Showing papers by "Icahn School of Medicine at Mount Sinai published in 2004"
Harvard University1, Brigham and Women's Hospital2, University of Wisconsin-Madison3, University of California, Berkeley4, Technical University of Denmark5, Icahn School of Medicine at Mount Sinai6, Vienna University of Technology7, University of Erlangen-Nuremberg8, German Cancer Research Center9, University of Milan10, Johns Hopkins University11, University of Washington12, Scripps Research Institute13, Walter and Eliza Hall Institute of Medical Research14, University of Iowa15
TL;DR: Details of the aims and methods of Bioconductor, the collaborative creation of extensible software for computational biology and bioinformatics, and current challenges are described.
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.
12,142 citations
TL;DR: Recent experimental and clinical data support the hypothesis that cigarette smoke exposure increases oxidative stress as a potential mechanism for initiating cardiovascular dysfunction.
2,064 citations
Albert Einstein College of Medicine1, Agency for Healthcare Research and Quality2, Harvard University3, United States Department of Veterans Affairs4, Icahn School of Medicine at Mount Sinai5, University of Birmingham6, University of California, Los Angeles7, MedStar Washington Hospital Center8, University of Texas Southwestern Medical Center9, University of Texas at San Antonio10, Mayo Clinic11, Loyola University Chicago12, Georgetown University13
TL;DR: The strength of the evidence that untreated subclinical thyroid disease is associated with clinical symptoms and adverse clinical outcomes was assessed and recommendations for clinical practice developed and insufficient evidence to support population-based screening was found.
Abstract: ContextPatients with serum thyroid-stimulating hormone (TSH) levels outside
the reference range and levels of free thyroxine (FT4) and triiodothyronine
(T3) within the reference range are common in clinical practice.
The necessity for further evaluation, possible treatment, and the urgency
of treatment have not been clearly established.ObjectivesTo define subclinical thyroid disease, review its epidemiology, recommend
an appropriate evaluation, explore the risks and benefits of treatment and
consequences of nontreatment, and determine whether population-based screening
is warranted.Data SourcesMEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality,
National Guideline Clearing House, the Cochrane Database of Systematic Reviews
and Controlled Trials Register, and several National Health Services (UK)
databases were searched for articles on subclinical thyroid disease published
between 1995 and 2002. Articles published before 1995 were recommended by
expert consultants.Study Selection and Data ExtractionA total of 195 English-language or translated papers were reviewed.
Editorials, individual case studies, studies enrolling fewer than 10 patients,
and nonsystematic reviews were excluded. Information related to authorship,
year of publication, number of subjects, study design, and results were extracted
and formed the basis for an evidence report, consisting of tables and summaries
of each subject area.Data SynthesisThe strength of the evidence that untreated subclinical thyroid disease
is associated with clinical symptoms and adverse clinical outcomes was assessed
and recommendations for clinical practice developed. Data relating the progression
of subclinical to overt hypothyroidism were rated as good, but data relating
treatment to prevention of progression were inadequate to determine a treatment
benefit. Data relating a serum TSH level higher than 10 mIU/L to elevations
in serum cholesterol were rated as fair but data relating to benefits of treatment
were rated as insufficient. All other associations of symptoms and benefit
of treatment were rated as insufficient or absent. Data relating a serum TSH
concentration lower than 0.1 mIU/L to the presence of atrial fibrillation
and progression to overt hyperthyroidism were rated as good, but no data supported
treatment to prevent these outcomes. Data relating restoration of the TSH
level to within the reference range with improvements in bone mineral density
were rated as fair. Data addressing all other associations of subclinical
hyperthyroid disease and adverse clinical outcomes or treatment benefits were
rated as insufficient or absent. Subclinical hypothyroid disease in pregnancy
is a special case and aggressive case finding and treatment in pregnant women
can be justified.ConclusionsData supporting associations of subclinical thyroid disease with symptoms
or adverse clinical outcomes or benefits of treatment are few. The consequences
of subclinical thyroid disease (serum TSH 0.1-0.45 mIU/L or 4.5-10.0 mIU/L)
are minimal and we recommend against routine treatment of patients with TSH
levels in these ranges. There is insufficient evidence to support population-based
screening. Aggressive case finding is appropriate in pregnant women, women
older than 60 years, and others at high risk for thyroid dysfunction.
