Podcasts about cxcl12

Guest Kristy Red-Horse is a biologist who specializes in coronary artery development and disease. She says the latest advances in treatment of blockages could do away with invasive bypass surgeries in favor of growing new arteries using molecules like CXCL12, known to promote artery regrowth in mice. Red-Horse explains how leaps forward in medical imaging, expanding atlases of gene expressions, and new drug delivery mechanisms could someday lead to trials in humans. But, before that day can arrive, much work remains, as Red-Horse tells host Russ Altman in this episode of Stanford Engineering's The Future of Everything podcast.Have a question for Russ? Send it our way in writing or via voice memo, and it might be featured on an upcoming episode. Please introduce yourself, let us know where you're listening from, and share your quest. You can send questions to thefutureofeverything@stanford.edu.Episode Reference Links:Stanford Profile: Kristy Red-HorseKristy's Lab: Red-Horse LabConnect With Us:Episode Transcripts >>> The Future of Everything WebsiteConnect with Russ >>> Threads / Bluesky / MastodonConnect with School of Engineering >>> Twitter/X / Instagram / LinkedIn / FacebookChapters:(00:00:00) IntroductionRuss Altman introduces Kristy Red-Horse, a professor of biology at Stanford University.(00:03:46) Replacing Open-Heart SurgeryWhy bypass surgery is invasive, risky, and requires long recovery.(00:05:09) Challenges in Artery GrowthThe difficulty of targeting artery growth with medical interventions.(00:07:32) The Role of Collateral ArteriesDefinition and function of collateral arteries as natural bypass.(00:09:37) Triggers for Natural Bypass FormationGenetic factors that may influence the growth of these bypass arteries.(00:10:49) Unique Properties of Coronary ArteriesChallenges of ensuring artificial growth replicates natural artery function.(00:13:04) The Discovery of CXCL12A key molecule that stimulates collateral artery formation.(00:16:16) Precise Artery Growth ControlThe results of targeted CXCL12 injections into mice hearts.(00:17:32) CXCL12's Overlooked RoleThe molecule's role in the immune system and stem cells.(00:20:27) Guinea Pigs and Heart Attack ResistanceHow guinea pigs naturally develop collaterals.(00:23:19) Preventing Heart DiseaseUsing artery growth treatments to target early-stage coronary disease.(00:25:25) Breakthroughs in Imaging TechnologyNew technology that enables identification of collateral growth pathways.(00:27:07) How Collateral Arteries FormThe two mechanisms in which new arteries form.(00:28:48) The Future of Medical Artery GrowthThe possibility of eliminating bypass surgery with targeted artery growth. Connect With Us:Episode Transcripts >>> The Future of Everything WebsiteConnect with Russ >>> Threads / Bluesky / MastodonConnect with School of Engineering >>>Twitter/X / Instagram / LinkedIn / Facebook

El Dr. Santiago Cabezas, oncólogo médico adscrito al Hospital Clínico Universitario San Carlos, en Madrid, España, nos habla sobre los estudios más relevantes en tumores del SNC presentados en ESMO 2023: CC-90010-GBM-002 GEINO 1602 Estudio fase II, multicéntrico, de un solo brazo, que evaluó la eficacia y seguridad de monoterapia con FCN-159 en pacientes pediátricos con glioma de bajo grado recurrente o progresivo REGOMA-OS Análisis retrospectivo de una cohorte de pacientes con glioblastoma recurrente tratados con terapia dirigida basada en el perfil de secuenciación de nueva generación Caracterización clínica y genómica del mundo real de los gliomas Validación de una biopsia líquida espectroscópica para la detección temprana del cáncer cerebral Estudio fase 0/Ib, con una fase de expansión de AZD1390 + radioterapia fraccionada en pacientes con glioma grado 4 recurrente y recién diagnosticado según la clasificación de la OMS Remodelación parcial del microentorno inmunológico tumoral después de la radioterapia y la inhibición de CXCL12 en glioblastoma en el estudio fase I/II GLORIA Fecha de grabación: 26 de octubre de 2023.   Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.27.538580v1?rss=1 Authors: Lee, S., Zhan, H. Abstract: Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/- and MPL-/- mice during aging. Despite severe thrombocytopenia, TPO-/- and MPL-/- mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/- and MPL-/- mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help develop novel therapeutic approaches for hematopoietic disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.15.531679v1?rss=1 Authors: Schyrr, F., Alonso-Calleja, A., Vijaykumar, A., Gebhard, S., Sarkis, R., Lopes, S. F., Oggier, A., De Leval, L., Nombela-Arrieta, C., Naveiras, O. Abstract: Hematopoietic Stem and Progenitor Cells (HSPCs) reside in the hematopoietic niche, a structure that regulates the balance of cellular quiescence, self-renewal and commitment in a demand-adapted manner. The bone marrow (BM) hematopoietic niche is formed by several cellular players, mainly endothelial cells, osteoblasts, adipocytes, and stromal cells. While the BM niche forms a complex structure, evidence exists for simpler, albeit functional, extramedullary hematopoietic niches. However, the composition of what constitutes the simplest unit of an HSPC supportive microenvironment remains largely unknown. Here, we show that the adult adrenal gland can be transformed into a hematopoietic supportive environment. Upon splenectomy and hormonal stimulation, the adult adrenal gland can be induced to recruit and host HSPC function, including serial transplantation. Furthermore, the adrenal stroma contains a CXCL12+ population, reminiscent of BM CXCL12-Abundant Reticular (CAR) cells. Mirroring this, we found CXCL12+ cells in patient samples obtained from a local cohort of myelolipoma, a benign adrenal tumor composed of adipose and hematopoietic tissue that constitutes the most common site of extramedullary hematopoiesis specific to the adult. We present our model as a novel tool to increase our understanding of the physiology of hematopoietic support and to facilitate the development of a boneless niche model. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.28.530397v1?rss=1 Authors: Verma, A., Asthana, S., Saini, D. K., Ayappa, K. G. Abstract: CXCR4 is a G-protein coupled receptor which mediates signalling for diverse functions such as cell proliferation and migration, hematopoiesis and plays a role in embryogenesis and development. Signal transduction occurs primarily through transmembrane helices that function in the multicomponent lipid environment of the plasma membrane. Elevated levels of plasma membrane oxysterols occur in cardiovascular and metabolic disorders, physiological stress and inflammatory conditions. We use experimental and simulation approaches to study the impact of oxysterol chemistry and composition on CXCL12-mediated CXCR4 signalling. Experiments on HeLa cells show a pronounced decrease in calcium oscillation response for the tail oxidized sterols in comparison with the ring oxidized sterols with 22(R) hydroxycholesterol showing a near complete loss of signalling followed by 27-hydroxycholesterol and 25-hydroxycholesterol. All-atom molecular dynamics simulations reveal that tail oxidized, 27-hydroxycholesterol, displaces cholesterol and ubiquitously binds to several critical signalling residues, as well as the dimer interface. Enhanced 27-hydroxycholesterol binding alters CXCR4 residue conformations, disrupts the toggle switch and induces secondary structure changes at both N and C termini. Our study provides a molecular view of the observed mitigated CXCR4 signalling in the presence of oxysterols revealing that disruption of cholesterol-protein interactions, important for regulating the active state, is a key factor in the loss of CXCR4 signalling. Additionally, a signalling class switching from Gi to Gs as revealed by increased CREB and ERK phosphorylation is observed in the experiments. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.12.528218v1?rss=1 Authors: Li, A., Yi, J., Li, X., Dong, L., Ostrow, L. W., Ma, J., Zhou, J. Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease that affects all voluntary muscles in the body, leading to paralysis and respiratory failure, while the extraocular muscles (EOMs) are largely spared even at the end-stage of ALS. Through whole-mount muscle imaging, we detected severe denervation along with depletion of Pax7+ satellite cells (SCs) peri-neuromuscular junction (NMJ) in hindlimb and diaphragm muscles of end-stage SOD1G93A mice (a familial ALS mouse model), but not in EOMs. Upon isolating SCs from different muscles using fluorescence activated cell sorting (FACS), the FACS profiles of hindlimb and diaphragm SCs of G93A mice exhibited activation and depletion phenotypes but not in wildtype controls. Importantly, both wildtype and G93A EOM SCs exhibited spontaneous activation behavior without significant differences in abundance. Examination of Pax7+ and Ki67+ cell ratios and RNA-Seq of SCs cultured in growth and differentiation medium revealed that EOM SCs maintained renewability and stemness better than diaphragm and hindlimb counterparts, especially in differentiation-favoring environments. Comparative functional annotation analyses indicate enrichment of axon guidance molecules, such as Cxcl12, in cultured EOM SCs. In neuromuscular coculture experiments, overexpressing Cxcl12 in G93A hindlimb SC-derived myotubes enhanced motor neuron axon extension and improved innervation, partially replicating the multi-innervation property of EOM SC-derived myotubes. The unique SC homeostasis regulation and the production of axon guidance molecules including Cxcl12 may explain the ALS resistant nature of EOMs. Intriguingly, feeding G93A mice with sodium butyrate extended the life span of G93A mice, alleviated NMJ denervation and SCs depletion. Butyrate treatment promoted renewability and stemness of cultured G93A hindlimb and diaphragm SCs, as well as Cxcl12 expression. Thus, butyrate-induced EOM SC-like transcriptomic patterns may contribute to its beneficiary effects observed in G93A mice. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.12.523842v1?rss=1 Authors: Marchand, T., Akinnola, K. E., Takeishi, S., Maryanovich, M., Pinho, S., Saint-Vanne, J., Birbrair, A., Lamy, T., Tarte, K., Frenette, P., Gritsman, K. Abstract: Functional stromal cells are known to support bone marrow regeneration after chemotherapy or radiation-induced injury to prevent prolonged myelosuppression. However, it is not known how stromal cells within the bone marrow are regenerated after injury. We have utilized a whole bone transplantation model that mimics the initial bone marrow necrosis and fatty infiltration that is seen after bone marrow injury and subsequent recovery. We demonstrate that periosteal skeletal stem cells (P-SSCs) can migrate into the bone marrow and contribute to stromal regeneration and hematopoietic recovery. Once in the bone marrow, P-SSCs are phenotypically and functionally reprogrammed into bone marrow mesenchymal stem cells (BM-MSCs), expressing high levels of hematopoietic stem cell (HSC) niche factors, such as Cxcl12 and Kitl. Additionally, our results further indicate that P-SSCs are more resistant to acute stress than BM-MSCs. Here, we report a new function of P-SSCs, highlighting their major plasticity and the role of the periosteum as a potential source of BM-MSCs following acute bone marrow injury. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.25.266361v1?rss=1 Authors: De Leo, F., Giacomo, Q., De Marchis, F., Malisa, M. V., Bianchi, M. E., Musco, G. Abstract: HMGB1 is a key molecule that both triggers and sustains inflammation following infection or injury, and is involved in a large number of pathologies, including cancer. HMGB1 participates to the recruitment of inflammatory cells forming a heterocomplex with the chemokine CXCL12 (HMGB1/CXCL12), herewith activating the G-protein coupled receptor CXCR4. Thus, identification of molecules that disrupt this heterocomplex can offer novel pharmacological opportunities to treat inflammation related diseases. To identify new HMGB1/CXCL12 inhibitors we have performed a study on the ligandability of the single HMG boxes of HMGB1 followed by a virtual screening campaign on both HMG boxes using Zbc Drugs and three different docking programs (Glide, AutoDock Vina, AutoDock 4.2.6). The best poses in terms of scoring functions, visual inspection and predicted ADME properties were further filtered according to a pharmacophore model based on known HMGB1 binders and clustered according to their structures. Eight compounds representative of the clusters were tested for HMGB1 binding by NMR. We identified 5,5' methylenedi-2,3-cresotic acid (2a) as binder of both HMGB1 and CXCL12; 2a also targets the HMGB1/CXCL12 heterocomplex. In cell migration assays 2a inhibited the chemotactic activity of HMGB1/CXCL12 with IC50 in the subnanomolar range, the best documented up to now. These results pave the way for future structure activity relationship studies to optimize the pharmacological targeting of HMGB1/CXCL12 for anti-inflammatory purposes. Copy rights belong to original authors. Visit the link for more info

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, also associate editor from VCU Health Systems, the Poly Heart Center in Richmond, Virginia. Dr Carolyn Lam:                So arrhythmogenic cardiomyopathy that will make most of us think of right ventricular disease and fatty infiltration of the muscle, but could arrhythmogenic cardiomyopathy really be a bi-ventricular disease? Well you've got to stay tuned to find out more in a fantastic interview coming right up after our little coffee chat. So Greg, what are your picks this week? Dr Greg Hundley:             My first paper is from Chris Lim at NYU in New York. And it's looking at the relationship between Mediterranean diet, air pollution and cardiovascular events.                                                 So, it's unknown whether usual individual dietary patterns can modify the association between long-term air pollution exposure and health outcomes. And so, in this large cohort with detailed diet information at the individual level, they had 548000 individuals across six states and two cities within the U.S. and a follow up period of 17 years. And that occurred between 1995 and 2011. And they evaluated whether a Mediterranean Diet modified the association between long-term exposure to ambient air pollution and then cardiovascular disease and mortality risk. And so, the average exposures to parts per billion and nitric oxide air pollution that the residential census track level were measured, and the investigators found that for the particulate matter there were elevated significant associations with cardiovascular disease. So, a hazard ratio of 1.13, ischemic heart disease similar hazard ratio and cerebrovascular disease with also a similar hazard ratio.                                                 For the nitric oxide, there were also significant associations with cardiovascular disease, as well as ischemic heart disease. And then the analysis indicated that Mediterranean diet modified the relationships. Those with a higher Mediterranean diet score had significantly lower rates of air pollution related mortality. These results therefore indicate Carolyn, that Mediterranean diet reduce cardiovascular disease mortality related to long-term exposure to air pollutants in a large perspective, U.S. cohort. Can you believe increased consumption of foods rich in antioxidant compounds actually may aid in reducing the considerable disease burden associated with ambient air pollution? Dr Carolyn Lam:                Oh wow. That is hugely interesting. Gosh, what do we do about this clinically now?  