Natural Killer Cell-like signature observed in locally advanced rectal cancer after neoadjuvant chemoradiotherapy in a tumour regression grade dependent manner

Background: Around 10-15% of patients with locally advanced rectal cancer (LARC) undergo a pathologically complete response (TRG4) to neoadjuvant chemoradiotherapy; the rest of patients exhibit a spectrum of tumour regression (TRG1-3). Understanding therapy-related genomic alterations may help us to identify underlying biology or novel targets associated with response that could increase the efficacy of therapy in patients that do not benefit from the current standard of care.
Methods: 48 FFPE rectal cancer biopsies and matched resections were analysed using the WG-DASL HumanHT-12_v4 Beadchip array on the illumina iScan. Bioinformatic analysis was conducted in Partek genomics suite and R studio. Limma and glmnet packages were used to identify genes differentially expressed between tumour regression grades. Validation of microarray results will be carried out using IHC, RNAscope and RT-PCR.
Results: Immune response genes were observed from supervised analysis of the biopsies which may have predictive value. Differential gene expression from the resections as well as pre and post therapy analysis revealed induction of genes in a tumour regression dependent manner. Pathway mapping and Gene Ontology analysis of these genes suggested antigen processing and natural killer mediated cytotoxicity respectively. The natural killer-like gene signature was switched off in non-responders and on in the responders. IHC has confirmed the presence of Natural killer cells through CD56+ staining.
Conclusion: Identification of NK cell genes and CD56+ cells in patients responding to neoadjuvant chemoradiotherapy warrants further investigation into their association with tumour regression grade in LARC. NK cells are known to lyse malignant cells and determining whether their presence is a cause or consequence of response is crucial. Interrogation of the cytokines upregulated in our NK-like signature will help guide future in vitro models.

Electron-impact excitation of Xe 26+ and its resultant spectral signature

We have carried out a 129 close-coupling level Dirac-Coulomb R-matrix calculation for the electron-impact excitation of Ni-like Xe. We have utilized this data to generate the spectral signature of Xe26+ in terms of feature photon-emissivity coefficients (F-PεCs). We have compared these F-PεCs with those generated using semi-relativistic plane-wave Born excitation data, which forms the heavy species baseline for the Atomic Data and Analysis Structure (ADAS), We find that the Born-based F-PεCs give a reasonable qualitative description of the spectral signature but that, quantitatively, the R-matrix-based F-PεCs differ by up to a factor of 2. The spectral signature of heavy species is key to diagnosing hot plasmas such as will be found in the International Thermonuclear Experimental Reactor.

A gene-signature progression approach to identifying candidate small-molecule cancer therapeutics with connectivity mapping

Gene expression connectivity mapping has gained much popularity recently with a number of successful applications in biomedical research testifying its utility and promise. Previously methodological research in connectivity mapping mainly focused on two of the key components in the framework, namely, the reference gene expression profiles and the connectivity mapping algorithms. The other key component in this framework, the query gene signature, has been left to users to construct without much consensus on how this should be done, albeit it has been an issue most relevant to end users. As a key input to the connectivity mapping process, gene signature is crucially important in returning biologically meaningful and relevant results. This paper intends to formulate a standardized procedure for constructing high quality gene signatures from a user’s perspective.

Estrategias pedagógicas basadas en el diseño universal para el aprendizaje: una aproximación desde la comunicación educativa

Libro que presenta estrategias pedagógicas para la educación inclusiva en las diferentes etapas educativas como preescolar, básica, media y universitaria.

Observatorio de la accesibilidad universal en la vivienda en España 2013

Estudio elaborado por Fundación ONCE y Vía Libre y cuenta con la colaboración del Comité Español de Representantes de Personas con Discapacidad (CERMI). El objetivo del Observatorio es analizar la accesibilidad del parque de viviendas familiares de uso principal en España, determinar posibles variables que están influyendo en la accesibilidad, proponer recomendaciones orientadas a la mejora y realizar mediciones posteriores para conocer la evolución en este ámbito. Para ello, la investigación se ha abordado desde una metodología cuantitativa, desarrollada a través de encuesta telefónica, que se ha completado con una fase cualitativa previa y una evaluación técnica de la accesibilidad “in situ” de una muestra de vivienda.

