CB2 cannabinoid receptor activation promotes colon cancer progression via AKT/GSK3β signaling pathway

The pharmacological activation of the cannabinoid receptor type 2, CB2, has been shown to elicit anti-tumoral mechanisms in different cancer types. However, little is known about its endogenous role in tumor pathophysiology, and different studies have attributed pro-tumorigenic properties to this receptor. In a previous work, we showed that CB2 expression is a poor prognostic factor in colon cancer patients. Here we report that activation of CB2 with low doses of specific agonists induce cell proliferation and favor the acquisition of aggressive molecular features in colon cancer cells. We show that sub-micromolar concentrations of CB2-specific agonists, JWH-133 and HU-308, promote an increase in cell proliferation rate through the activation of AKT/PKB pathway in colon cancer in vitro and in vivo. AKT activation promotes GSK3β inhibition and thus, a more aggressive cell phenotype with the subsequent elevation of SNAIL levels, E-cadherin degradation and β-catenin delocalization from cell membrane. Taken together, our data show that CB2 activation with sub-micromolar doses of agonists, which could be more similar to endogenous levels of cannabinoids, promote colon cancer progression, implicating that CB2 could have a pro-tumorigenic endogenous role in colon cancerThis work was supported by grants from Fondo de Investigaciones Sanitarias (ISCIII-PI10/00879 to JMG; Plan Nacional de I+D+I 2008-2011, FEDER funds co-financed), Red Temática de Investigación Cooperativa en Cáncer (ISCIII-RETIC RD12/0036/0041; Plan Estatal de I+D+I 2013-2016, FEDER funds cofinanced). JMG and PM were supported by ISCIII CP08/00217 and JR14/0018 contracts, respectively. EMM was recipient of ISCIII PFIS PhD studentship (FI11/00696) (Plan Nacional de I+D+I 2008-2011, FEDER funds co-financed); AMR was recipient of PhD contract from Department of Medical Oncology of H.U. Puerta de Hierro; VC was recipient of attending physician contract in Medical Oncology Department from H.U. Puerta de Hierro; MP was supported by Universidad Autónoma de Madrid (UAM) with Full Professor contrac

Thinning of the Monte Perdido Glacier in the Spanish Pyrenees since 1981

Producción CientíficaThis paper analyzes the evolution of the Monte Perdido Glacier, the third largest glacier in the Pyrenees, from 1981 to the present. We assessed the evolution of the glacier's surface area by analysis of aerial photographs from 1981, 1999, and 2006, and changes in ice volume by geodetic methods with digital elevation models (DEMs) generated from topographic maps (1981 and 1999), airborne lidar (2010) and terrestrial laser scanning (TLS, 2011, 2012, 2013, and 2014) data. We interpreted the changes in the glacier based on climate data from nearby meteorological stations. The results indicate that the degradation of this glacier accelerated after 1999. The rate of ice surface loss was almost three times greater during 1999–2006 than during earlier periods. Moreover, the rate of glacier thinning was 1.85 times faster during 1999–2010 (rate of surface elevation change  = −8.98 ± 1.80 m, glacier-wide mass balance  = −0.73 ± 0.14 m w.e. yr−1) than during 1981–1999 (rate of surface elevation change  = −8.35 ± 2.12 m, glacier-wide mass balance  = −0.42 ± 0.10 m w.e. yr−1). From 2011 to 2014, ice thinning continued at a slower rate (rate of surface elevation change  = −1.93 ± 0.4 m yr−1, glacier-wide mass balance  = −0.58 ± 0.36 m w.e. yr−1). This deceleration in ice thinning compared to the previous 17 years can be attributed, at least in part, to two consecutive anomalously wet winters and cool summers (2012–2013 and 2013–2014), counteracted to some degree by the intense thinning that occurred during the dry and warm 2011–2012 period. However, local climatic changes observed during the study period do not seem sufficient to explain the acceleration of ice thinning of this glacier, because precipitation and air temperature did not exhibit statistically significant trends during the study period. Rather, the accelerated degradation of this glacier in recent years can be explained by a strong disequilibrium between the glacier and the current climate, and likely by other factors affecting the energy balance (e.g., increased albedo in spring) and feedback mechanisms (e.g., heat emitted from recently exposed bedrock and debris covered areas).Ministerio de Economía, Industria y Competitividad - IBERNIEVE (project CGL2014-52599-P)Ministerio de Agricultura y Pesca, Alimentación y Medio Ambiente (project 844/2013

