tbuckley/cabot-search huggingface dataset:
Focal adhesion kinase inhibition as a therapeutic strategy in differentiated thyroid cancer.
Authors: Shalana O'Brien, Vita Golubovskaya, Maria Zajac-Kaye, Steven N. Hochwald, William G. Cance
Journal: Journal of Clinical Oncology (2013)

e13556 Background: Thyroid cancer, themost common endocrine malignancy, can be curable with resection of low stage tumors, but new treatments are needed for advanced differentiated cancers with radioiodine resistance. Focal Adhesion Kinase (FAK), a tyrosine kinase involved in protein-protein interactions regulating crucial cellular functions, is upregulated in thyroid cancer, and is a drug target along with its autophosphorylation site Y397. Clinical trials are ongoing for FAK inhibitors PF04554878 and GSK2256098. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15), a small molecule FAK scaffolding inhibitor targeting the Y397 autophosphorylation site, and TAE226, a FAK/Insulin-like Growth Factor-1 Receptor inhibitor are in preclinical studies . In this report, we compared the effects of these FAK inhibitors on thyroid cancer cell lines. Methods: Four human thyroid cancer cell lines were cultured in vitro: K1, BCPAP, TPC1 derived from papillary thyroid carcinoma, and TT derived from medullary thyroid carcinoma. Western blots detected expression of FAK and pY397 FAK. Clonogenicity and MTS assays measured effects of the inhibitors on cell viability and colony formation. Results: The most significant dose-dependent decrease of FAK Y397 autophosphorylation and p125FAK expression was seen with Y15, with significant decrease at 10μM and near complete inhibition at 50μM. PF04554878, GSK2256098 and TAE226 at 50μM showed lowered pY397 expression, but less effect than Y15 at 10μM concentrations. TAE226 had the most effect on clonogenicity, with complete colony inhibition at doses 1μM and higher. Least effect was with GSK2256098. Y15 and PF04554878 had moderate inhibition of clonogenicity. Y15 had greatest inhibition of cell viability, with IC50s less than 15μM, two to over five-fold more potent than TAE226, GSK2256098, and PF04554878. Conclusions: All FAK inhibitors caused dose-dependent effects on thyroid cancer cell viability, clonogenicity and expression of pY397 FAK. Y15 had the most potent effects on cell viability and expression of FAK and p397 FAK. Our data suggests targeting the FAK scaffold, as Y15 does, is more effective than targeting the kinase function as a potential therapeutic agent for thyroid cancer.
Deubiquitinating ALDH1A3 key to maintaining the culprit of aggressive brain cancer
Authors: Hiroaki Wakimoto
Journal: Journal of Clinical Investigation (2019)

