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Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1-4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5-9) and MPP8 (refs. 10-12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC-Sin3-NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.
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Retrovirus Endógenos , Inativação Gênica , Histonas , Peptídeos e Proteínas de Sinalização Intracelular , Lisina , Retroelementos , Animais , Humanos , Camundongos , Cromatina/genética , Cromatina/metabolismo , Proteínas Correpressoras/metabolismo , Retrovirus Endógenos/genética , Epigênese Genética , Perfilação da Expressão Gênica , Genoma/genética , Histona Desacetilases/metabolismo , Histonas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisina/metabolismo , Metilação , Domínios Proteicos , Retroelementos/genética , Sequências Repetidas Terminais/genética , Animais Recém-Nascidos , Linhagem CelularRESUMO
Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides. The in vivo production of CXCL4 thereby impedes both TLR9 responses in B cells and the establishment of central B cell tolerance. We conclude that TLR9 plays an essential early tolerogenic function required for the establishment of central B cell tolerance and that correcting defective TLR9 function in B cells from SSc patients may represent a novel therapeutic strategy to restore B cell tolerance.
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Fator Plaquetário 4 , Escleroderma Sistêmico , Receptor Toll-Like 9 , Animais , Humanos , Camundongos , Linfócitos B , Ligantes , Fator 88 de Diferenciação Mieloide/metabolismo , Fator Plaquetário 4/metabolismo , Escleroderma Sistêmico/metabolismo , Receptor 7 Toll-Like , Receptor Toll-Like 9/metabolismoRESUMO
BACKGROUNDThe KRAS proto-oncogene is among the most frequently mutated genes in cancer, yet for 40 years it remained an elusive therapeutic target. Recently, allosteric inhibitors that covalently bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. Although responses are observed, they are often short-lived, thus making in-depth characterization of the mechanisms of resistance of paramount importance.METHODSHere, we present a rapid-autopsy case of a patient who had a KRASG12C-mutant lung adenocarcinoma who initially responded to a KRAS G12C inhibitor but then rapidly developed resistance. Using deep-RNA and whole-exome sequencing comparing pretreatment, posttreatment, and matched normal tissues, we uncover numerous mechanisms of resistance to direct KRAS inhibition.RESULTSIn addition to decreased KRAS G12C-mutant allele frequency in refractory tumors, we also found reactivation of the MAPK pathway despite no new mutations in KRAS or its downstream mediators. Tumor cell-intrinsic and non-cell autonomous mechanisms included increased complement activation, coagulation, and tumor angiogenesis, and several lines of evidence of immunologic evasion.CONCLUSIONTogether, our findings reveal numerous mechanisms of resistance to current KRAS G12C inhibitors through enrichment of clonal populations, KRAS-independent downstream signaling, and diverse remodeling of the tumor microenvironment.FUNDINGRichard and Fran Duley, Jimmy and Kay Mann, the NIH, and the North Carolina Biotechnology Center.
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Adenocarcinoma de Pulmão , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais/genética , Microambiente Tumoral/genética , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/genética , Substituição de Aminoácidos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismoRESUMO
OBJECTIVE: India has seen a rapid rise in COVID-19 cases. Examine spatiotemporal variation of COVID-19 burden Tracker across Indian states and union territories using SMAART RAPID Tracker. METHOD: We used SMAART RAPID Tracker to visually display COVID-19 spread in space and time across various states and UTs of India. Data gathered from publicly available government information sources. Data analysis on COVID-19 conducted from March 1 2020 to October 1 2020. Variables recorded include COVID-19 cases and fatality, 7-day average change, recovery rate, labs and tests. Spatial and temporal trends of COVID-19 spread across Indian states and UTs is presented. RESULT: The total number of COVID-19 cases were 63, 12,584 and total fatality was 86,821 (October 1 2020). More than 85,000 new cases of COVID-19 were reported. There were 1,867 total COVID-19 labs throughout India. More than half of them were Government labs. The total number of COVID-19 tests was 76,717,728 and total recovered COVID-19 cases was 5,273,201. Results show an overall decline in the 7-day average change of new COVID-19 cases and new COVID-19 fatality. States such as Maharashtra, Chandigarh, Puducherry, Goa, Karnataka and Andhra Pradesh continue to have high COVID-19 infectivity rate. DISCUSSION: Findings highlight need for both national guidelines combined with state specific recommendations to help manage the spread of COVD-19. CONCLUSION: The heterogeneity represented in India in terms of its geography and various population groups highlight the need of state specific approach to monitor and combat the ongoing pandemic. This would further facilitate the tailored approach for each state to mitigate and contain the spread of the disease.
