tbuckley/cabot-search huggingface dataset:
Clustered Genomic Alterations in Chromosome 7p Dictate Outcomes and Targeted Treatment Responses of Lung Adenocarcinoma With<i>EGFR</i>-Activating Mutations
Authors: Shinsheng Yuan, Sung-Liang Yu, Hsuan-Yu Chen, Yi-Chiung Hsu, Kang-Yi Su, Huei-Wen Chen, Chih-Yi Chen, Chong-Jen Yu, Jin-Yuan Shih, Yih-Leong Chang, Chiou-Ling Cheng, Chung-Ping Hsu, Jiun-Yi Hsia, Chien-Yu Lin, Guani Wu, Chia-Hsin Liu, Chin-Di Wang, Kang-Chung Yang, Yi-Wei Chen, Yi-Ling Lai, Chu-Chun Hsu, Tai-Ching Lin, Tsung-Ying Yang, Kun-Cheieh Chen, Kuo-Hsuan Hsu, Jeremy J.W. Chen, Gee-Chen Chang, Ker-Chau Li, Pan-Chyr Yang
Journal: Journal of Clinical Oncology (2011)

Purpose Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been proven more effective for patients with lung adenocarcinoma with EGFR-activating mutation rather than wild type, the former group still includes approximately 30% nonresponders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to patients with EGFR-activating mutation. Patients and Methods We first investigated the molecular differences between tumors with EGFR-activating mutation and wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues. We then used an independent group of 114 patients to validate the clinical relevance of copy-number alterations (CNAs) in predicting overall and disease-free survival. Finally, focusing on 23 patients with EGFR mutation receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs. Results We identified chromosome regions with differential CNAs between tumors with EGFR-activating mutation and wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted overall and disease-free survival for patients with EGFR-activating mutation but not for those with wild type. Importantly, simultaneous presence of more genes with increased CNAs in this cluster correlated with less favorable response to EGFR-TKIs in patients with EGFR-activating mutation. Conclusion Our results shed light on why responses to EGFR-TKIs are heterogeneous among patients with EGFR-activating mutation. They may lead to better patient management in this population.
Hemoglobin decline, function, and mortality in the elderly: The cardiovascular health study
Authors: Neil A. Zakai, Benjamin French, Alice M. Arnold, Anne B. Newman, Linda F. Fried, John Robbins, Paulo Chaves, Mary Cushman
Journal: American Journal of Hematology (2012)

Abstract While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied. We evaluated the determinants and consequences of hemoglobin decline in 3,758 non‐anemic participants from the Cardiovascular Health Study, a prospective cohort of community‐dwelling elderly ≥65 years old at baseline and followed for up to 16 years. Hemoglobin was measured at baseline and 3 years later and anemia defined by World Health Organization (WHO) criteria. We modeled hemoglobin decline in two ways: (1) per each 1 g/dL decrease in hemoglobin and (2) development of anemia by the WHO criteria. Among participants without baseline anemia, hemoglobin decreased by 0.4 g/dL and 9% developed anemia over 3 years. Baseline increasing age, female sex, diabetes, and kidney disease predicted hemoglobin decline over 3 years. Baseline increasing age, being African‐American, and kidney disease predicted anemia development over 3 years. Hemoglobin decline was associated with subsequent worse cognitive function in men and anemia development with subsequent worse cognitive function in women. Both anemia development (HR 1.39, 95% CI 1.15, 1.69) and hemoglobin decline (HR 1.11, 95% CI 1.04, 1.18 per 1 g/dL decrease) predicted subsequent mortality in men and women. Hemoglobin decreases identified a large group of elderly individuals at risk for subsequent adverse outcomes who would not be identified using the WHO anemia criteria. These data may allow clinicians to identify at‐risk elderly individuals for early intervention to improve the quality and quantity of life. Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc.
Genomewide Linkage Analysis to Serum Creatinine, GFR, and Creatinine Clearance in a Community-Based Population
Authors: Caroline S. Fox, Qiong Yang, L. Adrienne Cupples, Chao-Yu Guo, Martin G. Larson, Eric P. Leip, Peter W.F. Wilson, Daniel Levy
Journal: Journal of the American Society of Nephrology (2004)

