tbuckley/cabot-search huggingface dataset:
Variability of Interpretive Accuracy Among Diagnostic Mammography Facilities
Authors: Sara L. Jackson, Stephen H. Taplin, Edward A. Sickles, Linn Abraham, William E. Barlow, Patricia A. Carney, Berta Geller, Eric A. Berns, Gary R. Cutter, Joann G. Elmore
Journal: JNCI Journal of the National Cancer Institute (2009)

Interpretive performance of screening mammography varies substantially by facility, but performance of diagnostic interpretation has not been studied.Facilities performing diagnostic mammography within three registries of the Breast Cancer Surveillance Consortium were surveyed about their structure, organization, and interpretive processes. Performance measurements (false-positive rate, sensitivity, and likelihood of cancer among women referred for biopsy [positive predictive value of biopsy recommendation {PPV2}]) from January 1, 1998, through December 31, 2005, were prospectively measured. Logistic regression and receiver operating characteristic (ROC) curve analyses, adjusted for patient and radiologist characteristics, were used to assess the association between facility characteristics and interpretive performance. All statistical tests were two-sided.Forty-five of the 53 facilities completed a facility survey (85% response rate), and 32 of the 45 facilities performed diagnostic mammography. The analyses included 28 100 diagnostic mammograms performed as an evaluation of a breast problem, and data were available for 118 radiologists who interpreted diagnostic mammograms at the facilities. Performance measurements demonstrated statistically significant interpretive variability among facilities (sensitivity, P = .006; false-positive rate, P < .001; and PPV2, P < .001) in unadjusted analyses. However, after adjustment for patient and radiologist characteristics, only false-positive rate variation remained statistically significant and facility traits associated with performance measures changed (false-positive rate = 6.5%, 95% confidence interval [CI] = 5.5% to 7.4%; sensitivity = 73.5%, 95% CI = 67.1% to 79.9%; and PPV2 = 33.8%, 95% CI = 29.1% to 38.5%). Facilities reporting that concern about malpractice had moderately or greatly increased diagnostic examination recommendations at the facility had a higher false-positive rate (odds ratio [OR] = 1.48, 95% CI = 1.09 to 2.01) and a non-statistically significantly higher sensitivity (OR = 1.74, 95% CI = 0.94 to 3.23). Facilities offering specialized interventional services had a non-statistically significantly higher false-positive rate (OR = 1.97, 95% CI = 0.94 to 4.1). No characteristics were associated with overall accuracy by ROC curve analyses.Variation in diagnostic mammography interpretation exists across facilities. Failure to adjust for patient characteristics when comparing facility performance could lead to erroneous conclusions. Malpractice concerns are associated with interpretive performance.
Review of Marion Danis, Emily Largent, David Wendler, Sara Chandros Hull, Seema Shah, Joseph Millum, Benjamin Berkman, and Christine Grady,<i>Research Ethics Consultation: A Casebook<sup>1</sup></i>
Authors: Emily E. Anderson
Journal: The American Journal of Bioethics (2012)

Click to increase image sizeClick to decrease image size Acknowledgments New York, NY: Oxford University Press, 2012, 259 pp.
The PYRIN Connection
Authors: Christian Stehlik, John C. Reed
Journal: The Journal of Experimental Medicine (2004)

Periodic fever syndromes (PFSs) comprise a subset of the hereditary autoinflammatory disorders that are defined by recurrent self-resolving attacks of systemic inflammatory reactions in the absence of infection or autoimmunity. Recent advances have led to the discovery that members of a new family of genes, the PYRIN family, account for several hereditary PFSs. Here we discuss new insights into the function of PYRIN proteins and the molecular basis of PFSs.
Chemical Genetics–Based Target Identification in Drug Discovery
Authors: Feng Cong, Atwood K. Cheung, Shih-Min A. Huang
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Identification of novel, validated targets remains a top priority in modern drug discovery. Chemical genetics represents a powerful approach to the discovery of new targets. Unlike the traditional target-based screen that relies on a predefined, sometimes poorly validated target, a chemical genetics-based phenotypic screen probes the entire molecular signaling pathway in an efficient and unbiased manner for the most drug-sensitive node. The most significant obstacle associated with this approach is identification of the efficacy targets of small-molecule probes. The huge potential of chemical genetics cannot be realized without the establishment of reliable mechanisms for target identification. In this article, we describe each essential element of the chemical genetics process, discuss common challenges that the field is facing, and critically review various biochemical and genetics approaches recently developed for target deconvolution. We also attempt to summarize lessons that we have collectively learned and provide a practical perspective to facilitate the advancement of chemical genetics.
Factors Associated With Racial Differences in Myocardial Infarction Outcomes
Authors: John A. Spertus
Journal: Annals of Internal Medicine (2009)

