tbuckley/cabot-search huggingface dataset:
Stat5-dependent cardioprotection in late remote ischaemia preconditioning
Authors: Hui Chen, Xin-Yue Jing, Yu-Jun Shen, Tian-Lin Wang, Chen Ou, Sheng-Feng Lu, Yun Cai, Qian Li, Xia Chen, Ya-Juan Ding, Xiao-Chun Yu, Bing-Mei Zhu
Journal: Cardiovascular Research (2018)

To study the protective effects of late remote ischaemic preconditioning (RIPC) against myocardial ischaemia/reperfusion (I/R) injury and determine whether Stat5 is involved in this protection by using cardiomyocyte-specific Stat5 knockout mice (Stat5-cKO). Mice were exposed to lower limb RIPC or sham ischaemia. After 24 h, the left anterior descending artery (LAD) was ligated for 30 min, then reperfused for 180 min. The myocardial infarct size (IS), apoptotic rate of cardiomyocytes, and serum myocardial enzymes were measured to evaluate for cardioprotective effects. Heart tissues were harvested to determine the cardiomyocytes' anti-apoptotic and survival signaling. When compared with the Stat5fl/fl mice without RIPC, Stat5fl/fl mice with RIPC (Stat5fl/fl+RIPC + I/R) displayed a decreased myocardial IS/LV (16 ± 1.5 vs. 30.1 ± 3.1%, P < 0.01; IS/ area at risk (AAR), 42.2 ± 3.5 vs. 69.2 ± 4.9%, P < 0.01), a reduced cardiomyocyte apoptotic rate (2.1 ± 0.37 vs. 5.5 ± 0.53%, P < 0.01), and lower creatine kinase (CK), lactate dehydrogenase (LDH), and creatine kinase-MB (CK-MB) levels. To the contrary, the Stat5-cKO mice (Stat5fl/fl; Tnnt2Cremice with Doxycycline treatment for 7 days) did not exhibit any effect of RIPC-induced cardioprotection. Activation of STAT5 protein was significantly higher in the Stat5fl/fl+RIPC + I/R group than in the Stat5fl/fl+I/R group, while there was no significant difference between the Stat5-cKO + RIPC + I/R and the Stat5-cKO + I/R group. Further analyses with heart tissues detected decreased protein expressions of cytochrome c (Cyt c) and cleaved Caspase-3 in the Stat5fl/fl+RIPC + I/R mice, along with increased anti-apoptotic molecules, including B-cell lymphoma-extra large (Bcl-xL) and B-cell lymphoma-2 (Bcl-2); such changes were not noted in the Stat5-cKO + RIPC + I/R mice. Additionally, RIPC increased cardiac hypoxia inducible factor-1 (HIF-1α) and interleukin-10 (IL10) protein levels and caused activation of AKT, phosphatidylinositol 3 kinase (PI3K), and vascular endothelial growth factor in the heart of the Stat5fl/fl mice. However, these changes were completely inhibited by the absence of Stat5. These results suggest that RIPC-induced late cardioprotection against myocardial I/R injury is Stat5-dependent and is correlated with the activation of anti-apoptotic signaling and cardiomyocyte-survival signaling.
Sustained Response Following Discontinuation of Methotrexate in Patients With Rheumatoid Arthritis Treated With Subcutaneous Tocilizumab
Authors: Joel M. Kremer, William Rigby, Nora G. Singer, Christine Birchwood, Darcy Gill, William Reiss, Jinglan Pei, Margaret Michalska
Journal: Arthritis & Rheumatology (2018)

