The role of octreotide in preventing complications after pancreatoduodenectomy for cancer

Background Although the mortality rate of pancreatoduodenectomy has fallen sharply over the last two decades, there is still a risk of serious complications resulting from leakage at the site of anastomosis between the pancreatic remnant and the gastrointestinal tract. Numerous techniques have been described to minimise the risk of these anastomotic leaks, but they can be difficult to avoid if the distal pancreas is unobstructed with a soft parenchyma and a non-dilated duct. The risk of leakage is largely dependent upon the presence of activated pancreatic enzymes, and this fact provides a rationale for the perioperative use of the somatostatin analogue octreotide to inhibit exocrine pancreatic secretion. Discussion Six prospective randomised controlled trials have been published on the use of prophylactic octreotide in pancreatic surgery, five from Europe and one from the USA. The five (multicentre) European studies have consistently shown that octreotide reduces the postoperative complication rate, but the American study does not confirm this benefit. Methodological differences may explain the discrepancy, notably the fact that most of the US patients had received preoperative chemoradiation which is likely to have reduced enzyme secretion. A meta-analysis of four of these studies showed that octreotide lowered the rate of postoperative complications from 37 to 21%, chiefly by reducing the risk of pancreatic fistula. Prophylactic octreotide therapy is cost effective and should be used at least in patients with normal pancreatic parenchyma

Massive NGS data analysis reveals hundreds of potential novel gene fusions in human cell lines

Background: Gene fusions derive from chromosomal rearrangements and the resulting chimeric transcripts are often endowed with oncogenic potential. Furthermore, they serve as diagnostic tools for the clinical classification of cancer subgroups with different prognosis and, in some cases, they can provide specific drug targets. So far, many efforts have been carried out to study gene fusion events occurring in tumor samples. In recent years, the availability of a comprehensive Next Generation Sequencing dataset for all the existing human tumor cell lines has provided the opportunity to further investigate these data in order to identify novel and still uncharacterized gene fusion events. Results: In our work, we have extensively reanalyzed 935 paired-end RNA-seq experiments downloaded from "The Cancer Cell Line Encyclopedia" repository, aiming at addressing novel putative cell-line specific gene fusion events in human malignancies. The bioinformatics analysis has been performed by the execution of four different gene fusion detection algorithms. The results have been further prioritized by running a bayesian classifier which makes an in silico validation. The collection of fusion events supported by all of the predictive softwares results in a robust set of ∼ 1,700 in-silico predicted novel candidates suitable for downstream analyses. Given the huge amount of data and information produced, computational results have been systematized in a database named LiGeA. The database can be browsed through a dynamical and interactive web portal, further integrated with validated data from other well known repositories. Taking advantage of the intuitive query forms, the users can easily access, navigate, filter and select the putative gene fusions for further validations and studies. They can also find suitable experimental models for a given fusion of interest. Conclusions: We believe that the LiGeA resource can represent not only the first compendium of both known and putative novel gene fusion events in the catalog of all of the human malignant cell lines, but it can also become a handy starting point for wet-lab biologists who wish to investigate novel cancer biomarkers and specific drug targets

Learning of a multilingual bitaxonomy of Wikipedia and its application to semantic predicates

