Showing papers by "Emory University published in 2008"
Roger E. McLendon1, Allan H. Friedman1, Darrell D. Bigner1, Erwin G. Van Meir2 +230 more•Institutions (23)
TL;DR: The interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated gliobeasts, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
Abstract: Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
6,761 citations
TL;DR: The features of nanoparticle therapeutics that distinguish them from previous anticancer therapies are highlighted, and how these features provide the potential for therapeutic effects that are not achievable with other modalities are described.
Abstract: Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can
show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, we
highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for
therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer.
3,975 citations
TL;DR: It is concluded that damage suffered in early life leads to permanent impairment, and might also affect future generations, as undernutrition is associated with lower human capital and its prevention will probably bring about important health, educational, and economic benefits.
3,341 citations
TL;DR: The authors comprehensively reexamine the performance of variables that have been suggested by the academic literature to be good predictors of the equity premium and find that by and large, these models have predicted poorly both in-sample and out-of-sample (OOS) for 30 years now.
Abstract: Our article comprehensively reexamines the performance of variables that have been suggested by the academic literature to be good predictors of the equity premium. We find that by and large, these models have predicted poorly both in-sample (IS) and out-of-sample (OOS) for 30 years now; these models seem unstable, as diagnosed by their out-of-sample predictions and other statistics; and these models would not have helped an investor with access only to available information to profitably time the market.
3,339 citations
Journal Article•
TL;DR: It is found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the ‘helpless’ CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load.
Abstract: Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analyzed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 9helpless9 CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections. This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.
2,983 citations
University of Texas MD Anderson Cancer Center1, Oregon Health & Science University2, Mount Sinai St. Luke's and Mount Sinai Roosevelt3, American Cancer Society4, Veterans Health Administration5, Emory University6, Johns Hopkins University School of Medicine7, University of Pennsylvania8, Eastern Virginia Medical School9, Mayo Clinic10, Kaiser Permanente11, University of Wisconsin-Madison12, Indiana University – Purdue University Indianapolis13, Creighton University14, Memorial Sloan Kettering Cancer Center15
TL;DR: Clinicians should be prepared to offer patients a choice between a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps and those that can detect cancer early and also can detect adenomatous polyps.
2,876 citations
TL;DR: In this paper, the authors proposed a passive targeting mechanism, active targeting strategies using ligands or antibodies directed against selected tumor targets amplify the specificity of these therapeutic nanoparticles, enabling them to carry their loaded active drugs to cancer cells by selectively using the unique pathophysiology of tumors.
Abstract: Cancer nanotherapeutics are rapidly progressing and are being implemented to solve several limitations of conventional drug delivery systems such as nonspecific biodistribution and targeting, lack of water solubility, poor oral bioavailability, and low therapeutic indices. To improve the biodistribution of cancer drugs, nanoparticles have been designed for optimal size and surface characteristics to increase their circulation time in the bloodstream. They are also able to carry their loaded active drugs to cancer cells by selectively using the unique pathophysiology of tumors, such as their enhanced permeability and retention effect and the tumor microenvironment. In addition to this passive targeting mechanism, active targeting strategies using ligands or antibodies directed against selected tumor targets amplify the specificity of these therapeutic nanoparticles. Drug resistance, another obstacle that impedes the efficacy of both molecularly targeted and conventional chemotherapeutic agents, might also be overcome, or at least reduced, using nanoparticles. Nanoparticles have the ability to accumulate in cells without being recognized by P-glycoprotein, one of the main mediators of multidrug resistance, resulting in the increased intracellular concentration of drugs. Multifunctional and multiplex nanoparticles are now being actively investigated and are on the horizon as the next generation of nanoparticles, facilitating personalized and tailored cancer treatment.
2,558 citations
Daniel J. Klionsky1, Hagai Abeliovich2, Patrizia Agostinis3, Devendra K. Agrawal4 +232 more•Institutions (137)
TL;DR: A set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes are presented.
Abstract: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms Recent reviews have described the range of assays that have been used for this purpose(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi) Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response
2,310 citations
TL;DR: An ecological framework for conceptualizing the many food environments and conditions that influence food choices is described, with an emphasis on current knowledge regarding the home, child care, school, work site, retail store, and restaurant settings.
