1,720,976 research outputs found
Parathyroid hormone-related protein (PTHrP)-dependent modulation of gene expression signatures in cancer cells
No full textPTHrP is encoded by PTHLH gene which can generate by alternative promoter usage and splicing mechanisms at least three mature peptides of 139, 141 and 173 amino acids with distinct carboxy terminus. PTHrP may undergo proteolytic processing into smaller bioactive forms, comprising an amino terminus peptide, which is the mediator of the “classical” PTH-like effect, as well as midregion and carboxy terminus peptides that act as multifaceted critical regulator of proliferation, differentiation and apoptosis via the reprogramming of gene expression in normal and neoplastic cells. Moreover, a nuclear/nucleolar localization signal sequence is present in the [87–107] domain allowing PTHrP nuclear import and “intracrine” effect additional to the autocrine/paracrine one. Within the large number of data available in the literature on PTHrP bioactivities, the goal of this chapter is to pick up selected studies that report the detection of molecular signatures of cancer cell exposure to PTHrP, either as full-length protein or discrete peptides, demonstrated by individual gene or whole genome expression profiling, briefly recapitulating the biological implications associated with the specific gene activation or silencing
Parathyroid Hormone Related Protein (PTHrP)-Associated Molecular Signatures in Tissue Differentiation and Non-Tumoral Diseases
Full text linkParathyroid-hormone-related protein (PTHrP) is encoded by the PTHLH gene which, via alternative promoter usage and splicing mechanisms, can give rise to at least three isoforms of 139, 141, and 173 amino acids with distinct C-terminals. PTHrP is subjected to different post-translational processing that generates smaller bioactive forms, comprising amino terminus, mid-region (containing a nuclear/nucleolar targeting signal), and carboxy terminus peptides. Both the full-length protein and the discrete peptides are key controllers of viability, proliferation, differentiation, and apoptosis in diverse normal and pathological biological systems via the reprogramming of gene expression and remodulation of PKA or PKC-mediated signalization mechanisms. The aim of this review is to pick up selected studies on PTHrP-associated signatures as revealed by molecular profiling assays, focusing on the available data about exemplary differentiating, differentiated, or nontumoral cell and tissue models. In particular, the data presented relate to adipose, bone, dental, cartilaginous, and skin tissues, as well as intestinal, renal, hepatic, pulmonary, and pancreatic epithelia, with a focus on hepatic fibrosis-, pancreatitis-, and diabetes-related changes as diseased states. When reported, the biochemical and/or physiological aspects associated with the specific molecular modulation of gene expression and signal transduction pathways in the target model systems under examination are also briefly described
Mid-region parathyroid hormone-related protein is a genome-wide chromatin-binding factor that promotes growth and differentiation of HB2 epithelial cells from the human breast
Full text linkHuman parathyroid hormone-related protein (PTHrP) is a polyhormone that undergoes proteolytic cleavage producing smaller peptides which exert diversified biological effects. PTHrP signalization is prominently involved in breast development and physiology, but the studies have been focused onto either N-terminal species or full-length protein introduced by gene transfer techniques. Our present work investigates for the first time the effect of the mid-region PTHrP secretory form, that is, the fragment [38–94], on HB2 non-tumoral breast epithelial cells. We examined viability/proliferation of cells grown in PTHrP-containing media supplemented with different serum concentration and on different substrates, extending our investigation to check whether (a) by analogy with MDA-MB231 cells, also HB2 cell chromatin possesses genome-wide binding sites for mid-region PTHrP, and (b) the peptide is endowed with modulating properties toward the expression of proliferation/differentiation signatures by HB2 cells. Our results indicate that mid-region PTHrP acts as a cell growth/differentiation stimulator in routine and “nutrient stress” culture conditions, accordingly reprogramming gene expression, and is able to bind to cytogenetic preparations from HB2 cells. This supports the concept that the physiological mechanisms involving PTHrP during breast development may include mature processed forms of the protein different from the N-terminal fragment. © 2018 BioFactors, 2018
Natural Anticancer Peptides from Marine Animal Species: Evidence from In Vitro Cell Model Systems