Objective To evaluate whether tocilizumab ( TCZ ) monotherapy is noninferior to treatment with TCZ plus methotrexate ( MTX ) for maintaining clinical responses in patients with rheumatoid arthritis ( RA ) in whom low disease activity is achieved with TCZ plus MTX . Methods Patients with RA who experienced an inadequate response to MTX received MTX plus TCZ 162 mg subcutaneously. At 24 weeks, patients who achieved a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate ( DAS 28‐ ESR ) of ≤3.2 were randomized to receive TCZ monotherapy or to continue treatment with TCZ plus MTX until week 52. The primary outcome measure was the comparison of the mean change in the DAS 28‐ ESR from week 24 to week 40 between the TCZ monotherapy and TCZ plus MTX arms (noninferiority margin of 0.6). Secondary outcome measures included worsening of the DAS 28‐ ESR by ≥1.2, achievement of a DAS 28‐ ESR of &lt;2.6 and ≤3.2, and safety and immunogenicity. Results Among the 718 patients enrolled, 296 were randomized at week 24 to receive TCZ monotherapy (n = 147) or TCZ plus MTX (n = 147). The mean changes in the DAS 28‐ ESR from week 24 to week 40 were 0.46 and 0.14 in the TCZ monotherapy arm and the TCZ plus MTX arm, respectively (weighted difference between the groups, 0.318 [95% confidence interval 0.045, 0.592]); discontinuing MTX in TCZ responders was noninferior to continuing MTX . Safety events were broadly similar between the randomized treatment groups; the most common serious adverse event was infection, which occurred in 2.1% of patients in the TCZ monotherapy group and 2.2% of patients receiving TCZ plus MTX . Conclusion Patients with RA receiving TCZ plus MTX who achieve low disease activity can discontinue MTX without significant worsening of disease activity during the 16 weeks following MTX discontinuation.
Ticagrelor vs Clopidogrel After Fibrinolytic Therapy in Patients With ST-Elevation Myocardial Infarction
Authors: Otavio Berwanger, Jose C. Nicolau, Antonio C. Carvalho, Lixin Jiang, Shaun G. Goodman, Stephen J. Nicholls, Alexander Parkhomenko, Oleg Averkov, Carlos Tajer, Germán Malaga, Jose F. K. Saraiva, Francisco A. Fonseca, Fábio A. De Luca, Helio P. Guimaraes, Pedro G. M. de Barros e Silva, Lucas P. Damiani, Denise M. Paisani, Camila M. R. Lasagno, Carolina T. Candido, Nanci Valeis, Diogo D. F. Moia, Leopoldo S. Piegas, Christopher B. Granger, Harvey D. White, Renato D. Lopes
Journal: JAMA Cardiology (2018)

The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain.
P104 Synovial fibroblast relationship status: it’s complicated
Authors: RA Byrne, I Olmos Calvo, F Kartnig, A Platzer, V Zheden, L Lovicar, J Holinka, G Steiner, P Ertl, JS Smolen, H-P Kiener
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> The synovium is primarily built by fibroblast-like-synoviocytes (FLS). In the healthy synovium FLS form a complex tissue network via long-distance intercellular connexions (nanotubes). Using a 3D synovial micromass culture system, our previous research demonstrated that FLS exchange cytoplasmic cargo, i.e. organelles like mitochondria, via transfer through direct cell-to-cell connexions. The adaptive synovial tissue response to inflammation (i.e. to TNFa) likely depends upon the concerted communication between FLS. <h3>Objectives</h3> To determine how the cellular organisation of the synovial tissue affects intercellular cargo exchange and how it changes under inflammatory conditions. <h3>Methods</h3> Human FLS were isolated from joint tissues after synovectomies; passaged FLS were used to generate 3D micromass cultures using Matrigel (BD). For ultrastructural 3D reconstruction ultrathin sections of fixed micromasses were cut with an ATUMtom for FE-SEM scanning, followed by alignment and reconstruction of individual cells with Fiji TrackEM. To compare unstimulated and TNF-stimulated micromass cultures, cells were dyed with Cell- and Mitotracker dyes (TF). Using confocal microscopy, micromass cultures were analysed for cellular organisation within the 3D sphere, cell volume of individual cells, cell-to-cell interconnectivity and cargo transfer between cells. Analyses of the 3D confocal imaging data were done in Bitplane Imaris. <h3>Results</h3> SEM 3D reconstruction of synovial micromass tissue revealed that FLS are compartmentalised, and thus, much larger and extended than expected. Thin membrane tubes not only connect different cells but also compartments of the same cell. Additionally, one nanotube may provide a link to several other cells and these connexions are in general separated by membranes. Treatment of micromasses with TNFa resulted in cellular condensation, reduced cell volume as well as diminished cellular connectivitiy when compared to unstimulated micromasses. In particular, the abundance of interconnecting nanotubes was significantly attenuated. The mitochondrial transfer rate increased as FLS clustered upon TNFa stimulation. <h3>Conclusions</h3> TNFa directs FLS cellular re-organisation that is associated with increased intercellular transfer of mitochondria. These studies may provide insight into the concerted cooperation of FLS that is likely critical for the adaptive synovial response to inflammation. <h3>Disclosure of interest</h3> None declared
What's on the web?
Authors: Stephen J Southern
Journal: BMJ (2005)

The NHS website www.informatics.nhs.uk with its NHS Information homepage is a useful starter site for people wanting to find out more about UK health informatics and forthcoming events. It has links to the National Electronic Library for Health, the Informatics Learning Network, and the NHS Information Authority.

