tbuckley/cabot-search huggingface dataset:
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Authors: Annabel Blasi, Virginia Hernandez‐Gea, Juan Carlos Reverter, Juan Carlos Garcia‐Pagán
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. We would like to thank the interest of Qi et al. in our study. They argue that the quality of anticoagulation therapy (AT) was lacking in the study and that this may impact the outcome of bleeding. Prothrombin time/international normalized ratio (PT/INR) is an independent prognostic indicator of survival in patients with cirrhosis, but it is not useful assessing the risk of bleeding. The mechanisms of PT/INR changes are different when caused by vitamin K antagonists or by liver disease. Vitamin K antagonists inhibit the coagulation factors II, VII, IX, and X, whereas liver disease causes a decreased production of all coagulation factors. At any given INR, patients with cirrhosis have different coagulation factor levels than anticoagulated patients. Fibrinogen or antithrombin, among others, are reduced in cirrhosis, but not affected by vitamin K antagonists. Additionally, liver disease increases von Willebrand factor (VWF) levels and decreased levels of ADAMTS 13, of which net effect on coagulation is unclear and is not reflected by INR.1 INR was designed to standardize PT during oral AT. However, in liver cirrhosis, PT standardization using the INR is inadequate, because the thromboplastin reagents differ in their sensitivities between warfarin‐treated and liver cirrhosis patients, and the thromboplastin international sensitivity index (ISI) used in the INR calculation does not reflect these differences because it is only established for patients treated with anti‐vitamin K drugs. Additionally, because INR/PT is prolonged in patients with cirrhosis, it is unclear which INR range is safe. A proof of that is the lack of guidelines about the INR levels that should be achieved under treatment. A target INR of 2‐3 is advocated, but this recommendation is based on empirical rules.1 In the studies on vitamin K antagonists, such as the SPORTIF study,3 the time in INR therapeutic range reflected the quality of anticoagulation. However, these studies excluded patients with liver disease, and given the nature of the coagulopathy of liver disease, there is no rationale to presume that INR works in a similar way than in patients without cirrhosis. Therefore, the quality of AT may impact the outcome of bleeding, but, unfortunately, the best way for its assessment remains unknown.
Adenosine Receptor Subtypes: Characterization and Therapeutic Regulation
Authors: M E Olah, G L Stiles
Journal: The Annual Review of Pharmacology and Toxicology (1995)

Adenosine receptors (ARs) are members of the G protein-coupled receptor family and mediate the multiple physiological effects of adenosine. Currently, four AR subtypes have been cloned: A1AR, A2aAR, A2bAR, and A3AR. All subtypes are distinctly distributed throughout the body and AR agonists and antagonists have potential therapeutic utility. Knowledge of AR amino acid structure has been utilized in mutagenesis studies to identify specific receptor regions that interact with distinct classes of ligands. Cloning of ARs has also permitted receptor regulatory processes such as desensitization to be studied in greater detail, in particular, the molecular mechanisms underlying this event. Cloning of the human A1AR has revealed that alternate splicing generates distinct receptor transcripts. The existence of a particular transcript in a tissue or cell apparently regulates the level of A1AR expression in the tissue. This review focuses on these aspects of AR structure and function and their therapeutic regulation.
Acute leukemia in two patients treated with high-dose melphalan and autologous marrow transplantation for malignant solid tumors.
Authors: O Hartmann, O Oberlin, J Lemerle, D Maraninchi, J A Gastaut, B Mascret, G Sebahoun, Y Carcassonne
Journal: Journal of Clinical Oncology (1984)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1984.2.12.1424 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 6392488 Acute leukemia in two patients treated with high-dose melphalan and autologous marrow transplantation for malignant solid tumors. O HartmannxO HartmannSearch for articles by this author , O OberlinxO OberlinSearch for articles by this author , J LemerlexJ LemerleSearch for articles by this author , D MaraninchixD MaraninchiSearch for articles by this author , J A GastautxJ A GastautSearch for articles by this author , B MascretxB MascretSearch for articles by this author , G SebahounxG SebahounSearch for articles by this author , Y CarcassonnexY CarcassonneSearch for articles by this author Show More https://doi.org/10.1200/JCO.1984.2.12.1424 PDF "Acute leukemia in two patients treated with high-dose melphalan and autologous marrow transplantation for malignant solid tumors.." Journal of Clinical Oncology, 2(12), pp. 1424–1425© 1984 by American Society of Clinical Oncology
Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus
Authors: Claire Jenkinson, Victoria L. Elliott, Anthony Evans, Lucy Oldfield, Rosalind E. Jenkins, Darragh P. O'Brien, Sophia Apostolidou, Aleksandra Gentry-Maharaj, Evangelia-O Fourkala, Ian J. Jacobs, Usha Menon, Trevor Cox, Fiona Campbell, Stephen P. Pereira, David A. Tuveson, B. Kevin Park, William Greenhalf, Robert Sutton, John F. Timms, John P. Neoptolemos, Eithne Costello
Journal: Clinical Cancer Research (2015)

Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with preclinical disease and at diagnosis were investigated.
Improving Survival Without Reducing Quality of Life in Small-Cell Lung Cancer Patients by Increasing the Dose-Intensity of Chemotherapy With Granulocyte Colony-Stimulating Factor Support: Results of a British Medical Research Council Multicenter Randomized Trial
Authors: Nicholas Thatcher, David J. Girling, Penelope Hopwood, Robert J. Sambrook, Wendi Qian, Richard J. Stephens
Journal: Journal of Clinical Oncology (2000)

PURPOSE: The treatment of small-cell lung cancer patients with good performance status aims to improve survival. Dose-intensification could be a way to achieve improved survival but can be limited by neutropenia and thrombocytopenia. Preliminary, nonrandomized feasibility studies showed that doxorubicin, cyclophosphamide, and etoposide (ACE) could be given every 2 (instead of the usual 3) weeks with granulocyte colony-stimulating factor (G-CSF) (lenograstim; Chugai-Rhône-Poulenc, Tokyo, Japan) support. The present multicenter randomized trial was designed to examine whether such dose-intensification improves survival while maintaining acceptable toxicity levels. PATIENTS AND METHODS: All patients were randomized to receive six cycles of ACE either every 3 weeks (control [C] group) or every 2 weeks with G-CSF (G group). The standard dose-intensity of ACE was increased by 50% in group G. RESULTS: Four hundred and three patients (G group: n = 201; C group: n = 202) were randomized. The received dose-intensity was 34% higher in the G group than in the C group. Complete response rates were 40% for the G group and 28% for the C group (P = .02), and overall rates were 78% for the G group and 79% for the C group. Survival was longer in the G group (hazard ratio = 0.80; 95% confidence interval, 0.65 to 0.99; P = .04), survival rates for the G and C groups being 47% and 39% at 12 months and 13% and 8% at 24 months, respectively. Metastasis-free survival, nonhematologic toxicity, and quality of life were similar in the two groups. In the G group, there was less neutropenia but more thrombocytopenia and more frequent blood and platelet transfusions. CONCLUSION: Increasing the dose-intensity of ACE with G-CSF support improved survival while maintaining acceptable toxicity.
Influenza Vaccination Coverage Among Pregnant Women — United States, 2016–17 Influenza Season
Authors: Helen Ding, Carla L. Black, Sarah Ball, Rebecca V. Fink, Walter W. Williams, Amy Parker Fiebelkorn, Peng-Jun Lu, Katherine E. Kahn, Denise V. D’Angelo, Rebecca Devlin, Stacie M. Greby
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Pregnant women and their infants are at increased risk for severe influenza-associated illness (1), and since 2004, the Advisory Committee on Immunization Practices (ACIP) has recommended influenza vaccination for all women who are or might be pregnant during the influenza season, regardless of the trimester of the pregnancy (2). To assess influenza vaccination coverage among pregnant women during the 2016-17 influenza season, CDC analyzed data from an Internet panel survey conducted during March 28-April 7, 2017. Among 1,893 survey respondents pregnant at any time during October 2016-January 2017, 53.6% reported having received influenza vaccination before (16.2%) or during (37.4%) pregnancy, similar to coverage during the preceding four influenza seasons. Also similar to the preceding influenza season, 67.3% of women reported receiving a provider offer for influenza vaccination, 11.9% reported receiving a recommendation but no offer, and 20.7% reported receiving no recommendation; among these women, reported influenza vaccination coverage was 70.5%, 43.7%, and 14.8%, respectively. Among women who received a provider offer for vaccination, vaccination coverage differed by race/ethnicity, education, insurance type, and other sociodemographic factors. Use of evidence-based practices such as provider reminders and standing orders could reduce missed opportunities for vaccination and increase vaccination coverage among pregnant women.
A pharmacokinetically (PK) and pharmacodynamically (PD) driven phase I trial of the pan-AKT inhibitor AZD5363 with expansion cohorts in <i>PIK3CA</i> mutant breast and gynecological cancers.
Authors: Udai Banerji, Emma Jane Dean, Jose Alejandro Perez-Fidalgo, Gerald Batist, Philippe L. Bedard, Benoit You, Shannon Neville Westin, Peter Kabos, Barry Davies, Paul Elvin, Peter Lawrence, James W T Yates, Helen Ambrose, Paul Rugman, Andrew Foxley, Shaista Salim, Ed Casson, Justin P O Lindemann, Jan H. M. Schellens
Journal: Journal of Clinical Oncology (2015)

