tbuckley/cabot-search huggingface dataset:
Role of HFE mutation in the brain tumors
Authors: Sang Y. Lee, Becky Slagle-Webb, Jonas M. Sheehan, James R. Connor
Journal: Cancer Research (2005)

3609  Hemochromatosis, an iron overload disease, is characterized by malfunctions in iron metabolism and has been associated with liver, colorectal, breast and brain cancer. Hemochromatosis is associated with a mutation in the HFE gene. There are primarily two mutations. In cancer studies, the C282Y mutation has been linked to breast cancer and is indicative of aggressive disease. In contrast, the H63D mutation was found with higher frequency (19.5% vs 12.5%) in malignant gliomas. To understand the role of HFE and the consequence of these mutations on brain tumors, we first determined the expression level of HFE in brain tumor tissue and cell lines using immunohistochemistry. In the normal glial cell line, SVG p12, there is no detectable level of HFE protein expression. However, high- grade glioma and cell lines from human brain tumors have relatively strong HFE expression compared to low-grade astrocytomas. To determine the cellular consequences of carrying an HFE mutation, a human neuronal cell line (SH-SY5Y) was stably transfected with wild type or C282Y mutant HFE cDNA. The presence of the HFE mutation altered expression of iron metabolism proteins (transferrin receptor, ferritin) and the cytoskeletal proteins (actin, tubulin). Interestingly, the expression of the C282Y but not the H63D mutation is associated with a rapid proliferation of cells. The C282Y cells also demonstrated decreased sensitivity to hydrogen peroxide. To identify the effect of the mutant form of HFE on the cells, we performed gene expression profiling in the stably transfected SH-SY5Y cells using target specific gene arrays: human metal transport & homeostasis gene array, human stress & toxicity pathway finder gene array, human stress response to cellular damage gene array, human signal transduction pathway finder gene array, and human cancer pathway finder gene array. C282Y transfected cells have increased expression of the angiogenesis gene (angiopoietin 1), signal transduction molecule & transcription factors genes (c-Fos, V-jun), copper-responsive gene (lysyl oxidase), TGF-β pathway genes (cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase inhibitor 2C), calcium & protein kinase C pathway gene (PKC beta), and phospholipase C pathway gene (COX-2) compare to wild type HFE transfected cells. In addition, compared to wild type HFE transfected cells, C282Y transfected cells have decreased expression of cell cycle control & DNA damage repair gene (cyclin D1), invasion & metastasis gene (gelatinase A), apoptosis & cell senescence gene (TNF receptor superfamily member 25), Jak-Stat pathway gene (β-casein), and retinoic acid pathway gene (homo sapiens retinal-binding protein 1, cellular). The gene expression profiling data and the cell growth data imply that C282Y mutation of HFE significantly affected expression of major genes affecting cellular functions and altering cellular growth. (This work was supported by the Alzheimer’s Association)
Abstract 1122: CD44 as potential therapeutic target for medulloblastoma metastasis
Authors: Dan Qi, Fengfei Wang, Ekokobe Fonkem, Jason H. Huang, Erxi Wu
Journal: Cancer Research (2019)

Abstract Medulloblastoma (MB) is a commonly diagnosed pediatric brain tumor that shows highly variable rates of morbidity and mortality. Metastasis is the leading cause of death in patients with MB, approximately 30% of MB patients have metastatic tumors right at diagnosis. Therefore, there is a critical need to dissect the molecular mechanisms that govern MB progression and metastasis. In our previous work, we found that DHA and VP16 synergistically inhibit MB cell proliferation and induce cell death accompanied with a marked reduction in the expression of CD44 standard form (CD44s). In this study, we show that MB cells express CD44s mainly and the elevated level of CD44s enhances MB cell invasion, suggesting that CD44s may play a crucial role in MB metastasis. In addition, we observed CD44s expression only in MB patients with metastasis using a small cohort of samples. Large database analysis show that MB patients with elevated levels of CD44 have poorer outcomes. Moreover, CD44 knockdown markedly reduces the expressions of transcription factor c-Myc and the platelet derived growth factor receptor (PDGFR) β, both are therapeutic targets for MB. Interestingly, PDGFRβ knockdown abolishes CD44s expression and downregulates the level of c-Myc. However, there is no expression change of CD44s and PDGFR β after the knockdown of c-Myc. These results indicate that the expression and function of CD44s could be critical to MB progression and metastasis, highlighting the potential therapeutic targets for MBs with metastasis. Citation Format: Dan Qi, Fengfei Wang, Ekokobe Fonkem, Jason H. Huang, Erxi Wu. CD44 as potential therapeutic target for medulloblastoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1122.
Abstract 536: Mechanical Properties of the Interaction Between Fibronectin and α5β1-Integrin on Cardiomyocytes Studied by Atomic Force Microscopy
Authors: Xin Wu, Zhe Sun, Jerome P Trzeciakowski, Gerald A Meininger, Mariappan Muthuchamy
Journal: Circulation (2006)

