Search

Glycogen synthase kinase-3β (GSK3β) is a multifunctional kinase whose inhibition is known to limit myocardial ischemia–reperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/endoplasmic reticulum (SR/ER) are key players in cell death signaling. Their involvement in myocardial ischemia–reperfusion injury has gained recognition recently, but the underlying mechanisms are not yet well understood. We questioned here whether GSK3β might have a role in the Ca2+transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3β protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3β specifically interacted with the inositol 1,4,5-trisphosphate receptors (IP3Rs) Ca2+channeling complex in MAMs. We demonstrated that both pharmacological and genetic inhibition of GSK3β decreased protein interaction of IP3R with the Ca2+channeling complex, impaired SR/ER Ca2+release and reduced the histamine-stimulated Ca2+exchange between SR/ER and mitochondria in cardiomyocytes. During hypoxia reoxygenation, cell death is associated with an increase of GSK3β activity and IP3R phosphorylation, which leads to enhanced transfer of Ca2+from SR/ER to mitochondria. Inhibition of GSK3β at reperfusion reduced both IP3R phosphorylation and SR/ER Ca2+release, which consequently diminished both cytosolic and mitochondrial Ca2+concentrations, as well as sensitivity to apoptosis. We conclude that inhibition of GSK3β at reperfusion diminishes Ca2+leak from IP3R at MAMs in the heart, which limits both cytosolic and mitochondrial Ca2+overload and subsequent cell death.

Comparer la tomosynthèse à la mammographie, l’échographie, l’IRM, l’histologie pour la détection et le bilan d’extension d’anomalies BI-RADS 4-5, en fonction de la densité mammaire, la localisation, la taille, l’histologie.

In this personal view, the first French supreme allied commander (Supreme Allied Commander Transformation—SACT) sets the evolution of NATO in perspective, reminds us of how the Alliance's strategy is developed and evokes the new synergies, internal and external, of his organisation. [ABSTRACT FROM AUTHOR]

Background. Since the improvement of chemotherapy with safe molecules is needed for better efficacy without supplementary toxicity, we investigated the feasibility and tolerability of the combination of docetaxel and curcumin, a polyphenolic derivative extracted from Curcuma longa Patients and methods. Patients with advanced or metastatic breast cancer were eligible. Docetaxel (100 mg/m2) was administered as a 1-hour i.v. infusion every 3 weeks on d1 for 6 cycles. Curcumin was orally given from 500 mg/d for 7 consecutive days by cycle (from d-4 to d+2) and escalated until a dose-limiting toxicity should occur. The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients. Secondary objectives included toxicity, safety, vascular endothelial growth factor and tumor markers measurements, and assessment of objective and clinical responses to the combination therapy. Results. Fourteen patients were accrued in this open-label phase I trial. At the last dose level of curcumin, 3 dose-limiting toxicities were observed and 2 out of 3 patients at this dose level refused to continue treatment, leading us to define the maximal tolerated dose of curcumin at 8000 mg/d. Eight patients out of 14 had measurable lesions according to RECIST criteria, with 5 PR and 3 SD. Some improvements as biological and clinical responses were observed in most patients. Conclusion. The recommended dose of curcumin is 6000 mg/d for 7 consecutive days every 3 weeks in combination with a standard dose of docetaxel. From the encouraging efficacy results, a comparative phase II trial of this regimen plus docetaxel versus docetaxel alone is ongoing in advanced and metastatic breast cancer patients.

Copyright of Défense Nationale et Sécurité Collective is the property of Comite d'Etudes de Defense Nationale and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aortic root aneurysm is a common cause of morbidity and mortality in Loeys-Dietz and Marfan syndromes, where perturbations in transforming growth factor beta (TGFβ) signaling play a causal or contributory role, respectively. Despite the advantages of cross-species disease modeling, animal models of aortic root aneurysm are largely restricted to genetically engineered mice. Here, we report that zebrafish devoid of the genes encoding latent-transforming growth factor beta-binding protein 1 and 3 (ltbp1 and ltbp3, respectively) develop rapid and severe aneurysm of the outflow tract (OFT), the aortic root equivalent. Similar to syndromic aneurysm tissue, the distended OFTs display evidence for paradoxical hyperactivated TGFβ signaling. RNA-sequencing revealed significant overlap between the molecular signatures of disease tissue from mutant zebrafish and a mouse model of Marfan syndrome. Moreover, chemical inhibition of TGFβ signaling in wild-type animals phenocopied mutants but chemical activation did not, demonstrating that TGFβ signaling is protective against aneurysm. Human relevance is supported by recent studies implicating genetic lesions in LTBP3 and, potentially, LTBP1 as heritable causes of aortic root aneurysm. Ultimately, our data demonstrate that zebrafish can now be leveraged to interrogate thoracic aneurysmal disease and identify novel lead compounds through small-molecule suppressor screens. This article has an associated First Person interview with the first author of the paper.

