Unraveling the potential of senescence-related genes in guiding clinical therapy of lung adenocarcinoma patients.

Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer. In recent years, cell senescence emerges as a potential therapeutic target of cancer therapy. However, the role of cell senescence in LUAD has not been comprehensively unveiled. One single cell RNA sequencing (scRNA-seq) dataset (GSE149655) and two bulk RNA-seq datasets (TCGA and GSE31210) of LUAD were included. Seurat R package was used to process scRNA-seq data and identify immune cell subgroups. Single sample gene set enrichment analysis (ssGSEA) was performed to calculate enrichment score of senescence-related pathways. Senescence-based molecular subtyping for LUAD samples was conducted through unsupervised consensus clustering. pRRophetic package was introduced to analysis drug sensitivity. The senescence-associated risk model was established using univariate regression and stepAIC methods. Western blot, RT-qPCR, immunofluorescence assay and CCK-8 were used to explore the effect of CYCS in LUAD cell lines. Malignant immune cells had remarkedly higher enrichment of senescence-related pathways than non-malignant cells. P53 signaling and DNA damage telomere stress induced senescence pathways were found to be significantly activated in LUAD samples compared with normal samples. We identified two clusters (clust1 and clust2) based on senescence-related genes. Clust1 had severe genomic instability, aggravated senescent features, and low immune and stromal infiltration. The senescence-associated risk model including CASP9, CHEK1, CYCS, SERPINE1, SESN2, TP53I3, LMNB1, RAD50 and TERF2IP, was effective to distinguish high- and low-risk groups. Moreover, low-risk group exhibited sensitive responses to immunotherapy and chemotherapeutic drugs. In vitro experiments results showed that CYCS expression was increased and promoted cell viability in LUAD cell lines. This study explored the important role of senescence in LUAD progression, and confirmed the potential of senescence-related genes in predicting LUAD prognosis and response to immunotherapy and chemotherapy.

Withdrawn: MicroRNA-214-3p protects against myocardial ischemia-reperfusion injury by targeting demethylase lysine demethylase 3A.

The above article from Cell Biology International, published online on 5 December 2022, on Wiley Online Library (https://doi.org/10.1002/cbin.11920), has been withdrawn by agreement between the journal Editor in Chief, Sergio Schenkman, and John Wiley and Sons Ltd. The withdrawal has been agreed due to a technical error at the publisher that caused the article to be mistakenly published online.

Tn3-like structures co-harboring of blaCTX-M-65, blaTEM-1 and blaOXA-10 in the plasmids of two Escherichia coli ST1508 strains originating from dairy cattle in China.

The purpose of this study was to determine the level of horizontal transmission of the blaCTX-M-65 gene and the role of its associated mobile genetic elements (MGEs) in the bovine-derived Escherichia coli. After PCR identification, two plasmids carrying blaCTX-M-65 were successfully transferred to the recipient E. coli J53 Azr through conjugation assays and subsequently selected for Whole-Genome sequencing (WGS) analysis. The resistance profiles of these two positive strains and their transconjugants were also determined through antimicrobial susceptibility tests. Whole genome data were acquired using both the PacBio sequencing platform and the Illumina data platform. The annotated results were then submitted to the Genbank database for accession number recording. For comparison, the genetic environment of plasmids carrying the resistance gene blaCTX-M-65 was mapped using the Easyfig software. WGS analysis revealed Tn3-like composite transposons bearing blaCTX-M-65, blaTEM-1, and blaOXA-10 in the IncHI2-type plasmids of these two E. coli ST1508 strains. A phylogenetic tree was generated from all 48 assembled E. coli isolates blaCTX-M-65, blaTEM-1, and blaOXA-10 from the NCBI Pathogen Detection database with our two isolates, showing the relationships and the contribution of SNPs to the diversity between genetic samples. This study suggests that the transmissibility of blaCTX-M-65 on Tn3-like composite transposons contributes to an increased risk of its transmission in E. coli derived from dairy cattle.

PET/CT morphology and cardiac conduction disorders help discriminate primary cardiac lymphoma from primary cardiac sarcoma.

