tbuckley/cabot-search huggingface dataset:
Abstract 13010: Endothelin-1 Increases ACVRL-1 Expression at the Transcriptional and Post-transcriptional Levels in Human Pulmonary Arterial Endothelial Cells via Gi, RhoA and Rho Kinase Pathway With Involvement of Sp-1
Authors: Koichi Sugimoto, Tetsuro Yokokawa, Tomofumi Misaka, Sayoko Yokokawa, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2020)

Backgrounds: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and organic stenosis due to abnormal proliferation of pulmonary vascular cells. Endothelin (ET)-1 induces pulmonary vasoconstriction hyperplasia and plays a pivotal role in the pathogenesis of PAH. The germline mutations of activin receptor-like kinase (ACVRL)-1, a serine/threonine kinase and receptor for TGF-β, have been reported in idiopathic and hereditary PAH. However, the relationship between ET-1 and ACVRL-1 in the pathogenesis of PAH is largely unknown. Thus, we investigated the molecular mechanism of ACVRL-1 expression induced by ET-1 in human pulmonary arterial endothelial cells (hPAECs). Methods: ACVRL-1 expression levels were measured using Western blotting and quantitative real-time polymerase chain reaction. The promoter activity of ACVRL-1 was evaluated using dual luciferase assay. hPAECs were pretreated with pertussis toxin (PTX), cell-permeable C3 toxin (C3T) and Y27632 to inhibit Gi, RhoA and Rho kinase, respectively. GTP-RhoA, an active form of RhoA, was assessed using pull-down assay. Results: ET-1 increased mRNA and protein expression of ACVRL-1 in hPAECs (1.8±0.2 folds, P&lt;0.05; 1.5±0.4 folds, P&lt;0.05, respectively). The pull-down assay showed that ET-1 induced GTP-loading of RhoA. ET-1-induced RhoA activation was suppressed by PTX pretreatment. Furthermore, PTX, C3T, and Y27632 suppressed ET-1-induced ACVRL-1 expression. The transcriptional activity of the ACVRL-1 promoter was increased by ET-1 by 1.2±0.17 folds (P&lt;0.05 vs. control). Moreover, ACVRL-1 mRNA was stabilized by ET-1 treatment, and the effect was canceled by Y27632. Finally, the expression of Sp-1, one of known transcriptional factors for ACVRL-1, was increased with a peak at 15 min after ET-1 treatment, and PTX, C3T and Y27632 significantly inhibited the Sp-1 induction by ET-1. Conclusion: These data indicate that ET-1 increases ACVRL-1 expression both at transcriptional and post-transcriptional mechanisms via the Gi/RhoA/Rho kinase/Sp-1 axis in human PAECs.
Feasibility and Performance of Noninvasive Ultrasound Therapy in Patients With Severe Symptomatic Aortic Valve Stenosis
Authors: Emmanuel Messas, Alexander IJsselmuiden, Guillaume Goudot, Selina Vlieger, Samuel Zarka, Etienne Puymirat, Bernard Cholley, Christian Spaulding, Albert A. Hagège, Eloi Marijon, Mickael Tanter, Benjamin Bertrand, Mathieu C. Rémond, Robin Penot, B. Ren, Peter den Heijer, Mathieu Pernot, René Spaargaren
Journal: Circulation (2021)
Expert consensus on the prevention, diagnosis and treatment of cold injury in China, 2020
Authors: Hong-Xu Jin, Yue Teng, Jing Dai, Xiao-Dong Zhao
Journal: Military Medical Research (2021)

