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Month: January 2022

Persistence of severe hepatic fibrosis despite substantial weight loss with bariatric surgery

Posted on by Graziella Cara

stéatose hépatique.

Detail of a steatosis, accumulation of a fat, triglyceride, in the liver cell. © Inserm/Hadchouel, Michelle

A research team from AP-HP, Inserm and Sorbonne University carried out work, within the IHU ICAN, on the effects of bariatric surgery on the severity of liver damage in patients with NASH (Non-Alcoholic Steatohepatitis or Metabolic Steatohepatitis) and severe fibrosis (bridge fibrosis or compensated cirrhosis). This study shows that in 50% of patients who underwent bariatric surgery, despite significant weight loss (20% to 30% of initial BMI) and improvement in metabolic risk factors (mainly type 2 diabetes), severe fibrosis persists in the medium term (5 years after surgery). The results of this work were published on January 25, 2022 in the journal Hepatology .

Obesity in France concerns 17% of the adult population and it increasingly affects children and adolescents. It has many consequences on the state of health of people who are affected, including the development of “fatty liver” (liver steatosis). Hepatic steatosis is defined by the accumulation of fat in liver cells favored by the presence of metabolic risk factors (particularly diabetes and obesity).

In France, liver steatosis affects 18% of the population and 25% of the general population worldwide. Eventually, this pathology, also called NASH, can lead to the appearance of more serious diseases such as cirrhosis or liver cancer. To date, there is no effective drug treatment for NASH, which makes research around other avenues of care for patients all the more important.

Previous work has shown dramatic improvement in NASH liver damage after bariatric surgery in parallel with weight loss. Nevertheless, efficacy data in patients with advanced forms of NASH remain limited.

The study, coordinated by Dr Raluca Pais (AP-HP, IHU ICAN), Dr Judith Aron-Wisnewsky (AP-HP, Inserm, Sorbonne University, IHU ICAN), Pr Vlad Ratziu (AP-HP, INSERM, Sorbonne University, IHU ICAN) and Pr Karine Clément (AP-HP, Inserm, Sorbonne University, NutriOmic Unit), analyzed the effects of bariatric surgery on the evolution of severe histological lesions of NASH. The patients, from the “BARICAN bariatric surgery” cohort coordinated by the nutrition department led by Pr Jean-Michel Oppert at the Pitié-Salpêtrière AP-HP hospital, had an initial liver biopsy at the time of surgery. bariatric and a follow-up biopsy.  

This study confirms the excellent results of bariatric surgery: overall, 29% of patients had normal histology at follow-up biopsy; 74% had NASH resolution without fibrosis progression; 70% had fibrosis regression.

However, in patients with severe fibrosis before surgery, severe fibrosis persisted in 47% of cases in the medium term after surgery, despite the resolution of NASH in 69% of cases.

Patients who do not respond to bariatric surgery have a lesser improvement in metabolic risk factors (less weight loss, remission of diabetes) even if clinically significant. The factors associated with the persistence of fibrosis after bariatric surgery, in addition to the follow-up interval, were age and type of surgery (less regression of fibrosis after the sleeve regardless of weight loss). The factors associated with the absence of liver lesions after bariatric surgery were greater weight loss, improved insulin resistance and less initial severity of necroinflammatory lesions.

In conclusion, Dr. Raluca Pais specifies that “ this study shows that, despite established efficacy for the regression of NASH, bariatric surgery is less effective for the regression of severe fibrosis. Fibrosis regression requires more time and probably additional mechanisms. Weight loss alone may not be enough to reverse severe fibrosis. »

Improvement in the Health of Two Infants with Severe Disharmonious Overgrowth Syndromes

Posted on by Graziella Cara

Co-labeling of mouse skin expressing a PIK3CA gene mutation. © Marina Firpion/Guillaume Canaud – Inserm unit 1151

 

Disharmonious overgrowth syndromes are rare genetic diseases associated with a PIK3CA gene mutation. Since 2016, a team of researchers from Inserm, Paris Public Hospitals Group (AP-HP), Université de Paris, the Disharmonious Overgrowth and Vascular Abnormalities Unit of Institut Necker-Enfants Malades and the clinical departments of Hospices Civils of Lyon has demonstrated the therapeutic efficacy of alpelisib, a molecule used to fight certain cancers, in treating a group of children and adults with severe forms of these diseases. In a new publication, the team reports clinical, biological, and imaging improvements in two infants with severe forms of disharmonious overgrowth syndromes treated with alpelisib. These are the first data obtained on the use of this molecule in severe neonatal forms of the disease. The results of this one-year follow-up have been published in Journal of Experimental Medicine (JEM).

