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Fusion inhibitors

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https://www.readbyqxmd.com/read/28923082/characterization-of-a-secreted-cystatin-of-the-parasitic-nematode-haemonchus-contortus-and-its-immune-modulatory-effect-on-goat-monocytes
#1
Yujian Wang, Lingyan Wu, Xinchao Liu, Shuai Wang, Muhammad Ehsan, RuoFeng Yan, XiaoKai Song, LiXin Xu, XiangRui Li
BACKGROUND: Haemonchosis is a disease of the small ruminant caused by a nematode parasite Haemonchus contortus, and it is most important and alarming challenges to the small ruminant's production. The infection of the H. contortus could cause high economic losses worldwide. H. contortus is a blood feeding parasite which penetrates into the abomasal mucosa to feed the blood of the host and causing the anemia and decreased total plasma protein. Modulation and suppression of the immune response of the host by nematode parasites have been reported extensively, and the cysteine protease inhibitor (cystatin) is identified as one of the major immunomodulators...
September 18, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28918902/mtor-controls-mitochondrial-dynamics-and-cell-survival-via-mtfp1
#2
Masahiro Morita, Julien Prudent, Kaustuv Basu, Vanessa Goyon, Sakie Katsumura, Laura Hulea, Dana Pearl, Nadeem Siddiqui, Stefan Strack, Shawn McGuirk, Julie St-Pierre, Ola Larsson, Ivan Topisirovic, Hojatollah Vali, Heidi M McBride, John J Bergeron, Nahum Sonenberg
The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission/fusion, ATP production, metabolite biogenesis, and apoptosis, are not well understood. Here, we demonstrate that the nutrient-sensing mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase dynamin-related protein 1 (DRP1)...
September 13, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28915648/synergistic-suppression-of-t-8-21-positive-leukemia-cell-growth-by-combining-oridonin-and-mapk1-erk2-inhibitors
#3
Pavel Spirin, Timofey Lebedev, Natalia Orlova, Alexey Morozov, Nadezhda Poymenova, Sergey E Dmitriev, Anton Buzdin, Carol Stocking, Olga Kovalchuk, Vladimir Prassolov
One of the most common chromosomal translocations in acute myeloid leukemia is t(8;21)(q22;q22), which results in the appearance of abnormal transcripts encoding for the fusion protein RUNX1-ETO. Therefore, this oncoprotein is considered to be a pertinent and promising target for treating t(8;21) leukemia. Previously, we have shown that downregulation of RUNX1-ETO leads to activation of intracellular signaling pathways enhancing cell survival and determined that the protein ERK2 can mediate activation of most of these pathways...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28912153/comprehensive-genomic-profiling-of-282-pediatric-low-and-high-grade-gliomas-reveals-genomic-drivers-tumor-mutational-burden-and-hypermutation-signatures
#4
Adrienne Johnson, Eric Severson, Laurie Gay, Jo-Anne Vergilio, Julia Elvin, James Suh, Sugganth Daniel, Mandy Covert, Garrett M Frampton, Sigmund Hsu, Glenn J Lesser, Kimberly Stogner-Underwood, Ryan T Mott, Sarah Z Rush, Jennifer J Stanke, Sonika Dahiya, James Sun, Prasanth Reddy, Zachary R Chalmers, Rachel Erlich, Yakov Chudnovsky, David Fabrizio, Alexa B Schrock, Siraj Ali, Vincent Miller, Philip J Stephens, Jeffrey Ross, John R Crawford, Shakti H Ramkissoon
BACKGROUND: Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making. MATERIALS AND METHODS: We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb])...
September 14, 2017: Oncologist
https://www.readbyqxmd.com/read/28906492/ndrg1-inhibition-sensitizes-osteosarcoma-cells-to-combretastatin-a-4-through-targeting-autophagy
#5
Hongsheng Wang, Wen Li, Jing Xu, Tao Zhang, Dongqing Zuo, Zifei Zhou, Binhui Lin, Gangyang Wang, Zhuoying Wang, Wei Sun, Mengxiong Sun, Shimin Chang, Zhengdong Cai, Yingqi Hua
Combretastatin A-4 (CA-4), a tubulin-depolymerizing agent, shows promising antitumor efficacy and has been under several clinical trials in solid tumors for 10 years. Autophagy has an important pro-survival role in cancer therapy, thus targeting autophagy may improve the efficacy of antitumor agents. N-myc downstream-regulated gene 1 (NDRG1) is a significant stress regulatory gene, which mediates cell survival and chemoresistance. Here we reported that CA-4 could induce cell-protective autophagy, and combination treatment of CA-4 and autophagy inhibitor chloroquine (CQ) exerted synergistic cytotoxic effect on human osteosarcoma (OS) cells...
