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https://www.readbyqxmd.com/read/29933059/immunomodulatory-and-enhanced-antitumor-activity-of-a-modified-thymosin-%C3%AE-1-in-melanoma-and-lung-cancer
#1
Fanwen Wang, Bin Li, Pengcheng Fu, Qingqing Li, Heng Zheng, Xingzhen Lao
Tumor-targeted therapy is an attractive strategy for cancer treatment. Peptide hormone thymosin α1 (Tα1) has been used against several diseases, including cancer, but its activity is pleiotropic. Herein, we designed a fusion protein Tα1-iRGD by introducing the tumor homing peptide iRGD to Tα1. Results show that Tα1-iRGD can promote T-cell activation and CD86 expression, thereby exerting better effect and stronger inhibitory against melanoma and lung cancer, respectively, than Tα1 in vivo. These effects are indicated by the reduced densities of tumor vessels and Tα1-iRGD accumulation in tumors...
June 19, 2018: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/29931826/the-two-faced-nature-of-bk-polyomavirus-lytic-infection-or-non-lytic-large-t-positive-carcinoma
#2
Volker Nickeleit, Harsharan K Singh, Daniel J Kenan, Piotr A Mieczkowski
In immunocompromised patients, reactivation of latent BK-polyomavirus (BKPyV) can cause disease with lytic infections of kidneys and the lower urinary tract. Emerging evidence also links BKPyV to oncogenesis and high grade intra-renal and transitional cell carcinomas. These neoplasms strongly express polyomavirus large-T antigen as a defining feature, i.e. they are "large-T positive carcinomas". Such neoplasms arise in immunocompromised patients, typically in renal allograft recipients and preferentially in tissues harboring latent BKPyV...
June 21, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29930762/overcoming-drug-tolerant-cancer-cell-subpopulations-showing-axl-activation-and-epithelial-mesenchymal-transition-is-critical-in-conquering-alk-positive-lung-cancer
#3
Shinji Nakamichi, Masahiro Seike, Akihiko Miyanaga, Mika Chiba, Fenfei Zou, Akiko Takahashi, Arimi Ishikawa, Shinobu Kunugi, Rintaro Noro, Kaoru Kubota, Akihiko Gemma
Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non-small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)-resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations...
June 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29930757/acute-telomere-deprotection-prevents-ongoing-bfb-cycles-and-rampant-instability-in-p16-ink4a-deficient-epithelial-cells
#4
Aina Bernal, Marc Moltó-Abad, Daniel Domínguez, Laura Tusell
Telomere dysfunction drives chromosome instability through endless breakage-fusion-bridge (BFB) cycles that promote the formation of highly rearranged genomes. However, reactivation of telomerase or ALT-pathway is required for genome stabilisation and full malignant transformation. To allow the unrestricted proliferation of cells at risk of transformation, we have established a conditional system of telomere deprotection in p16INK4a -deficient MCF-10A cells with modified checkpoints. After sustained expression of a dominant negative form of the shelterin protein TRF2 (TRF2ΔBΔM ), cells with telomere fusion did progress to anaphase but no signs of ongoing BFB cycles were observed, thus anticipating proliferation defects...
June 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29930278/the-aldose-reductase-inhibitor-epalrestat-exerts-nephritic-protection-on-diabetic-nephropathy-in-db-db-mice-through-metabolic-modulation
#5
Jun He, Hao-Xue Gao, Na Yang, Xiao-Dong Zhu, Run-Bin Sun, Yuan Xie, Cai-Hong Zeng, Jing-Wei Zhang, Jian-Kun Wang, Fei Ding, Ji-Ye Aa, Guang-Ji Wang
Epalrestat is an inhibitor of aldose reductase in the polyol pathway and is used for the management of diabetic neuropathy clinically. Our pilot experiments and accumulated evidences showed that epalrestat inhibited polyol pathway and reduced sorbitol production, and suggested the potential renal protection effects of epalrestat on diabetic nephropathy (DN). To evaluate the protective effect of epalrestat, the db/db mice were used and exposed to epalrestat for 8 weeks, both the physiopathological condition and function of kidney were examined...
