Vector genome loss and epigenetic modifications mediate decline in transgene expression of AAV5 vectors produced in mammalian and insect cells.

Recombinant adeno-associated virus (rAAV) vectors are often produced in HEK293 or Spodoptera frugiperda (Sf)-based cell lines. We compared expression profiles of "oversized" (∼5,000 bp) and "standard-sized" (4,600 bp) rAAV5-human α1-antitrypsin (rAAV5-hA1AT) vectors manufactured in HEK293 or Sf cells and investigated molecular mechanisms mediating expression decline. C57BL/6 mice received 6 × 1013 vg/kg of vector, and blood and liver samples were collected through week 57. For all vectors, peak expression (weeks 12-24) declined by 50% to week 57. For Sf- and HEK293-produced oversized vectors, serum hA1AT was initially comparable, but in weeks 12-57, Sf vectors provided significantly higher expression. For HEK293 oversized vectors, liver genomes decreased continuously through week 57 and significantly correlated with A1AT protein. In RNA-sequencing analysis, HEK293 vector-treated mice had significantly higher inflammatory responses in liver at 12 weeks compared with Sf vector- and vehicle-treated mice. Thus, HEK293 vector genome loss led to decreased transgene protein. For Sf-produced vectors, genomes did not decrease from peak expression. Instead, vector genome accessibility significantly decreased from peak to week 57 and correlated with transgene RNA. Vector DNA interactions with active histone marks (H3K27ac/H3K4me3) were significantly reduced from peak to week 57, suggesting that epigenetic regulation impacts transgene expression of Sf-produced vectors.

Effect of single-port video-assisted thoracoscopy on surgical site wound infection and healing in patients with lung cancer: A meta-analysis.

We performed a meta-analysis to comprehensively assess the effect of single-port video-assisted thoracoscopy on surgical site wound infection and healing in patients with lung cancer. A computerised search for studies on single-port video-assisted thoracoscopy treatment of lung cancer was conducted from the time of database creation through February 2023 using the PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases. Two investigators independently screened the literature, extracted information, and evaluated the quality of studies according to inclusion and exclusion criteria. Either a fixed or random-effects model was used in calculating the relative risk (RR) with 95% confidence intervals (CIs). Meta-analysis was performed using RevMan 5.4 software. The results showed that, compared with multi-port video-assisted thoracoscopy, single-port video-assisted thoracoscopy significantly reduced surgical site wound infection (RR: 0.38, 95% CI: 0.19-0.77, P = .007) and significantly promoted wound healing (RR: 0.37, 95% CI: 0.22-0.64, P < .001). Compared with multi-port video-assisted thoracoscopy, single-port video-assisted thoracoscopy significantly reduced surgical site wound infections and also promoted wound healing. However, because of large variations in study sample sizes, some of the literature reported methods of inferior quality. Additional high-quality studies containing large sample sizes are needed to further validate these results.

The protective effects of trelagliptin on high-fat diet-induced nonalcoholic fatty liver disease in mice.

Nonalcoholic fatty liver disease (NAFLD) occurs in patients with type 2 diabetes mellitus (T2DM). Trelagliptin is an important member of the Gliptins family, which has been recently licensed for the treatment of T2DM. However, the pharmacological function of trelagliptin in NAFLD has not been previously reported. In this study, we aimed to investigate the roles of trelagliptin in the development of NAFLD in a mouse model. To induce NAFLD disease, C57BL/6 mice were fed a high-fat diet for 10 weeks. Our results indicate that trelagliptin reduced plasma lipid levels in NAFLD mice by reducing triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Treatment with trelagliptin exhibited an improvement in insulin resistance. More important, trelagliptin improved liver function by reducing alanine transaminase, aspartate transaminase, lactate dehydrogenase, and total bile acid. In addition, trelagliptin ameliorated oxidative stress in the liver of NAFLD mice by reducing malondialdehyde and increasing the levels of reduced glutathione and superoxide dismutase activity. Also, the enzyme-linked immunosorbent assay results indicate that trelagliptin-treated mice displayed anti-inflammatory properties by reducing the levels of interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor-α. Hematoxylin and eosin and Oil red O staining show that trelagliptin treatment ameliorates liver tissue damage and hepatic lipid deposition. Mechanistically, we found that the administration of trelagliptin reduced the activity of hepatic nuclear factor-κB but increased the activity of AMP-activated protein kinase. These findings suggest that trelagliptin might become a promising therapeutic agent for the treatment of NAFLD.