The article discusses various reports published within the issue including one by Etienne de Durand on the use of air power and positions for political ends and another by Xavier Jarry describing the nuclear deterrent in the French Air Force (FAF) and the advantages of retaining an air-delivered component.

The author focuses on the French Air Force (FAF). Significant missions of the service are cited, such as supporting French foreign policy and cooperating with armed forces. He says that from a doctrinal perspective, the main concern of FAF deals with the development of insurgencies and the ways air power could bring advantages to the joint commander. Also mentioned are procurement plans of FAF, including the modernization of the Alpha Jet fleet.

A spatio-temporal analysis was carried out to see how the risk distribution of bovine spongiform encephalopathy (BSE) in France changed depending on the period of birth. The data concerned the 539 BSE cases born in France after the ban (BAB) of meat and bone meal (MBM) in 1990 and detected between July 1, 2001 and December 31, 2003, when the surveillance of BSE was comprehensive. Seventy-two of these cases were born after the reinforced (second) ban (BASB) in 1996, which involved the removal of BSE-risk materials and cadavers from the processing of MBM. The Ederer-Myers-Mantel (EMM) time and space cluster test was applied, after classifying the cases by trimester and region of birth, BAB or BASB status, and dairy or beef status. Then disease mapping was performed for four successive birth periods, three for the BAB cases (January 1991 through June 1994, July 1994 through June 1995, July 1995 through June 1996), and one for the BASB (July 1996 through October 1998). It was elaborated with the Bayesian graphical modelling methods and based on a Poisson distribution with spatial smoothing. The parameters were estimated by a Markov Chain Monte Carlo (MCMC) simulation method. The main finding was that the areas with the highest risk of BSE changed largely from one birth period to another; from the west, it reached the east of France for birth cohort 1994–1995 and the southwest for birth cohort 1995–1996. The EMM test identified a peak risk in this region both for dairy and beef cattle in the fall 1995. The spatial distribution of the risk for the BASB cases matched the spatial pattern of risk for the preceding BAB birth cohort quite well; this was in favour of a common origin of the infection of the BAB and BASB cases, despite the complementary control measures.

A spatial analysis was carried out in order to analyse the reason why the risk of Bovine Spongiform Encephalopathy (BSE) was spatially heterogeneous in France, during the period following the feed ban of Meat and Bone Meal to cattle. The hypothesis of cross-contamination between cattle feedstuff and monogastric feedstuff, which was strongly suggested from previous investigations, was assessed, with the assumption that the higher the pig or poultry density is in a given area, the higher the risk of cross-contamination and cattle infection might be. The data concerned the 467 BSE cases born in France after the ban of meat and bone meal (July 1990) and detected between July 1st, 2001 and December 31, 2003, when the surveillance system was optimal and not spatially biased. The disease mapping models were elaborated with the Bayesian graphical modelling methods and based on a Poisson distribution with spatial smoothing (hierarchical approach) and covariates. The parameters were estimated by a Markov Chain Monte Carlo simulation method. The main result was that the poultry density did not significantly influence the risk of BSE whereas the pig density was significantly associated with an increase in the risk of 2.4% per 10 000 pigs. The areas with a significant pig effect were located in regions with a high pig density as well as a high ratio of pigs to cattle. Despite the absence of a global effect of poultry density on the BSE risk, some areas had a significant poultry effect and the risk was better explained in some others when considering both pig and poultry densities. These findings were in agreement with the hypothesis of cross-contamination, which could take place at the feedstuff factory, during the shipment of food or on the farm. Further studies are needed to more precisely explore how the cross-contamination happened.

