Toxic Effects of Different Coating-Related Functionalized Nanoparticles on Aquatic Organisms.

The peculiar physico-chemical characteristics of nanomaterials (NMs) and the use of different coatings to improve their expected properties result in a huge amount of nanoforms, which vary in chemical composition, size, shape and surface characteristics. This makes it almost impossible to test all the nanoforms available, and efforts have been made to establish grouping or read-across strategies. The aim of this work was to find a behavior pattern of effect among nanoforms of different metallic core nanoparticles (NPs) (TiO2, CeO2 and Ag NP) with the same coatings (sodium citrate, poly (ethylene glycol), dodecylphosphonic acid or oleylamine). Daphnia magna, rainbow trout and two fish cell lines (PLHC-1 and RTH-149) were exposed to a range of concentrations (up to 100 mg/L) of the uncoated or coated NPs. Ag NPs were the most toxic, followed by CeO2 NPs and finally by TiO2 NPs. The results show that a clear pattern of toxicity in the studied species could not be established related to the coatings. However, it was possible to confirm different inter-species sensitivities. RTH-149 was the most sensitive cell line, and Daphnia magna was more sensitive than fish. Moreover, some differences in coating-core interactions were found between the metal oxide and the metal NPs in Daphnia magna.

Environmental and Health Impacts of Graphene and Other Two-Dimensional Materials: A Graphene Flagship Perspective.

Two-dimensional (2D) materials have attracted tremendous interest ever since the isolation of atomically thin sheets of graphene in 2004 due to the specific and versatile properties of these materials. However, the increasing production and use of 2D materials necessitate a thorough evaluation of the potential impact on human health and the environment. Furthermore, harmonized test protocols are needed with which to assess the safety of 2D materials. The Graphene Flagship project (2013-2023), funded by the European Commission, addressed the identification of the possible hazard of graphene-based materials as well as emerging 2D materials including transition metal dichalcogenides, hexagonal boron nitride, and others. Additionally, so-called green chemistry approaches were explored to achieve the goal of a safe and sustainable production and use of this fascinating family of nanomaterials. The present review provides a compact survey of the findings and the lessons learned in the Graphene Flagship.

Symptom-related screening programme for early detection of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: the SYSPPE study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is the most severe long-term complication of acute pulmonary embolism (PE). We aimed to evaluate the impact of a symptom screening programme to detect CTEPH in PE survivors. METHODS: This was a multicentre cohort study of patients diagnosed with acute symptomatic PE between January 2017 and December 2018 in 16 centres in Spain. Patients were contacted by phone 2 years after the index PE diagnosis. Those with dyspnoea corresponding to a New York Heart Association (NYHA)/WHO scale≥II, visited the outpatient clinic for echocardiography and further diagnostic tests including right heart catheterisation (RHC). The primary outcome was the new diagnosis of CTEPH confirmed by RHC. RESULTS: Out of 1077 patients with acute PE, 646 were included in the symptom screening. At 2 years, 21.8% (n=141) reported dyspnoea NYHA/WHO scale≥II. Before symptom screening protocol, five patients were diagnosed with CTEPH following routine care. In patients with NYHA/WHO scale≥II, after symptom screening protocol, the echocardiographic probability of pulmonary hypertension (PH) was low, intermediate and high in 76.6% (n=95), 21.8% (n=27) and 1.6% (n=2), respectively. After performing additional diagnostic test in the latter 2 groups, 12 additional CTEPH cases were confirmed. CONCLUSIONS: The implementation of this simple strategy based on symptom evaluation by phone diagnosed more than doubled the number of CTEPH cases. Dedicated follow-up algorithms for PE survivors help diagnosing CTEPH earlier. TRIAL REGISTRATION NUMBER: NCT03953560.

Fish acute toxicity of nine nanomaterials: Need of pre-tests to ensure comparability and reuse of data.

Fish acute toxicity tests are commonly used in aquatic environmental risk assessments, being required in different international substances regulations. A general trend in the toxicity testing of nanomaterials (NMs) has been to use standardized aquatic toxicity tests. However, as these tests were primarily developed for soluble chemical, issues regarding particle dissolution, agglomeration or sedimentation during the time of exposure are not considered when reporting the toxicity of NMs. The aim of this study was to characterize the NM behaviour throughout the fish acute test and to provide criteria to assay the toxicity of nine NMs based on TiO2, ZnO, SiO2, BaSO4, bentonite, and carbon nanotubes, on rainbow trout following OECD Test Guideline (TG) nº203. Our results showed the importance of conducting a preliminary test (without fish) when working with NMs. They provide valuable information on, sample monitoring, agglomeration, sedimentation, dissolution, actual concentrations of NMs, needed to design the test. Among the NMs tested, only bentonite nanoparticles were stable during the 96-h pre-test and test in aquarium water. In contrast, the remaining NMs exhibited considerable loss and sedimentation within the first 24 h. The high sedimentation observed for almost all NMs highlights the need of consistently measuring the concentrations throughout the entire duration of the fish acute toxicity test to make reliable concentration-response relationships. Notable differences emerged in LC50 values when using actual concentrations as nominal concentrations overestimated concentrations by up to 85.6%. Among all NMs tested, only ZnO NMs were toxic to rainbow trout. A flow chart was specifically developed for OECD TG 203, aiding users in making informed decisions regarding the selection of test systems and necessary modifications to ensure accurate, reliable, and reusable toxicity data. Our findings might contribute to the harmonization of TG 203 improving result reproducibility and interpretability and supporting the development of read-across and QSAR models.

