tbuckley/cabot-search huggingface dataset:
Abstract IA17: From functional genomics to new targets in pediatric oncology
Authors: Kimberly Stegmaier
Journal: Cancer Research (2020)

Abstract The sequencing of human genomes harkened a new era of pediatric cancer investigations. Indeed, genomic discoveries, such as the identification of ALK mutations in neuroblastoma, Philadelphia-like fusions in acute B-cell acute lymphoblastic leukemia (B-ALL), and NTRK fusions in infantile fibrosarcoma, have led to early successes in the application of genomically informed, targeted therapy for children with cancer. While these new drugs have become an important part of the pediatric cancer armamentarium, many children with cancer still lack targeted therapies. Thus, new therapeutic approaches are still needed. Approaches such as RNA interference and CRISPR-Cas9 have transformed the functionalizing of the genome and offer promise for identifying new cancer therapeutic targets. We have applied genome-scale CRISPR-CAS9 screening to identify novel therapeutic targets in pediatric malignancies through the development of a Pediatric Cancer Dependency Map. We screened the Broad Institute’s Avana library in over 100 pediatric cancer cell lines and compared their dependencies to over 600 nonpediatric cell lines. Novel targets emerging from these efforts will be discussed. Citation Format: Kimberly Stegmaier. From functional genomics to new targets in pediatric oncology [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA17.
High Respiratory Drive and Excessive Respiratory Efforts Predict Relapse of Respiratory Failure in Critically Ill Patients with COVID-19
Authors: Pierre Esnault, Michael Cardinale, Sami Hraiech, Philippe Goutorbe, Karine Baumstrack, Eloi Prud’homme, Julien Bordes, Jean-Marie Forel, Eric Meaudre, Laurent Papazian, Christophe Guervilly
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
AB0117 Saliva in patients with different rheumatic diseases
Authors: M Helenius, JH Meurman, I Helenius, K Kari, J Hietanen, R Suuronen, H Kautiainen, M Leirisalo-Repo, C Lindqvist
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Rheumatic diseases affect salivary glands.<sup>1</sup> However, data is sparse on saliva of patients with different disease subgroups with expected differencies. <h3>Objectives</h3> We studied salivary flow and biochemistry in 22 patients with spondyloarthropathy (SPA), 19 with ankylosing spondylitis (AS), 25 with rheumatic arthritis (RA) and 19 with mixed connective tissue disease (MCTD) and 85 age- and sex- matched controls. The mean age was 44.5 years and duration of disease 10.5 years. <h3>Methods</h3> Minor salivary gland biopsies were taken for inflammatory focus score, and salivary components analysed biochemically.<sup>2</sup> <h3>Results</h3> The results showed an inverse correlation between focus scores and decreased salivary flow rates (R = -0.48, CI 0.64–0.29 for resting flow, R = -0.49, CI 0.65–0.30 for stimulated flow). Compared with controls, decreased resting flow (&lt;0.1 mL/min) was most frequent in AS group (22% vs. 0%, p &lt; 0.05), while decreased stimulated flow (&lt;0.7 mL/min) was most frequent in the MCTD group (60% vs.16%, p &lt; 0.05). Lower concentrations of salivary amylase (p &lt; 0.001), but higher albumin (p &lt; 0.01), total protein (p &lt; 0.001), IgA (p &lt; 0.05), IgG (p &lt; 0.001) and IgM (p &lt; 0.001) were found in the patients. <h3>Conclusion</h3> Thus, the hypothesis was confirmed showing significant differences in salivary parameters between patients and controls, and also differences between the patients with various rheumatic diseases. <h3>References</h3> Daniels. Scand J Rheum. 1986;61:36–43 Pajukoski, <i>et al</i>. Oral Surg. 1997;84:265–71
AB0600 THE EFFECTS OF HYPERBARIC OXYGEN THERAPY TO QUALITY OF LIFE AND STATE OF MICROCIRCULATION IN PATIENTS WITH SYSTEMIC SCLEROSIS - A PILOT STUDY
Authors: S. Pavlov-Dolijanovic, V. Koletic, N. Vujasinovic Stupar, N. Damjanov
Journal: Annals of the Rheumatic Diseases (2020)

