Stress signalling in acellular slime moulds and its detection by conspecifics.

Unicellular organisms live in unpredictable environments. Therefore, they need to continuously assess environmental conditions and respond appropriately to survive and thrive. When subjected to rapid changes in their environment or to cellular damages, unicellular organisms such as bacteria exhibit strong physiological reactions called stress responses that can be sensed by conspecifics. The ability to detect and use stress-related cues released by conspecifics to acquire information about the environment constitutes an adaptive survival response by prompting the organism to avoid potential dangers. Here, we investigate stress signalling and its detection by conspecifics in a unicellular organism, Physarum polycephalum. Slime moulds were subjected to either biotic (i.e. nutritional) or abiotic (i.e. chemical and light) stressors or left undisturbed while they were exploring a homogeneous environment. Then, we observed the responses of slime moulds facing a choice between cues released by stressed clone mates and cues released by undisturbed ones. We found that slime moulds actively avoided environments previously explored by stressed clone mates. These results suggest that slime moulds, like bacteria or social amoeba, exhibit physiological responses to biotic and abiotic stresses that can be sensed by conspecifics. Our results establish slime moulds as a promising new model to investigate the use of social information in unicellular organisms. This article is part of the theme issue 'Signal detection theory in recognition systems: from evolving models to experimental tests'.

Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling.

Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/ß-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.

Pancreatic tumours escape from translational control through 4E-BP1 loss.

The mRNA cap-binding protein eIF4E (eukaryotic translation initiation factor 4E) permits ribosome recruitment to capped mRNAs, and its phosphorylated form has an important role in cell transformation. The oncogenic function of eIF4E is, however, antagonised by the hypophosphorylated forms of the inhibitory eIF4E-binding proteins 1 and 2. eIF4E-binding protein 1 and 2 (4E-BP1 and 2) are two major targets of the protein kinase mTOR, and are essential for the antiproliferative effects of mTOR inhibitors. Herein, we report that pancreas expresses specifically and massively 4E-BP1 (4E-BP2 is nearly undetectable). However, 4E-BP1 expression is extinguished in more than half of the human pancreatic ductal adenocarcinomas (PDAC). 4E-BP1 shutoff is recapitulated in a mouse genetic model of PDAC, which is based on a pancreas-specific mutation of Kras, the more frequently mutated oncogene in human pancreatic tumours. 4E-BP1 downregulation enhances eIF4E phosphorylation and facilitates pancreatic cancer cell proliferation in vitro and tumour development in vivo. Furthermore, 4E-BP1 loss combined with the absence of 4E-BP2 renders eIF4E phosphorylation, protein synthesis and cell proliferation resistant to mTOR inhibition. However, proliferation can be better limited by a recently developed compound that mimics the function of 4E-BP1 and 2 independently of mTOR inhibition.

Dual roles of hemidesmosomal proteins in the pancreatic epithelium: the phosphoinositide 3-kinase decides.

Given the failure of chemo- and biotherapies to fight advanced pancreatic cancer, one major challenge is to identify critical events that initiate invasion. One priming step in epithelia carcinogenesis is the disruption of epithelial cell anchorage to the basement membrane which can be provided by hemidesmosomes (HDs). However, the existence of HDs in pancreatic ductal epithelium and their role in carcinogenesis remain unexplored. HDs have been explored in normal and cancer pancreatic cells, and patient samples. Unique cancer cell models where HD assembly can be pharmacologically manipulated by somatostatin/sst2 signaling have been then used to investigate the role and molecular mechanisms of dynamic HD during pancreatic carcinogenesis. We surprisingly report the presence of mature type-1 HDs comprising the integrin α6ß4 and bullous pemphigoid antigen BP180 in the human pancreatic ductal epithelium. Importantly, HDs are shown to disassemble during pancreatic carcinogenesis. HD breakdown requires phosphoinositide 3-kinase (PI3K)-dependent induction of the matrix-metalloprotease MMP-9, which cleaves BP180. Consequently, integrin α6ß4 delocalizes to the cell-leading edges where it paradoxically promotes cell migration and invasion through S100A4 activation. As S100A4 in turn stimulates MMP-9 expression, a vicious cycle maintains BP180 cleavage. Inactivation of this PI3K-MMP-9-S100A4 signaling loop conversely blocks BP180 cleavage, induces HD reassembly and inhibits cell invasion. We conclude that mature type-1 HDs are critical anchoring structures for the pancreatic ductal epithelium whose disruption, upon PI3K activation during carcinogenesis, provokes pancreatic cancer cell migration and invasion.