1,774 citations
TL;DR: The clinical data suggest that levodopa either slows the progression of Parkinson's disease or has a prolonged effect on the symptoms of the disease, and the neuroimaging data suggest either thatlevodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter.
Abstract: background Despite the known benefit of levodopa in reducing the symptoms of Parkinson’s disease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson’s disease. methods In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson’s disease who were assigned to receive carbidopa–levodopa at a daily dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks, and then to undergo withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine-transporter density with the use of iodine-123–labeled 2- b -carboxymethoxy3- b -(4-iodophenyl)tropane ([ 123 I] b -CIT) uptake. results The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and i1.4 in those receiving 600 mg daily (P<0.001). In contrast, in a substudy of 116 patients the mean percent decline in the [ 123 I] b -CIT uptake was significantly greater with levodopa than placebo (–6 percent among those receiving levodopa at 150 mg daily, –4 percent in those receiving it at 300 mg daily, and –7.2 percent among those receiving it at 600 mg daily, as compared with –1.4 percent among those receiving placebo; 19 patients with no dopaminergic deficits on the baseline scans were excluded from the analysis) (P=0.036). The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo. conclusions The clinical data suggest that levodopa either slows the progression of Parkinson’s disease or has a prolonged effect on the symptoms of the disease. In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter. The potential long-term effects of levodopa on Parkinson’s disease remain uncertain.
1,646 citations
TL;DR: The recent successful clinical trial of anti-IgE therapy in patients with peanut allergy and the number of immunomodulatory therapies in the pipeline provide real hope that the authors will soon be able to treat patients with food allergy.
Abstract: Tremendous progress has been made in our understanding of food-based allergic disorders over the past 5 years. Recent epidemiologic studies suggest that nearly 4% of Americans are afflicted with food allergies, a prevalence much higher than appreciated in the past. In addition, the prevalence of peanut allergy was found to have doubled in American children less than 5 years of age in the past 5 years. Many food allergens have been characterized at the molecular level, which has contributed to our increased understanding of the immunopathogenesis of many allergic disorders and might soon lead to novel diagnostic and immunotherapeutic approaches. The management of food allergies continues to consist of educating patients on how to avoid relevant allergens, to recognize early symptoms of an allergic reaction in case of an accidental ingestion, and to initiate the appropriate emergency therapy. However, the recent successful clinical trial of anti-IgE therapy in patients with peanut allergy and the number of immunomodulatory therapies in the pipeline provide real hope that we will soon be able to treat patients with food allergy.
1,330 citations
TL;DR: The BACS was found to be as sensitive to cognitive impairment in patients with schizophrenia as a standard battery of tests that required over 2 h to administer and to be highly correlated with the standard battery composite scores in patients and healthy controls.
1,214 citations
TL;DR: Observations of mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization offer compelling support for the role of inflammation in colon carcinogenesis.
Abstract: Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer. To date, no known genetic basis has been identified to explain colorectal cancer predisp...
1,213 citations
TL;DR: Among patients infected with both HIV and HCV, the combination of peginterferon alfa-2a plus ribavirin was significantly more effective than either interferonalfa- 2a plus Ribavirin or pegin terferonAlfa-3a monotherapy.
Abstract: Background Hepatitis C virus (HCV) infection is highly prevalent and is associated with substantial morbidity and mortality among persons infected with the human immunodeficiency virus (HIV). We compared the efficacy and safety of pegylated interferon alfa-2a (peginterferon alfa-2a) plus either ribavirin or placebo with those of interferon alfa-2a plus ribavirin for the treatment of chronic HCV infection in patients who were also infected with HIV. Methods A total of 868 persons who were infected with both HIV and HCV and who had not previously been treated with interferon or ribavirin were randomly assigned to receive one of three regimens: peginterferon alfa-2a (180 μg per week) plus ribavirin (800 mg per day), peginterferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU three times a week) plus ribavirin. Patients were treated for 48 weeks and followed for an additional 24 weeks. The primary end point was a sustained virologic response (defined as a serum HCV RNA level below 50 IU per millil...
