Immune checkpoint inhibitors rechallenge in non-small cell lung cancer: Current evidence and future directions.

Immunotherapy, remarkably immune checkpoint inhibitors (ICIs), has significantly altered the treatment landscape for non-small cell lung cancer (NSCLC). Despite their success, the discontinuation of ICIs therapy may occur due to factors such as prior treatment completion, disease progression during ICIs treatment, or immune-related adverse events (irAEs). As numerous studies highlight the dynamic nature of immune responses and the sustained benefits of ICIs, ICIs rechallenge has become an attractive and feasible option. However, the decision-making process for ICIs rechallenge in clinical settings is complicated by numerous uncertainties. This review systematically analyses existing clinical research evidence, classifying ICIs rechallenge into distinct clinical scenarios, exploring methods to overcome ICIs resistance in rechallenge instances, and identifying biomarkers to select patients likely to benefit from rechallenge. By integrating recent studies and new technologies, we offer crucial recommendations for future clinical trial design and provide a practical guideline to maximize the therapeutic benefits of immunotherapy for NSCLC patients.

Intercellular adhesion molecule-1 (ICAM-1): From molecular functions to clinical applications in cancer investigation.

Intercellular adhesion molecule-1 (ICAM-1) is a versatile molecule that plays a critical role in various physiological and pathological processes, particularly in tumor development where its impact is bidirectional. On the one hand, it augments the immune response by promoting immune cell migration, infiltration, and the formation of immunological synapses, thus facilitating potent antitumor effects. Simultaneously, it contributes to tumor immune evasion and influences metastasis by mediating transendothelial migration (TEM), epithelial-to-mesenchymal transition (EMT), and epigenetic modification of tumor cells. Despite its significant potential, the full clinical utility of ICAM-1 has yet to be fully realized. In this review, we thoroughly examine recent advancements in understanding the role of ICAM-1 in tumor development, its relevance in predicting therapeutic efficacy and prognosis, as well as the progress in clinical translational research on anti-ICAM-1-based therapies, encompassing including monoclonal antibodies, immunotherapy, antibody-drug conjugate (ADC), and conventional treatments. By shedding light on these innovative strategies, we aim to underscore ICAM-1's significance as a valuable and multifaceted target for cancer treatment, igniting enthusiasm for further research and facilitating translation into clinical applications.

Efficacy and Safety of KRASG12C Inhibitor IBI351 Monotherapy in Patients With Advanced NSCLC: Results From a Phase 2 Pivotal Study.

INTRODUCTION: KRAS glycine-to-cysteine substitution at codon 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. METHODS: Eligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival. RESULTS: As of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7-58.6), and the disease control rate was 90.5% (95% CI: 83.7-95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6-11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 (STK11) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes (STK11, kelch-like ECH-associated protein 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05). CONCLUSIONS: IBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.

A bibliometric analysis of immune-related adverse events in cancer patients and a meta-analysis of immune-related adverse events in patients with hepatocellular carcinoma.

Background and Objectives: Immunotherapy has become the standard treatment for hepatocellular carcinoma (HCC), but it carries a risk of immune-related adverse events (irAEs) that can be life-threatening. This study employs bibliometric analysis to understand global scientific research on irAEs in cancer, focusing on characteristics and areas of interest. Additionally, a meta-analysis provides a comprehensive overview of irAEs in HCC patients receiving immune checkpoint inhibitor (ICI)-based therapies. Methods: We conducted a thorough search of Web of Science Core Collection (WoSCC) publications from 1999 to 2022. R and VOSviewer software were used for analysis. A meta-analysis was performed using data from PubMed, Embase, and the Cochrane Library databases up to March 22, 2022. Trials with HCC patients reporting irAE incidence were included. Quality assessment followed Cochrane risk of bias, Newcastle-Ottawa Scale (NOS), and Methodological Index for Non-Randomized Studies (MINORS). We used random-effects or fixed-effects models based on I2 values. Primary outcomes included any-grade irAEs and grade ≥ 3 irAEs. This review and meta-analysis are registered in PROSPERO as CRD42022318885. Results: In bibliometric analysis, we included 2946 papers, showing a consistent rise in annual publications on irAEs in cancer research. Frequent keywords were "nivolumab", "immune checkpoint inhibitor", and "immune-related adverse event". "Hepatocellular carcinoma" emerged as a prominent research focus linked to irAEs. We conducted a comprehensive meta-analysis on irAE incidence in HCC patients, including 29 studies. The overall incidence of any-grade irAEs was 61.0% (95% CI 38.5%-81.3%), and grade ≥ 3 irAEs was 13.2% (95% CI 7.9%-19.6%). Treatment-related mortality occurred in 3.1% (95% CI 0.8%-6.3%), with treatment discontinuation at 10.7% (95% CI 6.3%-16.0%). Reactive cutaneous capillary endothelial proliferation (RCCEP) was the most common any-grade irAE, while elevated aspartate aminotransferase (AST) was the most common grade ≥ 3 irAE. Treatment strategies were independently associated with specific irAEs, as indicated by multivariable analysis. Conclusion: This study provides valuable insights into the current research landscape of irAEs in cancer and ofers a comprehensive overview of irAEs in HCC patients undergoing ICI-based therapy. The relatively high incidence of irAEs and their association with treatment strategies emphasize the need for careful management by clinicians when treating HCC patients. These findings offer significant guidance for optimizing care and treatment for HCC patients.

