tbuckley/cabot-search huggingface dataset:
Abstract 694: PAWI-2 overcomes tumor stemness and drug resistance in pancreatic cancer stem cells
Authors: Jiongjia Cheng, John Cashman, Jorge Gomez-Galeno
Journal: Cancer Research (2020)

Abstract Today, pancreatic cancer (PC) remains a major health problem in the US and soon will be the second most common cause of mortality due to cancer. However, most of the front-line PC chemotherapies cause serious side effects and a majority of patients with PC are often resistant to clinical therapies. The fact that cancer stem cells (CSCs) become enriched after anti-cancer therapy implicates CSCs as key contributors to tumor dormancy, metastasis, and relapse in PC. Given the important role of human pancreatic cancer stem cells (hPCSCs) in PC, development of a novel treatment strategy that targets hPCSCs or their extrinsic and intrinsic regulators could be of great clinical utility to treat PC. Herein, we used a highly validated hPCSCs model (FGβ3 cells) to test a novel compound (PAWI-2) to target CSCs. In this hPCSC model, integrin αvβ3 expression was shown to be a marker/functional contributor to CSC progression and drug resistance attributed to its ability to trigger anchorage-independent cell survival and tumor metastasis. Specifically, integrin αvβ3 recruits KRAS and RalB to tumor cell plasma membranes to activate NF-κB signaling that triggers dysregulated KRAS-RalB-NF-κB pathways. This was shown to be a pharmacological target to reverse CSC-like properties or re-sensitize drug resistance (e.g., EGFR inhibitors, erlotinib) of established FGβ3 tumors. Compared to parental FG cells, PAWI-2 showed greater potency to inhibit cell viability and self-renewal capacity of FGβ3 cells. PAWI-2 inhibited dysregulated integrin β3-KRAS-RalB-NF-κB signaling independent of KRAS and Ral. This is clinically relevant because &amp;gt;90% of KRAS is activated by mutations in PC and RAS or Ral inhibitors have not proven effective clinically. PAWI-2 targeted downstream of KRAS signaling and was negatively regulated by other feedback mechanisms. This was further shown by genetic knockdown of key regulator and co-treatment of specific inhibitors. PAWI-2 overcomes erlotinib resistance in FGβ3 cells with greater potency than bortezomib. In the proposed mechanism of PAWI-2 action, key regulators link the inhibition of KRAS signaling and cell cycle arrest (G2/M). The great utility and pharmacological potency of PAWI-2 in FGβ3 cells (that possess stem-like properties) compared to FG cells provide a basis for further development. PAWI-2 as an efficient therapeutic to reverse tumor stemness and resensitize CSC tumors to drug inhibition. This work was supported by Inception Award from California Institute for Regenerative Medicine (CIRM) (DISC1-10583; J.R. Cashman) and by funds from the Human BioMolecular Research Institute. Citation Format: Jiongjia Cheng, John Cashman, Jorge Gomez-Galeno. PAWI-2 overcomes tumor stemness and drug resistance in pancreatic cancer stem cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 694.
Ticagrelor or Clopidogrel in Elderly Patients With Myocardial Infarction
Authors: Piera Capranzano, Dominick J. Angiolillo
Journal: Circulation (2020)

inhibitor (ticagrelor, low-dose prasugrel, or clopidogrel) in elderly patients after MI should account for a multitude of factors that need to be weighed up, as this choice can make the difference.
PRL-3 facilitates Hepatocellular Carcinoma progression by co-amplifying with and activating FAK
Authors: Qiming Zhou, Qianlei Zhou, Qinghua Liu, Zhanghai He, Yongcong Yan, Jianhong Lin, Zheng Chen, Chuanchao He, Kai Mao, Jie Wang, Zhenyu Zhou, Zhiyu Xiao, Jianlong Zhang
Journal: Theranostics (2020)

