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Showing papers by "Johns Hopkins University School of Medicine published in 2005"


Journal ArticleDOI
TL;DR: The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence, and focuses attention on the causes of organ-specific abnormalities to chronic GVHD.

4,122 citations


Journal ArticleDOI
03 Mar 2005-Nature
TL;DR: It is shown that the Sir2 homologue, SIRT1 controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α, and this findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.
Abstract: Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1--which modulates ageing in several species--controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.

2,841 citations


Journal ArticleDOI
TL;DR: Emotional stress can precipitate severe, reversible left ventricular dysfunction in patients without coronary disease andaggerated sympathetic stimulation is probably central to the cause of this syndrome.
Abstract: background Reversible left ventricular dysfunction precipitated by emotional stress has been reported, but the mechanism remains unknown. methods We evaluated 19 patients who presented with left ventricular dysfunction after sudden emotional stress. All patients underwent coronary angiography and serial echocardiography; five underwent endomyocardial biopsy. Plasma catecholamine levels in 13 patients with stress-related myocardial dysfunction were compared with those in 7 patients with Killip class III myocardial infarction. results The median age of patients with stress-induced cardiomyopathy was 63 years, and 95 percent were women. Clinical presentations included chest pain, pulmonary edema, and cardiogenic shock. Diffuse T-wave inversion and a prolonged QT interval occurred in most patients. Seventeen patients had mildly elevated serum troponin I levels, but only 1 of 19 had angiographic evidence of clinically significant coronary disease. Severe left ventricular dysfunction was present on admission (median ejection fraction, 0.20; interquartile range, 0.15 to 0.30) and rapidly resolved in all patients (ejection fraction at two to four weeks, 0.60; interquartile range, 0.55 to 0.65; P<0.001). Endomyocardial biopsy showed mononuclear infiltrates and contraction-band necrosis. Plasma catecholamine levels at presentation were markedly higher among patients with stressinduced cardiomyopathy than among those with Killip class III myocardial infarction (median epinephrine level, 1264 pg per milliliter [interquartile range, 916 to 1374] vs. 376 pg per milliliter [interquartile range, 275 to 476]; norepinephrine level, 2284 pg per milliliter [interquartile range, 1709 to 2910] vs. 1100 pg per milliliter [interquartile range, 914 to 1320]; and dopamine level, 111 pg per milliliter [interquartile range, 106 to 146] vs. 61 pg per milliliter [interquartile range, 46 to 77]; P<0.005 for all comparisons). conclusions Emotional stress can precipitate severe, reversible left ventricular dysfunction in patients without coronary disease. Exaggerated sympathetic stimulation is probably central to the cause of this syndrome.

2,830 citations


Journal ArticleDOI
09 Jun 2005-Nature
TL;DR: A mechanism through which c-Myc simultaneously activates E2F1 transcription and limits its translation, allowing a tightly controlled proliferative signal is revealed.
Abstract: MicroRNAs (miRNAs) are 21-23 nucleotide RNA molecules that regulate the stability or translational efficiency of target messenger RNAs. miRNAs have diverse functions, including the regulation of cellular differentiation, proliferation and apoptosis. Although strict tissue- and developmental-stage-specific expression is critical for appropriate miRNA function, mammalian transcription factors that regulate miRNAs have not yet been identified. The proto-oncogene c-MYC encodes a transcription factor that regulates cell proliferation, growth and apoptosis. Dysregulated expression or function of c-Myc is one of the most common abnormalities in human malignancy. Here we show that c-Myc activates expression of a cluster of six miRNAs on human chromosome 13. Chromatin immunoprecipation experiments show that c-Myc binds directly to this locus. The transcription factor E2F1 is an additional target of c-Myc that promotes cell cycle progression. We find that expression of E2F1 is negatively regulated by two miRNAs in this cluster, miR-17-5p and miR-20a. These findings expand the known classes of transcripts within the c-Myc target gene network, and reveal a mechanism through which c-Myc simultaneously activates E2F1 transcription and limits its translation, allowing a tightly controlled proliferative signal.