Disharmonious overgrowth syndromes are rare genetic diseases characterized by an increase in both the size and number of cells in the body. They manifest by an asymmetry that can affect any body part or tissue (fat, vessels, muscles, bones, etc.), including the brain. In 95% of cases, the disease is linked to a mutation, occurring during embryonic development, of the PIK3CA gene that regulates cell growth and proliferation.

When PIK3CA is overactivated, the parts of the body affected by the mutation grow excessively, leading to physical deformities that are more or less debilitating depending on the number of tissues affected. While some symptoms can be alleviated by surgery and other supportive care, there is currently no approved drug treatment for the disease.

In previous research, the drug alpelisib, a PIK3CA inhibitor recently approved for the treatment of certain forms of breast cancer1, had shown promising results – first in animal models of overgrowth syndrome, and then in a small number of adults and children. The drug is currently undergoing a series of larger-scale clinical trials, but until now there had been no data on its efficacy in infants.

In this new study, a team of researchers from Inserm, Paris Public Hospitals Group (AP-HP) and Université de Paris, coordinated by Professor Guillaume Canaud, reports encouraging results with alpelisib administered for one year to two infants – one girl and one boy aged 8 months and 9 months, respectively, at the start of treatment – presenting with a variety of severe symptoms caused by PIK3CA gene mutations. These symptoms included extreme blood vessel malformations, anemia, excessive asymmetric growth of the limbs and fingers and, in the boy, excessive growth of one of the brain hemispheres (hemimegaloencephaly) associated with epileptic seizures2. Before the start of treatment, the girl’s condition was life-threatening and the boy had a serious neurological prognosis, which did not respond to conventional epilepsy drugs.

Good tolerability

In both infants, daily oral doses of 25 mg alpelisib led to rapid and significant clinical improvement in the symptoms. Twelve months of treatment stopped the boy’s epileptic spasms and reduced the girl’s number of vascular malformations. The considerable decrease in the volume of her right leg has enabled her to remain upright and walk, with assistance. The anemia resolved in both children following initiation of the treatment.

The infants’ length and weight that initially were outside the norm for their age corrected themselves following the introduction of alpelisib. It is important to note that they had no side effects related to the treatment. Further analyses revealed that with a dose of 25 mg per day, their blood levels of alpelisib were much lower than those safely tolerated by adults3.

“The results of the alpelisib treatment in these two infants are encouraging because they show an improvement across all parameters, whether clinical, biological, or radiological. The high level of efficacy observed may be because alpelisib was started early. The patients had no history of surgery, which is relevant because we know that the remodeling caused by it can affect how well alpelisib is absorbed by the tissues. Furthermore, it is very likely that the plasticity of the tissues at this age enables the treatment to work better, explains Professor Canaud, coordinator of the study. These results should however be interpreted with caution and be confirmed over time and with further monitoring,” he says.

This use of alpelisib in overgrowth syndromes continues to be the subject of clinical trials in a population of consisting not just of adults but also of children from 6 years of age. These encouraging results make it possible to envisage extending the drug’s approval to include the clinical treatment of severe neonatal forms.

The treatment of these infants with alpelisib is provided as part of a compassionate use program, in which the French medicines agency (ANSM) issues exceptional approval to treat patients suffering from diseases with a severe prognosis and with no appropriate treatment available, in a given therapeutic indication.

 

1 The PIK3CA gene is frequently mutated in a certain number of cancers. This mutation is believed to occur in approximately 40% of breast cancers.

2 The boy had West syndrome, also known as infantile spasms, a rare form of epilepsy in infants.

3 When treating cancer, the daily dose of alpelisib administered to an adult (between 300 and 350 mg) is approximately 15 times higher.

Sickle cell disease and transfusion-dependent beta thalassemia: promising results of gene therapy treatment

Posted on by Graziella Cara

Globules rouges en forme de faucille (drépanocytose)

Sickle-shaped red blood cells (sickle cell disease) © Inserm/Chevance de Boisfleury, Anne-Marie

Teams from AP-HP, the University of Paris, Inserm, the Imagine Institute, the University of Paris-Est Créteil and the CEA conducted a clinical gene therapy study consisting of transplanting in the patient’s own genetically modified hematopoietic stem cells 1 . This phase I/II clinical trial, promoted by bluebird bio, was carried out in patients with sickle cell disease or transfusion-dependent beta thalassemia, common genetic diseases that affect red blood cells. The results of this work, coordinated by Pr Marina Cavazzana and Pr Philippe Leboulch, were published on January 24, 2022 in Nature Medicine .

