tbuckley/cabot-search huggingface dataset:
How To Do It: Commentary: Caution needed in introducing warfarin treatment
Authors: K G Sweeney, D J P. Gray, R J F Steele, P H Evans
Journal: BMJ (1995)

fibrillation in Britain, on the prevalence of indications and contraindications for anticoagulation, on factors that influence doctors' decisions to offer treatment and patients' decisions to accept it, and on the costs and benefits of anticoagulant treatment in primary and secondary care.Funding: CMS is funded by the Medical Research Council.Conflict of interest: The authors are involved in a study of the prevalence of atrial fibrillation and of indications and contraindications for treatment with warfarin, which is funded by the Stroke Association. 1
AEG35156, a XIAP antisense oligonucleotide, suppresses XIAP levels in targeted tissues isolated from pre-clinical models and from patients
Authors: Eric Lacasse, Stephen Morris, Tim Ward, Jeff Cumings, Lesley Robson, Katrina Di Tullio, Danielle Méthot, Lori Jerome, Peter Winocour, John W. Gillard, Jacques Jolivet, Duncan Jodrell, Malcolm Ranson, Jon Durkin
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4862 

X-linked inhibitor of apoptosis (XIAP) is a potent anti-apoptotic protein whose over expression and dysfunction is associated with resistance to chemotherapy and radiotherapy. [AEG35156][1] is a synthetic 19-mer, 2nd generation, mixed backbone antisense oligonucleotide to human XIAP. Inhibition of XIAP expression by [AEG35156][1] enhances cancer cell apoptosis both in vitro and in vivo , either as a single agent or in combination with chemotherapeutic agents. In animal models, [AEG35156][1] reduced XIAP-mRNA and protein levels in representative tissues at therapeutically feasible doses. In a H460 human lung carcinoma xenograft study in mice, [AEG35156][1], effectively suppressed XIAP protein levels in tumors at doses that achieved dramatic reductions in the rate of tumor growth, particularly when combined with suboptimal doses of docetaxel. A murine-specific variant of [AEG35156][1] attenuated XIAP protein in circulating PBMCs and bone marrow when administered s.c. to mice at  80%. Flow cytometric analysis of the patient’s circulating blasts indicated a loss of XIAP protein, and elevated levels of activated caspase 3 and PARP cleavage during [AEG35156][1] infusion. XIAP antisense also caused a dose-dependent reduction in XIAP-mRNA in PBMCs in most patients, suggesting that these cells could serve as a surrogate to target effects in solid tumor tissue. Other trials with [AEG35156][1] are currently underway: a Phase 1 trial in combination with docetaxel in Canada (sponsored by National Cancer Institute of Canada), and an AML trial, in combination with idarubicin and ara-C, in the US and Canada. ( )

 [1]: /lookup/external-ref?link_type=GENPEPT&access_num=AEG35156&atom=%2Fcanres%2F66%2F8_Supplement%2F1142.2.atom
 [2]: /lookup/external-ref?link_type=GENPEPT&access_num=AEG56156&atom=%2Fcanres%2F66%2F8_Supplement%2F1142.2.atom
Inhibition of leukemia growth by a recombinant gelonin conjugate of anti-FLT3 monoclonal antibody
Authors: Yiwen Li, Michael Rosenblum, Hongli Li, Rajiv Bassi, Wenzhi Tian, John W. Marks, Daniel Hicklin
Journal: Cancer Research (2007)

4114   The receptor tyrosine kinase FLT3 is overexpressed in blasts of the majority of acute myelogenous leukemia (AML) and B-lymphoid leukemia patients. Internal tandem duplications (ITDs) in the juxtamembrane region and point mutations in the kinase domain of FLT3 are found in ~37% of AML patients and are associated with a poor prognosis. We have recently developed a fully human monoclonal antibody (IMC-EB10) which binds with high affinity to FLT3 receptor on human leukemia cells. In the present study, a recombinant gelonin conjugate of the anti-FLT3 antibody was prepared that allows for the release of the gelonin toxin inside the antigen-positive cells. The EB10-Gelonin conjugates were stable in buffers. The conjugate retained the binding and internalizing capabilities of the antibody. EB10-Gelonin selectively killed FLT3-expressing leukemia cells with an IC50 of 0.1 nM and 0.4 nM for SEM-K2 and HL60 cells (both positive for FLT3) and 500 nM for JM1 (negative for FLT3). A gelonin conjugate with a control anti-VE-cadhelin antibody was not active in these cell lines (IC50s ~600 nM for SEM-K2 and 1000 nM for MOLM-14 cells). Prelinimary data show that reatment with the EB10-Gelonin conjugate (4 mg/kg, once weekly x 2) significantly inhibited leukemia growth and increased mouse survival in a SEM-K2 xenograft leukemia model in NOD-SCID mice.
Activity of an ethanolic extract of Cryptantha flava and Cryptantha cinerea against the MCF-7, BT-20, and HT-29 human tumor cell lines
Authors: David H. Kinder, Joshua R. Troike
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1924 

