External Exposure to BTEX, Internal Biomarker Response, and Health Risk Assessment of Nonoccupational Populations near a Coking Plant in Southwest China

Benzene, toluene, ethylbenzene and xylene isomers (BTEX) have raised increasing concern due to their adverse effects on human health. In this study, a coking factory and four communities nearby were selected as the research area. Atmospheric BTEX samples were collected and determined by a preconcentrator GC–MS method. Four biomarkers in the morning urine samples of 174 participants from the communities were measured by LC–MS. The health risks of BTEX exposure via inhalation were estimated. This study aimed to investigate the influence of external BTEX exposure on the internal biomarker levels and quantitatively evaluate the health risk of populations near the coking industry. The results showed that the average total BTEX concentration in residential area was 7.17 ± 7.24 μg m−3. Trans,trans-muconic acid (T,T-MA) was the urinary biomarker with the greatest average level (127 ± 285 μg g−1 crt). Similar spatial trends can be observed between atmospheric benzene concentration and internal biomarker levels. The mean values of the LCR for male and female residents were 2.15 × 10−5 and 2.05 × 10−5, respectively. The results of the risk assessment indicated that special attention was required for the non-occupational residents around the area.

Influence of Particle Size on Ecotoxicity of Low-Density Polyethylene Microplastics, with and without Adsorbed Benzo-a-Pyrene, in Clam Scrobicularia plana

This study investigated the ecotoxicological effects of differently sized (4–6 µm and 20–25 µm) low-density polyethylene (LDPE) microplastics (MPs), with and without adsorbed benzo-a-pyrene (BaP), in clam Scrobicularia plana. Biomarkers of oxidative stress (superoxide dismutase—SOD; catalase—CAT), biotransformation (glutathione-S-transferases—GST), oxidative damage (lipid peroxidation—LPO) and neurotoxicity (acetylcholinesterase—AChE) were analysed in gills and digestive glands at different time intervals for a total of 14 days of exposure. In order to have a better impact perspective of these contaminants, an integrated biomarker response index (IBR) and Health Index were applied. Biomarker alterations are apparently more related to smaller sized (4–6 µm) MPs in gills and to virgin LDPE MPs in the digestive gland according to IBR results, while the digestive gland was more affected by these MPs according to the health index.

Toxicity Evaluation of Chlorpyrifos Metabolite 3,5,6-trichloro-2-pyridinol to Eisenia Fetida in Different Soils

The present study utilized a biomarker response method to evaluate the effect of 3,5,6-trichloro-2-pyridinol (TCP) in artificial and natural soils on Eisenia fetida after 7, 14, 28, 42 and 56 days exposure. Results indicated that TCP induced excessive reactive oxygen species, caused oxidative stress and DNA damage to Eisenia fetida. Biomarker responses were standardized to calculate the Integrated Biomarker Response (IBR) index. The IBR index of three enzymes activities showed that TCP induced the enzymes activities of earthworm in red clay was stronger than the other three soils. Specifically, chlorpyrifos exposure group showed a lower toxicity than TCP exposure group after 28 days exposure but a higher toxicity than TCP exposure group after 56 days exposure. Despite the deficiencies of this study, the above information is of great significance for assessing the risk of chlorpyrifos and its metabolite TCP pollution in soil ecosystems.

Unraveling heterogeneity within ACPA-negative rheumatoid arthritis: the subgroup of patients with a strong clinical and serological response to initiation of DMARD treatment favor disease resolution

Background Rheumatoid arthritis (RA) is a heterogeneous disease, as evidenced by the differences in long-term outcomes. This applies especially to anti-citrullinated protein antibodies (ACPA)-negative RA, where a proportion achieves sustained DMARD-free remission (SDFR; sustained absence of synovitis after DMARD cessation). Differentiation of RA patients who will achieve SDFR can guide personalized treatment/tapering strategies. Although this subgroup remains scarcely discerned, previous research demonstrated that these RA patients are characterized by an early clinical response (DAS remission after 4 months) after DMARD start. We studied whether, in addition to this clinical response, a specific biomarker response can further distinguish the subgroup of RA patients most likely to achieve SDFR. Methods In 266 RA patients, levels of 12 biomarkers (SAA/CRP/MMP-1/MMP-3/resistin/leptin/IL-6/TNF-R1/YKL-40/EGF/VEGF/VCAM-1), in the first 2 years after diagnosis, were studied in relation to SDFR, stratified for ACPA status. Subsequently, biomarkers associated with SDFR development were combined with early DAS remission to study its additional value in defining subgroups. Since most biomarker levels are not routinely measured in clinical practice, we explored how this subgroup can be clinically recognized. Results ACPA-negative RA patients achieving SDFR were characterized by high baseline levels and stronger decline in MMP-1/MMP-3/SAA/CRP after DMARD-start, respectively 1.30×/1.44×/2.12×/2.24× stronger. This effect was absent in ACPA-positive RA. In ACPA-negative RA, a strong biomarker decline is associated with early DAS remission. The combination of both declines (clinical, biomarker) was present in a subgroup of ACPA-negative RA patients achieving SDFR. This subgroup can be clinically recognized by the combination of high baseline CRP levels (≥ 3 times ULN), and early DAS remission (DAS4 months < 1.6). This latter was replicated in independent ACPA-negative RA patients. Conclusions ACPA-negative RA patients with early DAS remission and a strong biomarker response (or baseline CRP levels ≥ 3× ULN) are most likely to achieve SDFR later on. This could guide personalized decisions on DMARD tapering/cessation in ACPA-negative RA.