Long noncoding RNA NSCLCAT1 increases non-small cell lung cancer cell invasion and migration through the Hippo signaling pathway by interacting with CDH1.

Metastatic growth is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC). Metastasis is believed to be initiated by an increase in cell motility mediated by the loss of cell-cell adhesion because of the suppression of E-cadherin [encoded by cadherin 1 ( CDH1)]. However, very little is known about the molecular mechanism of CDH1 regulation. Therefore, we hypothesized that non-small cell lung cancer-associated transcript-1 (NSCLCAT1) suppresses functional CDH1 and mediates the Hippo signaling pathway, resulting in increased cell migration and invasion, and reduced apoptosis. Initially, microarray profiling and target prediction programs were employed to identify whether NSCLCAT1 targets CDH1. Next, quantitative PCR was used to determine the expression pattern of NSCLCAT1 in 114 specimens. The biologic functions of NSCLCAT1 in NSCLC were assessed through the up-regulation and down-regulation of the levels of endogenous NSCLCAT1 with the use of NSCLCAT1 vector or small interfering RNA against NSCLCAT1 in NSCLC cells. Furthermore, the Hippo signaling pathway in NSCLC cells was blocked by applying the verteporfin treatment to have a better understanding on the pivotal role of the Hippo signaling pathway in NSCLC. Microarray expression profiles of long noncoding RNAs, GSE19804 and GSE27262), revealed that NSCLCAT1 was up-regulated in NSCLC. Among patients with NSCLC, we determined that the NSCLCAT1 was robustly induced, whereas CDH1 was suppressed. The luciferase activity determination identified CDH1 as a NSCLCAT1 target. NSCLCAT1 was found to increase cell viability, migration, and invasion and to reduce apoptosis in NSCLC cells. The results from the quantitative PCR and Western blot analysis revealed that NSCLCAT1 modulated the Hippo signaling pathway. Furthermore, the inhibition of the Hippo signaling pathway by verteporfin treatment led to the loss of the effect of NSCLCAT1 on NSCLC cells. In summary, our findings suggested that NSCLCAT1 potentially has a role in NSCLC and NSCLCAT1-mediated regulation of the Hippo signaling pathway through the transcriptional repression of CDH1; therefore, the functional suppression or inhibition of NSCLCAT1 could be used as a novel therapeutic pathway in the control of aggressive and metastatic NSCLC.-Zhao, W., Zhang, L.-N., Wang, X.-L., Zhang, J., Yu, H.-X. Long noncoding RNA NSCLCAT1 increases non-small cell lung cancer cell invasion and migration through the Hippo signaling pathway by interacting with CDH1.

Of mice and men: Plasma phenylalanine reduction in PKU corrects neurotransmitter pathways in the brain.

In phenylketonuria (PKU), mutations of the phenylalanine hydroxylase (PAH) gene decrease the ability of PAH to convert phenylalanine (Phe) to tyrosine (Tyr), resulting in Phe accumulation in the blood and brain and disruption of neurotransmitter (NT) biosynthesis and metabolism. The following translational study explored the relationship between pegvaliase-mediated Phe correction in plasma and the NT biosynthesis and metabolism pathway in mice and humans with PKU. Lower plasma Phe levels were associated with normalization of the NT biosynthesis pathway which correlated with an improvement in inattention symptoms in subjects with PKU.

Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice.

Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding the factor VIII (FVIII) coagulation protein. Bleeding episodes in patients are reduced by prophylactic therapy or treated acutely using recombinant or plasma-derived FVIII. We have made an adeno-associated virus 5 vector containing a B domain-deleted (BDD) FVIII gene (BMN 270) with a liver-specific promoter. BMN 270 injected into hemophilic mice resulted in a dose-dependent expression of BDD FVIII protein and a corresponding correction of bleeding time and blood loss. At the highest dose tested, complete correction was achieved. Similar corrections in bleeding were observed at approximately the same plasma levels of FVIII protein produced either endogenously by BMN 270 or following exogenous administration of recombinant BDD FVIII. No evidence of liver dysfunction or hepatocyte endoplasmic reticulum stress was observed. Comparable doses in primates produced similar levels of circulating FVIII. These preclinical data support evaluation of BMN 270 in hemophilia A patients.