Ethnobotanical literature is replete with information regarding the treatment of common illnesses, typically self limiting, but there is infrequent information regarding the use of plant materials to treat cancerous tumors. Indeed, it is unclear if natives of the Southwest United States prior to 100 years ago recognized the difference between a benign tumor and a malignancy. However, there is one report that the Hopi used an extract of the plant Crypthantha flava (Boraginaceae) for treating “tumors” (Moerman, D.E., Native American Ethnobotany, 1998 (ISBN 0-88192-453-9)). This plant is native to the desert southwest United states, and grows on the marginal edges of mesas, typically in sandy soils. We have collected this plant, as well as the closely related plant Crypthantha cinerea , from Chaco Canyon National Historic Park, to test whether an ethanolic extract of this plant has anticancer properties in cell culture. We found that an ethanol extract of both C. cinerea and C. flava have significant anticancer activity in the breast cancer cell lines BT-20 and MCF-7, as well as activity against the colon carcinoma line HT-29 (Extraction of dried leaves and stems: 95% ethanol, 24 hours, evaporation of solvent under vacuum to constant weight. HPLC analysis showed near identical fingerprints for extracts of C. flava and C. cinerea .). The extract did not have significant activity against the human melanoma cell line A-375 at concentrations above 10 ug/ml. IC50 for C. cinerea extract was, respectively, 7.0 ug/ml, 3 ug/ml, and 5 ug/ml for MCF-7, BT-20, and HT-29. Similar results were obtained for the C. flava extract. This work offers substantiation of the ethnobotanical information, and further elucidation of the active components is currently being pursued.
Postherpetic neuralgia
Authors: D. Bowsher
Journal: BMJ (2001)

Using patient identifiable data without consent Obtaining individual consent may hinder studiesEditor-The editorial by Al-Shahi and Warlow is timely and well argued. 1 The implications of a strict requirement for written consent from patients in observational and epidemiological research are extremely serious.Research in histopathology would be particularly severely affected.It is essential that patients' consent is obtained in interventional studies or where information, or, in the case of pathology, tissue, is collected solely for the purpose of research.However, applying this requirement for every study of archived biopsy, surgical or necropsy tissue blocks, or review of patient records, where diagnosis has been made and where patient management will not be affected, is impracticable.Studies of archival material have been the core of research in histopathology.A glance at the methods section of the papers of any pathology journal reveals that most have used archival tissue with no indication that specific patient consent has been obtained.For recent issues of the Journal of Pathology, Histopathology, and the Journal of Clinical Pathology the proportions of archi-val, non-consented research were 9/16, 9/9, and 11/13 papers, respectively.Until now, this form of research has been simple and cheap to undertake, and has provided valuable information on the causes and pathology of many human diseases.It is unlikely that any of the large studies of gastric biopsies, cancers, etc would have been conducted had every patient or their relatives had to be contacted to obtain consent.We would be left with only anecdotal information on which to base prognosis and treatment for many common cancers and we would know much less about many common diseases.Despite considerable problems in obtaining funding for research in histopathology, authors in the United Kingdom continue to produce papers of high quality, but it is doubtful that this will continue if individual consent for each study becomes a legal requirement.Either a general consent for use of residual tissues for research should be allowed or alternatively the NHS needs to fund the staff necessary to obtain the consent from central or regional research and development budgets, which could be accessed by researchers wishing to undertake archival studies.This would, however, be both cumbersome and costly.If observational research in pathology or other subjects and epidemiological studies are to be outlawed, the public interest will be damaged and patients in the future will be the losers.
Inequalities in health
Authors: D. Acheson, D. Baker, R. Illsley
Journal: BMJ (1998)

Editor—The editorial by Davey Smith et al1 devoted to the Report of the Independent Inquiry into Inequalities in Health2 is welcome in many ways but gives a misleading account of some aspects. The authors give the impression that the 39 recommendations were presented without any priority being given. In fact, we selected three clear priorities, which are the focus of our first three recommendations. These are paraphrased in the synopsis as follows:

“There are three areas which we regard as crucial:



all policies likely to have an impact on health should be evaluated in terms of their impact on health inequalities


a high priority should be given to the health of families with children 


further steps should be taken to reduce income inequalities and improve the living standards of poor households.”