Abstract Cold injury refers to local or systemic injury caused by a rapid, massive loss of body heat in a cold environment. The incidence of cold injury is high. However, the current situation regarding the diagnosis and treatment of cold injury in our country is not ideal. To standardize and improve the level of clinical diagnosis and treatment of cold injury in China, it is necessary to make a consensus that is practical and adapted to the conditions in China. We used the latest population-level epidemiological and clinical research data, combined with relevant literature from China and foreign countries. The consensus was developed by a joint committee of multidisciplinary experts. This expert consensus addresses the epidemiology, diagnosis, on-site emergency procedures, in-hospital treatment, and prevention of cold injury.
Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models
Authors: Vikas Daggubati, Jordan Hochstelter, Anirudh Bommireddy, Abrar Choudhury, Alexis Leigh Krup, Pervinder Kaur, Pakteema Tong, Amy Li, Libin Xu, Jeremy F. Reiter, David R. Raleigh
Journal: Journal of Clinical Investigation (2021)

Medulloblastoma is an aggressive pediatric brain tumor that can be driven by misactivation of the Hedgehog (HH) pathway. CDK6 is a critical effector of oncogenic HH signaling, but attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to single-agent molecular therapy. We identified mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma by performing orthogonal CRISPR and CRISPR interference screens in medulloblastoma cells treated with a CDK4/6 inhibitor and RNA-Seq of a mouse model of HH-associated medulloblastoma with genetic deletion of Cdk6. Our concordant in vitro and in vivo data revealed that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to ER stress and activation of the unfolded protein response (UPR). These pathways increased the activity of enzymes producing Smoothened-activating (SMO-activating) sterol lipids that sustained oncogenic HH signaling in medulloblastoma despite cell-cycle attenuation. We consistently demonstrated that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2, an enzyme producing SMO-activating lipids, additively blocked cancer growth in multiple mouse genetic models of HH-associated medulloblastoma. Our data reveal what we believe to be a novel pathway of resistance to CDK4/6 inhibition as well as a novel combination therapy to treat the most common malignant brain tumor in children.
Long-term safety and efficacy of lumacaftor–ivacaftor therapy in children aged 6–11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study
Authors: Mark A Chilvers, Jane C Davies, Carlos Milla, Simon Tian, Zifei Han, Alexandra G Cornell, Caroline A Owen, Felix Ratjen
Journal: The Lancet Respiratory Medicine (2021)
Adapting oncologic practice to COVID19 outbreak: From outpatient triage to risk assessment for specific treatment in Madrid, Spain
Authors: C. Gomez-Martin
Journal: Cancer Research (2020)

Since December 2019, when the first cases of pneumonia associated with a new coronavirus were reported inWuhan (China), we have witnessed the rapid and massive spread of this disease;affecting more than 2 millionpeople worldwide in mid-April  Cancer patients, especially those undergoing active chemotherapy, are especiallyvulnerable due to treatment-induced immunosuppression and their frequent comorbidities  Despite an increasingnumber of papers describing the characteristics of the disease and its possible treatments, oncology patients barelyrepresent a minority in the series reported so far, and their peculiar characteristics are not detailed in thesepublications  On March 6, 2020, when officially in Spain there were only 117 cases and 2 deceased from COVID19, a patientadmitted for another reason was diagnosed with Sars-CoV-2 related infection In the following 48 hours, a full set ofnew procedures were put in place that modified all the clinical care of our oncology patients  Regarding Day Hospital and Outpatient clinics on-site active screening by trained staff for all patients and companions were implemented  Also we limited the number of outpatient visits to minimum indispensable  Allchemo Treatments were reconsidered based on objectives, life expectancy, and type of therapy and clinical status ofevery patient  For all patients admitted routine blood test and Chest Xr or CT of the lungs performed previously to been transferredto Ward  Specifics and separate wards for suspected, confirmed and negative coronavirus patients were preparedas well as dedicated staff (including Oncologist, Infectious Diseases Consultants and Internist) to attend COVID19 +patients 24/7 Since March 9th, more than 280 cancer patients have been actively screened for Sars-coV-2 infection, and 90patients have been admitted to be specifically treated for this disease  Data on clinical characteristics and outcomes for the first 63 patients will be presented, with special mention to tumor burden, grade of immunosuppression, type of treatment and comorbidities  Preliminary data on To cilizumabtreatment on this setting will also be shared as well as some significant relationships between clinical and analyticalparameters and risk of severe pulmonary and vascular events in this population
Survivin Expression Is Differentially Regulated by a Selective Cross-talk between RBM38 and miRNAs let-7b or miR-203a
Authors: Christopher A. Lucchesi, Jin Zhang, Buyong Ma, Ruth Nussinov, Xinbin Chen
Journal: Cancer Research (2021)

