Multigenerational toxicity of microplastics derived from two types of agricultural mulching films to Folsomia candida.

Degradation and fragmentation of mulching films represents an increasing source of microplastics (MPs, plastic particles 1 µm to 5 mm in size) to agricultural soils. MPs have been shown to affect many soil invertebrates, including springtails. However, these studies typically use test materials representing less environmentally relevant particle types, such as pristine uniform MPs, which do not represent the large range of particle sizes and morphologies found in the field. This study aimed at providing insight into the adverse effects of MPs originating from agricultural mulching films, by using artificially aged MPs derived from both biodegradable (starch-polybutadiene adipate terephthalate (PBAT)) blend, as well as conventional (linear low-density polyethylene (LLDPE)) plastic polymers. The soil dwelling springtail Folsomia candida was exposed to these MPs for five generations in order to elucidate population effects due to possible reproduction toxicity, endocrine disruption, mutagenesis or developmental toxicity. F. candida were exposed to 0, 0.0016, 0.008, 0.04, 0.2, 1, 2, 3, 4 and 5 % (w/w dry soil) MPs in Lufa 2.2 soil, which includes concentrations within the range of environmental relevance. Juveniles produced at each concentration were transferred to the next generation, with the parental, F2 and F4 generations being exposed for four weeks and F1 and F3 generations for five weeks. No concentration-dependent effects on F. candida survival or reproduction were observed in exposures to either of the MPs, in any of the generations. These results suggest that the particular MPs used in this study, derived from mulching films used on agricultural soils, may not be potent toxicants to F. candida, even after long-term exposure and at elevated concentrations.

Production and characterisation of environmentally relevant microplastic test materials derived from agricultural plastics.

Soil environments across the globe, particularly in agricultural settings, have now been shown to be contaminated with microplastics. Agricultural plastics - such as mulching films - are used in close or direct contact with soils and there is growing evidence demonstrating that they represent a potential source of microplastics. There is a demand to undertake fate and effects studies to understand the behaviour and potential long-term ecological risks of this contamination. Yet, there is a lack of test materials available for this purpose. This study describes the manufacture and characterisation of five large (1-40 kg) batches of microplastic test materials derived from agricultural mulching films. Batches were produced from either polyethylene-based conventional mulching films or starch-polybutadiene adipate terephthalate blend mulching films that are certified biodegradable in soil. Challenges encountered and overcome during the micronisation process provide valuable insights into the future of microplastic test material generation from these material types. This includes difficulties in micronising virgin polyethylene film materials. All five batches were subjected to a thorough physical and chemical characterisation - both of the original virgin films and the subsequent microplastic particles generated - including a screening for the presence of chemical additives. This is a critical step to provide essential information for interpreting particle fate or effects in scientific testing. Trade-offs between obtaining preferred particle typologies and time and cost constraints are elucidated. Several recommendations emerging from the experiences gained in this study are put forward to advance the research field towards greater harmonisation and utilisation of environmentally relevant test materials.

Comments to "Degli-Innocenti, F. The pathology of hype, hyperbole and publication bias is creating an unwarranted concern towards biodegradable mulch films" [J. Hazard. Mater. 463 (2024) 132923].

Some narratives present biodegradable plastic use for soil mulching practices in agriculture as "environmentally friendly" and "sustainable" alternatives to conventional plastics. To verify these narratives, environmental research recently started focusing on their potential impact on soil health, highlighting some concerns. The paper by Degli-Innocenti criticizes this unfolding knowledge arguing that it is affected by communication hypes, alarmistic writing and a focus on exposure scenarios purposedly crafted to yield negative effects. The quest of scientists for increased impact - the paper concludes - is the driver of such behavior. As scholars devoted to the safeguarding of scientific integrity, we set to verify whether this serious claim is grounded in evidence. Through a bibliometric analysis (using number of paper reads, citations and mentions on social media to measure the impact of publications) we found that: i) the papers pointed out by Degli-Innocenti as examples of biased works do not score higher than the median of similar publications; ii) the methodology used to support the conclusion is non-scientific; and iii) the paper does not fulfil the requirements concerning disclosure of conflicts of interests. We conclude that this paper represents a non-scientific opinion, potentially biased by a conflict of interest. We ask the paper to be clearly tagged as such, after the necessary corrections on the ethic section have been made. That being said, the paper does offer some useful insights for the definition of exposure scenarios in risk assessment. We comment and elaborate on these proposed models, hoping that this can help to advance the field.

