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https://www.readbyqxmd.com/read/28526063/targeting-the-cxcr4-pathway-using-a-novel-anti-cxcr4-igg1-antibody-pf-06747143-in-chronic-lymphocytic-leukemia
#1
Manoj K Kashyap, Carlos I Amaya-Chanaga, Deepak Kumar, Brett Simmons, Nanni Huser, Yin Gu, Max Hallin, Kevin Lindquist, Rolla Yafawi, Michael Y Choi, Ale-Ali Amine, Laura Z Rassenti, Cathy Zhang, Shu-Hui Liu, Tod Smeal, Valeria R Fantin, Thomas J Kipps, Flavia Pernasetti, Januario E Castro
BACKGROUND: The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow...
May 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28523450/a-review-of-the-clinical-pharmacokinetics-pharmacodynamics-and-immunogenicity-of-vedolizumab
#2
REVIEW
Maria Rosario, Nathanael L Dirks, Catherine Milch, Asit Parikh, Michael Bargfrede, Tim Wyant, Eric Fedyk, Irving Fox
Vedolizumab is a humanized anti-α4β7 integrin monoclonal antibody that selectively blocks trafficking of memory T cells to inflamed gut tissue by inhibiting the α4β7-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interaction. Approved for treating patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), vedolizumab is administered as a 300 mg intravenous infusion. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations...
May 18, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28471202/-use-of-porous-hydrogel-as-a-3d-scaffold-for-the-growth-of-leukemic-b-lymphocytes
#3
R Studená, D Horák, J Baloun, Z Plichta, Š Pospíšilová
BACKGROUND: Primary human B cells chronic lymphocytic leukemia undergoes apoptosis, from which they can be rescued by contact with stromal cells or by the addition of specific soluble factor, when cultured in vitro. For research purposes of the behavior of CLL cells we created 3D in vitro model in which we simulated appropriate microenvironment for CLL cells to allow study the mechanism of survival of these cells in long-term cultivation. MATERIAL AND METHODS: Our aim was the scaffold structure to be geometrically similar to the 3D morphology of supporting bone marrow tissue in a trabecular bone; the 3D scaffold was also designed to conform to biocompatibility, sufficiently large surface area for cell attachment, high porosity for cell migration, proliferation and transport of nutrients...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/28465529/wnt5a-induces-ror1-to-complex-with-hs1-to-enhance-migration-of-chronic-lymphocytic-leukemia-cells
#4
K Hasan, J Yu, L Chen, B Cui, G F Widhopf, L Rassenti, Z Shen, S P Briggs, T J Kipps
ROR1 is a conserved, oncoembryonic surface-antigen expressed in chronic lymphocytic leukemia (CLL). We found that ROR1 associates with Hematopoietic-lineage-cell-Specific protein 1 (HS1) in freshly-isolated CLL cells or in CLL cells cultured with exogenous Wnt5a. Wnt5a also induced HS1 tyrosine phosphorylation, recruitment of ARHGEF1, activation of RhoA, and enhanced chemokine-directed migration; such effects could be inhibited by cirmtuzumab, a humanized anti-ROR1 mAb. We generated truncated forms of ROR1 and found its extra-cellular cysteine-rich domain or kringle domain was necessary for Wnt5a-induced HS1 phosphorylation...
May 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28465528/wnt5a-induces-ror1-to-associate-with-14-3-3%C3%AE-for-enhanced-chemotaxis-and-proliferation-of-chronic-lymphocytic-leukemia-cells
#5
J Yu, L Chen, Y Chen, K Hasan, E M Ghia, L Zhang, R Wu, L Z Rassenti, G F Widhopf, Z Shen, S P Briggs, T J Kipps
Wnt5a can activate Rho GTPases in chronic lymphocytic leukemia cells by inducing the recruitment of ARHGEF2 to ROR1. Mass spectrometry on immune-precipitates of Wnt5a-activated ROR1 identified 14-3-3ζ, which was confirmed by co-immunoprecipitation. The capacity of Wnt5a to induce ROR1 to complex with 14-3-3ζ could be blocked in CLL cells treated with cirmtuzumab, a humanized mAb targeting ROR1. Silencing 14-3-3ζ via siRNA impaired the capacity of Wnt5a to: (1) induce recruitment of ARHGEF2 to ROR1, (2) enhance in vitro exchange activity of ARHGEF2, and (3) induce activation of RhoA and Rac1 in CLL cells...
