Podcasts about calibr

Sortie du rêve, fin de la récréation !Du plus profond de nos mémoires, un vieux clou tordu et rouillé restait irréversiblement planté au mur de notre ancien dortoir.Un grand sac pesant, à l'étoffe incertaine, tout aussi oublié que quiconque l'ayant accroché là, le tirait vers le bas, se fatigant lui-même, ainsi qu'il fatiguait d'un contenu massif, sa patère de fortune.Il arrivait aux unes, aux uns, aux autres de faire ici la sieste, les hivers calfeutrés, l'été, fenêtres ouvertes aux sons de la campagne et de la maisonnée, auxquels, à notre insu, se mêlait la complainte discrète et continue qu'endurait la matière et du clou et du sac.Lieu de repos ou de passage, de rencontre et de partage, de séduction ou de conquête, de frottement ou de transgression et de compromission, de recul et de rupture, d'indifférence, de plénitude et/ou de solitude... Se vivaient là les rêves fous, ensommeillés ou engourdis du drame et de la comédie, les affres de la scène humaine, en ce théâtre de lumière, d'insouciance, d'allégresse, d'excitation, de tolérance ou d'étroitesse, de déception et de tracas.Nul ne prêtait attention aux grincements insignifiants d'un sac usé et tiraillé, pendu à un clou biscornu d'une arrière-salle de l'univers, s'empesant depuis la nuit des temps de l'épaisseur de l'erreur, par laquelle se séparaient, se dispersaient et s'enfermaient les esprits, s'allégeant par ailleurs de toute réalisation de la vérité, dont se nourrissent et s'illuminent les âmes.Calibré à l'équilibre, le clou ployait sous la charge depuis des millénaires, sa structure craquelante et l'anse déformée du sac gémissant en s'échangeant des tics tacs fondus dans le profond silence des ignorances.Tension jusqu'à l'extrême déchirure qui initia le grand vacarme de la chute du sac, dont la brutalité assourdissante fracassa toute individualité, depuis son lieu d'éloignement, sur l'unique et implacable vérité du Réel.C'était la fin du mirage, déjà oublié et ignoré, anéanti, enfoui, en même temps que tout son décorum, comme l'était aussi la sieste qui n'avait pas eu lieu.L'humanité l'ignorait. À force de s'enfoncer dans l'erreur et dans ses illusions, elle a lesté le sac jusqu'à le faire craquer. Chacun est tombé de sa chaise, d'où qu'il était dans son délire, a délaissé sa singularité pour revenir dans l'Unité qu'il n'avait jamais quitté.---------Texte déposé ©Renaud SoubiseMusique : ©Rossini - William Tell Overture - Part 1Hébergé par Ausha. Visitez ausha.co/politique-de-confidentialite pour plus d'informations.

Cliquez ici pour accéder gratuitement aux articles lus de Mediapart : https://m.audiomeans.fr/s/P-UmoTbNLs Considérant devoir sauver la face après l'attaque de son consulat à Damas, le 1er avril, la République islamique d'Iran a mené ses frappes sur Israël en cherchant à éviter un embrasement régional. L'événement est cependant historique et un cap a été franchi : la guerre de l'ombre pourrait devenir une guerre ouverte. Un article de Jean-Pierre Perrin, publié le 14 octobre 2024, lu par Christine Pâris.

