Circulating tumour DNA-Based molecular residual disease detection in resectable cancers: a systematic review and meta-analysis.

BACKGROUND: Circulating tumour DNA (ctDNA)-based molecular residual disease (MRD) detection technology has been widely used for recurrence evaluation, but there is no agreement on the efficacy of assessing recurrence and overall survival (OS) prognosis, as well as the sensitivity and specificity of landmark detection and longitudinal detection. METHODS: We systematically searched Pubmed, Embase, Cochrane, and Scopus for prospective studies or randomized controlled trials that collected blood samples prospectively. The search period was from Jan 1, 2013, to Sept 10, 2023. We excluded retrospective studies. The primary endpoint was to assess the hazard ratio (HR) between circulating tumour DNA positive (ctDNA+) and negative (ctDNA-) for recurrence-free survival incidence (RFS), disease-free survival (DFS), progression-free survival (PFS), event-free survival (EFS), time to recurrence (TTR), distant metastasis-free survival (DMFS) or OS in patients with resectable cancers. We calculated the pooled HR of recurrence and OS and 95% confidence interval (CI) in patients with resected cancers using a random-effects model. Pooled sensitivity and specificity were estimated using the bivariate random effects model. FINDINGS: This systematic review and meta-analysis returned 7578 records, yielding 80 included studies after exclusion. We found that the HR of recurrence across all included cancers between patients with ctDNA+ and ctDNA- was 7.48 (95% CI 6.39-8.77), and the OS was 5.58 (95% CI 4.17-7.48). We also found that the sensitivity, area under the summary receiver operating characteristic curve (AUSROC) and diagnostic odds ratio (DOR) of longitudinal tests were higher than that of landmark tests between patients with ctDNA+ and ctDNA- (0.74, 95% CI 0.68-0.80 vs 0.50, 95% CI 0.46-0.55; 0.88 vs. 0.80; 25.70, 95% CI 13.20-45.40 vs. 9.90, 95% CI 7.77-12.40). INTERPRETATION: Postoperative ctDNA testing was a significant prognosis factor for recurrence and OS in patients with resectable cancers. However, the overall sensitivity of ctDNA-MRD detection could be better. Longitudinal monitoring can improve the sensitivity, AUSROC, and DOR. FUNDING: Special fund project for clinical research of Qingyuan People's Hospital (QYRYCRC2023006), plan on enhancing scientific research in GMU (GZMU-SH-301).

Association of asthma and lung cancer risk: A pool of cohort studies and Mendelian randomization analysis.

BACKGROUND: Over the past 2 decades, population-based studies have shown an increased association between asthma and the risk of lung cancer. However, the causal links between these 2 conditions remain poorly understood. METHODS: We conducted a comprehensive search of various databases, including PubMed, Embase, Web of Science, and Cochrane Library, up until May 04, 2023. Only articles published in English were included in our study. We performed a meta-analysis using random-effects models to calculate the odds ratio (OR) and corresponding 95% confidence interval (CI). Subgroup analyses were conducted based on study design, gender, and histologic types. We also conducted a 2-sample Mendelian randomization (MR) using the genome-wide association study pooled data (408,422 people) published by the UK Biobank to explore further the potential causal relationship between asthma and lung cancer. RESULTS: Our meta-analysis reviewed 24 population-based cohort studies involving 1072,502 patients, revealing that asthma is significantly associated with an increased risk of lung cancer (OR = 1.29, 95% CI 1.19-1.38) in all individuals. Subgroup analysis showed a significantly higher risk of lung cancer in females with asthma (OR = 1.23, 95% CI 1.01-1.49). We found no significant association between asthma and lung adenocarcinoma (LUAD) (OR = 0.76, 95% CI 0.54-1.05), lung squamous carcinomas (LUSC) (OR = 1.09, 95% CI 0.79-1.50), or small-cell lung cancer (SCLC) (OR = 1.00, 95% CI 0.68-1.49). Interestingly, our MR analysis supported an increasing causality between asthma and lung cancer (OR = 1.11, 95% CI 1.04-1.17, P = .0008), specifically in those who ever smoker (OR = 1.09, 95% CI 1.01-1.16, P = .0173) and LUSC pathological type (OR = 1.15, 95% CI 1.05-1.26, P = .0038). CONCLUSION: Through meta-analysis, our study confirms that patients with asthma have a higher risk of developing lung cancer. Our MR study further support an increasing causal relationship between asthma and the risk of lung cancer, particularly in smokers and LUSC. Future studies examining the link between asthma and the risk of developing lung cancer should consider the bias of controlled and uncontrolled asthma.

