The cytoplasmic fraction of the histone lysine methyltransferase Setdb1 is essential for embryonic stem cells.

The major lysine methyltransferase (KMT) Setdb1 is essential for self-renewal and viability of mouse embryonic stem cells (mESCs). Setdb1 was primarily known to methylate the lysine 9 of histone 3 (H3K9) in the nucleus, where it regulates chromatin functions. However, Setdb1 is also massively localized in the cytoplasm, including in mESCs, where its role remains elusive. Here, we show that the cytoplasmic Setdb1 (cSetdb1) is essential for the survival of mESCs. Yeast two-hybrid analysis revealed that cSetdb1 interacts with several regulators of mRNA stability and protein translation machinery, such as the ESCs-specific E3 ubiquitin ligase and mRNA silencer Trim71/Lin41. We found that cSetdb1 is required for the integrity of Trim71 complex(es) involved in mRNA metabolism and translation. cSetdb1 modulates the abundance of mRNAs and the rate of newly synthesized proteins. Altogether, our data uncovered the cytoplasmic post-transcriptional regulation of gene expression mediated by a key epigenetic regulator.

Risk of complications after a non-ST segment elevation acute myocardial infarction in a Latin-American cohort: An application of the ACTION ICU score.

BACKGROUND: European Society of Cardiology (ESC) guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation (NSTEMI) recommend Intensive Care Unit (ICU) surveillance during the first 24-48 h. Interestingly, the in-hospital mortality of NSTEMI patients has consistently decreased, giving some patients the option to be managed in general hospital wards. The ACTION ICU score has been proposed to identify high-risk patients with NSTEMI and guide the selective risk-based need for ICU care. OBJECTIVE: To evaluate the usefulness of the ACTION ICU score to predict patients' risk of developing complications requiring ICU care in a Latin-American cohort with NSTEMI. METHODS: We applied the ACTION ICU score in a retrospective cohort. A composite primary outcome included: cardiorespiratory arrest, shock, high-grade atrio-ventricular block, respiratory failure, stroke, or death. The predictive performance of this model was estimated with a conditional multivariable logistic regression analysis. RESULTS: Of 1,062 patients with NSTEMI, the primary outcome was present in 75 patients (7.1%), and 1,019 (96%) were admitted to ICU. The most common event was respiratory failure (4.0%), followed by cardiogenic shock (3.7%), and cardiac arrest (1.7%). The presence of heart failure signs or symptoms had the highest association with the primary outcome (OR:2.16; 95%CI:1.61-2.92). The best cut-off point for this population was 3 (complications risk: 4.0%, SEN:96%, SP:15.4%, NPV:98.1%, PPV:7.9%). CONCLUSION: The ACTION ICU score may be a promising tool to identify the need for ICU care in Latin-American patients with NSTEMI. Furthermore, additional research is needed to evaluate the cost-effectiveness of this strategy.

Intrinsic Subtypes and Androgen Receptor Gene Expression in Primary Breast Cancer. A Meta-Analysis.

The androgen receptor (AR) is frequently expressed in breast cancer (BC), but its association with clinical and biological parameters of BC patients remains unclear. Here, we investigated the association of AR gene expression according to intrinsic BC subtypes by meta-analysis of large-scale microarray transcriptomic datasets. Sixty-two datasets including 10315 BC patients were used in the meta-analyses. Interestingly, AR mRNA level is significantly increased in patients categorized with less aggressive intrinsic molecular subtypes including, Luminal A compared to Basal-like (standardized mean difference, SMD: 2.12; 95% confidence interval, CI: 1.88 to 2.35; p < 0.001) or when comparing Luminal B to Basal-like (SMD: 1.53; CI: 1.33 to 1.72; p < 0.001). The same trend was observed when analyses were performed using immunohistochemistry-based surrogate subtypes. Consistently, the AR mRNA expression was higher in patients with low histological grade (p < 0.001). Furthermore, our data revealed higher levels of AR mRNA in BC patients expressing either estrogen or progesterone receptors (p < 0.001). Together, our findings indicate that high mRNA levels of AR are associated with BC subgroups with the less aggressive clinical features.