Cancer stem cells sustain propagation of the deadly primary brain cancer glioblastoma. Glioblastoma stem cells (GSCs) characterized by a mesenchymal phenotype are aggressive and resistant to therapies and represent a crucial therapeutic target. In this issue of the JCI, Chen et al. show that the intracellular levels of aldehyde dehydrogenase 1A3 (ALDH1A3), known as a functional marker of mesenchymal GSCs, are regulated posttranslationally by ubiquitin-specific protease 9X-mediated (USP9X-mediated) deubiquitination. Increased expression of USP9X stabilizes ALDH1A3, enabling GSCs to exhibit mesenchymal traits and the malignant phenotype. Thus, the USP9X-ALDH1A3 axis may offer a novel therapeutic target in glioblastoma.
A novel TLR4 binding protein, 40S ribosomal protein S3, has potential utility as an adjuvant in a dendritic cell-based vaccine
Authors: Hyun Jin Park, Gun-Young Jang, Young Seob Kim, Jung Hwa Park, Sung Eun Lee, Manh-Cuong Vo, Je-Jung Lee, Hee Dong Han, In Duk Jung, Tae Heung Kang, Yeong-Min Park
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Dendritic cells (DCs) are professional antigen presenting cells (APCs), which can activate antigen-specific CD8+ T cell immunity, resulting in tumor clearance. Immature DCs are usually stimulated by various adjuvants through their immune receptors. Among them, Toll-like receptor 4 (TLR4) has an important role in activating DCs to cause their maturation. In fact, TLR4 is well-known to induce innate and adaptive immune responses against various external microbial or internal damage associated molecular patterns (DAMP). LPS is widely regarded as a strong stimulator of TLR4 signaling. However, LPS is inappropriate for use in humans since it is an endotoxin. Unfortunately, other TLR4 ligands such as HMGB1 or heat shock proteins have weak adjuvant effects. Therefore, there is a need to identify novel, biocompatible, strong, TLR4 ligands. <h3>Methods</h3> 40S ribosomal protein S3 (RPS3) was screened through pull-down assay using TLR4. BMDCs from wild type (WT) and TLR4 knock-out mice were treated by RPS3 to identify the activation and maturation of DCs. T cell generation including memory T cells, tumor prevention, and treatment experiments were performed with BMDCs based vaccination. Also, human DCs originated from patients were treated by RPS3 to confirm the activation and maturation of DCs. <h3>Results</h3> In this study, we identified 40S ribosomal protein S3 (RPS3) through a pull-down assay using a variety of human cancer cell-derived proteins that could bind to TLR4. RPS3 was released from tumor cells following treatment with an anticancer drug, and it was shown that the released RPS3 binds to TLR4. Recombinant RPS3 induced maturation and activation of DCs, and following pulsing with tumor specific antigens, these DCs could be used as a vaccine to significantly increase tumor specific CD8<sup>+</sup>IFN-γ<sup>+</sup> T cells, and provide both tumor prevention and tumor treatment effects. The effect of RPS3 on DC maturation and its utility as a vaccine were shown to be dependent on TLR4 using TLR4 knockout mice. <h3>Conclusions</h3> This study therefore proved that human cancer cell-derived RPS3, a novel TLR4 ligand, has great potential as an adjuvant in tumor-specific antigen DC-based vaccines.
Regional differences in rate of FEV<sub>1</sub> decline in COPD: lessons from SUMMIT
Authors: Bartolomé R. Celli, Julie A. Anderson, Robert D. Brook, Peter M.A. Calverley, Nicholas J. Cowans, Courtney Crim, Fernando Martinez, David E. Newby, Julie Yates, Jørgen Vestbo
Journal: European Respiratory Journal (2019)

<b>This analysis of FEV</b><sub><b>1</b></sub><b>decline in patients who enrolled with spirometric GOLD stage II COPD (SUMMIT) showed regional differences in therapeutic response. Such variation should be considered when comparing pharmacotherapies across different global areas.</b>http://bit.ly/2YwMIgW
Infographic. International Olympic Committee consensus statement on pain management in athletes: non-pharmacological strategies
Authors: Brian Hainline, Wayne Derman, Alan Vernec, Richard Budgett, Masataka Deie, Jiri Dvorak, Christopher A Harle, Stanley Herring, Michael McNamee, Willem Meeuwisse, G Lorimer Moseley, Bade Omololu, John Orchard, Andrew Pipe, Babette M Pluim, Johan Raeder, Christian Siebert, Mike Stewart, Mark Campbell Stuart, Judith Turner, Mark Ware, David Zideman, Lars Engebretsen
Journal: British Journal of Sports Medicine (2019)

