Combined toxic effects of polyethylene microplastics and lambda-cyhalothrin on gut of zebrafish (Danio rerio).

Microplastics (MPs), which are prevalent and increasingly accumulating in aquatic environments. Other pollutants coexist with MPs in the water, such as pesticides, and may be carried or transferred to aquatic organisms, posing unpredictable ecological risks. This study sought to assess the adsorption of lambda-cyhalothrin (LCT) by virgin and aged polyethylene MPs (VPE and APE, respectively), and to examine their influence on LCT's toxicity in zebrafish, specifically regarding acute toxicity, oxidative stress, gut microbiota and immunity. The adsorption results showed that VPE and APE could adsorb LCT, with adsorption capacities of 34.4 mg∙g-1 and 39.0 mg∙g-1, respectively. Compared with LCT exposure alone, VPE and APE increased the acute toxicity of LCT to zebrafish. Additionally, exposure to LCT and PE-MPs alone can induce oxidative stress in the zebrafish gut, while combined exposure can exacerbate the oxidative stress response and intensify intestinal lipid peroxidation. Moreover, exposure to LCT or PE-MPs alone promotes inflammation, and combined exposure leads to downregulation of the myd88-nf-κb related gene expression, thus impacting intestinal immunity. Furthermore, exposure to APE increased LCT toxicity to zebrafish more than VPE. Meanwhile, exposure to PE-MPs and LCT alone or in combination has the potential to affect gut microbiota function and alter the abundance and diversity of the zebrafish gut flora. Collectively, the presence of PE-MPs may affect the toxicity of pesticides in zebrafish. The findings emphasize the importance of studying the interaction between MPs and pesticides in the aquatic environment.

Encephalitis-like episodes with cortical edema and enhancement in patients with neuronal intranuclear inclusion disease.

OBJECTIVES: Neuronal intranuclear inclusion disease (NIID) exhibited significant clinical heterogeneities. However, the clinical features, radiographic changes, and prognosis of patients with encephalitis-like NIID have yet to be systematically elucidated. METHODS: Clinical data including medical history, physical examination, and laboratory examinations were collected and analyzed. Skin and sural nerve biopsies were conducted on the patient. Repeat-primed PCR (RP-PCR) and fluorescence amplicon length PCR (AL-PCR) were used to detect the expansion of CGG repeat. We also reviewed the clinical and genetic data of NIID patients with cortical enhancement. RESULTS: A 54-year-old woman presented with encephalitis-like NIID, characterized by severe headache and agitative psychiatric symptoms. The brain MRI showed cortical swelling in the temporo-occipital lobes and significant enhancement of the cortical surface and dura, but without hyperintensities along the corticomedullary junction on diffusion-weighted image (DWI). A biopsy of the sural nerve revealed a demyelinating pathological change. The intranuclear inclusions were detected in nerve and skin tissues using the p62 antibody and electron microscopy. RP-PCR and AL-PCR unveiled the pathogenic expansion of CGG repeats in the NOTCH2NLC gene. A review of the literature indicated that nine out of the 16 patients with cortical lesions and linear enhancement exhibited encephalitis-like NIID. CONCLUSION: This study indicated that patients with encephalitis-like NIID typically exhibited headache and excitatory psychiatric symptoms, often accompanied by cortical edema and enhancement of posterior lobes, and responded well to glucocorticoid treatment. Furthermore, some patients may not exhibit hyperintensities along the corticomedullary junction on DWI, potentially leading to misdiagnosis.

Multiple intracellular pathogen infections with ocular pathologies associated with adult-onset immunodeficiency due to anti-interferon-γ autoantibodies: a case report.