Selection of the optimal extraction protocol to investigate the interaction between trace elements and environmental plastic.

The interaction between environmental plastic and trace elements is an issue of concern. Understanding their interaction mechanisms is key to evaluate the potential threats for the environment. To this regard, consolidating confidence in extraction protocols can help in understanding the amount of different species present on plastic surface, as well as the potential mobility of trace elements present inside the plastic matrix (e.g., additives). Here we tested the efficacy of different reagents to mimic the elemental phases bonded to meso- and microplastic in the environment, in relation to the grade of ageing and the polymer composition. Results showed that a relatively high portion of trace elements is bonded in a weak phase and that other phases abundant in other matrices (e.g., oxides and bonded to organic matter) are only present to a limited degree in the plastic samples. The comparison of different sample types highlighted the important role of plastic ageing in governing interactions with trace elements, while the polymer composition has a limited influence on this process. Finally, the future steps toward a tailored extraction scheme for environmental plastic are proposed.

Innovative reference materials for method validation in microplastic analysis including interlaboratory comparison exercises.

Reference materials (RMs) are vital tools in the validation of methods used to detect environmental pollutants. Microplastics, a relatively new environmental pollutant, require a variety of complex approaches to address their presence in environmental samples. Both interlaboratory comparison (ILC) studies and RMs are essential to support the validation of methods used in microplastic analysis. Presented here are results of quality assurance and quality control (QA/QC) performed on two types of candidate microplastic RMs: dissolvable gelatin capsules and soda tablets. These RMs have been used to support numerous international ILC studies in recent years (2019-2022). Dissolvable capsules containing polyethylene terephthalate (PET), polyvinyl chloride (PVC), polyethylene (PE), and polystyrene (PS), in different size fractions from 50 to 1000 µm, were produced for one ILC study, obtaining relative standard deviation (RSD) from 0 to 24%. The larger size fraction allowed for manual addition of particles to the capsules, yielding 0% error and 100% recovery during QA/QC. Dissolvable capsules were replaced by soda tablets in subsequent ILC studies and recovery test exercises because they were found to be a more reliable carrier for microplastic RMs. Batches of soda tablets were produced containing different single and multiple polymer mixtures, i.e., PE, PET, PS, PVC, polypropylene (PP), and polycarbonate (PC), with RSD ranging from 8 to 21%. Lastly, soda tablets consisting of a mixture of PE, PVC, and PS (125-355 µm) were produced and used for recovery testing during pretreatment of environmental samples. These had an RSD of 9%. Results showed that soda tablets and capsules containing microplastics >50 µm could be produced with sufficient precision for internal recovery tests and external ILC studies. Further work is required to optimize this method for smaller microplastics (< 50 µm) because variation was found to be too large during QA/QC. Nevertheless, this approach represents a valuable solution addressing many of the challenges associated with validating microplastic analytical methods.

Measuring riverine macroplastic: Methods, harmonisation, and quality control.

River systems are a key environmental recipient of macroplastic pollution. Understanding the sources of macroplastic to rivers and the mechanisms controlling fate and transport is essential to identify and tailor measures that can effectively reduce global plastic pollution. Several guidelines exist for monitoring macroplastic in rivers; yet, no single method has emerged representing the standard approach. This reflects the substantial variability in river systems globally and the need to adapt methods to the local environmental context and monitoring goals. Here we present a critical review of methods used to measure macroplastic flows in rivers, with a specific focus on opportunities for methods testing, harmonisation, and quality assurance and quality control (QA/QC). Several studies have already revealed important findings; however, there is significant disparity in the reporting of methodologies and data. There is a need to converge methods, and their adaptations, towards greater comparability. This can be achieved through: i) methods testing to better understand what each method effectively measures and how it can be applied in different contexts; ii) incorporating QA/QC procedures during sampling and analysis; and iii) reporting methodological details and data in a more harmonised way to facilitate comparability and the utilisation of data by several end users, including policy makers. Setting this as a priority now will facilitate the collection of rigorous and comparable monitoring data to help frame solutions to limit plastic pollution, including the forthcoming global treaty on plastic pollution.