Drs. John Sweetenham and Fred Locke discuss the FDA investigation on the risk of cancer from CAR T-cell therapy and share insights on the known number of cases and the potential implications on clinical research and patient care. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. CAR T-cell therapies have been game changers for treating certain cancers including lymphomas and leukemias, as well as multiple myeloma, since the vast majority of patients who have received CAR-T do not have other curative options with conventional non-cellular, anti-cancer therapies. But on November 28, the U.S. Food and Drug Administration announced that it is investigating whether CAR T-cell therapy can, in rare cases, cause secondary cancers. The FDA launched the probe after receiving reports from clinical trials and other data sources of T-cell malignancies in patients who received CAR T-cell immunotherapies. Joining me to discuss the investigation and its implications for the field is Dr. Fred Locke, a medical oncologist and translational researcher and a senior member and chair in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at the Moffitt Cancer Center in Tampa, Florida. Dr. Locke is an internationally renowned clinical research leader in the field of CAR T-cell therapy. You'll find our disclosures in the transcript of this episode, and disclosures of all guests on podcasts are available at asco.org/DNpod. Fred, it's great to have you on the podcast today. Dr. Fred Locke: Thanks, John, I'm really glad to be here. Dr. John Sweetenham: So, T-cells are the backbone of CAR T-cell therapies, and there are currently 6 CAR-T products approved by the FDA. As our listeners will know, CAR T-cell therapies manipulate a patient's T-cells, enabling them to recognize and attack antigens on cancer cells and induce potential long-standing changes in the immune system. In its statement on November 28, the FDA said it determined that the risk of T-cell malignancies is applicable to all of the currently approved BCMA- and CD19-directed, genetically modified, autologous CAR T-cell immunotherapies. Fred, could you comment for us on the investigation: How many patients are reported to have developed second malignancies from CAR T-cell therapy, and whether there are likely to be more secondary cancers reported? Dr. Fred Locke: Yes, so the FDA and the reports are coming out that there are 19 cases of T-cell malignancy that we're aware of that have occurred after the current FDA-approved CAR T-cell therapies were administered for the treatment of leukemia, lymphoma, or multiple myeloma. The majority of those cases were reported through the FDA Adverse Event Reporting System. And we don't know a lot of details of those 19 cases. We think that there's probably about 13,000 to 14,000 patients who've been treated with the commercial CAR T-cell therapies. So if you kind of do some crude math, you can come up with 19 out of say, 13,500; we're at about 0.1% of patients who could have developed T-cell lymphoma after treatment with these CAR T-cell therapies. It's not entirely out of the realm of possibility that T-cell lymphoma could develop from gene-modified T-cells, and these are all the patient's own T-cells that have been modified outside of the body. But I would still posit that this is a really low incidence of T-cell lymphomas in these patients who really are without other great treatment options. Dr. John Sweetenham: Yeah, and I think that's a point that we'll return to a little bit later on in the conversation around the fact that you know, clearly, there are major benefits that have been associated with CAR T-cell therapy and hematologic malignancies so far. And of course over the years, I think that many of us have become familiar with and learned a great deal about how to manage some of the more serious side effects of CAR T-cell therapy. And you, of course, have led several pivotal national trials of anti-CD19 CAR-Ts for lymphoma. Can you comment at all on whether you've seen previous data from your own practice or others on the risk of second malignancy from CAR T-cell therapy? And can you share your insights on the data and any new emerging data that warrants our attention for the concern or risk of second malignancy? And I guess to round up that series of questions, is there anything currently in yours or others research into CAR-T to explain what's happening and why this is going on? Dr. Fred Locke: I think what may have prompted the FDA's announcement of this is that on the same date that they came out with announcing their investigation, there was the release of the abstracts for the American Society of Hematology Annual Meeting. And within those abstracts, and unfortunately it was not selected for poster or oral abstract presentation, but discovered within those abstracts was one on a CAR+ T-cell lymphoma after ciltacabtagene autoleucel therapy for relapsed refractory multiple myeloma. And what these investigators and the company were reporting is that a patient with refractory multiple myeloma received the cilta-cel BCMA-directed CAR T-cell therapy and developed a stringent complete response, and about 5 months later developed a nasal facial plaque and PET+ cervical lymph nodes. And both the lymph nodes and the plaque were biopsied and showed a T-cell lymphoma in which 90% to 100% of the cells were positive by qPCR for the CAR construct and immunohistochemistry for the CAR protein. So this was a T-cell lymphoma growth where the cells were expressing the inserted protein, the chimeric antigen receptor protein, which is obviously not natural. And when they looked a little bit deeper at these patients, 91% of the cells have the same T-cell receptor sequence. So this was really a clonal sort of process. They did CAR integration analysis to see how the insertion of the CAR, the chimeric antigen receptor gene, could have potentially disrupted a gene within the T-cells. And what they found is that there were some dominant sort of insertions within certain genes suggesting monoclonality, but it wasn't within any sort of obvious activating genes that would be expected to lead to the T-cell lymphoma. They went on and did some additional analysis, and they showed that there was some existing TET2 mutations in the T-cells of this patient, prior to probably prior to the CAR T-cell manufacturer, and they weren't associated with clonal insertion. And I think, you know, it's possible that this patient who had a pre-existing mutation may have been susceptible to the development of a T-cell lymphoma prior to the CAR T-cell treatment. And TET2 was previously shown a number of years ago in a CLL patient treated with CD19 CAR T-cell therapy; it was shown that there was insertional mutagenesis, silencing the TET2 gene, and that associated with clonal expansion of the CAR T-cells in that patient and corresponded with remission of the CLL. However, the difference here is that that patient's T-cell clone went back down and contracted, and the patient remained in remission 5 years later with their T-cells still in the blood, but the minority of those T-cells had that that TET2 mutational insertional mutagenesis. All this is something we thought was theoretically possible, that T-cell lymphoma could develop after car T-cell therapy. And in fact, a prior trial using a different method of delivery of a CAR gene; instead of using a virus to insert the car into the into the T-cells, a transposon system called piggyBac was used. And in that trial, again, CD19 CAR trial, but in this case, it was allogeneic donor cells for patients who had relapsed after an allogeneic transplant. So it's sort of an autologous, you know, analogy, but it's using the donor cells. And in that trial, 2 out of like 10 patients developed clonal T-cell lymphoma, which was CAR+, but they weren't able to identify a clear insertional mutagenesis event in those cases. So, we've known this is possible, and it would have been great if this poster or if this