Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.

The leucine zipper-like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.

Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment.

The glucocorticoid receptor (GR) is a transcription factor of which the underlying gene regulatory mechanisms are complex and incompletely understood. The non-steroidal anti-inflammatory Compound A (CpdA), a selective GR modulating compound in various cell models, has been shown to favour GR-mediated gene repression but not GR-mediated gene activation. Shifting balances towards only a particular subset of GR gene regulatory events may be of benefit in the treatment of inflammatory diseases. We present evidence to support that the combination of CpdA with Dexamethasone (DEX), a classic steroidal GR ligand, can shape GR function towards a unique gene regulatory profile in a cell type-dependent manner. The molecular basis hereof is a changed GR phosphorylation status concomitant with a change in the GR cofactor recruitment profile. We subsequently identified and confirmed the orphan nuclear receptor SHP as a coregulator that is specifically enriched at GR when CpdA and DEX are combined. Combining CpdA with DEX not only leads to stronger suppression of pro-inflammatory gene expression, but also enhanced anti-inflammatory GR target gene expression in epithelial cells, making ligand combination strategies in future a potentially attractive alternative manner of skewing and fine-tuning GR effects towards an improved therapeutic benefit.

Leptin receptor antagonism of iNKT cell function: a novel strategy to combat multiple myeloma.

A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.

[Ten-year evolution in non-small-cell lung cancer according to sex. Results of the KBP-2010-CPHG study by the College of General Hospital Respiratory Physicians]. / Évolution en 10ans du cancer bronchique non à petites cellules en fonction du sexe. Résultats de l'étude KBP-2010-CPHG du Collège des pneumologues des hôpitaux généraux.

INTRODUCTION: Comparison by sex and presenting features between 2000 and 2010 of the characteristics of new cases of non-small-cell lung cancer (NSCLC). METHODS: Observational KBP-2010-CPHG study similar to KBP-2000-CPHG. Both studies were promoted by the French College of General Hospital Respiratory Physicians (CPHG). KBP-2010-CPHG collected data for 6083 NSCLC diagnosed between January 1st and December 31st, 2010, and followed in the respiratory departments of 119 French general hospitals. RESULTS: In 2010, 24.4 % of the patients were women (16 % in 2000, p<0.0001). Compared to men, women were more commonly non-smokers (34.2 vs 4.7 %) or lighter consumers (37.2 vs 43.7 pack per years) (p<0.0001). Their tumours (mostly adenocarcinoma: 64.6 vs 48.7 %, p<0.0001) were more frequently diagnosed at stage IV (62.4 vs 56.9 %, p=0.0008). EGFR mutation research was more frequently performed (48.5 vs 31.0 %, p<0.0001) and positive (20.6 vs 5.2 %, p<0.0001) in women than men. Their treatment more frequently included targeted therapy (13.4 vs 5.7 %, p<0.0001). Compared to 2000, the percentage of non-smokers increased in men (4.7 vs 2.5 %, p<0.0001) while remaining stable in women (36.1 vs 34.2 %, p=0.32). The percentage of adenocarcinomas increased, particularly in men (48.7 vs 31.5 %, p<0.0001). CONCLUSIONS: The percentage of women with NSCLC has increased in 10years in France. In 2010, the main gender differences persist, but have decreased with the increasing proportion of non-smokers and adenocarcinomas in men. Various hypotheses to explain these changes are discussed.

Getting RIDD of RNA: IRE1 in cell fate regulation.

Inositol-requiring enzyme 1 (IRE1) is the most conserved transducer of the unfolded protein response (UPR), a homeostatic response that preserves proteostasis. Intriguingly, via its endoribonuclease activity, IRE1 produces either adaptive or death signals. This occurs through both unconventional splicing of XBP1 mRNA and regulated IRE1-dependent decay of mRNA (RIDD). Whereas XBP1 mRNA splicing is cytoprotective in response to endoplasmic reticulum (ER) stress, RIDD has revealed many unexpected features. For instance, RIDD cleaves RNA at an XBP1-like consensus site but with an activity divergent from XBP1 mRNA splicing and can either preserve ER homeostasis or induce cell death. Here we review recent findings on RIDD and propose a model of how IRE1 RNase activity might control cell fate decisions.

The broiler breeder paradox: ethical, genetic and physiological perspectives, and suggestions for solutions.