June 21, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29930202/a-ca-2-stimulated-exosome-release-pathway-in-cancer-cells-is-regulated-by-munc13-4
#6
Scott W Messenger, Sang Su Woo, Zhongze Sun, Thomas F J Martin
Cancer cells secrete copious amounts of exosomes, and elevated intracellular Ca2+ is critical for tumor progression and metastasis, but the underlying cellular mechanisms are unknown. Munc13-4 is a Ca2+ -dependent SNAP receptor- and Rab-binding protein required for Ca2+ -dependent membrane fusion. Here we show that acute elevation of Ca2+ in cancer cells stimulated a fivefold increase in CD63+ , CD9+ , and ALIX+ exosome release that was eliminated by Munc13-4 knockdown and not restored by Ca2+ binding-deficient Munc13-4 mutants...
June 21, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29930007/shear-stress-and-ve-cadherin-the-molecular-mechanism-of-vascular-fusion
#7
Vincenza Caolo, Hanna M Peacock, Bahar Kasaai, Geertje Swennen, Emma Gordon, Lena Claesson-Welsh, Mark J Post, Peter Verhamme, Elizabeth A V Jones
OBJECTIVE: Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion. APPROACH AND RESULTS: We previously showed that both low shear stress and DAPT ( N -[ N -(3,5-difluorophenacetyl)-L-alanyl]- S -phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion...
June 21, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29929983/a-proximity-dependent-biotinylation-bioid-approach-flags-the-p62-sequestosome-1-protein-as-a-caspase-1-substrate
#8
Yvan Jamilloux, Brice Lagrange, Antonia Di MIcco, Emilie Bourdonnay, Angélina Provost, Rémy Tallant, Thomas Henry, Fabio Martinon
The inflammasome is a major component of the innate immune system, and its main function is to activate caspase-1, a cysteine protease that promotes inflammation by inducing interleukin-1β (IL-1β) maturation and release into the extracellular milieu. To prevent uncontrolled inflammation, this complex is highly regulated. Once it is assembled, the inflammasome is insoluble, which has long precluded the analysis of its interactions with other proteins. Here, we used the proximity-dependent biotinylation assay (BioID) to identify proteins associated with caspase-1 during inflammasome activation...
June 21, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29929981/molecular-mechanism-of-hiv-1-resistance-to-sifuvirtide-a-clinical-trial-approved-membrane-fusion-inhibitor
#9
Danwei Yu, Xiaohui Ding, Zixian Liu, Xiyuan Wu, Yuanmei Zhu, Huamian Wei, Huihui Chong, Sheng Cui, Yuxian He
Host cell infection with HIV-1 requires fusion of viral and cell membranes. Sifuvirtide (SFT) is a peptide-based HIV-1 fusion inhibitor approved for phase III clinical trials in China. Here, we focused on characterizing HIV-1 variants highly resistant to SFT to gain insight into the molecular resistance mechanism. Three primary substitutions (V38A, A47I, and Q52R) located at the inhibitor-binding site of HIV-1's envelope protein (Env) and one secondary substitution (N126K) located at the C-terminal heptad repeat region of the viral protein gp41, which is part of the envelope, conferred high SFT resistance and cross-resistance to the anti-HIV-1 drug T20 and the template peptide C34...
June 21, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29929453/the-anti-apoptotic-ubiquitin-conjugating-enzyme-birc6-bruce-regulates-autophagosome-lysosome-fusion
#10
Fumiyo Ikeda
The Inhibitor of Apoptosis (IAP) family member, BIRC6/BRUCE is a ubiquitin conjugating E2 enzyme and a well-established anti-apoptosis regulator. However, its role in mammalian autophagy has not been shown. We identified BIRC6 as an important positive regulator of macroautophagy/autophagy by performing an siRNA screen targeting enzymes in the ubiquitin pathway. Compared to wild-type cells, BIRC6-deficient cells show accumulation of lipidated LC3B both at basal and starved conditions. Furthermore, BIRC6 deficiency blocks starvation-induced autophagic flux monitored by a tandem fluorescent autophagy sensor, mCherry-GFP-LC3B...