Dr Greg Hundley:            Remember, first of all, this is an associate study, so we can't infer cause effect. And what we need next are some more independent studies from other cities around the world, prospective cohorts, examinations of clinical outcomes and randomize interventions. And so, I think the results add to a growing body of literature suggesting that dietary patterns may help reduce cardiovascular events in these high air pollution exposure areas. And how does this work? Well, potentially through augmenting antioxidants and reducing oxidative stress. Dr Carolyn Lam:                That's really cool. So from one region, talking about air pollution to another region that often reports about air pollution and that's China. But this study from China is actually the largest registry study to evaluate sex related differences and hospital management and outcomes of patients with acute coronary syndrome in China.                                                 This is from corresponding author Dr Zhao from Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Disease. With colleagues of the improving care for cardiovascular disease in China, Acute Coronary Syndrome project, which is an ongoing nationwide registry of the American Heart Association and the Chinese Society of Cardiology. So, the authors use data from this project and evaluate at sex differences in the acute management, medical therapies for secondary prevention and in hospital mortality in more than 82000 patients admitted for acute coronary syndrome in 192 hospitals across China from 2014 to 2018. Dr Greg Hundley:             What did they show in this study? Dr Carolyn Lam:                They showed that women hospitalized for acute coronary syndrome in China less frequently received acute treatments and strategies for secondary prevention and had a higher in hospital mortality rate than men. Now the observed sex differences in this in hospital mortality were likely due to older age, worse clinical profiles and fewer evidence base acute treatments provided to women. And that's because the sex differences were no longer observed after adjustment for these clinical characteristics and acute treatments.                                                 What this all means though is specifically targeted quality improvement programs may be warranted to narrow these sex related disparities in patients with acute coronary syndrome in China.  Dr Greg Hundley:            Very interesting. I'm going to take sort of the next paper and it's looking at a different aspect of acute myocardial infarction. And these papers from Yong Wang from the Division of Molecular and Translational Cardiology at Hannover Medical School in Hanover, Germany.                                                 Now as we know, the heart can undergo deleterious changes and left ventricular geometry and function during that vulnerable period before scar formation has stabilized the infarct area. And so inflammatory cell trafficking from hematopoietic organs like the spleen to sites of tissue injury is coordinated by chemokine chemokine receptor networks. Therapeutically modulating these chemokine chemokine receptor interactions may promote infarct healing by limiting excessive inflammation induced tissue damage or by enhancing the recruitment of angiogenic cell populations to the infarct or the wound. Inflammatory cell trafficking after a myocardial infarction is controlled by a CXC motif chemokine ligand 12 or CXCL12 and its receptor CXC motif chemokine receptor 4. CXC receptor 4 antagonists, mobilize inflammatory cells and promote infarct repair. But the cellular mechanisms are unclear.                                                 So, what do these investigators do? In mouse models, the investigators found that inflammatory cell trafficking between a hematopoietic organs and sites of tissue injury is controlled by CXCL12 and its receptor CXC receptor 4. And bolus injectives of a highly selected peptidic macrocycles CXC receptor 4 antagonist, enhanced tissue repair and functional recovery after re-perfused acute myocardial infarction in mice. And interestingly, the therapeutic effects require a dendritic cell priming and we're specifically mediated by t-regulator cells. Intermittent CXC R4 blockade mobilized the t-regulator cells from their splenic reservoir. Leading to their enhanced recruitment to the infarct region. Dr Carolyn Lam:                So bring it home for us, Greg. What does this mean clinically for MI management in humans? Dr Greg Hundley:             Right. Highlighting the translational potential. What we might infer is that CXC receptor 4 blockade reduces infarct volume and improved systolic function in a porcine close chest model of re-perfuse acute myocardial infarction.                                                 And so, the results of both the mouse experiments and this sort of translational model in pigs should stimulate further research into therapeutic potential of CXC R4 blockade after MI and in other acute conditions were excessive, innate or adaptive immune responses cause immunopathology. Dr Carolyn Lam:                Fascinating. So from one preclinical paper to another, but this time focused on heart failure. And focus specifically on titin. Titin is this giant elastic protein that spans the half-sarcomere from the Z-disk to the M band, and it acts like a molecular spring and a mechanosensor that has been linked to striated muscle disease. Now the pathways that govern tight independent cardiac growth and contribute to disease are diverse and have been really difficult to dissect. And so corresponding author Dr Gotthardt, from Max Delbruck Center for Molecular Medicine and the German Center for Cardiovascular Research and his colleagues aimed to study titin deficiency versus titin dysfunction.                                                 And how they did that is they generated and compared striatum muscles specific knockouts with progressive postnatal loss of the complete titin protein. And that's by removing Exxon 2. Or an M-band truncation that eliminates the proper structure and integration, but retains all the other functional domains. So they then evaluated cardiac function, cardiomyocytes mechanics, and the molecular basis of the phenotype. Now, what they found was that progressive depletion of titin led to sarcomere disassembly an atrophy in striated muscle. And in the complete knockout, remaining titin molecules had increased strain resulting in mechanically induce trophic signaling and eventual dilated cardiomyopathy.                                                 On the other hand, the truncated titin helped maintain passive properties and thus reduced mechanically and do signaling. In other words, truncations versus loss of titin, differentially affected cardiac pathology with atrophy versus dilated cardiomyopathy respectively. And together, these findings really contribute to the molecular understanding of why titin mutations differentially affect cardiac growth and have implications importantly for genotype, phenotype relations that support a personalized approach to the diverse titinopathy. Dr Greg Hundley:             Interesting, Carolyn. All this information on titin. So why is it clinically important? Dr Carolyn Lam:                Well, first of all, tightened mutations are the most common genetic basis of heart disease and the findings are clinically relevant, as I said, for understanding the genotype phenotype relations at the Titin mutation. But understanding the integration of Titin based signaling and sarcomere biology could indeed help personalize diagnostics by improved clinical decisions and maybe identify suitable therapeutic targets for these titinopathy. But that of course requires much further work. Well that brings us to the end of our summaries. Let's go to our feature discussion.  Dr Greg Hundley:            Welcome everyone to our second segment of our program. We're discussing an interesting paper today entitled Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy. And we want to welcome our coauthors Elijah Behr and Mary Sheppard from St George's University in London. And also, our own associate editor, Sami Viskin to discuss this paper. Mary, can you tell us a little bit about your study design here, the population and the hypothesis and some of your results? Dr Mary Sheppard:          I am a cardiac pathologist of 20 years and I have a special interest in sudden death. Over this time, I've established a national pathology database, where pathologists throughout the country when they have a sudden death, which is likely cardiac and non-ischemic, they will send the heart or tissue blocks insides to me for my opinion concerning the death. We have as a result developed a large number, over 5200 cases which has now built up to 6000. It's the largest pathological series in the world.                                                 