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https://www.readbyqxmd.com/read/29735552/hla-class-i-and-ii-diversity-contributes-to-the-etiologic-heterogeneity-of-non-hodgkin-lymphoma-subtypes
#1
Sophia S Wang, Mary Carrington, Sonja I Berndt, Susan L Slager, Paige M Bracci, Jenna Voutsinas, James R Cerhan, Karin Ekström Smedby, Henrik Hjalgrim, Joseph Vijai, Lindsay M Morton, Roel Vermeulen, Ora Paltiel, Claire M Vajdic, Martha S Linet, Alexandra Nieters, Silvia de Sanjosé, Wendy Cozen, Elizabeth E Brown, Jennifer Turner, John J Spinelli, Tongzhang Zheng, Brenda M Birmann, Christopher R Flowers, Nikolaus Becker, Elizabeth A Holly, Eleanor Kane, Dennis Weisenburger, Marc Maynadie, Pierluigi Cocco, Demetrius Albanes, Stephanie J Weinstein, Lauren R Teras, W Ryan Diver, Stephanie J Lax, Ruth C Travis, Rudolf Kaaks, Elio Riboli, Yolanda Benavente, Paul Brennan, James D McKay, Marie Helene Delfau-Larue, Brian K Link, Corrado Magnani, Maria G Ennas, Giancarlo Latte, Andrew L Feldman, Nicole Wong Doo, Graham G Giles, Melissa C Southey, Roger L Milne, Kenneth Offit, Jacob Muskinsky, Alan A Arslan, Mark P Purdue, Hans-Olov Adami, Mads Melbye, Bengt Glimelius, Lucia Conde, Nicola J Camp, Martha Glenn, Karen Curtin, Jacqueline Clavel, Alain Monnereau, David G Cox, Hervé Ghesquières, Gilles Salles, Paolo Boffetta, Lenka Foretova, Anthony Staines, Scott Davis, Richard K Severson, Qing Lan, Angela Brooks-Wilson, Martyn T Smith, Eve Roman, Anne Kricker, Yawei Zhang, Peter Kraft, Stephen J Chanock, Nathaniel Rothman, Patricia Hartge, Christine F Skibola
A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for: 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent...
May 7, 2018: Cancer Research
https://www.readbyqxmd.com/read/29735550/microrna-339-promotes-development-of-stem-cell-leukemia-lymphoma-syndrome-via-downregulation-of-the-bcl2l11-and-bax-pro-apoptotic-genes
#2
Tianxiang Hu, Yating Chong, Sumin Lu, Rebecca Wang, Haiyan Qin, Jeane Silva, Eiko Kitamura, Chang-Sheng Chang, LesleyAnn Hawthorn, John K Cowell
Development of myeloid and lymphoid neoplasms related to overexpression of FGFR1 kinases as a result of chromosome translocations depends on promotion of a stem cell phenotype, suppression of terminal differentiation, and resistance to apoptosis. These phenotypes are related to the stem cell leukemia/lymphoma syndrome (SCLL), which arises through the effects of activated FGFR1 kinase on gene transcription, including dysregulation of microRNAs. In a screen for miRNAs that are directly regulated by FGFR1 and that stimulate cell proliferation and survival, we identified miR-339-5p, which is highly upregulated in cells carrying various different chimeric kinases...
May 7, 2018: Cancer Research
https://www.readbyqxmd.com/read/29730931/analysis-of-circulating-micrornas-and-their-post-transcriptional-modifications-in-cancer-serum-by-on-line-solid-phase-extraction-capillary-electrophoresis-mass-spectrometry
#3
Roger Pero-Gascon, Victoria Sanz-Nebot, Maxim V Berezovski, Fernando Benavente
In this paper, an on-line solid-phase extraction capillary electrophoresis-mass spectrometry (SPE-CE-MS) method is described for purification, preconcentration, separation and characterization of endogenous microRNA (miRNA) and their post-transcriptional modifications in serum. First, analysis by CE-MS was optimized using a standard mixture of hsa-miR-21-5p (miR-21-5p) and hsa-let-7g-5p (let-7g-5p). For SPE-CE-MS, a commercial silicon carbide (SiC) resin was used to prepare the microcartridges. Under the optimized conditions using standards, microcartridge lifetime (>25 analyses) and repeatability (2...
