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31.
Matteo Monieri Paolo Rainone Angelina Sacchi Alessandro Gori Anna Maria Gasparri Angela Coliva Antonio Citro Benedetta Ferrara Martina Policardi Silvia Valtorta Arianna Pocaterra Massimo Alfano Dean Sheppard Lorenzo Piemonti Rosa Maria Moresco Angelo Corti Flavio Curnis 《International journal of biological sciences》2023,19(1):156
Rationale: The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many tumors and involved in the activation of the latency associated peptide (LAP)/TGFβ complex, represent potential targets for tumor imaging and therapy. We investigated the tumor-homing properties of a chromogranin A-derived peptide containing an RGDL motif followed by a chemically stapled alpha-helix (called “5a”), which selectively recognizes the LAP/TGFβ complex-binding site of αvβ6 and αvβ8.Methods: Peptide 5a was labeled with IRDye 800CW (a near-infrared fluorescent dye) or with 18F-NOTA (a label for positron emission tomography (PET)); the integrin-binding properties of free peptide and conjugates were then investigated using purified αvβ6/αvβ8 integrins and various αvβ6/αvβ8 single - or double-positive cancer cells; tumor-homing, biodistribution and imaging properties of the conjugates were investigated in subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, and in mice bearing subcutaneous αvβ8-positive prostate tumors.Results: In vitro studies showed that 5a can bind both integrins with high affinity and inhibits cell-mediated TGFβ activation. The 5a-IRDye and 5a-NOTA conjugates could bind purified αvβ6/αvβ8 integrins with no loss of affinity compared to free peptide, and selectively recognized various αvβ6/αvβ8 single- or double-positive cancer cells, including cells from pancreatic carcinoma, melanoma, oral mucosa, bladder and prostate cancer. In vivo static and dynamic optical near-infrared and PET/CT imaging and biodistribution studies, performed in mice with subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, showed high target-specific uptake of fluorescence- and radio-labeled peptide by tumors and low non-specific uptake in other organs and tissues, except for excretory organs. Significant target-specific uptake of fluorescence-labeled peptide was also observed in mice bearing αvβ8-positive prostate tumors.Conclusions: The results indicate that 5a can home to αvβ6- and/or αvβ8-positive tumors, suggesting that this peptide can be exploited as a ligand for delivering imaging or anticancer agents to αvβ6/αvβ8 single- or double-positive tumors, or as a tumor-homing inhibitor of these TGFβ activators. 相似文献
32.
Michal Grzmil Brian A. Hemmings 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(7):1371-1380
Glioblastoma is the most common and aggressive brain tumor type, with a mean patient survival of approximately 1 year. Many previous analyses of the glioma kinome have identified key deregulated pathways that converge and activate mammalian target of rapamycin (mTOR). Following the identification and characterization of mTOR-promoting activity in gliomagenesis, data from preclinical studies suggested the targeting of mTOR by rapamycin or its analogs (rapalogs) as a promising therapeutic approach. However, clinical trials with rapalogs have shown very limited efficacy on glioma due to the development of resistance mechanisms. Analysis of rapalog-insensitive glioma cells has revealed increased activity of growth and survival pathways compensating for mTOR inhibition by rapalogs that are suitable for therapeutic intervention. In addition, recently developed mTOR inhibitors show high anti-glioma activity. In this review, we recapitulate the regulation of mTOR signaling and its involvement in gliomagenesis, discuss mechanisms resulting in resistance to rapalogs, and speculate on strategies to overcome resistance. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012). 相似文献
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The absolute configurations (AC) of natural occurring 6-hydroxyeuryopsin (1), of its acetyl derivative 2, and of eremophilanolide 8 were confirmed by comparison of the experimental vibrational circular dichroism (VCD) spectra with theoretical curves generated from density functional theory (DFT) calculations. Initial analyses were carried out using a Monte Carlo searching with the MMFF94 molecular mechanics force field. All MMFF94 conformers were further optimized using DFT at the B3LYP/6-31G(d) level of theory, followed by calculations of their vibrational frequencies at the B3LYP/6-31G(d,p); the VCD spectra of 2 and 8 were also calculated at the B3PW91/DGDZVP level of theory. Good agreement between theoretical and experimental VCD curves unambiguously verified the 4S,5R,6S absolute configuration for 1 and 2, and the 1S,4S,5R,6S,8S,10S configuration for 8. 相似文献
35.