And I was also discovering the pathologists were either under or over diagnosing all types of cardiomyopathy but particularly ergogenic cardiomyopathy. And that is why with Chris Miles, our research fellow, we looked in detail at what I had diagnosed, or the pathologist as ergogenic cardiomyopathy and we actually honed are pathological diagnostic criteria for this very important entity. Establishing that left ventricular is five and ventricular and left and ventricular is the norm almost. That right or left ventricular is unusual by themselves and even in 20%, one in five, the heart can look macroscopically normal. So that histology is essential when you're making this diagnosis. You cannot make the diagnosis pathologically without histologically examining the heart. Dr Greg Hundley:             Very good, Mary. And did you also examine some genetic markers in some of the subsets of the patients? And how did you decide who those individuals would be that received the genetic analysis? Dr Mary Sheppard:          A small subset and I will hand over to Elijah Behr, my colleague concerning that. Dr Elijah Behr:                   The genetic tissue is only available in a minority of cases. We've developed a pipeline now with the referring pathologists who are increasingly they're sending samples of spleen suitable for DNA extraction that allow us then to do a retrospective postmortem genetic testing or molecular autopsy. But unfortunately, in this particular series we only had a small proportion. I think there were roughly about 24 out of the 202 cases, so just over ten percent. And interestingly, while we didn't necessarily mirror the expected yield of genetic testing that is seen in clinical cases, where you may see about 40% carrying pathogenic variance. We certainly picked up some important pathogenic variance, particularly those that are often associated with highly penetrant and more severe disease. In particular TMEM43 and desmoplakin. These findings may reflect the small size of the sample, but it also may reflect where the greatest risk for sudden death from ergogenic cardiomyopathy lies. Dr Greg Hundley:             Elijah, getting back to some of the patients that experienced the sudden death in the study population Mary was referring to, were there characteristics that were associated with the sudden death? For example, those that might be related to gender or activity? Dr Elijah Behr:                   So the majority of the cases were male. The majority has never had prior symptoms. These were unheralded deaths. The majority did not have a family history and I think the majority were addressed, but those that were athletes, we're much more likely to have died during exertion. So as we found with ergogenic cardiomyopathy in general and exertion is a trigger to sudden death. The risk was higher and compared to the athletes in death during exertion was associated with being younger as well. I think exertion and sports clearly play a role in ergogenic cardiomyopathy. It didn't appear to play a role in whether there was left ventricular involvement or not, but certainly a role at more severe presentation.  Dr Greg Hundley:            Maybe both Mary and Elijah answering this. You found histopathological evidence of fibrosis and fatty infiltration. How extensive was that? And do you think that could be identified with a test like maybe magnetic resonance imaging? Dr Mary Sheppard:          Yes. Our diagnostic criteria which is illustrated in the addendum is that it was at least two blocks of tissue. We always look at 10 to 12 to 15 blocks of tissue from both right and left ventricle. And at least two of the blocks had to have fibrosis with fat in 20% of the area examined. We did not include inflammation because inflammation is, an important histological criterion in our experience. We were very precise about that because you need that much at least to make the diagnosis. A little bit of fibrosis or a little bit of fat is not sufficient by itself. Dr Greg Hundley:             When you mention a block, for us clinically, how much myocardium would that be? For example, on an imaging test like an echo or an MRI scan. Dr Mary Sheppard:          One to two centimeters squared. Dr Greg Hundley:             So quite a bit. Dr Elijah Behr:                   You're looking at probably around two to four millimeters of potential depth of fibrosis. And what we've seen clinically in LV involvement of MRI scans is miss two epicardial late enhancement. Now the question is whether our scans are sensitive enough to pick that up? Given the technology available or a sense to the histopathology and I think that's why maybe some of the clinical studies have tended to miss the true proportion of left ventricular involvement. Because of the relative subtlety of the fibrosis compared to the technological ability to discriminate it. I mean certainly when you look at our cases that were diagnosed previously with cardiomyopathy, either they were arrhythmogenic or dilated, many did have imaging findings if MRI was performed, that would indicate or suggest some left ventricular involvement. But as you know, the task force criteria for arrhythmogenic cardiomyopathy having very much right ventricular focus. An LV imaging findings and LV ECG findings are just not part of those at the moment. Dr Greg Hundley:             Was there a particular location within the heart where there was a predilection toward the findings of fibrosis and fat? Dr Mary Sheppard:          In the posterior basal wall particularly, transmural involves going from the epicardium to the sub endocardium and also the interior walls of the left ventricular were the predilection areas. Dr Elijah Behr:                   I think that's what we see on our MRI scans as well. When you look at these patients, that posterior basal area, is the one that tends to light up the most. Dr Mary Sheppard:          It is believed that increased stress in that area gives more damage because of the stretching away from the septum. Dr Greg Hundley:             Very interesting. So Elijah, you had mentioned task force criteria. I want to shift to Sami now and ask, Sami, can you help us put this in perspective relative to the existing task force criteria and then the findings in this study? And how that could lead to subsequent changes down the road?  Dr Sami Viskin:                 Okay, so it is difficult to place this in the context of the task force because mentioned by Elijah, the taskforce are focused on a disease that is believed to be in the right ventricle. And the study shows that many of the sudden death cases will involve the left ventricle. One of the most important messages of this paper is importance of her forensic examination. And importance of making it for anything examination in the center of expertise. We know of patients that will travel a thousand miles to undergo surgery or an ablation procedure, but families do not think that way when there is casualty or family dies. You may take a postmortem as a given, but in many countries, including my own, most cases of sudden death would not be followed by a post mortem and will not go into center of expertise. And you cannot overemphasize the importance of doing that because then you have to know what you are looking for in the remaining relatives is extremely important. Dr Greg Hundley:             Very good. How about from the perspective as an electrophysiologist? Does this impact in any way how you might evaluate a younger person with syncope? Dr Sami Viskin:                  Well, it is difficult to conclude from this paper about how to evaluate patients with syncope because most of the cases in this series don't have symptoms at all. But this paper calls to very interesting investigations by Mario del Mar and others in New York. Looking about the electrophysiology consequences of a disease like right ventricle are like a bit mechanical in [inaudible 00:21:58] The tissues becomes editing the disease, the electrical properties how the patients in brugada can cause malfunction of this sodium channel and create a disease that is more like brugada and dysplasia at the beginning. So, the entire correlation between a morphologic disease and the metrical disease and we used to think they are two different things. And now we see that we can actually put them together and you can go through stages where one disease is before an electrical disease and only at later stages it becomes a morphological evident disease.  