Kidney disease is a risk factor for the development of cardiovascular disease, all-cause mortality, and ESRD. It is not known to what extent genetic factors play a role in the development of kidney disease in the general population. Multipoint variance components linkage analysis was performed using Genehunter on 330 families from the Framingham Heart Study offspring cohort, using a 10-cM genomewide scan for serum creatinine, GFR, and creatinine clearance (CRCL) measured from 1998 to 2001. GFR was estimated using the simplified Modification of Diet in Renal Disease Study equation, and CRCL was estimated using the Cockcroft-Gault equation. Covariates in the adjustment included age, gender, body mass index, diabetes, systolic BP, hypertension treatment, tobacco use, and HDL cholesterol. Overall, 1224 subjects (52% women), mean age 59, were available for analysis. Mean creatinine was 0.87 mg/dl, mean GFR was 87 ml/min per 1.73 m2, and mean creatinine clearance was 100 ml/min. The multivariable-adjusted heritability estimates for creatinine, GFR, and CRCL were 0.29, 0.33, and 0.46, respectively. The peak log of the odds ratio (LOD) scores for serum creatinine, GFR, and CRCL were 2.28 at 176 cM on chromosome 4, 2.19 at 78 cM on chromosome 4, and 1.91 at 103 cM on chromosome 3, respectively. In a community-based sample, measures of serum creatinine, GFR, and CRCL are heritable, suggesting an underlying genetic component. These results also provide suggestive evidence for linkage to measures of kidney function. Further research is necessary to identify the genes involved in the development of kidney disease and to understand their roles in this complex process.
Effects of antioxidant enzyme polymorphisms on ozone-induced lung function changes
Authors: C. Chen, M. Arjomandi, I. B. Tager, N. Holland, J. R. Balmes
Journal: European Respiratory Journal (2007)

Chronic exposure to ozone (O 3 ) can cause changes in lung function that may reflect remodelling of small airways. It is likely that antioxidant enzyme function affects susceptibility to O 3 . The aim of the present study was to determine whether polymorphisms in antioxidant enzyme ( GSTM1 , GSTP1 and NQO1 ) genes affect the risk of lung function changes related to chronic exposure to O 3 . In total, 210 young adults who participated in a previous study, which showed a relationship between lifetime exposure to O 3 and decreased lung function, were genotyped. Multivariable linear regression was used to model sex-specific associations between genotypes and O 3 -related lung function changes, adjusting for height, weight, lifetime exposure to nitrogen dioxide and particles with a 50% cut-off aerodynamic diameter of 10 μm, and self-identified race/ethnicity. The GSTM1 -null/ NQO1 Pro187Pro-combination genotype was significantly associated with increased risk of an O 3 -related decrease in mean forced expiratory flow between 25–75% of forced vital capacity in females (parameter estimate± se -75±35 mL·s −1 ), while the GSTP1 Val105 variant genotypes were significantly associated with greater risk of an O 3 -related decrease in mean forced expiratory flow at 75% of forced vital capacity in males (-81±31 mL·s −1 ). GSTM1 -null status was not significantly associated with any O 3 -related changes in lung function in either sex. The current authors conclude that the effects of antioxidant enzyme gene polymorphisms on the risk of decreased lung function related to chronic exposure to ozone may be modified by sex-specific factors.
Lister Jubilee Number: Remarks on Plugging with Iodoform Gauze in Operations Performed in Cavities of the Body
Authors: E. von Bergmann
Journal: BMJ (1902)

Glycosylation is a key modification of proteins and lipids and is involved in most intermolecular and intercellular interactions. The gastrointestinal mucus gel is continuous and can be divided into two layers: a secreted loosely associated layer and a layer firmly attached to the mucosa. In addition, the membrane-bound glycosylated proteins and lipids create a glycocalyx, which remains adherent on each cell and is dynamic and responsive to the physiological state and environment of the cell. The secreted glycans form a mucus gel layer that serves as a physicochemical sensor and barrier network and is primarily composed of mucins and associated peptides. These glycans protect gut epithelial cells from chemical, biological and physical insults and are continuously renewed. Pathogens colonise and invade the host epithelial cells using protein–protein and glycan–lectin interactions. During the process of colonisation and infection, the glycosylation state of both host and pathogen change in response to the presence of the other. This complex modulation of glycan expression critically determines pathogenesis and the host response in terms of structural changes and immune response. In addition, by influencing host immunity and gut glycosylation, the microbiota can further effect protection against pathogens. In this review, the roles of host glycosylation in interactions with two prevalent bacterial pathogens, <i>Campylobater jejuni</i> and <i>Helicobacter pylori</i>, are discussed to illustrate important concepts in pathogenesis.
Darzi review: Up to 5000 patients with long term conditions will have their own personal budgets next year
Authors: A. O'Dowd
Journal: BMJ (2008)

Patients with long term conditions are to have their own personal health budgets under the government’s plans for the NHS in England.