The H3K9 Methylation Writer SETDB1 and its Reader MPP8 Cooperate to Silence Satellite DNA Repeats in Mouse Embryonic Stem Cells.

SETDB1 (SET Domain Bifurcated histone lysine methyltransferase 1) is a key lysine methyltransferase (KMT) required in embryonic stem cells (ESCs), where it silences transposable elements and DNA repeats via histone H3 lysine 9 tri-methylation (H3K9me3), independently of DNA methylation. The H3K9 methylation reader M-Phase Phosphoprotein 8 (MPP8) is highly expressed in ESCs and germline cells. Although evidence of a cooperation between H3K9 KMTs and MPP8 in committed cells has emerged, the interplay between H3K9 methylation writers and MPP8 in ESCs remains elusive. Here, we show that MPP8 interacts physically and functionally with SETDB1 in ESCs. Indeed, combining biochemical, transcriptomic and genomic analyses, we found that MPP8 and SETDB1 co-regulate a significant number of common genomic targets, especially the DNA satellite repeats. Together, our data point to a model in which the silencing of a class of repeated sequences in ESCs involves the cooperation between the H3K9 methylation writer SETDB1 and its reader MPP8.

Expression of the Major and Pro-Oncogenic H3K9 Lysine Methyltransferase SETDB1 in Non-Small Cell Lung Cancer.

SETDB1 is a key histone lysine methyltransferase involved in gene silencing. The SETDB1 gene is amplified in human lung cancer, where the protein plays a driver role. Here, we investigated the clinical significance of SETDB1 expression in the two major forms of human non-small cell lung carcinoma (NSCLC), i.e., adenocarcinoma (ADC) and squamous cell carcinoma (SCC), by combining a meta-analysis of transcriptomic datasets and a systematic review of the literature. A total of 1140 NSCLC patients and 952 controls were included in the association analyses. Our data revealed higher levels of SETDB1 mRNA in ADC (standardized mean difference, SMD: 0.88; 95% confidence interval, CI: 0.73-1.02; p < 0.001) and SCC (SMD: 0.40; 95% CI: 0.13-0.66; p = 0.003) compared to non-cancerous tissues. For clinicopathological analyses, 2533 ADC and 903 SCC patients were included. Interestingly, SETDB1 mRNA level was increased in NSCLC patients who were current smokers compared to non-smokers (SMD: 0.26; 95% CI: 0.08-0.44; p = 0.004), and when comparing former smokers and non-smokers (p = 0.009). Furthermore, the area under the curve (AUC) given by the summary receiver operator characteristic curve (sROC) was 0.774 (Q = 0.713). Together, our findings suggest a strong foundation for further research to evaluate SETDB1 as a diagnostic biomarker and/or its potential use as a therapeutic target in NSCLC.

Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)--animal models as a proof of concept.

ASIA syndrome, "Autoimmune (Auto-inflammatory) Syndromes Induced by Adjuvants" includes at least four conditions which share a similar complex of signs and symptoms and have been defined by hyperactive immune responses: siliconosis, macrophagic myofasciitis syndrome, Gulf war syndrome and post-vaccination phenomena. Exposure to adjuvants has been documented in these four medical conditions, suggesting that the common denominator to these syndromes is a trigger entailing adjuvant activity. An important role of animal models in proving the ASIA concept has been established. Experimentally animal models of autoimmune diseases induced by adjuvants are currently widely used to understand the mechanisms and etiology and pathogenesis of these diseases and might thus promote the development of new diagnostic, predictive and therapeutic methods. In the current review we wish to unveil the variety of ASIA animal models associated with systemic and organ specific autoimmune diseases induced by adjuvants. We included in this review animal models for rheumatoid arthritis-like disease, for systemic lupus erythematosus-like disease, autoimmune thyroid disease-like disease, antiphospholipid syndrome, myocarditis and others. All these models support the concept of ASIA, as the Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants.