abstract at ASH was presented as an oral or a poster so we could get more detail, but it's possible that that's the likely reason for the FDA's announcement. Dr. John Sweetenham: Thanks. The bottom line, I guess, is that for now, the jury's still out on exactly what's underlying these observations, but something which I'm sure is going to be the subject of a lot of discussion during the ASH meeting this year and moving forward. I'd like to inform our listeners that ASCO released a statement on the FDA investigation, stating that the risk of T-cell malignancies due to CAR T-cell therapy appears to be very low. And we've just heard from Dr. Locke that, of the several thousand patients who've received CAR Ts, there are 19 cases so far, it's been reported, which puts us into some type of proportion. The ASCO statement goes on to say that based on available data, and while such malignancies have occurred in patients who have received CAR T-cell therapy, the causal relationship, whether these cases are spontaneous or are caused by the therapy, needs to be investigated further, and we've just heard a little about the detail of that. ASCO added that by issuing a warning but not revoking approval of these therapies, the FDA clearly believes that the current available evidence suggests the overall benefits of these products, used within their approved label, continue to outweigh the potential risks. So Fred, the risk of secondary malignancies is already included as a class warning in the U.S. prescribing information for these CAR T-cell therapies. But do you think that the CAR-T products could eventually be taken off the market, and how would your research be impacted if this were to happen? And maybe finally, how long will patients on CAR T-cell therapy need to be monitored moving forward? Dr. Fred Locke: I don't believe that CAR T-cell therapy will be taken off the market. As we've already talked about, the incidence is extraordinarily low and the causality is unclear. It would certainly impact my research, as I'm doing clinical trials with CAR T-cell therapies, but it would more importantly impact the way we treat patients. We did over 300 CAR T-cell therapy treatments last year here at Moffitt Cancer Center. We're one of the busiest programs in the world giving CAR T-cell therapy, and it is truly a transformative therapy for all the diseases that we administer these FDA-approved therapies for. For example, in diffuse large B-cell lymphoma, we participated in the ZUMA-7 clinical trial and recently reported that patients randomized to CAR T-cell therapy had improved overall survival. They were living longer than patients randomized in the second-line setting to get conventional chemotherapy and autologous transplant. This is clearly a therapy that can work. I would also add that the risk of secondary malignancies is real, but that's a risk for all cancer patients, particularly patients with hematologic malignancies, and for example, lymphoma patients who've gotten an autologous stem cell transplant are at a relatively high lifetime risk of developing a secondary myeloid malignancy, most commonly, treatment-related MDS or AML. And that risk is also present after CAR T-cell therapy. The degree of attribution of CAR-T versus the condition of chemotherapy for CAR-T versus the previous chemotherapy is all unclear, and more analysis needs to be done. But the risk of developing treatment-related MDS or leukemia is certainly higher than the small number of T-cell lymphomas reported. The other thing I want to point out is that there was an analysis of the SEER database that patients with B-cell lymphomas are at about a 5-fold higher risk of developing a T-cell lymphoma than the otherwise healthy population; and vice versa, by the way, T-cell lymphoma patients are at risk for developing B cell lymphoma. And in fact, in that SEER database, it's not a wildly different percentage chance of developing a T-cell lymphoma after a B-cell lymphoma. And this data came out before the advent of CAR T-cell therapy. So I really think we need more science to be done to understand what's happening for these patients. Will this impact the field? Well, certainly, there are treatments that are not CAR T-cell therapy that compete with CAR T-cell therapy or could; I'm a strong believer that they don't offer the same outcomes for patients, but we will certainly see people talking about this for some time. Then the other place where this could be relevant, I think, is as we look at CAR T-cell therapy for autoimmune disorders, and we're starting to see studies of that for lupus and other diseases, the risk to benefit ratio could be different in those cases. So this is something we really need to consider as we move forward with CAR T- cell therapy. Dr. John Sweetenham: Yeah, thanks, Fred. And as a major clinical investigator in the field of CAR-T at the moment, do you see any potential concerns about difficulties in getting patients onto the trials of CAR T-cell in the light of this information? Dr. Fred Locke: No, I really don't. We're not seeing hesitancy, at least in the patients who are referred in for CAR T-cell therapy. Again, it may give ammunition for those who are already predisposed to not refer patients in for CAR T-cell therapy, but I don't think it should. I think that these are low risks, and these therapies clearly have benefits to patients. And we should give their patients an opportunity to get these therapies, and I don't see it impacting our clinical trials at this point. Dr. John Sweetenham: Yeah, and your comments address what was going to be my final question to you and that is, as a referring oncologist, how would you advise a referring oncologist to talk with their patients about these data and their implications moving forward? Dr. Fred Locke: If the patient brings it up, I think the response should be that these are very few cases of very low incidence and very low risk. There are other risks to CAR T-cell therapy that are greater, and really speaking with a cell therapist who administers the treatment is probably the best way to give the patient the option to get CAR T-cell therapy if they want to, knowing all the risks and benefits. So, I would leave it up to the CAR-T treatment center to discuss those risks with the patient.   Dr. John Sweetenham: Well, thanks, Fred, for sharing your insights with us on these concerning developments in CAR T-cell therapy, and I think also for putting them into context in terms of the sort of magnitude of this problem in the context of the overall number of patients who are benefiting from this therapy right now. We truly appreciate your time, and thanks for sharing your thoughts with our listeners. Dr. Fred Locke: Thanks, John, my pleasure. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.    Find out more about today's speakers:      Dr. John Sweetenham Dr. Fred Locke @DrFredLocke     Follow ASCO on social media:         @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn         Disclosures:        Dr. John Sweetenham:    Consulting or Advisory Role: EMA Wellness     Dr. Fred Locke: Consulting or Advisory Role: Novartis, Celgene, Calibr, Allogene, Gerson Lehrman Group, EcoR1, Amgen, Bluebird Bio, Bristol Myers Squibb, Iovance Biotherapeutics, Legend Biotech, Cowen, Kite (Gilean), Umoja Biopharma, Takeda, Sana Biotechnology, Daiichi Sankyo/UCB Japan, Bristol-Myers Squibb/Celgene, Janssen, A2 Biotherapeutics, Mittenyi Biotec, Caribou Biosciences, Takeda, Umoja Biopharma Research Funding: Kite Pharma, Allogene, Novartis, Bluebird Bio, Bristol-Myers Squibb/Calgene Patients, Royalties, Other Intellectual Property: Double Mutant Survivin Vaccine. US010414810B2 CAR T Cells with Enhanced Metabolic Fitness; Serial Number: 62/939,727 Methods of Enhancing CAR T Cell Therapies. Serial Number: 62/892,292. Evolutionary Dynamics of Non-Hodgkin Lymphoma CAR-T cell therapy.  Serial Number: 62/879,534. Travel, Accommodations, Expenses: Kite Pharma, A2 Biotherapeutics

