Per- and polyfluoroalkyl substances (PFAS), specifically perfluorooctanesulfonate (PFOS) and its alternative, 2-[(6-chloro-1,1,2,2,3,3,4,4,5,5,6,6-dodecafluorohexyl)oxy]-1,1,2,2-tetrafluoroethanesulfonic acid (6:2 Cl-PFESA), are associated with environmental health concerns and potential cancer progression. However, their impact on multidrug resistance (MDR) in pancreatic cancer (PC) chemotherapy remains unclear. Here, we employed drug-sensitivity assays, including IC50 calculations, in vitro and in vivo models with various chemotherapeutics, and paclitaxel (PTX) as a representative agent, combined with transcriptomic/proteomic sequencing and clinical prognostic analysis, to identify MDR-related genes and validate their relevance, with the objective of establishing the correlation between PFOS/6:2 Cl-PFESA exposure and MDR in PC at molecular, cellular, and animal model levels. Our findings demonstrate that PFOS/6:2 Cl-PFESA exposure increases the drug IC50 in three different PC cell lines for various chemotherapeutic agents. Compared with PFOS, 6:2 Cl-PFESA demonstrated a more pro-MDR effect on PC cells in vitro. In vivo experiments further revealed that PFOS/6:2 Cl-PFESA exposures significantly reduced the efficacy of PTX in PC, with inhibition rates dropping from 78.3% to 23.8%/6.1%, respectively (p < 0.05). This effect was driven by the aberrant activation of the PI3K-ABCB1 pathway, with 6:2 Cl-PFESA demonstrating a stronger capacity to promote this signal pathway's expression and function compared with PFOS. These data suggest that exposure to PFAS may elevate the risk of MDR and subsequent disease progression. Although marketed as a safer alternative to PFOS, the notable impact of 6:2 Cl-PFESA on MDR highlights the necessity for a comprehensive assessment of its potential carcinogenic risks.

N-(1,3-dimethylbutyl)-N '-phenyl-p-phenylenediamine-quinone (6PPD-Q), an environmental pollutant derived from the ozonolysis of the widely used tire rubber antioxidant 6PPD, has been found to accumulate in air, dust, and water, posing significant health risks. While its reproductive toxicity in male organisms has been established, its effects on female reproductive health remain unclear. Polycystic ovary syndrome (PCOS), a common endocrine disorder in premenopausal women, is known to be influenced by environmental pollutants. In this study, we exposed BALB/c mice intraperitoneally to 6PPD-Q, and they exhibited PCOS-like changes after 40 days, including alterations in hormone levels, estrous cycle arrest, and polycystic ovarian morphology. Then we identified significantly elevated levels of 6PPD-Q in the follicular fluid of PCOS patients compared to those with tubal infertility, and these levels were associated with clinical parameters. In the human ovarian granulosa cell line (KGN) studies, we demonstrated that 6PPD-Q induced granulosa cell apoptosis by inhibiting the PI3K/AKT/ FOXO1 pathway, leading to ovarian damage and fertility decline. To our knowledge, this is the first study to report 6PPD-Q levels in human follicular fluid and its detrimental effects on female reproductive health, underscoring the need for further research on environmental impacts on PCOS.

Pancreatic ductal adenocarcinoma (PDAC)/pancreatic cancer, is a highly aggressive malignancy with poor prognosis. Gemcitabine-based chemotherapy remains the cornerstone of PDAC treatment. Nonetheless, the development of resistance to gemcitabine among patients is a major factor contributing to unfavorable prognostic outcomes. The resistance exhibited by tumors is modulated by a constellation of factors such as genetic mutations, tumor microenvironment transforms, environmental contaminants exposure. Currently, comprehension of the relationship between environmental pollutants and tumor drug resistance remains inadequate. Our study found that PFOS/6:2 Cl-PFESA exposure increases resistance to gemcitabine in PDAC. Subsequent in vivo trials confirmed that exposure to PFOS/6:2 Cl-PFESA reduces gemcitabine’s efficacy in suppressing PDAC, with the inhibition rate decreasing from 79.5% to 56.7%/38.7%, respectively. Integrative multi-omics sequencing and molecular biology analyses have identified the upregulation of ribonucleotide reductase catalytic subunit M1 (RRM1) as a critical factor in gemcitabine resistance. Subsequent research has demonstrated that exposure to PFOS and 6:2 Cl-PFESA results in the upregulation of the RRM1 pathway, consequently enhancing chemotherapy resistance. Remarkably, the influence exerted by 6:2 Cl-PFESA exceeds that of PFOS. Despite 6:2 Cl-PFESA being regarded as a safer substitute for PFOS, its pronounced effect on chemotherapeutic resistance in PDAC necessitates a thorough evaluation of its potential risks related to gastrointestinal toxicity.

