Characterization of the macrophage transcriptome in glomerulonephritis-susceptible and -resistant rat strains.

Crescentic glomerulonephritis (CRGN) is a major cause of rapidly progressive renal failure for which the underlying genetic basis is unknown. Wistar-Kyoto (WKY) rats show marked susceptibility to CRGN, whereas Lewis rats are resistant. Glomerular injury and crescent formation are macrophage dependent and mainly explained by seven quantitative trait loci (Crgn1-7). Here, we used microarray analysis in basal and lipopolysaccharide (LPS)-stimulated macrophages to identify genes that reside on pathways predisposing WKY rats to CRGN. We detected 97 novel positional candidates for the uncharacterized Crgn3-7. We identified 10 additional secondary effector genes with profound differences in expression between the two strains (>5-fold change, <1% false discovery rate) for basal and LPS-stimulated macrophages. Moreover, we identified eight genes with differentially expressed alternatively spliced isoforms, by using an in-depth analysis at the probe level that allowed us to discard false positives owing to polymorphisms between the two rat strains. Pathway analysis identified several common linked pathways, enriched for differentially expressed genes, which affect macrophage activation. In summary, our results identify distinct macrophage transcriptome profiles between two rat strains that differ in susceptibility to glomerulonephritis, provide novel positional candidates for Crgn3-7 and define groups of genes that play a significant role in differential regulation of macrophage activity.

Central Nervous System Metastases in Thymic Epithelial Tumors: A Brief Report of Real-World Insight From RYTHMIC.

Thymic epithelial tumors (TETs) are rare malignancies ranging from indolent thymoma A to aggressive thymic carcinomas (TCs). Brain metastases are extremely infrequent for TETs and have only been described in case reports or small single-center series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French nationwide network mandated to systematically review every TET case and prospectively includes all consecutive patients discussed by national or regional tumor boards. We analyzed patients with TETs and central nervous system (CNS) metastasis during their cancer history from this large French registry. In an 8-year period, 2909 patients were included in the database, including 248 TCs (8.5%). A total of 14 patients had CNS metastases, five (36%) at diagnosis and nine (64%) at relapse. Among them, 12 patients (86%) had a diagnosis of TC and two (14%) had thymoma A and B3. Surgical biopsies were performed, and the histologic subtype for non-TC tumors was centrally confirmed. Median overall survival was 22 months (95% confidence interval [CI]: 9.8-34.2), with longer, albeit not significant, overall survival when CNS metastases were present at diagnosis versus relapse (not reached versus 17 mo; p = 0.29); median progression-free survival was 13 versus 8 months (p = 0.06), respectively. A higher risk of death (hazard ratio = 5.34, 95% CI: 1.3-21.9, p = 0.02) and relapse (hazard ratio = 1.89, 95% CI: 0.9-3.7, p = 0.06) was observed for patients suffering from TC with brain metastases compared with those without CNS extension. CNS disease was extremely rare in our TET cohort (0.48%), reported at both diagnosis and progression, present primarily in TC, with prevalence rising to 4.9%.

[Stenting for superior vena cava obstruction associated with lung cancer: monocentric study]. / Mise en place précoce d'une endoprothèse dans les syndromes de la veine cave supérieure: étude monocentrique.

INTRODUCTION: Superior vena cava obstruction is an urgent complication of lung cancer. Superior vena cava stent insertion can be considered to provide rapid relief of the symptoms. METHODS: To estimate the efficiency and the complications of this procedure, we retrospectively analyzed 41 consecutive patients treated during the last 5 years by self-expanding nitinol stent insertion for superior vena cava obstruction due to lung cancer. It was combined with anticoagulation and corticosteroids. RESULTS: 41 patients benefited from this treatment (30 men and 11 women) with an average age of 59 years. Etiologies of the vena cava obstruction were: small cell carcinoma (11), adenocarcinoma (8), squamous cell carcinoma (9), large cell carcinoma (9) and others (4). All patients were symptomatic. The average period between the onset of symptoms and the vascular stenting was 14 days. Specific treatment was chemotherapy (18 patients), radiotherapy (1 patient), or both (14 patients), and no specific treatment for 6 patients. The procedure consisted of the insertion of 1 (73%) or 2 (27%) stents, with an average length and caliber of 7.5 cm and 14 mm respectively. No major complication was reported in short and long-term follow up. Symptomatic improvement was observed for all the patients within 48 hours. Median survival after the stenting was of 6.7 months. CONCLUSION: In our study, vascular stenting for malignant superior cava vena obstruction allows a rapid improvement of the symptoms with very few complications, suggesting a possible role as first line treatment for chemo or radio-resistant tumours.