2500 Background: AZD5363 is a novel potent pan-AKT inhibitor (IC50of AKT1, AKT2 and AKT3 of 3, 7 and 7nM respectively) with preclinical activity across a range of models. Methods: The trial had an adaptive design that allowed changes in schedule based on toxicity, PK, and PD findings. AZD5363 was administered orally (PO) twice a day (BID). Three schedules were explored: continuous dosing (7/7), four days a week, (4/7) and two days a week (2/7). PD biomarkers including pAKT, pGSK3β, and pPRAS40 were measured by IHC in pre- and post-treatment tumor biopsies. Once a RP2D was established, two expansion cohorts of PIK3CA-mutant ER+ve breast (B) and gynecological (G) cancers were explored. Results: 47, 21 and 22 patients were treated on the 7/7, 4/7 and 2/7 schedules respectively, with a further 27 and 18 patients recruited to the B and G cohorts to date. The MTDs of 7/7, 4/7 and 2/7 were 320mg BID, 480mg BID and 640mg BID respectively. The dose limiting toxicities (DLTs) were rash and diarrhea for 7/7, and hyperglycemia for 2/7. No DLTs were identified for 4/7. The most common causally-related adverse events ≥ CTC Grade 3 were hyperglycemia (20%), diarrhea (10%), rash (10%), nausea (3%) and fatigue (1%). PK profiles at the RP2D of 480mg BID (4/7) showed a multi-dose Css,max of 1426ng/mL and AUCssof 7952ng.hr/mL, which were consistent with exposures that gave tumor regression in preclinical models. Pre- and post-treatment biopsies confirmed target engagement in tumor tissue, with an increase in pAKT and reductions in pGSK3β and pPRAS40. Based on toxicity, PK and PD profiles 480mg BID (4/7) was chosen as the R2PD for single agent AZD5363, with the option of using 640mg BID (2/7) as a pharmacologically active dose for future combination studies. Target lesion shrinkage was observed in 7/15 and 4/14 in the B and G cohorts respectively to date, and with RECIST responses in evaluable patients of 3/15 (20%) and 1/14 (7%). Conclusions: Based on toxicity, PK and PD data two intermittent schedules of AZD5363 have been identified for further exploration. Promising single agent activity has been seen in PIK3CA-mutant breast cancer providing support for ongoing combination studies. Clinical trial information: NCT01226316.
The regulation of transendothelial migration: new knowledge and new questions
Authors: William A. Muller
Journal: Cardiovascular Research (2015)

