Indoor air quality and respiratory health in schools

What link is there between poor indoor air quality and the allergic and respiratory health of children in French schools? The “Epidemiology of Allergic and Respiratory Diseases” (EPAR) team led by Isabella Annesi-Maesano, Director of research at the joint research unit 707 “epidemiology, information systems and modeling” (Inserm/UPMC) has recently published an article in the review Thorax showing the results of its study on the quality of the air inside 108 primary schools in 6 French towns. Although the indoor air quality varies depending on the schools and the towns, the researchers reveal that around 30% of the 6590 children monitored during this study, i.e. 3 out of 10 children, are exposed to atmospheric pollution levels higher than the values recommended by the WHO and the French agency for Food, Environmentaland OccupationalHealth Safety (ANSES)1. This exposure is related to an increase in cases of asthma and rhinitis in school children, among whom those who suffer from allergies are the most at risk.

Children are more sensitive to the effects of pollution than adults. In children, indoor air pollution can lead to both short-term and long-term health problems, such as nasal congestion, skin and eye irritations, allergic reactions, asthma, headaches, tiredness, dizziness or even nausea. In industrialized countries, children spend roughly 80% of their time indoors, a large part of this at school. Although the American authorities have reported increased indoor air pollution in schools, very little research has been undergone into the relationships between the quality of the air in schools and the allergic and respiratory health of school children. For this reason, the EPAR team led by Isabella Annesi-Maesano, Director of Research at Inserm, carried out a study in six French towns (Bordeaux, Clermont-Ferrand, Créteil, Marseille, Strasbourg and Reims) on a large sample of 401 classes in 108 primary schools. The aim of the study was to assess the exposure of the 6590 children taking part (girls and boys, average age 10 years old) to the main atmospheric pollutants present in classrooms and to analyze the resulting association with the cases of asthma and rhinitis developed by the children in these classes. The study shows that 30% of the children are exposed to indoor air pollutant levels in the classroom that are higher than the values recommended by the WHO and the ANSES (1), in other words, 3 out of 10 children, even although they are not all subjected to exposure in the same way. “The advantage of our study was in having a large number of children from all the different regions of mainland France”, explained Isabella Annesi-Maesano, Director of Research at the Inserm institute. During an entire school year, the research scientists analyzed the concentrations of different atmospheric pollutants: fine particulates with diameters of less than 2.5 micrometers (PM2.5), nitrogen dioxide (NO2) and 3 aldehydes (formaldehyde, acetaldehyde and acroleine). The fine particulates and the nitrogen dioxide (NO2) are caused mainly by automobile combustion and can enter rooms by transfer (such as when the windows are opened). Aldehydes are indoor pollutants that can come from numerous sources: combustion products (cigarettes, candles, incense, chimneys, gas cookers), building and decoration products (wood, stratified parquet flooring, adhesives used for carpeting, wallpapers, and also varnish, foam insulation products), maintenance and cleaning products (detergents, disinfectants, cleaning wipes) and products used for treatment such as insecticides, etc. In parallel, the research team studied the clinical signs of the children using data collected from a medical check-up that included a skin test to detect the 11 most common allergenic products (dust mites, cat hairs, pollens, etc.), plus an exercise test to detect effort-induced asthma. To complete the data, a questionnaire was filled in by the parents. “Exposure to high concentrations of particulates and volatile organic compounds is related to an increase in the prevalence of clinical signs of asthma and rhinitis in school children. Children prone to allergies seem to be the most at risk“, revealed Isabella Annesi-Maesano. In detail, the results show that cases of rhinitis (in particular rhino conjunctivitis) are significantly related to high levels of formaldehyde in the classrooms and that an increase in the prevalence of asthma was observed in classrooms where there were high levels of PM2.5 fine particulates, formaldehyde and acroleine. The relation between the poor quality of the air and asthma nearly always concerns allergic asthma as defined by the skin test. “The poor quality of the indoor air could eventually undermine the allergic and respiratory health of children who spend an average of 8 hours per day at school. So it is important to ensure good quality air in the classroom. This would help to limit the risks of developing the clinical signs of rhinitis and asthma. But we must also closely monitor how children are exposed to pollutants at home and outdoors”, concluded the research team.