EMAAS: an extensible grid-based rich internet application for microarray data analysis and management.

BACKGROUND: Microarray experimentation requires the application of complex analysis methods as well as the use of non-trivial computer technologies to manage the resultant large data sets. This, together with the proliferation of tools and techniques for microarray data analysis, makes it very challenging for a laboratory scientist to keep up-to-date with the latest developments in this field. Our aim was to develop a distributed e-support system for microarray data analysis and management. RESULTS: EMAAS (Extensible MicroArray Analysis System) is a multi-user rich internet application (RIA) providing simple, robust access to up-to-date resources for microarray data storage and analysis, combined with integrated tools to optimise real time user support and training. The system leverages the power of distributed computing to perform microarray analyses, and provides seamless access to resources located at various remote facilities. The EMAAS framework allows users to import microarray data from several sources to an underlying database, to pre-process, quality assess and analyse the data, to perform functional analyses, and to track data analysis steps, all through a single easy to use web portal. This interface offers distance support to users both in the form of video tutorials and via live screen feeds using the web conferencing tool EVO. A number of analysis packages, including R-Bioconductor and Affymetrix Power Tools have been integrated on the server side and are available programmatically through the Postgres-PLR library or on grid compute clusters. Integrated distributed resources include the functional annotation tool DAVID, GeneCards and the microarray data repositories GEO, CELSIUS and MiMiR. EMAAS currently supports analysis of Affymetrix 3' and Exon expression arrays, and the system is extensible to cater for other microarray and transcriptomic platforms. CONCLUSION: EMAAS enables users to track and perform microarray data management and analysis tasks through a single easy-to-use web application. The system architecture is flexible and scalable to allow new array types, analysis algorithms and tools to be added with relative ease and to cope with large increases in data volume.

[Surgical management and outcomes of lung cancer in women - results from the Epithor database]. / Particularités de la prise en charge chirurgicale du cancer bronchique chez la femme. Données de la base nationale Epithor.

INTRODUCTION: Rates of lung cancer in women have been increasing continually for several years. The basic surgical management of this condition is the same in both sexes but a number of differences are apparent. METHODS: We analysed data entered onto the Epithor database between June 2002 and June 2006 concerning 8535 surgical resections performed in primary lung cancer. RESULTS: 22.5 percent of patients were women. They were significantly younger (59.6 years vs 62.7 years) and had a lower BMI (24.7 kg x m(-2) vs 25.5 kg x m(-2)). They were in a better physical condition in terms of American Society of Anaesthesiology score and performance status, with better preserved lung function and fewer co-morbidities (1.8 vs 2.1) compared to men. The percentage of adenocarcinomas was higher in women and a higher proportion had early stage disease. 30 day mortality was three times as high in men who also experienced much greater post-operative morbidity. Multivariate analysis revealed an odds ratio of 0.49 (95% CI 0.3-0.8) for mortality and 0.54 (95% CI 0.4-0.6) for morbidity in women compared to men. CONCLUSION: Women with lung cancer have less risk of post-operative morbidity and mortality than men. These data suggest that they might be able to benefit from more aggressive perioperative therapy.

Do physiological concentrations of IgG induce a direct aggregation of red blood cells: comparison with fibrinogen.

Under physiological conditions, red blood cells (RBCs) form aggregates that allow blood flow in all the circulatory system. RBC aggregation is the result of local flow shear stress, erythrocyte properties and macromolecular interactions between adjacent cells. Plasma proteins like fibrinogen or IgG are considered to promote RBC aggregation by a mechanism that remains to be explained. In the present study, we have examined the precise role of IgG on RBC fast-phase aggregation, in comparison with that of fibrinogen. Under our experimental conditions, we observed no fast-phase aggregating effect for IgG, at either physiological or supraphysiological concentrations, while fibrinogen induces strong aggregation of RBC. We also suspect the other plasma proteins to play a role in the RBC aggregating process.

[An unusual opacity of the right base]. / Une curieuse opacité de la base droite.