Leucocyte transendothelial migration (TEM) involves a co-operative series of interactions between surface molecules on the leucocyte and cognate counter-ligands on the endothelial cell. These interactions set up a cascade of signalling events inside the endothelial cell that both allow for the junctions to loosen and for membrane to be recruited from the lateral border recycling compartment (LBRC). The LBRC is thought to provide an increased surface area and unligated receptors to the leucocyte to continue the process. The relative importance of the individual adhesion/signalling molecules that promote transmigration may vary depending on the type of leucocyte, the vascular bed, the inflammatory stimulus, and the stage of the inflammatory response. However, the molecular interactions between leucocyte and endothelial cell activate signalling pathways that disengage the adherens and tight junctions and recruit the LBRC to the site of transmigration. With the exception of disengaging the junctions, similar molecules and mechanisms promote transcellular migration as paracellular migration of leucocytes. This review will discuss the molecular interactions and signalling pathways that regulate transmigration, and the common themes that emerge from studying TEM of different leucocyte subsets under different inflammatory conditions. We will also raise some unanswered questions in need of future research.
Resolution of Brassicaceae Phylogeny Using Nuclear Genes Uncovers Nested Radiations and Supports Convergent Morphological Evolution
Authors: Chien-Hsun Huang, Renran Sun, Yi Hu, Liping Zeng, Ning Zhang, Liming Cai, Qiang Zhang, Marcus A. Koch, Ihsan Al-Shehbaz, Patrick P. Edger, J. Chris Pires, Dun-Yan Tan, Yang Zhong, Hong Ma
Journal: Molecular Biology and Evolution (2015)

Brassicaceae is one of the most diverse and economically valuable angiosperm families with widely cultivated vegetable crops and scientifically important model plants, such as Arabidopsis thaliana. The evolutionary history, ecological, morphological, and genetic diversity, and abundant resources and knowledge of Brassicaceae make it an excellent model family for evolutionary studies. Recent phylogenetic analyses of the family revealed three major lineages (I, II, and III), but relationships among and within these lineages remain largely unclear. Here, we present a highly supported phylogeny with six major clades using nuclear markers from newly sequenced transcriptomes of 32 Brassicaceae species and large data sets from additional taxa for a total of 55 species spanning 29 out of 51 tribes. Clade A consisting of Lineage I and Macropodium nivale is sister to combined Clade B (with Lineage II and others) and a new Clade C. The ABC clade is sister to Clade D with species previously weakly associated with Lineage II and Clade E (Lineage III) is sister to the ABCD clade. Clade F (the tribe Aethionemeae) is sister to the remainder of the entire family. Molecular clock estimation reveals an early radiation of major clades near or shortly after the Eocene-Oligocene boundary and subsequent nested divergences of several tribes of the previously polytomous Expanded Lineage II. Reconstruction of ancestral morphological states during the Brassicaceae evolution indicates prevalent parallel (convergent) evolution of several traits over deep times across the entire family. These results form a foundation for future evolutionary analyses of structures and functions across Brassicaceae.
Embolism in Mitral Valve Prolapse
Authors: H J M Barnett
Journal: Annual Review of Medicine (1982)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Prayer can prevent the end of the world
Authors: H. Gordon
Journal: BMJ (1995)