The 6 towns used in the study: The French contribution to the ISAAC study 

The 6 major towns that took part in the ISAAC study (French part)

The specific aims of the study

The objective of the international study known as International Study of Asthma and Allergies in Childhood (ISAAC) is to measure the frequency and the severity of asthma and allergic diseases (phase I), to determine the risk factors (phase II) and to study the development of these diseases (phase III). The French part of the study took place in 6 major towns (Reims, Créteil, Strasbourg, Clermont Ferrand, Bordeaux, Marseille), selected for their different air qualities. The study initially involved 9615 children with an average age of 10 years, belonging to 401 classes from 108 schools. Sensors were set up to measure the exposure to gaseous pollutants and pumps measured the exposure to particulates both indoors (classrooms, school canteen) and outdoors (school yards, covered playgrounds). The ISAAC study was covered by several publications.

The European study SINPHONIE

  A European study known as SINPHONIE is currently under way in 27 European countries, including France. Its aim is to study how the quality of the air in schools affects the overall health of the schoolchildren.

 A question of healt

Isabella Annesi-Maesano will be present at the next Citizen’s conference as part of the cycle “A question of health”. It is organized by the Inserm and will take place on May 31, 2012 on the theme: “Asthma in children: how is it affected by tobacco smoke?” It will be held at the Palais de la découverte, a Universcience site in Paris and will be linked up with Numerica in Montbéliard (25).

Footnotes: (1) Fine particulates (PM2.5): 10μg/m3 according to the World Health Organization (WHO) Nitrogen dioxide (NO2): 40μ/m3 according to the (WHO) Formaldehydes: 10μg/m3 per year according to the French agency for health, food, environmental and occupational safety

(French) Une stratégie de prévention pour éviter la mort subite chez les patients atteints de la maladie de Steinert

Sorry, this press release is only available in French.

How sleep reduces our awareness of the outside world

While we sleep, our self-awareness and our awareness of the outside world are reduced. Why? Habib Benali, Director of Research at the Inserm functional imaging laboratory (Unit 678 Inserm/UPMC) and his team have been investigating this phenomenon. The research scientists have shown that during nonrapid eye movement sleep, the brain’s activity is re-organized into networks that communicate less with each other than during wakefulness. The results of this study on brain activity have been published in the PNAS review.

Deep slow sleep is a sleep phase in which our self-awareness and our consciousness of the outside world are considerably reduced. Yet the neurons in our brain are still highly active during this phase. So consciousness is not just associated to brain activity, but rather to its ability to process information. This is the conclusion of the study carried out by the research scientists from the functional imaging laboratory (Inserm/Université Pierre et Marie Curie) of Pitié Salpêtrière, and the Cyclotron research center of Liège.

© H. Benali / Inserm

Graphical representation showing the flow of information inside the brain during

wakefulness (on the left) and during nonrapid eye movement sleep

By measuring the quantity of information exchanged between different areas of the brain, the research scientists were able to show that the flow of information in the brain during sleep was different from that observed during wakefulness.

During sleep, the activity of the brain seems to be organized into a multitude of smaller networks. Inside each network, data exchange is just as active, even more active than during wakefulness, but communication between these networks decreases“, explains Habib Benali, Director of Research at Inserm.

The figure shows that the brain (B) contains different networks (colored circles) that group together several brain areas (small peripheral black dots). The longer the black lines connecting these structures (colored circles and black dots), the more able they are to process information independently. During sleep (situation on the right), the distance between these structures increases, meaning that the information in these small clusters of brain areas is processed on a more local scale.

The research team believes that this is due to a hierarchical reorganization of the flow of information during NREM sleep, since this has been observed repeatedly at several levels in the brain. “We suggest that the modification of the information flows between areas of the brain reduces the brain’s ability to generate a unified representation of the person and the outside World” states Habib Benali.

A step closer to morphine without side effects?