Background: Many treatments have been tried in therapy systemic sclerosis (SSc) patients but use of hyperbaric oxygen therapy (HBOT) is very limited. Objectives: To assess the effects of HBOT to quality of life and state of microcirculation in SSc patients. Methods: 18 female patients aged 29-68 years (mean 57 years) with limited SSc and digital or leg ulcers were included in this work. The HBOT protocol comprised 20 sessions 5 day/weekly, 60 min, 100% oxygen at 2.2 ATA. The treated patients were evaluated at baseline and after 20 HBOT sessions. Evaluation consisted of physical examination, capillaroscopy, pulmonary function tests, biochemical analyses, socio-demographic and clinimetric questionnaires: Systemic Sclerosis Questionnaire (SySQ) and Health Assessment Disaability index Questionnaire (HAQ-DI). Results: Mean value [before: after, mean (range)] for SySQ [15.5 (4-48) vs 9.0 (3-31)], HAQ-DI [0.60 (0-2.88) vs 0.35 (0 -1.75)], erythrocyte sedimentation rate [21 (4-42) vs 12 (3-27)], forced vital capacity (96.61±14.44% vs 115.94±16.69%), diffusing lung capacity of carbon monoxide (73.61±6.63% vs 87.33±9.30%) significantly improved after HBOT sessions (p&lt;0.001). There was no significant changes in the total number of capillaries (325 vs 338, p=0.235), mean number of enlarged capillaries (21 vs 27, p=0.182), giant capillaries (14 vs 14, p=0.235) and ramified/bushy capillaries (14 vs 13, p=0.178) before and after HOBT. All patients had digital ulcers, and 5 patients had bilateral lesions (digital and leg ulcers). Mean size of ulceration before HBOT was 12x11mm, and after therapy was 4x4mm (p&lt;0.001). Three patients had digital gangrene. Amputation was not require for any. Conclusion: Our data confirm the efficacy of HBOT in treating SSc patients. Further studies are required to evaluate the protocol and to understand the durattion of the clinical effect. References: [1]Mirasoglu B, Bagli BS, Aktas S. Hyperbaric oxygen therapy for chronic ulcers in systemic sclerosis - case series. Int J Dermatol. 2017;56(6):636-640. [2]Gerodimos C, Stefanidou S, Kotsiou M, et al. Hyperbaric oxygen treatment of intractable ulcers in a systemic sclerosis patient. Aristotle Un Med J . 2013;(40)3:19-22. [3]Wallace DJ, Silverman S, Goldstein J, Hughes D. Use of hyperbaric oxygen in rheumatic diseases: case report and critical analysis. Lupus. 1995;4(3):172-5. Disclosure of Interests: Slavica Pavlov-Dolijanovic: None declared, Vesna Koletic: None declared, Nada Vujasinovic Stupar: None declared, Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche
Abstract A48: YB-1-based oncolytic virotherapy in combination with CDK4/6-inhibitors against Ewing sarcoma
Authors: Sebastian J. Schober, Uwe Thiel, Melanie Thiede, Maximilian Ehrenfeld, Roman Nawroth, Guenther HS Richter, Stefan E.G. Burdach, Per Sonne Holm
Journal: Cancer Research (2020)

Abstract Oncolytic virotherapy is associated with immunogenic cell death and antitumor inflammatory immune responses. Thereby, a local as well as systemic immunosuppressive microenvironment might be abrogated, resulting in efficient phagocytic and antigen-presenting properties. Consecutively, priming of naive T cells against a multitude of de-repressed tumor and viral antigens is claimed to elicit strong antitumor immune responses accompanied by tumor-infiltrating T cells, especially in combination with immune checkpoint blockade. These features might be beneficial for patients with relapsed and metastatic Ewing sarcoma, who have poor prognosis and lack innovative therapy concepts, and whose tumor biopsies are characterized by low or absent T-cell infiltration. Here, we explore the efficacy of the oncolytic YB-1-selective adenovirus XVir-N-31 in combination with the CDK4/6-inhibitor abemaciclib (LY2835219) in established Ewing sarcoma cell lines. We demonstrate enhanced viral replication, particle formation, and oncolysis when combined with abemaciclib in vitro. Priming of tumor cells with abemaciclib before viral infection leads to cell cycle arrest in G1 phase, with consecutive decrease in Rb, pRb, and E2F1 protein levels. Interestingly, in the Rb-mutated hence CDK4/6-inhibitor-resistant cell line SK-N-MC, the combination with abemaciclib does not result in enhanced viral replication oor oncolysis. However, the same effects as for CDK4/6-inhibitor sensitive cell lines can be induced by siRNA-mediated E2F1 knockdown, indicating the crucial role of E2F1 as a repressor for initiation of viral replication. In summary, our results further support the hypothesis of E2F1 being a repressor of adenoviral replication (Holm et al., manuscript in preparation) and suggest the use of CDK4/6-inhibitors to boost oncolytic adenoviral efficacy. Further in vivo confirmation is planned in order to prepare a clinical phase I study of XVir-N-31 in combination with a CDK4/6-inhibitor and immune checkpoint blockade for treatment-refractory pediatric sarcoma patients. Citation Format: Sebastian J. Schober, Uwe Thiel, Melanie Thiede, Maximilian Ehrenfeld, Roman Nawroth, Guenther HS Richter, Stefan E.G. Burdach, Per Sonne Holm. YB-1-based oncolytic virotherapy in combination with CDK4/6-inhibitors against Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A48.