[Épisode 148] [Infographie 3D] [Mindset] Transformer son handicap ou ses faiblesses en une force : la devise de ce podcast... Mon mantra! - Info coaching : ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://www.photorealisme-3d.fr/coaching⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ - Groupe privé : ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠www.facebook.com/groups/491838749209075/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ - ⁠Page FB : ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠www.facebook.com/photorealisme3d⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ - Contact : kevin@photorealisme-3d.fr

Être productif et être occupé sont deux notions souvent confondues. Dans un cas, on court et on cours avec le sentiment d'avoir tout donné sans vraiment progresser et dans l'autre situation on accomplie ses activités les plus importantes le plus efficacement possible. Dans cette chronique, Patrice Ouellet, Expert haute performance et productivité partage 5 habiletés qu'on peut tous développer et qui permettent de diminuer la course folle du quotidien, avoir un plus grand sentiment d'accomplissement et une bonne réserve d'énergie pour prendre soin de soi et de ceux qui nous sont chers. Hosted on Acast. See acast.com/privacy for more information.

Le chanteur congolais Fally Ipupa vient de dévoiler, ce vendredi 16 décembre, un nouvel album intitulé Formule 7. Une sortie qui intervient plus d'un mois après un drame qui s'était produit à Kinshasa lors de l'un des concerts de la star, une bousculade qui avait fait onze morts. L'album qui vient de paraître est le 7e disque de sa carrière et le 5e consacré à la rumba. ► Retrouvez l'interview de Fally Ipupa consacré à « Formule 7 » sur RFI Musique.

