A robust genomic signature for the detection of colorectal cancer patients with microsatellite instability phenotype and high mutation frequency.

Microsatellite instability (MSI) occurs in 10-20% of colorectal tumours and is associated with good prognosis. Here we describe the development and validation of a genomic signature that identifies colorectal cancer patients with MSI caused by DNA mismatch repair deficiency with high accuracy. Microsatellite status for 276 stage II and III colorectal tumours has been determined. Full-genome expression data was used to identify genes that correlate with MSI status. A subset of these samples (n = 73) had sequencing data for 615 genes available. An MSI gene signature of 64 genes was developed and validated in two independent validation sets: the first consisting of frozen samples from 132 stage II patients; and the second consisting of FFPE samples from the PETACC-3 trial (n = 625). The 64-gene MSI signature identified MSI patients in the first validation set with a sensitivity of 90.3% and an overall accuracy of 84.8%, with an AUC of 0.942 (95% CI, 0.888-0.975). In the second validation, the signature also showed excellent performance, with a sensitivity 94.3% and an overall accuracy of 90.6%, with an AUC of 0.965 (95% CI, 0.943-0.988). Besides correct identification of MSI patients, the gene signature identified a group of MSI-like patients that were MSS by standard assessment but MSI by signature assessment. The MSI-signature could be linked to a deficient MMR phenotype, as both MSI and MSI-like patients showed a high mutation frequency (8.2% and 6.4% of 615 genes assayed, respectively) as compared to patients classified as MSS (1.6% mutation frequency). The MSI signature showed prognostic power in stage II patients (n = 215) with a hazard ratio of 0.252 (p = 0.0145). Patients with an MSI-like phenotype had also an improved survival when compared to MSS patients. The MSI signature was translated to a diagnostic microarray and technically and clinically validated in FFPE and frozen samples.

Discursos y representaciones médico-sanitarias en el cine documental colonial español de la posguerra (1939-1950)

El objetivo de este estudio es contribuir al entendimiento, desde un punto de vista histórico, del papel que juega el cine en los procesos de popularización de la ciencia, la medicina y la tecnología. El punto de partida es la consideración de la medicina y del cine como conjuntos complejos y multidimensionales de “prácticas y discursos” de carácter científico-tecnológico y, por tanto, como formas particulares de acción e interacción cotidiana entre personas, colectivos e instituciones que juegan un papel básico en los procesos de construcción y funcionamiento de las sociedades contemporáneas. Así, mediante el análisis de la representación y articulación de las prácticas y los discursos médico-sanitarios en el cine documental colonial español del primer franquismo, es decir, en el caso particular de la construcción, legitimación y consolidación de un régimen totalitario, se aportan algunas claves explicativas sobre las múltiples relaciones entre diferentes colectivos (expertos y no-expertos) en cuanto a la naturaleza y el nivel de intervención en los procesos de generación y gestión de conocimiento científico-tecnológico. Como resultado, el cine se revela como un espacio no sólo de evasión y entretenimiento, sino también de ciencia y educación, donde la capacidad de definir y solucionar problemas cotidianos de la población, y por tanto, su impacto en la construcción de la arquitectura social, ideológica, económica, política y cultural de las sociedades contemporáneas, se fundamenta en la combinación de sus aspectos como espectáculo narrativo y científico-tecnológico.

No experimental evidence that sibling competition induces young to switch nests in the colonial Alpine swift, Apus melba

Adoption is frequent in colonial animals where opportunities for dependent young to receive care from nonbiological parents are high. The departure of dependent young from their original family to seek adoption in neighbouring families is thought to be induced by sibling competition for access to limited resources provided by poor-quality parents. We tested this hypothesis in the colonial Alpine swift by manipulating the number of young reared per brood, with the prediction that offspring from enlarged broods switch nests more frequently than those from reduced broods. Although nestling swifts hatch with little locomotor activity, from 20 days until their first flight at 50-70 days they frequently move out of their nests to seek adoption in neighbouring families. Although nestlings reared in experimentally enlarged broods were lighter and their body mass at day 20 after hatching was more variable than in nestlings reared in reduced broods, there was no difference between the two treatments in the frequency of nests switching and in the age when nestlings switched nests for the first time. However, consistent with other evidence that nest switching by nestling swifts evolved as a strategy to reduce ectoparasite load, young from broods with naturally high numbers of the ectoparasitic louse fly Crataerina melbae were more prone to switch nests. This shows that ectoparasitism rather than sibling competition is a key proximate factor promoting the evolution of nest switching in the colonial Alpine swift. (c) 2006 The Association for the Study of Animal Behaviour Published by Elsevier Ltd. All rights reserved.

Genetic and environmental components of phenotypic variation in immune response and body size of a colonial bird, Delichon urbica (the house martin).

Directional selection for parasite resistance is often intense in highly social host species. Using a partial cross-fostering experiment we studied environmental and genetic variation in immune response and morphology in a highly colonial bird species, the house martin (Delichon urbica). We manipulated intensity of infestation of house martin nests by the haematophagous parasitic house martin bug Oeciacus hirundinis either by spraying nests with a weak pesticide or by inoculating them with 50 bugs. Parasitism significantly affected tarsus length, T cell response, immunoglobulin and leucocyte concentrations. We found evidence of strong environmental effects on nestling body mass, body condition, wing length and tarsus length, and evidence of significant additive genetic variance for wing length and haematocrit. We found significant environmental variance, but no significant additive genetic variance in immune response parameters such as T cell response to the antigenic phytohemagglutinin, immunoglobulins, and relative and absolute numbers of leucocytes. Environmental variances were generally greater than additive genetic variances, and the low heritabilities of phenotypic traits were mainly a consequence of large environmental variances and small additive genetic variances. Hence, highly social bird species such as the house martin, which are subject to intense selection by parasites, have a limited scope for immediate microevolutionary response to selection because of low heritabilities, but also a limited scope for long-term response to selection because evolvability as indicated by small additive genetic coefficients of variation is weak.