2,618 citations


Journal ArticleDOI
TL;DR: It is indicated that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.
Abstract: Autism is a neurodevelopmental disorder characterized by impaired communication and social interaction and may be accompanied by mental retardation and epilepsy. Its cause remains unknown, despite evidence that genetic, environmental, and immunological factors may play a role in its pathogenesis. To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.

1,845 citations


Journal ArticleDOI
TL;DR: Advances in the understanding of adult neurogenesis will not only shed light on the basic principles of adult plasticity, but also may lead to strategies for cell replacement therapy after injury or degenerative neurological diseases.
Abstract: Forty years since the initial discovery of neurogenesis in the postnatal rat hippocampus, investigators have now firmly established that active neurogenesis from neural progenitors continues throughout life in discrete regions of the central nervous systems (CNS) of all mammals, including humans. Significant progress has been made over the past few years in understanding the developmental process and regulation of adult neurogenesis, including proliferation, fate specification, neuronal maturation, targeting, and synaptic integration of the newborn neurons. The function of this evolutionarily conserved phenomenon, however, remains elusive in mammals. Adult neurogenesis represents a striking example of structural plasticity in the mature CNS environment. Advances in our understanding of adult neurogenesis will not only shed light on the basic principles of adult plasticity, but also may lead to strategies for cell replacement therapy after injury or degenerative neurological diseases.

1,817 citations


Journal ArticleDOI
TL;DR: In this paper, a double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11).
Abstract: Summary Background A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). Methods 277 young women (mean age 20·2 years [SD 1·7]) were randomly assigned to quadrivalent HPV (20 μg type 6, 40 μg type 11, 40 μg type 16, and 20 μg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20·0 years [1·7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. Findings Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71–97, p Interpretation A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types. Published online April 7, 2005 DOI 10.1016/S1470-2045(05)70101-7

1,627 citations


Journal ArticleDOI
27 Oct 2005-Nature
TL;DR: It is shown that adult hippocampal stem/progenitor cells (AHPs) express receptors and signalling components for Wnt proteins, which are key regulators of neural stem cell behaviour in embryonic development, and that the Wnt/β-catenin pathway is active and that Wnt3 is expressed in the hippocampal neurogenic niche.
Abstract: Neural stem/progenitor cells in the adult brain are able to generate both the brain's major cell types: glial cells, which are non-neuronal, and the active nerve cells or neurons. Neurons are produced in just two regions of the brain. Lie et al. have now identified a protein family that instructs the adult neural stem cells to produce neurons, rather than glial cells. The signal molecule Wnt3 is shown to be crucial for the production of neurons in the adult hippocampus, a region believed to be involved in learning and memory formation. Ultimately these studies may help develop therapies to repair brain damage caused by disease or trauma. The generation of new neurons from neural stem cells is restricted to two regions of the adult mammalian central nervous system: the subventricular zone of the lateral ventricle, and the subgranular zone of the hippocampal dentate gyrus1. In both regions, signals provided by the microenvironment regulate the maintenance, proliferation and neuronal fate commitment of the local stem cell population1. The identity of these signals is largely unknown. Here we show that adult hippocampal stem/progenitor cells (AHPs) express receptors and signalling components for Wnt proteins, which are key regulators of neural stem cell behaviour in embryonic development2. We also show that the Wnt/β-catenin pathway is active and that Wnt3 is expressed in the hippocampal neurogenic niche. Overexpression of Wnt3 is sufficient to increase neurogenesis from AHPs in vitro and in vivo. By contrast, blockade of Wnt signalling reduces neurogenesis from AHPs in vitro and abolishes neurogenesis almost completely in vivo. Our data show that Wnt signalling is a principal regulator of adult hippocampal neurogenesis and provide evidence that Wnt proteins have a role in adult hippocampal function.