This study investigated the efficacy and tolerability of FEC 100 (epirubicin 100 mg/m2with 5-fluorouracil 500 mg/m2and cyclophosphamide 500 mg/m2) every 21 days as neoadjuvant chemotherapy in women with stage I-III primary operable breast cancer. Forty patients were treated with 6 cycles of FEC 100, followed by surgery and radiation therapy. In addition, most patients also received an adjuvant treatment for residual disease (11 chemotherapies and 31 tamoxifen). After 6 cycles of FEC 100, the overall clinical response rate of 75% (CI 95%, 61.6-88.4) was achieved, 22.5% of which were complete responses. Breast conservation was achieved in 70% of patients. A pathologic complete response was confirmed in 6 patients (15%; CI 95%, 3.9—26.1) using Chevallier's classification and in 10 patients (25%; CI 95%, 11.6–38.4) using Sataloff's classification. After a median follow-up of 29.5 months, 3 metastatic relapses were observed. The principal toxicity of FEC 100 was myelosuppression; 51.3% of patients developed grade 3/4 neutropenia. Neoadjuvant FEC 100 was both effective and well tolerated in patients with early-stage operable breast cancer.

A bovine spongiform encephalopathy (BSE) testing programme at the abattoir started in 2001 in France. A total of 5 281 293 bovines were tested in 2001 and 2002; 87 were found positive in 2001 – 37 per million (95% CI 30-46) –, whereas only 71 in 2002 – 24 per million (95% CI 19-30). Logistic regression models were run to compare the prevalence of BSE on successive birth cohorts, using a pair-wise method of controlling for age at testing; the prevalence on the first one, determined on animals slaughtered in 2001, was compared to the prevalence on the following one determined on animals slaughtered in 2002. Five models were performed in order to compare the birth cohorts preceding and following the months of June 1993 (i.e. July 92–June 93 birth cohort compared to July 93–June 94 birth cohort) (8.5 years old cattle), June 1994 (7.5 years old cattle), June 1995 (6.5 years old cattle), June 1996 (5.5 years old cattle) and June 1997 (4.5 years old cattle). The models were adjusted for the production type of cattle and the test used. The results showed a significant increase (OR = 2.31, 95% CI 1.08-4.9) of the BSE prevalence between the July 93–June 94 and July 94–June 95 cohorts, and then a significant decrease over the next two birth cohorts; the July 95–June 96 birth cohort was significantly less affected than the July 94–June 95 one (OR = 0.46, 95% CI 0.27-0.78), and the July 96–June 97 birth cohort was significantly less affected than the July 95–June 96 one (OR = 0.17, 95% CI 0.07-0.37). The increase in BSE prevalence between the July 93–June 94 and July 94–June 95 cohorts was in agreement with modelling studies, but needs to be confronted to the data on fallen stock at the national level. The decrease in BSE prevalence on the birth cohorts born after June 1995 was in agreement with the findings on the fallen stock in the western part of France and matches the implementation of the removal of specified risk materials (SRM) and dead animals from the processing of meat and bone meal (MBM) since June 1996.

Between 1991 and mid 2000, the surveillance of Bovine Spongiform Encephalopathy (BSE) in France was based solely on clinical surveillance through a Mandatory Reporting System. Since 2000, the implementation of active surveillance programmes using rapid tests, as a complementary tool targeted at dead and slaughtered cattle has shown that part of the BSE cases were not detected with the clinical surveillance. In order to obtain a better knowledge of the strength of the clinical surveillance, we analysed a vigilance index defined as the ratio of negative clinical suspicions to the cattle population in the region and period of interest. The temporal analysis of the vigilance index showed that it did not vary much between 1991 and 1999, increased sharply since 2000, and then decreased partly in 2001. The geographical analysis of the variations of the vigilance index was performed at the department level by comparing the observed number of negative clinical suspicions per department to the expected number, computed on the basis of the national average index and standardised on the production type of the cattle — dairy versus beef suckling cattle. As assumed, the data followed a Poisson distribution. We observed a high geographical variation of the vigilance index: ten departments out of 91 presented a significantly higher vigilance index than the national one, and four a significantly lower vigilance index. The vigilance index showed that the clinical surveillance was heterogeneous during the past twelve years, both in time and geographic location, in a range of one to ten. So the apparent trend in the BSE epidemic during this period as well as the differences in the spatial incidence of BSE have to be analysed with caution.