Morphine has been used for centuries to relieve severe pain. However, its pain-relief properties are coupled with considerable side effects. Morphine imitates the action of molecules produced naturally by the brain (endorphins). So why does it have such harmful side effects? This question has recently been elucidated by Sébastien Granier, researcher at the Institute of Functional Genomics (Inserm/CNRS/Universités de Montpellier 1 and 2) and his team, in conjunction with collaborators in the US. The 3D structure of brain receptors is likely to differ, depending on the type of molecule bound upon it (morphine or endorphin): the body’s response will be completely and accordingly modified. Thanks to this discovery, the researchers have now set their sights on retaining the benefits of morphine while eliminating any undesired side effects.

The results were published in the Nature review on 21 March 12.

Opium is a natural poppy (papaver somniferum) extract and is one of the oldest drugs known to man, used for its psychotropic, sedative and analgesic properties. These effects are caused by its major component: morphine. Today morphine has widespread clinical pain-relief applications.

Morphine’s action is relayed by μ-opioid receptors expressed at the surface of cells in the central nervous system. These receptors are part of a superfamily of proteins, G protein-coupled receptors (GPCR), which are the target of around 30% of drugs currently on the market.

At a molecular level, morphine binds with μ-opioid receptors to imitate the action of molecules produced naturally in the brain: endorphins. However, its clinical use is limited by two effects. Firstly, the development of a tolerance phenomenon means that, in the case of repeated injections, the morphine dose must be increased to obtain the same therapeutic effect. Secondly, morphine consumption can lead to drug dependency (heroin, the acetylated form of morphine, is the most obvious example). Furthermore, morphine consumption has serious side effects: respiratory depression, constipation, physical and psychic dependency. These harmful effects can be explained by the fact that morphine triggers a cellular response that differs from that triggered by endorphins. Since morphine and endorphins bind with the same receptor, the two molecules stabilize the μ-opioid receptors in separate spatial conformations that cause the differences in biological responses.

It is therefore essential to understand the structural bases of morphine action, and opioids in general, if we are to develop molecules that retain the beneficial effects of morphine whilst eliminating the side effects,” explains Sébastien Granier, Inserm researcher and project leader.

The research produced by Sébastien Granier (and Brian Kobilka’s team in Stanford) resolved the 3D structure of μ-opioid receptors when associated with a molecule that has a similar chemical structure to morphine.

© Kobilka Lab
3D representation of μ-opioid receptors when associated with morphine antagonistic.

© Kobilka Lab

3D representation of a μ-opioid receptor dimer.

The images of the 3D structure above show that the specific area in the receptor where the opioid molecule binds is mostly open to the external medium, thus explaining the rapid action of these components.

The structure also reveals a very important characteristic of this receptor function: the formation of a receptor dimer (1). “This is the very first time that we have succeed in producing images of the 3D structure of a complex of this kind for this receptor family” he adds. This structure with a μ-opioid receptor dimer opens up avenues of research to study this phenomenon and improve understanding of these functional implications.

The 3D structure resolution of the μ-opioid receptor holds the key to treating pain and addictions, and could, in the long-run, lead to the production of new analgesic medicine with no side effects.


(1) Molecule produced by ‘associating’ two identical molecules

New discovery of proteins involved in positioning muscular nuclei

The position of cellular nuclei in muscle fibres has an important role in some muscle weaknesses. Edgar Gomes, an Inserm researcher in the myology group at the Institute of Myology (mixed Inserm/UPMC unit) recently made this discovery in collaboration with an American team. The researchers identified several proteins involved in “correctly” positioning nuclei, which is required for the muscles to function. Their results are published in a letter in the Nature review, dated 18 March.

In order to move, living beings need muscles, and, more specifically, skeletal muscles that are controlled by the nervous system. Skeletal muscles are composed of cylindrical muscle fibres with a multitude of peripheral nuclei. Until now, little was known about the mechanism used to position nuclei on the edge of muscle fibres. A team of French-American researchers has tried to better understand the reasons behind nuclei layout.

Edgar Gomes and his team of collaborators have identified the mechanism involved in positioning nuclei in muscle fibres. The researchers identified (in Drosophila and mice) two proteins involved in positioning the nuclei: protein Kif5B, which belongs to the kinesin family (molecular motor), and protein MAP7, which is used to move different organelles (1) in cells.

