Covering various Needs in Temporal Annotation: a Proposal of Extension of ISO TimeML that Preserves Upward Compatibility

International audienceThis paper reports a critical analysis of the ISO TimeML standard, in the light of several experiences of temporal annotation that were conducted on spoken French. It shows that the norm suffers from weaknesses that should be corrected to fit a larger variety of needs in NLP and in corpus linguistics. We present our proposition of some improvements of the norm before it will be revised by the ISO Committee in 2017. These modifications concern mainly (1) Enrichments of well identified features of the norm: temporal function of TIMEX time expressions, additional types for TLINK temporal relations; (2) Deeper modifications concerning the units or features annotated: clarification between time and tense for EVENT units, coherence of representation between temporal signals (the SIGNAL unit) and TIMEX modifiers (the MOD feature); (3) A recommendation to perform temporal annotation on top of a syntactic (rather than lexical) layer (temporal annotation on a treebank)

Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors

International audienceBackgroundOverexpression of syndecan-1 (CD138) in breast carcinoma correlates with a poor prognosis and an aggressive phenotype. The objective of this study was to evaluate the potential of targeting CD138 by immuno-PET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either 124I or 131I in nude mice engrafted with the triple-negative MDA-MB-468 breast cancer cell line.MethodThe immunoreactivity of 125I-B-B4 (80%) was determined, and the affinity of 125I-B-B4 and the expression of CD138 on MDA-MB-468 was measured in vitro by Scatchard analysis. CD138 expression on established tumors was confirmed by immunohistochemistry. A biodistribution study was performed in mice with subcutaneous MDA-MB-468 and 125I-B-B4 at 4, 24, 48, 72, and 96 h after injection and compared with an isotype-matched control. Tumor uptake of B-B4 was evaluated in vivo by immuno-PET imaging using the 124I-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with 131I-B-B4 and the RIT efficacy evaluated.Results 125I-B-B4 affinity was in the nanomolar range (Kd = 4.39 ± 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 × 104 ± 9.27 × 102 epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of 125I-B-B4 peaked at 14% injected dose (ID) per gram at 24 h and was higher than that of the isotype-matched control mAb (5% ID per gram at 24 h). Immuno-PET performed with 124I-B-B4 on tumor-bearing mice confirmed the specificity of B-B4 uptake and its retention within the tumor. The MTD was reached at 22.2 MBq. All mice treated with RIT (n = 8) as a single treatment at the MTD experienced a partial (n = 3) or complete (n = 5) response, with three of them remaining tumor-free 95 days after treatment.ConclusionThese results demonstrate that RIT with 131I-B-B4 could be considered for the treatment of metastatic triple-negative breast cancer that cannot benefit from hormone therapy or anti-Her2/neu immunotherapy. Immuno-PET for visualizing CD138-expressing tumors with 124I-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging

Identification of Sclerostin as a Putative New Myokine Involved in the Muscle-to-Bone Crosstalk