Happy New Year and welcome again to the Kenn Blanchard Show.  This week I was pleasantly surprised by the premiere issue of Calibr magazine.   https://calibrmag.com  https://www.youtube.com/channel/UCCPpweCEUSVwIhJnY_j7mjQ  Here's a look into it.  Thanks for following. Support the show: Https://patreon.com/blackmanwithagun  

Los españoles tratan de protegerse ante el nuevo repunte de casos de coronavirus en nuestro país, en una fecha en que es especialmente sensible para la hostelería. Abordamos las perspectivas del sector con el presidente de la patronal, José Luis 

Los españoles tratan de protegerse ante el nuevo repunte de casos de coronavirus en nuestro país, en una fecha en que es especialmente sensible para la hostelería. Abordamos las perspectivas del sector con el presidente de la patronal, José Luis 

La chanteuse du groupe The Dø lance son projet solo, Prudence. Un premier album "Beginnings" vient de sortir. Résolument pop et électronique, il surprendra les amateurs des premières productions de la formation française. Olivia Merilahti répond aux questions de Michel Masserey.

Deux heures d’actualité avec toute la rédaction d’Europe 1 autour de Julian Bugier. Des invités mais aussi des débats d'actualité, notamment à 18h30 avec les Grandes voix d'Europe 1 et à 19h15 autour de Julian Bugier et d'un invité.

ÉDITO - Avec la crise sanitaire, près d'un salarié français sur deux est désormais payé au titre du chômage partiel.

Talked with Dr. Ron Davis and Stacey DeLoye, Comm. Dir. from Scripps Research in Jupiter. Dr. Davis and his team are working on research advancements related to Alzheimer's and autism as well as other neurological diseases. There is a focus on finding therapeutic treatments that can prevent/stop Alzheimer's disease as right now only a few medications are available to the public and they don't provide long term treatment. Scripps has Calibr a component that helps them develop meds faster. Stacey is working on several different events where listeners can come and learn more about some of the research. They include: Food for Thought Lecture Series (includes luncheon), Front Row Lecture Series, Women in Science Education (WISE). They have internship opportunities and to find out more or to sign up for the lectures, listeners can go to www.scripps.edu

Dr. Kristen Johnson is a lead investigator at Calibr, the drug discovery division of Scripps Research. Dr. Maria Millan is the President and CEO of the California Institute for Regenerative Medicine (CIRM). Listen as we talk about the world’s largest stem cell bank, restoring healthy cartilage to patients, and the advantages of non-profit research. Show notes: Kristen’s talk in the Scripps Research Front Row Lecture Series https://www.youtube.com/watch?v=WRzQniqUlHo&t=1941s Coverage of KA34 in the San Diego Union Tribune https://www.sandiegouniontribune.com/business/biotech/sd-me-scripps-cartilage-drug-arthritis-20180624-story.html Maria’s profile at CIRM https://www.cirm.ca.gov/about-cirm/cirm-leadership Social Media: Follow @ScrippsResearch on Twitter, Instagram, Facebook and LinkedIn Follow CIRM on Twitter:@CIRMnews ; Instagram:@cirm_stemcells ; Facebook: @California InstituteForRegenerativeMedicine

Dr. Chatterjee is the Vice President of Medicinal Chemistry at Calibr, the biotechnology division of Scripps Research. Listen as we talk about re-purposing existing compounds for new diseases, the future of robotics in drug discovery and our favorite Superheroes. Show notes: About Calibr https://www.scripps.edu/science-and-medicine/calibr/about/index.html ReFRAME Initiative https://www.scripps.edu/news-and-events/press-room/2018/20181003-reframe-calibr.html Footage of Calibr’s robots in action https://www.statnews.com/2018/12/10/calibr-drug-compounds-mined-new-treatments/ Use of the ReFRAME library to treat Cryptosporidium infection https://www.pnas.org/content/115/42/10750