Autoimmune thyroid disease in rheumatoid arthritis: a global perspective.

Objective. To determine the prevalence and impact of autoimmune thyroid disease (AITD) in patients with rheumatoid arthritis (RA). Methods. Eight-hundred patients were included. The association between AITD and RA was analyzed was analyzed by bivariate and multivariate analysis. In addition, a literature review was done focusing on geographical variations. Results. In our cohort the prevalence of AITD was 9.8% while the presence of antibodies was 37.8% for antithyroperoxidase enzyme (TPOAb) and 20.8% for antithyroglobulin protein (TgAb). The presence of type 2 diabetes, thrombosis, abnormal body mass index, and a high educational level was positively associated with AITD. The literature review disclosed a geographical variation of AITD in RA ranging from 0.5% to 27%. Autoantibody prevalence ranges from 6% to 31% for TgAb, 5% to 37% for TPOAb, and from 11.4% to 32% for the presence of either of the two. Conclusion. AITD is not uncommon in RA and should be systematically assessed since it is a risk factor for developing diabetes and cardiovascular disease. These results may help to further study the common mechanisms of autoimmune diseases, to improve patients' outcome, and to define public health policies. An international consensus to accurately diagnose AITD is warranted.

Usefulness of patients-reported outcomes in rheumatoid arthritis focus group.

Objective. Patient-reported outcomes (PROs) have become an essential part of the assessment of patients with rheumatoid arthritis (RA). We aimed to evaluate the agreement and correlation between PROs and the physician's measurements. Methods. This was a cross-sectional analytical study in which 135 patients with RA were clinically evaluated during two different sessions of focus group interviews. Rheumatologist recorded 28 swollen (SJCs) and tender joint counts (TJCs). The patients filled out the PROs instruments (MDHAQ, RADAI, RAPID3, 4, and 5 and self-report articular index (SAI) diagram for pain and joint swelling). DAS28 was calculated (C-reactive protein). An adjusted multiple lineal regression model was done (DAS28 as dependent variable). Results. Highly significant agreements were found between SJC and TJC registered by the physician and patient. There was moderate correlation between DAS28 with patient SJC (r = 0.52), patient TJC (r = 0.55), RADAI (r = 0.56), RAPID3 (r = 0.52), RAPID4 (r = 0.56), RAPID5 (r = 0.66), and VAS-Global (r = 0.51). Likewise, we found moderate to high correlations between CDAI and SDAI with all variable measurements done by the patients. The resulting predictive equation was DAS28(CRP) = 2.02 + 0.037 × RAPID4 + 0.042× patient SJC. Conclusion. PROs applied in focus groups interview are a useful tool for managing patients with RA regardless of gender, educational level, and duration of disease.

Shared HLA Class II in Six Autoimmune Diseases in Latin America: A Meta-Analysis.

The prevalence and genetic susceptibility of autoimmune diseases (ADs) may vary depending on latitudinal gradient and ethnicity. The aims of this study were to identify common human leukocyte antigen (HLA) class II alleles that contribute to susceptibility to six ADs in Latin Americans through a meta-analysis and to review additional clinical, immunological, and genetic characteristics of those ADs sharing HLA alleles. DRB1(∗)03:01 (OR: 4.04; 95%CI: 1.41-11.53) was found to be a risk factor for systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and type 1 diabetes mellitus (T1D). DRB1(∗)04:05 (OR: 4.64; 95%CI: 2.14-10.05) influences autoimmune hepatitis (AIH), rheumatoid arthritis (RA), and T1D; DRB1(∗)04:01 (OR: 3.86; 95%CI: 2.32-6.42) is a susceptibility factor for RA and T1D. Opposite associations were found between multiple sclerosis (MS) and T1D. DQB1(∗)06:02 and DRB1(∗)15 alleles were risk factors for MS but protective factors for T1D. Likewise, DQB1(∗)06:03 allele was a risk factor for AIH but a protective one for T1D. Several common autoantibodies and clinical associations as well as additional shared genes have been reported in these ADs, which are reviewed herein. These results indicate that in Latin Americans ADs share major loci and immune characteristics.