Large-scale monitoring and risk assessment of microplastics in the Amazon River.

Microplastics (MPs) are one of the most widespread contaminants worldwide, yet their risks for freshwater ecosystems have seldom been investigated. In this study, we performed a large monitoring campaign to assess the presence and risks of MPs in Amazonian freshwater ecosystems. We investigated MP pollution in 40 samples collected along 1500 km in the Brazilian Amazon, including the Amazon River, three major tributaries, and several streams next to the most important urban areas. MPs in the 55-5000 µm size range were characterized (size, shape, color) by microscopy and identified (polymer composition) by infrared spectroscopy. Ecotoxicological risks were assessed using chronic Species Sensitivity Distributions for effects triggered by food dilution and tissue translocation using data alignment methods that correct for polydispersity of environmental MPs and bioaccessibility. This study shows that MPs are ubiquitous contaminants in Amazonian freshwater ecosystems, with measured concentrations (55-5000 µm) ranging between 5 and 152 MPs/m3 in the Amazon River and its main tributaries, and between 23 and 74,550 MPs/m3 in urban streams. The calculated Hazardous Concentration for the 5% of species (HC5) derived from the SSDs for the entire MP range (1-5000 µm) were 1.6 × 107 MPs/m3 (95% CI: 1.2 × 106 - 4.0 × 108) for food dilution, and 1.8 × 107 MPs/m3 (95% CI: 1.5 × 106 - 4.3 × 108) for translocation. Rescaled exposure concentrations (1-5000 µm) in the Amazon River and tributaries ranged between 6.0 × 103 and 1.8 × 105 MPs/m3, and were significantly lower than the calculated HC5 values. Rescaled concentrations in urban streams ranged between 1.7 × 105 and 5.7 × 108 MPs/m3, and exceeded both calculated HC5 values in 20% of the locations. This study shows that ecological impacts by MP contamination are not likely to happen in the Amazon River and its major tributaries. However, risks for freshwater organisms may be expected in near densely populated areas, such as the cities of Manaus or Belem, which have limited wastewater treatment facilities.

Plastic recycling plant as a point source of microplastics to sediment and macroinvertebrates in a remote stream.

Microplastic is now ubiquitous in freshwater, sediment and biota, globally. This is as a consequence of inputs from, for example, waste mismanagement, effluents from wastewater treatment plants and surface runoff from agricultural areas. In this study, we investigated point source pollution of plastic to an upland stream, originating from a recycling plant that recycles polyethylene film in a remote area of Norway. Sediment (~2 kg) and macroinvertebrates (549 individuals in total) were sampled at one site upstream and two sites downstream of the recycling plant to study microplastic deposition and food web uptake. In total, 340 microplastic films were identified through a combination of visual and µFTIR analysis in the sediment samples. This corresponded to a concentration of 0.23 (± 0.057) items per g sediment upstream of the plastic recycling plant and 0.45 (± 0.017) and 0.58 (± 0.34) items per g downstream. The dominant plastic polymer was polyethylene, which increased significantly downstream of the plastic recycling plant. This indicates the role of the plastic recycling plant as a point source for microplastic in this catchment. Among the three sites investigated, a fairly constant concentration of polypropylene was found, indicating a diffuse source of polypropylene films across the catchment possibly relating to low-intensity agricultural land-use. Low levels of polyethylene were also observed upstream, which may be linked to either local or longer-distance atmospheric transport. Despite the considerable presence of microplastic in sediments, concentrations in macroinvertebrates were extremely low with only a single microplastic particle identified in the total of 549 macroinvertebrates-belonging to three different feeding groups-investigated. Our study suggests that: 1) microplastic pollution can be transferred to remote areas as unintended losses from recycling facilities, 2) remote areas with limited land-use pressure still have detectable levels of microplastic and 3) microplastic is only taken up by stream macroinvertebrates to a limited degree despite relatively high sediment concentrations, and thus there are no strong indications for ecological risks posed by microplastic to this ecological group at this location. Supplementary Information: The online version contains supplementary material available at 10.1186/s43591-022-00045-z.

