Chlorpromazine inhibits EAG1 channels by altering the coupling between the PAS, CNBH and pore domains.

EAG1 depolarization-activated potassium selective channels are important targets for treatment of cancer and neurological disorders. EAG1 channels are formed by a tetrameric subunit assembly with each subunit containing an N-terminal Per-Arnt-Sim (PAS) domain and C-terminal cyclic nucleotide-binding homology (CNBH) domain. The PAS and CNBH domains from adjacent subunits interact and form an intracellular tetrameric ring that regulates the EAG1 channel gating, including the movement of the voltage sensor domain (VSD) from closed to open states. Small molecule ligands can inhibit EAG1 channels by binding to their PAS domains. However, the allosteric pathways of this inhibition are not known. Here we show that chlorpromazine, a PAS domain small molecule binder, alters interactions between the PAS and CNBH domains and decreases the coupling between the intracellular tetrameric ring and the pore of the channel, while having little effect on the coupling between the PAS and VSD domains. In addition, chlorpromazine binding to the PAS domain did not alter Cole-Moore shift characteristic of EAG1 channels, further indicating that chlorpromazine has no effect on VSD movement from the deep closed to opened states. Our study provides a framework for understanding global pathways of EAG1 channel regulation by small molecule PAS domain binders.

Integrated assessment of the pollution and risk of heavy metals in soils near chemical industry parks along the middle Yangtze River.

Industrialization in riparian areas of critical rivers has caused significant environmental and health impacts. Taking eight industrial parks along the middle Yangtze River as examples, this study proposes a multiple-criteria approach to investigate soil heavy metal pollution and associated ecological and health risks posed by industrial activities. Aiming at seven heavy metals, the results show that nickel (Ni), cadmium (Cd), and copper (Cu) exhibited the most significant accumulation above background levels. The comprehensive findings from Pearson correlation analysis, cluster analysis, principal component analysis, and industrial investigation uncover the primary sources of Cd, arsenic (As), mercury (Hg), and lead (Pb) to be chemical processing, while Ni and chromium (Cr) are predominantly derived from mechanical and electrical equipment manufacturing. In contrast, Cu exhibits a broad range of origins across various industrial processes. Soil heavy metals can cause serious ecological and carcinogenic health risks, of which Cd and Hg contribute to >70 % of the total ecological risk, and As contributes over 80 % of the total health risk. This study highlights the importance of employing multiple mathematical and statistical models in determining and evaluating environmental hazards, and may aid in planning the environmental remediation engineering and optimizing the industry standards.

Normalizing Flow-Based Distribution Estimation of Pharmacokinetic Parameters in Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

OBJECTIVE: The pharmacokinetic (PK) parameters estimated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provide valuable information for clinical research and diagnosis. However, these estimated PK parameters suffer from many sources of variability. Thus, the estimation of the posterior distributions of these PK parameters could provide a way to simultaneously quantify the values and uncertainties of the PK parameters. Our objective is to develop an efficient and flexible method to more closely approximate and estimate the underlying posterior distributions of the PK parameters. METHODS: The normalizing flow model-based parameters distribution estimation neural network (FPDEN) is proposed to adaptively learn and estimate the posterior distributions of the PK parameters. The maximum likelihood estimation (MLE) loss is directly constructed based on the parameter distributions learned by the normalizing flow model, rather than pre-defined distributions. RESULTS: Experimental analysis shows that the proposed method can improve parameter estimation accuracy. Moreover, the uncertainty derived from the parameter distribution constitutes an effective indicator to exclude unreliable parametric results. A successful demonstration is the improved classification performance of the glioma World Health Organization (WHO) grading task, specifically in terms of distinguishing between low and high grades, as well as between Grade III and Grade IV. CONCLUSION: The FPDEN method offers improved accuracy for estimation of PK parameters and boosts the performance of the glioma grading task. SIGNIFICANCE: By enhancing the precision and reliability of DCE-MRI, the proposed method promotes its further applications in clinical practice.

Molecular mechanism of EAG1 channel inhibition by imipramine binding to the PAS domain.

