Aberrant p15, p16, p53, and DAPK Gene Methylation in Myelomagenesis: Clinical and Prognostic Implications

BACKGROUND: Aberrant DNA methylation is considered a crucial mechanism in the pathogenesis of monoclonal gammopathies. We aimed to investigate the contribution of hypermethylation of 4 tumor suppressor genes to the multistep process of myelomagenesis. METHODS: The methylation status of p15, p16, p53, and DAPK genes was evaluated in bone marrow samples from 94 patients at diagnosis: monoclonal gammopathy of uncertain significance (MGUS) (n = 48), smoldering multiple myeloma (SMM) (n = 8) and symptomatic multiple myeloma (MM) (n = 38), and from 8 healthy controls by methylation-specific polymerase chain reaction analysis. RESULTS: Overall, 63% of patients with MM and 39% of patients with MGUS presented at least 1 hypermethylated gene (P < .05). No aberrant methylation was detected in normal bone marrow. The frequency of methylation for individual genes in patients with MGUS, SMM, and MM was p15, 15%, 50%, 21%; p16, 15%, 13%, 32%; p53, 2%, 12,5%, 5%, and DAPK, 19%, 25%, 39%, respectively (P < .05). No correlation was found between aberrant methylation and immunophenotypic markers, cytogenetic features, progression-free survival, and overall survival in patients with MM. CONCLUSIONS: The current study supports a relevant role for p15, p16, and DAPK hypermethylation in the genesis of the plasma cell neoplasm. DAPK hypermethylation also might be an important step in the progression from MGUS to MM.info:eu-repo/semantics/publishedVersio

Strategic negotiation and trust in diplomacy - the DipBlue approach

The study of games in Artificial Intelligence has a long tradition. Game playing has been a fertile environment for the development of novel approaches to build intelligent programs. Multi-agent systems (MAS), in particular, are a very useful paradigm in this regard, not only because multi-player games can be addressed using this technology, but most importantly because social aspects of agenthood that have been studied for years by MAS researchers can be applied in the attractive and controlled scenarios that games convey. Diplomacy is a multi-player strategic zero-sum board game, including as main research challenges an enormous search tree, the difficulty of determining the real strength of a position, and the accommodation of negotiation among players. Negotiation abilities bring along other social aspects, such as the need to perform trust reasoning in order to win the game. The majority of existing artificial players (bots) for Diplomacy do not exploit the strategic opportunities enabled by negotiation, focusing instead on search and heuristic approaches. This paper describes the development of DipBlue, an artificial player that uses negotiation in order to gain advantage over its opponents, through the use of peace treaties, formation of alliances and suggestion of actions to allies. A simple trust assessment approach is used as a means to detect and react to potential betrayals by allied players. DipBlue was built to work with DipGame, a MAS testbed for Diplomacy, and has been tested with other players of the same platform and variations of itself. Experimental results show that the use of negotiation increases the performance of bots involved in alliances, when full trust is assumed. In the presence of betrayals, being able to perform trust reasoning is an effective approach to reduce their impact. © Springer-Verlag Berlin Heidelberg 2015

Pleuroamniotic shunting--case report

Fetal hydrothorax refers to a collection of fluid within the fetal thorax that may be the result of chylous leak from the thoracic duct (primary hydrothorax) or generalized fluid retention associated with immune or no immune fetal hydrops (secondary hydrothorax). The authors' presents a case report occurred in 2002, of a pregnant woman that at 25 weeks' gestation that was referred to Maternidade Bissaya-Barreto-Coimbra because of a fetal hydrothorax at left, under tension and with cardiac decompensation signs. A fetal thoracocentesis was performed and the diagnosis was chylothorax. Because of a rapid reaccumulation of fluid a pleuroamniotic shunt was placed. The effusion and the cardiac decompensation signs regressed. The delivery was at 38 weeks' gestation. The newborn had been stable. Actually he has 10 months, is healthy and has a normal grow and development

Influence of P53 on the radiotherapy response of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it has a poor prognosis and few therapeutic options. Radiotherapy is one of the most effective forms of cancer treatment, and P53 protein is one of the key molecules determining how a cell responds to radiotherapy. The aim of this study was to determine the therapeutic efficacy of iodine-131 in three human HCC cell lines