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The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p = 1.47 × 10-54) and is also associated with increased levels of total cholesterol (p = 1.22 × 10-28) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p = 4.81 × 10-21) and alanine (p = 6.14 × 10-12) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p = 6.24 × 10-10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53 × 10-35). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.
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Doenças Cardiovasculares/genética , Variação Estrutural do Genoma/genética , Alelos , Colesterol/sangue , Variações do Número de Cópias de DNA/genética , Feminino , Finlândia , Genoma Humano/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Proteínas Mitocondriais/genética , Regiões Promotoras Genéticas/genética , Piruvato Desidrogenase (Lipoamida)-Fosfatase/genética , Ácido Pirúvico/metabolismo , Albumina Sérica Humana/genéticaRESUMO
The etiologic agent of plague, Yersinia pestis, is a globally distributed pathogen which poses both a natural and adversarial threat. Due largely to the rapid course and high mortality of pneumonic plague, vaccines are greatly needed. Two-component protein vaccines have been unreliable and potentially vulnerable to vaccine resistance. We evaluated the safety and efficacy of eight live Y. pestis strains derived from virulent strains CO92 or KIM6+ and mutated in one or more virulence-associated gene(s) or cured of plasmid pPst. Stringent, single-dose vaccination allowed down-selection of the two safest and most protective vaccine candidates, CO92 mutants pgm- pPst- and ΔyscN. Both completely protected BALB/c mice against subcutaneous and aerosol challenge with Y. pestis. Strain CD-1 outbred mice were more resistant to bubonic (but not pneumonic) plague than BALB/c mice, but the vaccines elicited partial protection of CD-1 mice against aerosol challenge, while providing full protection against subcutaneous challenge. A ΔyscN mutant of the nonencapsulated C12 strain was expected to display antigens previously concealed by the capsule. C12 ΔyscN elicited negligible titers to F1 but comparable antibody levels to whole killed bacteria, as did CO92 ΔyscN. Although one dose of C12 ΔyscN was not protective, vaccination with two doses of either CO92 ΔyscN, or a combination of the ΔyscN mutants of C12 and CO92, protected optimally against lethal bubonic or pneumonic plague. Protection against encapsulated Y. pestis required inclusion of F1 in the vaccine and was associated with high anti-F1 titers.
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A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.
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Variação Genética , Genoma Humano/genética , Sequenciamento Completo do Genoma , Alelos , Estudos de Casos e Controles , Epigênese Genética , Feminino , Dosagem de Genes/genética , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Anotação de Sequência Molecular , Locos de Características Quantitativas , Grupos Raciais/genética , SoftwareRESUMO
Alport syndrome (AS) is an inherited disorder of basement membranes caused by mutations affecting specific proteins of the type IV collagen family, presenting with nephropathy and extrarenal manifestations such as sensorineural deafness and ocular anomalies. Ten percentage to 15% of the patients with AS have autosomal recessive (ARAS) due to mutation in either COL4A3 or COL4A4 gene. We report a novel mutation in the COL4A3 gene in an Indian family with ARAS. The above-mentioned genetic anomaly was a missense variation in exon 26 of the COL4A3 gene (chr2:228137797G>A; c.1891G>A) that resulted in the amino acid substitution of Arginine for Glycine at codon 631 (p.Gly631Arg) that was present in the heterozygous state in the asymptomatic parents and homozygous state in the male offspring who presented with early-onset end-stage renal disease, lenticonus and hearing loss. The patient (male offspring) underwent successful renal transplantation with his mother as a donor.
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Autoantígenos/genética , Colágeno Tipo IV/genética , Transplante de Rim/métodos , Mutação , Nefrite Hereditária/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Nefrite Hereditária/cirurgia , Adulto JovemRESUMO
INTRODUCTION: Chondroblastoma is a rare primary benign tumor of bone with male predominance and is typically seen in an epiphyseal location. The pisiform is a carpal bone and chondroblastoma of the pisiform has not been reported in the literature to the best of our knowledge. CASE PRESENTATION: An 18-year-old male presented with painful swelling over his right wrist with restriction of ulnar deviation. Based on magnetic resonance imaging findings, two diagnostic possibilities were entertained, namely, giant cell tumor of bone and chondroblastoma. Wide local excision was performed, and histopathology confirmed the diagnosis of chondroblastoma of the pisiform. After 2 years of follow-up, the patient has gained pain-free wrist movements post excision, and there are no signs of recurrence. The Modified Mayo Wrist Score of 75 (fair) improved to 100 (excellent). CONCLUSION: Surgeon should always keep in mind the possibility of the tumor at the rare site and accurately diagnose the tumor with the help of imaging modalities and biopsy.
