Upregulation of Siglec-6 induces mitochondrial dysfunction by promoting GPR20 expression in early-onset preeclampsia.

BACKGROUND: Preeclampsia, especially early-onset preeclampsia (EO-PE), is a pregnancy complication that has serious consequences for the health of both the mother and the fetus. Although abnormal placentation due to mitochondrial dysfunction is speculated to contribute to the development of EO-PE, the underlying mechanisms have yet to be fully elucidated. METHODS: The expression and localization of Siglec-6 in the placenta from normal pregnancies, preterm birth and EO-PE patients were examined by RT-qPCR, Western blot and IHC. Transwell assays were performed to evaluate the effect of Siglec-6 on trophoblast cell migration and invasion. Seahorse experiments were conducted to assess the impact of disrupting Siglec-6 expression on mitochondrial function. Co-IP assay was used to examine the interaction of Siglec-6 with SHP1/SHP2. RNA-seq was employed to investigate the mechanism by which Siglec-6 inhibits mitochondrial function in trophoblast cells. RESULTS: The expression of Siglec-6 in extravillous trophoblasts is increased in placental tissues from EO-PE patients. Siglec-6 inhibits trophoblast cell migration and invasion and impairs mitochondrial function. Mechanismly, Siglec-6 inhibits the activation of NF-κB by recruiting SHP1/SHP2, leading to increased expression of GPR20. Notably, the importance of GPR20 function downstream of Siglec-6 in trophoblasts is supported by the observation that GPR20 downregulation rescues defects caused by Siglec-6 overexpression. Finally, overexpression of Siglec-6 in the placenta induces a preeclampsia-like phenotype in a pregnant mouse model. CONCLUSIONS: This study indicates that the regulatory pathway Siglec-6/GPR20 has a crucial role in regulating trophoblast mitochondrial function, and we suggest that Siglec-6 and GPR20 could serve as potential markers and targets for the clinical diagnosis and therapy of EO-PE.

Effect of Zinc and Severe Plastic Deformation on Mechanical Properties of AZ61 Magnesium Alloy.

This study investigates the effects of zinc (4 wt.%) and severe plastic deformation on the mechanical properties of AZ61 magnesium alloy through the stir-casting process. Severe plastic deformation (Equal Channel Angular Pressing (ECAP)) has been performed followed by T4 heat treatment. The microstructural examinations revealed that the addition of 4 wt.% Zn enhances the uniform distribution of ß-phase, contributing to a more uniformly corroded surface in corrosive environments. Additionally, dynamic recrystallization (DRX) significantly reduces the grain size of as-cast alloys after undergoing ECAP. The attained mechanical properties demonstrate that after a single ECAP pass, AZ61 + 4 wt.% Zn alloy exhibits the highest yield strength (YS), ultimate compression strength (UCS), and hardness. This research highlights the promising potential of AZ61 + 4 wt.% Zn alloy for enhanced mechanical and corrosion-resistant properties, offering valuable insights for applications in diverse engineering fields.

Facilitated transport of toluene and naphthalene with humic acid in high- and low-permeability systems: Role of ionic strength and cationic type.

The occurrence of colloids on pollutants transport in groundwater has attracted more attention. However, the research on the regulation mechanism of colloids on combined pollutants transport in heterogeneous aquifers is limited. In this study, a series of tank experiments were conducted to systematically investigate the effects of ionic strength, and cation type on humic acid (HA) facilitated transport of toluene (TOL), and naphthalene (NAP) in high- and low-permeability systems. The results showed that HA facilitated pollutants transport in low Na+ solution. In Ca2+ solution, the presence of HA hindered pollutants transport, and the inhibition increased with the increase of ionic strength. Both in Na+ solution and low Ca2+ solution, the influence of heterogeneous structure on pollutant transport played a dominant role, and TOL and NAP had a greater transport potential in the high permeability zone (HPZ) due to the preferential flow. Whereas, deposition of HA aggregates, and electrostatic attractive interaction had negative effects on transport than groundwater flow in high Ca2+ solution. Pollutants were prone to accumulate at the bottom of the HPZ, and the top of the low permeability zone (LPZ). These new findings provide insights into the mechanism of colloids influence on the pollutants transport in heterogenous aquifer.

E. coli cotransport with composite colloid in unsaturated porous media: Multi-risk on migration and biomolecular response.

