Trans-3, 5, 4'-trimethoxystilbene restrains non-small-cell lung carcinoma progression via suppressing M2 polarization through inhibition of m6A modified circPACRGL-mediated Hippo signaling.

BACKGROUND: Non-small-cell lung carcinoma (NSCLC) accounts for ∼85% of all lung carcinomas. Trans-3,5,4'-trimethoxystilbene (TMS) shows strong anti-tumor activity and induces tumor cell apoptosis. However, its function and mechanism in NSCLC still require investigation. METHODS: PMA was used to treated THP-1 cells for macrophage differentiation. The abundance and m6A modification of circPACRGL were examined with qRT-PCR and MeRIP. Colony forming, transwell, wound healing, and Western blotting assays were applied to analyze proliferation, invasion, migration, and EMT. Macrophage polarization was determined through flow cytometry analysis of M1 and M2 markers. The interplay between circPACRGL, IGF2BP2 and YAP1 was validated by RNA pull-down and RIP assays. Mice received subcutaneous injection of NSCLC cells as a mouse model of subcutaneous tumor. RESULTS: CircPACRGL was upregulated in NSCLC cells, but it was reduced by TMS treatment. CircPACRGL depletion blocked proliferation, migration, and invasion in H1299 and H1975 cells. TMS suppressed these malignant behaviors, but it was abolished by circPACRGL overexpression. In addition, NSCLC-derived exosomes delivered circPACRGL into THP-1 cells to promote its M2 polarization, but TMS inhibited these effects by downregulating exosomal circPACRGL. Mechanically, exosomal circPACRGL bound to IGF2BP2 to improve the stability of YAP1 mRNA and regulate Hippo signaling in polarized THP-1 cells. TMS inhibited NSCLC growth via suppressing Hippo signaling and M2 polarization in vivo. CONCLUSION: TMS restrains M2 polarization and NSCLC progression by reducing circPACRGL and inhibiting exosomal circPACRGL-mediated Hippo signaling. Thus, these findings provide a novel mechanism underlying NSCLC progression and potential therapeutic targets.

Identification of phytochemical compounds of Fagopyrum dibotrys and their targets by metabolomics, network pharmacology and molecular docking studies.

Acute lung injury (ALI) is a clinically severe lung illness with high incidence rate and mortality. Especially, coronavirus disease 2019 (COVID-19) poses a serious threat to world wide governmental fitness. It has distributed to almost from corner to corner of the universe, and the situation in the prevention and control of COVID-19 remains grave. Traditional Chinese medicine plays a vital role in the precaution and therapy of sicknesses. At present, there is a lack of drugs for treating these diseases, so it is necessary to develop drugs for treating COVID-19 related ALI. Fagopyrum dibotrys (D. Don) Hara is an annual plant of the Polygonaceae family and one of the long-history used traditional medicine in China. In recent years, its rhizomes (medicinal parts) have attracted the attention of scholars at home and abroad due to their significant anti-inflammatory, antibacterial and anticancer activities. It can work on SARS-COV-2 with numerous components, targets, and pathways, and has a certain effect on coronavirus disease 2019 (COVID-19) related acute lung injury (ALI). However, there are few systematic studies on its aerial parts (including stems and leaves) and its potential therapeutic mechanism has not been studied. The phytochemical constituents of rhizome of F. dibotrys were collected using TCMSP database. And metabolites of F. dibotrys' s aerial parts were detected by metabonomics. The phytochemical targets of F. dibotrys were predicted by the PharmMapper website tool. COVID-19 and ALI-related genes were retrieved from GeneCards. Cross targets and active phytochemicals of COVID-19 and ALI related genes in F. dibotrys were enriched by gene ontology (GO) and KEGG by metscape bioinformatics tools. The interplay network entre active phytochemicals and anti COVID-19 and ALI targets was established and broke down using Cytoscape software. Discovery Studio (version 2019) was used to perform molecular docking of crux active plant chemicals with anti COVID-19 and ALI targets. We identified 1136 chemicals from the aerial parts of F. dibotrys, among which 47 were active flavonoids and phenolic chemicals. A total of 61 chemicals were searched from the rhizome of F. dibotrys, and 15 of them were active chemicals. So there are 6 commonly key active chemicals at the aerial parts and the rhizome of F. dibotrys, 89 these phytochemicals's potential targets, and 211 COVID-19 and ALI related genes. GO enrichment bespoken that F. dibotrys might be involved in influencing gene targets contained numerous biological processes, for instance, negative regulation of megakaryocyte differentiation, regulation of DNA metabolic process, which could be put down to its anti COVID-19 associated ALI effects. KEGG pathway indicated that viral carcinogenesis, spliceosome, salmonella infection, coronavirus disease - COVID-19, legionellosis and human immunodeficiency virus 1 infection pathway are the primary pathways obsessed in the anti COVID-19 associated ALI effects of F. dibotrys. Molecular docking confirmed that the 6 critical active phytochemicals of F. dibotrys, such as luteolin, (+) -epicatechin, quercetin, isorhamnetin, (+) -catechin, and (-) -catechin gallate, can combine with kernel therapeutic targets NEDD8, SRPK1, DCUN1D1, and PARP1. In vitro activity experiments showed that the total antioxidant capacity of the aerial parts and rhizomes of F. dibotrys increased with the increase of concentration in a certain range. In addition, as a whole, the antioxidant capacity of the aerial part of F. dibotrys was stronger than that of the rhizome. Our research afford cues for farther exploration of the anti COVID-19 associated ALI chemical compositions and mechanisms of F. dibotrys and afford scientific foundation for progressing modern anti COVID-19 associated ALI drugs based on phytochemicals in F. dibotrys. We also fully developed the medicinal value of F. dibotrys' s aerial parts, which can effectively avoid the waste of resources. Meanwhile, our work provides a new strategy for integrating metabonomics, network pharmacology, and molecular docking techniques which was an efficient way for recognizing effective constituents and mechanisms valid to the pharmacologic actions of traditional Chinese medicine.