Yanqiu Wu 《生物化学与生物物理学报:生物膜》2007,1768(12):3206-3215
The transmembrane (TM) segment of the major coat protein from Ff bacteriophage has been extensively studied as an example of dimerization in detergent and lipid bilayer systems. However, almost all the information regarding this interaction has been gained through mutagenesis studies, with little direct structural information being available. To this end solution NMR has the potential to provide new insights into structure of the dimer. In order to evaluate the utility of this approach we have studied a selectively 15N-labeled peptide containing the TM segment of MCP (MCPTM) by solution NMR. This peptide was found to give rise to detergent concentration-dependent spectra that were assigned to monomeric and dimeric forms. The standard free energy of this interaction in SDS was estimated from these spectra and found to be consistent with weak but specific dimerization. In addition, similar spectra could be obtained in β-octyl glucoside with intermolecular paramagnetic relaxation experiments demonstrating a parallel arrangement of TM helices in the dimer. In both detergents backbone chemical shift differences between monomeric and dimeric forms of MCPTM showed that the largest changes occur around its GXXXG motif. The resulting structural model is consistent with observations made for MCP mutants previously characterized in biological membranes, opening the door to detailed structural characterization of this form of MCP. These results also have general implications for the study of weakly interacting TM segments by solution NMR since the use of similar sample conditions should allow structural data to be accessed for oligomeric states from a wide range systems that undergo biologically relevant but weak associations in the membrane. 相似文献
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37.
Crystallization of the first three domains of the human insulin-like growth factor-1 receptor. 下载免费PDF全文
N. M. McKern M. Lou M. J. Frenkel A. Verkuylen J. D. Bentley G. O. Lovrecz N. Ivancic T. C. Elleman T. P. Garrett L. J. Cosgrove C. W. Ward 《Protein science : a publication of the Protein Society》1997,6(12):2663-2666
The insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase receptor of central importance in cell proliferation. A fragment (residues 1-462) comprising the L1-cysteine rich-L2 domains of the human IGF-1R ectodomain has been overexpressed in glycosylation-deficient Lec8 cells and has been affinity-purified via a c-myc tag followed by gel filtration. The fragment was recognized by two anti-IGF-1R monoclonal antibodies, 24-31 and 24-60, but showed no detectable binding of IGF-1 or IGF-2. Isocratic elution of IGF-1R/462 on anion-exchange chromatography reduced sample heterogeneity, permitting the production of crystals that diffracted to 2.6 A resolution with cell dimensions a = 77.0 A, b = 99.5 A, c = 120.1 A, and space group P2(1)2(1)2(1). 相似文献
38.
Maria Assunta Piano Lisa Gianesello Angela Grassi Paola Del Bianco Adriana Mattiolo Anna Maria Cattelan Lolita Sasset Paola Zanovello Maria Luisa Calabr 《Journal of cellular and molecular medicine》2019,23(2):1486-1494
The aim of this study was to identify circulating microRNAs (miRNAs) that could be used as biomarkers in patients at risk for or affected by AIDS‐Kaposi's sarcoma (KS). Screening of 377 miRNAs was performed using low‐density arrays in pooled plasma samples of 10 HIV/human herpesvirus 8 (HHV8)‐infected asymptomatic and 10 AIDS‐KS patients before and after successful combined antiretroviral therapy (cART). MiR‐375 was identified as a potential marker of active KS, being the most down‐regulated in AIDS‐KS patients after cART and the most up‐regulated in naïve AIDS‐KS patients compared to naïve asymptomatic subjects. Validation on individual plasma samples confirmed that miR‐375 levels were higher in AIDS‐KS compared to asymptomatic patients, decreased after cART‐induced remission in most AIDS‐KS patients and increased in patients with active KS. In asymptomatic patients miR‐375 was up‐regulated after cART in both screening and validation. Statistical analyses revealed an association between miR‐375 changes and CD4 cell counts, which could explain the discordant cases and the opposite trend between asymptomatic and AIDS‐KS patients. These data suggest that circulating miR‐375 might be a good indicator of active AIDS‐KS. Moreover, changes in miR‐375 levels may have a prognostic value in HIV/HHV8‐infected patients undergoing treatment. Further large‐scale validation is needed. 相似文献
39.
Rahmani M Susidarti RA Ismail HB Sukari MA Hin TY Lian GE Ali AM Kulip J Waterman PG 《Phytochemistry》2003,64(4):873-877
In a continuation of our study of the Rutaceae, detailed chemical investigation on Micromelum minutum (Rutaceae) collected from Sepilok, Sabah, Malaysia gave four new coumarins. The structures of the coumarins have been fully characterised by spectroscopic methods as 3",4"-dihydrocapnolactone 1, 2',3'-epoxyisocapnolactone 2, 8-hydroxyisocapnolactone-2',3'-diol 3 and 8-hydroxy-3",4"-dihydrocapnolactone-2',3'-diol 4. 相似文献
40.
Silurian calcispheres (Calcitarcha) of Gotland (Sweden): Comparisons with calcareous dinoflagellates
Scanning electron microscope examinations of polished and etched surfaces of sediments from the Silurian carbonate platform of Gotland, Sweden, revealed the presence of numerous, morphologically diverse “calcispheres” (Calcitarcha). Some of these spherical calcareous microfossils display wall structures that are surprisingly similar to those of calcareous dinoflagellate cysts. In analogy to the interpretation of the biological affinities of Palaeozoic acritarchs as cysts of organisms that might have been the ancestors of organic-walled dinoflagellates, the Calcitarcha from Gotland can be compared and may possibly be related to organisms that may have been the ancestors of calcareous cyst-producing dinoflagellates that so far have not been observed before the Late Jurassic. 相似文献