Background: Little information is available about factors associated with racial differences across a broad spectrum of post–myocardial infarction outcomes, including patients' symptoms and quality of life. Objective: To determine racial differences in mortality, rehospitalization, angina, and quality of life after myocardial infarction and identify the factors associated with these differences. Design: Prospective cohort study. Setting: 10 hospitals in the United States. Patients: 1849 patients who had myocardial infarction, 28% of whom were black. Measurements: Demographic, economic, clinical, psychosocial, and treatment characteristics and outcomes were prospectively collected. Outcomes included time to 2-year all-cause mortality, 1-year rehospitalization, and Seattle Angina Questionnaire–assessed angina and quality of life. Results: Black patients had higher unadjusted mortality (19.9% vs. 9.3%; P < 0.001) and rehospitalization rates (45.4% vs. 40.4%; P = 0.130), more angina (28.0% vs. 17.8%; P < 0.001), and worse mean quality of life (80.6 [SD, 22.5] vs. 85.9 [SD, 17.2]; P < 0.001). After adjustment for patient characteristics, black patients trended toward greater mortality (hazard ratio, 1.29 [95% CI, 0.92 to 1.81]; P = 0.142), fewer rehospitalizations (hazard ratio, 0.82 [CI, 0.66 to 1.02]; P = 0.071), and higher likelihood of angina at 1 year (odds ratio, 1.41 [CI, 1.03 to 1.94]; P = 0.032) but similar quality of life (mean difference, −0.6 [CI, −3.4 to 2.2]). Adjustment for site of care further attenuated mortality differences (hazard ratio, 1.04 [CI, 0.71 to 1.52]; P = 0.84). Adjustment for treatments had minimal effect on any association. Limitation: Residual confounding and missing data may have introduced bias. Conclusion: Although black patients with myocardial infarction have worse outcomes than white patients, these differences did not persist after adjustment for patient factors and site of care. Further adjustment for treatments received minimally influenced observed differences. Strategies that focus on improving baseline cardiac risk and hospital factors may do more than treatment-focused strategies to attenuate racial differences in myocardial infarction outcomes. Funding: The National Heart, Lung, and Blood Institute Specialized Center of Clinically Oriented Research in Cardiac Dysfunction and Disease, CV Therapeutics, and Cardiovascular Outcomes.
A novel two-step genome editing strategy with CRISPR-Cas9 provides new insights into telomerase action and TERT gene expression
Authors: Linghe Xi, Jens C. Schmidt, Arthur J. Zaug, Dante R. Ascarrunz, Thomas R. Cech
Journal: Genome biology (2015)