BACKGROUND: Autoantibodies against interferon-γ (IFN-γ) can inhibit IFN-γ-dependent signal transducer and activator of transcription 1 phosphorylation and thus increase the risk of infection with intracellular pathogens, such as Talaromyces marneffei (TM), nontuberculous mycobacteria (NTMs), and Mycobacterium tuberculosis (TB). Here, we report a rare case of triple infection caused by TM, NTM, and TB in a human immunodeficiency virus-negative patient. CASE PRESENTATION: A middle-aged female was admitted to our hospital after experiencing recurrent rash, cough, and expectoration for 4 months. She was successively diagnosed with NTM, TM, and TB infections without conventional immunosuppression-associated factors. However, after effective anti-infective treatment, the patient was confirmed to have allergic conjunctivitis and was successfully treated with corticosteroids and immunosuppressants. The most conspicuous characteristics were recurrent infection and immune disorders. CONCLUSIONS: High-titer anti-IFN-γ autoantibodies are strongly associated with severe and disseminated infections, such as NTM, TM, and TB. It is characterized by persistently high degree of inflammation and high immunoglobin levels.

Multi-walled carbon nanotubes enhance the toxicity effects of dibutyl phthalate on early life stages of zebrafish (Danio rerio): Research in physiological, biochemical and molecular aspects.

Phthalate esters (PAEs) are widely used as plasticizers. PAEs are ubiquitous in natural water bodies, with dibutyl phthalate (DBP) being one of the most common PAEs. DBP is prone to leaching or migration into the environment, posing serious health and environmental risks. Carbon nanotubes (CNTs) have been widely used in various fields with the rapid development of nanotechnology. CNTs could alter the environmental behavior and toxicity of co-existing pollutants. CNTs have been shown to rapidly adsorb PEAs. However, current knowledge about the effects of CNTs on DBP toxicity is limited. Here we show that the toxic effects of single and combined exposure to DBP (0.1, 0.5, 1.0 mg/L) and different CNTs (MWCNTs/MWCNTs-COOH, 0.5 mg/L) on the early growth stage of zebrafish. The results suggested that a significant increase in heart rate and heart malformation rate was observed after co-exposure of DBP and MWCNTs/MWCNTs-COOH (p < 0.05). Furthermore, combined exposure increased antioxidant enzyme activity during early developmental stages in zebrafish (p < 0.05). The qRT-PCR results revealed that DBP and MWCNTs/MWCNTs-COOH co-exposure significantly interfered with the expression of genes related to oxidative stress, energy metabolism, development of cardiac function, and apoptosis (p < 0.05). In addition, for oxidative stress and cardiotoxicity, MWCNTs/MWCNTs-COOH aggravated the toxic effects of 0.5 mg/L DBP on embryos/larvae. The metabolomics results showed that co-exposure mitigated the disturbance of amino acid metabolism mediated by single DBP exposure. In general, MWCNTs/MWCNTs-COOH increased the impact of DBP in the early developmental stages of zebrafish. This study provides new insights into the toxicology of early developmental stages of aquatic organisms exposed to co-exist pollutants of DBP and CNTs.

Plasma membrane lipid composition and metabolomics analysis of Yorkshire boar sperms with high and low resistance to cryopreservation.