BACKGROUND: Primary cardiac lymphoma (PCL) and primary cardiac sarcoma (PCS) are similar in clinical presentation but differ in management and outcomes. We aim to explore the role of PET morphology and clinical characteristics in distinguishing PCL from PCS. METHODS: Pretreatment 18F-FDG PET/CT and contrast-enhanced CT were performed in PCL (n = 14) and PCS (n = 15) patients. Patient demographics, overall survival, and progression-free survival were reviewed. PET/CT morphological and metabolic features were extracted. Specifically, R_Kurtosis, a PET-morphology parameter reflecting the tumor expansion within the heart, was calculated. RESULTS: Compared with PCS, PCL occurred at an older age, resulted in more cardiac dysfunctions and arrhythmias, and showed higher glucometabolism (SUVmax, SUVpeak, SUVmean, MTV, and TLG). Curative treatments improved survival for PCL but not for PCS. Multivariable logistic regression identified R_Kurtosis (OR = 27.025, P = .007) and cardiac conduction disorders (OR = 37.732, P = .016) independently predictive of PCL, and classification and regression tree analysis stratified patients into three subgroups: R_Kurtosis ≥ 0.044 (probability of PCL 88.9%), R_Kurtosis < 0.044 with conduction disorders (80.0%), and R_Kurtosis < 0.044 without conduction disorders (13.3%). CONCLUSION: PET-derived tumor expansion pattern (R_Kurtosis) and cardiac conduction disorders were helpful in distinguishing PCL from PCS, which might assist the clinical management.

Novel Antibiofilm Inhibitor Ginkgetin as an Antibacterial Synergist against Escherichia coli.

As an opportunistic pathogen, Escherichia coli (E. coli) forms biofilm that increases the virulence of bacteria and antibiotic resistance, posing a serious threat to human and animal health. Recently, ginkgetin (Gin) has been discovered to have antiinflammatory, antioxidant, and antitumor properties. In the present study, we evaluated the antibiofilm and antibacterial synergist of Gin against E. coli. Additionally, Alamar Blue assay combined with confocal laser scanning microscope (CLSM) and crystal violet (CV) staining was used to evaluate the effect of antibiofilm and antibacterial synergist against E. coli. Results showed that Gin reduces biofilm formation, exopolysaccharide (EPS) production, and motility against E. coli without limiting its growth and metabolic activity. Furthermore, we identified the inhibitory effect of Gin on AI-2 signaling molecule production, which showed apparent anti-quorum sensing (QS) properties. The qRT-PCR also indicated that Gin reduced the transcription of curli-related genes (csgA, csgD), flagella-formation genes (flhC, flhD, fliC, fliM), and QS-related genes (luxS, lsrB, lsrK, lsrR). Moreover, Gin showed obvious antibacterial synergism to overcome antibiotic resistance in E. coli with marketed antibiotics, including gentamicin, colistin B, and colistin E. These results suggested the potent antibiofilm and novel antibacterial synergist effect of Gin for treating E. coli infections.

Primary cardiac lymphoma: the management and outcome of a single-centre cohort of 22 patients.

BACKGROUND: The incidence of primary cardiac lymphoma (PCL) is increasing, but the optimal management approach remains unclear. We assessed the clinical characteristics of a single-centre cohort with the goal of determining the optimal management approach. The treatment outcomes and prognostic factors are reported. MATERIAL AND METHODS: All PCL patients were diagnosed via biopsy guided by whole-body imaging (positron emission tomography/computed tomography [PET/CT] and/or contrast-enhanced CT]. Curative therapy involved either surgery or prephase steroids followed by definitive immunochemotherapy, depending on the histological type. The primary outcomes were overall survival (OS) and progression-free survival (PFS); the secondary outcome was the treatment response. RESULTS: Twenty-two PCL patients (14 males, 8 females; age: 59.5 ± 14.7 years [mean ± S.D.]) were histologically confirmed to have diffuse large B-cell lymphoma (DLBCL; n = 17 [77.3%]), fibrin-associated DLBCL (FA-DLBCL) (n = 4 [18.2%]) and Burkitt lymphoma (n = 1 [4.5%]). Seven patients underwent cardiotomy (three for biopsy, four with curative intent). The median and longest follow-up periods were 16.3 and 180.0 months, respectively. The 16 patients who received curative therapy (complete response [CR], n = 15 [93.8%]; partial response [PR], n = 1 [6.2%]) showed better survival than those who did not (5-year OS: 83.0 ± 11.3% vs. 0%; hazard ratio [HR]: 0.025[95% confidence interval, CI: 0.003-0.187], p < 0.001); 5-year PFS: 78.7 ± 11.0% vs. 0%, HR= 0.010[0.001-0.093], p < 0.001). The left ventricular ejection fractions (LVEF) before and after definitive treatment was 63.6 ± 2.4% and 64.6 ± 4.5%, respectively (p = 0.275, power = 0.318). Extrapericardial lesions were associated with poorer survival (5-year OS: 40.0 ± 29.7% vs. 100%, p = 0.027; 5-year PFS:40.0 ± 21.9% vs. 100%, p = 0.010). CONCLUSIONS: Whole-body imaging is essential for diagnosis and prognosis. Curative therapy provided reasonable outcomes and survival; extrapericardial lesions were associated with a poorer treatment response.