This result was achieved by mutating MAP7 and Kif5b protein-coding genes in the Drosophila and by studying the development of the embryo. In this case, they observed that the nuclei were not correctly aligned in the muscle fibres.

MAP7 is required to position nuclei in muscle fibre in Drosophila and in mammals” states Edgar Gomes, Inserm researcher. The research team succeeded in describing the nuclei-positioning mechanism in fibres, which involved the MAP7 protein and its interaction with the molecular motor: kinsin Kif5b. They demonstrated that a mutation of these proteins did not affect muscle extension or its attachment to the skeleton: only the position of the nuclei was affected.

By making both proteins interact together, Edgar Gomes’ team suggest that MAP7 binds with Kif5b to encourage nuclei positioning. “Furthermore, these proteins act together, both physically and genetically, and their physical bond is required for correct nuclei positioning. Our results show that they are required for the muscle to function correctly” underlines Edgar Gomes.

Muscular diseases lead to weaknesses in the fibres and can be associated with a cellular nuclei alignment failure. Edgar Gomes and his team have demonstrated that by correctly replacing the nuclei, the muscle recovers its functions. “We suggest that by correcting muscular positioning faults in patients suffering from myopathies, these patients may see improvements in their muscular functioning” concludes Edgar Gomes.


(1) Specialized structures in the cell contained in the cytoplasm

The Ravine jumping gene

Infantile anorexia with vomiting is a symptom observed in certain remote regions on Réunion, surrounded by ravines. It is from this geographical feature that the related neurological disease gets its name. The team led by Alexandra Henrion Caude, research associate at Inserm’s “Genetics and epigenetics of metabolic, neurosensory and development disorders” unit (Inserm/Université Paris Descartes) studied the genetic causes of what the team has called “Ravine” syndrome. This research has established, for the first time, a link between a human hereditary disease and a one-off mutation of a non-coding “jumping” gene. This type of gene is made up of elements repeated in the genome which were long thought to be useless. The results, published in the journal PNAS, show that a single gene change is responsible for this fatal disease, and that the same type of gene could play a significant role in the development of the brain.

In the south of Réunion, a French island in the Indian Ocean, wide ravines cutting into the mountains have, in the past, isolated some of the island’s population. As a result of its particular geographical location and socio-economic situation, this region has historically been marked by a high degree of inbreeding. As a result, genetic anomalies have been passed down from one generation to another. Alexandra Henrion Caudes and her team looked into the genetic causes of a serious disease, which has been named Ravine syndrome or Ravine encephalopathy owing to the fact that it is observed mainly in populations living in the vicinity of ravines. It occurs in some children on the island before they reach their first birthday. They show symptoms of infantile anorexia with uncontrollable vomiting, as well as a gradual disappearance of the brain’s white matter, which is what makes the disease fatal. “Ever since Darwin, islands have been renowned especially for their fauna and flora. Their isolation, however, also makes them an ideal site for studying genetic diseases,” points out Alexandra Henrion Caude, Inserm research associate and coordinator of this study.

According to the classical definition, genes only represent a minute part of the human genome, half of which is composed of repetitive DNA sequences, including what are known as “jumping” genes. The impact of variations in these genes has been largely unexplored until now. In this study, Alexandra Henrion Caude, François Cartault, a geneticist at La Réunion university hospital and their teams analysed the genetic profile of nine families, some of which had several affected children. In one jumping gene, they identified a one-off mutation that was common to the children with Ravine syndrome. If the child inherits this mutation from both parents, he or she contracts the disease. Based on this single variation, the researchers revealed the existence of a long, mutant non-coding RNA molecule that causes this neurological disease.

© Serge Gelaber

Ravine on the island of Réunion, where geographic isolation may have contributed to a founder effect

They simulated the production of the non-coding RNA observed in the diseased brain and observed the induction of neuronal death. The observed mutation is located in a hairpin RNA structure. Drawing on this RNA structure, the research team has put forward various hypotheses regarding the involvement of this jumping gene in maintaining neuronal balance: RNA editing, small RNA (micro RNA) maturation and/or functioning via specific proteins (PIWI, SRP).

