1,720,992 research outputs found
Stratergie di terapia anti-angiogenica con IFN-ALFA in un modello di neoplasia prostatica spontanea
No full textInterferon-alpha (IFN-alpha) is the prototype of anti-angiogenic cytokines with recognized therapeutic activity in transplantable and orthotopic tumors, and also in prostatic cancer models. This activity has been mainly attributed to indirect effects, such as the down-regulation of pro-angiogenic factors, or direct effects on proliferation and motility of endothelial cells. Aim of this study was to investigate the effects of IFN-alpha on the angiogenic switch occurring during the early phases of tumor development in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model in which tumorigenesis is driven by an androgen-regulated early gene (T/t antigen) of SV40. To provide sustained IFN-alpha production, TRAMP mice were injected i.p. with IFN-alpha-producing lentiviral vectors, followed by analysis of the IFN-mediated transcriptional and biologic effects.
In the prostate of TRAMP mice, IFN-alpha administration resulted in sustained up-regulation of IFN-alpha-regulated genes endowed with anti-angiogenic and anti-proliferative functions, including guanylate binding protein 1 (GBP-1), IFI16 protein and CXCL10-11; since the levels of these transcripts increased at early time points following treatment, they could be primary mediators of the biologic effects of IFN-alpha. These transcriptional changes were accompanied by effects on the tumor vasculature, including reduction of intraductal microvessel density and increased pericyte coverage, and marked reduction of tumor cell proliferation, whereas tumor cell apoptosis was unchanged. Intriguingly, a subgroup of human prostatic tumors analyzed (15 out of 31) disclosed GBP-1 protein expression, and this correlated with the expression of another IFN-regulated protein, MxA, thus hinting at endogenous IFN-alpha in a subset of prostate cancer patients.
Overall, our findings demonstrate that IFN-alpha is able to counteract the angiogenic switch and impair tumor cell proliferation during the early phases of prostatic cancer progression. The detection of GBP-1 and MxA expression in clinical samples of prostatic cancer may identify a tumor subset with distinct biological features.L’interferone alfa (IFN-alfa) è il prototipo delle citochine con effetto anti-angiogenico, di cui sono noti gli effetti terapeutici in numerosi modelli tumorali. Questa azione è stata attribuita principalmente ad effetti indiretti, come l’inibizione della produzione di fattori pro-angiogenici da parte delle cellule tumorali ed anche a effetti diretti di IFN-alfa sulla proliferazione e motilità delle cellule endoteliali. Lo scopo di questo lavoro è stato di investigare quali fossero gli effetti del trattamento con IFN-alfa sul processo angiogenico che viene indotto dalle cellule cancerose durante le prime fasi della progressione tumorale. A tal fine abbiamo utilizzato il modello del topo TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) in cui la cancerogenesi è guidata dall’espressione androgeno-regolata degli antigeni T/t di SV40. Per ottenere una produzione sostenuta di IFN-alfa, i topi TRAMP sono stati inoculati per via intraperitoneale con vettori lentivirali producenti IFN-alfa, e successivamente è seguita la valutazione degli effetti trascrizionali e biologici.
La somministrazione di IFN-alfa ha provocato una regolazione in senso positivo di trascritti coinvolti nell’inibizione dell’angiogenesi e della proliferazione cellulare quali GBP-1, IFI16 e CXCL10-11; poiché i livelli di questi trascritti sono stati riscontrati elevati già dalle prime fasi dopo il trattamento, potrebbero essere mediatori degli effetti biologici dell’IFN-alfa. A questi effetti trascrizionali si accompagnano gli effetti sulla vascolatura tumorale, quali la riduzione della densità vascolare intraduttale e l’aumento della maturità dei vasi, associati ad una marcata inibizione della proliferazione delle cellule tumorali, senza peraltro influenzare i livelli di apoptosi. Alla luce di questi risultati abbiamo voluto investigare se anche nel carcinoma prostatico umano ci potessero essere evidenze di espressione di IFN-alfa endogeno. La valutazione immunoistochimica di una serie di tumori prostatici umani ha evidenziato come una parte di questi (15/31) esprimano la proteina GBP-1 e che esiste una correlazione con un’altra proteina indotta da IFN-alfa quale MxA, indicando come in un sottogruppo di pazienti con carcinoma prostatico vi sia una produzione endogena di IFN-alfa.
