AAK1 GAK inhibitors for anti-COVID19 therapyAnton Yuryev
BenevolentAI has reported three AAK1 and GAK kinase inhibitors effective against #coronavirus #COVID19. I publish the list of 35 approved drugs and lead compounds that can inhibit AAK1 and GAK kinases and therefore can be effective against #COVID19. Drugs were found in #Elsevier #PathwayStudio and #Reaxys knowledgebases. To find more drugs that can be effective against #COVID19 please visit #Elsevier Coronavirus Information Center or read my blog about atrategies to find more drugs for #coronavirus
Sex Differences in Estrogen Regulation of Renal 11β-Hydroxysteroid Dehydrogen...Darren Roesch
There are profound sex differences in renal function that contribute to sex differences in cardiovascular function, the risk for hypertension, and subsequent development of cardiovascular disease. The effects of estrogens on cardiovascular function are controversial. Some studies suggest estrogens are cardioprotective and others studies suggest estrogens increase cardiovascular risk. Adrenocortical steroids such as the stress hormone, corticosterone, and the mineralocorticoid, aldosterone, can bind and stimulate renal salt reabsorption via the mineralocorticoid receptor (MR). Because corticosterone circulates at much higher levels and has a higher affinity for the MR than aldosterone, it might be expected that all activity at MR would be through corticosterone. However, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) inactivates corticosterone and protects MR from activation by circulating glucocorticoids. We have found that estrogen, a hormone that also increases circulating levels of corticosterone, increases levels of 11β-HSD-2 in males but not females. Therefore, we predict that estrogen increases stress hormone (corticosterone)-mediated salt reabsorption in females more than in males. Since many of the animal studies that predict cardioprotection by estrogen have been conducted in males, and most of the human clinical studies are conducted in females, we hypothesize that a sex/gender difference in renal 11β-HSD-2 responsiveness to estrogen may contribute to the apparent controversy over the effectiveness of estrogen in protecting against cardiovascular disease. Future studies in this laboratory will determine the mechanism of the sex/gender difference in the regulation of 11β-HSD-2 so that increases in 11β-HSD-2 activity might be pharmacologically induced in order to prevent estrogen and stress-associated increases in renal salt reabsorption and the associated increases in blood pressure and the risk for cardiovascular disease.
Differential gene expression in brest cancerShihYin Chen
Explored differential gene expression of immuno-genes using breast cancer patients’ samples from the Cancer Gene Atlas (TCGA) database. Separated patients by their estrogen receptors (ER) status and discovered significant expression differences between two groups (ER+ and ER-) of patients for several immuno-genes, such as IL12RB2 and IL1F5.
While genome-wide association studies of common genetic variants in alopecia areata have highlighted etiological contributions from specific immune cells and pathways, exome studies of rare variants in patients and family members are implicating components of the hair follicle extracellular matrix, suggesting a crucial point of communication between the hair follicle and the immune system.
AAK1 GAK inhibitors for anti-COVID19 therapyAnton Yuryev
BenevolentAI has reported three AAK1 and GAK kinase inhibitors effective against #coronavirus #COVID19. I publish the list of 35 approved drugs and lead compounds that can inhibit AAK1 and GAK kinases and therefore can be effective against #COVID19. Drugs were found in #Elsevier #PathwayStudio and #Reaxys knowledgebases. To find more drugs that can be effective against #COVID19 please visit #Elsevier Coronavirus Information Center or read my blog about atrategies to find more drugs for #coronavirus
Sex Differences in Estrogen Regulation of Renal 11β-Hydroxysteroid Dehydrogen...Darren Roesch
There are profound sex differences in renal function that contribute to sex differences in cardiovascular function, the risk for hypertension, and subsequent development of cardiovascular disease. The effects of estrogens on cardiovascular function are controversial. Some studies suggest estrogens are cardioprotective and others studies suggest estrogens increase cardiovascular risk. Adrenocortical steroids such as the stress hormone, corticosterone, and the mineralocorticoid, aldosterone, can bind and stimulate renal salt reabsorption via the mineralocorticoid receptor (MR). Because corticosterone circulates at much higher levels and has a higher affinity for the MR than aldosterone, it might be expected that all activity at MR would be through corticosterone. However, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) inactivates corticosterone and protects MR from activation by circulating glucocorticoids. We have found that estrogen, a hormone that also increases circulating levels of corticosterone, increases levels of 11β-HSD-2 in males but not females. Therefore, we predict that estrogen increases stress hormone (corticosterone)-mediated salt reabsorption in females more than in males. Since many of the animal studies that predict cardioprotection by estrogen have been conducted in males, and most of the human clinical studies are conducted in females, we hypothesize that a sex/gender difference in renal 11β-HSD-2 responsiveness to estrogen may contribute to the apparent controversy over the effectiveness of estrogen in protecting against cardiovascular disease. Future studies in this laboratory will determine the mechanism of the sex/gender difference in the regulation of 11β-HSD-2 so that increases in 11β-HSD-2 activity might be pharmacologically induced in order to prevent estrogen and stress-associated increases in renal salt reabsorption and the associated increases in blood pressure and the risk for cardiovascular disease.