The diversity of colloidal types and the differences in the composite ratios in porous media are important factors governing the migration and biological risk of pathogenic microorganisms in the subsurface environment. In this study, E. coli O157:H7 was subjected to co-migration experiments with different compositions of the composite colloid montmorillonite (MMT)-Fe2O3, and the biomolecular response of E. coli under the action of colloids was analyzed by Raman spectroscopy to quantify the risk of E. coli under the action of composite colloids based on both. The results showed that Fe2O3 colloids inhibited E. coli migration mainly by electrostatic adsorption and reduced E. coli metabolism. MMT colloid inhibited E. coli migration mainly by blockage, and E. coli metabolism increased, and surface macromolecules decreased to reduce E. coli adhesion. MMT-Fe2O3 complex colloids inhibited migration through electrostatic attraction between the two and formation of cohesive colloids, with reduced E. coli metabolism and insignificant biomolecular response. It was briefly assessed that the composite colloids reduced E. coli risk less strongly than single colloids, stemming from the difference in the mechanism of influence and the actual need to consider colloid interactions. This conclusion can inform the management and control of pathogen risk in porous media environments.

The landscape of implantation and placentation: deciphering the function of dynamic RNA methylation at the maternal-fetal interface.

The maternal-fetal interface is defined as the interface between maternal tissue and sections of the fetus in close contact. RNA methylation modifications are the most frequent kind of RNA alterations. It is effective throughout both normal and pathological implantation and placentation during pregnancy. By influencing early embryo development, embryo implantation, endometrium receptivity, immune microenvironment, as well as some implantation and placentation-related disorders like miscarriage and preeclampsia, it is essential for the establishment of the maternal-fetal interface. Our review focuses on the role of dynamic RNA methylation at the maternal-fetal interface, which has received little attention thus far. It has given the mechanistic underpinnings for both normal and abnormal implantation and placentation and could eventually provide an entirely novel approach to treating related complications.

Construction of Metastasis-Specific Regulation Network in Ovarian Cancer Based on Prognostic Stemness-Related Signatures.

WE aimed to reveal the correlation between ovarian cancer (OV) metastasis and cancer stemness in OV. RNA-seq data and clinical information of 591 OV samples (551 without metastasis and 40 with metastasis) were obtained from TCGA. The edgeR method was used to determine differentially expressed genes (DEGs) and transcription factors (DETFs). Then, mRNA expression-based stemness index was calculated using one-class logistic regression (OCLR). Weighted gene co-expression network analysis (WGCNA) was used to define stemness-related genes (SRGs). Univariate and multivariate Cox proportional hazard regression were conducted to identify the prognostic SRGs (PSRGs). PSRGs, DETFs, and 50 hallmark pathways quantified by gene set variation analysis (GSVA) were integrated into Pearson co-expression analysis. Significant co-expression interactions were utilized to construct an OV metastasis-specific regulation network. Cell communication analysis was carried out based on single cell RNA sequencing data to explore the molecular regulation mechanism of OV. Eventually, assay for targeting accessible-chromatin with high throughout sequencing (ATAC), chromatin immunoprecipitation sequencing (ChIP-seq) validation, and multiple data sets were used to validate the expression levels and prognostic values of key stemness-related signatures. Moreover, connectivity map (CMap) was used to identify potential inhibitors of stemness-related signatures. Based on edgeR, WGCNA, and Cox proportional hazard regression, 22 PSRGs were defined to construct a prognostic prediction model for metastatic OV. In the metastasis-specific regulation network, key TF-PSRS interaction pair was NR4A1-EGR3 (correlation coefficient = 0.81, p < 0.05, positive), and key PSRG-hallmark pathway interaction pair was EGR3-TNFα signaling via NFκB (correlation coefficient = 0.44, p < 0.05, positive), which were validated in multi-omics databases. Thioridazine was postulated to be the most significant compound in treatment of OV metastasis. PSRGs played critical roles in OV metastasis. Specifically, EGR3 was the most significant PSRG, which was positively regulated by DETF NR4A1, inducing metastasis via TNFα signaling.

Migration risk of Escherichia coli O157:H7 in unsaturated porous media in response to different colloid types and compositions.

