Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC.

BACKGROUND: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. CONCLUSIONS: Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

USP9X-mediated REV1 deubiquitination promotes lung cancer radioresistance via the action of REV1 as a Rad18 molecular scaffold for cystathionine γ-lyase.

BACKGROUND: Radioresistance is a key clinical constraint on the efficacy of radiotherapy in lung cancer patients. REV1 DNA directed polymerase (REV1) plays an important role in repairing DNA damage and maintaining genomic stability. However, its role in the resistance to radiotherapy in lung cancer is not clear. This study aims to clarify the role of REV1 in lung cancer radioresistance, identify the intrinsic mechanisms involved, and provide a theoretical basis for the clinical translation of this new target for lung cancer treatment. METHODS: The effect of targeting REV1 on the radiosensitivity was verified by in vivo and in vitro experiments. RNA sequencing (RNA-seq) combined with nontargeted metabolomics analysis was used to explore the downstream targets of REV1. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify the content of specific amino acids. The coimmunoprecipitation (co-IP) and GST pull-down assays were used to validate the interaction between proteins. A ubiquitination library screening system was constructed to investigate the regulatory proteins upstream of REV1. RESULTS: Targeting REV1 could enhance the radiosensitivity in vivo, while this effect was not obvious in vitro. RNA sequencing combined with nontargeted metabolomics revealed that the difference result was related to metabolism, and that the expression of glycine, serine, and threonine (Gly/Ser/Thr) metabolism signaling pathways was downregulated following REV1 knockdown. LC-MS/MS demonstrated that REV1 knockdown results in reduced levels of these three amino acids and that cystathionine γ-lyase (CTH) was the key to its function. REV1 enhances the interaction of CTH with the E3 ubiquitin ligase Rad18 and promotes ubiquitination degradation of CTH by Rad18. Screening of the ubiquitination compound library revealed that the ubiquitin-specific peptidase 9 X-linked (USP9X) is the upstream regulatory protein of REV1 by the ubiquitin-proteasome system, which remodels the intracellular Gly/Ser/Thr metabolism. CONCLUSION: USP9X mediates the deubiquitination of REV1, and aberrantly expressed REV1 acts as a scaffolding protein to assist Rad18 in interacting with CTH, promoting the ubiquitination and degradation of CTH and inducing remodeling of the Gly/Ser/Thr metabolism, which leads to radioresistance. A novel inhibitor of REV1, JH-RE-06, was shown to enhance lung cancer cell radiosensitivity, with good prospects for clinical translation.

Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial.

Importance: For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. Objective: To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled. Interventions: Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed. Main Outcomes and Measures: The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported. Results: Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Conclusions: Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT05184712.

Targeting polymerase θ impairs tumorigenesis and enhances radiosensitivity in lung adenocarcinoma.

Radioresistance remains a major obstacle to efficacious radiotherapy in non-small-cell lung cancer (NSCLC). DNA replication proteins are novel targets for radiosensitizers. POLQ is a DNA polymerase involved in DNA damage response and repair. We found that POLQ is overexpressed in NSCLC and is clinically correlated with high tumor stage, poor prognosis, increased tumor mutational burden, and ALK and TP5 mutation status; POLQ inhibition impaired lung tumorigenesis. Notably, POLQ expression was higher in radioresistant lung cancer cells than in wild-type cancer cells. Moreover, POLQ expression was further increased in radioresistant cells after radiation. Enhanced radioresistance is through a prolonged G2/M phase and faster repair of DNA damage, leading to reduced radiation-induced apoptosis. Novobiocin (NVB), a POLQ inhibitor, specifically targeted cancer cells. Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer-specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC.

Activation of NLRP3 inflammasome in lung epithelial cells triggers radiation-induced lung injury.