May 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28424416/loss-of-thyroid-hormone-receptor-interactor-13-inhibits-cell-proliferation-and-survival-in-human-chronic-lymphocytic-leukemia
#6
Keshu Zhou, Wentao Zhang, Qing Zhang, Ruirui Gui, Huifang Zhao, Xiaofei Chai, Yufu Li, Xudong Wei, Yongping Song
BACKGROUND: The genetic regulation of apoptosis and cell proliferation plays a role in the growth of chronic lymphocytic leukemia (CLL), the most common form of leukemia in the Western hemisphere. Although thyroid hormone receptor interactors (TRIPs) are known to play roles in cell cycle, the potential involvement of the novel family member TRIP13 in CLL has not yet been investigated. METHODS: Quantitative PCR (qPCR) was used to detect expression of TRIP13 in 36 CLL patients and 33 healthy donors CD19+ B cells...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424162/pembrolizumab-in-patients-with-chronic-lymphocytic-leukemia-with-richter-s-transformation-and-relapsed-cll
#7
Wei Ding, Betsy R LaPlant, Timothy G Call, Sameer A Parikh, Jose F Leis, Rong He, Tait D Shanafelt, Sutapa Sinha, Jennifer Le-Rademacher, Andrew L Feldman, Thomas M Habermann, Thomas E Witzig, Gregory A Wiseman, Yi Lin, Erik Asmus, Grzegorz S Nowakowski, Michael J Conte, Deborah A Bowen, Casey N Aitken, Daniel L Van Dyke, Patricia T Greipp, Xin Liu, Xiaosheng Wu, Henan Zhang, Charla R Secreto, Shulan Tian, Esteban Braggio, Linda E Wellik, Ivana Micallef, David S Viswanatha, Huihuang Yan, Asher A Chanan-Khan, Neil E Kay, Haidong Dong, Stephen M Ansell
CLL patients progressed early on ibrutinib often develop Richter's transformation (RT) with short survival about 4 months. Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL. This phase 2 study MC1485 (NCT02332980) was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled and 60% received prior ibrutinib...
April 19, 2017: Blood
https://www.readbyqxmd.com/read/28412730/the-long-noncoding-rna-trerna-decreases-dna-damage-and-is-associated-with-poor-response-to-chemotherapy-in-chronic-lymphocytic-leukemia
#8
Cecelia R Miller, Amy S Ruppert, Sydney Fobare, Timothy L Chen, Chaomei Liu, Amy Lehman, James S Blachly, Xiaoli Zhang, David M Lucas, Michael R Grever, Martin S Tallman, Ian W Flinn, Laura Z Rassenti, Thomas J Kipps, Deepa Sampath, Kevin R Coombes, Erin K Hertlein
The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28382095/prognostic-influence-of-bcl2-on-molecular-subtypes-of-breast-cancer
#9
Ki-Tae Hwang, Wonshik Han, Jongjin Kim, Hyeong-Gon Moon, Sohee Oh, Yun Seon Song, Young A Kim, Mee Soo Chang, Dong-Young Noh
PURPOSE: We aimed to reveal the prognostic influence of B-cell CLL/lymphoma 2 (BCL2) on molecular subtypes of breast cancer. METHODS: We analyzed 9,468 patients with primary breast cancer. We classified molecular subtypes according to the National Comprehensive Cancer Network (NCCN) and St. Gallen guidelines, mainly on the basis of the expression of hormonal receptor (HR), human epidermal growth factor receptor 2 (HER2), and Ki-67. RESULTS: Regarding NCCN classification, BCL2 was a strong favorable prognostic factor in the HR(+)/HER2(-) subtype (p<0...
