Exosomes are 50–100 nm membranous vesicles actively released by cells which can be indicative of a diseased cell status. They contain various kinds of molecule – proteins, mRNA, miRNA, lipids – that ...are actively being studied as potential biomarkers. Hereafter I put forward several arguments in favor of the potential use of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as biomarkers especially of cancerous diseases. I will briefly update readers on the exosome field and review various features of GPI-APs, before further discussing the advantages of this class of proteins as potential exosomal biomarkers. I will finish with a few examples of exosomal GPI-APs that have already been demonstrated to be good prognostic markers, as well as innovative approaches developed to quantify these exosomal biomarkers.
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•Exosomes are extracellular vesicles (80-100 nm) derived from an endosomal compartment.•GPI-anchored proteins are overexpressed in various cancers and can often be used as biomarkers.•GPI-anchored proteins are efficiently sorted in exosomes and are present in meaningful amounts.•GPI-anchored proteins are exposed on the surface of exosomes and thus easily quantified.
In the didactic treatment of Socially Acute Questions (SAQ), emotion is considered ambivalent, both a source of motivation and a possible hindrance to learning. We propose to change the affective ...dimension of perspective and to question the felt sense (Gendlin, 1962) as a source of learning. We question how, treated through two contemplative approaches, focusing and transitional image, it is likely to nourish critical, creative and attentive thinking (Lipman, 2003). These approaches are proposed to undergraduate students and applied to two ethical dilemmas associated with humusation and breeding. Explanatory interviews conducted with 8 students reveal that the processing of bodily meaning is likely to lead to a reconfiguration of the issues at stake in the dilemma, to the overcoming of the initial contradictions and to the expression of a feeling of connection to oneself, to humans and to nature. It can also give rise to strong emotions that are detrimental to the commitment to the SAQ. We examine how they are implemented in schools.
In recent years, the term “extracellular vesicle” (EV) has been used to define different types of vesicles released by various cells. It includes plasma membrane‐derived vesicles ...(ectosomes/microvesicles) and endosome‐derived vesicles (exosomes). Although it remains difficult to evaluate the compartment of origin of the two kinds of vesicles once released, it is critical to discriminate these vesicles because their mode of biogenesis is probably directly related to their physiologic function and/or to the physio‐pathologic state of the producing cell. The purpose of this review is to specifically consider exosome secretion and its consequences in terms of a material loss for producing cells, rather than on the effects of exosomes once they are taken up by recipient cells. I especially describe one putative basic function of exosomes, that is, to convey material out of cells for off‐site degradation by recipient cells. As illustrated by some examples, these components could be evacuated from cells for various reasons, for example, to promote “differentiation” or enhance homeostatic responses. This basic function might explain why so many diseases have made use of the exosomal pathway during pathogenesis.
The term “extracellular vesicle” (EV) was coined in recent years in reference to different kinds of cell‐secreted vesicles of various origins. Ectosomes (or microvesicles) are formed and released by plasma membrane budding, in contrast to exosomes secreted upon fusion of multivesicular endosomes with the plasma membrane. While exosomes are generally studied as means of intercellular communication, here I review the situation regarding the producing cell. How and why cell components can be secreted extracellularly in association with exosomes.
The human sirtuin silent information regulator 1 (SIRT1) is a NAD
+
-dependent deacetylase enzyme. It deacetylates many protein substrates, including histones and transcription factors, thereby ...controlling many physiological and pathological processes. Several synthetic inhibitors and activators of SIRT1 have been developed, and some therapeutic applications have been explored. The indole EX-527 and its derivatives are among the most potent and selective SIRT1 inhibitors. EX-527 has been often used as a pharmacological tool to explore the effect of SIRT1 inhibition in various cell types. Its therapeutic potential has, therefore, been evaluated in animal models for several pathologies, including cancer. It has also been tested in phase II clinical trial for the treatment of Huntington's disease (HD). In this review, we will provide an overview of the literature on EX-527, including its mechanism of inhibition and biological studies.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
DNA methylation can deactivate tumor suppressor genes thus causing cancers. Two DNA methylation inhibitors have been approved by the Food and Drug Administration (FDA) and have entered clinical use. ...However, these inhibitors are nucleoside analogues that can be incorporated into DNA or RNA and induce significant side effects. DNMT1 and DNMT3 are key enzymes involved in DNA methylation. In the acute myeloid leukemia model, a non-nucleoside DNMT1-specific inhibitor has shown lower toxicity and improved pharmacokinetics compared to traditional nucleoside drugs. DNMT3 is also implicated in certain specific cancers. Thus, developing non-nucleoside inhibitors for DNMT1 or DNMT3 can help in understanding their roles in carcinogenesis and provide targeted treatment options in certain cancers. Although no non-nucleoside inhibitors have yet entered clinical trials, in this review, we focus on DNMT1 or DNMT3 selective inhibitors. For DNMT1 selective inhibitors, we have compiled information on the repurposed drugs, derivative compounds and selective inhibitors identified through virtual screening. Additionally, we have outlined potential targets for DNMT1, including protein-protein complex, RNA mimics and aptamers. Compared to DNMT1, research on DNMT3-specific inhibitors has been less extensive. In this context, our exploration has identified a limited number of molecular inhibitors, and we have proposed specific long non-coding RNAs (lncRNAs) as potential contributors to the selective inhibition of DNMT3. This collective effort aims to offer valuable insights into the development of non-nucleoside inhibitors that selectively target DNMT1 or DNMT3.