The spatial heterogeneity of Bovine Spongiform Encephalopathy (BSE) was analysed on the 84 cases confirmed in western France (WF) between August and December 2000, when both the Mandatory Reporting System and an active surveillance on cattle at risk were running. Ninety-four percent of these cases were born between June 1993 and June 1996, and we analysed the location at birth. One disease mapping and two clustering methods (Scan of Kulldorff and the method of Besag and Newell) were used. In order to attenuate the contrasts artificially created by the standard disease mapping method (over-dispersion), we estimated the Standard Incidence Ratio (SIR) with a Bayesian method (Poisson-Gamma model) allowing a smoothing of the estimators. The geographical location of interest was the ”canton", that divided the total area into 526 geographical units. The background population (2.6 million cattle) was obtained from the Agricultural Census 2000. We tested the hypothesis of a homogenous spatial distribution of the BSE risk where the expected number of BSE cases per unit area was obtained by applying the overall BSE rate in WF to each ”canton”, standardised on the type of breed, dairy versus beef suckler. The SIR ranged from 0.80 to 2.18 and the spatial distribution of BSE cases was significantly heterogeneous. Two spatial clusters were detected with the spatial scan statistics of Kulldorff and the method of Besag and Newell (18 to 20 observed BSE-cases per cluster with a radius of 45 km) centred on the ”département" of Côtes-d'Armor and Mayenne. Another cluster was detected with the method of Besag and Newell (9 observed BSE-cases) in the ”département" of Finistère. The results proved that the risk of BSE is linked to the geographical location in the area of the study.

L'évolution spatio-temporelle de l'activité phosphatase alcaline spécifique (APA) (EC: 3.1.3.1) des peuplements phytoplanctoniques de la retenue de Grangent (Loire) a été étudiée. Cette activité enzymatique est maximale en été (comprise entre 20 et 69,4 μmol P-PO43-.h-1.mg-1au niveau de l'épilimnion) et minimale en automne et au printemps (variant de 0,1 à 10 μmol P-PO43-.h-1.mg-1). Elle diminue au fur et à mesure que l'on s'enfonce dans la colonne d'eau et est inversement corrélée à la teneur en orthophosphate du milieu. Par ailleurs, l'activité phosphatasique est étroitement liée aux fleurs d'eau cyanobactériennes. En présence d'une même concentration en orthophosphate, les algues semblent être de meilleures compétitrices que les Cyanobactéries dans l'assimilation du PO43-dissous. Les Cyanobactéries ont ainsi davantage recours à l'activité phosphatasique pour disposer du phosphore minéral indispensable à leur métabolisme. Cette différence de comportement dans l'utilisation du phosphore entre les Cyanobactéries et les algues pourrait représenter un critère explicatif supplémentaire des successions écologiques.

