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Pharmaceuticals and personal care products (PPCPs) are an indispensable component of a healthy society. However, they are well‐established environmental contaminants, and many can elicit biological disruption in exposed organisms. It is now a decade since the landmark review covering the top 20 questions on PPCPs in the environment (Boxall et al., 2012). In the present study we discuss key research priorities for the next 10 years with a focus on how regions where PPCPs pose the greatest risk to environmental and human health, either now or in the future, can be identified. Specifically, we discuss why this problem is of importance and review our current understanding of PPCPs in the aquatic environment. Foci include PPCP occurrence and what drives their environmental emission as well as our ability to both quantify and model their distribution. We highlight critical areas for future research including the involvement of citizen science for environmental monitoring and using modeling techniques to bridge the gap between research capacity and needs. Because prioritization of regions in need of environmental monitoring is needed to assess future/current risks, we also propose four criteria with which this may be achieved. By applying these criteria to available monitoring data, we narrow the focus on where monitoring efforts for PPCPs are most urgent. Specifically, we highlight 19 cities across Africa, Central America, the Caribbean, and Asia as priorities for future environmental monitoring and risk characterization and define four priority research questions for the next 10 years. Environ Toxicol Chem 2024;43:575–588. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

How can data on the occurrence of pharmaceuticals and personal care products (PPCPs) in the environment and the quality of ecosystems exposed to PPCPs be used to determine whether current regulatory risk assessment schemes are effective? This is one of 20 "big questions" concerning PPCPs in the environment posed in a landmark review paper in 2012. Ten years later, we review the developments around this question, focusing on the first P in PPCPs, that is, pharmaceuticals, or more specifically the active ingredients included in them (active pharmaceutical ingredients, APIs). We illustrate how extensive data on both the occurrence of APIs and the ecotoxicological sensitivity of aquatic species to them can be used in a retrospective risk assessment. In the Netherlands, current regulatory risk assessment schemes offer insufficient protection against direct ecotoxicological effects from APIs: the toxic pressure exerted by the 39 APIs included in our study exceeds the policy‐related protective threshold of 0.05 (the "95%‐protection level") in at least 13% of sampled surface waters. In general, anti‐inflammatory and antirheumatic products (e.g., diclofenac, ibuprofen) contributed most to the overall toxic pressure, followed by sex hormones and modulators of the genital system (e.g., ethinylestradiol) and psychoanaleptics (e.g., caffeine). We formulated three open questions for future research. The first relates to improving the availability and accessibility of good‐quality ecotoxicity data on pharmaceuticals for the global scientific, regulatory, and general public. The second relates to the adaptation of regulatory risk assessment frameworks for developing regions of the world. The third relates to the integration of effect‐based and ecological approaches into regulatory risk assessment practice. Environ Toxicol Chem 2024;43:611–622. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

[Display omitted] • High ENOX2 expression is associated with immune excluded/deserted phenotypes in NPC. • ENOX2 inhibitor, idronoxil enhances CD8+ memory T -cell immunity in response to chemotherapy. • Combined treatment with idronoxil and cisplatin enhances tumor response in humanized mice model. • Combined treatment increases CD8+ T -cell expansion with cytolytic effector memory (Tem) feature. • T -cell infiltrates and tumor-associated ENOX2 have predictive value for anti-tumor response. The immunosuppressive tumor microenvironment is a major barrier for chemotherapy. Different chemosensitization approaches to reinstate immunological surveillance for cancers that are immune quiescent at the outset, have thus been devised. Cancer-specific ENOX2 expression is correlated with abnormal cell growth and has been proposed as a cellular target for anti-cancer activity. However, the potential effects of ENOX2 on the interaction between immune system and tumor cells remain elusive. To understand the mechanisms by which tumor-intrinsic ENOX2-mediated alterations in anti-tumor activity of T -cells and response to chemotherapy. In situ multiplexed immunohistochemistry with single cell and bulk RNA sequencing data from nasopharyngeal carcinoma (NPC) human tissues were used to define tumor phenotypes. Two NPC cell lines, with distinct ENOX2 expression, were used in a co-culture platform to study tumor-immune interactions between cancer cells/spheroids and T -cells. The effect of cisplatin treatment with ENOX2 inhibition by idronoxil (IDX) were tested in vitro and in vivo. Multi-parametric flow cytometry was used to characterize T -cell infiltrates in an NPC tumor humanized mouse model treated with combined treatment. NPC predominantly displayed an immune-excluded profile. This "cold-phenotype" was shown to exhibit higher ENOX2 expression and was associate with poorer progression-free survival (PFS). The therapeutic combination of IDX with cisplatin was effective in promoting CD8+ effector memory T cell (Tem) differentiation and mobilization. This Tem signature was highly cytotoxic, with Tem-mediated preferential lysis of higher ENOX2-expressing NPC cells. A combination-treated humanized mouse model showing dramatic shrinkage in tumors, were intra-tumoral Tem-enriched. Tumor-intrinsic ENOX2 expression is associated with tumor phenotype and PFS in NPC. Targeting ENOX2 with IDX and cisplatin impose qualitative control of T -cell response by preferentially increasing immune cells infiltration, Tem differentiation and tumor suppression. We suggest that ENOX2 inhibition may be a promising therapeutic strategy to enhance the effects of chemotherapy. [ABSTRACT FROM AUTHOR]

