Disruption of DNA-PKcs-mediated cGAS retention on damaged chromatin potentiates DNA damage-inducing agent-induced anti-multiple myeloma activity.

BACKGROUND: Targeting DNA damage repair factors, such as DNA-dependent protein kinase catalytic subunit (DNA-PKcs), may offer an opportunity for effective treatment of multiple myeloma (MM). In combination with DNA damage-inducing agents, this strategy has been shown to improve chemotherapies partially via activation of cGAS-STING pathway by an elevated level of cytosolic DNA. However, as cGAS is primarily sequestered by chromatin in the nucleus, it remains unclear how cGAS is released from chromatin and translocated into the cytoplasm upon DNA damage, leading to cGAS-STING activation. METHODS: We examined the role of DNA-PKcs inhibition on cGAS-STING-mediated MM chemosensitivity by performing mass spectrometry and mechanism study. RESULTS: Here, we found DNA-PKcs inhibition potentiated DNA damage-inducing agent doxorubicin-induced anti-MM effect by activating cGAS-STING signaling. The cGAS-STING activation in MM cells caused cell death partly via IRF3-NOXA-BAK axis and induced M1 polarization of macrophages. Moreover, this activation was not caused by defective classical non-homologous end joining (c-NHEJ). Instead, upon DNA damage induced by doxorubicin, inhibition of DNA-PKcs promoted cGAS release from cytoplasmic chromatin fragments and increased the amount of cytosolic cGAS and DNA, activating cGAS-STING. CONCLUSIONS: Inhibition of DNA-PKcs could improve the efficacy of doxorubicin in treatment of MM by de-sequestrating cGAS in damaged chromatin.

Lung function benefits of traditional Chinese medicine Qiju granules against fine particulate air pollution exposure: a randomized controlled trial.

Introduction: Multiple targets are considered as the causes of ambient fine particulate matter [aerodynamic diameters of < 2.5 µm (PM2.5)] induced lung function injury. Qiju granules are derived from the traditional Chinese medicine (TCM) formula known as Qi-Ju-Di-Huang-Wan (Lycium, Chrysanthemum, and Rehmannia Formula, QJDHW), which has been traditionally used to treat symptoms such as cough with phlegm, dry mouth and throat, and liver heat. This treatment approach involves attenuating inflammation, oxidative stress, and fibrosis response. This study investigated the effects of Qiju granules on protecting lung function against PM2.5 exposure in a clinical trial. Methods: A randomized, double-blinded, and placebo-controlled trial was performed among 47 healthy college students in Hangzhou, Zhejiang Province in China. The participants were randomly assigned to the Qiju granules group or the control group based on gender. Clinical follow-ups were conducted once every 2 weeks during a total of 4 weeks of intervention. Real-time monitoring of PM2.5 concentrations in the individually exposed participants was carried out. Data on individual characteristics, heart rate (HR), blood pressure (BP), and lung function at baseline and during the follow-ups were collected. The effects of PM2.5 exposure on lung function were assessed within each group using linear mixed-effect models. Results: In total, 40 eligible participants completed the scheduled follow-ups. The average PM2.5 level was found to be 64.72 µg/m3 during the study period. A significant negative correlation of lung function with PM2.5 exposure concentrations was observed, and a 1-week lag effect was observed. Forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), maximal mid-expiratory flow (MMEF), forced expiratory flow at 75% of forced vital capacity (FVC) (FEF75), forced expiratory flow at 50% of FVC (FEF50), and forced expiratory flow at 25% of FVC (FEF25) were significantly decreased due to PM2.5 exposure in the control group. Small airway function was impaired more seriously than large airway function when PM2.5 exposure concentrations were increased. In the Qiju granules group, the associations between lung function and PM2.5 exposure were much weaker, and no statistical significance was observed. Conclusion: The results of the study showed that PM2.5 exposure was associated with reduced lung function. Qiju granules could potentially be effective in protecting lung functions from the adverse effects of PM2.5 exposure. Clinical Trial Registration: identifier: ChiCTR1900021235.

Analysis of factors affecting pregnancy rate after laparoscopic surgery for infertility associated with endometriosis.

