tbuckley/cabot-search huggingface dataset:
Evidence for Purifying Selection Against Synonymous Mutations in Mammalian Exonic Splicing Enhancers
Authors: Joanna L. Parmley, J. V. Chamary, Laurence D. Hurst
Journal: Molecular Biology and Evolution (2005)

Silent sites in mammals have classically been assumed to be free from selective pressures. Consequently, the synonymous substitution rate (Ks) is often used as a proxy for the mutation rate. Although accumulating evidence demonstrates that the assumption is not valid, the mechanism by which selection acts remain unclear. Recent work has revealed that the presence of exonic splicing enhancers (ESEs) in coding sequence might influence synonymous evolution. ESEs are predominantly located near intron-exon junctions, which may explain the reduced single-nucleotide polymorphism (SNP) density in these regions. Here we show that synonymous sites in putative ESEs evolve more slowly than the remaining exonic sequence. Differential mutabilities of ESEs do not appear to explain this difference. We observe that substitution frequency at fourfold synonymous sites decreases as one approaches the ends of exons, consistent with the existing SNP data. This gradient is at least in part explained by ESEs being more abundant near junctions. Between-gene variation in Ks is hence partly explained by the proportion of the gene that acts as an ESE. Given the relative abundance of ESEs and the reduced rates of synonymous divergence within them, we estimate that constraints on synonymous evolution within ESEs causes the true mutation rate to be underestimated by not more than approximately 8%. We also find that Ks outside of ESEs is much lower in alternatively spliced exons than in constitutive exons, implying that other causes of selection on synonymous mutations exist. Additionally, selection on ESEs appears to affect nonsynonymous sites and may explain why amino acid usage near intron-exon junctions is nonrandom.
Patients' Knowledge of Options at the End of Life
Authors: Maria J. Silveira, Albert DiPiero, Martha S. Gerrity, Chris Feudtner
Journal: JAMA (2000)

ContextEffectiveness of legislation promoting advance directives and legalizing physician-assisted suicide depends on patients' understanding their legal options about end-of-life care. However, outpatients' understanding of their legal options at the end of life has not been studied.ObjectivesTo estimate the percentage of outpatients who are informed about 4 areas relevant to end-of-life care: refusal and withdrawal of lifesaving treatments, physician-assisted suicide, active euthanasia, and double effect; and to determine whether authoring advance directives, experiencing illness, acting as a proxy for health care decisions, and caring for an ill loved one are associated with better knowledge in end-of-life care.DesignCross-sectional survey.Setting and ParticipantsOne thousand consecutive English-speaking, adult patients attending 1 university-based internal medicine clinic and 3 community-based, university-affiliated, mixed internal medicine and family practice clinics in Oregon during May and June 1999.Main Outcome MeasuresPercentage of correct responses in the 4 topic areas and total knowledge score, adjusted for demographic (eg, age, race, educational level, income level, marital status) and experiential (eg, health, proxy decision making, advance directives, and death of a loved one) factors.ResultsOf the 1000 patients invited to participate, 728 (73%) consented and completed the questionnaire and were included in the analysis. A total of 69% of respondents answered correctly regarding refusal of treatment, 46% for withdrawal of treatment, 23% for assisted suicide, 32% for active euthanasia, and 41% for double effect. Sixty-two percent of respondents did not distinguish between assisted suicide and euthanasia. After adjustment for other covariates, better knowledge was significantly associated with white race (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.3-4.2), having at least a college degree (OR, 3.0; 95% CI, 1.4-6.7), and having been a proxy for health care decisions (OR, 1.8; 95% CI, 1.2-2.6). Personal experience with illness (OR, 1.0; 95% CI, 0.6-1.5), death or illness of a loved one (OR, 1.6; 95% CI, 1.0-2.7), and authoring an advance directive (OR,1.3; 95% CI, 0.9-2.0) were not associated with better knowledge.ConclusionsA significant proportion of outpatients at university-affiliated clinics in Oregon appear to misunderstand options in end-of-life care. Our results suggest that greater public knowledge about end-of-life care is needed, and advance care planning must be preceded by education about options in end-of-life care.
Chronic myeloid leukemia as an immunological target
Authors: Seah H. Lim, Sharon Coleman
Journal: American Journal of Hematology (1997)

