1,720,964 research outputs found
High expression of lysosomal cathepsin D inhibits neuroblastoma cell growth, migration and invasion, and confers better prognosis in neuroblastoma patients
Full text linkNeuroblastoma (NB) is one of the most common extracranial solid tumors of childhood and it accounts for 15% of cancer-related deaths. NB is an embryonal malignancy arising during fetal or early postnatal life from neural crest-derived sympathetic cells. It is commonly found in the adrenal
medulla or along the sympathetic chain. Neuroblastoma shows heterogeneous clinical phenotypes with different rate of aggressiveness and responsiveness to therapies. The broad spectrum of clinical manifestations ranges from spontaneous regression, maturation into a benign ganglioneuroma or, in the worst cases, into an aggressive and metastatic disease.
Epidermal growth factor receptor (EGFR) is a protein involved in cellular growth and invasiveness, is found frequently overexpressed or aberrantly activated in human neuroblastoma cells, and its inhibition or decreased phosphorylation causes tumor growth suppression and apoptosis in neuroblastomas. Cathepsin D is a ubiquitous soluble aspartic endopeptidase found in acidic intracellular compartments. CD accomplishes bulk protein degradation and mediates the activation of hormones, as well as the inactivation of mature growth factors through extensive lysosomal degradation.
In the first original article published, we found that CD reduced the growth of neuroblastoma cells by downregulating EGFR/MAPK signaling and confers better prognosis in neuroblastoma patients. In the second research article, we demonstrated a dual role of cathepsin D in 2D and in 3D growth of neuroblastoma cells in response to EGF. CD upregulation is necessary to guarantee the survival and proliferation of NB cells grown in suspension (as 3D neurospheres) while it is necessary to downregulate its expression for allowing adherence and anchorage-dependent growth of the tumor cells. To our knowledge, this is the first evidence for such a role of CD in neuroblastomas. Another important novelty of the present work is the use of mixed clones expressing CD at different level to mimic cancer heterogeneity arising during tumor evolution. The differential expression and role of CD in the two culture systems, let to hypothesize that cathepsin D could be regulated via epigenetic mechanisms. The bioinformatic analysis performed in this work, identified 38 miRNAs that downregulate CD in human neuroblastomas, and these miRNAs are associated with biological processes involved in cell migration, cell motility, cell growth and EGFR signaling, among others. Collectively, we have uncovered a novel role of CD in the metastatic spreading of tumors. This finding may have a translational relevance, and we propose CD as a possible biomarker for metastatic neuroblastomas and for the stratification of patients in a view of personalized medicine. Modulators of CD synthesis and activity could be a novel therapeutic strategy to ameliorate patients’ outcome.
The third part of my work deals with the role of CD in the chaperone-mediated autophagy of annexin A2, which results in attenuation of the NB cell malignant phenotype
Methods for Monitoring Macroautophagy in Pancreatic Cancer Cells.
Full text linkpeer reviewedMacroautophagy is a catabolic process through which redundant, aged, or damaged cellular structures are first enclosed within double-membrane vesicles (called autophagosomes), and thereafter degraded within lysosomes. Macroautophagy provides a primary route for the turnover of macromolecules, membranes and organelles, and as such plays a major role in cell homeostasis. As part of the stress response, autophagy is crucial to determine the cell fate in response to extracellular or intracellular injuries. Autophagy is involved in cancerogenesis and in cancer progression. Here we illustrate the essential methods for monitoring autophagy in pancreatic cancer cells
Epigenetic control of autophagy in women’s tumors: role of non-coding RNAs
Full text linkCancer remains the second leading cause of death worldwide and a major public health and economic issue. To reduce the burden, new approaches are necessary to diagnose the disease at early stages and improve clinical outcomes of cancer patients, for which understanding the molecular mechanisms of carcinogenesis is crucial. Autophagy is a pro-survival pathway that ensures the removal and renewal of cellular macromolecular structures, thus playing a crucial role in the maintenance of cellular homeostasis. Dysregulation of autophagy can favor chemoresistance and survival of dormant cancer cells, thus favoring cancer progression and relapse. Several studies report dysregulated expression of long non-coding RNAs and micro-RNAs acting as tumor suppressors or tumor promoters by targeting genes involved in the autophagy pathway. Here, we focus on the role played by non-coding RNAs-mediated regulation of autophagy in development and progression of cancers in women. Understanding how epigenetics can impact autophagy might open novel therapeutic strategies in the fight against cancers in women
Dopamine exacerbates mutant Huntingtin toxicity via oxidative-mediated inhibition of autophagy in SH-SY5Y neuroblastoma cells: Beneficial effects of anti-oxidant therapeutics
Full text linkNeuronal cell death in Huntington's Disease (HD) is associated with the abnormal expansions of a polyglutamine (polyQ) tract in the huntingtin protein (Htt) at the N-terminus that causes the misfolding and aggregation of the mutated protein (mHtt). Autophagy-lysosomal degradation of Htt aggregates may protect the neurons in HD. HD patients eventually manifest parkinsonian-like symptoms, which underlie defects in the dopaminergic system. We hypothesized that dopamine (DA) exacerbates the toxicity in affected neurons by over-inducing an oxidative stress that negatively impinges on the autophagy clearance of mHtt and thus precipitating neuronal cell death. Here we show that the hyper-expression of mutant (>113/150) polyQ Htt is per se toxic to dopaminergic human neuroblastoma SH-SY5Y cells, and that DA exacerbates this toxicity leading to apoptosis and secondary necrosis. DA toxicity is mediated by ROS production (mainly anion superoxide) that elicits a block in the formation of autophagosomes. We found that the pre-incubation with N-Acetyl-l-Cysteine (a quinone reductase inducer) or Deferoxamine (an iron chelator) prevents the generation of ROS, restores the autophagy degradation of mHtt and preserves the cell viability in SH-SY5Y cells expressing the polyQ Htt and exposed to DA. The present findings suggest that DA-induced impairment of autophagy underlies the parkinsonism in HD patients. Our data provide a mechanistic explanation of the DA toxicity in dopaminergic neurons expressing the mHtt and support the use of anti-oxidative stress therapeutics to restore protective autophagy in order to slow down the neurodegeneration in HD patients
Epigenetic targeting of autophagy for cancer prevention and treatment by natural compounds
No full textDespite the undeniable progress made in the last decades, cancer continues to challenge the scientists engaged in searching for an effective treatment for its prevention and cure. One of the malignant hallmarks that characterize cancer cell biology is the altered metabolism of sugars and amino acids. Autophagy is a pathway allowing the macromolecular turnover via recycling of the substrates resulting from the lysosomal degradation of damaged or redundant cell molecules and organelles. As such, autophagy guarantees the proteome quality control and cell homeostasis. Data from in vitro, in animals and in patients researches show that dysregulation of autophagy favors carcinogenesis and cancer progression, making this process an ineluctable target of cancer therapy. The autophagy process is regulated at genetic, epigenetic and post-translational levels. Targeting autophagy with epigenetic modifiers could represent a valuable strategy to prevent or treat cancer. A wealth of natural products from terrestrial and marine living organisms possess anti-cancer activity. Here, we review the experimental proofs demonstrating the ability of natural compounds to regulate autophagy in cancer via epigenetics. The hope is that in the near future this knowledge could translate into effective intervention to prevent and cure cancer
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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