Differential gene expression in brest cancerShihYin Chen
Explored differential gene expression of immuno-genes using breast cancer patients’ samples from the Cancer Gene Atlas (TCGA) database. Separated patients by their estrogen receptors (ER) status and discovered significant expression differences between two groups (ER+ and ER-) of patients for several immuno-genes, such as IL12RB2 and IL1F5.
While genome-wide association studies of common genetic variants in alopecia areata have highlighted etiological contributions from specific immune cells and pathways, exome studies of rare variants in patients and family members are implicating components of the hair follicle extracellular matrix, suggesting a crucial point of communication between the hair follicle and the immune system.
Cardiac Inflammation and Repair Following Myocardial InfarctionInsideScientific
Join Dr. Merry Lindsey as she discusses her research involving the physiology of recovery from cardiac events.
Age plays a pivotal role in the deterioration of cardiovascular functionality, resulting in an increased risk of cardiovascular disease in older adults. The prevalence of cardiovascular disease has also been shown to increase with age, in both men and women, including the prevalence of atherosclerosis, stroke and, myocardial infarction.
Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of cardiac wound healing responses that involve both the stimulation of robust inflammation to clear necrotic myocytes and tissue debris and the induction of extracellular matrix (ECM) protein synthesis to generate an infarct scar. Collectively, this process in known as LV remodeling. Matrix metalloproteinase-9 (MMP-9) is a key regulator of LV remodeling post-MI, through direct effects on ECM turnover as well as indirect effects on the regulation of the major cell types that coordinate cardiac wound healing- namely the infiltrating leukocytes and the cardiac fibroblasts. We will discuss recent research that has expanded our understanding of MI LV remodeling, including recent proteomic advances focused on the ECM compartment to provide novel functional and translational insights. In summary, this webinar will provide an overview of how cardiac ECM research has evolved over the last decade and will provide insight into future directions that will drive further understanding of MMP directed cardiac ECM turnover after MI.
NSCLC: diagnóstico molecular, pronóstico y seguimiento; CTCMauricio Lema
Lo nuevo en diagnóstico molecular, pronóstico y seguimiento en NSCLC, y el impacto pronóstico de las Células Tumorales Circulantes. Para evento de cirugía de tórax, Hotel Intercontinental, Medellín, 22.05.2018 (se complementa con las la presentación de lo nuevo en terapia sistémica en NSCLC).
Innovación en terapia sistémica de cáncer de pulmónMauricio Lema
Para evento de cirugía de tórax, Hotel Intercontinental, Medellín, 22.05.2018 (se complementa con las otras dos presentaciones de hoy: qué hay de nuevo en diagnóstico molecular, pronóstico y seguimiento, y células tumorales circulantes en NSCLC).
Presentation delivered by Dr Steven M. Fruchtman, Chief Medical Officer, Onconova Therapeutics at the marcus evans Evolution Summit Spring 2017 held at the Ritz-Carlton Coconut Grove, FL, May 8-10.
ORAL PRESENTATION MADE BY ASARE, KUMI KWAME AT:
The Sixth Ghana Biomedical Convention Biomed – 2013 conference held at University of Cape Coast; Cape Coast, Ghana from July 29TH – 31ST 2013
Cardiac Inflammation and Repair Following Myocardial InfarctionInsideScientific
Join Dr. Merry Lindsey as she discusses her research involving the physiology of recovery from cardiac events.
Age plays a pivotal role in the deterioration of cardiovascular functionality, resulting in an increased risk of cardiovascular disease in older adults. The prevalence of cardiovascular disease has also been shown to increase with age, in both men and women, including the prevalence of atherosclerosis, stroke and, myocardial infarction.
Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of cardiac wound healing responses that involve both the stimulation of robust inflammation to clear necrotic myocytes and tissue debris and the induction of extracellular matrix (ECM) protein synthesis to generate an infarct scar. Collectively, this process in known as LV remodeling. Matrix metalloproteinase-9 (MMP-9) is a key regulator of LV remodeling post-MI, through direct effects on ECM turnover as well as indirect effects on the regulation of the major cell types that coordinate cardiac wound healing- namely the infiltrating leukocytes and the cardiac fibroblasts. We will discuss recent research that has expanded our understanding of MI LV remodeling, including recent proteomic advances focused on the ECM compartment to provide novel functional and translational insights. In summary, this webinar will provide an overview of how cardiac ECM research has evolved over the last decade and will provide insight into future directions that will drive further understanding of MMP directed cardiac ECM turnover after MI.
NSCLC: diagnóstico molecular, pronóstico y seguimiento; CTCMauricio Lema
Lo nuevo en diagnóstico molecular, pronóstico y seguimiento en NSCLC, y el impacto pronóstico de las Células Tumorales Circulantes. Para evento de cirugía de tórax, Hotel Intercontinental, Medellín, 22.05.2018 (se complementa con las la presentación de lo nuevo en terapia sistémica en NSCLC).
Innovación en terapia sistémica de cáncer de pulmónMauricio Lema
Para evento de cirugía de tórax, Hotel Intercontinental, Medellín, 22.05.2018 (se complementa con las otras dos presentaciones de hoy: qué hay de nuevo en diagnóstico molecular, pronóstico y seguimiento, y células tumorales circulantes en NSCLC).
Presentation delivered by Dr Steven M. Fruchtman, Chief Medical Officer, Onconova Therapeutics at the marcus evans Evolution Summit Spring 2017 held at the Ritz-Carlton Coconut Grove, FL, May 8-10.
ORAL PRESENTATION MADE BY ASARE, KUMI KWAME AT:
The Sixth Ghana Biomedical Convention Biomed – 2013 conference held at University of Cape Coast; Cape Coast, Ghana from July 29TH – 31ST 2013
A great deal is happening in lupus-related research. This presentation will update participants on recent research developments and their impact on those affected by lupus. Dr. Petri will provide an overview of current lupus research and the prospects for the future of lupus treatments. Learn how to better manage your lupus and make knowledgeable decisions regarding your treatment plan.
Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.
Fungal infections in hematology patients: advances in prophylaxis and treatment
Ewrr 2007 Final (Pc)
1. RADIOLOGICAL DAMAGE IN RHEUMATOID ARTHRTITIS IS ASSOCIATED WITH IL-6 AND IL-10 GENOTYPES INDEPENDENT OF AUTOANTIBODY PRODUCTION I Marinou, J Healy, D Mewar, D J Moore, M C Dickson, M H Binks, D S Montgomery, K Walters and A G Wilson Section of Musculoskeletal Sciences, School of Medicine & Biomedical Sciences, The University of Sheffield
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6. Associations of functional SNPs in IL-10 and IL-6 genes with radiographic severity of RA * Median modified Larsen scores †Cuzic’s test for trend 31 259 (30.1%) GG 0.01 † 27 415 (48.3%) AG (n=860) 24 186 (21.6%) AA IL-10-1082 32 587 (63.3%) CC 0.006 22 309 (33.3%) AC (n=928) 28 32 (3.4%) AA IL-10-592 34 282 (30.3%) GG 0.005 † 27 482 (51.8%) CG (n=930) 25 166 (17.8%) CC IL-6-174 p LS * Cases n (%) Genotype Gene D’=0.89 R 2 =0.24
7. Functional SNPs in IL-10 and IL-6 are not associated with autoantibody production The presence of anti-CCP and RF was compared for each SNP with reference to the commonest genotype 78 159 57 191 GG 0.8 1.0 (0.7-1.4) 129 253 0.2 0.8 (0.5-1.1) 113 291 AG 0.6 1.1 (0.7-1.8) 52 120 0.6 1.1 (0.7-1.9) 36 138 AA IL-10-1082 169 375 138 432 CC 0.5 0.9 (0.7-1.2) 96 191 0.9 1.0 (.07-1.4) 72 222 AC 0.6 1.4 (0.6-3.7) 8 25 0.5 1.5 (06-4.5) 6 28 AA IL-10-592 77 184 64 207 GG 0.6 0.9 (0.6-1.3) 140 304 0.9 1.0 (0.7-1.4) 112 351 CG 0.1 0.7 (0.5-1.1) 56 98 0.7 0.9 (0.6-1.5) 40 120 CC IL-6-174 p OR (95%CI) RF-ve RF+ve p OR (95%CI) CCP-ve CCP+ve Genotype Gene RF status CCP status
8. Associations of SNPs with RA severity are influenced by RF and CCP status Radiographic damage and genotypes stratified by CCP and RF status. Median LS is compared across genotypes according to CCP and RF status. 0.05 40 375 CC 0.002** 16 135 CC 0.002** 19 168 CC 11 103 AA/AC RF- 31 216 AA/AC RF+ 6 76 AA/AC CCP- 0.06 37 431 CC 29 250 AA/AC CCP+ IL-10 -592 p LS n Genotype Antibody status SNP
