tbuckley/cabot-search huggingface dataset:
Vascular Endothelial Growth Factor Pathway Polymorphisms as Prognostic and Pharmacogenetic Factors in Cancer: A Systematic Review and Meta-analysis
Authors: Lawson Eng, Abul Kalam Azad, Steven Habbous, Vincent Pang, Wei Xu, Anke H. Maitland-van der Zee, Sevtap Savas, Helen J. Mackay, Eitan Amir, Geoffrey Liu
Journal: Clinical Cancer Research (2012)

Abstract Angiogenesis is an important host process that interacts with cancer cells to promote growth, invasion, and metastasis. Numerous therapeutic agents targeting the VEGF pathway have been developed. Host variability in VEGF pathway can influence angiogenesis-dependent signaling, altering sensitivity to antiangiogenic drugs and prognosis. A systematic review and meta-analysis was conducted (May 1990–July 2011). Eligible studies involved cancer patients and compared polymorphisms in the VEGF pathway [VEGF and molecules directly interacting with VEGF: KDR, FLT1, FGF, FGF2, FGFR, NRP1, endostatin (encoded by COL18A1)], and reported one of the following outcomes: overall survival, progression-free survival, time to recurrence, disease-free survival, response rate, or drug toxicity. We identified 48 cancer studies assessing prognosis and 12 cancer studies exploring pharmacogenetics of anti-VEGF therapy across various VEGF pathway polymorphisms. There was marked inter- and intradisease site heterogeneity in the effect of polymorphisms on both outcome and response to therapy. Meta-analyses of 5 VEGF polymorphisms (+936C&amp;gt;T, −460T&amp;gt;C, +405G&amp;gt;C, −1154G&amp;gt;A, and −2578C&amp;gt;A) identified a significant prognostic relationship: VEGF +405G&amp;gt;C variants showed a highly statistically significant improvement in overall survival [HR, 0.74; 95% confidence interval, 0.60–0.91; P = 0.004]. Variants (heterozygotes and/or homozygotes) of VEGF +405G&amp;gt;C were significantly associated with improved survival in a meta-analysis of multiple cancer sites. Clin Cancer Res; 18(17); 4526–37. ©2012 AACR.
Cumulative Environmental Impacts: Science and Policy to Protect Communities
Authors: Gina M. Solomon, Rachel Morello-Frosch, Lauren Zeise, John B. Faust
Journal: Annual Review of Public Health (2015)

Many communities are located near multiple sources of pollution, including current and former industrial sites, major roadways, and agricultural operations. Populations in such locations are predominantly low-income, with a large percentage of minorities and non-English speakers. These communities face challenges that can affect the health of their residents, including limited access to health care, a shortage of grocery stores, poor housing quality, and a lack of parks and open spaces. Environmental exposures may interact with social stressors, thereby worsening health outcomes. Age, genetic characteristics, and preexisting health conditions increase the risk of adverse health effects from exposure to pollutants. There are existing approaches for characterizing cumulative exposures, cumulative risks, and cumulative health impacts. Although such approaches have merit, they also have significant constraints. New developments in exposure monitoring, mapping, toxicology, and epidemiology, especially when informed by community participation, have the potential to advance the science on cumulative impacts and to improve decision making.
Data sharing policy design for consortia: challenges for sustainability
Authors: Jane Kaye, Naomi Hawkins
Journal: Genome Medicine (2014)

The field of human genomics has led advances in the sharing of data with a view to facilitating translation of research into innovations for human health. This change in scientific practice has been implemented through new policy developed by many principal investigators, project managers and funders, which has ultimately led to new forms of practice and innovative governance models for data sharing. Here, we examine the development of the governance of data sharing in genomics, and explore some of the key challenges associated with the design and implementation of these policies. We examine how the incremental nature of policy design, the perennial problem of consent, the gridlock caused by multiple and overlapping access systems, the administrative burden and the problems with incentives and acknowledgment all have an impact on the potential for data sharing to be maximized. We conclude by proposing ways in which the scientific community can address these problems, to improve the sustainability of data sharing into the future.
Feasibility and safety of autotransplants with noncryopreserved marrow or peripheral blood stem cells: a systematic review
Authors: L. Wannesson, T. Panzarella, J. Mikhael, A. Keating
Journal: Annals of Oncology (2007)