1. Due to intensive selection, broiler chickens became the most efficient meat-producing animals because of their fast growth, supported by a virtually unlimited voluntary feed intake. These characteristics cause many problems in the management of broiler breeder hens because of the negative correlation between muscle growth and reproduction effectiveness. 2. This problem, namely the fast muscle growth versus reproduction health paradox, induces a second paradox, acceptable reproduction and health versus hunger stress and impaired welfare, because broiler breeder hens require dedicated programmes of feed restriction (1) to maximise egg and chick production and (2) to avoid metabolic disorders and mortality in broiler breeders. 3. Given that poultry selection is a global large-scale business and chickens are a prolific species, improvement in profit can only be obtained by selecting on feed conversion and/or for higher breast meat percentage, which will intensify the broiler-breeder paradox. 4. New feeding strategies are being studied, but it is questionable if the paradox can be solved by management tools alone. Because breeding and selection are long-term processes, involving animals, farmers, consumers, industry, environment etc., a more sustainable breeding goal needs to be determined by a multidisciplinary approach and an open debate between several actors in the discussion. 5. Using dwarf broiler breeder hens could be one alternative, because dwarf hens combine relatively good reproductive fitness with ad libitum feeding. Another possibility is to accept lower broiler productivity by assigning economic values to welfare and including integrity traits in an extended breeding goal.

Differential expression of the interleukin 5 receptor alpha isoforms in blood and tissue eosinophils of nasal polyp patients.

BACKGROUND: Given the key role of interleukin-5 (IL-5) in eosinophil function, we investigated the regulated expression of the membrane-anchored (TM-IL-5Ralpha) isoform, or a secreted (SOL IL-5Ralpha) isoform, on both protein and transcript level in vitro and in vivo. METHODS: A real-time PCR, FACS and ELISA were established to determine IL-5Ralpha isoform expression in peripheral blood and nasal tissue from control subjects and nasal polyp (NP) patients with or without asthma. Human peripheral blood eosinophils were incubated with IL-5 and were analyzed for SOL-IL-5Ralpha and TM-IL-5Ralpha mRNA and protein levels in comparison with CD-69 expression. RESULTS: SOL-IL-5Ralpha and TM-IL-5Ralpha mRNA and protein expression was significantly increased in NP vs controls. In polyp tissue, SOL-IL-5Ralpha expression correlated to disease severity and eosinophils counts, whereas TM-IL-5Ralpha levels were inversely correlated to eosinophils counts and SOL-IL-5Ralpha expression. FACS analysis revealed increased CD-69 and decreased TM-IL-5Ralpha expression in NP tissue eosinophils vs blood eosinophils. Incubation of blood eosinophils with IL-5 caused up-regulation of CD-69 and down-regulation of TM-IL-5Ralpha after 2 and 24 h. CONCLUSION: The expression of SOL-IL-5Ralpha and TM-IL-5Ralpha differs according to the eosinophil activation state and localization in the body (blood vs tissue) and may therefore be involved in the fine-tuning of the eosinophil homeostasis. Exposure of eosinophils to IL-5 reduces their responsiveness to IL-5 by regulated expression of the IL-5Ralpha isoforms. Since, TM-IL-5Ralpha is down-regulated and SOL-IL-5Ralpha (antagonistic) is upregulated in NP tissue, our findings are important to understand the clinical trials with anti-IL-5 in humans.

TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme.

Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kappaB (NF-kappaB). TLR, IL-1R and TNF-R signaling to NF-kappaB converge on a common IkappaB kinase complex that phosphorylates the NF-kappaB inhibitory protein IkappaBalpha. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kappaB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.

[Factors predicting mortality during an outbreak of Legionnaire's disease in the north of France]. / Epidémie de légionellose dans le Pas-de-Calais (2003--2004): analyse descriptive et facteurs prédictifs d'une évolution défavorable.

Between November 2003 and January 2004 in the North of France a large outbreak of legionnaire's disease affected 85 patients. The clinical, biological and radiological characteristics of the patients were investigated to determine factors associated with mortality. Two populations were defined and compared: patients who died within 28 days and those who survived. Eighty-five patients were included in this study. The median age was 75 years. The median fever was 39.3 +/- 0.1 degrees. Fifteen patients (17.6%) had at least 3 underlying co-morbidities. Cough, dyspnoea, confusion and diarrhoea were found in respectively 46, 68, 47, and 15% of the patients. The median of urea was 0.7 +/- 0.05 g/L, creatinine 16 +/- 1.5 mg/L, CRP 332 +/- 15 mg/L. On the chest X-ray, lung infiltrates were present in 64% and multilobar in 40%. The overall mortality rate was 21%. In univariate analysis, diabetes mellitus, dyspnoea, urea>0.90 g/l and CRP>350 mg/l were predictive factors of mortality. In multivariate analysis, diabetes mellitus, urea>0.90 g/l, and bilateral infiltrates on chest X ray were retained as independent risk factors for death.

Consumer perception versus scientific evidence about alternatives for manual catching of broilers in Belgium.