Flow cytometry and targeted immune transcriptomics identify distinct profiles in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors with or without interferon-α

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco mmons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the dat

Effect of partially purified fumonisins on cellular immune response in experimental murine paracoccidioidomycosis

Fumonisins are mycotoxins produced mainly by Fusarium verticillioides, which can modulate the immune response. Paracoccidioidomycosis (PCM), caused by the fungus Paracoccodioides brasiliensis (Pb), is one of the most important systemic mycoses in Latin America. The aim of this study was to evaluate the effect of the partially purified fumonisins on cellular immune response in mice infected with Pb. Four groups of male BALB/c mice were used. Groups PB and PB/FB were inoculated i.v. with 1 × 105 Pb yeast cells and, after 28 days, groups FB and PB/FB were inoculated (s.c.) with partially purified fumonisin B1 from F. verticillioides (5 × 2.25 mg FB1/kg body weight). After 7 days, cellular immune response was evaluated by delayed-type hypersensitivity (DTH) and lymphoproliferative assays (LA) using spleen cells. Nitric oxide (NO) production by spleen cells was also evaluated. The specific LA response to Pb antigen was higher in group PB than in FB and CTR groups (p&lt; 0.05) but not significant with PB/FB. The DTH response was higher in infected than non infected groups (p&lt;0.05) but also no significantly with PB and PB/FB groups. The lyphoproliferative response to ConA was decreased in FB or PB/FB in relation to CTR (p&lt;0.05) but not with PB/FB and also a reduction of NO levels was observed in fumonisin treated in relation to control group FB1/kg (p&lt;0.05). In conclusion, fumonisin B1 or other components of F. verticillioides extracts significantly suppress the unspecific cellular immune response and the NO production by splenocytes from P. brasiliensis infected or not infected BALB/c mice.Keywords: Fumonisin, Paracoccodioides brasiliensis, lymphoproliferative assay, nitric oxideAfrican Journal of Biotechnology Vol. 12(42), pp. 6126-613

Impact of splenic artery ligation after major hepatectomy on liver function, regeneration and viability

It was reported that prevention of acute portal overpressure in small-for-size livers by inflow modulation results in a better postoperative outcome. The aim is to investigate the impact of portal blood flow reduction by splenic artery ligation after major hepatectomy in a murine model. Forty-eight rats were subjected to an 85% hepatectomy or 85% hepatectomy and splenic artery ligation. Both groups were evaluated at 24, 48, 72 and 120 post-operative hours: liver function, regeneration and viability. All methods and experiments were carried out in accordance with Coimbra University guidelines. Splenic artery ligation produces viability increase after 24 h, induces a relative decrease in oxidative stress during the first 48 hours, allows antioxidant capacity increment after 24 h, which is reflected in a decrease of half-time normalized liver curve at 48 h and at 72 h and in an increase of mitotic index between 48 h and 72 h. Splenic artery ligation combined with 85% hepatectomy in a murine model, allows portal inflow modulation, promoting an increase in hepatocellular viability and regeneration, without impairing the function, probably by inducing a less marked elevation of oxidative stress at first 48 hours

RNAi-mediated suppression of vimentin or glial fibrillary acidic protein prevents the establishment of Müller glial cell hypertrophy in progressive retinal degeneration.

Gliosis is a complex process comprising upregulation of intermediate filament (IF) proteins, particularly glial fibrillary acidic protein (GFAP) and vimentin, changes in glial cell morphology (hypertrophy) and increased deposition of inhibitory extracellular matrix molecules. Gliosis is common to numerous pathologies and can have deleterious effects on tissue function and regeneration. The role of IFs in gliosis is controversial, but a key hypothesized function is the stabilization of glial cell hypertrophy. Here, we developed RNAi approaches to examine the role of GFAP and vimentin in vivo in a murine model of inherited retinal degeneration, the Rhodopsin knockout (Rho-/- ) mouse. Specifically, we sought to examine the role of these IFs in the establishment of Müller glial hypertrophy during progressive degeneration, as opposed to (more commonly assessed) acute injury. Prevention of Gfap upregulation had a significant effect on the morphology of reactive Müller glia cells in vivo and, more strikingly, the reduction of Vimentin expression almost completely prevented these cells from undergoing degeneration-associated hypertrophy. Moreover, and in contrast to studies in knockout mice, simultaneous suppression of both GFAP and vimentin expression led to severe changes in the cytoarchitecture of the retina, in both diseased and wild-type eyes. These data demonstrate a crucial role for Vimentin, as well as GFAP, in the establishment of glial hypertrophy and support the further exploration of RNAi-mediated knockdown of vimentin as a potential therapeutic approach for modulating scar formation in the degenerating retina