BACKGROUND: Radiation-induced lung injury (RILI) is the most common and serious complication of chest radiotherapy. However, reported radioprotective agents usually lead to radiation resistance in tumor cells. The key to solving this problem is to distinguish between the response of tumor cells and normal lung epithelial cells to radiation damage. METHODS: RNA-Seq was used to recognize potential target of alleviating the progression of RILI as well as inhibiting tumor growth. The activation of NLRP3 inflammasome in lung epithelial cells was screened by qRT-PCR, western blotting, immunofluorescence, and ELISA. An in vivo model of RILI and in vitro conditioned culture model were constructed to evaluate the effect of NLRP3/interleukin-1ß on fibroblasts activation. ROS, ATP, and (NADP)+/NADP(H) level in lung epithelial cells was detected to explore the mechanism of NLRP3 inflammasome activation. The lung macrophages of the mice were deleted to evaluate the role of lung epithelial cells in RILI. Moreover, primary cells were extracted to validate the results obtained from cell lines. RESULTS: NLRP3 activation in epithelial cells after radiation depends on glycolysis-related reactive oxygen species accumulation. DPYSL4 is activated and acts as a negative regulator of this process. The NLRP3 inflammasome triggers interleukin-1ß secretion, which directly affects fibroblast activation, proliferation, and migration, eventually leading to lung fibrosis. CONCLUSIONS: Our study suggests that NLRP3 inflammasome activation in lung epithelial cells is essential for radiation-induced lung injury. These data strongly indicate that targeting NLRP3 may be effective in reducing radiation-induced lung injury in clinical settings.

Maturation, Morphology, and Function: The Decisive Role of Intestinal Flora on Microglia: A Review.

Recent studies have shown that the gut microbiota regulates intestinal function and maintains intestinal homeostasis, as well as interacting with the central nervous system to affect brain function and human behavior. Microglia are the most common immune cell type in the central nervous system during homeostasis. These cells play an important role in immune surveillance by responding to infections and other pathological conditions. Microglia also play a major role in maintaining brain homeostasis in both developing and adult mice by phagocytosing cell debris and regulating the formation of neural networks. The specific signaling pathways and cytokines that control the maturation and activation of microglia are currently not fully established. However, research on germ-free (GF) mice and specific pathogen-free (SPF) mice indicate that gut microbiota have important interactions with microglia. Here, we review the latest research findings on how gut microbiota can affect the morphology, maturation, phenotype and function of microglia. We also discuss recent advances in the gut microbiota-microglia-disease axis.

E2F1-mediated repression of WNT5A expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer.

Brain metastasis (BM) is associated with poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutation reportedly enhances the development of BM. However, the exact mechanism of how EGFR-mutant NSCLC contributes to BM remains unknown. Herein, we found the protein WNT5A, was significantly downregulated in BM tissues and EGFR-mutant samples. In addition, the overexpression of WNT5A inhibited the growth, migration, and invasion of EGFR-mutant cells in vitro and retarded tumor growth and metastasis in vivo compared with the EGFR wide-type cells. We demonstrated a molecular mechanism whereby WNT5A be negatively regulated by transcription factor E2F1, and ERK1/2 inhibitor (U0126) suppressed E2F1's regulation of WNT5A expression in EGFR-mutant cells. Furthermore, WNT5A inhibited ß-catenin activity and the transcriptional levels of its downstream genes in cancer progression. Our research revealed the role of WNT5A in NSCLC BM with EGFR mutation, and proved that E2F1-mediated repression of WNT5A was dependent on the ERK1/2 pathway, supporting the notion that targeting the ERK1/2-E2F1-WNT5A pathway could be an effective strategy for treating BM in EGFR-mutant NSCLC.

Individualized model for predicting COVID-19 deterioration in patients with cancer: A multicenter retrospective study.

The 2019 novel coronavirus has spread rapidly around the world. Cancer patients seem to be more susceptible to infection and disease deterioration, but the factors affecting the deterioration remain unclear. We aimed to develop an individualized model for prediction of coronavirus disease (COVID-19) deterioration in cancer patients. The clinical data of 276 cancer patients diagnosed with COVID-19 in 33 designated hospitals of Hubei, China from December 21, 2019 to March 18, 2020, were collected and randomly divided into a training and a validation cohort by a ratio of 2:1. Cox stepwise regression analysis was carried out to select prognostic factors. The prediction model was developed in the training cohort. The predictive accuracy of the model was quantified by C-index and time-dependent area under the receiver operating characteristic curve (t-AUC). Internal validation was assessed by the validation cohort. Risk stratification based on the model was carried out. Decision curve analysis (DCA) were used to evaluate the clinical usefulness of the model. We found age, cancer type, computed tomography baseline image features (ground glass opacity and consolidation), laboratory findings (lymphocyte count, serum levels of C-reactive protein, aspartate aminotransferase, direct bilirubin, urea, and d-dimer) were significantly associated with symptomatic deterioration. The C-index of the model was 0.755 in the training cohort and 0.779 in the validation cohort. The t-AUC values were above 0.7 within 8 weeks both in the training and validation cohorts. Patients were divided into two risk groups based on the nomogram: low-risk (total points ≤ 9.98) and high-risk (total points > 9.98) group. The Kaplan-Meier deterioration-free survival of COVID-19 curves presented significant discrimination between the two risk groups in both training and validation cohorts. The model indicated good clinical applicability by DCA curves. This study presents an individualized nomogram model to individually predict the possibility of symptomatic deterioration of COVID-19 in patients with cancer.

