Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.

A mild form of SLC29A3 disorder: a frameshift deletion leads to the paradoxical translation of an otherwise noncoding mRNA splice variant

We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the"rescue" role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic.

Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media.

Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P < 0.001 vs. control) and decreased plasma nitric oxide concentration (10.1 ± 11.1 vs. 29.5 ± 8.0 μM) (P < 0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 μM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine (P < 0.008 vs. ART + vehicle), and prevented arterial hypertension (104.6 ± 3.4 mmHg, P < 0.003 vs. ART + vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.

New technologies and nursing: use and perception of primary healthcare nurses about electronic health record in Catalonia, Spain

This study was aimed to analyze and assess the use and perception of electronic health records (EHRs) by nurses. The study sample included 113 nurses from different shifts of primary health facilities in Catalonia, Spain, devoted to adult as well as pediatric outpatients using EHRs throughout the year 2010. A majority of the sample (87.5%) were women and 12.5% were men. The average age was 44.27 years and the average time working in primary healthcare was 47.15 months. A majority (80.4%) received specific training on the use of the EHR and 19.6% did not. The use of the application required side technical support (mean: 3.42) and it is considered necessary to learn more about the performance of the application (mean: 3.50). The relationship between the average ratings that nurses have about the EHR and age shows that there is no statistically significant linear relationship (r = - 0.002, p-value = 0.984). As to how long they have used the EHRs, there are significant differences (r= -0.304, p-value = 0.00), so the more time the nurse takes using the EHR, the greater degree of satisfaction is shown. In addition, there are significant differences between nurses" perceptions regarding the EHR and gender (t = - 0.421, p-value = 0.675). Nurses assessed as positive the contribution of the EHRs in their nursing care day work (average score: 2.55/5). Considering that the usability of the EHR device is assessed as satisfactory, the results of the perception of nurses show that we must also take into account the training and emphasize the need for a side technical support in the implementation process of the EHR. Doing so, the positive perception that nurses have in regard to information and communication technology in general and with respect to the EHR in particular may be increased.

New technologies and nursing: use and perception of primary healthcare nurses about electronic health record in Catalonia, Spain

This study was aimed to analyze and assess the use and perception of electronic health records (EHRs) by nurses. The study sample included 113 nurses from different shifts of primary health facilities in Catalonia, Spain, devoted to adult as well as pediatric outpatients using EHRs throughout the year 2010. A majority of the sample (87.5%) were women and 12.5% were men. The average age was 44.27 years and the average time working in primary healthcare was 47.15 months. A majority (80.4%) received specific training on the use of the EHR and 19.6% did not. The use of the application required side technical support (mean: 3.42) and it is considered necessary to learn more about the performance of the application (mean: 3.50). The relationship between the average ratings that nurses have about the EHR and age shows that there is no statistically significant linear relationship (r = - 0.002, p-value = 0.984). As to how long they have used the EHRs, there are significant differences (r= -0.304, p-value = 0.00), so the more time the nurse takes using the EHR, the greater degree of satisfaction is shown. In addition, there are significant differences between nurses" perceptions regarding the EHR and gender (t = - 0.421, p-value = 0.675). Nurses assessed as positive the contribution of the EHRs in their nursing care day work (average score: 2.55/5). Considering that the usability of the EHR device is assessed as satisfactory, the results of the perception of nurses show that we must also take into account the training and emphasize the need for a side technical support in the implementation process of the EHR. Doing so, the positive perception that nurses have in regard to information and communication technology in general and with respect to the EHR in particular may be increased.

Analyzing the temporal regulation of translation efficiency in mouse liver.

Mammalian physiology and behavior follow daily rhythms that are orchestrated by endogenous timekeepers known as circadian clocks. Rhythms in transcription are considered the main mechanism to engender rhythmic gene expression, but important roles for posttranscriptional mechanisms have recently emerged as well (reviewed in Lim and Allada (2013) [1]). We have recently reported on the use of ribosome profiling (RPF-seq), a method based on the high-throughput sequencing of ribosome protected mRNA fragments, to explore the temporal regulation of translation efficiency (Janich et al., 2015 [2]). Through the comparison of around-the-clock RPF-seq and matching RNA-seq data we were able to identify 150 genes, involved in ribosome biogenesis, iron metabolism and other pathways, whose rhythmicity is generated entirely at the level of protein synthesis. The temporal transcriptome and translatome data sets from this study have been deposited in NCBI's Gene Expression Omnibus under the accession number GSE67305. Here we provide additional information on the experimental setup and on important optimization steps pertaining to the ribosome profiling technique in mouse liver and to data analysis.