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Disruption of brain-derived neurotrophic factor (BDNF) biosynthesis and/or signaling has been implicated in the pathogenesis of Alzheimer's disease (AD). We used postmortem brain and fluid samples from 20 patients with variable severity of AD and 11 controls to investigate whether BDNF levels in serum and brain tissue correlated with hippocampal pathology. Total BDNF, precursor BDNF (pro-BDNF), and mature BDNF were measured in cerebrospinal fluid, serum, and 3 postmortem brain regions. Histological markers for AD pathology, the BDNF cognate receptor (TrkB), and glia were measured in the hippocampus (HIP). Lower pro-BDNF levels were observed in the entorhinal and frontal cortices in AD cases compared with controls. AD cases also exhibited significantly lower staining densities of the cognate BDNF receptor TrkB in the HIP compared with controls, and TrkB staining was inversely correlated with both Amylo-Glo and pTau staining in the same region, suggesting a relationship between the density of the cognate BDNF receptor and accumulation of AD pathology. In addition, higher serum pro-BDNF levels correlated with lower HIP pro-BDNF levels and higher pTau staining in the HIP. Total BDNF levels in cortical regions were also negatively correlated with Amylo-Glo staining in the HIP suggesting that reduced BDNF cortical levels might influence hippocampal amyloid accumulation. These results strongly suggest that altered BDNF and TrkB receptors are involved in AD pathology and therefore warrant investigations into therapies involving the BDNF pathway.
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Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Precursores de Proteínas/metabolismo , Coloração e Rotulagem/métodos , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/sangue , Feminino , Hipocampo/patologia , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Fosforilação , Precursores de Proteínas/sangue , Receptor trkB/metabolismoRESUMO
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.
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Sequenciamento do Exoma , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Variação Genética/genética , Locos de Características Quantitativas/genética , Alelos , HDL-Colesterol/genética , Análise por Conglomerados , Determinação de Ponto Final , Finlândia , Mapeamento Geográfico , Humanos , Herança Multifatorial/genética , Reprodutibilidade dos TestesRESUMO
Inflammation plays an important role in the pathogenesis of atherosclerosis and coronary syndromes; moreover, various lines of evidence suggest that genetic factors do contribute to the risk of coronary artery disease (CAD). The proinflammatory cytokine IL-6 is a central mediator of inflammation associated with CAD. The present study is aimed to investigate the association of single nucleotide polymorphism in the promoter region of the IL-6 gene (-174 G > C) and methylation with the susceptibility of CAD. Genotyping of IL-6 -174 G/C polymorphism was performed by PCR-RFLP. Methylation-specific PCR method was used to study the IL-6 gene promoter methylation. Analysis of 470 subjects (265 CAD patients and 205 controls) showed association of the -174 G/C variant with the CAD risk in dominant model (OR 1.58, 95% CI, 1.024-2.23, P = 0.04). Further, the analysis of the distribution of genotypes and alleles of -174 G > C polymorphism according to clinical features of CAD, revealed significant association of genotype and allele (OR 1.86, 95% CI 1.18-2.84 P = 0.01, and OR 1.71, 95% CI 1.09-2.23 P = 0.02 respectively) with diabetes, and we found no association with hypertension (OR 0.95, 95% CI 0.57-1.59, P = 0.8). We also analyzed the methylation status of IL-6 promoter region between cases and controls showed significant hypo methylation in CAD subjects (OR 2.36, 95% CI 1.51-4.259, P = 0.006). Additionally, GC, CC genotypes and C allele carriers show hypomethylation in CAD cases compared to controls (54.58 vs. 76.85%, 29.83 vs. 40% respectively). In conclusion, the promoter polymorphism -174 G/C is associated with CAD risk and further carriers of 'C' allele at -174 locus showed significant hypo methylation which could contribute to increased risk of CAD. The present study highlights the association of allele and genotypes with differential DNA methylation of CpG islands in the IL-6 promoter region which may affect IL-6 gene regulation.