L'?volution spatio-temporelle de l'activit? phosphatase alcaline sp?cifique (APA) (EC: 3.1.3.1) des peuplements phytoplanctoniques de la retenue de Grangent (Loire) a ?t? ?tudi?e. Cette activit? enzymatique est maximale en ?t? (comprise entre 20 et 69,4 ?mol P-PO43-.h-1.mg-1au niveau de l'?pilimnion) et minimale en automne et au printemps (variant de 0,1 ? 10 ?mol P-PO43-.h-1.mg-1). Elle diminue au fur et ? mesure que l'on s'enfonce dans la colonne d'eau et est inversement corr?l?e ? la teneur en orthophosphate du milieu. Par ailleurs, l'activit? phosphatasique est ?troitement li?e aux fleurs d'eau cyanobact?riennes. En pr?sence d'une m?me concentration en orthophosphate, les algues semblent ?tre de meilleures comp?titrices que les Cyanobact?ries dans l'assimilation du PO43-dissous. Les Cyanobact?ries ont ainsi davantage recours ? l'activit? phosphatasique pour disposer du phosphore min?ral indispensable ? leur m?tabolisme. Cette diff?rence de comportement dans l'utilisation du phosphore entre les Cyanobact?ries et les algues pourrait repr?senter un crit?re explicatif suppl?mentaire des successions ?cologiques.The seasonal and spatial changes of the specific alkaline phosphatase activity (APA) (EC: 3.1.3.1) were studied in relation to several abiotic and biotic factors in the Grangent reservoir (located on the Loire River). The enzymatic activity was maximal in summer (between 20 and 69,4 ?mol P-PO43-.h-1.mg-1in the epilimnion) and minimal in spring and in autumn (varying from 0,1 to 10 ?mol P-PO43-.h-1.mg-1). This activity was greatest in the epilimnion and became weaker with depth. APA appeared to be inversely related to the concentration of orthophosphate. Finally, the main peak of the alkaline phosphatase activity seemed to be strictly associated with blooms of Cyanobacteria. In the presence of a similar concentration of orthophosphate, algae showed a higher uptake rate of this nutrient than Cyanobacteria. Therefore, Cyanobacteria were more often obliged to resort to the phosphatase activity for mineralizing organic phosphorus. The observed differences in the phosphorus assimilation between algae and Cyanobacteria might explain ecological successions related to the seasonal variations.

The refractive indices of rubidium hydrogen selenate are measured for several wavelengths at room temperature, and the transmission spectrum is measured from the UV (240 nm) to the near IR (2000 nm). The orientation of the optical indicatrix with respect to the crystal axes is also determined at several wavelengths in the visible range. Using a new method based on the deflection of light by the ferroelastic domain structure, we also determine refined values for birefringence at several wavelengths. Finally, the dispersion of the three birefringences in the range 450–900 nm is deduced from polarimetric measurements. This set of results yields complete knowledge of the linear optical characteristics required for interpretation of the electro-optical and nonlinear optical properties of this compound.

First exploratory field work in the Campanian and Maastrichtian of the French Petites Pyrénées(Marnes d'Auzas Formation, Calcaires nankin Fm and Grès de Labarre Fm) has yielded marine and continental microvertebrate remains. It opens new perspectives in the knowledge of the vertebrate microfauna from the late Cretaceous of Europe which is still very poorly known, especially for the end of the period. The new remains discovered exemplify selachians (with several new species), amphibians (anourans, salamanders?), squamates (lacertilians, amphisbaenians?), small dinosaures (theropods, hadrosaures), and mammals (4–5 undetermined tooth fragments)-which are among the very few known in the late Cretaceous of Europe (two teeth previously known in France). The Marnes d'Auzas Fm and the Grès de Labarre Fm show especially promising facies for the search of latest Cretaceous continental microvertebrates in France.

L'activité phosphatase alcaline (APA) (EC: 3.1.3.1) de 3 peuplements quasi monospécifiques dominés successivement par Synedra capitata (Diatomée), Microcystis aeruginosa et Aphanizomenon flos aquae (Cyanobactéries) présente une périodicité nycthémérale avec des caractéristiques propres à l'espèce. Dans des conditions expérimentales rigoureusement identiques, l'APA moyenne de Microcystis aeruginosa est 32 fois plus importante (par unité de biomasse) que celle de Synedra capitata et 3 fois plus élevée que l'activité phosphatasique d'Aphanizomenon flos aquae. En conditions LD (16 : 8), l'activité enzymatique de Synedra capitata et d'Aphanizomenon flos aquae atteint des valeurs maximales durant le jour (de l'ordre de 425 µmol pNPP/l/h à 5h, 11h et 17 h pour la Diatomée et d'environ 850 µmol pNPP/l/h à 11 h, 15 h et 19 h pour la Cyanobactérie) alors que celle de Microcystis aeruginosa est maximale au début de la nuit (de l'ordre de 1500 µmol pNPP/l/h à 21 h). Enfin, les activités enzymatiques moyennes de Synedra et d'Aphanizomenon sont maximales quand ces espèces se trouvent en obscurité permanente et minimales en éclairement permanent. Les résultats inverses s'observent avec Microcystis aeruginosa. Les espèces phytoplanctoniques sont donc inégales dans leur aptitude à transformer le phosphore organique en orthophosphate grâce aux phosphatases. Cette différence de comportement enzymatique pourrait représenter un critère explicatif supplémentaire des successions écologiques observées au sein des communautés phytoplanctoniques.