The vadose zone is a critical zone for microbial entry into the subsurface environment, and various types of inorganic and organic colloids can affect the migration of pathogenic bacteria. In the study, we explored the migration behavior of Escherichia coli O157:H7 with humic acids (HA), iron oxides (Fe2O3) or their mixture, uncovering their migration mechanisms in the vadose zone. The effect of complex colloids on the physiological properties of E. coli O157:H7 was analyzed based on the measured particle size, zeta potential and contact angle. HA colloids significantly promoted the migration of E. coli O157:H7, where Fe2O3 was opposite. The migration mechanism of E. coli O157:H7 with HA and Fe2O3 is obviously different. Multiple colloids dominated by organic colloid will further highlight its promoting effect on E. coli O157:H7 under the guidance of electrostatic repulsion due to the influence of colloidal stability. Multiple colloids dominated by metallic colloid will inhibit the migration of E. coli O157:H7 under the control of capillary force due to the restriction of contact angle. The risk of secondary release of E. coli O157:H7 can be effectively reduced when the ratio of HA/Fe2O3 is ≥ 1. Combining this conclusion with the distribution characteristics of soil in China, an attempt was made to analyse the migration risk of E. coli O157:H7 on a national scale. In China, from north to south, the migration capacity of E. coli O157:H7 gradually decreased, and the risk of secondary release gradually increased. These results provide ideas for the subsequent study of the effect of other factors on the migration of pathogenic bacteria on a national scale and provide risk information about soil colloids for the construction of pathogen risk assessment model under comprehensive conditions in the future.

The dose- and time-dependent effectiveness and safety associated with COVID-19 vaccination during pregnancy: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to provide guidance for clinical treatment and increase public confidence in COVID-19 vaccines. METHODS: The Cochrane Library, Embase, PubMed, Web of Science, ClinicalKey, and other COVID-19 datasets were searched from December 2019 to May 2022. Case-control studies and prospective cohort studies of COVID-19 vaccine effectiveness and safety in pregnant women were included. RESULTS: From day 11 to day 13, after the first dose of the COVID-19 messenger RNA vaccine, the effectiveness was 54% (95% confidence interval: 0.33-0.69). On days 14 to 27, the effectiveness was 59%. There was a 14% increase in vaccine effectiveness 28 days after the first dose was given. The inactivated vaccines showed similar effectiveness. The proportions of placental abruptions, postpartum hemorrhages, miscarriages, stillbirths, premature births, and small for gestational age infants were not significantly different between vaccinated and nonvaccinated pregnant women. Fatigue and fever were also not associated with pregnancy. CONCLUSION: Our findings affirm that the effectiveness varies for different types of vaccines and is significantly and positively correlated with time in the pregnant population. COVID-19 vaccines have also been deemed safe for pregnant women. Thus, we developed a comprehensive understanding of the role of vaccines in pregnant women.

Postnatal eye size in mice is controlled by SREBP2-mediated transcriptional repression of Lrp2 and Bmp2.

Eye size is a key parameter of visual function, but the precise mechanisms of eye size control remain poorly understood. Here, we discovered that the lipogenic transcription factor sterol regulatory element-binding protein 2 (SREBP2) has an unanticipated function in the retinal pigment epithelium (RPE) to promote eye size in postnatal mice. SREBP2 transcriptionally represses low density lipoprotein receptor-related protein 2 (Lrp2), which has been shown to restrict eye overgrowth. Bone morphogenetic protein 2 (BMP2) is the downstream effector of Srebp2 and Lrp2, and Bmp2 is suppressed by SREBP2 transcriptionally but activated by Lrp2. During postnatal development, SREBP2 protein expression in the RPE decreases whereas that of Lrp2 and Bmp2 increases as the eye growth rate reduces. Bmp2 is the key determinant of eye size such that its level in mouse RPE inversely correlates with eye size. Notably, RPE-specific Bmp2 overexpression by adeno-associated virus effectively prevents the phenotypes caused by Lrp2 knock out. Together, our study shows that rapid postnatal eye size increase is governed by an RPE-derived signaling pathway, which consists of both positive and negative regulators of eye growth.

Scutellarein protects against cardiac hypertrophy via suppressing TRAF2/NF-κB signaling pathway.