Fondamentale dans l’imaginaire collectif et très présente au cinéma, la conquête spatiale est un vaste terrain à exploiter pour un réalisateur. Avec First Man, le premier homme sur la Lune, l’oscarisé Damien Chazelle s’en saisit pour tracer le portrait intime du légendaire astronaute Neil Armstrong. Comme dans ses précédents films, on suit le parcours d’un personnage héroïque, talentueux et passionné au point de se renfermer sur lui-même. La musique, une fois de plus composée par Justin Hurwitz, est partie prenante du film. Malgré l’excellente prestation de Claire Foy, le personnage de la femme de Neil Armstrong, ainsi que ses fils sont sous-écrits et donc mal exploités. Calibré pour les Oscars, First Man est finalement un film assez plat qui aurait mérité plus de prises de risque. Podcast animé par Thomas Rozec avec David Honnorat, Stéphane Moïssakis et Perrine Quennesson.LES RECOMMANDATIONS LA RECO DE DAVID : « Mission to mars » (Brian De Palma, 2000) le meilleur film pour comprendre les relations entre astronautes. Le podcast « This American Life » dont l’épisode avec Frank Borman, commandant de la mission Apollo 8. La série « The First » avec Sean Penn qui projète la première mission humaine sur Mars. LA RECO DE STEPHANE : « Armageddon » (Michael Bay, 1998), le plus grand film de conquête spatiale de l’histoire de l’humanité. LA RECO DE PERRINE : Le documentaire « Into Eternity » de Michael Madsen sur la gestion des déchets radioactifs nucléaires. RÉFÉRENCES CITÉES DANS L’ÉMISSIONGravity (Alfonso Cuarón, 2013), Apollo 13 (Ron Howard, 1995), Star Wars, Le voyage dans la Lune (Georges Méliès, 1902), 2001, l’Odyssée de l’espace (Stanley Kubrick, 1968), The Crown (Peter Morgan, 2016), Drive (Nicolas Winding Refn, 2011), La Mule (Clint Eastwood, 2018), Whiplash (Damien Chazelle, 2014), La La Land (Damien Chazelle, 2016)CRÉDITSEnregistré le 5 octobre 2018 à l’Antenne (Paris 11eme). Réalisation : Quentin Bresson. Chargée de production : Juliette Livartowski. Chargée d’édition : Judith Hillebrant. Direction de production : Joël Ronez. Direction de la rédaction : David Carzon. Direction générale : Gabrielle Boeri-Charles. Générique : « Soupir Articulé », Abstrackt Keal Agram (Tanguy Destable et Lionel Pierres). Production : Binge Audio. See acast.com/privacy for privacy and opt-out information.

Matt is the Vice President of Business Development at TSRI, as well as Chief Operating Officer at Calibr. Listen as we talk about what constitutes commercially valuable research, why TSRI is #1 for science innovation and how to design a home jungle gym. Show notes: Matt’s recent Biocom Catalyst Award http://www.scripps.edu/newsandviews/i_20171002/20171002tremblay_biocom.html?utm_source=newsviews&utm_medium=email&utm_campaign=internal20171002 Calibr Bio http://www.calibr.org/about/institute-leadership/ TSRI-Calibr partnership https://www.eurekalert.org/pub_releases/2016-10/sri-tac102016.php

Chiude un pezzo del centro storico di Rovigo, la libreria Calibrì. Come mai? Ne parliamo con il titolare Stefano Polo