The resistance of sperm to freezing varies widely among boars. The semen ejaculate of different boars can be grouped into poor freezability ejaculate (PFE) and good freezability ejaculate (GFE). In this study, five Yorkshire boars each of the GFE and PFE were selected by comparing the changes in sperm motility before and after cryopreservation. Firstly, we found that the sperm plasma membrane of the PFE group showed weak integrity after PI and 6-CFDA staining. Then the electron microscopy results verified that the plasma membrane condition of all segments of GFE was better than that of PFE segments. Furthermore, the lipid composition of sperm plasma membranes in GPE and PFE sperm was analyzed by using mass spectrometry, and 15 lipids showed differences between the two groups. Among those lipids, only phosphatidylcholine (PC) (14:0/20:4) and phosphatidylethanolamine (PE) (14:0/20:4) were higher in PFE. The remaining lipid contents, including those of dihydroceramide (18:0/18:0), four hexosylceramides (18:1/20:1, 18:0/22:1, 18:1/16:0, 18:1/18:0), lactosylceramide (18:1/16:0), two hemolyzed phosphatidylethanolamines (18:2, 20:2), five phosphatidylcholines (16:1/18:2, 18:2/16:1, 14:0/20:4, 16:0/18:3, 18:1/20:2), and two phosphatidylethanolamines (14:0/20:4, 18:1/18:3), were all positively correlated with resistance to cryopreservation (p < 0.05, r > 0.6). Moreover, we analyzed the metabolic profile of sperm using untarget metabolomic. KEGG annotation analysis revealed that the altered metabolites were mainly involved in fatty acid biosynthesis. Finally, we determined that the contents of oleic acid, oleamideetc, N8-acetylspermidine etc., were different between GFE and PFE sperm. In summary, the different lipid metabolism levels and long-chain polyunsaturated fatty acids (PUFAs) in plasma membrane may be key factors contributing to differences in sperm resistance to cryopreservation among boars.

Enantioselective toxic effects of the novel chiral antifungal agrochemical penthiopyrad in the early life stage of zebrafish (Danio rerio).

Penthiopyrad was extensively applied in agricultural production, however, the toxicities information of the penthiopyrad enantiomers on early life stages of aquatic organism were limited. This study investigated the enantioselective toxicity of penthiopyrad on the early life stage of zebrafish by acute toxicity, sublethal toxic effects and the mRNA relative expression levels of genes related to succinate dehydrogenase, cardiac development, and lipid metabolism. The results showed that the 96-h-LC50 of penthiopyrad racemate and enantiomers to zebrafish embryos were Rac-: 2.784 mg/L; R-(-)-: 3.528 mg/L; S-(+)-: 1.882 mg/L. Penthiopyrad exposure induced autonomous movement abnormalities, slowed heart rate and delayed hatching in zebrafish embryos, and caused developmental toxic effects such as pericardial edema and yolk sac edema. The mRNA relative expression levels results showed that penthiopyrad exposure induced significant enantioselectivity effect for the expression of the Sdha, Pr1 and Nkx2.5 with a 1.94-4.98-fold difference between different enantiomers, and significantly affected succinate dehydrogenase (energy metabolism), lipid metabolism and cardiac development-related genes expression. In general, S-(+)-penthiopyrad induced higher toxic effects in zebrafish embryos, and mitochondrial dysfunction may be an important cause of abnormal development. This study contributed to improve the comprehensive risk assessment and enantiomeric research system of penthiopyrad to early life stage of zebrafish.

Comparison of neoadjuvant chemoimmunotherapy and chemotherapy alone for resectable stage III non-small cell lung cancer: a real-world cohort study.

Background: We compared the real-world efficacy and safety of neoadjuvant chemoimmunotherapy to chemotherapy alone in patients with stage III non-small-cell lung cancer (NSCLC). Participants and methods: A total of 59 consecutive patients were finally selected and divided into two groups: the neoadjuvant chemotherapy group (n = 33) and the neoadjuvant chemoimmunotherapy group (n = 26). The primary endpoint was disease-free survival (DFS). The secondary endpoints were pathological response, clinical response, and adverse events. All patients were followed up to collect perioperative pathology and clinical data. Results: The objective response rate (ORR), pathological complete response (pCR), and major pathological response (MPR) were significantly higher in the neoadjuvant chemoimmunotherapy group than in the neoadjuvant chemotherapy group (73.1% vs. 45.5%, 34.6% vs. 3.0%, and 65.3% vs. 15.1%, respectively; P < 0.05). There was no statistically significant difference in disease-free survival between the neoadjuvant chemoimmunotherapy and neoadjuvant chemotherapy groups (P = 0.129). Patients in the neoadjuvant chemoimmunotherapy group had a higher rate of tumor regression than those in neoadjuvant chemotherapy group (37.0% [25 patients] vs. 29.0% [33 patients], P = 0.018). However, no discernible correlation between MPR achievement and the degree of tumor shrinkage was observed in either group (P > 0.05). The cumulative MPR rates were 42.3, 50, and 65.3% for 2, 3, and ≥ 4 cycles, respectively, in the neoadjuvant chemoimmunotherapy group and 9.1, 12.1, and 15.1% for ≤ 2, 3, and ≥ 4 cycles, respectively, in the neoadjuvant chemotherapy group. Moreover, No statistical difference was observed between the two groups regarding postoperative complications, resection range, operation time, surgical method, and extent of resection (P > 0.05). Although the incidence of grades III-IV adverse events was higher in the neoadjuvant chemotherapy group than in the neoadjuvant chemoimmunotherapy group (33.3% vs. 4.6%, P = 0.042), there was no significant difference in the incidence of adverse events between the two groups (64.6% vs. 83.6%, P = 0.072). Conclusion: In stage III NSCLC, neoadjuvant chemoimmunotherapy achieved higher pathological and clinical remission rates than chemotherapy alone, with compromising safety, making it an attractive choice for neoadjuvant therapy.