Infections and vaccines in the etiology of antiphospholipid syndrome.

PURPOSE OF REVIEW: To present scientific evidence supporting the infectious origin for the antiphospholipid syndrome (APS) by molecular mimicry between pathogens, infection and vaccination with ß2-glycoprotein I (ß2-GPI) molecule. RECENT FINDINGS: APS is characterized by the presence of pathogenic autoantibodies against ß2-GPI. The infection etiology of APS was well established. Likewise, a link between vaccination such as tetanus toxoid may trigger antibodies targeting tetanus toxoid and ß2-GPI, due to molecular mimicry between the two molecules. During the years, the pathogenic potential of anti-tetanus toxoid antibodies cross reactive with ß2-GPI were found to be pathogenic in animal models, inducing experimental APS. SUMMARY: Accumulated evidence supports that the presence of anti-ß2-GPI antibodies is associated with a history of infections and the main mechanism to explain this correlation is molecular mimicry. The relationship between tetanus toxoid vaccination and APS reveals a novel view on the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA).

Spondyloarthropathies in autoimmune diseases and vice versa.

Polyautoimmunity is one of the major clinical characteristics of autoimmune diseases (ADs). The aim of this study was to investigate the prevalence of ADs in spondyloarthropathies (SpAs) and vice versa. This was a two-phase cross-sectional study. First, we examined the presence of ADs in a cohort of patients with SpAs (N = 148). Second, we searched for the presence of SpAs in a well-defined group of patients with ADs (N = 1077) including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS). Among patients with SpAs, ankylosing spondylitis was observed in the majority of them (55.6%). There were two patients presenting with SS in the SpA group (1.4%) and 5 patients with autoimmune thyroiditis (3.5%). The global prevalence of ADs in SpAs was 4.86%. In the ADs group, there were 5 patients with SpAs (0.46%). Our results suggest a lack of association between SpAs and ADs. Accordingly, SpAs might correspond more to autoinflammatory diseases rather than to ADs.

HLA and Sjögren's syndrome susceptibility. A meta-analysis of worldwide studies.

The aim of this work was to identify common HLA Class II alleles contributing to primary Sjögren's syndrome (pSS) susceptibility worldwide and to analyze their biological implications through a binding prediction approach of peptides from major pSS auto-antigens. Case-control studies on HLA-DQ and HLA-DR in pSS were searched in various literature databases through April 2011 by a systematic review. The effect summary odds ratios and 95% confidence intervals were obtained by means of the random effect model. A total of 1166 cases and 6470 controls from 23 studies were analyzed. At the allelic level, DQA1*05:01, DQB1*02:01, and DRB1*03:01 alleles were found to be risk factors for disease. Conversely, the DQA1*02:01, DQA1*03:01 and DQB1*05:01 alleles were protective factors. The current study stresses the significant size effect HLA exhibits in the development of pSS. Analysis of susceptibility and protective alleles revealed physicochemical differences in critical amino acids located within the antigen-binding groove of DRß, DQα and DQß chains, allowing us to infer a mechanistic approach to understand the role of HLA in pSS and other autoimmune diseases.

ZC3H12A (MCPIP1): molecular characteristics and clinical implications.

BACKGROUND: ZC3H12A is a gene whose absence is related to autoimmune disorders and to other phenotypical alterations. METHODS: A comprehensive review of the structure, molecular functions and regulation of ZC3H12A gene and its protein MCPIP1 is done in order to understand their clinical implications. RESULTS: ZC3H12A, at 1p34.3, has 9860bp, six exons and 61 described SNPs. Eleven are non-synonymous thus leading to changes in MCPIP1, the protein encoded by ZC3H12A. MCPIP1 is induced by MCP-1 and IL-1 whose signals are transduced through the NF-kß and MAPkinase pathways. This protein acts as an RNAse by degrading chemokine transcripts such as IL-1 as well as its own mRNA and as a transcription factor by reducing the expression of other chemokines induced by NF-kß such as MCP-1. It also up-regulates genes involved in several differentiation processes and apoptosis. Therefore, ZC3H12A is an equilibrium gatekeeper that not only regulates its own inducers but also controls the regulation by degrading its own mRNA. CONCLUSION: Understanding ZC3H12A gives a comprehensive panorama that promises to improve our understanding of processes in which this gene is involved including autoimmune, infectious and cardiovascular diseases.