The molecular mechanisms that lead to hypertrophic cardiomyopathy are poorly understood. Integrins that link the extracellular matrix (ECM) and intracellular cytoskeleton function as mechanotransdu...
Abstract 15878: Decreased Vascular Nitric Oxide Production Due to S100A1 Deficiency Preserves Cardiovascular Function and Survival in a Murine Model of Polymycrobial Sepsis
Authors: James Tsoporis, Jean-Francois Desjardins, Shehla Izhar, Thomas G Parker
Journal: Circulation (2016)

Introduction: Sepsis-induced myocardial depression is a key component contributing to septic shock. The mechanisms responsible for myocardial dysfunction in sepsis remain undefined. S100A1 a member...
Disappearance of the National Guideline Clearinghouse
Authors: Arlene S. Bierman, Mary P. Nix
Journal: Annals of Internal Medicine (2019)

Letters2 July 2019Disappearance of the National Guideline ClearinghouseArlene S. Bierman, MD, MS and Mary P. Nix, MS, PMPArlene S. Bierman, MD, MSAgency for Healthcare Research and Quality, Rockville, Maryland (A.S.B., M.P.N.)Search for more papers by this author and Mary P. Nix, MS, PMPAgency for Healthcare Research and Quality, Rockville, Maryland (A.S.B., M.P.N.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L19-0152 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:The AHRQ appreciates Munn and colleagues' commentary (1). We, too, recognize the critical role of guidelines in making evidence available to clinicians, practices, health systems, and other decision makers. They are a necessary but insufficient element of the digital evidence ecosystem. The time is ripe for innovation (2) in the next generation of an online interactive platform for clinical practice guidelines.A new AHRQ study will help identify new models for disseminating and accessing evidence-based clinical practice guidelines. This 12-month project will be done by The MITRE Corporation and is intended to build on the AHRQ's previous ...References1. Munn Z, Qaseem A. American College of Physicians and the Joanna Briggs Institute. Disappearance of the National Guideline Clearinghouse: a huge loss for evidence-based health care. Ann Intern Med. 2018;169:648-9. [PMID: 30167676]. doi:10.7326/M18-2216 LinkGoogle Scholar2. Guise JM, Savitz LA, Friedman CP. Mind the gap: putting evidence into practice in the era of learning health systems. J Gen Intern Med. 2018;33:2237-9. [PMID: 30155611] doi:10.1007/s11606-018-4633-1 CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Agency for Healthcare Research and Quality, Rockville, Maryland (A.S.B., M.P.N.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L19-0152. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoDisappearance of the National Guideline Clearinghouse: A Huge Loss for Evidence-Based Health Care Zachary Munn , Amir Qaseem , and Disappearance of the National Guideline Clearinghouse Karen Schoelles Metrics 2 July 2019Volume 171, Issue 1Page: 71-72KeywordsDecision makingDisclosureTreatment guidelines ePublished: 2 July 2019 Issue Published: 2 July 2019 PDF downloadLoading ...
Abstract 1462: Novel oncolytic virus armed with interleukin-21 enhances immune oncotherapy
Authors: Rong Zhang, Tingting Wang, Yun Qing, Shuaijun Sun, Meili Liu, Fang Hu, Jin Fu
Journal: Cancer Research (2019)