OBJECTIVE: To analyze the factors that might influence the pregnancy rate in patients with infertility related to endometriosis (EMs) after undergoing laparoscopic surgery, providing guidance for our clinical diagnostic and therapeutic decision-making. METHODS: A retrospective analysis was conducted on clinical records and 1-year postoperative pregnancy outcomes of 335 patients diagnosed with endometriosis-related infertility via laparoscopic surgery, admitted to our department from January 2018 to December 2020. RESULTS: The overall pregnancy rate for patients with endometriosis (EMs) related infertility 1-year post-surgery was 57.3 %, with the highest pregnancy rate observed between 3 to 6 months after surgery. Factors such as Body Mass Index (BMI) (P = 0.515), presence of dysmenorrhea (P = 0.515), previous pelvic surgery (P = 0.247), type of EMs pathology (P = 0.893), and preoperative result of serum carbohydrate antigen 125 (CA125)（P = 0.615）had no statistically significant effect on postoperative pregnancy rates. The duration of infertility (P = 0.029), coexistence of adenomyosis (P = 0.042), surgery duration (P = 0.015), intraoperative blood loss (P = 0.050), preoperative result of serum anti-Müllerian hormone (AMH) (P = 0.002) and age greater than 35 (P = 0.000) significantly impacted postoperative pregnancy rates. The post-surgery pregnancy rate in patients with mild (Stage I-II) EMs was notably higher than those with moderate to severe (Stage III-IV) EMs (P = 0.009). Age (P = 0.002), EMs stage (P = 0.018), intraoperative blood loss (P = 0.010) and adenomyosis (P = 0.022) were the factors that affected the postoperative live birth rate. CONCLUSION: For patients with EMs-related infertility undergoing laparoscopic surgery, factors such as age > 35 years, infertility duration > 3 years, concurrent adenomyosis, severe EMs, surgery duration ≥ 2 h, intraoperative blood loss ≥ 50 ml, and low AMH before surgery are detrimental for the pregnancy rate within the first postoperative year. However, BMI, dysmenorrhea, past history of pelvic surgery, EMs pathology types (ovarian, peritoneal, deep infiltrating),and preoperative result of serum CA125 barely show any statistical difference in their effect on postoperative pregnancy rates. In terms of postoperative live birth rate, age > 35 years, severe EMs, intraoperative blood loss ≥ 50 ml, and adenomyosis were adverse factors.

Self-reporting electroswitchable colorimetric platform for smart ammonium recovery from wastewater.

Recovery of ammonium from wastewater represents a sustainable strategy within the context of global resource depletion, environmental pollution and carbon neutralization. The present study developed an advanced self-reporting electroswitchable colorimetric platform (SECP) to realize smart ammonium recovery based on the electrically stimulated transformation of Prussian blue/Prussian white (PB/PW) redox couple. The key to SECP was the selectivity of ammonium adsorption, sensitivity of desorption to electric signals and visualability of color change during switchable adsorption/desorption transformation. The results demonstrated the electrochemical intercalation-induced selective adsorption of NH4+ (selectivity coefficient of 3-19 versus other cations) and deintercalation-induced desorption on the PB-film electrode. At applied voltage of 1.2 V for 20 min, the negatively charged PB-film electrode achieved the maximum adsorption capacity of 3.2 mmol g-1. Reversing voltage to -0.2 V for 20 min resulted in desorption efficiency as high as 99%, indicating high adsorption/desorption reversibility and cyclic stability. The Fe(III)/Fe(II) redox dynamics were responsible for PB/PW transformation during reversible intercalation/deintercalation of NH4+. Based on the blue/transparence color change of PB/PW, the quantitative relationship was established between amounts of NH4+ adsorbed and extracted RGB values by multiple linear regression (R2 = 0.986, RMSE = 0.095). Then, the SECP was created upon the unique capability of real-time monitoring and feedback of color change of electrode to realize the automatic control of NH4+ adsorption/desorption. During five cycles of tests, the adsorption process consistently peaked at an average value of 3.15±0.04 mmol g-1, while desorption reliably approached the near-zero average of 0.06±0.04 mmol g-1. The average time of duration was 19.6±1.67 min for adsorption and 18.8±1.10 min for desorption, respectively. With electroswitchability, selectivity and self-reporting functionalities, the SECP represents a paradigm shift in smart ammonium recovery from wastewater, making wastewater treatment and resource recovery more efficient, more intelligent and more sustainable.