Ether-a-go-go (EAG) channels are key regulators of neuronal excitability and tumorigenesis. EAG channels contain an N-terminal Per-Arnt-Sim (PAS) domain that can regulate currents from EAG channels by binding small molecules. The molecular mechanism of this regulation is not clear. Using surface plasmon resonance and electrophysiology we show that a small molecule ligand imipramine can bind to the PAS domain of EAG1 channels and inhibit EAG1 currents via this binding. We further used a combination of molecular dynamics (MD) simulations, electrophysiology, and mutagenesis to investigate the molecular mechanism of EAG1 current inhibition by imipramine binding to the PAS domain. We found that Tyr71, located at the entrance to the PAS domain cavity, serves as a "gatekeeper" limiting access of imipramine to the cavity. MD simulations indicate that the hydrophobic electrostatic profile of the cavity facilitates imipramine binding and in silico mutations of hydrophobic cavity-lining residues to negatively charged glutamates decreased imipramine binding. Probing the PAS domain cavity-lining residues with site-directed mutagenesis, guided by MD simulations, identified D39 and R84 as residues essential for the EAG1 channel inhibition by imipramine binding to the PAS domain. Taken together, our study identified specific residues in the PAS domain that could increase or decrease EAG1 current inhibition by imipramine binding to the PAS domain. These findings should further the understanding of molecular mechanisms of EAG1 channel regulation by ligands and facilitate the development of therapeutic agents targeting these channels.

Mechanistic illustration on lipid-metabolism disorders induced by triclosan exposure from the viewpoint of m6A-RNA epigenetic modification.

As a typically anthropogenic contaminant, the toxicity effects of triclosan (TCS) were investigated in-depth from the viewpoint of m6A-pre-miRNAs modification. Based on miRNAs high-throughput sequencing, we unravelled the underlying molecular mechanisms regarding TCS-induced lipid-metabolism functional disorders. TCS exposure caused severe lipid accumulation in 120 hpf zebrafish liver and reduced their locomotor activity. Both bioinformatics analysis and experimental validation verified that TCS targeted miR-27b up-regulation to further trigger lipid-metabolism disorders and developmental malformations, including shortened body length, yolk cysts, curved spine and delayed yolk absorption. TCS exposure and miR-27b upregulation both caused the enhanced levels of triglyceride and total cholesterol. Knockdown and overexpression of miR-27b regulated the expression changes of several functional genes related to downstream lipid metabolism of miR-27b, and most downstream target genes of miR-27b were suppressed and enriched in the AMPK signaling pathway. The experiments of pathway inhibitors and agonists further evidenced that TCS caused lipid-metabolism disorders by suppressing the AMPK signaling pathway. In upstream of miR-27b, TCS decreased total m6A-RNA level by targeting upregulation of demethylase and downregulation of methylase reader ythdf1. Molecular docking and ythdf1 siRNA interference further confirmed that TCS targeted the expression change of ythdf1. Under ythdf1 knockdown in upstream of miR-27b, both abnormal lipid metabolism and miR-27b upregulation highlighted that TCS-induced lipid-metabolism disorders were attributable to the decreasing m6A-RNA methylation levels in vivo. These perspectives provide an innovative idea for prevention and treatment of the lipid metabolism-related diseases and these findings open a novel avene for TCS's risk assessment and early intervention of the contaminant.

[Acute hypoxia blunts cold sensitivity through the inhibition of the lateral parabrachial nucleus in rats].