[intro music] Host – Dan Keller Hello, and welcome to Episode Fifty-One of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features Dr. Luke Lairson of Scripps Research Institute, who discusses discovery of small molecules to induce remyelination and, in particular, some muscarinic receptor antagonists currently approved for other indications. But first, here are some new items in the MS Discovery Forum. According to our curated list of the latest scientific articles related to MS, 114 such articles were published in the first two weeks of August. We selected a few of these articles as our Editor’s Picks. One is a longitudinal study of gray matter lesions and cortical atrophy in MS published in PLOS ONE. The investigators obtained MRIs at baseline and five years later from subjects with clinically isolated syndrome, early and late relapsing-remitting MS, and secondary progressive MS, and examined lesion placement and cortical thinning in the different disease subtypes. To see this publication and the other articles we selected, go to msdiscovery.org and click on Papers. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week, we added 1 new trial, we updated information on 2 other trials, and we added 12 other pieces of information. The drugs with important additions and changes are ATX-MS-1467, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, and interferon beta-1b. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline. [transition music] And now to the interview. Dr. Luke Lairson is an assistant professor at the Scripps Research Institute and a principal investigator at Calibr, the California Institute for Biomedical Research, in La Jolla. We spoke at the research institute. Interviewer – Dan Keller Dr. Lairson, we're talking about the potential for remyelination. And your institution is taking a very systematic and maybe novel approach. Can you describe how you're going about looking at possible ways to induce remyelination? Interviewee – Luke Lairson Sure. So we're using a phenotypic assays to look for small molecules that selectively induce the differentiation of the precursor cell population which is required for remyelination, which are the so called oligodendrocyte precursor cells or OPCs. We developed imaging-based assays where we could look for small molecules that selectively induce that differentiation phenotype. MSDF And how are you going about screening compounds, and what is your institute set up to do? Dr. Lairson So at Scripps and Calibr we have the capacity to screen on a million compound scale capacity to look at molecules. In this particular assay, we do it in a 3D four-well format, which limits us to screening collections on the scale of hundreds of thousands. And to date, we've screened about 200,000 compounds with this assay. MSDF In terms of multiple sclerosis, what are you looking at now? Dr. Lairson From our preliminary screen of our collection of bioactive compounds, including FDA-approved drugs and drugs in late-stage clinical development, we identified a series of compounds for which OPC differentiation had not been previously reported, which are muscarinic receptor antagonists, which are clinically approved drugs and which work in the central nervous system. And we demonstrated a number of these compounds work in two different rodent models of remyelination in MS. And we're currently developing these as a lead class of compounds as a combination therapy when combined with existing immunosuppressant drugs, including Gilenya. MSDF What compounds have you focused on most? There's a multitude of approved antimuscarinic agents. Dr. Lairson Right. So this is actually a a critical point. So we identified a number of compounds which had antimuscarinic activity, which were active in our OPC differentiation assay. We used pharmacology to demonstrate that the antagonism of M1 or M3 receptor subtype is a required component of the mechanism of these drugs. However, we think that there's a second target, and it's a dual mechanism action through which these drugs are acting, which we're currently trying to elucidate what that second target is to fully characterize the mechanism. That second target actually provides the opportunity to identify compounds that have a potential to have a better therapeutic index in vivo. So the lead compound we published was benztropine. Jonah Chan's lab at UCSF later showed that clemastine also works, which was in our paper, as well. So these are drugs that have been demonstrated to work in vivo. What we did after we published that is we then looked at every compound that we could get our hands on that had antimuscarinic activity – specifically targeting M1/M3 receptor subtypes – and then characterized their activity in the OPC differentiation assay and, as well as profiling their potency on the M1/M3 receptor subtypes, with the goal of looking for compounds that have an optimal therapeutic index in terms of on-target toxicity. So benztropine induces OPC differentiation in the low micromolar range, but it antagonizes M1 and M3 receptors in the low nanomolar range so there's a discrepancy there. And we think that the on-target toxicity of antimuscarinic activity is going to limit the therapeutic potential of these drugs. We've since identified other FDA-approved drugs for which that index is improved and we compounds with approximately 100-fold improvement in therapeutic index, which we've demonstrated in the EAE model are active. And we're currently evaluating them in combination with immunosuppressant drugs to identify an optimal combination, which could well be benztropine or clemastine but may be another FDA-approved drug. MSDF You're at very early stage in terms of clinical utility of these things in MS. But is there any way to separate out the negative antimuscarinic effects that affect people taking drugs for overactive bladder and various other things from their therapeutic effect? Or is it really intrinsic to attacking that receptor? Dr. Lairson That's the key point. So we do think that it's that on-target toxicity which is going to potentially limit this class of compound, which is why we're looking for these other compounds and where we have an improved therapeutic index of inducing remyelination versus antagonizing those receptor subtypes. And likely this class of drugs – and any class of drugs that induces remyelination – is going to have to be used in combination with immunosuppressant drugs. It will require a careful clinical evaluation to figure out which combination will be the most effective and what doses will be safe. MSDF But you also have been doing T-cell assays I take it in looking at benztropine in your work. So what goes on with immune modulation? Is there any effect there? Dr. Lairson So we did extensive studies with benztropine to evaluate its activity in not just T-cell biology but also macrophage biology both in vitro and in vivo. And we found benztropine had no affect on in vitro or in vivo T cell numbers or activity in terms of cytokine production. It has no affect on macrophage polarization in vitro or in vivo, including looking at spinal cords of animals. We don't think that it's acting through a peripheral immune system effect. We can't rule out