The objective of this systematic review is to examine the feasibility and safety of autologous noncryopreserved stem-cell transplants. This technique avoids the cost of establishing and maintaining a cryopreservation facility and may be of value for transplant centers in regions with limited economic resources. The primary outcome was the graft failure rate. In addition, a detailed description of the high-dose therapy regimens employed was undertaken. Secondary outcomes were transplant-related mortality and neutrophil and platelet engraftments times. Sixteen well-conducted nonrandomized studies met the eligibility criteria. Only two cases of graft failure (0.36%) occurred among 560 assessable patients receiving high-dose therapy and autotransplant for non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, germ-cell tumors and acute leukemias. The most traditional high-dose schedules were used, although often modified to shorter regimens. High-dose melphalan appeared especially useful given its short half-life and was used to treat multiple myeloma by most groups. Secondary outcomes were comparable to those reported in the most relevant studies addressing standard (cryopreserved) autotransplant. According to this study, the use of autologous noncryopreserved hematopoietic progenitors to support patients undergoing high-dose therapy is feasible and safe.
von Willebrand factor antigen and plasminogen activator inhibitor in giant cell arteritis.
Authors: E Nordborg, R Andersson, L Tengborn, S Edén, B.A Bengtsson
Journal: Annals of the Rheumatic Diseases (1991)

Sixty three patients (51 women, 12 men) with giant cell arteritis were studied by serial analyses of von Willebrand factor antigen (vWF: Ag) concentration and plasminogen activator inhibitor activity. Their mean age at the time of diagnosis was 71 years. Two hundred and one randomly selected subjects from the general population, aged 75 years, served as controls. The mean concentration of vWF:Ag in the patients with giant cell arteritis before the start of corticosteroid treatment was 2.63 (SD 1.35) IU/ml compared with 1.71 (0.69) IU/ml in the general population. The vWF:Ag concentration slowly decreased and reached the control range about 18 months after the diagnosis. The vWF:Ag did not correlate with the clinical group of giant cell arteritis nor with the results of temporal artery biopsy. Flare ups and vascular complications were not indicated by the vWF:Ag. Plasminogen activator inhibitor activity in the patients was not significantly different from that of the general population at any time. It was concluded that the determination of vWF:Ag and plasminogen activator inhibitor activity is of limited clinical value in the diagnosis, prognosis, and monitoring of steroid treatment in patients with giant cell arteritis.
Coexistence in the Same Family of Both Focal and Diffuse Forms of Hyperinsulinism
Authors: Vassili Valayannopoulos, Martine Vaxillaire, Yves Aigrain, Francis Jaubert, Christine Bellanné-Chantelot, Maria-Joao Ribeiro, Francis Brunelle, Philippe Froguel, Jean-Jacques Robert, Michel Polak, Claire Nihoul-Fékété, Pascale de Lonlay
Journal: Diabetes Care (2007)

Neonatal hyperinsulinism is the most important cause of hypoglycemia in infancy (1,2). The inappropriate oversecretion of insulin is responsible for profound hypoglycemia, requiring aggressive treatment to prevent brain damage (1–3). Neonatal hyperinsulinism is often resistant to medical therapy (1–4), and pancreatectomy is required for many sufferers (1,5–6). The histopathological lesions associated with neonatal hyperinsulinism may be described as diffuse or focal (7–8). Focal adenomatous islet cell hyperplasia is sporadic and has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of the sulfonylurea receptor 1 ABCC8 gene (9,10) or the inward-rectifying potassium channel Kir6.2 (KCNJ11) (10) in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic β-cells (9–11). Diffuse hyperinsulinism may be familial and arises from the autosomal recessive inheritance of mutations in both ABCC8 (12) and KCNJ11 (13–14) genes. The therapeutic outcome for the patients is heavily dependent on distinguishing between the two histopathological lesions. Diffuse hyperinsulinisms, which are unresponsive to medical treatment, require extensive pancreatectomy, with a high risk of diabetes (5,15–16). Conversely, focal hyperinsulinism can be cured by limited pancreatectomy (6,17). Genetic counseling is dramatically different, as focal hyperinsulinism is considered a sporadic molecular event with a very low recurrence risk (10,18), while diffuse …
MALIGNANT MELANOMA IN SCOTLAND 1979-1983
Authors: R.M. Mackie, D.S. Soutar, A.C.H. Watson, K.M. Mclaren, J.L. Mcphie, A.W. Hutcheon, J.F. Smyth, K.C. Calman, J.A.A. Hunter, J.B. Macgillivray, R. Rankin, I.W. Kemp
Journal: The Lancet (1985)
Determinants of the Glittre ADL test in patients with chronic obstructive pulmonary disease
Authors: Naciye Vardar-Yagli, Filiz Erdem, Deniz Inal-Ince, Lutfi Coplu, Ebru Calik-Kutukcu, Melda Saglam, Hulya Arikan
Journal: European Respiratory Journal (2014)

