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https://www.readbyqxmd.com/read/28537899/nras-mutations-in-cutaneous-t-cell-lymphoma-ctcl-sensitize-tumors-towards-treatment-with-the-multikinase-inhibitor-sorafenib
#1
Michael K Kießling, Jan P Nicolay, Tabea Schlör, Claus-Detlev Klemke, Dorothee Süss, Peter H Krammer, Karsten Gülow
Therapy of cutaneous T cell lymphoma (CTCL) is complicated by a distinct resistance of the malignant T cells towards apoptosis that can be caused by NRAS mutations in late-stage patients. These mutations correlate with decreased overall survival, but sensitize the respective CTCL cells towards MEK-inhibition-induced apoptosis which represents a promising novel therapeutic target in CTCL. Here, we show that the multi-kinase inhibitor Sorafenib induces apoptosis in NRAS-mutated CTCL cells. CTCL cell lines and to a minor extent primary T cells from Sézary patients without NRAS mutations are also affected by Sorafenib-induced apoptosis suggesting a sensitizing role of NRAS mutations for Sorafenib-induced apoptosis...
May 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28533436/metformin-synergizes-with-bcl-xl-bcl-2-inhibitor-abt-263-to-induce-apoptosis-specifically-in-p53-defective-cancer-cells
#2
Xinzhe Li, Bo Li, Zhenhong Ni, Peng Zhou, Bin Wang, Jintao He, Haojun Xiong, Fan Yang, Yaran Wu, Xilin Lyu, Yan Zhang, Yijun Zeng, Jiqin Lian, Fengtian He
p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the pro-apoptotic machineries in various p53-defective cancer cells...
May 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28533399/correction-for-dash-et-al-apogossypol-derivative-bi-97c1-sabutoclax-targeting-mcl-1-sensitizes-prostate-cancer-cells-to-mda-7-il-24-mediated-toxicity
#3
(no author information available yet)
No abstract text is available yet for this article.
May 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28533307/sox11-promotes-tumor-protective-microenvironment-interactions-through-cxcr4-and-fak-regulation-in-mantle-cell-lymphoma
#4
Patricia Balsas, Jara Palomero, Álvaro Eguileor, Marta Leonor Rodriguez, Maria Carmela Vegliante, Ester Planas-Rigol, Marta Sureda-Gómez, Maria C Cid, Elias Campo, Virginia Amador
SOX11 overexpression in Mantle Cell Lymphoma (MCL) has been associated with more aggresive behavior and worse outcome. However, SOX11 oncogenic pathways driving MCL tumor progression are poorly known. Here, we demonstrate that SOX11 binds to regulatory regions of two important genes for microenvironment-signals in cancer, (C-X-C motif) chemokine receptor 4 (CXCR4) and PTK2 (encoding for focal adhesion kinase (FAK)). Moreover, SOX11-positive xenograft and human primary MCL tumors overexpress cell migration and stromal stimulation gene signatures compared to their SOX11-negative counterparts...
May 22, 2017: Blood
https://www.readbyqxmd.com/read/28529032/synergistic-cytotoxicity-of-lenalidomide-and-dexamethasone-in-mantle-cell-lymphoma-via-cereblon-dependent-targeting-of-the-il-6-stat3-pi3k-axis
#5
Jiexian Ma, Kefei Wu, Weiya Bai, Xiaoxian Cui, Yan Chen, Youhua Xie, Yanhui Xie
At our center, relapsed mantle cell lymphoma (MCL) can be treated with maintenance therapy composed of consecutive low-dose lenalidomide and short-term, high-dose dexamethasone (LD regimen), which achieves good responses (longer overall survival and progression-free survival) and low toxicity. Cereblon is probably targeted by both lenalidomide and dexamethasone, which leads to synergistic cytotoxicity in MCL by inhibiting the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3), phosphatidylinositol 3-kinase (PI3K)/AKT and AKT2/Forkhead box O3 (FOXO3A)/BCL2-like 11 (BIM) pathways...