Icariside II potentiates the anti-PD-1 antitumor effect by reducing chemotactic infiltration of myeloid-derived suppressor cells into the tumor microenvironment via ROS-mediated inactivation of the SRC/ERK/STAT3 signaling pathways.

BACKGROUND: Immune checkpoint blockade agents, such as anti-PD-1 antibodies, show promising antitumor efficacy but only a limited response in patients with non-small cell lung cancer (NSCLC). Icariside II (IS), a metabolite of Herba Epimedii, is a COX-2 and EGFR inhibitor that can enhance the anti-PD-1 effect. This study aimed to evaluate the antitumor effect of IS in combination with anti-PD-1 and explore the underlying mechanism. METHODS: Tumor growth was assessed in Lewis Lung Cancer (LLC) tumor-bearing mice in seven groups (control, IS 20 mg/kg, IS 40 mg/kg, anti-PD-1, IS 20 mg/kg+anti-PD-1, IS 40 mg/kg+anti-PD-1, ERK inhibitor+anti-PD-1). Tumor-infiltrating immune cells were measured by flow cytometry. The mechanisms were explored by tumor RNA-seq and validated in LLC cells through molecular biological experiments using qRT‒PCR, ELISA, and western blotting. RESULTS: Animal experiments showed that IS in combination with anti-PD-1 further inhibited tumor growth and remarkably reduced the infiltration of myeloid-derived suppressor cells (MDSCs) into the tumor compared with anti-PD-1 monotherapy. RNA-seq and in vitro experiments showed that IS suppressed the chemotactic migration of MDSCs by downregulating the expression of CXC chemokine ligands 2 (CXCL2) and CXCL3. Moreover, IS promoted reactive oxygen species (ROS) generation and inhibited the activation of SRC/ERK/STAT3 in LLC cells, which are upstream signaling pathways of these chemokines. CONCLUSION: IS potentiates the anti-PD-1 anti-tumor effect by reducing chemotactic infiltration of the myeloid-derived suppressor cell into the tumor microenvironment, via ROS-mediated inactivation of SRC/ERK/STAT3 signaling pathways.

Diterpene promptly executes a non-canonical autophagic cell death in doxorubicin-resistant lung cancer.