Anticoagulantes orales directos frente a antagonistas de la vitamina K en pacientes del «mundo real» con fibrilación auricular no valvular: estudio FANTASIIA

Observational study[Abstract] Introduction and objectives: To compare the long-term results of direct oral anticoagulants (DOAC) vs vitamin K antagonists (VKA) in real-world-patients with nonvalvular atrial fibrillation (NVAF) in a nationwide, prospective study. Methods: The FANTASIIA registry prospectively included outpatients with AF anticoagulated with DOAC or VKA (per protocol, proportion of VKA and DOAC 4:1), consecutively recruited from June 2013 to October 2014 in Spain. The incidence of major events was analyzed and compared according to the anticoagulant treatment received. Results: A total of 2178 patients were included in the study (mean age 73.8±9.4 years), and 43.8% were women. Of these, 533 (24.5%) received DOAC and 1645 (75.5%) VKA. After a median follow up of 32.4 months, patients receiving DOAC vs those receiving VKA had lower rates of stroke-0.40 (95%CI, 0.17-0.97) vs 1.07 (95%CI,0.79-1.46) patients/y, P=.032-, severe bleedings-2.13 (95%CI, 1.45-3.13) vs 3.28 (95%CI, 2.75-3.93) patients/y; P = .044-, cardiovascular death-1.20 (95%CI, 0.72-1.99) vs 2.45 (95%CI, 2.00-3.00) patients/y; P = .009-, and all-cause death-3.77 (95%CI, 2.83-5.01) vs 5.54 (95%CI, 4.83-6.34) patients/y; P = .016-. In a modified Cox regression model by the Andersen-Gill method for multiple events, hazard ratios for patients receiving DOAC were: 0.42 (0.16-1.07) for stroke; 0.47 (0.20-1.16) for total embolisms; 0.76 (0.50-1.15) for severe bleedings; 0.67 (0.39-1.18) for cardiovascular death; 0.86 (0.62-1.19) for all-cause death, and 0.82 (0.64-1.05) for the combined event consisting of stroke, embolism, severe bleeding, and all-cause death. Conclusions: Compared with VKA, DOAC is associated with a trend to a lower incidence of all major events, including death, in patients with NVAF in Spain.[Resumen] Introducción y objetivos. Comparar los resultados a largo plazo de los anticoagulantes orales directos (ACOD) frente a los antagonistas de la vitamina K (AVK) en pacientes del mundo real con fibrilación auricular no valvular (FANV) en un estudio nacional prospectivo. Métodos. El estudio FANTASIIA incluyó consecutivamente a pacientes ambulatorios con FANV anticoagulados con ACOD o AVK desde junio de 2013 hasta octubre de 2014. Se compararon las tasas de eventos según el anticoagulante administrado. Resultados. Se incluyó a 2.178 pacientes (edad, 73,8 ± 9,4 años; el 43,8% mujeres); de ellos, 533 (24,5%) recibían ACOD y 1.645 (75,5%), AVK. Tras una mediana de seguimiento de 32,4 meses, los pacientes con ACOD tuvieron tasas más bajas de ictus —0,40 (IC95%, 0,17-0,97) frente a 1,07 (IC95%, 0,79-1,46) pacientes/año; p = 0,032—, hemorragias mayores —2,13 (IC95%, 1,45-3,13) frente a 3,28 (IC95%, 2,75-3,93) pacientes/año; p = 0,044—, muerte cardiovascular —1,20 (IC95%, 0,72-1,99) frente a 2,45 (IC95%, 2,00-3,00) pacientes/año; p = 0,009— y muerte total —3,77 (IC95%, 2,83-5,01) frente a 5,54 (IC95%, 4,83-6,34) pacientes/año; p = 0,016—. En el análisis de Cox modificado según el método de Andersen-Gill para datos con múltiples eventos, las razones de riesgos instantáneos para los pacientes con ACOD fueron 0,42 (0,16-1,07) para el ictus; 0,47 (0,20-1,16) para la embolia sistémica en general; 0,76 (0,50-1,15) para las hemorragias mayores; 0,67 (0,39-1,18) para la muerte cardiovascular; 0,86 (0,62-1,19) para la mortalidad total y 0,82 (0,64-1,05) para el combinado de ictus, embolias, hemorragias mayores y muerte. Conclusiones. El tratamiento con ACOD se asocia con una tendencia a una menor tasa de todos los eventos graves, incluida la mortalidad, en relación con los AVK en pacientes con FANV en España