June 21, 2018: Autophagy
https://www.readbyqxmd.com/read/29929167/a-survey-on-chimeric-ureb-229-561-hpaa-protein-targeting-helicobacter-pylori-computational-and-in-vitro-urease-activity-valuation
#11
Alireza Salimi Chirani, Mona Ghazi, Mehdi Goudarzi, Shahin Najar Peerayeh, Hoorieh Soleimanjahi, Masoud Dadashi, Bahareh Hajikhani
Helicobacter pylori (H. pylori) as microaerophilic, Gram-negative bacterium colonize the human gastric milieu, where it impetuses chronic disorders. Vaccination is a complementary plan, along with antibiotic therapy, for clearance of H. pylori. Today, Computer based tools are essential for the evaluation, design, and experiment for novel chimeric targets for immunological administration. The purpose of this experiment was immunoinformatic analysis of UreB and HpaA molecules in a fusion arrangement and also, construction and expression of recombinant protein containing chimeric sequences...
May 5, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29928879/mitoflash-lights-single-mitochondrial-dynamics-events-in-mature-cardiomyocytes
#12
Yuan Qin, Meng Gao, Anqi Li, Jia Sun, Bilin Liu, Guohua Gong
Mitochondria, the powerhouse of eukaryotic cells, are highly dynamic organelle. Mitochondrial fission, fusion, kissing and contraction have been reported over and over again in non-static cells, such as fibroblast, with tubular mitochondrial networks. Even though the fluorescence propagation among mitochondria of mature cardiomyocytes had been captured using mitochondrial matrix targeted photoactivatable GFP (PAGFP) or MitoDendra proteins, there are no direct evidence that single real time mitochondrial dynamics events exist in mature cardiomyocytes with ball-like mitochondria...
June 18, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29928582/optimizing-fluorescent-protein-expression-for-quantitative-fluorescence-microscopy-and-spectroscopy-using-herpes-simplex-thymidine-kinase-promoter-sequences
#13
Rizwan Ali, Sivaramakrishnan Ramadurai, Frank Barry, Heinz Peter Nasheuer
The modulation of expression levels of fluorescent fusion proteins (FFPs) is central for recombinant DNA technologies in modern biology as overexpression of proteins contributes to artifacts in biological experiments. In addition, some microscopy techniques such as fluorescence correlation spectroscopy (FCS) and single-molecule-based techniques are very sensitive to high expression levels of FFPs. To reduce the levels of recombinant protein expression in comparison with the commonly used, very strong CMV promoter, the herpes simplex virus thymidine kinase (TK) gene promoter, and mutants thereof were analyzed...
June 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29928581/protatether-a-method-for-the-incorporation-of-variable-linkers-in-protein-fusions-reveals-impacts-of-linker-flexibility-in-a-pkac-gfp-fusion-protein
#14
Jessica L Norris, Robert M Hughes
Protein fusions are of fundamental importance in the study of cellular biology and the elucidation of cell signaling pathways, and the importance of linkers for the proper function of protein fusions is well documented in the literature. However, there are few convenient methods available to experimentalists for the systematic implementation of linkers in protein fusions. In this work, we describe a universal approach to the creation and insertion of focused linker libraries into protein fusions. This process, deemed protaTETHER, utilizes reiterative oligomer design, PCR-mediated linker library generation, and restriction enzyme-free cloning methods in a straightforward, three-step cloning process...
June 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29928519/can-muscle-protein-metabolism-be-specifically-targeted-by-exercise-training-in-copd
#15
REVIEW
Davina C M Simoes, Ioannis Vogiatzis
Patients with stable chronic obstructive pulmonary disease (COPD) frequently exhibit unintentional accentuated peripheral muscle loss and dysfunction. Skeletal muscle mass in these patients is a strong independent predictor of morbidity and mortality. Factors including protein anabolism/catabolism imbalance, hypoxia, physical inactivity, inflammation, and oxidative stress are involved in the initiation and progression of muscle wasting in these patients. Exercise training remains the most powerful intervention for reversing, in part, muscle wasting in COPD...
May 2018: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/29928397/construction-of-an-anti-programmed-death-ligand-1-chimeric-antigen-receptor-and-determination-of-its-antitumor-function-with-transduced-cells
#16
Jiasen Xie, Zishan Zhou, Shunchang Jiao, Xiaokun Li
A chimeric antigen receptor (CAR) is a type of fusion protein that comprises an antigen-recognition domain and signaling domains. In the present study, a programmed death-ligand 1 (PD-L1)-specific CAR, comprised of a single-chain variable fragment (scFv) derived from a monoclonal antibody, co-stimulatory domains of cluster of differentiation (CD) 28 and 4-1BB and a T-cell-activation domain derived from CD3ζ, was designed. The construction was cloned and packaged into the lentiviral vector pLVX. Flow cytometry confirmed that peripheral blood mononuclear cells were efficiently transduced and that the CAR was successfully expressed on T cells...