Abstract: Food and eating environments likely contribute to the increasing epidemic of obesity and chronic diseases, over and above individual factors such as knowledge, skills, and motivation. Environmental and policy interventions may be among the most effective strategies for creating population-wide improvements in eating. This review describes an ecological framework for conceptualizing the many food environments and conditions that influence food choices, with an emphasis on current knowledge regarding the home, child care, school, work site, retail store, and restaurant settings. Important issues of disparities in food access for low-income and minority groups and macrolevel issues are also reviewed. The status of measurement and evaluation of nutrition environments and the need for action to improve health are highlighted.
2,064 citations
TL;DR: No single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines, given the modest sensitivity and specificity of these parameters in this multicenter setting.
Abstract: Background— Data from single-center studies suggest that echocardiographic parameters of mechanical dyssynchrony may improve patient selection for cardiac resynchronization therapy (CRT). In a prospective, multicenter setting, the Predictors of Response to CRT (PROSPECT) study tested the performance of these parameters to predict CRT response. Methods and Results— Fifty-three centers in Europe, Hong Kong, and the United States enrolled 498 patients with standard CRT indications (New York Heart Association class III or IV heart failure, left ventricular ejection fraction ≤35%, QRS ≥130 ms, stable medical regimen). Twelve echocardiographic parameters of dyssynchrony, based on both conventional and tissue Doppler–based methods, were evaluated after site training in acquisition methods and blinded core laboratory analysis. Indicators of positive CRT response were improved clinical composite score and ≥15% reduction in left ventricular end-systolic volume at 6 months. Clinical composite score was improved in 6...
1,990 citations
TL;DR: Meditation can be conceptualized as a family of complex emotional and attentional regulatory training regimes developed for various ends, including the cultivation of well-being and emotional balance, which could have a long-term impact on the brain and behavior.
TL;DR: In this article, the authors described the nanostructures, methods of preparing nanostructure, methods for detecting targets in subjects, and methods of treating diseases in subjects. An embodiment, among others, includes a metallic gold surface-enhanced Raman scattering nanoparticle, a Raman reporter and a protection structure.
Abstract: Nanostructures, methods of preparing nanostructures, methods of detecting targets in subjects, and methods of treating diseases in subjects, are disclosed An embodiment, among others, of the nanostructure includes a metallic gold surface- enhanced Raman scattering nanoparticle, a Raman reporter and a protection structure The protection structure may include a thiol-polyethylene glycol to which may be attached a target-specific probe
TL;DR: This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level and Mechanisms for insufficient efficacy of the vaccine and the increased HIV- 1 infection rates in subgroups of vaccine recipients are being explored.
University of Lyon1, Los Angeles Biomedical Research Institute2, Federal University of São Paulo3, Emory University4, University of Trieste5, Vanderbilt University Medical Center6, University of California, Davis7, Karolinska Institutet8, French Institute of Health and Medical Research9, Baylor College of Medicine10, National Autonomous University of Mexico11, University of Würzburg12
TL;DR: An expert panel to review and develop standard terminologies and definitions related to wasting, cachexia, malnutrition, and inflammation in CKD and AKI recommends the term 'protein-energy wasting' for loss of body protein mass and fuel reserves.
Emory University1, Cedars-Sinai Medical Center2, Vanderbilt University3, University of British Columbia4, Christiana Care Health System5, Veterans Health Administration6, Hartford Hospital7, University of Missouri–Kansas City8, Saint Louis University9, Université de Montréal10, Geisinger Medical Center11, University of Western Ontario12, University of Rochester13, Foothills Medical Centre14, University of Michigan15, McMaster University16, University at Buffalo17
TL;DR: In COURAGE patients who underwent serial MPS, adding PCI to OMT resulted in greater reduction in ischemia compared with OMT alone, and the findings suggest a treatment target of ≥5% ischemic myocardium reduction with O MT with or without coronary revascularization.
