tbuckley/cabot-search huggingface dataset:
Abstract LB-293: IL-2 diphtheria toxin fusion protein with anti-PD1: in mouse B16-F10 melanoma model
Authors: Juan Fu, Drew Pardoll, Laurene Cheung
Journal: Cancer Research (2018)

Abstract In tumor immunotherapy, regulatory T lymphocytes (Tregs) play an important role in the suppression of beneficial anti-tumor responses. In the non-immunogenic B16-F10 mouse melanoma model, tumors are found to be highly infiltrated by Tregs. DAB389IL-2 (Ontak, denileukin diftitox) is an IL-2 diphtheria toxin-related fusion protein that has been showed to deplete Tregs in both humans and mice. We treated mice with established B16F10 tumors with s-DAB389IL-2 (produced as a secreted protein from C. diphtheria) and observed a significant decrease in tumor growth rate in C57BL/6 mice. Also, s-DAB389IL-2 treatment increased the frequency of CD8+IFNγ+ T cells (TILs) in tumors and spleens. S-DAB389IL-2 treatment followed by PD-1 blockade resulted in greater tumor growth inhibition than either monotherapy alone. These data suggest that s-DAB389IL-2 plus anti-PD1 treatment can improve anti-tumor responses in non-immunogenic B16F10 melanoma and inhibit tumor growth. Additionally, we mutated a vascular leak inducing motif to construct s-DAB389IL-2 (V6A), which cause less vascular leak in vitro. S-DAB389IL-2 (V6A) inhibited tumor growth with similar efficacy to the original fusion toxin. As vascular leak is the major adverse effect caused by Ontak, DAB389IL-2 (V6A) shows promise as a better tolerated drug for further studies as a cancer immunotherapy. Citation Format: Juan Fu, Drew Pardoll, Laurene Cheung. IL-2 diphtheria toxin fusion protein with anti-PD1: in mouse B16-F10 melanoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-293.
Management Considerations in Infective Endocarditis
Authors: Andrew Wang, Jeffrey G. Gaca, Vivian H. Chu
Journal: JAMA (2018)

<h3>Importance</h3> Infective endocarditis occurs in approximately 15 of 100 000 people in the United States and has increased in incidence. Clinicians must make treatment decisions with respect to prophylaxis, surgical management, specific antibiotics, and the length of treatment in the setting of emerging, sometimes inconclusive clinical research findings. <h3>Observations</h3> Community–associated infective endocarditis remains the predominant form of the disease; however, health care accounts for one-third of cases in high-income countries. As medical interventions are increasingly performed on older patients, the disease incidence from cardiac implanted electronic devices is also increasing. In addition, younger patients involved with intravenous drug use has increased in the past decade and with it the proportion of US hospitalization has increased to more than 10%. These epidemiological factors have led to<i>Staphylococcus aureus</i>being the most common cause in high-income countries, accounting for up to 40% of cases. The mainstays of diagnosis are still echocardiography and blood cultures. Adjunctive imaging such as cardiac computed tomographic and nuclear imaging can improve the sensitivity for diagnosis when echocardiography is not conclusive. Serological studies, histopathology, and polymerase chain reaction assays have distinct roles in the diagnosis of infective endocarditis when blood culture have tested negative with the highest yield obtained from serological studies. Increasing antibiotic resistance, particularly to<i>S aureus</i>, has led to a need for different antibiotic treatment options such as newer antibiotics and combination therapy regimens. Surgery can confer a survival benefit to patients with major complications; however, the decision to pursue surgery must balance the risks and benefits of operations in these frequently high-risk patients. <h3>Conclusions and Relevance</h3> The epidemiology and management of infective endocarditis are continually changing. Guidelines provide specific recommendations about management; however, careful attention to individual patient characteristics, pathogen, and risk of sequela must be considered when making therapeutic decisions.
The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study
Authors: Basile Stamatopoulos, Thomas Smith, Emerence Crompot, Karlien Pieters, Ruth Clifford, Marek Mraz, Pauline Robbe, Adam Burns, Adele Timbs, David Bruce, Peter Hillmen, Nathalie Meuleman, Philippe Mineur, Radu Firescu, Marie Maerevoet, Virginie De Wilde, André Efira, Jan Philippé, Bruno Verhasselt, Fritz Offner, David Sims, Andreas Heger, Hélène Dreau, Anna Schuh
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21. Experimental Design: We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free survival (TFS) and overall survival (OS) in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing. Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation initiation (P &amp;lt; 0.0001) as well as MYC target genes (P = 0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P &amp;lt; 0.05), particularly those with IgHV mutation. In each of the three independent validation cohorts, we showed that IgLV3-21 rearrangements—similar to UM IgHV status—conferred poor prognosis compared with mutated IgHV (P &amp;lt; 0.0001). Importantly, we confirmed by multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P &amp;lt; 0.0001). Conclusions: We have demonstrated for the first time that a light chain can affect CLL prognosis and that IgLV3-21 light chain usage defines a new subgroup of CLL patients with poor prognosis. Clin Cancer Res; 24(20); 5048–57. ©2018 AACR.
Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib
Authors: Marina Danilenko, Elaine Stamp, Deborah D. Stocken, Akhtar Husain, Monique Zangarini, Amy Cranston, Robert Stones, Naomi Sinclair, Kirsty Hodgson, Susan A. Bowett, David Roblin, Silvio Traversa, Ruth Plummer, Gareth Veal, James A. A. Langtry, Alan Ashworth, John Burn, Neil Rajan
Journal: JAMA Dermatology (2018)