Primary resistance to first-generation EGFR-TKIs induced by MDM2 amplification in NSCLC.

INTRODUCTION: Targeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. However, 20-30% of patients demonstrate primary resistance to EGFR-TKIs, which leads to the failure of EGFR-TKI treatment. The mechanisms of primary resistance to EGFR-TKIs require further study. METHODS: Targeted sequencing was used for the detection of genomic alterations among patients in our center. Regular cell culture and transfection with plasmids were used to establish NSCLC cell lines over-expressing MDM2 and vector control. We used the MTT assays to calculate the inhibition rate after exposure to erlotinib. Available datasets were used to determine the role of MDM2 in the prognosis of NSCLC. RESULTS: Four patients harboring concurrent sensitive EGFR mutations and MDM2 amplifications demonstrated insensitivity to EGFR-TKIs in our center. In vitro experiments suggested that MDM2 amplification induces primary resistance to erlotinib. Over-expressed MDM2 elevated the IC50 value of erlotinib in HCC2279 line and reduced the inhibition rate. In addition, MDM2 amplification predicted a poor prognosis in NSCLC patients and was associated with a short PFS in those treated with EGFR-TKIs. The ERBB2 pathway was identified as a potential pathway activated by MDM2 amplification could be the focus of further research. CONCLUSION: MDM2 amplification induces the primary resistance to EGFR-TKIs and predicts poor prognosis in NSCLC patients. MDM2 may serve as a novel biomarker and treatment target for NSCLC. Further studies are needed to confirm the mechanism by which amplified MDM2 leads to primary resistance to EGFR-TKIs.

Target animal safety testing of an oral salicylanilide suspension, oxyclozanide, for the treatment of fascioliasis in bovine in China.

The aim of this study was to determine the potential toxicity risk of an oxyclozanide suspension to the target animal, bovine. In this experiment, 32 Simmental beef cattle were fattened and fed a full-price diet without antimicrobial agents. The test cattle were divided into 4 groups, which were treated with 0, 1, 3, and 5 times the recommended dosage through continuous intermittent oral administration at intervals of 2 days. The body weight of the cattle was recorded before and after the experiment, and the weight changes were calculated. The safety of the drugs was evaluated by weight gain, observation of clinical toxicity, haematology, clinical chemistry and histopathology. The results showed that the cattle had different degrees of diarrhoea, loss of appetite and depression after administration. The results of clinicopathology had no significant effect. The results of pathological examination showed that there was a certain degree of damage in the 5 times recommended dose group. The recommended dose was safe to use. Thus, the recommended dose should be given by a single oral administration to ensure the safe use of this drug in the clinic.

ALK expression plays different roles in anaplastic large-cell lymphomas and outcome of crizotinib use in relapsed/refractory ALK+ patients in a Chinese population.