An estimated 5000 patients with complex, long term conditions will next year pilot new personal budgets, an idea that has already been tried in social care.

The report published this week by the junior health minister Ara Darzi says it is part of the government’s intention that all 15 million people with long term conditions will have a personal care plan. The idea is to give these patients greater control over the services they receive and over the providers of those services.

The report says that personal health budgets are likely to work …
Improved Survival with Bevacizumab in Advanced Cervical Cancer
Authors: Krishnansu S. Tewari, Michael W. Sill, Harry J. Long, Richard T. Penson, Helen Huang, Lois M. Ramondetta, Lisa M. Landrum, Ana Oaknin, Thomas J. Reid, Mario M. Leitao, Helen E. Michael, Bradley J. Monk
Journal: New England Journal of Medicine (2014)

Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer.Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important.Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%).The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).
Adverse Events in Hospital Practice
Authors: Anne Savage
Journal: Journal of the Royal Society of Medicine (2001)

I am getting increasingly concerned for clinicians in the NHS who, having been battered by politicians and the media, now have their own colleagues turning on them (July 2001 JRSM, pp. 322-330). In their previous article1, I thought Dr Graham Neale and his colleagues were too hard in their criticism of the ‘failure to manage leg ulcers aggressively’. I now work for Age Concern and have been visiting a woman regularly who has bilateral leg ulcers that three weeks' inpatient treatment and all the resources of a teaching hospital have failed to heal. Some problems defy solutions.

Ten operations over the past decade have given me ample opportunity to observe the difficulties faced by nursing staff. On one occasion my neighbour was Elsie, 92 years old and confused. She absolutely refused to change her posture when a sacral pressure sore threatened: ‘I'm a poor old woman. Please, can't I sleep as I like’. She also regularly rose from her bed, ran across the ward leaving puddles behind her crying, ‘Oh, I'm so sorry’. Could the nursing staff be blamed if she fell? Can they be blamed for the readmission of Lily, sent out with a care package, but readmitted with an infected wound because the community nurse had failed to appear, or Lizzie, who was reduced to phoning her fishmonger when her carer defaulted. It is pleasant to record that he left her not a piece of fish but a full meal. (I have changed the names.)

Much of what Dr Neale and his colleagues write is valid criticism, but failures in patient care are too often blamed on the hospital staff without further enquiry. Readers might be surprised if they knew how many community workers not only fail to do the work they are paid for but also fail to inform their clients. My ‘ulcer lady’ has had no home help for several days, relies on neighbours and is considering going into a home because her present state is so difficult and stressful. Also, why is it assumed that the hospital staff are always responsible for infections? What about the children, some with patches of impetigo, running from bed to bed, ‘Come and give me a kiss, darling’. Couldn't visitors be asked to ‘take their litter home’ and ‘leave this place as you would like to find it’ as is done in other places. Overworked nurses should not be asked to clean toilets.
Retinal Imaging and Image Analysis
Authors: Michael D. Abramoff, Mona K. Garvin, Milan Sonka
Journal: IEEE Reviews in Biomedical Engineering (2010)