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway as Survival Biomarkers in Colorectal Cancer.

Several studies have suggested that single nucleotide polymorphisms (SNPs) related to vitamin D metabolism may affect CRC carcinogenesis and survival. The aim of this study was to evaluate the influence of 13 SNPs involved in the vitamin D metabolic pathway on CRC survival. We conducted an observational retrospective cohort study, which included 127 Caucasian CRC patient from the south of Spain. SNPs in VDR, CYP27B1, CYP2R1, CYP24A1, and GC genes were analyzed by real-time polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were assessed. Cox regression analysis adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no family history of CRC showed that the VDR ApaI (p = 0.036), CYP24A1 rs6068816 (p < 0.001), and GC rs7041 (p = 0.006) were associated with OS in patients diagnosed with CRC, and CYP24A1 rs6068816 (p < 0.001) was associated with PFS adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no primary tumor resection. The rest of the SNPs showed no association with CRC survival. Thus, the SNPs mentioned above may have a key role as prognostic biomarkers of CRC.

Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype.

Omalizumab is a monoclonal antibody indicated for the treatment of severe uncontrolled asthma with an allergic phenotype. Its effectiveness could be influenced by clinical variables and single nucleotide polymorphisms (SNPs) in one or more of the genes involved in the mechanism of action and process of response to omalizumab, and these could be used as predictive biomarkers of response. We conducted an observational retrospective cohort study that included patients with severe uncontrolled allergic asthma treated with omalizumab in a tertiary hospital. Satisfactory response after 12 months of treatment was defined as (1) Reduction ≥ 50% of exacerbations or no exacerbations, (2) Improvement of lung function ≥ 10% FEV1, and (3) Reduction ≥ 50% of OCS courses or no OCS. Polymorphisms in the FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs1054485, rs569108), C3 (rs2230199), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), IL1RL1 (rs1420101, rs17026974, rs1921622), and GATA2 (rs4857855) genes were analyzed by real-time polymerase chain reaction (PCR) using TaqMan probes. A total of 110 patients under treatment with omalizumab were recruited. After 12 months of treatment, the variables associated with a reduction in exacerbations were the absence of polyposis (odds ratio [OR] = 4.22; 95% confidence interval [CI] = 0.95-19.63), IL1RL1 rs17026974-AG (OR = 19.07; 95% CI = 1.27-547), and IL1RL1 rs17026974-GG (OR = 16.76; 95% CI = 1.22-438.76). Reduction in oral corticosteroids (OCS) was associated with age of starting omalizumab treatment (OR = 0.95; 95% CI = 0.91-0.99) and blood eosinophil levels > 300 cells/µL (OR = 2.93; 95% CI = 1.01-9.29). Improved lung function showed a relationship to the absence of chronic obstructive pulmonary disease (COPD) (OR = 12.16; 95% CI = 2.45-79.49), FCGR2B rs3219018-C (OR = 8.6; 95% CI = 1.12-117.15), GATA2 rs4857855-T (OR = 15.98; 95% CI = 1.52-519.57) and FCGR2A rs1801274-G (OR = 13.75; 95% CI = 2.14-142.68; AG vs. AA and OR = 7.46; 95% CI = 0.94-89.12; GG vs. AA). Meeting one response criterion was related to FCER1A rs2251746-TT (OR = 24; 95% CI = 0.77-804.57), meeting two to age of asthma diagnosis (OR = 0.93; 95% CI = 0.88-0.99), and meeting all three to body mass index (BMI) < 25 (OR = 14.23; 95% CI = 3.31-100.77) and C3 rs2230199-C (OR = 3; 95% CI = 1.01-9.92). The results of this study show the possible influence of the polymorphisms studied on the response to omalizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.

Impact of emergency department management of isolated superficial vein thrombosis of the lower limbs: a secondary analysis of data from the ALTAMIRA study. / Impacto del manejo en urgencias en la evolución de los pacientes con trombosis venosa superficial aislada de miembros inferiores: subanálisis del estudio ALTAMIRA.