Various clinical observations have implicated T cells in the control of chronic myeloid leukemia (CML). These observations have in recent years been supported by laboratory results indicating the presence of CML-specific T cells in the lymphocyte repertoire of both normal healthy individuals and disease-bearing patients. Both MHC-unrestricted and MHC-restricted immune effector mechanisms are involved. Donor lymphocyte infusion has produced encouraging GvL effects. However, future adoptive immunotherapy may depend on the isolation and generation of leukemia-specific T cells. Although many proteins may potentially act as leukemia antigens in CML for MHC-restricted cytotoxicity, the bcr-abl fusion protein has been most extensively investigated. There is now much evidence to suggest that the bcr-abl junctional peptides are capable of eliciting both CD4 and CD8 responses in normal healthy donors and CML patients. Furthermore, the T-cell lines generated react with autologous or HLA-matched fresh CML cells, suggesting that the bcr-abl fusion protein can be processed in vivo so that the joining segment is bound to HLA molecules in a configuration and concentration similar to those of the immunizing peptide for antigen recognition by the antigen-specific T-cell receptor. These results also indicate that the bcr-abl junctional peptides may be used for immunotherapy of CML. Other strategies available for immunotherapy of CML include immunologically or genetically manipulated donor T-cell infusion, the use of cytokines, adoptive immunotherapy with leukemia-reactive T-cells expanded ex vivo, and immune gene therapy. Novel and rational immunotherapy may therefore play an important adjuvant role in future in the management of patients with CML.
Long-term Efficacy of Bivalirudin and Provisional Glycoprotein IIb/IIIa Blockade vs Heparin and Planned Glycoprotein IIb/IIIa Blockade During Percutaneous Coronary Revascularization&lt;SUBTITLE&gt;REPLACE-2 Randomized Trial&lt;/SUBTITLE&gt;
Authors: A. Michael Lincoff
Journal: JAMA (2004)

In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, bivalirudin with provisional glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition was found to be noninferior to heparin plus planned Gp IIb/IIIa blockade in the prevention of acute ischemic end points and was associated with significantly less bleeding by 30 days after percutaneous coronary intervention (PCI).To determine whether the efficacy of bivalirudin remains comparable with that of heparin plus Gp IIb/IIIa blockade over 6 months and 1 year.Follow-up study to 1 year of a randomized, double-blind trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002.Patients were randomly assigned to receive intravenously bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition, or to receive heparin (65 U/kg bolus), with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI.Incidence of death, myocardial infarction, or repeat revascularization by 6 months and death by 12 months after enrollment.At 6 months, death occurred in 1.4% of patients in the heparin plus Gp IIb/IIIa group and in 1.0% of patients in the bivalirudin group (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.43-1.14; P =.15). Myocardial infarction occurred in 7.4% and 8.2% of patients, respectively (HR, 1.12; 95% CI, 0.93-1.34; P =.24), and repeat revascularization was required in 11.4% and 12.1% of patients, respectively (HR, 1.06; 95% CI, 0.91-1.23; P =.45). By 1 year, death occurred in 2.46% of patients treated with heparin plus Gp IIb/IIIa blockade and in 1.89% of patients treated with bivalirudin (HR, 0.78; 95% CI, 0.55-1.11; P =.16). Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patients.Long-term clinical outcome with bivalirudin and provisional Gp IIb/IIIa blockade is comparable with that of heparin plus planned Gp IIb/IIIa inhibition during contemporary PCI.
Mode-of-Action, Efficacy, and Safety of a Homologous Multi-Epitope Vaccine in a Murine Model for Adjuvant Treatment of Renal Cell Carcinoma
Authors: Christian Doehn, Norbert Esser, Hans-Gerd Pauels, Stephan T. Kießig, Matthias Stelljes, Armin Grossmann, Dieter Jocham, Joachim Drevs
Journal: European Urology (2008)
High prevalence of hyperplastic polyposis syndrome (serrated polyposis) in the NHS bowel cancer screening programme: Table 1
Authors: Sujata Biswas, Antony J Ellis, Richard Guy, Helen Savage, Karen Madronal, James E East
Journal: Gut (2012)

