tbuckley/cabot-search huggingface dataset:
Abstract 19748: Mature Enterocytes Lose Their Ability to Secrete Pcsk9
Authors: François Moreau, Damien Garcon, Claire Blanchard, Audrey Ayer, Xavier Prieur, Michel Neunlist, Annik Prat, Nabil Seidah, Bertrand Cariou, Cedric Le May
Journal: Circulation (2016)

Introduction:  Proprotein Convertase Subtilisin Kexin of type 9 (PCSK9) promotes LDL receptor lysosomal degradation and is a key regulator of cholesterol metabolism. Beyond the liver, the small intestine is the second organ where PCSK9 is highly expressed, but its ability to secrete PCSK9 remains a matter of debate.   Hypothesis:  Our study aims to determine whether the small intestine and enterocytes are able to secrete PCSK9.   Methods:  In vivo , intestinal PCSK9 secretion was assessed by ELISA and western blot in wild-type (WT) and liver-specific PCSK9-deficient mice (L-PCSK9 KO).  Ex vivo , local PCSK9 secretion was evaluated from human and murine intestinal explants mounted in Ussing chambers.  In vitro , PCSK9 secretion was measured from human intestinal Caco-2 cells along their differentiation.   Results:  In vivo , PCSK9 concentrations were similar in tail and portal blood and mesenteric lymph from WT mice and undetectable in the portal blood from L-PCSK9 KO mice. Similarly, no local human and murine PCSK9 secretion was measured in Ussing Chambers. Interestingly, PCSK9 secretion was detected at significant level during the first 10 days of Caco-2 cells differentiation then dropped by more than 30 times to become null after 16 days. Despite no change in PCSK9 mRNA levels, intracellular PCSK9 protein content was reduced by 4 times between day 8 and 16 and was associated with a PCSK9 half-life reduction. While the cleavage and PCSK9 trafficking from ER to Golgi were not altered with differentiation, mature PCSK9 accumulated in the Golgi. 2D electrophoresis revealed that the PCSK9 isoelectric point was reduced at late stages of differentiation, suggesting a potential change in the PCSK9 phosphorylation status.   Conclusions:  We show that mature enterocyte lose their ability to secrete PCSK9. Underlying molecular mechanisms remain under investigation but involve at least a PCSK9 half-life decrease and a post-traductional modification altering the post-golgi trafficking of PCSK9.
Implementation of group visits to improve outpatient oncology advance care planning.
Authors: Sarah Lowry, Hillary Lum, Seiko Izumi, Erik K Fromme
Journal: Journal of Clinical Oncology (2017)

11 Background: Oncology patients that participate in advance care planning (ACP) and complete advance directives (AD) are more likely to receive goal-concordant end of life care. The AD documentation rate within our academically-affiliated community outpatient oncology clinic is below national and institutional averages. A group medical visit effectively facilitated ACP in a geriatric primary care setting. This quality improvement project implemented a similar ACP conversation group (ACPCG) in an outpatient oncology setting. Methods: Adult patients in a community oncology clinic were contacted and invited to participate in ACPCG by a nurse practitioner who works in the clinic. Using a facilitation guide, the 2-session intervention included sharing past ACP experiences, identifying surrogate decision makers, starting conversations, and discussing surrogate flexibility. Recruitment, retention, and patient ACP outcomes were measured. Results: Seventy-six patients were successfully contacted and seventeen signed up (22% recruitment rate). Twelve patients participated in the first session, and five attended the second session (42% retention). Recruitment was time intensive, and several patients responded that ACP was not relevant to their situation. Six participants completed an AD prior to attending the first session (50%) but only one had an AD in their medical record. Two had surrogate decision makers documented prior to the intervention (16%). Participants reported the ACPCG as helpful in making the process less overwhelming. There was no increase in AD documentation rates within the medical record four weeks after the intervention, but the rate of surrogate documentation increased to seven (58%). Conclusions: Participants had higher than average rates of AD completion prior to the intervention but had not shared the document with their providers. While the ACPCG was well received by patients, implementation faced multiple challenges. More efficient recruitment methods and strategies to facilitate better patient understanding of ACP are needed.
Lettre à la Rédaction : Epidémies de parvovirus B19
Authors: H Kelly, J Leydon
Journal: Eurosurveillance (2005)

