tbuckley/cabot-search huggingface dataset:
EXTH-55. TARGETING RECURRENT IDH MUTANT GLIOMA WITH CDK4/6 INHIBITION
Authors: Julie Miller, Daniel Cahill, Lisa Melamed, Hiroaki Nagashima
Journal: Neuro-Oncology (2021)

Abstract Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressively and lead to untimely death. Recurrent IDH mutant tumors are less responsive to conventional treatments, highlighting the need for improved therapeutic strategies at this stage of the disease. At least 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, which results in aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors, which are approved for use in a variety of other cancer types. We examined the relationship between CDK4/6 inhibitor sensitivity and CDKN2A loss using patient-derived models of IDH mutant glioma with endogenous CDKN2A homozygous deletion as well as with CRIPSR-mediated gene deletion. We observed enhanced cytotoxicity in glioma models with CDKN2A loss in vitro. Studies to examine the efficacy of CDK4/6 inhibitor treatment on slowing tumor growth in patient-derived xenograft models are ongoing. These preclinical results provide foundational data for design of a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.
Abstract 10199: Establishing Human Ipsc-Derived Vascular Organoids as Angiogenesis Model
Authors: Anja Trillhaase, Zouhair Aherrahrou, Jeanette Erdmann
Journal: Circulation (2021)

Recent large-scale GWA meta-analyses identified more than 240 risk loci associated with coronary artery disease (CAD) on a genome-wide significance level. Pathway analyses confirmed established pathomechanisms contributing to the progression of CAD like lipid metabolism, inflammation, extracellular matrix remodelling, or neoangiogenesis. Human induced pluripotent stem cells (iPSCs) offer a great source to derive 3D models, so-called organoids, allowing a more physiological environment to be analyzed in vitro . We aim to establish vascular organoids from iPSCs as 3D model of angiogenesis to investigate the role of CAD- and angiogenesis-associated risk genes like ADAMTS7 , ARNTL , and TBX20 .Four iPSC lines (UCSD18i-3-6, female, healthy; WC028i-5807-6, female, healthy; UCSD167i-99-1, female, healthy; UCSD179i-27-1, male, healthy; all from skin fibroblasts) will be differentiated into vascular organoids following the protocol published by Wimmer et al (2019). The first iPSC lines were differentiated to estimate the optimal seeding density for each cell line, and organoids were characterized. During embedding of aggregates for vascular sprouting organoids will be used for angiogenesis assay, and sprout length and number will be analysed. Different inhibitors and stimulators of angiogenesis can easily be applied proving that vascular organoids can be used as angiogenesis model. Using siRNA we will then knock-down (KD) above-mentioned risk genes, assessing their effect on angiogenesis. Additionally, cells will be edited using CRISPR/Cas to knockout the same risk genes.The first organoids showed expression of pericyte (PC) and endothelial cell (EC) markers on RNA level, while smooth muscle cell markers were not expressed. These results were confirmed in immunofluorescence stainings in whole organoids. Additionally, we performed cryosections which we also stained with immunofluorescence, showing an even distribution of cells. Staining of the cryosections further confirmed expression of PC- and EC markers. In conclusion, we successfully established iPSC-derived vascular organoids from iPSCs. We have now a 3D cell model in our hand to study GWAS candidate genes and their role in angiogenesis in the context of CAD.
Abstract 14196: Early Postoperative Atrial Fibrillation Combined With Preoperative Structural and Electrophysiological Parameters Are Good Predictors of Late Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery
Authors: Michal Kawczynski, Aaron Isaacs, Martijn Gilbers, Jos G Maessen, Elham Bidar, Ulrich Schotten
Journal: Circulation (2021)