[Predictive value of postural and dynamic walking parameters after high-volume lumbar puncture in normal pressure hydrocephalus]. / Intérêt prédictif de l'évolution des facteurs posturaux et locomoteurs après ponction lombaire soustractive dans l'hydrocéphalie chronique de l'adulte.

INTRODUCTION: Normal pressure hydrocephalus (NPH) was described by Adams et al. (1965). The common clinical presentation is the triad: gait disturbance, cognitive decline and urinary incontinence. Although these symptoms are suggestive, they are not specific to diagnosis. The improvement of symptoms after high-volume lumbar puncture (hVLP) could be a strong criterion for diagnosis. We tried to determine a specific pattern of dynamic walking and posture parameters in NPH. Additionally, we tried to specify the evolution of these criteria after hVLP and to determine predictive values of ventriculoperitoneal shunting (VPS) efficiency. PATIENTS AND METHODS: Sixty-four patients were followed during seven years from January 2002 to June 2009. We identified three periods: before (S1), after hVLP (S2) and after VPS (S3). The following criteria concerned walking and posture parameters: walking parameters were speed, step length and step rhythm; posture parameters were statokinesigram total length and surface, length according to the surface (LFS), average value of equilibration for lateral movements (Xmoyen), anteroposterior movements (Ymoyen), total movement length in lateral axis (longX) and anteroposterior axis (longY). RESULTS: Among the 64 patients included, 22 had VPS and 16 were investigated in S3. All kinematic criteria are decreased in S1 compared with normal values. hVLP improved these criteria significantly (S2). Among posture parameters, only total length and surface of statokinesigram showed improvement in S1, but no improvement in S2. A gain in speed greater or equal to 0.15m/s between S1 and S2 predicted the efficacy of VPS with a positive predictive value (PPV) of 87.1% and a negative predictive value (NPV) of 69.7% (area under the ROC curve [AUC]: 0.86). CONCLUSION: Kinematic walking parameters are the most disruptive and are partially improved after hVLP. These parameters could be an interesting test for selecting candidates for VPS. These data have to be confirmed in a larger cohort.

Anti-oncogenic potential of the eIF4E-binding proteins.

The eIF4E-binding proteins (4E-BPs) are inhibitors of protein synthesis that sequester the mRNA cap-binding protein eIF4E and consequently block cell growth and proliferation. In most tumors however, their inhibitory function is compromised by major oncogenic signaling pathways. Recently, thanks to the generation of mouse genetic models, considerable progress has been made in elucidating the involvement of 4E-BPs and their unique target, eIF4E, in the process of carcinogenesis. Increasing evidence indicates that an 'addiction' to protein synthesis emerges in cancer cells, highlighting the potential that 4E-BPs have as targets for therapeutics. In this review, we summarize the biochemical function, regulation and anti-oncogenic activity of the 4E-BPs.

A business rules design framework for a pharmaceutical validation and alert system.

OBJECTIVES: Several alert systems have been developed to improve the patient safety aspects of clinical information systems (CIS). Most studies have focused on the evaluation of these systems, with little information provided about the methodology leading to system implementation. We propose here an 'agile' business rule design framework (BRDF) supporting both the design of alerts for the validation of drug prescriptions and the incorporation of the end user into the design process. METHODS: We analyzed the unified process (UP) design life cycle and defined the activities, subactivities, actors and UML artifacts that could be used to enhance the agility of the proposed framework. We then applied the proposed framework to two different sets of data in the context of the Georges Pompidou University Hospital (HEGP) CIS. RESULTS: We introduced two new subactivities into UP: business rule specification and business rule instantiation activity. The pharmacist made an effective contribution to five of the eight BRDF design activities. Validation of the two new subactivities was effected in the context of drug dosage adaption to the patients' clinical and biological contexts. Pilot experiment shows that business rules modeled with BRDF and implemented as an alert system triggered an alert for 5824 of the 71,413 prescriptions considered (8.16%). CONCLUSION: A business rule design framework approach meets one of the strategic objectives for decision support design by taking into account three important criteria posing a particular challenge to system designers: 1) business processes, 2) knowledge modeling of the context of application, and 3) the agility of the various design steps.

Scaling of the structural relaxation in simulated liquid silica.