HLA class II polymorphism in Latin American patients with multiple sclerosis.

OBJECTIVE: To identify HLA-DRB1 alleles contributing to susceptibility to multiple sclerosis (MS) in a Colombian population and to estimate the common effect size of HLA class II on MS susceptibility in Latin American populations through a meta-analysis. METHODS: A total of 65 Colombian patients with MS and 184 matched controls were included. HLA-DRB1 typing was done using the sequence-specific oligonucleotide probe method. A bivariate and a multivariate logistic regression analyses were done. Case-control studies performed in Latin America were searched up to January 2009 through a systematic review of the literature. Effect summary odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by means of the random effect model. RESULTS: A total of 464 cases and 2581 controls from 7 studies and the results of the present study in Colombians were analyzed. HLA-DRB1*15 (OR: 2.3; 95% CI: 1.68-3.07; p<0.001) and HLA-DQB1*06 (OR: 2.2; 95% CI: 1.54-3.07; p<0.001) groups as well as DRB1*1501 (OR: 2.6; 95% CI: 1.67-4.02; p<0.001), DRB1*1503 (OR: 2.2; 95% CI: 1.39-3.62; p=0.001) and DQB1*0602 (OR: 2.5; 95% CI: 1.66-3.71; p<0.001) alleles were found to be risk factors for MS. The myelin basic protein immunodominant sequence (221)VHFFKNIVT(229) was predicted to strongly and simultaneously bind to HLA-DRB1*1501 and *1503. CONCLUSION: The current study highlights the effect size of HLA class II in MS in Latin America and confirms similar allelic risk factors across diverse populations. Receptor-ligand interactions in the HLA-antigenic peptide complex could have potential predictive and therapeutical implications.

Fundamento biológico y aplicación clínica de los marcadores tumorales séricos / Biological basis and clinical application of serum tumor markers

El cáncer es el resultado de la acumulación de alteraciones en moléculas con importante función en procesos celulares como proliferación, apoptosis, muerte celular y reparación génica. Las moléculas, sustancias o procesos alterados pueden constituirse en marcadores o biomarcadores tumorales de gran utilidad clínica en el seguimiento de pacientes oncológicos ya que han demostrado ser idóneos para la valoración del tratamiento y su eficiencia. La determinación de biomarcadores tumorales no ha sido muy exitosa debido a la baja sensibilidad y especificidad de las técnicas usadas y al requerimiento de muestras biológicas en volúmenes grandes o de métodos invasivos para su recolección. Los marcadores tumorales séricos surgen, entonces, como una herramienta útil en la obtención de información sobre el estado de la enfermedad y constituye un reto científico mejorar su aplicabilidad en el diagnóstico temprano, pronóstico, seguimiento de la enfermedad y evaluación de la eficacia terapéutica.

Cancer is the result of the accumulation of changes in molecules with important functions in processes such as cell proliferation, apoptosis, cell death and gene repair. Molecules, substances or altered pathways constitute tumor markers or biomarkers useful in clinical monitoring of cancer patients, because they have demonstrated to be suitable for the valuation of the patient's treatment and it efficiency. Determination of tumor markers has not been very successful due to the low sensitivity and specificity of the techniques used and the requirement of large volumes of biological samples or the use of invasive methods for collecting them. The serum tumor markers arise, as a useful tool to obtain information about the disease progress and constitute as a scientific challenge to improve its applicability in early diagnosis, prognosis, monitoring of the disease and evaluation of therapeutic efficacy.