In sintesi, questi risultati indicano che l’IFN-alfa è in grado di inibire il processo angiogenico e la proliferazione cellulare durante le prime fasi della tumorigenesi prostatica. L’espressione di GBP-1 e MxA in campioni clinici potrebbe identificare un sottogruppo di pazienti con peculiari caratteristiche biologiche
Anti-angiogenic gene therapy of cancer: Current status and future prospects
No full textThe discovery of endogenous inhibitors of angiogenesis has made it possible to test the hypothesis that blocking the angiogenic switch may keep tumor growth in check, and has added a new investigational arm to the field of cancer gene therapy. Angiogenesis inhibitors are heterogeneous in origin and potency, and their growing list includes proteolysis products of larger molecules with a different function, such as angiostatin, endostatin and vasostatin, modulators of vascular endothelial growth factor activity, such as sFLT-1, and some cytokines/chemokines with marked anti-endothelial activity, such as IL-12, IFN-alpha, and CXCL10. Pre-clinical studies have clearly indicated that these factors are essentially cytostatic and that they need long-term administration in order to obtain prolonged anti-tumor effects, representing a rational basis for their delivery by a gene therapy approach. The experimental approaches attempted to date, reviewed herein, indicate overall that anti-angiogenic gene therapy has efficacy mainly as an early intervention strategy and that a better understanding of the biological mechanisms underlying resistance to angiogenesis inhibition, as well as appropriate combined treatments, are required to generate a conceptual advancement which could drive the field towards successful management of established tumors
Wnt Signaling in Brain Tumors: A Challenging Therapeutic Target
Full text linkThe involvement of Wnt signaling in normal tissue homeostasis and disease has been widely demonstrated over the last 20 years. In particular, dysregulation of Wnt pathway components has been suggested as a relevant hallmark of several neoplastic malignancies, playing a role in cancer onset, progression, and response to treatments. In this review, we summarize the current knowledge on the instructions provided by Wnt signaling during organogenesis and, particularly, brain development. Moreover, we recapitulate the most relevant mechanisms through which aberrant Wnt pathway activation may impact on brain tumorigenesis and brain tumor aggressiveness, with a particular focus on the mutual interdependency existing between Wnt signaling components and the brain tumor microenvironment. Finally, the latest anti-cancer therapeutic approaches employing the specific targeting of Wnt signaling are extensively reviewed and discussed. In conclusion, here we provide evidence that Wnt signaling, due to its pleiotropic involvement in several brain tumor features, may represent a relevant target in this context, although additional efforts will be needed to: (i) demonstrate the real clinical impact of Wnt inhibition in these tumors; (ii) overcome some still unsolved concerns about the potential systemic effects of such approaches; (iii) achieve efficient brain penetration
Surviving the hunger games: Metabolic reprogramming in medulloblastoma
Full text link: Medulloblastoma is a highly malignant pediatric brain tumor characterized by its aggressive nature and limited treatment options. Metabolic changes have recently emerged as key factors in the development, progression, and response to therapy in various types of cancer. Cancer cells exhibit remarkable adaptability by modulating glucose, lipids, amino acids, and nucleotide metabolism to survive in nutrient- and oxygen-deprived environments. Although medulloblastoma has been extensively studied from a genomic perspective, leading to the identification of four subgroups and their respective subcategories, the investigation of its metabolic phenotype has remained relatively understudied. This review focus on the available literature, aiming to summarize the current knowledge about the main metabolic pathways that are deregulated in medulloblastoma tumors, while emphasizing the controversial aspects and the progress that is yet to be made. Furthermore, we underscored the insights gained so far regarding the impact of metabolism on the development of drug resistance in medulloblastoma and the therapeutic strategies employed to target specific metabolic pathways
Crosstalk between the mesothelium and lymphomatous cells: insight into the mechanisms involved in the progression of body cavity lymphomas.
No full textA yeast based assay establishes the pathogenicity of novel missense ACTA2 variants associated with aortic aneurysms
No full textThe ACTA2 gene codes for alpha-smooth muscle actin, a critical component of the contractile apparatus of the vascular smooth muscle cells. Autosomal dominant variants in the ACTA2 gene have been associated to familial non-syndromic thoracic aortic aneurysm/dissection (TAAD). They are thought to act through a dominant-negative mechanism. These variants display incomplete penetrance and variable expressivity, complicating the validation of ACTA2 variants pathogenicity by family segregation studies. In this study, we developed a yeast based assay to test putative TAAD-associated ACTA2 variants. We identified five new heterozygous ACTA2 missense variants in TAAD patients through next generation sequencing. We decided to test their pathogenicity in Saccharomyces cerevisiae, since yeast actin is very similar to human alpha-smooth muscle actin, and the residues at which the TAAD-associated variants occur in ACTA2 are well conserved. A wild type yeast strain was transformed with a vector expressing the different mutant alleles, to model the heterozygous condition of patients. Then, we evaluated yeast growth by spot test and cytoskeletal and mitochondrial morphology by fluorescence microscopy. We found that mutant yeast strains displayed only mild growth defects but a significant increase in the percentage of cells with abnormal mitochondrial distribution and abnormal organization of the actin cytoskeleton compared to controls. All variants appeared to interfere with the activity of wild type actin in yeast, suggesting a dominant-negative pathogenic mechanism. Our results demonstrate the utility of using the yeast actin model system to validate the pathogenicity of TAAD-associated ACTA2 variants
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
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