Abstract RNA-binding motif 38 (RBM38) is a member of a protein family with a highly conserved RNA-binding motif and has been shown to regulate mRNA processing, stability, and translation. Survivin is an essential modulator of apoptotic and nonapoptotic cell death as well as a stress responder. Survivin mRNA is the fourth most frequently overexpressed transcript in the human cancer transcriptome, and its aberrant expression is associated with chemo-/radioresistance and poor prognosis. In this study, we examined whether survivin expression is regulated by RBM38. RBM38 bound to survivin 3′-untranslated region and suppressed miRNA let-7b from binding to and degrading survivin mRNA, leading to increased survivin expression. RBM38 interacted with argonaute-2 (AGO2) and facilitated miR-203a–mediated degradation of survivin mRNA, leading to decreased survivin expression. Due to the abundance of let-7b over miR-203a, RBM38 ultimately increased survivin expression in HCT116 and MCF7 cells. In addition, Ser-195 in RBM38 interacted with Glu-73/-76 in AGO2, and Pep8, an eight-amino acid peptide spanning the region of Ser-195 in RBM38, blocked the RBM38–AGO2 interaction and inhibited miR-203a–mediated mRNA degradation, leading to enhanced survivin expression. Furthermore, Pep8 cooperated with YM155, an inhibitor of survivin, to suppress tumor spheroid growth and viability. Pep8 sensitized tumor cells to YM155-induced DNA damage in an RBM38-dependent manner. Together, our data indicate that RBM38 is a dual regulator of survivin and that Pep8/YM155 may be therapeutically explored for tumor suppression. Significance: These findings show that RBM38 exerts opposing effects on survivin expression via two miRNAs, and disruption of the RBM38–AGO2 complex by an eight-amino acid peptide sensitizes tumor spheroids to survivin inhibitor YM155.
OP0026 <i>in vivo</i>inhibition of endogenous tgf-beta activity reduces osteophyte size and cartilage proteoglycan content
Authors: A Scharstuhl, P Van der Kraan, E Vitters, H Van Beuningen, W Van der Berg
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Transforming Growth Factor-beta (TGF-beta) is considered to be a beneficial factor during cartilage repair. However, TGF-beta can also induce fibrosis and osteophytes. TGF-beta signalling starts with the binding of TGF-beta to the type II receptor, a constitutively active serine/threonine kinase. This complex then binds the type I receptor, which is subsequently phosphorylated by the type II receptor. This results in phosphorylation of downstream mediators by the type I receptor. Since the binding of TGF-beta to the extracellular domain of the type II receptor is one of high affinity, the soluble TGF-beta type II receptor, lacking cytoplasmic and membrane domains, was used as a TGF-beta antagonist. <h3>Objectives</h3> The objective of this study was to determine the effect of inhibition of endogenous TGF-beta during an experimental model of cartilage damage. <h3>Methods</h3> For the production of recombinant solRII, the methylotropic yeast Pichia pastoris was used. Intra-articular injection of papaine was used as a model for experimental cartilage damage and osteophyte formation. The effect of systemic delivery of solRII on endogenous TGF-beta was investigated in this model. Therefore, Alzet osmotic pumps containing either 10 mg of solRII or pumps containing solvent were implanted i.p. in C57Bl/6 mice. One day later, a 1.2% papaine solution was injected in the right knee joint. Knees were dissected on day 7 and processed for routine histology. <h3>Results</h3> Injection of papaine into murine knee joints resulted in the formation of osteophytes and a decrease in proteoglycan (PG) content of non-calcified articular cartilage. Blocking of endogenous TGF-beta via systemic administration of solRII resulted in a reduction of 75% in osteophyte size compared to controls. Moreover, cartilage PG content was significantly decreased in solRII treated animals compared to control animals. <h3>Conclusion</h3> This study shows for the first time that inhibition of endogenous TGF-beta leads to a reduction in osteophyte size in the papaine model of cartilage damage and osteophyte formation. This finding implicates a direct role for TGF-beta in the formation of osteophytes, a major characteristic of osteoarthritis. Furthermore, an important role for TGF-beta in the regulation of cartilage PG content is suggested, because systemic solRII treatment resulted in a decreased PG content in the papaine model. In conclusion, TGF-beta seems essential in osteophyte formation and protects against cartilage damage.
Dicer‐independent snRNA/snoRNA‐derived nuclear RNA 3 regulates tumor‐associated macrophage function by epigenetically repressing inducible nitric oxide synthase transcription
Authors: Yang Shi, Qingzhu Shi, Qicong Shen, Qian Zhang, Xuetao Cao
Journal: Cancer Communications (2021)