Loratidine is associated with improved prognosis and exerts antineoplastic effects via apoptotic and pyroptotic crosstalk in lung cancer.

BACKGROUND: Tumor-associated inflammation suggests that anti-inflammatory medication could be beneficial in cancer therapy. Loratadine, an antihistamine, has demonstrated improved survival in certain cancers. However, the anticancer mechanisms of loratadine in lung cancer remain unclear. OBJECTIVE: This study investigates the anticancer mechanisms of loratadine in lung cancer. METHODS: A retrospective cohort of 4,522 lung cancer patients from 2006 to 2018 was analyzed to identify noncancer drug exposures associated with prognosis. Cellular experiments, animal models, and RNA-seq data analysis were employed to validate the findings and explore the antitumor effects of loratadine. RESULTS: This retrospective study revealed a positive association between loratadine administration and ameliorated survival outcomes in lung cancer patients, exhibiting dose dependency. Rigorous in vitro and in vivo assays demonstrated that apoptosis induction and epithelial-mesenchymal transition (EMT) reduction were stimulated by moderate loratadine concentrations, whereas pyroptosis was triggered by elevated dosages. Intriguingly, loratadine was found to augment PPARγ levels, which acted as a gasdermin D transcription promoter and caspase-8 activation enhancer. Consequently, loratadine might incite a sophisticated interplay between apoptosis and pyroptosis, facilitated by the pivotal role of caspase-8. CONCLUSION: Loratadine use is linked to enhanced survival in lung cancer patients, potentially due to its role in modulating the interplay between apoptosis and pyroptosis via caspase-8.

Chemoselective Transformations of Amides: An Approach to Quinolones from ß-Amido Ynones.

An efficient and chemoselective transformation of ß-amido ynones to 3-acyl-substituted quinolones 2 and 3-H-quinolones 4 has been developed. In this reaction, ß-cyclic amido ynones can be selectively transformed into quinolones 2 in anhydrous EG via a selective C═O bond cleavage, 1,5-O migration, and C═C bond recombination process. The practical approach of this reaction renders it a viable alternative for the construction of various quinolones.

Rh(II)-Catalyzed Chemoselective Oxy-alkynylation of Acceptor-Acceptor Carbenes: Synthesis of C2-Quaternary Alkyne-Substituted 3(2H)-Furanones.

A Rh(II)-catalyzed oxy-alkynylation of acceptor-acceptor carbenes using EBX reagents was successfully developed. The key alkyne-transfer step is likely to occur through a tandem process involving a ß-addition, an α-elimination, and a 1,2-shift, which was supported by the formation of alkylidene carbene. Various diverse C2-quaternary alkyne-substituted benzofuran-3-ones and 2,2,4,5-tetrasubstituted 3(2H)-furanones can be synthesized smoothly, depending on the choice of diazo compounds and the base additives. Furthermore, this reaction is characterized by mild conditions, high functional group compatibility, and a broad substrate scope.

Intratumoral tertiary lymphoid structure (TLS) maturation is influenced by draining lymph nodes of lung cancer.