Garsorasib in patients with KRASG12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Garsorasib (D-1553; InventisBio, Shangai, China), a potent KRASG12C inhibitor, has shown promising antitumour activity in patients with KRASG12C-mutated (ie, Gly12Cys) non-small-cell lung cancer (NSCLC) in a phase 1 study. We report results from a phase 2 study conducted to evaluate the efficacy and safety of garsorasib in patients with locally advanced or metastatic KRASG12C-mutated NSCLC. METHODS: This open-label, multicentre, single-arm, phase 2 trial enrolled adult patients with KRASG12C-mutated NSCLC who had previously been treated with platinum-based chemotherapy and immune checkpoint inhibitors from 43 hospitals in China. Participants received 600 mg garsorasib orally twice per day. Tumour assessments were performed at baseline, at the end of every two cycles (of 21 days) for the first eight cycles, and at the end of every three cycles thereafter. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC) following the guidelines in Response Evaluation Criteria in Solid Tumours, version 1.1. Efficacy and safety were assessed in all patients who received at least one dose of garsorasib. This trial is registered at ClinicalTrials.gov, NCT05383898, and is active but no longer recruiting. FINDINGS: From June 17, 2022, to May 17, 2023, of 225 patients screened for eligibility, 123 patients were enrolled and treated with garsorasib. Of these 123 participants, the median age was 64 years (IQR 59-68), 108 (88%) were male and 15 (12%) were female. At data cutoff (Nov 17, 2023), the median follow-up duration was 7·9 months (IQR 6·3-10·4), and 82 (67%) of 123 patients had discontinued treatment. The IRC-confirmed ORR was 50% (61 of 123 patients; 95% CI 41-59). 117 (95%) of 123 patients reported treatment-related adverse events, with 61 (50%) experiencing grade 3 or higher events. The most common types of adverse events of grade 3 or higher associated with garsorasib were hepatic and gastrointestinal events, including increased liver enzymes, such as aspartate aminotransferase (21 [17%] of 123 participants), alanine aminotransferase (19 [15%] of 123 participants), and gamma-glutamyltransferase (28 [23%] of 123 participants); nausea (2 [2%] of 123 participants); and vomiting (2 [2%] of 123 participants). No new safety signals were identified, and most of the adverse events were well managed. INTERPRETATION: The results show that garsorasib has a high response rate, long duration of response, and an acceptable and manageable safety profile in patients with previously treated KRASG12C-mutated NSCLC. Garsorasib potentially provides a promising treatment option for this patient population. FUNDING: InventisBio.

[Neurodevelopment and cerebral blood flow in children aged 2-6 years with autism spectrum disorder]. / 2~6å²å­¤ç‹¬ç—‡è°±ç³»éšœç¢å„¿ç«¥ç¥žç»å‘è‚²ä¸Žè„‘è¡€æµé‡çš„ç ”ç©¶.

