Transcriptomic response of female adult moths to host and non-host plants in two closely related species.

BACKGROUND: Divergent selection has been shown to promote speciation in many taxa and especially in phytophagous insects. In the Ostrinia species complex, the European corn borer (ECB) and adzuki bean borer (ABB) are two sibling species specialized to different host plants. The first is a well-known maize pest, whereas the second is a polyphagous species associated with various dicotyledons. Their specialization to host plants is driven by morphological, behavioral and physiological adaptations. In particular, previous studies have shown that ECB and ABB display marked behavior with regard to plant choice during oviposition, involving specific preference and avoidance mechanisms. In this study, our goal was to identify the mechanisms underlying this host-plant specialization in adult females through an analysis of their gene expression. We assembled and annotated a de novo reference transcriptome and measured differences in gene expression between ECB and ABB females, and between environments. We related differentially expressed genes to host preference behavior, and highlighted the functional categories involved. We also conducted a specific analysis of chemosensory genes, which are considered to be good candidates for host recognition before oviposition. RESULTS: We recorded more differentially expressed genes in ECB than in ABB samples, and noticed that the majority of genes potentially involved in the host preference were different between the two species. At the functional level, the response to plant environment in adult females involved many processes, including the metabolism of carbohydrates, lipids, proteins, and amino acids; detoxification mechanisms and immunity; and the chemosensory repertoire (as expected). Until now, most of the olfactory receptors described in Ostrinia spp. had been tested for their putative role in pheromone recognition by males. Here we observed that one specific olfactory receptor was clearly associated with ECB's discrimination between maize and mugwort conditions, highlighting a potential new candidate involved in plant odor discrimination in adult females. CONCLUSIONS: Our results are a first step toward the identification of candidate genes and functions involved in chemosensory processes, carbohydrate metabolism, and virus and retrovirus dynamics. These candidates provide new avenues for research into understanding the role of divergent selection between different environments in species diversification.

Larval transcriptomic response to host plants in two related phytophagous lepidopteran species: implications for host specialization and species divergence.

BACKGROUND: Most phytophagous insects have morphological, behavioral and physiological adaptations allowing them to specialize on one or a few plant species. Identifying the mechanisms involved in host plant specialization is crucial to understand the role of divergent selection between different environments in species diversification, and to identify sustainable targets for the management of insect pest species. In the present study, we measured larval phenotypic and transcriptomic responses to host plants in two related phytophagous lepidopteran species: the European corn borer (ECB), a worldwide pest of maize, and the adzuki bean borer (ABB), which feeds of various dicotyledons. Our aim was to identify the genes and functions underlying host specialization and/or divergence between ECB and ABB. RESULTS: At the phenotypic level, we observed contrasted patterns of survival, weight gain and developmental time between ECB and ABB, and within ECB and ABB reared on two different host plants. At the transcriptomic level, around 8% of the genes were differentially expressed (DE) between species and/or host plant. 70% of these DE genes displayed a divergent pattern of expression between ECB and ABB, regardless of the host, while the remaining 30% were involved in the plastic response between hosts. We further categorized plastic DE genes according to their parallel or opposite pattern between ECB and ABB to specifically identify candidate genes involved in the species divergence by host specialization. These candidates highlighted a comprehensive response, involving functions related to plant recognition, digestion, detoxification, immunity and development. Last, we detected viral, bacterial, and yeast genes whose incidence contrasted ECB and ABB samples, and maize and mugwort conditions. We suggest that these microorganism communities might influence the survival, metabolism and defense patterns observed in ECB and ABB larvae. CONCLUSIONS: The comprehensive approach developed in the present study allowed to identify phenotypic specialization patterns and underlying candidate molecular mechanisms, and highlighted the putative role of microorganisms in the insect-host plant interaction. These findings offer the opportunity to pinpoint specific and sustainable molecular or physiological targets for the regulation of ECB pest populations.

Host specialization involving attraction, avoidance and performance, in two phytophagous moth species.

Host specialization plays a key role in the extreme diversification of phytophagous insects. Whereas proximate mechanisms of specialization have been studied extensively, their consequences for species divergence remain unclear. Preference for, and performance on hosts are thought to be a major source of divergence in phytophagous insects. We assessed these major components of specialization in two moth species, the European corn borer (ECB) and the Adzuki bean borer (ABB), by testing their oviposition behaviour in different conditions (choice or no-choice set-ups) and their performances, by reciprocal transplant at the larval stage on the usual host and an alternative host plant. We demonstrated that both ABB and ECB have a strong preference for their host plants for oviposition, but that relative larval performances on the usual host and an alternative host differed according to the experiment and the trait considered (weight or survival). Finally, we show for the first time that the preference for maize in ECB conceals a strong avoidance of mugwort. The differences in performance, attraction and avoidance between ECB and ABB are discussed in the light of the underlying mechanisms and divergence process.

