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Genomic lymphoma

Rishu Agarwal, Mark A Dawson, Martin Dreyling, Constantine S Tam
Novel targeted therapeutics has significantly improved the outlook of patients with relapsed/refractory mantle cell lymphoma (R/R MCL). Despite significant efficacy, one of the major limitations of these targeted agents is presence of primary or acquired resistance to these novel drugs. Patients who fail primary therapy especially with ibrutinib have poor outcomes and may respond poorly to subsequent therapies. Hence, it is important to understand resistance mechanisms a priori to identify patients who are unlikely to respond, and to explore alternative therapeutic strategies...
June 18, 2018: Leukemia & Lymphoma
Aubhishek Zaman, Trever G Bivona
In lung cancer, genomics-driven comprehensive molecular profiling has identified novel chemically and immunologically addressable vulnerabilities, resulting in an increasing application of precision medicine by targeted inactivation of tumor oncogenes and immunogenic activation of host anti-tumor surveillance as modes of treatment. However, initially profound response of these targeted therapies is followed by relapse due to therapy-resistant residual disease states. Although distinct mechanisms and frameworks for therapy resistance have been proposed, accounting for and upfront prediction of resistance trajectories has been challenging...
May 2018: Annals of Translational Medicine
Jikui Guan, Susanne Fransson, Joachim Tetteh T Siaw, Diana Treis, Jimmy Van den Eynden, Damini Chand, Ganesh Umapathy, Petter Svenberg, Kristina Ruuth, Sandra Wessman, Alia Shamikh, Hans Jacobsson, Lena Gordon, Jakob Stenman, Erik Larsson, Par-Johan Svensson, Magnus Hansson, Tommy Martinsson, Per Kogner, Ruth H Palmer, Bengt Hallberg
Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options...
June 15, 2018: Cold Spring Harbor Molecular Case Studies
Aaron M Goodman, David Piccioni, Shumei Kato, Amélie Boichard, Huan-You Wang, Garrett Frampton, Scott M Lippman, Caitlin Connelly, David Fabrizio, Vincent Miller, Jason K Sicklick, Razelle Kurzrock
Importance: Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors. Objectives: To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors...
June 14, 2018: JAMA Oncology
Anne Steininger, Grit Ebert, Benjamin V Becker, Chalid Assaf, Markus Möbs, Christian A Schmidt, Piotr Grabarczyk, Lars R Jensen, Grzegorz K Przybylski, Matthias Port, Andreas W Kuss, Reinhard Ullmann
In classical models of tumorigenesis, the accumulation of tumor promoting chromosomal aberrations is described as a gradual process. Next-generation sequencing-based methods have recently revealed complex patterns of chromosomal aberrations, which are beyond explanation by these classical models of karyotypic evolution of tumor genomes. Thus, the term chromothripsis has been introduced to describe a phenomenon, where temporarily and spatially confined genomic instability results in dramatic chromosomal rearrangements limited to segments of one or a few chromosomes...
2018: Frontiers in Oncology
Manuela Krumbholz, Wilhelm Woessmann, Jakob Zierk, David Seniuk, Paolo Ceppi, Martin Zimmermann, Vijay Kumar Singh, Markus Metzler, Christine Damm-Welk
Nucleophosmin-anaplastic lymphoma kinase ( NPM-ALK) fusion genes resulting from the translocation t(2;5)(p23;q35) are present in almost 90% of childhood ALK-positive anaplastic large-cell lymphomas (ALCL). Detection and quantification of minimal disseminated disease (MDD) by measuring NPM-ALK fusion transcript levels in the blood provide independent prognostic parameters. Characterization of the genomic breakpoints provides insights into the pathogenesis of the translocation and allows for DNA-based minimal disease monitoring...
May 29, 2018: Oncotarget
Lucy C Fox, Costas K Yannakou, Georgina Ryland, Stephen Lade, Michael Dickinson, Belinda A Campbell, Henry Miles Prince
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an MYD88 p...
June 13, 2018: International Journal of Molecular Sciences
Guy Journo, Carmel Tushinsky, Asia Shterngas, Nir Avital, Yonatan Eran, Marcela Viviana Karpuj, Milana Frenkel-Morgenstern, Meir Shamay
Kaposi's sarcoma associated herpesvirus (KSHV, HHV-8) is a gamma herpesvirus associated with several human malignancies. DNA methylation at CpG dinucleotides is an epigenetic mark dysregulated in many cancer types, and in KSHV infected cells. Several previous studies have analyzed in detail the CpG methylation of the KSHV episomal genomes, but little is known about the impact of KSHV on the human genome. Our knowledge of cellular CpG methylation in the context of KSHV infection is currently limited to four hyper-methylated human gene promoters...