OBJECTIVES: To investigate the neurodevelopmental characteristics of children with autism spectrum disorder (ASD), analyze the correlation between neurodevelopmental indicators and cerebral blood flow (CBF), and explore the potential mechanisms of neurodevelopment in ASD children. METHODS: A retrospective study was conducted on 145 children aged 2-6 years with newly-diagnosed ASD. Scores from the Gesell Developmental Diagnosis Scale and the Autism Behavior Checklist (ABC) and CBF results were collected to compare gender differences in the development of children with ASD and analyze the correlation between CBF and neurodevelopmental indicators. RESULTS: Fine motor and personal-social development quotient in boys with ASD were lower than those in girls with ASD (P<0.05). Gross motor development quotient in ASD children was negatively correlated with CBF in the left frontal lobe (r=-0.200, P=0.016), right frontal lobe (r=-0.279, P=0.001), left parietal lobe (r=-0.208, P=0.012), and right parietal lobe (r=-0.187, P=0.025). The total ABC score was positively correlated with CBF in the left amygdala (r=0.295, P<0.001). CONCLUSIONS: Early intervention training should pay attention to gender and developmental structural characteristics for precise intervention in ASD children. CBF has the potential to become a biological marker for assessing the severity of ASD.

Study on quality control methods and pharmacodynamic material basis of different specifications of Corydalis Rhizoma produced in Zhejiang Province.

ETHNOPHARMACOLOGICAL RELEVANCE: The quality control methods of different specifications of Corydalis Rhizoma in Zhejiang China (ZJ CR) are the same, so the quality of each specification couldnot be guaranteed. To clarify the quality control methods and pharmacodynamic material basis of ZJ CR with different specifications could provide reference for the quality control of ZJ CR. AIM OF THE STUDY: The purpose of this study was to establish a quality control method for ZJ CR with different specifications and to screen out the pharmacodynamic material basis of ZJ CR with different specifications. MATERIALS AND METHODS: Firstly, according to the existing grading standards, the medicinal materials were divided into specifications, and the character indexes of ZJ CR with different specifications were established. The quality indexes were established by HPLC, network pharmacology and literature retrieval. The correlation between the trait indexes and quality indexes of ZJ CR with different specifications was analyzed, and the best quality control method was established. Further combined with the pharmacodynamic indexes of ZJ CR with different specifications, the pharmacodynamic material basis of ZJ CR with different specifications was screened out by spectrum-effect analysis. The correlation between trait indexes and pharmacodynamic indexes was analyzed to verify the rationality of grade standard. RESULTS: The three specifications of ZJ CR were CR (Diameter ≥1.1 cm), CR (Diameter <1.1 cm), and CR (No size distinction). Diameter, width, thickness, grain weight, volume and 50 g grain number could be used as the trait indexes of ZJ CR. Protopine (CR1), palmatine hydrochloride (CR2), berberine hydrochloride (CR3), dehydrocorydaline (CR4), tetrahydropalmatine (CR5), tetrahydroberberine (CR6), corydaline (CR7), stylopine (CR8) and isoimperatorin (CR9) were identified. Total components, core components (CR5, CR6, CR7 and CR8), alcohol-soluble extracts (ASE) could be used as quality indexes. The best quality control methods of the three specifications respectively were: the larger the diameter and grain weight, the smaller the number of 50 g grains; The larger the diameter, the smaller the volume, thickness, width and number of 50 g particles; The larger the grain weight and volume, the smaller the number of 50 g grains. The main analgesic components of the three specifications respectively were: CR1, CR2 and core components; CR2, CR4; CR8, CR9. The larger the diameter and the less the number of 50 g grains, the better the analgesic effect of ZJ CR, and the grade standard was reasonable. CONCLUSIONS: This study showed that the quality control methods and pharmacodynamic material basis of ZJ CR with different specifications were different, which may be caused by the differences in traits and the contribution of main active ingredients. This study constructed an evaluation model combining external traits, internal quality and overall efficacy, and provided theoretical support for the rationality of ZJ CR grade standard.

Exploring new frontiers: cell surface vimentin as an emerging marker for circulating tumor cells and a promising therapeutic target in advanced gastric Cancer.

