Cyclooxygenase-2 Expression in Bladder Cancer and Patient Prognosis: Results from a Large Clinical Cohort and Meta-Analysis

Aberrant overexpression of cyclooxygenase-2 (COX2) is observed in urothelial carcinoma of the bladder (UCB). Studies evaluating COX2 as a prognostic marker in UCB report contradictory results. We determined the prognostic potential of COX2 expression in UCB and quantitatively summarize the results with those of the literature through a meta-analysis. Newly diagnosed UCB patients recruited between 1998–2001 in 18 Spanish hospitals were prospectively included in the study and followed-up (median, 70.7 months). Diagnostic slides were reviewed and uniformly classified by expert pathologists. Clinical data was retrieved from hospital charts. Tissue microarrays containing non-muscle invasive (n = 557) and muscle invasive (n = 216) tumours were analyzed by immunohistochemistry using quantitative image analysis. Expression was evaluated in Cox regression models to assess the risk of recurrence, progression and disease-specific mortality. Meta-hazard ratios were estimated using our results and those from 11 additional evaluable studies. COX2 expression was observed in 38% (211/557) of non-muscle invasive and 63% (137/216) of muscle invasive tumors. Expression was associated with advanced pathological stage and grade (p<0.0001). In the univariable analyses, COX2 expression - as a categorical variable - was not associated with any of the outcomes analyzed. As a continuous variable, a weak association with recurrence in non-muscle invasive tumors was observed (p-value = 0.048). In the multivariable analyses, COX2 expression did not independently predict any of the considered outcomes. The meta-analysis confirmed these results. We did not find evidence that COX2 expression is an independent prognostic marker of recurrence, progression or survival in patients with UCB.The work was partially supported by the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministry of Science and Innovation, Spain (G03/174, 00/0745, PI051436, PI061614 and G03/174); Red Temática de Investigación Cooperativa en Cáncer- RD06/0020-RTICC; Consolider ONCOBIO; EU-FP6-STREP-37739-DRoP-ToP; EU-FP7-HEALTH-F2-2008-201663-UROMOL; EU-FP7-HEALTH-F2-2008-201333-DECanBio; USA-NIH-RO1-CA089715; and a PhD fellowship awarded to MJC from the ‘‘la Caixa’’ foundation, Spain, and a postdoctoral fellowship awarded to AFSA from the Fundación Científica de la AEC

Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of Northern Spain

<p>Abstract</p> <p>Background</p> <p>Polymorphisms in DNA repair genes have been associated to repair DNA lesions, and might contribute to the individual susceptibility to develop different types of cancer. Nucleotide excision repair (NER), base excision repair (BER), and double-strand break repair (DSBR) are the main DNA repair pathways. We investigated the relationship between polymorphisms in two NER genes, <it>XPC </it>(poly (AT) insertion/deletion: PAT-/+) and <it>XPD </it>(Asp312Asn and Lys751Gln), the BER gene <it>XRCC1 </it>(Arg399Gln), and the DSBR gene <it>XRCC3 </it>(Thr241Met) and the risk of developing lung cancer.</p> <p>Methods</p> <p>A hospital-based case-control study was designed with 516 lung cancer patients and 533 control subjects, matched on ethnicity, age, and gender. Genotypes were determined by PCR-RFLP and the results were analysed using multivariate unconditional logistic regression, adjusting for age, gender and pack-years.</p> <p>Results</p> <p>Borderline association was found for <it>XPC </it>and <it>XPD </it>NER genes polymorphisms, while no association was observed for polymorphisms in BER and DSBR genes. <it>XPC PAT+/+ </it>genotype was associated with no statistically significant increased risk among ever smokers (OR = 1.40; 95%CI = 0.94–2.08), squamous cell carcinoma (OR = 1.44; 95%CI = 0.85–2.44), and adenocarcinoma (OR = 1.72; 95%CI = 0.97–3.04). <it>XPD </it>variant genotypes (<it>312Asn/Asn </it>and <it>751Gln/Gln</it>) presented a not statistically significant risk of developing lung cancer (OR = 1.52; 95%CI = 0.91–2.51; OR = 1.38; 95%CI = 0.85–2.25, respectively), especially among ever smokers (OR = 1.58; 95%CI = 0.96–2.60), heavy smokers (OR = 2.07; 95%CI = 0.74–5.75), and adenocarcinoma (OR = 1.88; 95%CI = 0.97–3.63). On the other hand, individuals homozygous for the XRCC1 <it>399Gln </it>allele presented no risk of developing lung cancer (OR = 0.87; 95%CI = 0.57–1.31) except for individuals carriers of <it>399Gln/Gln </it>genotype and without family history of cancer (OR = 0.57; 95%CI = 0.33–0.98) and no association was found between <it>XRCC3 </it>Thr241Met polymorphism and lung cancer risk (OR = 0.92; 95%CI = 0.56–1.50), except for the <it>241Met/Met </it>genotype and squamous cell carcinoma risk (OR = 0.47; 95%CI = 0.23–1.00).</p> <p>Conclusion</p> <p>In conclusion, we analysed the association between <it>XPC</it>, <it>XPD</it>, <it>XRCC1</it>, and <it>XRCC3 </it>polymorphisms and the individual susceptibility to develop lung cancer in the Spanish population, specifically with a highly tobacco exposed population. We attempt to contribute to the discovery of which biomarkers of DNA repair capacity are useful for screening this high-risk population for primary preventing and early detection of lung cancer.</p