BACKGROUND: Tertiary lymphoid structure (TLS) is an organized infiltration of immune cells, showing features of germinal center (GC) commonly seen in secondary lymphoid organs. However, its relationship with tumor-draining lymph nodes (TDLNs) has not been studied and we hypothesized that TDLN may influence maturation of intratumoral TLS in non-small cell lung cancer (NSCLC). METHODS: Tissue slides of 616 patients that had undergone surgeries were examined. Cox proportional hazard regression model was used to assess risk factors of patients' survival, and logistic regression model was used for their relationship with TLS. Single-cell RNA-sequencing (scRNA-seq) was employed to explore transcriptomic features of TDLNs. Immunohistochemistry, multiplex immunofluorescence and flow cytometry were performed to analyze cellular composition. Cellular components of NSCLC samples from The Cancer Genome Atlas database were inferred with Microenvironment Cell Populations-counter (MCP-counter) method. Murine NSCLC models were used to dissect underlying mechanisms for relationship between TDLN and TLS maturation. RESULTS: While GC+ TLS was associated with better prognosis, GC- TLS was not. TDLN metastasis reduced the prognostic relevance of TLS, and was associated with less GC formation. Primary tumor sites showed reduced B cell infiltration in TDLN-positive patients, and scRNA-seq revealed diminished memory B cell formation in tumor-invaded TDLNs, together with an emphasis on weakened interferon (IFN)-γ response. Murine NSCLC models revealed that IFN-γ signaling is involved in memory B cell differentiation in TDLNs and GC formation in primary tumors. CONCLUSIONS: Our research emphasizes the influence of TDLN on intratumoral TLS maturation and suggests a role of memory B cells and IFN-γ signaling in this communication.

Risk mapping of lung cancer: a comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies.

INTRODUCTION: A comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies was performed to map the different risk factors and assess the causality for lung cancer. METHODS: Systematic reviews and meta-analyses of observational and interventional studies were reviewed based on PubMed, Embase, Web of Science, and Cochrane Library. Mendelian randomization analyses were conducted to validate the causal associations of those various exposures with lung cancer using summary statistics from 10 genome-wide association studies (GWAS) consortia and other GWAS databases in MR-Base platform. RESULTS: In the review of meta-analyses, 105 risk factors associated with lung cancer were identified from 93 articles. It was found that 72 risk factors were nominally significant (P < 0.05) associated with lung cancer. Mendelian randomization analyses were performed to analyze 36 exposures based on 551 SNPs and 4,944,052 individuals, finding that 3 exposures had a consistent risk/protective effect on lung cancer with the results of the meta-analysis. In Mendelian randomization anaylses, smoking (OR 1.44, 95% CI 1.18-1.75; P = 0.001) and blood copper (OR 1.14, 95% CI 1.01-1.29; P = 0.039) significantly associated with increased risk of lung cancer, whereas aspirin use (OR 0.67, 95% CI 0.50-0.89; P = 0.006) showed protective effects. CONCLUSION: This study mapped putative associations of risk factors for lung cancer, revealing the causal hazard effect of smoking, blood copper, and the protective effect of aspirin use in the development of lung cancer. CLINICAL TRIAL REGISTRY: This study is registered with PROSPERO (CRD42020159082).

Gli1 promotes epithelial-mesenchymal transition and metastasis of non-small cell lung carcinoma by regulating snail transcriptional activity and stability.

Metastasis is crucial for the mortality of non-small cell lung carcinoma (NSCLC) patients. The epithelial-mesenchymal transition (EMT) plays a critical role in regulating tumor metastasis. Glioma-associated oncogene 1 (Gli1) is aberrantly active in a series of tumor tissues. However, the molecular regulatory relationships between Gli1 and NSCLC metastasis have not yet been identified. Herein, we reported Gli1 promoted NSCLC metastasis. High Gli1 expression was associated with poor survival of NSCLC patients. Ectopic expression of Gli1 in low metastatic A549 and NCI-H460 cells enhanced their migration, invasion abilities and facilitated EMT process, whereas knock-down of Gli1 in high metastatic NCI-H1299 and NCI-H1703 cells showed an opposite effect. Notably, Gli1 overexpression accelerated the lung and liver metastasis of NSCLC in the intravenously injected metastasis model. Further research showed that Gli1 positively regulated Snail expression by binding to its promoter and enhancing its protein stability, thereby facilitating the migration, invasion and EMT of NSCLC. In addition, administration of GANT-61, a Gli1 inhibitor, obviously suppressed the metastasis of NSCLC. Collectively, our study reveals that Gli1 is a critical regulator for NSCLC metastasis and suggests that targeting Gli1 is a prospective therapy strategy for metastatic NSCLC.

