specific antigen, and combinations of idiotype with classical and novel adjuvants were shown to stimulate robust humoral and cellular responses, though clinical efficacy was more variable. Cellular and in situ vaccination to help target a wider array of tumor-specific antigens have also been able to stimulate tumor-specific cellular responses, though their clinical success has also been limited. Our growing understanding of the role of regulatory cells and the immunosuppressive tumor microenvironment, along with a wide variety of immunomodulatory agents developed as of late, offer promising adjuvants to potentiate the immune responses elicited by these vaccine protocols and to achieve durable remissions...
November 2016: Immunotherapy
https://www.readbyqxmd.com/read/27990323/impaired-functional-responses-in-follicular-lymphoma-cd8-tim-3-t-lymphocytes-following-tcr-engagement
#14
Pauline Gravelle, Catherine Do, Camille Franchet, Sabina Mueller, Lucie Oberic, Loïc Ysebaert, Luigi Maria Larocca, Stefan Hohaus, Marie-Noëlle Calmels, François-Xavier Frenois, Robert Kridel, Randy D Gascoyne, Guy Laurent, Pierre Brousset, Salvatore Valitutti, Camille Laurent
Upregulation of T cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by ex vivo cytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8(+)TIM-3(+)T cells in lymph nodes of FL patients. When compared to their CD8(+)TIM-3(-) counterparts, CD8(+)TIM-3(+) T cells exhibited defective cytokine production following TCR engagement...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27974566/cd63-regulates-epstein-barr-virus-lmp1-exosomal-packaging-enhancement-of-vesicle-production-and-non-canonical-nf-%C3%AE%C2%BAb-signaling
#15
Stephanie N Hurwitz, Dingani Nkosi, Meghan M Conlon, Sara B York, Xia Liu, Deanna C Tremblay, David G Meckes
: Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) encoded oncoprotein that is packaged into small extracellular vesicles (EVs) called exosomes. Trafficking of LMP1 into multivesicular bodies (MVBs) alters the content and function of exosomes. LMP1-modified exosomes enhance the growth, migration, and invasion of malignant cells, demonstrating the capacity to manipulate the tumor microenvironment and enhance the progression of EBV-associated cancers. Despite the growing evidence surrounding the significance of LMP1-modified exosomes in cancer, very little is understood about the mechanisms that orchestrate LMP1 incorporation into these vesicles...
December 14, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27956631/the-idh2-r172k-mutation-associated-with-angioimmunoblastic-t-cell-lymphoma-produces-2hg-in-t-cells-and-impacts-lymphoid-development
#16
François Lemonnier, Rob A Cairns, Satoshi Inoue, Wanda Y Li, Aurélie Dupuy, Sophie Broutin, Nadine Martin, Virginie Fataccioli, Romain Pelletier, Andrew Wakeham, Bryan E Snow, Laurence de Leval, Anais Pujals, Corinne Haioun, Angelo Paci, Erica R Tobin, Rohini Narayanaswamy, Katherine Yen, Shengfang Jin, Philippe Gaulard, Tak W Mak
Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in angioimmunoblastic T-cell lymphoma (AITL), mutations are almost exclusively restricted to IDH2 R172, and levels of 2HG have not been comprehensively measured...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27943355/serum-level-of-cxcl10-is-associated-with-inflammatory-prognostic-biomarkers-in-patients-with-diffuse-large-b-cell-lymphoma
#17
Jung Yong Hong, Kyung Ju Ryu, Ji Yean Lee, Chaehwa Park, Young Hyeh Ko, Won Seog Kim, Seok Jin Kim
Inflammatory biomarkers, such as the neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and Glasgow Prognostic Score (GPS) have been proposed to predict prognosis in diffuse large B-cell lymphoma (DLBCL). C-X-C motif ligand 10 (CXCL10) is a chemokine released from inflammatory cells in the tumor microenvironment and is known to promote tumor cell migration and invasion. In this study, we investigated the clinical impact of pretreatment serum level of CXCL10 on the prognostic value of inflammatory biomarkers in 313 patients with DLBCL who were enrolled into a prospective cohort study...
December 12, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27940304/the-structure-of-polymer-carriers-controls-the-efficacy-of-the-experimental-combination-treatment-of-tumors-with-hpma-copolymer-conjugates-carrying-doxorubicin-and-docetaxel
#18
Milada Šírová, Jiří Strohalm, Petr Chytil, Ondřej Lidický, Jakub Tomala, Blanka Říhová, Tomáš Etrych
The tumor-specific targeting of cancerostatics using polymer drug carriers represents a potential strategy to achieve an effective treatment with reduced side toxicity. Synthetic water-soluble copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are carriers with tunable architecture and drug loading, tumor-specific accumulation of the drug, and its controlled release. We describe a combination treatment of murine EL4 T cell lymphoma with HPMA-based star conjugates (Mw 250,000gmol(-1)) of doxorubicin (Dox) or docetaxel (Dtx) designed for enhanced tumor accumulation and combination therapy...
December 6, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/27933753/mass-cytometry-of-follicular-lymphoma-tumors-reveals-intrinsic-heterogeneity-in-proteins-including-hla-dr-and-a-deficit-in-non-malignant-plasmablast-and-germinal-center-b-cell-populations
#19
Cara Ellen Wogsland, Allison Rae Greenplate, Arne Kolstad, June Helen Myklebust, Jonathan Michael Irish, Kanutte Huse
BACKGROUND: Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma that has a risk of transformation to more aggressive lymphoma. Relatively little is known about the non-malignant B-cell and T-cell subset composition within the tumor microenvironment and whether altered phenotypes are associated with patterns of lymphoma B-cell heterogeneity. METHODS: Two mass cytometry (CyTOF) panels were designed to immunophenotype B and T cells in FL tumors. Populations of malignant B cells, non-malignant B cells, and T cells from each FL tumor were identified and their phenotypes compared to B and T cells from healthy human tonsillar tissue...
December 9, 2016: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/27913493/novel-agents-in-follicular-lymphoma-choosing-the-best-target
#20
Laurie H Sehn
Outcomes in patients with follicular lymphoma (FL) have improved dramatically over the last decade. However, novel agents are greatly needed for those who exhibit treatment resistance, in order to minimize lifelong toxicity and to enable combinations that may allow us to achieve the elusive goal of cure. Biological advances have led to the discovery of a large number of potential therapeutic targets and the development of a plethora of novel agents designed to exploit these processes. Possible targets include tumor cell surface markers, key components of intracellular pathways and epigenetic mechanisms, and reactive cells of the microenvironment...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
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