Pain and injury are not synonymous. Pain can occur without sport injury, and sport injury may not necessarily manifest with pain. It is …
Tissue-Specific Oncogenic Activity of KRASA146T
Authors: Emily J. Poulin, Asim K. Bera, Jia Lu, Yi-Jang Lin, Samantha Dale Strasser, Joao A. Paulo, Tannie Q. Huang, Carolina Morales, Wei Yan, Joshua Cook, Jonathan A. Nowak, Douglas K. Brubaker, Brian A. Joughin, Christian W. Johnson, Rebecca A. DeStefanis, Phaedra C. Ghazi, Sudershan Gondi, Thomas E. Wales, Roxana E. Iacob, Lana Bogdanova, Jessica J. Gierut, Yina Li, John R. Engen, Pedro A. Perez-Mancera, Benjamin S. Braun, Steven P. Gygi, Douglas A. Lauffenburger, Kenneth D. Westover, Kevin M. Haigis
Journal: Cancer Discovery (2019)

Abstract KRAS is the most frequently mutated oncogene. The incidence of specific KRAS alleles varies between cancers from different sites, but it is unclear whether allelic selection results from biological selection for specific mutant KRAS proteins. We used a cross-disciplinary approach to compare KRASG12D, a common mutant form, and KRASA146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that KRASA146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates KRAS by promoting a high rate of intrinsic and guanine nucleotide exchange factor–induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that KRASG12D and KRASA146T exhibit distinct tissue-specific effects on homeostasis that mirror mutational frequencies in human cancers. These tissue-specific phenotypes result from allele-specific signaling properties, demonstrating that context-dependent variations in signaling downstream of different KRAS mutants drive the KRAS mutational pattern seen in cancer. Significance: Although epidemiologic and clinical studies have suggested allele-specific behaviors for KRAS, experimental evidence for allele-specific biological properties is limited. We combined structural biology, mass spectrometry, and mouse modeling to demonstrate that the selection for specific KRAS mutants in human cancers from different tissues is due to their distinct signaling properties. See related commentary by Hobbs and Der, p. 696. This article is highlighted in the In This Issue feature, p. 681
Abstract 18659: Inositol Monophosphatase 1 (IMPA1) and RAGE Interaction: The Role of a Novel Proliferative Pathway in Pulmonary Hypertension
Authors: Matthew L McBride, Elissa R Williams, Paul Langlais, Lawrence Mandarino, Ruslan Rafikov, Olga Rafikova
Journal: Circulation (2017)

Introduction: Pulmonary arterial hypertension (PAH) is a disease with high mortality and limited therapeutic options. It is characterized by a progressive pulmonary vascular remodeling, although th...
Spinal and Paraspinal Infections Associated with Contaminated Methylprednisolone Acetate Injections — Michigan, 2012–2013
Authors: Jennie Finks, Jim Collins, Corinne Miller, Jay Fiedler, Shannon Johnson, Joseph R. Coyle, Brenda M. Brennan, Anurag N. Malani, Varsha Moudgal, David Vandenberg, Karen M. Speirs, David Martin, Carmen Tichendelean, Dennis Sula, Christopher Ledtke, Robert A. Heyding, Taranisia MacCannell, Tom Chiller, Jevon McFadden, Raymund Dantes, Mawuli K. Nyaku
Journal: MMWR Morbidity and Mortality Weekly Report (2013)
Why does it take so long? The reasons behind tuberculosis treatment delay in Portugal
Authors: I. Zão, A.I. Ribeiro, D. Apolinário, R. Duarte
Journal: Pulmonology (2019)

