Mutations in epigenetic regulator KMT2C detected by liquid biopsy are associated with worse survival in prostate cancer patients

Background:KMT2(lysine methyltransferase)family enzymes are epigenetic regulators that activate gene transcription.KMT2C is mainly involved in enhancer-associated H3K4me1,and is also one of the top mutated genes in cancer(6.6%in pan-cancer).Currently,the clinical significance of KMT2C mutations in prostate cancer is understudied.Methods:We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cell-free DNA-based liquid biopsy test results in this study.We investigated the association between KMT2C mutations,other mutations,and pathways.Furthermore,we evaluated the prognostic value of KMT2C mutations,measured by overall survival(OS)and castration resistance-free survival(CRFS).Also,we explored the prognostic value of KMT2C mutations in different patient subgroups.Lastly,we investigated the predictive value of KMT2C mutations in individuals receiving conventional combined anti-androgen blockade(CAB)and abiraterone(ABI)as measured by PSA progression-free survival(PSA-PFS).Results:The KMT2C mutation rate in this cohort is 7.24%(16/221).KMT2C-mutated patients showed worse survival than KMT2C-wild type(WT)patients regarding both CRFS and OS(CRFS:mutated:9.9 vs.WT:22.0 months,p=0.015;OS:mutated:71.9 vs.WT 137.4 months,p=0.012).KMT2C mutations were also an independent risk factor in OS[hazard ratio:3.815(1.461,9.96),p=0.006]in multivariate analyses.Additionally,we explored the association of KMT2C mutations with other genes.This showed that KMT2C mutations were associated with Serine/Threonine-Protein Kinase 11(STK11,p=0.004)and Catenin Beta 1(CTNNB1,p=0.008)mutations.In the CAB treatment,KMT2C-mutated patients had a significantly shorter PSA-PFS compared to KMT2C-WT patients.(PSA-PFS:mutated:9.9 vs.WT:17.6 months,p=0.014).Moreover,KMT2C mutations could effectively predict shorter PSA-PFS in 10 out of 23 subgroups and exhibited a strong trend in the remaining subgroups.Conclusions:KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CRFS and OS,and KMT2C mutations were associated with STK11 and CTNNB1 mutations.Furthermore,KMT2C mutations indicated rapid progression during CAB therapy and could serve as a potential biomarker to predict therapeutic response in prostate cancer.

Identification of visible colored dissolved organic matter in biological and tertiary municipal effluents using multiple approaches including PARAFAC analysis

This study provided insights into the persistent yellowish color in biological and tertiary effluents of municipal wastewater through a multi-characterization approach and fluorescence excitation-emission matrix-parallel factor(EEM-PARAFAC)analysis.The characterization was performed on three to five full-scale municipal wastewater treatment plants(WWTPs),including differential log-transformed absorbance(DLn A)spectroscopy,resin fractionation,size-exclusion chromatography for apparent molecular weight analysis(SECAMW),and X-ray photoelectron spectroscopy(XPS)analysis.Hydrophobic acids(HPOA)were abundant in visible colored dissolved organic matter(DOM).The SEC-AMW result showed that the molecular weight of the colored substances in the secondary effluents is mainly distributed in the range of 2–3 k Da.Through XPS analysis,C-O/C-N and pyrrolic/pyridonic(N-5)were found to be positively correlated with chroma.PARAFAC component models were built on biological(two components)and tertiary effluent(three components)and the correlation analysis revealed that PARAFAC component 2 in biological effluent(BE-C2)and component 1in tertiary effluent(TE-C1),which were ascribed to Hydrophobic acids and Humic acid-like,were the responsible visible colored DOM components cause yellowish color.In addition,component similarity testing found that the identified visible colored DOM PARAFAC BE-C2,and PARAFAC TE-C1 were identical(0.96)in physicochemical properties,with 4%removal efficacy on average,compared with 11%for invisible colored DOM.This implied that tertiary effluents containing colorants(TE-C1)were resistant to degradation/removal using different disinfection and filtration processes in advanced treatments.This sheds light on many physicochemical aspects of PARAFAC-identified visible colored DOM components and provides spectral data to build an online monitoring system.

A comprehensive simulation approach for pollutant bio-transformation in the gravity sewer

Presently, several activated sludge models (ASMs) have been developed to describe a few biochemical processes. However, the commonly used ASM neither clearly describe the migratory transformation characteristics of fermentation nor depict the relationship between the carbon source and biochemical reactions. In addition, these models also do not describe both ammonification and the integrated metabolic processes in sewage transportation. In view of these limitations, we developed a new and comprehensive model that introduces anaerobic fermentation into the ASM and simulates the process of sulfate reduction, ammonification, hydrolysis, acidogenesis and methanogenesis in a gravity sewer. The model correctly predicts the transformation of organics including proteins, lipids, polysaccharides, etc. The simulation results show that the degradation of organics easily generates acetic acid in the sewer system and the high yield of acetic acid is closely linked to methanogenic metabolism. Moreover, propionic acid is the crucial substrate for sulfate reduction and ammonification tends to be affected by the concentration of amino acids. Our model provides a promising tool for simulating and predicting outcomes in response to variations in wastewater quality in sewers.