Dynamic Proteomic Changes in Tumor and Immune Organs Reveal Systemic Immune Response to Tumor Development.

In orthotopic mouse tumor models, tumor progression is a complex process, involving interactions among tumor cells, host cell-derived stromal cells, and immune cells. Much attention has been focused on the tumor and its tumor microenvironment, while the host's macroenvironment including immune organs in response to tumorigenesis is poorly understood. Here, we report a temporal proteomic analysis on a subcutaneous tumor and three immune organs (LN, MLN, and spleen) collected on Days 0, 3, 7, 10, 14, and 21 after inoculation of mouse forestomach cancer cells in a syngeneic mouse model. Bioinformatics analysis identified key biological processes during distinct tumor development phases, including an initial acute immune response, the attack by the host immune system, followed by the adaptive immune activation, and the build-up of extracellular matrix. Proteomic changes in LN and spleen largely recapitulated the dynamics of the immune response in the tumor, consistent with an acute defense response on D3, adaptive immune response on D10, and immune evasion by D21. In contrast, the immune response in MLN showed a gradual and sustained activation, suggesting a delayed response from a distal immune organ. Combined analyses of tumors and host immune organs allowed the identification of potential therapeutic targets. A proof-of-concept experiment demonstrated that significant growth reduction can be achieved by dual inhibition of MEK and DDR2. Together, our temporal proteomic dataset of tumors and immune organs provides a useful resource for understanding the interaction between tumors and the immune system and has the potential for identifying new therapeutic targets for cancer treatment.

Tuning the Interfacial Properties of Spinels to Improve the Antimony Adsorption Ability.

Structure and interfacial properties are important factors that affect a spinel's adsorption performance. In this article, by changing the water content in a precursor during synthesis, the interfacial properties of normal and inverse spinels were tuned to improve Sb adsorption. The results showed that changing the water content did not alter the crystal structure of synthesized zinc ferrite (ZnFe2O4) and cobalt ferrite (CoFe2O4), but it had a significant effect on the crystallite size and the number of surface hydroxyl groups. For normal spinel ZnFe2O4 and inverse spinel CoFe2O4, the crystallite size decreased while the surface hydroxyl groups increased when the water content gradually increased from 1 to 8 mL. Spinels with smaller crystallite size and more surface hydroxyl groups enhanced Sb adsorption. The adsorption capacity of ZnFe2O4 and CoFe2O4 for low concentrations of Sb(V) increased from 8.45 and 10.64 mg/g to 15.05 and 17.00 mg/g, respectively. This work has greatly improved the adsorption capacity of spinel materials through a simple tunable method and is expected to provide new ideas for the interfacial tuning of spinel materials, which shows great potential applications for wastewater treatment.

Efficacy and safety of anlotinib in patients with unresectable or metastatic well-differentiated/dedifferentiated liposarcoma: a single-center retrospective study.

Treatment options for unresectable local recurrence or metastatic well-differentiated/dedifferentiated liposarcoma (WDLS/DDLS) remain limited. Different liposarcoma subtypes have varying clinical features and sensitivities to treatment regimens. The multitarget tyrosine kinase inhibitors (TKIs), such as pazopanib and regorafenib, have been approved for use in nonadipocytic soft tissue sarcomas (STS). Anlotinib, another TKI, has been approved in China for treating metastatic STS that has progressed after the use of anthracycline-based regimens. In this study, we aimed to evaluate the role of anlotinib in the treatment of local recurrence or metastatic WDLS/DDLS. From August 2018 to June 2020, 17 patients with unresectable local recurrence or metastatic WDLS/DDLS treated with anlotinib in our center were included. The follow-up cutoff time was set as 20 October 2020. Baseline and observation indicators were collected and analyzed. Estimated median progression-free survival (PFS) was 27.9 weeks, the PFS rate at 24 weeks was 58.8%, overall survival (OS) was 56.6 weeks, the disease control rate was 64.7% and no complete response or partial response was detected. Grade 3/4 adverse events occurred in four cases and could be managed. Anlotinib is a potential treatment option for unresectable local recurrence or metastatic WDLS/DDLS.