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The study of samples subjected to high pressure gas is an important asset in materials research and has consequently been a priority of the sample environment development at the Oak Ridge National Laboratory's (ORNL) neutron program. Such effort has resulted in the availability of an extensive combination of pressure cells and gas intensifiers (both commercially available and custom made). These resources are available across both neutron facilities at ORNL: the Spallation Neutron Source and the High Flux Isotope Reactor. Current capabilities include, for example, in situ measurements up to 6 kbar and a 3 kbar hydrogen-capable intensifier with a gas recovery feature. In this communication, we will review the existing suite of high pressure gas capabilities, with special emphasis on recent in-house developments. A number of examples will be presented to illustrate how such capabilities are being deployed on neutron beamlines to enable frontier science.
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AIMS AND OBJECTIVES: The aim of this study is to compare the esthetic improvement of white spot lesions (WSLs) treated by icon, sodium fluoride (NaF), and bioactive glass using VITA Easyshade® spectrophotometer. METHODOLOGY: Ninety intact human maxillary central incisors were collected and artificial WSLs were created on facial surface having dimensions of 4 mm × 4 mm by immersing in demineralized solution for 4 days, baseline comparisons were performed by measuring the color of the WSLs compared to the adjacent sound enamel. All samples were divided into three groups of 30 each. Three groups were Group 1: Treated by NaF, Group 2: Treated by the bioactive glass, and Group 3: ICON®-DMG America (Resin infiltration). After treatment, the specimens of all groups were stored in artificial saliva and reevaluated at 4 and 8 weeks after the beginning of the treatments with VITA Easyshade® spectrophotometer. RESULTS: Statistical analysis was performed with One-way analysis of variance. Post hoc analysis with the Tukey's honest significant difference test was used to compare the data between the groups. Among three groups, resin infiltration has significant color change (ΔE) of infiltrated lesions when compared to other treatment groups (P < 0.001). CONCLUSION: Within the limitations of this study, it can be concluded resin infiltration (ICON®) can improve the esthetic characteristics of WSLs. Resin (ICON®) is a better treatment option when compared to bioactive glass and NaF as concerned to esthetics.
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Neuroinflammation is potentiated by early degeneration of the locus coeruleus noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In animal models, lipopolysaccharide (LPS) induces strong peripheral immune responses that can cause cognitive changes secondary to neuroinflammation. The influence of the peripheral immune response on cognition might be exacerbated by LC-NE degeneration, but this has not been well characterized previously. In this study, we investigated how systemic inflammation affects neuroinflammation and cognition in aged rats that have had either normal or damaged LC-NE transmitter systems. Rats were first exposed to the selective noradrenergic (NE) neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of central NE pathways. Two weeks later, the rats received a low dose of LPS. This resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several pro-inflammatory cytokines, increased astroglial and microglial activation in the hippocampus, and poorer performance in the novel object recognition task (NORT) compared to controls and LPS-treated rats. Additionally, serum and brain tissue levels of brain-derived neurotrophic factor (BDNF) were modulated over time in the DSP4+LPS group compared to the other two groups. Specifically, DSP4+LPS-treated rats in the short-term subgroup had lower hippocampal BDNF levels (~25%) than controls and LPS-treated rats, which negatively correlated with hippocampal astrogliosis and positively correlated with hippocampal IL-1ß levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the long-term subgroup returned to levels similar to the control group. These results show that systemic inflammation in LC-NE-lesioned aged rats promotes an exacerbated systemic and central inflammatory response compared to LC-NE-intact rats and alters BDNF levels, indicating the important role of this neurotransmitter system in response to neuroinflammation.
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Envelhecimento/patologia , Hipocampo/patologia , Inflamação/patologia , Norepinefrina/metabolismo , Análise de Variância , Animais , Astrócitos/patologia , Benzilaminas , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Quimiocinas/sangue , Discriminação Psicológica , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/fisiopatologia , Inflamação/sangue , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Locomoção , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/patologia , Degeneração Neural/patologia , Ratos Endogâmicos F344 , Análise e Desempenho de Tarefas , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
[This corrects the article DOI: 10.1371/journal.pmed.1002174.].