March 2017: Journal of Breast Cancer
https://www.readbyqxmd.com/read/28368400/interferon-%C3%AE-is-a-stat1-dependent-direct-inducer-of-bcl6-expression-in-imatinib-treated-chronic-myeloid-leukemia-cells
#10
H S Madapura, N Nagy, D Ujvari, T Kallas, M C L Kröhnke, S Amu, M Björkholm, L Stenke, P K Mandal, J S McMurray, M Keszei, L S Westerberg, H Cheng, F Xue, G Klein, E Klein, D Salamon
B-cell CLL/lymphoma 6 (BCL6) exerts oncogenic effects in several human hematopoietic malignancies including chronic myeloid leukemia (CML), where BCL6 expression was shown to be essential for CML stem cell survival and self-renewal during imatinib mesylate (IM) treatment. As several lines of evidence suggest that interferon γ (IFNγ) production in CML patients might have a central role in the response to tyrosine kinase inhibitor (TKI) therapy, we analyzed if IFNγ modulates BCL6 expression in CML cells. Although separate IFNγ or IM treatment only slightly upregulated BCL6 expression, combined treatment induced remarkable BCL6 upregulation in CML lines and primary human CD34+ CML stem cells...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28317752/facile-preparation-of-magnetic-carbon-nanotubes-immobilized-lipase-for-highly-efficient-synthesis-of-1-3-dioleoyl-2-palmitoylglycerol-rich-human-milk-fat-substitutes
#11
Mingming Zheng, Shi Wang, Xia Xiang, Jie Shi, Juan Huang, Qianchun Deng, Fenghong Huang, Junyong Xiao
In this study, Candida lipolytica lipase (CLL) was immobilized on magnetic multi-walled carbon nanotubes (mMWCNTs) via hydrophobic and cation-exchange interaction. The resultant immobilized CLL showed much better thermal stability, biocatalyst activity and easier recycling than the free form. A method for efficient enzymatic acidolysis of tripalmitin (PPP) with oleic acid (OA), to produce OPO-rich TAGs, was developed, using the immobilized CLL as the biocatalyst. Under optimized conditions (2% water, 20mg/ml enzyme, 1:6 PPP/OA, 50°C, 2h), the content of OPO in the final product reached 46...
August 1, 2017: Food Chemistry
https://www.readbyqxmd.com/read/28288980/human-neutrophils-mediate-trogocytosis-rather-than-phagocytosis-of-cll-b-cells-opsonized-with-anti-cd20-antibodies
#12
Rut Valgardsdottir, Irene Cattaneo, Christian Klein, Martino Introna, Marina Figliuzzi, Josée Golay
Polymorphonuclear neutrophils (PMN) have previously been reported to mediate phagocytosis of anti-CD20 opsonized B-cells from CLL patients. However recent data have suggested that PMN, like macrophages, can also mediate trogocytosis. We have performed experiments to more precisely investigate this point and discriminate between trogocytosis and phagocytosis. In live cell time-lapse microscopy experiments, we could not detect any significant phagocytosis by purified PMN of anti-CD20-opsonized CLL B-cells, but only the repeated close contact between effectors and targets, suggesting trogocytosis...
March 13, 2017: Blood
https://www.readbyqxmd.com/read/28282218/immunotoxins-in-cancer-therapy-review-and-update
#13
Bahman Akbari, Safar Farajnia, Shiva Ahdi Khosroshahi, Fatemeh Safari, Mohammadreza Yousefi, Hassan Dariushnejad, Leila Rahbarnia
Immunotoxins are a novel class of cancer therapeutics that contains a cytotoxic agent fused to a targeting moiety. Various toxic agents from different sources are used in immunotoxin development, including bacterial, plant and human origin cytotoxic elements. Although bacterial and plant-derived toxins are highly toxic and commonly used in immunotoxins, their immunogenicity for human restricted their application in cancer therapy. Here, we discuss the advantages and limitations of bacterial toxins such as Pseudomonas and Diphtheria toxins, plant toxins such as ricin and gelonin, and some endogenous protein of human origin such as RNases and Granzymes...
March 1, 2017: International Reviews of Immunology
https://www.readbyqxmd.com/read/28249016/hla-specificities-are-associated-with-prognosis-in-ighv-mutated-cll-like-high-count-monoclonal-b-cell-lymphocytosis
#14
María García-Álvarez, Miguel Alcoceba, Miriam López-Parra, Noemí Puig, Alicia Antón, Ana Balanzategui, Isabel Prieto-Conde, Cristina Jiménez, María E Sarasquete, M Carmen Chillón, María Laura Gutiérrez, Rocío Corral, José María Alonso, José Antonio Queizán, Julia Vidán, Emilia Pardal, María Jesús Peñarrubia, José M Bastida, Ramón García-Sanz, Luis Marín, Marcos González
INTRODUCTION: Molecular alterations leading progression of asymptomatic CLL-like high-count monoclonal B lymphocytosis (hiMBL) to chronic lymphocytic leukemia (CLL) remain poorly understood. Recently, genome-wide association studies have found 6p21.3, where the human leukocyte antigen (HLA) system is coded, to be a susceptibility risk region for CLL. Previous studies have produced discrepant results regarding the association between HLA and CLL development and outcome, but no studies have been performed on hiMBL...