Association between recent oncologic treatment and mortality among patients with carcinoma who are hospitalized with COVID-19: A multicenter study.

BACKGROUND: To the authors' knowledge, little is known regarding the association between recent oncologic treatment and mortality in patients with cancer who are infected with coronavirus disease 2019 (COVID-19). The objective of the current study was to determine whether recent oncologic treatment is associated with a higher risk of death among patients with carcinoma who are hospitalized with COVID-19. METHODS: Data regarding 248 consecutive patients with carcinoma who were hospitalized with COVID-19 were collected retrospectively from 33 hospitals in Hubei Province, China, from January 1, 2020, to March 25, 2020. The follow-up cutoff date was July 22, 2020. Univariable and multivariable logistic regression analyses were performed to identify variables associated with a higher risk of death. RESULTS: Of the 248 patients enrolled, the median age was 63 years and 128 patients (52%) were male. On admission, 147 patients (59%) did not undergo recent oncologic treatment, whereas 32 patients (13%), 25 patients (10%), 12 patients (5%), and 10 patients (4%), respectively, underwent chemotherapy, surgery, targeted therapy, and radiotherapy. At the time of last follow-up, 51 patients (21%) were critically ill during hospitalization, 40 of whom had died. Compared with patients without receipt of recent oncologic treatment, the mortality rate of patients who recently received oncologic treatment was significantly higher (24.8% vs 10.2%; hazard ratio, 2.010 [95% CI, 1.079-3.747; P = .027]). After controlling for confounders, recent receipt of chemotherapy (odds ratio [OR], 7.495; 95% CI, 1.398-34.187 [P = .015]), surgery (OR, 8.239; 95% CI, 1.637-41.955 [P = .012]), and radiotherapy (OR, 15.213; 95% CI, 2.091-110.691 [P = .007]) were identified as independently associated with a higher risk of death. CONCLUSIONS: The results of the current study demonstrated a possible association between recent receipt of oncologic treatment and a higher risk of death among patients with carcinoma who are hospitalized with COVID-19.

Precise pathological classification of non-small cell lung adenocarcinoma and squamous carcinoma based on an integrated platform of targeted metabolome and lipidome.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the most common subtypes of NSCLC. Despite genetic differences between LUAD and LUSC have been clarified in depth, the metabolic differences of these two subtypes are still unclear. METHODS: Totally, 128 plasma samples of NSCLC patients were collected before initial treatments, followed by determination of LC-ESI-Q TRAP-MS/MS. Differentially expressed metabolites were screened based on a strict standard. RESULTS: Based on the integrated platform of targeted metabolome and lipidome, a total of 1141 endogenous metabolites (including 809 lipids) were finally detected in the plasma of NSCLC patients, including 16 increased and 3 decreased endogenous compounds in LUAD group when compared with LUSC group. Thereafter, a logistic regression model integrating four differential metabolites [2-(Methylthio) ethanol, Cortisol, D-Glyceric Acid, and N-Acetylhistamine] was established and could accurately differentiate LUAD and LUSC with an area under the ROC curve of 0.946 (95% CI 0.886-1.000). The cut-off value showed a satisfactory efficacy with 92.0% sensitivity and 92.9% specificity. KEGG functional enrichment analysis showed these differentially expressed metabolites could be further enriched in riboflavin metabolism, steroid hormone biosynthesis, prostate cancer, etc. The endogenous metabolites identified in this study have the potential to be used as novel biomarkers to distinguish LUAD from LUSC. CONCLUSIONS: Our research might provide more evidence for exploring the pathogenesis and differentiation of NSCLC. This research could promote a deeper understanding and precise treatment of lung cancer.

