tbuckley/cabot-search huggingface dataset:
Comparison of Liquid-Based Cytology With Conventional Cytology for Detection of Cervical Cancer Precursors
Authors: Albertus G. Siebers, Paul J. J. M. Klinkhamer, Johanna M. M. Grefte, Leon F. A. G. Massuger, Judith E. M. Vedder, Angelique Beijers-Broos, Johan Bulten, Marc Arbyn
Journal: JAMA (2009)

Context Liquid-based cytology has been developed as an alternative for conventional cervical cytology.Despite numerous studies and systematic reviews, controversy remains about its diagnostic accuracy.Objective To assess the performance of liquid-based cytology compared with conventional cytology in terms of detection of histologically confirmed cervical intraepithelial neoplasia (CIN).Design, Setting, and Participants Cluster randomized controlled trial involving 89 784 women aged 30 to 60 years participating in the Dutch cervical screening program at 246 family practices.One hundred twenty-two practices were assigned to use liquid-based cytology and screened 49 222 patients and 124 practices were assigned to use the conventional Papanicolaou (Pap) test and screened 40 562 patients between April 2004 and July 1, 2006.Patients were followed up for 18 months through January 31, 2008.Intervention Screening for CIN using liquid-based cytology or conventional papanicolaou (Pap) test and the blinded review of all follow-up of screen-positive women (blinded to the type of cytology and the initial result). Main Outcome MeasuresIntention-to-treat and per-protocol analysis of the detection rates of and positive predictive values for histologically verified CIN in both cytology systems.Outcomes are presented as crude and adjusted rate ratios (adjustment for age, urbanization, study site, and period). ResultsThe adjusted detection rate ratios for CIN grade 1ϩ was 1.01 (95% confidence interval [CI], 0.85-1.19);for CIN grade 2ϩ, 1.00 (95% CI, 0.84-1.20);for CIN grade 3ϩ, 1.05 (95% CI, 0.86-1.29);and for carcinoma, 1.69 (95% CI, 0.96-2.99).The adjusted positive predictive value (PPV) ratios, considered at several cytological cutoffs and for various outcomes of CIN did not differ significantly from unity. ConclusionThis study indicates that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors.
Pharmacological activation of the p53 pathway by nutlin-3 exerts anti-tumoral effects in medulloblastomas
Authors: A. Kunkele, K. De Preter, L. Heukamp, T. Thor, K. W. Pajtler, W. Hartmann, M. Mittelbronn, M. A. Grotzer, H. E. Deubzer, F. Speleman, A. Schramm, A. Eggert, J. H. Schulte
Journal: Neuro-Oncology (2012)

Medulloblastomas account for 20% of pediatric brain tumors. With an overall survival of 40%–70%, their treatment is still a challenge. The majority of medulloblastomas lack p53 mutations, but even in cancers retaining wild-type p53, the tumor surveillance function of p53 is inhibited by the oncoprotein MDM2. Deregulation of the MDM2/p53 balance leads to malignant transformation. Here, we analyzed MDM2 mRNA and protein expression in primary medulloblastomas and normal cerebellum and assessed the mutational status of p53 and MDM2 expression in 6 medulloblastoma cell lines. MDM2 expression was elevated in medulloblastomas, compared with cerebellum. Four of 6 medulloblastoma cell lines expressed wild-type p53 and high levels of MDM2. The tumor-promoting p53-MDM2 interaction can be inhibited by the small molecule, nutlin-3, restoring p53 function. Targeting the p53-MDM2 axis using nutlin-3 significantly reduced cell viability and induced either cell cycle arrest or apoptosis and expression of the p53 target gene p21 in these 4 cell lines. In contrast, DAOY and UW-228 cells harboring TP53 mutations were almost unaffected by nutlin-3 treatment. MDM2 knockdown in medulloblastoma cells by siRNA mimicked nutlin-3 treatment, whereas expression of dominant negative p53 abrogated nutlin-3 effects. Oral nutlin-3 treatment of mice with established medulloblastoma xenografts inhibited tumor growth and significantly increased survival. Thus, nutlin-3 reduced medulloblastoma cell viability in vitro and in vivo by re-activating p53 function. We suggest that inhibition of the MDM2-p53 interaction with nutlin-3 is a promising therapeutic option for medulloblastomas with functional p53 that should be further evaluated in clinical trials.
Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study
Authors: Danish Saleheen, Robert Scott, Sundas Javad, Wei Zhao, Amrith Rodrigues, Antonino Picataggi, Daniya Lukmanova, Megan L Mucksavage, Robert Luben, Jeffery Billheimer, John J P Kastelein, S Matthijs Boekholdt, Kay-Tee Khaw, Nick Wareham, Daniel J Rader
Journal: The Lancet Diabetes & Endocrinology (2015)