9. Radiographic damage and genotypes stratified by CCP and RF status. Median LS is compared across genotypes according to CCP and RF status. 13 76 GG 0.5 17 139 GC 13 56 CC RF- 44 184 GG 0.01** 34 304 GC 30 98 CC RF+ 10 63 GG 0.9 13 109 GC 13 39 CC CCP- 41 207 GG 0.004** 32 350 GC 29 120 CC CCP+ IL-6 -174 p LS n Genotype Antibody status SNP
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Editor's Notes
The role of genetics in RA susceptibility is clearly established. However less is known of the genetic influences on disease severity. A relatively few reports have addressed the role of genetics to radiological joint damage. A relationship between DRB1 alleles and severity has been reported but recent evidence suggests that it is secondary to production of anti-CCP antibodies particularly in RF-ve patients.
A central feature of RA is the imbalance of cytokine production with relative excess of proinflammatory cytokines compared to anti-inflammatory mediators. We hypothesized that genetic variants associated with cytokine production may influence disease severity and we seek for associations between functional SNPs in candidate genes and joint damage.
Radiographic damage was measured using the modified Larsen score in a cross-sectional cohort of 965 RA patient all fulfilling the ARC criteria and had a minimum disease duration of 3 yrs. Radiographs of hands and feet were score blind by a single radiologist. To check consistency of the scoring 10% of the films were rescored. Taqman genotyping assays were designed for functional SNPs in IL-1, IL-6 and IL-10. Levels of RF and CCP antibodies were also measured.
We fist look for associations between functional SNPs in candidate genes and radiographic severity of RA. Carriers of the IL-6 -174G allele had more severe radiographic damage compared to those having the C allele. Strong LD was detected between the 2 IL-10 SNPs as measured by D’ and r2. Patients having a copy of the IL-10 -592 C allele had increased median Larsen score compared to those having a copy of the C allele. A similar pattern, although not that significant, was observed for IL-10 -1082. Patients carrying the IL-10 -1082G allele had more severe radiographic damage compared to patients carrying the A allele.
We then investigated if the presence of autoantibody-producing B-cells confound the association between genotypes and disease severity. No association between genotypes and autoantibodies was observed suggesting that the initial association with x-ray damage is not confounded by autoantibody production.
The relationship between antibody status, genotypes and radiological damage was then investigated. Stratification by RF and CCP status showed that the IL-10 -592C association with LS was restricted to either RF-ve or CCP-ve patients.
However the association of IL-6 -174G was only present if RF+ve or CCP+ve patients
The IL-6 -174G allele was associated with more severe x-ray damage. This could be a consequence of the higher gene expression that has been previously associated with this allele. The IL-0 -592C allele was significantly associated with increase joint damage. This association could be a result of lower production levels of this anti-inflammatory cytokine. Variation in IL-10 production has been extensively associated with individual promoter SNP genotypes or haplotypes Seropositivity for both RF and CCP are associated with a more severe RA raising the possibility that our findings of IL-6/IL-10 association with median LS may be independent to the production of these severity markers. RF and CCP were not associated with either IL-6 and IL-10 genotypes suggesting that they may be independent of these severity markers. The association between IL-6 and LS was restricted to either RF+ or CCP+ patients i.e. those with more severe disease Association of IL-10 with x-ray damage was only present in RF- or CCP- patients i.e. those with milder disease
Genotyping of these cytokines represent novels markers of RA severity that complement established biomarkers such as RF and CCP. These results could be useful in therapeutic targeting of expensive anti-rheumatic drugs to patients at risk of developing more severe RA