tbuckley/cabot-search huggingface dataset:
The effects of sepsis on endothelium and clinical implications
Authors: Elena V Dolmatova, Keke Wang, Rohan Mandavilli, Kathy K Griendling
Journal: Cardiovascular Research (2020)

Abstract Sepsis accounts for nearly 700 000 deaths in Europe annually and is caused by an overwhelming host response to infection resulting in organ failure. The endothelium is an active contributor to sepsis and as such represents a major target for therapy. During sepsis, endothelial cells amplify the immune response and activate the coagulation system. They are both a target and source of inflammation and serve as a link between local and systemic immune responses. In response to cytokines produced by immune cells, the endothelium expresses adhesion molecules and produces vasoactive compounds, inflammatory cytokines, and chemoattractants, thus switching from an anticoagulant to procoagulant state. These responses contribute to local control of infection, but systemic activation can lead to microvascular thrombosis, capillary permeability, hypotension, tissue hypoxia, and ultimately tissue damage. This review focuses on the role of the endothelium in leucocyte adhesion and transmigration as well as production of reactive oxygen and nitrogen species, microRNAs and cytokines, formation of signalling microparticles, and disseminated intravascular coagulation. We also discuss alterations in endothelial permeability and apoptosis. Finally, we review the diagnostic potential of endothelial markers and endothelial pathways as therapeutic targets for this devastating disease.
Abstract ES9-1: Discussing risk &amp; uncertainty with patients in the context of GEP testing
Authors: L Fallowfield
Journal: Cancer Research (2020)

Abstract Many discussions between physicians and their patients about the logic and rationale for different treatment recommendations are increasingly complex. The information required to aid educated decision-making requires careful balancing of the likely absolute benefits in terms of cure or preventing recurrence versus any treatment-related side effects. Few realise that medicine is an uncertain science where most facts are probabilities defined and refined by repeated hypothesis testing. In the context of life-threatening disease this can make communication with patients about risk and uncertainty challenging. Health literacy and numeracy skills in the general population are often poor, creating other communication difficulties; furthermore confusion increases when such conversations are set against a backdrop of fear and anxiety. Clinico-pathologic features traditionally help determine which women with early stage breast cancer are most likely to benefit from adjuvant chemotherapy, but many patients still believe that in life-threatening situations, more treatment must be better. Scores from gene expression profiling tests such as OncotypeDX®, EndoPredict® and Prosigna® may reduce some of the uncertainty and anxiety about omitting chemotherapy and increase the confidence of doctors helping patients with their decision-making.(1) However explaining high, intermediate and low risk test scores is not always straightforward especially when patients have widely varying personality and socio-educational characteristics. Both clinicians and their patients may also have a measurable intolerance to uncertainty that may contribute (irrespective of the recurrence score) to seemingly irrational decisions about treatment. This interactive session will incorporate materials from Talking About Risk in the context of Genomic Testing (TARGET), an evidence-based program (2) funded by the BCRF- This includes didactic presentations (PPT) exercises and video clips of doctors explaining risk scores from genomic tests. After attending the session participants should:- a) recognise how poor literacy and numeracy in general populations affects understanding about risk and decision-making b) understand how their own intolerance to uncertainty may ‘leak’ through into communication with patients and c) increase their repertoire of skills when explaining GEP scores to patients References 1. L Fallowfield, L Matthews, S May, V Jenkins, D Bloomfield. Psycho-oncology (2018) 27:4, 1264-1269 https://doi.org/10.1002/pon.4664 2. Fallowfield, L., Solis-Trapala, I., Starkings, R. et al. Breast Cancer Res Treat (2019) 177: 641. https://doi.org/10.1007/s10549-019-05316-7 Citation Format: L Fallowfield. Discussing risk &amp; uncertainty with patients in the context of GEP testing [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES9-1.
Stroke survivor should not have feeding tube withdrawn, rules judge in case heard by Skype
Authors: Clare Dyer
Journal: BMJ (2020)

A stroke survivor who repeatedly told carers that he wanted to die should not have his artificial feeding withdrawn, a High Court judge has ruled.1

In one of the first High Court cases to be heard by Skype because of the covid-19 pandemic, Mr Justice Mostyn decided that it would not be in the best interests of the man, referred to as AF, to be allowed to die.