Bone and muscle have been recognized as endocrine organs since they produce and secrete “hormone-like factors” that can mutually influence each other and other tissues, giving rise to a “bone–muscle crosstalk”. In our study, we made use of myogenic (C2C12 cells) and osteogenic (2T3 cells) cell lines to investigate the effects of muscle cell-produced factors on the maturation process of osteoblasts. We found that the myogenic medium has inhibitory effects on bone cell differentiation and we identified sclerostin as one of the myokines produced by muscle cells. Sclerostin is a secreted glycoprotein reportedly expressed by bone/cartilage cells and is considered a negative regulator of bone growth due to its role as an antagonist of the Wnt/β-catenin pathway. Given the inhibitory role of sclerostin in bone, we analyzed its expression by muscle cells and how it affects bone formation and homeostasis. Firstly, we characterized and quantified sclerostin synthesis by a myoblast cell line (C2C12) and by murine primary muscle cells by Western blotting, real-time PCR, immunofluorescence, and ELISA assay. Next, we investigated in vivo production of sclerostin in distinct muscle groups with different metabolic and mechanical loading characteristics. This analysis was done in mice of different ages (6 weeks, 5 and 18 months after birth) and revealed that sclerostin expression is dynamically modulated in a muscle-specific way during the lifespan. Finally, we transiently expressed sclerostin in the hind limb muscles of young mice (2 weeks of age) via in vivo electro-transfer of a plasmid containing the SOST gene in order to investigate the effects of muscle-specific overproduction of the protein. Our data disclosed an inhibitory role of the muscular sclerostin on the bones adjacent to the electroporated muscles. This observation suggests that sclerostin released by skeletal muscle might synergistically interact with osseous sclerostin and potentiate negative regulation of osteogenesis possibly by acting in a paracrine/local fashion. Our data point out a role for muscle as a new source of sclerostin.Bone and muscle have been recognized as endocrine organs since they produce and secrete “hormone-like factors” that can mutually influence each other and other tissues, giving rise to a “bone–muscle crosstalk”. In our study, we made use of myogenic (C2C12 cells) and osteogenic (2T3 cells) cell lines to investigate the effects of muscle cell-produced factors on the maturation process of osteoblasts. We found that the myogenic medium has inhibitory effects on bone cell differentiation and we identified sclerostin as one of the myokines produced by muscle cells. Sclerostin is a secreted glycoprotein reportedly expressed by bone/cartilage cells and is considered a negative regulator of bone growth due to its role as an antagonist of the Wnt/β-catenin pathway. Given the inhibitory role of sclerostin in bone, we analyzed its expression by muscle cells and how it affects bone formation and homeostasis. Firstly, we characterized and quantified sclerostin synthesis by a myoblast cell line (C2C12) and by murine primary muscle cells by Western blotting, real-time PCR, immunofluorescence, and ELISA assay. Next, we investigated in vivo production of sclerostin in distinct muscle groups with different metabolic and mechanical loading characteristics. This analysis was done in mice of different ages (6 weeks, 5 and 18 months after birth) and revealed that sclerostin expression is dynamically modulated in a muscle-specific way during the lifespan. Finally, we transiently expressed sclerostin in the hind limb muscles of young mice (2 weeks of age) via in vivo electro-transfer of a plasmid containing the SOST gene in order to investigate the effects of muscle-specific overproduction of the protein. Our data disclosed an inhibitory role of the muscular sclerostin on the bones adjacent to the electroporated muscles. This observation suggests that sclerostin released by skeletal muscle might synergistically interact with osseous sclerostin and potentiate negative regulation of osteogenesis possibly by acting in a paracrine/local fashion. Our data point out a role for muscle as a new source of sclerostin

The BioMart community portal: an innovative alternative to large, centralized data repositories.

The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations

Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation

International audienceAnterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein-protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes, through either autophagy-dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro-inflammatory responses

Chronic alcohol consumption, physical exercise and bone tissue : densitometric, microarchitectural, biomechanic and metabolic changes in the rat