The editorial also states that “the key fact that inequalities in health follow closely inequalities in wealth” is underestimated. On the contrary, in addition to nominating the reduction of income inequalities as a priority we note on page 33 of the text that “without a shift of resources to the less well off, both in and out of work, little will be accomplished in terms of a reduction of health inequalities by addressing particular ‘downstream’ influences.”

In line with our remit to identify priority areas for policy development we assembled and assessed a large volume of evidence on each major area. It is important that each recommendation should be read in conjunction with the accompanying text. This gives a summary of the scale and nature of the inequality at which the recommendation is directed, a review of the evidence on how that inequality might be reduced, and an assessment of the expected benefit from the recommended action.

In respect of the recommendations relating to the prevention of suicide and the reduction of the fear of violence, which Davey Smith et al find “too vague to be useful,” several specific suggestions as to how these goals could be achieved are summarised respectively on pages 54 and 55 (crime and violence) and 78 and 107 (suicide).

We believe that this report has assembled in one volume, which includes over 500 references, a wide ranging and up to date body of evidence on actions to tackle inequalities in health. It would be a pity if those who read the BMJ’s editorial were discouraged from making use of it.
Abstract P79: Application of the Video Self Instruction Kit (CPR Anytime <sup>®</sup> ) for The Mass CPR Training Courses and Its Impact on the CPR Quality
Authors: Sung Koo Jung, Joong Sik Jeong, Sang Do Shin, Tae Yun Kim, Joong Eui Rhee, Gil Jun Suh
Journal: Circulation (2008)

Background: We sought to determine whether the video self Instruction kit (CPR anytime ® ) could be a useful tool for the mass CPR training, and to evaluate its effects on the CPR quality compared to the traditional method of learning. Methods: The CPR training courses were designed to 3 different types by the learning method: 45 munites self learning with CPR anytime ® (group A), 1 hour lecture + 45 munites self learning with CPR anytime ® (group B), 1 hour lecture + 1 hour practice with instructors (group C). From July 2007 to August 2007, 405 (34%) participants out of the 1,178 applied trainees were seleted by stratified sampling according to their sex, age, the date of learning, and the learning method. The trainees with any respiratory, skeletal disease or incomplete informed consents were excluded. At the end of the courses, the skill test was done by the checklist and their skill performance was tested using the Laerdal PC SkillReporting System ® . Statistical analysis was performed using One Way ANOVA in continuous variables and x 2 analysis in categorical variables. Results: Two hundred twenty subjects were enrolled properly with 79(35.9%), 66(30.0%), 75(34.1%) belonging to group A, B, and C, respectively. The mean age was 36.3 years and females accounted for 77.3%. We found no significant differences in their willingness to participate, sex, weight, height, and educational status. The skill test indicated no differences among the three groups. In the skill performance, there were no significant differences between group A and B. When compared to group C, group A showed a higher rate of forceful ventilation (58.5 ±38.4% vs 41.3 ±37.9%, p =0.03), a larger amount of mean tidal volume (950.0±416.5 mL vs 745.6±343.8 mL, p =0.00), a lower rate of shallow compression (47.1±40.3% vs 65.4±40.6%, p =0.01), and a deeper depth of compression (38.6±9.6 mm vs 34.1±9.8 mm, p =0.01). Conclusion: The trainees of self leraning with CPR anytime ® showed similar results of the skill test with the trainees of other two longer leraning method, and presented relatively adequate chest compression with the tendency of frequent hyperventilation. On the condition of adding a solution to prevent hyperventilation, the CPR anytime ® can be a helpful tool for the mass CPR education.
Heparin-binding epidermal growth factor-like growth factor (HB) regulates mammary tumorigenesis through EGFR as well as Her2 signal
Authors: Fusanori Yotsumoto, Hiroshi Yagi, Tatsuya Fukami, Masahide Kuroki, Hiroto Mizushima, Eisuke Mekada, Shingo Miyamoto
Journal: Cancer Research (2008)