1,194 citations
TL;DR: Findings show berberine (BBR) as a new hypolipidemic drug with a mechanism of action different from that of statin drugs.
Abstract: We identify berberine (BBR), a compound isolated from a Chinese herb, as a new cholesterol-lowering drug. Oral administration of BBR in 32 hypercholesterolemic patients for 3 months reduced serum cholesterol by 29%, triglycerides by 35% and LDL-cholesterol by 25%. Treatment of hyperlipidemic hamsters with BBR reduced serum cholesterol by 40% and LDL-cholesterol by 42%, with a 3.5-fold increase in hepatic LDLR mRNA and a 2.6-fold increase in hepatic LDLR protein. Using human hepatoma cells, we show that BBR upregulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation. BBR elevates LDLR expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the 5' proximal section of the LDLR mRNA 3' untranslated region responsible for the regulatory effect of BBR. These findings show BBR as a new hypolipidemic drug with a mechanism of action different from that of statin drugs.
1,193 citations
Vanderbilt University1, University of Southern California2, University of Texas MD Anderson Cancer Center3, University of Wisconsin-Madison4, University of California, Los Angeles5, National Center for Genome Resources6, Portland VA Medical Center7, University of Colorado Boulder8, University of Pennsylvania9, Hannover Medical School10, Johns Hopkins University11, Oregon Health & Science University12, Cornell University13, University of Michigan14, University of Tennessee Health Science Center15, Washington University in St. Louis16, University of Toronto17, University of Memphis18, Medical Research Council19, University of Massachusetts Medical School20, Hebrew University of Jerusalem21, Université de Montréal22, Purdue University23, University of California, Davis24, Academy of Sciences of the Czech Republic25, University at Buffalo26, Emory University27, University of Cincinnati28, University of Texas Southwestern Medical Center29, New York University30, University of Groningen31, Rutgers University32, Stanford University33, Max Planck Society34, National Institutes of Health35, University of Alabama at Birmingham36, International Livestock Research Institute37, Heidelberg University38, Medical College of Wisconsin39, Icahn School of Medicine at Mount Sinai40, Oak Ridge National Laboratory41, Charité42, University of Antwerp43, RWTH Aachen University44, Paul Sabatier University45, University of California, San Francisco46, McGill University47, Pasteur Institute48, University of Western Australia49, Yale University50, University of Oxford51, Case Western Reserve University52, Roswell Park Cancer Institute53, University of Kentucky54, University of Helsinki55, University of Nebraska–Lincoln56, Harvard University57, Merck & Co.58, King's College London59, Northwestern University60, Shriners Hospitals for Children61, Thomas Jefferson University62, Novartis63, University of North Carolina at Chapel Hill64, Southern Illinois University Carbondale65, University of Rochester66
TL;DR: The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way the authors approach human health and disease.
Abstract: The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.
1,040 citations
TL;DR: Among inner-city children with atopic asthma, an individualized, home-based, comprehensive environmental intervention decreases exposure to indoor allergens, including cockroach and dust-mite allergen, resulting in reduced asthma-associated morbidity.
Abstract: background Children with asthma who live in the inner city are exposed to multiple indoor allergens and environmental tobacco smoke in their homes. Reductions in these triggers of asthma have been difficult to achieve and have seldom been associated with decreased morbidity from asthma. The objective of this study was to determine whether an environmental intervention tailored to each child’s allergic sensitization and environmental risk factors could improve asthma-related outcomes. methods We enrolled 937 children with atopic asthma (age, 5 to 11 years) in seven major U.S. cities in a randomized, controlled trial of an environmental intervention that lasted one year (intervention year) and included education and remediation for exposure to both allergens and environmental tobacco smoke. Home environmental exposures were assessed every six months, and asthma-related complications were assessed every two months during the intervention and for one year after the intervention. results For every 2-week period, the intervention group had fewer days with symptoms than did the control group both during the intervention year (3.39 vs. 4.20 days, P<0.001) and the year afterward (2.62 vs. 3.21 days, P<0.001), as well as greater declines in the levels of allergens at home, such as Dermatophagoides farinae (Der f1) allergen in the bed (P<0.001) and on the bedroom floor (P=0.004), D. pteronyssinus in the bed (P=0.007), and cockroach allergen on the bedroom floor (P<0.001). Reductions in the levels of cockroach allergen and dust-mite allergen (Der f1) on the bedroom floor were significantly correlated with reduced complications of asthma (P<0.001). conclusions Among inner-city children with atopic asthma, an individualized, home-based, comprehensive environmental intervention decreases exposure to indoor allergens, including cockroach and dust-mite allergens, resulting in reduced asthma-associated morbidity.
