IL-27: a double agent in the IL-6 family.

The cytokine interleukin (IL)-6 is a major therapeutic target for the treatment of various inflammatory and autoimmune diseases. While IL-6 receives considerable attention in studies of innate and adaptive immunity, the IL-6-related family member IL-27 is recognized increasingly for its effects on cellular proliferation, differentiation and leucocyte effector functions. Both cytokines activate responses in myeloid and stromal tissue cells, where they direct the transition from innate to adaptive immunity. However, they are identified frequently as lymphokines that control responses in T cells and B cells. In this regard, IL-27 often opposes the action of IL-6. Here, we will review the role of IL-6 and IL-27 in inflammation, with a particular focus on inflammatory arthritis, and discuss their importance in the diagnosis, stratification and treatment of autoimmune disease.

DNMT3A mutations mediate the epigenetic reactivation of the leukemogenic factor MEIS1 in acute myeloid leukemia.

This corrects the article DOI: 10.1038/onc.2015.359.

DNMT3A mutations mediate the epigenetic reactivation of the leukemogenic factor MEIS1 in acute myeloid leukemia.

Close to half of de novo acute myeloid leukemia (AML) cases do not exhibit any cytogenetic aberrations. In this regard, distortion of the DNA methylation setting and the presence of mutations in epigenetic modifier genes can also be molecular drivers of the disease. In recent years, somatic missense mutations of the DNA methyltransferase 3A (DNMT3A) have been reported in ~20% of AML patients; however, no obvious critical downstream gene has been identified that could explain the role of DNMT3A in the natural history of AML. Herein, using whole-genome bisulfite sequencing and DNA methylation microarrays, we have identified a key gene undergoing promoter hypomethylation-associated transcriptional reactivation in DNMT3 mutant patients, the leukemogenic HOX cofactor MEIS1. Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.

Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis.

The introduction of new therapies against particular genetic mutations in non-small-cell lung cancer is a promising avenue for improving patient survival, but the target population is small. There is a need to discover new potential actionable genetic lesions, to which end, non-conventional cancer pathways, such as RNA editing, are worth exploring. Herein we show that the adenosine-to-inosine editing enzyme ADAR1 undergoes gene amplification in non-small cancer cell lines and primary tumors in association with higher levels of the corresponding mRNA and protein. From a growth and invasion standpoint, the depletion of ADAR1 expression in amplified cells reduces their tumorigenic potential in cell culture and mouse models, whereas its overexpression has the opposite effects. From a functional perspective, ADAR1 overexpression enhances the editing frequencies of target transcripts such as NEIL1 and miR-381. In the clinical setting, patients with early-stage lung cancer, but harboring ADAR1 gene amplification, have poor outcomes. Overall, our results indicate a role for ADAR1 as a lung cancer oncogene undergoing gene amplification-associated activation that affects downstream RNA editing patterns and patient prognosis.

UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy.

BACKGROUND: The impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU. METHODS: Genotyping of TYMS (5'TRP and 3'UTR), UGT1A1(*)28, UGT1A9(*)22 and UGT1A7(*)3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study. Their association with response, toxicity and survival was investigated by univariate and multivariate statistical analysis. RESULTS: TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response (OR=5.87, 95% confidence interval (CI)=1.68-20.45; P=0.005). UGT1A1(*)28/(*)28 was predictive for haematologic toxicity (OR=6.27, 95% CI=1.09-36.12; P=0.04), specifically for neutropenia alone (OR=6.40, 95% CI=1.11-37.03; P=0.038) or together with diarrhoea (OR=18.87, 95% CI=2.14-166.67; P=0.008). UGT1A9(*)1/(*)1 was associated with non-haematologic toxicity (OR=2.70, 95% CI=1.07-6.82; P=0.035). Haplotype VII (all non-favourable alleles) was associated with non-haematologic toxicity (OR=2.11, 95% CI=1.12-3.98; P=0.02). CONCLUSION: TYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients. A genetic-based algorithm to optimise treatment individualisation is proposed.

