Showing papers by "Johns Hopkins University published in 2004"

Bioconductor: open software development for computational biology and bioinformatics

Abstract: The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.

Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.

Abstract: background We tested the hypothesis that prophylactic cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays. methods A total of 1520 patients who had advanced heart failure (New York Heart Association class III or IV) due to ischemic or nonischemic cardiomyopathies and a QRS interval of at least 120 msec were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy (diuretics, angiotensin-converting–enzyme inhibitors, beta-blockers, and spironolactone) alone or in combination with cardiac-resynchronization therapy with either a pacemaker or a pacemaker–defibrillator. The primary composite end point was the time to death from or hospitalization for any cause. results As compared with optimal pharmacologic therapy alone, cardiac-resynchronization therapy with a pacemaker decreased the risk of the primary end point (hazard ratio, 0.81; P=0.014), as did cardiac-resynchronization therapy with a pacemaker–defibrillator (hazard ratio, 0.80; P=0.01). The risk of the combined end point of death from or hospitalization for heart failure was reduced by 34 percent in the pacemaker group (P<0.002) and by 40 percent in the pacemaker–defibrillator group (P<0.001 for the comparison with the pharmacologic-therapy group). A pacemaker reduced the risk of the secondary end point of death from any cause by 24 percent (P=0.059), and a pacemaker–defibrillator reduced the risk by 36 percent (P=0.003). conclusions In patients with advanced heart failure and a prolonged QRS interval, cardiac-resynchronization therapy decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality.

affy---analysis of Affymetrix GeneChip data at the probe level

Abstract: Motivation: The processing of the Affymetrix GeneChip data has been a recent focus for data analysts. Alternatives to the original procedure have been proposed and some of these new methods are widely used. Results: The affy package is an R package of functions and classes for the analysis of oligonucleotide arrays manufactured by Affymetrix. The package is currently in its second release, affy provides the user with extreme flexibility when carrying out an analysis and make it possible to access and manipulate probe intensity data. In this paper, we present the main classes and functions in the package and demonstrate how they can be used to process probe-level data. We also demonstrate the importance of probe-level analysis when using the Affymetrix GeneChip platform.

Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.

Abstract: Regulatory T (T(reg)) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes mediated by T(reg) cells; however, definitive evidence that T(reg) cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4(+)CD25(+)FOXP3(+) T(reg) cells in 104 individuals affected with ovarian carcinoma, that human tumor T(reg) cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor T(reg) cells are associated with a high death hazard and reduced survival. Human T(reg) cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of T(reg) cells to the tumor. This specific recruitment of T(reg) cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking T(reg) cell migration or function may help to defeat human cancer.

Type Ia supernova discoveries at z > 1 from the Hubble Space Telescope: Evidence for past deceleration and constraints on dark energy evolution

Abstract: We have discovered 16 Type Ia supernovae (SNe Ia) with the Hubble Space Telescope (HST) and have used them to provide the first conclusive evidence for cosmic deceleration that preceded the current epoch of cosmic acceleration. These objects, discovered during the course of the GOODS ACS Treasury program, include 6 of the 7 highest redshift SNe Ia known, all at z > 1.25, and populate the Hubble diagram in unexplored territory. The luminosity distances to these objects and to 170 previously reported SNe Ia have been determined using empirical relations between light-curve shape and luminosity. A purely kinematic interpretation of the SN Ia sample provides evidence at the greater than 99% confidence level for a transition from deceleration to acceleration or, similarly, strong evidence for a cosmic jerk. Using a simple model of the expansion history, the transition between the two epochs is constrained to be at z = 0.46 ± 0.13. The data are consistent with the cosmic concordance model of ΩM ≈ 0.3, ΩΛ ≈ 0.7 (χ = 1.06) and are inconsistent with a simple model of evolution or dust as an alternative to dark energy. For a flat universe with a cosmological constant, we measure ΩM = 0.29 ± (equivalently, ΩΛ = 0.71). When combined with external flat-universe constraints, including the cosmic microwave background and large-scale structure, we find w = -1.02 ± (and w < -0.76 at the 95% confidence level) for an assumed static equation of state of dark energy, P = wρc2. Joint constraints on both the recent equation of state of dark energy, w0, and its time evolution, dw/dz, are a factor of ~8 more precise than the first estimates and twice as precise as those without the SNe Ia discovered with HST. Our constraints are consistent with the static nature of and value of w expected for a cosmological constant (i.e., w0 = -1.0, dw/dz = 0) and are inconsistent with very rapid evolution of dark energy. We address consequences of evolving dark energy for the fate of the universe.

Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment.

Abstract: The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.

Cosmological parameters from SDSS and WMAP

Abstract: We measure cosmological parameters using the three-dimensional power spectrum P(k) from over 200,000 galaxies in the Sloan Digital Sky Survey (SDSS) in combination with WMAP and other data. Our results are consistent with a "vanilla" flat adiabaticCDM model without tilt (ns = 1), running tilt, tensor modes or massive neutrinos. Adding SDSS information more than halves the WMAP-only error bars on some parameters, tightening 1� constraints on the Hubble parameter from h � 0.74 +0.18 −0.07 to h � 0.70 +0.04 −0.03, on the matter density from m � 0.25 ± 0.10 to m � 0.30 ± 0.04 (1�) and on neutrino masses from < 11 eV to < 0.6 eV (95%). SDSS helps even more when dropping prior assumptions about curvature, neutrinos, tensor modes and the equation of state. Our results are in substantial agreement with the joint analysis of WMAP and the 2dF Galaxy Redshift Survey, which is an impressive consistency check with independent redshift survey data and analysis techniques. In this paper, we place particular emphasis on clarifying the physical origin of the constraints, i.e., what we do and do not know when using different data sets and prior assumptions. For instance, dropping the assumption that space is perfectly flat, the WMAP-only constraint on the measured age of the Universe tightens from t0 � 16.3 +2.3

The Origin of the Mass-Metallicity Relation: Insights from 53,000 Star-forming Galaxies in the Sloan Digital Sky Survey

Abstract: We utilize Sloan Digital Sky Survey imaging and spectroscopy of ~53,000 star-forming galaxies at z ~ 0.1 to study the relation between stellar mass and gas-phase metallicity. We derive gas-phase oxygen abundances and stellar masses using new techniques that make use of the latest stellar evolutionary synthesis and photoionization models. We find a tight (?0.1 dex) correlation between stellar mass and metallicity spanning over 3 orders of magnitude in stellar mass and a factor of 10 in metallicity. The relation is relatively steep from 108.5 to 1010.5 M? h, in good accord with known trends between luminosity and metallicity, but flattens above 1010.5 M?. We use indirect estimates of the gas mass based on the H? luminosity to compare our data to predictions from simple closed box chemical evolution models. We show that metal loss is strongly anticorrelated with baryonic mass, with low-mass dwarf galaxies being 5 times more metal depleted than L* galaxies at z ~ 0.1. Evidence for metal depletion is not confined to dwarf galaxies but is found in galaxies with masses as high as 1010 M?. We interpret this as strong evidence of both the ubiquity of galactic winds and their effectiveness in removing metals from galaxy potential wells.

High frequency of mutations of the PIK3CA gene in human cancers

Abstract: Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate signaling pathways important for neoplasia, including cell proliferation, adhesion, survival, and motility ([ 1 ][1]–[ 3 ][2]). To determine if PI3Ks are genetically altered in tumorigenesis, we sequenced PI3K genes in human

Untangling the Concepts of Disability, Frailty, and Comorbidity: Implications for Improved Targeting and Care

Abstract: Three terms are commonly used interchangeably to identify vulnerable older adults: comorbidity, or multiple chronicconditions,frailty, anddisability. However, in geriatricmedicine,there isagrowingconsensusthatthese are distinct clinical entities that are causally related. Each, individually, occurs frequently and has high import clinically. This article provides a narrative review of current understanding of the definitions and distinguishing characteristics of each of these conditions,including theirclinical relevance and distinct prevention and therapeutic issues, and how they are related. Review of the current state of published knowledge is supplemented by targeted analysesin selectedareas where no current publisheddataexists. Overall,the goalof this articleis to providea basis fordistinguishingbetweenthesethreeimportantclinicalconditionsinolderadultsandshowinghowuseofseparate, distinct definitions of each can improve our understanding of the problems affecting older patients and lead to development of improved strategies for diagnosis, care, research, and medical education in this area.

