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Chronic lymphocytic leukemia

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https://www.readbyqxmd.com/read/28077796/tumor-cell-migration-is-inhibited-by-a-novel-therapeutic-strategy-antagonizing-the-alpha-7-receptor
#1
Chris Pepper, Henry Tu, Paul Morrill, Sara Garcia-Rates, Chris Fegan, Susan Greenfield
A 14mer peptide (T14) derived from the C-terminus of acetylcholinesterase (AChE) selectively activates metastatic breast cancer cells via the alpha-7 nicotinic receptor (α7 nAChR). This naturally occurring peptide is also present in brain, is elevated in Alzheimer's disease, and is antagonised by a cyclized variant (NBP-14). Here we investigated the effects of NBP-14 in six different cancer cell lines, primary leukemia B-cells and normal B-cells. All cells tested expressed α7 nAChR, intracellular and extracellular T14...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28077600/ibrutinib-therapy-increases-t-cell-repertoire-diversity-in-patients-with-chronic-lymphocytic-leukemia
#2
Qingsong Yin, Mariela Sivina, Harlan Robins, Erik Yusko, Marissa Vignali, Susan O'Brien, Michael J Keating, Alessandra Ferrajoli, Zeev Estrov, Nitin Jain, William G Wierda, Jan A Burger
The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy...
January 11, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28075457/high-resolution-melting-analysis-for-rapid-and-sensitive-notch1-screening-in-chronic-lymphocytic-leukemia
#3
Jing-Jing Xu, Fei-Rong Yao, Min Jiang, You-Tao Zhang, Feng Guo
Chronic lymphocytic leukemia (CLL) is a biological and clinical heterogeneous disease. Activating mutations of NOTCH1 have been implicated to be associated with adverse prognosis in CLL. The objective of the present study was to develop an effective high-resolution melting (HRM) assay for detecting NOTCH1 mutations. Genomic DNA (gDNA) extracted from 133 CLL patients was screened by HRM assay, and the results were compared with the data obtained using direct sequencing. The relative sensitivity of the HRM assay and direct sequencing was evaluated using diluted gDNA with different NOTCH1 mutational frequencies...
January 5, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28074067/expression-of-the-ctla-4-ligand-cd86-on-plasmacytoid-dendritic-cells-pdc-predicts-risk-of-disease-recurrence-after-treatment-discontinuation-in-cml
#4
C Schütz, S Inselmann, S Sausslele, C T Dietz, M C Müller, E Eigendorff, C A Brendel, S K Metzelder, T H Brümmendorf, C Waller, J Dengler, M E Goebeler, R Herbst, G Freunek, S Hanzel, T Illmer, Y Wang, T Lange, F Finkernagel, R Hehlmann, M Huber, A Neubauer, A Hochhaus, J Guilhot, F X Mahon, M Pfirrmann, A Burchert
It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86(+)pDC frequencies than normal donors (P<0·0024), whereas TFR patients had consistently low CD86(+)pDC (n=12)...
January 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28074063/direct-in-vivo-evidence-for-increased-proliferation-of-cll-cells-in-lymph-nodes-compared-to-bone-marrow-and-peripheral-blood
#5
T M Herndon, S-S Chen, N S Saba, J Valdez, C Emson, M Gatmaitan, X Tian, T E Hughes, C Sun, D C Arthur, M Stetler-Stevenson, C M Yuan, C U Niemann, G E Marti, G Aue, S Soto, M Z H Farooqui, S E M Herman, N Chiorazzi, A Wiestner
Chronic Lymphocytic Leukemia (CLL) is a progressive malignancy of mature B-cells that involves the peripheral blood (PB), lymph nodes (LNs) and bone marrow (BM). While the majority of CLL cells are in a resting state, small populations of proliferating cells exist; however, the anatomical site of active cell proliferation remains to be definitively determined. Based on findings that CLL cells in LNs have increased expression of B-cell activation genes, we tested the hypothesis that the fraction of 'newly born' cells would be highest in the LNs...
January 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28073846/extended-treatment-with-single-agent-ibrutinib-at-the-420-mg-dose-leads-to-durable-responses-in-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma
#6
Steven E Coutré, Richard R Furman, Ian W Flinn, Jan A Burger, Kristie Blum, Jeff Sharman, Jeffrey Jones, William Wierda, Weiqiang Zhao, Nyla A Heerema, Amy J Johnson, Anh Tran, Cathy Zhou, Elizabeth Bilotti, Danelle F James, John C Byrd, Susan O'Brien
PURPOSE: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28073173/expression-of-cd43-in-chronic-lymphoproliferative-leukemias
#7
Marc Sorigué, Jordi Juncà, Edurne Sarrate, Javier Grau
BACKGROUND: CD43 has been used on histological samples for the differential diagnosis of lymphoproliferative disorders but there is scarce data on its use by flow cytometry (FC). We set out to characterize the expression of CD43 by FC in B-cell lymphoproliferative disorders and to determine its possible role in the differential diagnosis of these malignancies. METHODS: We analyzed the expression of CD43 in clonal B-cell lymphoproliferative disorders with exclusive peripheral blood and/or bone marrow involvement based on their Moreau chronic lymphocytic leukemia (CLL) score with particular emphasis on Moreau CLL score 3 (MS3) cases, which often present a diagnostic challenge...