The prognostic value of anaplastic lymphoma kinase (ALK) expression in patients with anaplastic large-cell lymphoma (ALCL) remains controversial. Data on the clinical features of ALCL in a Chinese population are limited. We retrospectively reviewed 1293 patients with pathologically diagnosed lymphoma at Guangdong General Hospital from June 2007 through August 2016. We evaluated the incidence of ALCL, clinical characteristics, survival status, and outcome of crizotinib use in four relapsed/refractory ALK-positive patients. Among the 1293 patients, 1193 (92.3%) were non-Hodgkin's lymphoma, and 53 (4.4%) of whom were ALCL. Of the 50 ALCL patients, with a median age of 34 years, were evaluated. Among them, 33 (66.0%) were ALK-positive and 17 (34.0%) were ALK-negative. Significantly, more patients younger than 40 years old were ALK-positive than ALK-negative (66.7 vs. 23.5%; P = 0.003). The 5-year progression-free survival (PFS) for ALK-positive and ALK-negative patients were 61 and 11%, and the 5-year overall survival (OS) were 70 and 22%, respectively. Median PFS and OS were significantly better for patients with ALK-positive than ALK-negative (60.1 vs. 9.4 months, P = 0. 017; not reached vs. 32.7 months, P = 0.021). Multivariate analyses identified ALK expression, stage, and bone marrow involvement as independent prognostic factors for PFS and OS. Four relapsed ALK-positive patients were treated with crizotinib and two died. Our results suggest that ALK expression has different prognostic significance in patients with ALCL. Mechanisms underlying early relapse after chemotherapy and resistance to crizotinib need further investigation.

Determination of antibacterial agent tilmicosin in pig plasma by LC/MS/MS and its application to pharmacokinetics.

A rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify tilmicosin in pig plasma. Plasma samples were prepared by liquid-liquid extraction. Chromatographic separation was achieved on a C18 column (2.1 × 30 mm, 3.5 µm) using acetonitrile-water (90:10, v/v; water included 0.1% formic acid) as the mobile phase. Mass detection was carried out using positive electrospray ionization in multiple reaction monitoring mode. The calibration curve was linear from 0.5 to 2000 ng/mL (r2 = 0.9998). The intra- and inter-day accuracy and precision were within the acceptable limits of ±10% for all tilmicosin concentrations. The recoveries ranged from 95 to 99% for the three tested concentrations. The LC-MS/MS method described herein was simple, fast and less laborious than other methods, achieved high sensitivity using a small sample volume, and was successfully applied to pharmacokinetic studies of tilmicosin enteric granules after oral delivery to pigs. In comparison with tilmicosin premix, tilmicosin enteric granules slowed the elimination rate of tilmicosin, prolonged its period of action and significantly improved its bioavailability.

Co-expression of ILT4/HLA-G in human non-small cell lung cancer correlates with poor prognosis and ILT4-HLA-G interaction activates ERK signaling.

Non-small cell lung cancer (NSCLC) is the most common malignant tumor in the world, of which prognosis is generally poor due to insufficient mechanistic understanding. To explore the molecular pathogenesis of NSCLC, the co-expression of immunoglobulin-like transcript 4 (ILT4) and its ligand human leukocyte antigen G (HLA-G) in NSCLC tissues and cells were investigated. Here, we detected the expression of ILT4 and HLA-G in 81 tumor specimens from primary NSCLC patients, and we found that co-expression of ILT4/HLA-G was significantly associated with regional lymph node involvement, advanced stages, and the overall survival of patients. In NSCLC cell lines, HLA-G expression increased/decreased accordingly when ILT4 was up-/down-regulated, and ILT4 expression increased in a concentration-dependent manner via the stimulation of HLA-G fusion protein. Interestingly, HLA-G fusion protein could also up-regulate the phospho-ERK1/2 expression, which means the activation of extracellular signal-regulated kinase (ERK) signaling. All in all, our results indicate that the ILT4-HLA-G interaction might play an important role in NSCLC progression. Identification of ILT4 and HLA-G expression may provide an indicator to predict prognosis and guide prevention and treatment of NSCLC.

Bone marrow mesenchymal stem cell-derived microvesicles protect rat pheochromocytoma PC12 cells from glutamate-induced injury via a PI3K/Akt dependent pathway.