“This is the first time that a human hereditary disease has been associated with a one-off mutation in this type of jumping gene, transcribed as a long non-coding RNA,”

explains Alexandra Henrion Caude.

Her recent work points to intracellular dynamics in this type of non-coding RNA, based on the location of certain small RNA molecules in the mitochondria, and the important role played by these RNA molecules in human development.

“The history of how Réunion was populated partly explains how Ravine syndrome developed on the island. Our study explores the genetic origins of this disease and we suggest that jumping genes modify complex functioning networks of the human brain,” adds the researcher.

A predictive test to assess the risks of bowel cancer

A discovery presented by Catherine Seva, biologist at Inserm

Two research scientists, Catherine Seva and Audrey Ferrand, from a combined team of researchers from Inserm / Université Toulouse III – Paul Sabatier (Cancerology research center of Toulouse), have just developed a test to predict the risk of colorectal cancer. This test, based on the presence of a protein known as progastrine, can predict the risk of tumors occurring in patients who have already undergone surgery to remove polyps that were considered to be benign. In practice, these tests could be used for routine screening on resected polyps in order to identify patients presenting a high risk of developing precancerous lesions and for whom no monitoring is recommended at present. The results of this work are published in the review Cancer prevention research.

Bowel cancer is the 4th highest cause of death from cancer in France. So March 2012 has been named “Blue March”, colorectal cancer awareness month.

© Inserm

A predictive test to assess the risks of bowel cancer

Colorectal (or bowel) cancer is the second most frequent cancer. Hyperplasic polyps are the most frequently occurring colorectal lesions Nearly one quarter of the European population between the ages of 20 and 54 will develop this type of polyp. For a long time, these lesions were considered to be benign, so currently there is no recommended monitoring of these patients once the polyps have been removed surgically. However, some of these polyps could be precursory signs of bowel cancers. Up until now, we had no way of identifying the sub-group of polyps with potential for malignancy.

So with the aim of finding a biomarker that could predict the risk of bowel cancer in patients presenting with hyperplasic polyps – the most benign type – Catherine Seva and her co-workers carried out a 10-year retrospective clinical study. They analyzed the presence of a particular protein name progastrine in hyperplasic polyps from 74 patients. Progastrine is already known to play a part in colic cancerogenesis. This protein, produced by tumerous colorectal cells, is not present in healthy bowel cells. So the researchers tried to find out whether the expression of this protein could predict the occurrence of cancerous lesions in the years following surgical resection of the polyps. “When we first put forward this hypothesis, we had in mind the idea that this was a step towards ensuring suitable monitoring and very early detection of colorectal cancer”, explains Catherine Seva, Research Director at Inserm.

Thanks to these analyses, the research scientists showed that there was indeed a significant relationship between high levels of progastrine and future occurrence of precancerous lesions. And yet although these polyps had been considered as benign and risk-free, within a period of 2 to 10 years, 100% of patients who presented high levels of progastrine developed adenomas, renowned as early colorectal cancer lesions. Inversely, in patients who expressed little or no progastrine, no lesion developed at all over the 10 years following the removal of their polyps.

Based on these results, the researchers compiled a predictive test based on the age of the patient and prograstrine immunohistochemical marking. This highly sensitive and specific tests can predict tumors in patients who have developed hyperplasic polyps.

Immunohistochemical marking of a benign hyperplasic polyp with no progastrine marking

© C. Seva / Inserm

Immunohistochemical marking of a benign hyperplasic polyp with no progastrine marking

Immunohistochemical marking of a benign hyperplasic polyp that presents with progastrine marking

© C. Seva / Inserm

Immunohistochemical marking of a benign hyperplasic polyp that presents with progastrine marking

There is no recommended monitoring at the present time, and yet measuring the prograstrine expression in hyperplasic polyps could identify the population of patients who have a high risk of developing a precancerous lesion”, concludes Audrey Ferrand, research scientists at Inserm and signatory of this paper.