Concordance between circulating tumor cells and clinical status during follow-up in anaplastic lymphoma kinase (ALK) non-small-cell lung cancer patients

Background: The identification of anaplastic lymphoma kinase (ALK) rearrangements is found in approximately 5% of non-small-cell lung cancers (NSCLCs). However, the development of liquid biopsies as a diagnostic tool is less developed in these cases. This study investigates the use of CTCs during treatment, together with an extended follow-up to correlate with clinical evolution. Patients and Methods: A total of 13 patients out of a cohort of 212 patients with lung adenocarcinoma, presented ALK rearrangements (6%) confirmed by tumor biopsy. A total of 60 serial blood samples were collected from these patients who were prospectively enrolled in the study. Results: All patients had a positive CTC count at baseline (mean = 3). The median follow-up was 9 months (range 1-17 months). Three patients underwent surgery and their CTC counts decreased after the procedure but still remained detectable. After radiotherapy, 3 cases showed an average decrease of 5 CTCs. A total of 6 patients were treated with ALK inhibitors and a partial response was observed in 3 of them, who also presented decreased CTC counts. The other 3 patients presented primary resistance, and their CTC counts were higher than those obtained prior to progression. Conclusion: We believe that the use of CTCs for dynamic monitoring of NSCLC with ALK rearrangement and to detect disease persistence or recurrence may be a reliable technique. CTC counts may also have potential use to monitor the efficacy of ALK inhibitors, facilitating detection of resistance to treatmentThis study was supported by Carlos III Institute of Health, Spanish Ministry of Science and Innovation, and European Regional Development Fund (grant number: PI16/01818 and PIE14/00064), D. Pérez-Callejo is supported by SEOM-Río-Hortega contract, A Romero is supported by Joan Rodés fellowship (grant number: JR14/00017) and M Sánchez-Beato is supported by Miguel Servet contract (CP11/00018 and CPII16/00024

Peripheral artery disease and clinical outcomes in patients with atrial fibrillation: A report from the FANTASIIA registry

Observational study[Abstract] Background: Atrial fibrillation (AF) and peripheral artery disease (PAD) are common conditions that increase cardiovascular risk. We determined the association between PAD and prognosis in a cohort of real-world patients receiving oral anticoagulant therapy for nonvalvular AF. Methods: We prospectively included 1956 patients (mean age 73.8 ± 9.5 years, 44.0% women) receiving oral anticoagulant therapy for AF. Clinical characteristics were collected at baseline. Patients were followed for a period of 3 years. Survival analysis and multivariable regression analyses were performed to assess variables related to death, stroke, bleeding, myocardial infarction and major adverse cardiovascular events (MACE). Results: Patients with PAD (n = 118; 6%) exhibited higher rates of cardiovascular risk factors and cardiovascular diseases. After 3 years of follow-up, there were a total of 255 deaths (no PAD 233, vs PAD 22), 45 strokes (43 vs 2), 146 major bleedings (136 vs 10) and 168 MACE (148 vs 20). On univariate analysis, there was a higher risk of cardiovascular mortality (2.02%/year no PAD vs 4.08%/year PAD, P = .02), myocardial infarction (0.99%/year no PAD vs 2.43%/year PAD, P = .02) and MACE (3.18%/year no PAD vs 6.99%/year PAD, P < .01). There was no statistically significant association with these events after multivariable adjustment. Conclusions: In a large cohort of anticoagulated patients with AF, the presence of PAD represents a higher risk subgroup and is associated with worse crude outcomes. The exact contribution of the PAD independently of other cardiovascular diseases or risk factors requires further investigation.Instituto de Salud Carlos III; RD16/11/00420Instituto de Salud Carlos III; RD12/0042/0068Instituto de Salud Carlos III; RD12/0042/0010Instituto de Salud Carlos III; RD12/0042/0069Instituto de Salud Carlos III; RD12/0042/006

