1,720,958 research outputs found
AP3M2, NEW MOLECULAR TARGET IN COLORECTAL CANCER THERAPY
Full text linkAnnually, around 1 million cases of CRC are diagnosed, with 50% death rate, representing 8% of cancer-related deaths worldwide. The implementation of early diagnosis screening programs contributed to the reduction of the incidence and the mortality rates. The combination of chemotherapeutic regimens (5-FU, oxaliplatin and irinotecan) and targeted drugs (EGFR and VEGF inhibitors) have improved patients' prognosis. However, the combination of some types of chemical and biological therapies failed in the fourth line treatment and resistance to targeted therapies is the major limit in CRC.
Under these circumstances, we have conducted an RNAi screening aiming to identify new targetable oncogenes. Starting from the studies conducted by the Cancer Genome Atlas that identified a list of amplified genes in CRC, we analyzed putative genes that their Knockdown could negatively influence cell viability in different CRC cell lines, indicating the possible involvement in CRC. After a careful bioinformatic analysis I found that one gene called AP3M2 could be a successful candidate. AP3M2 (adaptor related protein complex 3 subunit mu 2) encodes for the neuronal Mu subunit of the heterotetrameric adaptor-related protein complex 3 (AP-3), which recognizes tyrosine-based sorting signals within the cytoplasmic domains of transmembrane cargo proteins and is involved in the biogenesis of lysosome-related organelles.
Deletion of this gene in mice was associated with susceptibility to drug-induced seizures and fewer synaptic vesicles. In the other hand, AP3M2 amplicons were observed in the primary tumor and maintained in at least two passages of breast cancer xenograft. AP3M2 is also in the list of genes in recurrent amplicons associated with reduced survival in breast cancer.
The new "druggable" gene was found to be altered in 6% of CRC patients and was associated with reduced survival rate according to the TGCA data. Our experiments confirmed it to be overexpressed in colon cancer patient tissues and cancer cell lines and proved to be a potent oncogene by promoting the colorectal cancer cell lines viability, adhesion and colony formation. Interestingly, AP3M2 levels affects the expression of other CRC associated protein such as P62, ATG7and ARF6 involved in autophagy and influenced ROS levels in colorectal cancer cell lines
Epigenetic mechanisms of salt-sensitive hypertension
No full textSalt-sensitive hypertension (SSH) is a complex and heterogeneous phenotype characterized by an abnormal blood pressure response to dietary salt intake. While genetic factors have been extensively explored, emerging evidence highlights the pivotal role of epigenetic mechanisms (DNA methylation, histone modifications and non-coding RNAs) in modulating gene expression without altering the DNA sequence. These modifications respond dynamically to environmental stimuli such as diet, aging, stress and prenatal conditions, contributing to both the development and progression of SSH. This review summarizes current knowledge on the epigenetic regulation of genes involved in sodium handling, vascular tone and inflammation, focusing on pathways such as the renin–angiotensin–aldosterone system, the Klotho–Wnt5a–RhoA axis and the influence of the intrauterine environment. Special attention is given to transgenerational epigenetic inheritance and aging-related changes, as well as the reversibility of some epigenetic marks through lifestyle interventions such as salt restriction and physical activity. Understanding the interplay between environmental exposures and epigenetic regulation offers a new frontier for precision medicine in hypertension, but despite the promising findings, SSH-specific human data remain limited and a unifying epigenetic signature distinguishing SSH from other hypertensive phenotypes has yet to be defined. Further longitudinal studies and biomarker discovery efforts are needed to translate these insights into personalized preventive and therapeutic strategies
A guide to PIN1 function and mutations across cancers
Full text linkPIN1 is a member of a family of peptidylprolyl isomerases that bind phosphoproteins and catalyze the rapid cis–trans isomerization of proline peptidyl bonds, resulting in an alteration of protein structure, function, and stability. PIN1 is overexpressed in human cancers, suggesting it promotes tumorigenesis, but depending on the cellular context, it also acts as a tumor suppressor. Here, we review the role of PIN1 in cancer and the regulation of PIN1 expression, and catalog the single nucleotide polymorphisms, and mutations in PIN1 gene associated with cancer. In addition, we provide a 3D model of the protein to localize the mutated residues
Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor
Full text linkMonoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC 50 = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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