14-3-3zeta is involved in the anticancer effect of metformin in colorectal carcinoma.

Metformin is a promising drug for cancer prevention and treatment, especially in the diabetic population. We aimed to test whether 14-3-3zeta affects the anticancer effect of metformin on colorectal carcinoma (CRC). In this study, we confirmed that higher 14-3-3zeta expression was found in CRC tissues than in pericarcinoma tissues, and in CRC tissue of patients with diabetes than in those without diabetes. A knockdown of 14-3-3zeta inhibited CRC proliferation and promoted apoptosis in vitro and in vivo. Then, we created stable cell lines with under-expressed 14-3-3zeta from SW480 and HCT15 cells after infection by a lentiviral vector carrying short hairpin RNA targeting 14-3-3zeta (named LV-sh14-3-3zeta). Of note, metformin induced apoptosis and retarded tumor growth in the CRCs with overexpressed 14-3-3zeta, whereas this action was attenuated when 14-3-3zeta was knocked down. Moreover, either metformin or downregulation of 14-3-3zeta noticeably activated AMP-dependent protein kinase (AMPK) signaling, whereas the effect of metformin was attenuated when the 14-3-3zeta expression was decreased. Taken together, our results suggest that 14-3-3zeta may be associated with carcinogenesis and poor prognosis of CRCs associated with diabetes, and metformin may reverse the AMPK inhibition caused by 14-3-3zeta in CRCs in the background of diabetes. Our study should lead to a better understanding of the anticancer activity of metformin and points to possible application of metformin to the treatment of cancers overexpressing 14-3-3zeta.

Polysulfone/SiO2 Hybrid Shell Microcapsules Synthesized by the Combination of Pickering Emulsification and the Solvent Evaporation Technique and Their Application in Self-Lubricating Composites.

Lubricant oil-filled polysulfone/SiO2 (PSF/SiO2) hybrid shell microcapsules are prepared by the combination of Pickering emulsification and the solvent evaporation technique. Silica particles are used as stabilizers. The structure and properties of the microcapsules are influenced by the silica particle concentration, agitation speed, and encapsulation temperature. The formation of PSF/SiO2 hybrid microcapsules is confirmed by a scanning electron microscope, Fourier transform infrared spectroscopy, and thermal gravimetric analysis. The resulting microcapsules prepared at the optimum synthetic parameters show a spherical, ideal structure with a rough outer surface, mean diameter of 5.0 ± 0.6 µm, shell thickness of 0.83 µm, core content of 50.5 wt %, and excellent thermal stability with an initial evaporating temperature of 250 °C. The synthesized microcapsules are embedded into epoxy for application in self-lubricating composites. Investigated by friction and wear tests, the tribological properties of the self-lubricating microcapsule-incorporated epoxy composites attain a significant improvement.

A Biocompatible Colorimetric Triphenylamine- Dicyanovinyl Conjugated Fluorescent Probe for Selective and Sensitive Detection of Cyanide Ion in Aqueous Media and Living Cells.

A colorimetric and turn-on fluorescent probe 1 bearing triphenylamine-thiophene and dicyanovinyl groups has been synthesized and used to detect cyanide anion via a nucleophilic addition reaction. Probe 1 exhibited prominent selectivity and sensitivity towards CN- in aqueous media, even in the presence of other anions such as S2-, HS-, SO32-, S2O32-, S2O82-, I-, Br-, Cl-, F-, NO2-, N3-, SO42-, SCN-, HCO3-, CO32- and AcO-. Moreover, a low detection limit (LOD, 51 nM) was observed. In addition, good cell membrane permeability and low cytotoxicity to HeLa cells were also observed, suggesting its promising potential in bio-imaging.

Generation and characterization of a novel human IgG1 antibody against vascular endothelial growth factor receptor 2.