AF, who is in his 70s, originally came from Ireland but lives in the Midlands. He lacks the capacity to take treatment decisions for himself. He lives in a long term care home, and the case was brought by the local clinical commissioning group (CCG). None of the parties in the case was identified, including the CCG …
Characterisation of genetic regulatory effects for osteoporosis risk variants in human osteoclasts
Authors: Benjamin H. Mullin, Jennifer Tickner, Kun Zhu, Jacob Kenny, Shelby Mullin, Suzanne J. Brown, Frank Dudbridge, Nathan J. Pavlos, Edward S. Mocarski, John P. Walsh, Jiake Xu, Scott G. Wilson
Journal: Genome biology (2020)

Abstract Background Osteoporosis is a complex disease with a strong genetic contribution. A recently published genome-wide association study (GWAS) for estimated bone mineral density (eBMD) identified 1103 independent genome-wide significant association signals. Most of these variants are non-coding, suggesting that regulatory effects may drive many of the associations. To identify genes with a role in osteoporosis, we integrate the eBMD GWAS association results with those from our previous osteoclast expression quantitative trait locus (eQTL) dataset. Results We identify sixty-nine significant cis -eQTL effects for eBMD GWAS variants after correction for multiple testing. We detect co-localisation of eBMD GWAS and osteoclast eQTL association signals for 21 of the 69 loci, implicating a number of genes including CCR5 , ZBTB38 , CPE , GNA12 , RIPK3 , IQGAP1 and FLCN . Summary-data-based Mendelian Randomisation analysis of the eBMD GWAS and osteoclast eQTL datasets identifies significant associations for 53 genes, with TULP4 presenting as a strong candidate for pleiotropic effects on eBMD and gene expression in osteoclasts. By performing analysis using the GARFIELD software, we demonstrate significant enrichment of osteoporosis risk variants among high-confidence osteoclast eQTL across multiple GWAS P value thresholds. Mice lacking one of the genes of interest, the apoptosis/necroptosis gene RIPK3 , show disturbed bone micro-architecture and increased osteoclast number, highlighting a new biological pathway relevant to osteoporosis. Conclusion We utilise a unique osteoclast eQTL dataset to identify a number of potential effector genes for osteoporosis risk variants, which will help focus functional studies in this area.
Epidemiology of Covid-19 in a Long-Term Care Facility in King County, Washington
Authors: Temet M. McMichael, Dustin W. Currie, Shauna Clark, Sargis Pogosjans, Meagan Kay, Noah G. Schwartz, James Lewis, Atar Baer, Vance Kawakami, Margaret D. Lukoff, Jessica Ferro, Claire Brostrom-Smith, Thomas D. Rea, Michael R. Sayre, Francis X. Riedo, Denny Russell, Brian Hiatt, Patricia Montgomery, Agam K. Rao, Eric J. Chow, Farrell Tobolowsky, Michael J. Hughes, Ana C. Bardossy, Lisa P. Oakley, Jesica R. Jacobs, Nimalie D. Stone, Sujan C. Reddy, John A. Jernigan, Margaret A. Honein, Thomas A. Clark, Jeffrey S. Duchin
Journal: New England Journal of Medicine (2020)