September 14, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28906430/identification-of-a-novel-inhibitor-against-middle-east-respiratory-syndrome-coronavirus
#6
Yaping Sun, Huaidong Zhang, Jian Shi, Zhe Zhang, Rui Gong
The Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated in 2012, and circulated worldwide with high mortality. The continual outbreaks of MERS-CoV highlight the importance of developing antiviral therapeutics. Here, we rationally designed a novel fusion inhibitor named MERS-five-helix bundle (MERS-5HB) derived from the six-helix bundle (MERS-6HB) which was formed by the process of membrane fusion. MERS-5HB consists of three copies of heptad repeat 1 (HR1) and two copies of heptad repeat 2 (HR2) while MERS-6HB includes three copies each of HR1 and HR2...
September 14, 2017: Viruses
https://www.readbyqxmd.com/read/28904204/distinct-roles-of-the-polarity-factors-boi1-and-boi2-in-the-control-of-exocytosis-and-abscission-in-budding-yeast
#7
Aina Masgrau, Andrea Battola, Trinidad Sanmartin, Leszek P Pryszcz, Toni Gabaldón, Manuel Mendoza
Boi1 and Boi2 (Boi1/2) are budding yeast plasma membrane proteins that function in polarized growth, and in cytokinesis inhibition in response to chromosome bridges via the NoCut abscission checkpoint. How Boi1/2 act in these two distinct processes is not understood. We demonstrate that Boi1/2 are required for a late step in the fusion of secretory vesicles with the plasma membrane of the growing bud. Cells lacking Boi1/2 accumulate secretory vesicles and are defective in bud growth. In contrast, Boi2 is specifically required for abscission inhibition in cells with chromatin bridges...
September 13, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28904193/mutations-in-the-fusion-protein-of-measles-virus-that-confer-resistance-to-the-membrane-fusion-inhibitors-carbobenzoxy-d-phe-l-phe-gly-and-as-48
#8
Michael N Ha, Sébastien Delpeut, Ryan S Noyce, Gary Sisson, Karen M Black, Liang-Tzung Lin, Darius Bilimoria, Richard K Plemper, Gilbert G Privé, Christopher D Richardson
The inhibitors Z-d-Phe-l-Phe Gly (fusion inhibitor peptide, FIP) and AS-48 have similar efficacy in blocking membrane fusion and syncytia formation mediated by measles virus. Other homologues such as Z-d-Phe are less effective, but may act through the same mechanism. In an attempt to map the site of action of these inhibitors, we generated mutant viruses which were resistant to the inhibitory effects of Z-d-Phe-l-Phe Gly. These 10 mutations were localized to the heptad repeat region (HRB) of the fusion protein and no changes were observed in the viral hemagglutinin, which is the receptor attachment protein...
September 13, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28903995/ros1-1
#9
REVIEW
Prodipto Pal, Zanobia Khan
ROS1 is a receptor tyrosine kinase that has recently been shown to undergo gene rearrangements in~1%-2% of non-small cell lung carcinoma (NSCLC) and in a variety of other tumours including cholangiocarcinoma, gastric carcinoma, colorectal carcinoma and in spitzoid neoplasms, glioblastoma and inflammatory myofibroblastic tumours. The ROS1 gene fusion undergoes constitutive activation, regulates cellular proliferation and is implicated in carcinogenesis. ROS1 fusions can be detected by fluorescence in situ hybridisation, real-time PCR, sequencing-based techniques and immunohistochemistry-based methods in clinical laboratories...