Introduction: Atrial fibrillation (AF) in the early postoperative phase (E-POAF) is likely caused by a combination of an arrhythmogenic substrate and surgery-induced stressors. Although E-POAF is regarded as a transient arrhythmia, recent findings suggest that patients with E-POAF also show late AF recurrences. The aim of this study is to determine the incidence of late postoperative AF (L-POAF) within 1 year of cardiac surgery and to identify its predictors. Hypothesis: The occurrence of L-POAF is associated with preexisting functional and structural atrial changes, and with occurrence of E-POAF. Methods: Ninety-two patients without history of AF undergoing first cardiac surgery were prospectively included. Intraoperatively, all patients received an implantable loop recorder (Reveal LINQ, Medtronic, USA) for continuous rhythm monitoring. Preoperative transthoracic echocardiograms (TTE), 12-lead electrocardiograms (ECG), blood samples, and clinical data were analyzed. Results: Eighty-five patients completed 1-year of follow-up. Incidence of L 5 -POAF (AF between 5-365 days after surgery) was 31.8%, whereas incidence of L 30 -POAF (AF between 30-365 days after surgery) was 15.3%. Independent predictors for L 5 -POAF were left atrial maximum volume indexed for body surface area (LAVi) and occurrence of E 5 -POAF (p=0.02, p&lt;0.01, respectively). Independent predictors for L 30 -POAF were PR-interval and occurrence of E 30 -POAF (p=0.02, p=0.01, respectively). Predictive models for L-POAF based on TTE, biomarkers, and ECG showed moderate performance while addition of E-POAF strongly improved sensitivity and specificity (L 5 -POAF: 94.1% &amp; 95.2%; L 30 -POAF: 83.3% &amp; 91.0%, respectively) to predict L-POAF (see figure). Conclusion: Predictive models based on preoperative LAVi, increased PR-interval, and occurrence of E-POAF show excellent diagnostic accuracy for predicting occurrence of L-POAF.
Abstract 13662: Superior Vena Cava Blood Up-Regulates RNA Expression of Vascular Remodeling Pathways in Lung Endothelial Cells
Authors: Andrew D Spearman, Todd M Gudausky, Susan R Foerster, Girija G Konduri, Ramani Ramchandran
Journal: Circulation (2021)

Introduction: Pulmonary arteriovenous malformations (PAVMs) are common sequelae of single ventricle congenital heart disease (CHD), yet their pathogenesis are poorly understood. Clinical observations indicate that superior vena cava (SVC) blood induces PAVMs, whereas hepatic vein (HV) blood prevents and resolves PAVMs. Using paired SVC and HV blood samples from children with single ventricle CHD, we previously identified multiple protein differences between HV and SVC serum. To determine whether HV and SVC serum differentially impact gene expression in lung endothelial cells, we compared mRNA levels after incubation with HV and SVC serum. Hypothesis: We hypothesize that HV serum induces gene expression associated with endothelial quiescence, whereas SVC serum promotes genes expression associated with vascular remodeling. Methods: HV and SVC blood were collected in the cardiac catheterization lab from children with single ventricle CHD and Glenn circulation. HV and SVC serum (10% concentration) were incubated with human pulmonary microvascular endothelial cells (PromoCell) for 48 hours. After RNA isolation and reverse transcription, mRNA levels of 84 target genes were quantified using Qiagen RT 2 Profiler Angiogenesis Array (PAHS-024Z). Statistically significant differences in expression were identified with absolute fold difference &gt;1.2 and p &lt; 0.05. Results: Samples from 8 patients (63% male, median age 40 months [25.75, 45.25]) were included. Fifteen genes were differentially expressed, including 2 over-expressed with HV treatment (ANGPTL4 [+1.78 fold] and FGF1 [+1.46]) and 13 over-expressed with SVC treatment. Multiple processes were up-regulated in the SVC cohort: VEGF signaling (VEGFR2 [-1.21 fold], NRP1 [-1.42], VEGFR1 [-1.49]), EC adhesion/migration (ITGB3 [-1.40], EFNA1 [-1.40], EFNB2 [-1.39]), angiopoietin-TIE signaling (TIE2 [-1.31]), pericyte signaling (PDGF-A [-1.50], monocyte recruitment (CCL2 [-2.09]), and matrix remodeling (MMP2 [-1.65], FN1 [-1.33]). Conclusions: SVC serum up-regulates multiple vascular remodeling pathways in lung microvascular endothelial cells, potentially representing a pathologically activated endothelial phenotype. In contrast, HV serum promotes endothelial quiescence.
The Impact of Age in Allogeneic Stem Cell Transplantation with Thiotepa Busulfan and Fludarabine (TBF) for Myelofibrosis : A Retrospective Analysis
Authors: Federica SORA, Patrizia Chiusolo, Sabrina Giammarco, Idanna Innocenti, Francesco Autore, Elisabetta Metafuni, Eugenio Galli, maria Assunta Limongello, Luca Laurenti, Simona Sica, Andrea Bacigalupo
Journal: Blood (2021)
Influence of timing of maternal antibiotic administration during caesarean section on infant microbial colonisation: a randomised controlled trial
Authors: Thomas Dierikx, Daniel Berkhout, Anat Eck, Sebastian Tims, Johan van Limbergen, Douwe Visser, Marjon de Boer, Nanne de Boer, Daan Touw, Marc Benninga, Nine Schierbeek, Laura Visser, Jan Knol, Guus Roeselers, Johanna de Vries, Tim de Meij
Journal: Gut (2021)

