Urokinase-type Plasminogen Activator Receptor Transcriptionally Controlled Adenoviruses Eradicate Pancreatic Tumors and Liver Metastasis in Mouse Models

Treatment options for pancreatic cancer have shown limited success mainly owing to poor selectivity for pancreatic tumor tissue and to a lack of activity in the tumor. In this study, we describe the ability of the urokinase-type plasminogen activator receptor (uPAR) promoter to efficiently and selectively target pancreatic tumors and metastases, which enables the successful management of pancreatic cancer. We have generated a replication-defective reporter adenovirus, AduPARLuc, and a conditionally replicating adenovirus, AduPARE1A, and we have studied the selectivity and antitumoral efficacy in pancreatic tumors and metastases. Toxicity was studied on intravascular delivery. We demonstrate that the uPAR promoter is highly active in pancreatic tumors but very weak in normal tissues. Tumor specificity is evidenced by a 100-fold increase in the tumor-to-liver ratio and by selective targeting of liver metastases (P < .001). Importantly, the AduPARE1A maintains the oncolytic activity of the wild-type virus, with reduced toxicity, and exhibits significant antitumoral activity (25% tumor eradication) and prolonged survival in pancreatic xenograft models (P < .0001). Furthermore, upon intravascular delivery, we demonstrate complete eradication of liver metastasis in 33% of mice, improving median survival (P = 5.43 x 10(-5)). The antitumoral selective activity of AduPARE1A shows the potential of uPAR promoter-based therapies in pancreatic cancer treatment

Формування політичних інститутів в країнах Центральної Азії в умовах незалежності

Останні досягнення і соціально-економічні успіхи країн Центральної Азії, що отримали незалежність з розпадом СРСР ґрунтуються на багатьох чинниках, серед яких, у першу чергу, проведення ефективних економічних реформ, становлення середнього класу і формування зрілого суспільства

Fate and removal of pharmaceuticals and illicit drugs in conventional and membrane bioreactor wastewater treatment plants and by riverbank filtration

26 pages, 3 tables, 3 figures.Pharmaceutically active compounds (PhACs) and drugs of abuse (DAs) are two important groups of emerging environmental contaminants that have raised an increasing interest in the scientific community. A number of studies revealed their presence in the environment. This is mainly due to the fact that some compounds are not efficiently removed during wastewater treatment processes, being able to reach surface and groundwater and subsequently, drinking waters. This paper reviews the data regarding the levels of pharmaceuticals and illicit drugs detected in wastewaters and gives an overview of their removal by conventional treatment technologies (applying activated sludge) as well as advanced treatments such as membrane bioreactor. The paper also gives an overview of bank filtration practices at managed aquifer recharge sites and discusses the potential of this approach to mitigate the contamination by PhACs and DAs.This work has been supported by the EU project INNOVA-MED (INCO-CT-2006-517728) and by the Spanish Ministry of Science and Innovation Projects CTM2007-30524-E and CEMAGUA (CGL2007-64551).Peer reviewe

Contribution of hospital effluents to the load of pharmaceuticals in urban wastewaters: Identification of ecologically relevant pharmaceuticals

The impact of effluent wastewaters from four different hospitals: a university (1456 beds), a general (350 beds), a pediatric (110 beds) and a maternity hospital (96 beds), which are conveyed to the same wastewater treatment plant (WWTP), was evaluated in the receiving urban wastewaters. The occurrence of 78 pharmaceuticals belonging to several therapeutic classes was assessed in hospital effluents and WWTP wastewaters (influent and effluent) as well as the contribution of each hospital in WWTP influent in terms of pharmaceutical load. Results indicate that pharmaceuticals are widespread pollutants in both hospital and urban wastewaters. The contribution of hospitals to the input of pharmaceuticals in urban wastewaters widely varies, according to their dimension. The estimated total mass loadings were 306 g d− 1 for the university hospital, 155 g d− 1 for the general one, 14 g d− 1 for the pediatric hospital and 1.5 g d− 1 for the maternity hospital, showing that the biggest hospitals have a greater contribution to the total mass load of pharmaceuticals. Furthermore, analysis of individual contributions of each therapeutic group showed that NSAIDs, analgesics and antibiotics are among the groups with the highest inputs. Removal efficiency can go from over 90% for pharmaceuticals like acetaminophen and ibuprofen to not removal for β-blockers and salbutamol. Total mass load of pharmaceuticals into receiving surface waters was estimated between 5 and 14 g/d/1000 inhabitants. Finally, the environmental risk posed by pharmaceuticals detected in hospital and WWTP effluents was assessed by means of hazard quotients toward different trophic levels (algae, daphnids and fish). Several pharmaceuticals present in the different matrices were identified as potentially hazardous to aquatic organisms, showing that especial attention should be paid to antibiotics such as ciprofloxacin, ofloxacin, sulfamethoxazole, azithromycin and clarithromycin, since their hazard quotients in WWTP effluent revealed that they could pose an ecotoxicological risk to algae