Influence of sex on long-term prognosis in patients with atrial fibrillation treated with oral anticoagulants. Results from the prospective, nationwide FANTASIIA study

[Abstract] Background: While many risk factors for Atrial Fibrillation (AF) have been identified, there are important differences in their relative impact between sexes. The aim of our study was to investigate the influence of sex as a long-term predictor of adverse events in “real world” AF patients treated with direct oral anticoagulants. Methods: The FANTASIIA registry is a prospective, national and multicentric study including outpatients with anticoagulated AF patients. Baseline characteristics and adverse events at 3 years of follow-up were collected and classified by sex. Cox multivariate analysis was performed to investigate the role of sex in major events and composite outcomes. Results: A total of 1956 patients were included in the study. 43.9% of them were women, with a mean age of 73.8 ± 9.4 years (women were older 76.5 ± 7.9 vs 71.7 ± 10.1, p<0.001). Women had higher rate of cardiovascular risk factors and higher mean of CHA2DS2-VASc (4.4 ± 1.4 vs 3.7 ± 1.6, p<0.001) and HAS-BLED (2.1 ± 1.0 vs 1.9 ± 1.1, p<0.001) than men. After 3 years of follow-up, rates of major events were similar in both groups with limit difference for all-cause mortality (4.4%/year in women vs 5.6%/year in men; p = 0.056). However, all the composite events were more frequent in women. We observed in the non-adjusted adverse events lower rate of all-cause mortality (HR 0.62, 95%CI 0.47–0.81; p<0.001), composite 1 outcomes (HR 0.80, 95%CI 0.65–0.98; p = 0.029) and composite 2 (HR 0.77, 95%CI 0.64–0.94; p = 0.010) in women compared with men. In multivariate Cox regression analysis observed that female sex was an independently protector factor for all-cause mortality and for the composite outcomes 1 and 2. Conclusions: In this “real world” study of anticoagulated AF patients, women could have a protective role against development of adverse events, mainly on all-cause mortality and combined events.Instituto de Salud Carlos III; RD12/0042/0068Instituto de Salud Carlos III; RD12/0042/0010Instituto de Salud Carlos III; RD12/0042/0069Instituto de Salud Carlos III; RD12/0042/006

Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition

Background: Platinum-based chemotherapy remains the standard of care for most lung cancer cases. However chemoresistance is often developed during the treatment, limiting clinical utility of this drug. Recently, the ability of tumor cells to adapt their metabolism has been associated to resistance to therapies. In this study, we first described the metabolic reprogramming of Non-Small Cell Lung Cancer (NSCLC) in response to cisplatin treatment. Methods: Cisplatin-resistant versions of the A549, H1299, and H460 cell lines were generated by continuous drug exposure. The long-term metabolic changes, as well as, the early response to cisplatin treatment were analyzed in both, parental and cisplatin-resistant cell lines. In addition, four Patient-derived xenograft models treated with cisplatin along with paired pre- and post-treatment biopsies from patients were studied. Furthermore, metabolic targeting of these changes in cell lines was performed downregulating PGC-1α expression through siRNA or using OXPHOS inhibitors (metformin and rotenone). Results: Two out of three cisplatin-resistant cell lines showed a stable increase in mitochondrial function, PGC1-α and mitochondrial mass with reduced glycolisis, that did not affect the cell cycle. This phenomenon was confirmed in vivo. Post-treatment NSCLC tumors showed an increase in mitochondrial mass, PGC-1α and a decrease in the GAPDH/MT-CO1 ratio. In addition, we demonstrated how a ROS-mediated metabolism reprogramming, involving PGC-1α and increased mitochondrial mass, is induced during short-time cisplatin exposure. Moreover, we tested how cells with increased PGC-1a induced by ZLN005 treatment, showed reduced cisplatin-driven apoptosis. Remarkably, the long-term metabolic changes, as well as the metabolic reprogramming during short-time cisplatin exposure can be exploited as an Achilles’ heel of NSCLC cells, as demonstrated by the increased sensitivity to PGC-1α interference or OXPHOS inhibition using metformin or rotenone. Conclusion: These results describe a new cisplatin resistance mechanism in NSCLC based on a metabolic reprogramming that is therapeutically exploitable through PGC-1α downregulation or OXPHOS inhibitors.Work in the authors’ laboratories is supported by ‘‘Instituto de Salud Carlos III’’ PI13/01806 and PIE14/0064 to M.P. A.C-B, received a Spanish Lung Cancer Group fellowship. R.L-B, is supported by Comunidad Autónoma de Madrid “Garantía juvenil” contrac