OBJECTIVES: To describe the management of superficial vein thrombosis (SVT) of the lower limbs in patients treated in Spanish hospital emergency departments (EDs). To evaluate the impact of ED management of venous thromboembolic complications on outcomes and to determine the characteristics of patients who develop complications. MATERIAL AND METHODS: The retrospective multicenter ALTAMIRA study (Spanish acronym for risk factors, complications, and assessment of Spanish ED management of SVT) used recorded data for consecutive patients with a diagnosis of isolated SVT treated in 18 EDs. We gathered data on symptomatic venous thromboembolic disease (deep vein thrombosis, pulmonary embolism, or the extension or recurrence of SVT), clinically significant bleeding, and 180-day mortality. Cox regression analysis was used to explore variables associated with complications. RESULTS: A total of 703 patients were included. Anticoagulation was prescribed for 84.1% of the patients for a median of 30 days (interquartile range, 15-42 days); 81.3% were treated with low molecular weight heparin. A prophylactic dose was prescribed for 48% and an intermediate therapeutic dose for 52%. Sixty-four patients (9.2%) developed symptomatic thromboembolic disease within 180 days, 12 (1.7%) experienced clinically significant bleeding, and 4 (0.6%) died. Complications developed later in patients receiving anticoagulant therapy than in those not taking an anticoagulant (66 vs 11 days , P=.009), and 76.6% of those developing complications were not on anticoagulant when symptoms appeared. A history of thromboembolic disease was associated with developing complications (adjusted hazard ratio, 2.20; 95% confidence interval, 1.34-3.62). CONCLUSION: ED treatment of SVT varies and is often suboptimal. The incidence of thromboembolic complications after SVT is high. Starting anticoagulation in the ED delays the development of complications. Patients with a history of thromboembolic disease are more at risk of complications.

OBJETIVO: Describir el manejo terapéutico de los pacientes con trombosis venosa superficial (TVS) aislada de miembros inferiores en servicios de urgencias hospitalarios (SUH) españoles. Evaluar el impacto del tratamiento instaurado en urgencias en la evolución, en términos de complicaciones de enfermedad tromboembólica venosa (ETV), y conocer las características de los pacientes que sufren complicaciones. METODO: El estudio multicentrico (18 SUH) ALTAMIRA (fActores de riesgo, compLicaciones y evaluación del manejo de la TVS de Miembros Inferiores en hospitales españoles atendidos en los seRvicios de urgenciAs) creó un cohorte retrospectivo de pacientes consecutivos con diagnóstico objetivo de TVS aislada. Se recogieron las complicaciones de ETV sintomáticas (trombosis venosa profunda, tromboembolia pulmonar y extensión o recurrencia de TVS), sangrados clínicamente relevantes y defunciones a 180 días. Se evaluaron las variables asociadas a las complicaciones mediante una regresión de Cox. RESULTADOS: Se incluyeron 703 pacientes. El 84,1% recibieron anticoagulación durante 30 días (rango intercuartil 15-42), 81,3% con heparina de bajo peso molecular (48% dosis profilácticas, 52% intermedias-terapéuticas). En 180 días, 64 pacientes (9,1%) tuvieron complicación de ETV, 12 (1,7%) tuvieron sangrado clínicamente relevante, y 4 fallecieron (0,6%). Los pacientes en que se instauró anticoagulación en urgencias tardaron más tiempo en desarrollar complicaciones (66 vs 11 días, p = 0,009). El 76,6% de los que se complicaron no estaban anticoagulados en ese momento. La ETV previa se asoció de forma independiente con el desarrollo de complicaciones (hazard ratio ajustada 2,20; intervalo de confianza del 95%: 1,34-3,62). CONCLUSIONES: El tratamiento en urgencias de la TVS aislada es heterogéneo y con frecuencia subóptimo. La incidencia de complicaciones de ETV es elevada. El tratamiento anticoagulante iniciado en urgencias supone un retraso en el desarrollo de complicaciones. Los pacientes con ETV previa tienen más riesgo de complicaciones.