Background: In addition to protein tyrosine kinases, accumulating evidence has shown that protein tyrosine phosphatases (PTPs) are suitable therapeutic targets in cancer. PRL-3 is a PTP member that has been well studied in many malignant tumours. The goal of the present study was to elucidate the role of PRL-3 in hepatocellular carcinoma (HCC), which remains largely unknown. Methods: Bioinformatic and immunohistochemical analyses were performed to analyse PRL-3 expression in HCC tissue samples and determine its clinical relevance. PRL-3 gene copy number variations were evaluated by bioinformatic analysis and quantitative-genomic polymerase chain reaction. The biological functions of PRL-3 were investigated in vivo and vitro. Gene microarray assays, RT-qPCR, western blotting and luciferase experiments were performed to identify the downstream effectors of PRL-3 that mediate its functions in HCC. Results: PRL-3 expression was upregulated in HCC samples from public databases and in cohort samples from our centre. High PRL-3 expression was associated with poor prognosis. Copy number gains and amplification of chromosome 8q24.3 in HCC were determined to be positively correlated with the PRL-3 overexpression. PRL-3 overexpression promoted HCC cell proliferation, migration and adhesion, while its loss had the opposite effects. Further study showed that focal adhesion kinase (FAK) was co-amplified and co-expressed with PRL-3 in HCC. Interestingly, PRL-3 also promoted the phosphorylation of FAK, which subsequently mediated the oncogenic functions of PRL-3 in HCC cells. Moreover, TGFB1 was identified as a downstream molecule of PRL-3. TGF-β signalling was shown to mediate the PRL-3-induced activation of FAK. Furthermore, the p38 and PI3K/AKT pathways were observed to mediate the PRL-3-induced expression of TGFB1 and the subsequent activation of FAK, while the activation of FAK in turn stimulated activation of the p38 and PI3K/AKT pathways, forming a PRL-3-triggered AKT/p38/TGFB1/FAK positive feedback loop. Conclusion: Collectively, our findings indicate that the PTP PRL-3 plays a crucial role in the progression of HCC and provides an example of how co-amplified genes work together in HCC.
Abstract 4651: Interaction between outdoor ultraviolet radiation and indoor tanning bed use on skin cancer risk
Authors: Jongeun Rhee, Tricia Li, Wen-Qing Li, Abrar A. Qureshi, Eunyoung Cho
Journal: Cancer Research (2020)

Abstract Background: Solar ultraviolet (UV) radiation and the use of UV-emitting tanning devices are risk factors for melanoma and non-melanoma skin cancer (NMSC). Despite abundant evidence, frequent outdoor sunbathers are more likely to use indoor tanning beds. In our study, we aim to investigate the interaction between indoor tanning bed use and exposure to solar UV radiation associated with the risk of skin cancer. Methods: The study population was participants of the Nurses' Health Study II, which started in 1989 including 116,430 registered female nurses aged 25-42. Participants biennially self-reported diagnosis of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Cases for melanoma and SCC were confirmed by medical records. Information on indoor tanning bed use during high school/college or age 25-35 was collected. Cumulative average UV exposure at residence during follow-up was calculated for each participant. We built Cox proportional hazards models adjusting for potential confounders. Interactions between cumulative UV exposure and indoor tanning use were tested in multivariable-adjusted models for three types of skin cancer. Results: We found significant interactions between cumulative average UV during follow-up and indoor tanning bed use during high school/college years (P for interaction=0.01) on the risk of BCC, but not during the age 25-35 (P for interaction=0.15). Subjects who were exposed to high UV and used tanning bed during high school/college (RR: 1.54, 95% CI 1.38, 1.72) or during age 25-35 (RR: 1.56, 95% CI: 1.43, 1.69) had nearly 50% increased risk of BCC compared to subjects who were exposed to low UV and did not use tanning bed. Increased risk but non-significant interactions were found for SCC (indoor tanning during high school/college years: P for interaction=0.29, during age 25-35: P for interaction=0.09). Subjects who were exposed to high UV and used tanning bed during age 25-35 had approximately double the risk of SCC (RR: 2.04, 95% CI: 1.51, 2.76), compared to the reference group. No significant interactions were found for the risk of melanoma. Conclusions: We found significant interaction between outdoor UV and indoor tanning bed use during high school/college years on the risk of BCC but not SCC or melanoma. Citation Format: Jongeun Rhee, Tricia Li, Wen-Qing Li, Abrar A. Qureshi, Eunyoung Cho. Interaction between outdoor ultraviolet radiation and indoor tanning bed use on skin cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4651.
EULAR/eumusc.net standards of care for rheumatoid arthritis: cross-sectional analyses of importance, level of implementation and care gaps experienced by patients and rheumatologists across 35 European countries
Authors: Rachelle Meisters, Polina Putrik, Sofia Ramiro, Monika Hifinger, Andras P Keszei, Yvonne van Eijk-Hustings, Anthony D Woolf, Josef S Smolen, Tanja A Stamm, Michaela Stoffer-Marx, Till Uhlig, Rikke Helene Moe, Maarten de Wit, Argjend Tafaj, Vahan Mukuchyan, Paul Studenic, Patrick Verschueren, Russka Shumnalieva, Paraskevi Charalambous, Jiří Vencovský, Melpomeni Varvouni, Mart Kull, Kari Puolakka, Laure Gossec, Nino Gobejishvili, Jacqueline Detert, Prodromos Sidiropoulos, Márta Péntek, David Kane, Carlo Alberto Scirè, Uri Arad, Daina Andersone, Mart van de Laar, Annette van der Helm-van Mil, Piotr Głuszko, Luís Cunha-Miranda, Florian Berghea, Nemanja S Damjanov, Matija Tomšič, Loreto Carmona, Carl Turesson, Adrian Ciurea, Surayo Shukurova, Nevsun Inanc, Suzanne MM Verstappen, Annelies Boonen
Journal: Annals of the Rheumatic Diseases (2020)