To explore the changes of cold sensitivity after exposure to acute hypoxia and its mechanisms, Sprague-Dawley rats were divided into normoxia control group (21% O2, 25 °C), 10% O2 hypoxia group (10% O2, 25 °C), 7% O2 hypoxia group (7% O2, 25 °C), normoxia cold group (21% O2, 10 °C) and hypoxia cold group (7% O2, 10 °C). Cold foot withdrawal latency and preference temperature of each group were measured, skin temperatures were estimated using an infrared thermographic imaging camera, body core temperature was recorded by wireless telemetry system, immunohistochemical staining was used to detect the expression of c-Fos in the lateral parabrachial nucleus (LPB). The results showed that acute hypoxia significantly prolonged the latency of cold foot withdrawal and significantly enhanced the intensity of cold stimulation for foot withdrawal, and the rats under hypoxia preferred cold temperature. Cold exposure (10 °C) for 1 h significantly enhanced the expression of c-Fos in LPB of rats in normoxia, while hypoxia inhibited cold-induced c-Fos expression. Acute hypoxia significantly increased the skin temperature of feet and tails, decreased the skin temperature of interscapular region, and decreased the body core temperature of rats. These results indicate that acute hypoxia can significantly blunt cold sensitivity through the inhibition of LPB, suggesting actively keeping warm measures should be taken at the early stage after ascent to high altitude to prevent the upper respiratory infection and acute mountain sickness.

The Consistence of Dynamic Contrast-Enhanced MRI and Filter-Exchange Imaging in Measuring Water Exchange Across the Blood-Brain Barrier in High-Grade Glioma.

BACKGROUND: Water exchange across blood-brain barrier (BBB) (WEXBBB ) is an emerging biomarker of BBB dysfunction with potential applications in many brain diseases. Several MRI methods have been proposed to measure WEXBBB , but evidence remains scarce whether different methods can produce comparable WEXBBB . PURPOSE: To explore whether dynamic contrast-enhanced (DCE)-MRI and vascular water exchange imaging (VEXI) could produce comparable WEXBBB in high-grade glioma (HGG) patients. STUDY TYPE: Prospective cross-sectional. SUBJECTS: 13 HGG patients (58.4 ± 9.4 years, 9 females, 4 WHO III and 9 WHO IV). FIELD STRENGTH/SEQUENCE: A 3 T, spoiled gradient-recalled-echo DCE-MRI and VEXI containing two pulsed-gradient spin-echo blocks separated by a mixing block. ASSESSMENTS: The enhanced tumor and contralateral normal-appearing white matter (cNAWM) volume-of-interests (VOIs) were drew by two neuroradiologists. And whole-brain NAWM and normal-appearing gray matter (NAGM) without tumor-affected regions were segmented by automated segmentation algorithm in FSL. STATISTICAL TESTS: Student's t-test was used to evaluate parameters difference between cNAWM and tumor, NAGM and NAWM, respectively. The correlation between vascular water efflux rate constant (kbo ) from DCE-MRI and apparent exchange rate across BBB (AXRBBB ) from VEXI was evaluated by Pearson correlation. P < 0.05 was considered statistically significant. RESULTS: Compared with cNAWM, both kbo and AXRBBB were significantly reduced in tumor (kbo = 3.50 ± 1.18 sec-1 vs. 1.03 ± 0.75 sec-1 ; AXRBBB = 3.54 ± 1.11 sec-1 vs. 1.94 ± 1.04 sec-1 ). Both kbo and AXRBBB showed significantly higher values in NAWM than NAGM (kbo = 3.50 ± 0.59 sec-1 vs. 2.10 ± 0.56 sec-1 ; AXRBBB = 3.35 ± 0.77 sec-1 vs. 2.07 ± 0.52 sec-1 ). The VOI-averaged kbo and AXRBBB were also linearly correlated in tumor, NAWM, and NAGM (r = 0.59). DATA CONCLUSION: DCE-MRI and VEXI showed comparable and correlated WEXBBB in HGG patients, suggesting that the consistence and reliability of these two MRI methods in measuring WEXBBB . EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 1.

The Role of Signaling Pathways in Pancreatic Cancer Targeted Therapy.