Abstract Oncolytic viruses have elucidated the broad anti-tumor properties through selectively destroying tumor cells, promoting tumor antigen release and inducing the activation of immune response. Vaccinia virus (VV) has been engineered for tumor selectivity by the deletion of two essential genes (DDvv), viral growth factor (VGF) and thymidine kinase (TK). However, it still has certain obstacles, such as spread of virus, tumor microenvironment barrier, immune cell infiltration and tumor infiltration lymphocytes (TILs) proliferation. In the present study, we engineered the novel oncolytic mV01 and hV01 viruses, recombinant DDvv viruses carrying human interleukin-21 (hIL-21) or mouse IL-21 (mIL-21), respectively. mV01 and hV01 exhibited potent inhibition of various tumor cells with IC50 &amp;lt; 0.5 MOI. When in combination with hNK cell, hV01 significantly enhanced the inhibition of cell proliferation in SK-HEP-1 cells and HepG2 cells as compared to mock virus. Animal studies showed that mV01 (i.t.) significantly reduced tumor burden in B16 C57/BL6 xenograph mice that were pre-treated with low dose cyclosporine A (i.p), compared to mock virus treatment. Simultaneously, mV01 regimens improved tumoral immune cell infiltration and TILs proliferation. Additionally, in HCT116 NCG xenograph mice, administration of hV01 (i.t.) exhibited significant inhibition of tumor growth (T/C &amp;lt; 40%) when in combination with hNK cells (i.v). Together, these data revealed that V01 is a promising candidate for tumor immunotherapy through viral oncolysis and anti-tumor immunity. Citation Format: Rong Zhang, Tingting Wang, Yun Qing, Shuaijun Sun, Meili Liu, Fang Hu, Jin Fu. Novel oncolytic virus armed with interleukin-21 enhances immune oncotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1462.
Studies on Digitalis
Authors: EDMUND H. SONNENBLICK, JOHN F. WILLIAMS, GERALD GLICK, DEAN T. MASON, EUGENE BRAUNWALD
Journal: Circulation (1966)

The effects of ouabain (0.01 mg/kg) on ventricular force-velocity relations were studied in six patients who had previously undergone corrective cardiac operations. The technique employed consisted of exposing cineradiograms at 30 frames per second and measuring the velocity of movement of roentgen-opaque markers that had been sutured to the external surfaces of the ventricles while simultaneously recording intraventricular pressures. A beat-to-beat analysis of the ventricular force-velocity relation was then accomplished by relating the velocity of marker movement and intraventricular pressure at constant ventricular dimensions. It was observed that ouabain always augmented myocardial contractility as reflected in the force-velocity relation. Velocity of shortening increased an average of 77±5 ( sem )% while intraventricular pressure rose by an average of 23±6%. Despite this improvement in contractility, no consistent changes in cardiac output were observed. Analogous changes in force-velocity curves were obtained when a cardiac glycoside was added to isolated papillary muscles removed from normal cats. It is concluded that the fundamental action of digitalis glycosides is to augment the contractile state of the heart, whether normal or failing, but that in the absence of heart failure this improvement is not translated into an increase in cardiac output.
Abstract 703: An anthelmintic drug, flubendazole, exerts antitumor effects in triple-negative breast cancer via targeting cancer stem-like properties
Authors: Yoon-Jae Kim, Eunhye Oh, Tae-Min Cho, Seojin Jang, Jung Min Park, Soeun Park, Minsu Park, Ji Young Kim, Jae Hong Seo
Journal: Cancer Research (2019)