As part of European League against Rheumatism (EULAR)/European Musculoskeletal Conditions Surveillance and Information Network, 20 user-focused standards of care (SoCs) for rheumatoid arthritis (RA) addressing 16 domains of care were developed. This study aimed to explore gaps in implementation of these SoCs across Europe.Two cross-sectional surveys on the importance, level of and barriers (patients only) to implementation of each SoC (0-10, 10 highest) were designed to be conducted among patients and rheumatologists in 50 European countries. Care gaps were calculated as the difference between the actual and maximum possible score for implementation (ie, 10) multiplied by the care importance score, resulting in care gaps (0-100, maximal gap). Factors associated with the problematic care gaps (ie, gap≥30 and importance≥6 and implementation<6) and strong barriers (≥6) were further analysed in multilevel logistic regression models.Overall, 26 and 31 countries provided data from 1873 patients and 1131 rheumatologists, respectively. 19 out of 20 SoCs were problematic from the perspectives of more than 20% of patients, while this was true for only 10 SoCs for rheumatologists. Rheumatologists in countries with lower gross domestic product and non-European Union countries were more likely to report problematic gaps in 15 of 20 SoCs, while virtually no differences were observed among patients. Lack of relevance of some SoCs (71%) and limited time of professionals (66%) were the most frequent implementation barriers identified by patients.Many problematic gaps were reported across several essential aspects of RA care. More efforts need to be devoted to implementation of EULAR SoCs.
Annals Graphic Medicine - Dr. Mom: Signs You Might Be a Physician Mom
Authors: Grace E. Farris
Journal: Annals of Internal Medicine (2020)

Web Exclusives1 September 2020Annals Graphic Medicine - Dr. Mom: Signs You Might Be a Physician MomFREEGrace E. Farris, MDGrace E. Farris, MDMount Sinai School of Medicine, New York, New York (G.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G20-0084 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Mount Sinai School of Medicine, New York, New York (G.E.F.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G18-0042.Author/Illustrator Information: Grace E. Farris, MD, is an assistant professor of medicine at Icahn School of Medicine at Mount Sinai and chief of hospital medicine at Mount Sinai West hospital in New York, New York. You can view her work at her website: www.farrisgrace.com.About Dr. Mom: In Dr. Mom, physician and cartoonist Grace Farris examines work–life balance while mothering and doctoring. Dr. Mom appears monthly in Annals Graphic Medicine at Annals.org. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 September 2020Volume 173, Issue 5Page: W80-W83KeywordsConflicts of interestDisclosureHospital medicineHospitalists ePublished: 1 September 2020 Issue Published: 1 September 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Author Correction: Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes
Authors: Matheus B. Victor, Michelle Richner, Hannah E. Olsen, Seong Won Lee, Alejandro M. Monteys, Chunyu Ma, Christine J. Huh, Bo Zhang, Beverly L. Davidson, X. William Yang, Andrew S. Yoo
Journal: Nature Neuroscience (2020)
National trends in heart failure mortality in men and women, <scp>United Kingdom</scp>, 2000–2017
Authors: Clare J. Taylor, José M. Ordóñez‐Mena, Nicholas R. Jones, Andrea K. Roalfe, Sarah Lay‐Flurrie, Tom Marshall, F.D. Richard Hobbs
Journal: European Journal of Heart Failure (2020)