<h2>Summary</h2><h3>Background</h3> Although HDL cholesterol concentrations are strongly and inversely associated with risk of coronary heart disease, interventions that raise HDL cholesterol do not reduce risk of coronary heart disease. HDL cholesterol efflux capacity—a prototypical measure of HDL function—has been associated with coronary heart disease after adjusting for HDL cholesterol, but its effect on incident coronary heart disease risk is uncertain. <h3>Methods</h3> We measured cholesterol efflux capacity and assessed its relation with vascular risk factors and incident coronary heart disease events in a nested case-control sample from the prospective EPIC-Norfolk study of 25 639 individuals aged 40–79 years, assessed in 1993–97 and followed up to 2009. We quantified cholesterol efflux capacity in 1745 patients with incident coronary heart disease and 1749 control participants free of any cardiovascular disorders by use of a validated ex-vivo radiotracer assay that involved incubation of cholesterol-labelled J774 macrophages with apoB-depleted serum from study participants. <h3>Findings</h3> Cholesterol efflux capacity was positively correlated with HDL cholesterol concentration (r=0·40; p<0·0001) and apoA-I concentration (r=0·22; p<0·0001). It was also inversely correlated with type 2 diabetes (r=–0·18; p<0·0001) and positively correlated with alcohol consumption (r=0·12; p<0·0001). In analyses comparing the top and bottom tertiles, cholesterol efflux capacity was significantly and inversely associated with incident coronary heart disease events, independent of age, sex, diabetes, hypertension, smoking and alcohol use, waist:hip ratio, BMI, LDL cholesterol concentration, log-triglycerides, and HDL cholesterol or apoA-I concentrations (odds ratio 0·64, 95% CI 0·51–0·80). After a similar multivariable adjustment the risk of incident coronary heart disease was 0·80 (95% CI 0·70–0·90) for a per-SD change in cholesterol efflux capacity. <h3>Interpretation</h3> HDL cholesterol efflux capacity might provide an alternative mechanism for therapeutic modulation of the HDL pathway beyond HDL cholesterol concentration to help reduce risk of coronary heart disease. <h3>Funding</h3> US National Institutes of Health, UK Medical Research Council, Cancer Research UK.
Hypertrophic Cardiomyopathy Caused by a Novel α-Tropomyosin Mutation (V95A) Is Associated With Mild Cardiac Phenotype, Abnormal Calcium Binding to Troponin, Abnormal Myosin Cycling, and Poor Prognosis
Authors: Akihiko Karibe, Larry S. Tobacman, James Strand, Carol Butters, Nick Back, Linda L. Bachinski, Andrew E. Arai, Anne Ortiz, Robert Roberts, Earl Homsher, Lameh Fananapazir
Journal: Circulation (2001)