The mechanism of lncRNAs in the crosstalk between epithelial-mesenchymal transition and tumor microenvironment for early colon adenocarcinoma based on molecular subtyping.

A large number of colon adenocarcinoma (COAD) patients are already advanced when diagnosed. In this study, we aimed to further understand the mechanism of tumor development in early COAD by focusing on epithelial-mesenchymal transition (EMT) and long non-coding RNAs (lncRNAs). Expression profiles of early COAD patients were obtained from public databases. EMT-related lncRNAs were used as a basis for constructing molecular subtypes through unsupervised consensus clustering. Genomic features, pathways and tumor microenvironment (TME) were compared between two subtypes. LncATLAS database was applied to analyze the relation between lncRNAs and transcription factors (TFs). First order partial correlation analysis was conducted to identify key EMT-related lncRNAs.C1 and C2 subtypes with distinct prognosis were constructed. Oncogenic pathways such as EMT, KRAS signaling, JAK-STAT signaling, and TGF-ß signaling were significantly enriched in C2 subtype. Higher immune infiltration and expression of immune checkpoints were also observed in C2 subtype, suggesting the key EMT-related lncRNAs may play a critical role in the modulation of TME. In addition, JAK-STAT signaling pathway was obviously enriched in upregulated TFs in C2 subtype, which indicated a link between key lncRNAs and JAK-STAT signaling that may regulate TME. The study further expanded the research on the role of EMT-related lncRNAs in the early COAD. The six identified EMT-related lncRNAs could serve as biomarkers for early screening COAD.

Enantioselective toxic effects of mefentrifluconazole in the early life stage of zebrafish (Danio rerio).

The research on the enantioselective toxic effects of chiral pesticides on non-target aquatic organisms has attracted more and more attention. This study investigated the enantioselective toxic effects of mefentrifluconazole (MFZ) on acute toxicity, developmental toxicity, locomotor behaviors, and the mRNA relative expression levels of genes related to neurodevelopment and cardiac development in zebrafish embryos or larvae. The 96-h lethal concentration 50 (LC50 ) values (exposed to racemate and enantiomers of MFZ, that is, rac-MFZ/(-)-MFZ/(+)-MFZ) were 1.010, 1.552, and 0.753 mg/L for embryo, and 0.753, 1.187, and 0.553 mg/L for larvae. The rac-MFZ/(-)-MFZ/(+)-MFZ can affect the heart development of zebrafish embryos, accompanied by heart rate inhibition, yolk sac deformities, pericardial deformities, and down-regulation of genes related to cardiotoxicity in larvae in an enantioselective manner. Moreover, the rac-MFZ/(-)-MFZ/(+)-MFZ also can affect the neural development of zebrafish embryos, accompanied by autonomic movement inhibition, swimming speed and swimming distance abnormalities, and down-regulation of genes related to neurotoxicity in larvae in an enantioselective manner. For all toxicity endpoints, the effect of the (+)-MFZ to early-staged zebrafish were significantly greater than that of (-)-MFZ. These results will help distinguishing the difference of MFZ enantiomers to zebrafish, and provide scientific reference for improving the risk assessment of chiral pesticides MFZ.