Pharmaceuticals in source separated sanitation systems: Fecal sludge and blackwater treatment

This study investigated, for the first time, the occurrence and fate of 29 multiple-class pharmaceuticals (PhACs) in two source separated sanitation systems based on: (i) batch experiments for the anaerobic digestion (AD) of fecal sludge under mesophilic (37 `C) and thermophilic (52 "C) conditions, and (ii) a full-scale blackwater treatment plant using wet composting and sanitation with urea addition. Results revealed high concentrations of PhACs in raw fecal sludge and blackwater samples, with concentrations up to hundreds of pg L-1 and fig kg-1 dry weight (dw) in liquid and solid fractions, respectively. For mesophilic and thermophilic treatments in the batch experiments, average PhACs removal rates of 31% and 45%, respectively, were observed. The average removal efficiency was slightly better for the full-scale blackwater treatment, with 49% average removal, and few compounds, such as atenolol, valsartan and hydrochlorothiazide, showed almost complete degradation. In the AD treatments, no significant differences were observed between mesophilic and thermophilic conditions. For the full-scale blackwater treatment, the aerobic wet composting step proved to be the most efficient in PhACs reduction, while urea addition had an almost negligible effect for most PhACs, except for citalopram, venlafaxine, oxazepam, valsartan and atorvastatin, for which minor reductions (on average 25%) were observed. Even though both treatment systems reduced initial PhACs loads considerably, significant PhAC concentrations remained in the treated effluents, indicating that fecal sludge and blackwater fertilizations could be a relevant vector for dissemination of PhACs into agricultural fields and thus the environment. (C) 2019 Elsevier B.V. All rights reserved

Occurrence and Fate of Emerging Wastewater Contaminants in Western Balkan Region

This paper reports on a comprehensive reconnaissance of over seventy individual wastewater contaminants in the region of Western Balkan (WB ; Bosnia and Herzegovina, Croatia and Serbia), including some prominent classes of emerging contaminants such as pharmaceuticals and personal care products, surfactants and their degradation products, plasticizers, pesticides, insect repellents, and flame retardants. All determinations were carried out using a multiresidue analytical approach, based on the application of gas chromatographic and liquid chromatographic techniques coupled to mass spectrometric detection. The results confirmed a widespread occurrence of the emerging contaminants in municipal wastewaters of the region. The most prominent contaminant classes, determined in municipal wastewaters, were those derived from aromatic surfactants, including linear alkylbenzene sulphonates (LAS) and alkylphenol polyethoxylates (APEO), with the concentrations in raw wastewater reaching into the mg/l range. All other contaminants were present in much lower concentrations, rarely exceeding few μ g/l. The most abundant individual compounds belonged to several classes of pharmaceuticals (antimicrobials, analgesics and antiinflammatories, b-blockers and lipid regulators) and personal care products (fragrances). Due to the rather poor wastewater management practices in WB countries, with less than 5 % of all wastewaters being biologically treated, most of the contaminants present in wastewaters reach ambient waters and may represent a significant environmental concer

Diseño de escenarios de aprendizaje basados en la indagación con soporte tecnológico. Estrategias de co-diseño entre docentes e investigadores.

En el marco del proyecto Design2Learn se presenta el proceso de codiseño docentes e investigadores de escenarios de aprendizaje basados en la indagación con soporte tecnológico. Se detallan los principios de diseño. Los resultados incluyen los retos identificados por profesores de distintas disciplinas, así como la secuencia seguida para el proceso de co-diseño y creación de escenarios de aprendizaje basado en el aprendizaje indagativo y potenciados por tecnología en la formación universitaria

Fate of pharmaceuticals and pesticides in fly larvae composting

A novel and efficient organic waste management strategy currently gaining great attention is fly larvae composting. High resource recovery efficiency can be achieved in this closed-looped system, but pharmaceuticals and pesticides in waste could potentially accumulate in every loop of the treatment system and spread to the environment. This study evaluated the fate of three pharmaceuticals (carbamazepine, roxithromycin, trimethoprim) and two pesticides (azoxystrobin, propiconazole) in a fly larvae composting system and in a control treatment with no larvae. It was found that the half-life of all five substances was shorter in the fly larvae compost (<10% of control) and no bioaccumulation was detected in the larvae. Fly larvae composting could thus impede the spread of pharmaceuticals and pesticides into the environment