1,445 citations


Journal ArticleDOI
TL;DR: These methods adequately control type I error in large and small samples and are computationally efficient and will be useful for quality assessment of genotype data and for the detection of genetic association or population stratification in very large data sets.
Abstract: Deviations from Hardy-Weinberg equilibrium (HWE) can indicate inbreeding, population stratification, and even problems in genotyping. In samples of affected individuals, these deviations can also provide evidence for association. Tests of HWE are commonly performed using a simple χ2 goodness-of-fit test. We show that this χ2 test can have inflated type I error rates, even in relatively large samples (e.g., samples of 1,000 individuals that include ∼100 copies of the minor allele). On the basis of previous work, we describe exact tests of HWE together with efficient computational methods for their implementation. Our methods adequately control type I error in large and small samples and are computationally efficient. They have been implemented in freely available code that will be useful for quality assessment of genotype data and for the detection of genetic association or population stratification in very large data sets.

1,374 citations


Journal ArticleDOI
TL;DR: Level I evidence was established for the postoperative adjuvant treatment of patients with selected high‐risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe and the United States.
Abstract: Background. In 2004, level I evidence was estab- lished for the postoperative adjuvant treatment of patients with selected high-risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe

1,372 citations


Journal ArticleDOI
Najib M. El-Sayed1, Peter J. Myler2, Peter J. Myler3, Daniella Castanheira Bartholomeu4, Daniel Nilsson5, Gautam Aggarwal2, Anh-Nhi Tran5, Elodie Ghedin1, Elizabeth A. Worthey2, Arthur L. Delcher, Gaëlle Blandin4, Scott J. Westenberger6, Elisabet Caler4, Gustavo C. Cerqueira7, Carole Branche5, Brian J. Haas4, Atashi Anupama2, Erik Arner5, Lena Åslund8, Philip Attipoe2, Esteban J. Bontempi5, Frédéric Bringaud9, Peter Burton10, Eithon Cadag2, David A. Campbell6, Mark Carrington11, Jonathan Crabtree4, Hamid Darban5, José Franco da Silveira12, Pieter J. de Jong13, Kimberly Edwards5, Paul T. Englund14, Gholam Fazelina2, Tamara Feldblyum4, Marcela Ferella5, Alberto C.C. Frasch15, Keith Gull16, David Horn17, Lihua Hou4, Yiting Huang2, Ellen Kindlund5, Michele M. Klingbeil18, Sindy Kluge5, Hean Koo4, Daniela R. Lacerda19, Mariano J. Levin20, Hernan Lorenzi20, Tin Louie2, Carlos Renato Machado7, Richard McCulloch10, Alan McKenna5, Yumi Mizuno5, Jeremy C. Mottram10, Siri Nelson2, Stephen Ochaya5, Kazutoyo Osoegawa13, Grace Pai4, Marilyn Parsons3, Marilyn Parsons2, Martin Pentony2, Ulf Pettersson8, Mihai Pop4, José Luis Ramírez21, Joel Rinta2, Laura Robertson2, Steven L. Salzberg, Daniel O. Sánchez15, Amber Seyler2, Reuben Sunil Kumar Sharma11, Jyoti Shetty4, Anjana J. Simpson4, Ellen Sisk2, Martti T. Tammi5, Martti T. Tammi22, Rick L. Tarleton23, Santuza M. R. Teixeira7, Susan Van Aken4, Christy Vogt2, Pauline N. Ward10, Bill Wickstead16, Jennifer R. Wortman4, Owen White4, Claire M. Fraser4, Kenneth Stuart3, Kenneth Stuart2, Björn Andersson5 
15 Jul 2005-Science
TL;DR: Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
Abstract: Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.

Journal ArticleDOI
17 Feb 2005-Nature
TL;DR: An anatomically distinct population of ‘giant’, melanopsin-expressing ganglion cells in the primate retina that, in addition to being intrinsically photosensitive, are strongly activated by rods and cones, and display a rare, S-Off, (L + M)-On type of colour-opponent receptive field.
Abstract: Human vision starts with the activation of rod photoreceptors in dim light and short (S)-, medium (M)-, and long (L)- wavelength-sensitive cone photoreceptors in daylight. Recently a parallel, non-rod, non-cone photoreceptive pathway, arising from a population of retinal ganglion cells, was discovered in nocturnal rodents. These ganglion cells express the putative photopigment melanopsin and by signalling gross changes in light intensity serve the subconscious, 'non-image-forming' functions of circadian photoentrainment and pupil constriction. Here we show an anatomically distinct population of 'giant', melanopsin-expressing ganglion cells in the primate retina that, in addition to being intrinsically photosensitive, are strongly activated by rods and cones, and display a rare, S-Off, (L + M)-On type of colour-opponent receptive field. The intrinsic, rod and (L + M) cone-derived light responses combine in these giant cells to signal irradiance over the full dynamic range of human vision. In accordance with cone-based colour opponency, the giant cells project to the lateral geniculate nucleus, the thalamic relay to primary visual cortex. Thus, in the diurnal trichromatic primate, 'non-image-forming' and conventional 'image-forming' retinal pathways are merged, and the melanopsin-based signal might contribute to conscious visual perception.