A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer.

PURPOSE: BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients. PATIENTS AND METHODS: Patients (n = 98) were dosed with veliparib 50-500 mg twice daily (BID). The BRCAmut cohort (n = 70) contained predominantly ovarian (53%) and breast (23%) cancers; the BRCAwt cohort (n = 28) consisted primarily of breast cancer (86%). The MTD, DLT, adverse events, PK, PD, and clinical response were assessed. RESULTS: DLTs were grade 3 nausea/vomiting at 400 mg BID in a BRCAmut carrier, grade 2 seizure at 400 mg BID in a patient with BRCAwt cancer, and grade 2 seizure at 500 mg BID in a BRCAmut carrier. Common toxicities included nausea (65%), fatigue (45%), and lymphopenia (38%). Grade 3/4 toxicities were rare (highest lymphopenia at 15%). Overall response rate (ORR) was 23% (95% CI 13-35%) in BRCAmut overall, and 37% (95% CI 21-55%) at 400 mg BID and above. In BRCAwt, ORR was 8% (95% CI 1-26%), and clinical benefit rate was 16% (95% CI 4-36%), reflecting prolonged stable disease in some patients. PK was linear with dose and was correlated with response and nausea. CONCLUSIONS: Continuous veliparib is safe and tolerable. The RP2D was 400 mg BID. There is evidence of clinical activity of veliparib in patients with BRCAmut and BRCAwt cancers.

Effects of Polyester Fibers and Car Tire Particles on Freshwater Invertebrates.

Microplastic ingestion has been shown for various organisms, but knowledge of the potential adverse effects on freshwater invertebrates remains limited. We assessed the ingestion capacity and the associated effects of polyester fibers (26-5761 µm) and car tire particles (25-75 µm) on freshwater invertebrates under acute and chronic exposure conditions. A range of microplastic concentrations was tested on Daphnia magna, Hyalella azteca, Asellus aquaticus, and Lumbriculus variegatus using water only (up to 0.15 g/L) or spiked sediment (up to 2 g/kg dry wt), depending on the habitat of the species. Daphnia magna did not ingest any fibers, but low levels of fibers were ingested by all tested benthic invertebrate species. Car tire particle ingestion rose with increasing exposure concentration for all tested invertebrates and was highest in D. magna and L. variegatus. In most cases, no statistically significant effects on mobility, survival, or reproductive output were observed after acute and chronic exposure at the tested concentrations. However, fibers affected the reproduction and survival of D. magna (no-observed-effect concentration [NOEC]: 0.15 mg/L) due to entanglement and limited mobility under chronic conditions. Car tire particles affected the reproduction (NOEC: 1.5 mg/L) and survival (NOEC: 0.15 mg/L) of D. magna after chronic exposure at concentrations in the same order of magnitude as modeled river water concentrations, suggesting that refined exposure and effect studies should be performed with these microplastics. Our results confirm that microplastic ingestion by freshwater invertebrates depends on particle shape and size and that ingestion quantity depends on the exposure pathway and the feeding strategy of the test organism. Environ Toxicol Chem 2022;41:1555-1567. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Anthropogenically impacted lake catchments in Denmark reveal low microplastic pollution.