BACKGROUND: Circulating tumor cells (CTCs) hold immense promise in guiding treatment strategies for advanced gastric cancer (GC). However, their clinical impact has been limited due to challenges in identifying epithelial-mesenchymal transition (EMT)-CTCs using conventional methods. METHODS: To bridge this knowledge gap, we established a detection platform for CTCs based on the distinctive biomarker cell surface vimentin (CSV). A prospective study involving 127 GC patients was conducted, comparing CTCs enumeration using both EpCAM and CSV. This approach enabled the detection of both regular and EMT-CTCs, providing a comprehensive analysis. Spiking assays and WES were employed to verify the reliability of this marker and technique. To explore the potential inducer of CSV+CTCs formation, a combination of Tandem Mass Tag (TMT) quantitative proteomics, m6A RNA immunoprecipitation-qPCR (MeRIP-qPCR), single-base elongation- and ligation-based qPCR amplification method (SELECT) and RNA sequencing (RNA-seq) were utilized to screen and confirm the potential target gene. Both in vitro and in vivo experiments were performed to explore the molecular mechanism of CSV expression regulation and its role in GC metastasis. RESULTS: Our findings revealed the potential of CSV in predicting therapeutic responses and long-term prognosis for advanced GC patients. Additionally, compared to the conventional EpCAM-based CTCs detection method, the CSV-specific positive selection CTCs assay was significantly better for evaluating the therapeutic response and prognosis in advanced GC patients and successfully predicted disease progression 14.25 months earlier than radiology evaluation. Apart from its excellent role as a detection marker, CSV emerges as a promising therapeutic target for attenuating GC metastasis. It was found that fat mass and obesity associated protein (FTO) could act as a potential catalyst for CSV+CTCs formation, and its impact on the insulin-like growth factor-I receptor (IGF-IR) mRNA decay through m6A modification. The activation of IGF-I/IGF-IR signaling enhanced the translocation of vimentin from the cytoplasm to the cell surface through phosphorylation of vimentin at serine 39 (S39). In a GC mouse model, the simultaneous inhibition of CSV and blockade of the IGF-IR pathway yielded promising outcomes. CONCLUSION: In summary, leveraging CSV as a universal CTCs marker represents a significant breakthrough in advancing personalized medicine for patients with advanced GC. This research not only paves the way for tailored therapeutic strategies but also underscores the pivotal role of CSV in enhancing GC management, opening new frontiers for precision medicine.

Study on the active components and mechanism of Atractylodis Macrocephalae Rhizoma for invigorating the spleen and tonifying qi based on spectrum-effect relationship and network pharmacology.

Spleen deficiency can lead to various abnormal physiological functions of the spleen. Atractylodis Macrocephalae Rhizoma (AMR) is a traditional Chinese medicine used to invigorate the spleen and tonify qi. The study aimed to identify the primary active components influencing the efficacy of AMR in strengthening the spleen and replenishing qi through spectrum-effect relationship and chemometrics. Network pharmacology was used to investigate the mechanism by which AMR strengthens the spleen and replenishes qi, with molecular docking utilized for validation purposes. The findings indicated that bran-fried AMR exhibited superior efficacy, with atractylenolides and atractylone identified as the primary active constituents. Atractylenolide II emerged as the most influential component impacting the effectiveness of AMR, while the key target was androgen receptor. Furthermore, crucial pathways implicated included the mitogen-activated protein cascade (MAPK) cascade, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding, and RNA polymerase II sequence-specific DNA-binding transcription factor binding. In summary, our study has identified the primary active components associated with the efficacy of AMR and has provided an initial exploration of its mechanism of action. This offers a theoretical foundation for future investigations into the material basis and molecular mechanisms underlying the pharmacodynamics of AMR.

Study on the quality of Corydalis Rhizoma in Zhejiang based on multidimensional evaluation method.