Palladium-Catalyzed Carbene Migratory Insertion/Carbonylation Cascade Reaction: Synthesis of 2-Indolones with a C3 All-Carbon Quaternary Center.

An attractive palladium-catalyzed three-component reaction of ortho-amino aryl diazo esters, allyl carboxylates, and carbon monoxide (CO) has been developed. This catalytic system rendered domino carbene migratory insertion and carbonylation. Remarkably, 2-indolones 3 with a C3 all-carbon quaternary center can be selectively obtained in good to excellent yields via one-pot synthesis, in which two different C-C bonds and one C-N bond were formed in a straightforward manner.

Artificial intelligence for stepwise diagnosis and monitoring of COVID-19.

BACKGROUND: Main challenges for COVID-19 include the lack of a rapid diagnostic test, a suitable tool to monitor and predict a patient's clinical course and an efficient way for data sharing among multicenters. We thus developed a novel artificial intelligence system based on deep learning (DL) and federated learning (FL) for the diagnosis, monitoring, and prediction of a patient's clinical course. METHODS: CT imaging derived from 6 different multicenter cohorts were used for stepwise diagnostic algorithm to diagnose COVID-19, with or without clinical data. Patients with more than 3 consecutive CT images were trained for the monitoring algorithm. FL has been applied for decentralized refinement of independently built DL models. RESULTS: A total of 1,552,988 CT slices from 4804 patients were used. The model can diagnose COVID-19 based on CT alone with the AUC being 0.98 (95% CI 0.97-0.99), and outperforms the radiologist's assessment. We have also successfully tested the incorporation of the DL diagnostic model with the FL framework. Its auto-segmentation analyses co-related well with those by radiologists and achieved a high Dice's coefficient of 0.77. It can produce a predictive curve of a patient's clinical course if serial CT assessments are available. INTERPRETATION: The system has high consistency in diagnosing COVID-19 based on CT, with or without clinical data. Alternatively, it can be implemented on a FL platform, which would potentially encourage the data sharing in the future. It also can produce an objective predictive curve of a patient's clinical course for visualization. KEY POINTS: • CoviDet could diagnose COVID-19 based on chest CT with high consistency; this outperformed the radiologist's assessment. Its auto-segmentation analyses co-related well with those by radiologists and could potentially monitor and predict a patient's clinical course if serial CT assessments are available. It can be integrated into the federated learning framework. • CoviDet can be used as an adjunct to aid clinicians with the CT diagnosis of COVID-19 and can potentially be used for disease monitoring; federated learning can potentially open opportunities for global collaboration.

Cooperative Rh(II)/Pd(0) Dual Catalysis: Synthesis of Highly Substituted 3(2H)-Furanones with a C2-Quaternary Center via a Cyclization/Allylic Alkylation Cascade of α-Diazo-δ-keto-esters.

A cooperative Rh(II)/Pd(0) dual-catalysis strategy that promotes a cyclization/allylic alkylation cascade of stable α-diazo-δ-keto-esters has been developed. Highly substituted 3(2H)-furanones with a C2-quaternary center can be obtained efficiently under mild conditions via one-pot synthesis. Remarkably, this binary catalytic system shows high chemo-, regio-, and stereoselectivity and excellent tolerance to various functionalities.

Gold(I)-Catalyzed Oxidative Amination of ß-Amino-ynones to Quaternary Ammonium-olate Salts: The Benefit of a P,N-Bidentate Ligand.