VEGF and its receptors, especially VEGFR2 (KDR), are known to play a critical role in angiogenesis under both physiological and pathological conditions, including cancer and angiogenic retinopathies. This study was aimed at developing a fully human IgG1 antibody (mAb-04) constructed from a phage-derived scFv, targeting the VEGF/VEGFR2 pathway. Firstly, an innovative transfection system, containing two recombinant expression vectors (pMH3 and pCApuro), were introduced into CHO-s cells and clones with higher yield selected accordingly. After an optimal fermentation condition was determined, fed-batch fermentation was performed in 5-L bioreactor with a final yield up to 60 mg/L. Further, cell proliferation, wound healing, transwell invasion, tube formation and chick embryo chorioallantoic membrane assays showed significant anti-angiogenic activity of mAb-04 in vitro and in vivo. In addition, the results of Western blotting indicated the ability of mAb-04 to inhibit VEGF-induced VEGFR2 signaling pathway. Finally, ADCC assay demonstrated that mAb-04 is capable of mediating tumor cell killing in presence of effector cells. This study has therefore proved that the full-length antibody targeting human VEGFR2 has potential clinical applications in the treatment of cancer and other diseases where pathological angiogenesis is involved.

Brain radiotherapy and anlotinib control primary cardiac angiosarcoma with metastases: A case report.

RATIONALE: Primary cardiac angiosarcoma (PCA) is a rare and fatal disease with a poor prognosis. Whether the survival of PCA patients can be prolonged with additional treatment following complete surgical excision is controversial. PATIENT CONCERNS: In this case study, a 52-year-old male complained of chest tightness and pain for 7 days before admission into the hospital. Subsequently, he revisited the hospital because of dizziness and headache. DIAGNOSES: Initially, the patient was diagnosed with PCA in the right atrium by thoracic computed tomography (CT). Palliative resection identified brain, lung, and liver metastases. INTERVENTION: The patient accepted multimodal combination therapy, including first-line chemotherapy and then second-line anlotinib concurrent with brain radiotherapy and immunotherapy. OUTCOME: Although anlotinib combined with brain radiotherapy controlled the growth of intracranial lesions, progression-free survival (PFS) was only 5 months, and the overall survival (OS) was only 12 months. LESSON: The treatment for metastatic PCA needs an in-depth exploration.

Functionalized γ-Boehmite Covalent Grafting Modified Polyethylene for Lithium-Ion Battery Separator.

In the field of lithium-ion batteries, the challenges posed by the low melting point and inadequate wettability of conventional polyolefin separators have increased the focus on ceramic-coated separators. This study introduces a highly efficient and stable boehmite/polydopamine/polyethylene (AlOOH-PDA-PE) separator. It is crafted by covalently attaching functionalized nanosized boehmite (γ-AlOOH) whiskers onto polyethylene (PE) surfaces. The presence of a covalent bond increases the stability at the interface, while amino groups on the surface of the separator enhance the infiltration of the electrolyte and facilitate the diffusion of lithium ions. The PE-PDA-AlOOH separator, when used in lithium-ion batteries, achieves a discharge capacity of 126 mAh g-1 at 5 C and retains 97.1% capacity after 400 cycles, indicating superior cycling stability due to its covalently bonded ceramic surface. Thus, covalent interface modification is a promising strategy to prevent delamination of ceramic coatings in separators.

Role of low-proportion, hydrophobic dissolved organic matter components in inhibiting methylmercury uptake by phytoplankton.