La accesibilidad y el diseño universal entendido por todos. De cómo Stephen Hawking viajó por el espacio

La publicación ‘La accesibilidad y el diseño universal entendido por todos. De cómo Stephen Hawking viajó por el espacio’ es un libro al alcance de todos los públicos para acercarse a la accesibilidad universal, al diseño para todos y a la importancia de la igualdad de oportunidades para todas las personas. Sin duda, el autor se esfuerza con este libro en recopilar y sintetizar gran parte del conocimiento que había disperso en la materia, para condensarlo en una obra amena y apta para cualquier persona, independientemente si es profesional de la accesibilidad o está relacionada con el mundo de la discapacidad.

Reflections of universal algebras into semilattices, their Galois theories, and related factorization systems

Estabelecemos uma condição suficiente para a preservação dos produtos finitos, pelo reflector de uma variedade de álgebras universais numa subvariedade, que é, também, condição necessária se a subvariedade for idempotente. Esta condição é estabelecida, seguidamente, num contexto mais geral e caracteriza reflexões para as quais a propriedade de ser semi-exacta à esquerda e a propriedade, mais forte, de ter unidades estáveis, coincidem. Prova-se que reflexões simples e semi-exactas à esquerda coincidem, no contexto das variedades de álgebras universais e caracterizam-se as classes do sistema de factorização derivado da reflexão. Estabelecem-se resultados que ajudam a caracterizar morfismos de cobertura e verticais-estáveis em álgebras universais e no contexto mais geral já referido. Caracterizam-se as classes de morfismos separáveis, puramente inseparáveis e normais. O estudo dos morfismos de descida de Galois conduz a condições suficientes para que o seu par kernel seja preservado pelo reflector.

Metabolic signature of lung cancer: a metabolomic study of human tissues and biofluids

This thesis reports the application of metabolomics to human tissues and biofluids (blood plasma and urine) to unveil the metabolic signature of primary lung cancer. In Chapter 1, a brief introduction on lung cancer epidemiology and pathogenesis, together with a review of the main metabolic dysregulations known to be associated with cancer, is presented. The metabolomics approach is also described, addressing the analytical and statistical methods employed, as well as the current state of the art on its application to clinical lung cancer studies. Chapter 2 provides the experimental details of this work, in regard to the subjects enrolled, sample collection and analysis, and data processing. In Chapter 3, the metabolic characterization of intact lung tissues (from 56 patients) by proton High Resolution Magic Angle Spinning (HRMAS) Nuclear Magnetic Resonance (NMR) spectroscopy is described. After careful assessment of acquisition conditions and thorough spectral assignment (over 50 metabolites identified), the metabolic profiles of tumour and adjacent control tissues were compared through multivariate analysis. The two tissue classes could be discriminated with 97% accuracy, with 13 metabolites significantly accounting for this discrimination: glucose and acetate (depleted in tumours), together with lactate, alanine, glutamate, GSH, taurine, creatine, phosphocholine, glycerophosphocholine, phosphoethanolamine, uracil nucleotides and peptides (increased in tumours). Some of these variations corroborated typical features of cancer metabolism (e.g., upregulated glycolysis and glutaminolysis), while others suggested less known pathways (e.g., antioxidant protection, protein degradation) to play important roles. Another major and novel finding described in this chapter was the dependence of this metabolic signature on tumour histological subtype. While main alterations in adenocarcinomas (AdC) related to phospholipid and protein metabolisms, squamous cell carcinomas (SqCC) were found to have stronger glycolytic and glutaminolytic profiles, making it possible to build a valid classification model to discriminate these two subtypes. Chapter 4 reports the NMR metabolomic study of blood plasma from over 100 patients and near 100 healthy controls, the multivariate model built having afforded a classification rate of 87%. The two groups were found to differ significantly in the levels of lactate, pyruvate, acetoacetate, LDL+VLDL lipoproteins and glycoproteins (increased in patients), together with glutamine, histidine, valine, methanol, HDL lipoproteins and two unassigned compounds (decreased in patients). Interestingly, these variations were detected from initial disease stages and the magnitude of some of them depended on the histological type, although not allowing AdC vs. SqCC discrimination. Moreover, it is shown in this chapter that age mismatch between control and cancer groups could not be ruled out as a possible confounding factor, and exploratory external validation afforded a classification rate of 85%. The NMR profiling of urine from lung cancer patients and healthy controls is presented in Chapter 5. Compared to plasma, the classification model built with urinary profiles resulted in a superior classification rate (97%). After careful assessment of possible bias from gender, age and smoking habits, a set of 19 metabolites was proposed to be cancer-related (out of which 3 were unknowns and 6 were partially identified as N-acetylated metabolites). As for plasma, these variations were detected regardless of disease stage and showed some dependency on histological subtype, the AdC vs. SqCC model built showing modest predictive power. In addition, preliminary external validation of the urine-based classification model afforded 100% sensitivity and 90% specificity, which are exciting results in terms of potential for future clinical application. Chapter 6 describes the analysis of urine from a subset of patients by a different profiling technique, namely, Ultra-Performance Liquid Chromatography coupled to Mass Spectrometry (UPLC-MS). Although the identification of discriminant metabolites was very limited, multivariate models showed high classification rate and predictive power, thus reinforcing the value of urine in the context of lung cancer diagnosis. Finally, the main conclusions of this thesis are presented in Chapter 7, highlighting the potential of integrated metabolomics of tissues and biofluids to improve current understanding of lung cancer altered metabolism and to reveal new marker profiles with diagnostic value.