BACKGROUND: Scutellarein, a widely studied ingredient of scutellaria herbs, has higher bioavailability and solubility than that of scutellarin. Although the scutellarein had been reported to modulate numerous biological functions, its ability in suppressing cardiac hypertrophy remains unclear. Hence, the present study attempted to investigate whether scutellarein played critical roles in preventing phenylephrine (PE)-induced cardiac hypertrophy. METHODS AND RESULTS: Immunocytochemistry (ICC) was employed for evaluating the morphology of the treated cardiomyocytes. Real-time PCR and western blot were respectively applied to assess the mRNA levels and protein expression of the relevant molecules. Bioinformatics analyses were carried out to investigate the potential mechanisms by which scutellarein modulated the PE-induced cardiac hypertrophy. The results showed that Scutellarein treatment significantly inhibited PE-induced increase in H9c2 and AC16 cardiomyocyte size. Besides, scutellarein treatment also dramatically suppressed the expression of the cardiac hypertrophic markers: ANP, BNP and ß-MHC. Furthermore, the effects of scutellarein on attenuating the cardiac hypertrophy might be mediated by suppressing the activity of TRAF2/NF-κB signaling pathway. CONCLUSIONS: Collectively, our data indicated that scutellarein could protect against PE-induced cardiac hypertrophy via regulating TRAF2/NF-κB signaling pathway using in vitro experiments.

Physiological characteristics, geochemical properties and hydrological variables influencing pathogen migration in subsurface system: What we know or not?

The global outbreak of coronavirus infectious disease-2019 (COVID-19) draws attentions in the transport and spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in aerosols, wastewater, surface water and solid wastes. As pathogens eventually enter the subsurface system, e.g., soils in the vadose zone and groundwater in the aquifers, they might survive for a prolonged period of time owing to the uniqueness of subsurface environment. In addition, pathogens can transport in groundwater and contaminate surrounding drinking water sources, possessing long-term and concealed risks to human society. This work critically reviews the influential factors of pathogen migration, unravelling the impacts of pathogenic characteristics, vadose zone physiochemical properties and hydrological variables on the migration of typical pathogens in subsurface system. An assessment algorithm and two rating/weighting schemes are proposed to evaluate the migration abilities and risks of pathogens in subsurface environment. As there is still no evidence about the presence and distribution of SARS-CoV-2 in the vadose zones and aquifers, this study also discusses the migration potential and behavior of SARS-CoV-2 viruses in subsurface environment, offering prospective clues and suggestions for its potential risks in drinking water and effective prevention and control from hydrogeological points of view.

Mechanisms of Progression and Heterogeneity in Multiple Nodules of Lung Adenocarcinoma.

Lung cancer remains the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD) is thought to be caused by precursor lesions of atypical adenoma-like hyperplasia and may have extensive in situ growth before infiltration. To explore the relevant factors in heterogeneity and evolution of lung adenocarcinoma subtypes, the authors perform single-cell RNA sequencing (scRNA-seq) on tumor and normal tissue from five multiple nodules' LUAD patients and conduct a thorough gene expression profiling of cancer cells and cells in their microenvironment at single-cell level. This study gives a deep understanding of heterogeneity and evolution in early glandular neoplasia of the lung. This dataset leads to discovery of the changes in the immune microenvironment during the development of LUAD, and the development process from adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IAC). This work sheds light on the direction of early tumor development and whether they are homologous.

mRNA Network: Solution for Tracking Chemotherapy Insensitivity in Small-Cell Lung Cancer.

Background: Small-cell lung cancer (SCLC) has poor prognosis and is prone to drug resistance. It is necessary to search for possible influencing factors for SCLC chemotherapy insensitivity. Therefore, we proposed an mRNA network to track the chemotherapy insensitivity in SCLC. Methods: Six samples of patients with SCLC were recruited for RNA sequencing. TopHat2 and Cufflinks were used to make differential analysis. Functional analysis was applied as well. Finally, multidimensional validation was applied for verifying the results we obtained by experiment. Results: This study was a trial of drug resistance in 6 SCLC patients after first-line chemotherapy. The top 10 downregulated genes differentially expressed in the chemo-insensitive group were SERPING1, DRD5, PARVG, PRAME, NKX1-1, MCTP2, PID1, PLEKHA4, SPP1, and SLN. Cell-cell signaling by Wnt (p=6.98E - 21) was the most significantly enriched GO term in biological process, while systemic lupus erythematosus (p=6.97E - 10), alcoholism (p=1.01E - 09), and transcriptional misregulation in cancer (p=0.00227988) were the top three ones of KEGG pathways. In multiple public databases, we also highlighted and verified the vital role of glycolysis/gluconeogenesis pathway and corresponding genes in chemo-insensitivity in SCLC. Conclusion: Our study confirmed some SCLC chemotherapy insensitivity-related genes, biological processes, and pathways, thus constructing the chemotherapy-insensitive network for SCLC.

A narrative review of tumor heterogeneity and challenges to tumor drug therapy.