Abstract Triple-negative breast cancer (TNBC) remains challenging due to the absence of established molecular targets for the phenotype. These tumors tend to be more aggressive with a higher risk of recurrence and metastasis, leading to poorer clinical outcomes. Flubendazole (FLU) is a widely used anthelmintic agent that also exhibits anticancer activity in several cancer types. The objective of the present study was to investigate the effects of FLU on cell proliferation, apoptosis and breast cancer stem cell (BCSC)-like properties in TNBC. The effect of FLU on TNBC cell lines in vitro was evaluated in terms of apoptosis, cell cycle distribution, caspase-3/-7 activity and BCSC-like characteristics. An orthotopic allograft model with 4T1 mammospheres was used to examine the effect of FLU on tumor growth and angiogenesis in vivo. FLU efficiently induced apoptosis with accompanied by activation of caspase-3 and -7, and PARP cleavage in TNBC. FLU-induced apoptosis is associated with the accumulation of G2/M phase cells by tubulin degradation, leading to mitotic catastrophe. Interestingly, FLU significantly suppressed BCSC-like properties in TNBC, as evidenced by a marked inhibition of ALDH1 activity, the CD44high/CD24low and CD49fhigh/CD24high subpopulations, and the subsequent impairment of mammosphere formation in vitro. This appears to contribute toward the suppression of BCSC-enriched tumor burden and intra-tumoral angiogenesis in TNBC allografts, together with a significant downregulation of ALDH1A1 and CD49f expression in vivo. Our findings suggest that FLU kills not only rapid proliferating tumor cells but also effectively eradicates BCSC-like cells in vitro and in vivo. These findings warrant further investigation of flubendazole as a potential treatment for triple-negative breast cancer. Citation Format: Yoon-Jae Kim, Eunhye Oh, Tae-Min Cho, Seojin Jang, Jung Min Park, Soeun Park, Minsu Park, Ji Young Kim, Jae Hong Seo. An anthelmintic drug, flubendazole, exerts antitumor effects in triple-negative breast cancer via targeting cancer stem-like properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 703.
Push Doctor’s online GP service has improved prescribing safety after previous concerns, says CQC
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The digital GP provider Push Doctor has been rated as “good” by the Care Quality Commission (CQC) in a significant turnaround for the service, which was previously the subject of safety concerns from the regulator.

A CQC report in 20171 said that the service, which offers patients video consultations and online prescriptions, had prescribed high risk medicines without proper checks and tests.2 A follow-up inspection in August 20183 found improvements but said that the service was still not providing safe care overall, citing specific concerns over the prescription of certain antibiotics.

But, in a report …
Health-related quality of life in RAS wild-type metastatic colorectal cancer patients treated with panitumumab plus FOLFOX followed by panitumumab or panitumumab plus 5-FU/LV maintenance: the secondary endpoint of the Valentino study
Authors: A. Raimondi, M. Di Maio, G. Peverelli, F. Morano, S. Corallo, F. Bergamo, C. Cremolini, V. Smiroldo, A. Amatu, M. Tampellini, L. Fanchini, R. Murialdo, M. Clavarezza, S. Noventa, V. Adamo, M. Ratti, F. Petrelli, L. Antonuzzo, M. Palermo, F. de Braud, M. Di Bartolomeo, F. Pietrantonio
Journal: Annals of Oncology (2019)
Optimal Blood Pressure Thresholds for Minimal Coronary Artery Disease Risk in Type 1 Diabetes
Authors: Jingchuan Guo, Maria M. Brooks, Matthew F. Muldoon, Ashely I. Naimi, Trevor J. Orchard, Tina Costacou
Journal: Diabetes Care (2019)

OBJECTIVE We aimed to determine optimal blood pressure (BP) thresholds for minimizing coronary artery disease (CAD) risk in people with childhood-onset type 1 diabetes. RESEARCH DESIGN AND METHODS The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study participants without known CAD at baseline (n = 605) were included and followed for 25 years. The associations of time-weighted BP measures (systolic BP [SBP], diastolic BP [DBP], and mean arterial pressure) with incident CAD were examined by using Cox models. Areas under the receiver operating characteristic curve (AUC) were summarized by different cut points of time-weighted BPs. Risk stratification analyses were then performed on the basis of BP (&amp;lt;120/80 vs. ≥120/80 mmHg) and HbA1c (&amp;lt;8% vs. ≥8%). RESULTS Baseline mean age was 27 years. Half of the cohort were women and 98% were white. A dose-gradient association was observed for categorized time-weighted BPs and CAD. According to AUC, the optimal cut point for SBP was 120 mmHg and for DBP was 80 mmHg. BP ≥120/80 mmHg was associated with a 1.9 times (95% CI 1.4, 2.6) greater risk of developing CAD than that for BP &amp;lt;120/80 mmHg. Participants with good control of both BP and HbA1c had BP &amp;lt;120/80 mmHg and HbA1c &amp;lt;8%. Those with only high BP (hazard ratio [HR] 2.0 [95% CI 1.1, 3.9]) carried a similar risk of developing CAD as those with only high HbA1c (HR 1.6 [95% CI 0.97, 2.8]). CONCLUSIONS The optimal BP threshold associated with minimal CAD risk is 120/80 mmHg in young adults with childhood-onset type 1 diabetes.
Abstract 15969: Aav9-wnt11 Gene Therapy Improves Survival of Myocarditis Mice Induced by Coxsackie Virus Through the Improvement of Cardiac Function
Authors: Yutaka Aoyama, Koichi Kobayashi, Kengo Maeda, Yoshihiro Morishita, Toyoaki Murohara
Journal: Circulation (2012)