May 7, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29727780/an-lc-ms-ms-method-for-simultaneous-determination-of-curcumin-curcumin-glucuronide-and-curcumin-sulfate-in-a-phase-ii-clinical-trial
#4
Sandeep R Kunati, Shuming Yang, Basem M William, Yan Xu
Curcumin, a principal curcuminoid of turmeric, gained a lot of attention recently due to its wide spectrum of pharmacological activities in prevention and treatment of various human conditions. The current clinical study is focused on the determination of efficacy and tolerability of curcumin and vitamin D3 combination in patients with early-stage chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). To support this work, an LC-MS/MS method has been developed for simultaneous determination of curcumin and its metabolites, curcumin glucuronide (COG) and curcumin sulfate (COS), in human plasma using curcumin-d6 as an internal standard for curcumin and BPAG-d6 as an internal standard for COG and COS...
April 23, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29725996/population-pharmacokinetic-analysis-of-alirocumab-in-healthy-volunteers-or-hypercholesterolemic-subjects-using-a-michaelis-menten-approximation-of-a-target-mediated-drug-disposition-model-support-for-a-biologics-license-application-submission-part-i
#5
Jean-Marie Martinez, Aurélie Brunet, Fabrice Hurbin, A Thomas DiCioccio, Clémence Rauch, David Fabre
BACKGROUND: Alirocumab, a human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to significantly reduce low-density lipoprotein cholesterol levels; pharmacokinetics (PK) are governed by non-linear, target-mediated drug disposition (TMDD). OBJECTIVES: We aimed to develop and qualify a population PK (PopPK) model to characterize the PK profile of alirocumab, evaluate the impact of covariates on alirocumab PK and on individual patient exposures, and estimate individual predicted concentrations for a subsequent PK/pharmacodynamic (PD) analysis...
May 3, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29725010/a-retinoic-acid-dependent-stroma-leukemia-crosstalk-promotes-chronic-lymphocytic-leukemia-progression
#6
Diego Farinello, Monika Wozińska, Elisa Lenti, Luca Genovese, Silvia Bianchessi, Edoardo Migliori, Nicolò Sacchetti, Alessia di Lillo, Maria Teresa Sabrina Bertilaccio, Claudia de Lalla, Roberta Valsecchi, Sabrina Bascones Gleave, David Lligé, Cristina Scielzo, Laura Mauri, Maria Grazia Ciampa, Lydia Scarfò, Rosa Bernardi, Dejan Lazarevic, Blanca Gonzalez-Farre, Lucia Bongiovanni, Elias Campo, Andrea Cerutti, Maurilio Ponzoni, Linda Pattini, Federico Caligaris-Cappio, Paolo Ghia, Andrea Brendolan
In chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival, and expansion. However, the nature of the stromal cells and molecular pathways involved remain largely unknown. Here, we demonstrate that leukemic B lymphocytes induce the activation of retinoid acid synthesis and signaling in the microenvironment. Inhibition of RA-signaling in stromal cells causes deregulation of genes associated with adhesion, tissue organization and chemokine secretion including the B-cell chemokine CXCL13...
