Integrated bioinformatic analysis and experimental validation for exploring the key immune checkpoint of COPD.

BACKGROUND: There is growing evidence indicating immune inflammation is a key factor in the progression of chronic obstructive pulmonary disease (COPD). Immune checkpoints (ICs) are crucial targets for modulating the functional activation and differentiation of immune cells, particularly in relation to immune inflammation and the regulation of T cell activation and exhaustion. However, the precise mechanisms of ICs in COPD remain understood. METHODS: COPD datasets were obtained from the Gene Expression Omnibus (GEO) and analyzed using GEO2R and Limma to identify differentially expressed genes. LASSO regression was then applied to screen ICs closely associated with COPD. Finally, target genes were selected based on gene expression profiles. Gene ontology (GO), immune infiltration analysis, and gene set enrichment analysis (GSEA) were utilized to assess the relationship between IC genes (ICGs) and immune cells. Subsequently, tobacco-exposed mice, anti-Tim3-treated mice, and HAVCR2-knockout mice were generated, with flow cytometry being used to confirm the results. RESULTS: Through the analysis of GSE38974 and LASSO regression, five ICGs were identified. Subsequent validation using GSE20257 and GSE76925 confirmed these findings. Gene expression profiling highlighted HAVCR2 as having the strongest correlation with COPD. Further investigation through immune infiltration analysis, GO, and GSEA indicated a link between HAVCR2 and CD8+ T cells in COPD. Flow cytometry experiments demonstrated high Tim3 expression in CD8+ T cells of mice exposed to tobacco, promoting Tc1 and inhibiting Tc17, thus affecting CD8+ Tem activation and CD8+ Tcm formation, leading to an immune imbalance within CD8+ T cells. CONCLUSION: Prolonged exposure to tobacco upregulates Tim3 in CD8+ T cells, triggering its regulatory effects on Tc1/Tc17. Knocking out HAVCR2 further upregulated the expression of CD8+ Tem while suppressing the expression of CD8+ Tcm, indicating that Tim3 plays a role in the activation and differentiation of CD8+ T cells in the context of tobacco exposure.

TIGIT Regulates T Cell Inflammation in Airway Inflammatory Diseases.

TIGIT, a co-inhibitory receptor found on T cells and NK cells, transmits inhibitory signals upon binding to its ligand. This interaction suppresses the activation of various signaling pathways, leading to functional exhaustion of cells, ultimately dampening excessive inflammatory responses or facilitating immune evasion in tumors. Dysregulated TIGIT expression has been noted in T cells across different inflammatory conditions, exhibiting varying effects based on T cell subsets. TIGIT predominantly restrains the effector function of pro-inflammatory T cells, upholds the suppressive function of regulatory T cells, and influences Tfh maturation. Mechanistically, the IL27-induced transcription factors c-Maf and Blimp-1 are believed to be key regulators of TIGIT expression in T cells. Notably, TIGIT expression in T cells is implicated in lung diseases, particularly airway inflammatory conditions such as lung cancer, obstructive pulmonary disease, interstitial lung disease, sarcoidosis, and COVID-19. This review emphasizes the significance of TIGIT in the context of T cell immunity and airway inflammatory diseases.

Enolase of Streptococcus suis serotype 2 promotes biomolecular condensation of ribosomal protein SA for HBMECs apoptosis.

BACKGROUND: Ribosomal protein SA (RPSA) of human brain microvascular endothelial cells (HBMECs) can transfer from the cytosol to the cell surface and act as a receptor for some pathogens, including Streptococcus suis serotype 2 (SS2), a zoonotic pathogen causing meningitis in pigs and humans. We previously reported that SS2 virulence factor enolase (ENO) binds to RPSA on the cell surface of HBMECs and induces apoptosis. However, the mechanism that activates RPSA translocation to the cell surface and induces ENO-mediated HBMEC apoptosis is unclear. RESULTS: Here, we show that RPSA localization and condensation on the host cell surface depend on its internally disordered region (IDR). ENO binds to the IDR of RPSA and promotes its interaction with RPSA and vimentin (VIM), which is significantly suppressed after 1,6-Hexanediol (1,6-Hex, a widely used tool to disrupt phase separation) treatment, indicating that ENO incorporation and thus the concentration of RPSA/VIM complexes via co-condensation. Furthermore, increasing intracellular calcium ions (Ca2+) in response to SS2 infection further facilitates the liquid-like condensation of RPSA and aggravates ENO-induced HBMEC cell apoptosis. CONCLUSIONS: Together, our study provides a previously underappreciated molecular mechanism illuminating that ENO-induced RPSA condensation activates the migration of RPSA to the bacterial cell surface and stimulates SS2-infected HBMEC death and, potentially, disease progression. This study offers a fresh avenue for investigation into the mechanism by which other harmful bacteria infect hosts via cell surfaces' RPSA.

