Immune related endonucleases and GTPases are not associated with tumor response in patients with advanced non-small cell lung cancer treated with checkpoint inhibitors

Immune related endonucleases have recently been described as potential therapeutic targets and predictors of response to treatment with immune checkpoint inhibitors (ICI). The aim is to evaluate the association between the expression of 5 biomarkers involved in the immune response (CD73, CD39, VISTA, Arl4d and Cytohesin-3) in parallel with the more common ICI-predictive markers, PD-L1 expression and Tumor Mutation Burden (TMB) with response to ICI therapy in an advanced non-small cell lung cancer (NSCLC) cohort. METHODS: Patients with advanced NSCLC treated with ICI single agent were divided into responders and non-responders according to RECIST v1.1 and duration of response (DOR) criteria. Immunohistochemistry was performed on pretreatment tumor tissue samples for PD-L1, CD73, CD39, VISTA, Arl4d, and Cytohesin-3 expression. TMB was estimated with NEOplus v2 RUO (NEO New Oncology GmbH) hybrid capture next generation sequencing assay. Resistance mutations in STK11/KEAP1 and positive predictive mutations in ARID1A/POLE were also evaluated. RESULTS: Included were 56 patients who were treated with ICI single agent. The median progression-free and overall survival for the whole cohort was 3.0 (95% CI, 2.4-3.6) and 15 (95% CI, 9.7-20.2) months, respectively. The distribution of CD73 in tumor cells and CD39, VISTA, Arl4d and Cytohesin-3 expression in immune cells were not different between responders and non-responders. Also, PD-L1 and TMB were not predictive for response. The frequency of STK11, KEAP1 and ARID1A mutations was low and only observed in the non-responder group. CONCLUSION: Separate and combined expression of 5 biomarkers involved in the immune response (CD73, CD39, VISTA, Arl4d, and Cytohesin-3) was not associated with response in our cohort of advanced NSCLC patients receiving single agent ICI. To confirm our findings the analysis of independent larger cohorts is warranted

Spatial surface-pattern analyses and boundary detection techniques applied in forest ecology

[EN] We review methods for uni- and multivariate surface pattern analysis and boundary detection used in forest ecology. A continuous surface pattern is defined as the locations of points (trees) in the space and the associated variable or variables. We illustrate useful methods to describe spatial patterns and infer the generating processes. We show the statistical basis and applied examples of univariate methods for binary (join counts) and quantitative variables (Moran and Geary correlograms, semivariograms, fractal dimension). We explain the calculus and interpretation of multivariate methods to describe surface patterns (Mantel test and correlogram) and their relationships with ordination methods. Finally, we show examples of techniques for boundary detection. Most analysed patterns corresponded to Pinus uncinata forests from the upper altitudinal limit in the Pyrenees or from a relict population. We discuss the advantages and disadvantages of each methodology and their applications in forest ecology.[ES] En este trabajo se revisan los métodos de análisis univariable y multivariable de los patrones de superficies y de detección de fronteras más utilizados en ecología forestal. El patrón de superficies es un patrón espacial continuo definido por las posiciones de los puntos (árboles) en el espacio y una o varias variables asociadas a cada punto. Se ilustran métodos útiles para describir patrones espaciales e inferir los procesos que los generaron. Se muestra el fundamento estadístico y ejemplos aplicados de métodos de análisis univariables para variables binarias (conteo contiguo) y cuantitativas (correlogramas de Moran y Geary, semivariogramas, dimensión fractal). Se detalla el cálculo e interpretación de métodos multivariables para la descripción de patrones de superficies (correlograma y test de Mantel) y su relación con los métodos de ordenación. Finalmente, se muestran ejemplos de métodos para la detección de fronteras. La mayor parte de los patrones reales analizados provienen de bosques de Pinus uncinata del límite altitudinal superior en los Pirineos o bien de una población relíctica. Se discuten las ventajas y desventajas de cada metodología y sus aplicaciones en ecología forestal.Los datos de Vinuesa se obtuvieron en el proyecto AMB95-0160 (CICyT).Peer reviewe

A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies

Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20-25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine β-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of >75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17-92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies

Система управления персоналом в Управлении железнодорожного транспорта Алмалыкского Горно-Металлургического комбината

Целью выпускной квалификационной работы является разработка направлений по совершенствованию системы управления персоналом в управлении железнодорожного транспорта АО "АГМК". В результате исследования были разработаны мероприятия по повышению уровня управления персоналом в управлении железнодорожного транспорта АО "АГМК" Степень внедрения: одно из разработанных предложений планируется на внедрение в управлении персоналом железнодорожного транспорта АО "АГМК". Область применения: разработанные мероприятия по управлению персоналом предприятия, может быть использован на предприятии, в организации, фирме любой отрасли.Научная новизна работы заключается в обосновании необходимости формирования новой концепции управления персоналом на предприятии, в обобщении основных методов управления персонThe goal of the final qualifying work is to develop directions for improving the personnel management system in the management of the railway transport of JSC "AGMK". As a result of the research, measures were developed to improve the level of personnel management in the management of the railway transport of JSC "AGMK" Degree of implementation: one of the developed proposals is planned for implementation in the management of railway transport personnel of JSC "AGMK". Scope: developed measures for the management of the company's personnel, can be used at the enterprise, in the organization, the firm of any industry. The scientific novelty of the work is to justify the need to formulate a new concept of personnel management at the enterprise, to generalize the basic methods of personnel ma

Business performance and angels presence: A fresh look from France 2008–2011

Business angels enjoy a strong reputation for being more efficient than other investors among policy makers, practitioners, and scholars. However, due to the limited availability of specific financial data, previous research has barely assessed the impact of angels on companies’ performance. This paper seeks to bridge this gap by providing evidence from a unique dataset made up of 432 angel-backed French companies which are compared to two control groups, one randomly selected and another one consisting of similar enterprises. This double comparison process enables us to purge our analysis of structural effect and to demonstrate the importance of the methodology in generating the sample. Indeed, the results we obtain significantly differ depending on the control group. Our results show that the positive influence of angels depends on the condition of the comparison. The set of BA-backed companies is more likely to exhibit superior performance when it is compared to a random sample whereas the companies’ performance is either identical or worse when it is compared to a sample composed of k-nearest neighbors. In addition, using a quantile regression technique makes it possible to differentiate the effect of business angels based on the distribution of the value of the growth rate. © 2017, Springer Science+Business Media New York