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101.
Stine Kjaer Urhoj Joan Morris Maria Loane Elisa Ballardini Laia Barrachina-Bonet Clara Cavero-Carbonell Alessio Coi Mika Gissler Joanne Given Anna Heino Sue Jordan Amanda Neville Michele Santoro Joachim Tan David Tucker Diana Wellesley Ester Garne Mads Damkjaer 《Acta paediatrica (Oslo, Norway : 1992)》2024,113(5):1024-1031
102.
Julin Valero Laia Civit Daniel M. Dupont Denis Selnihhin Line S. Reinert Manja Idorn Brett A. Israels Aleksandra M. Bednarz Claus Bus Benedikt Asbach David Peterhoff Finn S. Pedersen Victoria Birkedal Ralf Wagner Sren R. Paludan Jrgen Kjems 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(50)
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created an urgent need for new technologies to treat COVID-19. Here we report a 2′-fluoro protected RNA aptamer that binds with high affinity to the receptor binding domain (RBD) of SARS-CoV-2 spike protein, thereby preventing its interaction with the host receptor ACE2. A trimerized version of the RNA aptamer matching the three RBDs in each spike complex enhances binding affinity down to the low picomolar range. Binding mode and specificity for the aptamer–spike interaction is supported by biolayer interferometry, single-molecule fluorescence microscopy, and flow-induced dispersion analysis in vitro. Cell culture experiments using virus-like particles and live SARS-CoV-2 show that the aptamer and, to a larger extent, the trimeric aptamer can efficiently block viral infection at low concentration. Finally, the aptamer maintains its high binding affinity to spike from other circulating SARS-CoV-2 strains, suggesting that it could find widespread use for the detection and treatment of SARS-CoV-2 and emerging variants.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 2020–2021 has launched a global quest to find new molecular tools for the detection of the virus and treatment of the potential deadly disease it causes, COVID-19. Despite the exceptional efforts worldwide for containment and unprecedented technological progress in vaccine development, the challenge to find an effective cure remains, due to the limited access to SARS-CoV-2 vaccines, particularly in developing countries, and the emergence of new viral strains that can evade immune responses and potentially compromise the efficacy of current vaccines. Therefore, it is of utmost importance to focus efforts on developing affordable and easy-to-produce antiviral molecules against SARS-CoV-2 infection.Like other coronaviruses, SARS-CoV-2 expresses a surface spike (S) glycoprotein which is composed of two domains (S1 and S2) (1) and forms a trimeric structure capable of interacting with human cells (2, 3). In particular, the receptor binding domain (RBD) located on the S1 subunit of the spike protein binds with high affinity to human angiotensin-converting enzyme 2 (ACE2) (4, 5), which, in conjunction with the associated transmembrane protease, serine 2 (TMPRSS2), facilitates viral uptake. Efforts to neutralize viral infection have therefore mainly focused on inhibiting the spike–ACE2 interaction. Antibodies (Abs) have been developed and are currently used for SARS-CoV-2 detection, and some, primarily those targeting RBD, show therapeutic potential due to their potent neutralizing effect (6–13). However, the high costs of Ab production, the use of animals to generate them, and their poor stability at ambient temperatures remain a disadvantage. Moreover, Ab immunogenicity and the risk of Ab-dependent enhancement of infection associated with Fc-containing Abs put their therapeutic potential at risk (14).VHH Abs or nanobodies raised to the spike protein may overcome some of these drawbacks (15–20) but are more prone to immunological response (21, 22). Interesting alternatives such as de novo proteins based on the host ACE2 receptor (23) and other synthetic molecules (24) have been investigated and may, if potential immunogenicity and stability problems are solved, help develop efficient detection methods and drugs.Nucleic acid-based aptamers have gained increased attention as alternatives to Abs due to their ease of production, low immunogenicity, high thermal and chemical stability, and smaller size, while they still retain comparable target binding and specificity. Aptamers are short single-stranded oligonucleotides, developed through an in vitro selection process termed SELEX (systematic evolution of ligands by exponential enrichment), that bind with high affinity and selectivity to cognate targets (25–27). During the last few decades, a wide variety of aptamers binding to diverse biologically relevant targets (28), including viruses (29, 30), have been identified. However, selection of aptamers targeting spike protein has proven difficult. An explanation for this may be that highly glycosylated proteins such as SARS-CoV-2 spike are challenging to target with nucleic acid-based binders. Indeed, to date, there are only a few reports on DNA aptamers targeting SARS-CoV-2 spike where the authors report leading aptamers with affinities in the nanomolar range (31–35).Here we report the selection and characterization of a serum-stable RNA aptamer, RBD-PB6, that binds with nanomolar affinity to the RBD of SARS-CoV-2 spike protein and neutralizes viral infectivity. The aptamer contains 2′-fluoro pyrimidine modifications to increase its chemical stability and resistance to nucleases (36, 37), and it shows high selectivity to SARS-CoV-2 and related strains, including alpha and beta. Aptamer multimerization strongly enhances its affinity to the picomolar range as well as its SARS-CoV-2 neutralizing potency. These unique features open avenues for developing inexpensive, fast, and reliable detection platforms for SARS-CoV-2 and therapeutic application for COVID-19. 相似文献
103.