A scaling law for the alpha relaxation time tau , involving the ratio of a density-dependent energy to the thermal energy, has been found to hold in many fragile glass-forming liquids. This scaling has been recently linked to a local quantity n{loc}(rho,T) relating the variation of tau with density to its variation with temperature. In many fragile liquids, the variation of n{loc}(rho,T) is weak enough to take it as constant over the experimental temperature and density domain. We show that simulated liquid silica has an opposite behavior; close to T{g}, n{loc} is negative for moderate densities and exhibits a significant variation with rho and T, reaching positive values for higher temperature and/or densities. Moreover, those variations linearly correlate to a measure of the bonding properties of the liquid.

Electronic Healthcare Record and clinical research in cardiovascular radiology. HL7 CDA and CDISC ODM interoperability.

Integrating clinical research data entry with patient care data entry is a challenging issue. At the G. Pompidou European Hospital (HEGP), cardiovascular radiology reports are captured twice, first in the Electronic Health Record (EHR) and then in a national clinical research server. Informatics standards are different for EHR (HL7 CDA) and clinical research (CDISC ODM). The objective of this work is to feed both the EHR and a Clinical Research Data Management System (CDMS) from a single multipurpose form. We adopted and compared two approaches. First approach consists in implementing the single "care-research" form within the EHR and aligning XML structures of HL7 CDA document and CDISC ODM message to export relevant data from EHR to CDMS. Second approach consists in displaying a single "care-research" XForms form within the EHR and generating both HL7 CDA document and CDISC message to feed both EHR and CDMS. The solution based on XForms avoids overloading both EHR and CDMS with irrelevant information. Beyond syntactic interoperability, a perspective is to address the issue of semantic interoperability between both domains.

Novel synergistic mechanism for sst2 somatostatin and TNFalpha receptors to induce apoptosis: crosstalk between NF-kappaB and JNK pathways.

Somatostatin is a multifunctional hormone that modulates cell proliferation, differentiation and apoptosis. Mechanisms for somatostatin-induced apoptosis are at present mostly unsolved. Therefore, we investigated whether somatostatin receptor subtype 2 (sst2) induces apoptosis in the nontransformed murine fibroblastic NIH3T3 cells. Somatostatin receptor subtype 2 expression induced an executioner caspase-mediated apoptosis through a tyrosine phosphatase SHP-1 (Src homology domain phosphatase-1)-dependent stimulation of nuclear factor kappa B (NF-kappaB) activity and subsequent inhibition of the mitogen-activated protein kinase JNK. Tumor necrosis factor alpha (TNFalpha) stimulated both NF-kappaB and c-Jun NH2-terminal kinase (JNK) activities, which had opposite action on cell survival. Importantly, sst2 sensitized NIH3T3 cells to TNFalpha-induced apoptosis by (1) upregulating TNFalpha receptor protein expression, and sensitizing to TNFalpha-induced caspase-8 activation; (2) enhancing TNFalpha-mediated activation of NF-kappaB, resulting in JNK inhibition and subsequent executioner caspase activation and cell death. We have here unraveled a novel signaling mechanism for a G protein-coupled receptor, which directly triggers apoptosis and crosstalks with a death receptor to enhance death ligand-induced apoptosis.

Continuous supercritical synthesis and dielectric behaviour of the whole BST solid solution.

In this study we show that pure and well crystallized nanoparticles of Ba(x)Sr(1-x)TiO(3) (BST) can be synthesized over the entire range of composition through the hydrolysis and further crystallization of alkoxide precursors under supercritical conditions. To our knowledge, this is the first time that the whole ferroelectric solid solution has been produced in a continuous way, using the same experimental conditions. The composition of the powder can be easily controlled by adjusting the feed solution composition. The powders consist of soft-aggregated monocrystalline nanoparticles with an average particle size ranging from approximately 20 to 40 nm. Ferroelectric ceramics with accurately adjustable Curie temperature (100-390 K) can thus be obtained by sintering.

Physiology of somatostatin receptors.

Since its discovery three decades ago as an inhibitor of GH release from the pituitary gland, somatostatin has attracted much attention because of its functional role in the regulation of a wide variety of physiological functions in the brain, pituitary, pancreas, gastrointestinal tract, adrenals, thyroid, kidney and immune system. Its actions include inhibition of endocrine and exocrine secretions, modulation of neurotransmission, motor and cognitive functions, inhibition of intestinal motility, absorption of nutrients and ions and vascular contractility. In addition, the peptide controls the proliferation of normal and tumor cells. Its action is mediated by a family of G protein-coupled receptors [somatostatin receptor (SSTR)1-SSTR5] that are widely distributed in normal and cancer cells. Direct antitumor activities, mediated through SSTR expressed in tumor cells, include blockade of autocrine/paracrine growth-promoting hormone and growth factor production, inhibition of growth factor-mediated mitogenic signals and induction of apoptosis. Indirect antitumor effects include inhibition of growth-promoting hormone and growth factor secretion, and antiangiogenic actions. Many human tumors express more than one SSTR subtype, with SSTR2 being predominant. These receptors represent the molecular basis for the clinical use of somatostatin analogs in the treatment of endocrine tumors and their in vivo localization. This review covers the present knowledge in SSTR biology and signaling.