May 3, 2018: Nature Communications
https://www.readbyqxmd.com/read/29712773/chronic-lymphocytic-leukemia-derived-il-10-suppresses-antitumor-immunity
#7
Sara S Alhakeem, Mary K McKenna, Karine Z Oben, Sunil K Noothi, Jacqueline R Rivas, Gerhard C Hildebrandt, Roger A Fleischman, Vivek M Rangnekar, Natarajan Muthusamy, Subbarao Bondada
Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti-inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL-10 in response to BCR cross-linking. We used the transgenic Eμ-T cell leukemia oncogene-1 ( TCL1 ) mouse CLL model to study the role of IL-10 in CLL associated immunosuppression. Eμ-TCL mice spontaneously develop CLL because of a B cell-specific expression of the oncogene, TCL1. Eμ- TCL1 mouse CLL cells constitutively produce IL-10, which is further enhanced by BCR cross-linking, CLL-derived IL-10 did not directly affect survival of murine or human CLL cells in vitro...
April 30, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29696732/seshat-a-web-service-for-accurate-annotation-validation-and-analysis-of-tp53-variants-generated-by-conventional-and-next-generation-sequencing
#8
Tuomas Tikkanen, Bernard Leroy, Jean Louis Fournier, Rosa Ana Risques, Jitka Malcikova, Thierry Soussi
Accurate annotation of genomic variants in human diseases is essential to allow personalized medicine. Assessment of somatic and germline TP53 alterations has now reached the clinic and is required in several circumstances such as the identification of the most effective cancer therapy for patients with chronic lymphocytic leukemia (CLL). Here we present Seshat, a web service for annotating TP53 information derived from sequencing data. A flexible framework allows the use of standard file formats such as Mutation Annotation Format (MAF) or Variant Call Format (VCF), as well as common TXT files...
April 25, 2018: Human Mutation
https://www.readbyqxmd.com/read/29695515/novel-role-of-prostate-apoptosis-response-4-tumor-suppressor-in-b-cell-chronic-lymphocytic-leukemia
#9
Mary K McKenna, Sunil K Noothi, Sara S Alhakeem, Karine Z Oben, Joseph T Greene, Rajeswaran Mani, Kathryn L Perry, James P Collard, Jacqueline R Rivas, Gerhard Hildebrandt, Roger Fleischman, Eric B Durbin, John C Byrd, Chi Wang, Natarajan Muthusamy, Vivek M Rangnekar, Subbarao Bondada
Prostate apoptosis response-4 (Par-4), a pro-apoptotic tumor suppressor protein, is down regulated in many cancers including renal cell carcinoma, glioblastoma, endometrial and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from the Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1 to S cell cycle transition...
April 25, 2018: Blood
https://www.readbyqxmd.com/read/29678828/wnt5a-induces-ror1-to-recruit-dock2-to-activate-rac1-2-in-chronic-lymphocytic-leukemia
#10
Md Kamrul Hasan, Jian Yu, George F Widhopf, Laura Z Rassenti, Liguang Chen, Zhouxin Shen, Steven P Briggs, Donna S Neuberg, Thomas J Kipps
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncoembryonic protein expressed on chronic lymphocytic leukemia (CLL) that can serve as a receptor for Wnt5a, which can promote leukemia-cell migration, proliferation, and survival. We found Wnt5a could induce ROR1 to complex with DOCK2 and induce activation of Rac1/2; these effects could be blocked by cirmtuzumab, a humanized anti-ROR1 mAb. We find that silencing DOCK2 specifically impaired the capacity of Wnt5a to induce activation of Rac1/2 or enhance CLL-cell proliferation...
