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Despite impressive and durable responses, nonsmall cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase (ALK) inhibitors (ALK-Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next-generation sequencing (NGS) upon disease progression. We collected 26 plasma and two cerebrospinal fluid samples from 24 advanced ALK-positive NSCLC patients at disease progression to an ALK-I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool). We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first- and second-generation ALK-Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1), FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3, and CCND1. Specifically, a deletion in exon 19 in EGFR, a non-V600 BRAF mutation (G466V), and the F129L mutation in MAP2K1 were identified in four patients who showed no objective survival benefit from ALK-Is. Potential ALK-I-resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and FGFR3, was detected in a patient progressing on a first-line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK-I-resistance mutations in most cases and could be a valuable approach for therapy decision making.

Bone tissue is composed of several cell types, which express their own microRNAs (miRNAs) that will play a role in cell function. The set of total miRNAs expressed in all cell types configures the specific signature of the bone tissue in one physiological condition. The aim of this study was to explore the miRNA expression profile of bone tissue from postmenopausal women. Tissue was obtained from trabecular bone and was analyzed in fresh conditions (n = 6). Primary osteoblasts were also obtained from trabecular bone (n = 4) and human osteoclasts were obtained from monocyte precursors after in vitro differentiation (n = 5). MicroRNA expression profiling was obtained for each sample by microarray and a global miRNA analysis was performed combining the data acquired in all the microarray experiments. From the 641 miRNAs detected in bone tissue samples, 346 (54%) were present in osteoblasts and/or osteoclasts. The other 46% were not identified in any of the bone cells analyzed. Intersection of osteoblast and osteoclast arrays identified 101 miRNAs shared by both cell types, which accounts for 30-40% of miRNAs detected in these cells. In osteoblasts, 266 miRNAs were detected, of which 243 (91%) were also present in the total bone array, representing 38% of all bone miRNAs. In osteoclasts, 340 miRNAs were detected, of which 196 (58%) were also present in the bone tissue array, representing 31% of all miRNAs detected in total bone. These analyses provide an overview of miRNAs expressed in bone tissue, broadening our knowledge in the microRNA field.

We report on a generic cooling technique for atoms trapped in optical lattices. It consists in modulating the lattice depth with a proper frequency sweeping. This filtering technique removes the most energetic atoms, and provides with the onset of thermalization a cooling mechanism reminiscent of evaporative cooling. However, the selection is here performed in quasi-momentum space rather than in position space. Interband selection rules are used to protect the population with a zero quasi-momentum, namely the Bose Einstein condensate. Direct condensation of thermal atoms in an optical lattice is also achieved with this technique. It offers an interesting complementary cooling mechanism for quantum simulations performed with quantum gases trapped in optical lattices., Comment: 5 pages, 3 figures

En este documento se muestran las dificultades para seleccionar una definición de límite infinito de sucesiones entre profesores. Estas dificultades están propiciadas por el efecto que el término divergencia ocasiona en dichas definiciones. Las dificultades, mostradas a través de una consulta a expertos, están presentes tanto en profesores como en autores de libros de texto y en este documento se muestran ejemplos de las mismas. Se aporta además una nueva acepción de sucesión divergente y se prepara el camino para un estudio posterior de la definición seleccionada.

In the present study, mdr1 gene expression was investigated by a sensitive reverse transcriptase-PCR assay in advanced breast cancer and in corresponding adjacent normal tissues obtained before and after treatment with primary chemotherapy. Comparatively to normal tissues, a significant induction of mdr1 expression was observed in untreated tumors (p = 0.0222). Similarly, a significant induction of mdr1 expression was revealed when treated samples were compared to untreated counterparts (p = 0.0222), but no differences were detected between tumor and normal samples (p = 0.3199). Noteworthy, a significant induction of mdr1 gene expression occurred in treated normal samples comparatively to untreated ones (p = 0.0037), and this induction was even more important in normal than in tumoral tissue (p = 0.0627). However, neither the basal expression nor the induction of mdr1 were correlated with subsequent response to chemotherapy or with survival. Thus, in agreement with previous reports, our data show that chemotherapy induce mdr1 gene expression in breast cancer cells, but they also indicate that a similar phenomenon occurs in adjacent normal tissues. Therefore, our results strongly suggest that mdr1 gene overexpression is not a characteristic of breast malignant cells, but rather constitutes a general phenomenon occurring both in normal and tumor cells which could explain at least in part the absence of relationship between mdr1 expression and the clinical outcome of breast cancer patients.

Ceramic tile manufacture requires a great quantity of energy, mainly in the form of heat. The heat is principally used in the kilns and dryers, and it is obtained by natural gas combustion. The increasing cost of natural gas, as well as the application of a new gas tax, the new legislation in regard to emissions trading, and the difficult current economic situation have driven the ceramic tile sector to implement energy-saving actions in the production process with the twofold aim of reducing energy costs and abating carbon dioxide emissions. One such course of action is the European project REDUCER, funded by the European Commission and led by Azulev S.A.U., in which the Instituto de Tecnología Cerámica (ITC) also participates. This project seeks to implement energy-saving actions in company kilns and dryers in order to lower natural gas consumption and reduce carbon dioxide emissions in the tile manufacturing process. One of the saving actions envisaged is the installation of a system of waste heat recovery from one of the company kilns to the tile body dryers. This new waste heat recovery system is to be added to and will complement the already existing system at the company, thus achieving maximum heat recovery from the kiln stacks. The recovered heat will go entirely to the green tile body dryers, thus reducing natural gas consumption in the dryers. The designed installation seeks to recover 600 kW heat from the stacks of one of the kilns, entailing a natural gas saving of more than 120 k€/year and suppressing the emission into the atmosphere of 720 tons of CO2/year, savings that are to be added to those attained with other energy-saving measures. This paper describes the energy-saving actions implemented at the company, as well as the resulting energy savings.