Impacto del manejo en urgencias en la evolución de los pacientes con trombosis venosa superficial aislada de miembros inferiores: subanálisis del estudio ALTAMIRA / Impact of emergency department management of isolated superficial vein thrombosis of the lower limbs: a secondary analysis of data from the ALTAMIRA study

Objetivos: Describir el manejo terapéutico de los pacientes con trombosis venosa superficial (TVS) aislada de miembros inferiores en servicios de urgencias hospitalarios (SUH) españoles. Evaluar el impacto del tratamiento instaurado en urgencias en la evolución, en términos de complicaciones de enfermedad tromboembólica venosa (ETV), y conocer las características de los pacientes que sufren complicaciones. Métodos: Estudio de cohorte retrospectivo, multicéntrico (18 SUH), que incluyó pacientes consecutivos con diagnóstico objetivo de TVS aislada. Se recogieron las complicaciones de ETV sintomáticas (trombosis venosa profunda, tromboembolia pulmonar y extensión o recurrencia de TVS), sangrados clínicamente relevantes y defunciones a 180 días. Se evaluaron las variables asociadas a las complicaciones mediante una regresión de Cox. Resultados: Se incluyeron 703 pacientes. El 84,1% recibieron anticoagulación durante 30 días (rango intercuartil 15-42), 81,3% con heparina de bajo peso molecular (48% dosis profilácticas, 52% intermedias-terapéuticas). En 180 días, 64 pacientes (9,1 %) tuvieron complicación de ETV, 12 (1,7%) tuvieron sangrado clínicamente relevante, y 4 fallecieron (0,6 %). Los pacientes en que se instauró anticoagulación en urgencias tardaron más tiempo en desarrollar complicaciones (66 vs 11 días, p = 0,009). El 76,6% de los que se complicaron no estaban anticoagulados en ese momento. La ETV previa se asoció de forma independiente con el desarrollo de complicaciones (hazard ratio ajustada 2,20; intervalo de confianza del 95%: 1,34-3,62). (AU)

Objectives: To describe the management of superficial vein thrombosis (SVT) of the lower limbs in patients treated in Spanish hospital emergency departments (EDs). To evaluate the impact of ED management of venous thromboembolic complications on outcomes and to determine the characteristics of patients who develop complications.Methods: The retrospective multicenter ALTAMIRA study (Spanish acronym for risk factors, complications, and assessment of Spanish ED management of SVT) used recorded data for consecutive patients with a diagnosis of isolated SVT treated in 18 EDs. We gathered data on symptomatic venous thromboembolic disease (deep vein thrombosis, pulmonary embolism, or the extension or recurrence of SVT), clinically significant bleeding, and 180-day mortality. Cox regression analysis was used to explore variables associated with complications. Results: A total of 703 patients were included. Anticoagulation was prescribed for 84.1% of the patients for a median of 30 days (interquartile range, 15-42 days); 81.3% were treated with low molecular weight heparin. A prophylactic dose was prescribed for 48% and an intermediate therapeutic dose for 52%. Sixty-four patients (9.2%) developed symptomatic thromboembolic disease within 180 days, 12 (1.7%) experienced clinically significant bleeding, and 4 (0.6%) died. Complications developed later in patients receiving anticoagulant therapy than in those not taking an anticoagulant (66 vs 11 days , P=.009), and 76.6% of those developing complications were not on anticoagulant when symptoms appeared. A history of thromboembolic disease was associated with developing complications (adjusted hazard ratio, 2.20; 95% confidence interval, 1.34-3.62). (AU)

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway and Their Relationship with High Blood Pressure Risk.

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin-angiotensin-aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41-0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47-1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40-0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12-1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease.

Polymorphisms in VDR, CYP27B1, CYP2R1, GC and CYP24A1 Genes as Biomarkers of Survival in Non-Small Cell Lung Cancer: A Systematic Review.

The objective of this systematic review was to provide a compilation of all the literature available on the association between single-nucleotide polymorphisms (SNPs) in the genes involved in the metabolic pathway of vitamin D and overall survival (OS) and progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). This systematic review was conducted in accordance with the PRISMA guidelines. It included all the literature published up to 1 November 2022 and was carried out in four databases (Medline [PubMed], Scopus, Web of Science, and Embase), using the PICO strategy, with relevant keywords related to the objective. The quality of the studies included was evaluated with an assessment tool derived from the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. Six studies were included in this systematic review. Our findings showed that the BsmI (rs1544410), Cdx-2 (rs11568820), FokI (rs2228570), ApaI (rs7975232), TaqI (rs731236), rs4646536, rs6068816, rs7041, and rs10741657 SNPs in the genes that play a part in vitamin D synthesis (CYP2R1, CYP27B1), transport (GC), and metabolism (CYP24A1), as well as in the vitamin D receptor (VDR), are associated with OS and/or PFS in patients with NSCLC. The SNPs in VDR have been the most extensively analyzed. This systematic review summed up the available evidence concerning the association between 13 SNPs in the main genes involved in the vitamin D metabolic pathway and prognosis in NSCLC. It revealed that SNPs in the VDR, CYP27B1, CYP24A1, GC, and CYP2R1 genes could have an impact on survival in this disease. These findings suggest the identification of prognostic biomarkers in NSCLC patients. However, evidence remains sparse for each of the polymorphisms examined, so these findings should be treated with caution.

Association between Single Nucleotide Polymorphisms Related to Vitamin D Metabolism and the Risk of Developing Asthma.