TL;DR: Improvements in Nurses’ work environments in hospitals have the potential to simultaneously reduce nurses’ high levels of job burnout and risk of turnover and increase patients’ satisfaction with their care.
Abstract: The hospital nurse workforce is experiencing greater workloads resulting from shorter hospital stays, rising average patient acuity, fewer support resources, and a national nurse shortage. Higher nurse workloads are associated with burnout and job dissatisfaction, precursors to voluntary turnover that contribute to the understaffing of nurses in hospitals and poorer patient outcomes.1 Indeed, more than 40% of hospital staff nurses score in the high range for job-related burnout, and more than 1 in 5 hospital staff nurses say they intend to leave their hospital jobs within 1 year.2 The understaffing of nurses and the overwork of health professionals in hospitals are ranked by consumers as major threats to patient safety,3 and more patients are bringing their own caregivers to the hospital with them.4
Research on job-related burnout among human service workers, nurses in particular, suggests that organizational stressors in the work environment are important determinants of burnout and subsequent voluntary turnover.5-9 A largely separate research literature on patient satisfaction documents the importance of patients' satisfaction with nursing care in their overall ratings of satisfaction with their hospital care.10-13 This article examines the association between nurse burnout and patient satisfaction, and explores whether the factors that account for nurse burnout also account for patient dissatisfaction. The findings are important to understanding how to simultaneously stem the flight of nurses from hospital bedside care and improve patient satisfaction with care.
TL;DR: Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.
Abstract: Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 microM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein light-chain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H(+)-ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.
TL;DR: Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor-positive breast cancer.
Abstract: BACKGROUND In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy. METHODS Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor-node-metastasis classification), estrogen-receptor-positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer-specific survival, the time to distant metastasis, and overall survival. RESULTS The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). There were no significant differences between the two groups with regard to the rates of mastectomy for local recurrence, distant metastases, or five-year rates of overall survival (87 percent in the group given tamoxifen plus irradiation and 86 percent in the tamoxifen group, P=0.94). Assessment by physicians and patients of cosmetic results and adverse events uniformly rated tamoxifen plus irradiation inferior to tamoxifen alone. CONCLUSIONS Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor-positive breast cancer.
TL;DR: By better harnessing the immunizing functions of maturing dendritic cells, antibody-mediated antigen targeting via the DEC-205 receptor increases the efficiency of vaccination for T cell immunity, including systemic and mucosal resistance in disease models.
Abstract: The prevention and treatment of prevalent infectious diseases and tumors should benefit from improvements in the induction of antigen-specific T cell immunity. To assess the potential of antigen targeting to dendritic cells to improve immunity, we incorporated ovalbumin protein into a monoclonal antibody to the DEC-205 receptor, an endocytic receptor that is abundant on these cells in lymphoid tissues. Simultaneously, we injected agonistic α-CD40 antibody to mature the dendritic cells. We found that a single low dose of antibody-conjugated ovalbumin initiated immunity from the naive CD4+ and CD8+ T cell repertoire. Unexpectedly, the αDEC-205 antigen conjugates, given s.c., targeted to dendritic cells systemically and for long periods, and ovalbumin peptide was presented on MHC class I for 2 weeks. This was associated with stronger CD8+ T cell–mediated immunity relative to other forms of antigen delivery, even when the latter was given at a thousand times higher doses. In parallel, the mice showed enhanced resistance to an established rapidly growing tumor and to viral infection at a mucosal site. By better harnessing the immunizing functions of maturing dendritic cells, antibody-mediated antigen targeting via the DEC-205 receptor increases the efficiency of vaccination for T cell immunity, including systemic and mucosal resistance in disease models.