Involvement of the TLR4/NF-κB Signaling Pathway in the Repair of Esophageal Mucosa Injury in Rats with Gastroesophageal Reflux Disease.

BACKGROUND/AIMS: Numerous studies have highlighted the activation of NF-κB in the esophageal mucosa during the early stages of gastroesophageal reflux disease (GERD). The present study aimed to investigate the role of the TLR4/NF-κB signaling pathway in GERD rat models. METHODS: Wistar rats (n = 60) were recruited to establish a GERD animal model. Distal esophageal pH was assessed, followed by determination of the contents of thiobarbituric acid-reactive species (TBARS) and reactive oxygen species (ROS) in esophageal mucosa homogenate. ELISA was employed to detect the levels of inflammatory factors (IL-6, IL-8, IL-10 and TNF-α) in esophageal mucosa. The expression of MMP-3, MPP-9, Cldn1 and Cldn4 was determined by immunohistochemistry. RT-qPCR and western blot analysis were applied to evaluate the protein expressions in TLR4/NF-κB signaling pathway, while TUNEL staining was utilized to examine the apoptosis rate in the esophageal mucosal tissues. RESULTS: Distal esophageal pH of the rats was higher in the GERD + PDTC group than in other groups. Levels of inflammatory factors in esophageal mucosal tissues were downregulated with the inhibition of NF-κB, which was determined to be associated with the decreased contents of TBARS and ROS. Moreover, decreased MMP-3 and MPP-9 in addition to elevated Cldn1 and Cldn4 were detected in the esophageal mucosa as a result of the inactivation of NF-κB. The TLR4/NF-κB signaling pathway-related proteins (TLR4, NF-κB and IκBα); the rate of apoptosis was demonstrated to be suppressed in the GERD + PDTC group, while inactivating NF-κB was found to alleviate the tissue damage observed in the esophageal mucosa. CONCLUSION: The key findings of the current study demonstrate that the inactivation of the TLR4/NF-κB signaling pathway alleviates oxidative stress injury and promotes the repair of esophageal mucosal injury among rats with GERD, highlighting a potential novel GERD mechanism.

MicroRNAs used as novel biomarkers for detecting cancer metastasis.

The low survival rates of cancers are primarily due to late diagnosis and metastasis. Discriminating the metastasis is a crucial factor for prognosis and improving the survival rate of cancer patients. MicroRNAs (miRNAs) can regulate the expression of hundreds of downstream genes, which has a broad effect on the regulation of the whole cell cycle. Accumulating studies have found that the aberrant expression of miRNAs is associated with cancer genesis. The aim of this study is to evaluate the diagnostic value of miRNAs in detecting cancer metastasis. Medline, PubMed, Embase, and CNKI were searched for relevant articles. Sensitivity, specificity, positive and negative likelihood ratio (PLR, NLR) and diagnostic odds ratio (DOR), the summary receiver operator characteristic (SROC) curve and the calculated AUC (area under the SROC curve) were applied to explore the diagnostic accuracy of miRNAs in metastasis. Seven hundred seventy-one metastatic cancer patients and 552 non-metastatic cancer controls from 14 articles were involved in our meta-analysis. A sensitivity of 0.75 (95% confidence interval (CI), 0.72-0.79) and a specificity of 0.80 (95% CI, 0.76-0.84) were observed from metastatic patients and non-metastatic controls in the combined analysis. And the AUC was 0.83 (95% CI, 0.79-0.86). In addition, results from subgroup analyses suggested that a higher diagnostic value for metastasis was acquired in tissue sample other than blood sample (sensitivity, 0.82 versus 0.73; specificity, 0.84 versus 0.79; PLR, 5.0 versus 3.5; NLR, 0.22 versus 0.34; DOR, 23 versus 10; AUC, 0.88 versus 0.80). In summary, this meta-analysis proved the relatively high diagnostic value of miRNA in metastasis, which might be applied as a novel screening tool to detect metastasis along with other biomarkers. We also illustrated that tissue-based miRNAs may have a better diagnostic accuracy than blood-based miRNAs.

Blood-based multiple-microRNA assay displays a better diagnostic performance than single-microRNA assay in the diagnosis of breast tumor.