September 13, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28903424/identification-and-characterization-of-a-novel-scyl3-ntrk1-rearrangement-in-a-colorectal-cancer-patient
#10
Massimo Milione, Elena Ardini, Jason Christiansen, Emanuele Valtorta, Silvio Veronese, Roberta Bosotti, Alessio Pellegrinelli, Adele Testi, Filippo Pietrantonio, Giovanni Fucà, Ge Wei, Danielle Murphy, Salvatore Siena, Antonella Isacchi, Filippo De Braud
In colorectal cancer patients, chromosomal rearrangements involving NTRK1 gene (encoding the TRKA protein) are shown in a small subset of patients and are associated with the constitutive activation of the kinase domain of TRKA. In turn, activated TRKA-fusion proteins are associated with proliferation and survival in colorectal cancer tumors. Here we report the identification and functional characterization of a new SCYL3-NTRK1 fusion gene in a 61-year-old colorectal cancer patient. To our knowledge, this fusion protein has never been previously documented in oncological patients...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28903344/establishing-a-patient-derived-xenograft-model-of-human-myxoid-and-round-cell-liposarcoma
#11
Yiming Qi, Yu Hu, Hua Yang, Rongyuan Zhuang, Yingyong Hou, Hanxing Tong, Yi Feng, Yuan Huang, Quan Jiang, Qunsheng Ji, Qingyang Gu, Zhixiang Zhang, Xuzhen Tang, Weiqi Lu, Yuhong Zhou
Myxoid and round cell liposarcoma (MRCL) is a common type of soft tissue sarcoma. The lack of patient-derived tumor xenograft models that are highly consistent with human tumors has limited the drug experiments for this disease. Hence, we aimed to develop and validate a patient-derived tumor xenograft model of MRCL. A tumor sample from a patient with MRCL was implanted subcutaneously in an immunodeficient mouse shortly after resection to establish a patient-derived tumor xenograft model. After the tumor grew, it was resected and divided into several pieces for re-implantation and tumor passage...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28902850/copy-number-variation-analysis-in-cytochromes-and-glutathione-s-transferases-may-predict-efficacy-of-tyrosine-kinase-inhibitors-in-chronic-myeloid-leukemia
#12
Alexander V Lavrov, Oksana A Ustaeva, Elmira P Adilgereeva, Svetlana A Smirnikhina, Ekaterina Y Chelysheva, Oleg A Shukhov, Yuriy V Shatokhin, Sergey V Mordanov, Anna G Turkina, Sergey I Kutsev
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of BCR/ABL fusion gene in leukemic cells, which promotes uncontrolled cell proliferation. Up to 20% of CML patients show primary resistance or non-optimal response to tyrosine kinase inhibitor (TKI) therapy. We investigated the association between copy number variation (CNV) in glutathione S-transferases (GST) and cytochromes (CYP) and the response rate to TKI. We enrolled 47 patients with CML: 31 with an optimal response and 16 with failure at 6 months in accordance with European LeukemiaNet 2013 recommendations...
2017: PloS One
https://www.readbyqxmd.com/read/28900483/sulforaphane-induced-apoptosis-via-promotion-of-mitochondrial-fusion-and-erk1-2-mediated-26s-proteasome-degradation-of-novel-pro-survival-bim-and-upregulation-of-bax-in-human-non-small-cell-lung-cancer-cells
#13
Yang Geng, Yan Zhou, Sai Wu, Yabin Hu, Kai Lin, Yalin Wang, Zhongnan Zheng, Wei Wu
Previous studies in our laboratory showed that sulforaphane (SFN) induced apoptosis by sustained activation of extracellular regulated protein kinases 1/2 (ERK1/2). However, the underlying mechanisms associated with SFN-induced apoptosis and downstream cascades which are modulated by ERK1/2 were not elucidated. Herein we demonstrated for the first time that alteration of mitochondrial dynamics contributed to SFN-induced apoptosis in human non-small cell lung cancer (NSCLC) cells. Reports showed that protein Bim not only induced apoptosis but also promoted proliferation under certain circumstances...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28898434/cold-sensing-in-grapevine-which-signals-are-upstream-of-the-microtubular-thermometer
#14
Lixin Wang, Peter Nick
Plants can acquire freezing tolerance in response to cold, but non-freezing temperatures. To efficiently activate this cold acclimation, low temperature has to be sensed and processed swiftly, a process that is linked with a transient elimination of microtubules. Here, we address cold-induced microtubules elimination in a grapevine cell line stably expressing a GFP fusion of Arabidopsis TuB6, which allows to follow their response in vivo and to quantify this response by quantitative image analysis. We use time-course studies with several specific pharmacological inhibitors and activators to dissect the signalling events acting upstream of microtubules elimination...
September 12, 2017: Plant, Cell & Environment
https://www.readbyqxmd.com/read/28895639/the-pi3k-akt1-foxo1-translocation-pathway-mediates-exf-effects-on-nit-1-cell-survival
#15
Guo-Jiang Hou, Cai-Na Li, Yi Huan, Shuai-Nan Liu, Quan Liu, Min-Zhi Liu, Zhu-Fang Shen
EXf, a glucagon-like peptide 1 (GLP-1) receptor agonist, stimulates β-cell proliferation and reduces apoptosis in diabetic animal models, but the underlying mechanisms are not fully understood. We constructed a FoxO1-GFP fusion protein expression plasmid and transiently transfected it into NIT-1 cells to investigate whether FoxO1 mediates EXf effects on NIT-1 cell survival. Our results showed that EXf could increase cell viability by inhibiting apoptosis and stimulating proliferation, and it could also promote the translocation of the FoxO1-GFP fusion protein from the nucleus to the cytoplasm in NIT-1 cells...