April 20, 2018: Blood
https://www.readbyqxmd.com/read/29670635/chronic-lymphocytic-leukemia-b-cell-normal-cellular-counterpart-clues-from-a-functional-perspective
#11
REVIEW
Walaa Darwiche, Brigitte Gubler, Jean-Pierre Marolleau, Hussein Ghamlouch
Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of small mature-looking CD19+ CD23+ CD5+ B-cells that accumulate in the blood, bone marrow, and lymphoid organs. To date, no consensus has been reached concerning the normal cellular counterpart of CLL B-cells and several B-cell types have been proposed. CLL B-cells have remarkable phenotypic and gene expression profile homogeneity. In recent years, the molecular and cellular biology of CLL has been enriched by seminal insights that are leading to a better understanding of the natural history of the disease...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29660035/the-preventable-burden-of-work-related-ill-health
#12
P Cocco, R Agius
Background: The fraction of ill-health overall attributable to occupational conditions has not been extensively evaluated, thus contributing to the perception of a lesser relevance of education and research in occupational health in respect to other fields of medical research and practice. Aims: To assess the relevance of work-related conditions on the aetiology of human ill-health in different health domains. Methods: We extracted the risk estimates associated with heritability and with occupational risk factors for chronic lymphocytic leukaemia (CLL), major depressive disorder (MDD) and long QT syndrome (LQTS) from 13 published international reports...
April 12, 2018: Occupational Medicine
https://www.readbyqxmd.com/read/29658610/overexpression-of-il-9-induced-by-stat3-phosphorylation-is-mediated-by-mir-155-and-mir-21-in-chronic-lymphocytic-leukemia
#13
Na Chen, Lili Feng, Huiting Qu, Kang Lu, Peipei Li, Xiao Lv, Xin Wang
Interleukin‑9 (IL‑9) can function as both a positive and negative regulator of immune response, however the role of IL‑9 in tumor immunity is poorly understood. Chronic lymphocytic leukemia (CLL) is the most common chronic lympho‑proliferative disorder. Twenty CLL patients from 2010 to 2011 were recruited in the study. Expression and phosphorylation of transcription factor STAT3 and differential microRNAs (miRs) in peripheral blood mononuclear cells (PBMCs) from CLL patient samples were analyzed...
April 12, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29650518/secretory-igm-exacerbates-tumor-progression-by-inducing-accumulations-of-mdscs-in-mice
#14
Chih-Hang Anthony Tang, Shiun Chang, Ayumi Hashimoto, Yi-Ju Chen, Chang Won Kang, Anthony R Mato, Juan R Del Valle, Dmitry Gabrilovich, Chih-Chi Andrew Hu
Chronic lymphocytic leukemia cells can secrete immunoglobulin M. However, it is not clear whether secretory IgM (sIgM) plays a role in disease progression. We crossed the Eμ-TCL1 mouse model of CLL, in which the expression of human TCL1 oncogene was driven by the V(H) promoter-Ig(H)-Eμ enhancer, with MD4 mice whose B cells produced B cell receptor (membrane-bound IgM) and sIgM with specificity for hen egg lysozyme (HEL). CLL cells developed in these MD4/Eμ-TCL1 mice reactivated a parental Ig gene allele and secreted IgM, and did not recognize HEL...
April 12, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29644723/a-french-observational-study-describing-the-use-of-human-polyvalent-immunoglobulins-in-hematological-malignancy-associated-secondary-immunodeficiency
#15
Omar Benbrahim, Jean-François Viallard, Sylvain Choquet, Bruno Royer, Frédéric Bauduer, Olivier Decaux, Jean-Charles Crave, Yann Fardini, Pierre Clerson, Vincent Levy
OBJECTIVE: To describe the characteristics of patients suffering from secondary immunodeficiencies (SID) associated with hematological malignancies (HM), who started immunoglobulins replacement therapy (IgRT), physicians' expectations regarding IgRT and IgRT modalities. METHODS: Non-interventional, prospective French cross-sectional study. RESULTS: The analysis included 231 patients (66±12 years old) suffering from multiple myeloma (MM) (N=64), chronic lymphoid leukemia (CLL) (N=84), aggressive non-Hodgkin B-cell lymphoma (aNHL) (N=32), indolent NHL (N=39), acute leukemia (N=6), Hodgkin disease (N=6)...