A novel P,N-bidentate ligand-assisted gold-catalyzed oxidative amination of ß-amino-ynones has been developed, allowing the simple and efficient construction of various quaternary ammonium-olate salts in good to excellent yields. These unprecedented quaternary ammonium-olate salts can be isolated and purified via simple suction filtration. The broad substrate scope, easy purification, easy further transformation, and mild conditions make it a viable alternative for the synthesis of various quaternary ammonium-olate salts.

Butyrophilin-like 9 expression is associated with outcome in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most prevalent non-small cell lung cancer (NSCLC). Patients with LUAD have a poor 5-year survival rate. The use of immune checkpoint inhibitors (ICIs) for the treatment of LUAD has been on the rise in the past decade. This study explored the prognostic role of butyrophilin-like 9 (BTNL9) in LUAD. METHODS: Gene expression profile of buytrophilins (BTNs) was determined using the GEPIA database. The effect of BTNL9 on the survival of LUAD patients was assessed using Kaplan-Meier plotter and OncoLnc. Correlation between BTNL9 expression and tumor-infiltrating immune cells (TILs) was explored using TIMER and GEPIA databases. Further, the relationship between BTNL9 expression and drug response was evaluated using CARE. Besides, construction and evaluation of nomogram based on BTNL9 expression and TNM stage. RESULTS: BTNL9 expression was downregulated in LUAD and was associated with a poor probability of 1, 3, 5-years overall survival (OS). In addition, BTNL9 expression was regulated at epigenetic and post-transcriptional modification levels. Moreover, BTNL9 expression was significantly positively correlated with ImmuneScore and ESTIMATEScore. Furthermore, BTNL9 expression was positively associated with infiltration levels of B cells, CD4+ T cells, and macrophages. Kaplan-Meier analysis showed that BTNL9 expression in B cells and dendritic cells (DCs) was significantly associated with OS. BTNL9 expression was significantly positively correlated with CARE scores. CONCLUSIONS: These findings show that BTNL9 is a potential prognostic biomarker for LUAD. Low BTNL9 expression levels associated with low infiltration levels of naïve B cells, and DCs in the tumor microenvironment are unfavorable for OS in LUAD patients.

A Low-Producing Haplotype of Interleukin-6 Disrupting CTCF Binding Is Protective against Severe COVID-19.

Interleukin6 (IL-6) is a key driver of hyperinflammation in COVID-19, and its level strongly correlates with disease progression. To investigate whether variability in COVID-19 severity partially results from differential IL-6 expression, functional single-nucleotide polymorphisms (SNPs) of IL-6 were determined in Chinese COVID-19 patients with mild or severe illness. An Asian-common IL-6 haplotype defined by promoter SNP rs1800796 and intronic SNPs rs1524107 and rs2066992 correlated with COVID-19 severity. Homozygote carriers of C-T-T variant haplotype were at lower risk of developing severe symptoms (odds ratio, 0.256; 95% confidence interval, 0.088 to 0.739; P = 0.007). This protective haplotype was associated with lower levels of IL-6 and its antisense long noncoding RNA IL-6-AS1 by cis-expression quantitative trait loci analysis. The differences in expression resulted from the disturbance of stimulus-dependent bidirectional transcription of the IL-6/IL-6-AS1 locus by the polymorphisms. The protective rs2066992-T allele disrupted a conserved CTCF-binding locus at the enhancer elements of IL-6-AS1, which transcribed antisense to IL-6 and induces IL-6 expression in inflammatory responses. As a result, carriers of the protective allele had significantly reduced IL-6-AS1 expression and attenuated IL-6 induction in response to acute inflammatory stimuli and viral infection. Intriguingly, this low-producing variant that is endemic to present-day Asia was found in early humans who had inhabited mainland Asia since ∼40,000 years ago but not in other ancient humans, such as Neanderthals and Denisovans. The present study suggests that an individual's IL-6 genotype underlies COVID-19 outcome and may be used to guide IL-6 blockade therapy in Asian patients. IMPORTANCE Overproduction of cytokine interleukin-6 (IL-6) is a hallmark of severe COVID-19 and is believed to play a critical role in exacerbating the excessive inflammatory response. Polymorphisms in IL-6 account for the variability of IL-6 expression and disparities in infectious diseases, but its contribution to the clinical presentation of COVID-19 has not been reported. Here, we investigated IL-6 polymorphisms in severe and mild cases of COVID-19 in a Chinese population. The variant haplotype C-T-T, represented by rs1800796, rs1524107, and rs2066992 at the IL-6 locus, was reduced in patients with severe illness; in contrast, carriers of the wild-type haplotype G-C-G had higher risk of severe illness. Mechanistically, the protective variant haplotype lost CTCF binding at the IL-6 intron and responded poorly to inflammatory stimuli, which may protect the carriers from hyperinflammation in response to acute SARS-CoV-2 infection. These results point out the possibility that IL-6 genotypes underlie the differential viral virulence during the outbreak of COVID-19. The risk loci we identified may serve as a genetic marker to screen high-risk COVID-19 patients.