Journal ArticleDOI
TL;DR: Preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated and this newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.
Abstract: Genetic alteration is the driving force for thyroid tumorigenesis and progression, based upon which novel approaches to the management of thyroid cancer can be developed. A recent important genetic finding in thyroid cancer is the oncogenic T1799A transversion mutation of BRAF (the gene for the B-type Raf kinase, BRAF). Since the initial report of this mutation in thyroid cancer 2 years ago, rapid advancements have been made. BRAF mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs), particularly in the relatively aggressive subtypes, such as the tall-cell PTC. This mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role, as demonstrated by transgenic mouse studies that showed BRAF mutation-initiated development of PTC and its transition to anaplastic thyroid cancer. BRAF mutation is mutually exclusive with RET/PTC rearrangement, and also displays a reciprocal age association with this common genetic alteration in thyroid cancer. The T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is a specific diagnostic marker for this cancer when identified in cytological and histological specimens. This mutation is associated with a poorer clinicopathological outcome and is a novel independent molecular prognostic marker in the risk evaluation of thyroid cancer. Moreover, preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated. This newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.

Journal ArticleDOI
TL;DR: Increasing evidence indicates that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction may represent the principal molecular pathways or events that commonly underlie the pathogenesis of sporadic and familial forms of PD.

Journal ArticleDOI
16 Nov 2005-JAMA
TL;DR: In the setting of a healthful diet, partial substitution of carbohydrate with either protein or monounsaturated fat can further lower blood pressure, improve lipid levels, and reduce estimated cardiovascular risk.
Abstract: ContextReduced intake of saturated fat is widely recommended for prevention of cardiovascular disease. The type of macronutrient that should replace saturated fat remains uncertain.ObjectiveTo compare the effects of 3 healthful diets, each with reduced saturated fat intake, on blood pressure and serum lipids.Design, Setting, and ParticipantsRandomized, 3-period, crossover feeding study (April 2003 to June 2005) conducted in Baltimore, Md, and Boston, Mass. Participants were 164 adults with prehypertension or stage 1 hypertension. Each feeding period lasted 6 weeks and body weight was kept constant.InterventionsA diet rich in carbohydrates; a diet rich in protein, about half from plant sources; and a diet rich in unsaturated fat, predominantly monounsaturated fat.Main Outcome MeasuresSystolic blood pressure and low-density lipoprotein cholesterol.ResultsBlood pressure, low-density lipoprotein cholesterol, and estimated coronary heart disease risk were lower on each diet compared with baseline. Compared with the carbohydrate diet, the protein diet further decreased mean systolic blood pressure by 1.4 mm Hg (P = .002) and by 3.5 mm Hg (P = .006) among those with hypertension and decreased low-density lipoprotein cholesterol by 3.3 mg/dL (0.09 mmol/L; P = .01), high-density lipoprotein cholesterol by 1.3 mg/dL (0.03 mmol/L; P = .02), and triglycerides by 15.7 mg/dL (0.18 mmol/L; P<.001). Compared with the carbohydrate diet, the unsaturated fat diet decreased systolic blood pressure by 1.3 mm Hg (P = .005) and by 2.9 mm Hg among those with hypertension (P = .02), had no significant effect on low-density lipoprotein cholesterol, increased high-density lipoprotein cholesterol by 1.1 mg/dL (0.03 mmol/L; P = .03), and lowered triglycerides by 9.6 mg/dL (0.11 mmol/L; P = .02). Compared with the carbohydrate diet, estimated 10-year coronary heart disease risk was lower and similar on the protein and unsaturated fat diets.ConclusionIn the setting of a healthful diet, partial substitution of carbohydrate with either protein or monounsaturated fat can further lower blood pressure, improve lipid levels, and reduce estimated cardiovascular risk.Clinical Trials RegistrationClinicalTrials.gov Identifier: NCT00051350.