As part of the HGB-205 phase I/II clinical trial, four b-thalassemia patients and three sickle cell patients aged 13 to 21 were treated with lentiviral gene therapy. They were followed for a median of 4.5 years after inclusion in the specific dedicated protocols LTF-303 (for b-thalassemia patients) and LFT-307 (for sickle cell patients).

According to the results, the patients with b-thalassemia all became “transfusion independent”, from the first month after the treatment, with a marked improvement in iron overload and a correction of the biological parameters linked to chronic anemia.

A remission of all the clinical symptoms 2 and a correction of the biological parameters sustained over time were obtained in two of the three sickle cell patients treated. A reduction in the transfusion rate was obtained for the third patient with sickle cell disease.

All of these results are maintained over time with more than 4.5 years of follow-up for three patients. No adverse effects linked to the use of the therapeutic lentiviral vector have been observed.

For patients with b-thalassemia, the reported long-term results show that gene therapy by gene addition has become a potentially usable curative option in all patients who do not have a compatible hematopoietic stem cell donor.

In the case of sickle cell disease, the correction of the biological parameters linked to the chronic anemia of two out of three patients provides proof in principle of its effectiveness and opens the way for the introduction of further improvements with the aim of obtaining the same result in all sickle cell patients treated.

Sickle cell disease and transfusion-dependent beta thalassemia

Sickle cell disease and transfusion-dependent b-thalassemia are common genetic diseases. They are therefore a major public health problem. These two chronic anemias are due to mutations in the gene encoding the beta (b) chain of adult hemoglobin (HbA).

Transfusion-dependent b-thalassemia is characterized by an absence (b 0 ) or a marked reduction (b + ) of the synthesis of b-globin chains, responsible for inefficient production of red blood cells and chronic hemolytic anemia and severe, requiring lifelong red blood cell transfusions. The resulting iron accumulation can cause heart failure, cirrhosis, liver cancer and multiple endocrine abnormalities.

Sickle cell disease results from the mutation of an amino acid in position 6 of the b-globin chain (E6V mutation), resulting in the polymerization of sickle cell hemoglobin HbS (hemoglobin “sickle” in English) once the molecules of oxygen (O 2 ) delivered. The polymerization of HbS is at the origin of painful vaso-occlusive crises characterized by a local obstruction of the blood circulation which can affect all the organs and of a chronic haemolytic anemia 3 . Repetition of vaso-occlusive crises and vascular damage affect several vital organs such as the lungs, kidneys, central nervous system and heart, with a significant reduction in the average lifespan of affected subjects.

As with almost all genetic diseases of the hematopoietic system, the only curative option is to transplant hematopoietic stem cells. This approach gives very good clinical results and low mortality when an HLA-compatible sibling donor is available. Unfortunately, a limited percentage of patients can benefit from this treatment (<20%). The use of partially matched donors greatly limits the chances of success and carries significant long-term morbidity, particularly in older patients.

Genetical therapy

Gene therapy, through the transplantation of stem cells from the patient himself, genetically modified, is a promising alternative. It carries low risks of immunological toxicity since no immunosuppressive treatment is required. It can be set up for each patient who needs it, the patient being his own donor.

Gene therapy by gene addition is the first strategy to have emerged in this indication by exploiting the ability of lentiviral vectors 4 to transfer complex genetic information into the genome of hematopoietic stem cells without the cells needing perform cell division.

The lentiviral vector used in this phase I/II clinical trial was developed by the team led by Prof. Philippe Leboulch. This vector allows the synthesis of a modified form of the b-globin chain (b T87Q ), a genetic modification which has a double interest: it gives it an anti-polymerizing property comparable to that of the gamma (g) chain of fetal hemoglobin (HbF) in sickle cell patients and allows its specific dosage in the blood of treated patients. Indeed, the b T87Q -globin chain can be distinguished from other globin chains by high pressure liquid chromatography, in particular from the b-globin chain derived from adult hemoglobins (HbA), produced endogenously in b- patients. thalassemia carriers of mutations b+ and present in transfused red blood cells.

 

1 Hematopoietic stem cells are nestled in the bone marrow and are at the origin of the different blood cells: red blood cells, white blood cells and platelets.

2 The set of pathological clinical signs that characterize a disease.

3 This is an often hereditary pathology that affects the red blood cells with, ultimately, a pathological reduction in their number incompatible with life and requiring regular blood transfusions, the frequency of which is dictated by the level of Hemoglobin and the clinical symptoms.

4 These are the shuttles of genetic information in the nucleus of cells derived from the HIV-1 virus from which the genetic elements that allow it to replicate and give rise to the infectious disease for which it is responsible have been removed. The elements which enable them to cross the nuclear membrane and to integrate in a stable manner into the genome of the target cells have, on the other hand, been preserved.