Asthma is a chronic non-communicable disease that affects all age groups. The main challenge this condition poses is its heterogeneity. The role of vitamin D in asthma has aroused great interest, correlating low vitamin D levels and polymorphisms in the genes involved in its metabolic pathway with the risk of asthma. The aim of this study was to evaluate the influence of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolism on the susceptibility to asthma. An observational case-control study was performed, including 221 patients with asthma and 442 controls of Caucasian origin from southern Spain. The SNPs CYP24A1 (rs6068816, rs4809957), CYP27B1 (rs10877012, rs4646536, rs703842, rs3782130), GC (rs7041), CYP2R1 (rs10741657) and VDR (ApaI, BsmI, FokI, Cdx2, TaqI) were analyzed by real-time PCR, using TaqMan probes. The logistic regression model adjusted for body mass index revealed that in the genotype model, carriers of the Cdx2 rs11568820-AA genotype were associated with a higher risk of developing asthma (p = 0.005; OR = 2.73; 95% CI = 1.36-5.67; AA vs. GG). This association was maintained in the recessive model (p = 0.004). The haplotype analysis revealed an association between the ACTATGG haplotype and higher risk of asthma for the rs1544410, rs7975232, rs731236, rs4646536, rs703842, rs3782130 and rs10877012 genetic polymorphisms (p = 0.039). The other SNPs showed no effect on risk of developing asthma. The Cdx2 polymorphism was significantly associated with the susceptibility of asthma and could substantially act as a predictive biomarker of the disease.

Impact of Omalizumab in Patients with Severe Uncontrolled Asthma and Possible Predictive Biomarkers of Response: A Real-Life Study.

Most patients with asthma can control their symptoms with a basic standard of medical care and with maintenance and rescue medication. However, between 5% and 10% of asthmatics worldwide do not achieve control of their symptoms and have recurrent exacerbations and respiratory difficulties. The objective of the study was the real-life evaluation of the clinical improvement of patients with severe eosinophilic asthma treated with omalizumab, together with the search for biomarkers associated with the response. An observational retrospective cohort study was conducted that included patients with severe uncontrolled allergic asthma being treated with omalizumab. Three types of response were evaluated: lower use of oral corticosteroids, improvement in lung function, and reduction in exacerbations. A total of 110 patients under treatment with omalizumab were included, with a mean age of 48 ± 16 years. After 12 months had elapsed, significant reductions were found in the number of exacerbations, use of oral cortico-steroids and doses of inhaled corticosteroids (p < 0.001). Lung function and asthma control improved significantly (p < 0.001; p = 0.004) and eosinophil levels were significantly reduced (p = 0.004). Low scores in the Asthma Control Test were associated with the oral corticosteroid-saving effect; lower previous FEV1 levels and absence of chronic obstructive pulmonary disease (COPD) were related to improvement in lung function, and prior FEV1 values higher than 80% and absence of gastroesophageal reflux disease (GERD) with a reduction in exacerbations. The results of this study confirm the clinical benefit obtained after the introduction of omalizumab and the possible predictive biomarkers of response to the treatment.

Impact of Anti-IL5 Therapies on Patients with Severe Uncontrolled Asthma and Possible Predictive Biomarkers of Response: A Real-Life Study.

Severe Uncontrolled Asthma (SUA) counts for more than 25% of cases of severe asthma. The main factors that impair the quality of life of these patients are high doses of oral corticosteroids, the presence of exacerbations, and reduced lung function. The objective of this study was to evaluate, in real life, the clinical improvement of patients with SUA treated with anti-interleukin 5 (IL5) therapies: mepolizumab and benralizumab, together with the search for biomarkers associated with the response. We conducted a retrospective observational cohort study that included patients with severe uncontrolled eosinophilic asthma in a tertiary hospital receiving biological therapies. Three types of response were evaluated: improvement in lung function, reduction in exacerbations, and decrease in the use of oral corticosteroids. After 12 months of treatment, significant reductions were found in the number of exacerbations, the use of oral corticosteroids, and blood eosinophil levels for both biological therapies (p < 0.001). Lung function improved, achieving a significant improvement in %FEV1 (p < 0.001), as well as asthma control, with a significant increase in asthma control test (ACT) scores in both therapies. The markers associated with the corticosteroid-saving effect were the low doses of oral corticosteroids and absence of exacerbations for mepolizumab, and higher blood eosinophilia, absence of chronic obstructive pulmonary disease (COPD), and reduction in oral corticosteroid cycles for benralizumab. The greatest improvement in lung function in both therapies was linked to lower previous FEV1 levels and absence of other respiratory diseases. The reduction in exacerbations was associated with absence of exacerbations the previous year for mepolizumab and never smokers for benralizumab. The results of this real-life study confirm the clinical benefit obtained after the introduction of an anti-IL5 biological therapy and the possible predictive biomarkers of response to treatment.

