Podcasts about stat6

The J.P. Morgan Healthcare Conference kicked off Monday with a flood of high-value deals, reinvigorating sentiment across the biopharma industry. Johnson & Johnson made the biggest splash, acquiring neurology leader Intra-Cellular Therapies for $14.6 billion, while GSK picked up precision therapy specialist IDRx for $1B upfront and Eli Lilly laid down up to $2.5 billion for Scorpion's PI3Kα inhibitor program. Meanwhile, the immunology and inflammation space continues to fire on all cylinders as Gilead invests up to $1.7 billion for LEO Pharma's preclinical oral small molecule STAT6 program. And those are only the deals accepted by both parties. Prior to the conference, Biogen offered to acquire its struggling neuro partner Sage Therapeutics for around $469M. The proposal follows a catastrophic run for Sage, which has seen its shares fall more than 90% in the past two years. 2024 sales and earnings forecasts have also generated attention this week, with Sarepta reporting that Duchenne muscular dystrophy gene therapy Elevidys beat analysts' expectations in the fourth quarter, and Eli Lilly projecting a full-year revenue miss driven largely by lower-than-expected sales of GLP-1 blockbusters Zepbound and Mounjaro. As expected, obesity has been a hot topic at JPM, with Pfizer CEO Albert Bourla announcing that his company is going “all in” in the space. This follows new FDA guidance revealed last week recommending a minimum weight loss threshold for drug developers. Among the many companies taking notice is newcomer Verdiva Bio, which launched last week with more than $410 million in opening funds. Also debuting last week was Kardigan, which raised $300 million to tackle heart disease. Kadigan joins a resurgent cardiovascular space, where several companies—including those developing gene therapies—are targeting myriad diseases. Finally, BioSpace senior editor Annalee Armstrong caught up with Daphne Zohar, CEO of BioSpace NextGen 2025 company Seaport Therapeutics Daphne Zohar, who offered her thoughts on the current state of the neuropsychiatric space.

Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin The TWiPyzoites solve the case of the Uncommon Parasite, and discuss the role of eosinophils in promoting the growth of Trichinella in skeletal muscle.   Links for this episode: Eosinophils and IL-4 support nematode growth (PLoS Path) Balantidiasis (CDC) Letters read on TWiP 102  Case study for TWiP 102 This week's case involves a 24 yo housewife, from a village outside of Calcutta. Comes into a tertiary care hosp, 6 months coughing up blood, fever, no weight loss. Drinks rainwater, milks her cow. Dogs everywhere, no livestock except cows. Eats meat, well cooked. No extramarital encounters. Husband well. 4 children. Cistern for drinking water is covered.  No health issues. Reports salty, clear mucus. No blood in stool, no changes in stool. Exam: looks healthy, lungs clear. Lab tests: White count of 9000, 12% eosinophils (elevated). So she has eosinophilia. Chest X-ray and CT: lesion on left side in xray. CT: shows 4 cm cavity, with air pocket on left side, mid-lung. HIV negative. Dusty soil, birds. Send your diagnosis to twip@microbe.tv Send your questions and comments to twip@microbe.tv

Summary: Allergic diseases have exponentially increased during the last decades. The complexity of its aetiology is due to multifaceted interactions between genetic and environmental factors on the development of the immune system. While advances of technology have identified allergy susceptibility genes, functional assays are needed to better understand the underlying mechanisms. Epidemiological studies have consistently shown that rural/farm environments are protective for the development of allergic diseases, including asthma and atopic sensitization. Importantly, prenatal and early life exposures have been shown to confer the strongest protection effects. The mechanisms of how farming modulates the immune system are still not disentangled in detail but include regulation of innate receptors and Regulatory T cells. In the herewith presented thesis, the following main findings were achieved in the context of genetic and immunological influences on development of allergic disease in two different birth cohort studies: First, 200 neonates were assessed for genetic influence of polymorphisms on neonatal immune responses and development of allergic diseases in childhood. The present study suggested a role for polymorphisms in the Th2-pathway, particularly for STAT6 rs324011, on immune regulation at an early stage of immune maturation, namely significantly lower Treg-associated gene expression and Th1-polarization. Polymorphisms in the Th1-pathway, namely the transcription factors TBX21 and HLX1, were shown to be relevant in shaping early immune responses and mainly Th2 cytokines at birth. Th1 and Th2 genotype-related immune responses at birth were partially associated with development of allergic diseases and/or protection during early life. These children are currently followed until the age of 6 years to further investigate allergic and respiratory disease during age-related immune maturation. Secondly, almost 150 children were investigated at the age of 6 years to assess the role of regulatory T cells in relation to farm exposures and clinical outcomes of allergic diseases. Our data indicated an inverse association of farm exposures and the prevalence of asthma during childhood. Children exposed to hay, stable and farm milk had a lower prevalence of asthma. Regarding underlying immune mechanisms, we have detected that children with contact to hay have increased levels of Treg cells and that farm milk intake earlier during childhood can still be partially reflected on Treg cells levels at age 6 years. Assessing Treg functional mechanisms, changes in cytokine secretion were observed depending on the farming and asthmatic status of the children, however confirmation in a larger number of children is required In summary the present work indicated that Th1 and Th2 polymorphisms were associated with modulated immune responses already at birth and influenced allergic disease development during the first three years of life. Furthermore, farm exposures were associated with a lower prevalence of asthma and associated with modulation of regulatory T cell frequency in German children at age 6 years.