High Efficiency over 18.6% of Organic Solar Cells Enabled by PEDOT:PSS/Br-2PACz Dual-Anode Interface.

Organic solar cells (OSCs) with high performance were prepared using poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and [2-(3,6-dibromo-9H-carbazol-9-yl)ethyl]phosphonic acid (Br-2PACz) double-layer films as the anode interface. By spin-coating a layer of Br-2PACz on PEDOT:PSS to form a PEDOT:PSS/Br-2PACz dual-anode interface, both the Jsc and FF of the device can be increased simultaneously, resulting in a high Jsc of 27.84 mA cm-2 and a high FF of 78.18%. The promising result indicates that the PEDOT:PSS/Br-2PACz dual-anode interface is an effective way to improve the performance of OSCs. The improvement of device performance is mainly attributed to (1) improved interface conductivity; (2) increased hole mobility and more balanced carrier transport efficiency; and (3) optimized morphology, which well explains the increase of Jsc and FF of the device. In addition, the OSC based on the PEDOT:PSS/Br-2PACz dual-anode interface exhibits exceptional stability, as it can maintain 94.7% of its initial efficiency even after 500 h of storage in a nitrogen environment. This work provides a promising strategy for improving the efficiency and stability of OSCs by dual-anode interface modulation.

In vitro metabolism of the emerging contaminant 6PPD-quinone in human and rat liver microsomes: Kinetics, pathways, and mechanism.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) is an ozonation product of the rubber antioxidant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD). 6PPD-Q has recently been detected in various environmental media, which may enter the human body via inhalation and skin contact pathways. However, the human metabolism of 6PPD-Q has remained unknown. This study investigated the in vitro Cytochrome P450-mediated metabolism of 6PPD-Q in human and rat liver microsomes (HLMs and RLMs). 6PPD-Q was significantly metabolized at lower concentrations but slowed at high concentrations. The intrinsic clearance (CLint) of 6PPD-Q was 21.10 and 18.58 µL min-1 mg-1 protein of HLMs and RLMs, respectively, suggesting low metabolic ability compared with other reported pollutants. Seven metabolites and one intermediate were identified, and metabolites were predicted immunotoxic or mutagenic toxicity. Mono- and di-oxygenation reactions were the main phase I in vitro metabolic pathways. Enzyme inhibition experiments and molecular docking techniques were further used to reveal the metabolic mechanism. CYP1A2, 3A4, and 2C19, especially CYP1A2, play critical roles in 6PPD-Q metabolism in HLMs, whereas 6PPD-Q is extensively metabolized in RLMs. Our study is the first to demonstrate the in vitro metabolic profile of 6PPD-Q in HLMs and RLMs. The results will significantly contribute to future human health management targeting the emerging pollutant 6PPD-Q.

Trace analysis of 47 psychotropic medications in environmental samples by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).

Psychotropic medications are one of the most prescribed pharmaceuticals in the world. Given their frequent detection and ecotoxicity to the no-target organism, the emission of these medications into environments has gradually draw attention. The study developed a sensitive and reliable analytic method to simultaneously investigate 47 psychotropic medications in four matrices: wastewater, surface water, activated sludge, and sediment by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS). These 47 target analytes include 24 antidepressants, 17 antianxiety drugs, 5 anticonvulsants, and 1 relevant hormone. Solid phase extraction (SPE) was employed to extract analytes from water-phase samples. Ultrasonic Solvent Extraction method with Enhanced Matrix Removal clean-up (USE-EMR) was utilized to extract target compounds from solid-phase samples, which requires more straightforward and convenient procedures than previous methods. The extraction recoveries of all analytes ranged from 80 % to 120 % in these four sample matrices. In this study, The limit of quantitation for 47 psychotropic medications were 0.15 ng/L (estazolam) to 2.27 ng/L (lorazepam), 0.08 ng/L (desvenlafaxine) to 2 ng/L (mianserin), 0.22 ng/g (dry weight, dw) (nordiazepam) to 3.65 ng/g (dw) (lorazepam), and 0.07 ng/g (dw) (carbamazepine) to 2.85 ng/g (lorazepam), in wastewater, surface water, sludge, and sediment, respectively. In addition, the developed method was employed to analyse actual samples in two wastewater treatment plants and their receiving rivers. Carbamazepine, escitalopram, clozapine, desvenlafaxine, diazepam, lamotrigine, sertraline, temazepam, and venlafaxine were nearly ubiquitous in all matrices. Moreover, this study indicated that the inadequate removal efficiencies of psychotropic medications in wastewater treatment plants (WWTPs) had resulted in a persistent discharge of these contaminants from human sources into environments.

