Regulation of metabolic and transcriptional responses by the thyroid hormone in cellular models of murine macrophages.

Oncogene-immortalized bone marrow-derived macrophages are considered to be a good model for the study of immune cell functions, but the factors required for their survival and proliferation are still unknown. Although the effect of the thyroid hormones on global metabolic and transcriptional responses in macrophages has not yet been examined, there is increasing evidence that they could modulate macrophage functions. We show here that the thyroid hormone T3 is an absolute requirement for the growth of immortal macrophages. The hormone regulates the activity of the main signaling pathways required for proliferation and anabolic processes, including the phosphorylation of ERK and p38 MAPKs, AKT, ribosomal S6 protein, AMPK and Sirtuin-1. T3 also alters the levels of metabolites controlling transcriptional and post-transcriptional actions in macrophages, and causes widespread transcriptomic changes, up-regulating genes needed for protein synthesis and cell proliferation, while down-regulating genes involved in immune responses and endocytosis, among others. This is not observed in primary bone marrow-derived macrophages, where only p38 and AMPK activation is regulated by T3 and in which the metabolic and transcriptomic effects of the hormone are much weaker. However, the response to IFN-γ is reduced by T3 similarly in immortalized macrophages and in the primary cells, confirming previous results showing that the thyroid hormones can antagonize JAK/STAT-mediated signaling. These results provide new perspectives on the relevant pathways involved in proliferation and survival of macrophage cell culture models and on the crosstalk between the thyroid hormones and the immune system.

Thyroid Hormone Receptor ß Inhibits Self-Renewal Capacity of Breast Cancer Stem Cells.

Background: A subpopulation of cancer stem cells (CSCs) with capacity for self-renewal is believed to drive initiation, progression, and relapse of breast tumors. Methods: Since the thyroid hormone receptor ß (TRß) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that TRß could affect the CSC population using MCF-7 cells grown under adherent conditions or as mammospheres, as well as inoculation into immunodeficient mice. Results: Treatment of TRß-expressing MCF-7 cells (MCF7-TRß cells) with the thyroid hormone triiodothyronine (T3) decreased significantly CD44+/CD24- and ALDH+ cell subpopulations, the efficiency of mammosphere formation, the self-renewal capacity of CSCs in limiting dilution assays, the expression of the pluripotency factors in the mammospheres, and tumor initiating capacity in immunodeficient mice, indicating that the hormone reduces the CSC population present within the bulk MCF7-TRß cultures. T3 also decreased migration and invasion, a hallmark of CSCs. Transcriptome analysis showed downregulation of the estrogen receptor alpha (ERα) and ER-responsive genes by T3. Furthermore, among the T3-repressed genes, there was an enrichment in genes containing binding sites for transcription factors that are key determinants of luminal-type breast cancers and are required for ER binding to chromatin. Conclusion: We demonstrate a novel role of TRß in the biology of CSCs that may be related to its action as a tumor suppressor in breast cancer.

HEY1 functions are regulated by its phosphorylation at Ser-68.

HEY1 (hairy/enhancer-of-split related with YRPW motif 1) is a member of the basic helix-loop-helix-orange (bHLH-O) family of transcription repressors that mediate Notch signalling. HEY1 acts as a positive regulator of the tumour suppressor p53 via still unknown mechanisms. A MALDI-TOF/TOF MS analysis has uncovered a novel HEY1 regulatory phosphorylation event at Ser-68. Strikingly, this single phosphorylation event controls HEY1 stability and function: simulation of HEY1 Ser-68 phosphorylation increases HEY1 protein stability but inhibits its ability to enhance p53 transcriptional activity. Unlike wild-type HEY1, expression of the phosphomimetic mutant HEY1-S68D failed to induce p53-dependent cell cycle arrest and it did not sensitize U2OS cells to p53-activating chemotherapeutic drugs. We have identified two related kinases, STK38 (serine/threonine kinase 38) and STK38L (serine/threonine kinase 38 like), which interact with and phosphorylate HEY1 at Ser-68. HEY1 is phosphorylated at Ser-68 during mitosis and it accumulates in the centrosomes of mitotic cells, suggesting a possible integration of HEY1-dependent signalling in centrosome function. Moreover, HEY1 interacts with a subset of p53-activating ribosomal proteins. Ribosomal stress causes HEY1 relocalization from the nucleoplasm to perinucleolar structures termed nucleolar caps. HEY1 interacts physically with at least one of the ribosomal proteins, RPL11, and both proteins cooperate in the inhibition of MDM2-mediated p53 degradation resulting in a synergistic positive effect on p53 transcriptional activity. HEY1 itself also interacts directly with MDM2 and it is subjected to MDM2-mediated degradation. Simulation of HEY1 Ser-68 phosphorylation prevents its interaction with p53, RPL11 and MDM2 and abolishes HEY1 migration to nucleolar caps upon ribosomal stress. Our findings uncover a novel mechanism for cross-talk between Notch signalling and nucleolar stress.