September 11, 2017: Experimental and Clinical Endocrinology & Diabetes
https://www.readbyqxmd.com/read/28893947/small-molecule-wnt-agonists-correct-cleft-palates-in-pax9-mutant-mice-in-utero
#16
Shihai Jia, Jing Zhou, Christopher Fanelli, Yinshen Wee, John Bonds, Pascal Schneider, Gabriele Mues, Rena N D'Souza
Clefts of the palate and/or lip are the most common among human craniofacial malformations and involve multiple genetic and environmental factors. Defects can only be corrected surgically and require complex life-long treatments. Our studies utilized the well-characterized Pax9(-/-) mouse model with a consistent cleft palate phenotype to test small-molecule Wnt agonist therapies. We first show that the absence of Pax9 alters the expression of Wnt pathway genes including Dkk1 and Dkk2, proven antagonists of Wnt signaling...
September 11, 2017: Development
https://www.readbyqxmd.com/read/28888365/functional-reconstitution-of-cell-free-synthesized-purified-kv-channels
#17
Stéphane Renauld, Sandra Cortes, Beate Bersch, Xavier Henry, Michel De Waard, Béatrice Schaack
The study of ion channel activity and the screening of possible inhibitor molecules require reliable methods for production of active channel proteins, their insertion into artificial membranes and for the measurement of their activity. Here we report on cell-free expression of soluble and active Kv1.1 and Kv1.3 channels and their efficient insertion into liposomes. Two complementary methods for the determination of the electrical activity of the proteoliposome-embedded channels were compared using Kv1.1 as a model system: (1) single channel recordings in droplet interface bilayers (DIB) and (2) measurement of the membrane voltage potential generated by a potassium ion diffusion potential using the voltage-sensitive fluorescent dye oxonol VI...
September 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28886273/parpi-potentiates-with-current-conventional-therapy-in-mll-leukemia
#18
Lu Zhao, Chi Wai Eric So
Acute myeloid leukemias driven by MLL fusion proteins are commonly associated with poor prognosis and refractory treatment. Here, we provide evidence that olaparib can potentiate sensitivity of MLL leukemia cells to conventional chemotherapy and DNMT inhibitors offering new potential therapeutic strategies for MLL rearranged leukemias Using the primary mouse leukemia cells and human MLL-AF9 leukemic cell line, we demonstrate that treatment of MLL-AF9 leukemic cells with DNMT inhibitors or chemotherapies in combination with olaparib results in significant reduction in colony formation or cell growth while the single agent treatments had little impacts...
September 8, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28884193/neurotrophin-trk-receptors-new-targets-for-cancer-therapy
#19
Jacopo Meldolesi
In the last few years, exciting reports have emerged regarding the role of the two types of neurotrophin receptors, p75(NTR) and Trks, not only in neurons, where they were discovered, but also in non-neural cells and, especially, in numerous cancers, including breast, lung, colon-rectum, pancreas, prostate, glioblastoma, neuroblastoma, myeloma, and lymphoid tumors. Traditionally, p75(NTR), activated by all neurotrophins and their precursors, is an inhibitor. In various cancers, however, activated p75(NTR) induces variable effects, from inhibition to stimulation of cell proliferation, dependent on their direct or coordinate/indirect mechanism(s) of action...
September 8, 2017: Reviews of Physiology, Biochemistry and Pharmacology
https://www.readbyqxmd.com/read/28883017/nf%C3%AE%C2%BAb-signaling-in-alveolar-rhabdomyosarcoma
#20
Megan M Cleary, Atiya Mansoor, Teagan Settelmeyer, Yuichi Ijiri, Katherine J Ladner, Matthew N Svalina, Brian P Rubin, Denis C Guttridge, Charles Keller
Alveolar rhabdomyosarcoma (aRMS) is a pediatric soft tissue cancer commonly associated with a chromosomal translocation that leads to the expression of a Pax3:Foxo1 or Pax7:Foxo1 fusion protein, the developmental underpinnings of which may give clues to its therapeutic approaches. In aRMS, the NFκB-YY1-miR-29 regulatory circuit is dysregulated, resulting in repression of miR-29 and loss of the associated tumor suppressor activity. To further elucidate the role of NFκB in aRMS, we first tested 55 unique sarcoma cell lines and primary cell cultures in a large-scale chemical screen targeting diverse molecular pathways...
September 1, 2017: Disease Models & Mechanisms
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