Affiliated to the University of Iowa, Virtual Hospital—a digital library of health information (www.vh.org/) is an American website providing information for patients, doctors, medical students, and health reporters. Patients can search for their …
INFLUENCE OF INSTITUTIONAL VOLUME ON SURGICAL QUALITY IN SEPTAL MYECTOMY FOR OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY
Authors: Antonio Polanco, Jeremy J. Song, Yuting P. Chiang, Sarah N. Yu, Jonathan Ginns, Yuichi Shimada, Koki Nakanishi, Shepard Weiner, Hiroo Takayama
Journal: Journal of the American College of Cardiology (2018)
The Role Of Volunteers In Quality Palliative Care Delivery For Terminal Cancer Patient
Authors: Aditya Manna
Journal: Neuro-Oncology (2018)

Here in India almost 75% of cancer patient die a sad death of neglect due to lack of awareness about palliative care and low economic level. Surveys in India show that two third of cancer patient do not get proper care during the terminal phase of their life. Palliative care through volunteers can make a significant difference in this respect. Pain, fatigue are the main symptoms effecting these patients. In most patients pain and other symptoms control were grossly inadequate due to lack of properly trained manpower in the rural India. However regular homecare visits by a group of social workers were of immense help in the last few months of life. NGO team was well guided by a palliative care specialist. Feedback from patients and their relatives regarding the palliative care they receive from nursing home and from volunteers and compare the two. Also feedback from volunteers regarding their positive and negative experience while delivering palliative care service. Then evaluate the data to compare and improve the quality of service. We carried out two studies. One study was undertaken in nursing home palliative care and another was in home setting by volunteers. Both studies were in adult palliative care services. 496 cases were studied to enquire about their experience in both home based care and nursing home care. Both the studies fulfilled our quality appraisal criteria. One found that those families and patients who received home visits from volunteers were significantly more satisfied. The study highlighted the value of the role of volunteers in better satisfaction of patients and their families. Further research is needed to evaluate the role of volunteers in palliative care and how it can be delivered appropriately and effectively. We also wish to compare our findings with similar studies elsewhere.
Diagnosis of hepatocellular carcinoma with MRI
Authors: Martin H Maurer
Journal: Gut (2018)

In most cases, hepatocellular carcinoma (HCC) is associated with a known underlying risk factor like chronic viral hepatitis type B and C or alcoholic cirrhosis.1 Patients with chronic liver disease that are at risk for HCC should undergo surveillance ultrasound examinations every 6 months and dynamic cross-sectional imaging like CT and MRI if a detected hepatic nodule exceeds 1 cm in size.2 The established radiological hallmarks for diagnosing HCC non-invasively by imaging—strong contrast uptake in the arterial phase in conjunction with washout in the venous or later phases of dynamic contrast-enhanced studies—as proposed in practice guidelines of different specialised societies (eg, American Association for the Study of the Liver (AASLD) and European Association for the Study of the Liver (EASL) have not been changed for many years.3

Although these imaging features have proven to be very robust with specificities close to 100% even in detecting HCC lesions as small as 1–2 cm in size, their sensitivities continue to be unsatisfactorily low at around 70%.2 4 In this context, comparison of the two cross-sectional imaging modalities MRI and multidetector CT has shown MRI to have a better diagnostic accuracy than CT for detecting HCC.5 An extensive meta-analysis comparing the two imaging modalities on a per-lesion basis showed the sensitivity of MRI for detecting …
Improved systemic metabolism and adipocyte biology in miR-150 knockout mice
Authors: Minsung Kang, Xiaobing Liu, Yuchang Fu, W. Timothy Garvey
Journal: Metabolism (2018)

Short non-coding micro-RNAs (miRNAs) are post-transcriptional factors that directly regulate protein expression by degrading or inhibiting target mRNAs; however, the role of miRNAs in obesity and cardiometabolic disease remains unclarified. Based on our earlier study demonstrating that miR-150 influences lipid metabolism, we have studied effects of miR-150 on systemic metabolism and adipocyte biology.Metabolic phenotypes including body weight, food intake, body composition, glucose tolerance and insulin sensitivity were assessed in WT and global miR-150 KO male mice fed a high-fat diet. Molecular changes in epididymal adipose tissue were evaluated through qRT-PCR and Western blotting.miR-150 KO mice displayed lower body weight characterized by a reduction in % fat mass while % lean mass was increased. Lower body weight was associated with reduced food consumption and an increase in circulating leptin concentrations, as well as enhanced insulin sensitivity and glucose tolerance compared with WT mice. Absence of miR-150 resulted in increased mTOR expression known to participate in increased leptin production leading to reduction of food intake. Expression of PGC-1α, another target gene of miR-150, was also increased together with upregulation of PPARα and glycerol kinase in adipose tissue as well as other genes participating in triglyceride degradation and lipid oxidation.miR-150 KO mice showed metabolic benefits accompanied by reduced body weight, decreased energy intake, and enhanced lipid metabolism. miR-150 may represent both a biomarker and novel therapeutic target regarding obesity and insulin resistance.
Poor workforce planning is biggest internal threat to future of NHS, parliamentary inquiry finds
Authors: Abi Rimmer
Journal: BMJ (2017)