The ability to extract hypernymy information on a large scale is becoming increasingly important in natural language processing, an area of the artificial intelligence which deals with the processing and understanding of natural language. While initial studies extracted this type of information from textual corpora by means of lexico-syntactic patterns, over time researchers moved to alternative, more structured sources of knowledge, such as Wikipedia. After the first attempts to extract is-a information fromWikipedia categories, a full line of research gave birth to numerous knowledge bases containing information which, however, is either incomplete or irremediably bound to English. To this end we put forward MultiWiBi, the first approach to the construction of a multilingual bitaxonomy which exploits the inner connection between Wikipedia pages and Wikipedia categories to induce a wide-coverage and fine-grained integrated taxonomy. A series of experiments show state-of-the-art results against all the available taxonomic resources available in the literature, also with respect to two novel measures of comparison. Another dimension where existing resources usually fall short is their degree of multilingualism. While knowledge is typically language agnostic, currently resources are able to extract relevant information only in languages providing highquality tools. In contrast, MultiWiBi does not leave any language behind: we show how to taxonomize Wikipedia in an arbitrary language and in a way that is fully independent of additional resources. At the core of our approach lies, in fact, the idea that the English version of Wikipedia can be linguistically exploited as a pivot to project the taxonomic information extracted from English to any other Wikipedia language in order to have a bitaxonomy in a second, arbitrary language; as a result, not only concepts which have an English equivalent are covered, but also those concepts which are not lexicalized in the source language. We also present the impact of having the taxonomized encyclopedic knowledge offered by MultiWiBi embedded into a semantic model of predicates (SPred) which crucially leverages Wikipedia to generalize collections of related noun phrases to infer a probability distribution over expected semantic classes. We applied SPred to a word sense disambiguation task and show that, when MultiWiBi is plugged in to replace an internal component, SPred’s generalization power increases as well as its precision and recall. Finally, we also published MultiWiBi as linked data, a paradigm which fosters interoperability and interconnection among resources and tools through the publication of data on the Web, and developed a public interface which lets the users navigate through MultiWiBi’s taxonomic structure in a graphical, captivating manner

Genomic organization and cytokine-mediated inducibility of the human TRIM-8/Gerp gene.

Cytokine signaling is negatively regulated by a set of SH2 domain-containing proteins, the Suppressors of Cytokine Signaling (SOCS) acting as intracellular modulators. Experimental evidence indicates that SOCS gene expression is induced by cytokines and pro-inflammatory stimuli and is highly controlled both at transcription and translation level. Furthermore, SOCS proteins appear rapidly degraded inside the cells, mostly controlling their stability by interacting with specific molecules such as elongin B and C. It has been shown that SOCS-1/JAB, a member of the SOCS family, interacts with TRIM-8/Gerp, a new ring protein specifically binding SOCS-1 recombinant polypeptide in-vitro and in-vivo. Trim-8/Gerp, transcribes a 3.0-kb mRNA, spans 551 AA and is highly conserved during evolution. In addition, it can be induced by IFN-γ in epithelial and lymphoid cells and is expressed mostly ubiquitously in murine and human tissues. Here in this report we present the genomic organization of this new SOCS-1 interactor, and we add new tools for extending investigation of the complex mechanism that undergoes negatively regulation of cytokine signaling

Autophagy processes are dependent on EGF receptor signaling

Autophagy is a not well-understood conserved mechanism activated during nutritional deprivation in order to maintain cellular homeostasis. In the present study, we investigated the correlations between autophagy, apoptosis and the MAPK pathways in melanoma cell lines. We demonstrated that during starvation the EGF receptor mediated signaling activates many proteins involved in the MAPK pathway. Our data also suggest a previously unidentified link between the EGFR and Beclin-1 in melanoma cell line. We demonstrated that, following starvation, EGFR binds and tyrosine-phosphorylates Beclin-1, suggesting that it may play a key inhibitory role in the early stage of starvation, possibly through the Beclin-1 sequestration. Furthermore, EGFR releases Beclin-1 and allows initiating steps of the autophagic process. Interestingly enough, when the EGFR pathway was blocked by anti-EGF antibodies, immunoprecipitated Beclin-1 did not bind the phospho-EGFR. In addition, an extended binding of p-Bcl2 either with Beclin-1 or with Bax was observed with a decreased activation of the stress-induced JNK kinase, thus avoiding the transduction pathways that activate autophagy and apoptosis, respectively. For this reason, we advance the hypothesis that the activation of the EGFR is a necessary event that allows the ignition and progression of the autophagic process, at least in melanoma cells