Signaling pathways play significant roles in the occurrence, development, and treatment of pancreatic cancer (PC). The main treatment options are surgery, chemotherapy, radiotherapy, arterial infusion chemotherapy in interventional therapy, and immunotherapy. Many studies have shown that signaling pathways perform a function in the occurrence and development of PC, for instance, phosphoinositide 3-kinase (PI3K)/AKT, nuclear factor-κB, Ras, interleukin (IL)-17B/IL-17RB, Wnt, and hepatocyte growth factor/c-MET, which play roles in the proliferation, metastasis, invasion, inhibition of apoptosis, promotion of angiogenesis, and drug resistance of PC. Interaction of signaling pathways has an impact on the biological behavior of PC; for example, activation of the neurotensin/NTSR1 pathway, which can activate mitogen-activated protein kinase, nuclear factor-κB, and other pathways related to PC stem cells, play an important role in PC, and an increase in their number is associated with the Wnt/ß-catenin and PI3K pathways. Chemotherapy is the main method for the treatment of PC, but drug resistance limits its use. In addition, abnormal activation of IL-17B/IL-17RB signaling pathway is associated with drug resistance. This article discusses the signaling pathways that play different roles in the occurrence and development of PC, as well as current research on signaling pathways in PC treatment.

Humoral and cellular immunogenicity and efficacy of a coxsackievirus A10 vaccine in mice.

Coxsackievirus A10 (CV-A10) has become one of the major pathogens of hand, foot and mouth disease (HFMD), and studies on the vaccine and animal model of CV-A10 are still far from complete. Our study used a mouse-adapted CV-A10 strain, which was lethal for 14-day-old mice, to develop an infected mouse model. Then this model was employed to establish an actively immunized-challenged mouse model to evaluate the efficacy of a formaldehyde-inactivated CV-A10 vaccine, which was prepared from a Vero cell-adapted strain. CV-A10 vaccine at a dose of 0.5 or 2.0 µg was inoculated intraperitoneally in neonatal Kunming mice on the third and ninth day. Then the mice were challenged on day 14. The survival rate of mice immunized with 0.5 or 2.0 µg vaccine were 90% and 100%, respectively, while all Alum-inoculated mice died. Compared to those in the two vaccinated groups, the Alum-inoculated mice showed severe pathological damage, strong viral protein expression and high viral loads. The antisera from vaccinated mice showed high level of neutralizing antibodies against CV-A10. Meanwhile, three potential T cell epitopes located at the carboxyl-terminal regions of the VP1 and VP3 were identified and exhibited CV-A10 serotype-specific. The humoral and cellular immunogenicity analysis showed that immunization with two doses of the vaccine elicited CV-A10 specific neutralizing antibody and T cell response in BALB/c mice. Collectively, these findings indicated that this actively immunized-challenged mouse model will be invaluable in future studies on CV-A10 pathogenesis and evaluation of vaccine candidates.

Adipocytes Encapsulating Telratolimod Recruit and Polarize Tumor-Associated Macrophages for Cancer Immunotherapy.

Tumor-associated adipocytes (TAAs) recruit monocytes and promote their differentiation into tumor-associated macrophages (TAMs) that support tumor development. Here, TAAs are engineered to promote the polarization of TAMs to the tumor suppressive M1 phenotype. Telratolimod, a toll-like receptor 7/8 agonist, is loaded into the lipid droplets of adipocytes to be released at the tumor site upon tumor cell-triggered lipolysis. Locally administered drug-loaded adipocytes increased tumor suppressive M1 macrophages in both primary and distant tumors and suppressed tumor growth in a melanoma model. Furthermore, drug-loaded adipocytes improved CD8+ T cell-mediated immune responses within the tumor microenvironment and favored dendritic cell maturation in the tumor draining lymph nodes.

Transmembrane water-efflux rate measured by magnetic resonance imaging as a biomarker of the expression of aquaporin-4 in gliomas.

The water-selective channel protein aquaporin-4 (AQP4) contributes to the migration and proliferation of gliomas, and to their resistance to therapy. Here we show, in glioma cell cultures, in subcutaneous and orthotopic gliomas in rats, and in glioma tumours in patients, that transmembrane water-efflux rate is a sensitive biomarker of AQP4 expression and can be measured via conventional dynamic-contrast-enhanced magnetic resonance imaging. Water-efflux rates correlated with stages of glioma proliferation as well as with changes in the heterogeneity of intra-tumoural and inter-tumoural AQP4 in rodent and human gliomas following treatment with temozolomide and with the AQP4 inhibitor TGN020. Regions with low water-efflux rates contained higher fractions of stem-like slow-cycling cells and therapy-resistant cells, suggesting that maps of water-efflux rates could be used to identify gliomas that are resistant to therapies.