Including the workload effect in the parallel program signature

Performance prediction and application behavior modeling have been the subject of exten- sive research that aim to estimate applications performance with an acceptable precision. A novel approach to predict the performance of parallel applications is based in the con- cept of Parallel Application Signatures that consists in extract an application most relevant parts (phases) and the number of times they repeat (weights). Executing these phases in a target machine and multiplying its exeuction time by its weight an estimation of the application total execution time can be made. One of the problems is that the performance of an application depends on the program workload. Every type of workload affects differently how an application performs in a given system and so affects the signature execution time. Since the workloads used in most scientific parallel applications have dimensions and data ranges well known and the behavior of these applications are mostly deterministic, a model of how the programs workload affect its performance can be obtained. We create a new methodology to model how a program’s workload affect the parallel application signature. Using regression analysis we are able to generalize each phase time execution and weight function to predict an application performance in a target system for any type of workload within predefined range. We validate our methodology using a synthetic program, benchmarks applications and well known real scientific applications.

Detecting nanoscale vibrations as signature of life.

The existence of life in extreme conditions, in particular in extraterrestrial environments, is certainly one of the most intriguing scientific questions of our time. In this report, we demonstrate the use of an innovative nanoscale motion sensor in life-searching experiments in Earth-bound and interplanetary missions. This technique exploits the sensitivity of nanomechanical oscillators to transduce the small fluctuations that characterize living systems. The intensity of such movements is an indication of the viability of living specimens and conveys information related to their metabolic activity. Here, we show that the nanomotion detector can assess the viability of a vast range of biological specimens and that it could be the perfect complement to conventional chemical life-detection assays. Indeed, by combining chemical and dynamical measurements, we could achieve an unprecedented depth in the characterization of life in extreme and extraterrestrial environments.

The Quest for the Oracle Birds: Researching the Chinese Community in Colonial Mexico (1565-1700)

The Asian Diaspora in the Americas in the 16th and 17th has been neglected by scholars for a long time. This fact is baffling, not only for the great interest of this topic in of itself, but also because it could provide new knowledge of colonial Mexico, especially in terms of the interaction among the many groups that populated the colony. This early movement of people and ideas across the largest extension of water in the planet is characteristic of what has been called the ¿archaic globalization,¿ and thus research on these matters could contribute to the history of globalization.In this presentation, I seek to further elaborate on the themes outlined by Edward Slack in The Chinos in New Spain: A Corrective Lens for a Distorted Image, an article published in 2009 in the Journal of World History. Firstly, I would like to bring forth some evidence that indicates that Asian religious practices were present in Mexico in the 1600s. Furthermore, I will argue that the traces of these practices are still visible today, in the form of a popular fortune-telling tradition. Secondly, I intend to provide some information about the arrival, settlement and distribution of the Asian Diaspora. I will focus on their distribution within Mexico City. Thirdly, I will elaborate on their occupations, social status and daily life, as well as in the patterns in marriages and relations with other groups. And lastly, I will show how the guild of barbers served as an Asian immigrant reception network.

Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza.

INTRODUCTION Human host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1. METHODS We profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene. RESULTS Increased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1beta), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-gamma) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-alpha, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients. CONCLUSIONS While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness.

The molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights expansion of hematopoietic and prostate epithelial stem cell niches.

The reciprocal interaction between cancer cells and the tissue-specific stroma is critical for primary and metastatic tumor growth progression. Prostate cancer cells colonize preferentially bone (osteotropism), where they alter the physiological balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and elicit prevalently an osteoblastic response (osteoinduction). The molecular cues provided by osteoblasts for the survival and growth of bone metastatic prostate cancer cells are largely unknown. We exploited the sufficient divergence between human and mouse RNA sequences together with redefinition of highly species-specific gene arrays by computer-aided and experimental exclusion of cross-hybridizing oligonucleotide probes. This strategy allowed the dissection of the stroma (mouse) from the cancer cell (human) transcriptome in bone metastasis xenograft models of human osteoinductive prostate cancer cells (VCaP and C4-2B). As a result, we generated the osteoblastic bone metastasis-associated stroma transcriptome (OB-BMST). Subtraction of genes shared by inflammation, wound healing and desmoplastic responses, and by the tissue type-independent stroma responses to a variety of non-osteotropic and osteotropic primary cancers generated a curated gene signature ("Core" OB-BMST) putatively representing the bone marrow/bone-specific stroma response to prostate cancer-induced, osteoblastic bone metastasis. The expression pattern of three representative Core OB-BMST genes (PTN, EPHA3 and FSCN1) seems to confirm the bone specificity of this response. A robust induction of genes involved in osteogenesis and angiogenesis dominates both the OB-BMST and Core OB-BMST. This translates in an amplification of hematopoietic and, remarkably, prostate epithelial stem cell niche components that may function as a self-reinforcing bone metastatic niche providing a growth support specific for osteoinductive prostate cancer cells. The induction of this combinatorial stem cell niche is a novel mechanism that may also explain cancer cell osteotropism and local interference with hematopoiesis (myelophthisis). Accordingly, these stem cell niche components may represent innovative therapeutic targets and/or serum biomarkers in osteoblastic bone metastasis.