Study of gene therapy treatment in Wiskott-Aldrich syndrome

Posted on by Graziella Cara

ADN

DNA © Fotolia

Teams from the AP-HP, University of Paris, Inserm, within the Imagine Institute, the University College of London, and Généthon, have carried out work on treatment by gene therapy consisting of transplanting the patient’s own genetically modified hematopoietic stem cells as part of a phase I/II clinical trial, promoted by Genethon, in 8 patients with Wiskott-Aldrich syndrome (WAS). The results of this work, carried out in parallel at the Hôpital Necker-Enfants Malades AP-HP, at the Great Ormond Street Hospital and at the Royal Free Hospital in London and coordinated by Pr Marina Cavazzana, Pr Adrian Thrasher and Pr Emma Moris , were published January 24, 2022 in Nature Medicine.

Wiskott-Aldrich syndrome (WAS) is an X-linked complex immune deficiency caused by mutations in the WAS gene which codes for the WAS protein (WASp). This protein is key in the regulation of cytoskeletal actin 1 in hematopoietic cells.

Deficiency of this protein is responsible for small platelet 2 thrombocytopenia and poor function of white blood cells, especially T, B, natural killer and dendritic cells.

The more severe clinical phenotype is characterized by severe infections, bleeding, eczema and manifestations of autoimmunity with a significant risk of developing tumor complications. The severity of clinical expression is related to the level of WAS protein expression. Without curative treatment, patients do not survive beyond the second-third decade of life.

The treatment of choice consists of allogeneic transplantation 3 of HLA-geno-identical hematopoietic stem cells, which has very good results, especially if it is carried out early (<5 years).

The prognosis of the allogeneic transplant actually depends on a number of parameters in addition to the patient’s age, including the degree of HLA compatibility between donor and recipient and the level of hematopoietic uptake.

In the absence of an HLA-compatible donor, the research teams have proposed a treatment by gene therapy which consists of taking blood stem cells carrying the genetic anomaly from patients (CD34+ hematopoietic stem cells), then correct in the laboratory by introducing the healthy WAS gene using a lentiviral vector developed by Anne Galy’s team at Généthon, where the clinical batches of vectors were also produced. The corrected cells are then injected into the patients, previously treated with chemotherapy in order to eliminate the diseased cells and make room for the autologous cells corrected in vitro which will then give rise to the various cells that make up the blood (white and red blood cells, platelets) .

In the article which has just been published in Nature Medicine, the long-term clinical and biological results (median follow-up of 7.6 years) of the phase I/II trial in 8 patients with WAS are described with a special attention paid to two serious complications of this disease: thrombocytopenia and autoimmunity. It should be emphasized that all the patients included in this trial had the more severe form of this immune deficiency and were not eligible for an allogeneic bone marrow transplant.

After gene therapy, the genetically corrected hematopoietic cells showed stabilized engraftment, thus confirming the first results reported in JAMA a few years ago for 6 of them.

The stability of the grafted genetically modified stem cells has made it possible to correct the main symptoms of the disease such as recurrent severe infections or eczema and has made it possible to improve or resolve bleeding and signs of autoimmunity. T cell function was completely restored as demonstrated by the total number of naïve T cells, the restoration of the immunological synapse as well as the functions of these cells which are essential to fight infections.

No adverse effect linked to the use of a retroviral vector has been reported, nor has there been any lack of stability of the graft of genetically modified cells.

Analysis of lentiviral integration sites reveals a polyclonal profile without any clonal expansion or dangerous integration of the vector (risk of neoplastic transformation). Indeed, thanks to lentiviral vectors, the new genetic information is introduced in a stable and random way into the patient’s genome. The ability to sequence the entire genome makes it possible to follow exactly the sites of integration of the new genetic material and to ensure their harmlessness with regard to the physiological functions of the target cell. This sequencing made it possible to validate the long-term safety of these retroviral vectors because no genetic disturbance was observed.

Note: a 30-year-old patient was treated in this trial, thus showing the effectiveness of this treatment in adult patients with a thymus that could be thought to be little or not functional after long years of illness. Similarly, a complete correction of the B lymphocyte compartment was obtained, which made it possible to stop the immunoglobulin substitution in 5 treated patients and to see a significant reduction or even disappearance of the signs of autoimmunity.

All treated patients saw their episodes of spontaneous bleeding decrease significantly in frequency and severity, although for 5 patients the number of platelets remained below normal values.

All in all, gene therapy by gene addition confirms its therapeutic interest for a complex deficit of cellular immunity such as Wiskott Aldrich syndrome. New studies are underway to try to continue to optimize these long-term clinical results. 