As a result of this study, it could be envisaged to include a larger number of patients to valid this as a routine test.

This research has been patent-protected by Inserm Transfert.

Launch of “Health in Questions”, a new series of public conferences providing a fresh debate into health issues between the general public, civil society and scientists

With a view to strengthening dialogue into “science and society”, Inserm, in partnership with Universcience (1) and players from regional scientific and technical sectors, has launched “Health in questions”, a series of public conferences. The objective is to encourage interactivity with the public and to provide a platform for public information, reaction, expression and personal accounts; the participative conferences propose several annual events held on national or international health days. As such, these events will highlight an issue from health-related current affairs and then debate it in the presence of experts (researchers, doctors, sociologists, etc.) and representatives from civil society (patient associations, political groups, etc.).

Knowledge acquired in life sciences and health sectors helps produce treatments to combat disease; but this progress also has ethical, societal and economic consequences.

During the ‘Week of the Brain’, Inserm, Unverscience and their partners are pleased to invite you to join in discussions on:

“Parkinson’s disease: can we regenerate the brain?”

Thursday, 15 March, from 6.30pm to 8pm

at the Palais de la découverte, a Universcience venue in Paris

with live link-ups with the La Coupole theatre in Saint-Louis.

Parkinson’s disease is a neurodegenerative disorder characterized by the progressive loss of a single type of brain cell. Is transplanting healthy cells produced by induced pluripotent stem cells the solution?


  • Marianne Kuhn, Chairwoman of the France Parkinson Alsace association – rf.oodanaw@ennairam.nhuk // +33 (0)3 89 40 29 90
  • Pr Philippe Remy, neurology dept. at the Hôpital Henri Mondor in Créteil and leader of the “Clinical imaging of neurodegenerative diseases” research team, MIRCen, Orsay –rf.phpa.nmh@ymer.eppilihp-oruen // +33 (0)6 61 79 37 90
  • Dr Christine Tranchant, Neurology dept., Hôpitaux Universitaires, Strasbourg – rf.gruobsarts-urhc@tnahcnarT.enitsirhC // +33 (0)3 88 12 85 31

Debate chaired by Jean-Philippe Braly (La Recherche).

This first conference from the “Health in Questions” series will be inaugurated by Claudie Haigneré, Chairwoman of Universcience and Pr. André Syrota, Inserm Chairman and CEO, at the Palais de la découverte in Paris. Inaugurations will also be led by Gérard Binder, Chairman of the Nef des sciences in Mulhouse and Gilles Block, Inserm Grand Est Regional delegate, at the La Coupole theatre in Saint-Louis. This conference is part of a general partnership agreement that will be signed, during the event, by Inserm and Universcience.

(1) Public establishment run by the Palais de la découverte and the Cité des sciences et de l’industrie.

Discovery of a new type of bone sarcoma

A joint Institut Curie/Inserm team headed by Dr. Olivier Delattre has discovered the existence of a new form of bone sarcoma, affecting mainly adolescents and young adults.

Although similarities exist with Ewing’s tumor in the clinical field, a different chromosomal abnormality is responsible for the development of this sarcoma.

This new information should enable to improve patient management.

The results of this discovery have been published online in Nature Genetics on March 4.

Institut Curie is the French center of excellence for the detection and clinical management of Ewing’s tumors, performing the majority of molecular diagnostic tests for this pathology. The team of Olivier Delattre, research director of Inserm 830/Institut Curie “Genetics and Biology of Cancers” unit, was thus able to examine the genetic material of 594 children suspected to have Ewing’s tumor. Using a new sequencing technology called Next generation sequencing (NGS), they were able to analyze large volumes of genetic material simultaneously. During this study, the researchers discovered a different mutation than the one responsible for Ewing’s tumor, in some samples[1].

They managed to isolate 24 samples with this new mutation: an inversion of the X chromosome resulting in the fusion between two neighboring genes, BCOR and CCNB3. The very small distance separating these genes, which are located on the same chromosome, made them impossible to discover until now with the traditional diagnosis methods.