Uptake of methylmercury (MeHg), a potent neurotoxin, by phytoplankton is a major concern due to its role as the primary pathway for MeHg entry into aquatic food webs, thereby posing a significant risk to human health. While it is widely believed that the MeHg uptake by plankton is negatively correlated with the concentrations of dissolved organic matter (DOM) in the water, ongoing debates continue regarding the specific components of DOM that exerts the dominant influence on this process. In this study, we employed a widely-used resin fractionation approach to separate and classify DOM derived from algae (AOM) and natural rivers (NOM) into distinct components: strongly hydrophobic, weakly hydrophobic, and hydrophilic fractions. We conduct a comparative analysis of different DOM components using a combination of spectroscopy and mass spectrometry techniques, aiming to identify their impact on MeHg uptake by Microcystis elabens, a prevalent alga in freshwater environments. We found that the hydrophobic components had exhibited more pronounced spectral characteristics associated with the protein structures while protein-like compounds between hydrophobic and hydrophilic components displayed significant variations in both distributions and the values of m/z (mass-to-charge ratio) of the molecules. Regardless of DOM sources, the low-proportion hydrophobic components usually dominated inhibition of MeHg uptake by Microcystis elabens. Results inferred from the correlation analysis suggest that the uptake of MeHg by the phytoplankton was most strongly and negatively correlated with the presence of protein-like components. Our findings underscore the importance of considering the diverse impacts of different DOM fractions on inhibition of phytoplankton MeHg uptake. This information should be considered in future assessments and modeling endeavors aimed at understanding and predicting risks associated with aquatic Hg contamination.

Differential response of Hg-methylating and MeHg-demethylating microbiomes to dissolved organic matter components in eutrophic lake water.

Methylmercury (MeHg) production in aquatic ecosystems is a global concern because of its neurotoxic effect. Dissolved organic matter (DOM) plays a crucial role in biogeochemical cycling of Hg. However, owing to its complex composition, the effects of DOM on net MeHg production have not been fully understood. Here, the Hg isotope tracer technique combined with different DOM treatments was employed to explore the influences of DOM with divergent compositions on Hg methylation/demethylation and its microbial mechanisms in eutrophic lake waters. Our results showed that algae-derived DOM treatments enhanced MeHg concentrations by 1.42-1.53 times compared with terrestrial-derived DOM. Algae-derived DOM had largely increased the methylation rate constants by approximately 1-2 orders of magnitude compared to terrestrial-derived DOM, but its effects on demethylation rate constants were less pronounced, resulting in the enhancement of net MeHg formation. The abundance of hgcA and merB genes suggested that Hg-methylating and MeHg-demethylating microbiomes responded differently to DOM treatments. Specific DOM components (e.g., aromatic proteins and soluble microbial byproducts) were positively correlated with both methylation rate constants and the abundance of Hg-methylating microbiomes. Our results highlight that the DOM composition influences the Hg methylation and MeHg demethylation differently and should be incorporated into future Hg risk assessments in aquatic ecosystems.

[Construction of anti-VEGFR-2 IgG1 like human antibody and its expression in CHO-k cells].

Anti-angiogenesis mechanism plays a vital role in tumor targeting immunotherapy. Based on the amino acid sequence of an anti-VEGFR-2 scFv-Fc fusion antibody (AK404R-Fc), this article is aimed to generate an anti-VEGFR-2 human IgG1-like full length antibody (Mab-04). Firstly, the light chain (L-chain) and heavy chain (H-chain) were obtained by overlap PCR and then linked to eukaryotic expression vector pcDNA3.1, separately. The recombinant plasmids (pcDNA3.1-L-chain and pcDNA3.1-H-chain) were then co-transfected into CHO-k cells using liposome transient transfection. Subsequently, Mab-04 antibody was expressed and purified by Protein A affinity chromatography. Western blotting was applied to identify the expression of Mab-04 and its affinity was detected by ELISA assay. DNA sequencing revealed the successful construction of recombinant plasmids and Western blotting assay proved the successful expression of full-length antibody (1 microg x mL(-1)). Finally, ELISA assay illustrated that the binding of the antibody to its antigen was in a concentration-dependent manner (IC50: 50 nmol x L(-1)). These outcomes above indicated that Mab-04 was successfully expressed and assembled, which laid the foundation for further preparation and antineoplastic activity study.