May 10, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28526264/celecoxib-aggravates-cardiac-apoptosis-in-l-name-induced-pressure-overload-model-in-rats-immunohistochemical-determination-of-cardiac-caspase-3-mcl-1-bax-and-bcl-2
#6
Sarah M Mosaad, Sawsan A Zaitone, Abdelazim Ibrahim, Amani A El-Baz, Dina M Abo-Elmatty, Yasser M Moustafa
The mechanism of celecoxib cardiovascular adverse events was earlier investigated; yet in-depth investigations are needed to assess the involvement of its pro-apoptotic effect throughout this process. An in-vivo chronic rat model of pressure overload employing Nʷ-nitro-l-arginine methyl ester (L-NAME) was tested at different time intervals to ensure the occurrence of persistent myocardial apoptosis along with pressure overload. Seven groups of male Wistar rats were assigned as (i) distilled water; (ii-iv) L-NAME (60 mg/kg) for 6, 12 or 16 weeks; (v-vii) L-NAME [16 weeks] + celecoxib (25, 50 or 100 mg/kg), from week 13 to week 16...
May 16, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28522751/targeting-fbw7-as-a-strategy-to-overcome-resistance-to-targeted-therapy-in-non-small-cell-lung-cancer
#7
Mingxiang Ye, Yong Zhang, Xinxin Zhang, Jian-Bin Zhang, Pengyu Jing, Liang Cao, Nan Li, Xia Li, Libo Yao, Jian Zhang, Jian Zhang
Inhibition of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non-small cell lung cancer (NSCLC) patients with distinct clinicopathological features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt- and MEK/Erk-independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) leads to targeted therapy resistance via stabilization of anti-apoptotic protein MCL-1...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28522750/inhibition-of-mitochondrial-matrix-chaperones-and-anti-apoptotic-bcl-2-family-proteins-empower-antitumor-therapeutic-responses
#8
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Dario C Altieri, Markus D Siegelin
Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28520795/birc6-mediates-imatinib-resistance-independently-of-mcl-1
#9
Denis O Okumu, Michael P East, Merlin Levine, Laura E Herring, Raymond Zhang, Thomas S K Gilbert, David W Litchfield, Yanping Zhang, Lee M Graves
Baculoviral IAP repeat containing 6 (BIRC6) is a member of the inhibitors of apoptosis proteins (IAPs), a family of functionally and structurally related proteins that inhibit apoptosis. BIRC6 has been implicated in drug resistance in several different human cancers, however mechanisms regulating BIRC6 have not been extensively explored. Our phosphoproteomic analysis of an imatinib-resistant chronic myelogenous leukemia (CML) cell line (MYL-R) identified increased amounts of a BIRC6 peptide phosphorylated at S480, S482, and S486 compared to imatinib-sensitive CML cells (MYL)...
2017: PloS One
https://www.readbyqxmd.com/read/28515366/experimental-lupus-is-aggravated-in-mouse-strains-with-impaired-induction-of-neutrophil-extracellular-traps
#10
Deborah Kienhöfer, Jonas Hahn, Julia Stoof, Janka Zsófia Csepregi, Christiane Reinwald, Vilma Urbonaviciute, Caroline Johnsson, Christian Maueröder, Malgorzata J Podolska, Mona H Biermann, Moritz Leppkes, Thomas Harrer, Malin Hultqvist, Peter Olofsson, Luis E Munoz, Attila Mocsai, Martin Herrmann, Georg Schett, Rikard Holmdahl, Markus H Hoffmann
Many effector mechanisms of neutrophils have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) have been assigned a particularly detrimental role. Here we investigated the functional impact of neutrophils and NETs on a mouse model of lupus triggered by intraperitoneal injection of the cell death-inducing alkane pristane. Pristane-induced lupus (PIL) was aggravated in 2 mouse strains with impaired induction of NET formation, i.e., NOX2-deficient (Ncf1-mutated) and peptidyl arginine deiminase 4-deficient (PAD4-deficient) mice, as seen from elevated levels of antinuclear autoantibodies (ANAs) and exacerbated glomerulonephritis...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515282/talin-plays-a-critical-role-in-the-maintenance-of-the-regulatory-t-cell-pool
#11
Jane E Klann, Kelly A Remedios, Stephanie H Kim, Patrick J Metz, Justine Lopez, Lauren A Mack, Ye Zheng, Mark H Ginsberg, Brian G Petrich, John T Chang
Talin, a cytoskeletal protein essential in mediating integrin activation, has been previously shown to be involved in the regulation of T cell proliferation and function. In this study, we describe a role for talin in maintaining the homeostasis and survival of the regulatory T (Treg) cell pool. T cell-specific deletion of talin in Tln1(fl/fl)Cd4(Cre) mice resulted in spontaneous lymphocyte activation, primarily due to numerical and functional deficiencies of Treg cells in the periphery. Peripheral talin-deficient Treg cells were unable to maintain high expression of IL-2Rα, resulting in impaired IL-2 signaling and ultimately leading to increased apoptosis through downregulation of prosurvival proteins Bcl-2 and Mcl-1...