Microplastics have been detected in lake environments globally, including in remote regions. Agricultural and populated areas are known to congregate several inputs and release pathways for microplastic. This study investigated microplastic (50-5000 µm) contamination in five Danish freshwater lakes with catchments dominated by arable land use. The concentrations in sediments (n = 3/site) and the zebra mussel, Dreissena polymorpha (n = 30/site), were calculated and compared with catchment characteristics and environmental parameters. Microplastic concentrations in sediment were relatively low (average 0.028 ± 0.017 items/g dry weight sediment) whilst only a single microplastic was found in the mussels (average 0.067 ± 0.249 items/10 individual). Hence, no relationship between the number of observed microplastics in sediment and mussels could be identified, nor could a relationship between concentration in sediment and environmental parameters. As all lakes studied received their water from moderate to heavily anthropogenically impacted catchments, it was expected that they would be sinks for microplastic with high bioavailability. Based on the results of the present study, D. polymorpha were found to not be contaminated by microplastics in the five study lakes. Thus, our results suggest that these mussels do not interact with microplastics at low concentrations. We speculate that the results on sediment and biota could be explained by several factors related to regional differences in plastic use, species characteristics, sampling size, and the fact that finding no microplastic is not always reported in the scientific literature. Thus, the paper provides insight into the dynamics between the catchment, lake, and biota in systems with low microplastic concentration.

Interlinkage Between Persistent Organic Pollutants and Plastic in the Waste Management System of India: An Overview.

Improper handling of plastic waste and related chemical pollution has garnered much attention in recent years owing to the associated detrimental impacts on human health and the environment. This article reports an overview of the main interlinkages between persistent organic pollutants (POPs) and plastic in the waste management system of India. Both plastics and POPs share certain common traits such as persistence, resistance to biological degradation, and the ability to get transported over long distances. Throughout the processes of production, consumption, and disposal, plastics interact with and accumulate POPs through several mechanisms and end up co-existing in the environment. Plastic waste can undergo long-range transport through rivers and the oceans, break down into microplastics and get transported through the air, or remain locked in waste dump yards and landfills. Over time, environmental processes lead to the leaching and release of accumulated POPs from these plastic wastes. Plastic recycling in the Indian informal sector including smelting, scrubbing, and shredding of plastic waste, is also a potential major POPs source that demands further investigation. The presence of POPs in plastic waste and their fate in the plastic recycling process have not yet been elucidated. By enhancing our understanding of these processes, this paper may aid policy decisions to combat the release of POPs from different waste types and processes in India.

Fate of microplastics in agricultural soils amended with sewage sludge: Is surface water runoff a relevant environmental pathway?

Sewage sludge used as agricultural fertilizer has been identified as an important source of microplastics (MPs) to the environment. However, the fate of MPs added to agricultural soils is largely unknown. This study investigated the fate of MPs in agricultural soils amended with sewage sludge and the role of surface water runoff as a mechanism driving their transfer to aquatic ecosystems. This was assessed using three experimental plots located in a semi-arid area of Central Spain, which were planted with barley. The experimental plots received the following treatments: (1) control or no sludge application; (2) historical sludge application, five years prior to the experiment; and (3) sludge application at the beginning of the experiment. MPs were analyzed in surface water runoff and in different soil layers to investigate transport and infiltration for one year. The sewage sludge used in our experiment contained 5972-7771 MPs/kg dw. Based on this, we estimated that about 16,000 MPs were added to the agricultural plot amended with sludge. As expected, the sludge application significantly increased the MP concentration in soils. The control plot contained low MP concentrations (31-120 MPs kg-1 dw), potentially originating from atmospheric deposition. The plot treated five years prior to the experiment contained 226-412 and 177-235 MPs kg-1 dw at the start and end of the experiment, respectively; while the recently treated plot contained 182-231 and 138-288 MPs kg-1 dw. Our study shows that MP concentrations remain relatively constant in agricultural soils and that the MP infiltration capacity is very low. Surface water runoff had a negligible influence on the export of MPs from agricultural soils, mobilizing only 0.2-0.4% of the MPs added with sludge. We conclude that, in semi-arid regions, agricultural soils can be considered as long-term accumulators of MPs.

Controlling Factors of Microplastic Riverine Flux and Implications for Reliable Monitoring Strategy.