Effect of lesion length on functional significance of intermediate long coronary lesions.

OBJECTIVE: To assess the relationship between lesion length and other angiographic parameters on the functional significance of long coronary lesions with moderate stenosis. BACKGROUND: Coronary revascularization is usually based on angiographic percent stenosis. Coronary stenosis length is not usually considered in daily clinical practice for revascularization decision-making. The relevance of lesion length might be greater in longer lesions with intermediate stenosis. METHODS: All coronary lesions >20 mm and of 40-70% percent stenosis assessed by intracoronary pressure wire between 2007 and 2009 were included. Interventionists performing digital quantification of lesion stenosis were blinded to the result of fractional flow reserve (FFR). Correlations between angiographic data and FFR were analyzed. RESULTS: One hundred and six lesions from 103 patients were included. Reference diameter: 2.9 ± 0.56 mm; maximal stenosis: 49.0 ± 8.7%; minimal luminal diameter (MinimalLD): 1.48 ± 0.4 mm; mean luminal diameter (MeanLD): 2.3 ± 0.5 mm; mean lesion length: 28.7 ± 10.6 mm. Lesions with FFR <0.75 accounted for 33% (n = 35). Weak correlations were obtained between FFR and MinimalLD (r = 0.36; P < 0.0005), MeanLD (r = 0.24; P = 0.014), maximal stenosis (r = 0.31; P = 0.001), and mean stenosis (r = 0.018; P = 0.85); strong correlations were observed between FFR and lesion length (r = 0.63; P < 0.0005), lesion length/MinimalLD (r = 0.67; P < 0.0005), and lesion length/MeanLD (0.72; P < 0.0005). The predictive values of lesion length, lesion length/MinimalLD, and lesion length/MeanLD for FFR <0.75 were 0.86, 0.91, and 0.92, respectively. CONCLUSIONS: In long lesions (>20 mm) with moderate angiographic stenosis, lesion length might be the strongest determinant of functional repercussion. Lesion length should be considered when judging the benefit of revascularization or perform functional functional measures that overcome the limitations of simple stenosis quantification.

The transcription factor CREBZF is a novel positive regulator of p53.

CREBZF is a member of the mammalian ATF/CREB family of transcription factors. Here, we describe a novel functional interaction between CREBZF and the tumor suppressor p53. CREBZF was identified in a yeast two-hybrid screen using HEY1, recently characterized as an indirect p53 activator, as bait. CREBZF interacts in vitro with both HEY1 and p53, and CREBZF expression stabilizes and activates p53. Moreover, CREBZF cooperates synergistically with HEY1 to enhance p53 transcriptional activity. On the other hand, partial depletion of endogenous CREBZF diminishes p53 protein levels and inhibits HEY1-mediated activation of p53. CREBZF-positive effects on p53 signaling may reflect, at least in part, an observed induction of posttranslational modifications in p53 known to prevent its degradation. CREBZF expression protects HCT116 cells from UV radiation-induced cell death. In addition, CREBZF expression confers sensitivity to 5-fluorouracil, a p53-activating chemotherapeutic drug. Our study suggests that CREBZF may participate in the modulation of p53 tumor suppressor function.

Carotid resistive index in treated hypertensive patients: relationship with target organ damage.

AIM: The resistive index (RI) is a hemodynamic parameter that reflects local wall extensibility and related vascular resistance. We analyze the relationship between common carotid RI and target organ damage in treated hypertensive patients. METHODS: We analyzed 265 consecutive hypertensive patients. Risk factors, cardiovascular history and treatments were collected; blood test, urinary albumin excretion (UAE), echocardiography to determine left ventricular mass index (LVMI), ankle-brachial index (ABI) and carotid echo-Doppler ultrasound to calculate the carotid intima-media thickness (IMT) and RI of both common carotids arteries were performed. RESULTS: A positive correlation was found between carotid RI and age, systolic blood pressure, heart rate, carotid IMT, LVMI, UAE and a negative correlation was found with diastolic blood pressure and ABI. Subjects at the top quartile of carotid RI showed a higher prevalence of left ventricular hypertrophy and peripheral artery disease (increased IMT, carotid plaques and lower ABI) compared with those with low RI (p < 0.05). Multiple regression analysis demonstrated that age, systolic and diastolic blood pressure and LVMI independently influence carotid RI. CONCLUSION: Carotid RI is related with age, systolic-diastolic blood pressure and LVMI in hypertensive patient. This evaluation could predict the presence of early cardiovascular damage and provide an accurate estimation of overall risk in this population.