Mutation Variants and Co-Mutations as Genomic Modifiers of Response to Afatinib in HER2-Mutant Lung Adenocarcinoma.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-mutant lung cancer remains an orphan of specific targeted therapy. The variable responses to anti-HER2 therapies in these patients prompt us to examine impact of HER2 variants and co-mutations on responses to anti-HER2 treatments in lung cancer. PATIENTS AND METHODS: Patients with stage IV/recurrent HER2-mutant lung cancers identified through next-generation sequencings were recruited from seven hospitals. The study comprised a cohort A to establish the patterns of HER2 variants and co-mutations in lung cancer and a cohort B to assess associations between HER2 variants, co-mutations, and clinical outcomes. RESULTS: The study included 118 patients (cohort A, n = 86; cohort B, n = 32). Thirty-one HER2 variants and 35 co-mutations were detected. Predominant variants were A775_G776insYVMA (49/118, 42%), G778_P780dup (11/118, 9%), and G776delinsVC (9/118, 8%). TP53 was the most common co-mutation (61/118, 52%). In cohort B, objective response rates with afatinib were 0% (0/14, 95% confidence interval [CI], 0%-26.8%), 40% (4/10, 14.7%-72.6%), and 13% (1/8, 0.7%-53.3%) in group 1 (A775_G776insYVMA, n = 14), group 2 (G778_P780dup, G776delinsVC, n = 10), and group 3 (missense mutation, n = 8), respectively (p = .018). Median progression-free survival in group 1 (1.2 months; 95% CI, 0-2.4) was shorter than those in group 2 (7.6 months, 4.9-10.4; hazard ratio [HR], 0.009; 95% CI, 0.001-0.079; p < .001) and group 3 (3.6 months, 2.6-4.5; HR, 0.184; 95% CI, 0.062-0.552; p = .003). TP53 co-mutations (6.317; 95% CI, 2.180-18.302; p = .001) and PI3K/AKT/mTOR pathway activations (19.422; 95% CI, 4.098-92.039; p < .001) conferred additional resistance to afatinib. CONCLUSION: G778_P780dup and G776delinsVC derived the greatest benefits from afatinib among HER2 variants. Co-mutation patterns were additional response modifiers. Refining patient population based on patterns of HER2 variants and co-mutations may help improve the efficacy of anti-HER2 treatment in lung cancer. IMPLICATIONS FOR PRACTICE: Human epidermal growth factor receptor 2 (HER2)-mutant lung cancers are a group of heterogenous diseases with up to 31 different variants and 35 concomitant genomic aberrations. Different HER2 variants exhibit divergent sensitivities to anti-HER2 treatments. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A775_G776insYVMA, is resistant to most anti-HER2 treatments. TP53 is the most common co-mutation in HER2-mutant lung cancers. Co-mutations in TP53 and the PI3K/AKT/mTOR pathway confer additional resistance to anti-HER2 treatments in lung cancer. The present data suggest that different HER2 mutations in lung cancer, like its sibling epidermal growth factor receptor, should be analyzed independently in future studies.

Catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages.

PURPOSE: Elevated catecholamines in the tumor microenvironment often correlate with tumor development. However, the mechanisms by which catecholamines modulate lung cancer growth are still poorly understood. This study is aimed at examining the functions and mechanisms of catecholamine-induced macrophage polarization in angiogenesis and tumor development. EXPERIMENTAL DESIGN: We established in vitro and in vivo models to investigate the relationship between catecholamines and macrophages in lung cancer. Flow cytometry, cytokine detection, tube formation assay, immunofluorescence, and western blot analysis were performed, and animal models were also used to explore the underlying mechanism of catecholamine-induced macrophage polarization and host immunological response. RESULTS: Catecholamines were shown to be secreted into tumor under the control of the sympathetic nerve system to maintain the pro-tumoral microenvironment. In vivo, the chemical depletion of the natural catecholamine stock with 6OHDA could reduce the release of catecholamines within tumor tissues, restrain the function of alternatively activated M2 macrophage, attenuate tumor neovascularization, and inhibit tumor growth. In vitro, catecholamine treatment triggered the M2 polarization of macrophages, enhanced the expression of VEGF, promoted tumor angiogenesis, and these catecholamine-stimulated effects could be reversed by the adrenergic receptor antagonist propranolol. In addition to regulating tumor-associated macrophages (TAM) recruitment, decreasing catecholamine levels could also shift the immunosuppressive microenvironment by decreasing myeloid-derived suppressor cells' (MDSCs) recruitment and facilitating dendritic cells' (DCs) activation, potentially resulting in a positive antitumor immune response. CONCLUSION: Our study demonstrates the potential of adrenergic stress and catecholamine-driven adrenergic signaling of TAMs to regulate the immune status of a tumor microenvironment and provides promising targets for anticancer therapies.