ETHNOPHARMACOLOGICAL RELEVANCE: The quality requirements of Corydalis Rhizoma (CR) in different producing areas are uniform, resulting in uneven efficacy. As a genuine producing area, the effective quality control of CR in Zhejiang Province (ZJ) could provide a theoretical basis for the rational application of medicinal materials. AIM OF THE STUDY: The purpose of this study was to effectively distinguish the CR inside and outside ZJ, and provided a theoretical basis for the quality control and material basis research of ZJ CR. MATERIALS AND METHODS: The core components of ZJ CR could be identified by HPLC combined with chemometrics screening, and the quality of CR from different producing areas was evaluated by a genetic algorithm-back propagation (GA-BP) neural network. Chromaticity and near-infrared (NIR) spectroscopy were used to identify CR inside and outside ZJ, and rapid content prediction was realized. The analgesic effect of CR in different regions was compared by a zebrafish analgesic experiment. Analgesic experiments in rats and analysis of the research status of quality components were used to screen the quality control components of ZJ CR. RESULTS: The contents of palmatine hydrochloride (YSBMT), dehydrocorydaline (TQZJJ), tetrahydropalmatine (YHSYS), tetrahydroberberine (SQXBJ), corydaline (YHSJS), stylopine (SQHLJ), and isoimperatorin (YOQHS) in ZJ CR were higher than those in CR from outside ZJ, but the content of protopine (YAPJ) and berberine hydrochloride (YSXBJ) was lower than that in CR from outside ZJ. YHSJS and SQHLJ could be used as the core components to identify ZJ CR. The GA-BP neural network showed that the relative importance of ZJ CR was the strongest. Chroma-content correlation analysis and the NIR qualitative model could effectively distinguish CR from inside and outside of ZJ, and the NIR quantitative model could quickly predict the content of CR from inside and outside of ZJ. Zebrafish experiments showed that ZJ, Shaanxi (SX), Henan (HN), and Sichuan (SC) CR had significant analgesic effects, while Hebei (HB) CR had no significant analgesic effect. Overall comparison, the analgesic effect of ZJ CR was better than that of CR outside ZJ. The comprehensive score of the grey correlation degree between YAPJ, YSBMT, YSXBJ, TQZJJ, YHSYS, YHSJS, SQXBJ, and SQHLJ were higher than 0.9, and the research frequency were extremely high. CONCLUSIONS: The relative importance of the content and origin of most components of ZJ CR was higher than that of CR outside ZJ. The holistic analgesic effect of ZJ CR was better than that of CR outside ZJ, but slightly lower than that of SX CR. YHSJS and SQHLJ could be used as the core components to identify ZJ CR. YAPJ, YSBMT, YSXBJ, TQZJJ, YHSYS, SQXBJ, YHSJS, and SQHLJ could be used as the quality control components of ZJ CR. The multidimensional evaluation method used in this study provided a reference for the quality control and material basis research of ZJ CR.

Analysis of Quality Differences in Radix Dipsaci before and after Processing with Salt Based on Quantitative Control of HPLC Multi-Indicator Components Combined with Chemometrics.

Radix Dipsaci (RD) is the dry root of the Dipsacus asper Wall. ex DC., which is commonly used for tonifying the kidney and strengthening bone. The purpose of this study was to analyze the difference between raw and salt-processed RD from the chemical composition comprehensively. The fingerprints of raw and salt-processed RD were established by HPLC-DAD to determine the contents of loganin (LN), asperosaponin VI (AVI), caffeic acid (CaA), dipsanoside A (DA), dipsanoside B (DB), chlorogenic acid (CA), loganic acid (LA), isochlorogenic acid A (IA), isochlorogenic acid B (IB), and isochlorogenic acid C (IC). The results showed that after processing with salt, the components with increased contents were LA, CaA, DA, and AVI, and the components with decreased contents were CA, LN, IB, IA, IC, and DB. Then, the chemometric methods such as principal component analysis (PCA) and fisher discriminant analysis (FDA) were used to evaluate the quality of raw and salt-processed RD. In the classification of raw and salt-processed RD, the order of importance of each chemical component was LA > DB > IA > IC > IB > LN > CA > DA > AVI > CaA. These integrated methods successfully assessed the quality of raw and salt-processed RD, which will provide guidance for the development of RD as a clinical medication.

Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of YK-029A in Treatment-Naive Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations: A Phase 1 Trial.

INTRODUCTION: Treatment options for treatment-naive patients with advanced NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations are limited. This study evaluated the safety, tolerability, and pharmacokinetics of YK-029A, a third-generation EGFR tyrosine kinase inhibitor, and the preliminary efficacy of YK-029A in treatment-naive patients with EGFR ex20ins mutation. METHODS: This multicenter, dose-escalation, and dose-expansion phase 1 clinical trial enrolled patients with NSCLC harboring EGFR mutations. During the dose-escalation phase, YK-029A was orally administered using the traditional 3+3 principle at 50, 100, 150, 200, and 250 mg/d. In the dose-expansion phase, treatment-naive patients with EGFR ex20ins mutations were enrolled and administered YK-029A 200 mg/d. The primary end point was safety and tolerability. RESULTS: The safety analysis included 108 patients. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common treatment-emergent adverse events were anemia (50.9%), diarrhea (49.1%), and rash (34.3%). There was minimal drug accumulation after multiple doses. A total of 28 treatment-naive patients with EGFR ex20ins mutations were enrolled in the dose-expansion and 26 were included in the efficacy analysis. According to the independent review committee evaluation, the objective response rate was 73.1% (95% confidence interval: 52.21%-88.43%), and the disease control rate was 92.3% (95% confidence interval: 74.87%-99.05%). CONCLUSIONS: YK-029A was found to have manageable safety and be tolerable in patients with NSCLC harboring EGFR mutations and have promising antitumor activity in untreated patients with EGFR ex20ins mutations.

