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1.
Vilde Yuli Stenberg Roy Hartvig Larsen Li-Wei Ma Qian Peng Petras Juzenas
yvind Sverre Bruland Asta Juzeniene 《International journal of molecular sciences》2021,22(9)
Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with 212Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of 212Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer. The cytotoxic effect of 212Pb-NG001 was tested in human prostate C4-2 spheroids. Biodistribution at various time points and therapeutic effects of different activities of the radioligand were investigated in male athymic nude mice bearing C4-2 tumours, while long-term toxicity was studied in immunocompetent BALB/c mice. The radioligand induced a selective cytotoxic effect in spheroids at activity concentrations of 3–10 kBq/mL. In mice, the radioligand accumulated rapidly in tumours and was retained over 24 h, while it rapidly cleared from nontargeted tissues. Treatment with 0.25, 0.30 or 0.40 MBq of 212Pb-NG001 significantly inhibited tumour growth and improved median survival with therapeutic indexes of 1.5, 2.3 and 2.7, respectively. In BALB/c mice, no signs of long-term radiation toxicity were observed at activities of 0.05 and 0.33 MBq. The obtained results warrant clinical studies to evaluate the biodistribution, therapeutic efficacy and toxicity of 212Pb-NG001. 相似文献
2.
Understanding the metabolic burden of recombinant antibody production in Saccharomyces cerevisiae using a quantitative metabolomics approach 下载免费PDF全文
Jorg C. de Ruijter Essi V. Koskela Jatin Nandania Alexander D. Frey Vidya Velagapudi 《Yeast (Chichester, England)》2018,35(4):331-341
The cellular changes induced by heterologous protein expression in the yeast Saccharomyces cerevisiae have been analysed on many levels and found to be significant. However, even though high‐level protein production poses a metabolic burden, evaluation of the expression host at the level of the metabolome has often been neglected. We present a comparison of metabolite profiles of a wild‐type strain with those of three strains producing recombinant antibody variants of increasing size and complexity: an scFv fragment, an scFv–Fc fusion protein and a full‐length IgG molecule. Under producing conditions, all three recombinant strains showed a clear decrease in growth rate compared with the wild‐type strain and the severity of the growth phenotype increased with size of the protein. The levels of 76 intracellular metabolites were determined using a targeted (semi) quantitative mass spectrometry based approach. Based on unsupervised and supervised multivariate analysis of metabolite profiles, together with pathway activity profiling, the recombinant strains were found to be significantly different from each other and from the wild‐type strain. We observed the most prominent changes in metabolite levels for metabolites involved in amino acid and redox metabolism. Induction of the unfolded protein response was detected in all producing strains and is considered to be a contributing factor to the overall metabolic burden on the cells. 相似文献
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Italia Falcone Fabiana Conciatori Chiara Bazzichetto Emilio Bria Luisa Carbognin Paola Malaguti Gianluigi Ferretti Francesco Cognetti Michele Milella Ludovica Ciuffreda 《International journal of molecular sciences》2020,21(22)
Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family. In this review, we will illustrate the biological role played by AXL in breast tumor cells, highlighting its molecular and biological features, its involvement in tumor progression and its implication as a target in ongoing clinical trials. 相似文献
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如今,深度学习已被广泛应用于图像分类和图像识别的问题中,取得了令人满意的实际效果,成为许多人工智能应用的关键所在.在对于模型准确率的不断探究中,研究人员在近期提出了“对抗样本”这一概念.通过在原有样本中添加微小扰动的方法,成功地大幅度降低原有分类深度模型的准确率,实现了对于深度学习的对抗目的,同时也给深度学习的攻方提供了新的思路,对如何开展防御提出了新的要求.在介绍对抗样本生成技术的起源和原理的基础上,对近年来有关对抗样本的研究和文献进行了总结,按照各自的算法原理将经典的生成算法分成两大类——全像素添加扰动和部分像素添加扰动.之后,以目标定向和目标非定向、黑盒测试和白盒测试、肉眼可见和肉眼不可见的二级分类标准进行二次分类.同时,使用MNIST数据集对各类代表性的方法进行了实验验证,以探究各种方法的优缺点.最后总结了生成对抗样本所面临的挑战及其可以发展的方向,并就该技术的发展前景进行了探讨. 相似文献
7.
Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM. 相似文献
8.
Benjamin Diethelm-Varela 《ChemMedChem》2021,16(5):725-742
Against the challenge of providing personalized cancer care, the development of targeted therapies stands as a promising approach. The discovery of these agents can benefit from fragment-based drug discovery (FBDD) methods that help guide ligand design and provide key structural information on the targets of interest. In particular, nuclear magnetic resonance spectroscopy is a promising biophysical tool in fragment discovery due to its detection capabilities and versatility. This review provides an overview of FBDD, describes the basis of NMR-based fragment screening, summarizes some exciting technical advances reported over the past decades, and closes with a discussion of selected case studies where this technique has been used as part of drug discovery campaigns to produce lead compounds towards the design of anti-cancer targeted therapies. 相似文献
9.
This study investigated the external operational factors that would reduce the thermodynamic constrains preventing the simultaneous achievement of high hydrogen productivities (HPs) and hydrogen yields (HYs) in the bioreactor. At hydraulic retention time (HRT) of 1, the maximum HPs and HYs achieved was 35 L H2/h and 3.91 mol H2/mol glucose, respectively. At this stage, the bacterial granules occupied approximately 75% of the bioreactor and consisted of the settled biomass density of 40.6 g/L (settled granule bed height = 13.8 cm). The formation of bacterial granules improved the bioreactor performance and resulted in higher substrate conversion efficiency (95%), nutrient influent (7.5 L/h) and de-gassed effluent recycle rates (3.5 L/min). In conclusion, this study demonstrated that high nutrient influent and high de-gassed effluent recycle rates reduced the thermodynamic constrains preventing the achievement of higher H2 productivities in the bioreactor system. 相似文献
10.
Vivek Pandey Michael Seese João M. Maia David A. Schiraldi 《Polymer Engineering and Science》2020,60(10):2511-2516
Three chain extenders, pyromellitic dianhydride (PMDA), ethylene carbonate (EC), and a polymeric-epoxide, were investigated for improving recycled p(ethylene terephthalate) (r-PET) properties with melt extrusion. The amount of additives and processing temperatures were also varied to check for melt degradation. Small amplitude oscillatory shear experiments were performed to probe rheological changes with different chain extenders. Capillary rheometry with haul-off was also performed to measure extensional viscosity and melt strength. Higher loadings of the chain extenders were found to improve properties of r-PET. These chain extenders definitely increased melt viscosities when incorporated at the higher level of the ranges examined, matching that of virgin PET. EC addition resulted in high shear thinning of the polymer. Epoxy and PMDA added to r-PET produced products with the same extensional viscosity as v-PET. Haul-off experiments demonstrate superior performance by epoxy-modified r-PET compared to v-PET. 相似文献