April 12, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29562857/obinutuzumab-induces-depletion-of-nk-cells-in-patients-with-chronic-lymphocytic-leukemia
#16
Ricardo García-Muñoz, Lorea Aguinaga, Jesus Feliu, Judit Anton-Remirez, Lorena Jorge-Del-Val, Andrea Casajús-Navasal, María José Nebot-Villacampa, Isabel Daroca-Fernandez, Elena Domínguez-Garrido, Pilar Rabasa, Carlos Panizo
AIM: Obinutuzumab induces NK cell antibody-dependent cell-mediated cytotoxicity. OBJECTIVE: Investigate the effects on the human immune system after obinutuzumab monotherapy treatment in patients with chronic lymphocytic leukemia (CLL). METHOD: To evaluate these effects, we analyzed the distribution of CD4+ and CD8+ T cells, B cells and NK cells in the peripheral blood of eight CLL patients who were treated with obinutuzumab in monotherapy...
March 1, 2018: Immunotherapy
https://www.readbyqxmd.com/read/29560128/first-in-human-phase-1-study-of-the-btk-inhibitor-gdc-0853-in-relapsed-or-refractory-b-cell-nhl-and-cll
#17
John C Byrd, Stephen Smith, Nina Wagner-Johnston, Jeff Sharman, Andy I Chen, Ranjana Advani, Bradley Augustson, Paula Marlton, S Renee Commerford, Kwame Okrah, Lichuan Liu, Elaine Murray, Elicia Penuel, Ashley F Ward, Ian W Flinn
GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally...
February 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29559479/oral-bruton-tyrosine-kinase-inhibitors-selectively-block-atherosclerotic-plaque-triggered-thrombus-formation
#18
Kristina Busygina, Janina Jamasbi, Till Seiler, Hans Deckmyn, Christian Weber, Richard Brandl, Reinhard Lorenz, Wolfgang Siess
Interaction of Von Willebrand factor (VWF) with platelet glycoprotein (GP) Ib and of collagen with GPVI is essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk) which can irreversibly be blocked by oral application of ibrutinib, an established therapy for chronic lymphocytic leukemia (CLL) with long term safety. We found that ibrutinib and the novel Btk-inhibitors acalabrutinib and ONO/GS-4059 block GPVI-dependent static platelet aggregation in blood exposed to human plaque homogenate and collagen but not to ADP or arachidonic acid...
March 20, 2018: Blood
https://www.readbyqxmd.com/read/29510136/interferon-%C3%AE-is-a-strong-stat1-dependent-direct-inducer-of-bcl6-expression-in-multiple-myeloma-cells
#19
Dorina Ujvari, Noemi Nagy, Harsha S Madapura, Tomasz Kallas, Marijke C L Kröhnke, Leif Stenke, Eva Klein, Daniel Salamon
B-cell CLL/lymphoma 6 (BCL6) is a transcriptional master regulator that can repress more than 1200 potential target genes. It exerts oncogenic effects through the inhibition of differentiation, DNA damage sensing and apoptosis in several human hematopoietic malignancies, including multiple myeloma (MM). The multifunctional cytokine interferon γ (IFNγ) exerts pro-apoptotic and anti-proliferative effects on MM cells in vitro, at least partially through the inhibition of the effects of interleukin 6 (IL6), one of the most important growth factor of MM and a strong inducer of BCL6 expression...
April 6, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29408410/the-role-of-mtor-mediated-signaling-in-the-regulation-of-cellular-migration
#20
REVIEW
Ailsa K Holroyd, Alison M Michie
Mechanistic target for rapamycin (mTOR) is a serine/threonine protein kinase that forms two distinct complexes mTORC1 and mTORC2, integrating mitogen and nutrient signals to regulate cell survival and proliferation; processes which are commonly deregulated in human cancers. mTORC1 and mTORC2 have divergent molecular associations and cellular functions: mTORC1 regulates in mRNA translation and protein synthesis, while mTORC2 is involved in the regulation of cellular survival and metabolism. Through AKT phosphorylation/activation, mTORC2 has also been reported to regulate cell migration...
April 2018: Immunology Letters
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