Small RNAs (sRNAs) extensively mediate gene-specific chromatin regulation in lower organisms. As a dominant type of functional sRNAs in mature mammals, microRNAs mainly regulate gene expression at post-transcription level in the cytoplasm. Currently, whether there exists a type of nuclear-localized sRNAs mediating gene-specific epigenetic regulation in mature mammalian cells remains largely unclear. Here, we profiled sRNAs enriched in the nucleus and investigated their function in mediating gene-specific epigenetic regulation in anti-tumor immunity.
Abstract 13036: Optimal Two Stent Strategies for Non Left Main Trunc Coronary Bifurcation Lesions Differ According to the Lesion Locations
Authors: Tomohiko Sato
Journal: Circulation (2019)

Introduction: Optimal two stent strategy for treating coronary bifurcation lesion is still controversial. Hypothesis: If the outcomes of each strategy might differ according to the lesion locations...
Expression Quantitative Trait Locus Analysis in Systemic Sclerosis Identifies New Candidate Genes Associated With Multiple Aspects of Disease Pathology
Authors: Martin Kerick, David González‐Serna, Elena Carnero‐Montoro, Maria Teruel, Marialbert Acosta‐Herrera, Zuzanna Makowska, Anne Buttgereit, Sepideh Babaei, Guillermo Barturen, Elena López‐Isac, Ralf Lesche, Lorenzo Beretta, Marta E. Alarcon‐Riquelme, Javier Martin
Journal: Arthritis & Rheumatology (2021)