 

1 This is a protein in the cell membrane whose contraction and relaxation activity allows each blood cell to do its job well, such as moving from place to place or eliminating a “diseased” cell. in the case of killer cells.

2 This is the pathological decrease in the number of platelets which, in addition, have a reduced size compared to the physiological value.

3 The term allogeneic refers to cells, tissues or organs taken from a healthy donor to be transplanted into a recipient who is strongly, but not entirely, genetically compatible with the donor.

New Brain Abnormalities Associated with Child Abuse

Posted on by Graziella Cara

Immunolabeling of parvalbumin neurons (in green) surrounded by perineuronal nets (in red) in the human prefrontal cortex. © Arnaud Tanti/Inserm

 

In collaboration with a Canadian team, scientists from Inserm and Université de Tours, at Unit 1253 Imaging & Brain1, have shown in post-mortem brain samples that victims of child abuse present specific brain characteristics. The teams have revealed for the first time in humans an increase in the number and maturation of perineuronal nets, dense protein structures surrounding the neurons. In animals, this phenomenon regulates brain plasticity by inhibiting the remodeling of neural networks. This research suggests that abuse could cause lasting changes to the developmental trajectories of certain brain regions with potential effects on psychological health. The study has been published in Molecular Psychiatry.

Child abuse has effects on psychological development, including an increased risk of depression and suicide during the course of life. Sexual violence, physical violence or chronic neglect during childhood or adolescence are suspected to cause lasting structural and functional changes in the brain. It is during these periods that personality traits, attachment patterns, cognitive functions and emotional responses are shaped by our experiences, including traumatic ones.

To better understand the neurobiological changes associated with child abuse, researchers from Inserm and Université de Tours, in collaboration with McGill University – Douglas Mental Health University Institute in Montreal, Canada, investigated the ventromedial prefrontal cortex, a brain region that regulates emotional responses. They took a closer look at “perineuronal nets” – particularly compact and dense structures that encircle certain neurons, especially parvalbumin neurons, whose inhibitory action plays a role in controlling the activity of large groups of neurons.

Perineuronal nets emerge in early childhood and continue to develop until the end of adolescence, increasing in size and number. In animals, their development represents an important stage of brain maturation, with their emergence marking the closure of “critical periods” of plasticity during which the development of the neural circuitry can be easily modified by experiments.

The researchers estimate that these perineuronal nets could play a role in childhood trauma by immobilizing the neural networks associated with these memories, predisposing the individual to future depressive or behavioral disorders.

Denser perineuronal nets

To study these structures, the researchers analyzed post-mortem brain sections from adults (from brain donations with informed consent from the next of kin) who had committed suicide an episode of major depression. Of the 28 subjects concerned, 12 had a marked history of child abuse. These sections were also compared with those of control subjects having died of natural causes and with no history of abuse or psychiatric illness. The different types of analyses performed by the researchers led them to make several observations.

Firstly, in the subjects who were abused during childhood, the perineuronal nets were denser and more numerous than those of the other individuals. They also presented more marked maturation characteristics, including increased structural development around the parvalbumin neurons. Finally, the researchers showed that the cells producing the main proteins that make up the perineuronal nets are oligodendrocyte progenitors, cells which are found throughout the brain.

The researchers will now use mice to explore the consequences of these observations in more detail, particularly on the persistence of traumatic memories linked to early adversity.

“These observations reinforce the hypothesis of a correlation between early stress and increased perineuronal net development. It remains to be discovered whether there is a causal link, that is to say whether these changes contribute to the development of behaviors associated with abuse, and how. Perhaps in the longer term we could consider a procedure targeting the perineuronal nets to help restore some plasticity and reduce the impact of trauma and the subsequent psychiatric risk,” explains Arnaud Tanti, Inserm researcher and first author of this study.

 

1 JRU 1253, iBrain, Inserm, Université de Tours

Cyclists and Pedestrians Inhale More Road Traffic Particles Than Motorized Transport Users

Posted on by Graziella Cara

pollution transports

Users of different transport types breathe in over twice the dose of black carbon per 30-minute period when traveling compared with when not traveling (when at home or at work, for example). © Unsplash

The measurements of individual exposure to pollution, which are generally taken at the place of residence, overlook two major parameters: the much higher exposure occurring during travel and the variations in air volumes, and consequently the varying levels of air pollutants, which are inhaled according to the intensity of physical exertion involved by the journey. A team of scientists led by Inserm Research Director Basile Chaix at the Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université) studied the impact of these parameters on exposure to black carbon, an air pollutant produced by road traffic. In research published in Environment International, the team compares different modes of transport and shows that although walking and cycling expose the user to much lower levels of black carbon than motorized transport (public or private), the increase in ventilation caused by the physical activity leads to greater quantities of this pollutant being inhaled.