Poor workforce planning is the biggest internal threat to the sustainability of the NHS, a major parliamentary inquiry has concluded.

The report, from the House of Lords committee on the long term sustainability of the NHS, highlighted concern at the absence of any comprehensive, national, long term NHS workforce strategy.1 “Much of the work being carried out to reshape the workforce is fragmented across different bodies with little strategic direction from the Department of Health,” it said.

The inquiry report, published on Wednesday 5 April, said that Health Education England (HEE) was “unable to deliver” and recommended that the organisation should be “transformed into a new single, integrated strategic workforce planning body for health and social care.”

“This will enable it to produce and implement a joined-up place-based national strategy …
Phase II study of epacadostat with pembrolizumab in metastatic or unresectable gastroesophageal junction and gastric adenocarcinoma requiring paired biopsies.
Authors: Adel Kardosh, Diane Tseng, Bita Sahaf, Ativ Zomet, Julia Krupa, George A. Fisher, David S Wang, Crystal Mackall, Pamela L. Kunz
Journal: Journal of Clinical Oncology (2018)

TPS191 Background: Gastroesophageal junction (GEJ) and gastric adenocarcinomas constitute a major health problem worldwide. Gastric cancer is the fourth most prevalent malignancy and the second leading cause of cancer death worldwide. Furthermore, the incidence of adenocarcinoma of the esophagus, GEJ and gastric cardia has risen faster than any other malignancy in the last 25 years in the United States and other Western countries. Cytotoxic chemotherapy remains the standard treatment, with progression free survival (PFS) for advanced disease of 4 to 6 months and median overall survival (OS) of 7 to 10 months. Pembrolizumab, a PD-1 inhibitor, was recently approved for advanced gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-1, on the basis of a response rate of 13% seen in KEYNOTE 059 (NCT02335411). Combination immunotherapies are hypothesized to build on this response. Methods: This is a single arm, phase II clinical trial of epacadostat, a novel inhibitor of the enzyme indoleamine 2,3 dioxygenase-1 (IDO-1), in combination with pembrolizumab, in metastatic or unresectable gastroesophageal junction or gastric adenocarcinoma. A 6-month PFS of 20% with single agent pembrolizumab is the basis for the null hypothesis. We will enroll 30 patients over 18 months and follow patients for at least 6 months. This design has 80% power to reject a 20% PFS rate, if the true PFS is 39%. Eligible patients must have: adenocarcinoma of the distal esophagus, gastroesophageal junction or stomach; progression on at least one line of prior therapy for metastatic disease, and for HER2+ disease should have received prior trastuzumab; ECOG performance status 0 or 1; willing to undergo two newly-obtained biopsies - before and on-treatment, provided the procedure is not deemed high-risk and is clinically feasible. Notably, PDL-1 expression is not required. The primary endpoint is 6-month PFS, with secondary endpoints of response rate (RR), OS, and the safety and tolerability of the combination. Furthermore, comprehensive immune profiling from patient blood and tumor tissue will be performed. The study opened to accrual in September 2017 (NCT03196232). Clinical trial information: NCT03196232.
Changeable prognosis and associated prognostic factors for conditional survival estimates in metastatic renal cell carcinoma patients receiving the first-line targeted therapy.
Authors: Minyong Kang, Hyun Hwan Sung, Hwang Gyun Jeon, Byong Chang Jeong, Se Hoon Park, Seong Soo Jeon, Hyun Moo Lee, Han Yong Choi, Seong Il Seo
Journal: Journal of Clinical Oncology (2018)