LncRNA HOTAIR promotes proliferation, invasion and migration in NSCLC cells via the CCL22 signaling pathway.

Long noncoding RNA (LncRNA) is a new type of regulatory RNA. LncRNA HOX antisense intergenic RNA (HOTAIR), as an oncogene in non-small cell lung cancer (NSCLC), is one of the key determinants of tumor progression. However, its possible molecular mechanism and the immunomodulatory pathway involved in NSCLC are still unclear. This study aims to explore whether HOTAIR promotes proliferation, migration and invasion of the NSCLC cells by inhibiting the expression of C-C Motif Chemokine Ligand 22 (CCL22). We collected 30 clinical samples of cancer and adjacent normal tissues from the patients with NSCLC, using real-time quantitative polymerase chain reaction (RT-qPCR) to detect the LncRNA HOTAIR and CCL22 mRNA expression in tissues. Immunohistochemistry was used to detect the protein expression of CCL22 in cancer and adjacent normal tissues. Cell experiments were conducted to verify that LncRNA HOTAIR regulates the expression of CCL22 and participates in the progress of NSCLC. The antisense oligonucleotide (ASO) probe interfering with LncRNA HOTAIR and the interference fragment of CCL22 (si-CCL22) were constructed. A549 cells were co-transfected with ASO-HOTAIR and si-CCL22. We used RT-qPCR to detect the expression of LncRNA HOTAIR and CCL22 mRNA in the cells, enzyme-linked immunosorbent assay (ELISA) used to detect the CCL22 protein level in the cell supernatant. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was applied to detect cell proliferation, the Flow cytometry to detect cell apoptosis. Finally, the Transwell test was utilized to detect cell migration and invasion. In conclusion, this study suggests that HOTAIR may promote proliferation, migration and invasion of the NSCLC cells by inhibiting CCL22 expression, which may play a key role in NSCLC cell immunity.

Multi-walled carbon nanotubes impact on the enantioselective bioaccumulation and toxicity of the chiral insecticide bifenthrin to zebrafish (Danio rerio).

The effects of different multi-walled carbon nanotubes on the enantioselective bioaccumulation and toxicity of the chiral pesticide bifenthrin to zebrafish were investigated in this work. The results showed that MWCNTs and MWCNTs-COOH did not affect the preferential bioaccumulation of 1R-cis-BF in zebrafish following exposure to cis-BF enantiomers for 28 days, but which increased cis-BF accumulation amount by 1.03-1.48 times. Further research demonstrated that the genes related to immunity, endocrine activity and neurotoxicity showed enantioselective expression in different zebrafish tissues, and sex-specific differences were observed. The levels of c-fos, th, syn2a, 17ß-hsd and cc-chem were expressed as 1.09-2.84 times higher in females and males treated with 1R-cis-BF than in the 1S-cis-BF-treated groups. However, in the presence of MWCNTs or MWCNTs-COOH, c-fos, th, syn2a, 17ß-hsd and cc-chem levels were expressed as 1.53-14.92 times higher in females and males treated with 1S-cis-BF than in 1R-cis-BF-treated groups, which indicated that enantioselective expression was altered. The effects of different types of MWCNTs on the enantioselective bioaccumulation and toxicity of BF in zebrafish have little difference. In summary, the presence of MWCNTs or MWCNTs-COOH increased the impact of BF on zebrafish. Therefore, the risks posed by coexisting nanomaterials and chiral pesticides in aquatic environments should be considered.