Identification of Cancer Stem Cell-related Gene by Single-cell and Machine Learning Predicts Immune Status, Chemotherapy Drug, and Prognosis in Lung Adenocarcinoma.

AIM: This study aimed to identify the molecular type and prognostic model of lung adenocarcinoma (LUAD) based on cancer stem cell-related genes. Studies have shown that cancer stem cells (CSC) are involved in the development, recurrence, metastasis, and drug resistance of tumors. METHOD: The clinical information and RNA-seq of LUAD were obtained from the TCGA database. scRNA dataset GSE131907 and 5 GSE datasets were downloaded from the GEO database. Molecular subtypes were identified by ConsensusClusterPlus. A CSC-related prognostic signature was then constructed via univariate Cox and LASSO Cox-regression analysis. RESULT: A scRNA-seq GSE131907 dataset was employed to obtain 11 cell clusters, among which, 173 differentially expressed genes in CSC were identified. Moreover, the CSC score and mRNAsi were higher in tumor samples. 18 of 173 genes were survival time-associated genes in both the TCGA-LUDA dataset and the GSE dataset. Next, two molecular subtypes (namely, CSC1 and CSC2) were identified based on 18 survival-related CSC genes with distinct immune profiles and noticeably different prognoses as well as differences in the sensitivity of chemotherapy drugs. 8 genes were used to build a prognostic model in the TCGA-LUAD dataset. High-risk patients faced worse survival than those with a low risk. The robust predictive ability of the risk score was validated by the time-dependent ROC curve revealed as well as the GSE dataset. TIDE analysis showed a higher sensitivity of patients in the low group to immunotherapy. CONCLUSION: This study has revealed the effect of CSC on the heterogeneity of LUAD, and created an 8 genes prognosis model that can be potentially valuable for predicting the prognosis of LUAD and response to immunotherapy.

Water Flow-Driven Coupling Process of Anodic Oxygen Evolution and Cathodic Oxygen Activation for Water Decontamination and Prevention of Chlorinated Byproducts.

Electrochemical advanced oxidation process (EAOP) is a promising technology for decentralized water decontamination but is subject to parasitic anodic oxygen evolution and formation of toxic chlorinated byproducts in the presence of Cl-. To address this issue, we developed a novel electrolytic process by water flow-driven coupling of anodic oxygen evolution reaction (OER) and cathodic molecular oxygen activation (MOA). When water flows from anode to cathode, O2 produced from OER is carried by water through convection, followed by being activated by atomic hydrogen (H*) on Pd cathode to produce •OH. The water flow-driven OER/MOA process enables the anode to be polarized at low potential (1.7 V vs SHE) that is lower than that of conventional EAOP whose •OH is produced from direct water oxidation (>2.3 V vs SHE). At a flow rate of 30 mL min-1, the process could achieve 94.8% removal of 2,4-dichlorophenol (2,4-DCP) and 71.5% removal of chemical oxygen demand (COD) within 45 min at an anode potential of 1.7 V vs SHE and cathode potential of -0.5 V vs SHE. To achieve the comparable 2,4-DCP removal performance, 4.3-fold higher energy consumption was needed for the conventional EAOP with titanium suboxide anode (anode potential of 2.9 V vs SHE), but current efficiency declined by 3.5 folds. Unlike conventional EAOP, chlorate and perchlorate were not detected in the OER/MOA process, because low anode potential <2.0 V vs SHE was thermodynamically unfavorable for the formation of chlorinated byproducts by anodic oxidation, indicated by theoretical calculations and experimental data. This study provides a proof-in-concept demonstration of water flow-driven OER/MOA process, representing a paradigm shift of electrochemical technology for water decontamination and prevention of chlorinated byproducts, making electrochemical water decontamination more efficient, more economic, and more sustainable.

CUDC-101 as a dual-target inhibitor of EGFR and HDAC enhances the anti-myeloma effects of bortezomib by regulating G2/M cell cycle arrest. / EGFR和HDAC双靶点抑制剂CUDC-101通过调控G2/M期阻滞增强硼替佐米抗骨髓瘤的作用.