Towards harmonisation of testing of nanomaterials for EU regulatory requirements on chemical safety - A proposal for further actions.

Over the recent years, EU chemicals legislation, guidance and test guidelines have been developed or adapted for nanomaterials to facilitate safe use of nanomaterials. This paper provides an overview of the information requirements across different EU regulatory areas. For each information requirement, a group of 22 experts identified potential needs for further action to accommodate guidance and test guidelines to nanomaterials. Eleven different needs for action were identified, capturing twenty-two information requirements that are specific to nanomaterials and relevant to multiple regulatory areas. These were further reduced to three overarching issues: 1) resolve issues around nanomaterial dispersion stability and dosing in toxicity testing, in particular for human health endpoints, 2) further develop tests or guidance on degradation and transformation of organic nanomaterials or nanomaterials with organic components, and 3) further develop tests and guidance to measure (a)cellular reactivity of nanomaterials. Efforts towards addressing these issues will result in better fit-for-purpose test methods for (EU) regulatory compliance. Moreover, it secures validity of hazard and risk assessments of nanomaterials. The results of the study accentuate the need for a structural process of identification of information needs and knowledge generation, preferably as part of risk governance and closely connected to technological innovation policy.

Hypoxia-Inducible Factor-1 Alpha Expression Is Predictive of Pathological Complete Response in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy.

To demonstrate the value of hypoxia-inducible factor-1α (HIF-1α) in predicting response in patients with breast cancer receiving standard neoadjuvant chemotherapy (NAC). METHODS: Ninety-five women enrolled in two prospective studies underwent biopsies for the histopathological diagnosis of breast carcinoma before receiving NAC, based on anthracyclines and taxanes. For expression of HIF-1α, EGFR, pAKT and pMAPK, tumor samples were analyzed by immunohistochemistry in tissues microarrays. Standard statistical methods (Pearson chi-square test, Fisher exact test, Kruskal-Wallis test, Mann-Whitney test and Kaplan-Meier method) were used to study the association of HIF-1α with tumor response, survival and other clinicopathologic variables/biomarkers. RESULTS: HIF-1α expression was positive in 35 (39.7%) cases and was significantly associated to complete pathological response (pCR) (p = 0.014). HIF-1α expression was correlated positively with tumor grade (p = 0.015) and Ki-67 expression (p = 0.001) and negativity with progesterone receptors (PR) (p = 0.04) and luminal A phenotype expression (p = 0.005). No correlation was found between HIF-1α expression and EGFR, pAKT and pMAPK. In terms of survival, HIF-1α expression was associated with a significantly shorter disease-free survival (p = 0.013), being identified as an independent prognostic factor in multivariate analysis. CONCLUSIONS: Overexpression of HIF-1α is a predictor of pCR and shorter DFS; it would be valuable to confirm these results in prospective studies.

Effect of Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway on Susceptibility to Non-Small-Cell Lung Cancer.

The pathogenesis of non-small-cell lung cancer (NSCLC) is complex, since many risk factors have been identified. Recent research indicates that polymorphisms in the metabolic pathway of vitamin D may be involved in both risk and survival of the disease. The objective of this study is to assess the effect of 13 genetic polymorphisms involved in the vitamin D metabolic pathway on the risk of suffering from NSCLC. We conducted an observational case-control study, which included 204 patients with NSCLC and 408 controls, of Caucasian origin, from southern Spain. The CYP27B1 (rs4646536, rs3782130, rs703842, rs10877012), CYP2R1 (rs10741657), GC (rs7041), CYP24A1, and VDR (BsmI, Cdx-2, FokI, ApaI, TaqI) gene polymorphisms were analyzed by real-time polymerase chain reaction. The logistic regression model, adjusted for smoking and family history of cancer, revealed that in the genotypic model, carriers of the VDR BsmI rs1544410-AA genotype were associated with a lower risk of developing NSCLC compared to the GG genotype (p = 0.0377; OR = 0.51; CI95% = 0.27-0.95; AA vs. GG). This association was maintained in the recessive model (p = 0.0140). Haplotype analysis revealed that the AACATGG and GACATGG haplotypes for the rs1544410, rs7975232, rs731236, rs4646536, rs703842, rs3782130, and rs10877012 polymorphisms were associated with a lower risk of NSCLC (p = 0.015 and p = 0.044 respectively). The remaining polymorphisms showed no effect on susceptibility to NSCLC. The BsmI rs1544410 polymorphism was significantly associated with lower risk of NSCLC and could be of considerable value as a predictive biomarker of the disease.

Cytotoxicity inhibition of catechol's type molecules by grafting on TiO2 and Fe2O3 nanoparticles surface.