O processo de fabricação de placas cerâmicas consome uma grande quantidade de energia, maioritariamente energia térmica, que se obtém da combustão de gás natural. O aumento do custo deste combustível, assim como a situação económica do presente, faz com que este custo seja crítico para as empresas e pode minar a sua competitividade. O processo de cozedura das placas cerâmicas em fornos de rolos não se destaca precisamente pelo aproveitamento da energia utilizada, visto que aproximadamente 50% perdese através das chaminés de fumos e de arrefecimento do forno. Com o propósito de melhorar o aproveitamento da energia consumida durante a operação de cozedura instalaramse, nas chaminés de um forno, dois permutadores de calor, nos quais os gases provenientes do forno cedem o seu calor sensível a um óleo térmico, que posteriormente o transfere, através de outros dois permutadores, aos gases de secagem nas condutas de recirculação de um secador vertical. Neste trabalho apresenta-se uma instalação industrial experimental, na qual os resultados obtidos de economia energética se situam num valor médio de 650 kW, dependendo das condições de funcionamento e dos materiais processados.

The gadd153 gene belongs to the CCAAT/enhancer binding protein (C/EBP) family of transcription factors. The role of these proteins in the control of proliferation and differentiation have mostly been studied in vitro. The involvement of gadd153 gene expression in human disease, and most particularly in breast cancer, is largely unknown. Since gadd153 gene is normally expressed at very low levels in most cells, we developed a sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) technique that permits the detection of low amounts of RNA. In these conditions, 24 breast tumors and 14 corresponding normal samples were analysed, and levels of expression between tumor and normal tissues were compared. Statistical analysis indicated a significant induction of gadd153 gene expression in tumor samples in comparison to normal ones (p

FATE is a project funded by the European Union under the program CIP/ICT-PSP with the main objective of organizing a big pilot on the automatic falls detection in aging people living at home. Automatic detection of falls is done in indoors and outdoors conditions, and in both cases the detection generates an alarm sent to a call center. The detection system is designed around a sensor sub-system based on accelerometers and gyroscopes able to detect falls with a high reliability. The complete system is based on a communications layer based in ZigBee and Bluetooth protocols. The gateway for sending the alarm to the call center is a mobile phone. Pilots are organized in three different countries (Spain, Italy and Ireland) where different models of health service and implemented call centers are available. Pilots duration will be one year, involving 175 users and one of the main final objectives is to gain experience with the integration of an automatic fall detection service in an already care/health existing service.

The massive improvement in food production, as a result of effective genetic selection combined with advancements in farming practices, has been one of the greatest achievements of modern agriculture. For instance, the dairy cattle industry has more than doubled milk production over the past five decades, while the total number of cows has been reduced dramatically. This was achieved mainly through the intensification of production systems, direct genetic selection for milk yield and a limited number of related traits, and the use of modern technologies (e.g., artificial insemination and genomic selection). Despite the great betterment in production efficiency, strong drawbacks have occurred along the way. First, across-breed genetic diversity reduced dramatically, with the worldwide use of few common dairy breeds, as well as a substantial reduction in within-breed genetic diversity. Intensive selection for milk yield has also resulted in unfavorable genetic responses for traits related to fertility, health, longevity, and environmental sensitivity. Moving forward, the dairy industry needs to continue refining the current selection indexes and breeding goals to put greater emphasis on traits related to animal welfare, health, longevity, environmental efficiency (e.g., methane emission and feed efficiency), and overall resilience. This needs to be done through the definition of criteria (traits) that (a) represent well the biological mechanisms underlying the respective phenotypes, (b) are heritable, and (c) can be cost-effectively measured in a large number of animals and as early in life as possible. The long-term sustainability of the dairy cattle industry will also require diversification of production systems, with greater investments in the development of genetic resources that are resilient to perturbations occurring in specific farming systems with lesser control over the environment (e.g., organic, agroecological, and pasture-based, mountain-grazing farming systems). The conservation, genetic improvement, and use of local breeds should be integrated into the modern dairy cattle industry and greater care should be taken to avoid further genetic diversity losses in dairy cattle populations. In this review, we acknowledge the genetic progress achieved in high-yielding dairy cattle, closely related to dairy farm intensification, that reaches its limits. We discuss key points that need to be addressed toward the development of a robust and long-term sustainable dairy industry that maximize animal welfare (fundamental needs of individual animals and positive welfare) and productive efficiency, while also minimizing the environmental footprint, inputs required, and sensitivity to external factors.

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To characterize the biological features of advanced breast cancer associated with poor chemotherapy response and worse prognosis, sequential tumor samples obtained from 75 patients receiving primary chemotherapy were analysed for MDR1 and TS gene expression before and after treatment. MDR1 gene expression was also analysed in 36 sequential normal samples. The levels of MDR1 and TS genes expression were determined by reverse transcription-PCR method, and examined in relation to p53 gene status, and the clinical outcome of the patients. After treatment, MDR1 expression levels were significantly enhanced in tumor (p = 0.0033) and normal (p = 0.0098) samples, whereas a significant decrease in TS expression was observed (p = 0.0054). There was no significant correlation between MDR1 or TS expressions and the presence of p53 mutations (detected in 24% of the cases), chemoresponsiveness, or survival. Only p53 mutations were associated with reduced disease-free survival (p = 0.0473). These results demonstrate that MDR1 and TS gene expressions were affected by drug exposure, but not by p53 gene status. Furthermore, the increase of MDR1 gene expression in normal and tumor tissues is in favor of an induced MDR1 expression rather than of a selection of resistant tumoral clones, which can be responsible for the absence of relationship of MDR1 expression with clinical outcome of advanced breast cancer patients.