Marc Sorigue Anna Oliveira Santiago Mercadal Gustavo Tapia Fina Climent Laia Perez‐Roca Irian Lorences Eva Domingo‐Domenech Marta Cabezon Jose‐Tomas Navarro Eva Gonzalez‐Barca Lurdes Zamora Josep‐María Ribera Anna Sureda Maria‐Pilar Armengol Juan‐Manuel Sancho 《Hematological oncology》2019,37(5):564-568
Patients with follicular lymphoma (FL) refractory to front‐line immunochemotherapy (ICT) have a poor overall survival (OS). Gene mutation analysis may be more accurate than classical risk factors to pick out these patients before treatment. This study aimed to describe the prevalence of selected genetic mutations in a cohort of patients with high‐risk FL. Twenty‐five patients with FL refractory to front‐line ICT and 10 non‐refractory patients matched for age, sex, and FLIPI score were included. We sequenced 18 genes (custom targeted sequencing panel) previously reported to potentially have prognostic impact, including the seven genes necessary to determine m7FLIPI risk. The 35 patients had a median age of 62. The FLIPI and FLIPI2 were high in 27 (84%) and 14 (48%), respectively. Three‐year progression‐free survival (PFS) and OS probabilities were 25% (95% CI, 13%‐41%) and 53% (34%‐69%), respectively. There were 73 variants in the 18 genes among the 35 patients. The median number of mutations per patient was 1 (interquartile range, 0‐3). The most commonly mutated genes were CREBBP (11 of 35, 31%) and EP300 (10 of 35, 29%). EP300 mutations were associated with refractoriness to treatment (10 of 25 among refractory and 0 of 10 among non‐refractory). In conclusion, in this study, patients with high‐risk follicular lymphoma were genetically heterogeneous. 相似文献
104.
105.
106.
Olatz Etxaniz Cristina Carrato Itziar de Aguirre Cristina Queralt Ana Muñoz José L. Ramirez Rafael Rosell Salvador Villà Rocio Diaz Ana Estival Pilar Teixidor Alberto Indacochea Sara Ahjal Laia Vilà Carme Balañá 《Journal of neuro-oncology》2017,135(2):273-284
Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS). Mean age of patients was 45 years; 71% were classified as low-risk by the Pignatti system. IDH mutations were detected in 62%, p53 mutations in 17%, the 1p/19q codeletion in 46%, and MGMT methylation in 40% of patients. Survival analyses were performed in the 49 patients without contrast enhancement. In the univariate analysis, IDH mutations, the 1p/19q codeletion, and the combination of IDH mutations with the 1p/19q codeletion were associated with both longer PFS (P?=?0.006, P?=?0.037, and P?=?0.003, respectively) and longer OS (P?<?0.001, P?=?0.02, and P?<?0.001, respectively). The multivariate analysis identified absence of IDH mutations as a factor for greater risk of progression [hazard ratio (HR)?=?3.1; P?=?0.007]and death (HR?=?6.4; P?<?0.001). We suggest that IDH mutations may be more effective than the Pignatti score in discriminating low- and high-risk patients with LGG. 相似文献
107.