Enantioselective toxic effects of mefentrifluconazole in the liver of adult zebrafish (Danio rerio) based on transcription level and metabolomic profile.

Mefentrifluconazole, a new type of chiral triazole fungicide, is widely applied to control a variety of fungal diseases in crops. However, the toxicological effects of mefentrifluconazole on aquatic organisms are unknown, especially at the enantiomer level. In the present study, zebrafish were selected as a typical model for mefentrifluconazole enantiomer exposure. Metabolomic and transcription analyses were performed with 0.01 and 0.10 mg/L mefentrifluconazole and its enantiomers (i.e., rac-mfz/(-)-mfz/(+)-mfz) at 28 days. The 1H nuclear magnetic resonance (NMR)-based metabolomics analysis showed that 9, 10 and 4 metabolites were changed significantly in the rac-mfz, (+)-mfz and (-)-mfz treatment groups compared with the control group, respectively. The differential metabolites were related to energy metabolism, lipid metabolism and amino acid metabolism. The qRT-PCR analysis revealed that the expression of lipid metabolism-, apoptosis- and CYP-related genes in the livers of female zebrafish in rac-mfz and (+)-mfz was 1.61-108.92 times and 2.37-551.34 times higher than that in (-)-mfz, respectively. The results above indicate that exposure to mefentrifluconazole induced enantioselective liver toxicity in zebrafish. Our study underlined the importance of distinguishing different enantiomers, which will contribute to environmental protection.

Enantioselective bioaccumulation and toxicity of the novel chiral antifungal agrochemical penthiopyrad in zebrafish (Danio rerio).

Succinate dehydrogenase inhibitor (SDHI) fungicides has been extensively used in agricultural production, which are not easily degrade in the environment and have various toxic effects on aquatic organisms. However, the toxic effects information to non-target organisms were mostly at the racemate level, which were poorly understood at the enantiomers level. Thus, this study aimed to investigate the enantioselective bioaccumulation behavior and toxic effects of penthiopyrad in zebrafish. Significant enantioselective bioaccumulation was observed when exposed to penthiopyrad at two dose levels: S-(+)-penthiopyrad was preferentially accumulated. Moreover, S-(+)-penthiopyrad caused oxidative stress in zebrafish liver. The results of real-time RT-PCR analyses revealed that exposure to penthiopyrad also enantioselectivity interfered with the expression of mitochondrial respiratory complexes, mtDNA synthesis, lipid metabolism and apoptosis-related genes. S-(+)-penthiopyrad significantly decreased most of the expression of the above gene, which showed higher toxic effects. We inferred that the toxicity mechanism of penthiopyrad was caused by lipid metabolism disorder and mitochondrial dysfunction in zebrafish, and further leads to apoptosis even DNA damage. This study provides more accurate data to investigate the environmental impact of penthiopyrad at the enantiomer level.

Metabolomic Analysis and Identification of Sperm Freezability-Related Metabolites in Boar Seminal Plasma.

Some potential markers of boar sperm freezability have been found in spermatozoa, but little attention has been paid to seminal plasma. The seminal plasma is composed of secretions from the testis, epididymis, and accessory sex glands. The exposure of spermatozoa to small molecules such as metabolites can affect sperm function. However, details and significance of the seminal plasma metabolome related to boar sperm freezability are unknown. Therefore, the main aim of this study was to explore the differences in the metabolic level of seminal plasma between boars with differential freezability and to explore the candidate biomarkers of semen freezability. A total of 953 metabolites were identified in boar semen plasma by UHPLC-qTOF-MS analysis, and 50 metabolites showed significant change between the GFE group and PFE group. Further, twelve metabolites were subjected to metabolic target analysis, and three metabolites (D-aspartic acid, N-acetyl-L-glutamate (NAG), and inosine) showed differences. In conclusion, there is significant difference in the metabolome of seminal plasma between GFE and PFE individuals. D-aspartic acid, NAG, and inosine in seminal plasma may be potential markers for assessing sperm cryopreservation resistance in boars.