Objective Revised guidelines for caesarean section (CS) advise maternal antibiotic administration prior to skin incision instead of after umbilical cord clamping, unintentionally exposing the infant to antibiotics antenatally. We aimed to investigate if timing of intrapartum antibiotics contributes to the impairment of microbiota colonisation in CS born infants. Design In this randomised controlled trial, women delivering via CS received antibiotics prior to skin incision (n=20) or after umbilical cord clamping (n=20). A third control group of vaginally delivering women (n=23) was included. Faecal microbiota was determined from all infants at 1, 7 and 28 days after birth and at 3 years by 16S rRNA gene sequencing and whole-metagenome shotgun sequencing. Results Compared with vaginally born infants, profound differences were found in microbial diversity and composition in both CS groups in the first month of life. A decreased abundance in species belonging to the genera Bacteroides and Bifidobacterium was found with a concurrent increase in members belonging to the phylum Proteobacteria. These differences could not be observed at 3 years of age. No statistically significant differences were observed in taxonomic and functional composition of the microbiome between both CS groups at any of the time points. Conclusion We confirmed that microbiome colonisation is strongly affected by CS delivery. Our findings suggest that maternal antibiotic administration prior to CS does not result in a second hit on the compromised microbiome. Future, larger studies should confirm that antenatal antibiotic exposure in CS born infants does not aggravate colonisation impairment and impact long-term health.
개암풀 ( 보골지 (補骨脂) ; Psoralea corylifolia ) 에 의한 급성 간염 1 예
Authors: 황성하(Sung Ha Hwang), 박진아(Jin Ah Park), 장이선(Yi Sun Jang), 이강문(Kang Moon Lee), 이동수(Dong Soo Lee), 안병민(Byung Min Ahn), 이은희(Eun Hee Lee)
Journal: Clinical and Molecular Hepatology (2001)

The potential hepatotoxicity of herbal remedies is usually ignored in daily life. One such compound, Boh-Gol-Zhee (in Chinese, Bu Ku Zi), appeared to be the cause for acute cholestatic hepatic injury in the following case. Psoralea corylifolia is known to contain a sufficient amount of phyto-estrogen. Some alternative medicine therapists claim that Psoralea corylifolia is effective for the treatment of osteoporosis. So far, at least 35 chemical components in the fruits of Psoralea corylifolia have been identified. High concentrations of phyto-estrogen, such as genistein, have been found in the leaves of Psoralea corylifolia. Phyto-estrogen has structural similarity to estrogen and exhibits beneficial effects on osteoporosis under estrogen-deficient conditions. The authors observed a case of acute cholestatic hepatitis in a post-menopausal woman caused by seeds of Psoralea corylifolia in amounts over 10 times the usual dose. Other possible causes of liver injury were excluded by laboratory te.,ts anJ imaging studies. After discontinuation of this remedy, elevated liver enzyme and total bilirubin rapialy returned to normal. Liver biopsy showed zone 3 necrosis, degenerating cells, cholestasis and infiltrations with inflammatory cells. This case stresses the need to warn the potential hepatotoxicity of Psoralea corylifolia seeds, especially in a large dose. (Korean J Hepatol 2001;7:341-344)
Abstract 10987: Effect of False Lumen Status on Systemic Inflammatory Response Induced by Acute Aortic Dissection
Authors: Naoyuki Kimuira, Yojiro Machii, Akio Matsuda, Daijiro Hori, Manabu Shiraishi, Kenji Matsumoro, Atsushi Yamagishi, MASASHI TANAKA
Journal: Circulation (2021)