Serum protein profiling reveals baseline and pharmacodynamic biomarker signatures associated with clinical outcome in mCRC patients treated with chemotherapy ± cediranib.

BACKGROUND: This study evaluated soluble serum proteins as biomarkers to subset patients with metastatic colorectal cancer (mCRC) treated with chemotherapy±cediranib, a vascular endothelial growth factor (VEGF) signalling inhibitor (VEGFi). Exploring biomarkers at pre- and on-treatment may identify patient subgroups showing clinical benefit on cediranib combination. METHODS: Two hundred and seven serum proteins were analysed in 588 mCRC patients at pre- and on-treatment with chemotherapy (FOLFOX/CAPOX)±cediranib 20 mg. Patients were enrolled in the phase III trial HORIZON II. We correlated baseline biomarker signatures and pharmacodynamic (PD) biomarkers with PFS and OS. RESULTS: We identified a baseline signature (BS) of 47 biomarkers that included VEGFA, VEGFD, VEGFR2, VEGFR3 and TIE-2, which defined two distinct subgroups of patients. Patients treated with chemotherapy plus cediranib who had 'high' BS had shorter PFS (HR=1.82, P=0.003) than patients with 'low' BS. This BS did not correlate with PFS of the patients treated with chemotherapy plus placebo. In addition, we identified a profile of 16 PD proteins on treatment associated with PFS (HR=0.58, P<0.001) and OS (HR=0.52, P<0.001) in patients treated with chemotherapy plus cediranib. This PD profile did not correlate with PFS and OS in patients treated with chemotherapy plus placebo. CONCLUSIONS: Serum proteins may represent relevant biomarkers to predict the outcome of patients treated with VEGFi-based therapies. We report a BS and PD biomarkers that may identify mCRC patients showing increased benefit of combining cediranib with chemotherapy. These exploratory findings need to be validated in future prospective studies.

Prognostic/predictive value of 207 serum factors in colorectal cancer treated with cediranib and/or chemotherapy.

BACKGROUND: The prognostic and predictive value of multiple serum biomarkers was evaluated using samples from a randomised phase III study (HORIZON II) investigating chemotherapy with or without cediranib in metastatic colorectal cancer (mCRC). METHODS: Baseline levels of 207 protein markers were measured in serum samples from 582 HORIZON II (FOLFOX/XELOX plus cediranib 20 mg (n=330) or placebo (n=252)) patients. Median baseline values of each biomarker were used to categorise patients as high or low. Markers were then assessed for their association with efficacy, defined by progression-free survival (PFS) and overall survival (OS). A generalised boosted regression model identified markers of particular interest. RESULTS: Correlation of protein levels with PFS and OS suggested that multiple factors had a prognostic value, independent of treatment arm, including IL-6, IL-8, C-reactive protein (CRP), ICAM-1 and carcinoembryonic antigen (CEA). Among the angiogenesis regulators, low levels of vascular endothelial growth factor (VEGF), VEGF-D, VEGFR-1, VEGFR-3, NRP1 and Tie-2 correlated with better outcome. CONCLUSION: This large data set generated using serum samples from mCRC patients treated with chemotherapy and VEGF inhibitors, defines baseline characteristics for 207 serum proteins. Multiple prognostic factors were identified that could be disease related or predict which patients derive most benefit from 5-fluorouracil (5-FU)-based chemotherapy, meriting further exploration in prospective studies.

Exploitation of the chick embryo chorioallantoic membrane (CAM) as a platform for anti-metastatic drug testing.