CUDC-101, an effective and multi-target inhibitor of epidermal growth factor receptor (EGFR), histone deacetylase (HDAC), and human epidermal growth factor receptor 2 (HER2), has been reported to inhibit many kinds of cancers, such as acute promyelocytic leukemia and non-Hodgkin's lymphoma. However, no studies have yet investigated whether CUDC-101 is effective against myeloma. Herein, we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma (MM) cell lines and induces cell apoptosis in a time- and dose-dependent manner. Moreover, CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase (PI3K) and HDAC, and regulated the cell cycle G2/M arrest. Moreover, we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug. Bortezomib is one of the important drugs in MM treatment, and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib. The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade. Collectively, our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib, which provides insights into exploring new strategies for MM treatment.

Modulation of Molecular Stacking via Tuning 2-Ethylhexyl Alkyl Chain Enables Improved Efficiency for All-Small-Molecule Organic Solar Cells.

There is always a dilemma between strong π-π stacking/crystallinity and suitable domain size for all-small-molecule organic solar cells (ASM-OSCs), which puts forward higher requirements for the design of molecular donors. In this work, a series of novel molecular donors with different positional 2-ethylhexy (EH) attachments are designed and synthesized, named SM-R, SM-REH, SM-EH-R, and SM-EH-REH. It is found that EH-substitution on end groups (SM-REH) enables improved π-π interaction and crystallinity but with decreased solubility and phase size, leading to the improved efficiency of 15.6% as compared to 14.0% of SM-R. In contrast, EH-substitution on the π-bridge (SM-EH-R) significantly suppresses π-π stacking and increases the solubility, resulting in the lower efficiency of 11.9%. The further EH-substitution on end-groups of SM-EH-R, namely, SM-EH-REH, recovers the π-π stacking strength and obtains a moderate efficiency of 14.4%. Despite the higher crystallinity and increased π-π stacking in some molecules, the blend films show the gradually decreased domain size in the sequence of SM-R, SM-REH, SM-EH-R, and SM-EH-REH owing to the steric hindrance of the EH-chain. Overall, this work indicates that obtaining the higher π-π stacking/crystallinity and decreased domain size is achievable by tuning the EH-chain substitution, which paves the way to further improve the photovoltaic performance of ASM-OSCs.

New insights into mycelial pellets for aerobic sludge granulation in membrane bioreactor: Bio-functional interactions among metazoans, microbial communities and protein expression.

Direct cultivation of aerobic granular sludge (AGS) in membrane bioreactor (MBR) has gained increasing attention. Mycelial pellets (MPs) has been shown capable of promoting rapid granulation of aerobic sludge in MBR, yet mechanisms remain unclear and in-depth insight into cross-scale interactions between MPs and indigenous microbiota as well as the corresponding protein expression functions is necessary. Herein, we found that the addition of MPs in MBR resulted in massive growth of metazoans with 40-400 /mL for rotifers, 20-140 /mL for nematodes and 2-420 /mL for oligochaetes in the initial phase of granulation. This facilitated the MPs to rapidly aggregate with bacteria to form defensive granules for physical protection from predation by metazoans, which inhibited the overgrowth of filamentous bacteria Thiothrix and promoted the reproduction of functional bacteria related to nitrogen removal (Nitrospira, Trichococcus and Acinetobacter). Proteomic analysis demonstrated that the upregulation of functional proteins was mainly ascribed to the decrease of Thiothrix and the increase of Nitrospira, resulting in the enhancement of metabolic pathways involved in glycolysis/gluconeogenesis, citrate (TCA) cycle, oxidative phosphorylation, pyruvate metabolism, nitrogen metabolism and biosynthesis of amino acids, which was responsible for MPs-induced AGS with denser structure, more abundant proteins and ß-polysaccharides, higher species diversity, significant nitrogen removal (33.12-42.33%) and lower membrane fouling potential. This study provided a novel and comprehensive insight into the enhanced granulation of aerobic sludge by MPs and the functional superiority of MPs-induced AGS in MBR system.

Flow electrochemical inactivation of waterborne bacterial endospores.