PB-LNet: a model for predicting pathological subtypes of pulmonary nodules on CT images.

OBJECTIVE: To investigate the correlation between CT imaging features and pathological subtypes of pulmonary nodules and construct a prediction model using deep learning. METHODS: We collected information of patients with pulmonary nodules treated by surgery and the reference standard for diagnosis was post-operative pathology. After using elastic distortion for data augmentation, the CT images were divided into a training set, a validation set and a test set in a ratio of 6:2:2. We used PB-LNet to analyze the nodules in pre-operative CT and predict their pathological subtypes. Accuracy was used as the model evaluation index and Class Activation Map was applied to interpreting the results. Comparative experiments with other models were carried out to achieve the best results. Finally, images from the test set without data augmentation were analyzed to judge the clinical utility. RESULTS: Four hundred seventy-seven patients were included and the nodules were divided into six groups: benign lesions, precursor glandular lesions, minimally invasive adenocarcinoma, invasive adenocarcinoma Grade 1, Grade 2 and Grade 3. The accuracy of the test set was 0.84. Class Activation Map confirmed that PB-LNet classified the nodules mainly based on the lungs in CT images, which is in line with the actual situation in clinical practice. In comparative experiments, PB-LNet obtained the highest accuracy. Finally, 96 images from the test set without data augmentation were analyzed and the accuracy was 0.89. CONCLUSIONS: In classifying CT images of lung nodules into six categories based on pathological subtypes, PB-LNet demonstrates satisfactory accuracy without the need of delineating nodules, while the results are interpretable. A high level of accuracy was also obtained when validating on real data, therefore demonstrates its usefulness in clinical practice.

Revealing a causal relationship between gut microbiota and lung cancer: a Mendelian randomization study.

Background: The gut microbiota has been found to be associated with the risk of lung cancer. However, its causal relationship with various types of lung cancer remains unclear. Methods: We conducted a Mendelian randomization (MR) study using the largest genome-wide association analysis of gut microbiota data to date from the MiBioGen consortium, with pooled statistics for various types of lung cancer from the Transdisciplinary Research in Cancer of the Lung, the International Lung Cancer Consortium, and FinnGen Consortium R7 release data. Inverse variance weighted, weighted model, MR-Egger regression, and weighted median were adapted to assess the causal relationship between gut microbiota and various types of lung cancer. Sensitivity analysis was used to test for the presence of pleiotropy and heterogeneity in instrumental variables. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. Multivariable Mendelian randomization (MVMR) was conducted to assess the direct causal impact of gut microbiota on the risk of various types of lung cancer. Results: Using IVW as the primary analytical method, we identified a total of 40 groups of gut microbiota with potential causal associations with various subtypes of lung cancer, of which 10 were associated with lung cancer, 10 with lung adenocarcinoma, 9 with squamous cell lung cancer, and 11 groups of bacteria associated with small cell lung cancer. After performing FDR correction, we further found that there was still a significant causal relationship between Peptococcaceae and lung adenocarcinoma. Sensitivity analyses demonstrated the robustness of these results, with no heterogeneity or pleiotropy found. Conclusions: Our results confirm a causal relationship between specific gut microbiota and lung cancer, providing new insights into the role of gut microbiota in mediating the development of lung cancer.