Molecular characterization of STEAP3 in lung squamous cell carcinoma: Regulating EGFR to affect cell proliferation and ferroptosis.

Six-transmembrane epithelial antigen of the prostate 3 (STEAP3) has been reported to play a regulatory role in various types of cancers. However, its involvement in lung squamous cell carcinoma (LUSC) remains understudied. Here, we aimed to explore the biological functions and underlying mechanisms of STEAP3 in LUSC. Intersection genes associated with LUSC and ferroptosis were analyzed using the Venn method, STRING, GEPIA and UALCAN databases. The expression of STEAP3 was detected by qPCR and western blotting assay. Cell proliferation and viability were determined using the cell counting kit-8 assay and EDU staining. Oxidative stress and lipid peroxidation were measured by corresponding kits and DCFH-DA staining. Ferroptosis was evaluated by Phen Green SK and Western blot assay. The correlation between STEAP3 and EGFR was predicted by the TIMER and starBase database. Co-immunoprecipitation was conducted to verify the binding of STEAP3 and EGFR. The data demonstrated a significant upregulation of STEAP3 expression in LUSC cell lines. Silencing of STEAP3 suppressed H2170 cell viability and proliferation while promoting oxidative stress and lipid peroxidation through increased levels of MDA and ROS, as well as inhibited SOD activity. In addition, knockdown of STEAP3 induced ferroptosis through the regulation of ferroptosis-related proteins. Moreover, the binding between STEAP3 and EGFR was predicted and confirmed in LUSC. EGFR overexpression reversed the effects of STEAP3 silencing on H2170 cell viability, proliferation, oxidative stress, and ferroptosis. To summarize, the inhibition of STEAP3/EGFR may serve as a promising therapeutic target for LUSC treatment, as it can suppress LUSC proliferation and promote lipid peroxidation and ferroptosis.

Immunotherapy as a later-line option for HER2-altered advanced non-small-cell lung cancer: taxane might be a favorable partner.

Aim: To assess the effectiveness of different types of taxanes, including nab-paclitaxel, paclitaxel and docetaxel, and further compare the effectiveness of taxane-based chemotherapy, taxane-based chemotherapy plus angiogenesis inhibitors or taxane-based chemotherapy plus immune checkpoint inhibitors in HER2-altered non-small-cell lung cancer in the second- or third-line setting. Materials & methods: A total of 52 patients were included in the study. Progression-free survival was compared between subgroups. Results: A clinically meaningful improvement in progression-free survival was observed among patients in the nab-paclitaxel group compared with the docetaxel group. Taxane-based chemotherapy plus immune checkpoint inhibitors achieved longer progression-free survival than taxane-based chemotherapy. There was no difference between taxane-based chemotherapy plus immune checkpoint inhibitors and taxane-based chemotherapy plus angiogenesis inhibitors. Conclusion: Nab-paclitaxel appears to be a reasonable alternative to docetaxel. Chemotherapy plus immune checkpoint inhibitors might yield more survival benefits than chemotherapy alone.

Pyrotinib plus antiangiogenic agents for HER2-altered advanced non-small cell lung cancer: A retrospective real-world study.

BACKGROUND: Although some targeted therapies have been shown to be effective in treating HER2-altered non-small cell lung cancer (NSCLC), the survival demands have not yet been met due to the high cost and limited availability. This study aimed to assess the effectiveness and safety of pyrotinib plus antiangiogenic agents, including apatinib, anlotinib, and bevacizumab, in previously treated patients with HER2-altered advanced NSCLC. METHODS: In this retrospective real-world study, patients with HER2-altered NSCLC who received pyrotinib plus antiangiogenic agents as a second- or later-line treatment between November 2015 and January 2022 were reviewed. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profiles of patients were analyzed. RESULTS: A total of 107 patients were included in the analysis, of which 59 patients (55.1%) had received at least two lines of prior chemotherapy or tyrosine kinase inhibitors. Most of them (87.9%) were identified as harboring HER2 exon 20 insertions. At the data cutoff date (May 13, 2022), the ORR, DCR, median PFS, and median OS were 19.6% (21/107), 94.4% (101/107), 7.13 months (95% confidence interval [CI]: 6.26-8.01), and 19.50 months (95% CI: 12.83-26.17), respectively. There was no difference in the PFS between patients receiving apatinib or anlotinib/bevacizumab (median PFS, 7.13 vs. 6.27 months, hazard ratio [HR] = 1.49, 95% CI: 0.87-2.54, p = 0.15). The most frequent grade 3 or higher treatment-related adverse events was diarrhea (17.6%), followed by hypertension (11.0%) and nausea (3.3%). No treatment-related death occurred. CONCLUSION: In this study, pyrotinib plus antiangiogenic agents demonstrated promising efficacy and were tolerable in HER2-altered NSCLC patients.