July 2018: Oncology Letters
https://www.readbyqxmd.com/read/29926749/six-years-and-counting-restoration-of-photopic-retinal-function-and-visual-behavior-following-gene-augmentation-therapy-in-a-sheep-model-of-cnga3-achromatopsia
#17
Ron Ofri, Edward Averbukh, Raaya Ezra-Elia, Maya Ross, Hen Honig, Alexey Obolensky, Alexander Rosov, William W Hauswirth, Elisha Gootwine, Eyal Banin
Achromatopsia causes severely reduced visual acuity, photoaversion and inability to discern colors due to cone photoreceptor dysfunction. In 2010, we reported on day blindness in sheep caused by a stop codon mutation of the ovine CNGA3 gene, and began gene augmentation therapy trials in this naturally occurring large animal model of CNGA3 achromatopsia. The purpose of this study was to evaluate long-term efficacy and safety results of treatment, findings that hold great relevance for clinical trials in CNGA3 achromatopsia patients that started recently...
June 21, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29926352/stability-of-the-abcd1-protein-with-a-missense-mutation-a-novel-approach-to-finding-therapeutic-compounds-for-x-linked-adrenoleukodystrophy
#18
Masashi Morita, Shun Matsumoto, Airi Sato, Kengo Inoue, Dzmitry G Kostsin, Kozue Yamazaki, Kosuke Kawaguchi, Nobuyuki Shimozawa, Stephan Kemp, Ronald J Wanders, Hirotatsu Kojima, Takayoshi Okabe, Tsuneo Imanaka
Mutations in the ABCD1 gene that encodes peroxisomal ABCD1 protein cause X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disorder. More than 70% of the patient fibroblasts with this missense mutation display either a lack or reduction of the ABCD1 protein because of posttranslational degradation. In this study, we analyzed the stability of the missense mutant ABCD1 proteins (p.A616T, p.R617H, and p.R660W) in X-ALD fibroblasts and found that the mutant ABCD1 protein p.A616T has the capacity to recover its function by incubating at low temperature...
June 21, 2018: JIMD Reports
https://www.readbyqxmd.com/read/29925898/cytotoxic-response-of-5-fluorouracil-resistant-cells-to-gene-and-cell-directed-enzyme-prodrug-treatment
#19
Erika Durinikova, Jana Plava, Silvia Tyciakova, Pavel Skvara, Andrea Vojs Stanova, Zuzana Kozovska, Lucia Kucerova, Miroslava Matuskova
Gene-directed enzyme/prodrug therapy (GDEPT) mediated by mesenchymal stromal cells (MSC) was already approved for clinical study on a progressive disease refractory to standard therapy. In this work, we examined the effect of several GDEPT approaches on chemoresistant cells. First, we derived 5-fluorouracil (5-FU)-resistant variant of human colorectal adenocarcinoma cells HT-29 designated HT-29/EGFP/FUR. Our data show that the upregulation of thymidylate synthase (TS) and downregulation of thymidine phosphorylase (TP), orotate phosphoribosyl transferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) contributed to the 5-FU resistance in cancer cells...
June 21, 2018: Cancer Gene Therapy
https://www.readbyqxmd.com/read/29925790/human-granzyme-b-based-targeted-cytolytic-fusion-proteins
#20
REVIEW
Precious Hlongwane, Neelakshi Mungra, Suresh Madheswaran, Olusiji A Akinrinmade, Shivan Chetty, Stefan Barth
Cancer immunotherapy aims to selectively target and kill tumor cells whilst limiting the damage to healthy tissues. Controlled delivery of plant, bacterial and human toxins or enzymes has been shown to promote the induction of apoptosis in cancerous cells. The 4th generation of targeted effectors are being designed to be as humanized as possible—a solution to the problem of immunogenicity encountered with existing generations. Granzymes are serine proteases which naturally function in humans as integral cytolytic effectors during the programmed cell death of cancerous and pathogen-infected cells...
June 20, 2018: Biomedicines
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