Delayed diagnosis and treatment of tuberculosis contributes to the spread of the disease. In this study, we aimed to determine the patient and healthcare system delay among tuberculosis patients in Portugal and identify associated factors at individual and contextual level. We analysed all TB cases notified in Portugal between 2010 and 2014 using data from the national surveillance system. Patient and healthcare system delay were computed, log-transformed, and used as outcomes. Adjusted generalized linear models were fitted to identify sociodemographic, contextual and clinical determinants. The study included 6838 patients. The median of patient and healthcare system were 33 and 17 days, respectively. Adjusted regression models revealed that higher patient delay occurred in foreign patients (exponentiated beta: 1.177, 95%CI 1.091–1.270) and those addicted to alcohol (1.169, 1.072–1.276) and drugs (1.153, 1.027–1.295). Higher healthcare system delay was observed among patients with extra-pulmonary TB (2.067, 1.885–2.268) and pulmonary comorbidities – lung cancer (2.391, 1.656–3.452), sarcoidosis (3.316, 1.370–8.022) and COPD (1.295, 1.059–1.584) – and in patients residing further from a healthcare service (1.040, 1.018–1.062). We found that various individual and contextual factors affect the time delay in tuberculosis treatment. Our findings indicate that some strategies, such as facilitating the access to healthcare services among foreign patients and patients with addictions and increasing the awareness towards TB among healthcare professionals, may result in better TB control.
Abstract 16574: Association Between Visit-to-Visit Variability of Systolic Blood Pressure and All-Cause Mortality
Authors: Brian A Clements, Nathan A Allred, Erik R Riessen, Benjamin D Horne, Raymond O McCubrey, Heidi T May, Joseph B Muhlestein
Journal: Circulation (2017)

Introduction: Visit-to-visit blood pressure variability (VVV) is a proposed risk predictor of CV events, but a more complete understanding of this association is desired. We analyzed >10 years of d...
Clinical factors related to morbidity and mortality in high‐risk heart failure patients: the GUIDE‐IT predictive model and risk score
Authors: Christopher O'Connor, Mona Fiuzat, Hillary Mulder, Adrian Coles, Tariq Ahmad, Justin A. Ezekowitz, Kirkwood F. Adams, Ileana L. Piña, Kevin J. Anstrom, Lawton S. Cooper, Daniel B. Mark, David J. Whellan, James L. Januzzi, Eric S. Leifer, G. Michael Felker
Journal: European Journal of Heart Failure (2019)
What Are Polygenic Scores and Why Are They Important?
Authors: Leo P. Sugrue, Rahul S. Desikan
Journal: JAMA (2019)

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
The unknown pathophysiological relevance of right ventricular hypertrophy in pulmonary arterial hypertension
Authors: Frances S. de Man, M. Louis Handoko, Anton Vonk-Noordegraaf
Journal: European Respiratory Journal (2019)

<b>A recent study clearly demonstrates that right ventricular (RV) hypertrophy is a prognostic marker of pulmonary arterial hypertension, triggering us to rethink the concept of RV hypertrophy</b>http://ow.ly/vD0e30nHvFm
A Manual of the Practice of Medicine.
Authors: George Johnson
Journal: JAMA (1898)

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
Single-Cell RNA Sequencing Identifies Candidate Renal Resident Macrophage Gene Expression Signatures across Species
Authors: Kurt A. Zimmerman, Melissa R. Bentley, Jeremie M. Lever, Zhang Li, David K. Crossman, Cheng Jack Song, Shanrun Liu, Michael R. Crowley, James F. George, Michal Mrug, Bradley K. Yoder
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Despite abundant research focused on understanding the importance of mouse renal resident macrophages in homeostatic and disease settings, these findings have unknown relevance to higher-order species, including humans, because markers to identify a similar population of cells across species are lacking. This hinders translating data obtained in animal model systems to human patients. In this study, the authors used a single-cell RNA sequencing approach, followed by validation using flow cytometry, to identify novel markers of mouse resident macrophages and show that these markers also identify a population of macrophages in rat, pig, and human kidney tissue. Over all, their findings serve as an entry point to study candidate kidney resident macrophages across species. Background Resident macrophages regulate homeostatic and disease processes in multiple tissues, including the kidney. Despite having well defined markers to identify these cells in mice, technical limitations have prevented identification of a similar cell type across species. The inability to identify resident macrophage populations across species hinders the translation of data obtained from animal model to human patients. Methods As an entry point to determine novel markers that could identify resident macrophages across species, we performed single-cell RNA sequencing (scRNAseq) analysis of all T and B cell–negative CD45 + innate immune cells in mouse, rat, pig, and human kidney tissue. Results We identified genes with enriched expression in mouse renal resident macrophages that were also present in candidate resident macrophage populations across species. Using the scRNAseq data, we defined a novel set of possible cell surface markers (Cd74 and Cd81) for these candidate kidney resident macrophages. We confirmed, using parabiosis and flow cytometry, that these proteins are indeed enriched in mouse resident macrophages. Flow cytometry data also indicated the existence of a defined population of innate immune cells in rat and human kidney tissue that coexpress CD74 and CD81, suggesting the presence of renal resident macrophages in multiple species. Conclusions Based on transcriptional signatures, our data indicate that there is a conserved population of innate immune cells across multiple species that have been defined as resident macrophages in the mouse. Further, we identified potential cell surface markers to allow for future identification and characterization of this candidate resident macrophage population in mouse, rat, and pig translational studies.
Clare Gerada: Mandatory training needs a fundamental review
Authors: Clare Gerada
Journal: BMJ (2019)