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BACKGROUND: Metastasis is the main cause of cancer patient deaths and remains a poorly characterized process. It is still unclear when in tumor progression the ability to metastasize arises and whether this ability is inherent to the primary tumor or is acquired well after primary tumor formation. Next-generation sequencing and analytical methods to define clonal heterogeneity provide a means for identifying genetic events and the temporal relationships between these events in the primary and metastatic tumors within an individual. METHODS AND FINDINGS: We performed DNA whole genome and mRNA sequencing on two primary tumors, each with either four or five distinct tissue site-specific metastases, from two individuals with triple-negative/basal-like breast cancers. As evidenced by their case histories, each patient had an aggressive disease course with abbreviated survival. In each patient, the overall gene expression signatures, DNA copy number patterns, and somatic mutation patterns were highly similar across each primary tumor and its associated metastases. Almost every mutation found in the primary was found in a metastasis (for the two patients, 52/54 and 75/75). Many of these mutations were found in every tumor (11/54 and 65/75, respectively). In addition, each metastasis had fewer metastatic-specific events and shared at least 50% of its somatic mutation repertoire with the primary tumor, and all samples from each patient grouped together by gene expression clustering analysis. TP53 was the only mutated gene in common between both patients and was present in every tumor in this study. Strikingly, each metastasis resulted from multiclonal seeding instead of from a single cell of origin, and few of the new mutations, present only in the metastases, were expressed in mRNAs. Because of the clinical differences between these two patients and the small sample size of our study, the generalizability of these findings will need to be further examined in larger cohorts of patients. CONCLUSIONS: Our findings suggest that multiclonal seeding may be common amongst basal-like breast cancers. In these two patients, mutations and DNA copy number changes in the primary tumors appear to have had a biologic impact on metastatic potential, whereas mutations arising in the metastases were much more likely to be passengers.
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Neoplasias da Mama/genética , Progressão da Doença , Neoplasia de Células Basais/genética , Idoso , Neoplasias da Mama/secundário , Feminino , Genômica , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasia de Células Basais/secundário , Estudos RetrospectivosRESUMO
Esophageal melanocytosis is a rare benign condition characterized by melanocytic proliferation in esophageal squamous epithelium and melanin deposition in the mucosa. Because of its uncommon nature, pathologists and gastroenterologists lack experience with this entity. We present a case of esophageal melanocytosis in a 66 years old male patient who presented with atypical chest pain and dysphagia. Endoscopic guided biopsy was done, provisional diagnosis of esophageal melanocytosis was made. Bleaching and immunohistochemistry confirmed the diagnosis.
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Endoscopia do Sistema Digestório/métodos , Doenças do Esôfago/patologia , Melanócitos/patologia , Melanose/patologia , Idoso , Biópsia , Transtornos de Deglutição , Esôfago , Humanos , Masculino , Melaninas/metabolismo , Melanócitos/metabolismo , Melanose/metabolismoRESUMO
BACKGROUND: Common variants have been associated with prostate cancer risk. Unfortunately, few are reproducibly linked to aggressive disease, the phenotype of greatest clinical relevance. One possible explanation is that rare genetic variants underlie a significant proportion of the risk for aggressive disease. METHOD: To identify such variants, we performed a two-stage approach using whole-exome sequencing followed by targeted sequencing of 800 genes in 652 aggressive prostate cancer patients and 752 disease-free controls in both African and European Americans. In each population, we tested rare variants for association using two gene-based aggregation tests. We established a study-wide significance threshold of 3.125 × 10-5 to correct for multiple testing. RESULTS: TET2 in African Americans was associated with aggressive disease, with 24.4% of cases harboring a rare deleterious variant compared with 9.6% of controls (FET P = 1.84 × 10-5, OR = 3.0; SKAT-O P = 2.74 × 10-5). We report 8 additional genes with suggestive evidence of association, including the DNA repair genes PARP2 and MSH6 Finally, we observed an excess of rare truncation variants in 5 genes, including the DNA repair genes MSH6, BRCA1, and BRCA2 This adds to the growing body of evidence that DNA repair pathway defects may influence susceptibility to aggressive prostate cancer. CONCLUSIONS: Our findings suggest that rare variants influence risk of clinically relevant prostate cancer and, if validated, could serve to identify men for screening, prophylaxis, and treatment. IMPACT: This study provides evidence that rare variants in TET2 may help identify African American men at increased risk for clinically relevant prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(11); 1456-63. ©2016 AACR.