We report hypertrophic cardiomyopathy (HCM) in a Spanish-American family caused by a novel alpha-tropomyosin (TPM1) mutation and examine the pathogenesis of the clinical disease by characterizing functional defects in the purified mutant protein.HCM was linked to the TPM1 gene (logarithm of the odds [LOD] score 3.17). Sequencing and restriction digestion analysis demonstrated a TPM1 mutation V95A that cosegregated with HCM. The mutation has been associated with 13 deaths in 26 affected members (11 sudden deaths and 2 related to heart failure), with a cumulative survival rate of 73+/-10% at the age of 40 years. Left ventricular wall thickness (mean 16+/-6 mm) and disease penetrance (53%) were similar to those for the ss-myosin mutations L908V and G256E previously associated with a benign prognosis. Left ventricular hypertrophy was milder than with the ss-myosin mutation R403Q, but the prognosis was similarly poor. With the use of recombinant tropomyosins, we identified several functional alterations at the protein level. The mutation caused a 40% to 50% increase in calcium affinity in regulated thin filament-myosin subfragment-1 (S1) MgATPase assays, a 20% decrease in MgATPase rates in the presence of saturating calcium, a 5% decrease in unloaded shortening velocity in in vitro motility assays, and no change in cooperative myosin S1 binding to regulated thin filaments.In contrast to other reported TPM1 mutations, V95A-associated HCM exhibits unusual features of mild phenotype but poor prognosis. Both myosin cycling and calcium binding to troponin are abnormal in the presence of the mutant tropomyosin. The genetic diagnosis afforded by this mutation will be valuable in the management of HCM.
Effects of Exemestane and Tamoxifen in a Postmenopausal Breast Cancer Model
Authors: Danijela Jelovac, Luciana Macedo, Venkatesh Handratta, Brian J. Long, Olga G. Goloubeva, James N. Ingle, Angela M. H. Brodie
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To optimize treatment strategies for postmenopausal breast cancer patients, we investigated the efficacy of the steroidal aromatase inhibitor exemestane alone or in combination with the antiestrogen tamoxifen in a xenograft model of postmenopausal breast cancer. We also determined the effects of these agents in sequential second-line therapy and the effect of the nonsteroidal aromatase inhibitor letrozole on tumors that progressed on the above treatments. Experimental: Aromatase-transfected human estrogen receptor-positive breast cancer cells (MCF-7Ca) were grown as tumors in ovariectomized athymic mice. Animals received subcutaneous injection with vehicle, tamoxifen, exemestane, tamoxifen plus exemestane, and letrozole. Tumor volumes were measured weekly. Results: All treatments were effective initially in suppressing tumor growth as first-line therapy compared with vehicle treatment. Exemestane suppressed tumor growth to a greater extent than tamoxifen. However, the combination of tamoxifen plus exemestane was more effective than either drug alone. After tumor volumes doubled on initial treatment, the mice were crossed over to receive exemestane or tamoxifen. Tumor growth slowed briefly in mice treated with tamoxifen and crossed over to exemestane, but tumor growth continued unabated in those changed from exemestane to tamoxifen. However, letrozole was effective in both groups as third-line therapy for a limited period. Letrozole as initial single agent was the best overall treatment in terms of the degree of tumor suppression and the length of effectiveness of treatment. Conclusion: Exemestane was more effective in controlling tumor growth than tamoxifen. In addition, the combination of exemestane plus tamoxifen was clearly more effective than sequential use of these agents in the tumor model. However, the nonsteroidal aromatase inhibitor letrozole as first-line therapy was overall the most effective treatment in controlling tumor growth.
Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells
Authors: Tomohisa Horibe, Aya Torisawa, Masayuki Kohno, Koji Kawakami
Journal: Molecular Cancer (2012)

Abstract Background Heat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo . Results In this study, we investigated the functional cancer-cell killing mechanism of Antp-TPR hybrid peptide in glioblastoma (GB) cell lines. It was demonstrated that Antp-TPR peptide induced effective cytotoxic activity in GB cells through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf. Antp-TPR also did not induce the up-regulation of Hsp70 and Hsp90 proteins, although a small-molecule inhibitor of Hsp90, 17-AAG, induced the up-regulation of these proteins. It was also found that Antp-TPR peptide increased the endoplasmic reticulum unfolded protein response, and the cytotoxic activity of this hybrid peptide to GB cells in the endoplasmic reticulum stress condition. Conclusion These results show that targeting of Hsp90 by Antp-TPR could be an attractive approach to selective cancer-cell killing because no other Hsp90-targeted compounds show selective cytotoxic activity. Antp-TPR might provide potent and selective therapeutic options for the treatment of cancer.
Influenza vaccines: present and future
Authors: Peter Palese, Adolfo García-Sastre
Journal: Journal of Clinical Investigation (2002)

The future of vaccine designThe impact of influenza on individuals and on society remains underappreciated.Up to 20% of the population may develop influenza in any given year, and epidemics of influenza are responsible -on average -for 20,000 deaths per year in the US.In some epidemics, this number may climb to more than 40,000 deaths, with over 300,000 influenza-related hospitalizations in a single winter season (1).By far the most catastrophic impact of influenza during the past 100 years was the pandemic of 1918, which cost more than 500,000 lives in the United States (2) and lowered the average life expectancy by almost 10 years.
Ectopic restriction of DNA repair reveals that UNG2 excises AID-induced uracils predominantly or exclusively during G1 phase
Authors: George Sharbeen, Christine W.Y. Yee, Adrian L. Smith, Christopher J. Jolly
Journal: The Journal of Experimental Medicine (2012)