Then the researchers compared the gene expression profiles of the samples with those of Ewing’s tumor samples. The “ID card” of the new form of sarcoma indicates a different expression for approximately 3,000 genes. “This ‘new’ fusion is certainly responsible for a different sarcoma rather than a variant of Ewing’s tumor”, declared Dr. Olivier Delattre.

“It is the first time that the possibility of identifying a new tumor entity using high throughput sequencing tools is established”, added Inserm researcher Franck Tirode, co-author of the published study. He then noted: “In a single study, we have detected 24 positive cases for this translocation, and that is a significant number”. “In absolute value, these 24 cases are equivalent to the number of cases due to rare translocations of Ewing’s tumor”, added co-author Gaëlle Pierron, coordinator of Institut Curie’s Somatic Genetics unit.

Presence of the fusion protein was verified on tumor samples using immunohistochemistry techniques that enable to locate specific proteins. “Detection of the over-expression of the CCNB3 protein, because of its fusion with BCOR, is extremely specific to these tumors, enabling a simple diagnostic test”, explained Gaëlle Pierron.

Towards improved patient management

“Currently, patients are treated similarly to patients with Ewing’s tumors. It will now be possible to carry out clinical studies to look for the possibility of other treatment methods”, declared Olivier Delattre.

It will be possible to detect other patients affected by this new type of sarcoma. Identification of the fusion between the two genes could enable diagnosis of this new form of tumor in new patients, who will then benefit from adapted treatment.

“Actual advances in oncology result from the dialogue between physicians and researchers. It is important to provide everyone with the means to strengthen this exchange”, concluded Dr. Olivier Delattre.

Researchers will now work to decipher the active mechanism of the fusion protein that results in the formation of the tumor. In particular, they will try to understand why this new type of sarcoma is clinically similar to Ewing’s tumor, while the tumors are not biologically similar. Common activation of specific intracellular signaling pathways could be the cause.

Sections of bone sarcoma with marking of the CCNB3 fusion protein

Coupe de tumeur d'Ewing, le marquage brun révélant la protéine de fusion spécifique du nouveau sarcome n'apparaît pas car la protéine CCNB3 n'est pas exprimée.

© JM Coindre/Institut Bergonié

Coupe de tumeur nouvellement identifiée. Le marquage brun révèle l'expression de la protéine de fusion BCOR-CCNB3 dans les cellules.

© JM Coindre/Institut Bergonié

Left: Section of Ewing’s tumor, the brown staining showing the specific fusion protein of the new sarcoma does not appear because the CCNB3 protein is not expressed.

Right: Section of the newly identified tumor. The brown staining shows the expression of the BCOR-CCNB3 fusion protein in cells.


  • Tumors arising in mesenchymal tissues, sarcomas are a very heterogeneous group of tumors, which can be divided in more than 100 different subtypes according to clinical, pathological, immunohistological and genetic criteria.
  • A distinction is made between malignant bone tumors and sarcomas of soft tissues outside the bone.
  • In children, adolescents and young adults (under 30), osteosarcomas and Ewing’s tumors are the two most common bone sarcomas. The incidence rate at age 15 is 3.6% for osteosarcomas and 3 % for Ewing’s tumors.
  • As for osteosarcomas, no gene translocation has yet been reported.
  • It is in Olivier Delattre’s unit at Institut Curie that the chromosomal abnormality responsible for the development of Ewing tumor was discovered in 1984, and characterized in 1992. It is a translocation that occurs in 90 % of the cases between chromosomes 11 and 22, resulting in the synthesis of an abnormal EWS-FLI-1 protein, and in 10 % of the cases between chromosomes 22 and 21, resulting in the synthesis of an abnormal EWS-ERG protein. Other rare alterations can occur. The discovery of genetic alterations enabled the creation of a molecular diagnostic test for Ewing’s tumor at Institut Curie in 1994.
  • Initially relying mainly on radiotherapy, treatment has significantly evolved in the past 30 years. Today, localized forms are mainly treated using a combination of chemotherapy and surgery. Postoperative surgery, and sometimes radiotherapy, complete the treatment. The prognosis of Ewing’s tumor has benefited from new chemotherapies.