The potential toxicity deriving from the interaction between chemicals and manufactured nanoparticles (NPs) represents an emerging threat to the environment and human health. Several studies have focused on the risks and (eco)toxicity of manufactured NPs as a consequence of their extensive use in recent years, however, there is still a limited understanding of the combined effects caused by manufactured NPs in the presence of other environmental contaminants. This is particularly relevant to aquatic environments, where many types of pollutants are inevitably released and can be involved in many kinds of reactions. In this context, the interaction between catecholate type ligands and two different nanomaterials, namely TiO2 and Fe2O3 NPs, was investigated by performing cytotoxicity assays with the topminnow fish hepatoma cell line (PLHC-1) using: i) the original organic molecules, ii) pristine NPs alone, and iii) modified NPs obtained by grafting the ligands on the NPs surface. Cytotoxic effects were explored at three different levels, specifically on cellular metabolism, membrane integrity and lysosomal activity. The outcomes from these assays showed cytotoxicity only for the free catechol type ligands, while in general no significant decrease in cell viability was observed for pristine NPs, as well as for the modified NPs, regardless the initial cytotoxicity level of the organic ligands These results suggest that the binding of catechols on the NPs' surface inhibited their cytotoxicity, indicating that TiO2 and Fe2O3 NPs may act as sorbents of these contaminants, thus reducing their possible detrimental effects.

Vitamin D-Related Single Nucleotide Polymorphisms as Risk Biomarker of Cardiovascular Disease.

Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels. In addition to environmental risk factors, genetic predisposition increases the risk; this includes alterations in the vitamin D receptor gene (VDR). These alterations play a key role in modifying vitamin D uptake, being able to modify its function and increasing susceptibility to cardiovascular disorders. The aim of this study was to evaluate the association of polymorphisms in the VDR gene and risk of CVD in a Caucasian population. A retrospective case-control study was conducted comprising 246 CVD patients and 246 controls of Caucasian origin from Southern Spain. The genetic polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232), FokI (rs2228570) and Cdx2 (rs11568820) were determined by means of real-time polymerase chain reaction (PCR) for allelic discrimination using TaqMan® probes. The logistic regression analysis adjusted for body mass index and diabetes revealed that the TT genotype was associated with a higher risk of CVD in both the genotypic model (p = 0.0430; OR = 2.30; 95% CI = 1.06-5.37; TT vs. CC) and the recessive model (p = 0.0099; OR = 2.71; 95% CI = 1.31-6.07; TT vs. C). Haplotype analysis revealed that the haplotype GAC (p = 0.047; OR = 0.34; 95% CI = 0.12-0.98) was associated with increased risk of CVD. The VDR polymorphisms FokI (rs2228570) was significantly associated with the development of CVD. No influence was observed of the VDR polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and Cdx2 (rs11568820) on the risk of developing CVD in the patients studied.

Características y manejo diagnóstico-terapéutico de los pacientes con trombosis venosa superficial aislada en los servicios de urgencias hospitalarios españoles. Estudio ALTAMIRA / Characteristics of isolated superficial vein thrombosis and diagnostic-therapeutic management in Spanish hospital emergency departments: the ALTAMIRA study

Objetivo: Describir las características de los pacientes diagnosticados de trombosis venosa superficial (TVS) aislada de miembros inferiores en servicios de urgencias hospitalarios (SUH), y evaluar la adherencia a las guías de práctica clínica en el manejo diagnóstico y terapéutico (realización de ecografía venosa e instauración de tratamiento anticoagulante). Método: Estudio de cohortes retrospectivo en 18 SUH españoles. Se incluyeron todos los pacientes atendidos en los SUH con diagnóstico final de TVS en miembros inferiores, con edad $ 18 años, de enero de 2016 a mayo de 2017. Para evaluar la no adherencia a las recomendaciones de las guías de práctica clínica (realización de ecografía venosa, e instauración de tratamiento anticoagulante) se ajustó un modelo de regresión logística múltiple por pasos hacia atrás. Resultados: Mil ciento sesenta y seis pacientes fueron incluidos. La edad media fue de 59,6 años, el 67,9% eran mujeres. El 24,4% tenían antecedentes de enfermedad tromboembólica venosa (ETV). El 8,9% tuvieron alguna complicación a 180 días [4,6% recurrencia y 3,6% progresión de TVS, 1,8% trombosis venosa profunda (TVP) y 0,9% tromboembolia pulmonar (TEP)]. Hubo 17 pacientes (1,5%) con hemorragia y 16 (1,4%) muertes. Se realizó ecografía venosa a 703 (60,3%) pacientes. Recibieron tratamiento anticoagulante 898 (77%), con una mediana de 22 días. Las variables asociadas con la decisión de anticoagular fueron: antecedentes ETV (OR 1,60; IC 95%: 1,12-2,30), varices (OR 1,40; IC 95%: 1,12-2,30), dolor de la extremidad (OR 1,44; IC 95%: 1,08-191), presencia de cordón doloroso (OR 1,30; IC 95%: 0,97-1,73) y realización de ecografía venosa (OR 1,60; IC 95%: 1,94-3,45). (AU)