Research on the effect of Dipsaci Radix before and after salt-processed on kidney yang deficiency syndrome rats and the preliminary mechanism study through the BMP-Smad signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Dipsaci Radix (DR) is the dry root of Dipsacus asper Wall. ex DC. AIM OF THE STUDY: The purpose of this study was to compare the effects of DR on rats before and after salt-processed with kidney yang deficiency syndrome (KYDS), and we selected the BMP-Smad signaling pathway to explore the mechanism of DR. MATERIALS AND METHODS: The model of KYDS was established by subcutaneous injection of hydrocortisone, the crude DR (CDR) and salt-processed DR (SDR) were given the corresponding dose (2 g/kg, 4 g/kg, and 6 g/kg). The organ index and the contents of adrenocorticotropic hormone (ACTH), cortistatin (CORT), thyroid hormone (T4), tumor necrosis factor-alpha (TNF-α), testosterone (T), estradiol (E2), cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), Na+-K+-ATPase, and growth hormone (GH) in serum were measured to evaluate the intervention effect of DR on KYDS rats. The expression of Smad 1, Smad 4, Smad 5, Smad 8, and BMP 7 protein in kidney was determined by immunohistochemistry, quantitative PCR (qPCR) and Western blot analysis. The effects of DR on 5 expression factors in the BMP-Smad signaling pathway were studied. Constituents absorbed into blood were identified by UPLC-Q-TOF/MS. RESULTS: The results showed that compared with the model group, the thymus and kidney index, as well as the contents of ACTH, CORT, cAMP, GH, Na+-K+-ATPase, T, T4, and E2 were significantly increased in the CDR and SDR groups, and the contents of cGMP and TNF-α were significantly decreased. Compared with the CDR high dose group, ACTH, Na+-K+-ATPase, T, and T4 were significantly increased in the SDR high dose group. The results of immunohistochemistry, qPCR, and Western blot analysis showed that compared with the model group, the expression levels of Smad 1, Smad 4, Smad 5, Smad 8 and BMP 7 proteins in the kidney of DR groups were significantly increased. And SDR groups tended to be better than CDR groups. 8 constituents migrating to blood were identified. CONCLUSION: This study showed that both CDR and SDR could have a good therapeutic effect on KYDS, and SDR was better than CDR. This study chose the BMP-Smad signaling pathway to study the mechanism of DR in the treatment of KYDS and provided a scientific basis for the processing mechanism of salt-processed.

Exploring active ingredients of anti-osteoarthritis in raw and wine-processed Dipsaci Radix based on spectrum-effect relationship combined with chemometrics.

ETHNOPHARMACOLOGICAL RELEVANCE: Dipsaci Radix (DR) is the dry root of the Dipsacus asper Wall. ex DC., which has the function of tonifying the liver and kidney, continuing tendons and bones, and regulating blood vessels. However, there are few reports on the main active ingredients. AIM OF THE STUDY: This study aimed to find the main active components of DR in the treatment of osteoarthritis (OA) by spectrum-effect relationship and compare the differences between RDR and WDR. MATERIALS AND METHODS: Firstly, the high-performance liquid chromatography (HPLC) method was used to establish the fingerprint of DR, and 10 peaks of them were determined by UPLC-Q-TOF/MS. Then, the OA rat model was established by injecting sodium iodoacetate to study the effect of DR on OA. The spectrum-effect relationship was analyzed by grey relational analysis (GRA) and Pearson correlation analysis. RESULTS: According to the pharmacological results, compared with the model group, the cartilage score, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), and Mankin score of rats in low, medium and high dose groups were decreased, and the therapeutic effect of wine-processed DR tended to be better than raw DR at the same dose. Finally, the active components of DR were preliminarily determined as 4 (loganic acid), 6 (chlorogenic acid), 8 (caffeic acid), 14 (dipsanoside B), 16, and 17 (asperosaponin VI) which had a large correlation in GRA and Pearson correlation analysis. CONCLUSION: This study established the spectrum-effect relationship between the raw and wine-processed DR for the first time, which provided a theoretical basis for the study of the pharmacodynamic substance basis of DR before and after processing. This research provided a reference for the subsequent study of DR.

SMARCA4: Current status and future perspectives in non-small-cell lung cancer.

SMARCA4, also known as transcription activator, is an ATP-dependent catalytic subunit of SWI/SNF (SWItch/Sucrose NonFermentable) chromatin-remodeling complexes that participates in the regulation of chromatin structure and gene expression by supplying energy. As a tumor suppressor that has aberrant expression in ∼10% of non-small-cell lung cancers (NSCLCs), SMARCA4 possesses many biological functions, including regulating gene expression, differentiation and transcription. Furthermore, NSCLC patients with SMARCA4 alterations have a weak response to conventional chemotherapy and poor prognosis. Therefore, the mechanisms of SMARCA4 in NSCLC development urgently need to be explored to identify novel biomarkers and precise therapeutic strategies for this subtype. This review systematically describes the biological functions of SMARCA4 and its role in NSCLC development, metastasis, functional epigenetics and potential therapeutic approaches for NSCLCs with SMARCA4 alterations. Additionally, this paper explores the relationship and regulatory mechanisms shared by SMARCA4 and its mutually exclusive catalytic subunit SMARCA2. We aim to provide innovative treatment strategies and improve clinical outcomes for NSCLC patients with SMARCA4 alterations.

Chinese expert consensus on the diagnosis and treatment of bone metastasis in lung cancer (2022 edition).