To facilitate indefinite proliferation, stem cells and most cancer cells require the activity of telomerase, which counteracts the successive shortening of telomeres caused by incomplete DNA replication at the very end of each chromosome. Human telomerase activity is often determined by the expression level of telomerase reverse transcriptase (TERT), the catalytic subunit of the ribonucleoprotein complex. The low expression level of TERT and the lack of adequate antibodies have made it difficult to study telomerase-related processes in human cells.To overcome the low CRISPR-Cas9 editing efficiency at the TERT locus, we develop a two-step "pop-in/pop-out" strategy to enrich cells that underwent homologous recombination (HR). Using this technique, we fuse an N-terminal FLAG-SNAP-tag to TERT, which allows us to reliably detect TERT in western blots, immunopurify it for biochemical analysis, and determine its subcellular localization by fluorescence microscopy. TERT co-localizes detectably with only 5-7 % of the telomeres at a time in S-phase HeLa cells; no nucleolar localization is detected. Furthermore, we extend this approach to perform single base-pair modifications in the TERT promoter; reverting a recurrent cancer-associated TERT promoter mutation in a urothelial cancer cell line results in decreased telomerase activity, indicating the mutation is causal for telomerase reactivation.We develop a two-step CRISPR-Cas9 genome editing strategy to introduce precise modifications at the endogenous TERT locus in human cell lines. This method provides a useful tool for studying telomerase biology, and suggests a general approach to edit loci with low targeting efficiency and to purify and visualize low abundance proteins.
Visualization of the Genesis and Fate of Isotype-switched B Cells during a Primary Immune Response
Authors: Kathryn A. Pape, Valerie Kouskoff, David Nemazee, H. Lucy Tang, Jason G. Cyster, Lina E. Tze, Keli L. Hippen, Timothy W. Behrens, Marc K. Jenkins
Journal: The Journal of Experimental Medicine (2003)

The life history of isotype-switched B cells is unclear, in part, because of an inability to detect rare antigen-specific B cells at early times during the immune response. To address this issue, a small population of B cells carrying targeted antibody transgenes capable of class switching was monitored in immunized mice. After contacting helper T cells, the first switched B cells appeared in follicles rather than in the red pulp, as was expected. Later, some of the switched B cells transiently occupied the red pulp and marginal zone, whereas others persisted in germinal centers (GCs). Antigen-experienced IgM B cells were rarely found in GCs, indicating that these cells switched rapidly after entering GCs or did not persist in this environment.
Single Oral Dose of Geranylgeranylacetone Induces Heat-Shock Protein 72 and Renders Protection Against Ischemia/Reperfusion Injury in Rat Heart
Authors: Tatsuhiko Ooie, Naohiko Takahashi, Tetsunori Saikawa, Tomoko Nawata, Masaya Arikawa, Kunitoshi Yamanaka, Masahide Hara, Tatsuo Shimada, Toshiie Sakata
Journal: Circulation (2001)

Induction of heat-shock proteins (HSPs) results in cardioprotection against ischemic insult. Geranylgeranylacetone (GGA), known as an antiulcer agent, reportedly induces HSP72 in the gastric mucosa and small intestine of rats. The present study tested the hypothesis that oral GGA would induce HSP72 in the heart and thus render cardioprotection against ischemia/reperfusion injury in rats.Cardiac expression of HSPs was quantitatively evaluated in rats by Western blot analysis. Ten minutes of whole-body hyperthermia induced HSP72 expression in the rat hearts. A single oral dose of GGA (200 mg/kg) also induced expression of HSP72, which peaked at 24 hours after administration. Therefore, isolated perfused heart experiments using a Langendorff apparatus were performed 24 hours after administration of 200 mg/kg GGA (GGA group) or vehicle (control group). After a 5-minute stabilization period, no-flow global ischemia was given for 20, 40, or 60 minutes, followed by 30 minutes of reperfusion. During reperfusion, the functional recovery was greater and the released creatine kinase was less in the GGA group than in the control group. Electron microscopy findings revealed that the ischemia/reperfusion-induced damage of myocardial cells was prevented in GGA-treated myocytes.The results suggest that oral GGA is cardioprotective against ischemic insult through its induction of HSP72.
Statement on Use of DNA Testing for Presymptomatic Identification of Cancer Risk
Authors: Francis S. Collins, Lennette J. Benjamin, David Botstein, Jerome R. Cox, Norman Davidson, Joe W. Gray, Neil Holtzman, David E. Housman, Kay R. Jamison, Rodney Rothstein, Diane C. Smith, Lloyd M. Smith, M. Anne Spence, Shirley M. Tilghman
Journal: JAMA (1994)