Prevalence of COVID-19 in Out-of-Hospital Cardiac Arrest
Authors: Michael R. Sayre, Leslie M. Barnard, Catherine R. Counts, Christopher J. Drucker, Peter J. Kudenchuk, Thomas D. Rea, Mickey S. Eisenberg
Journal: Circulation (2020)

◼ heart arrest T he first US case of coronavirus disease 2019 (COVID-19) was documented locally on January 20, 2020, with unrecognized viral transmission until the first death on February 26, 2020. 1 Resuscitation of patients in out-of-hospital cardiac arrest (OHCA), which depends on rapid, coordinated efforts involving laypersons, telecommunicators, prehospital professionals, and hospital providers, may be adversely affected by COVID-19 concerns.The American Heart Association published interim guidelines to help inform the conduct of bystander cardiopulmonary resuscitation (CPR) during the COVID-19 pandemic. 2These guidelines acknowledged the limited supporting science, including the prevalence of COVID-19 in people with OHCA.We aimed to estimate the frequency of COVID-19 among the total OHCA population.We undertook a cohort investigation of OHCA attended by emergency medical services (EMS) in Seattle and King County, Washington, from January 1 to April 15, 2020.Patients for whom EMS attempted resuscitation (EMS treated) and for whom EMS responded but did not provide resuscitation because of signs of irreversible death (dead on EMS arrival) were included.Our population-based OHCA registry systematically abstracts information about OHCA presentation, treatment, and outcome from dispatch audio recordings, defibrillator electronic data, prehospital and hospital records, death certificates, and medical examiner reports, organized according to the Utstein template.In this region of 2.2 million persons, EMS is a 2-tiered system, administered by Public Health-Seattle & King County, enabling direct engagement for comprehensive disease surveillance.The study was approved by the University of Washington Institutional Review Board.We undertook a hierarchical COVID-19 classification strategy that prioritized polymerase chain reaction (PCR) testing obtained before death or postmortem and clinical classification of a COVID-19-like illness (CLI) if PCR testing was not performed.Beginning in March, the medical examiner prioritized laboratory testing in decedents with an uncertain cause of death or respiratory symptoms before death.To identify patients with laboratory-confirmed COVID-19, we linked the state's COVID-19 surveillance system to EMS electronic records.For patients with EMS OHCA without PCR results, 2 authors (Drs Sayre and Rea) classified CLI status using EMS records by determining whether the arrest was preceded by febrile or respiratory illness or COVID-19 exposure.Disagreements were resolved by a third author (Dr Kudenchuk).Death certificates were processed using the US Centers for Disease Control and Prevention algorithm to classify death attributable to CLI.The interreviewer agreement of clinical CLI classification had a κ of 0.81.We performed a blinded review of EMS records in 98 cases with PCR results to determine the accuracy of clinical CLI classification.Using PCR results as a
Immunotherapy Is Now First-line Therapy for Some Colorectal Cancers
Authors: Rebecca Voelker
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
COVAN is the new HIVAN: the re-emergence of collapsing glomerulopathy with COVID-19
Authors: Juan Carlos Q. Velez, Tiffany Caza, Christopher P. Larsen
Journal: Nature Reviews Nephrology (2020)

Reports of collapsing glomerulopathy in patients of African ancestry and high-risk APOL1 genotype infected with SARS-CoV-2 have emerged during the COVID-19 pandemic. This new entity, which we term COVID-19-associated nephropathy (COVAN), may particularly impact individuals in some regions of the world. Awareness of this potentially ominous complication of COVID-19 must be raised.