June 13, 2018: Journal of Virology
Harutaka Katano
Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8, or HHV-8) was firstly discovered in Kaposi's sarcoma tissue derived from patients with acquired immune deficiency syndrome. KSHV infection is associated with malignancies and certain inflammatory conditions. In addition to Kaposi's sarcoma, KSHV has been detected in primary effusion lymphoma, KSHV-associated lymphoma, and some cases of multicentric Castleman disease (MCD). Recently, KSHV inflammatory cytokine syndrome (KICS) was also defined as a KSHV-associated disease...
2018: Advances in Experimental Medicine and Biology
Keiji Ueda
Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8), is the eighth human herpesvirus found by Yuan Chang and Patrick Moore, 1992. It is a Rhadinovirus belonging to the gamma herpesvirus subfamily. As known for many gamma herpesviruses, KSHV is also well-correlated to several cancer formations such as Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Different from the other herpesvirus subfamily, gamma herpesviruses establish latency as a default infection strategy when they infect to the target cells, as KSHV is present as the latent form in the related cancers...
2018: Advances in Experimental Medicine and Biology
Andrew M Intlekofer, Erel Joffe, Connie L Batlevi, Patrick Hilden, Jie He, Venkatraman E Seshan, Andrew D Zelenetz, M Lia Palomba, Craig H Moskowitz, Carol Portlock, David J Straus, Ariela Noy, Steven M Horwitz, John F Gerecitano, Alison Moskowitz, Paul Hamlin, Matthew J Matasar, Anita Kumar, Marcel R van den Brink, Kristina M Knapp, Janine D Pichardo, Michelle K Nahas, Sally E Trabucco, Tariq Mughal, Amanda R Copeland, Elli Papaemmanuil, Mathai Moarii, Ross L Levine, Ahmet Dogan, Vincent A Miller, Anas Younes
We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma)...
June 12, 2018: Blood Cancer Journal
Christiane Querfeld, Samantha Leung, Patricia L Myskowski, Shane A Curran, Debra A Goldman, Glenn Heller, Xiwei Wu, Sung Hee Kil, Sneh Sharma, Kathleen J Finn, Steven Horwitz, Alison Moskowitz, Babak Mehrara, Steven T Rosen, Allan C Halpern, James W Young
Cutaneous T-cell lymphoma (CTCL) develops from clonally expanded CD4+ T cells in a background of chronic inflammation. Although dendritic cells (DCs) stimulate T cells and are present in skin, cutaneous T cells in CTCL do not respond with effective antitumor immunity. We evaluated primary T-cell and DC émigrés from epidermal and dermal explant cultures of skin biopsies from CTCL patients (n = 37) and healthy donors (n = 5). Compared with healthy skin, CD4+ CTCL populations contained more T cells expressing PD-1, CTLA-4, and LAG-3...
June 12, 2018: Cancer Immunology Research
Marc A Weniger, Enrico Tiacci, Stefanie Schneider, Judith Arnolds, Sabrina Rüschenbaum, Janine Duppach, Marc Seifert, Claudia Döring, Martin-Leo Hansmann, Ralf Küppers
Very few B cells in germinal centers (GCs) and extrafollicular (EF) regions of lymph nodes express CD30. Their specific features and relationship to CD30-expressing Hodgkin and Reed/Sternberg (HRS) cells of Hodgkin lymphoma are unclear but highly relevant, because numerous patients with lymphoma are currently treated with an anti-CD30 immunotoxin. We performed a comprehensive analysis of human CD30+ B cells. Phenotypic and IgV gene analyses indicated that CD30+ GC B lymphocytes represent typical GC B cells, and that CD30+ EF B cells are mostly post-GC B cells...
June 11, 2018: Journal of Clinical Investigation
Veronica Garcia-Carpizo, Sergio Ruiz-Llorente, Jacinto Sarmentero, Osvaldo Graña-Castro, David G Pisano, Maria J Barrero
BACKGROUND: The reported antitumor activity of the BET family bromodomain inhibitors has prompted the development of inhibitors against other bromodomains. However, the human genome encodes more than 60 different bromodomains and most of them remain unexplored. RESULTS: We report that the bromodomains of the histone acetyltransferases CREBBP/EP300 are critical to sustain the proliferation of human leukemia and lymphoma cell lines. EP300 is very abundant at super-enhancers in K562 and is coincident with sites of GATA1 and MYC occupancy...