The establishment of clinically relevant models for tumor metastasis and drug testing is a major challenge in cancer research. Here we report a physiologically relevant assay enabling quantitative analysis of metastatic capacity of tumor cells following implantation into the chorioallantoic membrane (CAM). Engraftment of as few as 103 non-small cell lung cancer (NSCLC) and prostate cancer (PCa) cell lines was sufficient for both primary tumor and metastasis formation. Standard 2D-imaging as well as 3D optical tomography imaging were used for the detection of fluorescent metastatic foci in the chick embryo. H2228- and H1975-initiated metastases were confirmed by genomic analysis. We quantified the inhibitory effect of docetaxel on LNCaP, and that of cisplatin on A549- and H1299-initiated metastatic growths. The CAM assay also mimicked the sensitivity of ALK-rearranged H2228 and EGFR-mutated H1975 NSCLC cells to tyrosine kinase inhibitors crizotinib and gefitinib respectively, as well as sensitivity of LNCaP cells to androgen-dependent enzalutamide therapy. The assay was suggested to reconstitute the bone metastatic tropism of PCa cells. We show that the CAM chick embryo model may be a powerful preclinical platform for testing and targeting of the metastatic capacity of cancer cells.

Functional characterization and phenotypic spectrum of three recurrent disease-causing deep intronic variants of the CFTR gene.

BACKGROUND: The CFTR genotype remains incomplete in 1% of Cystic Fibrosis (CF) cases, because only one or no disease-causing variants is detected after extended analysis. This fraction is probably higher in CFTR-Related Disorders (CFTR-RD). Deep-intronic CFTR variants are putative candidates to fill this gap. However, the recurrence, phenotypic spectrum and full molecular characterization of newly reported variants are unknown. METHODS: Minigenes and analysis of CFTR transcripts in nasal epithelial cells were used to determine the impact on CFTR splicing of intronic variants that we previously identified by next generation sequencing of the whole CFTR locus. Phenotypic data were collected in 19 patients with CF and CFTR-RD, in whom one of the deep intronic variants has been detected. RESULTS: Three deep-intronic variants promoted the inclusion of pseudo-exons (PE) in the CFTR transcript, hindering the synthesis of a functional protein. The c.2989-313A > T variant, detected in four patients with CF or CFTR-RD from three different families, led to the inclusion of a 118 bp PE. The c.3469-1304C > G variant promoted the inclusion of a 214 bp-PE and was identified in five patients with CF from four families. Haplotype analysis confirmed that this variant was associated with one CF chromosome of African origin. The most represented variant in our cohort was the c.3874-4522A > G, detected in 10 patients with various phenotypes, from male infertility to CF with pancreatic insufficiency. CONCLUSION: These three deep intronic CFTR variants are associated with a large phenotypic spectrum, including typical CF. They should be included in CF diagnostic testing and carrier screening strategies.

[Sports and blood pressure: association in a population of wage-earners]. / Sport et tension artérielle: association dans une population de salariés.

In a cross-sectional epidemiological survey, we examined the association between the practice of sports and blood pressure (BP). The study included 3,388 male employees (representing 90.1% of the target population) who were questioned about their habitual sports activity, in terms of average duration per week and intensity. The proportion of subjects who stated to engage in sports activity decreased with age, from 50.9% in the age class 20-29 years to 16.4% in the age class 50-59 years. We found a negative relationship between both systolic and diastolic BP and the weekly duration of sports activity. However this association increased with age and reached the statistical significance only in the age classes 40-49 years and 50-59 years (p less than 0.01 and p less than 0.001, respectively). Similar results were obtained when intensity of sports was used instead of duration. In order to test the independence of the observed association, the duration of sports activity (hours/week) was included as an independent variable in a multiple linear regression analysis, along with the following potential confounders: age, Quetelet index, alcohol consumption, cigarette smoking, heart rate, and level of education. In this analysis the sports-BP relationship was considerably attenuated or entirely disappeared. It remained statistically significant only in the age class 50-59 (p less than 0.01 for systolic BP an p less than 0.05 for diastolic BP). Our results support those of others showing a modest beneficial effect of leisure time physical exercise on BP.(ABSTRACT TRUNCATED AT 250 WORDS)

[Are there risk factors for pure systolic hypertension?]. / Existe-t-il des facteurs de risque de l'hypertension systolique pure?