The physical properties of star-forming galaxies in the low-redshift universe

Abstract: We present a comprehensive study of the physical properties of ∼ 10 5 galaxies with measurable star formation in the Sloan Digital Sky Survey (SDSS). By comparing physical information extracted from the emission lines with continuum properties, we build up a picture of the nature of star-forming galaxies at z < 0.2. We develop a method for aperture correction using resolved imaging and show that our method takes out essentially all aperture bias in the star formation rate (SFR) estimates, allowing an accurate estimate of the total SFRs in galaxies. We determine the SFR density to be 1.915 +0.02 −0.01 (random) +0.14

The medial temporal lobe

Abstract: The medial temporal lobe includes a system of anatomically related structures that are essential for declarative memory (conscious memory for facts and events). The system consists of the hippocampal region (CA fields, dentate gyrus, and subicular complex) and the adjacent perirhinal, entorhinal, and parahippocampal cortices. Here, we review findings from humans, monkeys, and rodents that illuminate the function of these structures. Our analysis draws on studies of human memory impairment and animal models of memory impairment, as well as neurophysiological and neuroimaging data, to show that this system (a) is principally concerned with memory, (b) operates with neocortex to establish and maintain long-term memory, and (c) ultimately, through a process of consolidation, becomes independent of long-term memory, though questions remain about the role of perirhinal and parahippocampal cortices in this process and about spatial memory in rodents. Data from neurophysiology, neuroimaging, and neuroanatomy point to a division of labor within the medial temporal lobe. However, the available data do not support simple dichotomies between the functions of the hippocampus and the adjacent medial temporal cortex, such as associative versus nonassociative memory, episodic versus semantic memory, and recollection versus familiarity.

Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.

Abstract: After a median follow-up of 45.9 months, the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone (hazard ratio for local or regional recurrence, 0.61; 95 percent confidence interval, 0.41 to 0.91; P=0.01). The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group, as compared with 72 percent in the radiotherapy group. Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group (hazard ratio for disease or death, 0.78; 95 percent confidence interval, 0.61 to 0.99; P=0.04), but overall survival was not (hazard ratio for death, 0.84; 95 percent confidence interval, 0.65 to 1.09; P=0.19). The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group (P<0.001). Four patients who received combined therapy died as a direct result of the treatment. conclusions Among high-risk patients with resected head and neck cancer, concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival. However, the combined treatment is associated with a substantial increase in adverse effects.

Prevalence of age-related macular degeneration in the United States.

Abstract: Objective: To estimate the prevalence and distribution of age-related macular degeneration (AMD) in the United States by age, race/ethnicity, and gender.Methods: Summary prevalence estimates of drusen 125 pin or larger, neovascular AMD, and geographic atrophy were prepared separately for black and white persons in 5-year age intervals starting at 40 years. The estimated rates were based on a meta-analysis of recent population-based studies in the United States, Australia, and Europe. These rates were applied to 2000 US Census data and to projected US population figures for 2020 to estimate the number of the US population with drusen and AMD.Results: The overall prevalence of neovascular AMD and/or geographic atrophy in the US population 40 years and older is estimated to be 1.47% (95% confidence interval, 1.38%-1.55%), with 1.75 million citizens having AMD. The prevalence of AMD increased dramatically with age, with more than 15% of the white women older than 80 years having neovascular AMD and/or geographic atrophy. More than 7 million individuals had drusen measuring 125 pin or larger and were, therefore, at substantial risk of developing AMD. Owing to the rapidly aging population, the number of persons having AMD will increase by 50% to 2.95 million in 2020. Age-related macular degeneration was far more prevalent among white than among black persons.Conclusion: Age-related macular degeneration affects more than 1.75 million individuals in the United States. Owing to the rapid aging of the US population, this number will increase to almost 3 million by 2020.