BackgroundLong-term care facilities are high-risk settings for severe outcomes from outbreaks of Covid-19, owing to both the advanced age and frequent chronic underlying health conditions of the residents and the movement of health care personnel among facilities in a region.MethodsAfter identification on February 28, 2020, of a confirmed case of Covid-19 in a skilled nursing facility in King County, Washington, Public Health–Seattle and King County, aided by the Centers for Disease Control and Prevention, launched a case investigation, contact tracing, quarantine of exposed persons, isolation of confirmed and suspected cases, and on-site enhancement of infection prevention and control.ResultsAs of March 18, a total of 167 confirmed cases of Covid-19 affecting 101 residents, 50 health care personnel, and 16 visitors were found to be epidemiologically linked to the facility. Most cases among residents included respiratory illness consistent with Covid-19; however, in 7 residents no symptoms were documented. Hospitalization rates for facility residents, visitors, and staff were 54.5%, 50.0%, and 6.0%, respectively. The case fatality rate for residents was 33.7% (34 of 101). As of March 18, a total of 30 long-term care facilities with at least one confirmed case of Covid-19 had been identified in King County.ConclusionsIn the context of rapidly escalating Covid-19 outbreaks, proactive steps by long-term care facilities to identify and exclude potentially infected staff and visitors, actively monitor for potentially infected patients, and implement appropriate infection prevention and control measures are needed to prevent the introduction of Covid-19.
MRI and ultrasonography are useful tools for a non-invasive diagnosis of IgG4-related disease
Authors: Augustin Lecler, Thomas Sené
Journal: Annals of the Rheumatic Diseases (2020)

We read with much interest the 2019 classification criteria for IgG4-related disease by the American College of Rheumatology and the European League Against Rheumatism.1

This new classification driven by scientific evidence and research provides a substantial amount of new information, which will considerably improve the identification and management of patients with IgG4-related disease.

Despite the fact that radiology is integrated into the diagnostic criteria, only CT and/or positron emission tomography-CT are mentioned. We humbly suggest that the use of ultrasonography and/or MRI …
Matters of the Mind—Sleep Medications and Dementia Risk, Depression and Weight Gain, Opioids and Mental Disorders
Authors: Rita Rubin
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 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
Abstract P5-14-17: Musculoskeletal side effects over time and association with adherence in women taking neoadjuvant letrozole for estrogen receptor positive DCIS: CALGB 40903 (Alliance)
Authors: Gretchen Kimmick, Amylou C Dueck, Rebecca Shelby, Michelle Naughton, Abigail Caudle, Briant Fruth, E. Shelley Hwang
Journal: Cancer Research (2020)

Abstract Background: Side effects of and adherence to aromatase inhibitors in women with ductal carcinoma in situ are not well described. Methods: Postmenopausal women in a prospective phase II study of neoadjuvant letrozole for estrogen receptor positive DCIS completed questionnaires on side effects [Menopause Specific Quality of Life Questionnaire (MENQOL), Brief Pain Inventory-short form (BPI-SF), Arthritis Impact Measurement Scales (AIMS2)], well-being (FACT-G), and adherence [Medication-Taking questionnaire] at baseline, 1, 3 and 6 months (mo), and study completion. We used descriptive statistics and paired t-tests to compare 1, 3 and 6 mo results to baseline. Hierarchical linear mixed modeling, controlling for baseline symptom or well-being level, was used to examine effect of symptoms and well-being on intentional and nonintentional nonadherence, based on the Medication-Taking Questionnaire. Results: Included were 84 women, mean age 63 (39-83) years. In univariate analyses, compared to baseline, menopausal symptoms increased [physical (p=0.001 at 3, p&amp;lt;0.001 at 6 mo); vasomotor (p&amp;lt;0.001 at 1, 3, 6 mo), psychosocial (p=0.006 at 6 mo) and sexual (p=0.01 at 6 mo)]. Joint pain and stiffness increased [BPI-SF pain subscale (p=0.048 at 3, p=0.01 at 6 mo); AIMS2 joint pain subscale (p=0.03 at 1, p&amp;lt;0.001 at 3 and 6 mo); AIMS2 stiffness subscale (p=0.004 at 3, p=0.01 at 6 mo)]. Intentional and nonintentional adherence did not significantly change over time (p&amp;gt;0.05). Lower emotional (p=0.049) and functional (p=0.002) well-being by FACT-G and higher joint pain (p=0.03) by AIMS2 were associated with higher nonintentional nonadherence; higher physical side effects of menopause (p=0.001) by MENQOL were associated with lower intentional nonadherence. Conclusions: Among women taking letrozole for DCIS, menopausal symptoms and joint pain/stiffness increased over time with most differences noted at 3 and 6 mo. Lower well-being and higher symptom levels were associated with higher nonintentional nonadherence. NCT01439711.U10CA180821, U10CA180882, UG1CA189823, Breast Cancer Research Foundation, https://acknowledgments.alliancefound.org. Citation Format: Gretchen Kimmick, Amylou C Dueck, Rebecca Shelby, Michelle Naughton, Abigail Caudle, Briant Fruth, E. Shelley Hwang. Musculoskeletal side effects over time and association with adherence in women taking neoadjuvant letrozole for estrogen receptor positive DCIS: CALGB 40903 (Alliance) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-17.
Abstract ES9-2: Communicating risk information: talking by numbers
Authors: V Jenkins
Journal: Cancer Research (2020)