Interactive Effects of Microplastics and Tetracycline on Bioaccumulation and Biochemical Status in Jian Carp (Cyprinus carpio var. Jian)

Microplastics (MPs) and tetracycline (TC) are severe emerging pollutants in the aquatic environment. But there is a lack of research to investigate the interactive effects of MPs and TC in vivo. This study used Jian carp (Cyprinus carpio var. Jian) as the model organism to explore the bioaccumulation and biochemical status when exposed to MPs and TC, alone and combined. The accumulation of TC and MPs in intestine, variation of enzyme activities in intestine, and expression of immune-related genes in muscle were evaluated. Our results found the bioaccumulation of MPs was not affected by TC, but the presence of MPs would change the content of TC within 48 h. The superoxide dismutase (SOD) and lactate dehydrogenase (LDH) activity showed that TC-MP combined exposure could reduce oxidative damage to Jian carps compared to MP exposure alone. The integrated biomarker response (IBR) index showed that SOD activity was sensitive to TC-MP exposure. In addition, co-exposure to MPs and TC could alleviate the overexpression of interleukin 1 beta (IL-1β), interleukin 10 (IL-10), transforming growth factor beta (TGF-β), and toll like receptor 2 (TLR-2) induced by TC in muscles. TLR-2 gene has the potential to be the candidate gene reflecting the injury of TC exposure. In conclusion, it is inferred that co-exposure may reduce the toxicity of individual exposure in the living organisms. This study provides essential information for the risk assessment of pollution with MPs and TC, individually and combined, as well as a foundation to investigate the interactive effects of MPs and antibiotics on aquatic ecosystems.

Biosimulation Using the Cellworks Computational Omics Biology Model (CBM)-Based Assessment of Cytarabine (ARA-C) and Anthracycline Response and Novel Biomarker Response Criteria for the Addition of Etoposide (VP16) in Acute Myeloid Leukemia (AML)