Dr Greg Hundley:            A fantastic discussion on pathologic findings. Sami making the point that certainly in cases for young individuals having a postmortem examination performed at centers that have expertise such as what Mary's described, can be very important. And then Elijah, helping us to understand with arrhythmogenic cardiomyopathy, number one, findings are not, we shouldn't just be thinking about the right ventricle in isolation, but also the left ventricle. Fibro fatty infiltration, particularly in the posterior basal wall could be an important thing to look for, for those that are performing the magnetic resonance imaging exams. And then lastly, many of the patients in the study like this, the first presentation was of sudden death. And we need to be cognizant that this condition could be prevalent in the population and not necessarily appreciated by some of our current task force guidelines and examinations. So, what an outstanding discussion. And I think for today, we want to thank our authors and our associate editor and wish everyone a great week.                                                 On behalf of Carolyn and myself, we look forward to seeing you next week. Thank you very much. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Commentary by Dr. Valentin Fuster

Title - Screening of cancer tissue arrays identifies CXCR4 on adrenocortical carcinoma: correlates with expression and quantification on metastases using 64Cu-plerixafor PET Abstract - Expression of the chemokine receptor CXCR4 by many cancers correlates with aggressive clinical behavior. As part of the initial studies in a project whose goal was to quantify CXCR4 expression on cancers non-invasively, we examined CXCR4 expression in cancer samples by immunohistochemistry using a validated anti-CXCR4 antibody. Among solid tumors, we found expression of CXCR4 on significant percentages of major types of kidney, lung, and pancreatic adenocarcinomas, and, notably, on metastases of clear cell renal cell carcinoma and squamous cell carcinoma of the lung. We found particularly high expression of CXCR4 on adrenocortical cancer (ACC) metastases. Microarrays of ACC metastases revealed correlations between expression of CXCR4 and other chemokine system genes, particularly CXCR7/ACKR3, which encodes an atypical chemokine receptor that shares a ligand, CXCL12, with CXCR4. A first-in-human study using 64Cu-plerixafor for PET in an ACC patient prior to resection of metastases showed heterogeneity among metastatic nodules and good correlations among PET SUVs, CXCR4 staining, and CXCR4 mRNA. Additionally, we were able to show that CXCR4 expression correlated with the rates of growth of the pulmonary lesions in this patient. Further studies are needed to understand better the role of CXCR4 in ACC and whether targeting it may be beneficial. In this regard, non-invasive methods for assessing CXCR4 expression, such as PET using 64Cu-plerixafor, should be important investigative tools. Full text - http://bit.ly/2hwPKOq Facebook - bit.ly/2xznxjV Twitter - bit.ly/2xzWvsu LinkedIn - bit.ly/2xzJ6kc Pintrest - bit.ly/2xzX8SS Reddit - bit.ly/2hoxI0N www.Oncotarget.com

Dr. Carolyn Lam:               Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our journal this week features an in-depth review on transcatheter therapy for mitral regurgitation, a very, very hot and interesting topic. You have to listen on, coming up right after these summaries.                                                 Our first original paper this week sheds light on the influence of aging on aldosterone secretion and physiology. First author Dr. Nanba, corresponding author Dr. Rainey and colleagues from the University of Michigan in United States, examine the relationship between age and adrenal aldosterone synthase in 127 normal adrenals from deceased kidney donors. The donors' ages ranged from nine months to 68 years. The authors found that adrenals from older individuals displayed less normal aldosterone synthase expression and zona glomerulosa, and greater content of abnormal foci of aldosterone synthase expressing cells.                                                 Furthermore, older age was independently associated with dysregulated and autonomous aldosterone physiology, in an ancillary clinical study of subjects without primary aldosteronism. This study therefore suggests that aging may be associated with a sub-clinical form of aldosterone excess and provides at least one potential explanation for age related cardiovascular risk.                                                 The next study shows, for the first time, that the chemokine receptor, CXCR4, in vascular cells, limits atherosclerosis. The CXCL12 and CXCR4 chemokine ligand receptor axis is known to control cell homeostasis and trafficking. However, its specific in atheroprotection has thus far been unclear. This is addressed in today's study by first author Dr. During, corresponding author Dr. Weber, and colleagues of The Institute for Cardiovascular Prevention in Munich, Germany. In hyperlipidemic mice, the authors showed that cell-specific deletion of CXCR4 in arterial endothelial cells, or smooth muscle cells, marked the increase atherosclerotic lesion formation. Mechanistically, CXCR4 axis promoted endothelial barrier function through VE-cadherin expression and a stabilization of junctional VE-cadherin complexes. In arterial smooth muscle cells, CXCR4 sustained vascular reactivity responses, and a contractile smooth muscle cell phenotype. Whereas, CXCR4 deficiency favored the occurrence of macrophage-like smooth muscle cells in atherosclerotic plaques and impaired cholesterol efflux.                                                 Finally, in humans, the authors identified a common allele variant within the CXCR4 locus that was associated with reduced CXCR4 expression in carotid RG plaques, and increased risk for coronary heart disease. Thus, the study suggests that enhancing the atheroprotective effect of arterial CXCR4 by selective modulators may open normal therapeutic options in atherosclerosis.                                                 The next paper is the first to study the effects of rosuvastatin on carotid intima-media thickness in children, with heterozygous familial hypercholesterolemia. First author Dr. Braamskamp, corresponding author Dr. Hutten, and colleagues from Academic Medical Center Amsterdam in the Netherlands, study children with heterozygous familial hypercholesterolemia aged 6 to less than 18 years, with LDL cholesterol more than 4.9, or more than 4.1 millimoles per liter in combination with other risk factors, who received rosuvastatin for 2 years, starting at 5 milligrams once daily, with uptitration to 10 milligrams for children aged 6 to 10 years old, or 20 milligrams daily for those aged 10 to 18 years old.                                                 