Association of body mass index with clinical outcomes in patients with atrial fibrillation: a report from the FANTASIIA Registry

[Abstract] Background. Obesity and atrial fibrillation (AF) frequently coexist and independently increase mortality. We sought to assess the association between obesity and adverse events in patients receiving oral anticoagulants for AF. Methods and Results. Consecutive AF outpatients receiving anticoagulant agents (both vitamin K antagonists and direct oral anticoagulants) were recruited into the FANTASIIA (Atrial fibrillation: influence of the level and type of anticoagulation on the incidence of ischemic and hemorrhagic stroke) registry. This observational, multicenter, and prospective registry of AF patients analyzes the quality of anticoagulation, incidence of events, and differences between oral anticoagulant therapies. We analyzed baseline patient characteristics according to body mass index, normal: <25 kg/m2, overweight: 25–30 kg/m2, and obese: ≥30 kg/m2), assessing all‐cause mortality, stroke, major bleeding and major adverse cardiovascular events (a composite of ischemic stroke, myocardial infarction, and total mortality) at 3 years’ follow‐up. In this secondary prespecified substudy, the association of weight on prognosis was evaluated. We recruited 1956 patients (56% men, mean age 73.8±9.4 years): 358 (18.3%) had normal body mass index, 871 (44.5%) were overweight, and 727 (37.2%) were obese. Obese patients were younger (P<0.01) and had more comorbidities. Mean time in the therapeutic range was similar across body mass index categories (P=0.42). After a median follow‐up of 1070 days, 255 patients died (13%), 45 had a stroke (2.3%), 146 a major bleeding episode (7.5%) and 168 a major adverse cardiovascular event (8.6%). Event rates were similar between groups for total mortality (P=0.29), stroke (P=0.90), major bleeding (P=0.31), and major adverse cardiovascular events (P=0.24). On multivariate Cox analysis, body mass index was not independently associated with all‐cause mortality, cardiovascular mortality, stroke, major bleeding, or major adverse cardiovascular events. Conclusions. In this prospective cohort of patients anticoagulated for AF, obesity was highly prevalent and was associated with more comorbidities, but not with poor prognosis

Association of Body Mass Index With Clinical Outcomes in Patients With Atrial Fibrillation: A Report From the FANTASIIA Registry

Background Obesity and atrial fibrillation (AF) frequently coexist and independently increase mortality. We sought to assess the association between obesity and adverse events in patients receiving oral anticoagulants for AF. Methods and Results Consecutive AF outpatients receiving anticoagulant agents (both vitamin K antagonists and direct oral anticoagulants) were recruited into the FANTASIIA (Atrial fibrillation: influence of the level and type of anticoagulation on the incidence of ischemic and hemorrhagic stroke) registry. This observational, multicenter, and prospective registry of AF patients analyzes the quality of anticoagulation, incidence of events, and differences between oral anticoagulant therapies. We analyzed baseline patient characteristics according to body mass index, normal: <25 kg/m2, overweight: 25-30 kg/m2, and obese: ≥30 kg/m2), assessing all‐cause mortality, stroke, major bleeding and major adverse cardiovascular events (a composite of ischemic stroke, myocardial infarction, and total mortality) at 3 years' follow‐up. In this secondary prespecified substudy, the association of weight on prognosis was evaluated. We recruited 1956 patients (56% men, mean age 73.8±9.4 years): 358 (18.3%) had normal body mass index, 871 (44.5%) were overweight, and 727 (37.2%) were obese. Obese patients were younger (P<0.01) and had more comorbidities. Mean time in the therapeutic range was similar across body mass index categories (P=0.42). After a median follow‐up of 1070 days, 255 patients died (13%), 45 had a stroke (2.3%), 146 a major bleeding episode (7.5%) and 168 a major adverse cardiovascular event (8.6%). Event rates were similar between groups for total mortality (P=0.29), stroke (P=0.90), major bleeding (P=0.31), and major adverse cardiovascular events (P=0.24). On multivariate Cox analysis, body mass index was not independently associated with all‐cause mortality, cardiovascular mortality, stroke, major bleeding, or major adverse cardiovascular events. Conclusions In this prospective cohort of patients anticoagulated for AF, obesity was highly prevalent and was associated with more comorbidities, but not with poor prognosis