Pure systolic hypertension (PSH) is mainly observed in subjects over 60 years of age, and it is always due to a loss of compliance of the greater arteries. Blood pressure itself is partly responsible for loss of compliance, but other factors have been suggested. We have investigated this matter in a study of 3,388 subjects aged from 20 to 69 years. In a first stage, PSH patients (systolic BP greater than or equal to 160; diastolic BP less than 95 mmHg), aged from 50 to 59 years, were compared with normotensive subjects (systolic BP less than 140; diastolic BP less than 95 mmHg) and with other types of hypertensive patients with regard to cigarette smoking, alcohol consumption, obesity and plasma cholesterol, triglycerides, gamma-GT, glucose and uric acid levels. Several of these variables were significantly higher in all hypertensive patients than in normotensive subjects, but cigarette smoking and gamma-GT levels were predominantly or exclusively higher in PSH patients. In a second stage, correlations between differential BP and the variables listed above were studied in subjects with two levels of diastolic BP: 70-79 and 80-89 mmHg, thus taking into account all degrees between normal BP and PSH proper. Weakly positive correlations were found with alcohol consumption, plasma gamma-GT and glucose levels, and with percentages of smokers or ex-smokers. It is therefore conceivable that in addition to BP itself other factors, such as alcohol consumption, cigarette smoking and hyperglycaemia, contribute to the loss of arterial compliance progressively leading to pure systolic hypertension.

[Relation of alcohol consumption and blood lipids and apolipoproteins--a study of a population of 3,897 wage-earners from the Lyon region]. / Relations entre consommation d'alcool, et lipides et apolipoprotéines sériques--étude dans une population de 3,897 salariés de la région lyonnaise.

Between June 1982, and September 1984, a survey was conducted among 3,897 employees in the Region of Lyon to study the relationship between alcohol consumption and serum concentrations of total cholesterol and triglycerides. In 400 randomly selected men, the following data were also obtained: concentrations of the cholesterol of the high density lipoproteins (HDL) and of their subfractions, and concentrations of the apoproteins A-I, A-II and B. All these biochemical concentrations increased, more or less, with alcohol consumption. Relative to non drinkers, the concentrations increased among males who declared drinking more than 80 grams of alcohol per day: for total cholesterol, by 10.0%; for triglycerides, by 24.7%; for HDL-cholesterol, by 26.7%; for HDL2-cholesterol, by 76.0%; for HDL3-cholesterol, by 15.0%; for apoprotein A-I, by 30.0%; for apoprotein A-II, by 52.2%; for apoprotein B, by 5.1%. These results, with the limitations inherent in a cross-sectional study, suggest that regular consumption of alcohol raises the concentrations of blood lipid components, both atherogenic and non-atherogenic.

Liver X Receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells.

Cholesterol is a structural component of lipid rafts within the plasma membrane. These domains, used as platforms for various signaling molecules, regulate cellular processes including cell survival. Cholesterol contents are tightly correlated with the structure and function of lipid rafts. Liver X receptors (LXRs) have a central role in the regulation of cholesterol homeostasis within the cell. Therefore, we investigated whether these nuclear receptors could modulate lipid raft signaling and consequently alter prostate cancer (PCa) cell survival. Treatment with the synthetic LXR agonist T0901317 downregulated the AKT survival pathway and thus induced apoptosis of LNCaP PCa cells in both xenografted nude mice and cell culture. The decrease in tumor cholesterol content resulted from the upregulation of ABCG1 and the subsequent increase in reverse cholesterol transport. RNA interference experiments showed that these effects were mediated by LXRs. Atomic force microscopy scanning of the inner plasma membrane sheet showed smaller and thinner lipid rafts after LXR stimulation, associated with the downregulation of AKT phosphorylation in these lipid rafts. Replenishment of cell membranes with exogenous cholesterol antagonized these effects, showing that cholesterol is a key modulator in this process. Altogether, pharmacological modulation of LXR activity could thus reduce prostate tumor growth by enhancing apoptosis in a lipid raft-dependent manner.

Manejo clínico del traumatismo encefalocraneano grave / Clinical management of the severe encephalocranial injuries

El TEC es la causa más frecuente de mortalidad e invalidez en niños y adultos jóvenes. Si bien el neurocirujano no puede prevenir los daños traumáticos primarios, la atención está dirigida a la prevención de los daños secundarios causados por hipotensión, hipoxemia y la prevención de complicaciones intracraneanas y sistémicas. Será fundamental el manejo de la presión intracraneana (PIC) con el fin de mantener una presión de perfusión cerebral (PPC) adecuada. Requiriendo todo paciente con un puntaje de 8 o menos en la escala de coma de glasgow (GCS) monitoreo de su PIC. Descartada la presencia de una lesión susceptible de manejo quirúrgico, las medidas indicadas son la hiperventilación moderada (pCO230-35 mm Hg) y el uso de sustancias hiperosmolares (manitol). En pacientes refractarios a estas medidas deberá discutirse como medida adicional el coma barbitúrico y la craneotomía decompresiva