La consommation d’alcool a des effets sur le tissu osseux. L’alcoolisme est une des causes d’ostéoporose secondaire chez l’homme. Dans ce travail nous avons mené différentes expérimentations chez le rat afin d’étudier les effets d’une consommation chronique d’alcool combinée ou non à un entraînement aérobie sur le tissu osseux. Nous avons montré qu’une faible dose d’alcool administrée pendant une période courte peut avoir un effet positif sur la densité minérale osseuse et l’épaisseur trabéculaire. En revanche, la combinaison activité physique et consommation modérée d’alcool n’a pas d’effet additif sur la potentialisation du tissu osseux. Nous avons également démontré un effet dose de l’alcool indiquant des effets délétères majorés sur la densité minérale osseuse (DMO), la microarchitecture corticale et la résistance osseuse avec des apports croissants (25%, 30% et 35% v/v). La modification de DMO s’accompagne d’un changement de composition corporelle et d’une diminution de la leptine systémique. Cependant, le nombre d’adipocytes augmente dans la moelle osseuse. Nous avons mis en évidence dans ce modèle d’ostéoporose secondaire due à l’alcool une augmentation de l’apoptose des ostéocytes, corrélée à la diminution de la DMO et à l’augmentation de l’adiposité médullaire. Nous avons de plus mis en évidence une incorporation de lipides dans les ostéocytes, incorporation fortement corrélée à l’apoptose de ces cellules. Enfin, nos résultats montrent qu’un exercice physique régulier combiné à une consommation chronique et excessive d’alcool permet de prévenir les effets délétères de l’alcool sur les paramètres osseux (porosité corticale, épaisseur corticale) et limite la diminution de la DMO. Cette diminution est associée à une régulation de l’apoptose des ostéocytes.Heavy chronic alcohol consumption has deleterious effects on bone tissue. It is one of the major causes of secondary osteoporosis in men. In this work, we draw several experimentations to assess the effects of chronic alcohol consumption on bone, combined or not to an aerobic training in the rat. We showed that light to moderate chronic alcohol consumption during a short time lead to an increase of bone mineral density (BMD) and trabecular thickness, whith no additive effects of physical exercise on bone tissue. When the alcohol doses were increased, we showed deleterious effects on BMD, microarchitecture, bone resistance with a dose effect with increasing alcohol doses (25%, 30% and 35% v/v): the more alcohol was concentrated and the more the bone parameters were decreased. The BMD decrease was associated with a change in body composition, and with a decrease in serum leptin. However, the number of lipid droplets in the bone marrow was increased dramatically. We demonstrated that there was a huge increase in osteocyte apoptosis with alcohol (35% v/v) in this alcohol-induced osteoporosis model, which was correlated with BMD and bone marrow adiposity. We have also shown that there was lipid incorporation in bone micro vessels and in osteocytes, which was correlated with osteocyte apoptosis. Lastly, we showed that when regular exercise was associated with heavy chronic alcohol consumption, the bone parameters were normal (trabecular, cortical thickness, femur length) and the BMD was less decreased compared to alcohol-fed and sedentary rats. These effects were associated with a regulation of osteocyte apoptosis

Chronic alcohol consumption, physical exercise and bone tissue : densitometric, microarchitectural, biomechanic and metabolic changes in the rat

La consommation d’alcool a des effets sur le tissu osseux. L’alcoolisme est une des causes d’ostéoporose secondaire chez l’homme. Dans ce travail nous avons mené différentes expérimentations chez le rat afin d’étudier les effets d’une consommation chronique d’alcool combinée ou non à un entraînement aérobie sur le tissu osseux. Nous avons montré qu’une faible dose d’alcool administrée pendant une période courte peut avoir un effet positif sur la densité minérale osseuse et l’épaisseur trabéculaire. En revanche, la combinaison activité physique et consommation modérée d’alcool n’a pas d’effet additif sur la potentialisation du tissu osseux. Nous avons également démontré un effet dose de l’alcool indiquant des effets délétères majorés sur la densité minérale osseuse (DMO), la microarchitecture corticale et la résistance osseuse avec des apports croissants (25%, 30% et 35% v/v). La modification de DMO s’accompagne d’un changement de composition corporelle et d’une diminution de la leptine systémique. Cependant, le nombre d’adipocytes augmente dans la moelle osseuse. Nous avons mis en évidence dans ce modèle d’ostéoporose secondaire due à l’alcool une augmentation de l’apoptose des ostéocytes, corrélée à la diminution de la DMO et à l’augmentation de l’adiposité médullaire. Nous avons de plus mis en évidence une incorporation de lipides dans les ostéocytes, incorporation fortement corrélée à l’apoptose de ces cellules. Enfin, nos résultats montrent qu’un exercice physique régulier combiné à une consommation chronique et excessive d’alcool permet de prévenir les effets délétères de l’alcool sur les paramètres osseux (porosité corticale, épaisseur corticale) et limite la diminution de la DMO. Cette diminution est associée à une régulation de l’apoptose des ostéocytes.Heavy chronic alcohol consumption has deleterious effects on bone tissue. It is one of the major causes of secondary osteoporosis in men. In this work, we draw several experimentations to assess the effects of chronic alcohol consumption on bone, combined or not to an aerobic training in the rat. We showed that light to moderate chronic alcohol consumption during a short time lead to an increase of bone mineral density (BMD) and trabecular thickness, whith no additive effects of physical exercise on bone tissue. When the alcohol doses were increased, we showed deleterious effects on BMD, microarchitecture, bone resistance with a dose effect with increasing alcohol doses (25%, 30% and 35% v/v): the more alcohol was concentrated and the more the bone parameters were decreased. The BMD decrease was associated with a change in body composition, and with a decrease in serum leptin. However, the number of lipid droplets in the bone marrow was increased dramatically. We demonstrated that there was a huge increase in osteocyte apoptosis with alcohol (35% v/v) in this alcohol-induced osteoporosis model, which was correlated with BMD and bone marrow adiposity. We have also shown that there was lipid incorporation in bone micro vessels and in osteocytes, which was correlated with osteocyte apoptosis. Lastly, we showed that when regular exercise was associated with heavy chronic alcohol consumption, the bone parameters were normal (trabecular, cortical thickness, femur length) and the BMD was less decreased compared to alcohol-fed and sedentary rats. These effects were associated with a regulation of osteocyte apoptosis

