tbuckley/cabot-search huggingface dataset:
Apixaban versus Warfarin in Patients with Atrial Fibrillation
Authors: Christopher B. Granger, John H. Alexander, John J.V. McMurray, Renato D. Lopes, Elaine M. Hylek, Michael Hanna, Hussein R. Al-Khalidi, Jack Ansell, Dan Atar, Alvaro Avezum, M. Cecilia Bahit, Rafael Diaz, J. Donald Easton, Justin A. Ezekowitz, Greg Flaker, David Garcia, Margarida Geraldes, Bernard J. Gersh, Sergey Golitsyn, Shinya Goto, Antonio G. Hermosillo, Stefan H. Hohnloser, John Horowitz, Puneet Mohan, Petr Jansky, Basil S. Lewis, Jose Luis Lopez-Sendon, Prem Pais, Alexander Parkhomenko, Freek W.A. Verheugt, Jun Zhu, Lars Wallentin
Journal: New England Journal of Medicine (2011)

Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin.In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause.The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42).In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).
PMS2 Mutations in Childhood Cancer
Authors: Michel De Vos, Bruce E. Hayward, Ruth Charlton, Graham R. Taylor, Adam W. Glaser, Susan Picton, Trevor R. Cole, Eamonn R. Maher, Carole M. E. McKeown, Jill R. Mann, John R. Yates, Diana Baralle, Julia Rankin, David T. Bonthron, Eamonn Sheridan
Journal: JNCI Journal of the National Cancer Institute (2006)

Until recently, the PMS2 DNA mismatch repair gene has only rarely been implicated as a cancer susceptibility locus. New studies have shown, however, that earlier analyses of this gene have had technical limitations and also that the genetic behavior of mutant PMS2 alleles is unusual, in that, unlike MLH1 or MSH2 mutations, PMS2 mutations show low heterozygote penetrance. As a result, a dominantly inherited cancer predisposition has not been a feature reported in families with PMS2 mutations. Such families have instead been ascertained through childhood-onset cancers in homozygotes or through apparently sporadic colorectal cancer in heterozygotes. We present further information on the phenotype associated with homozygous PMS2 deficiency in 13 patients from six families of Pakistani origin living in the United Kingdom. This syndrome is characterized by café-au-lait skin pigmentation and a characteristic tumor spectrum, including leukemias, lymphomas, cerebral malignancies (such as supratentorial primitive neuroectodermal tumors, astrocytomas, and glioblastomas), and colorectal neoplasia with an onset in early adult life. We present evidence for a founder effect in five families, all of which carried the same R802-->X mutation (i.e., arginine-802 to stop) in PMS2. This cancer syndrome can be mistaken for neurofibromatosis type 1, with important management implications including the risk of the disorder occurring in siblings and the likelihood of tumor development in affected individuals.
Cardiovascular Disease in Adult Survivors of Childhood Cancer
Authors: Steven E. Lipshultz, Vivian I. Franco, Tracie L. Miller, Steven D. Colan, Stephen E. Sallan
Journal: Annual Review of Medicine (2015)

Treatment advances have increased survival in children with cancer, but subclinical, progressive, irreversible, and sometimes fatal treatment-related cardiovascular effects may appear years later. Cardio-oncologists have identified promising preventive and treatment strategies. Dexrazoxane provides long-term cardioprotection from doxorubicin-associated cardiotoxicity without compromising the efficacy of anticancer treatment. Continuous infusion of doxorubicin is as effective as bolus administration in leukemia treatment, but no evidence has indicated that it provides long-term cardioprotection; continuous infusions should be eliminated from pediatric cancer treatment. Angiotensin-converting enzyme inhibitors can delay the progression of subclinical and clinical cardiotoxicity. All survivors, regardless of whether they were treated with anthracyclines or radiation, should be monitored for systemic inflammation and the risk of premature cardiovascular disease. Echocardiographic screening must be supplemented with screening for biomarkers of cardiotoxicity and perhaps by identification of genetic susceptibilities to cardiovascular diseases; optimal strategies need to be identified. The health burden related to cancer treatment will increase as this population expands and ages.
Clinical and microbiological epidemiology of Streptococcus pneumoniae bacteremia in cancer patients
Authors: Carolina Garcia-Vidal, Carmen Ardanuy, Carlota Gudiol, Guillermo Cuervo, Laura Calatayud, Marta Bodro, Rafael Duarte, Alberto Fernández-Sevilla, Maite Antonio, Josefina Liñares, Jordi Carratalà
Journal: Journal of Infection (2012)
Simultaneous and independent detection of C9ORF72 alleles with low and high number of GGGGCC repeats using an optimised protocol of Southern blot hybridisation
Authors: Vladimir L Buchman, Johnathan Cooper-Knock, Natalie Connor-Robson, Adrian Higginbottom, Janine Kirby, Olga D Razinskaya, Natalia Ninkina, Pamela J Shaw
Journal: Molecular Neurodegeneration (2013)

