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https://www.readbyqxmd.com/read/28797244/a-lowered-26s-proteasome-activity-correlates-with-mantle-lymphoma-cell-lines-resistance-to-genotoxic-stress
#1
Khaoula Ben Younes, Simon Body, Élodie Costé, Pierre-Julien Viailly, Hadjer Miloudi, Clémence Coudre, Fabrice Jardin, Fatma Ben Aissa-Fennira, Brigitte Sola
BACKGROUND: Mantle cell lymphoma (MCL) is a B-cell hemopathy characterized by the t(11;14) translocation and the aberrant overexpression of cyclin D1. This results in an unrestrained cell proliferation. Other genetic alterations are common in MCL cells such as SOX11 expression, mutations of ATM and/or TP53 genes, activation of the NF-κB signaling pathway and NOTCH receptors. These alterations lead to the deregulation of the apoptotic machinery and resistance to drugs. We observed that among a panel of MCL cell lines, REC1 cells were resistant towards genotoxic stress...
August 10, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28783166/anti-leukemic-activity-of-microrna-26a-in-a-chronic-lymphocytic-leukemia-mouse-model
#2
L D'Abundo, E Callegari, A Bresin, A Chillemi, B K Elamin, P Guerriero, X Huang, E Saccenti, E M A A Hussein, F Casciano, P Secchiero, G Zauli, G A Calin, G Russo, L J Lee, C M Croce, G Marcucci, S Sabbioni, F Malavasi, M Negrini
Dysregulation of microRNAs (miRNAs) plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). The Eμ-TCL1 transgenic mouse develops a form of leukemia that is similar to the aggressive type of human B-CLL, and this valuable model has been widely used for testing novel therapeutic approaches. Here, we adopted this model to investigate the potential effects of miR-26a, miR-130an and antimiR-155 in CLL therapy. Improved delivery of miRNA molecules into CLL cells was obtained by developing a novel system based on lipid nanoparticles conjugated with an anti-CD38 monoclonal antibody...
August 7, 2017: Oncogene
https://www.readbyqxmd.com/read/28751770/enhancing-venetoclax-activity-in-acute-myeloid-leukemia-by-co-targeting-mcl1
#3
T-C Teh, N-Yn Nguyen, D M Moujalled, D Segal, G Pomilio, S Rijal, A Jabbour, K Cummins, K Lackovic, P Blombery, E Thompson, P G Ekert, G Lessene, S P Glaser, D C S Huang, A W Roberts, M A Guthridge, A H Wei
Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the BCL-2 family of proteins is an attractive option to combat chemoresistance in leukemia. Pre-clinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (e.g. venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase anti-leukemic efficacy in a TP53 dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53...
July 28, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28723622/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#4
Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28716899/hdac1-upregulation-by-nanog-promotes-multidrug-resistance-and-a-stem-like-phenotype-in-immune-edited-tumor-cells
#5
Kwon-Ho Song, Chel Hun Choi, Hyo-Jung Lee, Se Jin Oh, Seon Rang Woo, Soon-Oh Hong, Kyung Hee Noh, Hanbyoul Cho, Eun Joo Chung, Jae-Hoon Kim, Joon-Yong Chung, Stephen M Hewitt, Seungki Baek, Kyung-Mi Lee, Cassian Yee, Minjoo Son, Chih-Ping Mao, T-C Wu, Tae Woo Kim
Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell cycle inhibitor CDKN2D and CDKN1B induced stem-like features...
July 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28685948/role-of-zoledronic-acid-in-oncolytic-virotherapy-promotion-of-antitumor-effect-and-prevention-of-bone-destruction
#6
Yasuaki Yamakawa, Hiroshi Tazawa, Joe Hasei, Shuhei Osaki, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Kouji Uotani, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara
Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS-2)...
July 7, 2017: Cancer Science
https://www.readbyqxmd.com/read/28670929/exploiting-the-pro-apoptotic-function-of-noxa-as-a-therapeutic-modality-in-cancer
#7
REVIEW
Jeroen E Guikema, Martine Amiot, Eric Eldering
Direct targeting of Bcl-2 members for therapeutic purposes in cancer has become a clinical reality with the FDA approval of ABT-199/Venetoclax. Other highly specific BH3-mimetics are in pre-clinical development. Understanding the functional interactions among the Bcl-2 family is of prime importance to fully exploit their potential. NOXA is considered a rather weak BH3-only member but it has unexplored potential in various settings, which are of relevance in cancer. NOXA is best known as a selective inhibitor of MCL1, itself overexpressed in many cancers, and this protein pair forms an important rheostat in many forms of cell stress...