Water exchange detected by shutter speed dynamic contrast enhanced-MRI help distinguish solitary brain metastasis from glioblastoma.

PURPOSE: This study aimed to explore the feasibility of transmembrane water exchange parameters detected by brain shutter speed (BSS) dynamic contrast enhanced (DCE)MRI, which is validated to be associated with aquaporin-4 expression, in distinguishing glioblastoma (GBM) from solitary brain metastasis (SBM). METHODS: 40 patients (mean age: 58.6 ± 11.7 years old, male/female: 23/17) with GBM and 48 patients (mean age: 61.7 ± 10.5 years old, male/female: 28/20) with SBM were enrolled in this observational study. BSS DCE-MRI was performed before operation. Intravascular water efflux rate constant (kbo) and intracellular water efflux rate constant (kio) within the peritumoral region and enhancing tumor were calculated from SS-DCE, respectively. The difference of these two parameters between GBM and SBM was explored. Immunohistochemical staining aquaporin-4 of was performed to validate its underlying biological mechanism. RESULTS: The kbo was found to be statistically different within both peritumoral region {SBM vs. GBM (s-1): 1.0[0.4,1.7] vs. 1.5[0.9,2.1], p = 0.009} and enhanced tumor {SBM vs. GBM (s-1): 0.2[0.1,0.5] vs. 0.4[0.1,1.3], p = 0.034}. Immunohistochemical analysis reveals the high perivascular aquaporin-4 expression in GBM may contribute the higher kbo value than that of SBM. CONCLUSIONS: kbo derived from BSS DCE-MRI was an independent pathophysiological parameter for separating GBM from SBM, in which kbo might be associated with the perivascular aquaporin-4 expression.

SAHmap: Synergistic-antagonistic heatmap to evaluate the combined synergistic effect of mixtures of three pesticides on multiple endpoints of Caenorhabditis elegans.

The environmental pollution caused by toxic chemicals such as pesticides has become a global problem. The mixture of dichlorvos (DIC), dimethoate (DIM), aldicarb (ALD) poses potential risks to the environment and human health. To fully explore the interaction of complex mixtures on Caenorhabditis elegans behavioral toxicity endpoint. This study created a synergistic-antagonistic heatmap (SAHmap) based on the combination index to systematically describe the toxicological interaction prospect of the mixture system. It was shown that the three pesticides and their binary as well as ternary mixture rays have significant concentration-response relationship on three behavioral endpoints of nematodes, From the perspective of synergistic-antagonistic heatmaps, all the mixture rays in the DIC-DIM mixture system showed strong synergism on the three behavioral and lethal endpoints. In the ternary mixture system, the five mixture rays showed different interaction between the behavioral endpoint and the lethal endpoint, and showed slight synergism to two behavioral endpoints as a whole. The emergence of synergism should arouse our attention to these hazardous chemicals. In addition, the use of SAHmap and the significant linear correlation among three behavioral endpoints further improved the efficiency of the study on the behavioral toxicity of pesticide mixtures to Caenorhabditis elegans.

Association of sleep duration, sleep apnea, and shift work with risk of colorectal neoplasms: a systematic review and meta-analysis.