Journal ArticleDOI
TL;DR: This review examines alteration in DNA methylation in cancer, effects on gene expression, and implications for the use of hypomethylating agents in the treatment of cancer.
Abstract: Epigenetic changes such as DNA methylation act to regulate gene expression in normal mammalian development. However, promoter hypermethylation also plays a major role in cancer through transcriptional silencing of critical growth regulators such as tumor suppressor genes. Other chromatin modifications, such as histone deacetylation and chromatin-binding proteins, affect local chromatin structure and, in concert with DNA methylation, regulate gene transcription. The DNA methylation inhibitors azacitidine and decitabine can induce functional re-expression of aberrantly silenced genes in cancer, causing growth arrest and apoptosis in tumor cells. These agents, along with inhibitors of histone deacetylation, have shown clinical activity in the treatment of certain hematologic malignancies where gene hypermethylation occurs. This review examines alteration in DNA methylation in cancer, effects on gene expression, and implications for the use of hypomethylating agents in the treatment of cancer.

Journal ArticleDOI
TL;DR: In vitro kinase assays using full-length recombinant LRRK2 reveal an increase in activity caused by familial-linked mutations in both autophosphorylation and the phosphorylation of a generic substrate, suggesting a gain-of-function mechanism for L RRK2-linked disease with a central role for kinase activity in the development of PD.
Abstract: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease (PD) with a clinical appearance indistinguishable from idiopathic PD. Initial studies suggest that LRRK2 mutations are the most common yet identified determinant of PD susceptibility, transmitted in an autosomal-dominant mode of inheritance. Herein, we characterize the LRRK2 gene and transcript in human brain and subclone the predominant ORF. Exogenously expressed LRRK2 protein migrates at approximately 280 kDa and is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Familial-linked mutations G2019S or R1441C do not have an obvious effect on protein steady-state levels, turnover, or localization. However, in vitro kinase assays using full-length recombinant LRRK2 reveal an increase in activity caused by familial-linked mutations in both autophosphorylation and the phosphorylation of a generic substrate. These results suggest a gain-of-function mechanism for LRRK2-linked disease with a central role for kinase activity in the development of PD.

Journal ArticleDOI
15 Jan 2005-Blood
TL;DR: Infection of endothelial cells with AdCA5 under nonhypoxic conditions was sufficient to induce increased basement membrane invasion and tube formation similar to the responses induced by hypoxia, indicating that HIF-1 mediates cell-autonomous activation of endothelium cells.

Journal ArticleDOI
TL;DR: A signalling pathway in which nitric oxide generation that follows apoptotic stimulation elicits S-nitrosylation of GAPDH, which triggers binding to Siah1 (an E3 ubiquitin ligase), nuclear translocation and apoptosis, which is prevented by NO deletion is reported.
Abstract: S -nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding

Journal ArticleDOI
TL;DR: Members of the TRP superfamily function in various processes, although their roles are best established in sensory modalities ranging from vision to hearing, taste, pheromone detection, pain perception, and osmosensation, which have relevance for human health.
Abstract: The transient receptor potential (TRP) protein superfamily consists of a diverse group of cation channels that bear structural similarities to Drosophila TRP. TRP channels play important roles in nonexcitable cells; however, an emerging theme is that many TRP-related proteins are expressed predominantly in the nervous system and function in sensory physiology. The TRP superfamily is divided into seven subfamilies, the first of which is composed of the "classical" TRPs" (TRPC subfamily). Some TRPCs may be store-operated channels, whereas others appear to be activated by production of diacylglycerol or regulated through an exocytotic mechanism. Many members of a second subfamily (TRPV) function in sensory physiology and respond to heat, changes in osmolarity, odorants, and mechanical stimuli. Two members of the TRPM family function in sensory perception and three TRPM proteins are chanzymes, which contain C-terminal enzyme domains. The fourth and fifth subfamilies, TRPN and TRPA, include proteins with many ankyrin repeats. TRPN proteins function in mechanotransduction, whereas TRPA1 is activated by noxious cold and is also required for the auditory response. In addition to these five closely related TRP subfamilies, which comprise the Group 1 TRPs, members of the two Group 2 TRP subfamilies, TRPP and TRPML, are distantly related to the group 1 TRPs. Mutations in the founding members of these latter subfamilies are responsible for human diseases. Each of the TRP subfamilies are represented by members in worms and flies, providing the potential for using genetic approaches to characterize the normal functions and activation mechanisms of these channels.