Abstract Health literacy and numeracy skills amongst the general population are frequently poor, which impedes their understanding of important health information. Even those patients fully conversant with percentages and ratios can suffer with math anxiety when involved in stressful environments, making it difficult to process complex information effectively. This may be especially true for women with breast cancer having to decide about adjuvant treatments after receiving risk of recurrence genomic expression profiling (GEP) test results. Explaining risk of recurrence clearly can be a challenge for the clinician and nurse too. They need a wide repertoire of communication skills to accommodate the needs of patients with different social and educational backgrounds. Some health care professionals (HCPs) use analogies to explain risk, which may not always be of benefit. In order to help HCPs discuss GEP test results we developed and evaluated an educational program called TARGET (Talking About Risk in the Context of GEnomic Tests). As part of the evaluation we measured participants’ own numeracy skills and intolerance to uncertainty. In this talk the audience will be invited to participate in various numeracy exercises, and be able to compare their results with UK data from 56 breast cancer clinicians and 78 specialist breast care nurses. The presentation will conclude with suggestions of different ways to communicate risk. Citation Format: V Jenkins. Communicating risk information: talking by numbers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES9-2.
The Pharmacokinetic–Pharmacodynamic (PKPD) Relationships of AZD3229, a Novel and Selective Inhibitor of KIT, in a Range of Mouse Xenograft Models of GIST
Authors: Venkatesh Pilla Reddy, Rana Anjum, Michael Grondine, Aaron Smith, Deepa Bhavsar, Evan Barry, Sylvie M. Guichard, Wenlin Shao, Jason G. Kettle, Crystal Brown, Erica Banks, Rhys D.O. Jones
Journal: Clinical Cancer Research (2020)

The emergence of secondary mutations is a cause of resistance to current KIT inhibitors used in the treatment of patients with gastrointestinal stromal tumors (GIST). AZD3229 is a selective inhibitor of wild-type KIT and a wide spectrum of primary and secondary mutations seen in patients with GIST. The objective of this analysis is to establish the pharmacokinetic-pharmacodynamic (PKPD) relationship of AZD3229 in a range of mouse GIST tumor models harboring primary and secondary KIT mutations, and to benchmark AZD3229 against other KIT inhibitors.A PKPD model was developed for AZD3229 linking plasma concentrations to inhibition of phosphorylated KIT using data generated from several in vivo preclinical tumor models, and in vitro data generated in a panel of Ba/F3 cell lines.AZD3229 drives inhibition of phosphorylated KIT in an exposure-dependent manner, and optimal efficacy is observed when >90% inhibition of KIT phosphorylation is sustained over the dosing interval. Integrating the predicted human pharmacokinetics into the mouse PKPD model predicts that an oral twice daily human dose greater than 34 mg is required to ensure adequate coverage across the mutations investigated. Benchmarking shows that compared with standard-of-care KIT inhibitors, AZD3229 has the potential to deliver the required target coverage across a wider spectrum of primary or secondary mutations.We demonstrate that AZD3229 warrants clinical investigation as a new treatment for patients with GIST based on its ability to inhibit both ATP-binding and A-loop mutations of KIT at clinically relevant exposures.
Combined heart-liver transplantation – First series in Poland
Authors: Krzysztof Zieniewicz, Mariusz Kusmierczyk, Krzysztof Dudek, Marcin Kotulski, Piotr Remiszewski, Tadeusz Wroblewski, Maciej Krasnodebski, Grzegorz Niewinski, Ewa Sitkowska-Rysiak, Joanna Raszeja-Wyszomirska, Malgorzata Sobieszczanska-Malek, Tomasz Zielinski, Krzysztof Zajac
Journal: International Journal of Surgery (2020)
Abstract P1-07-01: Cholinergic receptor muscarinic 3 (<i>CHRM3</i>) contributes to breast cancer tumorigenesis through angiogenesis regulation
Authors: Jiawei Chen, Vivian Y Shin, Isabella Cheuk, Jennifer Siu, Ava Kwong
Journal: Cancer Research (2020)