A Model-Based Background Adjustment for Oligonucleotide Expression Arrays

Abstract: High-density oligonucleotide expression arrays are widely used in many areas of biomedical research. Affymetrix GeneChip arrays are the most popular. In the Affymetrix system, a fair amount of further preprocessing and data reduction occurs after the image-processing step. Statistical procedures developed by academic groups have been successful in improving the default algorithms provided by the Affymetrix system. In this article we present a solution to one of the preprocessing steps—background adjustment—based on a formal statistical framework. Our solution greatly improves the performance of the technology in various practical applications. These arrays use short oligonucleotides to probe for genes in an RNA sample. Typically, each gene is represented by 11–20 pairs of oligonucleotide probes. The first component of these pairs is referred to as a perfect match probe and is designed to hybridize only with transcripts from the intended gene (i. e., specific hybridization). However, hybridization by other...

Prophylactic Defibrillator Implantation in Patients with Nonischemic Dilated Cardiomyopathy

Abstract: background Patients with nonischemic dilated cardiomyopathy are at substantial risk for sudden death from cardiac causes. However, the value of prophylactic implantation of an implantable cardioverter–defibrillator (ICD) to prevent sudden death in such patients is unknown. methods We enrolled 458 patients with nonischemic dilated cardiomyopathy, a left ventricular ejection fraction of less than 36 percent, and premature ventricular complexes or nonsustained ventricular tachycardia. A total of 229 patients were randomly assigned to receive standard medical therapy, and 229 to receive standard medical therapy plus a single-chamber ICD. results Patients were followed for a mean (±SD) of 29.0±14.4 months. The mean left ventricular ejection fraction was 21 percent. The vast majority of patients were treated with angiotensin-converting–enzyme (ACE) inhibitors (86 percent) and beta-blockers (85 percent). There were 68 deaths: 28 in the ICD group, as compared with 40 in the standard-therapy group (hazard ratio, 0.65; 95 percent confidence interval, 0.40 to 1.06; P=0.08). The mortality rate at two years was 14.1 percent in the standard-therapy group (annual mortality rate, 7 percent) and 7.9 percent in the ICD group. There were 17 sudden deaths from arrhythmia: 3 in the ICD group, as compared with 14 in the standardtherapy group (hazard ratio, 0.20; 95 percent confidence interval, 0.06 to 0.71; P=0.006). conclusions In patients with severe, nonischemic dilated cardiomyopathy who were treated with ACE inhibitors and beta-blockers, the implantation of a cardioverter–defibrillator significantly reduced the risk of sudden death from arrhythmia and was associated with a nonsignificant reduction in the risk of death from any cause.

The three-dimensional power spectrum of galaxies from the sloan digital sky survey

Abstract: We measure the large-scale real-space power spectrum P(k) by using a sample of 205,443 galaxies from the Sloan Digital Sky Survey, covering 2417 effective square degrees with mean redshift z ≈ 0.1. We employ a matrix-based method using pseudo-Karhunen-Loeve eigenmodes, producing uncorrelated minimum-variance measurements in 22 k-bands of both the clustering power and its anisotropy due to redshift-space distortions, with narrow and well-behaved window functions in the range 0.02 h Mpc-1 < k < 0.3 h Mpc-1. We pay particular attention to modeling, quantifying, and correcting for potential systematic errors, nonlinear redshift distortions, and the artificial red-tilt caused by luminosity-dependent bias. Our results are robust to omitting angular and radial density fluctuations and are consistent between different parts of the sky. Our final result is a measurement of the real-space matter power spectrum P(k) up to an unknown overall multiplicative bias factor. Our calculations suggest that this bias factor is independent of scale to better than a few percent for k < 0.1 h Mpc-1, thereby making our results useful for precision measurements of cosmological parameters in conjunction with data from other experiments such as the Wilkinson Microwave Anisotropy Probe satellite. The power spectrum is not well-characterized by a single power law but unambiguously shows curvature. As a simple characterization of the data, our measurements are well fitted by a flat scale-invariant adiabatic cosmological model with h Ωm = 0.213 ± 0.023 and σ8 = 0.89 ± 0.02 for L* galaxies, when fixing the baryon fraction Ωb/Ωm = 0.17 and the Hubble parameter h = 0.72; cosmological interpretation is given in a companion paper.