2017: PloS One
https://www.readbyqxmd.com/read/28202953/fully-human-cd19-specific-chimeric-antigen-receptors-for-t-cell-therapy
#15
D Sommermeyer, T Hill, S M Shamah, A I Salter, Y Chen, K M Mohler, S R Riddell
Impressive results have been achieved by adoptively transferring T-cells expressing CD19-specific CARs with binding domains from murine mAbs to treat B-cell malignancies. T-cell mediated immune responses specific for peptides from the murine scFv antigen-binding domain of the CAR can develop in patients and result in premature elimination of CAR T-cells increasing the risk of tumor relapse. As fully human scFv might reduce immunogenicity, we generated CD19-specific human scFvs with similar binding characteristics as the murine FMC63-derived scFv using human Ab/DNA libraries...
March 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28182141/obinutuzumab-in-chronic-lymphocytic-leukemia-design-development-and-place-in-therapy
#16
REVIEW
Othman Al-Sawaf, Kirsten Fischer, Anja Engelke, Natali Pflug, Michael Hallek, Valentin Goede
For decades, treatment of chronic lymphocytic leukemia (CLL) has been based on chemotherapy. This changed when the first CD20 antibody rituximab was introduced. Since 2008, the combination of chemotherapy and CD20 antibodies has become the standard of care for most patients, and a significant fraction of patients had very long-lasting remissions after chemoimmunotherapy. Despite the improvement of response rates and overall survival (OS) by the use of chemoimmunotherapy, most CLL patients will relapse eventually...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28125682/the-number-of-overlapping-aid-hotspots-in-germline-ighv-genes-is-inversely-correlated-with-mutation-frequency-in-chronic-lymphocytic-leukemia
#17
Chaohui Yuan, Charles C Chu, Xiao-Jie Yan, Davide Bagnara, Nicholas Chiorazzi, Thomas MacCarthy
The targeting of mutations by Activation-Induced Deaminase (AID) is a key step in generating antibody diversity at the Immunoglobulin (Ig) loci but is also implicated in B-cell malignancies such as chronic lymphocytic leukemia (CLL). AID has previously been shown to preferentially deaminate WRC (W = A/T, R = A/G) hotspots. WGCW sites, which contain an overlapping WRC hotspot on both DNA strands, mutate at much higher frequency than single hotspots. Human Ig heavy chain (IGHV) genes differ in terms of WGCW numbers, ranging from 4 for IGHV3-48*03 to as many as 12 in IGHV1-69*01...
2017: PloS One
https://www.readbyqxmd.com/read/28097289/binding-of-cll-subset-4-b-cell-receptor-immunoglobulins-to-viable-human-memory-b-lymphocytes-requires-a-distinctive-igkv-somatic-mutation
#18
Rosa Catera, Yun Liu, Chao Gao, Xiao-Jie Yan, Amanda Magli, Steven L Allen, Jonathan E Kolitz, Kanti R Rai, Charles C Chu, Ten Feizi, Kostas Stamatopoulos, Nicholas Chiorazzi
Amino acid replacement mutations in certain CLL stereotyped B-cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34(+) IGs, we found IGs from both subset 4 and non-subset 4 IGHV4-34-expressing CLL cases bind naïve B cells...
January 12, 2017: Molecular Medicine
https://www.readbyqxmd.com/read/28070536/establishment-a-cho-cell-line-expressing-human-cd52-molecule
#19
Tati Kadijeh, Yazdanpanah-Samani Mahsa, Ramezani Amin, Mahmoudi Maymand Elham, Ghaderi Abbas
BACKGROUND: CD52 is a small glycoprotein with a GPI anchor at its C-terminus. CD52 is expressed by Normal and malignant T and B lymphocytes and monocytes. There are detectable amounts of soluble CD52 in plasma of patients with CLL and could be used as a tumor marker. Although the biological function of CD52 is unknown but it seems that CD52 may be involved in migration and activation of T-cells .The aim of this study was to clone and express human CD52 gene in CHO cell line and studying its function in more details...
October 2016: Reports of Biochemistry & Molecular Biology
https://www.readbyqxmd.com/read/28024470/-establishment-of-human-chronic-lymphocytic-leukemia-model-in-the-balb-c-nude-mice-by-using-mec-1-and-hg3-cell-lines
#20
Chun-Ling Fu, Yan-Qing Gong, Yan Wan, Kai-Lin Xu
OBJECTIVE: To explore the the optimal condition for establishing immune deficiency mouse(BALB/c) model with CLL via subcutaneous inoculation of human chronic lymphocytic leukemia (CLL) cells at different inoculative locations and different cell concentrations. METHODS: Firstly, Two CLL cell lines (MEC-1-GFP and HG3-GFP)with the green fluorescent protein (GFP) were established by lentivirus system respectively, and then the MEC-1-GFP cells (5×10(7)/ml) were inoculated into forelimb, hindlimb and abdomen to observe the tumorigenesis...
December 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
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