Sizing of GGGGCC hexanucleotide repeat expansions within the C9ORF72 locus, which account for approximately 10% of all amyotrophic lateral sclerosis (ALS) cases, is urgently required to answer fundamental questions about mechanisms of pathogenesis in this important genetic variant. Currently employed PCR protocols are limited to discrimination between the presence and absence of a modified allele with more than 30 copies of the repeat, while Southern hybridisation-based methods are confounded by the somatic heterogeneity commonly present in blood samples, which might cause false-negative or ambiguous results.We describe an optimised Southern hybridisation-based protocol that allows confident detection of the presence of a C9ORF72 repeat expansion alongside independent assessment of its heterogeneity and the number of repeat units. The protocol can be used with either a radiolabeled or non-radiolabeled probe. Using this method we have successfully sized the C9ORF72 repeat expansion in lymphoblastoid cells, peripheral blood, and post-mortem central nervous system (CNS) tissue from ALS patients. It was also possible to confidently demonstrate the presence of repeat expansion, although of different magnitude, in both C9ORF72 alleles of the genome of one patient.The suggested protocol has sufficient advantages to warrant adoption as a standard for Southern blot hybridisation analysis of GGGGCC repeat expansions in the C9ORF72 locus.
Arsenic-Specific Stem Cell Selection During Malignant Transformation
Authors: Erik J. Tokar, Wei Qu, Jie Liu, Wei Liu, Mukta M. Webber, James M. Phang, Michael P. Waalkes
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundArsenic is a carcinogen that targets the urogenital system, including the prostate. Although the mechanisms for arsenic-induced carcinogenesis are undefined, arsenic drives overaccumulation of stem cells and cancer stem cells (CSCs) in vivo and in vitro, indicating that these cells are a key target population. Disruption of stem cell population dynamics may be critical to acquisition of cancer phenotype. We tested the hypothesis that prostate stem cells have a survival selection advantage during arsenic exposure that favors their accumulation and facilitates their malignant transformation.
Stress-Activated Mitogen-Activated Protein Kinases c-Jun NH2-Terminal Kinase and p38 Target Cdc25B for Degradation
Authors: Sanae Uchida, Katsuji Yoshioka, Ryoichi Kizu, Hitoshi Nakagama, Tsukasa Matsunaga, Yukihito Ishizaka, Randy Y.C. Poon, Katsumi Yamashita
Journal: Cancer Research (2009)

Abstract Cdc25 dual specificity phosphatases positively regulate the cell cycle by activating cyclin-dependent kinase/cyclin complexes. Of the three mammalian Cdc25 isoforms, Cdc25A is phosphorylated by genotoxic stress–activated Chk1 or Chk2, which triggers its SCFβ-TrCP–mediated degradation. However, the roles of Cdc25B and Cdc25C in cell stress checkpoints remain inconclusive. We herein report that c-Jun NH2-terminal kinase (JNK) induces the degradation of Cdc25B. Nongenotoxic stress induced by anisomycin caused rapid degradation of Cdc25B as well as Cdc25A. Cdc25B degradation was dependent mainly on JNK and partially on p38 mitogen-activated protein kinase (p38). Accordingly, cotransfection with JNK1, JNK2, or p38 destabilized Cdc25B. In vitro kinase assays and site-directed mutagenesis experiments revealed that the critical JNK and p38 phosphorylation site in Cdc25B was Ser101. Cdc25B with Ser101 mutated to alanine was refractory to anisomycin-induced degradation, and cells expressing such mutant Cdc25B proteins were able to override the anisomycin-induced G2 arrest. These results highlight the importance of a novel JNK/p38-Cdc25B axis for a nongenotoxic stress–induced cell cycle checkpoint. [Cancer Res 2009;69(16):6438–44]
A Cost-Effectiveness Analysis of Adjuvant Trastuzumab Regimens in Early HER2/<i>neu</i>–Positive Breast Cancer
Authors: Allison W. Kurian, Rebecca Newton Thompson, Allison F. Gaw, Sally Arai, Rafael Ortiz, Alan M. Garber
Journal: Journal of Clinical Oncology (2007)