Cardamonin inhibits the proliferation and metastasis of non-small-cell lung cancer cells by suppressing the PI3K/Akt/mTOR pathway.

Cardamonin, a natural chalcone compound, has been reported to exert anticancer effects in several cancers. However, the specific pharmacological actions of cardamonin on human non-small-cell lung cancer (NSCLC) and the potential mechanisms still remain obscure. Here, we investigated the antineoplastic role of cardamonin in NSCLC both in vitro and in vivo. The proliferation of five NSCLC cell lines was inhibited in a dose-dependent and time-dependent manner with cardamonin treatment. In A549 and H460 cells, cardamonin induced apoptosis by activating caspase-3, upregulating Bax, and downregulating Bcl-2. In addition, cardamonin arrested cells in the G2/M phase and inhibited the expression levels of cyclin D1/CDK4. Moreover, cell migration and invasion were suppressed by reversing epithelial-mesenchymal transition with cardamonin treatment. Further study showed that cardamonin reduced the phosphorylation levels of the downstream effectors of phosphoinositide 3-kinase (PI3K), including protein kinase-B (Akt/PKB) and mammalian target of rapamycin (mTOR). Moreover, in the H460 xenograft model, cardamonin significantly retarded tumor growth. Also, in tumor tissues, we found that cardamonin treatment decreased the expression rates of Ki-67, p-Akt, and p-mTOR. These data suggest that cardamonin suppressed NSCLC cell proliferation and inhibited metastasis partly by restraining the PI3K/Akt/mTOR pathway and it might be an effective therapeutic compound for NSCLC in the future.

Epidemiological characteristics of malaria from control to elimination in Hubei Province, China, 2005-2016.

BACKGROUND: Hubei Province, China, has been operating a malaria elimination programme. This study aimed at investigating the epidemiologic characteristics of malaria in Hubei Province (2005-2016) to plan resource allocation for malaria elimination. METHODS: Data on all malaria cases from 2005 to 2016 in all counties of Hubei Province were extracted from a web-based reporting system. The numbers of indigenous and imported cases during the disease control (2005-2010) and elimination (2011-2016) stages, as well as their spatiotemporal distribution, were compared. RESULTS: A total of 8109 malaria cases were reported from 2005 to 2016 (7270 and 839 cases during the control and elimination stages, respectively). Between 2005 and 2010, indigenous malaria cases comprised the majority of total cases (7114/7270; 97.9%), and Plasmodium vivax malaria cases accounted for most malaria cases (5572/7270; 76.6%). No indigenous malaria cases have been reported in Hubei Province since 2013. Imported malaria cases showed a gradually increasing trend from 2011 to 2016, Plasmodium falciparum was the predominant species in these cases, and the number of counties with imported cases increased from 4 in 2005 to 47 in 2016. During the control and elimination stages, the most likely spatial clusters for indigenous cases included 13 and 11 counties, respectively. However, the cluster of indigenous malaria cases has not been identified since September 2011. For imported cases, the most likely cluster and three secondary clusters during both stages were identified. CONCLUSIONS: Hubei Province has made significant achievements in controlling and eliminating malaria; however, the region now faces some challenges associated with the increasing number and distribution of imported malaria cases. Priorities for malaria elimination should include better management of imported malaria cases, prevention of secondary malaria transmission, and ensuring the sustainability of malaria surveillance.

Interference with HMGB1 increases the sensitivity to chemotherapy drugs by inhibiting HMGB1-mediated cell autophagy and inducing cell apoptosis.