The distinction between Xanthogranulomatous Cholecystitis (XGC) and Gallbladder Carcinoma (GBC) is challenging due to their similar imaging features. This study aimed to differentiate between XGC and GBC using a deep learning nomogram model built from contrast enhanced computed tomography (CT) scans. 297 patients were included with confirmed XGC (94) and GBC (203) as the training and internal validation cohort from 2017 to 2021. The deep learning model Resnet-18 with Fourier transformation named FCovResnet18, shows most impressive potential in distinguishing XGC from GBC using 3-phase merged images. The accuracy, precision and area under the curve (AUC) of the model were then calculated. An additional cohort of 74 patients consisting of 22 XGC and 52 GBC patients was enrolled from two subsidiary hospitals as the external validation cohort. The accuracy, precision and AUC achieve 0.98, 0.99, 1.00 in the internal validation cohort and 0.89, 0.92, 0.92 in external validation cohort. A nomogram model combining clinical characteristics and deep learning prediction score showed improved predicting value. Altogether, FCovResnet18 nomogram has demonstrated its ability to effectively differentiate XGC from GBC preoperatively, which significantly aid surgeons in making informed and accurate surgical decisions for XGC and GBC patients.

以烘干球磨后的原状磷石膏、粉煤灰、矿渣粉为主要原料,生石灰作为激发剂,制备磷石膏地聚物注浆材料(PGGM).采用响应曲面法中的Box-Behnken设计,探究磷石膏掺量、生石灰掺量、液固比对PGGM流动度、凝结时间和抗压强度的影响及揭示强度形成机理,构建回归模型,探究各因素及其之间交互作用的影响程度,获得性能最优配比.结果表明:三因素对各响应值影响显著,交互项存在部分显著,各因素与响应值呈二次多项式模型,各模型的回归系数R2皆大于0.99,表明模型合理且拟合性好.当磷石膏掺量为56.08％、生石灰掺量4.43％、液固比0.34时,PGGM各项性能基本满足固化软土的相关要求.

Each year, China produces a substantial amount of municipal sludge, industrial waste (slag, fly ash, and desulfurized gypsum), and construction waste, while its recycling rate is low. If not disposed in a properly and timely manner, this inequity can have serious environmental impacts. This study aimed to prepare a new type of modified sludge material with high strength, low shrinkage, and low permeability by curing municipal sludge with industrial waste (slag, desulfurized gypsum, and fly ash) and powdered construction waste. At specific maintenance ages, the modified sludge material was examined for shrinkage deformation, water content, compressive strength, and hydraulic conductivity. The modified sludge material was also tested by scanning electron microscopy (SEM + EDS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) tests. The hydration products, micromorphology, and elemental composition of modified sludge were also analyzed at specific maintenance ages. These analyses revealed the mechanism of solidification of municipal sludge by industrial waste and powdered construction waste and the changes in the microstructure of the sludge. The results showed that the compressive strength of the modified sludge ranged from 3.83 to 8.63 MPa, volumetric shrinkage ranged from 2.12 to 12.68%, and hydraulic conductivity ranged from 1.65 × 10−8 to 2.21 × 10−7 cm/s after 28 d of maintenance. The active substances, such as SiO2, Al2O3, and CaO, in the industrial waste, powdered construction waste, and municipal sludge were subjected to a hydration reaction in an alkaline environment to produce dense blocks, agglomerates of C-S-H, ettringite, gismondine, and other hydration products. The compressive strength of the modified sludge increased, and its internal structure was dense.