Influence of PD-L1 expression on the efficacy of EGFR-TKIs in EGFR-mutant non-small cell lung cancer.

BACKGROUND: Evidence on the influence of programmed death-ligand 1 (PD-L1) expression on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients is at variance. METHODS: A single-center retrospective study was conducted to evaluate the influence of PD-L1 expression on the efficacy of EGFR-TKIs for NSCLC patients with EGFR mutation. Clinical information was retrieved from electronic medical records. The patients were divided into three subgroups according to PD-L1 expression level: PD-L1 < 1% (negative), PD-L1 1%-49% and PD-L1 ≥ 50%. The clinicopathological features, overall response rate (ORR), progression-free survival (PFS) and comutation information were collected and compared between the three subgroups. RESULTS: A total of 117 patients were included. For PD-L1 < 1%, PD-L1 1%-49% and PD-L1 ≥ 50% group, there were 39 (33.3%), 51 (43.5%) and 27 (23.0%) patients respectively, and the ORR was 43.2%, 64.0%, and 51.9%, respectively (p = 0.162), and the median progression-free survival (mPFS) was 22.0 months (95% CI: 14.0-29.9 months), 15.4 months (95% CI: 8.9-21.8 months) and 13.0 months (95% CI: 10.6-15.3 months), respectively (log-rank, p = 0.01). The mPFS was negatively correlated with PD-L1 expression level (r = -0.264, p = 0.041) and PD-L1 expression was an independent risk factor for worse PFS of EGFR-TKIs in multivariate Cox regression. Patients with concurrent TP53 mutation had shorter PFS (p = 0.039) and the patients harboring both mutant TP53 and positive PD-L1 had the shortest PFS (p = 0.006). CONCLUSIONS: The efficacy of EGFR-TKIs was influenced by the baseline PD-L1 expression. Higher PD-L1 expression was associated with shorter PFS. The combined indicators of TP53 and PD-L1 identified subgroups showing divergent benefits from EGFR-TKIs.

Comparison between ESD and RFA in patients with total or near-total circumferential early esophageal squamous cell neoplasia.

BACKGROUND: Patients with early esophageal squamous cell neoplasias (ESCNs) that are totally or nearly totally circumferential face challenges in their clinical work. Endoscopic submucosal dissection (ESD) frequently leads to esophageal strictures. Endoscopic radiofrequency ablation (RFA), which stands out for its simplicity of use and low rate of stenosis, is a rapidly evolving therapeutic strategy for early ESCNs. We contrast ESD with RFA in order to find which method is best for the treatment of a wide range of esophageal diseases. METHODS: Patients who had flat-type, early, large ESCNs (extending more than 3/4 of the esophageal circumference) treated endoscopically were enrolled retrospectively. The primary outcome measurements were adverse events and local control of the neoplastic lesion. RESULTS: A total of 105 patients received treatment; 60 had ESD and 45 received RFA. Despite the patients receiving RFA typically having larger tumors (14.27 vs. 5.70 cm, P < 0.05), the local control of the neoplastic lesion and procedure-related complications were comparable between the ESD and RFA groups. A considerably higher risk of esophageal stenosis was observed in patients with extensive lesions in the ESD group compared to the RFA group (60% vs. 31%; P < 0.05), and the rate of refractory stricture is also higher than that of the RFA. CONCLUSION: Both RFA and ESD are effective in treating large, flat, early ESCNs; however, ESD is more likely to cause side effects, such as esophageal stricture, particularly in lesions that are larger than 3/4 of the diameter. Before RFA, a more precise and thorough pretreatment examination should be performed. A more accurate pretreatment evaluation will be an important development direction for early esophageal cancer in future. After surgery, a strict routine review is crucial.