16-hydroxycleroda-3,13-dien-15,16-olide (HCD) has antitumor activity reported in numerous types of cancers. However, the efficacy of HCD treatment in non-small-cell lung cancer (NSCLC) cells and doxorubicin-resistant (Dox-R)-NSCLC cells remains to be unraveled. The underlying anti-cancer mechanism of HCD on Dox-R and Dox-sensitive (Dox-S) of A549 cells was also investigated. Cytotoxicity of HCD against two cell lines (Dox-S and Dox-R) were determined via MTT assay, flow cytometry, and Western blot. A further examination of its anti-cancer efficacy was performed in A549-bearing xenograft mice via orthotopic intratrachea (IT) inoculation, which showed that HCD could arrest both Dox-S and Dox-R cells at G2/M phase without altering the sub-G1 cycle along with increasing of cleaved-PARP. HCD downregulated the mTOR/Akt/PI3K-p85 and PI3K-ClassIII/Beclin-1 signals and upregulated p62/LC3-I/II expressions to further confirm that the cell autophagy of NSCLC cells after being HCD-induced. Morphological observations of mouse lung sections illustrated that fewer cancer cells accumulated close to the trachea while less neoplastic activities were found in HCD orthotopic treated mice without liver, kidney, and spleen toxicity. Lastly, Dox, HCD, and target therapy medicines of EGFR and ALK were nicely docked with EGFR, ALK, and mTOR. Conclusively, HCD was demonstrated the chemotherapeutic potential regardless of Dox-R and Dox-S cells, suggesting natural autophagic inducer HCD provides a promising lead compound for new drug discovery and development of lung cancer therapies.

The efficacy of adding hyperthermia to the treatment of advanced NSCLC patients based on the states of EGFR.

BACKGROUND: The study aims to explore the efficacy of adding hyperthermia to the treatment of advanced NSCLC patients based on the states of epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: We included 205 advanced NSCLC patients who were received hyperthermia plus other treatment (hyperthermia group) or non- hyperthermia and other treatments (non- hyperthermia group). The OS and progression free survival (PFS) were retrospectively estimated. Using Kaplan-Meier and the log-rank test compare the OS and PFS between the groups. RESULTS: The median follow-up was 22 months. The Univariate analysis have shown that 1-year OS and PFSfirst rates in the hyperthermia group and non- hyperthermia group were 83.3% vs 71.5% (P=0.010) and 62.0% vs 42.7% (P=0.001). The subgroup analyses revealed that patients didn't have EGFR mutant who received hyperthermia had significantly higher 1 year OS and PFSfirst rates than those treated with non- hyperthermia (OS: 79.1% vs 65.2% P=0.037, PFS: 64.2% vs 36.5%, P=0.001). For patients with EGFR mutation, there was no significant difference between the two groups. The PFSfirst in first-line and PFSpost in posterior-line was no significant difference between the groups. CONCLUSIONS: This retrospective study revealed that adding hyperthermia to the treatment of NSCLC patients without EGFR mutation had better prognosis than those who did not adding hyperthermia to the regimen. Moreover, adding hyperthermia in first-line or in posterior-line treatment was no significant difference. However, these results need more prospective studies to confirm the conclusions.

Treatment Effectiveness and Tolerability of Long-term Adjuvant First- and Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor at Different Doses in Patients With Stage IIA-IIIB Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: A Retrospective Study.

Introduction: For patients with epidermal growth factor receptor (EGFR)-mutated lung cancer who undergo surgery, adjuvant tyrosine kinase inhibitor (TKI) therapy other than osimertinib is an alternative option. We aimed to discuss the long-term safety and efficacy of TKI treatment in real-world data. Methods: From January 2011 to May 2020, patients with stage II-III EGFR-mutated adenocarcinoma who underwent cancer resection surgery at a single center were enrolled. The primary endpoint was disease relapse, and the secondary endpoint was overall survival. In total, 30 patients were included in the study. In our study, all patients underwent complete resection using video-assisted thoracoscopic surgery. The patients were divided into a dose interruption (prolonged interval use) group and non-dose adjustment group. Results: The patients' pathological stages were II-III. The initial EGFR TKIs were mostly gefitinib (n = 25, 83%), and others were erlotinib (n = 3, 10%) and afatinib (n = 2, 6%). The mean disease-free survival (DFS) was 53.3 months. The 2- and 5-year DFS rate was 90.0 and 73.3%, respectively. The median TKI treatment duration in this study was 44.5 months (range, 6-133 months), which was the longest in the literature review. Of these patients, nine had dose interruption. We compared the two groups and found no treatment differences between them. There were no significant side effect potentials between both groups. Conclusion: To our knowledge, this study provides the longest experience of TKI in patients with resected EGFR mutations and also provided a dose reduction strategy (prolonged medication interval) for patients who had intolerable side effects.