Introduction: Acute aortic dissection (AAD) frequently induces a systemic inflammatory reaction. However, the influence of dissection morphology on immune response remains to be elucidated. Hypothesis: False lumen (FL) status influences peripheral blood cytokine expression in patients with AAD. Methods: Serum concentrations of 29 cytokines were measured on admission (within 48 hours of symptom onset) in 44 patients with AAD. None were suffering shock or aortic rupture and none had an autoimmune or hematologic disease. The 44 patients were divided into 2 groups based on FL patency: those with a thrombosed FL (Group T [n=21]: median age, 76 years) and those with a partially thrombosed or fully patent FL (Group P [n=23]: median age, 61 years). Stanford classes did not differ between these groups (Group T: type A, n=7; type B, n=14 vs. Group P: type A, n=14; type B, n=9) (p=0.068). Laboratory values, including cytokine concentrations, were compared between these groups and a control group (Group C—patients with a non-ruptured atherosclerotic thoracic aortic aneurysm—n=20]: median age, 75 years) by Mann-Whitney test, with multiple comparisons subjected to Bonferroni correction. Results: Leukocyte counts (x10e3/μL) were increased in both groups (Group T: 9.5 [7.7, 11.7]; Group P: 14.0 [10.4, 18.0] vs. Group C: 5.8 [5.0. 7.1]) (both p&lt;0.001), but CRP concentrations (mg/dL) were not (0.51 [0.15, 3.3], p=0.077 and 0.38 [0.10, 2.7], p=0.165 vs. 0.2 [0.1, 0.21]). D-dimer concentrations (μg/mL) were increased in Group P (28.8 [8.6, 108], p&lt;0.001) but not in Group T (2.9 [1.5, 5.3], p=0.87) (vs. Group C: 2.5 [1.4, 4.9]). Seventeen cytokines [IFNγ, IL-2, IL-4, IL-17α, TNFα, etc.] did not differ significantly between the 2 AAD groups; 12 did differ significantly. The differentially expressed cytokines fell into 3 hierarchical clusters: cluster A (increased expression in both groups [G-CSF, IL-6, IL-10, IL-15]), cluster B (increased expression only in Group P [GM-CSF, IL-1Ra, IL-1b, IL-8, IL-12p70, IP-10], and cluster C (increased expression only in Group T [IL-5, VEGF]). Conclusions: A robust inflammatory response occurs regardless of FL status, but the response is somewhat attenuated in patients with a thrombosed FL vs. those with a patent FL.
ESCMID COVID-19 living guidelines: drug treatment and clinical management
Authors: Michele Bartoletti, Ozlem Azap, Aleksandra Barac, Linda Bussini, Onder Ergonul, Robert Krause, José Ramón Paño-Pardo, Nicholas R. Power, Marcella Sibani, Balint Gergely Szabo, Sotirios Tsiodras, Paul E. Verweij, Ines Zollner-Schwetz, Jesús Rodríguez-Baño
Journal: Clinical Microbiology and Infection (2021)
Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses
Authors: Gesine Behrens, Stephanie L. Edelmann, Timsse Raj, Nina Kronbeck, Thomas Monecke, Elena Davydova, Elaine H. Wong, Lisa Kifinger, Florian Giesert, Martin E. Kirmaier, Christine Hohn, Laura S. de Jonge, Mariano Gonzalez Pisfil, Mingui Fu, Sebastian Theurich, Stefan Feske, Naoto Kawakami, Wolfgang Wurst, Dierk Niessing, Vigo Heissmeyer
Journal: Nature Immunology (2021)
Abstract 10727: Results from First-in-Human Clinical Trial of RP-A501 (AAV9:LAMP2B) Gene Therapy Treatment for Danon Disease
Authors: Barry Greenberg, Emily Eshraghian, Pavan Battiprolu, David Ricks, Paul Yarabe, Jonathan Schwartz, Kinnari Patel, Guarav Shah, Jose Trevejo
Journal: Circulation (2021)

Background: Danon disease (DD) is an X-linked disorder caused by mutations in the LAMP2 gene that is essential for autophagy. DD is characterized by severe cardiomyopathy for which treatment options are limited. Median survival for male patients (pts) is approximately 19 years (y). DD natural history is notable for modest cardiac abnormalities in early phases detectable by measurement of left ventricular global longitudinal strain (GLS) or natriuretic peptides (NPs) followed by rapid progression, particularly in males during the second and third decade. Methods: This open-label Phase 1 study evaluates the safety of a single IV infusion of RP-A501 (AAV9. LAMP2B ) at dose levels of 6.7 x 10 13 GC/kg (low dose) and 1.1 x 10 14 GC/kg (high dose) in male DD pts in two age groups: ≥15 y and 8-14 y. Eligibility criteria include a DD diagnosis with LAMP2 mutation and cardiac involvement. Results: In Cohort 1 (N=3 pts, ≥15 y, 6.7 x 10 13 GC/kg), RP-A501 increased cardiac LAMP2B expression by Western blot (WB) and immunohistochemistry (IHC) in myocardial tissue. The two pts in Cohort 1 with observed immunosuppressive regimen compliance had high cardiac LAMP2B expression: 67.8% and 92.4% vs. normal control by IHC; up to 61% by WB. In both pts, NYHA Class improved from II to I. NPs were reduced by 59% and 42% at 9 and 12 months, respectively. All 3 pts had similar or mildly improved 6MWT, improved myocardial EM morphology with decreased autophagic vacuoles, improved/stabilized GLS and reported increases in physical activity. Adverse events were mostly manageable with transient immunosuppression. Reversible platelet decreases and transaminase elevations that returned to baseline within 2 months were seen. One patient treated with 1.1 x 10 14 GC/kg had complement-mediated thrombocytopenia and acute kidney injury requiring transient hemodialysis that fully recovered. An exacerbation of skeletal myopathy in 3 of the 5 patients resolved with steroid taper. Conclusions: This ongoing first-in-human trial demonstrates that the low dose of RP-A501 gene therapy for DD was generally well-tolerated, confers cardiac LAMP2B gene expression, and is associated with preliminary evidence of cardiac and clinical benefits.
Abstract 12186: The Role of Extracellular Matrix Turnover in Early Diastolic Recoil Efficiency
Authors: Kevin G Tayon, James P MacNamara, Graeme C Carrick-Ranson, Spinale G Francis, Ben D Levine, Satyam Sarma
Journal: Circulation (2021)