Assessment of nitrogen and phosphorus in the soil of longitudinal direction affected by in-situ oxidation remediation.

The application of in-situ chemical oxidative remediation for contaminated soils has attracted extensive attention, but the effects of remediation processes on soil physical and chemical properties are rarely studied. Herein, a ferrous-activated persulphate oxidation system for remediating dibutyl phthalate (DBP)-polluted soil was simulated in the soil column to explore the effects of in-situ oxidative remediation on soil properties in the longitudinal direction. The DBP content in the soil column was used as an indicator of oxidation strength and the correlation between N, P, soil particle size and oxidation strength was analysed. The experiment results showed that the settling performance of polluted soil after remediation improved and the distribution of the soil particle size at 128 nm disappeared after oxidation, indicating that the suspended solids in the experimental soil were mainly fine clay particles. The oxidation system can promote the conversion of organic nitrogen to inorganic nitrogen and migration characteristics of nitrogen and phosphorus, to aggravate the loss of TN and TP in the soil. The average soil particle size (d50), TN, NH4-N, available phosphorus (Ava-P), exchangeable phosphorus (Ex-P) and organic phosphorus(Or-P) were significantly correlated with oxidation strength; and stable pH in the soil column (pH = 3), showing that the changes in the longitudinal direction of d50 (smaller), TN, NH4-N, Ava-P, Ex-P, and Or-P resulted from the weakening of the longitudinal oxidation strength in the direction of the soil column.

Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report.

Primary malignant melanoma of the parotid gland (PGMM) is extremely rare, with a poor prognosis. Surgery is the main treatment option followed by adjuvant treatments such as radiotherapy, but which adjuvant treatment to be optimal is still controversial. In this case, a 63-year-old male PGMM patient was first misdiagnosed as a "myoepithelial tumor" and then treated with surgery, postoperative immunotherapy (sintilimab), chemotherapy, and radiotherapy successfully. The progression free survival was more than 19 months without signs of metastasis or recurrence to date. To our best knowledge, this is the first report of postoperative immunotherapy combined with chemotherapy and radiotherapy for PGMM. Our case indicated that combination therapy including surgery, adjuvant immunotherapy (sintilimab) combined with chemotherapy and radiotherapy may be a potential treatment option for PGMM, which needs further research.

Metachronous double primary malignant tumors with nasopharyngeal carcinoma and diffuse malignant peritoneal mesothelioma accompanied with paraneoplastic syndromes treated with nivolumab: A case report.

RATIONALE: Multiple primary malignant tumors are rare and challenging to diagnose. Diffuse malignant peritoneal mesothelioma (DMPM) originate from the peritoneum, which lacks specific clinical manifestations and is difficult to diagnose, with a short survival about 10 to 13 months for inoperable ones. This is the first report of metachronous double primary malignant tumors in nasopharyngeal carcinoma and DMPM accompanied with paraneoplastic syndromes. PATIENT CONCERNS: A 61-year-old man presented with abdominal discomfort with a history of nasopharyngeal carcinoma 5 years ago. DIAGNOSES: The diagnosis of DMPM was finally confirmed by laparoscopic mesenteric biopsies. Paraneoplastic syndromes including increased platelets were present when diagnosis, followed by increased neutrophils after disease progression. INTERVENTIONS: Due to intolerable for surgery, he was treated with pemetrexed combined with nivolumab, intraperitoneal infusion of nivolumab, radiotherapy, anlotinib and maintenance treatment of nivolumab. OUTCOMES: Progression-free survival in first line is 12 months, overall survival is 23 months. LESSONS: This indicate that comprehensive treatment including immunotherapy may be helpful for inoperable DMPM patients with nasopharyngeal carcinoma accompanied with paraneoplastic syndromes.

Impacts of autochthonous dissolved organic matter on the accumulation of methylmercury by phytoplankton and zooplankton in a eutrophic coastal ecosystem.