Studies have suggested that mesenchymal stem cells (MSCs) can protect neuronal cells from excitotoxicity, but the underlying mechanisms are still remaining elusive. In the study, we show that microvesicles released by rat bone marrow-derived MSCs (rBMSC-MVs) protect rat pheochromocytoma PC12 cells from glutamate-induced excitotoxicity. BMSC-MVs upregulate Akt phosphorylation and Bcl-2 expression, downregulate Bax expression, and reduce the cleavage of caspase-3 in glutamate-treated PC12 cells. Such protective effects are partially abrogated by inhibiting PI3K, indicating that rBMSC-MVs act via the PI3K/Akt pathway. Transplantation of rBMSC-MVs may, therefore, be a promising strategy to treat cerebral injury or some other neuronal diseases involving excitotoxicity.

Potential diagnostic markers shared between non-alcoholic fatty liver disease and atherosclerosis determined by machine learning and bioinformatic analysis.

Background: Evidence indicates that chronic non-alcoholic fatty liver disease (NAFLD) can increase the risk of atherosclerosis (AS), but the underlying mechanism remains unclear. Objective: This study is intended for confirming key genes shared between NAFLD and AS, and their clinical diagnostic value to establish a foundation for searching novel therapeutic targets. Methods: We downloaded the Gene Expression Omnibus (GEO) datasets, GSE48452 and GSE89632 for NAFLD and GSE100927, GSE40231 and GSE28829 for AS. The progression of NAFLD co-expression gene modules were recognized via weighted gene co-expression network analysis (WGCNA). We screened for differentially expressed genes (DEGs) associated with AS and identified common genes associated with NAFLD and AS using Venn diagrams. We investigated the most significant core genes between NAFLD and AS using machine learning algorithms. We then constructed a diagnostic model by creating a nomogram and evaluating its performance using ROC curves. Furthermore, the CIBERSORT algorithm was utilized to explore the immune cell infiltration between the two diseases, and evaluate the relationship between diagnostic genes and immune cells. Results: The WGCNA findings associated 1,129 key genes with NAFLD, and the difference analysis results identified 625 DEGs in AS, and 47 genes that were common to both diseases. We screened the core RPS6KA1 and SERPINA3 genes associated with NAFLD and AS using three machine learning algorithms. A nomogram and ROC curves demonstrated that these genes had great clinical meaning. We found differential expression of RPS6KA1 in patients with steatosis and NASH, and of SERPINA3 only in those with NASH compared with normal individuals. Immune infiltration findings revealed that macrophage and mast cell infiltration play important roles in the development of NAFLD and AS. Notably, SERPINA3 correlated negatively, whereas RPS6KA1 correlated positively with macrophages and mast cells. Conclusion: We identified RPS6KA1 and SERPINA3 as potential diagnostic markers for NAFLD and AS. The most promising marker for a diagnosis of NAFLD and AS might be RPS6KA1, whereas SERPINA3 is the most closely related gene for NASH and AS. We believe that further exploration of these core genes will reveal the etiology and a pathological relationship between NAFLD and AS.

Global research trends of antibiotic-loaded bone cement: A bibliometric and visualized study.

