Tumour heterogeneity and immune-modulation.

Recent advances in sequencing technologies have revealed extensive intratumour heterogeneity (ITH) both within individual tumours and between primary and metastatic tumours for different cancer types. Such genetic diversity may have clinical implications for both cancer diagnosis and treatment with increasing evidence linking ITH and therapeutic resistance. Nonetheless, whilst limiting the activity of targeted agents, tumour genetic heterogeneity may provide a new therapeutic opportunity through generation of neo-antigens that could be recognised and targeted by the patient's own immune system in response to immune-modulatory therapies. Longitudinal genomic studies assessing tumour clonal architecture and its correlation with the underlying immune response to cancer in each particular patient are needed to follow tumour evolutionary dynamics over time and through therapy, in order to further understand the mechanisms behind drug resistance and to inform the development of new combinatorial therapeutic strategies

Haematological and pathological findings of pigs experimentally inoculated with a Chilean isolate of porcine reproductive and respiratory syndrome virus

The aims of this study were to characterize the haematological and bone marrow changes, gross and microscopic lesions of pigs experimentally inoculated with the Chilean isolate of porcine reproductive and respiratory syndrome virus. Twelve 3-week-old pigs were divided in 4 groups of 3, one of which corresponded to the negative control group sacrificed at 0 days post-inoculation (dpi), and the 3 remaining groups corresponded to the inoculated pigs sacrificed at 7, 14 and 21 dpi. For each sampling period blood was collected for complete haemograme and at the necropsy time gross lesions were registered and samples for both bone marrow smears and histopathology were taken. The results of this study revealed haematological alterations characterized by a significant reduction (P<0.05) in the haematocrit and a significant increase (P<0.05) in the total leukocyte count associated with an increase in the monocytes and baciliforms. The bone marrow did not show significant variations in the ratio of myeloid to erythroid cells (P>0.05). At the same time, the gross lesions were mild and mainly characterized by the presence of conjunctivitis, periocular edema and a slight increase in the size of the lymph nodes. Microscopic lesions were characterized by the presence of interstitial pneumonia, depletion and necrosis in lymphoid organs, rhinitis, hepatitis, myocarditis and non-purulent encephalitis. These findings suggest that the Chilean isolate of the vPRRS to a strain with a low virulenc

Seedling vigor variation among 80 recombinant chromosome substitution lines (RCSL) of barley (Hordeum vulgare)

del Pozo, A (del Pozo, Alejandro). Univ Talca, Fac Ciencias Agr, Talca, Chile.Seedling vigor of 80 recombinant chromosome substitution lines (RCSL) of barley (Hordeum vulgare). Cien. Inv. Agr. 38 (1): 137-147. The seedling vigor of 80 barley recombinant chromosome substitution lines (RCSLs) was measured for selecting high seedling vigor genotypes. The RCSLs were derived from a cross between H. vulgare subsp. spontaneum and H. vulgare subsp. vulgare 'Harrington'. The work was carried out under greenhouse conditions during the summer of 2008. The experimental design was an alpha lattice with 3 replicates. In each replicate, 40 plants were established, distributed in eight polyethylene pots containing sand as substrate, which were fertilized an irrigated. The emergence of seedlings, number of leaves and shoots, dry matter of leaves, shoots and roots and leaf area of fully expanded leaves were measured. In addition, growth indices were calculated: emergence rate, leaf appearance rate, relative leaf expansion rate, relative growth rate (RGR), net assimilation rate (NAR), leaf area ratio (LAR) and the allometric coefficient (K) between root and shoot thy matter. All calculated indices varied significantly among genotypes (P <= 0.05) and some RCSLs showed better early vigor associated traits than 'Harrington'. The dry matter accumulation 30 DAS (when the experiment ended) was significant and positively correlated with the RGR (r=0.61; P <= 0.05) and NAR (r=0.41; P <= 0.05). The K coefficient was negatively correlated with NAR (r=-0.40, P <= 0.05). The genotypes with the greatest seminal vigor were the RCSLs 45, 92, 112 and 'Harrington', whereas the RCSLs 5, 19,47 and 121 presented the lowest seminal vigor