Waterborne pathogens have the risk of spreading waterborne diseases and even pandemics. Some Gram-positive bacteria can form endospores, the hardiest known life form that can withstand heat, radiation, and chemicals. Electrochemical inactivation may offer a promising solution, but is hindered by low inactivation efficiencies resulting from limitation of electrode/endospores interaction in terms of electrochemical reaction selectivity and mass transfer. Herein, these issues were addressed through modifying selectivity of active species formation using electroactive ceramic membrane with high oxygen evolution potential, improving mass transfer property by flow-through operation. In this way, inactivation (6.0-log) of Bacillus atrophaeus endospores was achieved. Theoretical and experimental results demonstrated synergistic inactivation to occur through fragmentation of coat via interfacial electron transfer and electro-produced transient radicals (•OH primarily, •Cl and Cl2•- secondarily), thereby increasing cell permeability to facilitate penetration of electro-produced persistent active chlorine for subsequent rupture of intracellular structures. Numbering-up electrode module strategy was proposed to scale up the system, achieving average 5.3-log inactivation of pathogenic Bacillus anthracis endospores for 30 days. This study demonstrates a proof-of-concept manner for effective inactivation of waterborne bacterial endospores, which may provide an appealing strategy for wide-range applications like water disinfection, bio-safety control and defense against biological warfare.

Sex difference in effects of intermittent heat exposure on hepatic lipid and glucose metabolisms.

Global climate warming has drawn worldwide attention. However, the health impact of heat exposure is still controversial. This study aimed to explore the exact effects and sex differential vulnerability under intermittent heat exposure (IHE) patterns and tried to elucidate the potential mechanisms by which IHE modulated hepatic lipid and glucose homeostasis. Both female and male C57BL/6 N mice were randomly allocated to control group (22 ± 1 °C) or intermittent heat group (37 ± 1 °C for 6 h) for 9 consecutive days followed by 4-day recovery at 22 ± 1 °C in a whole-body exposure chamber. Male mice, but not female, being influenced by IHE with decreased body weight, improved insulin sensitivity and glucose tolerance. Next, the levels of hepatic triglyceride (TG) were decreased and free fatty acid (FFA) increased in male mice exposed to intermittent heat, accompanied with upregulated expression of anti-oxidative enzymes in the liver. In addition, IHE led to enhanced lipid catabolism in male mice by inducing fatty acid uptake, lipid lipolysis, mitochondrial/peroxisomal fatty acid oxidation and lipid export. And glycolysis and glucose utilization were induced by IHE in male mice as well. Mechanically, heat shock protein 70 (HSP70)/insulin receptor substrate 1 (IRS1)/AMPKα pathways were activated in response to IHE. These findings provide new evidence that IHE sex-dependently enhanced the metabolism of lipid and glucose in male mice through HSP70/IRS1/AMPKα signaling.

High serum IL-17A is associated with bone destruction in newly diagnosed multiple myeloma patients.

Background: Multiple myeloma (MM) is a malignant proliferative disease of the blood system, characterized by the abnormal growth of clonal plasma cells in the bone marrow. The bone marrow microenvironment (BMM) is highly critical in the pathological process of MM. Many studies have shown that serum interleukin-17A (IL-17A) plays a key role in various infectious diseases, autoimmune diseases, and cancers. However, more clinical studies need to be performed to further prove the influence of serum IL-17A levels on multiple myeloma patients. Methods: Among a total of 357 participants in our institution's MM cohort, 175 were eligible for the retrospective study. Multivariate regression models adjusted by potential confounding factors, the violin plots, the generalized additive model and smooth curve fittings, receiver operating characteristic (ROC) curve, and Kaplan-Meier (K-M) curve analysis were applied to the research. Results: A total of 175 patients with newly diagnosed MM were enrolled in this study. The multivariate linear regression analysis showed that serum IL-17A level in MM patients correlated with the degree of bone lesions and fracture incidence (fully adjusted model, pbone lesion < 0.0001, pfracture < 0.0001). The violin plot showed that MM patients with higher serum IL-17A levels had more severe bone lesions and higher fracture incidence than those with lower serum IL-17A levels. A total of 171 patients were included in the study of the relationship between serum IL-17A and best overall effect (BOE). We found that serum IL-17A levels were independently related to the best inductive therapeutic efficacy (fully adjusted model, p = 0.037), and the relationship was especially obvious in the light chain group (fully adjusted model, p = 0.009) and IgA group (fully adjusted model, p = 0.0456). It could be deduced from the smooth curve that the higher the serum IL-17A level, the worse the BOE (p = 0.0163). The ROC prediction curve suggested that serum IL-17A could predict the BOE to a certain extent (area under the curve (AUC) = 0.717, p = 0.0327). A total of 148 MM patients were observed in the longitudinal study of the relationship between serum IL-17A and progression-free survival/overall survival (PFS/OS). The K-M curve analysis indicated that serum IL-17A levels in MM patients were not significantly correlated with PFS and OS. However, in the light chain subgroup, MM patients with high serum IL-17A had worse PFS (p = 0.015) and OS (p = 0.0076) compared to those with low serum IL-17A. In the IgA type subgroup, the higher IL-17A level was related to worse OS (p = 0.0061). Conclusion: This retrospective study found that higher levels of serum IL-17A were independently correlated with higher severity of bone disease and fracture incidence in newly diagnosed MM patients. High serum IL-17A level was related to poor best overall efficacy in the light chain type. High serum IL-17A was also associated with poor PFS and OS in the light chain type and OS in the IgA type subgroup.