Metabolomic differences of seminal plasma between boars with high and low average conception rates after artificial insemination.

Seminal plasma is a complex biological fluid containing many metabolites including amino acids, fructose, carbohydrates and lipids Metabolites play important roles in multiple biological processes, but details and significance of the seminal plasma metabolome related to boar fertility are unknown. The aim of the present study was to compare the comprehensive metabolome of seminal plasma from boars with different conception rate after artificial insemination and to identify the potential biomarkers. Semen samples were collected from boars which divided into two groups according to the conception rates in the offspring. Seminal plasma metabolites were isolated, purified, and then subjected to Ultra-high Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (UHPLC-qTOF-MS) procession. A total of 576 (Positive ion mode) and 377 (Negative ion mode) metabolites were identified in seminal plasma. Metabolites were identified and categorized according to their major chemical classes, including carboxylic acids and derivatives, organooxygen compounds, amino acids, peptides, and alogues, fatty amides, fatty acyls, benzene and substituted derivatives, purine nucleotides, pyrimidine nucleotides, glycosyl compounds, fatty acids and conjugates. The results showed that 4-Aminobenzoate, Pro-Asn, Ile-Tyr, Homoveratric acid and D-Biotin were higher in semen of boar with higher conception rate (HG) versus lower conception rate (LG) (p < .05), whereas L-Serine, Butoxyacetic acid, S-Methyl-5'-thioadenosine, Capsaicin and 1-O-(cis-9-Octadecenyl)-2-O-acetyl-sn-glycero-3-phosphocholine (PAF) were lower in HG than in LG (p < .05). These metabolites may be considered as candidate biomarkers for different fertility in boars.

Influence of multi-walled carbon nanotubes on enantioselective bioaccumulation and oxidative stress toxicity of indoxacarb in zebrafish(Danio rerio).

Carbon nanotubes (CNTs) have been widely used in various fields with the rapid development of nanotechnology. Pesticides have an irreplaceable role in agricultural production, which leads to their massive utilization and their inevitably penetrate into the aquatic environment. However, limited information is available regarding the impact of CNTs on the toxicity and enrichment of chiral compounds to organisms. Using zebrafish as a model to study whether the enantioselective bioaccumulation and oxidative stress of chiral pollutants may be altered in the presence of MWCNTs. Significant enantioselective bioaccumulation was observed in zebrafish with the preferential accumulation of R-(-)-indoxacarb during the 28-day bioaccumulation. The combined exposure of MWCNTs does not affect the enantioselectivity of zebrafish bioaccumulation, but increase the bioaccumulation amount of R-(-)-indoxacarb by 65%. Moreover, the average degradation half-life of indoxacarb enantiomers was 1.30 days. The indoxacarb causes oxidative stress toxicity in zebrafish liver and exhibited enantioselectivity, while the addition of MWCNTs did not significantly change the enantioselectivity of oxidative stress toxicity of indoxacarb, but enhanced the toxicity 20% with increased MWCNTs concentrations. This study suggests that the risk of the co-presence of nanomaterials and chiral pesticides in aquatic environments should be taken into consideration.

Effects of multi-walled carbon nanotubes on the enantioselective toxicity of the chiral insecticide indoxacarb toward zebrafish (Danio rerio).