August 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28668293/mechanisms-of-resistance-of-chemotherapy-in-early-stage-triple-negative-breast-cancer-tnbc
#8
Lironne Wein, Sherene Loi
Triple negative breast cancer (TNBC) a clinically aggressive subtype of breast cancer with poor outcomes. Chromosomal instability is a hallmark of many TNBCs, and likely underlies its ability to adapt and rapidly become resistant to chemotherapy. A study of residual disease after neoadjuvant chemotherapy have identified biological mechanisms driving this resistance to chemotherapy. Copy number amplifications such as MCL1, MYC and JAK2, as well as PTEN deletions or mutations have all been identified at a higher frequency in residual disease, suggesting they may play a role in de novo or acquired chemotherapy resistance...
June 28, 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/28659496/secretion-of-interleukin-6-by-bone-marrow-mesenchymal-stem-cells-promotes-metastasis-in-hepatocellular-carcinoma
#9
Fei Mi, Liansheng Gong
Mesenchymal stem cells (MSCs) interact with tumor cells and regulate tumorigenesis and metastasis. As one of the important components of the tumor microenvironment, MSC-secreted cytokines play a critical role in cancer development. However, whether and how bone marrow MSCs (BMSCs) and their secreted cytokines participate in hepatocellular carcinoma (HCC) progression, still remains largely unknown. In the present study, we first measured the concentration of interleukin-6 (IL-6) in BMSC conditioned medium (BMSC-CM)...
June 28, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28648936/diagnostic-pathology-of-alzheimer-s-disease-from-routine-microscopy-to-immunohistochemistry-and-experimental-correlations
#10
Gerard Nuovo, Bernard Paniccia, Louisa Mezache, Maria Quiñónez, James Williams, Paige Vandiver, Paolo Fadda, Vicky Amann
The absence of any histologic correlate for Alzheimer's disease despite its commonness and severe clinical sequelae may offers clues to its etiology. Recent evidence strongly suggests that the central event of this disease is the hyperphosphorylation of neuronal tau protein and not the beta amyloid precipitates. In each case, essential and soluble neuronal proteins derivatives form insoluble aggregates that can readily be detected by immunohistochemistry using antibodies specific for the misfolded proteins...
June 2017: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/28622513/comprehensive-and-integrative-genomic-characterization-of-hepatocellular-carcinoma
#11
(no author information available yet)
Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed...
June 15, 2017: Cell
https://www.readbyqxmd.com/read/28611106/a-novel-combination-treatment-targeting-bcl-xl-and-mcl1-for-kras-braf-mutated-and-bcl2l1-amplified-colorectal-cancers
#12
Sung-Yup Cho, Jee Yun Han, Deukchae Na, Wonyoung Kang, Ahra Lee, Jooyoung Kim, Jieun Lee, Seoyeon Min, Jinjoo Kang, Jeesoo Chae, Jong-Il Kim, Hansoo Park, Won-Suk Lee, Charles Lee
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature and drug responsiveness. Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups has been limited. KRAS and BRAF mutations are prevalent genetic alterations in CRCs, and patients with mutations in either of these genes have a worse prognosis and are resistant to anti-EGFR treatments...
June 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28594854/identification-of-key-micrornas-and-genes-in-preeclampsia-by-bioinformatics-analysis
#13
Shouling Luo, Nannan Cao, Yao Tang, Weirong Gu
Preeclampsia is a leading cause of perinatal maternal-foetal mortality and morbidity. The aim of this study is to identify the key microRNAs and genes in preeclampsia and uncover their potential functions. We downloaded the miRNA expression profile of GSE84260 and the gene expression profile of GSE73374 from the Gene Expression Omnibus database. Differentially expressed miRNAs and genes were identified and compared to miRNA-target information from MiRWalk 2.0, and a total of 65 differentially expressed miRNAs (DEMIs), including 32 up-regulated miRNAs and 33 down-regulated miRNAs, and 91 differentially expressed genes (DEGs), including 83 up-regulated genes and 8 down-regulated genes, were identified...
2017: PloS One
https://www.readbyqxmd.com/read/28586207/primadorac-a-free-web-interface-for-the-assignment-of-partial-charges-chemical-topology-and-bonded-parameters-in-organic-or-drug-molecules
#14
Piero Procacci
We present PrimaDORAC, a simple and freely accessible web interface for generating the topology and the parameter files of organic or drug molecules to be used in molecular mechanics or molecular dynamics calculations. The interface relies on our in-house FORTRAN90 parser, working on the recently released Generalized Amber Force Field parameter set (GAFF2). AM1/BCC charges are computed using the Public Domain MOPAC7 program and the bond charge corrections (BCC) reported in Jakalian, A.; Jack, D. B.; Bayly, C...