Sanguinarine Represses the Growth and Metastasis of Non-small Cell Lung Cancer by Facilitating Ferroptosis.

OBJECTIVE: Ethnopharmacological relevance: Sanguinarine (SAG), a natural benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis Linn. (Bloodroot), possesses a potential anticancer activity. Lung carcinoma is the chief cause of malignancy-related mortality in China. Non-small cell lung carcinoma (NSCLC) is the main subtype of lung carcinoma and accounts for about eighty-five percent of this disease. Current treatment in controlling and curing NSCLC remains deficient. AIM: The role and underlying mechanism of SAG in repressing the growth and metastasis of NSCLC were explored. MATERIALS AND METHODS: The role of SAG in regulating the proliferation and invasion of NSCLC cells was evaluated in vitro and in a xenograft model. After treatment with SAG, Fe2+ concentration, reactive oxygen species (ROS) levels, malondialdehyde (MDA), and glutathione (GSH) content in NSCLC cells were assessed to evaluate the effect of SAG on facilitating ferroptosis. RESULTS: SAG exhibited a dose- and time-dependent cytotoxicity in A549 and H3122 cells. SAG treatment effectively repressed the growth and metastasis of NSCLC in a xenograft model. We, for the first time, verified that SAG triggered ferroptosis of NSCLC cells, as evidenced by increased Fe2+ concentration, ROS level, and MDA content, and decreased GSH content. Mechanistically, SAG decreased the protein stability of glutathione peroxide 4 (GPX4) through E3 ligase STUB1-mediated ubiquitination and degradation of endogenous GPX4. GPX4 overexpression restored the proliferation and invasion of NSCLC cells treated with SAG through inhibiting ferroptosis. CONCLUSION: SAG inhibits the growth and metastasis of NSCLC by regulating STUB1/GPX4-dependent ferroptosis.

Non-Small Cell Lung Cancer Symptom Assessment Questionnaire: Psychometric Performance and Regulatory Qualification of a Novel Patient-Reported Symptom Measure.

BACKGROUND: The Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) was developed to incorporate the patient's perspective into evaluation of clinical benefit in advanced non-small cell lung cancer trials and meet regulatory expectations for doing so. Qualitative evidence supported 7 items covering 5 symptom concepts. OBJECTIVE: This study evaluated measurement properties of the NSCLC-SAQ's items, overall scale, and total score. METHODS: In this observational cross-sectional study, a purposive sample of patients with clinician-diagnosed advanced non-small cell lung cancer, initiating or undergoing treatment, provided sociodemographic information and completed the NSCLC-SAQ, National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lung Symptom Index (FLSI-17), and a Patient Global Impression of Severity item. Rasch analyses, factor analyses, and assessments of construct validity and reliability were completed. RESULTS: The 152 participants had a mean age of 64 years, 57% were women, and 87% where White. The majority were Stage IV (83%), 51% had an Eastern Cooperative Oncology Group performance status of 1 (32% performance status 0 and 17% performance status 2), and 33% were treatment naïve. Rasch analyses showed ordered thresholds for response options. Factor analyses demonstrated that items could be combined for a total score. Internal consistency (Cronbach  α = 0.78) and test-retest reliability (intraclass correlation coefficient = 0.87) were quite satisfactory. NSCLC-SAQ total score correlation was 0.83 with the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lung Symptom Index-17. The NSCLC-SAQ was able to differentiate between symptom severity levels and performance status (both P values < .001). CONCLUSIONS: The NSCLC-SAQ generated highly reliable scores with substantial evidence of construct validity. The Food and Drug Administration's qualification supports the NSCLC-SAQ as a measure of symptoms in drug development. Further evaluation is needed on its longitudinal measurement properties and interepretation of meaningful within-patient score change. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).

Adjuvant Treatment with Tyrosine Kinase Inhibitors in Epidermal Growth Factor Receptor Mutated Non-Small-Cell Lung Carcinoma Patients, Past, Present and Future.