Black carbon is considered one of the best markers of road traffic. It is notably generated by the incomplete combustion of fossil fuels and other molecules produced by road traffic. Previous studies have shown that exposure to black carbon can cause chronic respiratory disease, neurological damage, and cardiovascular disease.

In general, individual exposure to air pollutants is defined by the quantity of these pollutants in the air that is estimated or measured at the place of residence. However, this method overlooks the considerable variations in exposure related to travel and exertion. Yet it is these variations that are responsible for a large proportion of the daily exposure to air pollutants.

A certain number of epidemiological studies have suggested that users of motorized transport (private or public) are more exposed to air pollution than users of so-called “active” modes of transport, even if cyclists ride in close proximity to traffic. However, these studies do not take into account the role of minute ventilation (quantity of air moved into and out of the lungs in one minute), which is specific to each individual and varies very widely depending on the level of exertion, and which therefore has an effect on the dose of pollutants inhaled by each individual.

Doctoral student Sanjeev Bista and Inserm Research Director Basile Chaix, at the Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université) sought to quantify the black carbon levels to which users of different types of transport are exposed and how much of it they breathe in during their daily trips. The data was collected in the Grand Paris region between 2018 and 2020 as part of the MobiliSense study funded by the European Research Council.

The research team followed 283 participants for 6 days each. During their trips (locations obtained by GPS) and between two trips (when they were at home or work, for example), a portable monitor strapped on each participant’s shoulder measured levels of airborne black carbon their breathing zone (close to the nose and mouth). The trips were segmented according to the different modes of transport used. In the end, around 7,500 segments were analyzed. By taking into account the minute ventilation of each person in each segment (estimated using an accelerometer that measures physical activity), the dose of black carbon inhaled by the participants during each trip could therefore be quantified.

The results of the analyses show that the participants breathe in over twice the dose of black carbon per 30-minute period when traveling compared with when they are not traveling (when they are at home or at work, for example).

Furthermore, the so-called “active” modes of transport are associated with average black carbon levels in the breathing zone that are lower than those observed with motorized transport (and with an even lower exposure for walking than for cycling). Compared with walking, this represents +2.20 μg black carbon per m3 of air on average in public transport with a maximum of +3.08 μg/m3 in the subway– i.e. almost twice as much as during active transport – and +2.29 μg/m3 in private motor vehicles.

However, the ranking of transport modes by exposure is largely reversed when considering the dose actually inhaled instead of the level measured in the breathing zone. Cycling is associated with the highest level of black carbon inhalation (+0.41 µg for 30 minutes of travel compared with walking), whereas other modes of public transport (except the subway, however) involve less black carbon inhalation (e.g. -0.94 µg for the tramway for 30 minutes of travel compared with walking). Similarly, the use of a private motor vehicle is associated with less black carbon inhalation, whereas this mode is associated with higher levels compared with walking.

Therefore, although less exposed in terms of black carbon levels than users of motorized transport, pedestrians and cyclists inhale more of this pollutant for an equivalent journey time.

“The fact that the amount of black carbon inhaled is greater in active modes of transport when the user is exposed to a lower airborne concentration than a user of motorized transport is explained by a much greater minute ventilation when using active transport,” specifies Chaix. Indeed, the volume of air absorbed increases with the intensity of physical activity. Variations in the latter from one mode of transport to another therefore have a decisive impact on the amount of pollutants inhaled. Therefore, if cyclists inhale more black carbon, it is because cycling combines higher levels of physical activity and greater proximity to road traffic than walking.

“However, it is important to clarify that the inhalation of air pollutants is only one part of the picture of the benefits and risks associated with the different modes of transport, and that the other pieces of the puzzle must also be considered, namely exposure to noise, stress in the transport environments, and the physical activity carried out, for which walking and cycling are widely recommended” concludes the researcher. Future studies by the team will explore the physiological response of the study participants, in terms of blood pressure and lung function, to air pollutants in transport microenvironments.

Des mesures qui payent pour lutter contre la pollution atmosphérique

Posted on by Graziella Cara

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Fine particle pollution event (smog) in Grenoble, 2016. © Rémy Slama

    • Fine particle pollution affects most of the world’s population, causing respiratory and cardiovascular diseases as well as premature deaths, all at a cost to society.
    • Based on a study of the city of Grenoble in south-eastern France, a multidisciplinary research team has drawn up various scenarios that would reduce the mortality caused by fine particles by two thirds over the entire conurbation, and has shown that the benefits obtained would exceed the costs of the policies implemented.