Journal ArticleDOI
TL;DR: It is shown that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis.
Abstract: The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3(-/-) hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell- and NK cell-dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.

Journal ArticleDOI
TL;DR: In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence, and may be a useful molecular marker to assist in risk stratification for patients withPTC.
Abstract: Context: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. Objective: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. Design, Setting, and Subjects: In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. Main Outcome Measure: Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. Results: We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjus...

Journal ArticleDOI
TL;DR: The existence of patterns of mechanical forces that originate from the contraction of cells, emerge from their multicellular organization, and result in patterns of growth are demonstrated, demonstrating that tissue form itself can feed back to regulate patterns of proliferation.
Abstract: Spatial patterns of cellular growth generate mechanical stresses that help to push, fold, expand, and deform tissues into their specific forms. Genetic factors are thought to specify patterns of growth and other behaviors to drive morphogenesis. Here, we show that tissue form itself can feed back to regulate patterns of proliferation. Using microfabrication to control the organization of sheets of cells, we demonstrated the emergence of stable patterns of proliferative foci. Regions of concentrated growth corresponded to regions of high tractional stress generated within the sheet, as predicted by a finite-element model of multicellular mechanics and measured directly by using a micromechanical force sensor array. Inhibiting actomyosin-based tension or cadherin-mediated connections between cells disrupted the spatial pattern of proliferation. These findings demonstrate the existence of patterns of mechanical forces that originate from the contraction of cells, emerge from their multicellular organization, and result in patterns of growth. Thus, tissue form is not only a consequence but also an active regulator of tissue growth.

Journal ArticleDOI
TL;DR: It is shown that the molecular regulation of two critical elements of self-renewal, inhibition of differentiation and induction of proliferation, can be uncoupled, and Notch signaling is identified as a key factor in inhibiting differentiation.
Abstract: A fundamental question in hematopoietic stem cell (HSC) biology is how self-renewal is controlled. Here we show that the molecular regulation of two critical elements of self-renewal, inhibition of differentiation and induction of proliferation, can be uncoupled, and we identify Notch signaling as a key factor in inhibiting differentiation. Using transgenic Notch reporter mice, we found that Notch signaling was active in HSCs in vivo and downregulated as HSCs differentiated. Inhibition of Notch signaling led to accelerated differentiation of HSCs in vitro and depletion of HSCs in vivo. Finally, intact Notch signaling was required for Wnt-mediated maintenance of undifferentiated HSCs but not for survival or entry into the cell cycle in vitro. These data suggest that Notch signaling has a dominant function in inhibiting differentiation and provide a model for how HSCs may integrate multiple signals to maintain the stem cell state.

Journal ArticleDOI
TL;DR: These complexes provide new insights into cell architecture, as a foundation for the understanding of the molecular mechanisms that underlie the human laminopathies — clinical disorders that range from Emery–Dreifuss muscular dystrophy to the accelerated ageing seen in Hutchinson–Gilford progeria syndrome.
Abstract: Many nuclear proteins form lamin-dependent complexes, including LEM-domain proteins, nesprins and SUN-domain proteins. These complexes have roles in chromatin organization, gene regulation and signal transduction. Some link the nucleoskeleton to cytoskeletal structures, ensuring that the nucleus and centrosome assume appropriate intracellular positions. These complexes provide new insights into cell architecture, as well as a foundation for the understanding of the molecular mechanisms that underlie the human laminopathies — clinical disorders that range from Emery-Dreifuss muscular dystrophy to the accelerated ageing seen in Hutchinson-Gilford progeria syndrome.