In a recent issue of Eurosurveillance, Goncalves and colleagues reported that outbreaks of a rash illness in a kindergarten, a primary and a secondary school in the local health area of Braga in northern Portugal were due to human parvovirus B19 [1]. Although human parvovirus was suspected clinically, laboratory investigations were undertaken to exclude both measles and rubella as the cause of the outbreak, given that Portugal is approaching measles elimination. The authors noted that human parvovirus has been reported as a cause of rash illness, potentially as a differential diagnosis for measles and rubella, in developing and developed countries [1].
Effect of Oral Capsule– vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent <i>Clostridium difficile</i> Infection
Authors: Dina Kao, Brandi Roach, Marisela Silva, Paul Beck, Kevin Rioux, Gilaad G. Kaplan, Hsiu-Ju Chang, Stephanie Coward, Karen J. Goodman, Huiping Xu, Karen Madsen, Andrew Mason, Gane Ka-Shu Wong, Juan Jovel, Jordan Patterson, Thomas Louie
Journal: JAMA (2017)

<h3>Importance</h3> Fecal microbiota transplantation (FMT) is effective in preventing recurrent<i>Clostridium difficile</i>infection (RCDI). However, it is not known whether clinical efficacy differs by route of delivery. <h3>Objective</h3> To determine whether FMT by oral capsule is noninferior to colonoscopy delivery in efficacy. <h3>Design, Setting, and Participants</h3> Noninferiority, unblinded, randomized trial conducted in 3 academic centers in Alberta, Canada. A total of 116 adult patients with RCDI were enrolled between October 2014 and September 2016, with follow-up to December 2016. The noninferiority margin was 15%. <h3>Interventions</h3> Participants were randomly assigned to FMT by capsule or by colonoscopy at a 1:1 ratio. <h3>Main Outcomes and Measures</h3> The primary outcome was the proportion of patients without RCDI 12 weeks after FMT. Secondary outcomes included (1) serious and minor adverse events, (2) changes in quality of life by the 36-Item Short Form Survey on a scale of 0 (worst possible quality of life) to 100 (best quality of life), and (3) patient perception on a scale of 1 (not at all unpleasant) to 10 (extremely unpleasant) and satisfaction on a scale of 1 (best) to 10 (worst). <h3>Results</h3> Among 116 patients randomized (mean [SD] age, 58 [19] years; 79 women [68%]), 105 (91%) completed the trial, with 57 patients randomized to the capsule group and 59 to the colonoscopy group. In per-protocol analysis, prevention of RCDI after a single treatment was achieved in 96.2% in both the capsule group (51/53) and the colonoscopy group (50/52) (difference, 0%; 1-sided 95% CI, −6.1% to infinity;<i>P</i> &lt; .001), meeting the criterion for noninferiority. One patient in each group died of underlying cardiopulmonary illness unrelated to FMT. Rates of minor adverse events were 5.4% for the capsule group vs 12.5% for the colonoscopy group. There was no significant between-group difference in improvement in quality of life. A significantly greater proportion of participants receiving capsules rated their experience as "not at all unpleasant" (66% vs 44%; difference, 22% [95% CI, 3%-40%];<i>P</i> = .01). <h3>Conclusions and Relevance</h3> Among adults with RCDI, FMT via oral capsules was not inferior to delivery by colonoscopy for preventing recurrent infection over 12 weeks. Treatment with oral capsules may be an effective approach to treating RCDI. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT02254811
Detection of adamantane-sensitive influenza A(H3N2) viruses in Australia, 2017: a cause for hope?
Authors: Aeron Hurt, Naomi Komadina, Yi-Mo Deng, Matthew Kaye, Sheena Sullivan, Kanta Subbarao, Ian Barr
Journal: Eurosurveillance (2017)

For over a decade virtually all A(H3N2) influenza viruses have been resistant to the adamantane class of antivirals. However, during the 2017 influenza season in Australia, 15/461 (3.3%) adamantane-sensitive A(H3N2) viruses encoding serine at residue 31 of the M2 protein were detected, more than the total number identified globally during the last 6 years. A return to wide circulation of adamantane-sensitive A(H3N2) viruses would revive the option of using these drugs for treatment and prophylaxis.
Letter by Braillon Regarding Article, “Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting”
Authors: Alain Braillon
Journal: Circulation (2017)