High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85 x 10(-20) and 7.08 x 10(-19) in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78 x 10(-4) and P = 1.95 x 10(-3)). The ``top'' SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28 x 10(-7) -4.46 x 10(-8)) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.

Atopische Erkrankungen und Asthma bronchiale beeinträchtigen einen Großteil der in den Industriestaaten lebenden Menschen und sind weltweit verbreitet. Es ist zunehmend Konsens, dass die Entstehung von Asthma bronchiale und atopischen Erkrankungen im Kontext einer Interaktion zwischen determinierter, aber modulationsfähiger genetischer Gegebenheit und Umweltbedingungen gesehen werden muss. Dabei wird immer häufiger die Beobachtung gemacht, dass bestimmte Zeitfenster in der immunologischen Reifung eines Individuums Einfluss auf die Entstehung der Erkrankungen haben können. Daher war die Untersuchung einer genetisch weitgehend homogenen, durch politische Umstände jedoch im Kleinkindalter deutlich differenten Umweltbedingungen ausgesetzten Population ein vielversprechender Ansatz zur Klärung der Einflüsse von Genveränderungen im Interleukin-4-Rezeptor-alpha-Gen und seiner unmittelbaren Liganden auf die Entstehung von Allergie-bedingten Erkrankungen. Hierfür wurde die DNS von 1120 Kindern der ISAAC-Studie aus Leipzig und München auf drei vorbeschriebene Single-Nukleotid-Polymorphismen genotypisiert, mit den Daten aus den Fragebogen korreliert und auf ihre Assoziation mit den Erkrankungen Asthma bronchiale, Heuschnupfen, atopische Dermatitis, positiver Haut-Prick-Test und IgE-Spiegel getestet. Keiner der untersuchten SNPs war in dieser Population mit Asthma, Heuschnupfen oder atopischer Dermatitis assoziiert. Der extrazelluläre SNP IL-4Ra_A148G zeigte eine tendenzielle Assoziation mit erhöhtem Gesamt-IgE der Studienkinder. Bei weitgehend gleichen Allelfrequenzen wurden keine deutlichen Unterschiede in der Erkrankungshäufigkeit gesehen, wenn nach den Herkunftsorten stratifiziert wurde. Bei der Haplotypanalyse innerhalb des IL-4Ra beeinflussten die kombinierten SNPs IL-4Ra_A148G und A1652G die IgE-Spiegel der Population, jedoch nicht stabil in allen drei eingesetzten Verfahren der Berechnung. In der Haplotypanalyse mit vorbeschrieben SNPs des Liganden IL-13 konnte ein Risiko-Haplotyp für erhöhtes IgE, IL-4Ra+ IL-13_GAA, identifiziert werden, welcher die additiven und multiplikativen Erwartungen der Einzelassoziationen deutlich übersteigt. Dies macht eine weitere Analyse dieses Haplotyps in funktionellen Studien interessant. Die weiteren untersuchten Haplotypen mit den Genen von IL-4 und dem intrazellulären Signalübermittler STAT6 konnten keine signifikanten Ergebnisse erzielen, welche kritischen Betrachtungen hinsichtlich der klinischen Plausibilität und der Limitationen der Berechnungsmodi standhielten. Daher muss eine entscheidende Rolle der untersuchten SNPs im IL-4Ra-Protein auf die getesteten Phänotypen als unwahrscheinlich angesehen werden, wobei einzelne tendenzielle Effekte auf den Serum-IgE-Spiegel insbesondere in der Haplotypanalyse aufgrund der großen Studienpopulation herausgearbeitet werden konnten. Ein modulierender Einfluss der SNPs und der gebildeten Haplotypen in dieser Signalkaskade auf IgE-vermittelte Erkrankungen kann als wahrscheinlich angesehen werden, konnte jedoch in dieser Assoziationsstudie nicht zweifelsfrei verifiziert werden. Im Rahmen eines „Risikopanels“ für die Entwicklung eines hohen IgEs, beziehungsweise IgE-vermittelter Erkrankungen sind die SNPs IL-4Ra_A148G und A1652G somit weiterhin interessante Kandidaten.

Die akute Pankreatitis beginnt in den Azinuszellen, allerdings bestimmen die sich anschließenden außerazinären, immunologischen Geschehnisse den Schweregrad der Erkrankung. Diese immunologische Reaktion wird über Zytokine vermittelt, die hauptsächlich von Immunzellen, zusätzlich aber auch von Pankreasazinuszellen selbst sezerniert werden. In dieser Arbeit wurde untersucht, ob Pankreasazinuszellen in der Lage sind, auf autokrin oder parakrin freigesetzte Zytokine zu reagieren. Der JAK/STAT-Signaltransduktionsweg, eine Phosphorylierungskaskade, die von Oberflächenrezeptoren initiierte Signale in den Zellkern weiterleitet, stellt den Haupteffektor der meisten Zytokine dar. Wir konnten mittels Immunopräzipitation und Western-Blot die meisten JAK und STAT Proteine in Pankreasazinuszellen nachweisen (JAK1, JAK2 und TYK2 sowie STAT1, STAT2, STAT3, STAT5 und STAT6). Darüber hinaus konnten wir zeigen, dass einige dieser Proteine in Pankreasazinustellen durch physiologische (Zytokine), aber auch unphysiologische (Stress) Stimuli phosphoryliert und damit aktiviert werden. Dies belegt neben der Expression zusätzlich eine Regulation dieser Proteine und damit eine funktionelle Rolle des JAK/STATSignaltransduktionsweges im Pankreas. Exemplarisch wurde mitttels Immunhistochemie gezeigt, dass IFN-