INR during stroke and bleeding in patients with atrial fibrillation and on vitamin K antagonists

[Resumen] Introducción y objetivos. La fibrilación auricular tiene un mal pronóstico asociado fundamentalmente al desarrollo de ictus. A pesar del uso de anticoagulantes, algunos pacientes pueden sufrir ictus y también hemorragias graves. El tratamiento con antagonistas de la vitamina K (AVK) se controla mediante la razón internacional normalizada (INR). Nuestro objetivo fue estudiar la incidencia de ictus y hemorragias mayores, e investigar los valores de la INR y el tiempo en rango terapéutico en los 6 meses previos durante dichos episodios en pacientes con fibrilación auricular tratados con AVK. Métodos. Se incluyeron 1.483 pacientes con fibrilación auricular tratados con AVK durante al menos los 6 meses previos, incluidos consecutivamente desde junio de 2013 hasta octubre de 2014, con una mediana de seguimiento de 32,4 meses. Se identificaron aquellos pacientes que ingresaron por ictus o hemorragia mayor y se determinó la INR en cada episodio. Resultados. Se registraron 40 ictus (1,07/100 pacientes/año) y 120 hemorragias mayores (3,28/100 pacientes/año). La INR durante los ictus fue 2,33 ± 0,59, y durante las hemorragias 3,17 ± 1,48. El 57,5% de los pacientes tenían una INR de 2-3 durante los ictus y el 48,3% durante las hemorragias. Los pacientes que sufrieron un ictus con una INR fuera de rango durante el episodio presentaron un tiempo en rango terapéutico más bajo que aquellos con la INR en rango (49,2 ± 20,8% frente a 68,8 ± 19,4%; p = 0,043). Conclusiones. La mitad de los ictus y hemorragias mayores se producen con valores de la INR «adecuados» (2 a 3). Cambios en la estrategia de anticoagulación pueden ser necesarios para disminuir esta elevada tasa de eventos.[Abstract] Introduction and objectives. Atrial fibrillation has a poor prognosis, mainly due to the occurrence of cardioembolic stroke. Despite the use of anticoagulants some patients can develop stroke as well as severe bleeding. Treatment with vitamin K antagonists is usually controlled by means of the international normalized ratio (INR). The aim of this study was to investigate the incidence of stroke and major bleedings, as well the values of INR and the time in therapeutic range within the previous 6 months during these events. Methods. The study included 1483 patients with atrial fibrillation treated with vitamin K antagonists for at least 6 months prior to inclusion, consecutively recruited from June 2013 to October 2014, with a median follow-up of 32.4 months. Those patients admitted due to an episode of stroke or severe bleeding were identified, and an analysis was performed on the INR values obtained for each episode. Results. There was a total of 40 strokes (1.07/100 patients/year) and 120 severe bleedings (3.28/100 patients/year) during the study period. The mean INR value during stroke episodes was 2.33 ± 0.59, and during severe bleeding 3.17 ± 1.48, with 57.5% of patients having had an INR of 2-3 during strokes, and 48.3% during bleedings. Patients with an INR out of range during the stroke had a time in therapeutic range lower than those with an INR between 2 and 3 during the event (49.2 ± 20.8% vs. 68.8 ± 19.4%; P = .043). Conclusions. More than 50% of strokes and almost 50% of severe bleedings occur with ‘adequate’ (2 to 3) INR values. Changes in the anticoagulation strategy seem to be necessary to decrease this high rate of severe events