TL;DR: It is demonstrated that endoderm develops from a brachyury+ population that also displays mesoderm potential, and this differentiation system is established as a unique murine model for studying the development and specification of this germ layer.
Abstract: The cellular and molecular events regulating the induction and tissue-specific differentiation of endoderm are central to our understanding of the development and function of many organ systems. To define and characterize key components in this process, we have investigated the potential of embryonic stem (ES) cells to generate endoderm following their differentiation to embryoid bodies (EBs) in culture. We found that endoderm can be induced in EBs, either by limited exposure to serum or by culturing in the presence of activin A (activin) under serum-free conditions. By using an ES cell line with the green fluorescent protein (GFP) cDNA targeted to the brachyury locus, we demonstrate that endoderm develops from a brachyury(+) population that also displays mesoderm potential. Transplantation of cells generated from activin-induced brachyury(+) cells to the kidney capsule of recipient mice resulted in the development of endoderm-derived structures. These findings demonstrate that ES cells can generate endoderm in culture and, as such, establish this differentiation system as a unique murine model for studying the development and specification of this germ layer.
TL;DR: The clinical importance of polycystic kidney diseases is outlined and the cell biology and molecular mechanisms that cause the formation of hundreds of cystic lesions in the renal parenchyma are discussed.
Abstract: Polycystic kidney diseases are inherited renal disorders due mainly to mutations in genes that regulate the development and function of cells that line renal tubules. This review outlines the clinical importance of polycystic kidney diseases and discusses the cell biology and molecular mechanisms that cause the formation of hundreds of cystic lesions in the renal parenchyma.
TL;DR: Treatment with a monoclonal antibody against interleukin-12 may induce clinical responses and remissions in patients with active Crohn's disease and is associated with decreases in Th1-mediated inflammatory cytokines at the site of disease.
Abstract: background Crohn’s disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses. methods This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti–interleukin-12) in 79 patients with active Crohn’s disease. Patients were randomly assigned to receive seven weekly subcutaneous injections of 1 mg or 3 mg of anti–interleukin-12 per kilogram of body weight or placebo, with either a four-week interval between the first and second injection (Cohort 1) or no interruption between the two injections (Cohort 2). Safety was the primary end point, and the rates of clinical response (defined by a reduction in the score for the Crohn’s Disease Activity Index [CDAI] of at least 100 points) and remission (defined by a CDAI score of 150 or less) were secondary end points. results
TL;DR: Although the majority of neoplastic lesions identified by colonoscopy were not detected by either noninvasive test, the multitarget analysis of fecal DNA detected a greater proportion of important colorectal neoplasia than did Hemoccult II without compromising specificity.
Abstract: Background Although fecal occult-blood testing is the only available noninvasive screening method that reduces the risk of death from colorectal cancer, it has limited sensitivity. We compared an approach that identifies abnormal DNA in stool samples with the Hemoccult II fecal occult-blood test in average-risk, asymptomatic persons 50 years of age or older. Methods Eligible subjects submitted one stool specimen for DNA analysis, underwent standard Hemoccult II testing, and then underwent colonoscopy. Of 5486 subjects enrolled, 4404 completed all aspects of the study. A subgroup of 2507 subjects was analyzed, including all those with a diagnosis of invasive adenocarcinoma or advanced adenoma plus randomly chosen subjects with no polyps or minor polyps. The fecal DNA panel consisted of 21 mutations. Results The fecal DNA panel detected 16 of 31 invasive cancers, whereas Hemoccult II identified 4 of 31 (51.6 percent vs. 12.9 percent, P=0.003). The DNA panel detected 29 of 71 invasive cancers plus adenomas w...
University of California, Los Angeles1, University of Maryland, Baltimore2, Washington University in St. Louis3, Princeton University4, Icahn School of Medicine at Mount Sinai5, National Institutes of Health6, Northeast Ohio Medical University7, University of California, San Diego8, Duke University9, Stanford University10
TL;DR: In the first MATRICS consensus conference as discussed by the authors, the goal was to identify the cognitive domains that should be represented in a consensus cognitive battery and prioritize key criteria for selection of tests for the battery.