There are no medical interventions for the orphan disease CYLD cutaneous syndrome (CCS). Transcriptomic profiling of CCS skin tumors previously highlighted tropomyosin receptor kinases (TRKs) as candidate therapeutic targets.To investigate if topical targeting of TRK with an existing topical TRK inhibitor, pegcantratinib, 0.5% (wt/wt), is safe and efficacious in CCS.A phase 1b open-label safety study, followed by a phase 2a within-patient randomized (by tumor), double-blind, placebo-controlled trial (the Tropomyosin Receptor Antagonism in Cylindromatosis [TRAC] trial). The setting was a single-center trial based at a tertiary dermatogenetics referral center for CCS (Royal Victoria Infirmary, Newcastle, United Kingdom). Patients who had germline mutations in CYLD or who satisfied clinical diagnostic criteria for CCS were recruited between March 1, 2015, and July 1, 2016.In phase 1b, patients with CCS applied pegcantratinib for 4 weeks to a single skin tumor. In phase 2a, allocation of tumors was to either receive active treatment on the right side and placebo on the left side (arm A) or active treatment on the left side and placebo on the right side (arm B). Patients were eligible if they had 10 small skin tumors, with 5 matched lesions on each body side; patients were randomized to receive active treatment (pegcantratinib) to one body side and placebo to the other side once daily for 12 weeks.The primary outcome measure was the number of tumors meeting the criteria for response in a prespecified critical number of pegcantratinib-treated tumors. Secondary clinical outcome measures included an assessment for safety of application, pain in early tumors, and compliance with the trial protocol.In phase 1b, 8 female patients with a median age of 60 years (age range, 41-80 years) were recruited and completed the study. None of the participants experienced any adverse treatment site reactions. Three patients reported reduced pain in treated tumors. In phase 2a (15 patients [13 female; median age, 51 years], with 150 tumors), 2 tumors treated with pegcantratinib achieved the primary outcome measure of response compared with 6 tumors treated with placebo. The primary prespecified number of responses was not met. The incidence of adverse events was low.In this study, pegcantratinib, 0.5% (wt/wt), applied once daily appeared to be well tolerated and to penetrate the tumor tissue; however, the low tumor drug concentrations demonstrated are likely to account for the lack of response. Dose-escalation studies to assess the maximal tolerated dose may be beneficial in future studies of CCS.isrctn.org Identifier: ISRCTN75715723.
Dupilumab Treatment of Very Severe Refractory Atopic Hand Eczema
Authors: Jart A. F. Oosterhaven, Geertruida L. E. Romeijn, Marie L. A. Schuttelaar
Journal: JAMA Dermatology (2018)

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 Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Dermatology journal
NIH-Sponsored Trial of Universal Influenza Vaccine
Authors: Rita Rubin
Journal: JAMA (2018)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Reappraisal of Reported Genes for Sudden Arrhythmic Death
Authors: S. Mohsen Hosseini, Raymond Kim, Sharmila Udupa, Gregory Costain, Rebekah Jobling, Eriskay Liston, Seema M. Jamal, Marta Szybowska, Chantal F. Morel, Sarah Bowdin, John Garcia, Melanie Care, Amy C. Sturm, Valeria Novelli, Michael J. Ackerman, James S. Ware, Ray E. Hershberger, Arthur A.M. Wilde, Michael H. Gollob
Journal: Circulation (2018)