May 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28511583/deciphering-the-crucial-residues-involved-in-heterodimerization-of-bak-peptide-and-anti-apoptotic-proteins-for-apoptosis
#12
Parthiban Marimuthu, Kalaimathy Singaravelu
B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of apoptosis, function via mitochondrial outer membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions. This overexpression is modulated or inhibited by heterodimerization of pro-apoptotic BH3 domain or BH3-only peptides to the hydrophobic groove present at the surface of anti-apoptotic proteins. Additionally, the heterodimerization displayed differences in binding affinity profile among the pro-apoptotic peptides binding to anti-apoptotic proteins...
May 16, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28503147/an-ethanolic-extract-of-ampelopsis-radix-exerts-anti-colorectal-cancer-effects-and-potently-inhibits-stat3-signaling-in-vitro
#13
Tao Su, Jing-Xuan Bai, Ying-Jie Chen, Xin-Ning Wang, Xiu-Qiong Fu, Ting Li, Hui Guo, Pei-Li Zhu, Yue Wang, Zhi-Ling Yu
Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide. Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in CRC, and has been proposed as a pathogenic factor and a therapeutic target of CRC. Ampelopsis Radix (AR), a traditional Chinese medicinal herb, possesses low toxicity and has long been used clinically for the treatment of cancers including CRC. Some constituents of AR have been reported to exert anti-cancer properties by targeting STAT3...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28502307/-knock-down-of-dab2-interacting-protein-dab2ip-promotes-proliferation-and-inhibits-apoptosis-of-bladder-cancer-cells
#14
Kai Zhang, Weiyi Wang, Kaijie Wu, Chen Ding, Jianning Zhu, Yiqing DU, Zhenfeng Guan, Xinyang Wang, Jinhai Fan
Objective To study the expression of DAB2 interacting protein (DAB2IP) in human bladder cancer tissues and analyze its relationship with pathological grade and clinical stage, and observe its role in drug resistance of bladder cancer cells. Methods The expression of DAB2IP in primary and recurrent bladder cancers was detected by immunohistochemical staining. RNA interference (RNAi) technique was used to down-regulate the expression of DAB2IP in 5637 and 253J bladder cancer cells. MTT assay and clone formation assay were performed to test the sensitivity of cancer cells to pirarubicin...
May 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28502064/optimization-of-water-oil-surfactant-system-for-preparation-of-medium-chain-length-poly-3-hydroxyalkanoates-mcl-pha-incorporated-nanoparticles-via-nanoemulsion-templating-technique
#15
K A Ishak, M Suffian M Annuar, N Ahmad
Polymeric nanoparticles gain a widespread interest in food and pharmaceutical industries as delivery systems that encapsulate, protect, and release lipophilic compounds such as omega-3 fatty acids, fat-soluble vitamins, carotenoids, carvedilol, cyclosporine, and ketoprofen. In this study, medium-chain-length poly-3-hydroxyalkanoate (mcl-PHA)-incorporated nanoparticle was developed via facile organic solvent-free nanoemulsion templating technique. The water content (W/surfactant-to-oil (S/O)), S/O, and Cremophor EL-to-Span 80 (Cremo/Sp80) ratios were first optimized using response surface methodology (RSM) to obtain nanoemulsion template prior to incorporation of mcl-PHA...