January 10, 2017: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/28069603/treatment-of-b-cell-disorder-improves-renal-outcome-of-patients-with-monoclonal-gammopathy-associated-c3-glomerulopathy
#8
Sophie Chauvet, Véronique Frémeaux-Bacchi, Florent Petitprez, Alexandre Karras, Laurent Daniel, Stéphane Burtey, Gabriel Choukroun, Yahsou Delmas, Dominique Guerrot, Arnaud François, Moglie Le Quintrec, Vincent Javaugue, David Ribes, Laurence Vrigneaud, Bertrand Arnulf, Jean Michel Goujon, Pierre Ronco, Guy Touchard, Frank Bridoux
The high frequency of monoclonal gammopathy in adult patients with C3 glomerulopathy (C3G) emphasizes the role of the monoclonal immunoglobulin (MIg) in the occurrence of renal disease and raises the issue of the therapeutic management. The aim of the study was to evaluate the effect of chemotherapy in a large cohort of patients with MIg-associated C3G. Fifty adult patients with MIg and biopsy-proven C3G were extracted from the French national database of C3G. We retrospectively compared renal outcomes in patients who received or not chemotherapy targeting the underlying B-cell clone...
January 9, 2017: Blood
https://www.readbyqxmd.com/read/28069558/from-genome-to-proteome-looking-beyond-dna-and-rna-in-chronic-lymphocytic-leukemia
#9
Lauren A Thurgood, Karen M Lower, Bryone J Kuss, Tim K Chataway
Chronic lymphocytic leukemia (CLL) remains the most common leukemia in the Western world. Whilst its disease course is extremely heterogeneous (ranging from indolent to aggressive), current methods are unable to accurately predict the clinical journey of each patient. There is clearly a pressing need for both improved prognostication and treatment options for patients with this disease.Whilst molecular studies have analyzed both genetic mutations and gene expression profiles of these malignant B-cells, and as a result have shed light on the pathogenesis of CLL, proteomic studies have been largely overlooked to date...
January 6, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28067179/cd20-based-immunotherapy-of-b-cell-derived-hematologic-malignancies
#10
Dariush Shanehbandi, Jafar Majidi, Tohid Kazemi, Behzad Baradaran, Leili Aghebati-Maleki
CD20 is a surface antigen which is expressed at certain stages of B-cell differentiation. Targeting the CD20-positive B-cells with therapeutic monoclonal antibodies (MAbs) has been an effectual strategy in the treatment of hematologic malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Initial success with Rituximab (RTX) has encouraged the creation and development of more effective CD20 based therapeutics. However, treatment with conventional MAbs has not been adequate to overcome the problems such as refractory/relapsed disease...
January 9, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28063304/splenic-irradiation-for-splenomegaly-a-systematic-review
#11
REVIEW
Nicholas G Zaorsky, Graeme R Williams, Stefan K Barta, Nestor F Esnaola, Patricia L Kropf, Shelly B Hayes, Joshua E Meyer
Splenic irradiation (SI) is a palliative treatment option for symptomatic splenomegaly (i.e. for pain, early satiety, pancytopenia from sequestration) secondary to hematologic malignancies and disorders. The purpose of the current article is to review the literature on SI for hematologic malignancies and disorders, including: (1) patient selection and optimal technique; (2) efficacy of SI; and (3) toxicities of SI. PICOS/PRISMA methods are used to select 27 articles including 766 courses of SI for 486 patients from 1960 to 2016...
December 22, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28062906/programmed-cell-death-1-pathway-inhibition-in-myeloid-malignancies-implications-for-myeloproliferative-neoplasms
#12
REVIEW
D C Choi, D Tremblay, C Iancu-Rubin, J Mascarenhas
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic diseases that belong to the spectrum of myeloid malignancies (MyMs), which also include myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelogenous leukemia (CML). While hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic approach to many MyMs, the associated morbidity and mortality have necessitated the development of non-HSCT therapeutics for symptom management and disease course modification...
January 6, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28062113/indirect-treatment-comparisons-of-ibrutinib-versus-physician-s-choice-and-idelalisib-plus-ofatumumab-in-patients-with-previously-treated-chronic-lymphocytic-leukemia
#13
REVIEW
Sonja Sorensen, Mark Wildgust, Nishan Sengupta, Cristina Trambitas, Joris Diels, Suzy van Sanden, Yingxin Xu, Emily Dorman
PURPOSE: Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0...
January 3, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28061982/pi3k-signaling-pathway-in-normal-b-cells-and-indolent-b-cell-malignancies
#14
REVIEW
Georgios Pongas, Bruce D Cheson
In chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas (NHLs), B-cell receptor signaling leads to activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Idelalisib, a PI3Kδ inhibitor was approved in 2014 by the US Food and Drug Administration (FDA) in combination with rituximab for the treatment of patients with CLL for whom single-agent rituximab would be considered appropriate and as a single agent for patients with relapsed small lymphocytic lymphoma (SLL) and relapsed follicular lymphoma (FL)...