Carotid intima-media thickness was assessed by ultrasonography at baseline, 12 months and 24 months in all patients and in age-matched, unaffected siblings. Carotid intima-media thickness was measured at 3 locations, the common carotid artery, the carotid ball, and the internal carotid artery in both the left and right carotid arteries. At baseline, the mean carotid intima-media thickness was significantly greater for the 197 children with heterozygous familial hypercholesterolemia compared with the 65 unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid intima-media thickness in children with heterozygous familial hypercholesterolemia than in the untreated, or unaffected siblings. As a result, there was no difference in carotid intima-media thickness between the two groups after two years of rosuvastatin. These findings, therefore, support the value of early initiation of statin treatment for LDL cholesterol reduction in children with heterozygous familial hypercholesterolemia.                                                 The final study highlights the therapeutic potential of a novel alpha calcitonin gene-related peptide for the treatment of heart failure. First author Dr. Aubdool, corresponding author Dr. Brain, and colleagues from King's College London in United Kingdom, tested the stable alpha analog of calcitonin gene-related peptide in 2 models ... First, an angiotensin 2 infused mouse, and secondly, pressure overload cardiac hypertrophy mouse model using suprarenal aortic ligation. They showed that systemic colon injection of the alpha analog blunted the angiotensin 2 induced rise in blood pressure, as well as the vascular and cardiac remodeling, changes in water consumption, and renal injury, that are normally associated with angiotensin 2 infusion. Furthermore, protective effects were also seen when starting the alpha analog treatment, only during the last week of the 2-week angiotensin 2 infusion, in other words, when hypertension was already established. Finally, the alpha analog preserved heart function, and diminished the degree of hypertrophy and fibrosis in the aortic ligation model.                                                 Thus, these results demonstrate the therapeutic potential of the alpha calcitonin gene-related peptide pathway, and the possibility that this injectable alpha analog may be effective in cardiac disease.                                                 Well, that wraps it up for this week's summaries! Now, for our featured discussion.                                                 For our feature discussion this week, we're talking about trans-catheter therapy for mitral regurgitation, a very hot field and a field in which there have been a lot of advances. To help us break it down, and get right into the insights, the challenges, and potential solutions, I am so pleased to have the first author of this in-depth review paper, Dr. Paul Sorajja from Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital, as well as Dr. Manos Brilakis, associate editor from UT Southwestern, here with us today!                                                 Paul, could I start with you, and just ask you first to give us an idea of what we're talking about here when we talk about mitral regurgitation ... There are different kinds, which are we referring to, and what are the challenges involved in a trans-catheter therapy for mitral regurgitation? Dr. Paul Sorajja:                I think there are a number of challenges, I think the first thing is that MR is often thought of as one disease, but it's really an incredibly heterogeneous disease ... Broadly, we talk about primary versus secondary MR, but the mitral valve is so complex, with multiple different components, any one of which can disrupt and cause MR. When we're talking about trans-catheter therapy, it's often very easy, again, to think we could have one therapy that could treat a simply insufficient valve, but it's way more complex than that, and as a result, there have been many different approaches that have been developed, adding to the complexity of how we manage these patients. Dr. Carolyn Lam:               Right, and in your paper, I loved the way you grouped them, very logically, under those from mitral valve repair, and that for mitral valve replacement ... And then, under repair, you grouped it into leaflet versus targeting the LV ... Could you maybe give us some top-line insights on these techniques? Dr. Paul Sorajja:                Yeah, there are a number of different approaches that have mechanistically gone after the different components through the pathophysiology of MR, where there is leaflets, where there's analysts, cords, or ventricular approach ... I think it's somewhat simplistic to think of it that way, but as catheter-based technology, we are technically limited by what we can do from a catheter standpoint. I think it's inevitable to think about these catheter technologies as eventually being combined, rather than singular, in order to approach what surgeons do in the OR. Dr. Carolyn Lam:               Right, but then even going further, you spent quite a bit of the paper talking about trans-catheter mitral valve implantation ... So, replacing the mitral valve, that's really cool, could you tell us a bit about that, and about that important issue brought up about patient selection. Dr. Paul Sorajja:                Yes, it's a very good point, I think in terms of trans-catheter mitral replacement, I think that that's really where the future is going to go ... The simple analogy is that people think that it will follow the route of TAVR, but I think it will follow the route of TAVR more quickly so, because when you look at how the mitral valve is currently treated in the OR, sometimes, a lot of the times, patients can end up worse. Whereas, a trans-catheter solution actually, I think in terms of the safety margin, actually will equate a degree of safety relative to surgery, if it's done and developed correctly, as opposed to how TAVR's done. I think for TAVR, it's been a number of years for our field to be equivalent or superior to surgery, whereas I think with mitral, I think there's a lot of potential for mitral to have equated a degree of safety. As an example, in the Tendine Feasibility Study, it was published this past January ... A high-risk population, there was not a single procedure death, out of 30 patients ... And for these patients who would go to the OR with an eject fraction of 30 to 40 percent, I think that's quite remarkable. Dr. Carolyn Lam:               Wow, that's really exciting indeed! Manos, you handled this paper, and it's just so beautifully laid out ... That flow chart, I just want to refer all our listeners to the flow chart in Figure 7, that talks about maybe an approach that can be considered. Manos, could you share some thoughts on how this developed? Dr. Manos Brilakis:           Yeah, absolutely, and obviously Paul is the expert on this, but I think it's very important about this paper, and through discussions with Paul and through the development of the paper, is that there's more of a collaboration between the surgeons and the interventionists. So instead, if it's additional style of ... Or the interventionists are doing one thing and the surgeon is doing another, I think the key to success in the mitral field is working very closely together ... Many of those valves right now, the percutaneous valves, are done through a cut down and a typical approach, so working very closely to addressing the anatomic components of the mitral valve problem is a big plus.                                                 