Immunoglobulin (Ig) affinity maturation requires the enzyme AID, which converts cytosines (C) in Ig genes into uracils (U). This alone produces C:G to T:A transition mutations. Processing of U:G base pairs via U N-glycosylase 2 (UNG2) or MutSα generates further point mutations, predominantly at G:C or A:T base pairs, respectively, but it is unclear why processing is mutagenic. We aimed to test whether the cell cycle phase of U processing determines fidelity. Accordingly, we ectopically restricted UNG2 activity in vivo to predefined cell cycle phases by fusing a UNG2 inhibitor peptide to cell cycle–regulated degradation motifs. We found that excision of AID-induced U by UNG2 occurs predominantly during G1 phase, inducing faithful repair, mutagenic processing, and class switching. Surprisingly, UNG2 does not appear to process U:G base pairs at all in Ig genes outside G1 phase.
Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial
Authors: Anthony H Barnett, Holger Huisman, Russell Jones, Maximilian von Eynatten, Sanjay Patel, Hans-Juergen Woerle
Journal: The Lancet (2013)
Coexistence of Foam Cells and Hypocholesterolemia in Mice Lacking the ABC Transporters A1 and G1
Authors: Ruud Out, Wendy Jessup, Wilfried Le Goff, Menno Hoekstra, Ingrid C. Gelissen, Ying Zhao, Leonard Kritharides, Giovanna Chimini, Johan Kuiper, M. John Chapman, Thierry Huby, Theo J.C. Van Berkel, Miranda Van Eck
Journal: Circulation Research (2007)

The concept that macrophages can become foam cells as a result of a disturbed balance between the uptake of cholesterol from lipoproteins and cholesterol efflux is generally accepted. ABCA1 and ABCG1 are two cholesterol transporters that may act sequentially to remove cellular cholesterol, but currently their combined role in vivo is unknown. We report here that targeted disruption of both ABCA1 and ABCG1 in mice, despite severe plasma hypocholesterolemia, leads to massive lipid accumulation and foam cell formation of tissue macrophages. A complete ablation of cellular cholesterol efflux in vitro is observed, whereas in vivo macrophage-specific reverse cholesterol transport to the feces is markedly decreased. Despite the massive foam cell formation of tissue macrophages, no lipid accumulation was observed in the vascular wall, even in mice of 1 year old, indicating that the double knockout mice, possibly because of their hypocholesterolemia, lack the trigger to attract macrophages to the vessel wall. In conclusion, even under hypocholesterolemic conditions macrophages can be converted into foam cells, and ABCA1 and ABCG1 play an essential role in the prevention of foam cell formation.
Health Policy Basics: Health Insurance Marketplaces
Authors: Ryan A. Crowley, Thomas G. Tape
Journal: Annals of Internal Medicine (2013)

Starting on 1 October 2013, most individuals and small businesses will be able to shop for and enroll in health insurance coverage through their state's health insurance marketplace, also known as an exchange. The health insurance marketplaces will serve as a one-stop resource to help the uninsured and the underinsured find comprehensive health coverage that fits their needs and budget and determine whether they qualify for health insurance tax credits provided by the Patient Protection and Affordable Care Act. Physicians may benefit because insured patients are more likely to have a regular source of care, adhere to medical regimens, and access preventive care. However, implementation of the marketplaces may prove challenging if enrollment numbers are insufficient, technical problems arise, and patients are unable to access providers. Despite these potential issues, physicians are encouraged to educate themselves about how the marketplaces work so they can direct their patients to find the coverage that best meets their medical needs.
Junior doctors' experience, competence and confidence in pleural procedures in two district general hospitals in Ayrshire, Scotland
Authors: Sheonagh Law, Cathy Anderson, Clare Ricketts, Anur Guhan
Journal: European Respiratory Journal (2013)

