1,720,962 research outputs found
NETs: Organ-related epigenetic derangements and potential clinical applications
Full text linkHigh-throughput next-generation sequencing methods have recently provided a detailed picture of the genetic landscape of neuroendocrine tumors (NETs), revealing recurrent mutations of chromatin-remodeling genes and little-to-no pathogenetic role for oncogenes commonly mutated in cancer. Concurrently, multiple epigenetic modifications have been described across the whole spectrum of NETs, and their putative function as tumorigenic drivers has been envisaged. As result, it is still unclear whether or not NETs are epigenetically-driven, rather than genetically-induced malignancies. Although the NET epigenome profiling has led to the identification of molecularly-distinct tumor subsets, validation studies in larger cohorts of patients are needed to translate the use of NET epitypes in clinical practice. In the precision medicine era, recognition of subpopulations of patients more likely to respond to therapeutic agents is critical, and future studies testing epigenetic biomarkers are therefore awaited. Restoration of the aberrant chromatin remodeling machinery is an attractive approach for future treatment of cancer and in several hematological malignancies a few epigenetic agents have been already approved. Although clinical outcomes of epigenetic therapies in NETs have been disappointing so far, further clinical trials are required to investigate the efficacy of these drugs. In this context, given the immune-stimulating effects of epidrugs, combination therapies with immune checkpoint inhibitors should be tested. In this review, we provide an overview of the epigenetic changes in both hereditary and sporadic NETs of the gastroenteropancreatic and bronchial tract, focusing on their diagnostic, prognostic and therapeutic implications
Lanreotide dopo octreotide LAR nel pNET in progressione: descrizione di un caso
No full textPresentiamo il caso di un uomo di 47 anni affetto da tumore neuroendocrino G2 del pancreas in progressio- ne strumentale di malattia dopo trattamento con octreotide ed everolimus. Il paziente ha sospeso octreotide e intrapreso terapia con lanreotide; le indagini strumentali eseguite dopo 12 mesi dallo switch del farmaco hanno documentato stazionarietà di malattia, suggerendo un potenziale beneficio clinico dell’impiego di analoghi della somatostatina in successione
New insights into the molecular pathogenesis of langerhans cell histiocytosis
No full textLangerhans cell histiocytosis (LCH) is a rare proliferative
disorder characterized by an accumulation of cells sharing the
major phenotypic features of cutaneous Langerhans cells.
Given its variable clinical evolution, ranging from self-limiting
lesions to multisystemic forms with a poor prognosis, in the last
decades it has been debated whether LCH might not have
a neoplastic rather than an inflammatory nature. However,
although the fundamental events underlying the pathogenesis
of LCH are still elusive, recent advances have strikingly
improved our understanding of the disease. In particular, the
identification of multiple interplays between LCH cells and
their tumor microenvironment, along with the recognition of the lesional cytokine storm as a key determinant of LCH
progression, has substantiated new opportunities for devising
targeted therapeutic approaches. Strikingly, the detection of
the rapidly accelerated fibrosarcoma isoform BV600E gain-of-function
mutation as a genetic alteration recurring in more
than 50% of patients has fueled the paradoxical picture of LCH
as a tumor of the antigen-presenting cells that can evade
rejection by the immune system.Thus, new evidence regarding
the ontogeny of LCH cells, as well as a better understanding of
the putative immune system frustrating strategy in LCH, may
help to define the precise pathogenesis
Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications
Full text linkObesity is an important risk factor for breast cancer (BC) in postmenopausal women; interlinked molecular mechanisms might be involved in the pathogenesis. Increased levels of estrogens due to aromatization of the adipose tissue, inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and prostaglandin E2, insulin resistance and hyperactivation of insulin-like growth factors pathways, adipokines, and oxidative stress are all abnormally regulated in obese women and contribute to cancerogenesis. These molecular factors interfere with intracellular signaling in the mitogen-activated protein kinase and phosphatydilinositol-3-phosphate/mammalian target of rapamycin (mTOR) pathways, which regulate the progression of the cell cycle, apoptosis, and protein synthesis. In this context, structural defects of typical genes related to both BC and obesity, such as leptin, leptin receptor, serum paraoxonase/arylesterase 1, the fat mass and obesity-associated gene and melanocortin receptor 4, have been associated with a high or low risk of BC development. The early detection of these gene alterations might be useful as risk predictors in obese women, and targeting these pathways involved in the BC pathogenesis in obese women is a potential therapeutic tool. In particular, mTOR pathway deregulation concurs in both obesity and BC, and inhibition of this might disrupt the molecular interlinks in a similar manner to that of metformin, which exerts definite anticancer activity and is currently used as an antidiabetic drug with a weight-reducing property. The identification of both genetic and pharmacological implications on the prevention and management of BC is the ultimate aim of these studies
Bendamustine overcomes resistance to melphalan in myeloma cell lines by inducing cell death through mitotic catastrophe
No full textMelphalan has been a mainstay of multiple myeloma (MM) therapy for many years. However, following treatment
with this alkylator, malignant plasma cells usually escape both apoptosis and cell cycle control, and acquire
drug-resistance resulting in tumor progression. Bendamustine is being used inMMpatients refractory to conventional
DNA-damaging agents, although the mechanisms driving this lack of cross-resistance are still undefined.
Here, we investigated the molecular pathway of bendamustine-induced cell death in melphalan-sensitive and
melphalan-resistant MM cell lines. Bendamustine affected cell survival resulting in secondary necrosis, and
prompted cell death primarily through caspase-2 activation. Also, bendamustine blocked the cell cycle in the
G2/M phase and induced micronucleation, erratic chromosome spreading and mitotic spindle perturbations in
melphalan-resistant MM cells. In these cells, both Aurora kinase A (AURKA) and Polo-like kinase-1 (PLK-1), key
components of the spindle-assembly checkpoint,were down-regulated following incubationwith bendamustine,
whereas levels of Cyclin B1 increased as a consequence of the prolonged mitotic arrest induced by the drug. These
findings indicate that, at least in vitro, bendamustine drives cell death by promoting mitotic catastrophe in
melphalan-resistantMMcells. Hence, activation of this alternative pathway of cell death may be a novel approach
to the treatment of apoptosis-resistant myelomas
The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications
No full textNeuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross-talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including VEGF, PDGF, FGF, semaphorins and angiopoietins, that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher then epithelial tumors. Also, NETs operate multi-faceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, CTGF and TGF-β primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely major complications of functioning NETs. However, at present little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoint molecules are heterogeneously expressed in NETs' surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are anti-tumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs' microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.
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
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