L'activit? phosphatase alcaline (APA) (EC: 3.1.3.1) de 3 peuplements quasi monosp?cifiques domin?s successivement par Synedra capitata (Diatom?e), Microcystis aeruginosa et Aphanizomenon flos aquae (Cyanobact?ries) pr?sente une p?riodicit? nycth?m?rale avec des caract?ristiques propres ? l'esp?ce. Dans des conditions exp?rimentales rigoureusement identiques, l'APA moyenne de Microcystis aeruginosa est 32 fois plus importante (par unit? de biomasse) que celle de Synedra capitata et 3 fois plus ?lev?e que l'activit? phosphatasique d'Aphanizomenon flos aquae. En conditions LD (16 : 8), l'activit? enzymatique de Synedra capitata et d'Aphanizomenon flos aquae atteint des valeurs maximales durant le jour (de l'ordre de 425 ?mol pNPP/l/h ? 5h, 11h et 17 h pour la Diatom?e et d'environ 850 ?mol pNPP/l/h ? 11 h, 15 h et 19 h pour la Cyanobact?rie) alors que celle de Microcystis aeruginosa est maximale au d?but de la nuit (de l'ordre de 1500 ?mol pNPP/l/h ? 21 h). Enfin, les activit?s enzymatiques moyennes de Synedra et d'Aphanizomenon sont maximales quand ces esp?ces se trouvent en obscurit? permanente et minimales en ?clairement permanent. Les r?sultats inverses s'observent avec Microcystis aeruginosa. Les esp?ces phytoplanctoniques sont donc in?gales dans leur aptitude ? transformer le phosphore organique en orthophosphate gr?ce aux phosphatases. Cette diff?rence de comportement enzymatique pourrait repr?senter un crit?re explicatif suppl?mentaire des successions ?cologiques observ?es au sein des communaut?s phytoplanctoniques.The results we present here were on three quasi monospecific settlements : Synedra capitata (Diatom), Microcystis aeruginosa and Aphanizomenon flos aquae (Cyanobacteria). The alkaline phosphatase activity (APA) (EC : 3.1.3.1) exhibited a nycthemeral variation for Diatoms as well as Cyanobacteria, though every species had its own characteristic. Under similar experimental conditions, the enzymatic activity was, in the average, 32 times higher (per unit of biomass) for Microcystis aeruginosa than for Synedra capitata and 3 times higher for Microcystis aeruginosa than for Aphanizomenon flos aquae. Under LD (16 : 8), Synedra capitata and Aphanizomenon flos aquae had a maximal enzymatic activity during the day time (maximal APA around 425 ?mol pNPP/l/h at 5 a.m., 11 a.m. and 5 p.m. for the Diatom and around 850 ?mol pNPP/l/h at 11 a.m., 3 p.m. and 7 p.m. for the Cyanobacteria) while the enzymatic activity of Microcystis aeruginosa was maximal at the beginnique of the night time (maximal APA around 1500 ?mol pNPP/l/h at 9 p.m.). The observed daily rythm disappeared when the samples were placed in the darkness (DD) or under permanent light (LL). In the last case (LL), the mean enzymatic activity of Microcystis aeruginosa was maximal and, on the contrary, the mean APA of both Synedra capitata and Aphanizomenon flos aquae was minimal. There was a difference between the phytoplanktonic species in the orthophosphate assimilation and in the capacity for mineralizing organic phosphorus because of the phosphatases. This difference in the enzymatic behaviour might explain ecological successions within the planktonic settlements.

Bacterial pathogens have evolved to secrete strong anti-inflammatory proteins that target the immune system. It was long speculated whether these virulence factors could serve as therapeutics in diseases in which abnormal immune activation plays a role. We adopted the secreted chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) as a model virulence factor-based therapeutic agent for diseases in which C5AR1 stimulation plays an important role. We show that the administration of CHIPS in human C5AR1 knock-in mice successfully dampens C5a-mediated neutrophil migration during immune complex-initiated inflammation. Subsequent CHIPS toxicology studies in animal models were promising. However, during a small phase I trial, healthy human volunteers showed adverse effects directly after CHIPS administration. Subjects showed clinical signs of anaphylaxis with mild leukocytopenia and increased C-reactive protein concentrations, which are possibly related to the presence of relatively high circulating anti-CHIPS antibodies and suggest an inflammatory response. Even though our data in mice show CHIPS as a potential anti-inflammatory agent, safety issues in human subjects temper the use of CHIPS in its current form as a therapeutic candidate. The use of staphylococcal proteins, or other bacterial proteins, as therapeutics or immune-modulators in humans is severely hampered by pre-existing circulating antibodies.