Use of UAV for the generation of digital cartography

El ser humano en su afán de reconocer el lugar donde habita, históricamente ha intentado fotografiar desde más allá de donde sus ojos le permiten observar la superficie terrestre. La fotogrametría para esta tarea ha sido fundamental en la historia del hombre, siendo el pionero Gaspard-Félix Tournachon en el año 1859 desde un globo cautivo obtener la primera fotografía área de la superficie terrestre, Hoy en día hemos sido capaces de poder observar y plasmar en imágenes la tierra desde el espacio de grandes extensiones de del globo. Es así que por décadas ha teniendo mejoras ya sea en la óptica, la aeronáutica y también en los procesos de esta técnica de teledetección por diversos motivos como fueron las guerras mundiales a principios del siglo XX y también en la carrera espacial en épocas de polarización del mundo a mediados del mismo siglo. En los últimos años no ha estado exenta de esta evolución significativa. Hoy en día vivimos en un importante momento tecnológico de la historia de la humanidad donde día a día la tecnología cambia y crece exponencialmente y esto no deja atrás nuestro campo de desempeño en las ciencias de la tierra ni tampoco a la fotogrametría, sino más bien avanzan juntas. Hoy por hoy hemos logrado volar naves desde la tierra, sin ir a bordo de ellas. Estas aeronaves son denominadas como UAV (Unmanned Aerial Vehicle) o vehículo Aéreo No Tripulado (VANT), comúnmente «dron». Un VANT es un vehículo sin tripulación, capaz de mantener de manera autónoma un nivel de vuelo controlado, sostenido y propulsado por un motor de explosión, eléctrico o de reacción. A los cuales podemos montar una cámara o sensor, con esta a bordo, somos capaces de poder captar información de la superficie terrestre y con ello, la generación de ortoimagenes logrando así cartografía a escalas grandes de áreas pequeñas, en poco tiempo y abaratando costos de forma sustancial

Repetitive mild traumatic brain injury causes optic nerve and retinal damage in a mouse model

There is increasing evidence that long-lasting morphologic and functional consequences can be present in the human visual system after repetitive mild traumatic brain injury (r-mTBI). The exact lo- cation and extent of the damage in this condition are not well un- derstood. Using a recently developed mouse model of r-mTBI, we assessed the effects on the retina and optic nerve using histology and immunohistochemistry, electroretinography (ERG), and spectral- domain optical coherence tomography (SD-OCT) at 10 and 13 weeks after injury. Control mice received repetitive anesthesia alone (r-sham). We observed decreased optic nerve diameters and increased cellularity and areas of demyelination in optic nerves in r-mTBI versus r-sham mice. There were concomitant areas of decreased cellularity in the retinal ganglion cell layer and approximately 67% decrease in brain- specific homeobox/POU domain protein 3AYpositive retinal ganglion cells in retinal flat mounts. Furthermore, SD-OCT demonstrated a de- tectable thinning of the inner retina; ERG demonstrated a decrease in the amplitude of the photopic negative response without any change in a- or b-wave amplitude or timing. Thus, the ERG and SD-OCT data correlated well with changes detected by morphometric, histologic, and immunohistochemical methods, thereby supporting the use of these noninvasive methods in the assessment of visual function and morphology in clinical cases of mTBI

Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma

Background: Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer. Patients and methods: Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression. Results: In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024). Conclusions: The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted

Electrochemical oxidation of tamoxifen revisited

Tamoxifen is a selective estrogen receptor modulator that is used as an adjuvant and/or chemotherapeutic agent for the treatment of all stages of hormone-dependent breast cancer. Currently there is a deep interest in the study of tamoxifen biotransformation and identification of metabolites since they can significantly contribute to the overall pharmacological or adverse effects of the drug. Accordingly, the study of the electrochemical behavior of tamoxifen in aqueous solution is reported. To clarify the occurring oxidative process and to assess the influence of the functional groups on the oxidation mechanism, the voltammetric assessment was extended to the study of tamoxifen’s analogues (E)-tamoxifen and dihydrotamoxifen, and to its main phase I oxidative metabolite, N-desmethyl tamoxifen. The data found shows that the oxidative processes occurring in tamoxifen are essentially related with the two chemical moieties present in the molecule: the substituted aromatic nucleus and the tertiary amine group. Moreover, the results obtained suggest that the ethylenic linkage is not critical for tamoxifen’s oxidation although it could play an important role in the course of the oxidation process. These results could contribute to highlight some remaining questions regarding tamoxifen’s metabolic behavior and to the development of new analytical strategies, based on electrochemical approaches

Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis

Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122+CD49b+ cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122+CD49b+ cells remain confined to a NK1.1lowNKp46low stage, but differentiate into NK1.1+NKp46+ cells in the presence of γc-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state γc-signalling