Implicit in the genetic evaluation of patients with suspected genetic diseases is the assumption that the genes evaluated are causative for the disease based on robust scientific and statistical evidence. However, in the past 20 years, considerable variability has existed in the study design and quality of evidence supporting reported gene-disease associations, raising concerns of the validity of many published disease-causing genes. Brugada syndrome (BrS) is an arrhythmia syndrome with a risk of sudden death. More than 20 genes have been reported to cause BrS and are assessed routinely on genetic testing panels in the absence of a systematic, evidence-based evaluation of the evidence supporting the causality of these genes.We evaluated the clinical validity of genes tested by diagnostic laboratories for BrS by assembling 3 gene curation teams. Using an evidence-based semiquantitative scoring system of genetic and experimental evidence for gene-disease associations, curation teams independently classified genes as demonstrating limited, moderate, strong, or definitive evidence for disease causation in BrS. The classification of curator teams was reviewed by a clinical domain expert panel that could modify the classifications based on their independent review and consensus.Of 21 genes curated for clinical validity, biocurators classified only 1 gene ( SCN5A) as definitive evidence, whereas all other genes were classified as limited evidence. After comprehensive review by the clinical domain Expert panel, all 20 genes classified as limited evidence were reclassified as disputed with regard to any assertions of disease causality for BrS.Our results contest the clinical validity of all but 1 gene clinically tested and reported to be associated with BrS. These findings warrant a systematic, evidence-based evaluation for reported gene-disease associations before use in patient care.
Efficacy, immunogenicity, and safety of a parenteral vaccine against Helicobacter pylori in healthy volunteers challenged with a Cag-positive strain: a randomised, placebo-controlled phase 1/2 study
Authors: Peter Malfertheiner, Michael Selgrad, Thomas Wex, Benedetta Romi, Erica Borgogni, Fabiana Spensieri, Luisanna Zedda, Paolo Ruggiero, Laura Pancotto, Stefano Censini, Emanuela Palla, Niranjan Kanesa-Thasan, Bruce Scharschmidt, Rino Rappuoli, David Y Graham, Francesca Schiavetti, Giuseppe Del Giudice
Journal: The Lancet. Gastroenterology & hepatology (2018)
Abstract 1473: Role of acetyltransferases CBP and p300 in de novo fatty acid synthesis in colorectal cancer
Authors: Aaron Waddell, Iqbal Mahmud, Daiqing Liao
Journal: Cancer Research (2018)

Abstract CBP/p300 are two paralogous lysine acetyltransferases that acetylate protein substrates including histones, and serve as transcriptional co-activators for numerous signaling pathways involved in tumorigenesis and cancer progression. Recently, evidence has emerged that p300 regulates the transcription of genes involved in lipogenesis in cancers. Dysregulated lipogenesis and increased de novo production of fatty acids (FA) represent a major metabolic shift in cancer. De novo FA synthesis in cancer is suggested to be a source of lipids for membrane biogenesis, a reservoir of energy, and a source of pro-survival signaling molecules. Therefore, de novo FA synthesis has been linked to survival and increased proliferation of cancer cells, representing a potential area for therapeutic intervention. While emerging evidence indicates CBP/p300 may play a key role in regulating lipogenesis, little is known about the mechanism of how these proteins control lipid production in different cancers. Colorectal cancer (CRC) is a commonly diagnosed human cancer and is a major cause of cancer-related mortality. Key regulators for de novo FA synthesis, such as FASN, have been reported to be elevated in colorectal cancer. We analyzed publically available data sets and report that in colon adenocarcinoma, the mRNA levels of CBP/p300 positively correlate with the expression of genes involved in lipogenesis, such as FASN, SREBP1 and SREBP2. Furthermore, our analysis shows that EP300 expression is negatively correlated with patient survival. Strikingly, our preliminary data suggests that HDAC inhibitors may regulate p300 activity and could serve as a therapeutic approach for suppressing lipogenesis. We are currently utilizing small molecule inhibitors, genetic manipulation of the CREBBP/EP300 genes, and biochemical experiments to investigate the role of CBP/p300 in de novo FA synthesis in colorectal cancer. We hypothesize that inhibition of CBP/p300 could be an attractive therapeutic option for inhibiting tumor growth through downregulating de novo FA synthesis in colorectal cancer. (Supported by grants from James and Esther King Biomedical Research Program and Bankhead-Coly Cancer Research Program, Florida Department of Health.) Citation Format: Aaron Waddell, Iqbal Mahmud, Daiqing Liao. Role of acetyltransferases CBP and p300 in de novo fatty acid synthesis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1473.
해설논문 : 급성 A형간염의 역학 변화 및 임상양상: 국내 보고를 중심으로
Authors: 정영걸 ( Young Kul Jung ), 김주현 ( Ju Hyun Kim )
Journal: Clinical and Molecular Hepatology (2009)