Commercial broiler chickens are exposed to a number of potential stressors prior to slaughter, including catching, crating, and transportation. To ameliorate animal welfare and prevent product quality loss during these processes, numerous scientific studies have been performed. As a result, different technical innovations have been presented such as mechanical catching instead of manual catching. The success of a catching machine as an alternative for manual catching of broilers will not only depend on its economic, animal, and human welfare benefits but also on its acceptance by society and consumers. The aim of this research was to assess if individuals' subjective perceptions of catching methods align with objective scientific facts. This research was focused on questions and issues related to the consumers' expected bottlenecks and motives for accepting these technologies after being exposed to video segments of each catching method. In general, the gap between consumer perception and scientific evidence related to manual and mechanical catching is limited. For those bottlenecks where science is inconclusive, respondents also have no explicit preference. Despite absence of major gaps between consumer perception and expert knowledge, preferences of particular consumer segments do not align well with scientific evidence. This holds in particular for female, younger, urban individuals who attach high importance to animal welfare issues.

Novel role of WD40 and SOCS box protein-2 in steady-state distribution of granulocyte colony-stimulating factor receptor and G-CSF-controlled proliferation and differentiation signaling.

Signals induced by granulocyte colony-stimulating factor (G-CSF), the major cytokine involved in neutrophil development, are tightly controlled by ligand-induced receptor internalization. Truncated G-CSF receptors (G-CSF-Rs) that fail to internalize show sustained proliferation and defective differentiation signaling. Steady-state forward routing also determines cell surface levels of cytokine receptors, but mechanisms controlling this are poorly understood. Here, we show that WD40 and suppressor of cytokine signaling (SOCS) box protein-2 (Wsb-2), an SOCS box-containing WD40 protein with currently unknown function, binds to the COOH-terminal region of G-CSF-R. Removal of this region did not affect internalization, yet resulted in increased membrane expression of G-CSF-R and enhanced proliferation signaling at the expense of differentiation induction. Conversely, Wsb-2 binding to the G-CSF-R reduced its cell surface expression and inhibited proliferation signaling. These effects depended on the SOCS box involved in ubiquitylation and on cytosolic lysines of G-CSF-R and imply a major role for ubiquitylation through the G-CSF-R C-terminus in forward routing of the receptor. Importantly, the Wsb-2 gene is commonly disrupted by virus integrations in mouse leukemia. We conclude that control of forward routing of G-CSF-R is essential for a balanced response of myeloid progenitors to G-CSF and suggest that disturbance of this balance may contribute to myeloid leukemia.

Consumers' preferences toward techniques for improving manual catching of poultry.

Growing interest in ameliorating animal welfare has prompted numerous studies that compare various aspects of manual and mechanical catching. In general, mechanical catching has been adopted as a realistic alternative for manual catching. The success of a catching machine as an alternative for manual catching does not only depend on its practical applicability, but also on its acceptance by "the general public." In the history of technological change, public perception of new technologies has often been ambivalent. Against this background, it is important to know how consumers perceive the production methods. This paper provides an evaluation of the preferences for catching methods by "society" to investigate whether there is a shift in preference due to the confrontation with video segments and the potential effect of awareness and importance attached to animal welfare on preference. Data were gathered through a questionnaire-based survey, including 450 respondents, performed in Belgium. For this study, the data indicated that when subjects were provided information concerning catching methods of broilers, they liked the technology much more. However, for those respondents without prior awareness of both catching methods or with high importance attached to animal welfare, giving information could not convince them of the advantage of using a mechanical catching machine. It is obvious that preference varies with the awareness and experience of the respondents. Future research should move forward from simple assessments of consumer concerns about the technologies and focus more directly on questions and issues related to the consumer's expected bottlenecks of these technologies. In this way, working at a better understanding can directly influence the acceptance of these technologies.

Analysis of leptin signalling in hematopoietic cells using an adapted MAPPIT strategy.

The adipocyte-secreted hormone leptin participates in the regulation of hematopoiesis and enhances proliferation of hematopoietic cells. We used an adaptation of the MAPPIT mammalian two-hybrid method to study leptin signalling in a hematopoietic setting. We confirmed the known interactions of suppressor of cytokine signalling 3 (SOCS3) and STAT5 with the Y985 and Y1077 motifs of the leptin receptor, respectively. We also provide evidence for novel interactions at the Y1077 motif, including phospholipase C gamma and several members of the SOCS protein family, further underscoring the important role of the Y1077 motif in leptin signalling.

A role for leptin in the systemic inflammatory response syndrome (SIRS) and in immune response, an update.

Leptin was originally identified as an adipocyte-derived cytokine with a key role in the regulation of the energy balance. Subsequent research revealed that leptin's biological action is not restricted to its effects on appetite and food intake, but instead has a much more pleiotropic character. There is now ample evidence that leptin has important functions in reproduction, hematopoiesis, HPA-axis endocrinology and angiogenesis. In this review we have focused on the effects of leptin in the antigen-specific immunity and in the inflammatory effector system.