Accumulating evidence has suggested that concentrations of blood-based circulating micro-ribonucleic acids (microRNAs, miRNAs) in breast tumor patients are significantly higher/lower than that in normal individuals, indicating that circulating miRNAs may serve as novel blood-based biomarkers for breast tumor. However, the results of previous studies on this issue have been inconclusive. Therefore, we perform a meta-analysis to determine whether aberrant miRNA expression can be used as molecular markers in blood for the diagnosis of breast tumor. PubMed and other databases were searched to identify eligible studies. The sensitivity and specificity were used to plot the summary receiver operator characteristic curve and calculate the area under the curve (AUC). Finally, 15 articles with a total of 1,428 breast tumor patients and 952 healthy individuals were involved. The summary estimates revealed that the pooled sensitivity was 76 % with 95 % confidence interval (CI) of 67-83 %; the specificity was 87 % with 95 % CI of 77-93 %; the PLR was 5.9 with 95 % CI of 3.3-10.4; the NLR was 0.28 with 95 % CI of 0.20-0.39; the DOR was 21 with 95 % CI of 10-44; and the AUC was 0.88 with 95 % CI of 0.84-0.90. The most noteworthy is that multiple-miRNA assay displayed a better diagnostic performance than single-miRNA assay. In summary, the results of the present meta-analysis suggested that blood-based miRNAs may serve as novel molecular biomarkers for breast tumor, with a relative high level of accuracy, especially based on multiple-miRNA assay. Further large-scale prospective studies are necessary to validate their potential applicability for breast tumor prognosis, treatment, and surveillance.

Cognitive dysfunction in antiphospholipid antibody (aPL)-negative systemic lupus erythematosus (SLE) versus aPL-positive non-SLE patients.

OBJECTIVES: The aim of this study was to compare the cognitive function of antiphospholipid antibody (aPL)-negative systemic lupus erythematosus (SLE) and aPL-positive non-SLE patients. METHODS: Twenty aPL-negative SLE and 20 aPL-positive non-SLE female patients with no history of overt neuropsychiatric manifestations took standardised cognitive tests of learning and memory, attention and working memory, executive functions, verbal fluency, visuoconstruction, and motor function. The primary outcome measure was an established global cognitive impairment index (CII). Cranial magnetic resonance imaging (MRI) was also obtained on all patients. RESULTS: Twelve of 20 (60%) of the SLE and 8/20 (40%) of the aPL-positive patients had global cognitive impairment on CII; there were no group differences on CII or on individual measures. Cognitive impairment was not associated with duration of disease, level of disease activity, or prednisone use. No correlations were found between clinical disease factors and cognitive impairment, and neither group showed an association between incidental or major MRI abnormalities and cognitive dysfunction. CONCLUSIONS: Both aPL-negative SLE and aPL-positive non-SLE patients, without other overt neuropsychiatric disease, demonstrated high levels of cognitive impairment. No clinical, serologic, or radiologic characteristics were associated with cognitive impairment. Cognitive dysfunction is common in APS and in SLE, but its mechanisms remain unknown.

The link between early onset drinking and early onset alcohol-impaired driving in young males.

BACKGROUND: Young drivers represent a disproportionate number of the individuals involved in alcohol-impaired driving. Although there is a known association between drinking and alcohol-impaired driving in young drivers, the link between early onset drinking and early onset alcohol-impaired driving has not been explored. OBJECTIVES: The present study aimed to assess this link along with potentially confounding factors. METHODS: The assessment used a proportional hazards model with data collected from the Buffalo Longitudinal Study of Young Men, a population-based sample of 625 males at aged 16-19. RESULTS: Controlling for the effects of potentially relevant confounds, the early onset of drinking was the most influential factor in predicting the early onset of alcohol-impaired driving. Race and the early onset of other forms of delinquency also played a significant role in the early onset of alcohol-impaired driving. CONCLUSION: Preventing an early start of drinking among adolescents may be the most critical factor to address in preventing an early start of alcohol-impaired driving.

Cu2+-Citrate-Chitosan Complex Nanoparticles for the Chemodynamic Therapy of Lung Cancer.