First-line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non-small cell lung cancer with EGFR exon 20 insertions: Real-world evidence from China.

BACKGROUND: Currently, survival benefit of immunotherapy in advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins) is controversial, though it generally indicates poor response and activity. Compared with standard chemotherapy in combination with bevacizumab, first-line chemotherapy plus immune checkpoint inhibitor (ICI) in advanced NSCLC with EGFR ex20ins remains elusive and lacks real-world evidence. PATIENTS AND METHODS: A retrospective real-world study was conducted to evaluate clinical outcomes of chemotherapy alone (C), chemotherapy plus ICI (C + I), or chemotherapy plus angiogenesis inhibitors (C + A) as first-line strategies for advanced NSCLC patients with EGFR ex20ins. Investigator-assessed response and survival outcomes were compared between subgroups. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to reveal concomitant alterations and explore the molecular landscape of ex20ins. RESULTS: A total of 164 patients were screened, identifying 35 kinds of ex20ins, and 122 cases treated with C, C + I, and C + A were finally included in the first-line analysis. C + A achieved much better objective response rate (ORR, 38.1% vs. 18.2%) and significant progression-free survival (PFS) benefit compared with C (median, 7.73 vs.5.93 months, HR = 0.60, 95% CI: 0.40-0.90, p = 0.014), and it showed similar ORR (38.1% vs. 40.0%), but higher disease control rate (DCR, 96.8% vs. 80.0%) and numerically longer median PFS (7.73 vs. 6.53 months, HR = 0.83, 95% CI: 0.44-1.56, p = 0.30) than C + I. There was no PFS difference between C + I and C, despite of PD-L1 expression or tumor mutational burden. KEGG analysis revealed concomitant upregulation of PI3K/AKT signaling might mediate intrinsic resistance to ICI in ex20ins. CONCLUSION: First-line chemotherapy plus angiogenesis inhibitors might yield more survival benefits than chemotherapy alone for NSCLC with EGFR ex20ins, whereas, it suggests that chemotherapy in combination with ICI might not obtain a better survival benefit for this subset of patients. Activation of PI3K/AKT signaling might mediate intrinsic immunosuppression in NSCLC with EGFR ex20ins.

Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study).

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

Treatment patterns and outcomes of immunotherapy in extensive-stage small-cell lung cancer based on real-world practice.

BACKGROUND: The application of immune checkpoint inhibitors (ICIs) represents a breakthrough in the current landscape for the treatment of extensive-stage small-cell lung cancer (ES-SCLC), but the real-world outcome is limited. This study aimed to investigate the treatment options and efficacy evaluation of first-line, second-line, and subsequent-line immunotherapy in routine practice. METHODS: A retrospective analysis of ES-SCLC patients treated with ICIs was conducted between May 2016 and September 2021. Objective response rate, disease control rate, progression-free survival (PFS) and overall survival were assessed between groups to explore the value of ICIs at different treatment time periods. PFS1 and PFS2 were defined as the duration from initial therapy to disease progression or death in first-line or second-line treatment. RESULTS: Ninety-six patients with ES-SCLC were included. PFS1 was prolonged in patients treated with first-line ICIs-combined therapy (median PFS1 7.20 months vs. 5.30 months, hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.36-087, p = 0.0085). For patients who progressed after first-line ICIs treatment (N = 22), PFS1 + PFS2 was longer in the second-line ICIs continuation group with no significant difference (median PFS1 + PFS2 11.27 months vs. 7.20 months, HR 0.45, 95% CI 0.14-1.51, p = 0.19). For patients who experienced a progression event after first-line chemotherapy (N = 50), PFS2 and PFS1 + PFS2 were prolonged in patients who accepted second-line ICIs-combined therapy without significant difference (median PFS2 4.00 months vs. 2.43 months, HR 0.59, 95% CI 0.33-1.05, p = 0.070; median PFS1 + PFS2 11.30 months vs. 8.70 months, HR 0.53, 95% CI 0.29-0.98, p = 0.056). CONCLUSION: First-line ICIs plus chemotherapy should be applied in the clinical practice of ES-SCLC. If patients did not receive ICIs plus chemotherapy in first-line treatment, therapies that include ICIs in second-line treatment should be considered.

Efficacy and safety of concomitant immunotherapy and denosumab in patients with advanced non-small cell lung cancer carrying bone metastases: A retrospective chart review.