Natarajan et al 1 must be commended for providing the number needed to treat when analyzing the prevention of 1 coronary heart disease event according to genetic risk.However, they did not express it with a time frame.According to Table 3 in their article, 1 the number needed to treat during 1 year to avoid 1 coronary heart disease event ranged from 207 to 480 among the 3 studies (WOSCOPS [West of Scotland Coronary Artery Revascularisation in Diabetes and Coronary Prevention Study], CARDIA [Coronary Artery Risk Development inYoung Adults], and BioImage).Moreover, in the real-life setting, the number may be twice as high because of poor compliance.This figure must also be balanced with a 9% rate of statin-related adverse events. 2 In the "Clinical Perspective," 1 box, the response to the question, "What are the clinical implications?"was, "Stratifying by genetic risk may identify a subset of adults…and derive the greatest benefit from statin therapy."This response was scientifically correct but may seem out of the scope of clinical implications.First, the majority of vascular events can be prevented by avoiding smoking, participating in regular physical activity, maintaining a normal body mass index, and eating a healthy diet, as can the majority of premature deaths, including those from cancers. 3 Primary prevention must be a comprehensive framework.Second, considering the plateauing high prevalence of smoking, inactivity, obesity, and poor nutrition after coronary heart disease events in serial surveys from the United States and Europe, 4,5 looking for primary prevention with statins for healthy people with a genetic risk may seem a desperate rush ahead.
P2.02-017 A Clinical Outcome of Resected Small-Sized Non-Small Cell Lung Cancer 1 cm or Less in Diameter with N2 Lymph Node Metastasis
Authors: Yasufumi Kato, Hideyuki Furumoto, Shunsuke Shigefuku, Junichi Maeda, Koichi Yoshida, Masaru Hagiwara, Masatoshi Kakihana, Naohiro Kajiwara, Tatsuo Ohira, Kinya Furukawa, Norihiko Ikeda
Journal: Journal of Thoracic Oncology (2017)
Abstract 16574: Heart Failure Biomarkers (NT-proBNP, Gal-3, sST2) Correlate With Right Ventricular Systolic Pressure and Provide Insight to Poor CRT Response: A BIOCRT Substudy
Authors: Roderick C Deaño, Jackie Szymonifka, Qing Zhou, Jigar H Contractor, Zachary Lavender, James L Januzzi, Jagmeet P Singh, Quynh A Truong
Journal: Circulation (2015)

Objective: Patients with heart failure (HF) and pulmonary hypertension (PH) have worse outcomes after cardiac resynchronization therapy (CRT). The relationship of circulating HF biomarkers and right ventricular systolic pressure (RVSP) may provide insight to the mechanism between PH and poor CRT response. Methods: In 90 patients (age 65 ± 13, 78% male, EF 26 ± 8%, RVSP 44 ± 12 mmHg) undergoing CRT, we measured baseline RVSP by echocardiography and obtained peripheral blood samples drawn at the time of device implantation. We measured levels of established and emerging HF biomarkers (Table 1). CRT non-response was defined as no improvement of adjudicated HF Clinical Composite Score at 6 months. Major adverse cardiac event (MACE) was defined as composite endpoint of death, cardiac transplant, left ventricular assist device, and HF hospitalization within 2 years. Results: There were 34% CRT non-responders and 27% had MACE. Per 1 unit increase in log-transformed RVSP, there was an 11-fold increase risk of having CRT non-response (odd ratio [OR] 11.0, p=0.01) and over 5-fold increase of developing 2-year MACE (hazard ratio [HR] 5.8, p=0.02). When comparing patients with severe PH (RVSP&gt;60 mmHg) to those without PH (RVSP &lt; 35 mmHg), there was an 8-fold increase in CRT nonresponse (OR 8.4, p=0.03) but no difference in MACE (p=NS). RVSP was correlated with increased biomarker levels of myocardial stretch and fibrosis, but not myocardial necrosis (Table 1). Conclusions: Higher RVSP is associated with greater rates of CRT non-response and adverse clinical outcomes. The mechanistic association between severe PH and CRT nonresponse may be explained by the biomarker profile reflective of myocardial wall stretch and fibrosis.
Genotoxicity of alpha-acetoxy-N-nitrosodiethanolamine, 3-nitrosooxazolidinones and methyl-3-nitrosooxazolidinones in human blood and V79-cells
Authors: Matthias Baum, Michelle Hoffmann, Silke Thielen, Richard N. Loeppky, Gerhard Eisenbrand
Journal: Cancer Research (2006)