The other thing I think that is very important is the new emergence of imaging, trying to understand whether the new mitral valve is going to create issues with LVOT obstruction or not. I think that's leading to a whole new understanding of when and how patients are even candidates for this approach, and I think Paul can elaborate more on this, but as things evolve, fewer and fewer patients are going to be excluded from these new technologies. Dr. Carolyn Lam:               Paul, would you like to take that? What do you think is happening and will happen with patient selection? Dr. Paul Sorajja:                There has been a challenge in current feasibility studies, in terms of getting patients in, the anatomical restraints are exactly what Dr. Brilakis has outlined. There's a certain bulkiness and size to the valve, which essentially poses risk for LVOT obstruction if the valve is too big ... As a feasibility study that's still early, or a field that's still early in its development, there's been a really conservative approach in terms of patient selection to ensure that LVOT obstruction doesn't happen. I think we're pushing the boundaries for that, and I think we've learned a lot from CT imaging, in terms of predicting LVOT obstruction, and I think the valves are also getting to be shorter in profile, which makes it less likely ... But that is definitely one of the limitations, and it's a limitation that exists, not just for trans-cat therapy but also for surgical therapy. Dr. Carolyn Lam:               Right, and then maybe a question for both of you ... What do you think the future is going to hold? What do we need to make this more mainstream, and where do you think this will leave surgical approaches? I know you said a combined approach, but maybe you could elaborate a little bit more? Dr. Paul Sorajja:                I do think, and I agree, I think Manos' point is spot on about that ... This will have to be multidisciplinary, the surgeons and cardiologists absolutely need to continue to work together, that's what's led to the successful development of TAVR, and I think that will be even more so for mitral, because the mitral valve is just infinitely more complex, and we have a lot to learn from the surgeons. But I think going forward, the collaboration is going to be a requirement, and then the training is also going to be a significant portion ... Putting in a mitral valve is much more complex than putting in an aortic valve ... I think if there's a safety margin that's demonstrated, I still think that it will be more appealing and more rapidly adopted than aortic disease. Dr. Carolyn Lam:               Well, Manos? Dr. Manos Brilakis:           No, I completely agree with Paul on that respect. I think, in my mind, at least, an again, this is from an early standpoint, the next big step would be to make it completely percutaneous, right now, you still have to do the cut down, and it's a little more invasive, although still safer than the completely open surgery, but maybe having a complete percutaneous system would be the next big step ... There's no question in my mind, as well ... And watching very closely how Paul and the surgical team are handling this, I think this is definitely the way for the future. Sometimes, in TAVR, it's not as technically demanding, and you don't really need to have too many people in the room, but for this procedure, it's definitely more important to have everyone in the room, and benefit from everyone's expertise. Dr. Carolyn Lam:               Manos, could I switch tracks for a moment now, and ask you to comment on the question that I get a lot ... You're an Interventionist, you handle a lot of the interventional papers for Circulation, and a lot of people are wondering, what makes papers like Paul's ... What makes interventional papers something that we would want to publish in Circulation? Could you share some thoughts? Dr. Manos Brilakis:           Absolutely, thanks Carolyn ... That's a big part, I think, of the appeal of Circulation right now. We're really trying to communicate to people that cutting-edge, clinical science is actually at the heart and the core of Circulation, and clinical content is what drives a lot of editorial ... Especially in intervention, where particularly interesting and new, cutting-edge technologies, new trials, observational studies ... But essentially, things that are cutting-edge, and are going to have a specific implication and impact in the way the field is going ... And this is part of Dr. Sorajja's paper, showing where the future lies in terms of trans-catheter mitral technologies, but along the same lines, we love to have cutting-edge papers on various aspects ... Coronary, peripheral, all aspects of interventional cardiologies, as well as interventional imaging ... The goal, again is to make the submission easy, there are not many honors requirements for submitting the papers, it's very simple to submit, and there's an answer going out very quick, so we're looking forward to receiving more and more interventional papers on cutting-edge science. Dr. Carolyn Lam:               Thank you so much for joining us today, and don't forget to tune in again next week.  

In dieser Studie wurde die Kompetenz des Immunsystems von Turopolje (TxT), Deutsche Landrasse x Pietrain (LxP) und Deutsche Landrasse x Turopolje (LxT) verglichen. Die verschiedenen Rassen sind Vertreter einer alten und einer modernen Rasse und einer Kreuzung von beiden. Hauptziel war es zu untersuchen, ob sich die verschiedenen Rassen in ihrer Immunabwehr gegenüber einer Infektion unterscheiden und wie das Immunsystem durch Stressoren belastet wird. Außerdem wurde untersucht, ob sich LxT zur kommerziellen Mast eignet. Unterschiede in der Sekretion von Immunglobulin G und M im Kolostrum und reifen Milch der Deutsche Landrasse und Turopolje Sauen, sowie deren Aufnahme durch die Ferkel wurde mittels ELISA untersucht. Nach dem Absetzen der Ferkel wurden zwei getrennte Gruppen gebildet: Die erste Gruppe wurde mit einem attenuierten Lebendimpfstoff gegen das Porzine Reproduktive und Respiratorische Syndrom Virus (PRRS MLV) immunisiert, um eine Infektion zu simulieren. Die Fragmente des PRRS MLV wurden aus dem Serum, den Leukozyten, den Tonsillen und dem Lymphonodus tracheobronchale extrahiert und mittels qRT-PCR gemessen. Durch ELISA wurden die Konzentrationen der Interleukine-1β, 6, 10 und 12 gemessen. Die Genexpression von CD163, SIGLEC1, Mx1, TLR7 und TLR8, TRAF6, Myd88, Interleukin 1, 6, 8, 10, 12, TNFα, TGFβ und CXCL12 wurde näher untersucht. Innerhalb der nicht geimpften Gruppe untersuchte man den Einfluss von Stress auf das Immunsystem. Hierbei wurde die Konzentration von Interleukin 6, 10, 12 im Plasma mittels ELISA, die Genexpression in den Lymphozyten durch qRT-PCR von Interleukin 1β, 6, 10, 12 und TNFα bestimmt. Außerdem wurde eine mitogenstimulierte Lymphozytenproliferation mittels Lumineszenzmessung durchgeführt. Bei beiden Gruppen wurde ein Differentialblutbild angefertigt, um Veränderungen im weißen Blutbild untersuchen zu können. Weiterhin wurde mittels ELISA die Immunglobulinkonzentration G und M im Serum untersucht. Es wurde in der Gruppe der immunisierten Tiere sichtbar, dass die Rassen unterschiedlich auf die Vakzination reagierten. TxT zeigt keine Konzentrationsveränderung von Interleukin 1β im Plasma. Durch die unveränderte Konzentration des Interleukins könnten vermehrt zytotoxische T Zellen gebildet werden. Als Folge wird TNFα aufreguliert. TNFα inhibiert CD163, daher wird nur eine geringe Anzahl von B-Zellen aktiviert und es werden spezifische Antikörper gebildet. Im Gegensatz dazu reagieren die beiden anderen Rassen mit einer Immunantwort des Typs 2. Die oben beschriebene Inhibierung kann nicht stattfinden und es kommt zur Synthese der B-Zellen und zu einer erhöhten Konzentration an Immunglobulinen und spezifischen Antikörpern. Die Ergebnisse meiner Studie können tendenziell den Einfluss des Stresses auf das Immunsystem bestätigen. So deuten bei TxT die geringere Immunglobulinkonzentration und das Differentialblutbild darauf hin, dass die Immunreaktion auf Stress eher auf T-Zellen basiert (Immunreaktion Typ 1). Auch bei LxT und LxP scheint es, dass die Immunantwort Typ2 und eine Hochregulation der Genexpression von IL6 und die Konzentration im Plasma dominieren. Weiterhin besteht eine Tendenz, dass TxT auf Stress robuster reagieren als die beiden anderen Rassen. Nach der Schlachtung wurden die Schweinehälften aller Rassen und Gruppen mittels der SEUROP-Klassifizierung eingeteilt und bewertet. Bei Schweinen, die in der 25. Lebenswoche geschlachtet wurden, untersuchte man zusätzlich den Tropfsaftverlust und das intramuskuläre Fett. Im Vergleich der Schachtkörper und Fleischqualität schnitten die Tiere der Kreuzungsrasse (LxT) qualitativ am besten ab. Schlussfolgernd ist die Kreuzungsrasse (LxT) zur Mästung als Nutzungsrasse geeignet. Sie stellt eine Bereicherung innerhalb der kommerziellen Schweinefleischproduktion dar.