Two papers have recently been published in Gut by Boparai et al .1 and Edelstein et al .2 regarding the risks of hyperplastic polyposis syndrome (HPS), also called serrated polyposis. Both suggest a substantial cancer risk and continued development of serrated polyps associated with the syndrome. Previous reports have suggested that the prevalence of hyperplastic polyposis syndrome is relatively low in the general population (1:3000; 0.033%)3 with recent correspondence in Gut from Orlowska4 on this issue suggesting even lower levels (1:100 000). However, we noticed a number of cases during bowel cancer screening colonoscopy based on guaiac faecal occult blood testing (gFOBT) and, therefore, formally assessed this within our screening cohort in an audit as part of service development. Currently, the NHS Bowel Cancer Screening Programme (BCSP) …
A common language in neoadjuvant breast cancer clinical trials: proposals for standard definitions and endpoints
Authors: Debora Fumagalli, Philippe L Bedard, Zeina Nahleh, Stefan Michiels, Christos Sotiriou, Sherene Loi, Joseph A Sparano, Matthew Ellis, Nola Hylton, Jo Anne Zujewski, Clifford Hudis, Laura Esserman, Martine Piccart
Journal: The Lancet Oncology (2012)
Genetic Testing in the Workplace: Ethical, Legal, and Social Implications
Authors: Paul W. Brandt-Rauf, Sherry I. Brandt-Rauf
Journal: Annual Review of Public Health (2004)

With the completion of the Human Genome Project, it is likely that genetic testing for susceptibility to a wide range of diseases will increase in society. One venue for such increased testing is likely to be the workplace as employers attempt to protect workers from unhealthy gene-environment interactions, improve productivity, and control escalating health care costs. Past and recent examples of genetic testing in the workplace raise serious concerns that such testing could pose a significant threat to workers' privacy, autonomy, and dignity. Thus, defining the ethically, legally, and socially appropriate and inappropriate uses of genetic testing in the workplace presents a major challenge for occupational health professionals in the years ahead.
Nasal nitric oxide in objective evaluation of chronic rhinosinusitis therapy
Authors: S. M. Ragab, V. J. Lund, H. A. Saleh, G. Scadding
Journal: Allergy (2006)

The assessment of the response of chronic rhinosinusitis (CRS) to therapy is difficult. Computerized tomographic (CT) scans cannot be repeatedly used so measures such as symptom scores, endoscopic findings, and parallel measures such as saccharin clearance time are employed instead.To study the effect of CRS therapy on nasal nitric oxide and to see whether nasal nitric oxide level changes correlate with other assessments.The study was a prospective randomized trial of patients with CRS, with or without polyps, who had failed initial medical therapy with douching and nasal corticosteroids and who then had abnormal CT scans. They were treated either medically or surgically, with follow up at 6 and 12 months whilst still taking nasal corticosteroids. Nasal nitric oxide was measured initially and at 6 and 12 months as well as symptom scores, endoscopy, polyp grading, and saccharin clearance time.Initial absolute nasal nitric oxide levels correlated inversely with CT scan changes, (P<0.001). The percentage rise in nasal nitric oxide seen on both medical and surgical treatment correlated with changes in symptom scores (P<0.001), saccharin clearance time (P<0.001), endoscopic changes (P<0.001), polyp grades (P<0.05 at 6 months, P<0.01 at 12 months) and surgical scores (P<0.01). There was no significant correlation with age, sex, smoking or allergy.Nasal nitric oxide, which is easily measured, provides a valuable non-invasive objective measure of the response of CRS to therapy. Topical nasal corticosteroids may be needed to reduce the contribution of nasal epithelial nitric oxide and allow that emanating from the sinuses to be measured.
Therapeutic potential of Galectin‐9 in human disease
Authors: Valerie R. Wiersma, Marco de Bruyn, Wijnand Helfrich, Edwin Bremer
Journal: Medicinal Research Reviews (2011)

In recent years, an important role has emerged for the glycan‐binding protein Galectin‐9 (Gal‐9) in health and disease. In normal physiology, Gal‐9 seems to be a pivotal modulator of T‐cell immunity by inducing apoptosis in specific T‐cell subpopulations. Because these T‐cell populations are associated with autoimmunity, inflammatory disease, and graft rejection, it was postulated that application of exogenous Gal‐9 may limit pathogenic T‐cell activity. Indeed, treatment with recombinant Gal‐9 ameliorates disease activity in various preclinical models of autoimmunity and allograft graft rejection. In many solid cancers, the loss of Gal‐9 expression is closely associated with metastatic progression. In line with this observation, treatment with recombinant Gal‐9 prevents metastatic spread in various preclinical cancer models. In addition, various hematological malignancies are sensitive to apoptotic elimination by recombinant Gal‐9. Here, we review the biology and physiological role of this versatile lectin and discuss the therapeutic potential of Gal‐9 in various diseases, including autoimmunity, asthma, infection, and cancer.
Continuous versus intermittent inhaled corticosteroids for mild persistent asthma in children: not too much, not too little
Authors: Francine M Ducharme
Journal: Thorax (2011)