Abstract: Background— Extent and severity of myocardial ischemia are determinants of risk for patients with coronary artery disease, and ischemia reduction is an important therapeutic goal. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) nuclear substudy compared the effectiveness of percutaneous coronary intervention (PCI) for ischemia reduction added to optimal medical therapy (OMT) with the use of myocardial perfusion single photon emission computed tomography (MPS). Methods and Results— Of the 2287 COURAGE patients, 314 were enrolled in this substudy of serial rest/stress MPS performed before treatment and 6 to 18 months (mean=374±50 days) after randomization using paired exercise (n=84) or vasodilator stress (n=230). A blinded core laboratory analyzed quantitative MPS measures of percent ischemic myocardium. Moderate to severe ischemia encumbered ≥10% myocardium. The primary end point was ≥5% reduction in ischemic myocardium at follow-up. Treatment groups had similar ...
TL;DR: A common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent is identified.
Abstract: Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.
TL;DR: There is growing evidence that the neuropeptides oxytocin and vasopressin modulate complex social behavior and social cognition and suggest that variation in the genes encoding their receptors may contribute to variation in human social behavior by altering brain function.
Abstract: There is growing evidence that the neuropeptides oxytocin and vasopressin modulate complex social behavior and social cognition. These ancient neuropeptides display a marked conservation in gene structure and expression, yet diversity in the genetic regulation of their receptors seems to underlie natural variation in social behavior, both between and within species. Human studies are beginning to explore the roles of these neuropeptides in social cognition and behavior and suggest that variation in the genes encoding their receptors may contribute to variation in human social behavior by altering brain function. Understanding the neurobiology and neurogenetics of social cognition and behavior has important implications, both clinically and for society.
TL;DR: Results from a series of clinical studies suggesting that childhood trauma in humans is associated with sensitization of the neuroendocrine stress response, glucocorticoid resistance, increased central corticotropin-releasing factor activity, immune activation, and reduced hippocampal volume are summarized, indicating the existence of biologically distinguishable subtypes of depression as a function of childhood trauma.
University of Texas MD Anderson Cancer Center1, Oregon Health & Science University2, Washington University in St. Louis3, American Cancer Society4, Emory University5, Johns Hopkins University School of Medicine6, University of Pennsylvania7, Kaiser Permanente8, University of Wisconsin-Madison9, Indiana University – Purdue University Indianapolis10, Creighton University11, University of Nebraska Omaha12, Memorial Sloan Kettering Cancer Center13
TL;DR: In the United States, colorectal cancer is the third most common cancer diagnosed among men and women and the second leading cause of death from cancer CRC largely can be prevented by the detection and removal of adenomatous polyps, and survival is significantly better when CRC is diagnosed while still localized.
Abstract: In the United States, colorectal cancer (CRC) is the third most common cancer diagnosed among men and women and the second leading cause of death from cancer CRC largely can be prevented by the detection and removal of adenomatous polyps, and survival is significantly better when CRC is diagnosed while still localized In 2006 to 2007, the American Cancer Society, the US Multi Society Task Force on Colorectal Cancer, and the American College of Radiology came together to develop consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average-risk adults In this update of each organization's guidelines, screening tests are grouped into those that primarily detect cancer early and those that can detect cancer early and also can detect adenomatous polyps, thus providing a greater potential for prevention through polypectomy When possible, clinicians should make patients aware of the full range of screening options, but at a minimum they should be prepared to offer patients a choice between a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps and a screening test that primarily is effective at early cancer detection It is the strong opinion of these 3 organizations that colon cancer prevention should be the primary goal of screening
11 Feb 2008
TL;DR: This paper introduces a general classification framework for combining the evidence from different sources of information, that can be tuned automatically for a given social media type and quality definition, and shows that its system is able to separate high-quality items from the rest with an accuracy close to that of humans.