Dr Gilbert talks to ecancer at the 2013 ASCO GU symposium about prediction of relapse in stage I nonseminomatous germ cell tumors (NSGCT) by CXCL12. Results from the MRC TE08 and TE22 clinical trials showed that patients who need to get chemotherapy can be picked out and those who don't can be spared. CXCL12 intensity is prognostic for relapse independently of VI. This additional prognostic information can identify groups at very low and very high risk of relapse with potential clinical utility.

Summary and hypothesis Role of pro-inflammatory chemokines in diabetic nephropathy Beyond hemodynamic and metabolic abnormalities associated with diabetes, the role of inflammation in development and progression of diabetic nephropathy is well accepted. Recruitment and activation of macrophages in different renal compartment is considered to be hallmark of all inflammation in diabetic nephropathy. Although recruitment of macrophages to the renal compartment has been extensively studied, the exact mechanisms involved are still to be explored. The chemokine-chemokine receptor interactions are implicated to be mainly responsible for trafficking and infiltration of different monocytes and macrophages. Contribution of macrophages to the development of DN can be addressed in either by inhibiting chemokines or chemokine receptor associated with diabetes. We hypothesized that inhibition of CCL2 may inhibit macrophages infiltrating into different compartments in kidney and inhibition started at earlier stage of disease progression may show more beneficial effects than CCL2 blockade at late stage of DN. To address the involvement of additional chemokine receptors we hypothesized that blocking CCR5 and CCR2 simultaneously might have some additive or synergistic effects. Role of homeostatic chemokines in diabetic nephropathy Homeostatic chemokies are mainly involved in hematopoeisis, immune cell survival and adaptive immune responses. CXCL12 attracted our attention as it is being extensively studied and reported to be responsible for different functions like stem cell survival and homing and trafficking to different compartments. The role of CXCL12 in diabetic nephropathy has not been explored yet. CXCL12 is constitutively expressed by different renal cells. It may contribute to tissue repair and inhibit disease progression by stem cell recruitment or may cause increased tissue fibrosis and aggravate the disease. We hypothesized that CXCL12 plays role in development and progression of diabetic nephropathy. In order to address this question we used CXCL12 blocker in a mouse model of diabetic nephropathy.

CXCR7 (RDC1), the recently discovered second receptor for CXCL12, is phylogenetically closely related to chemokine receptors, but fails to couple to G-proteins and to induce typical chemokine receptor mediated cellular responses. The function of CXCR7 is controversial. Some studies suggest a signaling activity in mammalian cells and zebrafish embryos, while others indicate a decoy activity in fish. Here we investigated the two propositions in human tissues. We provide evidence and mechanistic insight that CXCR7 acts as specific scavenger for CXCL12 and CXCL11 mediating effective ligand internalization and targeting of the chemokine cargo for degradation. Consistently, CXCR7 continuously cycles between the plasma membrane and intracellular compartments in the absence and presence of ligand, both in mammalian cells and in zebrafish. In accordance with the proposed activity as a scavenger receptor CXCR7-dependent chemokine degradation does not become saturated with increasing ligand concentrations. Active CXCL12 sequestration by CXCR7 is demonstrated in adult mouse heart valves and human umbilical vein endothelium. The finding that CXCR7 specifically scavenges CXCL12 suggests a critical function of the receptor in modulating the activity of the ubiquitously expressed CXCR4 in development and tumor formation. Scavenger activity of CXCR7 might also be important for the fine tuning of the mobility of hematopoietic cells in the bone marrow and lymphoid organs.

Background: The chemokine CXCL13 is known to dictate homing and motility of B cells in lymphoid tissue and has been implicated in the formation of ectopic lymphoid tissue in chronic inflammation. Whether it influences B cell trafficking during acute infection, is largely unclear. In previous studies, we showed that (I) CXCL13 levels are markedly increased in the B cell-rich cerebrospinal fluid (CSF) of patients with acute Lyme neuroborreliosis (LNB), and (II) CXCL13 is released by monocytes upon recognition of borrelial outer surface proteins by Toll-like receptor 2. Here, we assessed the role of CXCL13 - in comparison to other chemokines - in the recruitment of B cells to the CSF of patients with acute LNB. Methods: Measurement of chemokines was done by ELISA. B cells were isolated from whole blood using magnetic cell separation (MACS). For migration experiments, a modified Boyden chamber assay was used and the migrated B cells were further analysed by FACS. The migration was inhibited either by preincubation of the CSF samples with neutralizing antibodies, heating to 60 C, removal of proteins >3 kDa, or by pre-treatment of the B cells with pertussis toxin. The principal statistical tests used were one-way analysis of variance and Bonferroni test (chemokine measurements) as well as paired Student's t-test (migration experiments). Results: Measurements of chemokine levels revealed an increase in three of the four known major B cell chemoattractants CXCL13, CCL19 and CXCL12 in LNB CSF. The CXCL13 CSF: serum ratio, as a measure of the chemotactic gradient, was substantially higher than that of CCL19 and CXCL12. Moreover, the chemotactic activity of LNB CSF was reduced up to 56% after preincubation with a neutralizing CXCL13 antibody, while combined preincubation with antibodies against CXCL13, CCL19, and CXCL12 did not lead to further reduction. Since treatment with pertussis toxin, heating to 60 degrees C, and removal of proteins >3 kDa abrogated the chemotactic activity, further not yet identified chemokines seem to be involved in B cell recruitment to LNB CSF. Conclusion: Combined, our study suggests a key role of CXCL13 in B cell migration to sites of infection as shown here for the CSF of LNB patients.