587 Background: Conditional survival (CS) indicates the probability that patient would survive additional periods, given that the patients has previous survivorship after diagnosis or initial treatment. Here, we aim to evaluate the CS probabilities in mRCC patients who underwent targeted therapy with tyrosine kinase inhibitors (TKI) and to identify the significant prognostic factors of the CS over time. Methods: A total of 1,498 mRCC patients receiving 1 st line TKI was finally analyzed from Korean multicenter database of mRCC. Kaplan-Meier survival estimates was used to calculate overall and cancer-specific CS rates by using following formula: CS(α│β) = S(α+β)/S(β), where CS(α│β) indicates the likelihood of additional α years survivorship in the person who has already survived for β years after initial diagnosis or treatment, and S(χ) is the actual survival rate. The Cox regression analysis was used to determine the predictors of CS depended on clinicopathological features. Results: We observed that 1, 2, 3, 4, and 5-year conditional cancer-specific survival (CSS) gradually increased as patients who have all additional survivorships after initial treatment, compared to those with baseline survival estimation. Also, 1, 2, 3, 4, and 5-year conditional OS rates also increased after additional 1, 2, 3, 4, and 5 year survivorships following first-line TKI treatment. Furthermore, we found that key predictive factors of OS and CSS were changed over time in multivariate analysis. While several variables, such as BMI, histologic subtypes, pT stage, were identified as prognosticators of CSS at baseline, they were not remained as independent predictors after 1 yr survivorship. Conversely, only previous metastatectomy was determined as a key prognostic factor for conditional OS over time until 4 yr survivorship after initial TKI treatment. Conclusions: Our study offers valuable information for practical survival estimation and relevant predictive factors for patients with mRCC receiving targeted therapy.
Annals Graphic Medicine - Memento Mori
Authors: Kevin Dueck
Journal: Annals of Internal Medicine (2018)

Web Exclusives6 February 2018Annals Graphic Medicine - Memento MoriFREEKevin Dueck, MD, MScKevin Dueck, MD, MScFrom McMaster University, Hamilton, Ontario, Canada. (K.D.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G17-0014 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Adam KortowskiSolo internist9 February 2018 Invisible truth How true and deep a thought Author, Article, and Disclosure InformationAffiliations: From McMaster University, Hamilton, Ontario, Canada. (K.D.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G17-0014.Author/Illustrator Information: Dr. Kevin Dueck is a family medicine resident at McMaster University in Canada. His work includes poetry, short stories, and graphic medicine addressing medical culture, education, and stories of illness and health. He is the author of https://abootmedicine.wordpress.com/ and is active on Twitter: @AbootMedicine.Author Contributions: Conception and design: K. Dueck.Drafting of the article: K. Dueck.Critical revision for important intellectual content: K. Dueck.Final approval of the article: K. Dueck. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 6 February 2018Volume 168, Issue 3Page: W7-W8KeywordsConflicts of interestDisclosureHealth careMedical education ePublished: 6 February 2018 Issue Published: 6 February 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Nuclease-free Adeno-Associated Virus-Mediated Il2rg Gene Editing in X-SCID Mice
Authors: Takafumi Hiramoto, Li B. Li, Sarah E. Funk, Roli K. Hirata, David W. Russell
Journal: Molecular Therapy (2018)

X-linked severe combined immunodeficiency (X-SCID) has been successfully treated by hematopoietic stem cell (HSC) transduction with retroviral vectors expressing the interleukin-2 receptor subunit gamma gene (IL2RG), but several patients developed malignancies due to vector integration near cellular oncogenes. This adverse side effect could in principle be avoided by accurate IL2RG gene editing with a vector that does not contain a functional promoter or IL2RG gene. Here, we show that adeno-associated virus (AAV) gene editing vectors can insert a partial Il2rg cDNA at the endogenous Il2rg locus in X-SCID murine bone marrow cells and that these ex vivo-edited cells repopulate transplant recipients and produce CD4+ and CD8+ T cells. Circulating, edited lymphocytes increased over time and appeared in secondary transplant recipients, demonstrating successful editing in long-term repopulating cells. Random vector integration events were nearly undetectable, and malignant transformation of the transplanted cells was not observed. Similar editing frequencies were observed in human hematopoietic cells. Our results demonstrate that therapeutically relevant HSC gene editing can be achieved by AAV vectors in the absence of site-specific nucleases and suggest that this may be a safe and effective therapy for hematopoietic diseases where in vivo selection can increase edited cell numbers.
WHERE DO WE GO FROM HERE? BEYOND THE NEJM MAGNASAFE TRIAL: A FOCUS BEYOND A MYOPIC CMR ‘SAFETY-FIRST’ NOTION
Authors: Robert W.W. Biederman, Loretta Gevenosky, Huma Samar, Ronald Williams, Richard Lombardi, Moneal Shah, Christopher Bonnet, Mark Doyle
Journal: Journal of the American College of Cardiology (2018)