Abstract: The quality of user-generated content varies drastically from excellent to abuse and spam. As the availability of such content increases, the task of identifying high-quality content sites based on user contributions --social media sites -- becomes increasingly important. Social media in general exhibit a rich variety of information sources: in addition to the content itself, there is a wide array of non-content information available, such as links between items and explicit quality ratings from members of the community. In this paper we investigate methods for exploiting such community feedback to automatically identify high quality content. As a test case, we focus on Yahoo! Answers, a large community question/answering portal that is particularly rich in the amount and types of content and social interactions available in it. We introduce a general classification framework for combining the evidence from different sources of information, that can be tuned automatically for a given social media type and quality definition. In particular, for the community question/answering domain, we show that our system is able to separate high-quality items from the rest with an accuracy close to that of humans
TL;DR: There were no main effects of the SNPs on PTSD symptoms and no significant genetic interactions with level of non-child abuse trauma as predictor of adult PTSD symptoms, suggesting a potential gene-childhood environment interaction for adult PTSD.
Abstract: Context In addition to trauma exposure, other factors contribute to risk for development of posttraumatic stress disorder (PTSD) in adulthood. Both genetic and environmental factors are contributory, with child abuse providing significant risk liability. Objective To increase understanding of genetic and environmental risk factors as well as their interaction in the development of PTSD by gene × environment interactions of child abuse, level of non–child abuse trauma exposure, and genetic polymorphisms at the stress-related gene FKBP5. Design, Setting, and Participants A cross-sectional study examining genetic and psychological risk factors in 900 nonpsychiatric clinic patients (762 included for all genotype studies) with significant levels of childhood abuse as well as non–child abuse trauma using a verbally presented survey combined with single-nucleotide polymorphism (SNP) genotyping. Participants were primarily urban, low-income, black (>95%) men and women seeking care in the general medical care and obstetrics-gynecology clinics of an urban public hospital in Atlanta, Georgia, between 2005 and 2007. Main Outcome Measures Severity of adult PTSD symptomatology, measured with the modified PTSD Symptom Scale, non–child abuse (primarily adult) trauma exposure and child abuse measured using the traumatic events inventory and 8 SNPs spanning the FKBP5 locus. Results Level of child abuse and non–child abuse trauma each separately predicted level of adult PTSD symptomatology (mean [SD], PTSD Symptom Scale for no child abuse, 8.03 [10.48] vs ≥2 types of abuse, 20.93 [14.32]; and for no non–child abuse trauma, 3.58 [6.27] vs ≥4 types, 16.74 [12.90]; P Conclusions Four SNPs of the FKBP5 gene interacted with severity of child abuse as a predictor of adult PTSD symptoms. There were no main effects of the SNPs on PTSD symptoms and no significant genetic interactions with level of non–child abuse trauma as predictor of adult PTSD symptoms, suggesting a potential gene-childhood environment interaction for adult PTSD.
TL;DR: These findings demonstrate that prospective ascertainment of individuals at risk for psychosis is feasible, with a level of predictive accuracy comparable to that in other areas of preventive medicine.
Abstract: Context Early detection and prospective evaluation of individuals who will develop schizophrenia or other psychotic disorders are critical to efforts to isolate mechanisms underlying psychosis onset and to the testing of preventive interventions, but existing risk prediction approaches have achieved only modest predictive accuracy. Objectives To determine the risk of conversion to psychosis and to evaluate a set of prediction algorithms maximizing positive predictive power in a clinical high-risk sample. Design, Setting, and Participants Longitudinal study with a 2½-year follow-up of 291 prospectively identified treatment-seeking patients meeting Structured Interview for Prodromal Syndromes criteria. The patients were recruited and underwent evaluation across 8 clinical research centers as part of the North American Prodrome Longitudinal Study. Main Outcome Measure Time to conversion to a fully psychotic form of mental illness. Results The risk of conversion to psychosis was 35%, with a decelerating rate of transition during the 2½-year follow-up. Five features assessed at baseline contributed uniquely to the prediction of psychosis: a genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Prediction algorithms combining 2 or 3 of these variables resulted in dramatic increases in positive predictive power (ie, 68%-80%) compared with the prodromal criteria alone. Conclusions These findings demonstrate that prospective ascertainment of individuals at risk for psychosis is feasible, with a level of predictive accuracy comparable to that in other areas of preventive medicine. They provide a benchmark for the rate and shape of the psychosis risk function against which standardized preventive intervention programs can be compared.