Background: Hepatocellular carcinoma (HCC) was one of the most prevalent life-threatening cancers. Metastasis is the leading cause of cancer-related death in HCC. MiRNAs play essential roles in cancer metastasis. Methods: Expression of miR-652-3p in HCC was assessed. Function experiments of miR-652-3p and trinucleotide repeat-containing gene 6A protein (TNRC6A) were performed both in vitro and in vivo. mRNA sequencing, PCR, and western blot were performed to verify the target genes and pathway of miR-652-3p. The lung metastasis and xenograft cancer model in nude mice was established to investigate the effects of the miR-652-3p and TRNC6A on tumor metastasis in vivo. The relationship between the expression of the miR-652-3p, TNRC6A and the prognosis of HCC patients was analyzed. Results: Upregulated miR-652-3p was found in the tumor tissues of HCC, especially in metastatic HCC patients. Overexpression of miR-652-3p promoted and knockdown of miR-652-3p suppressed HCC metastasis both in vitro and in vivo. MiR-652-3p promoted HCC metastasis via regulating the EMT pathway. TNRC6A was identified as a direct target of miR-652-3p, and the knockdown of TNRC6A restored repressed EMT and HCC metastasis caused by the inhibition of miR-652-3p. Clinical results revealed that high expression of miR-652-3p and low expression of TNRC6A were positively correlated to shortened overall survival and disease-free survival in HCC patients. Conclusions: MiR-652-3p promotes EMT and HCC metastasis by inhibiting TNRC6A expression in HCC. MiR-652-3p and TNRC6A may serve as potential biomarkers to predict prognosis in HCC patients with metastasis. (c) 2022 Elsevier Inc. All rights reserved.

Abstract Background Metastasis serves as the leading cause of treatment failure and cancer-related death in HCC. The role of metastasis-associated miRNAs in HCC was elusive. Methods Combined analysis of TCGA data and exosomal miRNA sequencing data was performed. Expression of miR-652-3p in HCC was assessed. Function experiments of miR-652-3p and TNRC6A were performed both in vitro and in vivo. MRNA sequencing, PCR and western blot were performed to verify target genes and pathway of miR-652-3p. The lung metastasis and xenograft cancer model in nude mice was established to investigate the effects of miR-652-3p/TRNC6A axis on tumor metastasis in vivo. The potential transcription regulator of miR-652-3p was verified. The relationship of the expression of miR-652-3p/TNRC6A axis and prognosis of HCC patients was analyzed. Results Upregulated miR-652-3p was found in the tumor tissues of HCC, especially in metastatic HCC patients. Overexpression of miR-652-3p promoted and knockdown of miR-652-3p suppressed HCC metastasis both in vitro and in vivo. What’s more, miR-652-3p promoted HCC metastasis via regulating EMT pathway. Trinucleotide repeat-containing gene 6A protein (TNRC6A) was identified as a direct target of miR-652-3p, whose expression is negatively related with AFP level in HCC, and knockdown of TNRC6A promoted HCC metastasis. And knockdown of TNRC6A restored repressed EMT and HCC metastasis caused by inhibition of miR-652-3p. E2F1 transcriptionally promoted the expression of miR-652-3p through binding in the specific site in its DNA sequence. Besides, clinical results revealed that high expression of miR-652-3p and low expression of TNRC6A was positively correlated to shortened overall survival and disease-free survival in HCC patients. Conclusions The present study showed that E2F1 increases the expression of miR-652-3p, and miR-652-3p promotes EMT and HCC metastasis by directly inhibiting the expression of TNRC6A in HCC.