Prenatal Exposure to Cigarette Smoke and Anogenital Distance at 4 Years in the INMA-Asturias Cohort

Smoking by women is associated with adverse pregnancy outcomes such as spontaneous abortion, preterm delivery, low birth weight, infertility, and prolonged time to pregnancy. Anogenital distance (AGD) is a sensitive biomarker of prenatal androgen and antiandrogen exposure. We investigated the effect of smoking and passive smoke exposure during pregnancy on anogenital distance in offspring at 4 years in the INMA-Asturias cohort (Spain). Women were interviewed during pregnancy to collect information on tobacco consumption, and anogenital distance was measured in 381 children: Anoscrotal distance in boys and anofourchetal distance in girls. We also measured maternal urinary cotinine levels at 32 weeks of pregnancy. We constructed linear regression models to analyze the association between prenatal smoke exposure and anogenital distance and adjusted the models by relevant covariates. Reported prenatal smoke exposure was associated with statistically significant increased anogenital index (AGI), both at week 12 of pregnancy (β = 0.31, 95% confidence interval: 0.00, 0.63) and at week 32 of pregnancy (β = 0.31, 95% confidence interval: 0.00, 0.63) in male children, suggesting altered androgenic signaling.Funding was provided by CIBERESP (PhD employment contract and fellowship for short stays abroad—2019), FIS-FEDER (grants PI04/2018, PI09/02311, PI13/02429, and PI18/00909), Obra Social Cajastur/Fundación Liberbank, and Universidad de Oviedo

Early-Life Exposure to Outdoor Air Pollution and Respiratory Health, Ear Infections, and Eczema in Infants from the INMA Study

Background: Prenatal and early-life periods may be critical windows for harmful effects of air pollution on infant health.Objectives: We studied the association of air pollution exposure during pregnancy and the first year of life with respiratory illnesses, ear infections, and eczema during the first 12–18 months of age in a Spanish birth cohort of 2,199 infants.Methods: We obtained parentally reported information on doctor-diagnosed lower respiratory tract infections (LRTI) and parental reports of wheezing, eczema, and ear infections. We estimated individual exposures to nitrogen dioxide (NO2) and benzene with temporally adjusted land use regression models. We used log-binomial regression models and a combined random-effects meta-analysis to estimate the effects of air pollution exposure on health outcomes across the four study locations.Results: A 10-µg/m3 increase in average NO2 during pregnancy was associated with LRTI [relative risk (RR) = 1.05; 95% CI: 0.98, 1.12] and ear infections (RR = 1.18; 95% CI: 0.98, 1.41). The RRs for an interquartile range (IQR) increase in NO2 were 1.08 (95% CI: 0.97, 1.21) for LRTI and 1.31 (95% CI: 0.97, 1.76) for ear infections. Compared with NO2, the association for an IQR increase in average benzene exposure was similar for LRTI (RR = 1.06; 95% CI: 0.94, 1.19) and slightly lower for ear infections (RR = 1.17; 95% CI: 0.93, 1.46). Associations were slightly stronger among infants whose mothers spent more time at home during pregnancy. Air pollution exposure during the first year was highly correlated with prenatal exposure, so we were unable to discern the relative importance of each exposure period.Conclusions: Our findings support the hypothesis that early-life exposure to ambient air pollution may increase the risk of upper and lower respiratory tract infections in infants

Prenatal exposure to persistent organic pollutants and anogenital distance in children at 18 months