Lung cancer poses a significant threat to human health. Surgical intervention is the preferred treatment modality for lung cancer, but a large number of patients are deprived of the opportunity for surgery for various reasons and are compelled to undergo radiotherapy and chemotherapy, which entail systemic adverse reactions. In recent years, with the advancement of nanomedicine, chemodynamic therapy (CDT) based on free radicals has been extensively investigated. In this study, we fabricated copper-citrate-chitosan composite nanoparticles (CuCC NPs) by encapsulating copper-citrate complexes with natural chitosan polymers, resulting in a substantial reduction in the biotoxicity of copper ions. The CuCC NPs selectively accumulated in tumor tissues through the enhanced permeability and retention effect (EPR) and gradually degraded within the acidic and glutathione (GSH)-rich microenvironment of the tumor, thereby releasing the loaded copper ions. Through CDT, the copper ions converted the overexpressed hydrogen peroxide (H2O2) in the tumor tissue into hydroxyl radicals (•OH), leading to the eradication of tumor cells. In animal experiments, CuCC NPs exhibited remarkable efficacy in CDT. Further histopathological and hematological analyses demonstrated that CuCC NPs could induce substantial apoptosis in tumor tissues while maintaining an extremely high level of safety.

Efficient construction of functionalized pyrroloindolines through cascade radical cyclization/intermolecular coupling.

Pyrroloindolines are important structural units in nature and the pharmaceutical industry, however, most approaches to such structures involve transition-metal or photoredox catalysts. Herein, we describe the first tandem SET/radical cyclization/intermolecular coupling between 2-azaallyl anions and indole acetamides. This method enables the transition-metal-free synthesis of C3a-substituted pyrroloindolines under mild and convenient conditions. The synthetic utility of this transformation is demonstrated by the construction of an array of C3a-methylamine pyrroloindolines with good functional group tolerance and yields. Gram-scale sequential one-pot synthesis and hydrolysis reactions demonstrate the potential synthetic utility and scalability of this approach.

The prognostic value of the preoperative albumin/globulin and monocyte ratio in resected early-stage non-small cell lung cancer.

OBJECTIVE: This study investigated the prognostic value of the preoperative albumin/globulin to monocyte ratio (AGMR) in patients with resected non-small cell lung cancer (NSCLC). METHODS: The study retrospectively enrolled patients with resected NSCLC from the Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University from January 2016 to December 2017. Baseline demographic and clinicopathological data were collected. The preoperative AGMR was calculated. Propensity score matching (PSM) analysis was applied. The receiver operating characteristic curve was used to determine the optimal AGMR cut-off value. The Kaplan-Meier method was used to calculate the overall survival (OS) and disease-free survival (DFS). The Cox proportional hazards regression model was used to evaluate the prognostic value of the AGMR. RESULTS: A total of 305 NSCLC patients were included. The optimal AGMR value was 2.80. Before PSM. The high AGMR (>2.80) group had a significantly longer OS (41.34 + 11.32 vs. 32.03 + 17.01 months; P < 0.01) and DFS (39.00 + 14.49 vs. 28.78 + 19.13 months; P < 0.01) compared with the low AGMR (≤2.80) group. Multivariate analyses showed that AGMR (P < 0.01) in addition to sex (P < 0.05), body mass index (P < 0.01), history of respiratory diseases (P < 0.01), lymph node metastasis (P < 0.01), and tumor size (P < 0.01) were associated with OS and DFS. After PSM, AGMR remained as an independent prognostic factor for OS (hazard ratio [HR] 2.572, 95% confidence interval [CI]: 1.470-4.502; P = 0.001) and DFS (HR 2.110, 95% CI: 1.228-3.626; P = 0.007). CONCLUSION: The preoperative AGMR is a potential prognostic indicator for OS and DFS in resected early-stage NSCLC.

Sulfonamides as N-Centered Radical Precursors for C-N Coupling Reactions To Generate Amidines.

Nitrogen-centered radicals (NCRs) are valuable intermediates for the construction of C-N bonds. Traditional methods for the generation of NCRs employ toxic radical initiators, transition metal catalysts, photocatalysts, or organometallic reagents. Herein, we report a novel strategy for the generation of NCRs toward the construction of C-N bonds under transition-metal-free conditions. Thus, super-electron-donor (SED) 2-azaallyl anions undergo single-electron transfer (SET) with sulfonamides, forming aminyl radicals (R2N•, R = alkyl) and culminating in the generation of amidines bearing various functional groups (33 examples, up to 96% yield). Broad substrate scope and gram-scale telescoped preparation demonstrate the practicality of this method. Radical clock and electron paramagnetic resonance (EPR) experiments support the proposed radical coupling pathway between the generated N-centered radical and the C-centered 2-azaallyl radical.