One-year adjuvant trastuzumab (AT) therapy, with or without anthracyclines, increases disease-free and overall survival in early-stage HER2/neu-positive breast cancer. We sought to evaluate the cost effectiveness of these regimens, which are expensive and potentially toxic.We used a Markov health-state transition model to simulate three adjuvant therapy options for a cohort of 49-year-old women with HER2/neu-positive early-stage breast cancer: conventional chemotherapy without trastuzumab; anthracycline-based AT regimens used in the National Surgical Adjuvant Breast and Bowel Project B-31 and North Central Cancer Treatment Group N9831 trials; and the nonanthracycline AT regimen used in the Breast Cancer International Research group 006 trial. The base case used treatment efficacy measures reported in the randomized clinical trials of AT. We measured health outcomes in quality-adjusted life-years (QALYs) and costs in 2005 United States dollars (US dollars) and subjected results to probabilistic sensitivity analysis.In the base case, the anthracycline-based AT arm has an incremental cost-effectiveness ratio (ICER) of 39,982 dollars/QALY, whereas the nonanthracycline AT arm is more expensive and less effective; this result is insensitive to changes in recurrence rates, but if there is no benefit after 4 years, ICERs exceed 100,000 dollars/QALY for both AT arms. Results are moderately sensitive to variation in breast cancer survival rates and trastuzumab cost, and less sensitive to variations in cardiac toxicity.AT has an ICER comparable to those for other widely used interventions. Longer clinical follow-up is warranted to evaluate the long-term efficacy and toxicity of different AT regimens.
Medicinal Applications of Cyclodextrins
Authors: J. Szejtli
Journal: Medicinal Research Reviews (1994)

Some cyclodextrins are produced industrially, and available in pharmaceutical quality, at reasonable prices. Their medicinal use means mainly--but not exclusively--the complexation of problematic drugs (poorly soluble, unstable, irritating, difficult to formulate substances). The CD complexation generally results in improved wettability, dissolution, and solubility; improved stability; reduced side effects; or in mildering of other undesired properties (e.g., bitter tastes, bad smells). CDs can be used advantageously practically in any drug forms: oral, rectal, pulmonary, external, ocular, etc. formulations. In oral solid and liquid formulations the chemical and physical stability and bioavailability, but particularly the role of absorption is improved. With appropriate highly soluble chemically modified CDs aqueous parenteral formulations can be prepared from poorly soluble drugs. Using CDs the transdermal penetration or nasal absorption of such drugs becomes possible, which earlier could not be administered through these ways. The direct therapeutic effects of CDs (or their derivatives) are demonstrated in several examples as well as the use of beta CD as vehicle in tabletting.
Linitis plastica due to gastric diverticulosis
Authors: S D Patel
Journal: Journal of the Royal Society of Medicine (2005)