NF-κB: blending metabolism, immunity, and inflammation

The procurement and management of nutrients and ability to fight infections are fundamental requirements for survival. These defense responses are bioenergetically costly, requiring the immune system to balance protection against pathogens with the need to maintain metabolic homeostasis. NF-κB transcription factors are central regulators of immunity and inflammation. Over the last two decades, these factors have emerged as a pivotal node coordinating the immune and metabolic systems in physiology and the etiopathogenesis of major threats to human health, including cancer, autoimmunity, chronic inflammation, and others. In this review, we discuss recent advances in understanding how NF-κB-dependent metabolic programs control inflammation, metabolism, and immunity and how improved knowledge of them may lead to better diagnostics and therapeutics for widespread human diseases

Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?

Amino acids can modulate cell metabolism and control cell fate by regulating cell survival and cell death. The molecular mechanisms involved are mediated by the mTOR complexes mTORC1 and mTORC2 activity. These complexes are finely regulated and the continuous advancement of the knowledge on their composition and function is revealing that their balance may represent the condition that determines the cell fate. This is important for normal healthy cells but it is becoming clear, and it is even more important, that the balance of the mTORCs activity may also condition the cell fate of cancer cells. Here, we discuss the evidences supporting the amino acids supplementation as a cancer fighting weapon and a possible strategy to counteract the myocyte toxicity associated with chemotherapy, possibly by tipping the balance of mTORCs activity

Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

Background and aims: Docetaxel (DTX) modestly increases patient survival of metastatic castration-resistant prostate cancer (mCRPC) due to insurgence of pharmacological resistance. Deregulation of Chromosome Region Maintenance (CRM-1)/ exportin-1 (XPO-1)-mediated nuclear export may play a crucial role in this phenomenon. Material and methods: Here, we evaluated the effects of two Selective Inhibitor of Nuclear Export (SINE) compounds, selinexor (KPT-330) and KPT-251, in association with DTX by using 22rv1, PC3 and DU145 cell lines with their. DTX resistant derivatives. Results and conclusions: We show that DTX resistance may involve overexpression of β-III tubulin (TUBB3) and P-glycoprotein as well as increased cytoplasmic accumulation of Foxo3a. Increased levels of XPO-1 were also observed in DTX resistant cells suggesting that SINE compounds may modulate DTX effectiveness in sensitive cells as well as restore the sensitivity to DTX in resistant ones. Pretreatment with SINE compounds, indeed, sensitized to DTX through increased tumor shrinkage and apoptosis by preventing DTX-induced cell cycle arrest. Basally SINE compounds induce FOXO3a activation and nuclear accumulation increasing the expression of FOXO-responsive genes including p21, p27 and Bim causing cell cycle arrest. SINE compounds-catenin and survivin supporting apoptosis. βdown-regulated Cyclin D1, c-myc, Nuclear sequestration of p-Foxo3a was able to reduce ABCB1 and TUBB3 H2AX levels, prolonged γ expression. Selinexor treatment increased DTX-mediated double strand breaks (DSB), and reduced the levels of DNA repairing proteins including DNA PKc and Topo2A. Our results provide supportive evidence for the therapeutic use of SINE compounds in combination with DTX suggesting their clinical use in mCRPC patients

Language resources and linked data: a practical perspective

Recently, experts and practitioners in language resources have started recognizing the benefits of the linked data (LD) paradigm for the representation and exploitation of linguistic data on the Web. The adoption of the LD principles is leading to an emerging ecosystem of multilingual open resources that conform to the Linguistic Linked Open Data Cloud, in which datasets of linguistic data are interconnected and represented following common vocabularies, which facilitates linguistic information discovery, integration and access. In order to contribute to this initiative, this paper summarizes several key aspects of the representation of linguistic information as linked data from a practical perspective. The main goal of this document is to provide the basic ideas and tools for migrating language resources (lexicons, corpora, etc.) as LD on the Web and to develop some useful NLP tasks with them (e.g., word sense disambiguation). Such material was the basis of a tutorial imparted at the EKAW’14 conference, which is also reported in the paper