PKD1-Dependent Renal Cystogenesis in Human Induced Pluripotent Stem Cell-Derived Ureteric Bud/Collecting Duct Organoids
Authors: Shohei Kuraoka, Shunsuke Tanigawa, Atsuhiro Taguchi, Akitsu Hotta, Hitoshi Nakazato, Kenji Osafune, Akio Kobayashi, Ryuichi Nishinakamura
Journal: Journal of the American Society of Nephrology (2020)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease leading to renal failure, wherein multiple cysts form in renal tubules and collecting ducts derived from distinct precursors: the nephron progenitor and ureteric bud (UB), respectively. Recent progress in induced pluripotent stem cell (iPSC) biology has enabled cyst formation in nephron progenitor-derived human kidney organoids in which PKD1 or PKD2, the major causative genes for ADPKD, are deleted. However, cysts have not been generated in UB organoids, despite the prevalence of collecting duct cysts in patients with ADPKD.CRISPR-Cas9 technology deleted PKD1 in human iPSCs and the cells induced to differentiate along pathways leading to formation of either nephron progenitor or UB organoids. Cyst formation was investigated in both types of kidney organoid derived from PKD1-deleted iPSCs and in UB organoids generated from iPSCs from a patient with ADPKD who had a missense mutation.Cysts formed in UB organoids with homozygous PKD1 mutations upon cAMP stimulation and, to a lesser extent, in heterozygous mutant organoids. Furthermore, UB organoids generated from iPSCs from a patient with ADPKD who had a heterozygous missense mutation developed cysts upon cAMP stimulation.Cysts form in PKD1 mutant UB organoids as well as in iPSCs derived from a patient with ADPKD. The organoids provide a robust model of the genesis of ADPKD.
Abstract 15109: Racial Variability in Severity of Coronary Calcification Among Patients Undergoing Percutaneous Coronary Intervention: Results From a Single-Center Multiethnic Registry
Authors: Solomon Bienstock, Rajeev Samtani, Melissa Aquino, Usman Baber, Joseph Sweeny, Nitin Barman, Jason C Kovacic, Roxana Mehran, Annapoorna Kini, Samin K Sharma, Martin Goldman
Journal: Circulation (2019)

Introduction: Quantifying coronary artery calcium (CAC) is frequently performed prior to invasive coronary angiography and percutaneous coronary intervention (PCI). Although population-based studie...
CYC202 (R-Roscovitine) induces apoptosis in multiple myeloma cells by down regulation of Mcl-1
Authors: David E. Maccallum, Jean Melville, Kathryn Watt, Sian Anderson, Sheelagh Frame, Athos Gianella-Borradori, David P. Lane, Simon R. Green
Journal: Cancer Research (2004)

823  CYC202 is a potent cyclin dependent kinase (CDK) inhibitor, competing with ATP for its binding site on the kinase. It has greatest in vitro activity against CDK2/Cyclin E (Ki=0.12 μM), CDK7/Cyclin H (Ki=0.21 μM) and CDK9/Cyclin T (Ki=0.39 μM). CYC202 inhibits cell cycle progression and transcription of RNA polymerase II. CYC202 induces apoptosis from all phases of the cell cycle in tumour cell lines and reduces growth of human tumour xenografts in nude mice. CYC202 is currently in phase IIa clinical trials in combination therapy with capecitabine for breast cancer and with gemcitabine/cisplatin for non-small cell lung cancer. To identify tumours that are especially sensitive to treatment with CYC202, we have focused on clonal tumours, in particular mature B-cell malignancies including multiple myeloma, B cell chronic lymphocytic leukaemia and mantle cell lymphoma. These diseases are characterised by cells that have extended survival caused by disruption of the balance between pro- and anti-apoptotic factors. Work will be presented analysing the effects of CYC202 on multiple myeloma cell lines. Multiple myeloma is characterised by plasma cell accumulation in the bone marrow causing osteolytic lesions. Although treatment with current chemotherapeutic agents reduces tumour burden, the disease is incurable with patients having an average survival time of three years from diagnosis. In myeloma cells treated in vitro, CYC202 induced rapid dephosphorylation of the C terminal domain (CTD) of RNA polymerase II. Phosphorylation at these sites is crucial for the role of RNA polymerase II in transcriptional elongation. CDK2/cyclin E, CDK7/cyclin H and CDK9/cyclin T can each regulate phosphorylation of the CTD, consistent