The Great Observatories Origins Deep Survey: Initial results from optical and near-infrared imaging

Abstract: This special issue of the Astrophysical Journal Letters is dedicated to presenting initial results from the Great Observatories Origins Deep Survey (GOODS) that are primarily, but not exclusively, based on multiband imaging data obtained with the Hubble Space Telescope and the Advanced Camera for Surveys (ACS). The survey covers roughly 320 arcmin2 in the ACS F435W, F606W, F814W, and F850LP bands, divided into two well-studied fields. Existing deep observations from the Chandra X-Ray Observatory and ground-based facilities are supplemented with new, deep imaging in the optical and near-infrared from the European Southern Observatory and from the Kitt Peak National Observatory. Deep observations with the Space Infrared Telescope Facility are scheduled. Reduced data from all facilities are being released worldwide within 3-6 months of acquisition. Together, this data set provides two deep reference fields for studies of distant normal and active galaxies, supernovae, and faint stars in our own Galaxy. This Letter serves to outline the survey strategy and describe the specific data that have been used in the accompanying letters, summarizing the reduction procedures and sensitivity limits.

Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000

Abstract: Background— Peripheral arterial disease (PAD) is associated with significant morbidity and mortality and is an important marker of subclinical coronary heart disease. However, estimates of PAD prevalence in the general US population have varied widely. Methods and Results— We analyzed data from 2174 participants aged 40 years and older from the 1999–2000 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial index <0.90 in either leg. The prevalence of PAD among adults aged 40 years and over in the United States was 4.3% (95% CI 3.1% to 5.5%), which corresponds to ≈5 million individuals (95% CI 4 to 7 million). Among those aged 70 years or over, the prevalence was 14.5% (95% CI 10.8% to 18.2%). In age- and gender-adjusted logistic regression analyses, black race/ethnicity (OR 2.83, 95% CI 1.48 to 5.42) current smoking (OR 4.46, 95% CI 2.25 to 8.84), diabetes (OR 2.71, 95% CI 1.03 to 7.12), hypertension (OR 1.75, 95% CI 0.97 to 3.13), hypercholesterolemia (OR 1.68, 95% CI 1....

Meta-Analysis: Glycosylated Hemoglobin and Cardiovascular Disease in Diabetes Mellitus

Abstract: This meta-analysis of observational studies in patients with diabetes shows that increased serum hemoglobin A1c levels are associated with an increased risk for cardiovascular disease in both type ...

Quantifying the Bimodal Color-Magnitude Distribution of Galaxies

Abstract: We analyze the bivariate distribution, in color versus absolute magnitude (u-r vs. Mr), of a low-redshift sample of galaxies from the Sloan Digital Sky Survey (2400 deg2, 0.004 < z < 0.08, -23.5 < Mr < -15.5). We trace the bimodality of the distribution from luminous to faint galaxies by fitting double Gaussians to the color functions separated in absolute magnitude bins. Color-magnitude (CM) relations are obtained for red and blue distributions (early- and late-type, predominantly field, galaxies) without using any cut in morphology. Instead, the analysis is based on the assumption of normal Gaussian distributions in color. We find that the CM relations are well fitted by a straight line plus a tanh function. Both relations can be described by a shallow CM trend (slopes of about -0.04, -0.05) plus a steeper transition in the average galaxy properties over about 2 mag. The midpoints of the transitions (Mr = -19.8 and -20.8 for the red and blue distributions, respectively) occur around 2 × 1010 ☉ after converting luminosities to stellar mass. Separate luminosity functions are obtained for the two distributions. The red distribution has a more luminous characteristic magnitude and a shallower faint-end slope (M* = -21.5, α = -0.8) compared to the blue distribution (α ≈ -1.3, depending on the parameterization). These are approximately converted to galaxy stellar mass functions. The red distribution galaxies have a higher number density per magnitude for masses greater than about 3 × 1010 ☉. Using a simple merger model, we show that the differences between the two functions are consistent with the red distribution being formed from major galaxy mergers.