Introduction: Diastolic recoil is an important component of cardiac relaxation and depends on the efficient recovery of energy stored in cardiac tissue during systolic deformation. Abnormalities in the cardiac extracellular matrix (ECM) have been implicated in cardiovascular remodeling and diastolic dysfunction. Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of MMPs (TIMPs) regulate protein deposition and degradation in the ECM. We compared MMP and TIMP profiles in healthy seniors to study the role of ECM turnover in diastolic recoil efficiency. Hypothesis: Increased levels of MMPs and TIMPs involved in ECM protein turnover will be associated with improved diastolic recoil efficiency. Methods: Healthy but sedentary seniors (13 men, 9 women; age 68 ± 8 yrs) underwent echocardiogram and plasma biomarker assay for human MMP 1, 2, 3, 7, 9 and TIMP 1, 2, 3, 4. Diastolic recoil efficiency was modeled as an elastic spring and measured as the ratio of systolic longitudinal excursion (Sexc) and early diastolic excursion (EDexc) obtained from tissue doppler velocity-time integrals. Results: Increasing EDexc/Sexc ratios were directly associated with TIMP-1 levels (R=0.45, p=0.035) and TIMP-4 levels (R=0.50, p=0.019). There was a trend towards an association with MMP-2 (R=0.76, p=0.076). There were no significant correlations between the EDexc/Sex ratio and MMPs 1, 3, 7 or 9, TIMPs 2 or 3, MMP2/TIMP1, MMP2/TIMP4, MMP9/TIMP1, or MMP9/TIMP4 ratios. Conclusions: Abnormalities in ECM deposition and degradation via MMPs and TIMPs may impact cardiac relaxation by altering the efficiency of energy recovery in the transition from systole to diastole. TIMP-1 and -4 may preserve diastolic efficiency by attenuating fibrillar collagen fragmentation and pathologic remodeling of the ECM. MMP-2 trended towards a positive association with diastolic recoil efficiency and likely mediates a beneficial effect outside of its proteolytic action.
Expression of alpha v beta 3 integrin in patients with high and low grade glioma
Authors: Oliver Schnell, Bjarne Krebs, Erika Wagner, Ambros J. Beer, Stefan J. Grau, Roland H. Goldbrunner, Claudia Goetz, Hans A. Kretzschmar, Jörg-Christian Tonn
Journal: Cancer Research (2006)

226  Objective: The integrin alpha v beta 3 (αvβ3) has been appointed a key player in the angiogenesis of a large variety of solid tumors (e.g. melanoma, sarcoma) as well as malignant gliomas. Aim of our study was to assess the extent of αvβ3 expression by tumor as well as endothelial cells within gliomas compared to other solid tumors. Methods: Cryosectioned tumor biopsies of histopathologically confirmed high (n=25) and low (n=10) grade gliomas were immunostained with the monoclonal antibody LM609 for detection of αvβ3-expression. Microvascular density of the samples was determined by co-staining with endothelial cell specific markers (CD31, CD105). Moreover, Western blot analysis of consecutive cryosections was performed to investigate the relative vascularisation and integrin expression in these tumors. Results: Immunohistochemistry confirmed that high grade gliomas not only show a higher rate of αvβ3-positive proliferating endothelial cells but have a higher number of αvβ3-expressing tumor cells compared to low grade gliomas. Western blot analysis revealed that αvβ3-expression in malignant gliomas was higher as seen in low grade gliomas. Interestingly, all glial tumors showed less integrin expression and less αvβ3-positive endothelial cells compared to solid non-CNS tumors (melanomas, sarcomas). In return, the rate of integrin-positive tumor cells was higher in all gliomas compared to the peripheral tumors. Conclusion: Due to the relative strong expression of αvβ3 by glioma cells, the function of this integrin in gliomas can not be restricted to angiogenesis alone. Therefore, the effects of novel “antiangiogenic“ drugs targeting this integrin receptor might also exert effects on glioma cells and should be evaluated in this new context.