Objective: Antibiotic-loaded bone cement (ALBC) plays an indispensable role in the treatment of infectious diseases of bone and joint. Here, we intended to analyze the research status, hot spots and frontiers in the field of ALBC, and to provide reference for future research ideas. Methods: The related English literature in the field of ALBC in the Web of Science Core Collection database was retrieved from January 1, 2009 to July 11, 2023. VOSviewer was used to extract the information of research constituents or bibliometric items such as authors, institutions, countries, and journals. CiteSpace was used to perform cluster analysis and frontier analysis of key words in ALBC research field. Results: A total of 1091 literatures related to ALBC research were retrieved, and the annual number of publications showed a steady upward trend in the past 15 years. The high-yield countries and regions are mainly represented by the United States, China (including Taiwan, China) and several European countries, such as Germany, England, Spain, Italy, the Netherlands, etc. The top three institutions with the highest number of publications were Shanghai Jiao Tong University, Chang Gung University and Chang Gung Memorial Hospital in China. Four of the top 10 influential scholars come from Germany, namely Konstantinos Anagnostakos, Volker Alt, Andrej Trampuz, and Bernd Fink. The top 10 high-yield journals had an average of 25 articles per journal and an average of 618.9 citations. The top 3 high-yield journals were Journal of Arthroplasty (57 articles, 1213 citations), Clinical Orthopaedics and Related Research (35 articles, 1119 times cited), and Journal of Orthopaedic Research (29 papers, 488 times cited). The keywords with high frequency were infection (266 times), vancomycin (239 times), bone-cement (219 times), gentamicin (216 times), antibiotics (168 times), osteomyelitis (163 times), etc. The clustering knowledge map of high-frequency keywords could be divided into 4 categories: (1) elution, release, mechanical and antibacterial properties of ALBC; (2) Application of ALBC in revision of prosthetic joint infections (PJIs); (3) Antibiotic types and application forms of ALBC; (4) Application of ALBC in the treatment of osteomyelitis. The keywords with the strongest citation bursts analysis revealed a core ("replacement/arthroplasty") and two stages of development in the field of ALBC research. The first stage (2009-2018) focused more on ALBC drug delivery, release, and infection prevention, while the second stage (2018-2023) mainly focused on ALBC drug elution, mechanical properties, and PJIs revision. Starting from 2018, the keyword with the strongest citation bursts had shifted from "acrylic bone cement" to "periprosthetic joint infection". Conclusion: ALBC research is steadily on the rise. Arthroplasty related applications continue to be the core of ALBC research. The research hotspot and trend are mainly the application in the prevention and treatment of bone and joint infectious diseases and the elution, release, mechanical and antibacterial properties of ALBC.

T-cell lymphoma patient harboring BCL11B mutations had favorable overall survival.

BACKGROUND: Molecular genetics serve a critical role in constructing risk stratification for hematological malignancies, but T-cell lymphoma (TCL) still lacks molecular genetic information for supplement risk stratification in predicting the prognosis of TCL patients. In the present study, we characterized the mutation patterns of B-cell leukemia/lymphoma 11B gene (BCL11B) and its prognostic importance in TCL patients. METHODS: BCL11B mutations were characterized based on the data from two datasets, one is from our clinical center (GDPH dataset, n = 79) and the other is from COSMIC dataset (n = 154). RESULTS: The overall mutation rate of BCL11B was 6.4% (15/233) in TCL, and there were no hotspot mutation sites in TCL. Among these mutations, the missense and splice site mutation were significantly prominent. Moreover, TCL patients harboring BCL11B mutations had a favorable overall survival (OS) in our center (GDPH dataset) (adjusted hazard ratio [HR] = .001, p = 0.109), although there were not yet significantly statistical at this point. In addition, TCL patients harboring BCL11B mutation had a longer 5-year restricted mean survival time (RMST) than those without a BCL11B mutation (60 vs. 32 months). Notably, BCL11B mutations were not associated with TCL entities having better prognosis. CONCLUSIONS: BCL11B mutations were associated with favorable clinical outcome for TCL patients; it might be considered as a novel biomarker for TCL prognostic stratification.

The prevalent dynamic and genetic characterization of mcr-1 encoding multidrug resistant Escherichia coli strains recovered from poultry in Hebei, China.

OBJECTIVES: Colistin is known as the last resort antibiotic to treat the infections caused by multidrug resistant foodborne pathogens. The emergence and widespread dissemination of plasmid-mediated colistin resistance gene mcr-1 in the Escherichia coli (E. coli) incurs potential threat to public health. Here, we investigated the epidemiology, transmission dynamics, and genetic characterization of mcr-1 harbouring E. coli isolates from poultry originated in Hebei Province, China. METHODS: A total of 297 faecal samples were collected from the two large poultry farms in Hebei Province, China. The samples were processed for E. coli identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry and 16S rDNA sequencing. Then, the mcr-1 gene harbouring E. coli strains were identified by polymerase chain reaction and subjected to antimicrobial susceptibility testing by broth microdilution assay. The genomic characterization of the isolates was done by whole genome sequencing using the various bioinformatics tools, and multi-locus sequence typing was done by sequence analysis of the seven housekeeping genes. The conjugation experiment was done to check the transferability of mcr-1 along with the plasmid stability testing. RESULTS: A total of six mcr-1 E. coli isolates with minimum inhibitory concentration of 4 µg/mL were identified from 297 samples (2.02%). The mcr-1 harbouring E. coli were identified as multidrug resistant and belonged to ST101 (n = 4) and ST410 (n = 2). The genetic environment of mcr-1 presented its position on IncHI2 plasmid in 4 isolates and p0111 in 2 isolates, which is a rarely reported plasmid type for mcr-1. Moreover, both type of plasmids was transferable to recipient J53, and mcr-1 was flanked by 3 mobile elements ISApl1, Tn3, and IS26 forming a novel backbone Tn3-IS26-mcr-1- pap2-ISApl1 on the p0111 plasmid. The phylogenetic analysis shared a common lineage with mcr-1 harbouring isolates from the environment, humans, and animals, which indicate its horizontal spread among the diverse sources, species, and hosts. CONCLUSION: This study recommends the one health approach for future surveillance across multiple sources and bacterial species to adopt relevant measures and reduce global resistance crises.