What is universal and what differs in language development?

Goldin-Meadow (2015) presents an exceptional synthesis of work from studies of children acquiring language under variable circumstances of input or processing abilities. Deaf children who acquire homesign without any well- formed model from which to learn language represent a powerful example. Goldin-Meadow argues that the resilient properties of language that nevertheless emerge include simple syntactic structures, hierarchical organisa- tion, markers modulating the meaning of sentences, and social-communicative functions. Among the fragile or input-dependent properties are the orders that the language follows, the parts into which words are decomposed, and the features that distinguish nominals from predicates. Separation of these two types of properties poses questions concerning the innate constraints on language acquisition (perhaps these equate to the resilient properties) and con‐ cerning the specificity of processes to language (e.g., whether properties such as hierarchical organisation are specific to language or originate in the structure of thought). The study of the resilient properties of human language in the face of adversity and the relation of these properties to the information that is encoded in the human genome represent a research strategy that draws inferences about species universals (properties that all humans share) from data about individual differences (IDs; factors that make humans different from one another). In the following, we suggest three reasons to be cautious about this approach.

Success or failure in knowledge management systems: a universal issue

This paper takes a sociotechnical viewpoint of knowledge management system (KMS) implementation in organizations considering issues such as stakeholder disenfranchisement, lack of communication, and the low involvement of key personnel in system design asking whether KMS designers could learn from applying sociotechnical principles to their systems. The paper discusses design elements drawn from the sociotechnical principles essential for the success of IS and makes recommendations to increase the success of KMS in organizations. It also provides guidelines derived from Clegg’s Principles (2000) for KMS designers to enhance their designs. Our data comes from the application of a plurality of analysis methods on a large comprehensive global survey conducted from 2007 to 2011 of 1034 participants from 76 countries. The survey covers a variety of organizations of all types and sizes from a comprehensive selection of economic sectors and industries. Our results showed that users were not satisfied with the information and knowledge systems that they were being offered. In addition to multiple technology and usability issues, there were human and organisational barriers that prevented the systems from being used to their full potential. We recommend that users of KMS are integrated into the design team so that these usability and other barriers can be addressed during the feasibility stage as well as the actual design and implementation phases.

