•Degradation of clofibric acid (CA) was studied by UV/PS and UV/chlorine.•The second-order rate constants of CA with SO4−, OH and Cl were determined.•Impacts of different conditions including oxidant ...dosage, pH, Cl− and HCO3− were discussed.•UV/chlorine was found to be more cost-effective.•The disinfection by-products (DBPs) formation was evaluated during followed chlor(am)ination.
This study investigated the UV/persulfate (UV/PS) and UV/chlorine processes as alternative method for the removal of clofibric acid (CA). The formation of disinfection byproducts (DBPs) during subsequent chlor(am)ination was also evaluated. The degradation of CA followed the pseudo-first order kinetics. The second-order rate constants of CA with SO4−, OH and Cl were respectively determined as kSO4-,CA=(1.73±0.01)×109M−1s−1, kOH,CA=(2.72±0.08)×109M−1s−1 and kCl,CA=(9.76±0.15)×1010M−1s−1. The degradation rate constant increased with increasing oxidant dosage in UV/PS and UV/chlorine processes. The degradation rate constant was found to be the highest at pH 9 and decreased dramatically at pH 11 in UV/PS process. For UV/chlorine, the rate constant continuously decreased with increasing pH from 3 to 11. Presence of HCO3− and Cl− had different effects (promotion and/or inhibition) on CA degradation in both processes. An inhibition effect was observed in the presence of NOM for the two UV-based processes. The higher CA removal in real water suggested the two processes were suitable for treating water containing CA, and the UV/chlorine was more cost-effective than UV/PS based on the total cost of electrical energy. Compared with the chlor(am)ination of CA, the UV/PS and UV/chlorine pre-oxidation significantly impacted the DBP formation during subsequent chlor(am)ination, which indicated the application of the two UV-based processes needs to be carefully balanced against the downstream effect on DBP formation.
Abstract Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional treatment, the outcome for ...patients remains almost universally fatal. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. However, over the past decade, molecular targeted therapy has held the promise of transforming the care of malignant glioma patients. Significant progress in understanding the molecular pathology of gliomagenesis and maintenance of the malignant phenotypes will open opportunities to rationally develop new molecular targeted therapy options. Recently, therapeutic strategies have focused on targeting pro-growth signaling mediated by receptor tyrosine kinase/RAS/phosphatidylinositol 3-kinase pathway, proangiogenic pathways, and several other vital intracellular signaling networks, such as proteasome and histone deacetylase. However, several factors such as cross-talk between the altered pathways, intratumoral molecular heterogeneity, and therapeutic resistance of glioma stem cells (GSCs) have limited the activity of single agents. Efforts are ongoing to study in depth the complex molecular biology of glioma, develop novel regimens targeting GSCs, and identify biomarkers to stratify patients with the individualized molecular targeted therapy. Here, we review the molecular alterations relevant to the pathology of malignant glioma, review current advances in clinical targeted trials, and discuss the challenges, controversies, and future directions of molecular targeted therapy.
We describe a rapid target enrichment method for next-generation sequencing, termed anchored multiplex PCR (AMP), that is compatible with low nucleic acid input from formalin-fixed paraffin-embedded ...(FFPE) specimens. AMP is effective in detecting gene rearrangements (without prior knowledge of the fusion partners), single nucleotide variants, insertions, deletions and copy number changes. Validation of a gene rearrangement panel using 319 FFPE samples showed 100% sensitivity (95% confidence limit: 96.5-100%) and 100% specificity (95% confidence limit: 99.3-100%) compared with reference assays. On the basis of our experience with performing AMP on 986 clinical FFPE samples, we show its potential as both a robust clinical assay and a powerful discovery tool, which we used to identify new therapeutically important gene fusions: ARHGEF2-NTRK1 and CHTOP-NTRK1 in glioblastoma, MSN-ROS1, TRIM4-BRAF, VAMP2-NRG1, TPM3-NTRK1 and RUFY2-RET in lung cancer, FGFR2-CREB5 in cholangiocarcinoma and PPL-NTRK1 in thyroid carcinoma. AMP is a scalable and efficient next-generation sequencing target enrichment method for research and clinical applications.
Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites ...include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.
Overwhelming studies show that dysregulation of the Hippo pathway is positively correlated with cell proliferation, growth, and tumorigenesis. Paradoxically, the detailed molecular roles of the Hippo ...pathway in cell invasion remain debatable. Using a Drosophila invasion model in wing epithelium, we show herein that activated Hippo signaling promotes cell invasion and epithelial-mesenchymal transition through JNK, as inhibition of JNK signaling dramatically blocked Hippo pathway activation-induced matrix metalloproteinase 1 expression and cell invasion. Furthermore, we identify bantam-Rox8 modules as essential components downstream of Yorkie in mediating JNK-dependent cell invasion. Finally, we confirm that YAP (Yes-associated protein) expression negatively regulates TIA1 (Rox8 ortholog) expression and cell invasion in human cancer cells. Together, these findings provide molecular insights into Hippo pathway-mediated cell invasion and also raise a noteworthy concern in therapeutic interventions of Hippo-related cancers, as simply inhibiting Yorkie or YAP activity might paradoxically accelerate cell invasion and metastasis.