Background: Synergistic anti-tumor effects were observed in vivo and in vitro when immune checkpoint inhibitors (ICIs) were combined with denosumab. However, the clinical benefit and safety of this synergy have not been adequately evaluated in non-small cell lung cancer (NSCLC). Methods: Consecutive charts of NSCLC patients with bone metastases between December 2020 and December 2021 in the Chinese National Cancer Center were reviewed. The entire cohort was divided into one experimental group (denosumab + ICIs [DI]) and three control groups (denosumab + non-ICIs [DnI], phosphates + ICIs [PI], phosphates + non-ICIs [PnI]). Real-world objective response rates (ORRs), median progression-free survival (mPFS), skeletal-related events (SREs), and adverse events (AEs) were compared between groups. Results: A total of 171/410 (41.7%) patients with advanced or recurrent NSCLC carrying bone metastases who received bone-targeted therapy were eligible for analysis. Although the DI group showed a better benefit trend, differences were not statistically significant concerning the therapeutic efficacy among the DI group (n = 40), PI group (n = 74), DnI group (n = 15), and PnI group (n = 42) (ORRs: 47.5%, 43.2%, 33.3%, and 40.5%, respectively, p = 0.799; and mPFS: 378, 190, 170, and 172 days, respectively, p = 0.115; SREs: 5%, 10.8%, 13.3%, and 11.9%, respectively, p = 0.733). Nevertheless, further analysis in the NON-DRIVER cohort revealed a greater benefit for the DI group (p = 0.045). Additionally, the AEs of the DI group were not significantly different from those of the PI, DnI, and PnI groups (AEs: 27.5%, 39.2%, 26.7%, and 28.6%, respectively, p = 0.742). Furthermore, the multivariate analysis revealed the independent prognostic role of DI treatment for PFS in the overall cohort. Within the DI group, we did not observe differences in benefit among different mutational subgroups (p = 0.814), but patients with single-site bone metastasis (p = 0.319) and high PD-L1 expression (p = 0.100) appeared to benefit more, though no significant differences were observed. Conclusions: Denosumab exhibited synergistic antitumor efficacy without increasing toxicity when used concomitantly with ICIs in patients with advanced non-small cell lung cancer carrying bone metastases.

[Research Progress of Circulating Tumor DNA in Non-small Cell Lung Cancer].

With the concept of "Precision Medicine" in malignant tumors popularized, many substances carrying valuable clinical information have emerged in the process of exploring the occurrence and development of tumors from a microscopic perspective. Circulating tumor DNA (ctDNA) is one of them. In various clinical stages of cancer, ctDNA exhibits rich diagnostic values including demonstrating the efficacy of treatment, predicting prognosis, and monitoring disease recurrence. This article mainly describes the application and research progress of ctDNA in different stages of clinical diagnosis and treatment of non-small cell lung cancer .
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Host HSPD1 Translocation from Mitochondria to the Cytoplasm Induced by Streptococcus suis Serovar 2 Enolase Mediates Apoptosis and Loss of Blood-Brain Barrier Integrity.

Streptococcus suis serovar 2 (S. suis serovar 2) is a zoonotic pathogen that causes meningitis in pigs and humans, and is a serious threat to the swine industry and public health. Understanding the mechanism(s) by which S. suis serovar 2 penetrates the blood-brain barrier (BBB) is crucial to elucidating the pathogenesis of meningitis. In a previous study, we found that expression of the virulence factor enolase (Eno) by S. suis serovar 2 promotes the expression of host heat shock protein family D member 1 (HSPD1) in brain tissue, which leads to the apoptosis of porcine brain microvascular endothelial cells (PBMECs) and increased BBB permeability, which in turn promotes bacterial translocation across the BBB. However, the mechanism by which HSPD1 mediates Eno-induced apoptosis remains unclear. In this study, we demonstrate that Eno promotes the translocation of HSPD1 from mitochondria to the cytoplasm, where HSPD1 binds to ß-actin (ACTB), the translocated HSPD1, and its interaction with ACTB led to adverse changes in cell morphology and promoted the expression of apoptosis-related proteins, second mitochondria-derived activator of caspases (Smac), and cleaved caspase-3; inhibited the expression of X-linked inhibitor of apoptosis protein (XIAP); and finally promoted cell apoptosis. These results further elucidate the role of HSPD1 in the process of Eno-induced apoptosis and increased BBB permeability, increasing our understanding of the pathogenic mechanisms of meningitis, and providing a framework for novel therapeutic strategies.

Efficacy of dacomitinib in patients with non-small cell lung cancer carrying complex EGFR mutations: a real-world study.

Background: Dacomitinib is a first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on NSCLC with complex EGFR mutations is limited. Methods: Patients harboring complex (common mutations co-existing with uncommon mutations), or common (comparison cohort) EGFR mutations, who were treated with dacomitinib, were retrospectively evaluated in the Chinese National Cancer Center and the China PLA hospital between August 2019 and August 2021. Results: In total, 72 patients with NSCLC harboring complex (C+U group, n=18) or common (C group, n=54) EGFR mutations and being treated with dacomitinib were enrolled. In the C+U group, 16 cases (88.9%) harbored L858R mutations co-existing with uncommon mutations located from exon 18 to exon 25 of EGFR (mostly E709X), and two cases harbored exon 19 deletion co-existing with G724S or K754E. Among the 15 evaluable patients, the objective response rate (ORR) was 40% (6/15), and the disease control rate (DCR) was 73.3% (11/15). The median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI), 4.4-10.6 months]. Except for the application line of dacomitinib (P=0.039), no significant statistical differences were found in other characteristics and adverse events between the two groups. The Kaplan-Meier method revealed no significant differences in PFS (P=0.889) and overall survival (OS) (P=0.703). However, the stratified analysis found worse PFS in the C+U group than that observed in the C group when receiving 1st and ≥3rd line dacomitinib treatment, while its OS was worse than that of group C when receiving ≥3rd line treatment. Furthermore, in a multivariate analysis, complex mutation status was an independent prognostic factor for OS (P=0.038) in the entire cohort. Conclusions: This study indicated a worse response and prognosis of patients with NSCLC harboring complex EGFR mutations than those harboring common EGFR mutations when treated with dacomitinib. Further studies and data are needed to confirm this conclusion.

Epidemiological Features, Risk Factors, and Disease Burden of Respiratory Viruses among Hospitalized Children with Acute Respiratory Tract Infections in Xiamen, China.

Well-established surveillance and monitoring systems for respiratory viruses need to be improved, and epidemiological data on respiratory viruses in China are scarce. This study aimed to investigate the epidemiological characteristics of respiratory viruses among hospitalized children aged ≤2 years with acute respiratory tract infections (ARTIs) in Xiamen, China, from October 2014 to September 2017. The clinical records of 7,248 children hospitalized for ARTIs were retrospectively analyzed. Respiratory syncytial virus (RSV) (22.3%) was the most common virus among hospitalized children aged ≤2 years, followed by parainfluenza (5.0%), adenovirus (3.5%), and influenza (1.7%). RSV-infected children had a higher disease burden, including a higher intensive care unit (ICU) admission rate (12.7%) and higher hospital charges ($635.36). Particularly, infants aged <6 months had the highest risk of RSV infection (odds ratio = 2.4; 95% CI, 1.9-2.9) and a higher ICU admission rate (12.1% vs. 4.5%, 4.6%) and hospital cost ($923.3 vs. $785.5, $811.7) than the other age groups. Therefore, infants aged 0-6 months, particularly premature infants and children with congenital diseases, should receive more attention. There is an urgent need to develop effective immunization strategies to protect these infants during the first 6 months of life and in the RSV season.

From part to whole, operative link on to endoscopic grading of gastric intestinal metaplasia, pathology to endoscopy: gastric intestinal metaplasia graded by endoscopy.

Objective: To conduct a systematic review and meta-analysis on the prediction of severity of gastric intestinal metaplasia (GIM) in localized and entire gastric mucosa using endoscopy. Methods: The authors searched Web of Science, PubMed, Embase and Cochrane Central Register of Controlled Trials and performed systematic searches on endoscopic grading of GIM of the entire stomach using Meta-DiSc and Stata. Results: Sensitivity and specificity for the stratified prediction of overall GIM were 0.91 (95% CI: 0.85-0.95) and 0.91 (95% CI: 0.88-0.93), respectively. Sensitivity in predicting the different grades of GIM was higher in operative link on GIM assessment grades 0, III and IV but lower in grades I and II. Conclusion: Digital chromoendoscopy is well suited to predicting the severity of localized and overall GIM.