Banca de cozinha: projeto de design universal

Mais do que uma dissertação sobre o envelhecimento da população e o impacto que ela tem na sociedade, a presente tese visa documentar todo o processo projetual desenvolvido para a criação de uma banca de cozinha. Para tal foram tidas em conta, não apenas o tipo de tarefas desenvolvidas nesta zona da habitação como também os índices de fragilidade e de debilidade que os utilizadores mais envelhecidos apresentam. O facto da população envelhecida estar cada vez mais a aumentar, atingindo em alguns países valores preocupantes, associados ao facto de esses mesmos idosos atingirem cada vez mais idades mais avançadas, faz com que haja um aumento do número de pessoas incapacitadas. Assim sendo, o principal objectivo será o desenvolvimento de um projeto assente nas premissas defendidas pelo design universal. Tal projeto tentará encontrar as respostas que melhor respondam às necessidades e problemáticas, não apenas dos utilizadores mais idosos, mas do resto da população, independentemente da sua idade, estatura e condição física.

A novel gene expression signature in peripheral blood mononuclear cells for early detection of colorectal cancer.

BACKGROUND: Early detection and treatment of colorectal adenomatous polyps (AP) and colorectal cancer (CRC) is associated with decreased mortality for CRC. However, accurate, non-invasive and compliant tests to screen for AP and early stages of CRC are not yet available. A blood-based screening test is highly attractive due to limited invasiveness and high acceptance rate among patients. AIM: To demonstrate whether gene expression signatures in the peripheral blood mononuclear cells (PBMC) were able to detect the presence of AP and early stages CRC. METHODS: A total of 85 PBMC samples derived from colonoscopy-verified subjects without lesion (controls) (n = 41), with AP (n = 21) or with CRC (n = 23) were used as training sets. A 42-gene panel for CRC and AP discrimination, including genes identified by Digital Gene Expression-tag profiling of PBMC, and genes previously characterised and reported in the literature, was validated on the training set by qPCR. Logistic regression analysis followed by bootstrap validation determined CRC- and AP-specific classifiers, which discriminate patients with CRC and AP from controls. RESULTS: The CRC and AP classifiers were able to detect CRC with a sensitivity of 78% and AP with a sensitivity of 46% respectively. Both classifiers had a specificity of 92% with very low false-positive detection when applied on subjects with inflammatory bowel disease (n = 23) or tumours other than CRC (n = 14). CONCLUSION: This pilot study demonstrates the potential of developing a minimally invasive, accurate test to screen patients at average risk for colorectal cancer, based on gene expression analysis of peripheral blood mononuclear cells obtained from a simple blood sample.

An atlas of human gene expression from massively parallel signature sequencing (MPSS).

We have used massively parallel signature sequencing (MPSS) to sample the transcriptomes of 32 normal human tissues to an unprecedented depth, thus documenting the patterns of expression of almost 20,000 genes with high sensitivity and specificity. The data confirm the widely held belief that differences in gene expression between cell and tissue types are largely determined by transcripts derived from a limited number of tissue-specific genes, rather than by combinations of more promiscuously expressed genes. Expression of a little more than half of all known human genes seems to account for both the common requirements and the specific functions of the tissues sampled. A classification of tissues based on patterns of gene expression largely reproduces classifications based on anatomical and biochemical properties. The unbiased sampling of the human transcriptome achieved by MPSS supports the idea that most human genes have been mapped, if not functionally characterized. This data set should prove useful for the identification of tissue-specific genes, for the study of global changes induced by pathological conditions, and for the definition of a minimal set of genes necessary for basic cell maintenance. The data are available on the Web at http://mpss.licr.org and http://sgb.lynxgen.com.

Characterization of a genomic signature of pregnancy identified in the breast.

The objective of this study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts, scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression, and significance analysis of microarrays were used to identify statistically significant differences in expression of genes. The false discovery rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at an FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell-cycle control, adhesion, and differentiation. The results provide initial evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer.