Identifying optimal surgical approach among T1N2-3M0 non-small cell lung cancer patients: a population-based analysis.

Background: Whether stage T1N2-3M0 non-small cell lung cancer (NSCLC) patients could benefit from surgery and the optimal surgical procedure have remained controversial and unclear. This study aimed to investigate whether stage T1N2-3M0 NSCLC can benefit from different surgery types and develop a tool for survival prediction. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with stage T1N2-3M0 NSCLC between 2000 and 2015. A 1:1 propensity score-matched (PSM) analysis was used to balance the distribution of clinical characteristics. Survival analyses were performed by using the Kaplan-Meier (KM) curves and Cox proportional hazards regression. All patients were randomly split at a ratio of 7:3 into training and validation cohorts. The nomogram was constructed by integrating all independent predictors for overall survival (OS) and cancer-specific survival (CSS). The model's performance was evaluated by discrimination, calibration ability, and risk stratification ability. Results: A total of 4,671 patients were enrolled. After 1:1 PSM, the distribution proportions of clinical characteristics in 1,146 patients were balanced (all P>0.05). The non-surgical approach was associated with worse survival compared with sublobectomy and lobectomy in the unmatched and matched cohorts. The multivariate Cox analysis showed that sublobectomy and lobectomy were both related to better OS and CSS rates compared with no surgery (P<0.001). Moreover, the results of subgroup analyses based on age, N stage, and radiotherapy or chemotherapy strategy were consistent. A total of 801 patients were included in the training cohort and 345 cases constituted the validation cohort. The nomogram constructed for the 1-, 3-, and 5-year OS and CSS prediction showed good discrimination, performance, and calibration both in the training and validation sets. Significant distinctions in survival curves between different risk groups stratified by prognostic scores were also observed (all P<0.001). Conclusions: Stage T1N2-3M0 NSCLC patients could benefit from sublobectomy or lobectomy, and lobectomy provides better survival benefits. We developed and validated nomograms, which could offer clinicians instructions for strategy making.

PD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featured with enhanced adaptive immunosuppression.

Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

A comprehensive study on machine learning models combining with oversampling for bronchopulmonary dysplasia-associated pulmonary hypertension in very preterm infants.

BACKGROUND: Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) remains a devastating clinical complication seriously affecting the therapeutic outcome of preterm infants. Hence, early prevention and timely diagnosis prior to pathological change is the key to reducing morbidity and improving prognosis. Our primary objective is to utilize machine learning techniques to build predictive models that could accurately identify BPD infants at risk of developing PH. METHODS: The data utilized in this study were collected from neonatology departments of four tertiary-level hospitals in China. To address the issue of imbalanced data, oversampling algorithms synthetic minority over-sampling technique (SMOTE) was applied to improve the model. RESULTS: Seven hundred sixty one clinical records were collected in our study. Following data pre-processing and feature selection, 5 of the 46 features were used to build models, including duration of invasive respiratory support (day), the severity of BPD, ventilator-associated pneumonia, pulmonary hemorrhage, and early-onset PH. Four machine learning models were applied to predictive learning, and after comprehensive selection a model was ultimately selected. The model achieved 93.8% sensitivity, 85.0% accuracy, and 0.933 AUC. A score of the logistic regression formula greater than 0 was identified as a warning sign of BPD-PH. CONCLUSIONS: We comprehensively compared different machine learning models and ultimately obtained a good prognosis model which was sufficient to support pediatric clinicians to make early diagnosis and formulate a better treatment plan for pediatric patients with BPD-PH.

New genetic insights into immunotherapy outcomes in gastric cancer via single-cell RNA sequencing and random forest model.

OBJECTIVE: The high mortality rate of gastric cancer, traditionally managed through surgery, underscores the urgent need for advanced therapeutic strategies. Despite advancements in treatment modalities, outcomes remain suboptimal, necessitating the identification of novel biomarkers to predict sensitivity to immunotherapy. This study focuses on utilizing single-cell sequencing for gene identification and developing a random forest model to predict immunotherapy sensitivity in gastric cancer patients. METHODS: Differentially expressed genes were identified using single-cell RNA sequencing (scRNA-seq) and gene set enrichment analysis (GESA). A random forest model was constructed based on these genes, and its effectiveness was validated through prognostic analysis. Further, analyses of immune cell infiltration, immune checkpoints, and the random forest model provided deeper insights. RESULTS: High METTL1 expression was found to correlate with improved survival rates in gastric cancer patients (P = 0.042), and the random forest model, based on METTL1 and associated prognostic genes, achieved a significant predictive performance (AUC = 0.863). It showed associations with various immune cell types and negative correlations with CTLA4 and PDCD1 immune checkpoints. Experiments in vitro and in vivo demonstrated that METTL1 enhances gastric cancer cell activity by suppressing T cell proliferation and upregulating CTLA4 and PDCD1. CONCLUSION: The random forest model, based on scRNA-seq, shows high predictive value for survival and immunotherapy sensitivity in gastric cancer patients. This study underscores the potential of METTL1 as a biomarker in enhancing the efficacy of gastric cancer immunotherapy.

EGC enhances tumor antigen presentation and CD8+ T cell-mediated antitumor immunity via targeting oncoprotein SND1.

The Staphylococcal nuclease and Tudor domain containing 1 (SND1) has been identified as an oncoprotein. Our previous study demonstrated that SND1 impedes the major histocompatibility complex class I (MHC-I) assembly by hijacking the nascent heavy chain of MHC-I to endoplasmic reticulum-associated degradation. Herein, we aimed to identify inhibitors to block SND1-MHC-I binding, to facilitate the MHC-I presentation and tumor immunotherapy. Our findings validated the importance of the K490-containing sites in SND1-MHC-I complex. Through structure-based virtual screening and docking analysis, (-)-Epigallocatechin (EGC) exhibited the highest docking score to prevent the binding of MHC-I to SND1 by altering the spatial conformation of SND1. Additionally, EGC treatment resulted in increased expression levels of membrane-presented MHC-I in tumor cells. The C57BL/6J murine orthotopic melanoma model validated that EGC increases infiltration and activity of CD8+ T cells in both the tumor and spleen. Furthermore, the combination of EGC with programmed death-1 (PD-1) antibody demonstrated a superior antitumor effect. In summary, we identified EGC as a novel inhibitor of SND1-MHC-I interaction, prompting MHC-I presentation to improve CD8+ T cell response within the tumor microenvironment. This discovery presents a promising immunotherapeutic candidate for tumors.

[Retracted] Downregulation of CKS1B restrains the proliferation, migration, invasion and angiogenesis of retinoblastoma cells through the MEK/ERK signaling pathway.

Following the publication of the above paper, it has been drawn to the Editors' attention by a concerned reader that certain of the lumen formation assay data shown in Fig. 5A on p. 112 were strikingly similar to data appearing in different form in another article written by different authors at different research institute, which had already been published in the journal Biomedicine & Pharmacotherapy prior to the submission of this paper to International Journal of Molecular Medicine, and which has also subsequently been retracted. In view of the fact that the contentious data had already apparently been published previously, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 103­114, 2019; DOI: 10.3892/ijmm.2019.4183].

Nutrition Risk Screening 2002 for Adult Cancer Patients: A Systematic Review and Meta-Analysis.

It is critical to screen and assess malnutrition in cancer patients early. However, there is no uniform standard for nutritional risk screening and malnutrition assessment. We aimed to analyze the effects of the Nutrition Risk Screening 2002 (NRS2002) in screening for nutritional risk among adult cancer patients, using the Patient-Generated Subjective Global Assessment (PG-SGA) as the reference standard. A systematic search was performed using PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, and China Science and Technology Journal Database (VIP). Studies comparing NRS2002 with PG-SGA in adult cancer patients were included. To assess the quality of the included studies, the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used. The combined sensitivity, specificity, diagnostic odds ratio (DOR), and the area under the receiver-operating characteristic curve (AUC) were calculated. In addition, sensitivity, subgroup, and publication bias analyses were performed. Thirteen articles involving 3,373 participants were included. The combined sensitivity, specificity, DOR, and AUC were 0.62 (95% CI, 0.60-0.64), 0.86 (95% CI, 0.84-0.88), 11.23 (95% CI, 8.26-15.27), and 0.85 (95% CI, 0.82-0.88), respectively. For adult cancer patients, NRS2002 has moderate sensitivity, high specificity, and high AUC in screening for nutritional risk.

Knocking-down long non-coding RNA LINC01094 prohibits chondrocyte apoptosis via regulating microRNA-577/metal-regulatory transcription factor 1 axis.

PURPOSE: The abnormal function and survival of chondrocytes result in articular cartilage failure, which may accelerate the onset and development of osteoarthritis (OA). This study is aimed to investigate the role of LINC01094 in chondrocyte apoptosis. METHODS: The viability and apoptosis of lipopolysaccharide (LPS)-induced chondrocytes were evaluated through CCK-8 assay and flow cytometry analysis, respectively. The expression levels of LINC01094, miR-577 and MTF1 were detected by qRT-PCR. Dual luciferase reporter tests were implemented for the verification of targeted relationships among them. Western blotting was employed to measure the levels of pro-apoptotic proteins (Caspase3 and Caspase9). RESULTS: The viability of LPS-induced chondrocytes was overtly promoted by loss of LINC01094 or miR-577 upregulation, but could be repressed via MTF1 overexpression. The opposite results were observed in apoptosis rate and the levels of Caspase3 and Caspase9. LINC01094 directly bound to miR-577, while MTF1 was verified to be modulated by miR-577. Both LINC01094 and MTF1 were at high levels, whereas miR-577 was at low level in OA synovial fluid and LPS-induced chondrocytes. Furthermore, the highly expressed miR-577 abolished the influences of MTF1 overexpression on LPS-induced chondrocytes. CONCLUSIONS: Silencing of LINC01094 represses the apoptosis of chondrocytes through upregulating miR-577 expression and downregulating MTF1 levels, providing a preliminary insight for the treatment of OA in the future.

Improvement of skin wound healing by giant salamander skin mucus gel wrapped with bone marrow mesenchymal stem cells via affecting integrin family molecules.

BACKGROUND: Traditional bandages, gauze, and cotton balls are increasingly insufficient for addressing complex war injuries characterized by severe bleeding and diverse wound conditions. The giant salamander, a species of high medical value, secretes a unique mucus when stimulated, which has potential applications in wound care. MATERIALS: Giant salamander skin mucus gel dressing wrapped with bone marrow mesenchymal stem cells (BMSCs-GSSM-gel) was prepared and validated. Skin wound injury of rabbit and mouse models were established. Hematoxylin and Eosin, Masson's trichrome, and Sirius red staining were performed. The platelet aggregation rate and coagulation items were measured. Transcriptome sequencing was performed to find potential differential expression genes. RESULTS: Preparation and characterization of BMSCs-GSSM-gel were performed, and BMSCs-GSSM-gel particles with a diameter of about 200 nm were obtained. BMSCs-GSSM-gel accelerated wound healing in both rabbit and mouse models. BMSCs-GSSM-gel significantly promoted hemostasis via increasing platelet aggregation rate and fibrinogen, but decreasing activated partial thromboplastin time, thrombin time, and prothrombin time. BMSCs-GSSM-gel treatment significantly impacted several genes associated with cell adhesion, inflammatory response, collagen-containing extracellular matrix, and the positive regulation of cell migration based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Integrin Subunit Beta 4 (ITGB4), Integrin Subunit Alpha 3 (ITGA3), and Laminin Subunit Beta 3 (LAMB3) might be involved in the wound healing process by BMSCs-GSSM-gel. CONCLUSIONS: We proved the BMSCs-GSSM-gel greatly improved the skin wound healing, and it might play a crucial role in the application fields of skin damage repair.

Endovascular treatment versus standard medical treatment in patients with established large infarct: a cohort study.

BACKGROUND: Previous trials confirmed the benefit of endovascular treatment (EVT) in acute large core stroke, but the effect of EVT on outcomes in these patients based on non-contrast computed tomography (NCCT) in real-world clinical practice was unclear. The aim of this study was to explore the effect of EVT versus standard medical treatment (SMT) in patients with large ischemic core stroke defined as Alberta Stroke Program Early CT Score (ASPECTS)≤5 based on NCCT alone. MATERIALS AND METHODS: Patients with acute large core stroke at 38 Chinese centers between November 2021 and February 2023 were reviewed from prospectively maintained databases. The primary outcome was favorable functional outcome (modified Rankin Scale score [mRS], 0-3) at 90 days. Safety outcomes included 48-hour symptomatic intracerebral hemorrhage (sICH) and 90-day mortality. RESULTS: Of 745 eligible patients recruited at 38 stroke centers between November 2021 and February 2023, 490 were treated with EVT and 255 with SMT alone. One hundred and eighty-one (36.9%) in the EVT group achieved favorable functional independence versus 48 (18.8%) treated with SMT only (adjusted risk ratio [RR], 1.86; 95% CI, 1.43 to 2.42, P<0.001; adjusted risk difference [RD], 13.77; 95% CI, 7.40 to 20.15, P<0.001). The proportion of sICH was significantly higher in patients undergoing EVT (13.3% vs. 2.4%; adjusted RR, 5.17; 95% CI, 2.17 to 12.32, P<0.001; adjusted RD, 10.10; 95% CI, 6.12 to 14.09, P<0.001). No significant difference of mortality between the groups was observed (41.8% vs. 49.0%; adjusted RR, 0.91; 95% CI, 0.77 to 1.07, P=0.24; adjusted RD, -5.91; 95% CI, -12.91 to 1.09, P=0.1). CONCLUSION: Among patients with acute large core stroke based on NCCT in real world, EVT is associated with better functional outcomes at 90 days despite of higher risk of sICH. Rates of procedure-related complications were high in the EVT group.

Antitumor Activity and Mechanistic Insights of a Mitochondria-Targeting Cu(I) Complex.

Using copper-ionophores to translocate extracellular copper into mitochondria is a clinically validated anticancer strategy that has been identified as a new type of regulated cell death termed "cuproptosis." This study reports a mitochondria-targeting Cu(I) complex, Cu(I)Br(PPh3)3 (CBP), consisting of a cuprous ion coordinated by three triphenylphosphine moieties and a Br atom. CBP exhibited antitumor and antimetastatic efficacy in vitro and in vivo by specifically targeting mitochondria instigating mitochondrial dysfunction. The cytotoxicity of CBP could only be reversed by a copper chelator rather than inhibitors of the known cell death, indicating copper-dependent cytotoxicity. Furthermore, CBP induced the oligomerization of lipoylated proteins and the loss of Fe-S cluster proteins, consistent with characteristic features of cuproptosis. Additionally, CBP induced remarkable intracellular generation of reactive oxygen species (ROS) through a Fenton-like reaction, indicating a complex antitumor mechanism. This is a proof-of-concept study exploiting the antitumor activity and mechanism of the Cu(I)-based mitochondria-targeting therapy.

Association of healthy lifestyle with self-reported sleep disordered breathing: A cross-sectional study.

Some healthy lifestyle components have been linked with sleep disordered breathing (SDB), yet little is known about the relationship between comprehensive lifestyle factors and SDB. This study aimed to examine the healthy lifestyle with SDB in community-dwelling adults. We conducted a cross-sectional analysis of the Suzhou Food Consumption and Health Survey in China between 2018 and 2020. The healthy lifestyle index (HLI) was created by combining smoking, alcohol drinking, diet, physical activity, and body mass index (BMI). Its association with SDB was assessed by multiple logistic regression analysis. Subgroup analysis and sensitivity analysis were conducted to assess the robustness of our results. The final analysis included 3788 participants (2859 without SDB and 929 with SDB). In multivariable-adjusted analyses, non-smoking (OR: 0.58, 95 % CI: 0.47-0.71), non-drinking (OR: 0.55, 95 % CI: 0.45-0.68), healthy diet (OR: 0.79, 95 % CI: 0.65-0.95), and healthy BMI (OR: 0.72, 95 % CI: 0.6-0.86) were associated with SDB. Compared with participants with HLI score of 0-1, participants with HLI score of 2, 3, 4, and 5 had OR of 0.68 (95 % CI: 0.51-0.91), 0.49 (95 % CI: 0.37-0.64), 0.29 (95 % CI: 0.21-0.38), and 0.22 (95 % CI: 0.15-0.33), respectively, after adjustment for confounding factors (P-trend<0.001). An inverse dose-response relationship between HLI and SDB was also observed. The association was similar in subgroups stratified by sex, marital status, diabetes and dyslipidemia. A higher score of HLI was associated with reduced odds of SDB in Chinese adults. Our findings suggest the potential of addressing five modifiable lifestyle factors for the prevention of SDB.

Sensitive and effective method with 96-well plate for determination of levamlodipine in human plasma using LC-MS/MS.

we developed an effective protein precipitation method for determination of levamlodipine in human plasma using LC-MS/MS. Sample extraction was carried out by using liquid-liquid extraction in 96-well plate format. (S)-Amlodipine-d4 was used as internal standard (IS). The chromatographic separation was achieved using Philomen Chiral MX (2) column (3 µm, 2.1 × 100 mm). Mobile phase A was comprised of Acetonitrile (ACN), Mono ethanol amine (MEA) and Iso-Propyl alcohol (IPA) (1000:1:10, v/v/v), Mobile phase B was IPA-ACN (2:1, v/v). The flow rate was 0.4 mL/min. The total run time of each sample was 4.0 min with gradient elution. LC-MS/MS spectra were generated in positive ion mode, and multiple reaction monitoring (MRM) was used to detect the following transitions: m/z 409.20 â†’ 238.15 for levamlodipine and 415.25 â†’ 240.20 for (S)-Amlodipine-d4 (the IS). The method was linear from 50 to 10000 pg/mL（R2＝0.9988489）,and the lower limit of quantification (LLOQ) was 50 pg/mL. This method was applied to a bioequivalence study of levamlodipine.

Facilely Modified Nickel-Based Hole Transporting Layers for Organic Solar Cells with 19.12% Efficiency and Enhanced Stability.

Hole transporting layers (HTLs), strategically positioned between electrode and light absorber, play a pivotal role in shaping charge extraction and transport in organic solar cells (OSCs). However, the commonly used poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) HTL, with its hygroscopic and acidic nature, undermines the operational durability of OSC devices. Herein, an environmentally friendly approach is developed utilizing nickel acetate tetrahydrate (NiAc·4H2O) and [2-(9H-carbazol-9-yl)ethyl] phosphonic acid (2PACz) as the NiAc·4H2O/2PACz HTL, aiming at overcoming the limitations posed by the conventional PEDOT:PSS one. Encouragingly, a remarkable power conversion efficiency (PCE) of 19.12% is obtained for the OSCs employing NiAc·4H2O/2PACz as the HTL, surpassing that of devices with the PEDOT:PSS HTL (17.59%), which is ranked among the highest ones of OSCs. This improvement is attributed to the appropriate work function, enhanced hole mobility, facilitated exciton dissociation efficiency, and lower recombination loss of NiAc·4H2O/2PACz-based devices. Furthermore, the NiAc·4H2O/2PACz-based OSCs exhibit superior operational stability compared to their PEDOT:PSS-based counterparts. Of significant note, the NiAc·4H2O/2PACz HTL demonstrates a broad generality, boosting the PCE of the PM6:PY-IT and PM6:Y6-based OSCs from 16.47% and 16.79% (with PEDOT:PSS-based analogs as HTLs) to 17.36% and 17.57%, respectively. These findings underscore the substantial potential of the NiAc·4H2O/2PACz HTL in advancing OSCs, offering improved performance and stability, thereby opening avenue for highly efficient and reliable solar energy harvesting technologies.

Codonopsis Radix inhibits the inflammatory response and oxidative stress in Chronic Obstructive Pulmonary Disease mice through regulation of the Nrf2/NF-κB signaling pathway.

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is a non-specific chronic inflammatory lung disease with no known cure. Codonopsis Radix(CR) has been shown to exhibit anti-inflammatory and antioxidant effects. Therefore, this study aimed to investigate the potential anti-inflammatory effects of different CR variety on COPD mice. METHODS: 60 male specified pathogen free (SPF)-grade C57BL/6J mice were randomly divided into 6 groups, 10 mice in each group. The COPD mice model was induced by cigarette smoke extract (CSE) combined with lipopolysaccharide (LPS), and the mice in each group were given corresponding drugs. Lung function was assessed in all mice. Lung tissues were stained with hematoxylin-eosin (HE), Masson, and periodic acid shiff (PAS) stains, and serum levels of interleukin (IL)-8 and tumor necrosis factor (TNF)-α were detected using an enzyme-linked immunosorbent assay (ELISA). Further, serum and lung tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by colorimetric assay. Network pharmacology and molecular docking was used to predict signalling pathways, which were validated by western blot analysis. RESULTS: Compared with the COPD group, the mice in each dosing group of CR exhibited significant reductions in serum IL-8 and TNF-α levels, serum and lung tissue MDA levels, and pathological lung tissue damage, alongside elevations in lung function and SOD levels (P<0.01). Western blot analysis also indicated significant down-regulation of p-p65/p65 and p-IκB-α/IκB-α protein expression, alongside significant up-regulation of Nrf2 protein expression in the lung tissues of mice treated with CR (P<0.01). CONCLUSION: In summary, CR effectively enhances lung function, minimizes lung tissue damage, and inhibits inflammation and oxidative stress in mice with COPD. Additionally, these findings suggest that inhibition of the Nrf2/NF-κB axis may be a key mechanism of action of CR in the alleviation of COPD.

Quinoline-based compounds can inhibit diverse enzymes that act on DNA.

DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a crucial epigenetic mechanism driving numerous vital biological processes. Developing non-nucleoside inhibitors to cause DNA hypomethylation is a high priority, in order to treat a variety of significant medical conditions without the toxicities associated with existing cytidine-based hypomethylating agents. In this study, we have characterized fifteen quinoline-based analogs. Notably, compounds with additions like a methylamine ( 9 ) or methylpiperazine ( 11 ) demonstrate similar low micromolar inhibitory potency against both human DNMT1 (which generates C5-methylcytosine) and Clostridioides difficile CamA (which generates N6-methyladenine). Structurally, compounds 9 and 11 specifically intercalate into CamA-bound DNA via the minor groove, adjacent to the target adenine, leading to a substantial conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation, following the discovery of dicyanopyridine-based inhibitors for DNMT1. Furthermore, our study shows that some of these quinoline-based analogs inhibit other enzymes that act on DNA, such as polymerases and base excision repair glycosylases. Finally, in cancer cells compound 11 elicits DNA damage response via p53 activation. Highlights: Six of fifteen quinoline-based derivatives demonstrated comparable low micromolar inhibitory effects on human cytosine methyltransferase DNMT1, and the bacterial adenine methyltransferases Clostridioides difficile CamA and Caulobacter crescentus CcrM. Compounds 9 and 11 were found to intercalate into a DNA substrate bound by CamA. These quinoline-based derivatives also showed inhibitory activity against various base excision repair DNA glycosylases, and DNA and RNA polymerases. Compound 11 provokes DNA damage response via p53 activation in cancer cells.