Molecular Evolution of Attachment Glycoprotein (G) and Fusion Protein (F) Genes of Respiratory Syncytial Virus ON1 and BA9 Strains in Xiamen, China.

Monitoring viral transmission and analyzing the genetic diversity of a virus are imperative to better understand its evolutionary history and the mechanism driving its evolution and spread. Especially, effective monitoring of key antigenic mutations and immune escape variants caused by these mutations has great scientific importance. Thus, to further understand the molecular evolutionary dynamics of respiratory syncytial virus (RSV) circulating in China, we analyzed nasopharyngeal swab specimens derived from hospitalized children ≤5 years old with acute respiratory tract infections (ARIs) in Xiamen during 2016 to 2019. We found that infants under 6 months of age (52.0%) were the main population with RSV infection. The prevalent pattern "BBAA" of RSV was observed during the epidemic seasons. RSV ON1 and BA9 genotypes were the dominant circulating strains in Xiamen. Interestingly, we observed four Xiamen-specific amino acid substitution combinations in the G protein and several amino acid mutations primarily occurring at antigenic sites Ø and V in the F protein. Our analyses suggest that introduction of new viruses and local evolution are shaping the diversification of RSV strains in Xiamen. This study provides new insights on the evolution and spread of the ON1 and BA9 genotypes at local and global scales. IMPORTANCE Monitoring the amino acid diversity of the RSV G and F genes helps us to find the novel genotypes, key antigenic mutations affecting antigenicity, or neutralizing antibody-resistant variants produced by natural evolution. In this study, we analyzed the molecular evolution of G and F genes from RSV strains circulating in Xiamen, China. These data provide new insights on local and global transmission and could inform the development of control measures for RSV infections.

A meta-analysis and systematic review on subtypes of gastric intestinal metaplasia and neoplasia risk.

BACKGROUND: Gastric intestinal metaplasia (GIM) is a significant risk factor for gastric cancer. Risk of gastric cancer/dysplasia between complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM) was controversial. Our study aimed to pool relative risk (RR) of cancer/dysplasia of IIM compared with CIM in GIM patients. METHODS: PubMed, EMBASE, Cochrane Library and Web of Science were searched for studies concerning cancer/dysplasia in GIM patients. Random-effects or fixed-effects model was utilized for pooling RR. Sensitivity and publication bias analyses were conducted. Stability of results would be evaluated in case of publication bias. RESULTS: 12 studies were included. Compared with CIM, pooled RR of cancer/dysplasia in IIM patients was 4.48 (95% CI 2.50-8.03), and the RR was 4.96 (95% CI 2.72-9.04) for cancer, and 4.82 (95% CI 1.45-16.0) for dysplasia. The pooled RR for cancer/dysplasia in type III IM was 6.27 (95% CI 1.89-20.77) compared with type II + I IM, while it was 5.55 (95% CI 2.07-14.92) compared with type II IM. Pooled RR between type II IM and type I IM was 1.62 (95% CI 1.16-2.27). Subgroup analyses showed that IIM was associated with a higher risk of gastric cancer/dysplasia in Western population (pooled RR = 4.65 95% CI 2.30-9.42), but not in East Asian population (pooled RR = 4.01 95% CI 0.82-19.61). CONCLUSIONS: IIM was related to a higher risk of cancer/dysplasia compared with CIM. Risk of developing cancer/dysplasia from type I, II, and III intestinal metaplasia increased gradually.

Streptococcus suis serotype 2 enolase interaction with host brain microvascular endothelial cells and RPSA-induced apoptosis lead to loss of BBB integrity.

Host proteins interacting with pathogens are receiving more attention as potential therapeutic targets in molecular medicine. Streptococcus suis serotype 2 (SS2) is an important cause of meningitis in both humans and pigs worldwide. SS2 Enolase (Eno) has previously been identified as a virulence factor with a role in altering blood brain barrier (BBB) integrity, but the host cell membrane receptor of Eno and The mechanism(s) involved are unclear. This study identified that SS2 Eno binds to 40S ribosomal protein SA (RPSA) on the surface of porcine brain microvascular endothelial cells leading to activation of intracellular p38/ERK-eIF4E signalling, which promotes intracellular expression of HSPD1 (heat-shock protein family D member 1), and initiation of host-cell apoptosis, and increased BBB permeability facilitating bacterial invasion. This study reveals novel functions for the host-interactional molecules RPSA and HSPD1 in BBB integrity, and provides insight for new therapeutic strategies in meningitis.