5175   [Introduction]Her2, a member of ErbB family, plays an important role in the progression of breast cancer (BRCA). Herceptin, which is an anti-cancer agent for Her2, has sufficiently improved clinical outcomes of patients. However, 70 % of patients with BRCA have not displayed the overexpression of Her2. We have demonstrated that HB is a promising target for BRCA therapy in spite of the status of Her2 gene. To provide a promising agent for BRCA patients with or without overexpression of Her2, we examined the suppression of tumorigenicity and alterations in ErbB signals in the use of CRM197, a specific inhibitor for HB.  [Method]BRCA cell lines, MDA-MB-231, MDA-MB-468, BT549, MCF7, SK-BR-3 and CRL1500 were used in this study. All tissue specimens were obtained from 10 cases with BRCA. Informed consent was already obtained from all patients. We examined mRNA expression index (EI) of EGFR, EGFR ligand and Her2 by real-time PCR and the soluble forms of the EGFR ligands in culture medium by ELISA. We assessed the expression of EGFR, Her2 and tyrosine phosphorylation of EGFR and Her2 by immunoprecipitation and immunoblotting as well as the number of apoptotic cells by flow cytometry after the addition of CRM197, Trastuzumab and Erlotinib into these cell lines. To evaluate the antitumor effects of CRM197, 5x10 6  cells were subcutaneously inoculated on nude mice, and CRM197 (1mg/kg) were injected intraperitoneally each week for four weeks. Each tumor volume was estimated from two dimensional tumor measurements. Data were analyzed using the Mann-Whitney  U  test. P 3  and 1.56x10 4  , respectively. The addition of CRM197 significantly increased the numbers of apoptotic cells with attenuation of EGFR and/or Her2 activation in all BRCA cell lines. On the other hand, Erlotinib showed in vitro anti-tumor effect with suppression of EGFR signaling in MDA-MB-231 and BT549, while Trastuzumab showed in vitro anti-tumor effect with suppression of Her2 signaling in MCF7 and CRL1500. In the administration of CRM197, the tumor volume on treated mice was significantly reduced, compared to that on untreated mice in all BRCA cell lines. CRM197 induced the attenuation of EGFR signals and the reduction of Her2 expression. These results indicated that CRM197 inhibited the tumor formation through the blockade of EGFR as well as Her2 signals.[Conclusion]HB is a validating target for BRCA with or without overexpression of Her2, and CRM 197 is a broad applicable anti-cancer agent for BRCA therapy.
Quantitative measurement of multiple avenues of MEK regulation by capillary immunoassay.
Authors: Nineveh Parker, Christine Pratilas, Eric Joseph, Poulikos Poulikakos, Neal Rosen, Erik Gentalen
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

LB-278 

Activation of the MAPK pathway involves a complicated web of MEK phosphorylations. The two MEK isoforms are regulated by at least three other enzymes- PAK, RAF and ERK. Up until now it has been impossible to quantitate and determine the stoichiometry of the various multiply phosphorylated MEK forms. We have developed a new capillary immunoassay which resolves the different MEK variants, and allows measurement of the relative abundance of each form with a single antibody. This measurement of how the multiply phosphorylated forms change gives insight into how the dynamics of pathway feedback and activity change in response to drug treatment.    We have shown that signaling upstream of MEK kinase is inhibited by negative feedback in tumor cells in which the pathway is driven by HER kinases. In these cells, MEK1 is phosphorylated at ERK- and PAK-dependent sites (T292, S298), whereas phosphorylation on RAF-dependent sites is undetectable. A selective MEK inhibitor inhibits ERK phosphorylation, relieves the negative feedback, and activates MEK phosphorylation in these cells. Under these conditions, phosphorylation of both kinases on the RAF dependent sites (S217, S222) is markedly induced.    Thus, inhibition of MEK/MAPK signaling in these cells abrogates upstream feedback of the pathway and results in a complex change in phosphorylation of MEK due to multiple kinases. The capillary immunoassay allows determination of complex changes in phosphorylation of MEK kinase by PAK, RAF and ERK kinases in response to MEK inhibition. This technique will be useful in mapping pathway network response to targeted drugs in vitro and in vivo.
Strain features and distributions in pneumococci from children with invasive disease before and after 13-valent conjugate vaccine implementation in the USA
Authors: B.J. Metcalf, R.E. Gertz, R.A. Gladstone, H. Walker, L.K. Sherwood, D. Jackson, Z. Li, C. Law, P.A. Hawkins, S. Chochua, M. Sheth, N. Rayamajhi, S.D. Bentley, L. Kim, C.G. Whitney, L. McGee, B. Beall
Journal: Clinical Microbiology and Infection (2015)