Consommation chronique d'alcool, exercice physique et tissu osseux : modifications densitométriques, architecturales, biomécaniques et métaboliques chez le rat

Heavy chronic alcohol consumption has deleterious effects on bone tissue. It is one of the major causes of secondary osteoporosis in men. In this work, we draw several experimentations to assess the effects of chronic alcohol consumption on bone, combined or not to an aerobic training in the rat. We showed that light to moderate chronic alcohol consumption during a short time lead to an increase of bone mineral density (BMD) and trabecular thickness, whith no additive effects of physical exercise on bone tissue. When the alcohol doses were increased, we showed deleterious effects on BMD, microarchitecture, bone resistance with a dose effect with increasing alcohol doses (25%, 30% and 35% v/v): the more alcohol was concentrated and the more the bone parameters were decreased. The BMD decrease was associated with a change in body composition, and with a decrease in serum leptin. However, the number of lipid droplets in the bone marrow was increased dramatically. We demonstrated that there was a huge increase in osteocyte apoptosis with alcohol (35% v/v) in this alcohol-induced osteoporosis model, which was correlated with BMD and bone marrow adiposity. We have also shown that there was lipid incorporation in bone micro vessels and in osteocytes, which was correlated with osteocyte apoptosis. Lastly, we showed that when regular exercise was associated with heavy chronic alcohol consumption, the bone parameters were normal (trabecular, cortical thickness, femur length) and the BMD was less decreased compared to alcohol-fed and sedentary rats. These effects were associated with a regulation of osteocyte apoptosis.La consommation d’alcool a des effets sur le tissu osseux. L’alcoolisme est une des causes d’ostéoporose secondaire chez l’homme. Dans ce travail nous avons mené différentes expérimentations chez le rat afin d’étudier les effets d’une consommation chronique d’alcool combinée ou non à un entraînement aérobie sur le tissu osseux. Nous avons montré qu’une faible dose d’alcool administrée pendant une période courte peut avoir un effet positif sur la densité minérale osseuse et l’épaisseur trabéculaire. En revanche, la combinaison activité physique et consommation modérée d’alcool n’a pas d’effet additif sur la potentialisation du tissu osseux. Nous avons également démontré un effet dose de l’alcool indiquant des effets délétères majorés sur la densité minérale osseuse (DMO), la microarchitecture corticale et la résistance osseuse avec des apports croissants (25%, 30% et 35% v/v). La modification de DMO s’accompagne d’un changement de composition corporelle et d’une diminution de la leptine systémique. Cependant, le nombre d’adipocytes augmente dans la moelle osseuse. Nous avons mis en évidence dans ce modèle d’ostéoporose secondaire due à l’alcool une augmentation de l’apoptose des ostéocytes, corrélée à la diminution de la DMO et à l’augmentation de l’adiposité médullaire. Nous avons de plus mis en évidence une incorporation de lipides dans les ostéocytes, incorporation fortement corrélée à l’apoptose de ces cellules. Enfin, nos résultats montrent qu’un exercice physique régulier combiné à une consommation chronique et excessive d’alcool permet de prévenir les effets délétères de l’alcool sur les paramètres osseux (porosité corticale, épaisseur corticale) et limite la diminution de la DMO. Cette diminution est associée à une régulation de l’apoptose des ostéocytes

