New generation anaplastic lymphoma kinase inhibitors

Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3*7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features. The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. Moreover, 60-90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting

Advances in molecular mechanisms and immunotherapy involving the immune cell-promoted epithelial-to-mesenchymal transition in lung cancer

none8noImmunotherapy has offered a new opportunity for the treatment of many malignancies. In patients with lung cancer, immune checkpoint inhibitors have significantly improved survival. However, little is known about predictive factors or primary and acquired resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is a complex of phenotypic changes involved in carcinogenesis and resistance to cancer treatments. Specifically, immune cells in the tumor microenvironment can promote EMT, and mesenchymal phenotype acquisition negatively regulates the anticancer immune response. EMT is associated with higher expression of PD-L1 and other immune checkpoints. In this review, we focused on the role of EMT in the interplay between tumor cells and the immune system, with particular emphasis on lung cancer. On the basis of our findings, we hypothesize that the effects of EMT on immune cells could be overcome in this disease by a new combination of immune checkpoint inhibitors.openDe Matteis S.; Canale M.; Verlicchi A.; Bronte G.; Delmonte A.; Crino L.; Martinelli G.; Ulivi P.De Matteis, S.; Canale, M.; Verlicchi, A.; Bronte, G.; Delmonte, A.; Crino, L.; Martinelli, G.; Ulivi, P

Case Report: Circulating Myeloid-Derived Suppressive-Like Cells and Exhausted Immune Cells in Non-Small Cell Lung Cancer Patients Treated With Three Immune Checkpoint Inhibitors

none12noImmune checkpoint inhibition induced a great step forward in the treatment of non-small cell lung cancer patients. In cancer immune microenvironment many checkpoints were studied and their involvement could represent a mechanism of resistance to cancer immunotherapy. For this reason, the inhibition of multiple immune checkpoints is under development. However, myeloid-derived suppressor cells (MDSC) and exhausted immune cells could limit the efficacy of cancer immunotherapy. We analyzed the variation of circulating immune suppressive-like cell subsets and exhausted immune cells in three non-small cell lung cancer patients treated with the combination of anti-CTLA-4 plus anti-PD-1 plus anti-LAG-3 at T0 (baseline), T1 (after 2 months) and T2 (after 4 months). We also describe the clinical and radiological course of the disease during this treatment in all three patients. We observed both clinical differences and changes in the composition of immune suppressive-like cell subsets and exhausted immune cells between the patients receiving the same schedule of treatment with immune checkpoint inhibitors. The study on a wider patient population and experimental model design could help to clarify the kinetics of these cell subpopulations with the perspective to find new targets for treatment or new biomarkers for resistance to cancer immunotherapy.openBronte G.; Verlicchi A.; De Matteis S.; Rossi A.; Affatato A.; Sullo F.G.; Gianni C.; Canale M.; Burgio M.A.; Delmonte A.; Milella M.; Crino L.Bronte, G.; Verlicchi, A.; De Matteis, S.; Rossi, A.; Affatato, A.; Sullo, F. G.; Gianni, C.; Canale, M.; Burgio, M. A.; Delmonte, A.; Milella, M.; Crino, L

Continuous fungal treatment of non-sterile veterinary hospital effluent: pharmaceuticals removal and microbial community assessment

Source point treatment of effluents with a high load of pharmaceutical active compounds (PhACs), such as hospital wastewater, is a matter of discussion among the scientific community. Fungal treatments have been reported to be successful in degrading this type of pollutants and, therefore, the white-rot fungus Trametes versicolor was applied for the removal of PhACs from veterinary hospital wastewater. Sixty-six percent removal was achieved in a non-sterile batch bioreactor inoculated with T. versicolor pellets. On the other hand, the study of microbial communities by means of DGGE and phylogenetic analyses led us to identify some microbial interactions and helped us moving to a continuous process. PhAC removal efficiency achieved in the fungal treatment operated in non-sterile continuous mode was 44 % after adjusting the C/N ratio with respect to the previously calculated one for sterile treatments. Fungal and bacterial communities in the continuous bioreactors were monitored as well.Authors want to acknowledge the UAB veterinary hospital staff for their kind permission and help for the samplings. This work has been funded by the Spanish Ministry of Economy and Competitiveness and FEDER (projects CTM2013-48545-C2 and AIB2010PT-00169) and supported by the Generalitat de Catalunya (Consolidated Research Groups 2014-SGR-476 and 2014-SGR-291). The Department of Chemical Engineering of the Universitat Autonoma de Barcelona (UAB) is a member of the Xarxa de Referencia en Biotecnologia de la Generalitat de Catalunya. M. Badia-Fabregat and D. Lucas acknowledge the predoctoral grants from UAB and from the Spanish Ministry of Education, Culture and Sports (AP-2010-4926), respectively. The authors also thank the Portuguese Foundation for Science and Technology (FCT) Strategic Project PEst-OE/EQB/LA0023/2013, Project FCOMP-01-0124-FEDER-027462 co-funded by Operational Competitiveness Programme, FEDER, and Project "BioEnv-Biotechnology and Bioengineering for a sustainable world," REF. NORTE-07-0124-FEDER-000048, co-funded by Programa Operacional Regional do Norte (ON.2 - O Novo Norte), QREN, FEDER

Environmental Emission of Pharmaceuticals from Wastewater Treatment Plants in the USA