Target residence of Cas9-sgRNA influences DNA double-strand break repair pathway choices in CRISPR/Cas9 genome editing.

BACKGROUND: Due to post-cleavage residence of the Cas9-sgRNA complex at its target, Cas9-induced DNA double-strand breaks (DSBs) have to be exposed to engage DSB repair pathways. Target interaction of Cas9-sgRNA determines its target binding affinity and modulates its post-cleavage target residence duration and exposure of Cas9-induced DSBs. This exposure, via different mechanisms, may initiate variable DNA damage responses, influencing DSB repair pathway choices and contributing to mutational heterogeneity in genome editing. However, this regulation of DSB repair pathway choices is poorly understood. RESULTS: In repair of Cas9-induced DSBs, repair pathway choices vary widely at different target sites and classical nonhomologous end joining (c-NHEJ) is not even engaged at some sites. In mouse embryonic stem cells, weakening the target interaction of Cas9-sgRNA promotes bias towards c-NHEJ and increases target dissociation and reduces target residence of Cas9-sgRNAs in vitro. As an important strategy for enhancing homology-directed repair, inactivation of c-NHEJ aggravates off-target activities of Cas9-sgRNA due to its weak interaction with off-target sites. By dislodging Cas9-sgRNA from its cleaved targets, DNA replication alters DSB end configurations and suppresses c-NHEJ in favor of other repair pathways, whereas transcription has little effect on c-NHEJ engagement. Dissociation of Cas9-sgRNA from its cleaved target by DNA replication may generate three-ended DSBs, resulting in palindromic fusion of sister chromatids, a potential source for CRISPR/Cas9-induced on-target chromosomal rearrangements. CONCLUSIONS: Target residence of Cas9-sgRNA modulates DSB repair pathway choices likely through varying dissociation of Cas9-sgRNA from cleaved DNA, thus widening on-target and off-target mutational spectra in CRISPR/Cas9 genome editing.

Qianjinweijing Decoction Protects Against Fine Particulate Matter Exposure-mediated Lung Function Disorder.

Fine particulate matter (PM2.5) is well known to impair lung function. Strategies protecting against PM2.5-exerted lung dysfunction have been less investigated. Qianjinweijing decoction (QJWJ), a decoction of a herbal medicine of natural origin, has been used to treat lung disorders as it inhibits oxidation and inflammation. However, no clinical trial has yet evaluated the role of QJWJ in PM2.5-induced lung dysfunction. Therefore, we conducted a randomized, double-blind, placebo-controlled trial to assess whether QJWJ provided lung benefits against the adverse effects of PM2.5 exposure among adults. Eligible participants (n = 65) were recruited and randomized to receive QJWJ decoction (n = 32) or placebo (n = 33) for 4 weeks. The restrictive ventilatory defect (RVD), lung function parameters, and induced sputum were analyzed. The PM2.5 exposure concentration was significantly associated with the vital capacity (VC), peak expiratory flow (PEF), and forced expiratory flow at 75% of the forced vital capacity (FEF75). The negative associations between PM2.5 and the lung function parameters were eliminated in response to the QJWJ intervention. Additionally, the percentage of RVD (P = 0.018) and the proportion of eosinophils (Eo%) in induced sputum (P = 0.014) in the QJWJ group was significantly lower than that in the placebo group. This study demonstrated that QJWJ could alleviated PM2.5-induced lung dysfunction and could be a potential treatment for air pollution-related chronic respiratory disease.