BACKGROUND:Mammalian Ste20-like kinase 4 (MST4), also known as serine/threonine kinase 26 (STK26), promotes development of several cancers and is found to be highly expressed in the placenta. However, in choriocarcinoma that originated from the placenta, the expression of MST4 was undetermined and its mechanism was unknown. In this study, the expression of MST4 in choriocarcinoma as well as the underlying mechanism was explored. PURPOSE:To detect the expression of MST4 in patient samples and mechanism of mediating EMT by MST4 in choriocarcinoma. PATIENTS AND METHODS:The metastatic lesions of choriocarcinoma (n=17) and volunteer villus (n=17) were collected to determine MST4 expression using immunohistochemistry and H&E staining. We use siRNA and lentiviral vector to knockdown MST4 and use plasmid to overexpress MST4 in choriocarcinoma. Then, we apply real-time polymerase chain reaction (RT-PCR), Western blot assay and immunofluorescence assay to detect target protein expressions. Cell invasion and migration and cell proliferation were detected by transwell assay and wound healing assay and CCK-8 and cell colony formation. RESULTS:MST4 is lowly expressed in the metastatic lesions of choriocarcinoma patients when compared with normal villus. Knockdown of MST4 activated epithelial-mesenchymal transition (EMT) process, significantly increasing the ability of invasion and migration in choriocarcinoma cell lines (JAR and JEG-3). In contrast, the EMT process was restrained in choriocarcinoma cell lines with overexpressed MST4. Meanwhile, genome-wide gene expression array, Western blot and ELISA revealed that tumor growth factor-beta 1 (TGF-β1) has significantly increased. The EMT process and metastatic prompting biofunction were reversed after using TGF-β1 inhibitor (LY364947) in the choriocarcinoma cell lines with MST4 knockdown. CONCLUSION:Our studies demonstrated that MST4 was lowly expressed in patient samples. Additionally, JAR and JEG-3 increase cell invasion and migration ability while there is no influence on cell proliferation with MST4 knockdown. Conversely, the metastatic ability of JAR and JEG-3 was decreased with overexpressed MST4. Moreover, TGF-β1 was a key factor after MST4 knockdown. In conclusion, MST4 affects choriocarcinoma EMT by mediating TGF-β1 expression.

Exosomes play an important role in intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). However, cellular communication between heterogeneous HCC cells with different metastatic potentials and the resultant cancer progression are not fully understood in HCC. Here, HCC cells with high-metastatic capacity (97hm and Huhm) were constructed by continually exerting selective pressure on primary HCC cells (MHCC-97H and Huh7). Through performing exosomal miRNA sequencing in HCC cells with different metastatic potentials (MHCC-97H and 97hm), many significantly different miRNA candidates were found. Among these miRNAs, miR-92a-3p was the most abundant miRNA in the exosomes of highly metastatic HCC cells. Exosomal miR92a-3p was also found enriched in the plasma of HCC patient-derived xenograft mice (PDX) model with high-metastatic potential. Exosomal miR-92a-3p promotes epithelial-mesenchymal transition (EMT) in recipient cancer cells via targeting PTEN and regulating its downstream Akt/Snail signaling. Furthermore, through mRNA sequencing in HCC cells with different metastatic potentials and predicting potential transcription factors of miR92a-3p, upregulated transcript factors E2F1 and c-Myc were found in high-metastatic HCC cells promote the expression of cellular and exosomal miR-92a-3p in HCC by directly binding the promoter of its host gene,miR17HG. Clinical data showed that a high plasma exosomal miR92a-3p level was correlated with shortened overall survival and disease-free survival, indicating poor prognosis in HCC patients. In conclusion, hepatoma-derived exosomal miR92a-3p plays a critical role in the EMT progression and promoting metastasis by inhibiting PTEN and activating Akt/Snail signaling. Exosomal miR92a-3p is a potential predictive biomarker for HCC metastasis, and this may provoke the development of novel therapeutic and preventing strategies against metastasis of HCC.

Liver cancer is a kind of lethal and aggressive malignant neoplasm with a high rate of relapse and metastasis after therapy. An important cause for the relapse and metastasis is the existence of liver cancer stem cells (CSCs), which have high resistance to chemotherapy and high tumorigenic potential. Therefore, it is crucial to develop new methods to eradicate CSCs in tumors. Herein, we develop a photodynamic therapy (PDT) that features bimodal metallacage-loaded nanoparticles (MNPs) for integrated chemotherapy. This platform achieves chemo-photodynamic combinational therapy. Organoplatinum(ii) metallacage-loaded nanoparticles show excellent ability to kill liver CSCs, decreasing their mobility and sphenoid formation ability under near-infrared laser irradiation. Importantly, MNPs can successfully penetrate into 3D tumor spheroids, which display higher drug resistance compared to traditional 2D cultured cells. This destroys CSCs and prevents subsequent tumor formation in vivo. With the excellent combinational therapeutic results in hand, the working mechanisms of MNPs were then studied. MNPs under NIR light irradiation can generate reactive oxygen species (ROS), resulting in damage of mitochondrial membrane and subsequent cell apoptosis with chemotherapeutic platinum. This study proves the great potential of MNPs for combinational cancer therapy, providing a new insight for the next generation of nanomedicines.