with one or more of these kinases being a target for CYC202. Inhibition of transcription would be predicted to exert its greatest effect on gene products where both mRNA and protein have short half-lives, resulting in rapid decline of the protein levels. One such gene product is the anti-apoptotic factor Mcl-1 that contains homology to Bcl-2. Mcl-1 acts by inhibiting pro-apoptotic proteins such as Bax and is crucial for survival of a range of cell types including multiple myeloma. As hypothesised following the inhibition of RNA polymerase II phosphorylation, treatment of multiple myeloma cells with CYC202 caused rapid down regulation of Mcl-1 that corresponded with induction of apoptosis determined by TUNEL and PARP cleavage. These results suggest that CYC202 causes myeloma cell death by disrupting the balance from cell survival to apoptosis through inhibition of transcription, and down regulation of Mcl-1. Therefore, CYC202 could be useful for treating multiple myeloma as well as other malignancies that have defects in the apoptosis pathway.
Response by Lewis and de Lemos to Letter Regarding Article, “Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study”
Authors: Alana A. Lewis, James A. de Lemos
Journal: Circulation (2020)

In Response:We appreciate the interest and comments by Chen et al regarding our recent publication.In our study, 1 we examined the "malignant" subphenotype of left ventricular hypertrophy and determined that a higher prevalence of malignant left ventricular hypertrophy among black individuals may contribute to racial disparities observed in heart failure (HF) risk.We defined malignant left ventricular hypertrophies as those with ECG left ventricular hypertrophy and abnormal levels of either hs-cTnT (high-sensitivity cardiac troponin-T) or NT-proBNP (N-terminal pro-B-type natriuretic peptide).Chen et al inquired about our decision to define an abnormal NT-proBNP level as ≥100 pg/mL instead of ≥125 pg/mL, which is an age-independent cutoff value that has been shown to have a high sensitivity and negative predictive value for the diagnosis of clinical HF.However, the 125 pg/mL cut point was derived among patients with symptoms concerning for HF.In our study, individuals with evidence of any cardiovascular disease, including HF, at baseline were excluded.In the general population, associations of NT-proBNP with structural heart disease and risk begin well below 125 pg/mL, 2,3 thus lower thresholds to define risk are appropriate.Our chosen cutoff of ≥100 pg/mL was also consistent with previously published studies in this area. 4,5Using a clinical NT-proBNP cutoff for HF would not be relevant to the aims or purposes of our study.Chen et al also requested clarification on our chosen cutoffs in our subgroup analyses based on body mass index categories (<25, 25 to <30, and >30 kg/m 2 ), and inquired why the 4 categories defined by the World Health Organization were not used instead.The only difference between our categories and the World Health Organization categories is further stratification of body mass index <25 to <18.5 and 18.5 to 24.9 kg/m 2 .However, only 0.8% of our study individuals (and 0.7% of black participants) had a body mass index <18.5 kg/m 2 , thus the inclusion of this additional category would not have affected our findings.With regards to Dr. Chen's inquiry regarding statistical methods to account for the influence of hypertension and diabetes mellitus, we described in our statistical methods section that "logistic regression analyses were performed separately in men and women, adjusting for age, systolic blood pressure, antihypertensive therapy, current smoking, diabetes mellitus, total and HDL cholesterol, and eGFR."This method adequately accounts for potential confounding from hypertension and diabetes mellitus, and, because we did not have specific hypotheses related to these variables, did not prespecify subgroup analyses.
Modelling the impact of testing, contact tracing and household quarantine on second waves of COVID-19
Authors: Alberto Aleta, David Martín-Corral, Ana Pastore y Piontti, Marco Ajelli, Maria Litvinova, Matteo Chinazzi, Natalie E. Dean, M. Elizabeth Halloran, Ira M. Longini Jr, Stefano Merler, Alex Pentland, Alessandro Vespignani, Esteban Moro, Yamir Moreno
Journal: Nature Human Behaviour (2020)