Reducing fine particle mortality in a conurbation by two-thirds could be achieved at a cost that is much lower than the value of the societal and economic benefits obtained, according to a study by a multidisciplinary team from CNRS, INSERM, INRAE, Grenoble Alpes University (UGA) and Atmo Auvergne-Rhône-Alpes. The study identifies specific public policies that could achieve health objectives set by local decision makers, as well as their expected co-benefits. The findings are published in Environment International on January 15, 2022.

Every year in France, fine particle pollution (particles with a diameter of less than 2.5 micrometres1) leads to the premature death of around 40,000 people. The associated cost is estimated at €100 billion per year. Despite this, public policies to combat air pollution are generally implemented without first assessing their future health and economic impacts.

The  MobilAir  project attempts to address this problem by identifying specific policies that would meet the health objectives set by decision-makers in the Grenoble conurbation, namely, a 67% reduction in the mortality rate associated with fine particles from 2016 to 2030. A cost-benefit analysis of various options was carried out by a collaboration involving the Grenoble Applied Economics Lab (CNRS / INRAE / UGA), the Institute for Advanced Biosciences (INSERM / CNRS / UGA), the Centre for Economics and Sociology applied to Agriculture and Rural Areas (AgroSup Dijon / INRAE) and Atmo Auvergne-Rhône-Alpes.

The team targeted the two local sectors that emit the most fine particles: wood heating and transport. They show that the health objectives can be met by combining two measures: replacing all inefficient wood heaters by modern pellet stoves, and reducing personal motor vehicle traffic within the conurbation by 36%. Specifically, these policies would need to be accompanied by financial assistance to households, the development of infrastructure (public transport and/or cycle paths, etc.) and carefully targeted public awareness programmes.

Successful implementation of such policies would result in a series of additional health benefits going beyond the health gains directly related to fine particles, since this would promote physical activity, and reduce urban noise pollution and greenhouse gas emissions.

Scenarios involving the most widespread development of active modes of transport (walking and cycling) would lead to a net benefit of €8.7 billion over the period 2016-2045, i.e. an annual benefit of €629 per capita in the conurbation2.

This is the first study in France to demonstrate that the societal benefits associated with measures to improve air quality would outweigh the cost of such measures. It thus provides decision-makers with scientifically validated approaches to significantly improving health throughout the conurbation. 

 

This work was funded by the Initiative of Excellence (Idex) of Grenoble Alpes University and by ADEME.

 

  1. More than 30 times finer than a hair.
  2. This benefit was calculated as the difference between the health benefits of the measures (whether tangible, such as lower medical costs and sick leave, or intangible, such as improved quality of life and mortality rates), and the investments and costs, both private and for the community, associated with these measures. Put another way, depending on the scenario, each euro invested by the community would generate between €1.1 and €4.7 of societal benefit.

Identification d’une nouvelle cible thérapeutique du myélome multiple

Posted on by Graziella Cara

Multiple Myeloma cells © KGH, CC BY-SA 3.0, via Wikimedia Commons

Multiple myeloma is a cancer of the bone marrow, with a life expectancy of less than 5 years post-diagnosis. Proteasome inhibitors, the therapeutic backbone of current treatments, are very effective in treating newly diagnosed cancers but resistance or intolerance to these molecules inevitably develop, leading to relapses. While studying a neglected tropical disease[1], Buruli ulcer, researchers from the Institut Pasteur and Inserm discovered a novel therapeutic target for multiple myeloma that could allow to bypass this resistance. The results of this study were published in EMBO Molecular Medicine on January 11th, 2022.

Multiple myeloma is a cancer caused by the abnormal proliferation of plasma cells, white blood cells producing antibodies, in the bone marrow. Scientists from the Institut Pasteur and Inserm, in collaboration with the University of Paris and the Saint Louis Hospital (AP-HP) describe a new mechanism to selectively kill these cancer cells.

Researchers in the Immunobiology of Infection Unit at the Institut Pasteur made this discovery while working on a completely different disease: Buruli ulcer. This neglected tropical disease, caused by infection with a bacterium (Mycobacterium ulcerans), can provoke severe and irreversible skin necrosis. Lesions are due to bacterial production of a toxin called “mycolactone” in infected skin. In 2016, this team discovered how mycolactone causes the clinical manifestations of Buruli ulcer: by targeting the translocon (Sec61).

The translocon is a channel anchored in the wall of a cell compartment called the endoplasmic reticulum that plays a crucial role in the synthesis of a subset of proteins: those that are destined to be secreted in the extracellular medium. The translocon controls the import of these proteins into the endoplasmic reticulum, and it is the main gateway to the secretory pathway. By blocking Sec61, mycolactone retains these proteins inside the cell and provokes their degradation by the proteasome, a stressful process that can evolve towards programmed cell death.