Background and purpose:  The Glittre ADL test is a specifically designed test for patients with chronic obstructive pulmonary disease (COPD) to assess functional limitation in daily life. The aim of this study was to investigate the determinants of Glittre ADL test in patients with stable COPD.   Methods:  Sixty-five patients with COPD (38 males, 18 females, mean FEV 1 =58%) were included. Pulmonary function test was performed. Respiratory muscle strength was evaluated using a portable mouth pressure device. Muscle strength was determined as quadriceps and hand-grip strength using a hand-held dynamometer. Exercise capacity was assessed using the six-minute walk test (6MWT). Dyspnea and fatigue perception were evaluated using the modified Medical Research Council Dyspnea Scale (MMRC) and the Fatigue Severity Scale (FSS), respectively. Activities of daily living performance was assessed using the Glittre ADL test.   Results:  The Glittre ADL test time was significantly correlated with age (r=0.479, p 1  (r=-0.289, p=0.020), MIP (r=-0.399, p=0.001), MMRC (r=0.282, p=0.020), quadriceps strength (r=- 0.341, p=0.005), hand grip strength (r=-0.337, p=0.006), 6MWT distance (r=-0.583, p 2 =0.473, F (1-61) = 0.014)   Conclusions:  The longer the Glittre ADL test duration is determined by older age, lower MIP, and a shorter 6MWT distance in COPD patients. The effects of specific exercise training on ADL performance needs to be determined.
Sorafenib in Combination With Capecitabine: An Oral Regimen for Patients With HER2-Negative Locally Advanced or Metastatic Breast Cancer
Authors: José Baselga, José Getúlio Martins Segalla, Henri Roché, Auro del Giglio, Hélio Pinczowski, Eva M. Ciruelos, Sebastião Cabral Filho, Patricia Gómez, Brigitte Van Eyll, Begoña Bermejo, Antonio Llombart, Bernardo Garicochea, Miguel Ángel Climent Durán, Paulo Marcelo Gehm Hoff, Marc Espié, Andre Augusto Junior Gemeinder de Moraes, Ronaldo Albuquerque Ribeiro, Clarissa Mathias, Miguel Gil Gil, Belén Ojeda, Josefa Morales, Sunhee Kwon Ro, Shell Li, Frederico Costa
Journal: Journal of Clinical Oncology (2012)

Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) -negative breast cancer.Patients were randomly assigned to first- or second-line capecitabine 1,000 mg/m(2) orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS).In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand- foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively).Addition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.
Volatile anesthetics block intercellular communication between neonatal rat myocardial cells.
Authors: J M Burt, D C Spray
Journal: Circulation Research (1989)

The effects of halothane and ethrane on gap junction-mediated intercellular communication and on membrane excitability were examined in cultured neonatal rat cardiac myocytes using whole-cell voltage-clamp and current-clamp techniques. Excitability was maintained at doses of both anesthetics that reversibly abolished current flow through junctional membranes. The degree of reduction of junctional conductance was a steep function of the dose of anesthetic; complete block occurred at lower aqueous concentrations of halothane than ethrane. The time course for loss of communication was rapid; 90% reduction of initial junctional conductance occurred in less than 15 seconds after exposure to 2 mM halothane or 4 mM ethrane. Recovery of junctional conductance and junctional permeability to intracellularly injected Lucifer yellow was rapid and complete on washout of the anesthetics. As junctional conductance was reduced by halothane or ethrane exposure, unitary conductance of the gap junctional channels remained constant at about 50 pS. Uncoupling by these anesthetics is thus attributable to a decrease in the number of conducting channels rather than to reduction of the channel's unitary conductance. The data are discussed with regard to the possible role of this intercellular communication pathway in the arrhythmias and alterations of conduction velocity and contractility produced by volatile anesthetics.
THE PERSONAL ELEMENT IN PSYCHIATRIC RESEARCH
Authors: PAUL E. FELDMAN
Journal: American Journal of Psychiatry (1956)

This study provides evidence that all research workers are not uniformly successful in their evaluation of the clinical effectiveness of new drugs. It is not the province of this paper to enter into factors that are responsible for the wide variations of attitudes and success displayed by various workers, but it is suggested that both conscious and unconscious factors determine how any given individual will report the efficacy of a drug. There is need to record the characteristics of the research worker as carefully as the other elements of the research design. The bias of a single investigator may in some cases be offset by using multiple evaluators.
Asthmatic bronchial hyperresponsiveness varies with ambient levels of summertime air pollution
Authors: SC Taggart, A Custovic, HC Francis, EB Faragher, CJ Yates, BG Higgins, A Woodcock
Journal: European Respiratory Journal (1996)