Background: Anogenital distance (AGD) is a measure of in utero exposure to hormonally active agents. The aim of the present study was to evaluate the association between prenatal exposure to persistent organic pollutants (POPs) and AGD. Methods: POP levels were measured in pregnant women, and the AGD was recorded in 43 offspring at 18 months. We used linear regression models to analyze the association between maternal POP exposure and offspring AGD. We defined the anogenital index (AGI) as AGD divided by weight at 18 months (AGI = AGD / weight at 18 months [mm/kg]) and included this variable in the regression models. Results: AGI measure was 2.35 (0.61) and 1.38 (0.45) in males and females, respectively. AGI was inversely associated with lipid-adjusted concentrations of PBDE-99 (β = -0.28, 95% confidence interval [CI]: -0.51, -0.04) and PBDE-153 (β = -0.61, 95% CI: -1.11, -0.11) in males. We did not find any statistically significant relationship between any POPs and AGI in females. Conclusions: Environmental exposure to POPs may affect genital development and result in reproductive tract alterations with potentially relevant health consequences in maturity. © 2018 The Author(s). Published by S. Karger AG, Basel.This study was funded by grants from FIS-FEDER (PI04/2018, PI09/02311, and PI13/02429), Fundación Cajastur-Liberbank, and Universidad de Oviedo.Peer reviewe

Lung cancer risk and pollution in an industrial region of Northern Spain: a hospital-based case-control study

<p>Abstract</p> <p>Background</p> <p>Asturias, an Autonomous Region in Northern Spain with a large industrial area, registers high lung cancer incidence and mortality. While this excess risk of lung cancer might be partially attributable to smoking habit and occupational exposure, the role of industrial and urban pollution also needs to be assessed. The objective was to ascertain the possible effect of air pollution, both urban and industrial, on lung cancer risk in Asturias.</p> <p>Methods</p> <p>This was a hospital-based case-control study covering 626 lung cancer patients and 626 controls recruited in Asturias and matched by ethnicity, hospital, age, and sex. Distances from the respective participants' residential locations to industrial facilities and city centers were computed. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to urban and industrial pollution sources were calculated, with adjustment for sex, age, hospital area, tobacco consumption, family history of cancer, and occupation.</p> <p>Results</p> <p>Whereas individuals living near industries displayed an excess risk of lung cancer (OR = 1.49; 95%CI = 0.93-2.39), which attained statistical significance for small cell carcinomas (OR = 2.23; 95%CI = 1.01-4.92), residents in urban areas showed a statistically significant increased risk for adenocarcinoma (OR = 1.92; 95%CI = 1.09-3.38). In the Gijon health area, residents in the urban area registered a statistically significant increased risk of lung cancer (OR = 2.17; 95%CI = 1.25-3.76), whereas in the Aviles health area, no differences in risk were found by area of exposure.</p> <p>Conclusions</p> <p>This study provides further evidence that air pollution is a moderate risk factor for lung cancer.</p

Effect of employment and domestic load on fetal development and length of gestation in a birth cohort study