<h2>Abstract</h2> The effect of second-generation pneumococcal conjugate vaccines on invasive pneumococcal disease (IPD) strain distributions have not yet been well described. We analysed IPD isolates recovered from children aged <5 years through Active Bacterial Core surveillance before (2008–2009; <i>n</i> = 828) and after (2011–2013; <i>n</i> = 600) 13-valent pneumococcal conjugate vaccine (PCV13) implementation. We employed conventional testing, PCR/electrospray ionization mass spectrometry and whole genome sequence (WGS) analysis to identify serotypes, resistance features, genotypes, and pilus types. PCV13, licensed in February 2010, effectively targeted all major 19A and 7F genotypes, and decreased antimicrobial resistance, primarily owing to removal of the 19A/ST320 complex. The strain complex contributing most to the remaining β-lactam resistance during 2011–2013 was 35B/ST558. Significant emergence of non-vaccine clonal complexes was not evident. Because of the removal of vaccine serotype strains, positivity for one or both pilus types (PI-1 and PI-2) decreased in the post-PCV13 years 2011–2013 relative to 2008–2009 (decreases of 32–55% for PI-1, and >95% for PI-2 and combined PI-1 + PI-2). β-Lactam susceptibility phenotypes correlated consistently with transpeptidase region sequence combinations of the three major penicillin-binding proteins (PBPs) determined through WGS analysis. Other major resistance features were predictable by DNA signatures from WGS analysis. Multilocus sequence data combined with PBP combinations identified progeny, serotype donors and recipient strains in serotype switch events. PCV13 decreased the frequency of all PCV13 serotype clones and concurrently decreased the frequency of strain subsets with resistance and/or adherence features conducive to successful carriage. Our results serve as a reference describing key features of current paediatric IPD strains in the USA after PCV13 implementation.
Combination of prostate-specific antigen (PSA) exposure and Gleason score as prognostic factors for prostate cancer (PC) patients
Authors: A. Banu, S. Oudard, E. Banu, D. Kamioneur, M. Housset, N. Thiounn, F. Scotte, A. Jenabian, A. Mejean, J. M. Andrieu
Journal: Journal of Clinical Oncology (2005)

4709 Background: Predicting outcome for men with PC, treated with curative intent, remains imprecise and further evaluation of accepted and potential predictive factors is needed. Methods: The PSA exposure (PSA dynamics during lifetime) was estimated by corrected area under PSA curve [(PSA c-AUC), abstract 9579, ASCO 2004]. Based on their PSA c-AUC values (< 60 vs ≥ 60 ng/mL) and Gleason score (5–7 vs 8–10), patients (pts) were analyzed according to time from primary diagnosis (TPD) as major survival endpoint. TPD was calculated from primary diagnosis until death or last follow-up. A prognostic scoring system was created using the Kaplan-Meier test to classify pts according to risk of death. Our model identified four risk groups with predicted 3-, 5-, 7-, 10-, 13-, 15- and 18-year TPD percentages. Associated 95% confidence interval (CI) were calculated. Results: Characteristics of the 449 PC pts: median age at initial diagnosis was 64 years (range 41–82 years), median PSA follow-up duration of 2.7 years (range 0.1–16.1 years). Median number of PSA determinations was 15 (range 2–59). There were significant TPD differences (P = 0.00001) according to risk group (Table). The median TPD for the low PSA c-AUC level (< 60 ng/mL) groups was similar, independently of Gleason score [10.3 years (95% CI 8.7–11.9 years) vs 9.7 years (95% CI 7.1–13.1 years)]. Only 22% of pts in high risk group (Gleason > 8 and PSA c-AUC ≥ 60 ng/mL) are alive at 5 years, with a median TPD of 3 years (95% CI 2.3–3.8 years), two times lower than Gleason 5–7 and PSA c-AUC ≥ 60 ng/mL group [median of 7.3 years (95% CI 5.3–9.4 years), 67% alive]. Conclusions: By combining PSA c-AUC with Gleason score, we were able to predict TPD survival probabilities and to identify a high-risk group. A higher PSA exposure (≥ 60 ng/mL) during lifetime was correlated with a higher mortality. Consequently, these patients are candidates for early aggressive treatments in phase II-III clinical trials. No significant financial relationships to disclose.
Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy
Authors: Laurence Tiret, Christine Mallet, Odette Poirier, Viviane Nicaud, Alain Millaire, Jean-Brieuc Bouhour, Gérard Roizès, Michel Desnos, Richard Dorent, Ketty Schwartz, François Cambien, Michel Komajda
Journal: Journal of the American College of Cardiology (2000)