PTPLAD1 Regulates PHB-Raf Interaction to Orchestrate Epithelial-Mesenchymal and Mitofusion-Fission Transitions in Colorectal Cancer.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The poor prognosis of this malignancy is attributed mainly to the persistent activation of cancer signaling for metastasis. Here, we showed that protein tyrosine phosphatase-like A domain containing 1 (PTPLAD1) is down-regulated in highly metastatic CRC cells and negatively associated with poor survival of CRC patients. Systematic analysis reveals that epithelial-to-mesenchymal transition (EMT) and mitochondrial fusion-to-fission (MFT) transition are two critical features for CRC patients with low expression of PTPLAD1. PTPLAD1 overexpression suppresses the metastasis of CRC in vivo and in vitro by inhibiting the Raf/ERK signaling-mediated EMT and mitofission. Mechanically, PTPLAD1 binds with PHB via its middle fragment (141-178 amino acids) and induces dephosphorylation of PHB-Y259 to disrupt the interaction of PHB-Raf, resulting in the inactivation of Raf/ERK signaling. Our results unveil a novel mechanism in which Raf/ERK signaling activated in metastatic CRC induces EMT and mitochondrial fission simultaneously, which can be suppressed by PTPLAD1. This finding may provide a new paradigm for developing more effective treatment strategies for CRC.

The Impact of New Regulations on Prevention and Control of E-Cigarettes on Adolescents in Middle Schools - A City in China, 2022-2023.

What is already known about this topic?: To protect the health of young people from the harmful impacts of electronic cigarettes (e-cigarettes), China has enacted various policies and regulations since 2018. As of October 1, 2022, the Electronic Cigarette Management Measures were put into action. They prohibited the sale of flavored e-cigarettes, permitting only those of plain tobacco flavor to be sold. What is added by this report?: The illegal market for flavored e-cigarettes, often disguised as milk tea cups, cola cans, and violent bear images, continues to flourish. There is an increased need to bolster support for the prohibition of flavored e-cigarettes and enhance public awareness of associated regulations. What are the implications for public health practice?: To advance the health of China's youth, it is crucial to improve the implementation and understanding of e-cigarette policies and guidelines.

Transcranial Direct Current Stimulation for Anxiety During Laparoscopic Colorectal Cancer Surgery: A Randomized Clinical Trial.