Expression analysis of genes involved in oxaliplatin response and development of oxaliplatin-resistant HT29 colon cancer cells.

The interrelationship between platinum resistance and clinical response is not well established. The purpose of this study is to evaluate the expression of 14 genes involved in platinum resistance in a colon cancer cell line (HT29) and its oxaliplatin (OXA)-resistant sublines. Resistant cells exhibited lower expression of many of these genes suggesting that several pathways may be implicated in OXA resistance. Particularly, OXA resistance is accompanied by defects in drug uptake (downregulation of the hCTR1 transporter) and enhanced DNA repair (upregulation of the XPD gene). Our data also confirmed that copper transporters and chaperones are involved in OXA resistance in colorectal cancer cells as evidenced by the overexpression of ATP7A and CCS in response to OXA exposure. Moreover, increased CCS expression suggests a role for SOD1 in OXA detoxification. Whereas exposure to OXA in HT29 induced significant changes in expression of many of the genes analyzed, only ATP7A, XPD and SRPK1 gene expression was increased in OXA-treated HTOXAR3 resistant cells. To our knowledge, this is the first report of implicating SRPK1 in OXA resistance. This study provides the basis for further evaluation of these putative markers of OXA response and resistance in colorectal cancer patients who are candidates for treatment with OXA.

1,25-Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway.

Atherosclerosis is a complex process characterized by an increase in the wall thickness owing to the accumulation of cells and extracellular matrix between the endothelium and the smooth muscle cell wall. This process is associated with different pathologies and it is accelerated in patients with chronic renal failure. In these patients, decreased synthesis of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) leads to secondary complications, like hyperparathyroidism, and treatment with 1,25(OH)(2)D(3) is a common practice. The effect of 1,25(OH)(2)D(3) on vascular smooth muscle cells (VSMCs) calcification has been widely studied, but the role of 1,25(OH)(2)D(3) on VSMC proliferation remains obscure. We have analyzed the effects of 1,25(OH)(2)D(3) in the proliferation of VSMC. We found that 1,25(OH)(2)D(3) (5-100 nM) induces a dose-dependent increase in VSMC proliferation in quiescent cells and in cells stimulated to grow. This increase in proliferation is achieved by shortening the G1 phase. The effect of 1,25(OH)(2)D(3) on VSMC proliferation is mediated by an increase of the expression of vascular endothelial growth factor A (VEGF), as the inhibition of VEGF activity totally blunted the 1,25(OH)(2) D(3)-induced VSMC proliferation. We found this increase in proliferation in vitro, ex vivo in aortic rings incubated with 1,25(OH)(2)D(3), and in vivo in animals with a model of chronic renal failure (5/6 nephrectomy) treated with 1,25(OH)(2)D(3) (1 mug/kg three times a week for 8 weeks). Thus, we conclude that 1,25(OH)(2)D(3) induces increases in VSMC proliferation through an increase on VEGF expression.

[Influence of the vitamin D receptor gene polymorphism and 25-hydroxyvitamin D on arterial pressure in health individuals]. / Influencia del polimorfismo del gen receptor de la vitamina D y de la 25-hidroxivitamina D en la tensión arterial de individuos sanos.

UNLABELLED: The role of vitamin D in the regulation of blood pressure is unclear. There are no studies that relate Bsm I polymorphism with blood pressure. OBJECTIVE: To analyze if Bsm I polymorphism and 25-hydroxyvitamin D (25OHD3) influence blood pressure in healthy individuals with normal blood pressure. METHODS: Systolic (SBP) and diastolic (DBP) blood pressure, Body Mass Index (BMI), plasma creatinine, serum calcium, serum phosphorus, serum iPTH, serum 25OHD3 and Bsm I genotype were determined in 590 healthy individuals (260 men and 330 women). Data were analysed using a multiple linear regression model. SBP and DBP were defined as dependent variables and the rest of variables as independent. RESULTS: Gender was strongly associated with both SBP (beta: -12.01, p: 0.000) and DBP (beta: -4.78, p: 0.000). Therefore, a separate analysis was performed according to gender. In males, SBP was associated with BMI (beta: 0.83, p: 0.001), 25OHD3, (beta: 0.36, p: 0.000) and genotype (beta: -3.90, p: 0.002); and DBP with 25OHD 3 (beta: 0.16, p: 0.018) and age (beta: 0.28, p: 0.000). Differences of blood pressure among the three genotypes were explored by analysis of variance. SBP was higher in men with bb genotype than in the other genotypes (p: 0.007). In females, 25OHD3 and genotype were not associated with blood pressure. CONCLUSIONS: Healthy men with higher levels of vitamin D have higher levels of SBP and DBP. Moreover, men with bb genotype have the highest levels of SBP. Blood pressure levels in women are not influenced by vitamin D nor by Bsml genotype. Our data suggest a possible pathophysiological interaction between vitamin D and sex hormones in blood pressure control.