TL;DR: In this paper, the effects of behavioral stress on the medial prefrontal cortex (mPFC) were investigated using the repeated restraint stress paradigm, and cellular reconstructions were performed on apical and basal dendrites of pyramidal neurons in the anterior cingulate and prelimbic cortices.
TL;DR: Adipocytes contain specific structural proteins as well as lipid metabolic enzymes; the structural reorganization of lipid droplets in response to the hormonal stimulation of lipolysis is accompanied by increases in the relative mass of several proteins and the recruitment of additional proteins.
TL;DR: Detailed mapping studies reveal that haemangioblasts are found at highest frequency in the posterior region of the primitive streak, indicating that initial stages of haematopoietic and vascular commitment occur before blood island development in the yolk sac.
Abstract: Haematopoietic and vascular cells are thought to arise from a common progenitor called the haemangioblast. Support for this concept has been provided by embryonic stem (ES) cell differentiation studies that identified the blast colony-forming cell (BL-CFC), a progenitor with both haematopoietic and vascular potential1,2. Using conditions that support the growth of BL-CFCs, we identify comparable progenitors that can form blast cell colonies (displaying haematopoietic and vascular potential) in gastrulating mouse embryos. Cell mixing and limiting dilution analyses provide evidence that these colonies are clonal, indicating that they develop from a progenitor with haemangioblast potential. Embryo-derived haemangioblasts are first detected at the mid-streak stage of gastrulation and peak in number during the neural plate stage. Analysis of embryos carrying complementary DNA of the green fluorescent protein targeted to the brachyury locus demonstrates that the haemangioblast is a subpopulation of mesoderm that co-expresses brachyury (also known as T) and Flk-1 (also known as Kdr). Detailed mapping studies reveal that haemangioblasts are found at highest frequency in the posterior region of the primitive streak, indicating that initial stages of haematopoietic and vascular commitment occur before blood island development in the yolk sac.
TL;DR: Results imply that 17beta-estradiol is synthesized by P45017alpha and P450 aromatase localized in hippocampal neurons from endogenous cholesterol, and may be regulated by a glutamate-mediated synaptic communication that evokes Ca(2+) signals.
Abstract: In adult mammalian brain, occurrence of the synthesis of estradiol from endogenous cholesterol has been doubted because of the inability to detect dehydroepiandrosterone synthase, P45017α. In adult male rat hippocampal formation, significant localization was demonstrated for both cytochromes P45017α and P450 aromatase, in pyramidal neurons in the CA1–CA3 regions, as well as in the granule cells in the dentate gyrus, by means of immunohistochemical staining of slices. Only a weak immunoreaction of these P450s was observed in astrocytes and oligodendrocytes. ImmunoGold electron microscopy revealed that P45017α and P450 aromatase were localized in pre- and postsynaptic compartments as well as in the endoplasmic reticulum in principal neurons. The expression of these cytochromes was further verified by using Western blot analysis and RT-PCR. Stimulation of hippocampal neurons with N-methyl-d-aspartate induced a significant net production of estradiol. Analysis of radioactive metabolites demonstrated the conversion from [3H]pregnenolone to [3H]estradiol through dehydroepiandrosterone and testosterone. This activity was abolished by the application of specific inhibitors of cytochrome P450s. Interestingly, estradiol was not significantly converted to other steroid metabolites. Taken together with our previous finding of a P450scc-containing neuronal system for pregnenolone synthesis, these results imply that 17β-estradiol is synthesized by P45017α and P450 aromatase localized in hippocampal neurons from endogenous cholesterol. This synthesis may be regulated by a glutamate-mediated synaptic communication that evokes Ca2+ signals.
Katholieke Universiteit Leuven1, Beth Israel Medical Center2, French Institute of Health and Medical Research3, Columbia University4, University of Melbourne5, Saint Louis University6, University of Florida7, University of Birmingham8, Boston Children's Hospital9, Cedars-Sinai Medical Center10, University of Groningen11, University of Cambridge12, Kurume University13, Kanazawa University14, University of Western Australia15, Yonsei University16, Indiana University17, Royal Free Hospital18, Icahn School of Medicine at Mount Sinai19, Toronto General Hospital20, New York University21
TL;DR: This international group of liver pathologists and hepatologists seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of the field.