Importance: Perioperative anxiety is prevalent among patients undergoing surgical treatment of cancer and often influences their prognosis. Transcranial direct current stimulation (tDCS) has shown potential in the treatment of various anxiety-related disorders, but data on the impact of tDCS on perioperative anxiety are limited. Objective: To evaluate the effect of tDCS in reducing perioperative anxiety among patients undergoing laparoscopic colorectal cancer (CRC) resection. Design, Setting, And Participants: This randomized clinical trial was conducted from March to August 2023 at the Affiliated Hospital of Xuzhou Medical University. Patients aged 18 years or older undergoing elective laparoscopic radical resection for CRC were randomly assigned to either the active tDCS group or the sham tDCS group. Intention-to-treat data analysis was performed in September 2023. Interventions: Patients were randomly assigned to receive 2 sessions of either active tDCS or sham tDCS over the left dorsolateral prefrontal cortex on the afternoon of the day before the operation and in the morning of the day of operation. Main Outcomes and Measures: The main outcome was the incidence of perioperative anxiety from the day of the operation up to 3 days after the procedure, as measured using the Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale (range: 0-21, with higher scores indicating more anxiety). Secondary outcomes included postoperative delirium (assessed by the Confusion Assessment Method or Confusion Assessment Method intensive care unit scale); pain (assessed by the 10-point Numeric Rating Scale [NRS], with scores ranging from 0 [no pain] to 10 [worst pain]); frailty (assessed by the Fatigue, Resistance, Ambulation, Illness and Loss of Weight [FRAIL] Index, with scores ranging from 0 [most robust] to 5 [most frail]; and sleep quality (assessed by the Pittsburgh Sleep Quality Index [PSQI], with scores ranging from 0 to 21 and higher scores indicating worse sleep quality) after the 2 sessions of the tDCS intervention. Results: A total of 196 patients (mean [SD] age, 63.5 [11.0] years; 124 [63.3%] men) were recruited and randomly assigned to the active tDCS group (98 patients) or the sham tDCS group (98 patients). After the second tDCS intervention on the day of the operation, the incidence of perioperative anxiety was 38.8% in the active tDCS group and 70.4% in the sham tDCS group (relative risk, 0.55 [95% CI, 0.42-0.73]; P < .001). Patients in the active tDCS group vs the sham tDCS group were less likely to have postoperative delirium (8.2% vs 25.5%) and, at 3 days after the operation, had lower median (IQR) pain scores (NRS, 1.0 [1.0-1.0] vs 2.0 [2.0-2.0]), better median (IQR) sleep quality scores (PSQI, 10.5 [10.0-11.0] vs 12.0 [11.0-13.0]), and lower median (IQR) FRAIL Index (2.0 [1.0-2.0] vs 2.0 [2.0-3.0]). Conclusions and Relevance: Findings of this randomized clinical trial indicate that administration of 2 preoperative sessions of tDCS was associated with a decreased incidence of perioperative anxiety in patients undergoing elective CRC resection. Active tDCS was also associated with better anxiety scores, pain levels, and sleep quality as well as reduced postoperative delirium and frailty. The findings suggest that tDCS may be a novel strategy for improving perioperative anxiety in patients undergoing CRC resection. Trial Registration: Chinese Clinical Trial Register Identifier: ChiCTR2300068859.

Extracellular vesicles derived from M2-like macrophages alleviate acute lung injury in a miR-709-mediated manner.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is characterised by an uncontrolled inflammatory response, and current treatment strategies have limited efficacy. Although the protective effect of M2-like macrophages (M2φ) and their extracellular vesicles (EVs) has been well-documented in other inflammatory diseases, the role of M2φ-derived EVs (M2φ-EVs) in the pathogenesis of ALI/ARDS remains poorly understood. The present study utilised a mouse model of lipopolysaccharide-induced ALI to first demonstrate a decrease in endogenous M2-like alveolar macrophage-derived EVs. And then, intratracheal instillation of exogenous M2φ-EVs from the mouse alveolar macrophage cell line (MH-S) primarily led to a take up by alveolar macrophages, resulting in reduced lung inflammation and injury. Mechanistically, the M2φ-EVs effectively suppressed the pyroptosis of alveolar macrophages and inhibited the release of excessive cytokines such as IL-6, TNF-α and IL-1ß both in vivo and in vitro, which were closely related to NF-κB/NLRP3 signalling pathway inhibition. Of note, the protective effect of M2φ-EVs was partly mediated by miR-709, as evidenced by the inhibition of miR-709 expression in M2φ-EVs mitigated their protective effect against lipopolysaccharide-induced ALI in mice. In addition, we found that the expression of miR-709 in EVs derived from bronchoalveolar lavage fluid was correlated negatively with disease severity in ARDS patients, indicating its potential as a marker for ARDS severity. Altogether, our study revealed that M2φ-EVs played a protective role in the pathogenesis of ALI/ARDS, partly mediated by miR-709, offering a potential strategy for assessing disease severity and treating ALI/ARDS.