Linitis plastica is typically due to an infiltrating adenocarcinoma.The term, however, is descriptive rather than diagnostic. CASE HISTORYA man of 63 was admitted because of long-term weight loss and worsening symptoms of gastric outlet obstruction.There had been no abdominal pain or change in bowel habit, no haematemesis or melaena.Initial treatment was nasogastric aspiration, intravenous hydration and an intravenous proton pump inhibitor.Endoscopy showed moderate reflux and a poorly distensible stomach with gastric outlet obstruction; the appearances were in keeping with infiltrating adenocarcinoma (linitis plastica) but repeated biopsies showed only inflammatory changes.On CT there was pronounced thickening of the wall of the entire stomach, measuring up to 2 cm, with severe narrowing of the lumen (Figure 1).No gas bubbles were evident in the stomach walls.These findings supported the provisional diagnosis of carcinoma and staging laparoscopy was undertaken.This showed a greatly thickened and rigid stomach with the consistency of rubber.Because there was no evidence of spread beyond the stomach, a total gastrectomy was performed.Postoperative recovery was satisfactory.On histological examination the stomach showed typical changes of diverticular disease, with pouches of mucosa extending through the muscularis propria into adjacent fat (Figure 2).The muscularis propria was hypertrophic and the submucosa showed oedema and fibrosis.In the mucosa there were areas of chronic inflammation with some ulceration; no metaplasia, dysplasia or malignancy was seen.
FEV<sub>6</sub> Is an Acceptable Surrogate for FVC in the Spirometric Diagnosis of Airway Obstruction and Restriction
Authors: MAUREEN P. SWANNEY, ROBERT L. JENSEN, DAVID A. CRICHTON, LUTZ E. BECKERT, LAUREN A. CARDNO, ROBERT O. CRAPO
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We analyzed the FEV(1)/FEV(6) and FEV(1)/FVC results of 502 consecutive patients in the spirometric diagnosis of airway obstruction. We also examined the agreement between FEV(6) and FVC in the spirometric diagnosis of restriction. Technically acceptable test results were obtained from 337 subjects (67%). The sensitivity of FEV(1)/FEV(6) for diagnosing airway obstruction as defined by FEV(1)/ FVC was 95.0%; the specificity was 97.4%. When interpretations differed, the measured values were all close to the lower limits of the reference ranges. When analysis included +/- 100-ml variability in FEV(1) and FEV(6), the sensitivity increased to 99.5% and the specificity to 100%. The reproducibility of FEV(6) was superior to that of FVC. These results suggest that FEV(6) is an accurate, reliable alternative to FVC for diagnosing airway obstruction and that FEV(6) is reasonably comparable to FVC for the spirometric diagnosis of restriction. FEV(6) is more reproducible and less physically demanding for patients.
Podocyte-Derived BMP7 Is Critical for Nephron Development
Authors: Itsuro Kazama, Zhen Mahoney, Jeffrey H. Miner, Daniel Graf, Aris N. Economides, Jordan A. Kreidberg
Journal: Journal of the American Society of Nephrology (2008)

Individuals with congenital renal hypoplasia display a defect in the growth of nephrons during development. Many genes that affect the initial induction of nephrons have been identified, but little is known about the regulation of postinductive stages of kidney development. In the absence of the growth factor bone morphogenic protein 7 (BMP7), kidney development arrests after induction of a small number of nephrons. The role of BMP7 after induction, however, has not been fully investigated. Here, we generated a podocyte-specific conditional knockout of BMP7 (Bmp7(flox/flox);Nphs2-Cre(+) [BMP7 CKO]) to study the role of podocyte-derived BMP7 in nephron maturation. By postnatal day 4, 65% of BMP7 CKO mice had hypoplastic kidneys, but glomeruli demonstrated normal patterns of laminin and collagen IV subunit expression. Developing proximal tubules, however, were reduced in number and demonstrated impaired cellular proliferation. We examined signaling pathways downstream of BMP7; the level of cortical phosphorylated Smad1, 5, and 8 was unchanged in BMP CKO kidneys, but phosphorylated p38 mitogen-activated protein kinase was significantly decreased. In addition, beta-catenin was reduced in BMP7 CKO kidneys, and its localization to intracellular vesicles suggested that it had been targeted for degradation. In summary, these results define a BMP7-mediated regulatory axis between glomeruli and proximal tubules during kidney development.
NAD(P)H Oxidase 4 Mediates Transforming Growth Factor-β1–Induced Differentiation of Cardiac Fibroblasts Into Myofibroblasts
Authors: Ioan Cucoranu, Roza Clempus, Anna Dikalova, Patrick J. Phelan, Srividya Ariyan, Sergey Dikalov, Dan Sorescu
Journal: Circulation Research (2005)