Repercusiones sanitarias de la calidad del agua: los residuos de medicamentos en el agua

This manuscript summarizes the main results obtained in various monitoring studies conducted in the Llobregat and the Ebro River basins to evaluate the occurrence of pharmaceuticals and drugs of abuse in their aquatic environments and the potentially derived risks for environmental and human health. The occurrence of these compounds in surface waters, located downstream the point of discharge of sewage treatment plants (STP), points out STPs effluents as the main source of these substances in the aquatic environment. Both river basins had similar pharmaceutical contamination patterns. However, hazard quotients (HQ) calculated for three different trophic levels (algae, daphnia and fish) pointed out sulfamethoxazol (sulfamide antibiotic) for algae, gemfibrozil (lipid regulator) for algae and fish, clofibric acid (lipid regulator) and erythromycine (macrolide antibiotic) for daphnia, and ibuprofen (analgesic anti-inflammatory) for all investigated tropic levels, as the compounds with the highest ecotoxicological risk in the Llobregat. In the Ebro River, the most problematic pharmaceuticals were sulfamethoxazol for algae, and erythromycine, clofibric acid and fluoxetine (anti-depressive) for daphnids. Levels of drugs of abuse measured in surface waters of the Ebro River were one and two orders of magnitude lower than those observed in effluent and influent sewage waters, respectively. Lack of data about their ecotoxicity does not allow calculation of HQ for these compounds. The presence of pharmaceuticals and drugs of abuse in surface and drinking waters is not subjected to regulation; hence, they are not considered priority pollutants to be included in monitoring programs. However, due to their possible harmful outcomes in wildlife, research on their potential effects in human health is indispensable.Este trabajo resume varios estudios de monitorización de fármacos y drogas de abuso llevados a cabo en el medio ambiente acuático de las cuencas de los ríos Llobregat y Ebro con el fin de evaluar la calidad del agua en relación a la presencia de estas substancias y su potencial riesgo para la salud ambiental y pública. La identificación de estos compuestos aguas abajo del punto de vertido de las plantas depuradoras apunta a la descarga de agua residual tratada como la principal fuente de emisión de estos contaminantes en el medio acuático. El perfil de contaminación por fármacos fue bastante similar en ambas cuencas. No obstante, los índices de riesgo (HQ) calculados para los fármacos en diferentes niveles tróficos (algas, dáfnidos y peces) indican que los compuestos que presentan un mayor riesgo ecotóxico en el Llobregat son el sulfametoxazol (antibiótico sulfamida) para las algas, el gemfibrozil (regulador de lípidos) para las algas y los peces, el ácido clofíbrico (regulador de lípidos) y la eritromicina (antibiótico macrólido) para los dáfnidos, y el ibuprofeno (analgésico anti-inflamatorio) para todos los eslabones tróficos. En el Ebro, los compuestos más problemáticos son el sulfametoxazol para las algas, y la eritromicina, el ácido clofíbrico y la fluoxetina (antidepresivo) para los dáfnidos.Los niveles de drogas de abuso (y sus metabolitos) determinados en la cuenca del Ebro son aproximadamente uno y dos órdenes de magnitud más bajos respectivamente que los determinados en las aguas de salida y de entrada a las depuradoras. Sin embargo, debido a la falta de datos sobre su ecotoxicidad, no se han podido calcular índices de riesgo.La presencia de estos compuestos (fármacos y drogas) en aguas superficiales y de bebida aun no está regulada y, por lo tanto, no constituyen parámetros de obligado control. Aún es imprescindible seguir investigando para poder evaluar su posible efecto en la salud humana

Impacts of exhaust gas cleaning systems (EGCS) discharge waters on planktonic biological indicators

Exhaust Gas Cleaning Systems (EGCS), operating in open-loop mode, continuously release acidic effluents (scrubber waters) to marine waters. Furthermore, scrubber waters contain high concentrations of metals, polycyclic aromatic hydrocarbons (PAHs), and alkylated PAHs, potentially affecting the plankton in the receiving waters. Toxicity tests evidenced significant impairments in planktonic indicators after acute, early-life stage, and long-term exposures to scrubber water produced by a vessel operating with high sulphur fuel. Acute effects on bacterial bioluminescence (Aliivibrio fischeri), algal growth (Phaeodactylum tricornutum, Dunaliella tertiolecta), and copepod survival (Acartia tonsa) were evident at 10 % and 20 % scrubber water, while larval development in mussels (Mytilus galloprovincialis) showed a 50 % reduction at ∼5 % scrubber water. Conversely, larval development and reproductive success of A. tonsa were severely affected at scrubber water concentrations ≤1.1 %, indicating the risk of severe impacts on copepod populations which in turn may result in impairment of the whole food web