1,721,113 research outputs found
2Fluid Dynamics Measurements and Optical Visualization of the Evolution of a Submerged Slot Jet of Air
No full textClinical efficiency of epigenetic drugs therapy in bone malignancies
No full textA great interest in the scientific community is focused on the improvement of the cure rate in patients with bone malignancies that have a poor response to the first line of therapies. Novel treatments currently include epigenetic compounds or molecules targeting epigenetic-sensitive pathways. Here, we offer an exhaustive review of such agents in these clinical settings. Carefully designed preclinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as Decitabine, histone deacetylase classes I-II (HDACIs), as Entinostat, Belinostat, lysine-specific histone demethylase (LSD1), as INCB059872 or FT-2102 (Olutasidenib), inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 (Tazemetostat) To enhance the therapeutic effect, the prevalent approach in phase II trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade. Optimization of drug dosing and regimens of Phase II trials may improve the clinical efficiency of such novel therapeutic approaches against these devastating cancers
Combination of Genomic Landsscape and 3D Culture Functional Assays Bridges Sarcoma Phenotype to Target and Immunotherapy
No full text: Genomic-based precision medicine has not only improved tumour therapy but has also shown its weaknesses. Genomic profiling and mutation analysis have identified alterations that play a major role in sarcoma pathogenesis and evolution. However, they have not been sufficient in predicting tumour vulnerability and advancing treatment. The relative rarity of sarcomas and the genetic heterogeneity between subtypes also stand in the way of gaining statistically significant results from clinical trials. Personalized three-dimensional tumour models that reflect the specific histologic subtype are emerging as functional assays to test anticancer drugs, complementing genomic screening. Here, we provide an overview of current target therapy for sarcomas and discuss functional assays based on 3D models that, by recapitulating the molecular pathways and tumour microenvironment, may predict patient response to treatments. This approach opens new avenues to improve precision medicine when genomic and pathway alterations are not sufficient to guide the choice of the most promising treatment. Furthermore, we discuss the aspects of the 3D culture assays that need to be improved, such as the standardisation of growth conditions and the definition of in vitro responses that can be used as a cut-off for clinical implementation
Clinical Epigenetics of Neuroendocrine Tumors: The Road Ahead
No full textNeuroendocrine tumors, or NETs, are cancer originating in neuroendocrine cells. They are mostly found in the gastrointestinal tract or lungs. Functional NETs are characterized by signs and symptoms caused by the oversecretion of hormones and other substances, but most NETs are non-functioning and diagnosis in advanced stages is common. Thus, novel diagnostic and therapeutic strategies are warranted. Epigenetics may contribute to refining the diagnosis, as well as to identify targeted therapy interfering with epigenetic-sensitive pathways. The goal of this review was to discuss the recent advancement in the epigenetic characterization of NETs highlighting their role in clinical findings
Epigenetic dysregulation in advanced kidney cancer: Opportunities for therapeutic interventions
No full textUnderstanding the complex epigenome of advanced renal cell carcinoma may lead to novel epigenomic-based pharmaceutical strategies and identify new targets for therapeutic interventions. Epigenetic changes, such as DNA methylation and histone acetylation, modulate the activity of significant oncogenic signaling pathways by regulating gene expression. Such pathways include the WNT-ß-catenin pathway, the von Hippel-Lindau-hypoxia-inducible factor pathway, and epithelial-mesenchymal transition pathway. Common genetic alterations in histone modifier genes in renal cell carcinoma may not only be responsible for the pathogenesis of this disease but also represent potential biomarkers of response to immunotherapies. Rational combinations strategies with histone deacetylase inhibitors are being tested in clinic trials. Renal cell carcinoma represents an ideal setting to dissect the epigenetic-driven changes in the tumor microenvironment that modulate the response to targeted therapies
Intracranial arteries of human fetuses are more resistant to hypercholesterolemia-induced fatty streak formation that extracranial arteries.
No full textAtherosclerotic lesions in intracranial arteries occur later and are less extensive than in extracranial arteries. To investigate potential mechanisms responsible for this difference, in particular the atherogenic response to hypercholesterolemia and LDL oxidation, we compared the extent of fatty streak formation and the composition of these very early lesions in intracranial arteries of human fetuses from normocholesterolemic and hypercholesterolemic mothers with those in extracranial arteries. METHODS AND RESULTS: Lesions were quantified by computer-assisted image analysis of 30 oil red O-stained sections, each from the middle cerebral, basilar, and common carotid arteries and the abdominal aorta of human fetuses (spontaneous abortions and premature newborns who died within 12 hours of birth; both of fetal age 6.2+/-1.3 months) from 43 hypercholesterolemic mothers and 34 normocholesterolemic mothers. Macrophages, apolipoprotein B, and 2 epitopes of oxidized LDL in lesions were determined immunocytochemically. Activities of superoxide dismutase, catalase, and glutathione peroxidase in the arterial wall were also determined. Lesion numbers and sizes were dramatically greater in the abdominal aorta (area of the largest lesion per section: 66.5+/-10.9 x10(3) microm2) and the carotid (11. 6+/-5.3 x10(3) microm2) than in the basilar and middle cerebral artery (0.4+/-0.1 and 0.8+/-0.2 x10(3) microm2, respectively; P<0. 0001). Hypercholesterolemia resulted in a significant increase of lesion size in extracranial arteries but only a marginal increase in intracranial arteries. In analogy, hypercholesterolemia induced a much greater increase in the intimal presence of macrophages, apolipoprotein B, and oxidized LDL (oxidation-specific epitopes) in extracranial than in intracranial arteries. Immunocytochemistry did not indicate that lesions of intracranial arteries contain relatively less oxidized LDL than similar-size lesions of extracranial arteries. Activities of Mn-superoxide dismutase but not of Zn-superoxide dismutase, catalase, or glutathione peroxidase were significantly higher in both intracranial arteries. CONCLUSIONS: Exposure to hypercholesterolemia during fetal development results in extensive formation of fatty streaks in extracranial but not intracranial arteries. The fact that such a difference in lesion formation occurs in the absence of many other atherogenic risk factors found later in life suggests that differences in the atherogenic response to hypercholesterolemia are an important contributor to the slower onset of the disease in intracranial vessels in adults. Fetal arteries may allow elucidation of the mechanisms responsible, for example, better protection of intracranial arteries against free radical-mediated atherogenic processe
Modulation by α- and γ-tochopherol and oxidized low density lipoprotein in human coronaric smooth muscle cells
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