The impact of bolus on clinical outcomes for post-mastectomy breast cancer patients treated with IMRT: data from China.

PURPOSE: This study aims to investigate the effects of chest wall bolus in intensity-modulated radiotherapy (IMRT) technology on clinical outcomes for post-mastectomy breast cancer patients. MATERIALS AND METHODS: This retrospective study included patients with invasive carcinoma ((y)pT0-4, (y)pN0-3) who received photon IMRT after mastectomy at the Affiliated Hospital of Qingdao University from 2014 to 2019. The patients were divided into two groups based on whether they received daily bolus application or not, and the baseline characteristics were matched using propensity score matching (PSM). Cumulative incidence (CI) of local recurrence (LR), locoregional recurrence (LRR), overall survival (OS) and disease-free survival (DFS) were evaluated with a log-rank test. Acute skin toxicity and late radiation pneumonia was analyzed using chi-square test. RESULTS: A total of 529 patients were included in this study, among whom 254 (48%) patients received bolus application. The median follow-up time was 60 months. After matching, 175 well-paired patients were selected. The adjusted 5-year outcomes (95% confidence interval) in patients treated with and without bolus were, respectively: CI of LR 2.42% (0.04-4.74) versus 2.38% (0.05-4.65), CI of LRR 2.42% (0.04-4.74) versus 3.59% (0.73-6.37), DFS 88.12% (83.35-93.18) versus 84.69% (79.42-90.30), OS 94.21% (90.79-97.76) versus 95.86% (92.91-98.91). No correlation between bolus application and skin toxicity (P = 0.555) and late pneumonia (P = 0.333) was observed. CONCLUSIONS: The study revealed a low recurrence rate using IMRT technology. The daily used 5 mm chest wall bolus was not associated with improved clinical outcomes.

Polyene phosphatidylcholine enhances the therapeutic response of oxaliplatin in gastric cancer through Nrf2/HMOX1 mediated ferroptosis.

Oxaliplatin (OXA)-based chemotherapy is one of the first-line treatments for advanced gastric cancer. However, the potential risk for chemotherapy-induced hepatic injury can hinder its effectiveness. Polyene phosphatidylcholine (PPC) is often used as a hepatoprotective agent to counter OXA-induced hepatic injury; however, its impact on the antitumour effectiveness of OXA remains uncertain. Our retrospective study examined 98 patients with stage IV gastric cancer to assess the impact of PPC on progression-free survival (PFS) and disease control rate (DCR). Furthermore, in vitro and in vivo assays were conducted to elucidate the combined biological effects of OXA and PPC (OXA+PPC) on gastric cancer. RNA sequencing, luciferase reporter assays, live/dead cell assays, immunofluorescence, and western blotting were used to identify the activated signalling pathways and downstream factors post OXA+PPC treatment. The findings indicated that PPC served as an independent prognostic factor, correlating with prolonged PFS and improved DCR in patients with gastric cancer. The combination of OXA and PPC significantly inhibited tumour cell growth both in vitro and in vivo. RNA sequencing revealed that OXA+PPC treatment amplified reactive oxygen species and ferroptosis signalling pathways. Mechanistically, OXA+PPC upregulated the expression of haem oxygenase-1 by promoting the nuclear migration of nuclear factor erythroid 2-related factor (Nrf2), thereby enhancing its transcriptional activity. Drug-molecule docking analysis demonstrated that PPC competitively bound to the peptide structural domains of both Nrf2 and Kelch-like ECH-associated protein 1 (KEAP1), accounting for the increased translocation of Nrf2. In conclusion, our study reveals the synergistic antitumour potential of PPC and OXA while protecting patients against hepatic injury. This suggests a promising combined treatment approach for patients with advanced gastric cancer.