The deinstitutionalization of American marriage

Abstract: This article argues that marriage has undergone a process of deinstitutionalization—a weakening of the social norms that define partners’ behavior—over the past few decades. Examples are presented involving the increasing number and complexity of cohabiting unions and the emergence of same-sex marriage. Two transitions in the meaning of marriage that occurred in the United States during the 20th century have created the social context for deinstitutionalization. The first transition, noted by Ernest Burgess, was from the institutional marriage to the companionate marriage. The second transition was to the individualized marriage in which the emphasis on personal choice and self-development expanded. Although the practical importance of marriage has declined, its symbolic significance has remained high and may even have increased. It has become a marker of prestige and personal achievement. Examples of its symbolic significance are presented. The implications for the current state of marriage and its future direction are discussed. A quarter century ago, in an article entitled ‘‘Remarriage as an Incomplete Institution’’ (Cherlin, 1978), I argued that American society lacked norms about the way that members of stepfamilies should act toward each other. Parents and children in first marriages, in contrast, could rely on well-established norms, such as when it is appropriate to discipline a child. I predicted that, over time, as remarriage after divorce became common, norms would begin to emerge concerning proper behavior in stepfamilies—for example, what kind of relationship a stepfather should have with his stepchildren. In other words, I expected that remarriage would become institutionalized, that it would become more like first marriage. But just the opposite has happened. Remarriage has not become more like first marriage; rather, first marriage has become more like remarriage. Instead of the institutionalization of remarriage,

Gene expression profiling identifies clinically relevant subtypes of prostate cancer

Abstract: Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing ≈26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with “aggressive” clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.

Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase

Abstract: Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and γ-secretase to release amyloid peptides (Aβ40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Aβ40/42 is generated by γ-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in patients with early-onset familial AD (FAD), and previous studies in transgenic mice and cultured cell models demonstrated that FAD-PS1 variants shift the ratio of Aβ40 : 42 to favor Aβ42. One hypothesis to explain this outcome is that mutant PS alters the specificity of γ-secretase to favor production of Aβ42 at the expense of Aβ40. To test this hypothesis in vivo, we studied Aβ40 and 42 levels in a series of transgenic mice that co-express the Swedish mutation of APP (APPswe) with two FAD-PS1 variants that differentially accelerate amyloid pathology in the brain. We demonstrate a direct correlation between the concentration of Aβ42 and the rate of amyloid deposition. We further show that the shift in Aβ42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Aβ42, while maintaining a constant level of Aβ40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for γ-secretase, but rather that they have more complex effects on the regulation of γ-secretase and its access to substrates.

The environmental dependence of the relations between stellar mass, structure, star formation and nuclear activity in galaxies

Abstract: We use a complete sample of galaxies drawn from the Sloan Digital Sky Survey to study how structure, star formation and nuclear activity depend on local density and on stellar mass. Local density is estimated by counting galaxies above a fixed absolute magnitude limit within cylinders 2 Mpc in projected radius and ±500 km s -1 in depth. The stellar mass distribution of galaxies shifts by almost a factor of two towards higher masses between low-and high-density regions. At fixed stellar mass both star formation and nuclear activity depend strongly on local density, while structural parameters such as size and concentration are almost independent of it. Only for low-mass galaxies (M * 1-Gyr) time-scales. Since structure does not depend on environment for galaxies with masses greater than 3 x 10 10 M ○. , the trends in recent SFH, dust and nuclear activity in these systems cannot be driven by processes that alter structure, for example mergers or harassment. The SFH-density correlation is strongest for small-scale estimates of local density. We see no evidence that star formation history depends on environment more than 1 Mpc from a galaxy. Finally, we highlight a striking similarity between the changes in the galaxy population as a function of density and as a function of redshift. We use mock catalogues derived from N-body simulations to explain how this may be understood.