Human cardiac fibroblasts are the main source of cardiac fibrosis associated with cardiac hypertrophy and heart failure. Transforming growth factor-beta1 (TGF-beta1) irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin (SM alpha-actin) de novo and produce extracellular matrix. We hypothesized that TGF-beta1-stimulated conversion of fibroblasts to myofibroblasts requires reactive oxygen species derived from NAD(P)H oxidases (Nox). We found that TGF-beta1 potently upregulates the contractile marker SM alpha-actin mRNA (7.5+/-0.8-fold versus control). To determine whether Nox enzymes are involved, we first performed quantitative real time polymerase chain reaction and found that Nox5 and Nox4 are abundantly expressed in cardiac fibroblasts, whereas Nox1 and Nox2 are barely detectable. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated by 16.2+/-0.8-fold (n=3, P<0.005), whereas Nox5 is downregulated. Small interference RNA against Nox4 downregulates Nox4 mRNA by 80+/-5%, inhibits NADPH-driven superoxide production in response to TGF-beta1 by 65+/-7%, and reduces TGF-beta1-induced expression of SM alpha-actin by 95+/-2% (n=6, P<0.05). Because activation of small mothers against decapentaplegic (Smads) 2/3 is critical for myofibroblast conversion in response to TGF-beta1, we also determined whether Nox4 affects Smad 2/3 phosphorylation. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation by 75+/-5% and 68+/-3%, respectively (n=7, P<0.0001). We conclude that Nox 4 mediates TGF-beta1-induced conversion of fibroblasts to myofibroblasts by regulating Smad 2/3 activation. Thus, Nox4 may play a critical role in the pathological activation of cardiac fibroblasts in cardiac fibrosis associated with human heart failure.
Erythroplasia of Queyrat treated by topical aminolaevulinic acid photodynamic therapy: a cautionary tale
Authors: S. Varma, P.J.A. Holt, A.V. Anstey
Journal: British Journal of Dermatology (2000)

Journal Article Erythroplasia of Queyrat treated by topical aminolaevulinic acid photodynamic therapy: a cautionary tale Get access S. Varma, S. Varma Department of Dermatology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, U.K. Search for other works by this author on: Oxford Academic Google Scholar P.J.A. Holt, P.J.A. Holt Department of Dermatology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, U.K. Search for other works by this author on: Oxford Academic Google Scholar A.V. Anstey A.V. Anstey Department of Dermatology, Royal Gwent Hospital, Newport, Gwent NP9 2UB, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 4, 1 April 2000, Pages 825–826, https://doi.org/10.1046/j.1365-2133.2000.03441.x Published: 01 April 2000
Brain activity and perceived exertion during cycling exercise: an fMRI study
Authors: Eduardo B Fontes, Alexandre H Okano, François De Guio, Elske J Schabort, Li Li Min, Fabien A Basset, Dan J Stein, Timothy D Noakes
Journal: British Journal of Sports Medicine (2013)

Background/aim Currently, the equipment and techniques available to assess brain function during dynamic exercise are limited, which has restricted our knowledge of how the brain regulates exercise. This study assessed the brain areas activated during cycling by making use of a novel cycle ergometer, constructed to measure functional MRI (fMRI) brain images during dynamic exercise. Furthermore, we compared brain activation at different levels of ratings of perceived exertion (RPE) generated during the exercise. Methods Seven healthy adults performed cycling exercise in a novel MRI compatible cycle ergometer while undergoing brain fMRI. Participants completed a cycling block protocol comprising six trials of 2 min cycling with 16-s intervals between trials. Participants reported their RPE every minute through an audio link. The MRI cycling ergometer transferred the torque generated on the ergometer through a cardan system to a cycling ergometer positioned outside the MRI room. For data analysis, the effects of cycling as opposed to rest periods were examined after motion correction. Results The multiparticipant analysis revealed in particular the activation of the cerebellar vermis and precentral and postcentral gyrus when periods of cycling versus rest were compared. Single participant analysis in four participants revealed that activation of the posterior cingulate gyrus and precuneus occurred in cycling blocks perceived as ‘hard’ compared with exercise blocks that were less demanding. Conclusions The present study offers a new approach to assess brain activation during dynamic cycling exercise, and suggests that specific brain areas could be involved in the sensations generating the rating of perceived exertion.