Two-year clinical outcome from the Iberian registry patients after left atrial appendage closure

AIMS: The aim of this study was to observe the percentage of thromboembolic and haemorrhagic events over a 2-year follow-up in patients with non-valvular atrial fibrillation (NVAF) undergoing closure of the left atrial appendage (LAA) with an occlusion device. Observed events and CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke history), CHA2DS2-VASc (also adding: vascular disease and sex) and HAS-BLED (hypertension, abnormal liver/renal function, stroke history, bleeding predisposition, labile international normalised ratios, elderly, drugs/alcohol use)-predicted events were compared. METHODS: LAA closure with an occlusion device was performed in 167 NVAF patients contraindicated for oral anticoagulants and recruited from 12 hospitals between 2009 and 2013. At least two transoesophageal echocardiograms were performed in the first 6 months postimplantation. Antithrombotics included clopidogrel and aspirin. Patients were monitored for death, stroke, major and relevant bleeding and hospitalisation for concomitant conditions. Mean age was 74.68±8.58, median follow-up was 24 months, 5.38% had intraoperative complications and implantation was successful in 94.6% of subjects. Mortality during follow-up was 10.8%, mostly (9.5%) non-cardiac related. Bleeding occurred in 10.1% of subjects, 5.7% major and 4.4% minor though relevant, and 4.4% suffered stroke. Major bleeding and stroke/transient ischaemic attack events within 2 years (annual event rates, 290 patients/year) were less frequent than expected from CHADS2 (2.4% vs 9.6%), CHA2DS2-VASc (2.4% vs 8.3%) and HAS-BLED (3.1% vs 6.6%) risk scores (p<0.001, p=0.003, p=0.047, respectively). CONCLUSIONS: LAA closure with an occlusion device in patients contraindicated for oral anticoagulants is a therapeutic option associated with fewer thromboembolic and haemorrhagic events than expected from risk scores, particularly in the second year postimplantation

Identifying priority questions regarding rapid systematic reviews’ methods: protocol for an eDelphi study

Introduction: Rapid systematic reviews (RRs) have the potential to provide timely information to decision-makers, thus directly impacting healthcare. However, consensus regarding the most efficient approaches to performing RRs and the presence of several unaddressed methodological issues pose challenges. With such a large potential research agenda for RRs, it is unclear what should be prioritised.// Objective: To elicit a consensus from RR experts and interested parties on what are the most important methodological questions (from the generation of the question to the writing of the report) for the field to address in order to guide the effective and efficient development of RRs.// Methods and analysis: An eDelphi study will be conducted. Researchers with experience in evidence synthesis and other interested parties (eg, knowledge users, patients, community members, policymaker, industry, journal editors and healthcare providers) will be invited to participate. The following steps will be taken: (1) a core group of experts in evidence synthesis will generate the first list of items based on the available literature; (2) using LimeSurvey, participants will be invited to rate and rank the importance of suggested RR methodological questions. Questions with open format responses will allow for modifications to the wording of items or the addition of new items; (3) three survey rounds will be performed asking participants to re-rate items, with items deemed of low importance being removed at each round; (4) a list of items will be generated with items believed to be of high importance by ≥75% of participants being included and (5) this list will be discussed at an online consensus meeting that will generate a summary document containing the final priority list. Data analysis will be performed using raw numbers, means and frequencies.// Ethics and dissemination: This study was approved by the Concordia University Human Research Ethics Committee (#30015229). Both traditional, for example, scientific conference presentations and publication in scientific journals, and non-traditional, for example, lay summaries and infographics, knowledge translation products will be created