Lung cancer is the most common malignancy across the world. The new era in lung cancer treatments, especially this past decade, has yielded novel categories of targeted therapy for specific mutations and adjuvant therapy, both of which have led to improved survival rates. In the present study, we review the changes and development of treatments, with a special focus on adjuvant therapy using tyrosine kinase inhibitors (TKIs) administered to non-small-cell lung carcinoma patients who had a complete resection of the tumor harboring a mutated epidermal growth factor receptor. The clinical trials are dating from the past (chemotherapy trials), present (TKIs), and future (ongoing trials).

Ammonium Ferric Citrate induced Ferroptosis in Non-Small-Cell Lung Carcinoma through the inhibition of GPX4-GSS/GSR-GGT axis activity.

The morbidity and mortality rates associated with non-small-cell lung carcinoma (NSCLC) are increasing every year, placing new demands on existing therapies and drugs. Ammonium ferric citrate (AFC) is often used as a food additive for iron supplementation; however, to our knowledge, no studies have investigated whether AFC can induce ferroptosis in NSCLC. In this study, we demonstrated that specific concentrations of AFC effectively inhibit the proliferation and invasion of lung cancer cell lines in vitro using a cell proliferation inhibition test, a transwell assay, and flow cytometry analysis of cell cycle and apoptosis. In addition, AFC significantly induced oxidative stress injury in lung cancer cell lines. A quantitative polymerase chain reaction assay showed that AFC markedly reduced the expression levels of cell growth factors, negative regulators of ferroptosis, and autophagy regulators. Lastly, a protein-protein interaction analysis revealed that glutathione peroxidase 4 (GPX4) exerted its biological role through the regulation of the GSS/GSR complex and downstream GGT family proteins. When the expression of GPX4 changes, its biological activities, such as the glutathione metabolic process, cellular biosynthetic process, cellular response to chemical stimulus, and antioxidant activity, change accordingly, thereby affecting the survival quality and physiological and biochemical activities of cells. Overall, this study verifies that AFC has the biological activity of activating oxidative stress injury in NSCLC cell lines, leading to a decrease in their autophagy and inducing ferroptosis. We also confirmed that the GPX4-GSS/GSR-GGT axis is a crucial target of AFC-induced ferroptosis.

Physalis alkekengi var. franchetii Extracts Exert Antitumor Effects on Non-Small Cell Lung Cancer and Multiple Myeloma by Inhibiting STAT3 Signaling.

BACKGROUND: Physalis alkekengi var. franchetii is an herb that possesses various ethnopharmacological applications. Herein, our current study focuses on the antitumor effect of a combination of physalins, which are regarded as the most representative secondary metabolites from calyces of Physalis alkekengi var. franchetii. MATERIALS AND METHODS: We mainly investigated the antitumor activity of the physalins extracted from Physalis alkekengi var. franchetii on both solid and hematologic cancers. The main cells used in this study were NCI-H1975 and U266 cells. The major assays used were the CCK-8 assay, Western blot analyses, immunofluorescence assay and Annexin V assay, and a xenograft mouse model was used. RESULTS: The results showed that physalins exhibited a strong antitumoural effect on both non-small cell lung cancer (NSCLC) and multiple myeloma (MM) cells by suppressing constitutive STAT3 activity and further inhibiting the downstream target gene expression induced by STAT3 signaling, which resulted in the enhanced apoptosis of tumor cells. Moreover, physalins significantly reduced tumor growth in xenograft models of lung cancer. CONCLUSION: Collectively, these findings demonstrated that the physalins from Physalis alkekengi var. franchetii may potentially act as cancer preventive or chemotherapeutic agents for NSCLC and MM by inhibiting the STAT3 signaling pathway. The present study served as a promising guide to further explore the precise mechanism of Physalis alkekengi var. franchetii in cancer treatment.

Botrychium schaffneri Underw. extract acts via DIABLO to induce apoptosis and inhibit proliferation of non-small cell lung carcinoma in vitro and in vivo.