On a quiet Sunday afternoon, I decided to update my compulsory online safeguarding training. Confronted by photos of bruised children, tales of abuse, and parental drug taking, I could bear no more.

Who on earth thought that such training should be done in sterile cyberspace, without recourse to discussion between peers? The instructional impact of doing this online amounted to anti-education. What with fire training, manual handling, and the other dozen or so mandatory requirements, my schedule is filled with having to “learn” what others decide is important for me to know to practise safely as a doctor.

When I look more closely at the requirements I’m struck by how confused they are. To start with, the training is often described interchangeably as statutory and mandatory, yet these are different (the former required by law, the latter determined by the employing …
Ambient Air Pollution, Noise, and Late-Life Cognitive Decline and Dementia Risk
Authors: Kimberly C. Paul, Mary Haan, Elizabeth Rose Mayeda, Beate R. Ritz
Journal: Annual Review of Public Health (2019)

Exposure to ambient air pollution and noise is ubiquitous globally. A strong body of evidence links air pollution, and recently noise, to cardiovascular conditions that eventually may also affect cognition in the elderly. Data that support a broader influence of these exposures on cognitive function during aging is just starting to emerge. This review summarizes current findings and discusses methodological challenges and opportunities for research. Although current evidence is still limited, especially for chronic noise exposure, high exposure has been associated with faster cognitive decline either mediated through cerebrovascular events or resulting in Alzheimer's disease. Ambient environmental exposures are chronic and affect large populations. While they may yield relatively modest-sized risks, they nevertheless result in large numbers of cases. Reducing environmental pollution is clearly feasible, though lowering levels requires collective action and long-term policies such as standard setting, often at the national level as well as at the local level.
Second-Hit, Postzygotic <i>PMVK</i> and <i>MVD</i> Mutations in Linear Porokeratosis
Authors: Lihi Atzmony, Habib M. Khan, Young H. Lim, Amy S. Paller, Jonathan L. Levinsohn, Kristen E. Holland, Fatima Nadeem Mirza, Emily Yin, Christine J. Ko, Jonathan S. Leventhal, Keith A. Choate
Journal: JAMA Dermatology (2019)

<h3>Importance</h3> Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. <h3>Objective</h3> To identify genetic mutations associated with linear porokeratosis. <h3>Design, Setting, and Participants</h3> Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. <h3>Interventions or Exposures</h3> Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. <h3>Main Outcomes and Measures</h3> Germline and somatic genomic characteristics of participants with linear porokeratosis. <h3>Results</h3> Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous<i>PMVK</i>c.329G&gt;A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous<i>PMVK</i>c.79G&gt;T mutation and an additional<i>PMVK</i>c.379C&gt;T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in<i>MVD</i>(c.70 + 5G&gt;A) and a somatic deletion in<i>MVD</i>causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). <h3>Conclusions and Relevance</h3> Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.