Aims To understand gender differences in the prognosis of women and men with heart failure, we compared mortality, cause of death and survival trends over time. Methods and results We analysed UK primary care data for 26 725 women and 29 234 men over age 45 years with a new diagnosis of heart failure between 1 January 2000 and 31 December 2017 using the Clinical Practice Research Datalink, inpatient Hospital Episode Statistics and the Office for National Statistics death registry. Age‐specific overall survival and cause‐specific mortality rates were calculated by gender and year. During the study period 15 084 women and 15 822 men with heart failure died. Women were on average 5 years older at diagnosis (79.6 vs. 74.8 years). Median survival was lower in women compared to men (3.99 vs. 4.47 years), but women had a 14% age‐adjusted lower risk of all‐cause mortality [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.84–0.88]. Heart failure was equally likely to be cause of death in women and men (HR 1.03, 95% CI 0.96–1.12). There were modest improvements in survival for both genders, but these were greater in men. The reduction in mortality risk in women was greatest for those diagnosed in the community (HR 0.83, 95% CI 0.80–0.85). Conclusions Women are diagnosed with heart failure older than men but have a better age‐adjusted prognosis. Survival gains were less in women over the last two decades. Addressing gender differences in heart failure diagnostic and treatment pathways should be a clinical and research priority.
Abstract 523: Advanced engineering using CAR-T display libraries: Ultra-high throughput functional screen
Authors: Sawsan Youssef, Joyce Chou, Devin Pineda, Sarah Ives, Valerie Chiou, Jean-Philippe Buerckert, Raymond Newland, Shahrad Daraeikia, Sindy Liao, Chelsea Jones, Christina Pettus, Jessica Salas, Emelia Padilla, Christopher Smith, Giles Day, David Maurer, Ian Waddell, Jacob Glanville
Journal: Cancer Research (2020)

Abstract CAR-T-cell therapies represent a new area of synthetic biology success in cancer immunotherapy. However, the complexity of their adverse events related to their activity are still a major challenge. Using our in-house fully human computationally optimized phage display library, we established a novel cell-based ultra-high throughput panning and screening CAR-T platform. Our proprietary CAR-T vector is designed as a series of cassettes incorporating our SuperHuman phage library with an optimal backbone. This allows us to design CAR-T with desired properties, including: Range of Affinities, Humanness, Epitope Diversity, Thermostability, Immunogenicity, Tonic activation, Toxicity, and Functional Activity. Our library's encoding ensures a single CAR-T construct per one reporter cell. Moreover, to confirm CAR-T-specific-activation, we incorporated three different markers that will be upregulated simultaneously. We used CD19 and BCMA to validate our platform selecting target-specific functionally active scFv candidates against both targets, which are selective to activation conditions such as tonic signaling, and tissue specific silencing. Collectively we show that our platform can be readily used to characterize CAR-T in high-speed and - throughput fashion. Citation Format: Sawsan Youssef, Joyce Chou, Devin Pineda, Sarah Ives, Valerie Chiou, Jean-Philippe Buerckert, Raymond Newland, Shahrad Daraeikia, Sindy Liao, Chelsea Jones, Christina Pettus, Jessica Salas, Emelia Padilla, Christopher Smith, Giles Day, David Maurer, Ian Waddell, Jacob Glanville. Advanced engineering using CAR-T display libraries: Ultra-high throughput functional screen [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 523.
Evidence for Dopamine Abnormalities in the Substantia Nigra in Cocaine Addiction Revealed by Neuromelanin-Sensitive MRI
Authors: Clifford M. Cassidy, Kenneth M. Carpenter, Anna B. Konova, Victoria Cheung, Alexander Grassetti, Luigi Zecca, Anissa Abi-Dargham, Diana Martinez, Guillermo Horga
Journal: American Journal of Psychiatry (2020)