In addition to Inserm and Institut Curie, this research was financed by the French League Against Cancer and by the French National Cancer Institute.

In addition, Dr. Olivier Delattre’s team also receives financial support from APAESIC (Association of Parents and Friends of Children Treated at Institut Curie), Les Bagouz à Manon, Pas du Géant, Olivier Chape, Les Amis de Claire and Courir pour Mathieu, as well as the Fédération Enfants et Santé.

[1] Ewing’s tumor is characterized by an accidental exchange of genetic material between two chromosomes, resulting in the formation of a mutated gene producing an abnormal protein called EWS/FLI-1.

How does cannabis affect working memory?

A deterioration of working memory is observed in people who consume drugs containing cannabinoid compounds found in cannabis leaves and buds. A team led by Giovanni Marsicano, Supervisor of Inserm Research Unit 862 (Magendie Neurocentre, University of Bordeaux), in collaboration with a team led by Xia Zhang (University of Ottawa, Canada), has recently identified the mechanism by which these substances affect working memory. These researchers have demonstrated for the first time that the adverse effect of cannabinoids on working memory is exerted via receptors located in the glial cells (brain cells present in large numbers and scarcely studied). This effect is associated with a decrease in neural connections in the hippocampus, the region of the brain that coordinates working memory processes.

These results were published in Cell on 2 March 2012.

Working memory is used perform common cognitive operations (thinking, reading, writing, calculating, etc.) on information stored temporarily (for periods ranging from a few seconds to a few minutes). This allows for the integration audio, visual and spatial information. One of the major effects of intoxication with cannabinoids is the alteration of working memory, as observed in both humans and animals. Cannabis disturbs this function, thus preventing the consumer from performing common daily tasks. Cannabinoid receptors are expressed in the glial cells of the hippocampus, a cerebral structure essential for memory modulation. The cellular mechanisms responsible for the adverse effects of cannabis on this memorization process were previously unknown.

Giovanni Marsicano and his collaborators at the Magendie Neurocentre (Inserm Research Unit 862, University of Bordeaux 2) have successfully identified a mechanism by which cannabis causes adverse effects on working memory. The researchers have demonstrated that cannabinoids, when connected to their receptors, can decrease the strength of neural connections in the hippocampus.

Cannabinoids are a group of approximately 60 compounds present in cannabis leaves and buds. They act on the brain via cannabinoid receptors. In this study, the researchers have focused on cannabinoid receptor CB1, present in large quantities in nerve terminals within the brain (see diagram below). Cannabinoid receptor CB1 is present both in neural membranes (shown in yellow) and in the membranes of astroglial cells (shown in pink) located in the hippocampus (en orange) and used to provide support for neurons.

The connection of cannabinoids (shown in green) to CB1 receptors (shown in pink) activates the transmission of glutamate signals (shown in light blue) to the glutamate receptors (shown in dark blue) of nerve terminals used to transfer information between neurons. This mechanism modulates the strength of connections between hippocampal neurons (signal depression), thereby disturbing working memory.

In order to identify the action mechanisms of cannabinoids, the researchers have evaluated spatial working memory in the presence of THC, the best known cannabinoid (shown in green). Two groups of mice were studied in which CB1 receptors had been suppressed (in astroglial and neural cells, respectively).

When CB1 receptors are suppressed only in neural cells, the presence of THC causes spatial working memory deficits. On the contrary, when CB1 receptors are suppressed only in astroglial cells, spatial working memory performance is preserved. Therefore, the CB1 receptors located in astroglial cells are responsible for the adverse effects of THC on spatial working memory.

“These in vitro and in vivo results surprisingly demonstrate the importance of the activation of the CB1 receptors of astroglial cells, and not those of neural cells, in the mediation of the effects of cannabinoids on working memory”, explains Giovanni Marsicano.

Over the past years, a large number of studies have demonstrated the interest of cannabis for the treatment of various diseases. “The description of cannabinoid-specific action mechanisms in the hippocampus should enable optimization of the therapeutic potential of cannabinoids, which is currently limited by significant adverse effects associated with their consumption”.