OBJECTIVE: To accurately evaluate tumor heterogeneity, make multidimensional diagnosis according to the causes and phenotypes of tumor heterogeneity, and assist in the individualized treatment of tumors. BACKGROUND: Tumor heterogeneity is one of the most essential characteristics of malignant tumors. In tumor recurrence, development, and evolution, tumor heterogeneity can lead to the formation of different cell groups with other molecular characteristics. Tumor heterogeneity can be characterized by the uneven distribution of tumor cell subsets of other genes between and within the disease site (spatial heterogeneity) or the time change of cancer cell molecular composition (temporal heterogeneity). The discovery of tumor targeting drugs has dramatically promoted tumor therapy. However, the existence of heterogeneity seriously affects the effect of tumor treatment and the prognosis of patients. METHODS: The literature discussing tumor heterogeneity and its resistance to tumor therapy was broadly searched to analyze tumor heterogeneity as well as the challenges and solutions for gene detection and tumor drug therapy. CONCLUSIONS: Tumor heterogeneity is affected by many factors consist of internal cell factors and cell microenvironment. Tumor heterogeneity greatly hinders effective and individualized tumor treatment. Understanding the fickle of tumors in multiple dimensions and flexibly using a variety of detection methods to capture the changes of tumors can help to improve the design of diagnosis and treatment plans for cancer and benefit millions of patients.

Risk-score model to predict prognosis of malignant airway obstruction after interventional bronchoscopy.

BACKGROUND: Interventional bronchoscopy exhibits substantial effects for patients with malignant airway obstruction (MAO), while little information is available regarding the potential prognostic factors for these patients. METHODS: Between October 31, 2016, and July 31, 2019, a total of 150 patients undergoing interventional bronchoscopy and histologically-confirmed MAO were collected, in which 112 eligible participants formed the cohort for survival study. External validation cohort from another independent institution comprised 33 MAO patients with therapeutic bronchoscopy. The least absolute shrinkage and selection operator regression (LASSO) was applied to the model development dataset for selecting features correlated with MAO survival for inclusion in the Cox regression from which we elaborated the risk score system. A nomogram algorithm was also utilized. RESULTS: In our study, we observed a significant decline of stenosis rate after interventional bronchoscopy from 71.7%±2.1% to 36.6%±2.7% (P<0.001) and interventional bronchoscopy dilated airway effectively. Patients in our study undergoing interventional bronchoscopy had a median survival time of 614.000 days (95% CI: 269.876-958.124). Patients receiving distinct therapeutic methods of interventional bronchoscopy had different prognosis (P=0.022), and patients receiving treatment of electrocoagulation in combination with stenting and electrosurgical snare had worse survival than those receiving other options. Multivariate Cox analysis revealed that nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, as independent predictive factors for better overall survival (OS) of MAO patients. Then, the nomogram based on Cox regression and risk score system based on results from LASSO regression were elaborated respectively. Importantly, this risk score system was proved to have better performance than the nomogram and other single biomarkers such as traditional staging system (area under the curve 0.855 vs. 0.392-0.739). Survival curves showed that patients with the higher risk-score had poorer prognosis than those with lower risk-score (third quantile of OS: 126.000 days, 95% CI: 73.588-178.412 vs. 532.000 days, 95% CI: 0.000-1,110.372; P<0.001). CONCLUSIONS: Nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, were independent predictive factors for better OS of MAO patients. We proposed a nomogram and risk score system for survival prediction of MAO patients undergoing interventional bronchoscopy with good performance.

Collection on reports of molecules linked to epithelial-mesenchymal transition in the process of treating metastasizing cancer: a narrative review.

Epithelial-mesenchymal transition (EMT) is a morphological process in which epithelial cells transform into mesenchymal cells via a specific procedure. EMT plays an important role in the cancer invasion-metastasis cascade and the current treatment of metastatic cancer, influences the migration, polarity, and adhesion of tumor cells, promotes their migration, invasiveness, anti-apoptotic ability. It contributes to the changes of the tumor microenvironment and suppresses the sensitivity of tumor cells to chemotherapy, causing cancer metastasis and worse, hindering the control and therapy of it. This paper reviews the mechanisms, detection, and treatments of cancer metastasis that have been identified and applied to date, summarizes the EMT-related biological molecules, providing a reference for EMT-targeted research and therapy. As EMT is significant in the progress of tumor metastasis, it is meaningful for the therapy and control of metastatic cancer to understand the mechanism of EMT at the molecular level. We summarized the mechanisms, detection and therapeutic implications of EMT, listed the research progress of molecules like genes, miRNAs, signaling pathways in EMT. We also discussed the prospects of EMT-targeted treatment in cancer metastasis interventions and the challenges the treatment and researches are facing. The summary is conducive to the treatment and further research of EMT and metastatic cancer.