BACKGROUND: Botrychium schaffneri Underw. has been popularly consumed since ancient times as a traditional medicine in China to treat whooping cough, bronchial asthma, and febrile convulsive twitch disease. This led us to investigate whether Botrychium schaffneri Underw. extract (BSE) may be effective against lung cancer, especially non-small cell lung carcinoma (NSCLC). METHODS: In this study, we extracted the ethanolic root extract of the grass, Botrychium schaffneri Underw. In vitro study, the change of NCI-H1299 cell proliferation was observed with CCK8 and MTT assays. Cell apoptosis was assessed using a kit based on staining with FITC-conjugated annexin V. In vivo study, we establish a stable animal model of NSCLC in nude mice, tumor volume and weight was measured twice a week. We conduct gene microarray screened for differentially expressed genes (DEGs), between NCI-H1299 cells treated by BSE or not. Then the DEGs were functionally annotated and path enriched. RESULTS: It was revealed that BSE significantly suppressed NSCLC cell proliferation (IC50 134 µg/mL) and induced apoptosis. It also slowed tumor growth without affecting body weight, and a dose of 25 g/kg led to significantly smaller tumors than in control animals (13.85±3.36 vs. 23.40±6.05, P=0.044). Apoptosis-related protein direct IAP Binding protein with low PI (DIABLO) expression was up-regulated by BSE, and DIABLO knockdown significantly attenuated the anti-tumor effects of the extract. CONCLUSIONS: In conclusion, BSE reduces the viability of NSCLC cells and promotes apoptosis, and these effects may be mediated by DIABLO.

Efficacy and safety of Kanglaite injection combined with first-line platinum-based chemotherapy in patients with advanced NSCLC: a systematic review and meta-analysis of 32 RCTs.

BACKGROUND: As a Chinese medicine injections, Kanglaite injection (KLT) is a complementary or alternative therapy for first-line platinum-based chemotherapy. However, the effect that certain factors, including the dose of KLT, chemotherapy cycles, evaluation criteria, or supportive treatment, have on the efficacy of the objective response rate (ORR), median survival time (MST), and adverse reactions is still unknown. METHODS: Eight databases were systematically searched from the inception dates to December 1, 2019, using the keywords Kanglaite, chemotherapy, and non small cell lung carcinoma to identify randomized clinical trials (RCTs). Analyses were performed using Review Manager 5.3 and Stata 15.1. RESULTS: There were 32 randomized controlled trials, involving 2,577 participants, that fulfilled the inclusion criteria. Compared with first-line platinum-based chemotherapy alone, KLT combined with chemotherapy could increase the ORR [risk ratio (RR), 1.41 (95% CI: 1.28 to 1.56); absolute risk difference (ARD), 0.13 (95% CI: 0.1 to 0.17)], decrease the risk ratio of adverse reactions [nausea and vomiting: RR, 0.58 (95% CI: 0.42 to 0.81); ARD, -0.17 (95% CI: -0.26 to -0.08); leukopenia: RR, 0.61 (95% CI: 0.44 to 0.86); ARD, -0.16 (95% CI: -0.24 to -0.08)], prolong MST, and increase disease control rate and Karnofsky performance status. According to the subgroup analyses, KLT combined with cisplatin or paraplatin plus paclitaxel (TP) failed to demonstrate a significant association with the ORR. And when lacking the use of supportive treatment, this combination would not decrease the RR of both adverse reactions compared with chemotherapy alone. CONCLUSIONS: KLT plus first-line platinum-based chemotherapy, except when chemotherapy regimens were TP, increased efficacy and quality of life in patients with advanced NSCLC. We are unsure whether this combination offers a low risk of adverse reactions. Additional high-quality RCTs are warranted to assess the effects of the combined therapy further.

Four generations of EGFR TKIs associated with different pathogenic mutations in non-small cell lung carcinoma.

Non-small cell lung carcinoma (NSCLC) is a malignant tumour with poor prognosis and high mortality. Platinum-based dual-agent chemotherapy is the main therapeutic regimen for this disease. In recent years, because of the introduction of molecular targeted therapy, various targeted therapeutic agents against epidermal growth factor receptor (EGFR) have been rapidly developed, which has become a research hotspot for NSCLC treatment. Here, we review the latest studies describing the features and types of EGFR pathogenic mutations, currently established EGFR-tyrosine kinase inhibitors from the first to fourth generation, including their action mechanisms, acquired resistance, and clinical applications, and potential challenges and perspectives that current researchers should address.

Clinical efficacy and safety of aidi injection combination with vinorelbine and cisplatin for advanced non-small-cell lung carcinoma: A systematic review and meta-analysis of 54 randomized controlled trials.