Background: Genomic heterogeneity in leukemic blasts characterizes Acute Myeloid Leukemia (AML) patients and is associated to variable drug response. However, use of genomics to guide therapy has generally been restricted to a single-gene approach, which rarely has sufficient predictive power to be clinically useful. Comprehensive DNA sequencing and biosimulation of the Computational Omics Biology Model (CBM) provide the opportunity and means of predicting treatment outcome in advance of treatment. Methods: The Cellworks CBM is a computational multi-omic biology software model created using artificial intelligence heuristics and literature sourced from PubMed, to generate a patient-specific protein network map. The CBM permits mapping of biological pathways associated with tumorigenesis and drug resistance using mathematical principles to yield a virtual tumor model that can be used in biosimulation. Aberration and copy number variations from each case served as input to the CBM to generate individual patient-specific protein network maps. We used the Cellworks Biosimulation Platform to identify novel genomic biomarkers associated with response among AML patients treated with Cytarabine (ARA-C) + idarubicin or daunorubicin (anthracycline) with or without Etoposide (VP16). 539 AML patients were selected for this study based largely on genomic data published in TCGA and PubMed: ARA-C + daunorubicin [N=111, 92 responders (R) & 19 non-responders (NR)]ARA-C + idarubicin [N=109, 94 R & 15 NR]ARA-C + daunorubicin + VP16 [N=6, 4 R & 2 NR]ARA-C + idarubicin + VP16 [N=313, 261 R & 52 NR] Drug impact on individual disease networks was simulated to determine efficacy value by measuring the effect of chemotherapy on the cell growth score, a composite of cell proliferation, viability, apoptosis, metastasis, DNA damage and other cancer hallmarks. The mechanism of action of each drug was used to map its biological consequences to each patient's cancer genome to predict treatment response. Results: Biosimulation of ARA-C + anthracycline with and without VP16 identified biomarkers responsible for therapy response. Additionally, the Cellworks Biosimulation Platform identified novel drug combinations for NR to these standard combinations. There were 186/220 patients treated with ARA-C + anthracycline that had clinical responses. Major biomarkers predictive of response included: IDH2 mut, TOPBP1 del, ATR del, NPM1 mut, IDH1 mut, XRCC2 del, CDK5 del, AKR1B1 del and other genes (Table 1). The frequency of these genes was significantly higher (exact binomial: p-value &lt; 0.0001) in R (N=186) vs. NR (N=34). Notably, 7/34 NR to the two-drug combination had favorable biomarkers for VP16 response, which included RAD52 del, FANCD2 del, STAG2 mut, MPO amp, and NHEJ del. On the other hand, among 265 R treated with triplet therapy (ARA-C + anthracycline + VP16), 30 patients were unlikely to have derived incremental benefit from the addition of VP16. In these patients, the biosimulation predicted that they would have benefited equally from doublet therapy (ARA-C + anthracycline without VP16). In this subgroup of R, ARID1A del, FLT3-ITD mut, GSTA1 amp, KEAP1 del, or RNF1 del generated resistance to VP16 in the biosimulation. Among 54 NR to triplet therapy, 40/54 had genomic alterations predicting a benefit from JQ1, BRD2/4 inhibitors, including KMT2C del, FLT3 GOF, NPM1 del, DNMT3A LOF, and TP53 del, while 12 patients had 5q del highlighting a potential benefit from lenalidomide. Altogether, 89/539 (16.5%) could have been managed with a potentially superior treatment approach based on the biosimulation by either adding or omitting VP16 or being treated with an alternative therapy. Conclusions: Cellworks Biosimulation Platform applied to the patient-specific CBM identifies novel biomarkers of response and can be employed to determine the optimal therapy for AML patients. This study highlights patients for whom triplet therapy promises potentially superior benefit, others who would benefit equally from doublet therapy without VP16, and others unlikely to respond to standard or triplet therapy for whom an alternative personalized approach might offer better outcomes. In AML, biosimulation offers the possibility to tailor the chemotherapy regimen to each patient to improve disease control and minimize toxicity. Figure 1 Figure 1. Disclosures Castro: Caris Life Sciences Inc.: Consultancy; Guardant Health Inc.: Speakers Bureau; Bugworks: Consultancy; Cellworks Group Inc.: Current Employment; Omicure Inc: Consultancy; Exact sciences Inc.: Consultancy. Howard: Servier: Consultancy; Cellworks Group Inc.: Consultancy; Sanofi: Consultancy, Other: Speaker fees. Kumar: Cellworks Group Inc.: Current Employment. Patil: Cellworks Group Inc.: Current Employment. Khandelwal: Cellworks Group Inc.: Current Employment. Watson: BioAi Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlloVir: Consultancy, Membership on an entity's Board of Directors or advisory committees; CellMax Life: Consultancy, Other: Advisor; Cellworks Group Inc.: Consultancy, Other: Advisor. Kapoor: Cellworks Group Inc.: Current Employment. Kumari: Cellworks Group Inc.: Current Employment. Prasad: Cellworks Group Inc.: Current Employment. Gupta: Cellworks Group Inc.: Current Employment. Lunkad: Cellworks Group Inc.: Current Employment. Mitra: Cellworks Group Inc.: Current Employment. G: Cellworks Group Inc.: Current Employment. Kumar: Cellworks Group Inc.: Current Employment. Choudhury: Cellworks Group Inc.: Current Employment. Kulkarni: Cellworks Group Inc.: Current Employment. Choudhary: Cellworks Group Inc.: Current Employment. Prakash: Cellworks Group Inc.: Current Employment. Husain: Cellworks Group Inc.: Current Employment. Ghosh: Cellworks Group Inc.: Current Employment. Narvekar: Cellworks Group Inc.: Current Employment. Amara: Cellworks Group Inc.: Current Employment. Yuvavani: Cellworks Group Inc.: Current Employment. Patel: Cellworks Group Inc.: Current Employment. Macpherson: Cellworks Group Inc.: Current Employment. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings.

Lethal and Sublethal Responses of Hydropsyche pellucidula (Insecta, Trichoptera) to Commercial Polypropylene Microplastics after Different Preconditioning Treatments

Microplastics (MPs) pose biological and chemical hazards in aquatic and terrestrial food webs across the globe. Research on microplastic contamination has long focused on marine ecosystems, whereas the toxicological impact on freshwater organisms is still little explored. In this study, the lethal and sublethal response of the freshwater macroinvertebrate Hydropsyche pellucidula exposed to polypropylene MPs after different pre-conditioning treatments was assessed. Field samples were collected in a riverine system (Vipacco river; northeast Italy) to assess the characteristics of the MPs in the aquatic environment Both water and sediment were contaminated by MPs (3.73 ± 2.11 items m−3 per min and 3.33 ± 4.16 items dm−3, respectively). The chemical MPs composition included polystyrene, polyethylene terephthalate, polyurethane, polyamide, polypropylene, and polyethylene. Polypropylene (PP), although not the most abundant polymer recorded in the study area, was preferred over the other types according to its abundance in freshwater and H. pellucidula feeding behavior. A housing test was performed to recreate the natural conditions of larvae sampled for a reliable response to the ecotoxicological tests. The microplastics underwent either preconditioning with Vipacco River water (PP-river) and surfactant Triton X-100 (PP-sf) or no pre-treatment (PP). Submersion of microplastics in 10 µg L−1 of surfactant solution for 24 h was sufficient to induce consistent spectral changes and modify the chemical profile of the plastic surface. Mortality rate differed according to treatment: PP and PP-river > positive control > PP-sf > negative control. Integrated biomarker response (IBRv2) and analysis of oxidative stress biomarker levels showed a greater response of superoxide dismutase and lipid peroxidation (malondialdehyde) in larvae treated with PP conditioned in surfactant. Our findings enhance knowledge on the toxicity of PP and conditioning phases on H. pellucidula larvae.