Our results were obtained with budesonide, and efficacy/safety profiles with different ICS treatments are drug and dose dependent.The meta-analysis of Sharek and Bergman, 22 10 years ago, claimed that fluticasone slowed the growth less down than beclomethasone or budesonide.With increasing doses of fluticasone, the systemic effects may, however, seem quite significant. 23 Ciclesonide seems to have little effect on growth. 24 Nevertheless, our results accord the clinical experience.Most school-aged asthma children cope with intermittent ICS therapy, which also is favoured by parents and especially by those with corticosteroid fears.
Respiratory health of elite athletes – preventing airway injury: a critical review
Authors: Pascale Kippelen, Kenneth D Fitch, Sandra Doreen Anderson, Valerie Bougault, Louis-Philippe Boulet, Kenneth William Rundell, Malcolm Sue-Chu, Donald C McKenzie
Journal: British Journal of Sports Medicine (2012)

Elite athletes, particularly those engaged in endurance sports and those exposed chronically to airborne pollutants/irritants or allergens, are at increased risk for upper and lower airway dysfunction. Airway epithelial injury may be caused by dehydration and physical stress applied to the airways during severe exercise hyperpnoea and/or by inhalation of noxious agents. This is thought to initiate an inflammatory cascade/repair process that, ultimately, could lead to airway hyperresponsiveness (AHR) and asthma in susceptible athletes. The authors review the evidence relating to prevention or reduction of the risk of AHR/asthma development. Appropriate measures should be implemented when athletes exercise strenuously in an attempt to attenuate the dehydration stress and reduce the exposure to noxious airborne agents. Environmental interventions are the most important. Non-pharmacological strategies can assist, but currently, pharmacological measures have not been demonstrated to be effective. Whether early prevention of airway injury in elite athletes can prevent or reduce progression to AHR/asthma remains to be established.
Receptor Tyrosine Kinase Signaling Favors a Protumorigenic State in Breast Cancer Cells by Inhibiting the Adaptive Immune Response
Authors: Josie Ursini-Siegel, Sean Cory, Dongmei Zuo, William R. Hardy, Elton Rexhepaj, Sonya Lam, Babette Schade, Karin Jirstrom, Eva Bjur, Ciriaco A. Piccirillo, David DeNardo, Lisa M. Coussens, Donal J. Brennan, William M. Gallagher, Morag Park, Tony Pawson, Michael Hallett, William J. Muller
Journal: Cancer Research (2010)

Using transgenic mouse models of breast cancer that ablate Src homology and collagen A (ShcA) expression or oncogene-coupled ShcA signaling, we previously showed that this adaptor is critical for mammary tumor onset and progression. We now provide the first evidence that ShcA regulates mammary tumorigenesis, in part, through its ability to regulate the adaptive immune response. Inactivation of ShcA signaling within tumor cells results in extensive CD4(+) T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA-deficient hyperplasias is accelerated in a T cell-deficient background. We also uncover a clinically relevant correlation between high ShcA expression and low CTL infiltration in human breast cancers. Finally, we define a novel ShcA-regulated immune signature that functions as an independent prognostic marker of survival in human epidermal growth factor receptor 2(+) and basal breast cancers. We reveal a novel role for tumor cell-derived ShcA in the establishment and maintenance of an immunosuppressive state.
Thrombomodulin: A marker for endothelial damage during orthotopic liver transplantation
Authors: G. Himmelreich, M. Riewald, R. Rosch, G. Blumhard, P. Neuhaus, R. Roissant, H. Riess
Journal: American Journal of Hematology (1994)