Validez diagnóstica del NT-proBNP frente al electrocardiograma en la detección de hipertrofia ventricular izquierda de origen hipertensivo / Diagnostic accuracy of NT-proBNP compared with electrocardiography in detecting left ventricular hypertrophy of hypertensive origin

El electrocardiograma (ECG) es el método más utilizado para el diagnóstico de hipertrofia ventricular izquierda (HVI) en pacientes hipertensos. Analizamos la utilidad del propéptido natriurético cerebral N-terminal (NT-proBNP) en la identificación de HVI comparado con el ECG en 336 pacientes hipertensos consecutivos con función sistólica conservada. Se encontró una correlación significativa entre concentración de NT-proBNP y masa ventricular izquierda ajustada por superficie corporal (r=0,41; p<0,001). El área bajo la curva receiver operating characteristic fue de 0,75 (intervalo de confianza del 95%, 0,7-0,8). Un punto de corte de 74,2 pg/ml presentaba una sensibilidad superior que el ECG (el 76,6 frente al 25,5%; p<0,001) y un mayor valor predictivo negativo (el 87,8 frente al 76,6%; p<0,001) en la identificación de HVI. El NT-proBNP puede ser una buena herramienta en el cribado de HVI en pacientes hipertensos (AU)

Electrocardiography (ECG) is the most widely used method for diagnosing left ventricular hypertrophy (LVH) in hypertensive patients. We assessed the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) determination compared with ECG for detecting LVH in 336 consecutive hypertensive patients with preserved systolic function. We found a significant correlation between NT-proBNP levels and left ventricular mass adjusted for body surface area (r=.41; P<.001). The area under the receiver operating characteristic curve was 0.75 (95% CI, 0.7-0.8). A cut-off of 74.2 pg/mL had a greater sensitivity than ECG (76.6% vs 25.5%; P<.001) and a higher negative predictive value (87.8% vs 76.6%; P<.001) in the identification of LVH. NT-proBNP determination may be a useful tool for LVH screening in hypertensive patients (AU)

Burden of systemic hypertension in patients admitted to cardiology hospitalization units.

Hypertension is 1 of the most prevalent cardiovascular risk factors; nevertheless, some studies have reported that the antecedent of hypertension does not impair prognosis in patients with established cardiovascular disease. The objective of this study was to describe the impact of hypertension on readmission and 1-year mortality in patients admitted to a single cardiology hospitalization unit. All consecutive hospitalizations in a single cardiology department through 10 months were included, and 1-year follow-up was performed. Clinical antecedents, risk factors, and main discharge diagnoses were collected. A total of 1,007 patients were included (mean age 71.1 ± 13.5 years). The antecedent of hypertension was present in 69.0%, and these patients had older mean age and higher prevalence of risk factors and previous cardiovascular disease. No differences in hospital discharge main diagnoses were observed according to the antecedent of hypertension. During a mean follow-up period of 404.82 ± 122.2 days, patients with hypertension had higher rates of rehospitalization for cardiac causes (31.1% vs 17.9%, p = 0.01) and of total (17.4% vs 9.3%, p <0.01) and cardiovascular (13.9% vs 5.9%, p <0.01) mortality. Multivariate analysis identified the antecedent of hypertension as an independent risk factor for cardiovascular readmission (hazard ratio 1.46, 95% confidence interval 1.10 to 1.98) and the combined end point of readmission or mortality (hazard ratio 1.45, 95% confidence interval 1.12 to 1.88); no independent association was observed for total mortality. In conclusion, hypertension was present in most patients admitted to a cardiology unit, and they had higher rates of rehospitalization and mortality at 1-year follow-up.

[Diagnostic accuracy of NT-proBNP compared with electrocardiography in detecting left ventricular hypertrophy of hypertensive origin]. / Validez diagnóstica del NT-proBNP frente al electrocardiograma en la detección de hipertrofia ventricular izquierda de origen hipertensivo.

Electrocardiography (ECG) is the most widely used method for diagnosing left ventricular hypertrophy (LVH) in hypertensive patients. We assessed the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) determination compared with ECG for detecting LVH in 336 consecutive hypertensive patients with preserved systolic function. We found a significant correlation between NT-proBNP levels and left ventricular mass adjusted for body surface area (r=.41; P<.001). The area under the receiver operating characteristic curve was 0.75 (95% CI, 0.7-0.8). A cut-off of 74.2 pg/mL had a greater sensitivity than ECG (76.6% vs 25.5%; P<.001) and a higher negative predictive value (87.8% vs 76.6%; P<.001) in the identification of LVH. NT-proBNP determination may be a useful tool for LVH screening in hypertensive patients.

¿Qué medida del grosor íntima-media carotídeo caracteriza mejor la carga aterosclerótica del paciente hipertenso: valor máximo o medio? / What Measure of Carotid Wall Thickening Is the Best Atherosclerotic Loading Score in the Hypertensive Patient: Maximum or Mean Value?