an important concept that came out at a recent meeting was we need to look at the affect of these compounds on microglial cell activation in the brain and also in astrocyte activation. MSDF So it looks like it's a pure remyelination effect at this point and not really an immunosuppressive effect, which would argue for having to use it in conjunction with today's drugs for MS. Dr. Lairson Correct, that's our current reasoning, yeah. MSDF Have you looked at other models other than cuprizone? Dr. Lairson Yeah, we looked at the EAE…PLP-induced EAE model of relapsing-remitting MS, and we've looked at the MOG model of progressive MS and the cuprizone model. Yeah, those are the models we've looked at to date. MSDF With similar results? Dr. Lairson The compounds we've evaluated have all been active in in those models. MSDF Do you have an idea of the mechanism of action how this is actually working in the oligodendrocyte precursor cells? Dr. Lairson Downstream of the muscarinic receptor…so as I said, based on pharmacology, these classes of compounds – these neurotransmitter receptor modulating agents – are notoriously pleiotropic in that they had multiple receptor subtypes in the brain. So benztropine, for example, it hits nicotine and histamine receptors in this dopamine reuptake inhibitor in addition to being an antimuscarinic. We've shown that those activities are not responsible for inducing OPC differentiation. However, as I said, we've identified multiple compounds that do inhibit muscarinic receptors – specifically receptor subtypes 1 and 3 – that do not induce OPC differentiation. So we think there's a second target; we're actively trying to identify what that second target and downstream mechanism is. MSDF Do you think the same compound would attack both targets, or are you going to need to give multiple compounds to hit multiple targets very selectively as I would think would be the hope? Dr. Lairson The existing compounds we have the argument is that they are hitting both of these targets to induce the differentiation. In that, there's a number of compounds that do hit the M1/M3 receptors that do not induce differentiation, which argue that you need both. The compounds we've identified fortuitously hit both of the necessary targets. MSDF In the antimuscarinic field, often the goal is to be very selective and limit activity at different receptors, but it sounds like you want some overlap here. Dr. Lairson Exactly. We've also initiated some medicinal chemistry where we're trying to see if we can dial in potency for the second target. So we know if benztropine is active on muscarinic and low nanomolar can we improve its potency in the OPC assay by dialing in potency on that second target? MSDF By modifying the molecule? Dr. Lairson Yeah, so making analogs of existing active antimuscarinic agents and then evaluating their activity in the OPC differentiation assay, as well as evaluate their antimuscarinic activity. MSDF Are you hoping that the same active part of the molecule hits both receptors, or have you ever considered making a bifunctional molecule that would be best at both receptors? Dr. Lairson If we knew what the other receptor was, we could potentially address that, or you could argue a bifunctional versus having two unique compounds so it would be you'd have to evaluate that in vivo I think, yeah. The other argument for moving away from this is that as soon as you make a change to that compound it's no longer an approved drug, and you have to go through the rigor of bringing that to the clinic. MSDF Now in your screening, you're using a lot of drugs – a lot of compounds at this point – that have already passed phase 1 screening or phase 1 clinical testing, and this has shown safety. Does that speed up do you think the approval process if these things look active? Dr. Lairson It does. So UCSF has actually initiated a phase 2 trial to evaluate clemastine in MS. So they were able to immediately proceed from a screening result to a clinical trial because it's an approved drug. MSDF And just about Calibr, your institute. You have full facilities for taking this from screening up to what stage? Dr. Lairson Up to the rodent proof of concept stage. So we have a high throughput screening facility, as I mentioned, and then we have a medicinal chemistry group, a pharmacology group where we can do pharmacokinetics in-house and then in core biology. So we take it to the rodent proof of concept. MSDF Do you do any synthetic chemistry, or this is all screening of existing molecules? Dr. Lairson Yeah, we do significant amount of synthetic chemistry so we have a group of 20 chemists – medicinal chemists – that are making analogs. And we do a significant amount of contract research to get compounds and analogs made. MSDF What have we missed, or what do you think is important to add, if anything? Dr. Lairson The other aspect of our program is we've identified novel compounds for which their mechanism of action is unclear. So we've identified multiple scaffolds. We've focused on three of those, which have been subjected to medicinal chemistry optimization. So we identified screening hits, which we were unable to evaluate in the rodent models due to their pharmacokinetic property. But we've now identified analogs of those compounds which are potent in the OPC assay, in which we can achieve reasonable levels in the brain. So we're currently evaluating those in these preclinical rodent models. And once we demonstrate efficacy there, we'll then go and evaluate their mechanism of action. MSDF You test these compounds first in a phenotypic sense to see if they actually do something that you want done. And then you trace it back to mechanism of action? Dr. Lairson Correct. That's our general approach for a lot of assays. So rather than looking at a validated, biochemical target, typically we'll just look for small molecules that induce the cell fate decision that we're interested in. For me, personally, it's the most interesting part of the project is I’m figuring out how those compounds that we rule out known mechanisms how they're actually acting. So we do the mass spec-based proteomics to figure out the specific protein target. And then we use standard cellular molecular biology techniques to elucidate the downstream mechanism of action. MSDF So I suppose the phenotype you're looking for in the case of this research we've been discussing is remyelination. How do you look for that activity? Dr. Lairson The remyelination activity in vitro? We use a co-culture assay, which we collaborate with Rusty Gage at Salk where we pre-differentiate neurons in a dish and then co-culture with our oligodendrocyte precursors plus or minus drug and then look at the ability of those drugs to enhance the rate of myelination of co-cultured axons. MSDF And you just stain the cells in vitro looking for myelin production or myelin basic protein? Dr. Lairson Exactly, yeah. So we just look at myelin basic protein co-localization with axon. MSDF Very good. I appreciate it, thanks. Dr. Lairson Absolutely. Thanks very much for your interest. [transition music] MSDF Thank you for listening to Episode Fifty-One of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. [outro music]