June 8, 2018: Epigenetics & Chromatin
Zhenhua Yang, Kushani Shah, Theodore Busby, Keith Giles, Alireza Khodadadi-Jamayran, Wei Li, Hao Jiang
While the genomic binding of MYC protein correlates with active epigenetic marks on chromatin, it remains largely unclear how major epigenetic mechanisms functionally impact the tumorigenic potential of MYC. Here we showed that compared to the catalytic subunits, the core subunits, including DPY30, of the major H3K4 methyltransferase complexes were frequently amplified in human cancers, and selectively upregulated in Burkitt lymphoma. We showed that DPY30 promoted expression of endogenous MYC, and was also functionally important for efficient binding of MYC to its genomic targets by regulating chromatin accessibility...
June 5, 2018: Journal of Clinical Investigation
Hsiao-Mei Liao, Hebing Liu, Heiyan Lei, Bingjie Li, Pei-Ju Chin, Shien Tsai, Kishor Bhatia, Marina Gutierrez, Sidnei Epelman, Robert J Biggar, Francis Nkrumah, Janet Neequaye, Martin D Ogwang, Steven J Reynolds, Shyh-Ching Lo, Sam M Mbulaiteye
Epstein-Barr virus (EBV) is linked to several cancers, including endemic Burkitt lymphoma (eBL), but causal variants are unknown. We recently reported novel sequence variants in the LMP-1 gene and promoter in EBV genomes sequenced from 13 of 14 BL biopsies. Alignments of the novel sequence variants for 114 published EBV genomes, including 27 from BL cases, revealed four LMP-1 variant patterns, designated A to D. Pattern A variant was found in 48% of BL EBV genomes. Here, we used PCR-Sanger sequencing to evaluate 50 additional BL biopsies from Ghana, Brazil, and Argentina, and peripheral blood samples from 113 eBL cases and 115 controls in Uganda...
June 2, 2018: Cancers
Dimitrios C Ziogas, Anna Tsiara, Georgios Tsironis, Maria Lykka, Michalis Liontos, Aristotelis Bamias, Meletios-Athanasios Dimopoulos
Targeting genomic alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, have radically changed the treatment of patients with non-small cell lung cancer (NSCLC). In the case of ALK-rearranged gene, subsequent rapid development of effective genotype-directed therapies with ALK tyrosine kinase inhibitors (TKIs) triggered major advances in the personalized molecularly based approach of NSCLC. Crizotinib was the first-in-class ALK TKI with proven superiority over standard platinum-based chemotherapy for the 1st-line therapy of ALK-rearranged NSCLC patients...
April 2018: Annals of Translational Medicine
Hua Wang, Yongxiang Wang, Jinshan He, Chunyu Diao, Junying Sun, Jingcheng Wang
The aim of the present study was to investigate the key gene network in fracture healing. The dataset GSE45156 was downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified using the linear models for microarray data package of Bioconductor. Subsequently, Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted for DEGs in day 2 and 6 fractured samples via the Database for Annotation, Visualization and Integrated Discovery...
May 17, 2018: Molecular Medicine Reports
Ertao Zhai, Wei Liang, Yi Lin, Linlin Huang, Xin He, Shirong Cai, Jianhui Chen, Ning Zhang, Jiali Li, Qiuyang Zhang, Yulong He, Zhirong Zeng, Minhu Chen, Lixia Xu, Sui Peng
BACKGROUND/AIMS: HSP70/HSP90-organizing protein (HOP) is an adaptor protein that mediates heat shock protein 70 (HSP70) and HSP90 folding. HOP can be secreted by cancer cells and promote malignant cell growth in an autocrine manner. Here, we studied its role in gastric cancer (GC). METHODS: HOP mRNA and protein levels were detected by quantitative real-time PCR and western blotting, respectively, and enzyme-linked immunosorbent assay was used to determine the serum levels...
May 22, 2018: Cellular Physiology and Biochemistry
Angelo Fama, Jinhua Xiang, Brian K Link, Cristine Allmer, Donna Klinzman, Andrew L Feldman, Grzegorz S Nowakowski, Mark Liebow, Melissa C Larson, Matthew J Maurer, Stephen M Ansell, Anne J Novak, Yan W Asmann, Susan L Slager, Timothy G Call, Thomas M Habermann, James R Cerhan, Jack T Stapleton
We evaluated the association of Human Pegivirus (HPgV) viraemia with risk of developing lymphoma, overall and by major subtypes. Because this virus has also been associated with better prognosis in the setting of co-infection with human immunodeficiency virus, we further assessed the association of HPgV with prognosis. We used risk factor data and banked plasma samples from 2094 lymphoma cases newly diagnosed between 2002 and 2009 and 1572 frequency-matched controls. Plasma samples were tested for HPgV RNA by reverse transcription polymerase chain reaction (RT-PCR), and those with RNA concentrations <5000 genome equivalents/ml were confirmed using nested RT-PCR methods...
May 29, 2018: British Journal of Haematology
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