Thrombomodulin is a surface protein of vascular endothelial cells. A smaller form of thrombomodulin in blood and urine, the soluble (s)thrombomodulin, appears to be derived from injured endothelial cells or to be proteolytically cleaved from thrombomodulin by proteases. Several in vitro and in vivo studies have suggested (s)thrombomodulin as a marker of endothelial damage. In orthotopic liver transplantation, platelet and leukocyte activation as well as prothrombin activation are suspected of being caused by damaged endothelial cells in the graft liver. We determined (s)thrombomodulin antigen as well as thrombin-antithrombin III complexes, protein C, and antithrombin III activities in the course of 23 orthotopic liver transplantations. Samples were taken at 7 different time-points intraoperatively, as well as out of the perfusate released from the graft liver vein during the flushing procedure with arterial blood prior to the opening of the hepatocaval anastomosis. Levels of (s)thrombomodulin antigen and thrombin-antithrombin III complexes showed a significant increase with reperfusion of the graft liver and levels in the perfusate were higher (both: P = 0.0001) than the corresponding systemic levels. In parallel, antithrombin III decreased significantly with reperfusion and perfusate levels of antithrombin III and protein C activities were lower in the systemic circulation (both: P = 0.0001). In conclusion, high levels of (s)thrombomodulin antigen in the early reperfusion phase and in the perfusate strongly indicate endothelial damage to the graft liver vascular bed, paralleled and followed by signs of prothrombin activation.
Oxygen Concentration Determines the Biological Effects of NOTCH-1 Signaling in Adenocarcinoma of the Lung
Authors: Yuanbin Chen, Melissa A. De Marco, Irene Graziani, Adi F. Gazdar, Peter R. Strack, Lucio Miele, Maurizio Bocchetta
Journal: Cancer Research (2007)

NOTCH signaling is an evolutionarily conserved signaling pathway that regulates cell fate during development and postnatal life. It has been increasingly linked to carcinogenesis, although its role in cancer seems to be highly context and tissue specific. Although NOTCH signaling is required for lung development, little is known about its role in lung cancer. In this study, we show that NOTCH signaling, as measured by the gamma-secretase cleavage product N(IC)-1, is active in both normal human and lung tumor samples; however, downstream NOTCH readouts (i.e., HES-1 and HES-5) are elevated in lung tumors. Levels of NOTCH signaling components in primary human lung cells reflect observations in tissue samples, yet lung tumor cell lines showed little NOTCH signaling. Because oxygen concentrations are important in normal lung physiology and lung tumors are hypoxic, the effect of low oxygen on these lung tumor cell lines was evaluated. We found that hypoxia dramatically elevates NOTCH signaling (especially NOTCH-1) in lung tumor cell lines and concomitantly sensitizes them to inhibition via small-molecule gamma-secretase inhibitors or NOTCH-1 RNA interference. gamma-Secretase inhibitor-induced apoptosis of lung tumor cells grown under hypoxic conditions could be rescued by reintroduction of active NOTCH-1. Our data strengthen the role of NOTCH in lung cancer and as a therapeutic target for the treatment of lung and other hypoxic tumor types.
Differing Amygdala Responses to Facial Expressions in Children and Adults With Bipolar Disorder
Authors: Pilyoung Kim, Laura A. Thomas, Brooke H. Rosen, Alexander M. Moscicki, Melissa A. Brotman, Carlos A. Zarate, Jr., R. James R. Blair, Daniel S. Pine, Ellen Leibenluft
Journal: American Journal of Psychiatry (2012)

Child and adult bipolar patients show both behavioral deficits in face emotion processing and abnormal amygdala activation. However, amygdala function in pediatric relative to adult bipolar patients has not been compared directly. The authors used functional MRI to compare amygdala activity during a face processing task in children and adults with bipolar disorder and in healthy comparison subjects.Amygdala responses to emotional facial expressions were examined in pediatric (N=18) and adult (N=17) bipolar patients and in healthy child (N=15) and adult (N=22) volunteers. Participants performed a gender identification task while viewing fearful, angry, and neutral faces.In response to fearful faces, bipolar patients across age groups exhibited right amygdala hyperactivity relative to healthy volunteers. However, when responses to all facial expressions were combined, pediatric patients exhibited greater right amygdala activation than bipolar adults and healthy children.Amygdala hyperactivity in response to fearful faces is present in both youths and adults with bipolar disorder. However, compared with bipolar adults and healthy child volunteers, pediatric bipolar patients showed amygdala hyperactivity in response to a broad array of emotional faces. Thus, abnormal amygdala activation during face processing appears to be more pervasive in children than in adults with bipolar disorder. Longitudinal studies are needed to elucidate the mechanisms of this developmental difference, thus facilitating developmentally sensitive diagnosis and treatment.