The bioaccumulation of methylmercury (MeHg) within the pelagic food webs is a crucial determinant of the MeHg concentration in the organisms at higher trophic levels. Dissolved organic matter (DOM) is recognized for its influence on mercury (Hg) cycling in the aquatic environment because of its role in providing metabolic substrate for heterotrophic organism and serving as a strong ligand for MeHg. However, the impact of DOM on MeHg bioaccumulation in pelagic food chains remain controversial. Here, we explored MeHg bioaccumulation within a pelagic food web in China, in the eutrophic Bohai Sea and adjacent seas, covering a range of DOM concentrations and compositions. Our findings show that elevated concentrations of dissolved organic carbon (DOC) and phytoplankton biomass may contribute to a reduction in MeHg uptake by phytoplankton. Moreover, we observe that a higher level of autochthonous DOM in the water may result in more significant MeHg biomagnification in zooplankton. This can be explained by alterations in the structure of pelagic food webs and/or an increase in the direct consumption of DOM and particulate organic matter (POM) containing MeHg. Our study offers direct field monitoring evidence of dual roles played by DOM in regulating MeHg transfers from water to phytoplankton and zooplankton in coastal pelagic food webs. A thorough understanding of the intricate interactions is essential for a more comprehensive evaluation of ecological risks associated with MeHg exposure in coastal ecosystems.

Biodegradability of algal-derived dissolved organic matter and its influence on methylmercury uptake by phytoplankton.

Methylmercury (MeHg) uptake by phytoplankton represents a key step in determining the exposure risks of aquatic organisms and human beings to this potent neurotoxin. Phytoplankton uptake is believed to be negatively related to dissolved organic matter (DOM) concentration in water. However, microorganisms can rapidly change DOM concentration and composition and subsequent impact on MeHg uptake by phytoplankton has rarely been tested. Here, we explored the influences of microbial degradation on the concentrations and molecular compositions of DOM derived from three common algal sources and tested their subsequent impacts on MeHg uptake by the widespread phytoplankton species Microcystis elabens. Our results indicated that dissolved organic carbon was degraded by 64.3‒74.1% within 28 days of incubating water with microbial consortia from a natural meso­eutrophic river. Protein-like components in DOM were more readily degraded, while the numbers of molecular formula for peptides-like compounds had increased after 28 days' incubation, probably due to the production and release of bacterial metabolites. Microbial degradation made DOM more humic-like which was consistent with the positive correlations between changes in proportions of Peaks A and C and bacterial abundance in bacterial community structures as illustrated by 16S rRNA gene sequencing. Despite rapid losses of the bulk DOM during the incubation, we found that DOM degraded after 28 days still reduced the MeHg uptake by Microcystis elabens by 32.7‒52.7% relative to a control without microbial decomposers. Our findings emphasize that microbial degradation of DOM would not necessarily enhance the MeHg uptakes by phytoplankton and may become more powerful in inhibiting MeHg uptakes by phytoplankton. The potential roles of microbes in degrading DOM and changing the uptakes of MeHg at the base of food webs should now be incorporated into future risk assessments of aquatic Hg cycling.

[Research status and development of humanized anti-tumor antibody drugs].

With the development of therapeutic monoclonal antibodies, the therapeutic antibodies have increasingly dominated the global pharmacy market in recent years, which are concentrated on the treatment of carcinoma, transplant rejection, auto-immune diseases etc. Meanwhile, the therapeutic antibodies could be categorized on the humanized proportion into several different types, such as murine-derived antibody, chimeric antibody, humanized antibody and human antibody. Herein, we focused both on antibody research hot spots and humanized anti-tumor antibody drugs. Moreover, in accordance with the classical examples of humanized anti-tumor antibody drugs approved by relevant authorities worldwide, we explained the research status and situation from both the humanized technologies and production of humanized antibodies. Additionally, it seemingly rational and reasonable to demonstrate the trend of further humanized anti-tumor antibody drugs in the prospect of the present situation either domestic or overseas.

WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis.