The mass production and usage of carbon nanotubes (CNTs) have led to the inevitable release into the environment, and the effects of CNTs on the toxicity of co-existing pollutants have been well documented. However, knowledge of the effects of CNTs on the enantioselective toxicity of chiral compounds is limited. Using zebrafish as an experimental model, the enantioselective expression of the apoptosis, CYP3C and EAAT-related genes were analyzed following exposure to multi-walled carbon nanotubes (MWCNTs) (0.05 and 0.5 mg/L), rac-/R-/S-indoxacarb (0.01 mg/L), or the combination of rac-/R-/S-indoxacarb mixed with MWCNTs for 28d. Sex-specific differences were observed in both the liver and brain of zebrafish. The expression of apoptosis and CYP3C-related genes was 16.55-44.29 times higher in the livers of males treated with R-indoxacarb than in S-indoxacarb treated groups. The EAAT-related genes were expressed at 1.38-2.56 times higher levels in the brain of females treated with R-indoxacarb than in S-indoxacarb-treated groups. In the presence of MWCNTs, the expression of caspase-3, cyp3c3, cyp3c4, eaat1a, eaat1b and eaat2 in the livers of males and brains of females treated with S-indoxacarb were 1.65-15.33 times higher than in fish treated with R-indoxacarb. Based on these results, MWCNTs affected the enantioselective toxicity of indoxacarb toward zebrafish.

Phase III randomized, placebo-controlled, double-blind study of monosialotetrahexosylganglioside for the prevention of oxaliplatin-induced peripheral neurotoxicity in stage II/III colorectal cancer.

BACKGROUND: Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin-based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin-induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin-based chemotherapy. METHODS: In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI-CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ-CIPN20), time to grade 2 neurotoxicity (NCI-CTCAE or the oxaliplatin-specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3-year disease-free survival (DFS) and adverse events. RESULTS: There were no significant differences between the arms in the rate of NCI-CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ-CIPN20 or time to grade 2 neurotoxicity using NCI-CTCAE and the oxaliplatin-specific neuropathy scale. GM1 substantially decreased participant-reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3-year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms. CONCLUSION: Patients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (ClinicalTrials.gov number, NCT02251977).

Successful treatment of metastatic extramammary Paget's disease with pemetrexed monotherapy systemically and 5-fluorouracil topically.

Advanced extramammary Paget's disease does not have a standardized treatment guideline as its incidence is low and has been rarely reported in literature. Here we describe a case of metastatic extramammary Paget's disease successfully treated with topical 5-fluorouracil (5-FU) and systemic pemetrexed. The therapy was safe without any appreciable adverse effects like diarrhea, rash, neutropenia or fatigue; maintaining remission for more than 6 months. Thus, we propose 5-FU and pemetrexed as the first-line therapy for advanced extramammary Paget's disease, especially for aged patients with unresectable skin lesions.

[Expression of secreted frizzled-related protein 4 in DNA mismatch repair-deficient and mismatch repair-proficient colorectal cancers].

OBJECTIVE: To investigate the expressions of secreted frizzled-related protein 4 (SFRP4) in stage Ⅱ DNA mismatch repair-deficient (dMMR) and mismatch repair- proficient (pMMR) colorectal cancers and explore their clinical significance. METHODS: We collected fresh stage Ⅱ colon cancer tissues with different MMR status detected by immunohistochemistry (IHC). The differentially expressed mRNAs between dMMR and pMMR tumors were identified by Affymetrix Human oeLncRNA gene chip, and the expression of SFRP4 in these cancer tissues and in colorectal cancer cell lines were detected using Western blotting and real- time quantitative PCR. The apoptosis rates of HCT116 cells with and without siRNA- mediated transient SFRP4 knockdown were determined using flow cytometry. We further investigated the expression pattern of Ki-67 and its correlation with SFRP4 expression. RESULTS: Compared with pMMR colon cancer tissues or cells, both dMMR colon cancer tissues (P=0.014) and cells (P=0.0079) showed significantly increased expression of SFRP4, which was in negative correlation with Ki-67 (P=0.041). In HCT116 cells, transient SFRP4 knockdown resulted in decreased cell apoptosis, including both early apoptosis (P=0.003) and late apoptosis (P=0.024). CONCLUSIONS: Up-regulation of SFRP4 in dMMR stage Ⅱ colon cancer promotes apoptosis and inhibits proliferation of the cancer cells, and may improve the prognosis of dMMR colon cancer.