Objectives: To describe the characteristics of patients with isolated lower-limb superficial vein thrombosis (SVT) treated in hospital emergency departments and to evaluate adherence to clinical practice guidelines on diagnosis (vein ultrasound imaging) and therapeutic management (start of anticoagulant therapy). Material and methods: Retrospective cohort study in 18 Spanish emergency departments. We included all patients with a final emergency department diagnosis of lower-limb SVT aged 18 years or older between January 2016 and May 2017. Backward stepwise multiple logistic regression analysis was used to evaluate adherence to clinical practice guidelines on ordering vein ultrasound imaging and starting anticoagulant therapy. Results: A total of 1166 patients were included. The mean patient age was 59.6 years, and 67.9% were women. About a quarter of the patients (24.4%) had a history of venous thromboembolic disease. Complications developed in 8.9% within 180 days: 4.6% experienced a recurrence and 3.6% progressed to SVT and 1.8% to deep vein thrombosis; pulmonary thromboembolism occurred in 0.9%. Hemorrhagic complications developed in 17 patients (1.5%). Sixteen patients (1.4%) died. Vein ultrasound imagine was ordered for 703 patients (60.3%). Anticoagulant agents were prescribed for 898 (77%) for a median period of 22 days. Variables associated with a decision to order anticoagulants were a history of venous thromboembolic disease (odds ratio [OR], 1.60; 95% CI, 1.12-2.30), varicose veins (OR, 1.40; 95% CI, 1.12-2.30); limb pain (OR, 1.44; 95% CI, 1.08-1.91); painful cord (OR, 1.30; 95% CI, 0.97-1.73); and availability of vein ultrasound images (OR, 1.60; 95% CI, 1.94-3.45). (AU)

Secreted Frizzled – Related Protein 4 y el cáncer de mama / Secreted Frizzled – Related Protein 4 and breast cancer

Introducción: el correcto funcionamiento y la supervivencia de la célula vienen mediados por multitud de procesos clave. El delicado equilibrio que se requiere entre dichos fenómenos hace que un error en los mecanismos de control desencadene el inicio de la carcinogénesis. Dentro de las rutas metabólicas encargadas de su regulación se encuentran las vías de señalización del Wnt. De esta forma, aquellas moléculas que intervengan en dichas vías presentarán un papel clave para el estudio de la patología, entre las que destaca secreted Frizzled – Related Protein 4 (sFRP4). Método: se ha llevado a cabo una búsqueda bibliográfica en bases de datos de referencia, como es el caso de Medline, Scopus o Web of Science. Resultados: a sFRP4 se le ha otorgado el papel de modulador negativo de las vías de Wnt debido a su capacidad de competir por los ligandos Wnt y evitar el inicio de dichas rutas. Por lo tanto, sFRP4 será esencial en el control del inicio y desarrollo del cáncer en aquellos tejidos donde se exprese la proteína, dentro de los que se considera el tejido mamario. Conclusiones: los recientes estudios acerca de la implicación de sFRP4 en el desarrollo de diversas patologías, justifican que la proteína haya captado la atención en los últimos años. De esta forma, se puede afirmar que sFRP4 presenta un interesante potencial como biomarcador en el tratamiento, diagnóstico y pronóstico del cáncer de mama, entre otras enfermedades. (AU)

Introduction: cell’s correct functionality and surveillance are brokered by a wide range of essential proceedings. The delicate equilibrium required between those phenomenon means that an error in the control mechanisms pro-voke the carcinogenesis commencement. In those metabolic pathways in charge of controlling the mechanisms are found the Wnt signaling pathways. Therefore, molecules that interact with the pathways mentioned, where secret-ed Frizzled – Related Protein 4 is located, will play a key role in the pathology knowledge. Method: a bibliographic research has been done in referral databases, such as Medline and Scopus. Results: sFRP4 has been identified as a negative modulator of the Wnt signaling pathways. This is due to its capacity of competing for the Wnt ligands and avoiding the commencement of the pathways. Otherwise, sFRP4 is essential for the control of the cancer beginning and development in those tissues where the protein is expressed, being mammary tissues considered into them. Conclusions: recent studies about the implications of sFRP4 in the development of several pathologies justify that the protein had garnered attention in recent years. Furthermore, it can be affirmed that sFRP4 presents an inter-esting potential as biomarker in the breast cancer treatment, diagnosis and prognosis, among other pathologies. (AU)