The scimitar syndrome or pulmonary venolobar syndrome is a rare, complex and variable malformation of the right lung characterized by an abnormal right sided pulmonary venous drainage in the inferior vena cava, malformation of the right lung, abnormal arterial supply and sometimes cardiac malformations. We present a case in which this diagnosis was suspected on an abnormal routine chest radiograph in a 38-year-old asymptomatic woman. Most patients are asymptomatic; symptomatic patients have a marked left-to-right shunt or a severe congenital heart disease. They usually suffer from shortness of breath, asthenia or repeated chest infections. Usually, the posteroanterior chest radiograph can confirm the diagnostic. It shows the abnormal vein draining into the inferior vena cava as a curved vascular shadow with a scimitar like appearance. However, in some cases, when the scimitar vein is masked by the overlying cardiac shadow, computed tomography, angiography and magnetic resonance imaging can be helpful by showing the abnormal vein and its insertion into the inferior vena cava. Scimitar syndrome seldom necessitates surgical intervention. However, repeated lung infections can sometimes require lobectomy or pneumonectomy, left-to-right shunt vascular surgery to redirect the scimitar vein into the left atrium.

[An analysis of treatment delays of thoracic cancers: a prospective study]. / Analyse des délais de prise en charge des cancers thoraciques: étude prospective.

INTRODUCTION: Lung cancer is the main cause of cancer death in France. The diagnosis is often late and the delay between the onset of symptoms and management is considered an aggravating factor. MATERIAL AND METHODS: Our prospective study collected the dates of the start of management of 139 consecutive patients receiving first line treatment for thoracic cancer in our hospital between November 2008 and May 2009. The aim of this study was to evaluate the delays in medical or surgical treatments in patients with thoracic cancer and to determine the cause of these delays. RESULTS: The median delay between the first abnormal chest X-ray and treatment was 9.6 weeks. The delays were significantly shorter in the late stages and in small cell cancer (P=0.001). There was a tendency for shorter delays in women and for longer delays in older patients. CONCLUSION: Evaluation of the delays in treatment, particularly in the early stages, is part of the quality control of management of these diseases.

Directional next-generation RNA sequencing and examination of premature termination codon mutations in endoglin/hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a disease characterised by abnormal vascular structures, and most commonly caused by mutations in ENG, ACVRL1 or SMAD4 encoding endothelial cell-expressed proteins involved in TGF-ß superfamily signalling. The majority of mutations reported on the HHT mutation database are predicted to lead to stop codons, either due to frameshifts or direct nonsense substitutions. The proportion is higher for ENG (67%) and SMAD4 (65%) than for ACVRL1 (42%), p < 0.0001. Here, by focussing on ENG, we report why conventional views of these mutations may need to be revised. Of the 111 stop codon-generating ENG mutations, on ExPASy translation, all except one were premature termination codons (PTCs), sited at least 50-55 bp upstream of the final exon-exon boundary of the main endoglin isoform, L-endoglin. This strongly suggests that the mutated RNA species will undergo nonsense-mediated decay. We provide new in vitro expression data to support dominant negative activity of stable truncated endoglin proteins but suggest these will not generate HHT: the single natural stop codon mutation in L-endoglin (sited within 50-55 nucleotides of the final exon-exon boundary) is unlikely to generate functional protein since it replaces the entire transmembrane domain, as would 8 further natural stop codon mutations, if the minor S-endoglin isoform were implicated in HHT pathogenesis. Finally, next-generation RNA sequencing data of 7 different RNA libraries from primary human endothelial cells demonstrate that multiple intronic regions of ENG are transcribed. The potential consequences of heterozygous deletions or duplications of such regions are discussed. These data support the haploinsufficiency model for HHT pathogenesis, explain why final exon mutations have not been detected to date in HHT, emphasise the potential need for functional examination of non-PTC-generating mutations, and lead to proposals for an alternate stratification system of mutational types for HHT genotype-phenotype correlations.

An integrated map of human 6q22.3-q24 including a 3-Mb high-resolution BAC/PAC contig encompassing a QTL for fetal hemoglobin.

Genetic studies have previously assigned a quantitative trait locus (QTL) for hemoglobin F and F cells to a region of approximately 4 Mb between the markers D6S408 and D6S292 on chromosome 6q23. An initial yeast artificial chromosome contig of 13 clones spanning this region was generated. Further linkage analysis of an extended kindred refined the candidate interval to 1-2 cM, and key recombination events now place the QTL within a region of <800 kb. We describe a high-resolution bacterial clone contig spanning 3 Mb covering this critical region. The map consists of 223 bacterial artificial chromosome (BAC) and 100 P1 artificial chromosome (PAC) clones ordered by sequence-tagged site (STS) content and restriction fragment fingerprinting with a minimum tiling path of 22 BACs and 1 PAC. A total of 194 STSs map to this interval of 3 Mb, giving an average marker resolution of approximately one per 15 kb. About half of the markers were novel and were isolated in the present study, including three CA repeats and 13 single nucleotide polymorphisms. Altogether 24 expressed sequence tags, 6 of which are unique genes, have been mapped to the contig.