To identify the genetic variants that affect gene expression (expression quantitative trait loci [eQTLs]) in systemic sclerosis (SSc) and to investigate their role in the pathogenesis of the disease.We performed an eQTL analysis using whole-blood sequencing data from 333 SSc patients and 524 controls and integrated them with SSc genome-wide association study (GWAS) data. We integrated our findings from expression modeling, differential expression analysis, and transcription factor binding site enrichment with key clinical features of SSc.We detected 49,123 validated cis-eQTLs from 4,539 SSc-associated single-nucleotide polymorphisms (SNPs) (PGWAS < 10-5 ). A total of 1,436 genes were within 1 Mb of the 4,539 SSc-associated SNPs. Of those 1,436 genes, 565 were detected as having ≥1 eQTL with an SSc-associated SNP. We developed a strategy to prioritize disease-associated genes based on their expression variance explained by SSc eQTLs (r2 > 0.05). As a result, 233 candidates were identified, 134 (58%) of them associated with hallmarks of SSc and 105 (45%) of them differentially expressed in the blood cells, skin, or lung tissue of SSc patients. Transcription factor binding site analysis revealed enriched motifs of 24 transcription factors (5%) among SSc eQTLs, 5 of which were found to be differentially regulated in the blood cells (ELF1 and MGA), skin (KLF4 and ID4), and lungs (TBX4) of SSc patients. Ten candidate genes (4%) can be targeted by approved medications for immune-mediated diseases, of which only 3 have been tested in clinical trials in patients with SSc.The findings of the present study indicate a new layer to the molecular complexity of SSc, contributing to a better understanding of the pathogenesis of the disease.
Author Correction: The effect of LRRK2 loss-of-function variants in humans
Authors: Nicola Whiffin, Irina M. Armean, Aaron Kleinman, Jamie L. Marshall, Eric V. Minikel, Julia K. Goodrich, Nicholas M. Quaife, Joanne B. Cole, Qingbo Wang, Konrad J. Karczewski, Beryl B. Cummings, Laurent Francioli, Kristen Laricchia, Anna Guan, Babak Alipanahi, Peter Morrison, Marco A. S. Baptista, Kalpana M. Merchant, James S. Ware, Aki S. Havulinna, Bozenna Iliadou, Jung-Jin Lee, Girish N. Nadkarni, Cole Whiteman, Mark Daly, Tõnu Esko, Christina Hultman, Ruth J. F. Loos, Lili Milani, Aarno Palotie, Carlos Pato, Michele Pato, Danish Saleheen, Patrick F. Sullivan, Jessica Alföldi, Paul Cannon, Daniel G. MacArthur
Journal: Nature Medicine (2021)
SAT0094 ASSESMENT OF BONE MINERAL DENSITY AND FRACTURE RISK IN PATIENTS WITH RHEUMATOID ARTHRITIS AND SARCOPENIA
Authors: O. Dobrovolskaya, Z. Kolkhidova, A. Menshikova, N. Demin, N. Toroptsova
Journal: Annals of the Rheumatic Diseases (2020)

Background: The problem of sarcopenia (SP) in rheumatoid arthritis (RA) is particularly significant in terms of assessing the risk of fractures, since SP leads to falls, which are an independent risk factor for fractures along with RA and osteoporosis. Objectives: To evaluate the bone mineral density (BMD) and fracture risk in women with RA and SP. Methods: 79 women with RA based on the 2010 ACR/EULAR classification criteria were included: 20 (25%) women with confirmed SP (age median 59 [53; 64]) according to EWGSOP2 criteria and 59 (75%) women without SP (age median 60 [55; 67]) (p&gt;0.05). We assessed clinical data: age, body mass index (BMI), disease duration, anthropometric measurements, C-reactive protein level, disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR), previous medication use including glucocorticoids and methotrexate, muscle strength and function. Dual-energy X-ray absorptiometry (DXA) to measure BMD of lumbar spine (LS), femoral neck (FN) and total hip (TH) was performed. The 10-year probability of major osteoporotic fracture (clinical spine, forearm, hip or shoulder fracture) and the 10-year probability hip fracture was calculated using the Russian version of the FRAX® tool. Statistical analysis was performed using non-parametric methods. All patients signed an informed consent to participate. Results: Median BMD in LS was 0.892 [0.772; 1.024] g/cm 2 in patients with SP and 0.910 [0.785; 1.028] g/cm 2 - without SP (p&gt;0.05). There was significant difference between groups in the proximal femur BMD: 0.760 [0.731; 0.826] g/cm 2 in TH and 0.681 [0.607; 0.703] g/cm 2 in FN in patients with SP and 0.838 [0.735; 0.921] g/cm 2 in TH and 0.719 [0.622; 0.804] g/cm 2 in FN in patients without SP (p=0.009 and p=0.048, respectively). The frequency of osteoporosis was 35% and 22% in patients with and without SP (p&gt;0,05). The 10-year probability of major osteoporotic fracture with / without femoral neck BMD data was 22,0% [17,0; 32,0] / 19,5% [18,5; 22,5 and 13,3% [9,8; 18,5] / 12,8% [9,3; 17,0] in patients with SP and without SP (р&lt;0.05) and the 10-year probability of hip fracture with / without femoral neck BMD data - 3,1% [3,0; 7,5] / 3,1% [2,3; 3,3] and 1,4% [0,9; 2,78] / 0,65 [0,4; 1,7], respectively (р&lt;0.05). Conclusion: There were no differences in the frequency of osteoporosis between patients with SP and without SP, however women with SP had proximal femur BMD less than women without SP. The probability of major osteoporotic fracture and hip fracture was significantly higher in patients with RA and SP compared with patients without SP. Disclosure of Interests: None declared
Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission
Authors: Fulvia Milena Cribiù, Roberta Erra, Lorenza Pugni, Carlota Rubio-Perez, Lidia Alonso, Sara Simonetti, Giorgio Alberto Croci, Garazi Serna, Andrea Ronchi, Carlo Pietrasanta, Giovanna Lunghi, Anna Maria Fagnani, Maria Piñana, Matthias Matter, Alexandar Tzankov, Luigi Terracciano, Andres Anton, Enrico Ferrazzi, Stefano Ferrero, Enrico Iurlaro, Joan Seoane, Paolo Nuciforo
Journal: Journal of Clinical Investigation (2021)