1082   NDELA is a potent carcinogen to which humans are exposed. Significant concentrations have been found in metalworking fluids, cosmetics, and other personal care items. We have compared the genotoxic activities of alpha-acetoxy-N-nitroso-diethanolamine, a progenitor of alpha-activated NDELA, and N-nitrosooxazolidinones, three of which are derived from the nitrosation of amino acids in the presence of dietary aldehydes, using an HPRT gene mutation assay in V79 mammalian cells, and single cell gel electrophoresis (comet assay) in lymphocytes after exposure of human whole blood. DNA-damage was expressed as tail intensity (%). After hydrolysis these N-nitroso compounds generate electrophilic, highly reactive diazonium ions that are known or expected to react with nucleophilic centers in DNA. The comet assay was modified by additional treatment of lymphocyte-DNA with the DNA repair enzyme formamido-pyrimidine-DNA-glycosylase (FPG). FPG recognizes apurinic and apyrimidinic sites (AP sites) as well as ring-opened purines (formamido-pyrimidines) and oxidized purines, rendering these lesions detectable by inducing additional DNA-strandbreaks. The putative hydroxyethylating agents alpha-AcO-NDELA and 3-nitroso-oxazolidine-2-one, which produce the same diazonium ion, induced DNA-strand breaks in the comet assay and mutations in HPRT-test concentration-dependant at 10-100 μM. In contrast, the amino acid derived putative carboxyalkylating compounds 3-nitrosooxazolidin-5-one and 2-methyl-3-nitrosooxazolidin-5-one are only marginally active in the comet assay without FPG-treatment. After FPG-treatment, the response in the comet assay was significantly enhanced for 3-nitrosooxazolidin-5-one (0.1 μM) while it remains largely unchanged for 2-methyl-3-nitrosooxazolidin-5-one. Additionally in V79 cells, 3-nitroso-oxazolidin-5-one dose-dependently induced HPRT mutants becoming significant at 10 μM. In the comet assay with and without FPG-treatment, 4-methyl-3-nitroso-oxazolidin-5-one was only slightly active at 100 μM and higher concentrations. In summary, whereas the hydroxyethylating agents were potently genotoxic and mutagenic, the carboxyalkylating agents were significantly less potent. 3-Nitrosooxazolidin-5-one was not unique within the latter group, since FPG-treatment led to strongly enhanced and concentration-dependant response in the comet assay.
Bilirubin is predictive of transplant-free survival even within the normal range in primary biliary cholangitis patients
Authors: Carla F Murillo Perez, Aliya Gulamhusein, Henk R van Buuren, Willem J Lammers, Jorn C Goet, Cyriel Y Ponsioen, Marco Carbone, Andrew Mason, Christophe Corpechot, Marlyn J Mayo, Pietro Invernizzi, Pier Maria Battezzati, Annarosa Floreani, Albert Pares, Frederik Nevens, Kris Kowdley, Tony Bruns, George N Dalekos, Kalliopi Zachou, Douglas Thorburn, Gideon M Hirschfield, Nicholas F LaRusso, Keith D Lindor, Raoul Poupon, Palak J Trivedi, Xavier Verhelst, Harry L Janssen, Bettina E Hansen
Journal: Hepatology (2017)
mRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma
Authors: Yuhua Wang, Lu Zhang, Zhenghong Xu, Lei Miao, Leaf Huang
Journal: Molecular Therapy (2017)

We reported a preclinical cancer vaccine that simultaneously introduced an mRNA antigen and an immune checkpoint blocking siRNA into the antigen-presenting cells. This was achieved by formulating both nucleic acid-based immunotherapeutics into a lipid-coated calcium phosphate (LCP) nanoparticle (NP) as a carrier to address the delivery challenge. The PEGylated lipid NPs were functionalized with mannose as the targeting ligand to facilitate the preferential uptake by the dendritic cells (DCs) in the lymph nodes after subcutaneous administration. The calcium phosphate core allowed acid-mediated dissolution in the endo-lysosomal compartment, which prompted rapid release of cargoes after cellular internalization of NP. LCP mRNA vaccine encoding TRP2 elicited a robust antigen-specific cytotoxic T cell response and a humoral immune response in a C57BL/6 mouse model of B16F10 melanoma. The immune responses efficaciously inhibited the melanoma growth. Moreover, co-delivery of PD-L1 siRNA and mRNA vaccine resulted in the downregulation of PD-L1 in the DCs that presented tumor antigens, significantly prompting T cell activation and proliferation. The enhanced T cell response had a profound inhibitory effect on tumor growth and metastasis. Generally, the work provided a paradigm for the development of an mRNA vaccine carrier to boost the anticancer immune response. We reported a preclinical cancer vaccine that simultaneously introduced an mRNA antigen and an immune checkpoint blocking siRNA into the antigen-presenting cells. This was achieved by formulating both nucleic acid-based immunotherapeutics into a lipid-coated calcium phosphate (LCP) nanoparticle (NP) as a carrier to address the delivery challenge. The PEGylated lipid NPs were functionalized with mannose as the targeting ligand to facilitate the preferential uptake by the dendritic cells (DCs) in the lymph nodes after subcutaneous administration. The calcium phosphate core allowed acid-mediated dissolution in the endo-lysosomal compartment, which prompted rapid release of cargoes after cellular internalization of NP. LCP mRNA vaccine encoding TRP2 elicited a robust antigen-specific cytotoxic T cell response and a humoral immune response in a C57BL/6 mouse model of B16F10 melanoma. The immune responses efficaciously inhibited the melanoma growth. Moreover, co-delivery of PD-L1 siRNA and mRNA vaccine resulted in the downregulation of PD-L1 in the DCs that presented tumor antigens, significantly prompting T cell activation and proliferation. The enhanced T cell response had a profound inhibitory effect on tumor growth and metastasis. Generally, the work provided a paradigm for the development of an mRNA vaccine carrier to boost the anticancer immune response.
Cluster analysis of novel isometric strength measures produces a valid and evidence-based classification structure for wheelchair track racing
Authors: Mark J Connick, Emma Beckman, Yves Vanlandewijck, Laurie A Malone, Sven Blomqvist, Sean M Tweedy
Journal: British Journal of Sports Medicine (2017)