Lung cancer is the leading cause of cancer-related deaths worldwide. Bone is a common metastatic site of lung cancer, about 50% of bone metastatic patients will experience skeletal related events (SREs). SREs not only seriously impact the quality of life of patients, but also shorten their survival time. The treatment of bone metastasis requires multi-disciplinary therapy (MDT) and development of individualized treatment plan. In order to standardize the diagnosis and treatment of bone metastasis in lung cancer, the expert group of the MDT Committee of the Chinese Medical Doctor Association has developed the expert consensus on the diagnosis and treatment of lung cancer bone metastasis.

Identification of the Mechanism of Matrine Combined with Glycyrrhizin for Hepatocellular Carcinoma Treatment through Network Pharmacology and Bioinformatics Analysis.

Matrine and glycyrrhizin are representative active ingredients of traditional Chinese medicine (TCM) used in clinical practice. Studies have demonstrated that matrine has antitumor pharmacological effects and that glycyrrhizin protects liver function. However, the potential bioactive compounds and mechanisms remain unknown, as well as whether they have synergistic effects in killing cancer cells and protecting liver cells. To investigate the synergistic effects and mechanism of matrine combined with glycyrrhizin in hepatocellular carcinoma (HCC) treatment, we used both network pharmacology and bioinformatics analyses. First, the chemical gene interaction information of matrine and glycyrrhizin was obtained from the PubChem database. The pathogenic genes of HCC were accessed from five public databases. The RNA sequencing data and clinical information of HCC patients were downloaded from The Cancer Genome Atlas (TCGA). Next, the overlapping genes among the potential targets of matrine and glycyrrhizin and HCC-related targets were determined using bioinformatics analysis. We constructed the drug-target interaction network. Prognosis-associated genes were acquired through the univariate Cox regression model and Lasso-Cox regression model. The results were verified by the International Cancer Genome Consortium (ICGC) database. Finally, we predicted the immune function of the samples. The drug-target interaction network consisted of 10 matrine and glycyrrhizin targets. We selected a Lasso-Cox regression model consisting of 3 differentially expressed genes (DEGs) to predict the efficacy of the combination in HCC. Subsequently, we successfully predicted the overall survival of HCC patients using the constructed prognostic model and investigated the correlation of the immune response. Matrine and glycyrrhizin have synergistic effects on HCC. The model we obtained consisted of three drug-target genes by Lasso-Cox regression analysis. The model independently predicted the combined effect of matrine and glycyrrhizin in HCC treatment and OS, which will be helpful for guiding clinical treatment. The prognostic model was correlated with the immune cells and immune checkpoints of patients, which had an adjuvant effect on HCC immunotherapy. Matrine and glycyrrhizin can have therapeutic effects on HCC by promoting the production or enhancing the core gene activity in the drug network and improving the immune system function of patients.

miR-3168 promotes hepatocellular carcinoma progression via downregulating p53.

Hepatocellular carcinoma (HCC) is a highly malignant disease with poor prognosis, which is partly due to the presence of liver cancer stem cells (CSCs). CSCs participate in tumor recurrence, metastasis, and chemoresistance. However, the mechanisms underlying liver CSC regulation are unknown. In this study, we found that miR-3168 expression is increased in HCC and that it predicts poor prognosis. Functional assays showed that miR-3168 promotes HCC cells' proliferation and facilitates liver CSC self-renewal and tumorigenicity. Mechanistically, bioinformatics and the luciferase reporter assay demonstrated that miR-3168 targets the 3'UTR of the p53 mRNA. MiR-3168 expression was negatively correlated with p53 mRNA in HCC tissue samples. Rescue assays demonstrated that p53 knockdown abrogates the discrepancies in proliferation, self-renewal, and tumorigenicity between miR-3168 knockdown HCC cells and control HCC cells. Furthermore, miR-3168 expression was negatively correlated with p53 in HCC tissues. The combined HCC panels exhibited a worse prognostic value for HCC patients than any of these components alone. Moreover, miR-3168 expression was increased in cisplatin-resistant HCC cells and patient-derived xenografts. Clinical cohort analysis revealed that HCC patients with low miR-3168 levels have a superior survival rate when treated with postoperative transcatheter arterial chemoembolization compared with that of patients with high miR-3168 levels. In conclusion, our study uncovered a novel mechanism of liver CSC regulation and provided a potential therapeutic target for liver CSCs.