Background: Although studies have reported that certain sleep characteristics, such as sleep duration and sleep apnea, are linked to the risk of colorectal cancer (CRC), this link remains contentious because of the limited evidence from individual studies. Furthermore, evidence indicated that shift work involving circadian disruption as a probable human carcinogen. This systematic review and meta-analysis aimed to examine the associations between sleep duration, sleep apnea, and shift work with the risk of colorectal neoplasms, including CRC and colorectal adenoma (CRA). Methods: We conducted a comprehensive literature search in PubMed, Embase, and Web of Science databases. The inclusion criteria were determined using PICOS principles. Observational studies reporting associations of sleep duration, sleep apnea, or shift work with risk of CRC or CRA were included. We assessed the risk of bias on the basis of the Newcastle-Ottawa Scale. Results: A total of 18 observational studies were included. Of these studies, nine studies reported the effect of sleep duration on risk of colorectal neoplasms, five reported the effect of sleep apnea, and six reported the effect of shift work. The relative risk (RR) for colorectal neoplasms was 1.06 [95% confidence interval (CI): 0.94, 1.20] in the short sleep duration group compared with the moderate sleep duration group. Long sleep duration was associated with an increased risk of colorectal neoplasms (RR: 1.33, 95% CI: 1.07, 1.65). The pooled results showed that sleep apnea was associated with an increased risk of colorectal neoplasms (RR: 1.75, 95% CI: 1.56, 1.97). Furthermore, results showed that the association between shift work and the risk of colorectal neoplasms was not significant (RR: 1.06, 95% CI: 0.95, 1.17). No publication bias was observed in all the analyses (all P>0.05). The sensitivity analysis showed that no individual study substantially influenced the pooled RRs for colorectal neoplasms and CRC. Conclusions: Our findings suggest the significant positive association of long sleep duration and sleep apnea with risk of colorectal neoplasms and CRC. Given that sleep characteristics may be a potentially modifiable risk factor for colorectal neoplasms, further understanding of its role in carcinogenesis will provide valuable insight for cancer prevention.

CTHRC1 is a Potential Prognostic Biomarker and Correlated with Macrophage Infiltration in Breast Cancer.

Background: Tumor immune cell infiltration is closely associated with the occurrence and development of tumors. Collagen triple helix repeats containing 1 (CTHRC1), a regulator of collagen expression and cell migration, is involved in the metastasis and invasion of tumors. However, the role of CTHRC1 in breast cancer remains unclear. This study aimed to investigate the prognostic value of CTHRC1, and further explore its association with immune infiltration in breast cancer. Methods: CTHRC1 expression pattern and prognostic value were analyzed using ONCOMINE, PrognoScan, GEPIA, and Kaplan-Meier Plotter databases. We then detected CTHRC1 mRNA levels in breast cancer tissues and paired normal breast tissues by Q-PCR. Subsequently, the University of California Santa Cruz (UCSC) database was used to determine the methylation status of CTHRC1. Furthermore, CTHRC1 mutations were investigated using the Catalogue of Somatic mutations in Cancer (COSMIC) and cBioPortal databases. We also assessed the correlation between CTHRC1 expression and immune cell infiltration using TIMER. In addition, The relationship of CTHRC1 expression with the immune marker sets of various immune cells was evaluated using GEPIA and TIMER. Results: CTHRC1 was highly expressed in a variety of tumors, including breast cancer. Elevated CTHRC1 expression was related to a poor prognosis. Notably, CTHRC1 expression was significantly associated with macrophage infiltration, especially the immune infiltration gene marker set of M2. Copy number variations, DNA mutations and methylation states might be potential mechanisms for regulating CTHRC1 expression. Protein digestion and absorption, human papillomavirus infection, ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling pathways were identified as the potential CTHRC1-driven signaling pathways. Conclusion: These findings suggest that CTHRC1 could be a promising immune-related biomarker for the treatment of breast cancer patients.

Scattered seeding of CAR T cells in solid tumors augments anticancer efficacy.

Chimeric antigen receptor T cell (CAR T) therapy was a milestone in the treatment of relapsed and refractory B cell malignancies. However, beneficial effects of CAR T cells have not been obtained in solid tumors yet. Herein, we implement a porous microneedle patch that accommodates CAR T cells and allows in situ penetration-mediated seeding of CAR T cells when implanted in the tumor bed or in the post-surgical resection cavity. CAR T cells loaded in the pores of the microneedle tips were readily escorted to the tumor in an evenly scattered manner without losing their activity. Such microneedle-mediated local delivery enhanced infiltration and immunostimulation of CAR T cells as compared to direct intratumoral injection. This tailorable patch offers a transformative platform for scattered seeding of living cells for treating a variety of tumors.

Deriving the predicted no effect concentrations of 35 pesticides by the QSAR-SSD method.