Introduction and Objectives   The 2008 NPSA [1] report and the British Thoracic Society (BTS) [2] recommend measures of safe practice to reduce risk of serious complications during pleural procedures (PP). We aimed to ascertain the experience, competence and confidence of 47 post-registration junior doctors (PRJD) in Ayrshire hospitals, to inform a PP training program development.   Method   47 PRJD were surveyed about experience in PP, clinical skills course attendance, knowledge of BTS guidelines on PP [2], and objective evidence of competency. A self-scoring Visual Analog Scale was used to measure confidence in: diagnostic/therapeutic aspiration (DA/TA), intercostal chest drain insertion (ICDI) and removal (ICDR) and pleurodesis.   Results   51% returned the survey. PRJD ranged from one to five years post-registration.   Conclusions   67% PRJD were confident in DA/TA and ICDR. While 50% were deemed competent in ICDI, self-certified confidence for independent practice was low. This may reflect PRJD experience across the NHS. Any PP training program should aim to address the gap between deemed competence and confidence, using innovative ways of increasing PRJD experience in PP.   References   1. NPSA: NHS National Patient Safety Agency Rapid Response Report, Risk of Chest Drain Insertion, 15th May 2008. Ref NPSA/2008/RRR003.  2. British Thoracic Society Pleural Disease Guideline 2010 Thorax, Vol 65, Suppl.
Restoration of decreased suppressor cells by vitamin B<sub>12</sub> therapy in a patient with pernicious anemia
Authors: Kazuo Kubota, Toshimasa Arai, Jun'Ichi Tamura, Takuo Shirakura, Toyoho Morita
Journal: American Journal of Hematology (1987)

Abstract A unique case of pernicious anemia is described. Initially, the percentage of OKT8‐positive blood cells was markedly decreased, resulting in an increase in the OKT4/OKT8 ratio. The level of OKT8‐positive blood cells was, however, returned to normal after vitamin B 12 therapy. The finding may propose a possible role of the imbalance of blood lymphocyte subpopulations on the pathogenesis of pernicious anemia and also a responsibility of vitamin B 12 for such a selective reduction in the OKT8‐positive blood cells.
Incomplete surgical resection of DCIS results in activation of HER-2 in residual breast cancer cells
Authors: C. F. Singer, G. Hudelist, E. Fuchs, W. Köstler, A. Fink-Retter, D. Gschwantler-Kaulich, M. Gnant, W. Lamm, W. Lamm, M. Rudas, E. Kubista
Journal: Journal of Clinical Oncology (2009)

e22035 Background: HER-2 amplification and consecutive overexpression is a predictor for poor prognosis in breast cancer patients. In addition, incomplete resection of HER2 overexpressing tumors leads to increased proliferation of residual breast cancer cells. While the local release of cytokines is thought to be responsible for the malignant behaviour of remaining tumor tissue, the exact mechanism is still unknown. Methods: We have analyzed EGFR, activated (p)EGFR, and activated (p)HER2 protein expression in HER2 overexpressing and in non-HER2 overexpressing tumors from patients who underwent breast surgery and consecutive reexcision for involved margins, and compared expression levels by IHC. Results: While overall HER2 protein expression in the initial and the reexcised sample were comparable, we observed an increase in pHER2 in DCIS in both, HER2 overexpressing (16/21 vs 24/24; p=0.018, Chi Square test) and non-HER2 overexpressing tumors (3/28 vs 5/12; p=0.025, Chi Square test). pHER2 was not increased in invasive tumors, regardless on whether the samples had been taken from a HER2 overexpressing (9/25 vs 6/17; p=0.261, Chi Square test), or a non-HER2 overexpressing tumor (1/27 vs 0/8; p=0.581, Chi Square test). EGFR expression was only detected in 1/47 HER2 overexpressing primary tumors and 2/48 non-HER2 overexpressing tumors, and was undetectable in reexcised specimen. Conclusions: Taken together, we have demonstrated an increase in HER2 receptor activation in incompletely resected preinvasive breast cancer. We hypothesize that receptor phosphorylation is caused by growth factor stimulation in response to intraoperative tissue damage, and perioperative inhibition of specific cytokines could become a promising therapeutic strategy. No significant financial relationships to disclose.
Assisted ventilation using cuirass respirators
Authors: W Kinnear, M Petch, G Taylor, J Shneerson
Journal: European Respiratory Journal (1988)

The effects of cuirass-assisted ventilation have been studied in 25 subjects with chest wall disease. Cuirass respirators increase ventilation in proportion to the peak negative pressure within the cuirass shell and the respiratory rate. Positive pressure applied during expiration produces little additional ventilation. During cuirass-assisted ventilation end-expiratory volume increases, arterial carbon dioxide tension (PaCO2) falls and arterial oxygen tension (PaO2) rises. Cardiac output is unchanged. Paradoxical chest wall motion is corrected by cuirass-assisted ventilation and restriction of chest wall expansion by the cuirass shell is minimal. Jacket-type respirators can produce larger tidal volumes than the cuirass at the same peak negative pressure, but are associated with greater air leakage.