FOXP3-based immune risk model for recurrence prediction in small-cell lung cancer at stages I-III.

BACKGROUND: Immunotherapies may prolong the survival of patients with small-cell lung cancer (SCLC) to some extent. The role of forkhead box protein P3 (FOXP3) in tumor microenvironment (TME) remains controversial. We aimed to examine FOXP3-related expression characteristics and prognostic values and to develop a clinically relevant predictive system for SCLC. METHODS: We enrolled 102 patients with histologically confirmed SCLC at stages I-III. Through immunohistochemistry, we determined the expression pattern of FOXP3 and its association with other immune biomarkers. By machine learning and statistical analysis, we constructed effective immune risk score models. Furthermore, we examined FOXP3-related enrichment pathways and TME traits in distinct cohorts. RESULTS: In SCLC, FOXP3 level was significantly associated with status of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), CD4, CD8, and CD3 (p=0.002, p=0.001, p=0.002, p=0.030, and p<0.001). High FOXP3 expression showed longer relapse-free survival (RFS) than the low-level group (41.200 months, 95% CI 26.937 to 55.463, vs 14.000 months, 95% CI 8.133 to 19.867; p=0.008). For tumor-infiltrating lymphocytes (TILs), subgroup analysis demonstrated FOXP3 and PD-1, PD-L1, lymphocyte activation gene-3, CD3, CD4, or CD8 double positive were significantly correlated with longer RFS. We further performed importance evaluation for immune biomarkers, constructed an immune risk score incorporating the top three important biomarkers, FOXP3, TIL PD-L1, and CD8, and found their independently prognostic role to predict SCLC relapse. Better predictive performance was achieved in this immune risk model compared with single-indicator-based or two-indicator-based prediction systems (area under the curve 0.715 vs 0.312-0.711). Then, relapse prediction system integrating clinical staging and immune risk score was established, which performed well in different cohorts. High FOXP3-related genes were enriched in several immune-related pathways, and the close relationships of interleukin-2, CD28, basic excision repair genes MUTYH, POLD1, POLD2, and oxidative phosphorylation related gene cytochrome c oxidase subunit 8A with FOXP3 expression were revealed. Moreover, we found low-immune risk score group had statistically higher activated CD4+ memory T cells (p=0.014) and plasma cells (p=0.049) than the high-risk group. The heterogeneity of tumor-infiltrating immune cells might represent a promising feature for risk prediction in SCLC. CONCLUSION: FOXP3 interacts closely with immune biomarkers on tumor-infiltrating cells in TME. This study highlighted the crucial prognostic value and promising clinical applications of FOXP3 in SCLC.

Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma.

INTRODUCTION: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies. METHODS: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics. RESULTS: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes. CONCLUSION: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.

Research progress on the molecular mechanisms of hepatic metastasis in lung cancer: a narrative review.

The liver is one of the most common sites of metastatic spread of lung cancer, and the process of metastasis is regulated by many factors. A number of genes, including multiple tumor suppressor 1 (mts1), p120 catenin, and CT45A1, increase the possibility of hepatic metastasis in lung cancer, whereas Tip30/CC3, CUL5, and SOCS3 expression in lung tumors inhibit tumor metastasis. microRNAs (miRNAs), such as miRNA-126, miRNA-338, and miRNA-218, can affect the metastasis of lung cancer cells to the liver. The D114-Notch signaling pathway can inhibit liver metastasis in small cell lung cancer. Serum tumor markers cytokeratin 19 fragment antigen 21-1 and neuron-specific enolase (NSE) are closely related to the risk of hepatic metastasis in lung cancer. Based on previously published literature, we found that the metastasis and invasion of lung cancer to the liver are determined by molecular factors. Therefore, the selective identification and intervention of these erroneous signals can predict early lung cancer metastasis to the liver. In this review article, we describe the mechanisms and influencing factors (genes, signal pathways, chemicals, proteins, miRNAs) of hepatic metastasis in lung cancer. We hope to provide a summary of the evidence for the mechanisms by which related genes or proteins affect the malignancy of liver metastasis from lung cancer so that doctors and researchers can improve treatment options.