Using murine models and tumors from patient biopsies, researchers demonstrated that mycolactone is highly toxic to multiple myeloma cells, including those that have become resistant to proteasome inhibitors, at doses that are non-toxic to normal cells. In addition, they showed that mycolactone and proteasome inhibitors work in synergy, mutually potentiating their anti-cancer effects.

“This study provides the proof of concept that the translocon is a new therapeutic target in multiple myeloma. The next step will be to identify drug-like molecules inhibiting Sec61, which could constitute a new treatment for this cancer. In addition, we aim to study whether this target could be common to other cancers.” explains Caroline Demangel, head of the Immunobiology of Infection Unit at the Institut Pasteur.

 

[1] WHO definition: Neglected tropical diseases (NTDs) are a diverse group of 20 diseases with one thing in common: their impact on impoverished communities. Together, NTDs affect over a billion people with devastating consequences on public health and economy.

La consommation de cannabis dès l’adolescence serait associée à un risque plus élevé de chômage à l’âge adulte

Posted on by Graziella Cara

cannabis

Among the 17.1 million young Europeans who declared having used cannabis in the previous year, 10 million were between the ages of 15 and 24. © Unsplash

 

France has one of the world’s highest levels of cannabis use, with around 40% of 17-year-olds reported to have used it in the previous year. While previous studies highlighted the existence of a possible causal relationship between initiation of cannabis use during adolescence and the subsequent level of educational attainment, researchers from Inserm and Sorbonne Université at the Pierre-Louis Institute of Epidemiology and Public Health have looked at the impact of this early experimentation on employment in adulthood. Their findings indicate that those having used cannabis are more likely to experience a period of unemployment later, especially if they were under 16 when they started. Their findings, based on the follow-up of 1,500 people over a nine-year period, have been published in Drug and Alcohol Dependence.

Among the 17.1 million young Europeans (aged 15 to 34) who declared having used cannabis in the previous year, 10 million were between the ages of 15 and 241. Neuroscientific research data showing specific lesions in adolescent consumers support the idea that there is a direct negative effect of cannabis use on young people’s concentration, motivation and, ultimately, academic success.

Researchers from Inserm and Sorbonne Université looked at the age at which cannabis use began and its impact on the future professional integration of young people. Thanks to data collected from the Tempo2 cohort, they have identified a link between early drug experimentation (before the age of 16) and difficulties in occupational integration in adulthood.

Their analysis focused more precisely on a sample of 1,487 young adults followed over a nine-year period between 2009 and 20183. On four occasions during that period, the participants were asked how old they were when they first used cannabis and about their employment status. Other elements were also taken into account to avoid biasing the analysis, such as socioeconomic status, family situation, school difficulties encountered during childhood and adolescence, as well as the psychological assessment of the participants.

The findings suggest that those who declared having started their cannabis use at the age of 16 or younger are about twice as likely to experience a period of unemployment in adulthood4 than those having never used cannabis.

Whereas those who began their cannabis use after the age of 16 are 39% more likely to experience a period of unemployment in adulthood than those having never used the drug.

Early consumption: a risk marker for repeated episodes of unemployment

The researchers also looked at the potential impact of early cannabis use on the risk of repeated episodes of unemployment. Those who began their cannabis use at an early age are three times more likely to experience several episodes of unemployment than those having never used cannabis.

According to the results of the study, those experimenting with cannabis at a later stage (over 16 years of age at first use) are 51% more likely to experience at least one period of unemployment compared with those having never used cannabis and twice as likely to experience repeated episodes of unemployment.

Furthermore, by comparing early and late cannabis users, the researchers found that the likelihood of experiencing repeated episodes of unemployment was 92% higher in the youngest consumer group than in those over 16 years of age at the time of initiation.

“These findings supplement the literature which shows that in addition to the frequency of cannabis use, the age at first use is associated with adverse consequences, not just on health but also on people’s social and economic lives. Cannabis use before the age of 16 can therefore be considered as a risk marker for unemployment. Delaying its use for as long as possible should be a public policy objective,” explains Maria Melchior, Inserm Research Director and last author of the study.

Based on the data collected from the Tempo cohort over a period of around 30 years, the researchers now wish to identify the factors that are predictive of cannabis use trajectories over time. An approach that is all the more important, given that those whose first use takes place during adolescence are increasingly likely to continue using in adulthood without the underlying mechanisms being well known.

 

1 European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), 2017

2 The Tempo cohort is a long-term health research project set up by Inserm public health researchers

3 The participants were between 22 and 35 years-old at the time of their inclusion in 2009

4 Here this adult age corresponds to the 31-44 age group, the participants being between 22 and 35 years-old at the time of their inclusion in 2009

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