May 13, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28499784/gsk-3-as-a-novel-prognostic-indicator-in-leukemia
#16
REVIEW
Peter P Ruvolo
While leukemias represent a diverse set of diseases with malignant cells derived from myeloid or lymphoid origin, a common feature is the dysregulation of signal transduction pathways that influence leukemogeneisis, promote drug resistance, and favor leukemia stem cells. Mutations in PI3K, PTEN, RAS, or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival. A major target of AKT is Glycogen Synthase Kinase 3 (GSK3). GSK3 has two isoforms (alpha and beta) that were studied as regulators of metabolism but emerged as central players in cancer in the early 1990s...
May 8, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28497290/medium-chain-length-polyhydroxyalkanoates-synthesis-by-pseudomonas-putida-kt2440-rela-spot-mutant-bioprocess-characterization-and-transcriptome-analysis
#17
Justyna Mozejko-Ciesielska, Dorota Dabrowska, Agnieszka Szalewska-Palasz, Slawomir Ciesielski
Pseudomonas putida KT2440 is a model bacteria used commonly for medium-chain-length polyhydroxyalkanoates (mcl-PHAs) production using various substrates. However, despite many studies conducted on P. putida KT2440 strain, the molecular mechanisms of leading to mcl-PHAs synthesis in reaction to environmental stimuli are still not clear. The rearrangement of the metabolism in response to environmental stress could be controlled by stringent response that modulates the transcription of many genes in order to promote survival under nutritional deprivation conditions...
December 2017: AMB Express
https://www.readbyqxmd.com/read/28493974/serum-%C3%AE-1-antitrypsin-aat-antagonizes-intrinsic-apoptosis-induction-in-neutrophils-from-patients-with-systemic-inflammatory-response-syndrome
#18
Theresia Sarabhai, Christoph Peter, Anne-Kathrin Bär, Joachim Windolf, Borna Relja, Sebastian Wesselborg, Thorsten Wahlers, Adnana Paunel-Görgülü
Excessive neutrophil activation accompanied by delayed apoptotic cell death in inflammatory conditions causes progressive damage of cells and tissues, leading to life-threatening multiple organ dysfunction syndrome. Previous work suggested that circulating serum factors during inflammation are critically involved in the suppression of neutrophil cell death although the identity of these antiapoptotic mediators remained elusive. In this study, we identified the acute phase protein α-1 Antitrypsin (AAT) as a potent suppressor of staurosporine (STS)-induced apoptosis in human neutrophils through a mechanism implicating caspases-independent pathways...
2017: PloS One
https://www.readbyqxmd.com/read/28493826/targeting-the-apoptotic-mcl-1-puma-interface-with-a-dual-acting-compound
#19
Jiyuan Liu, Zhen Tian, Nan Zhou, Xueying Liu, Chenyi Liao, Beilei Lei, Jianing Li, Shengyong Zhang, Hui Chen
Despite intensive efforts in the search for small molecules with anti-cancer activity, it remains challenging to achieve both high effectiveness and safety, since many agents lack the selectivity to only act on cancer cells. The interface of two apoptotic proteins, myeloid cell leukemia-1 (Mcl-1) and p53 upregulated modulator of apoptosis (PUMA), has been recently affirmed as a target for treating cancers, as the disruption of Mcl-1-PUMA binding can reduce cancer cell survival and protect normal cells from apoptosis...
April 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28492347/the-soy-derived-peptide-vglycin-inhibits-the-growth-of-colon-cancer-cells-in%C3%A2-vitro-and-in%C3%A2-vivo
#20
Chang Gao, Rui Sun, Ya-Rong Xie, An-Li Jiang, Mei Lin, Min Li, Zheng-Wang Chen, Ping Zhang, Honglin Jin, Jue-Ping Feng
Vglycin, a novel natural polypeptide isolated from pea seeds, possesses antidiabetic properties. Our previous studies have shown that Vglycin can induce the differentiation of human colon adenocarcinoma cells. We aimed to determine the anticancer activity of Vglycin against colon cancer cells and to elucidate related apoptosis-inducing mechanisms. Treatment with purified Vglycin significantly reduced growth, viability, and colony formation of CT-26, SW480, and NCL-H716 colon cancer cells in a dose-dependent manner while down-regulating the expression of proliferating cell nuclear antigen...
May 2017: Experimental Biology and Medicine
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