Recent evidence supports the use of neuromelanin-sensitive MRI (NM-MRI) as a novel tool to investigate dopamine function in the human brain. The authors investigated the NM-MRI signal in individuals with cocaine use disorder, compared with age- and sex-matched control subjects, based on previous imaging studies showing that this disorder is associated with blunted presynaptic striatal dopamine.
AB0164 Postural symptoms and the effect of treatment with plantars and/or prismatic lenses
Authors: A Teixeira, F Espinheira, J Landeiro, P Araújo, L Miranda, M Parente
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To review and evaluate in a prospective study the most frequent postural symptoms and examine the effect of treatment with plantars and/or prismatic lenses correction (legs length dismetry, functional and structural scoliosis). <h3>Methods</h3> A group of 100 patients with postural symptoms were evaluated and treated in our institution for more than 36 months. Their symptoms were graduated from 0 to 4 and compared before and after a year of treatment. An x-ray film of the rachis from anteroposterior view was obtained. The aim of the corrections was to obtain the nearest horizontal equilibrium for the different plans of the body and equal distribution of weight. Leg length dismetry was corrected according to the position of the femoral heads and searching for the relative inclination degree of both femoral heads and sacred with the horizontal plan. Correction with prismatic lenses was performed in the cases without leg length dismetry, horizontal sacral base, inclination of the head or shoulder plans. <h3>Results</h3> Of the 100 patients, 71 were female and reported mean age 33.7 ± 20.2 SD years. The symptoms more commonly found are shown in table below by frequency sequence at first observation. Improvement after completed treatment was obtained for all analysis symptoms with statistical significance except for temporomandibular joint, hip, knee and foot pain. <h3>Conclusion</h3> The treatment of different postural symptoms with plantars, prismatic lenses or both together revealed a global improvement in low back and cervical pain, dizziness, astenopia, headache, dorsal pain, unbalance, migraine, vertigo. The different treatments analysed revealed a clinically significant improvement in low back pain (p = 0,001), cervical pain (p = 0,001), headache (p = 0,000), dizziness (p = 0,000), astenopia (p = 0,005), dorsal pain (p = 0,022), unbalance (p = 0,002), vertigo (p = 0,027), migraine (p = 0,05). This statistical significance improvement difference is higher with the follow-up.
Abstract IA10: Traditional and modern approaches for prevention and early detection
Authors: Douglas A. Levine
Journal: Clinical Cancer Research (2020)

Abstract Conventionally, serum CA-125 measurements and ultrasonography have been used to try to detect ovarian carcinoma at early stage. These methods have not been proven to result in early-stage detection and seem to convey little survival benefit. It is now widely accepted that such methods are not justified for widespread use in cancer screening, and the US Preventative Services Task Force recommends against their use. CA-125 and human epididymis protein 4 (HE4) are involved in ovarian tumorigenesis, overexpressed by malignant epithelial cells, and found in patient serum. Increased levels of these proteins as well as others in patient ascites, and uterine fluid, as compared to serum, suggest that their detection may be enhanced by measurements taken from within the uterine cavity or other locations more proximal to the ovaries and fallopian tube where tumors most commonly originate. The knowledge that most high-grade serous carcinomas originate from the distal fallopian tube creates an opportunity for new screening and prevention approaches that were previously impractical when the site of origin was thought to be the ovarian surface epithelium. The fallopian tube can be accessed via a transvaginal/transuterine route, and the fallopian tubes are not necessary for normal biologic function once childbearing is complete. Based on the hypothesis that serous tubal intraepithelial carcinoma (STIC) is the precursor of most high-grade serous carcinomas (HGSCs), innovative studies aimed at providing a realistic clinical method for reducing the burden of ovarian cancer are under way. In this presentation we will discuss the latest knowledge regarding approaches for prevention and early detection of ovarian cancer. We will discuss the role of precursor lesions in the development and metastatic spread of invasive ovarian cancers. We will review ongoing and planned clinical trials of surgical prevention and discuss missed opportunities for chemoprevention. We will also discuss more innovative approaches to early detection through minimally invasive access to the distal fallopian tube and nanotechnology for highly sensitive protein detection. The approaches and others hold great promise to transform the paradigm of early ovarian cancer detection from one of traditional serum-based biomarkers to one that incorporates the current concepts of ovarian cancer origins, proximal measurements of tissue-based biomarkers, and novel circulating biomarkers. Citation Format: Douglas A. Levine. Traditional and modern approaches for prevention and early detection [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA10.