Consommation chronique d'alcool, exercice physique et tissu osseux (modifications densitométriques, architecturales, biomécaniques et métaboliques chez le rat)

La consommation d alcool a des effets sur le tissu osseux. L alcoolisme est une des causes d ostéoporose secondaire chez l homme. Dans ce travail nous avons mené différentes expérimentations chez le rat afin d étudier les effets d une consommation chronique d alcool combinée ou non à un entraînement aérobie sur le tissu osseux. Nous avons montré qu une faible dose d alcool administrée pendant une période courte peut avoir un effet positif sur la densité minérale osseuse et l épaisseur trabéculaire. En revanche, la combinaison activité physique et consommation modérée d alcool n a pas d effet additif sur la potentialisation du tissu osseux. Nous avons également démontré un effet dose de l alcool indiquant des effets délétères majorés sur la densité minérale osseuse (DMO), la microarchitecture corticale et la résistance osseuse avec des apports croissants (25%, 30% et 35% v/v). La modification de DMO s accompagne d un changement de composition corporelle et d une diminution de la leptine systémique. Cependant, le nombre d adipocytes augmente dans la moelle osseuse. Nous avons mis en évidence dans ce modèle d ostéoporose secondaire due à l alcool une augmentation de l apoptose des ostéocytes, corrélée à la diminution de la DMO et à l augmentation de l adiposité médullaire. Nous avons de plus mis en évidence une incorporation de lipides dans les ostéocytes, incorporation fortement corrélée à l apoptose de ces cellules. Enfin, nos résultats montrent qu un exercice physique régulier combiné à une consommation chronique et excessive d alcool permet de prévenir les effets délétères de l alcool sur les paramètres osseux (porosité corticale, épaisseur corticale) et limite la diminution de la DMO. Cette diminution est associée à une régulation de l apoptose des ostéocytes.Heavy chronic alcohol consumption has deleterious effects on bone tissue. It is one of the major causes of secondary osteoporosis in men. In this work, we draw several experimentations to assess the effects of chronic alcohol consumption on bone, combined or not to an aerobic training in the rat. We showed that light to moderate chronic alcohol consumption during a short time lead to an increase of bone mineral density (BMD) and trabecular thickness, whith no additive effects of physical exercise on bone tissue. When the alcohol doses were increased, we showed deleterious effects on BMD, microarchitecture, bone resistance with a dose effect with increasing alcohol doses (25%, 30% and 35% v/v): the more alcohol was concentrated and the more the bone parameters were decreased. The BMD decrease was associated with a change in body composition, and with a decrease in serum leptin. However, the number of lipid droplets in the bone marrow was increased dramatically. We demonstrated that there was a huge increase in osteocyte apoptosis with alcohol (35% v/v) in this alcohol-induced osteoporosis model, which was correlated with BMD and bone marrow adiposity. We have also shown that there was lipid incorporation in bone micro vessels and in osteocytes, which was correlated with osteocyte apoptosis. Lastly, we showed that when regular exercise was associated with heavy chronic alcohol consumption, the bone parameters were normal (trabecular, cortical thickness, femur length) and the BMD was less decreased compared to alcohol-fed and sedentary rats. These effects were associated with a regulation of osteocyte apoptosis.ORLEANS-SCD-Bib. electronique (452349901) / SudocSudocFranceF