The residual drugs, drug bioconjugates, and their metabolites, mostly from human and veterinary usage, are routinely flushed down the drain, and enter wastewater treatment plants (WWTP). Increasing population, excessive use of allopathic medicine, continual introduction of novel drugs, and existing inefficient wastewater treatment processes result in the discharge of large volumes of pharmaceuticals and their metabolites from the WWTPs into the environment. The effluent from the WWTPs globally contaminate ~25% of rivers and the lakes. Pharmaceuticals in the environment, as contaminants of emerging concerns, behave as pseudo-persistent despite their relatively short environmental half-lives in the environment. Therefore, residual levels of pharmaceuticals in the environment not only pose a threat to the wildlife but also affect human health through contaminated food and drinking water. This chapter highlights WWTPs as point-sources of their environmental emissions and various effects on the aquatic and terrestrial ecosystem

Occurrence, Distribution, and Ecological Risk of Fluoroquinolones in Rivers and Wastewaters

The use of fluoroquinolones for the treatment of infections in humans and animals has increased in Argentina, and they can be found in large amounts in water bodies. The present study investigated the occurrence and associated ecological risk of 5 fluoroquinolones in rivers and farm wastewaters of San Luis, Santa Fe, Córdoba, Entre Ríos, and Buenos Aires provinces of Argentina by high-performance liquid chromatography coupled to fast-scanning fluorescence detection and ultra–high-performance liquid chromatography coupled to triple quadrupole mass spectrometry detection. The maximum concentrations of ciprofloxacin, enrofloxacin, ofloxacin, enoxacin, and difloxacin found in wastewater were 1.14, 11.9, 1.78, 22.1, and 14.2 μg L–1, respectively. In the case of river samples, only enrofloxacin was found, at a concentration of 0.97 μg L–1. The individual risk of aquatic organisms associated with water pollution due to fluoroquinolones was higher in bacteria, cyanobacteria, algae, plants, and anurans than in crustaceae and fish, with, in some cases, risk quotients >1. The proportion of samples classified as high risk was 87.5% for ofloxacin, 63.5% for enrofloxacin, 57.1% for ciprofloxacin, and 25% for enoxacin. Our results suggest that the prevalence of fluoroquinolones in water could be potentially risky for the aquatic ecosystem, and harmful to biodiversity.Fil: Teglia, Carla Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Desarrollo Analítico y Quimiometría; ArgentinaFil: Perez, Florencia Antonella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Desarrollo Analítico y Quimiometría; ArgentinaFil: Michlig, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Ingeniería Química. Programa de Investigación y Análisis de Residuos y Contaminantes Químicos; ArgentinaFil: Repetti, María Rosa. Universidad Nacional del Litoral. Facultad de Ingeniería Química. Programa de Investigación y Análisis de Residuos y Contaminantes Químicos; ArgentinaFil: Goicoechea, Hector Casimiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Desarrollo Analítico y Quimiometría; ArgentinaFil: Culzoni, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Desarrollo Analítico y Quimiometría; Argentin

Impacts of design configuration and plants on the functionality of the microbial community of mesocosm-scale constructed wetlands treating ibuprofen

Microbial degradation is an important pathway during the removal of pharmaceuticals in constructed wetlands (CWs). However, the effects of CW design, plant presence, and different plant species on the microbial community in CWs have not been fully explored. This study aims to investigate the microbial community metabolic function of different types of CWs used to treat ibuprofen via community-level physiological profiling (CLPP) analysis. We studied the interactions between three CW designs (unsaturated, saturated and aerated) and six types of mesocosms (one unplanted and five planted, with Juncus, Typha, Berula, Phragmites and Iris) treating synthetic wastewater. Results show that the microbial activity and metabolic richness found in the interstitial water and biofilm of the unsaturated designs were lower than those of the saturated and aerated designs. Compared to other CW designs, the aerated mesocosms had the highest microbial activity and metabolic richness in the interstitial water, but similar levels of biofilm microbial activity and metabolic richness to the saturated mesocosms. In all three designs, biofilm microbial metabolic richness was significantly higher (p < .05) than that of interstitial water. Both the interstitial water and biofilm microbial community metabolic function were influenced by CW design, plant presence and species, but design had a greater influence than plants. Moreover, canonical correlation analysis indicated that biofilm microbial communities in the three designs played a key role in ibuprofen degradation. The important factors identified as influencing ibuprofen removal were microbial AWCD (average well color development), microbial metabolic richness, and the utilization of amino acids and amine/amides. The enzymes associated with co-metabolism of l-arginine, l-phenyloalanine and putrescine may be linked to ibuprofen transformations. These results provide useful information for optimizing the operational parameters of CWs to improve ibuprofen removal

The importance of over-the-counter-sales and product format in the environmental exposure assessment of active pharmaceutical ingredients

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Ibuprofen results in alterations of human fetal testis development

International audienceAmong pregnant women ibuprofen is one of the most frequently used pharmaceutical compounds with up to 28% reporting use. Regardless of this, it remains unknown whether ibuprofen could act as an endocrine disruptor as reported for fellow analgesics paracetamol and aspirin. To investigate this, we exposed human fetal testes (7-17 gestational weeks (GW)) to ibuprofen using ex vivo culture and xenograft systems. Ibuprofen suppressed testosterone and Leydig cell hormone INSL3 during culture of 8-9 GW fetal testes with concomitant reduction in expression of the steroidogenic enzymes CYP11A1, CYP17A1 and HSD17B3, and of INSL3. Testosterone was not suppressed in testes from fetuses younger than 8 GW, older than 10-12 GW, or in second trimester xenografted testes (14-17 GW). Ex vivo, ibuprofen also affected Sertoli cell by suppressing AMH production and mRNA expression of AMH, SOX9, DHH, and COL2A1. While PGE2 production was suppressed by ibuprofen, PGD2 production was not. Germ cell transcripts POU5F1, TFAP2C, LIN28A, ALPP and KIT were also reduced by ibuprofen. We conclude that, at concentrations relevant to human exposure and within a particular narrow 'early window' of sensitivity within first trimester, ibuprofen causes direct endocrine disturbances in the human fetal testis and alteration of the germ cell biology