Journal ArticleDOI
TL;DR: SCS is more effective than reoperation as a treatment for persistent radicular pain after lumbosacral spine surgery, and in the great majority of patients, it obviates the need for reoperation.
Abstract: OBJECTIVE Persistent or recurrent radicular pain after lumbosacral spine surgery is often associated with nerve root compression and is treated by repeated operation or, as a last resort, by spinal cord stimulation (SCS). We conducted a prospective, randomized, controlled trial to test our hypothesis that SCS is more likely than reoperation to result in a successful outcome by standard measures of pain relief and treatment outcome, including subsequent use of health care resources. METHODS For an average of 3 years postoperatively, disinterested third-party interviewers followed 50 patients selected for reoperation by standard criteria and randomized to SCS or reoperation. If the results of the randomized treatment were unsatisfactory, patients could cross over to the alternative. Success was based on self-reported pain relief and patient satisfaction. Crossover to the alternative procedure was an outcome measure. Use of analgesics, activities of daily living, and work status were self-reported. RESULTS Among 45 patients (90%) available for follow-up, SCS was more successful than reoperation (9 of 19 patients versus 3 of 26 patients, P <0.01). Patients initially randomized to SCS were significantly less likely to cross over than were those randomized to reoperation (5 of 24 patients versus 14 of 26 patients, P=0.02). Patients randomized to reoperation required increased opiate analgesics significantly more often than those randomized to SCS (P <0.025). Other measures of activities of daily living and work status did not differ significantly. CONCLUSION SCS is more effective than reoperation as a treatment for persistent radicular pain after lumbosacral spine surgery, and in the great majority of patients, it obviates the need for reoperation.

Journal ArticleDOI
TL;DR: In vivo magnetic resonance tracking of magnetically labeled cells is feasible in humans for detecting very low numbers of dendritic cells in conjunction with detailed anatomical information and appears clinically safe and well suited to monitor cellular therapy in humans.
Abstract: The success of cellular therapies will depend in part on accurate delivery of cells to target organs. In dendritic cell therapy, in particular, delivery and subsequent migration of cells to regional lymph nodes is essential for effective stimulation of the immune system. We show here that in vivo magnetic resonance tracking of magnetically labeled cells is feasible in humans for detecting very low numbers of dendritic cells in conjunction with detailed anatomical information. Autologous dendritic cells were labeled with a clinical superparamagnetic iron oxide formulation or (111)In-oxine and were co-injected intranodally in melanoma patients under ultrasound guidance. In contrast to scintigraphic imaging, magnetic resonance imaging (MRI) allowed assessment of the accuracy of dendritic cell delivery and of inter- and intra-nodal cell migration patterns. MRI cell tracking using iron oxides appears clinically safe and well suited to monitor cellular therapy in humans.

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TL;DR: It is suggested that protein aggregation is pathogenic, but several lines of evidence indicate that inclusion bodies are not the main cause of toxicity, and probably represent a cellular protective response.
Abstract: Neurodegenerative diseases typically involve deposits of inclusion bodies that contain abnormal aggregated proteins. Therefore, it has been suggested that protein aggregation is pathogenic. However, several lines of evidence indicate that inclusion bodies are not the main cause of toxicity, and probably represent a cellular protective response. Aggregation is a complex multi-step process of protein conformational change and accretion. The early species in this process might be most toxic, perhaps through the exposure of buried moieties such as main chain NH and CO groups that could serve as hydrogen bond donors or acceptors in abnormal interactions with other cellular proteins. This model implies that the pathogenesis of diverse neurodegenerative diseases arises by common mechanisms, and might yield common therapeutic targets.

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TL;DR: The existence of multifaceted roles of glycolytic proteins suggests that links between metabolic sensors and transcription are established directly through enzymes that participate in metabolism.

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TL;DR: The literature was systematically reviewed to determine whether a prolonged prothrombin time or elevated international normalized ratio predicts bleeding during invasive diagnostic procedures.