Non-small cell lung cancer is commonly seen with higher morbidity and mortality. High-mobility group protein 1 (HMGB1) is a highly conserved nuclear protein, which is involved in multiple human diseases including cancers. However, the mechanisms of HMGB1 in non-small cell lung cancer remain unclear. The goal of the present study is to identify the relationship between HMGB1 and the progresssion of non-small cell lung cancer and investigate the molecular mechanism of HMGB1 in non-small lung cancer cell lines. Firstly, we detected the expression levels of HMGB1 by by real-time PCR and western blotting analysis, and the results demonstrated that HMGB1 was much higher expressed in non-small cell lung cancer cell lines, including A549, SPC-1-1, NCI-2170, SK-MES-1, and NCI-H1299, compared with that of WI-38. Next, 5 µM of adriamycin (AMD), 20 µM of cisplatin (DDP), and 50 µM of methotrexate (MTX) were used to treat A549 cells and SPC-A-1 cells for 48 h. The results showed that treatment with chemotherapy drugs significantly increased the levels of HMGB1 in A549 cells and SPC-A-1 cells. Moreover, the expression levels of HMGB1 increased in a time-dependent manner being treated with DDP. Then, the endogenous HMGB1 expression was successfully interferred with shRNA specific to HMGB1 in A549 and SPC-A-1 cells, which was detected by western blotting analysis. Then, the cisplatin-sensitive A549 cells and cisplatin-resistant A549/DDP cells were treated with increasing concentrations of cisplatin for 24, 48, and 72 h; cell viability were analyzed by MTT assay; and IC50 values were calculated. The results demonstrated that the expression level of HMGB1 in A549/DDP cells was much higher than that of A549 cells; moreover, transfection with HMGB1 shRNA in A549/DDP cells decreased the IC50 value of cisplatin in A549/DDP cells. The expression levels of autophagy-related proteins beclin-1 and LC3-II were significantly higher in A549/DDP cells or the A549 cells treated with chemotherapeutic drugs, compared with that in A549 cells. However, interference with endogenous HMGB1 obviously suppressed autophagy-related proteins and increased cell apoptosis rate and the expression of cleaved caspase-3 in A549/DDP cells. All of the data suggested that interference with the endogenous HMGB1 significantly inhibited cell autophagy and increased cell apoptosis of A549/DDP cells. Thus, the study on the resistance of chemotherapy drugs would provide a theoretical reference for clinical treatment of non-small cell lung cancer.

Shenqi fuzheng injection attenuates irradiation-induced brain injury in mice via inhibition of the NF-κB signaling pathway and microglial activation.

AIM: Radiation-induced brain injury (RIBI) is the most common and severe adverse effect induced by cranial radiation therapy (CRT). In the present study, we examined the effects of the traditional Chinese medicine Shenqi Fuzheng Injection (SFI) on RIBI in mice, and explored the underlying mechanisms. METHODS: C57BL/6J mice were subjected to a single dose of 20-Gy CRT. The mice were treated with SFI (20 mL·kg(-1)·d(-1), ip) for 4 weeks. Morris water maze test was used to assess the cognitive changes. Evans blue leakage and a horseradish peroxidase (HRP) assay were used to evaluate the integrity of the blood-brain barrier (BBB). The expression of inflammatory factors and microglial activation in brain tissues were detected using RT-PCR, Western blotting and immunofluorescence staining. RESULTS: CRT caused marked reductions in the body weight and life span of the mice, and significantly impaired their spatial learning. Furthermore, CRT significantly increased the BBB permeability, number of activated microglia, expression levels of TNF-α and IL-1ß, and the levels of phosphorylated p65 and PIDD-CC (the twice-cleaved fragment of p53-induced protein with a death domain) in the brain tissues. Four-week SFI treatment (administered for 2 weeks before and 2 weeks after CRT) not only significantly improved the physical status, survival, and spatial learning in CRT-treated mice, but also attenuated all the CRT-induced changes in the brain tissues. Four-week SFI pretreatment (administered for 4 weeks before CRT) was less effective. CONCLUSION: Administration of SFI effectively attenuates irradiation-induced brain injury via inhibition of the NF-κB signaling pathway and microglial activation.

Multi-functional ion-sensor based on a photochromic diarylethene with a 1H-imidazo [4,5-f][1,10] phenanthroline unit.

A new asymmetrical diarylethene containing a 1H-imidazo [4,5-f][1,10] phenanthroline unit was synthesized. The compound showed typical photochromism and functioned as a notable fluorescence switch upon alternating irradiation with ultraviolet (UV) and visible light. Its closed-ring isomer could be used as a selective 'naked-eye' colorimetric sensor for Cu(2+), accompanied by a notable color change from blue to colorless. Furthermore, the compound was found to be selective towards Ca(2+), Mg(2+), and Sr(2+) with significant fluorescence changes. On the basis of this characteristic, a logic circuit was constructed by utilizing both light and chemical stimuli as inputs and fluorescence intensity at 487 nm as output.