TL;DR: In this article, the AGE content of commonly consumed foods and the effects of various methods of food preparation on AGE production were evaluated using an enzyme-linked immunosorbent assay based on an anti-CML monoclonal antibody.
Abstract: Objective Advanced glycoxidation end products (AGEs), the derivatives of glucose-protein or glucose-lipid interactions, are implicated in the complications of diabetes and aging The objective of this article was to determine the AGE content of commonly consumed foods and to evaluate the effects of various methods of food preparation on AGE production Design Two-hundred fifty foods were tested for their content in a common AGE marker ϵ N-carboxymethyllysine (CML), using an enzyme-linked immunosorbent assay based on an anti-CML monoclonal antibody Lipid and protein AGEs were represented in units of AGEs per gram of food Results Foods of the fat group showed the highest amount of AGE content with a mean of 100±19 kU/g High values were also observed for the meat and meat-substitute group, 43±7 kU/g The carbohydrate group contained the lowest values of AGEs, 34±18 kU/g The amount of AGEs present in all food categories was related to cooking temperature, length of cooking time, and presence of moisture Broiling (225°C) and frying (177°C) resulted in the highest levels of AGEs, followed by roasting (177°C) and boiling (100°C) Conclusions The results indicate that diet can be a significant environmental source of AGEs, which may constitute a chronic risk factor for cardiovascular and kidney damage
TL;DR: It is found that diet‐induced insulin resistance promoted amyloidogenic β‐amyloid (Aβ) A β1–40 and Aβ1–42 peptide generation in the brain that corresponded with increased γ‐secretase activities and decreased insulin degrading enzyme (IDE) activities.
Abstract: Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.
TL;DR: The various aspects of the E‐ to N‐cadherin switching in epithelial carcinomas and its potential impact on metastatic progression are summarized.
Abstract: The loss of E-cadherin expression or function in epithelial carcinomas has long been thought as a primary reason for disruption of tight epithelial cell-cell contacts and release of invasive tumor cells from the primary tumor. Indeed, E-cadherin serves as a widely acting suppressor of invasion and growth of epithelial cancers, and its functional elimination represents a key step in the acquisition of the invasive phenotype for many tumors. Recent evidence indicates, however, that in addition to the loss of the "invasion-suppressor" E-cadherin, another adhesion molecule, N-cadherin, becomes upregulated in invasive tumor cell lines. N-cadherin was shown to be present in the most invasive and dedifferentiated breast cancer cell lines, and its exogenous expression in tumor cells induces a scattered morphology and heightened motility, invasion, and metastasis. N-cadherin cooperates with the FGF receptor, resulting in signals that lead to the up-modulation of MMP-9 and, hence, cellular invasion. In addition to a signaling function in metastasis, N-cadherin probably also supports the systemic dissemination of tumor cells by enabling circulating tumor cells to associate with the stroma and the endothelium at distant sites. Here, we summarize the various aspects of the E- to N-cadherin switching in epithelial carcinomas and its potential impact on metastatic progression.
TL;DR: Reconstruction of the genes of the 1918 pandemic virus and studies on their contribution to virulence will be important steps toward understanding the biological capabilities of this lethal virus.
Abstract: Influenza remains an important disease in humans and animals. In contrast to measles, smallpox and poliomyelitis, influenza is caused by viruses that undergo continuous antigenic change and that possess an animal reservoir. Thus, new epidemics and pandemics are likely to occur in the future, and eradication of the disease will be difficult to achieve. Although it is not clear whether a new pandemic is imminent, it would be prudent to take into account the lessons we have learned from studying different human and animal influenza viruses. Specifically, reconstruction of the genes of the 1918 pandemic virus and studies on their contribution to virulence will be important steps toward understanding the biological capabilities of this lethal virus. Increasing the availability of new antiviral drugs and developing superior vaccines will provide us with better approaches to control influenza and to have a positive impact on disease load. A concern is that the imposition of new rules for working with infectious influenza viruses under high security and high containment conditions will stifle scientific progress. The complex questions of what makes an influenza virus transmissible from one human to another and from one species to another, as well as how the immune system interacts with the virus, will require the active collaboration and unencumbered work of many scientific groups.