Role of lymphatic endothelial cells in the tumor microenvironment-a narrative review of recent advances.

BACKGROUND: As lymphatic vessel is a major route for solid tumor metastasis, they are considered an essential part of tumor drainage conduits. Apart from forming the walls of lymphatic vessels, lymphatic endothelial cells (LECs) have been found to play multiple other roles in the tumor microenvironment, calling for a more in-depth review. We hope that this review may help researchers gain a detailed understanding of this fast-developing field and shed some light upon future research. METHODS: To achieve an informative review of recent advance, we carefully searched the Medline database for English literature that are openly published from the January 1995 to December 2020 and covered the topic of LEC or lymphangiogenesis in tumor progression and therapies. Two different authors independently examined the literature abstracts to exclude possible unqualified ones, and 310 papers with full texts were finally retrieved. RESULTS: In this paper, we discussed the structural and molecular basis of tumor-associated LECs, together with their roles in tumor metastasis and drug therapy. We then focused on their impacts on tumor cells, tumor stroma, and anti-tumor immunity, and the molecular and cellular mechanisms involved. Special emphasis on lung cancer and possible therapeutic targets based on LECs were also discussed. CONCLUSIONS: LECs can play a much more complex role than simply forming conduits for tumor cell dissemination. Therapies targeting tumor-associated lymphatics for lung cancer and other tumors are promising, but more research is needed to clarify the mechanisms involved.

Toxicity profile of epidermal growth factor receptor tyrosine kinase inhibitors for patients with lung cancer: A systematic review and network meta-analysis.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are treatments commonly used for lung cancer. The toxicity profile including toxicity incidence, severity, and spectrum (involving various specific adverse events) of each EGFR-TKI are of particular clinical interest and importance. Data from phase II and III randomized controlled trials comparing treatments among EGFR-TKIs (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib) and chemotherapy for lung cancer were synthesized with Bayesian network meta-analysis. The primary outcome was systemic all-grade and grade ≥3 adverse events. The secondary outcome was specific all-grade adverse events including those of the skin, gastrointestinal tract, lung, etc. 40 trials randomizing 13,352 patients were included. Generally greater toxicity for dacomitinib and afatinib, and safety for icotinib were suggested. Furthermore, we found individual EGFR-TKIs had different toxicity spectrums. These findings provide a compelling safety reference for the individualized use of EGFR-TKIs for patients with lung cancer.

Establishment and validation of an eight-gene metabolic-related prognostic signature model for lung adenocarcinoma.

In this study, we constructed an eight-gene metabolic related signature for LUAD. The eight-gene prognostic signature (including PLAUR, F2, UGT2B17, GNG7, IDO2, ST3GAL6, PIK3CG, and GLS2) exhibited a good prognostic value in the TCGA LUAD training dataset and testing dataset. In addition, the risk score based on the signature model was significantly correlated with immune cell infiltration and expression levels of immune markers in LUAD patients. LUAD cohorts from GEO were used to validate the model, indicating the usefulness of the model. In summary, we developed and validated an eight-gene signature model for LUAD, which can reflect the immune microenvironment characteristics and predict the prognostic outcomes for LUAD patients.