The Aidi injection contains multiple active ingredients, including astragaloside (Re, Rb1, and Rg1), ginsenoside, cantharidin, elentheroside E, and syringin, and it is administered with vinorelbine and cisplatin (NP) to treat non-small-cell lung carcinoma (NSCLC). In this study, we performed a systematic review and meta-analysis to determine the clinical efficacy and safety of the Aidi injection with NP, and the optimal threshold and treatment regimen to produce the desired responses. We collected all studies regarding the Aidi injection with NP for NSCLC from Chinese and English databases (up to April 2019). Risk of methodological bias was evaluated for each study. Data for analysis were extracted using a standard data extraction form. Evidence quality was assessed following the Grading of Recommendations Assessment, Development and Evaluation approach. We included 54 trials containing 4,053 patients for analysis. Combining the Aidi injection with NP significantly increased the objective response rate (odds ratio [OR], 1.32; confidence interval [CI], 1.23, 1.42), disease control rate (OR, 1.14; CI, 1.11, 1.18), and quality of life (OR, 1.80; CI, 1.61, 1.98), with decreased risks of myelosuppression, neutropenia, thrombocytopenia, anemia, gastrointestinal reaction, and liver dysfunction. For patients with a Karnofsky Performance Status score of ≥60, the Aidi injection (50 mL/day, two weeks/cycle, with two to three cycles) treatment with vinorelbine (25 mg/m2) and cisplatin (30-35 mg/m2 or 40-50 mg/m2) might be the optimal regimen for producing the desired tumor response and achieving a good safety level. Most results were robust, and their quality was moderate. The results suggest that administration of the Aidi injection and concomitant NP is beneficial to NSCLC, and provide evidence for the optimal threshold and treatment regimen that may improve tumor response with a good safety level.

Complementary value of electron microscopy and immunohistochemistry in the diagnosis of non-small cell lung cancer: A potential role for electron microscopy in the era of targeted therapy.

With the identification of therapeutic targets for lung adenocarcinoma, it has become mandatory to distinguish it from other entities. Some cases remain classified as non-small cell lung carcinoma, not otherwise specified (NSCLC-NOS) with immunohistochemistry. Electron microscopy (EM) can be useful, allowing the identification of glandular differentiation. The aim of this study was to determine the complementary value of immunohistochemistry and EM.Forty-eight NSCLC-NOS cases were selected (PSMAR-Biobank, Barcelona, Spain). Immunohistochemistry (TTF-1, p40) was performed. Tissue was retrieved from paraffin blocks. Results were compared to the final diagnosis, derived from combination of light microscopy, immunohistochemistry, EM, molecular studies and resection specimen.Immunohistochemistry concurred with final diagnosis in 36 cases (75%, Kappa = 0.517). EM agreed with final diagnosis in 35 (72.9%, Kappa = 0.471). Immunohistochemistry had a sensitivity = 73%, specificity = 100%, positive predictive value (PPV) = 100% and negative predictive value (NPV) = 52.4% for adenocarcinoma. All adenocarcinoma cases not solved by immunohistochemistry (n = 10) were classified by EM, and vice versa. Data from EM were identical to those of immunohistochemistry: sensitivity = 73%, specificity = 100%, PPV = 100% and NPV = 52.4%. Combining both techniques, 47 cases were coincident with final diagnosis (97.9%, Kappa = 0.943).EM can provide valuable information in subtyping NSCLC-NOS, being particularly useful when immunohistochemistry is inconclusive. EM could be considered as a complementary tool for decision-making in NSCLC-NOS.

Applications and analysis of targeted genomic sequencing in cancer studies.

Next Generation Sequencing (NGS) has dramatically improved the flexibility and outcomes of cancer research and clinical trials, providing highly sensitive and accurate high-throughput platforms for large-scale genomic testing. In contrast to whole-genome (WGS) or whole-exome sequencing (WES), targeted genomic sequencing (TS) focuses on a panel of genes or targets known to have strong associations with pathogenesis of disease and/or clinical relevance, offering greater sequencing depth with reduced costs and data burden. This allows targeted sequencing to identify low frequency variants in targeted regions with high confidence, thus suitable for profiling low-quality and fragmented clinical DNA samples. As a result, TS has been widely used in clinical research and trials for patient stratification and the development of targeted therapeutics. However, its transition to routine clinical use has been slow. Many technical and analytical obstacles still remain and need to be discussed and addressed before large-scale and cross-centre implementation. Gold-standard and state-of-the-art procedures and pipelines are urgently needed to accelerate this transition. In this review we first present how TS is conducted in cancer research, including various target enrichment platforms, the construction of target panels, and selected research and clinical studies utilising TS to profile clinical samples. We then present a generalised analytical workflow for TS data discussing important parameters and filters in detail, aiming to provide the best practices of TS usage and analyses.