Many important eye diseases as well as systemic diseases manifest themselves in the retina. While a number of other anatomical structures contribute to the process of vision, this review focuses on retinal imaging and image analysis. Following a brief overview of the most prevalent causes of blindness in the industrialized world that includes age-related macular degeneration, diabetic retinopathy, and glaucoma, the review is devoted to retinal imaging and image analysis methods and their clinical implications. Methods for 2-D fundus imaging and techniques for 3-D optical coherence tomography (OCT) imaging are reviewed. Special attention is given to quantitative techniques for analysis of fundus photographs with a focus on clinically relevant assessment of retinal vasculature, identification of retinal lesions, assessment of optic nerve head (ONH) shape, building retinal atlases, and to automated methods for population screening for retinal diseases. A separate section is devoted to 3-D analysis of OCT images, describing methods for segmentation and analysis of retinal layers, retinal vasculature, and 2-D/3-D detection of symptomatic exudate-associated derangements, as well as to OCT-based analysis of ONH morphology and shape. Throughout the paper, aspects of image acquisition, image analysis, and clinical relevance are treated together considering their mutually interlinked relationships.
Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells
Authors: Ajit Lalvani, Ansar A Pathan, Helen Durkan, Katalin A Wilkinson, Adam Whelan, Jonathan J Deeks, William HH Reece, Mohammed Latif, Geoffrey Pasvol, Adrian VS Hill
Journal: The Lancet (2001)
A Phase I and Pharmacokinetic Study of Ixabepilone in Combination with Carboplatin in Patients with Advanced Solid Malignancies
Authors: Ruth Plummer, Penella Woll, David Fyfe, Alan V. Boddy, Melanie Griffin, Paula Hewitt, James Carmichael, Fouad Namouni, Marvin Cohen, Mark Verrill
Journal: Clinical Cancer Research (2008)

To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety.Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B).Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B).Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin, with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle.
Focal Adhesion Kinase: Targeting Adhesion Signaling Pathways for Therapeutic Intervention
Authors: J. Thomas Parsons, Jill Slack-Davis, Robert Tilghman, W. Gregory Roberts
Journal: Clinical Cancer Research (2008)

Abstract The tumor microenvironment plays a central role in cancer progression and metastasis. Within this environment, cancer cells respond to a host of signals including growth factors and chemotactic factors, as well as signals from adjacent cells, cells in the surrounding stroma, and signals from the extracellular matrix. Targeting the pathways that mediate many of these signals has been a major goal in the effort to develop therapeutics.
Screening for Prostate Cancer: A Guidance Statement From the Clinical Guidelines Committee of the American College of Physicians
Authors: Amir Qaseem, Michael J. Barry, Thomas D. Denberg, Douglas K. Owens, Paul Shekelle
Journal: Annals of Internal Medicine (2013)

Prostate cancer is an important health problem in men. It rarely causes death in men younger than 50 years; most deaths associated with it occur in men older than 75 years. The benefits of screening with the prostate-specific antigen (PSA) test are outweighed by the harms for most men. Prostate cancer never becomes clinically significant in a patient's lifetime in a considerable proportion of men with prostate cancer detected with the PSA test. They will receive no benefit and are subject to substantial harms from the treatment of prostate cancer. The American College of Physicians (ACP) developed this guidance statement for clinicians by assessing current prostate cancer screening guidelines developed by other organizations. ACP believes that it is more valuable to provide clinicians with a rigorous review of available guidelines rather than develop a new guideline on the same topic when several guidelines are available on a topic or when existing guidelines conflict. The purpose of this guidance statement is to critically review available guidelines to help guide internists and other clinicians in making decisions about screening for prostate cancer. The target patient population for this guidance statement is all adult men.This guidance statement is derived from an appraisal of available guidelines on screening for prostate cancer. Authors searched the National Guideline Clearinghouse to identify prostate cancer screening guidelines in the United States and selected 4 developed by the American College of Preventive Medicine, American Cancer Society, American Urological Association, and U.S. Preventive Services Task Force. The AGREE II (Appraisal of Guidelines, Research and Evaluation in Europe) instrument was used to evaluate the guidelines.ACP recommends that clinicians inform men between the age of 50 and 69 years about the limited potential benefits and substantial harms of screening for prostate cancer. ACP recommends that clinicians base the decision to screen for prostate cancer using the prostate-specific antigen test on the risk for prostate cancer, a discussion of the benefits and harms of screening, the patient's general health and life expectancy, and patient preferences. ACP recommends that clinicians should not screen for prostate cancer using the prostate-specific antigen test in patients who do not express a clear preference for screening. GUIDANCE STATEMENT 2: ACP recommends that clinicians should not screen for prostate cancer using the prostate-specific antigen test in average-risk men under the age of 50 years, men over the age of 69 years, or men with a life expectancy of less than 10 to 15 years.