Fundamentos: Los estudios publicados no son concluyentes sobre el impacto de determinadas exposiciones ocupacionales en el embarazo, evidenciando la necesidad de considerar el doble rol, profesional y familiar, de las mujeres. El objetivo del presente trabajo fue evaluar el efecto de la situación laboral y de la carga doméstica de trabajo en la duración de la gestación y en el desarrollo fetal. Métodos: Mediante modelos de regresión univariante y multivariante, se estudió la asociación entre partos pretérmino (PPT) (<37 semanas), recién nacidos con bajo peso a término (BPT) (<2500g) y pequeños para su edad gestacional (PEG) (<percentil 10) en peso, talla y perímetro cefálico en función de la situación laboral materna (empleo/no empleo) y la carga doméstica (baja/media/alta) en 2506 mujeres. Los análisis se hicieron utilizando SPSS y R. Resultados: Las mujeres con carga doméstica media tenían menos riesgo que el resto de mujeres de PPT (OR=0,41; IC95%:0,21-0,81), PEG en peso (OR=0,47; IC95%:0,32-0,69), talla (OR=0,57; IC95%:0,39-0,83) y perímetro cefálico (OR=0,58; IC95%:0,40-0,83); las mujeres con carga doméstica elevada también reducían su riesgo de PEG en peso: (OR=0,72; IC95%:0,54-0,98) y perímetro cefálico (OR=0,73; IC95%:0,54-0,99). Al analizar conjuntamente la situación laboral y la carga doméstica, las mujeres con carga doméstica media tenían menos riesgo de PPT (OR=0,29; IC95%:0,14-0,58) que las mujeres sin carga doméstica o con carga elevada. Conclusiones: Los resultados muestran un efecto protector de la carga de trabajo doméstico de grado medio y elevado, reduciendo la probabilidad de parto pretérmino y de nacidos pequeños para su edad gestacional.Background: Published studies are not conclusive on the impact of certain occupational exposures in pregnancy, stressing the need to consider the double role, professional and family, of women. The objective of this study is to evaluate the effect of employment and domestic load on the duration of pregnancy and fetal development. Methods: Using Univariate and Multivariate regression models, we studied the association of preterm deliveries (PPT) (<37 weeks), full term newborns with low weight (BPT) (<2500g) and small for their gestational age (PEG) (<10th percentile) in weight, length and head circumference according to work situation (employment/non-employment) and domestic load (low/ medium/ high) in 2506 women. The analyses were carried out using SPSS and R. Results: Women with medium domestic load have lower risk of PPT (OR=0.41, 95%CI:0.21-0.81), PEG in weight (OR=0.47, 95%CI:0.32-0.69), length (OR=0.57, 95%CI:0.39-0.83) and head circumference (OR=0.58, 95% CI:0.40-0.83) and with high load PEG in weight (OR=0.72, 95%CI:0.54-0.98) and head circumference (OR = 0.73, 95% CI:0.54-0.99). When analyzing employment situation and domestic load, women with medium domestic load have less risk of PPT (OR=0.29, 95%CI:0.14-0.58) than the absence of load or high domestic load. Conclusions: The results show a protective effect of the medium and high domestic load, reducing the probability of preterm birth and small for gestational age babies.Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041), (FIS-PI13/2429, PI041436, PI042018, PI06/0867, PI07/0252, PI08/1151, PI09/02311, y FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647, y MS13/00054), Generalitat de Catalunya-CIRIT 1999SGR 00241, Conselleria de Sanitat, Generalitat Valenciana, Departamento de Salud del Gobierno Vasco (2005111093 y 2009111069), Gobierno Provincial de Guipúzcoa (DFG06/004 and DFG08/001), Obra Social Cajastur, Universidad de Oviedo, European Union Commission (QLK4-1999-01422, QLK4-2002-00603 and CONTAMED FP7-ENV-212502), Consejería de Salud de la Junta de Andalucía (183/07), y Fundació Roger Torné

Estudio de la evolución de la exposición a plomo en la población infantil española en los últimos 20 años. ¿Un ejemplo no reconocido de «salud en todas las políticas»?

ResumenObjetivoDescribir la evolución temporal de las concentraciones de plomo en el aire en España, desde antes de su prohibición como aditivo de la gasolina hasta la actualidad, así como estudiar la evolución de la carga corporal de plomo en la población infantil española.MétodosSe obtuvieron las concentraciones medias anuales de plomo en el aire en diversas ciudades españolas, desde la década de 1980 hasta la actualidad. Se realizó una búsqueda bibliográfica con el fin de identificar estudios publicados sobre concentraciones de plomo en la población infantil española.ResultadosEn general se observó una disminución de las concentraciones de plomo, de mayor magnitud entre 1991 y 1999. Esta evolución decreciente se asocia con una disminución de las concentraciones de plomo en la población infantil española, desde 1989 (año en que se publica el primer estudio sobre exposición infantil al plomo) hasta hoy. La disminución, tanto en el aire como en la población infantil, es muy probable que sea consecuencia de las medidas legislativas que han regulado la cantidad máxima de plomo en la gasolina, desde 1987 hasta su prohibición total en agosto de 2001.ConclusionesDesde el punto de vista de la salud pública, la prohibición del uso de gasolina con plomo fue una acción que aumentó la protección de la salud de la población española.AbstractObjectiveTo describe the time trend in atmospheric lead concentrations in Spain, from before lead was banned as a gasoline additive to the present, and to determine the trend in lead body burden in the Spanish child population.MethodsWe obtained the annual average for atmospheric lead levels in several Spanish cities from the 1980s to the present. A literature search was conducted to identify published studies on lead concentrations in populations of Spanish children.ResultsOverall, atmospheric lead levels decreased, particularly between 1991 and 1999. This downward trend was related to a decrease in lead concentrations in Spanish children from 1989, the year in which the first study of childhood lead exposure was published, until the present. The decreased concentrations in both air and in children was most probably a result of legislative measures regulating the maximum amount of lead in gasoline in 1987 until a complete ban in August 2001.ConclusionsFrom a public health point of view, the banning of leaded gasoline has significantly increased health protection in the Spanish population