Breast cancer is the most common malignancy and the second most common cause of cancer-related death in women. Endocrine therapy has been used for more than a century to treat advanced-stage breast cancer. The results obtained with the third-generation aromatase inhibitor letrozole demonstrated an actual improvement in patient outcome compared with tamoxifen. This benefit translates into disease-free survival improvement for adjuvant treatment and overall survival in patients with metastatic disease. The present clinical situation of hormonal therapy is stable; however, recently, new anticancer agents (temsirolimus and everolimus) that inhibit mammalian target of rapamycin protein kinase have been developed and seem to be very promising because of their synergistic activity with letrozole. The phase II study of a combination of temsirolimus or everolimus with letrozole demonstrated a better progression-free survival in the combination arm than in the letrozole alone arm. Consequently, the results of ongoing phase III studies are eagerly awaited.

La dysfonction des télomères, comme des mécanismes de réparation de l’ADN, joue un rôle majeur dans la progression tumorale. Nous avons étudié les paramètres télomériques et l’expression d’ERCC1, une protéine impliquée à la fois dans de nombreux mécanismes de réparation de l’ADN et dans la maintenance des télomères, pour évaluer leur valeur pronostique dans 90 résidus tumoraux de cancer du sein après chimiothérapie néoadjuvante.

Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating the established number of cardiomyocytes.

Les manifestations cutanées liées aux dépôts d’une substance amyloïde AL sont nombreuses et polymorphes. Leur connaissance peut parfois amener les cliniciens à un diagnostic plus précoce de cette affection de mauvais pronostic. Nous rapportons une observation rare d’infiltration sclérodermiforme péribuccale révélant une amylose AL satellite d’un myélome multiple à chaîne légère.

Microdeletions involving TBX1 result in variable congenital malformations known collectively as 22q11.2 deletion syndrome (22q11.2DS). Tbx1-deficient mice and zebrafish recapitulate several disease phenotypes, including pharyngeal arch artery (PAA), head muscle (HM), and cardiac outflow tract (OFT) deficiencies. In zebrafish, these structures arise from nkx2.5+progenitors in pharyngeal arches 2–6. Because pharyngeal arch morphogenesis is compromised in Tbx1-deficient animals, the malformations were considered secondary. Here, we report that the PAA, HM, and OFT phenotypes in tbx1mutant zebrafish are primary and arise prior to pharyngeal arch morphogenesis from failed specification of the nkx2.5+pharyngeal lineage. Through in situanalysis and lineage tracing, we reveal that nkx2.5and tbx1are co-expressed in this progenitor population. Furthermore, we present evidence suggesting that gdf3-ALK4 signaling is a downstream mediator of nkx2.5+pharyngeal lineage specification. Collectively, these studies support a cellular mechanism potentially underlying the cardiovascular and craniofacial defects observed in the 22q11.2DS population.

L’activation de la télomérase est essentielle pour la survie des cellules tumorales. L’expression de sa sous-unité catalytique hTERTest le facteur limitant pour cette activation. Notre objectif était d’étudier les mécanismes de la surexpression de hTERTet leur impact clinique dans le cancer du sein.

The epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), has been identified as an important cytokine in allergic inflammation. Various studies demonstrated elevate levels and expression of TSLP in airways of asthmatic. Environmental factors such as toll-like receptor ligands, viruses, microbes, allergen sources, diesel exhaust and cigarette smoke trigger TSLP production by epithelial cells. It has been described that TSLP amplifies the differentiation of peritoneal macrophages and bone marrow derived macrophages in M2-type in mice. Our aims were to investigate the role of TSLP in the M1/M2 polarization of human lung macrophages (LM).