A significant proportion of marine plastic debris and microplastics is assumed to be derived from river systems. In order to effectively manage plastic contamination of the marine environment, an accurate quantification of riverine flux of land-based plastics and microplastics is imperative. Rivers not only represent pathways to the ocean, but are also complex ecosystems that support many life processes and ecosystem services. Yet riverine microplastics research is still in its infancy, and many uncertainties still remain. Major barriers exist in two aspects. First, nonharmonized sampling methodologies make it problematic for compiling data across studies to better estimate riverine fluxes of microplastics globally; Second, the significant spatiotemporal variation of microplastics in rivers which was affected by the river characteristics, MPs properties, etc. also have important influence on the estimation of riverine MPs fluxes. In this study, we made a comprehensive review from the above two aspects based on published peer-reviewed studies and provide recommendations and suggestions for a reliable monitoring strategy of riverine MPs, which is beneficial to the further establish sampling methods for rivers in different geographical locations. Besides, methods for achieving a high level of comparability across studies in different geographical contexts are highlighted. Riverine microplastic flux monitoring is another important part of this manuscript. The influential factors and calculation methods of microplastic flux in rivers are also discussed in this paper.

CHFR and Paclitaxel Sensitivity of Ovarian Cancer.

The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease. In the present study, tissue microarrays containing ovarian carcinoma samples from 417 women who underwent initial surgical debulking were stained with anti-CHFR antibody and scored in a blinded fashion. CHFR levels, expressed as a modified H-score, were examined for association with histology, grade, time to progression (TTP) and overall survival (OS). In addition, patient-derived xenografts from 69 ovarian carcinoma patients were examined for CHFR expression and sensitivity to paclitaxel monotherapy. In clinical ovarian cancer specimens, CHFR expression was positively associated with serous histology (p = 0.0048), higher grade (p = 0.000014) and higher stage (p = 0.016). After correction for stage and debulking, there was no significant association between CHFR staining and overall survival (p = 0.62) or time to progression (p = 0.91) in patients with high grade serous cancers treated with platinum/taxane chemotherapy (N = 249). Likewise, no association between CHFR expression and paclitaxel sensitivity was observed in ovarian cancer PDXs treated with paclitaxel monotherapy. Accordingly, differences in CHFR expression are unlikely to play a major role in paclitaxel sensitivity of high grade serous ovarian cancer.

Moving forward in microplastic research: A Norwegian perspective.

Given the increasing attention on the occurrence of microplastics in the environment, and the potential environmental threats they pose, there is a need for researchers to move quickly from basic understanding to applied science that supports decision makers in finding feasible mitigation measures and solutions. At the same time, they must provide sufficient, accurate and clear information to the media, public and other relevant groups (e.g., NGOs). Key requirements include systematic and coordinated research efforts to enable evidence-based decision making and to develop efficient policy measures on all scales (national, regional and global). To achieve this, collaboration between key actors is essential and should include researchers from multiple disciplines, policymakers, authorities, civil and industry organizations, and the public. This further requires clear and informative communication processes, and open and continuous dialogues between all actors. Cross-discipline dialogues between researchers should focus on scientific quality and harmonization, defining and accurately communicating the state of knowledge, and prioritization of topics that are critical for both research and policy, with the common goal to establish and update action plans for holistic benefit. In Norway, cross-sectoral collaboration has been fundamental in supporting the national strategy to address plastic pollution. Researchers, stakeholders and the environmental authorities have come together to exchange knowledge, identify knowledge gaps, and set targeted and feasible measures to tackle one of the most challenging aspects of plastic pollution: microplastic. In this article, we present a Norwegian perspective on the state of knowledge on microplastic research efforts. Norway's involvement in international efforts to combat plastic pollution aims at serving as an example of how key actors can collaborate synergistically to share knowledge, address shortcomings, and outline ways forward to address environmental challenges.

Characterization of a RAD51C-silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance.

Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment in vivo. PH039 acquired PARPi resistance by the third treatment cycle and grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profiling throughout the course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated an association between loss of RAD51C methylation prior to on-study biopsy and limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide a model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

Spatio-temporal distribution of microplastics in a Mediterranean river catchment: The importance of wastewater as an environmental pathway.