Prophylactic Prednisolone Promotes AAV5 Hepatocyte Transduction Through the Novel Mechanism of AAV5 Coreceptor Platelet-Derived Growth Factor Receptor Alpha Upregulation and Innate Immune Suppression.

Adeno-associated virus (AAV) vectors are used to deliver therapeutic transgenes, but host immune responses may interfere with transduction and transgene expression. We evaluated prophylactic corticosteroid treatment on AAV5-mediated expression in liver tissue. Wild-type C57BL/6 mice received 6 × 1013 vg/kg AAV5-HLP-hA1AT, an AAV5 vector carrying a human α1-antitrypsin (hA1AT) gene with a hepatocyte-specific promoter. Mice received 4 weeks of daily 2 mg/kg prednisolone or water starting day -1 or 0 before vector dosing. Mice that received prophylactic corticosteroids had significantly higher serum hA1AT protein than mice that did not, starting at 6 weeks and persisting to the study end at 12 weeks, potentially through a decrease in the number of low responders. RNAseq and proteomic analyses investigating mechanisms mediating the improvement of transgene expression found that prophylactic corticosteroid treatment upregulated the AAV5 coreceptor platelet-derived growth factor receptor alpha (PDGFRα) on hepatocytes and downregulated its competitive ligand PDGFα, thus increasing the uptake of AAV5 vectors. Evidently, prophylactic corticosteroid treatment also suppressed acute immune responses to AAV. Together, these mechanisms resulted in increased uptake and preservation of the transgene, allowing more vector genomes to be available to assemble into stable, full-length structures mediating long-term transgene expression. Prophylactic corticosteroids represent a potential actionable strategy to improve AAV5-mediated transgene expression and decrease intersubject variability.

Regulation of post-translational modification of PD-L1 and advances in tumor immunotherapy.

The immune checkpoint molecules programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) are one of the most promising targets for tumor immunotherapy. PD-L1 is overexpressed on the surface of tumor cells and inhibits T cell activation upon binding to PD⁃1 on the surface of T cells, resulting in tumor immune escape. The therapeutic strategy of targeting PD-1/PD-L1 involves blocking this binding and restoring the tumor-killing effect of immune cells. However, in clinical settings, a relatively low proportion of cancer patients have responded well to PD-1/PD-L1 blockade, and clinical outcomes have reached a bottleneck and no substantial progress has been made. In recent years, PD-L1 post-translation modifications (PTMs) have gradually become a hot topic in the field of PD-L1 research, which will provide new insights to improve the efficacy of current anti-PD-1/PD-L1 therapies. Here, we summarized and discussed multiple PTMs of PD-L1, including glycosylation, ubiquitination, phosphorylation, acetylation and palmitoylation, with a major emphasis on mechanism-based therapeutic strategies (including relevant enzymes and targets that are already in clinical use and that may become drugs in the future). We also summarized the latest research progress of PTMs of PD-L1/PD-1 in regulating immunotherapy. The review provided novel strategies and directions for tumor immunotherapy research based on the PTMs of PD-L1/PD-1.

Fe3O4 Composite Superparticles with RGD/Magnetic Dual-Targeting Capabilities for the Imaging and Treatment of Non-Small Cell Lung Cancer.

In clinical practice, the incidence and mortality of non-small cell lung cancer are increasing year by year, which is a serious threat to the health of patients. Once the optimal surgical window is missed, the toxic side effects of chemotherapy have to be confronted. With the rapid development of nanotechnology in recent years, medical science and health have been greatly impacted. Therefore, in this manuscript, we design and prepare chemotherapeutic drug vinorelbine (VRL)-loaded polydopamine (PDA) shell-coated Fe3O4 superparticles, and further graft the targeted ligand RGD onto their surface. Because of the introduction of the PDA shell, the toxicity of the prepared Fe3O4@PDA/VRL-RGD SPs is greatly reduced. At the same time, due to the existence of Fe3O4, the Fe3O4@PDA/VRL-RGD SPs also have MRI contrast capability. Under the dual-targeting effect of RGD peptide and external magnetic field, Fe3O4@PDA/VRL-RGD SPs can accumulate into tumors effectively. The accumulated superparticles in the tumor sites can not only effectively identify and mark the location and boundary of the tumor under MRI, guideing the application of near-infrared laser, but also release the loaded VRL under the stimulation of the acidic microenvironment of the tumor to play the role of chemotherapy. On further combination with photothermal therapy under laser irradiation, A549 tumors are completely eliminated without recurrence. Our proposed RGD/magnetic field dual-targeting strategy can effectively improve the bioavailability of nanomaterials and contribute to better imaging and therapeutic effects, which has a promising application prospect in the future.