The widespread use of pesticides results in their frequent detection in water bodies and other environmental media. Pesticide residues may cause certain risks to the environment and human health, and reliable predicted no effect concentrations (PNEC) must be obtained when assessing environmental risks. Species sensitivity distribution (SSD) is an important method for the derivation of chemical PNECs. Construction of the SSD model requires sufficient toxicity data to various species including at least eight families in three phyla, suitable nonlinear fitting functions and assessment factors (AFs) with certain uncertainty. However, most chemicals could not collect sufficient species toxicity data, while some chemicals had sufficient species toxicity data but could not find suitable fitting functions, thus hindering the construction of effective SSD models. To this end, the established QSAR models were applied to predict toxicity of chemicals to specific species to fill in the toxicity data gaps required for SSD and selecting multiple nonlinear functions to optimize the SSD model. Combined with QSAR and SSD methods, a new method of PNEC derivation was developed and successfully applied to the derivation of PNEC for 35 pesticides. Three QSAR models were used to predict the toxicities of six pesticides with few toxicity data. Nine two-parameter nonlinear functions were used to fit the toxicity-cumulative probability data one by one to determine the optimal SSD models. The hazardous concentrations at the cumulative probability of 5% and 10%, i. e, HC5 and HC10, respectively, were calculated by the optimal SSD model. The assessment factor used to determine the PNEC of the chemical based on the HC10 was derived from the quantitative correlation between HC10 and HC5 of pesticides found in this study. When the toxicity data are insufficient, it may be more appropriate to calculate the PNECs of chemicals using HC10 than using HC5.

Portable air-fed cold atmospheric plasma device for postsurgical cancer treatment.

Surgery represents the major option for treating most solid tumors. Despite continuous improvements in surgical techniques, cancer recurrence after surgical resection remains the most common cause of treatment failure. Here, we report cold atmospheric plasma (CAP)­mediated postsurgical cancer treatment, using a portable air-fed CAP (aCAP) device. The aCAP device we developed uses the local ambient air as the source gas to generate cold plasma discharge with only joule energy level electrical input, thus providing a device that is simple and highly tunable for a wide range of biomedical applications. We demonstrate that local aCAP treatment on residual tumor cells at the surgical cavities effectively induces cancer immunogenic cell death in situ and evokes strong T cell­mediated immune responses to combat the residual tumor cells. In both 4T1 breast tumor and B16F10 melanoma models, aCAP treatment after incomplete tumor resection contributes to inhibiting tumor growth and prolonging survival.

Combined lethal toxicities of pesticides with similar structures to Caenorhabditis elegans are not necessarily concentration additives.

Studies have shown that the mixture toxicity of compounds with similar modes of action (MOAs) is usually predicted by the concentration addition (CA) model. However, due to the lack of toxicological information on compounds, more evidence is needed to determine whether the above conclusion is generally applicable. In general, the same type of compounds with similar chemical structures have similar MOAs, so whether the toxicities of the mixture of these compounds are additive needs to be further studied. In this paper, three types of pesticides with similar chemical structures (three organophosphoruses, two carbamates and two neonicotinoids) that may have similar MOAs were selected and five binary mixture systems were constructed. For each system, five mixture rays with different concentration ratios were designed by the direct equipartition ray design (EquRay) method. The mortality of Caenorhabditis elegans was regarded as the endpoint for the toxicity exposure to single pesticides and binary mixtures. The combined toxicities were evaluated simultaneously using the CA model, isobologram and combination index. The structural similarity of the same type of pesticides was quantitatively analyzed according to the MACCS molecular fingerprint and the slope of dose-response curve at pEC50. The results show that the toxicities of neonicotinoid mixtures and carbamate mixtures are almost antagonistic. The entire mixture system of dichlorvos and dimethoate produced synergism, and four of the five mixture rays of dimethoate and methamidophos induced antagonism, while among the mixture rays of dichlorvos and methamidophos, different concentrations showed different interaction types. The results of structural similarity analysis show that the size of structural similarity showed a certain quantitative relationship with the toxicity interaction of mixtures, that is, the structural similarity of the same type of pesticides may show an additive action in a certain range.