1,720,958 research outputs found
Role of calcium in polycystic kidney disease: From signaling to pathology
No full textAutosomal dominant polycystic kidney disease (ADPKD) is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimately leads to end-stage renal disease. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, while mutations in the PKD2 gene account for the remaining 15% of cases. The PKD1 gene encodes for polycystin-1 (PC1), a large multi-functional membrane receptor protein able to regulate ion channel complexes, whereas polycystin-2 (PC2), encoded by the PKD2 gene, is an integral membrane protein that functions as a calcium-permeable cation channel, located mainly in the endoplasmic reticulum (ER). In the primary cilia of the epithelial cells, PC1 interacts with PC2 to form a polycystin complex that acts as a mechanosensor, regulating signaling pathways involved in the differentiation of kidney tubular epithelial cells. Despite progress in understanding the function of these proteins, the molecular mechanisms associated with the pathogenesis of ADPKD remain unclear. In this review we discuss how an imbalance between functional PC1 and PC2 proteins may disrupt calcium channel activities in the cilium, plasma membrane and ER, thereby altering intracellular calcium signaling and leading to the aberrant cell proliferation and apoptosis associated with the development and growth of renal cysts. Research in this field could lead to the discovery of new molecules able to rebalance intracellular calcium, thereby normalizing cell proliferation and reducing kidney cyst progression
INHIBITION OF AUTOPHAGY INCREASES THE RESPONSE TO SUNITINIB IN CCRCC CELL LINES
No full textIntroduction: Renal cell carcinoma (RCC) represents about 3% of all cancers and is the kidney malignancy with the
highest mortality rate of urinary neoplasms. The most common subtype of RCC is clear cell RCC (ccRCC) that
accounts for 70-80% of RCC cases (1, 2). One third of cases presents metastasis at diagnosis with a 30% of disease recurrence for RCC patients undergoing surgery. Moreover, treatment with tyrosine kinase inhibitors in RCC subjects with advanced disease has not shown any advantage on overall survival (1). Therefore, research on new therapeutic targets focuses on molecules that can enhance therapy response. This is a crucial point to improve the management of RCC patient. The kidney cancer progression could be induced by the activation of autophagy, the biological process used by cancer cells to produce energy in hypoxic and acidic environment. Thus, the use of autophagy inhibitors could be considered as a novel antitumor therapy (3). In addition, there is emerging evidence that the use of autophagy inhibitors could sensitize cancer cells to anticancer drugs. Therefore, the combination of both tyrosine kinase and autophagy inhibitors could improve therapy response in ccRCC patients. Materials
and Methods: Combined treatment with the autophagy inhibitor (Chloroquine) and anti-tyrosine kinase (Sunitinib)
was performed in two different ccRCC cell lines (KJ29 and Caki-2). Cell growth was analyzed by Cell Tyter System
(Promega, Madison, WI, USA), culturing cells in presence of both Chloroquine and Sunitinib for 24 and 48 h. Cell density after different treatments of ccRCC cells was evaluated by using a phase-contrast microscope at 10× magnification. Apoptosis was analyzed by the Hoechst method. Apoptotic nuclei were observed by a fluorescence microscope at 50× magnification after cell treatment with chloroquine and sunitinib. Results and Discussion: We observed that the upregulation of miR501-5p in ccRCC tissues is associated with a poor prognosis for ccRCC patients (2). Moreover, the overexpression of this miR induced the activation of autophagy in ccRCC cells. Cancer cells might use autophagy to trap and destroy molecular drugs by lysosomal vesicles. Therefore, the inhibition of autophagy should restore drug response. Consistently, we have observed that pre-treatment with Chloroquine, an autophagy inhibitor, in KJ29 ccRCC cells potentiated the Sunitinib-induced inhibition of cell growth compared to Sunitinib used alone. This finding was confirmed treating Caki-2, another ccRCC cell line, with both Chloroquine and Sunitinib. Moreover, the double treatment with these molecules reduced cell density compared to Chloroquine or Sunitinib, individually applied. The reduction of cell proliferation induced by the inhibition of both autophagy and tyrosine kinase receptors is associated with stimulation of apoptosis. In fact, the formation of apoptotic nuclei in double treated ccRCC cells, compared to those treated with the single compound, was observed. These results show that the inhibition of autophagy increases the efficacy of Sunitinib by the activation of apoptosis in ccRCC
cells. Conclusion: These data suggest that the double treatment with both autophagy and tyrosine kinase inhibitors
could be considered as a new therapeutic approach for the treatment of ccRCC patients.
1 Greef B and Eisen T: Medical treatment of renal cancer: new horizons. Br J Cancer 115: 505-516, 2016.
2 Mangolini A, Bonon A, Volinia S, Lanza G, Gambari R, Pinton P, Russo GR, Del Senno L, Dell'Atti L and Aguiari
G: Differential expression of microRNA501-5p affects the aggressiveness of clear cell renal carcinoma. FEBS Open
Bio 4: 952-965, 2014.
3 Kimura T, Takabatake Y, Takahashi A and Isaka Y: Chloroquine in cancer therapy: a doubleedged sword of
autophagy. Cancer Res 73: 3-7, 2013
Double inhibition of cAMP and mTOR signalling may potentiate the reduction of cell growth in ADPKD cells.
No full textBACKGROUND: ADPKD is a renal pathology caused by mutations of PKD1 and PKD2 genes, which encode for polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 plays an important role regulating several signal transducers, including cAMP and mTOR, which are involved in abnormal cell proliferation of ADPKD cells leading to the development and expansion of kidney cysts that are a typical hallmark of this disease. Therefore, the inhibition of both pathways could potentiate the reduction of cell proliferation enhancing benefits for ADPKD patients.
METHODS: The inhibition of cAMP- and mTOR-related signalling was performed by Cl-IB-MECA, an agonist of A3 receptors, and rapamycin, respectively. Protein kinase activity was evaluated by immunoblot and cell growth was analyzed by direct cell counting.
RESULTS: The activation of A3AR by the specific agonist Cl-IB-MECA causes a marked reduction of CREB, mTOR, and ERK phosphorylation in kidney tissues of Pkd1 flox/-: Ksp-Cre polycystic mice and reduces cell growth in ADPKD cell lines, but not affects the kidney weight. The combined sequential treatment with rapamycin and Cl-IB-MECA in ADPKD cells potentiates the reduction of cell proliferation compared with the individual compound by the inhibition of CREB, mTOR, and ERK kinase activity. Conversely, the simultaneous application of these drugs counteracts their effect on cell growth, because the inhibition of ERK kinase activity is lost.
CONCLUSION: The double treatment with rapamycin and Cl-IB-MECA may have synergistic effects on the inhibition of cell proliferation in ADPKD cells suggesting that combined therapies could improve renal function in ADPKD patients
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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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