RECENT advances in the genetics of cancer have raised the possibility of widespread DNA testing for the detection of predisposition to cancer. This may allow individuals at high risk to avail themselves of preventive measures and potentially avoid early death. At least one company has already announced plans to begin offering testing for genetic cancer risk. While much alleviation of human suffering may eventually result from these advances in cancer genetics, a number of important questions must be addressed before widespread testing of this sort can be recommended.  Two relatively common heritable cancer risk genes have recently been located. Among people with colon cancer, it appears that as many as 10% carry an altered germline copy of a gene called MSH2 . 1-3 Individuals with an altered MSH2 gene face an approximately 80% risk of colon cancer; women also have an elevated risk of endometrial and ovarian cancer. Intense medical surveillance
Addition of either irinotecan or methotrexate to bolus5-fluorouracil and high-dose folinic acid every 2 weeks in advanced colorectal carcinoma: a randomised study by the Southern Italy Cooperative Oncology Group
Authors: P. Comella, E. Crucitta, F. De Vita, L. De Lucia, A. Farris, F. Del Gaizo, S. Palmeri, A. Iannelli, S. Mancarella, S. Tafuto, L. Maiorino, F. Buzzi, G. De Cataldis
Journal: Annals of Oncology (2002)
Dying to be big: a review of anabolic steroid use.
Authors: H M Perry, D Wright, B N Littlepage
Journal: British Journal of Sports Medicine (1992)

Anabolic steroids use is commonly perceived to be the domain of the higher echelons of competitive athletes. However, a great deal of anabolic steroid use occurs in private gymnasia (non-local authority) among non-competitive recreational athletes. Our study has attempted to give an insight into the prevalence of the use of these drugs, the hazards associated with it, and the public health responses which we have adopted.
Relevant to today's society? Evidence
Authors: George T Lewith
Journal: Journal of the Royal Society of Medicine (2009)

One hundred and fifty years ago the conventional medical profession believed in blood letting and chiropractors believed that they could treat meningitis by manipulating the spine. Now both professions are medically registered and neither believes in these myths! As Professor Ernst suggests, chiropractors now adhere to the ethics of evidence-based medicine.

As has been pointed out to Baum (and Singh) repeatedly, the evidence for harm in the paediatric population receiving chiropractic is based on limited and questionable case reports. The evidence for chiropractic causing harm in the adult population is even flimsier with good solid case-controlled studies suggesting that chiropractic manipulation of the neck is not unsafe and appears not to cause stroke.1

I have great respect for Professor Baum but unfortunately he has a particular blind spot with respect to complementary and alternative medicine (CAM) which fails to create a thoughtful and informed debate.2 There is no doubt that we all have much to learn about CAM and the evidence for the safety and effectiveness of chiropractic will no doubt change chiropractic practice over the coming years as it has done already with respect to the way we manage back pain within the NHS. To a very large extent Dr Singh brought this battle upon himself and appears to have created a cause celebre around the libel laws possibly because he failed to win the initial hearing against the chiropractors.
Bleomycin in Testicular Cancer: Will Pharmacogenomics Improve Treatment Regimens?
Authors: Carsten Bokemeyer
Journal: Journal of Clinical Oncology (2008)

Bleomycin is an antibiotic with anticancer properties produced by Streptomyces verticillus. It was identified in 1966, and one of its mechanisms of action is breaking the DNA double helix by the production of free radicals, a process that is oxygen and iron dependent. Bleomycin is metabolized in the kidney, with 50% of the dose eliminated within 4 hours after administration. 1 Furthermore, it is inactivated by an enzyme, bleomycin hydrolase, which is present in both in normal and tumor cells. 2 Bleomycin has a long history in cancer treatment, and it has been used as cytotoxic agent against many malignant tumors such as germ cell cancers, lymphomas, Hodgkin’s disease,headandneckcancer,andKaposi’ssarcoma. 3 Amongitsside effects are allergic reactions, mucositis, mild myelosuppression, hyperkeratosis and pigmentation changes of the skin, and, in particular, pulmonaryfibrosis.Itisthelattertoxicitythathasledtoalimitationof the total cumulative dose of bleomycin applied in cancer patients to a maximum of approximately 360 mg. Bleomycin has been most intensively studied in patients with germ cell cancer. The treatment of metastatic germ cell cancer with modern cisplatin-based combination regimens such as cisplatin, etoposide, and bleomycin (PEB) today results in cure in approximately 80% of patients. 4 The factors known to be associated with treatment
Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils.
Authors: Y Kameyoshi, A Dörschner, A I Mallet, E Christophers, J M Schröder
Journal: The Journal of Experimental Medicine (1992)