June 14, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28586114/a-phosphokinome-based-screen-uncovers-new-drug-synergies-for-cancer-driven-by-liver-specific-gain-of-non-oncogenic-rtks
#15
Yannan Fan, Maria Arechederra, Sylvie Richelme, Fabrice Daian, Chiara Novello, Julien Calderaro, Luca Di Tommaso, Guillaume Morcrette, Sandra Rebouissou, Matteo Donadon, Emanuela Morenghi, Jessica Zucman-Rossi, Massimo Roncalli, Rosanna Dono, Flavio Maina
Genetic mutations leading to oncogenic variants of receptor tyrosine kinases (RTKs) are frequent events during tumorigenesis; however, the cellular vulnerability to non-oncogenic RTK fluctuations has not been characterized. Here, we demonstrated genetically that liver subtle increases in wild-type Met RTK levels are sufficient for spontaneous tumors in mice (Alb-R26(Met) ), conceptually illustrating how the shift from physiological to pathological conditions results from slight perturbations in signaling dosage...
June 6, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28560413/coptidis%C3%A2-rhizoma-induces-intrinsic-apoptosis-through-bax-and-bak-activation-in-human-melanoma
#16
Xiaoou Xu, Satoru Yokoyama, Yoshihiro Hayakawa, Ikuo Saiki
Malignant melanoma has exhibited a rising incidence in recent years worldwide. Although various molecular targeted drugs are being researched and developed for melanoma patients, their efficacy appears to be unsatisfactory. Over the past few years, several reports have demonstrated that Coptidis Rhizoma water extracts (CR) or its major active chemical component, berberine, has anticancer activities in various types of cancer, including melanoma. However, their underlying mechanisms have not been well understood...
May 26, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28548464/control-of-cell-death-and-mitochondrial-fission-by-erk1-2-map-kinase-signalling
#17
REVIEW
Simon J Cook, Kate Stuart, Rebecca Gilley, Matthew J Sale
The ERK1/2 signalling pathway is best known for its role in connecting activated growth factor receptors to changes in gene expression due to activated ERK1/2 entering the nucleus and phosphorylating transcription factors. However, active ERK1/2 also translocate to a variety of other organelles including the endoplasmic reticulum, endosomes, golgi and mitochondria to access specific substrates and influence cell physiology. In this article, we review two aspects of ERK1/2 signalling at the mitochondria that are involved in regulating cell fate decisions...
May 26, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28513465/the-role-of-srsf1-in-cancer
#18
Elżbieta Sokół, Joanna Bogusławska, Agnieszka Piekiełko-Witkowska
SRSF1 jest wielofunkcyjnym białkiem biorącym udział w procesach związanych z metabolizmem RNA. Następstwem zaburzeń ekspresji SRSF1, obserwowanych w wielu typach nowotworów, są nieprawidłowości w składaniu pre-mRNA, zmiany stabilności transkryptów i poziomu translacji onkogenów oraz genów supresorowych. Regulując różnicowe składanie transkryptów genów CCND1, RAC1, KLF6, BCL2L1, MCL1 oraz CASP9, SRSF1 indukuje zmiany w cyklu komórkowym, proliferacji i apoptozie. Czynnik SRSF1 wpływa także na angiogenezę nowotworową i przerzutowanie, m...
May 17, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28504646/the-rna-binding-protein-tristetraprolin-schedules-apoptosis-of-pathogen-engaged-neutrophils-during-bacterial-infection
#19
Florian Ebner, Vitaly Sedlyarov, Saren Tasciyan, Masa Ivin, Franz Kratochvill, Nina Gratz, Lukas Kenner, Andreas Villunger, Michael Sixt, Pavel Kovarik
Protective responses against pathogens require a rapid mobilization of resting neutrophils and the timely removal of activated ones. Neutrophils are exceptionally short-lived leukocytes, yet it remains unclear whether the lifespan of pathogen-engaged neutrophils is regulated differently from that in the circulating steady-state pool. Here, we have found that under homeostatic conditions, the mRNA-destabilizing protein tristetraprolin (TTP) regulates apoptosis and the numbers of activated infiltrating murine neutrophils but not neutrophil cellularity...
June 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28499919/long-non-coding-rna-ac023115-3-suppresses-chemoresistance-of-glioblastoma-by-reducing-autophagy
#20
Binbin Ma, Zhongbo Yuan, Li Zhang, Peng Lv, Ting Yang, Jinxia Gao, Ning Pan, Qiong Wu, Jiacheng Lou, Chuanchun Han, Bo Zhang
Malignant glioma is an aggressive brain cancer that responds poorly to chemotherapy. However, the molecular mechanism underlying the development of chemoresistance in glioma is not well-understood. In this study, we show that long non-coding RNA AC023115.3 is induced by cisplatin in human glioblastoma cells and that elevated AC023115.3 promotes cisplatin-induced apoptosis by inhibiting autophagy. Further mechanistic studies revealed that AC023115.3 acts as a competing endogenous RNA for miR-26a and attenuates the inhibitory effect of miR-26a on GSK3β, a proline-directed serine-threonine kinase that promotes the degradation of Mcl1, leading to an increase in GSK3β and a decrease in autophagy...
May 9, 2017: Biochimica et Biophysica Acta
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