Sinus CT scans and mediator release in nasal secretions after nasal challenge with cypress pollens.

BACKGROUND: Involvement of paranasal sinuses has been suggested in allergic rhinitis but not clearly demonstrated. AIMS: To investigate the relationship between intermittent allergic rhinitis and computerized tomography (CT). METHODS: Twenty patients with intermittent rhinitis and sensitized to cypress pollens underwent unilateral nasal provocation tests (NPTs) using increasing concentrations of cypress pollens out of the pollen season. Sinus CT-scans were carried out just before a NPT and 24 h later. Nasal lavage was carried out just before a NPT, 30 min after a positive challenge and again 24 h later. Leucotriene C4/D4, intracellular adhesion molecule-1 and eosinophil cationic protein were measured in nasal secretions. RESULTS: Thirteen patients (65%) showed an alteration in their CT-scans after allergen challenge. Ten of them showed sinus changes controlateral to their allergenic provocation. Radiological changes mainly affected the osteomeatal complex and the ethmoid sinuses. Pre-existing abnormalities (13 of 20 cases) mainly concerned the maxillary sinuses. There was no correlation between CT-scan abnormalities and levels of mediators released in nasal secretions. CONCLUSIONS: We have shown that nasal allergen challenge can produce radiological changes in the paranasal sinuses. This mainly concerned the ethmoid sinuses.

Somatostatin receptors and regulation of cell proliferation.

Somatostatin is an inhibitory neuropeptide, which acts on various targets throughout the body to regulate a variety of physiological functions including inhibition of endocrine and exocrine secretions, modulation of neurotransmission, motor and cognitive functions, inhibition of intestinal motility, absorption of nutrients and ions, vascular contractility and inhibition of normal and tumour cell proliferation. It exerts its effects through interaction with five somatostatin receptors (sst1-sst5), which belong to the family of G-protein-coupled receptors with seven transmembrane spanning domains and are variably expressed in a variety of tumours such as gastroenteropancreatic tumours, pituitary tumours, and carcinoid tumours. This review covers the present knowledge regarding the molecular mechanisms involved in somatostatin antineoplastic activity. Evidence that sst2 receptor acts as a tumour suppressor is also discussed.

[Value of thoracic CT in the management of severe hemoptysis]. / Hémoptysies sévères: apport de la tomodensitométrie thoracique.

PURPOSE: To assess the value of thoracic CT in the management of patients with severe hemoptysis. PATIENTS AND METHODS: Between January 1997 and January 2001, 62 patients were investigated for severe hemoptysis (>300 ml/24H). The protocol, performed before angiography and embolization, included bronchial fiberoptic examination (BFE) followed by thoracic spiral CT-angiography. Data recorded at CT and BFE were the presence and location of bleeding, the etiology of hemoptysis and the therapeutic modality. RESULTS: Nine patients with life-threatening hemoptysis directly underwent bronchial embolization. CT was available in the 53 remaining patients. No abnormality was found in 4 patients. CT assessed the presence (n=49) and the location (n=38) of the bleeding. The etiology was determined in 49 patients. BFE was feasible in 38/53 patients. BFE assessed the presence (n=38) and location (n=15) of the bleeding. The etiology was determined in 12 cases of bronchial tumour. The available findings of CT and BFE for the presence and the location of the bleeding were concordant. Comparing fiberoptic examination and thoracic CT, the percentages of localized bleedings (39% and 72%) and demonstrated etiologies (32% and 92%), were significantly different (p<0,005 and p<0.0001 respectively). CONCLUSION: Although retrospective and limited by the small number of cases, our study provides arguments to perform thoracic CT before bronchial fiberoptic examination for the management of severe hemoptysis.

[Intracranial primary epidermoid carcinoma]. / Carcinome épidermoïde primitif intracrânien.

We report a case of intracranial primitive epidermoid carcinoma localized in the right temporal fossa in a 40-year-old man. The patient was submitted to surgical removal of his tumor and radiotherapy. Unfortunately, the survival time was six weeks after the operation. Clinical, radiological, anatomopathological features and the interest of the radiotherapy are discussed.