La Incidencia de las nuevas tecnologías en los hábitos formativos de los estudiantes de magisterio = The Impact of new technologies in the learning habits of teacher students

Este trabajo persigue dos objetivos: el primero es analizar el uso de las TIC en un grupo de estudiantes de segundo curso de Magisterio de la Universidad de Girona; el segundo es analizar los documentos normativos legales que establecen el currículum de educación primaria en Cataluña para observar qué tipo de papel juegan las TIC en las nuevas programaciones educativas. La primera parte se ha llevado a cabo mediante una encuesta, cuyos resultados permiten observar tres aspectos distintos: el primero, que una parte considerable del grupo considera las TIC más como un complemento para el aprendizaje que como una forma de aprendizaje; el segundo, que a pesar de hacer un uso considerable de las TIC, el conocimiento que tienen de ellas es muy básico y utilizan aplicaciones muy genéricas; y el tercero es que una parte de sus propuestas didácticas para el uso de las TIC son propuestas tradicionales simplemente adaptadas a un nuevo instrumento, sin buscar realmente la innovación que puede suponer la incorporación de las TIC. En la segunda parte del artículo, a partir del análisis e interpretación de los documentos legales que establecen el currículum de Educación Primaria, se observa que en un mismo documento conviven aserciones sobre las TIC como complemento al aprendizaje de contenidos con otras formulaciones que consideran las TIC como constructoras de conocimiento. A partir del perfil de los estudiantes y del estado de los documentos legales, al final del artículo se hacen propuestas para formar al futuro maestro teniendo en cuenta las TIC como herramientas básicas de conocimiento

A Gendered Voice in Translation: Translating Like a Feminist

This paper addresses some of the challenges inherent in finding and showing a gendered voice in translation. The starting point is my own experience as a feminist translator of both feminist and non-feminist texts. Textual practices like translating necessarily interact with current theoretical debates. In turn, theoretical writing on feminism enriches and informs one’s translating activity. This interplay between theoretical models and textual practices was particularly made evident to me as I rendered Essentially speaking, by Diana Fuss, into Catalan. In this article I intend to transcend anecdotes of translating individual texts and consider how translating equals rewriting oneself; it involves rethinking writing practices. I will specifically address the rethinking of (1) one’s identity when translating ‘like’ a feminist, (2) performativity in gender and in translation, and (3) agency and (In)visibility.

Rule-based machine translation between Bulgarian and Macedonian

This paper describes the development of a two-way shallow-transfer rule-based machine translation system between Bulgarian and Macedonian. It gives an account of the resources and the methods used for constructing the system, including the development of monolingual and bilingual dictionaries, syntactic transfer rules and constraint grammars. An evaluation of thesystem's performance was carried out and compared to another commercially available MT system for the two languages. Some future work was suggested.

Infancia, Adolescencia y Tecnologías de la Información y la Comunicación (TICs) en Perspectiva Psicosocial = Childhood, Adolescence and Information Communication Technologies (ICTs) in Psychosocial Perspective

Sobre el impacto que las TIC pueden tener en las relaciones interpersonales, ya sean en la familia y/o con los amigos/as, desde una perspectiva psicosocial

Readout electronics for low dark count pixel detectors based on geiger mode avalanche photodiodes fabricated in conventional CMOS technologies for future linear colliders

The high sensitivity and excellent timing accuracy of Geiger mode avalanche photodiodes makes them ideal sensors as pixel detectors for particle tracking in high energy physics experiments to be performed in future linear colliders. Nevertheless, it is well known that these sensors suffer from dark counts and afterpulsing noise, which induce false hits (indistinguishable from event detection) as well as an increase of the necessary area of the readout system. In this work, we present a comparison between APDs fabricated in a high voltage 0.35 µm and a high integration 0.13 µm commercially available CMOS technologies that has been performed to determine which of them best fits the particle collider requirements. In addition, a readout circuit that allows low noise operation is introduced. Experimental characterization of the proposed pixel is also presented in this work.

Low dark count geiger mode avalanche photodiodes fabricated in conventional CMOS technologies

Avalanche photodiodes operated in the Geiger mode present very high intrinsic gain and fast time response, which make the sensor an ideal option for those applications in which detectors with high sensitivity and velocity are required. Moreover, they are compatible with conventional CMOS technologies, allowing sensor and front-end electronics integration within the pixel cell. Despite these excellent qualities, the photodiode suffers from high intrinsic noise, which degrades the performance of the detector and increases the memory area to store the total amount of information generated. In this work, a new front-end circuit that allows low reverse bias overvoltage sensor operation to reduce the noise in Geiger mode avalanche photodiode pixel detectors is presented. The proposed front-end circuit also enables to operate the sensor in the gated acquisition mode to further reduce the noise. Experimental characterization of the fabricated pixel with the conventional HV-AMS 0.35µm technology is also presented in this article.