Clinical application of VATS combined with 3D-CTBA in anatomical basal segmentectomy.

Objective: This study aimed to summarize the clinical application experience of video-assisted thoracic surgery (VATS) combined with three-dimensional computed tomography-bronchography and angiography (3D-CTBA) in anatomical basal segmentectomy. Methods: Clinical data of 42 patients who underwent bilateral lower sub-basal segmentectomy by VATS combined with 3D-CTBA in our hospital from January 2020 to June 2022 were retrospectively analyzed; the patients included 20 males and 22 females, with a median age of 48 (30-65) years. Combined with the preoperative enhanced CT and 3D-CTBA techniques to identify the altered bronchi, arteries, and veins during the operation, the anatomical resection of each basal segment of both lower lungs was completed through the fissure approach or inferior pulmonary vein approach. Results: All operations were successfully completed without conversion to thoracotomy or lobectomy. The median operation time was 125 (90-176) min, the median intraoperative blood loss was 15 (10-50) mL, the median postoperative thoracic drainage time was 3 (2-17) days, and the median postoperative hospital stay was 5 (3-20) days. The median number of resected lymph nodes was 6 (5-8). There was no in-hospital death. Postoperative pulmonary infection occurred in 1 case, lower extremity deep vein thrombosis (DVT) in 3 cases, pulmonary embolism in 1 case, and persistent air leakage in the chest in 5 cases, all of which were improved by conservative treatment. Two cases of pleural effusion after discharge were improved after ultrasound guided drainage. Postoperative pathology showed 31 cases of minimally invasive adenocarcinoma, 6 cases of adenocarcinoma in situ (AIS), 3 cases of severe atypical adenomatous hyperplasia (AAH), and 2 cases of other benign nodules. All cases were lymph node-negative. Conclusion: VATS combined with 3D-CTBA is safe and feasible in anatomical basal segmentectomy; consequently, this approach should be promoted and applied in clinical work.

Early-onset chronic obstructive pulmonary disease is associated with female sex, maternal factors, and African American race in the COPDGene Study.

RATIONALE: The characterization of young adults who develop late-onset diseases may augment the detection of novel genes and promote new pathogenic insights. METHODS: We analyzed data from 2,500 individuals of African and European ancestry in the COPDGene Study. Subjects with severe, early-onset chronic obstructive pulmonary disease (COPD) (n=70, age < 55 yr, FEV1 < 50% predicted) were compared with older subjects with COPD (n =306, age >64 yr, FEV1 <50% predicted). MEASUREMENTS AND MAIN RESULTS: Subjects with severe, early-onset COPD were predominantly females (66%), P =0.0004. Proportionally,early-onset COPD was seen in 42% (25 of 59) of African Americans versus 14% (45 of 317) of non-Hispanic whites, P <0.0001. Other risk factors included current smoking (56 vs. 17%, P < 0.0001) and self-report of asthma (39 vs. 25%, P =0.008). Maternal smoking (70 vs. 44%, P=0.0001) and maternal COPD (23 vs.12%, P=0.03) were reported more commonly in subjects with early-onset COPD. Multivariable regression analysis found association with African American race, odds ratio (OR), 7.5 (95% confidence interval [CI], 2.3­24; P »=0.0007); maternal COPD, OR, 4.7 (95% CI,1.3­17; P=0.02); female sex, OR, 3.1 (95% CI, 1.1­8.7; P=0.03); and each pack-year of smoking, OR, 0.98 (95% CI, 0.96­1.0; P » 0.03). CONCLUSIONS: These observations support the hypothesis that severe, early-onset COPD is prevalent in females and is influenced by maternal factors. Future genetic studies should evaluate (1) gene-by-sex interactions to address sex-specific genetic contributions and (2) gene-by-race interactions.