Thrombin stimulation of human platelets results in the release of a preformed proteinaceous human eosinophil (Eo)-chemotactic activity. By the use of different high-performance liquid chromatography techniques, two Eo-chemotactic polypeptides (EoCPs), tentatively termed EoCP-1 and EoCP-2, were purified to homogeneity. Upon SDS-PAGE analysis, these chemotaxins showed molecular masses near 8 kD. NH2-terminal amino acid sequence analysis revealed identical sequences for both EoCP-1 and EoCP-2, which are also identical to that of RANTES, a cytokine that structurally belongs to the interleukin 8 superfamily of leukocyte selective attractants, and that is known to be a "memory-type" T lymphocyte-selective attractant. In the major Eo chemotaxin, EoCP-1, the residues 4 and 5, which in EoCP-2 were found to be serine residues, could not be identified. Electrospray mass spectrometry (ESP-MS) of EoCPs revealed for EoCP-2 a molecular mass of 7,862.8 +/- 1.1 daltons, which is 15.8 mass units higher than the calculated value of RANTES, indicating that EoCP-2 is identical to the full-length cytokine, and oxygenation, probably at methionine residue number 64, has taken place. Upon ESP-MS, EoCP-1 showed an average molecular mass of 8,355 +/- 10 daltons, suggesting O-glycosylation at these serine residues. Both natural forms of RANTES showed strong Eo-chemotactic activity (ED50 = 2 nM) with optimal chemotactic migration at concentrations near 10 nM, however, there were no significant migratory responses with human neutrophils. Chemotactic activity of RANTES for human Eos could be confirmed using recombinant material, which has been found to be as active as the natural forms. Since RANTES gene expression has been detected in activated T lymphocytes, and recombinant RANTES was shown to be a "memory" T lymphocyte-selective attractant, it is now tempting to speculate about an important role of RANTES in clinical situations such as allergene-induced late-phase skin reactions in atopic subjects or asthma, where in affected tissues both memory T cells and Eos are characteristic.
Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H)
Authors: M Walsh, A Chaudhry, D Jayne
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> Lymphocytes are a contributor to the pathogenesis of anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AASV). Conventional immunosuppressive therapy is associated with high rates of relapse and toxicity. Humanised monoclonal anti-CD52 antibodies (alemtuzumab, CAMPATH-1H) selectively deplete lymphocytes. We present long-term follow-up results of patients with relapsing/refractory AASV treated with CAMPATH-1H. <h3>Patients and methods:</h3> Between 1991 and 1999, 71 patients with refractory or relapsing AASV received CAMPATH-1H at Addenbrooke's Hospital, Cambridge, UK. Other immunosuppressive drugs were discontinued and prednisolone was tapered to 10 mg/day. <h3>Results:</h3> The mean follow-up time was 5 years. In all, 79% had previously received cyclophosphamide (median dose 150 g). At the time of treatment, 42% had renal involvement (median creatinine for the cohort 101 μmol/litre excluding six patients who were dialysis dependent) and 18% were critically ill from AASV and required the intensive care unit. A total of 60 patients (85%) obtained a remission after treatment with CAMPATH-1H but 43 relapsed (median 9.2 months); 24 had a remission greater than 1 year, of which 10 had a remission of at least 3 years. A total of 31 patients died (median survival time of 106 months). Age &gt;50 years, dialysis dependency and the development of a severe infection at the time of treatment were associated with an increased risk of death in multivariable analysis. Adverse events were common; 28 patients developed an infection, 3 malignancy and 8 thyroid disease. <h3>Conclusions:</h3> CAMPATH-1H induced remission in most patients with difficult to treat AASV. However, relapse and adverse events were common. Further study of CAMPATH-1H as an induction agent in AASV is warranted.