TL;DR: It is concluded that the enumeration of white blood cells from blood smears can provide a reliable assessment of stress in all vertebrate taxa because of the universal and consistent nature of the haematological response to stress.
Abstract: Summary 1. A growing number of ecologists are turning to the enumeration of white blood cells from blood smears (leukocyte profiles) to assess stress in animals. There has been some inconsistency and controversy in the ecological literature, however, regarding their interpretation. The inconsistencies may stem partly from a lack of information regarding how stress affects leukocytes in different taxa, and partly from a failure on the part of researchers in one discipline to consult potentially informative literature from another. 2. Here, we seek to address both issues by reviewing the literature on the leukocyte response to stress, spanning the taxa of mammals (including humans), birds, amphibians, reptiles and fish. 3. We show that much of the early literature points to a close link between leukocyte profiles and glucocorticoid levels. Specifically, these hormones act to increase the number and percentage of neutrophils (heterophils in birds and reptiles), while decreasing the number and percentage of lymphocytes. This phenomenon is seen in all five vertebrate taxa in response to either natural stressors or exogenous administration of stress hormones. For the ecologist, therefore, high ratios of heterophils or neutrophils to lymphocytes (‘H : L’ or ‘N : L’ ratios) in blood samples reliably indicate high glucocorticoid levels. Furthermore, this close relationship between stress hormones and N : L or H : L ratios needs to be highlighted more prominently in haematological assessments of stress, as it aids the interpretation of results. 4. As with hormone assays, there are challenges to overcome in the use of leukocytes profiles to assess levels of stress; however, there are also advantages to this approach, and we outline each. Given the universal and consistent nature of the haematological response to stress, plus the overwhelming evidence from the veterinary, biomedical and ecological literature reviewed here, we conclude that this method can provide a reliable assessment of stress in all vertebrate taxa.
TL;DR: This is, to the authors' knowledge, the first worldwide analysis of cancer survival, with standard quality-control procedures and identical analytic methods for all datasets, and should eventually facilitate joint assessment of international trends in incidence, survival, and mortality as indicators of cancer control.
Abstract: Summary Background Cancer survival varies widely between countries. The CONCORD study provides survival estimates for 1·9 million adults (aged 15–99 years) diagnosed with a first, primary, invasive cancer of the breast (women), colon, rectum, or prostate during 1990–94 and followed up to 1999, by use of individual tumour records from 101 population-based cancer registries in 31 countries on five continents. This is, to our knowledge, the first worldwide analysis of cancer survival, with standard quality-control procedures and identical analytic methods for all datasets. Methods To compensate for wide international differences in general population (background) mortality by age, sex, country, region, calendar period, and (in the USA) ethnic origin, we estimated relative survival, the ratio of survival noted in the patients with cancer, and the survival that would have been expected had they been subject only to the background mortality rates. 2800 life tables were constructed. Survival estimates were also adjusted for differences in the age structure of populations of patients with cancer. Findings Global variation in cancer survival was very wide. 5-year relative survival for breast, colorectal, and prostate cancer was generally higher in North America, Australia, Japan, and northern, western, and southern Europe, and lower in Algeria, Brazil, and eastern Europe. CONCORD has provided the first opportunity to estimate cancer survival in 11 states in USA covered by the National Program of Cancer Registries (NPCR), and the study covers 42% of the US population, four-fold more than previously available. Cancer survival in black men and women was systematically and substantially lower than in white men and women in all 16 states and six metropolitan areas included. Relative survival for all ethnicities combined was 2–4% lower in states covered by NPCR than in areas covered by the Surveillance Epidemiology and End Results (SEER) Program. Age-standardised relative survival by use of the appropriate race-specific and state-specific life tables was up to 2% lower for breast cancer and up to 5% lower for prostate cancer than with the census-derived national life tables used by the SEER Program. These differences in population coverage and analytical method have both contributed to the survival deficit noted between Europe and the USA, from which only SEER data have been available until now. Interpretation Until now, direct comparisons of cancer survival between high-income and low-income countries have not generally been available. The information provided here might therefore be a useful stimulus for change. The findings should eventually facilitate joint assessment of international trends in incidence, survival, and mortality as indicators of cancer control. Funding Centers for Disease Control and Prevention (Atlanta, GA, USA), Department of Health (London, UK), Cancer Research UK (London, UK).