Background: Melanoma is the most lethal skin malignant tumor with a short survival once stepping into the metastatic status and poses a therapeutic challenge. Apatinib (a tyrosine kinase inhibitor) is a promising antiangiogenic agent for the treatment of metastatic melanoma. However, antiangiogenic monotherapy is prone to acquired drug resistance and has a limited therapeutic effect. The persistence dependence of glycolytic metabolism in antiangiogenic therapy-resistant cells provides evidence that glycolysis inhibitors may enhance the effect of antiangiogenic therapy. So, this study aimed to investigate whether WZB117 (a specific GLUT1 inhibitor) could enhance the anti-tumor effect of apatinib against melanoma and its potential mechanisms. Methods: We investigated the anti-tumor effects of apatinib alone or in combination with WZB117 on human melanoma cell lines (A375 and SK-MEL-28). The MTT assay determined cell viability and the half-maximal inhibitory concentration (IC50). Multiple drug effect/combination indexes (CI) analysis was conducted to assess interactions between apatinib and WZB117. Signal transducer and activator of transcription 3 (STAT3) pathway measured by western blotting and immunofluorescence staining. RNA expression analyses were performed using the reverse transcription-quantitative PCR method. Results: Apatinib and WZB117 showed dose and time-dependent growth inhibitory effects in both melanoma cells. The IC50 of apatinib at 48 h in A375 and SK-MEL-28 cells was 62.58 and 59.61 µM, respectively, while the IC50 of WZB117 was 116.85 and 113.91 µM, respectively. The CI values of the two drugs were 0.538 and 0.544, respectively, indicating a synergistic effect of apatinib combined with WZB117. We also found that glucose consumption and lactate production were suppressed by apatinib plus WZB117 in a dose-dependent manner, paralleled by reducing glycolytic enzyme pyruvate kinase M2 (PKM2). The potential mechanism of the combination was to suppress the phosphorylation of STAT3. Knockdown of STAT3 by siRNA inhibited the expression of PKM2, while the activation of STAT3 by IL-6 increased the expression of PKM2. The effects of IL-6 were attenuated by apatinib combined with WZB117 treatment. Conclusion: WZB117 enhanced the anti-tumor effect of apatinib against melanoma via modulating glycolysis by blocking the STAT3/PKM2 axis, which suggested the combination of apatinib with WZB117 could be a potential therapeutic candidate for melanoma.

Impact of dissolved organic matter and environmental factors on methylmercury concentrations across aquatic ecosystems inferred from a global dataset.

Mercury (Hg) input into ecosystems is estimated to have increased by twofold to fivefold since the industrial revolution. In aquatic ecosystems, methylmercury (MeHg) receives the most attentions of all the Hg species due to its neurotoxicity and strong bioaccumulation capacity in food chain. Dissolved organic matter (DOM) is crucial in impacting aquatic Hg transformation. However, only few spatially constrained studies have attempted to quantify the relative importance of DOM and other factors (e.g., Hg availability, temperature, pH, and land-use type) on MeHg concentration. In this study, we collected data of 585 water samples at 373 sites globally, including lakes, rivers, estuaries, and wetlands, and characterized the global pattern of MeHg distribution and environmental drivers of aquatic MeHg concentration. Our results showed that MeHg concentrations ranged from detection limits to 11 (geometric mean 0.11 and average 0.29) ng/L, and the highest MeHg concentration and Hg methylation potential were observed in wetlands. A positive relationship was observed between MeHg fraction in the total mercury (THg) and DOM for all the aquatic ecosystems. Using the structural equation modeling, we found that Hg availability was a dominant factor in impacting water MeHg concentration followed by DOM. According to 129 samples of specific DOM source information, we found that the percentage of THg as MeHg (%MeHg) in water dominated by the autochthonous DOM was higher than that dominated by the allochthonous DOM. Our results could advance understanding of aquatic Hg cycling and their environmental drivers, which are fundamental for predicting and mitigating MeHg productions and its potential health risks for humans.