December 2016: Seminars in Oncology
https://www.readbyqxmd.com/read/28061439/synthetic-high-density-lipoproteins-as-targeted-monotherapy-for-chronic-lymphocytic-leukemia
#15
Kaylin M McMahon, Cristina Scielzo, Nicholas L Angeloni, Elad Deiss-Yehiely, Lydia Scarfo, Pamela Ranghetti, Shuo Ma, Jason Kaplan, Federica Barbaglio, Leo I Gordon, Francis J Giles, C. Shad Thaxton, Paolo Ghia
Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new drugs. Therapies targeting receptors and pathways active specifically in malignant B cells might provide better treatment options. For instance, in B cell lymphoma, our group has previously shown that scavenger receptor type B-1 (SR-B1), the high-affinity receptor for cholesterol-rich high-density lipoproteins (HDL), is a therapeutic target. As evidence suggests that targeting cholesterol metabolism in CLL cells may have therapeutic benefit, we examined SR-B1 expression in primary CLL cells from patients...
4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28056525/venetoclax
#16
Amber C King, Tim J Peterson, Troy Z Horvat, Mabel Rodriguez, Laura A Tang
OBJECTIVE: To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. DATA SOURCES: A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta...
December 1, 2016: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/28054750/somatic-med12-nonsense-mutation-escapes-mrna-decay-and-reveals-a-motif-required-for-nuclear-entry
#17
Tuomas Heikkinen, Kati Kämpjärvi, Salla Keskitalo, Pernilla von Nandelstadh, Xiaonan Liu, Ville Rantanen, Esa Pitkänen, Matias Kinnunen, Heikki Kuusanmäki, Mika Kontro, Mikko Turunen, Netta Mäkinen, Jussi Taipale, Caroline Heckman, Kaisa Lehti, Satu Mustjoki, Markku Varjosalo, Pia Vahteristo
MED12 is a key component of the transcription-regulating Mediator complex. Specific missense and in-frame insertion/deletion mutations in exons 1 and 2 have been identified in uterine leiomyomas, breast tumors, and chronic lymphocytic leukemia. Here, we characterize the first MED12 5' end nonsense mutation (c.97G>T, p.E33X) identified in acute lymphoblastic leukemia and show that it escapes nonsense-mediated mRNA decay (NMD) by using an alternative translation initiation site. The resulting N-terminally truncated protein is unable to enter the nucleus due to the lack of identified nuclear localization signal (NLS)...
January 5, 2017: Human Mutation
https://www.readbyqxmd.com/read/28053325/effects-of-mirna-15-and-mirna-16-expression-replacement-in-chronic-lymphocytic-leukemia-implication-for-therapy
#18
G Cutrona, S Matis, M Colombo, C Massucco, G Baio, F Valdora, L Emionite, S Fabris, A G Recchia, M Gentile, C E Neumaier, D Reverberi, R Massara, S Boccardo, L Basso, S Salvi, F Rosa, M Cilli, S Zupo, M Truini, P Tassone, M Calabrese, M Negrini, A Neri, F Morabito, F Fais, M Ferrarini
Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, [del(13)(q14)] involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion...
January 5, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28052338/quantitative-prediction-of-the-effect-of-cyp3a-inhibitors-and-inducers-on-venetoclax-pharmacokinetics-using-a-physiologically-based-pharmacokinetic-model
#19
Kevin J Freise, Mohamad Shebley, Ahmed Hamed Salem
The objectives of the analysis were to develop and verify a venetoclax physiologically based pharmacokinetic (PBPK) model to predict the effects of cytochrome P450 3A (CYP3A) inhibitors and inducers on the PK of venetoclax and inform dosing recommendations. A minimal PBPK model was developed based on prior in vitro and in vivo clinical data using a "middle-out" approach. The PBPK model was independently verified against clinical studies of the strong CYP3A inhibitor ketoconazole, the strong CYP3A inducer, multiple-dose rifampin, and the steady-state venetoclax PK in chronic lymphocytic leukemia (CLL) subjects by comparing predicted to observed ratios of the venetoclax maximum concentration (Cmax R) and area under the curve from time 0 to infinity (AUC∞ R) from these studies...
January 4, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28050012/ppar-delta-promotes-survival-of-chronic-lymphocytic-leukemia-cells-in-energetically-unfavorable-conditions
#20
Y-J Li, L Sun, Y Shi, G Wang, X Wang, S Dunn, C Iorio, R A Screaton, D E Spaner
Targeting the mechanisms that allow Chronic Lymphocytic Leukemia (CLL) cells to survive in harsh cancer microenvironments should improve patient outcomes. The nuclear receptor peroxisome proliferator activated receptor delta (PPARδ) sustains other cancers and in silico analysis showed higher PPARD expression in CLL cells than normal lymphocytes and other hematologic cancers. A direct association was found between PPARδ protein levels in CLL cells and clinical score. Transgenic expression of PPARδ increased the growth and survival of CD5(+) Daudi cells and primary CLL cells in stressful conditions including exhausted tissue culture media, low extracellular glucose, hypoxia, and exposure to cytotoxic drugs...
January 4, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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