Leptin, immune responses and autoimmune disease. Perspectives on the use of leptin antagonists.

The pivotal role of leptin in regulating body weight and energy homeostasis is very well established. More recently, leptin also emerged as an important regulator of T-cell-dependent immunity. Reduced leptin levels, as observed during periods of starvation, correlate with an impaired cellular immune response, whereby especially the T(H)1 pro-inflammatory immune response appears to be affected. Physiologically, this could reflect the high energy demand of such processes, which are suppressed in animals or people with nutrient shortage. Several autoimmune diseases are T(H)1 T-cell dependent. In line with a pro-inflammatory role for leptin, animal models of leptin deficiency are markedly resistant to a variety of T-cell dependent autoimmune diseases. Here, we review the role of leptin in immune responses, with emphasis on autoimmune diseases. The design and potential use of leptin antagonists is also discussed.

[Langerhans cell histiocytosis and sclerosing cholangitis in adults]. / Association histiocytose pulmonaire langerhansienne et cholangite sclerosante de l'adulte.

INTRODUCTION: Langerhans cell histiocytosis and sclerosing cholangitis are two rare diseases that are frequently linked in children, but very rarely so in adults. CASE REPORT: A 40 year old woman with a 17 year history of Langerhans cell histiocytosis with chronic respiratory failure and diabetes insipidus presented with cholestatic jaundice whilst being assessed for lung transplantation. Pathological examination demonstrated sclerosing cholangitis. No Langerhans histiocytosis lesions were found in the liver or the biliary tract. Plans for pulmonary and hepatic transplantation were abandoned after cerebral involvement was detected, and the patient died of acute hepatic failure. CONCLUSION: This case underlines the need to monitor liver function in adult patients with disseminated Langerhans histiocytosis associated in adults, as coexisting sclerosing cholangitis is associated with a poor prognosis.

Leptin: linking adipocyte metabolism with cardiovascular and autoimmune diseases.

Leptin was originally discovered as an adipocyte-derived hormone involved in the central control of body weight and energy homeostasis. It is now clear that leptin is a pleiotropic cytokine, with activities on many peripheral cell types. These findings may help explain the surprising role of leptin in pathophysiological processes. Recent evidence suggests that leptin contributes to atherosclerosis and to the increased risk of cardiovascular disease in obese people. Leptin also appears to be involved in T-cell-dependent immunity and possibly in the development and maintenance of certain autoimmune diseases. Here, we review the role of leptin in cardiovascular and autoimmune diseases, and also briefly address the potential therapeutic use of leptin antagonists.

[Multifocal epithelioid haemangioendothelioma: a difficult diagnosis]. / Hémangioendothéliome épithélioïde multifocal de diagnostic difficile.

INTRODUCTION: Epithelioid haemangioendothelioma is a rare vascular tumour of slow growth and unfavourable outlook, with occasional spontaneous and complete remissions. CASE REPORT: We report the case of a 69 year old woman admitted to hospital on account of haemoptysis. The clinical and radiological findings were compatible with diffuse pulmonary haemorrhage of unknown aetiology. Lung biopsy revealed a picture of pulmonary haemorrhage without vascular changes or tumour cells. Further progress was characterised by recurrent haemoptysis and the development of a haemothorax, liver nodules and skin lesions, biopsy of which confirmed the diagnosis of epithelioid haemangioendothelioma. The patient died several weeks later. CONCLUSION: The pulmonary localisation of epithelioid haemangioendothelioma is non specific, represented mainly by parenchymatous nodules with or without accompanying haemoptysis. Haemothorax is a more uncommon presentation of this disorder and a pleural localisation is often associated with a multifocal and aggressive form. The pathological diagnosis is most often made by surgical lung biopsy. Nevertheless in certain cases it can be difficult to make and this case report shows that, in the presence of a haemothorax, the search for extrapulmonary deposits accessible for biopsy may prove useful.

[Severe varicella zoster pneumonia during the course of treatment with azathioprine for Crohn's disease]. / Pneumopathie varicelleuse sévère au cours d'un traitement par azathioprine pour une maladie de Cröhn.

INTRODUCTION: Disseminated varicella zoster infection has only rarely been reported in patients with inflammatory bowel disease, despite the frequent use of azathioprine for this disorder. CASE REPORT: We report the case of an 18-year-old woman who developed severe varicella zoster pneumonia 9 months after starting azathioprine for Crohn's disease. The patient recovered after prompt treatment with acyclovir and discontinuation of the azathioprine. CONCLUSIONS: Strategies concerning the treatment and the prevention of varicella infection in the immunocompromised patient are discussed.