Abstract Objectives: Cholinergic muscarinic receptors are widely distributed in different human organs with various biological functionals such as synaptic transmission. Accumulating evidence revealed the overexpression of these receptors especially cholinergic receptor muscarinic 3 (CHRM3) with multiple roles in cancer behaviors such as proliferation, apoptosis, angiogenic phenotypes and even epithelial-mesenchymal transition (EMT) through various signaling pathways. However, its roles in breast cancer and angiogenesis still remain elusive. Methods: Gene expression and patient survival data were from the TCGA and the GTEx projects database. Cells were transfected with scrambled shRNA or CHRM3 shRNA to knockdown gene expression. pcDNA1.3 empty expression vector or CHRM3 expressing vector was used for ectopic expression in the cells. Cell proliferation was examined in different treatment groups by MTT assay and further subjected to cell cycle and apoptosis assay. Expression levels of CHRM3 in paired breast cancer tissues and different cell lines as well as angiogenesis-related markers in cells with different treatments were investigated by qRT-PCR. Results: CHRM3 expressions were significantly upregulated in triple negative breast cancer (TNBC) subtype, but not other subtypes of breast cancer, and was consistent with the data in TCGA database. Further investigation in different breast cancer cells revealed that CHRM3 expressions were higher in MDA-MB-231 and MDA-MB-468, which are both TNBC cell lines. After treatment with CHRM3-specific inhibitor, 4-DAMP, cell viability was significantly decreased in both MDA-MB-231 and MDA-MB-468 cells. G1-phase arrest and decreased S-phase cell populations and early apoptosis were increased upon 4-DAMP. Moreover, angiogenic markers such as ANG1 and VEGFD were significantly decreased upon CHRM3 knockdown in breast cancer cells or human umbilical vein endothelial cells (HUVEC). Gene correlation analysis from TCGA database indicated a significant positive correlation between CHRM3 and ANG1. Furthermore, CHRM3 shRNA or 4-DAMP treatment inhibited cell proliferation in both MDA-MB-231 and HUVEC. Conclusions: We found that CHRM3 is upregulated in TNBC tissues and cell lines. CHRM3 confers tumor oncogenic roles, and for the first time, we identified a potential relationship between CHRM3 and angiogenesis in breast cancer. Further experiments are warranted to explore the underlying mechanism of CHRM3 in regulating angiogenesis. Citation Format: Jiawei Chen, Vivian Y Shin, Isabella Cheuk, Jennifer Siu, Ava Kwong. Cholinergic receptor muscarinic 3 (CHRM3) contributes to breast cancer tumorigenesis through angiogenesis regulation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-07-01.
EVIDENCE OF GLYCOLYSIS UPREGULATION AND PYRUVATE MITOCHONDRIAL OXIDATION MISMATCH DURING MECHANICAL UNLOADING OF THE FAILING HUMAN HEART: IMPLICATIONS FOR CARDIAC RELOADING AND CONDITIONING
Authors: Nikolaos Diakos, Sutip Navankasattusas, Jared Rutter, Josef Stehlik, Ralph Deberardinis, Stephen McKellar, Lauren McCreath, Peter Ferrin, Dylan Miller, Song Park, Russell Richardson, Abdallah Kfoury, Craig Selzman, Dean Li, James Fang, Stavros Drakos
Journal: Journal of the American College of Cardiology (2016)