The Para athletics wheelchair-racing classification system employs best practice to ensure that classes comprise athletes whose impairments cause a comparable degree of activity limitation. However, decision-making is largely subjective and scientific evidence which reduces this subjectivity is required.To evaluate whether isometric strength tests were valid for the purposes of classifying wheelchair racers and whether cluster analysis of the strength measures produced a valid classification structure.Thirty-two international level, male wheelchair racers from classes T51-54 completed six isometric strength tests evaluating elbow extensors, shoulder flexors, trunk flexors and forearm pronators and two wheelchair performance tests-Top-Speed (0-15 m) and Top-Speed (absolute). Strength tests significantly correlated with wheelchair performance were included in a cluster analysis and the validity of the resulting clusters was assessed.All six strength tests correlated with performance (r=0.54-0.88). Cluster analysis yielded four clusters with reasonable overall structure (mean silhouette coefficient=0.58) and large intercluster strength differences. Six athletes (19%) were allocated to clusters that did not align with their current class. While the mean wheelchair racing performance of the resulting clusters was unequivocally hierarchical, the mean performance of current classes was not, with no difference between current classes T53 and T54.Cluster analysis of isometric strength tests produced classes comprising athletes who experienced a similar degree of activity limitation. The strength tests reported can provide the basis for a new, more transparent, less subjective wheelchair racing classification system, pending replication of these findings in a larger, representative sample. This paper also provides guidance for development of evidence-based systems in other Para sports.
Impact of direct-acting antiviral therapy on the need for liver transplantation related to hepatitis C in Germany
Authors: Kerstin Herzer, Thomas Berg, Frank Tacke, Peter R. Galle, Ulrich Spengler, Karl Heinz Weiss, Martina R. Sterneck, Tim Zimmermann, Hauke Heinzow, Sven Pischke, Adam Herber, Martin W. Welker, Arianeb Mehrabi, Daniela C. Kroy, Christian P. Strassburg, Yvonne Serfert, Heiner Wedemeyer, Michael P. Manns, Hartmut H. Schmidt, Julius Plewe, Stefan Zeuzem, Dennis Eurich, Guido Gerken, Thomas von Hahn
Journal: Hepatology (2017)
Clinical outcome and prognostic factors for patients treated in a phase I study at the National University Cancer Institute, Singapore (NCIS)
Authors: C.E. Chee, R. Soo, B-C Goh, W.P. Yong, S.C. Lee, D.S. Tan, A. Wong, W.J. Chng, V. Heong, B.C. Tai
Journal: Annals of Oncology (2017)
P3.02a-008 EML4-ALK in Plasma Exosomes from a Cohort of NSCLC Patients
Authors: Kay Brinkmann, Daniel Enderle, Claudia Flinspach, Romy Mueller, James Hurley, Elena Castellanos-Rizaldos, Graham Brock, Johan Skog, Mikkel Noerholm
Journal: Journal of Thoracic Oncology (2017)
P2.03a-056 Phase II Trial of Weekly Nab-Paclitaxel for Previously Treated Advanced Non–Small Cell Lung Cancer: KTOSG Trial 1301
Authors: Shinya Sakata, Sho Saeki, Isamu Okamoto, Kohei Otsubo, Kazutoshi Komiya, Ryotaro Morinaga, Yasuto Yoneshima, Yuichiro Koga, Aimi Enokizu, Hiroto Kishi, Susumu Hirosako, Emi Yamaguchi, Naoko Aragane, Shinji Fujii, Taishi Harada, Eiji Iwama, Yoichi Nakanishi, Hirotsugu Kohrogi
Journal: Journal of Thoracic Oncology (2017)