Implantation of 125I radioactive seeds via c-TBNA combined with chemotherapy in an advanced non-small-cell lung carcinoma patient.

BACKGROUND: The critical management of advanced non-small-cell lung carcinoma (NSCLC), especially when complicated by severe airway stenosis, is difficult and often leads to high clinical risks and medical costs. CASE PRESENTATION: A 51-year-old previously healthy male was admitted to the Department of Respiratory and Critical Care Medicine, Taizhou People's Hospital, in November 2018 for haemoptysis and difficulty breathing during a 15-d period. Following admission, chest computed tomography (CT) showed a large mass in the left hilum with atelectasis in the left upper lobe and obstructive pneumonia in the left lower lobe. Bronchoscopy revealed that the lesions occurred in the distal segment of the left main trachea, with occlusion of the left upper bronchus and significant narrowing of the lower bronchus. A basal mucosal biopsy of the lump tissue was performed after haemostasis treatment with sub-plasma coagulation (APC), and squamous lung carcinoma was confirmed. Following the final diagnosis, the patient was successfully treated with implantation of 125I radioactive seeds via transbronchial needle aspiration (c-TBNA) combined with chemotherapy. CONCLUSION: We believe that implantation of 125I radioactive seeds via c-TBNA is an effective treatment for patients with advanced lung cancer and those presenting with severe and mixed main bronchus stenosis.

Berberine induces apoptosis in non-small-cell lung cancer cells by upregulating miR-19a targeting tissue factor.

BACKGROUND: Berberine (BBR) from the widely used Chinese herbal medicine Huanglian has an array of pharmacological and biochemical properties, including anti-neoplastic activity. However, the specific mechanisms underlying these properties are unknown. The aim of this study was to explore the anti-tumor mechanisms of BBR in non-small cell lung cancer (NSCLC). METHODS: The effects of BBR on NSCLC tumor development and programmed cell death were investigated both in vivo and in vitro. Luciferase reporter assays were used to determine whether tissue factor (TF) was a target of miR-19a. RESULTS: BBR suppressed NSCLC growth and promoted apoptosis in NSCLC cells by modulating miR-19a and TF expression. Luciferase assays showed that TF was a direct inhibitory target of miR-19a in NSCLC cells. BBR induced apoptosis through the miR-19a/TF/MAPK axis. CONCLUSION: The results suggest that BBR induces apoptosis of NSCLC cells via the miR-19a/TF/MAPK signaling pathway.

Hyaluronic acid-modified selenium nanoparticles for enhancing the therapeutic efficacy of paclitaxel in lung cancer therapy.

Targeted delivery of chemotherapeutics by functionalized nanoparticles exhibits a wonderful prospect for cancer treatment. In this paper, selenium nanoparticles (SeNPs) was linked with hyaluronic acid (HA) to prepare tumor-targeted delivery vehicle HA-SeNPs, and HA-SeNPs was loaded with paclitaxel (PTX) to fabricate functionalized selenium nanoparticles HA-Se@PTX. HA-Se@PTX showed greater uptake in A549 cells in comparison with that in HUVEC, verifying HA-mediated specific uptake of HA-Se@PTX. HA-Se@PTX was capable of entering A549 cells via clathrin-associated endocytosis and showed faster drug release in cancer cell microenvironment in comparison with normal physiological environment. HA-Se@PTX could obviously inhibit the proliferation, migration and invasion of A549 cells and trigger A549 cells apoptosis. Moreover, active targeting functionalized selenium nanoparticles HA-Se@PTX showed greater in vivo antitumor activity compared with free PTX or passive targeting delivery system Se@PTX. In addition, HA-Se@PTX exhibited negligible toxicity on the major organs of mice. In a word, HA-Se@PTX may develop into a valuable nanoscale antitumor drug agent for lung cancer treatment.