Caja L Sancho P Bertran E Ortiz C Campbell JS Fausto N Fabregat I 《Biochemical pharmacology》2011,(11):1583-1592
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death. Different signaling pathways are de-regulated in this pathogenesis, among them the epidermal growth factor receptor one (EGFR/Erb1). Here we show that blockage of this pathway by the tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) in different liver tumor cell lines promotes both inhibition of cell proliferation and induction of cell death, which are coincident with arrest in the G1 phase of the cell cycle, caspase-3 activation and DNA fragmentation. AG1478 up-regulates the expression of the pro-apoptotic member of the BCL-2 family BIM and down-regulates the expression of the anti-apoptotic BCL-XL and MCL1. Furthermore, it also decreases the levels of the caspase inhibitors HIAP2 and XIAP. The treatment of HCC cells with AG1478 enhanced the apoptosis induced by other pro-apoptotic stimuli, such as the physiological cytokine, TGF-β, highly expressed in liver tumors, or the chemotherapeutic drug doxorubicin. The effects observed by AG1478 were broader than the ones seen by silencing of the EGFR with siRNA, which indicates that this drug might act on other targets different from the EGFR. In this same line of evidence, AG1478 retained some cytotoxic effects in cells where EGFR has been targeted knock-down with shRNA. Interestingly, AG1478 preferentially acts on liver tumor cells, being untransformed cells much less responsive to its cytotoxic effects. In conclusion, AG1478 could be a potential therapeutic drug to be used in HCC. 相似文献
108.
L Ros-Blanco J Anido R Bosser J Esté B Clotet A Kosoy L Ruíz-Ávila J Teixidó J Seoane JI Borrell 《Journal of medicinal chemistry》2012,55(17):7560-7570
The three stereoisomers of the noncyclam compound 1 (1(R,R), 1(S,S), and the meso form 1(S,R)) and their corresponding tetrahydrochlorides 11 were prepared from (S)- and (R)-2-methylpiperidine. We have evaluated their inhibitory activity on the CXC chemokine receptor type 4 (CXCR4), toxicity properties, and assessment of their effect on glioma initiating cells (GICs) in comparison with the prototype compound AMD3100. The IC(50) values determined on human recombinant (CHO) cells showed very similar inhibitory activities albeit a lower K(B) for AMD3100, with the 1(R,R) isomer being second in potency. All the compounds showed low cardiac toxicity but, contrary to AMD3100, gave maximum nonlethal doses of around 2.0 mg/kg. The CXCR4 inhibitors had an effect on the state of differentiation of GICs, decreasing the percentage of CD44+ cells in glioblastoma multiform neurospheres in vitro. Moreover, these CXCR4 inhibitors blocked the capacity of cells to initiate orthotopic tumors in immunocompromised mice. 相似文献
109.
Disruption of the DNA methylation landscape is one of the most common features of human tumors. However, genetic alterations of DNA methyltransferases (DNMTs) have not been described in carcinogenesis. Herein, we show that pancreatic and breast cancer cells undergo gene amplification of the DNA methyltransferase 3B (DNMT3B). The presence of extra copies of the DNMT3B gene is linked to higher levels of the corresponding mRNA and protein. Most importantly, the elevated gene dosage of DNMT3B is associated with increased resistance to the growth-inhibitory effect mediated by DNA demethylating agents. In particular, cancer cells harboring DNMT3B gene amplification are less sensitive to the decrease in cell viability caused by 5-azacytidine (Vidaza), 5-aza-2-deoxycytidine (Decitabine), and SGI-1027. Overall, the data confirm DNMT3B as a bona fide oncogene in human cancer and support the incorporation of the DNMT3B copy number assay into current clinical trials assessing the efficacy of DNA demethylating drugs in solid tumors. 相似文献
110.
Rodríguez G Cócera M Rubio L López-Iglesias C Pons R de la Maza A López O 《Molecular pharmaceutics》2012,9(3):482-491
In this work a new composition (dioleylphosphatidylcholine, DOPC, and dihexanoylphosphocholine, DHPC) is used to form the bicellar system and to evaluate their effect on stratum corneum (SC) lipids. Through this article, "bicellar system" will refer to a lipid binary system in which lipids are self-assembled forming different nanostructures. DOPC/DHPC system is characterized by dynamic light scattering and cryo-transmission electron microscopy showing two different nanostructures: unilamellar vesicles and tubular structures. In order to study the SC lipid organization attenuated total reflectance Fourier transform infrared spectroscopy, freeze-substitution applied to transmission electron microscopy and X-ray scattering are used. This work compares for the first time the use of two different X-ray scattering methods, transmission with synchrotron radiation and grazing incidence with conventional source, for skin studies. Our results indicate that vesicle-shaped structures remain adhered to the SC surface being unable to penetrate into the skin probably due to their large and voluminous size, while a proportion of structures could have interaction with SC lipids increasing the lamellar organization. Thus, the different nanostructures present in the system have different effects on SC lipids. The appropriate combination of both effects and the possibility to incorporate drugs offer a range of possibilities for the DOPC/DHPC system in development for skin care products. 相似文献