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pathophysiology of the placenta and its impact on pregnancy outcome has not yet been fully elucidated. Here, we present a comprehensive clinical, morphological, and molecular analysis of placental tissues from pregnant women with and without SARS-CoV-2 infection. SARS-CoV-2 could be detected in half of placental tissues from SARS-CoV-2–positive women. The presence of the virus was not associated with any distinctive pathological, maternal, or neonatal outcome features. SARS-CoV-2 tissue load was low in all but one patient who exhibited severe placental damage leading to neonatal neurological manifestations. The placental transcriptional response induced by high viral load of SARS-CoV-2 showed an immunopathology phenotype similar to autopsy lung tissues from patients with severe coronavirus disease 2019. This finding contrasted with the lack of inflammatory response in placental tissues from SARS-CoV-2–positive women with low viral tissue load and from SARS-CoV-2–negative women. Importantly, no evidence of vertical transmission of SARS-CoV-2 was found in any newborns, suggesting that the placenta may be an effective maternal-neonatal barrier against the virus even in the presence of severe infection. Our observations suggest that severe placental damage induced by the virus may be detrimental for the neonate independently of vertical transmission.
Integrating Linguistics, Social Structure, and Geography to Model Genetic Diversity within India
Authors: Aritra Bose, Daniel E Platt, Laxmi Parida, Petros Drineas, Peristera Paschou
Journal: Molecular Biology and Evolution (2021)

India represents an intricate tapestry of population substructure shaped by geography, language, culture, and social stratification. Although geography closely correlates with genetic structure in other parts of the world, the strict endogamy imposed by the Indian caste system and the large number of spoken languages add further levels of complexity to understand Indian population structure. To date, no study has attempted to model and evaluate how these factors have interacted to shape the patterns of genetic diversity within India. We merged all publicly available data from the Indian subcontinent into a data set of 891 individuals from 90 well-defined groups. Bringing together geography, genetics, and demographic factors, we developed Correlation Optimization of Genetics and Geodemographics to build a model that explains the observed population genetic substructure. We show that shared language along with social structure have been the most powerful forces in creating paths of gene flow in the subcontinent. Furthermore, we discover the ethnic groups that best capture the diverse genetic substructure using a ridge leverage score statistic. Integrating data from India with a data set of additional 1,323 individuals from 50 Eurasian populations, we find that Indo-European and Dravidian speakers of India show shared genetic drift with Europeans, whereas the Tibeto-Burman speaking tribal groups have maximum shared genetic drift with East Asians.