The treatment of bone metastases is a thorny issue. Immunotherapy may be one of the few hopes for patients with unresectable bone metastases. Immune checkpoint inhibitors are the most commonly used ...immunotherapy drugs currently. In this review, the characteristics and interaction of bone metastases and their immune microenvironment were systematically discussed, and the relevant research progress of the immunological mechanism of tumor bone metastasis was reviewed. On this basis, we expounded the clinical application of immune checkpoint inhibitors for bone metastasis of common tumors, including non-small-cell lung cancer, renal cell carcinoma, prostate cancer, melanoma, and breast cancer. Then, the deficiencies and limitations in current researches were summarized. In-depth basic research on bone metastases and optimization of clinical treatment is needed.
The methyltransferase like 3 (METTL3) has been generally recognized as a nuclear protein bearing oncogenic properties. We find predominantly cytoplasmic METTL3 expression inversely correlates with ...node metastasis in human cancers. It remains unclear if nuclear METTL3 is functionally distinct from cytosolic METTL3 in driving tumorigenesis and, if any, how tumor cells sense oncogenic insults to coordinate METTL3 functions within these intracellular compartments. Here, we report an acetylation-dependent regulation of METTL3 localization that impacts on metastatic dissemination. We identify an IL-6-dependent positive feedback axis to facilitate nuclear METTL3 functions, eliciting breast cancer metastasis. IL-6, whose mRNA transcript is subjected to METTL3-mediated m
A modification, promotes METTL3 deacetylation and nuclear translocation, thereby inducing global m
A abundance. This deacetylation-mediated nuclear shift of METTL3 can be counterbalanced by SIRT1 inhibition, a process that is further enforced by aspirin treatment, leading to ablated lung metastasis via impaired m
A methylation. Intriguingly, acetylation-mimetic METTL3 mutant reconstitution results in enhanced translation and compromised metastatic potential. Our study identifies an acetylation-dependent regulatory mechanism determining the subcellular localization of METTL3, which may provide mechanistic clues for developing therapeutic strategies to combat breast cancer metastasis.
Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer ...progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this study, we demonstrate that, in glioma, upregulation of IGF2BP3 enhances the expression of E3 ubiquitin protein ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway. This results in increased m6A-mediated CSF3 release and NET formation. Oncolytic herpes simplex virus (oHSV) stimulates IGF2BP3-induced NET formation in malignant glioma. In glioma models in female mice, a BET inhibitor enhances the oncolytic activity of oHSV by impeding IGF2BP3-induced NETosis, reinforcing virus replication through BRD4 recruitment with the CDK9/RPB-1 complex to HSV gene promoters. Our findings unveil the regulation of m6A-mediated NET formation, highlight oncolytic virus-induced NETosis as a critical checkpoint hindering oncolytic potential, and propose targeting NETosis as a strategy to overcome resistance in oncolytic virotherapy.
To study the efficacy of LITT for BM patients experiencing in-field recurrence following SRS.
A literature search was conducted to identify studies investigating local control (LC) rate and overall ...survival (OS) of LITT for BMs with IFR following SRS.
Analysis included 14 studies (470 patients with 542 lesions). The 6-month (LC-6) and 12-month (LC-12) local control rates were 78.5% (95% CI: 70.6-84.8%) and 69.0% (95% CI: 60.0-76.7%) separately. Pooled median OS was 17.15 months (95% CI: 13.27-24.8). The overall OS-6 and OS-12 rates were 76.0% (95% CI: 71.4-80.0%) and 63.4% (95% CI: 52.9-72.7%) separately. LITT provided more favorable local control efficacy in RN than BM recurrence (LC-6: 87.4% vs. 67.9%, p = 0.009; LC-12: 76.3% vs. 59.9%, p = 0.041).
LITT is an effective treatment for BM patients experiencing IFR following SRS. For different pathological entities, LITT showed more satisfactory local control efficacy on RN than BM recurrence.
Traditional rigorous limit equilibrium methods satisfy all equilibrium conditions and usually have high accuracy, however, which are less efficient for slope reliability analysis. The main reason is ...that the limit state functions are highly nonlinear implicit functions of safety factor. Complex numerical iterations are required, which may sometimes lead to computational convergence problems. A new method for computing slope reliability calculation with high efficiency and accuracy was proposed. This method was based on the rigorous limit equilibrium method by modifying normal stresses over the slip surface. The critical horizontal acceleration factor
, which can be expressed explicitly, was used to replace the implicit safety factor as a representation of slope stability. The difference between
and the known value
was used as the limit state function. Two slope examples were analyzed. The results showed that the calculation results of this method were in good agreement with those of the traditional Morgenstern–Price limit equilibrium method, but the computational efficiency was significantly improved. When this method was combined with the subset simulation method, the calculation time was only a few seconds. Therefore, this method can be used for rapid calculation of slope reliability.
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