Acute viral hepatitis A has recently become a major public health problem in Korea, and the incidence of symptomatic hepatitis A is growing rapidly. With improvements in socioeconomic conditions and environmental hygiene, the chances of exposure to hepatitis A virus (HAV) during childhood have decreased and, in turn, the proportion of young adults with positive anti-HAV has significantly decreased. This has led to the incidence of symptomatic acute hepatitis A increasing since the late 1990s. The incidence of serious complications including fulminant hepatic failure and acute kidney injury has also showed an increasing trend. Variation of the genotype of virus isolated from recent hepatitis A patients suggests an inflow of the hepatitis virus from other countries. In this review article, we present the situation and epidemiology of hepatitis A in Korea, and recommend further investigation and policies for vaccination on a national level. (Korean J Hepatol 2009;15:438-445)
Abstract 1115: A CRISPR/Cas9 kinome screen identifies GRK5 as a novel regulator of rhabdomyosarcoma (RMS) self-renewal
Authors: Thao Q. Pham, Terra Vleeshouwer-Neumann, Eleanor Chen
Journal: Cancer Research (2018)

Abstract Rhabdomyosarcoma (RMS) is a devastating pediatric soft tissue sarcoma. Clinical outcome for patients with relapsed or metastatic disease remains poor. However, current treatment options remain relatively unchanged over the last two decades, so there remains an urgent need for more effective treatment options for disease relapse. Cancer stem cells (CSCs), also known as tumor-propagating cells (TPCs), have the capacity for self-renewal and have been proposed to be responsible for tumor relapse and metastasis. RMS has been shown to follow the CSC model of tumor progression. We have previously performed an siRNA library screen against the human kinome (714) and a secondary CRISPR/Cas9 screen of top candidates to narrow down to 11 novel kinase candidates that are potentially essential for self-renewal of human RMS cells. GRK5, a G-protein coupled receptor kinase, was among the top candidate genes. Preliminary data from in vitro cell-based assays and in vivo limiting-dilution experiments in xenografts showed that CRISPR/Cas9-mediated targeted disruption of GRK5 resulted in significant reduction in the self-renewal capacity of RMS cells. GRK5-deficient RMS cells also displayed significant reduction in growth secondary to cell cycle arrest at the G2/M checkpoint. The functional effects on tumor growth and self-renewal appeared unique to GRK5 among the GRK kinase subfamily, as targeted disruption of closely-related GRK4 and GRK6 did not significantly affect RMS tumor cell growth and self-renewal. We propose that targeted disruption of GRK5 by CRISPR/Cas9 results in elevated p53 protein stability and activity, leading to inhibition of proteins required for cell cycle progression. We are also characterizing the loss-of-function effects of GRK5 in a RMS TPC reporter cell line created using a CRISPR/Cas9 knockin approach that will allow for direct assessment of GRK5 and other candidate gene function within the TPC population. By characterizing the biologic role of TPC as well as the function of GRK5 in RMS, we hope to provide new biologic insights into cancer stem cell biology and GRK5 as a novel therapeutic target for the treatment of advanced RMS. Citation Format: Thao Q. Pham, Terra Vleeshouwer-Neumann, Eleanor Chen. A CRISPR/Cas9 kinome screen identifies GRK5 as a novel regulator of rhabdomyosarcoma (RMS) self-renewal [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1115.
Swallow and Aspiration in Chronic Obstructive Pulmonary Disease
Authors: Lydia Cvejic, Philip G. Bardin
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Swallowing is a complex biomechanical process that is synchronized with breathing to protect the airway. In chronic obstructive pulmonary disease (COPD) altered upper airway protective mechanisms coupled to ventilatory adaptations may lead to laryngeal penetration during swallow that can be followed by pulmonary aspiration. To date investigations have reported a spectrum of swallow and breathing dysfunction in COPD ranging from mild (laryngeal penetration) to severe abnormality (pulmonary aspiration). However, the prevalence of penetration and aspiration in COPD is uncertain and important aspects such as a role in recurrent lung infections and repeated exacerbations are not understood. Current evidence indicates that aspiration during swallow occurs in up to 25% of individuals with COPD. Factors putatively associated with aspiration include increased respiratory rate, reduced laryngeal elevation during swallow, post-swallow pharyngeal residue and inspiration-swallow patterns. Timely identification of indi...
Hypogonadism as a Reversible Cause of Torsades de Pointes in Men
Authors: Joe-Elie Salem, Xavier Waintraub, Carine Courtillot, Christian M. Shaffer, Estelle Gandjbakhch, Carole Maupain, Javid J. Moslehi, Fabio Badilini, Julien Haroche, Paul Gougis, Veronique Fressart, Andrew M. Glazer, Francoise Hidden-Lucet, Philippe Touraine, Benedicte Lebrun-Vignes, Dan M. Roden, Anne Bachelot, Christian Funck-Brentano
Journal: Circulation (2018)