It is widely believed that the mechanisms of action of outdoor air pollutants are the same as those found in the laboratory, although few studies have attempted to clarify this issue. This study investigates the relationship of asthmatic bronchial hyperresponsiveness (BHR), a marker of airway inflammation, and pulmonary function to ambient levels of summertime air pollution. Thirty eight nonsmoking adult asthmatic subjects underwent repeated measurement of methacholine BHR, using Yan's method, at differing levels of air pollution (O3, SO2, NO2, smoke) during summer 1993. A total of 109 evaluable tests were performed: 31 subjects completed three or more challenge tests, and seven managed two. Levels of all pollutants remained within current World Health Organization (WHO) Guidelines for Health. Changes in BHR were found to correlate significantly with changes in the levels of 24 h mean SO2, NO2 and smoke; 48 h mean NO2 and smoke; 24 h lag NO2; although the effect was only small, accounting for approximately 10% of the variability in within-subject BHR between visits. Twenty four hour lag NO2 was also associated with forced vital capacity (FVC). In conclusion, in subjects with asthma, methacholine bronchial hyperresponsiveness varies with ambient levels of summertime air pollution. This suggests that changes in airway inflammation underlie the increased respiratory morbidity known to accompany pollution episodes.
An antibiotic policy for bacterial infections after thoracic and other injuries
Authors: S. T. Atherton, D. M. Wright, D. J. White, E. S. Jones
Journal: Thorax (1977)

<b>Atherton, S. T., Wright, D. M., White, D. J., and Jones, E. S. (1977).</b><i>Thorax,</i><b>32,</b> 596-600. <b>An antibiotic policy for bacterial infections after thoracic and other injuries.</b> Twenty-four patients suffering from thoracic and other injuries were admitted to an intensive care unit over a three-year period. The first four patients died from infection by Gram-negative bacilli with associated features of bacterial toxaemia although it was anticipated that most, if not all, of the patients would have recovered with intensive care. Antibiotics had been started when a patient showed signs of bacterial toxaemia but were ineffective. Retrospective analysis showed that, in each patient, a rapid rise in rectal temperature, white cell count, and blood sugar preceded the clinical features of bacterial toxaemia by one or two days. These observations were incorporated into an antibiotic policy for patients with similar injuries. The criteria for starting two or three wide spectrum antibiotics were as follows: (1) Gram-negative bacilli in the tracheal aspirate together with radiological evidence of consolidation or absorption collapse; (ii) two of the following three signs—a rectal temperature of 38·5°C or more, a white blood cell count of 11·0 × 10<sup>9</sup>/l or above, a blood glucose of 11·2 mmol/l or above; (iii) laparotomy. This policy was tested out over two years on 20 patients with thoracic and other injuries. Sixteen of the patients fulfilled the criteria for antibiotic therapy. Two of the six deaths were due to bacterial infection with toxaemia, a result which suggests that the policy was beneficial.
A Novel RING-Type Ubiquitin Ligase <i>Breast Cancer-Associated Gene 2</i> Correlates with Outcome in Invasive Breast Cancer
Authors: Angelika M. Burger, Yuguang Gao, Yutaka Amemiya, Harriette J. Kahn, Richard Kitching, Yili Yang, Ping Sun, Steven A. Narod, Wedad M. Hanna, Arun K. Seth
Journal: Cancer Research (2005)

Abstract The RING finger family of proteins possess ubiquitin ligase activity and play pivotal roles in protein degradation and receptor-mediated endocytosis. In this study, we examined whether the breast cancer-associated gene 2 (BCA2), a novel RING domain protein, has E3 ubiquitin ligase activity and investigated its expression status in breast tumors. The full-length BCA2 gene was cloned from the human breast cancer cell line MDA-MB-468. It encodes an open reading frame of 304 amino acids and contains a RING-H2 domain. BCA2 maps to chromosome 1q21.1, a region known to harbor cytogenetic aberrations in breast cancers. We found that the BCA2 protein has an intrinsic autoubiquitination activity, the hallmark of E3 ligases, whereas mutant RING protein is not autoubiquitinated. This indicates that the BCA2 ubiquitin ligase activity is dependent on the RING-H2 domain. Using tissue microarrays and immunohistochemistry, we found strong to intermediate BCA2 staining in 56% of 945 invasive breast cancers cases, which was significantly correlated with positive estrogen receptor status [odds ratio (OR), 1.51; P = 0.004], negative lymph node status (OR, 0.73; P = 0.02), and an increase in disease-free survival for regional recurrence (OR, 0.45; P = 0.03). Overexpression of BCA2 increased proliferation and small interfering RNA inhibited growth of T47D human breast cancer cells and NIH3T3 mouse cells. The autoubiquitination activity of BCA2 indicates that it is a novel RING-type E3 ligase. Its association with clinical measures and its effects on cell growth indicate that BCA2 may be important for the ubiquitin modification of proteins crucial to breast carcinogenesis and growth.