Background: The wnt signaling pathway plays important roles in development and diseases. Recent reports suggest a relationship between the noncanonical Wnt signaling and the regulation of inflammat...
Abstract 1803: Openarray profiling of the systemic change of microRNAs in rhenium-188 liposome treated human head and neck cancer cells
Authors: Bing-Ze Lin, Chun-Yuan Chang, Chih-Hsien Chang, Yi-Jang Lee
Journal: Cancer Research (2019)

Abstract Purpose188Re-liposome has been used for evaluating the theranostic efficacy in various human cancers. However, whether the therapeutic efficacy of 188Re-liposome directly related to microRNAs regulation and specific signaling pathways are largely unknown. In this project, we investigated the 188Re-liposome induced systemic microRNA expressive responses in human head and neck cancer (HNSCC) cells. Methods The FaDu-3R cells were implanted into the nude mice at the position of buccal cavity. After two weeks of implantation, the tumors were palpable and the bioluminescent imaging indicated the location of this orthotopic tumor model. The PEGylated 188Re-liposome was intravenously injected single and dual dose respectively. We harvested all of the tumors after 188Re-liposome injection one month ago, and used Taqman Openarray MicroRNA (Thermo, USA) to detect the expression of miRNAs in different groups. The dataset we observed was further analyzed by using Ingenuity Pathway Analysis (IPA) software to establish the molecular signaling pathway of 188Re-liposome radiopharmaceutical. Results Quantification of the photon signals showed that the tumor growth of the dual 188Re-liposome treated mice was slower than that of control ones. The survival rate of 188Re-liposome treated animals were also better than control ones. The microRNA Openarray showed that, compared to untreated control, 17 miRNA were significantly changed in expressive levels over 5 fold after 188Re-liposome treatment. Subsequently, we used IPA to determine the role of these miRNA, and found these miRNA with oncogenic and tumor suppressive properties were down-regulated and up-regulated, respectively. Among them, we focused on miR-152-5p that is closed related to cancer occurrence and development, and showed that knockdown of miR-152-5p could decreased the effects of 188Re-liposome on suppressing the growth of HNSCC xenograft tumors. Conclusion HNSCC tumor model treated with dual dose of 188Re-liposome exhibited significant response to this radiopharmaceutical. We also found that 17 miRNA could be gsignificantly re-regulated, and miR-152-5p is one example to be involved in mediating the efficacy of 188Re-liposome. Targeting on specific miRNA may enhance the application value of 188Re-liposome.in cancer treatment. Citation Format: Bing-Ze Lin, Chun-Yuan Chang, Chih-Hsien Chang, Yi-Jang Lee. Openarray profiling of the systemic change of microRNAs in rhenium-188 liposome treated human head and neck cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1803.
NHS will focus on investigating serious incidents with the best learning opportunities
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The NHS has set out plans to alter how it investigates serious incidents, as part of a new national patient safety strategy in England.

Published by NHS Improvement and NHS England,1 the strategy says that the NHS should move away from current thresholds for investigating serious incidents and should prioritise incidents that give the best opportunity for learning.

The strategy is designed to encourage staff to speak up and contribute to continuous improvement, by learning and acting when things go wrong. It includes a raft of recommendations (see box) which, if implemented successfully, could save around 1000 lives and £100m (€111m; $126m) in care costs a year by 2023-24, said NHS Improvement.

A significant part of the strategy is the new Patient Safety Incident Response Framework, due to be implemented throughout England by …