Influencing factors of lung cancer patients' participation in shared decision-making: a cross-sectional study.

PURPOSE: The purpose of this study was to investigate and analyze the level of actual participation and perceived importance of shared decision-making on treatment and care of lung cancer patients, to compare their differences and to explore their influencing factors. METHODS: A total of 290 lung cancer patients were collected from oncology and thoracic surgery departments of a comprehensive medical center in Qingdao from October 2018 to December 2019. Participants completed a cross-sectional questionnaire to assess their actual participation and perceived importance in shared decision-making on treatment and care. Descriptive analysis and non-parametric tests were carried out to assess the status quo of patients' shared decision-making on treatment and care. Binary logistic regression analysis with a stepwise back-wards was applied to predict factors that affected patients' participation in shared decision-making. RESULTS: The results showed that patients with lung cancer had a low degree of participation in shared decision-making. There were significant differences between actual participation and perceived importance of shared decision-making on treatment and care. Education level, age, gender, income, marital status, personality, the course of the disease (> 6 months), and the pathological TNM staging (III) affected patient's level of participation in shared decision-making. CONCLUSION: Actual participation in shared decision-making on the treatment and care of lung cancer patients was low and considered unimportant. We could train oncology nurses to use patient decision aids to help patients and families participate in shared decision-making on patients' value, preferences and needs.

Baseline peripheral neuropathy was associated with age and a prognostic factor in newly diagnosed multiple myeloma patients.

Multiple myeloma (MM) is an incurable plasma cell hematological malignancy. Bortezomib has become the primary drug in the treatment of patients with MM. However, its negative effects, especially peripheral neuropathy (PN), affect the patients' life quality and treatment continuity. However, there are few studies on baseline PN of MM, and little is known of the impact of baseline PN on the prognosis of MM patients. Therefore, we reviewed the clinical data of newly diagnosed MM patients in our center, explored the influencing factors of baseline PN, and evaluated PN's influence on the prognosis of MM patients undergoing induction therapy with bortezomib. According to the inclusion and exclusion criteria, 155 MM patients were eligible for the retrospective study. The multivariate regression analysis, generalized additive fitting smooth curve, the receiver operating characteristic curve (ROC) and K-M curve were conducted in this study. We found that baseline PN in patients with MM was age-related; MM patients with baseline PN have more severe bortezomib induced PN (BiPN) during the four courses of induction therapy with bortezomib as the primary regimen and worse PN outcome after induction therapy. Additionally, the progression-free survival (PFS) and overall survival (OS) of MM patients with baseline PN were worse than those of the MM patients without baseline PN.

Flow-through electrochemical removal of benzotriazole by electroactive ceramic membrane.

Benzotriazole (BTA) is a widely used anticorrosive additive that is of endurance, bioaccumulation and toxicity, and BTA industrial wastewater treatment remains a challenge. This study reports efficient electrochemical removal of BTA by titanium oxide (TiSO) electroactive ceramic membrane (ECM), indicated by 98.1% removal at current density of 20 mA∙cm-2 and permeate flux of 692 LHM under cathode-to-anode flow pattern (1 h). Electrochemical analysis demonstrated the pH-dependent formation of anti-corrosive BTA film on the TiSO anode, which was responsible for improved BTA removal for cathode-to-anode (CA) flow pattern compared with that for anode-to-cathode (AC). The modelling results showed the CA flow pattern to be more favourable for BTA oxidation mediated by electro-generated •OH by preventing the formation of deactivation film via creating an alkaline boundary layer at the anode/electrolyte interface. Intermediates and essential active sites were identified by using experimental analysis and theoretical density functional theory (DFT) calculations, thereby the most likely degradation pathways were underlined. Toxicity analysis revealed remarkable decrease in oral rat LD50 values and bioaccumulation factor during electrochemical degradation of BTA. This study provides a proof-in-concept demonstration of effective removal for anti-corrosive emerging pollutants by TiSO-ECM under flow-through pattern.