El aumento del grosor íntima-media carotídeo (GIMc) es un marcador de lesión de órgano diana establecido en las guías de hipertensión arterial, si bien no especifica si debemos utilizar el GIMc máximo o medio. Nuestro objetivo es comparar ambas medidas y su relación con la carga aterosclerótica. Hemos analizado consecutivamente a 215 pacientes hipertensos que han sido clasificados en tres grupos: GIMc máximo > 0,9 mm (GIMc medio<0,9 mm), GIMc medio>0,9 mm (GIMc medio y máximo>0,9 mm) y grupo GIMc normal. Los pacientes con GIMc patológico (máximo o medio) presentaban mayor prevalencia de dislipemia, mayor edad, mayor tiempo de evolución de la hipertensión y peor filtrado glomerular e índice tobillo-brazo. Además, los pacientes con GIMc medio>0,9 mm tenían mayor prevalencia de placas y estenosis carotÍdeas y peor índice tobillo-brazo que los pacientes con GIMc máximo>0,9 mm. El GIMc medio supone una mejor aproximación de la carga aterosclerótica del paciente hipertenso (AU)

Recent guidelines on arterial hypertension regard increased carotid intima–media thickness (IMT) as a marker of end-organ damage. However, these guidelines do not specify whether the maximum or mean IMT should be used as an indicator. The aim of this study was to compare these two measures and their relationship to atherosclerotic burden. The study involved 215 consecutive hypertensive patients who were divided into three groups according to their IMT: maximum IMT >0.9mm (with mean IMT<0.9mm); mean IMT >0.9mm (i.e. mean and maximum IMT >0.9mm); and normal IMT. Patients with a pathologically raised IMT (whether maximum or mean value) were more likely to be dyslipidemic, were older, had a longer history of hypertension, and had a poorer glomerular filtration rate and ankle–brachial index. Patients with a mean IMT >0.9mm were more likely to have carotid plaque, carotid stenosis and a low ankle–brachial index than those with a maximum IMT >0.9mm. The mean IMT provided a better indication of atherosclerotic burden in patients with hypertension (AU)

Identification and characterization of novel potentially oncogenic mutations in the human BAF57 gene in a breast cancer patient.

BAF57 is a core subunit present in all mammalian SWI/SNF ATP-dependent chromatin remodeling complexes, which regulates important biological processes including gene transcription, DNA recombination, DNA repair, and DNA replication. Among other functions, BAF57 mediates the recruitment of SWI/SNF to sequence-specific transcription factors. Thus, BAF57 plays a crucial role in regulating estrogen-dependent gene expression and proliferation in human cell lines derived from breast tumors. Increasing genetic and biochemical evidences suggest that mutations in BAF57 or alterations in its expression could play an oncogenic role in the mammary gland. Here, we describe two novel mutations in the BAF57 gene found in a breast cancer patient. Both mutations originate premature stop codons, leading to truncated proteins, structurally similar to another BAF57 mutant previously found in a human cell line derived from a breast tumor (BT-549). The expression of these novel BAF57 mutants has abnormally high estrogen receptor alpha (ERα) coactivating potential, suggesting that they might be involved in the aberrant estrogen-dependent proliferation that occur in the majority of breast tumors that retain ERα expression. In addition, the mutations in BAF57 affect its functional interaction with the androgen receptor and ETS2, two transcription factors that play an important role in breast cell biology. Therefore, mutations in BAF57 could impinge on several oncogenic signaling pathways contributing to the origin and/or development of breast cancer.

[What measure of carotid wall thickening is the best atherosclerotic loading score in the hypertensive patient: maximum or mean value?]. / ¿Qué medida del grosor íntima-media carotídeo caracteriza mejor la carga aterosclerótica del paciente hipertenso: valor máximo o medio?

Recent guidelines on arterial hypertension regard increased carotid intima-media thickness (IMT) as a marker of end-organ damage. However, these guidelines do not specify whether the maximum or mean IMT should be used as an indicator. The aim of this study was to compare these two measures and their relationship to atherosclerotic burden. The study involved 215 consecutive hypertensive patients who were divided into three groups according to their IMT: maximum IMT>0.9mm (with mean IMT<0.9mm); mean IMT>0.9mm (i.e. mean and maximum IMT>0.9mm); and normal IMT. Patients with a pathologically raised IMT (whether maximum or mean value) were more likely to be dyslipidemic, were older, had a longer history of hypertension, and had a poorer glomerular filtration rate and ankle-brachial index. Patients with a mean IMT>0.9mm were more likely to have carotid plaque, carotid stenosis and a low ankle-brachial index than those with a maximum IMT>0.9mm. The mean IMT provided a better indication of atherosclerotic burden in patients with hypertension.