Full text linkAnticancer peptides are short and structurally heterogeneous aminoacidic chains, which display selective cytotoxicity mostly against tumor cells, but not healthy cells, based on their different cell surface properties. Their anti-tumoral activity is carried out through interference with intracellular homeostasis, such as plasmalemma integrity, cell cycle control, enzymatic activities and mitochondrial functions, ultimately acting as angiogenesis-, drug resistance- and metastasis-inhibiting agents, immune stimulators, differentiation inducers and necrosis or extrinsic/intrinsic apoptosis promoters. The marine environment features an ever-growing level of biodiversity, and seas and oceans are poorly exploited mines in terms of natural products of biomedical interest. Adaptation processes to extreme and competitive environmental conditions led marine species to produce unique metabolites as a chemical strategy to allow inter-individual signalization and ensure survival against predators, infectious agents or UV radiation. These natural metabolites have found broad use in various applications in healthcare management, due to their anticancer, anti-angiogenic, anti-inflammatory and regeneration abilities. The aim of this review is to pick selected studies that report on the isolation of marine animal-derived peptides and the identification of their anticancer activity in in vitro cultures of cancer cells, and list them with respect to the taxonomical hierarchy of the source organism
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
BIOLOGICAL EFFECTS OF JAHA, A NEW HISTONE DEACETYLASE INHIBITOR, ON CANCER CELLS FROM HUMAN BREAST EPITHELIUM
Full text linkThe histone deacetylase inhibitors (HDACis) are a class of chemically heterogeneous anticancer agents of which suberoylanilide hydroxamic acid (SAHA) is a prototypical member. SAHA derivatives may be obtained by the three-dimensional manipulation of the SAHA aryl cap, such as the incorporation of a ferrocene unit like that present in Jay Amin hydroxamic acid (JAHA) and homo-JAHA (Spencer et al., 2011). These metal-based SAHA analogues have been tested for their cytotoxic activity toward triple-negative MDA-MB231 breast cancer cells. The results obtained indicate that of the two compounds tested, only JAHA was prominently active on breast cancer cells with an IC50 of 8.45 μM at 72 h of treatment. For this reason JAHA only was used for the subsequent experiment at 8.45 μM concentration. Biological assays showed that exposure of MDA-MB231 cells to the HDACi resulted in cell cycle perturbation with an alteration of S phase entry and a delay at G2/M transition and in an early production of reactive oxygen species followed by mitochondrial membrane potential (MMP) dissipation and autophagy inhibition. No annexin binding was observed after short-(5 h) and longer (24 and 48 h) term incubation with JAHA, thereby excluding the promotion of apoptosis by the HDACi (Librizzi et al., 2012). An in vitro “scratch assay” has also been performed to measure migration of cells treated with JAHA for 24 h, but preliminary indications suggested that JAHA had no effect on the motile behaviour of MDA-MB231 cells. Subsequently, in order to identify protein signatures associated to its cytotoxic activity, we utilized a proteomic approach to reveal protein expression changes after 18, 24 and 48 h of exposure. Protein identification was performed by mass spectrometry, and a total of eleven differentially-expressed proteins were visualized. In parallel, Differential Display (DD) gene expression analysis was used to identify gene signatures in the MDA-MB231 human breast cancer cell line after exposure to JAHA. The result obtained by DD-PCR were confirmed by Real Time PCR analysis. Further study were required to compare the reported signature pattern with that obtained after exposure of MDA-MB231 cells with the parental molecule SAHA, and to understand the biological implications of the expression changes found. A further set of assays was designed to check the effect of JAHA on the intracellular signaling pathways of MDA-MB231 breast cancer cells. Concerning the MEK pathway JAHA repressed MAP kinase (ERK) activation after 18 h and up to 30 h of treatment, and also down-regulated DNA (cytosine-5-)-methyltransferase 1 (DNMT1), a downstream ERK target, already at 18 h with an increase up to 48 h of exposure.
To check the occurrence of changes in the extent of global DNA methylation, genomic DNA was submitted to MeSAP (Methylation Sensitive Restriction Arbitrarily-Primed) PCR (Naselli et al., 2014) using Afa and then HpaII enzymes followed by PCR amplification with an arbitrary primer binding preferentially to guanine and cytosine (GC)-rich regions of DNA, including CpG islands. Preliminary indications suggest the ability of JAHA to induce hypomethylation patterns in tumoral breast cancer cells after 30 h of the treatment. Collectively, these data demonstrate that the HDACi JAHA, by inhibiting ERK activity, regulates DNMT1 expression and ultimately DNA methylation. Although caution must be exercised in extrapolation of the vitro results to the in vivo situation for which research on animals and human trials are needed, nevertheless JAHA treatment possesses the potential for its development as an agent for prevention and/or therapy of “aggressive” breast carcinoma, thus prompting us to get more insight into the molecular basis of its anti-breast cancer activity
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
- …