PD-(L)1 inhibitors plus bevacizumab and chemotherapy as first-line therapy in PD-L1-negative metastatic lung adenocarcinoma: a real-world data.

BACKGROUND: Chemotherapy combined with immune checkpoint inhibitors (IC), bevacizumab (BC), or both (IBC) is the preferred first-line therapy for PD-L1-negative and oncogenic-driver wild-type metastatic lung adenocarcinoma. However, the optimal strategy is still undetermined. METHODS: This retrospective study enrolled PD-L1-negative metastatic lung adenocarcinoma patients from four cancer centers between January 1, 2018 and June 30, 2022. All the patients received IC, BC, or IBC as the first-line therapies. The efficacy and safety were evaluated. RESULTS: A total of 205 patients were included, with 60, 83, and 62 patients in IC, BC, and IBC groups, respectively. The baseline characteristics among three groups were well balanced. Patients treated with IBC had the highest objective response rate (ORR) (43.5%) and disease control rate (DCR) (100%) relative to those treated with IC (40.4%, 84.2%) or BC (40.5%, 96.2%) (ORR: P = 0.919, DCR: P < 0.01). Compared with the IC (6.74 m) or BC (8.28 m), IBC treatment significantly improved median progression-free survival (mPFS) (9.53 m, P = 0.005). However, no difference in overall survival (OS) was observed. When stratified by different clinical and molecular information, we found that male gender, ever smoking, wild-type genes mutations, and adrenal metastasis predict superior PFS benefit when treated with IBC. In patients with liver metastasis, IBC or BC treatment displayed better PFS compared with IC. No additional adverse reactions were observed in IBC group compared with other two groups. CONCLUSION: Combined IBC treatment achieved superior DCR and PFS compared with IC or BC in patients with PD-L1-negative metastatic lung adenocarcinoma, while did not increase the adverse events.

Enhanced osteochondral regeneration with a 3D-Printed biomimetic scaffold featuring a calcified interfacial layer.

The integrative regeneration of both articular cartilage and subchondral bone remains an unmet clinical need due to the difficulties of mimicking spatial complexity in native osteochondral tissues for artificial implants. Layer-by-layer fabrication strategies, such as 3D printing, have emerged as a promising technology replicating the stratified zonal architecture and varying microstructures and mechanical properties. However, the dynamic and circulating physiological environments, such as mass transportation or cell migration, usually distort the pre-confined biological properties in the layered implants, leading to undistinguished spatial variations and subsequently inefficient regenerations. This study introduced a biomimetic calcified interfacial layer into the scaffold as a compact barrier between a cartilage layer and a subchondral bone layer to facilitate osteogenic-chondrogenic repair. The calcified interfacial layer consisting of compact polycaprolactone (PCL), nano-hydroxyapatite, and tasquinimod (TA) can physically and biologically separate the cartilage layer (TA-mixed, chondrocytes-load gelatin methacrylate) from the subchondral bond layer (porous PCL). This introduction preserved the as-designed independent biological environment in each layer for both cartilage and bone regeneration, successfully inhibiting vascular invasion into the cartilage layer and preventing hyaluronic cartilage calcification owing to devascularization of TA. The improved integrative regeneration of cartilage and subchondral bone was validated through gross examination, micro-computed tomography (micro-CT), and histological and immunohistochemical analyses based on an in vivo rat model. Moreover, gene and protein expression studies identified a key role of Caveolin (CAV-1) in promoting angiogenesis through the Wnt/ß-catenin pathway and indicated that TA in the calcified layer blocked angiogenesis by inhibiting CAV-1.