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Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival ...in cancer patients.
The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans.
Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013).
Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Reticulocytes release small membrane vesicles termed exosomes during their maturation into erythrocytes. Exosomes are intraluminal vesicles of multivesicular endosomes released into the extracellular ...medium by fusion of these endosomal compartments with the plasma membrane. This secretion pathway contributes to reticulocyte plasma membrane remodeling by eliminating certain membrane glycoproteins. We show in this study that galectin-5, although mainly cytosolic, is also present on the cell surface of rat reticulocytes and erythrocytes. In addition, in reticulocytes, it resides in the endosomal compartment. We document galectin-5 translocation from the cytosol into the endosome lumen, leading to its secretion in association with exosomes. Galectin-5 bound onto the vesicle surface may function in sorting galactose-bearing glycoconjugates. Fittingly, we found that Lamp2, a major cellular glycoprotein presenting galectin-reactive poly-N-acetylactosamine chains, is lost during reticulocyte maturation. It is associated with released exosomes, suggestive of binding to galectin-5. Finally, we reveal that the uptake of rat reticulocyte exosomes by macrophages is dependent on temperature and the mechanoenzyme dynamin and that exosome uptake is decreased by adding galectin-5. These data imply galectin-5 functionality in the exosomal sorting pathway during rat reticulocyte maturation.
The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside ...placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.
•Robust and sensitive LC–MS/MS method to simultaneously quantify five tyrosine kinase inhibitors.•First bioanalytical assay for the simultaneous analysis of three generations of EGFR ...inhibitors.•First validated bioanalytical assay for nintedanib in human plasma.•Suitable for therapeutic drug monitoring in lung cancer.
A new method for the quantitative analysis by liquid chromatography-tandem mass spectrometry (LC–MS/MS) of five tyrosine kinase inhibitors (afatinib, crizotinib, osimertinib, erlotinib and nintedanib) used in the treatment of non-small cell lung cancer (NSCLC) was developed and validated in human plasma. Separation was performed on an Accucore® C18 (2.1 × 50 mm; 2.6 μm) column using a gradient elution of water acidified with 0.1% (v/v) formic acid (A) and acetonitrile containing 0.1% (v/v) formic acid (B) at a flow rate of 500 μL/min. The analytes were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer after positive ionization with heated electrospray interface. After addition of three isotopically labeled internal standards, plasma pretreatment consisted in a simple protein precipitation. This method presented satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-assay coefficient of variation from 2.6% to 10.6%), accuracy (from 96.1% to 108.5%), recovery and matrix effects. The lower limit of quantification and the linearity of these five tyrosine kinases inhibitors are suitable with the expected concentrations in clinical practice. This new bioanalytical method can be used in daily clinical practice for therapeutic drug monitoring of these tyrosine kinase inhibitors in NSCLC patients.
In the last two decades, extracellular vesicle-mediated communication between cells has become a major field in cell biology. However, the function of extracellular vesicles is far from clear, ...especially due to the disparity of released vesicles by cells. Basically, one must consider vesicles budding from the cell plasma membrane (ectosomes) and vesicles released upon fusion of an endosomal multivesicular compartment (exosomes). Moreover, even for exosomes, we report and discuss here the possibility that different routes regulated by specific Rab GTPases might produce exosomes having various biologic functions.
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