Microplastics (MPs) are considered to be ubiquitous contaminants in freshwater ecosystems, yet their sources and pathways at the river catchment scale need to be better determined. This study assessed MP (55-5000 µm) pollution in a Mediterranean river catchment (central Spain) and aimed to identify the importance of wastewater as an environmental pathway. We sampled treated and untreated wastewaters, and raw and digested sludge from five WWTPs during two seasons. River water and sediments were sampled at three locations with different anthropogenic influences during three seasons. On average, 93% (47-99%) of MPs were retained by WWTPs. Concentrations in river water and sediment ranged between 1 and 227 MPs/m3 and 0-2630 MPs/kg dw, respectively. Concentrations strongly depended upon land-use, with pollution levels increasing significantly downstream of urban and industrial areas. Seasonality influenced the observed MP concentrations strongly. During high flow periods, higher water but lower sediment concentrations were observed compared to low flow periods. We estimate that 1 × 1010 MPs are discharged into the catchment via treated and untreated wastewater annually, which constitutes up to 50% of the total MP catchment discharge. Thus, we conclude that the wastewater system represents a major environmental pathway for MPs into Mediterranean rivers with low dilution capacity.

Acquired RAD51C Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma.

In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (meRAD51C) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the RAD51C promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with RAD51C gene silencing and homologous recombination deficiency (HRD). PDX models lost meRAD51C following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of RAD51C was sufficient to drive PARPi resistance. Genomic copy number profiling of one of the PDX models using SNP arrays revealed that this resistance was acquired independently in two genetically distinct lineages.In a cohort of 12 patients with RAD51C-methylated HGSC, various patterns of meRAD51C were associated with genomic "scarring," indicative of HRD history, but exhibited no clear correlations with clinical outcome. Differences in methylation stability under treatment pressure were also observed between patients, where one HGSC was found to maintain meRAD51C after six lines of therapy (four platinum-based), whereas another HGSC sample was found to have heterozygous meRAD51C and elevated RAD51C gene expression (relative to homozygous meRAD51C controls) after only neoadjuvant chemotherapy.As meRAD51C loss in a single gene copy was sufficient to cause PARPi resistance in PDX, methylation zygosity should be carefully assessed in previously treated patients when considering PARPi therapy. SIGNIFICANCE: Homozygous RAD51C methylation is a positive predictive biomarker for sensitivity to PARP inhibitors, whereas a single unmethylated gene copy is sufficient to confer resistance.

Exploring the impacts of microplastics and associated chemicals in the terrestrial environment - Exposure of soil invertebrates to tire particles.

Abrasion of tire wear is one of the largest sources of microplastics to the environment. Although most tire particles settle into soils, studies on their ecotoxicological impacts on the terrestrial environment are scarce. Here, the effects of tire particles (<180 µm) on three ecologically relevant soil invertebrate species, the enchytraeid worm Enchytraeus crypticus, the springtail Folsomia candida and the woodlouse Porcellio scaber, were studied. These species were exposed to tire particles spiked in soil or in food at concentrations of 0.02%, 0.06%, 0.17%, 0.5% and 1.5% (w/w). Tire particles contained a variety of potentially harmful substances. Zinc (21 900 mg kg-1) was the dominant trace element, whilst the highest concentrations of the measured organic compounds were detected for benzothiazole (89.2 mg kg-1), pyrene (4.85 mg kg-1), chlorpyrifos (0.351 mg kg-1), HCB (0.134 mg kg-1), methoxychlor (0.116 mg kg-1) and BDE 28 (0.100 mg kg-1). At the highest test concentration in soil (1.5%), the tire particles decreased F. candida reproduction by 38% and survival by 24%, and acetylcholinesterase (AChE) activity of P. scaber by 65%, whilst the slight decrease in the reproduction of E. crypticus was not dose-dependent. In food, the highest test concentration of tire particles reduced F. candida survival by 38%. These results suggest that micro-sized tire particles can affect soil invertebrates at concentrations found at roadsides, whilst short-term impacts at concentrations found further from the roadsides are unlikely.