[Differential effect of vitamin D analogues on the proliferation of vascular smooth muscle cells]. / Efecto diferencial de los análogos de la vitamina D en la proliferación de células de músculo liso vascular.

Atherosclerosis is the principal cause of myocardial infarction, stroke, and peripheral vascular disease, accounting for nearly half of all mortality in developed countries. The excessive growth of vascular smooth muscle cells is an important component in the development of atherosclerotic lesion. The direct effect of calcitriol and vitamin D analogs on the VSMCs proliferation is not clear. In this study we have analysed if calcitriol, Paricalcitol (19-nor-1,25-dihydroxy-vitamin D2) and EB1089 (experimental analog used as anticancerous) modify proliferation and the expression of vitamin D receptor (VDR) gene that is regulated at the transcriptional level by itself in the VSMCs. VSMCs proliferation was analysed by BrdU incorporation and VDR gene expression using RT-PCR. VSMCs proliferation was stimulated when calcitriol was added to the culture. VSMCs proliferation was significantly lower with analogs at the same dose. With regard to the functional study, the expression of VDR gene was upregulated by calcitriol at a concentration of 100 nM. There were no changes in this expression with the analogs. In conclusion, calcitriol, do not modify VSMCs proliferation. Therefore, Paricalcitol could have a minor proliferating effect on the wall of vessels that vitamin D.

Influencia del polimorfismo del gen receptor de la vitamina D y de la 25-hidroxivitamina D en la tensión arterial de individuos sanos / Vitamin D receptor genotype and 25 hydroxyvitamin D influence on blood pressure in healthy individuals

El efecto de la vitamina D sobre la tensión arterial (TA) no está bien establecido. No existen estudios que relacionen el polimorfismo del gen del VDR con la TA. Objetivo: Analizar la posible influencia del genotipo Bsm I y de la 25 hidroxivitamina D3 (25OHD3) en la TA en individuos sanos y normotensos. Métodos: Analizamos en 590 individuos sanos (260 varones y 330 mujeres) la posible asociación de la edad, sexo, IMC, creatinina, calcio, fósforo, PTHi, 25OHD3 y genotipo Bsm I con la tensión arterial sistólica (TAS) y diastólica (TAD) mediante un análisis de regresión lineal múltiple. Resultados: El sexo se asoció fuertemente a la TAS (β: –12,01, p: 0,000) y a la TAD (β: –4,78, p: 0,000), por lo que se realizó un análisis multivariante en función del mismo. En varones, la TAS se asoció a: 25OHD3 (β: 0,36, p: 0,000), genotipo (β: –3,90, p: 0,002) e IMC (β: 0,83, p: 0,001); y la TAD a: 25OHD3 (β: 0,16, p: 0,018) y edad (β: 0,28, p: 0,000). El análisis de la varianza mostró que los varones con genotipo bb presentaron una TAS superior al resto de genotipos (p: 0,007). En las mujeres, no encontramos asociación de la 25OHD3 ni del genotipo con la TA. Conclusiones: Los varones con mayores niveles de vitamina D presentan una mayor TAS y TAD. Los varones con genotipo bb tienen una mayor TAS. No existe dicha relación en el sexo femenino. Ello sugiere un posible nexo fisiopatológico entre las hormonas sexuales y la vitamina D en el control de la tensión arterial (AU)

The role of vitamin D in the regulation of blood pressure is unclear. There are no studies that relate Bsm I polymorphism with blood pressure. Objective: To analyze if Bsm I polymorphism and 25-hydroxyvitamin D (25OHD3) influence blood pressure in healthy individuals with normal blood pressure. Methods: Systolic (SBP) and diastolic (DBP) blood pressure, Body Mass Index (BMI), plasma creatinine, serum calcium, serum phosphorus, serum iPTH, serum 25OHD3 and Bsm I genotype were determined in 590 healthy individuals (260 men and 330 women). Data were analysed using a multiple linear regression model. SBP and DBP were defined as dependent variables and the rest of variables as independent. Results: Gender was strongly associated with both SBP (β: –12.01, p: 0.000) and DBP (β: –4.78, p: 0.000). Therefore, a separate analysis was performed according to gender. In males, SBP was associated with BMI (β: 0.83, p: 0.001), 25OHD3 (β: 0.36, p: 0.000) and genotype (β: –3.90, p: 0.002); and DBP with 25OHD3 (β: 0.16, p: 0.018) and age (β: 0.28, p: 0.000). Differences of blood pressure among the three genotypes were explored by analysis of variance. SBP was higher in men with bb genotype than in the other genotypes (p: 0.007). In females, 25OHD3 and genotype were not associated with blood pressure. Conclusions: Healthy men with higher levels of vitamin D have higher levels of SBP and DBP. Moreover, men with bb genotype have the highest levels of SBP. Blood pressure levels in women are not influenced by vitamin D nor by BsmI genotype. Our data suggest a possible pathophysiological interaction between vitamin D and sex hormones in blood pressure control (AU)

Efecto diferencial de los análogos de la vitamina D en la proliferación de células de músculo liso vascular / Vascular and tissue calcifications in haemodialysis patients

Existen datos experimentales contradictorios respecto al comportamiento de las células de músculo liso vascular (CMLV) expuestas al calcitriol. Determinar el efecto del calcitriol y de sus análogos a nivel vascular tiene una considerable trascendencia clínica ya que la proliferación de las CMLV está implicada en el mecanismo patogénico de la arteriosclerosis y de la resistencia tras angioplastia. En este trabajo demostramos mediante incorporación de BrdU que el calcitriol estimula la proliferación en las CMLV. La proliferación es menor al añadir al medio de cultivo Paracalcitol o EB1089 a dosis equimolar. En concordancia con estos hechos, también observamos que el calcitriol induce la expresión del mRNA VDR mientras que no existe este efecto con ninguno de los análogos estudiados. En conclusión, el calcitriol tiene un efecto directo estimulador de la proliferación de las CMLV que no se observa con el Paracalcitol y EB1089 a concentración equimolar (AU)

Atherosclerosis is the principal cause of myocardial infarction, stroke, and peripheral vascular disease, accounting for nearly half of all mortality in developed countries. The excessive growth of vascular smooth muscle cells is an important component in the development of atherosclerotic lesion. The direct effect of calcitriol and vitamin D analogs on the VSMCs proliferation is not clear. In this study we have analysed if calcitriol, Paracalcitol (19-nor-1,25-dihydroxyvitamin D2) and EB1089 (experimental analog used as anticancerous) modify proliferation and the expression of vitamin D receptor (VDR) gene that is regulated at the transcriptional level by itself in the VSMCs. VSMCs proliferation was analysed by BrdU incorporation and VDR gene expression using RT-PCR. VSMCs proliferation was stimulated when calcitriol was added to the culture. VSMCs proliferation was significantly lower with analogs at the same dose. With regard to the functional study, the expression of VDR gene was upregulated by calcitriol at a concentration of 100 nM. There were no changes in this expression with the analogs. In conclusion, calcitriol, do not modify VSMCs proliferation. Therefore, Paracalcitol could have a minor proliferating effect on the wall of vessels that vitamin D (AU)