functions) and devolution of decisions on staffing to the local level.Crown health enterprises (similar to NHS trusts) contract for services and negotiate pay and conditions with their workers.Local pay bargaining, which is currently being debated in Britain, began to operate in the early stages of New Zealand's health reforms despite protestations by the nurses' and junior doctors' unions.Industrial action by the junior doctors'
Treatment of Severe Veno-Occlusive Disease With Defibrotide: Compassionate Use Results in Response Without Significant Toxicity in a High-Risk Population
Authors: Paul G. Richardson, Anthony D. Elias, Amrita Krishnan, Catherine Wheeler, Raj Nath, Debra Hoppensteadt, Nancy M. Kinchla, Donna Neuberg, Edmund K. Waller, Joseph H. Antin, Robert Soiffer, James Vredenburgh, Michael Lill, Ann E. Woolfrey, Scott I. Bearman, Massimo Iacobelli, Jawed Fareed, Eva C. Guinan
Journal: Blood (1998)
“Health consequences associated with frequent wheezing in adolescents without asthma diagnosis.” K. Yeatts, K. Johnston Davis, D. Peden and C. Shy. <i>Eur Respir J</i> 2003; 22: 781–786.
Authors: Karin Yeatts
Journal: European Respiratory Journal (2015)

consequences associated with frequent wheezing in adolescents without asthma diagnosis" [1].It was subsequently brought to our attention that another article by two of the same authors, "Health consequences for children with undiagnosed asthma-like symptoms," had been published in the Archives of Pediatric and Adolescent Medicine (now JAMA Pediatrics) [2]; the National Library of Medicine has decided that these two articles represent duplicate publication, and both articles have been labelled as duplicate publications in MEDLINE.
Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors.
Authors: S O'Reilly, L B Grochow, R C Donehower, T L Chen, K Bowling, N R Hartman, R F Struck, E K Rowinsky
Journal: Journal of Clinical Oncology (1997)

PURPOSE To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. PATIENTS AND METHODS Penclomedine (45 to 550 mg/ m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. RESULTS On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. CONCLUSION Neurotoxicity was the dose-limiting toxicity (DLT) of penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated.
The T Lymphocyte in Experimental Allergic Encephalomyelitis
Authors: S S Zamvil, L Steinman
Journal: Annual Review of Immunology (1990)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Proatherogenic role of interleukin-18: effects on inflammation and action on vascular cells: AUTHORS' RETROSPECTIVE
Authors: R. Elhage, H.-G. Ljunggren, G. K. Hansson
Journal: Cardiovascular Research (2012)

This editorial refers to an article by R. Elhage et al . [31][1] published in Cardiovascular Research in 2003. It is accompanied by an editorial by L. Badimon (doi:10.1093/cvr/cvs226) as part of this Spotlight on Landmark Papers in Cardiovascular Research . 

Today, multiple different pieces of evidence set inflammation as a key pathogenetic mechanism in the development of atherosclerosis and its complications.1–4 A better characterization of the role of inflammatory mediators in atherosclerosis will provide clinical insight and practical tools that may help patient management. Inflammatory responses are generated through the innate as well as adaptive arm of immunity. In addition to vascular endothelial and smooth muscle cells, leucocyte populations including monocyte-derived macrophages, T lymphocytes, dendritic cells (DC), and mast cells contribute to building up the atherosclerotic plaque5 in a process orchestrated by several cytokines, chemokines, growth factors, and hormones.1 Activated immune cells contribute not only to the growth of lesions but also to their activation, leading to atherothrombosis and acute ischaemic disease.

Macrophages are a major source of cytokines in atherosclerotic plaques. They produce pro-inflammatory cytokines such as TNF-α, interleukin-1 (IL-1), IL-6, IL-12, IL-15, and IL-18, as well as anti-inflammatory cytokines such as IL-10 and TGF-β, which perpetuate the local inflammatory environment in early as well as in complicated lesions.

IFN-γ can be produced by CD4+ Th1 cells, CD8+ T cells, NK cells, and possibly also by certain activated macrophages. Both CD4+ T cells and IFN-γ have been shown to aggravate disease.6,7

IL-1α and IL-1β are secreted in the vascular wall by endothelial and smooth muscle cells as well as by monocytes/macrophages.8 IL-1β can be generated when the inflammasome is activated by intracellular cholesterol crystals.9,10 IL-1β enhances recruitment of effector cells into the plaque and has direct effects …

 [1]: #ref-31