TL;DR: A new variant of the hit theory model of microbial infection was developed to estimate the variation in Norwalk virus infectivity, as well as the degree of virus aggregation, consistent with independent (electron microscopic) observations.
Abstract: Noroviruses are major agents of viral gastroenteritis worldwide. The infectivity of Norwalk virus, the prototype norovirus, has been studied in susceptible human volunteers. A new variant of the hit theory model of microbial infection was developed to estimate the variation in Norwalk virus infectivity, as well as the degree of virus aggregation, consistent with independent (electron microscopic) observations. Explicit modeling of viral aggregation allows us to express virus infectivity per single infectious unit (particle). Comparison of a primary and a secondary inoculum showed that passage through a human host does not change Norwalk virus infectivity. We estimate the average probability of infection for a single Norwalk virus particle to be close to 0.5, exceeding that reported for any other virus studied to date. Infected subjects had a dose-dependent probability of becoming ill, ranging from 0.1 (at a dose of 10(3) NV genomes) to 0.7 (at 10(8) virus genomes). A norovirus dose response model is important for understanding its transmission and essential for development of a quantitative risk model. Norwalk virus is a valuable model system to study virulence because genetic factors are known for both complete and partial protection; the latter can be quantitatively described as heterogeneity in dose response models.
TL;DR: The synthesis and development of state-of-the-art QD probes and their use for molecular and cellular imaging are discussed and key issues for in vivo imaging and therapy, such as nanoparticle biodistribution, pharmacokinetics, and toxicology are examined.
TL;DR: In this paper, a review of the theorized sources of self-efficacy beliefs proposed by A. Bandura (1986) are described and explained, including how they are typically assessed and analyzed, and problems and oversights in current research and in conceptualizations of the sources.
Abstract: The purpose of this review was threefold. First, the theorized sources of self-efficacy beliefs proposed by A. Bandura (1986) are described and explained, including how they are typically assessed and analyzed. Second, findings from investigations of these sources in academic contexts are reviewed and critiqued, and problems and oversights in current research and in conceptualizations of the sources are identified. Although mastery experience is typically the most influential source of self-efficacy, the strength and influence of the sources differ as a function of contextual factors such as gender, ethnicity, academic ability, and academic domain. Finally, suggestions are offered to help guide researchers investigating the psychological mechanisms at work in the formation of self-efficacy beliefs in academic contexts.
Book•
08 Sep 2008TL;DR: The use of institutions to co-opt 4. Institutions and policies under dictatorship 5. Instit institutions and outcomes under dictatorship as mentioned in this paper 6. The world of dictatorial institutions and the survival of dictators
Abstract: 1. The world of dictatorial institutions 2. Three illustrative cases 3. The use of institutions to co-opt 4. Institutions and policies under dictatorship 5. Institutions and outcomes under dictatorship 6. Institutions and the survival of dictators.
TL;DR: Data is summarized supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals, which is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation.
Abstract: Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the “redox hypothesis,” is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to two-electron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-κB), receptor activation (e.g., αIIbβ3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.
Cardiff University1, University of Oxford2, University of Cambridge3, Ludwig Maximilian University of Munich4, Trinity College, Dublin5, Shanghai Jiao Tong University6, University of Bonn7, National Institutes of Health8, Fujita Health University9, Hebrew University of Jerusalem10, Northwestern University11, Stanford University12, Louisiana State University13, QIMR Berghofer Medical Research Institute14, Anschutz Medical Campus15, Emory University16, University of Iowa17, Icahn School of Medicine at Mount Sinai18, University of California, San Francisco19, Washington University in St. Louis20
TL;DR: Meta-analysis provided strongest evidence for association around ZNF804A and this strengthened when the affected phenotype including bipolar disorder included bipolar disorder and the overall pattern of replication was unlikely to occur by chance.
Abstract: We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).