INTRODUCTION: With a 5-year of only 11 % pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest diseases. This is partly attributed to the tumour’s resistance to currently available treatment, resulting from a complex and highly heterogeneous tumour microenvironment (TME). A key challenge in cancer tissue engineering is to mimic the different key features of the TME. In this work we have developed robust PDAC biomimetic models for in vitro therapeutic assessment. EXPERIMENTAL: We have advanced our previously developed 3D polyurethane (PU) based polymeric scaffold PDAC model by incorporating biological complexity (multiple cell types: pancreatic cancer, pancreatic activated stellate and endothelial cells), spatial complexity (scaffold compartmentalization) and fluid flow (perfusion). Chemotherapy (with Gemcitabine-GEM) as well as proton therapy were carried out within our models. Imaging of cellular proliferation/spatial organization, apoptosis of the different cell types and ECM secretion was carried out along with assessment of biomarkers linked to chemo-resistance. RESULTS AND DISCUSSION: For chemotherapy treatment, within our static models, we observed that the dual scaffold showed a higher resistance to GEM in comparison to the single scaffold. Our results highlight that the spatial arrangement of the cells, within a 3D model, affect the response to chemotherapy. For proton therapy treatment, pancreatic cancer was more susceptible to proton beam therapy as opposed to photon therapy, the latter resulting in a higher cell viability and lower expression of apoptotic markers post-treatment. Furthermore, the introduction of dynamic flow affected the cell spatial organization, and biomarker expression involved with EMT, matrix remodeling highlighting the importance of fluid flow in PDAC’s evolution and response to chemotherapy. CONCLUSIONS: Our work highlights the importance of spatio-temporal cellular arrangement and interstitial fluid flow for accurate in vitro studies of the chemoradiotherapy resistance for PDAC. [ABSTRACT FROM AUTHOR]

England's 10 national parks are renowned for their landscapes, wildlife, and recreational value. However, surface waters in the national parks may be vulnerable to pollution from human-use chemicals, such as active pharmaceutical ingredients (APIs), because of factors like ineffective wastewater treatment, seasonal tourism, a high proportion of elderly residents, and the presence of low-flow water bodies that limit dilution. The present study determined the extent of API contamination in the English national parks by monitoring 54 APIs in 37 rivers across all national parks over two seasons. Results were compared to existing data sets for UK cities and to concentration thresholds for ecological impacts and antimicrobial resistance selection. Results revealed widespread contamination of the national parks, with APIs detected at 52 out of 54 sites and in both seasons. Thirty-one APIs were detected, with metformin, caffeine, and paracetamol showing the highest mean concentrations and cetirizine, metformin, and fexofenadine being the most frequently detected. While total API concentrations were generally lower than seen previously in UK cities, locations in the Peak District and Exmoor had higher concentrations than most city rivers. Fourteen locations had concentrations of either amitriptyline, carbamazepine, clarithromycin, diltiazem, metformin, paracetamol, or propranolol above levels of concern for fish, invertebrates, and algae or for selection for antimicrobial resistance. Therefore, API pollution of the English national parks appears to pose risks to ecological health and potentially human health through recreational water use. Given that these parks are biodiversity hotspots with protected ecosystems, there is an urgent need for improved monitoring and management of pharmaceutical pollution and pollution more generally not only in national parks in England but also in similar environments across the world. Environ Toxicol Chem 2024;00:1-14. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD + ) and NADH levels. Consistent with this observation, the major mitochondrial NAD + -dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption.