Identification of nine mutant genes and establishment of three prediction models of organ tropism metastases of non-small cell lung cancer.

BACKGROUND: Most Non-small cell lung cancer (NSCLC) patients tend to have metastases at the initial diagnosis. However, limited knowledge has been established regarding which factors, are associated with its metastases. This study aims to identify more biomarkers associated with its organ tropism metastasis and to establish models for prediction of its metastatic organs. METHODS: We performed targeted next-generation sequencing (NGS) to detect genes related to lung cancer in 272 patients with primary advanced NSCLC from Northeast China. We adopted Fisher test, multivariate logistic regression analysis to identify metastasis-related gene mutations and to establish prediction models. RESULTS: Mutations of EGFR (p = 0.0003, OR = 2.554) (especially EGFR L858R [p = 0.02, OR = 2.009]), ATM (p = 0.008, OR = 11.032), and JAK2 (p = 0.009, OR = Inf) were positively and of TP53 exon4mut (p = 0.001, OR = 0.173) was negatively correlated with lung metastasis, and those of CSF1R (p = 0.01, OR = Inf), KIT (p = 0.03, OR = 4.746), MYC (p = 0.05, OR = 7.938), and ERBB2 (p = 0.02, OR = 2.666) were positively correlated with pleural dissemination; those of TP53 (p = 0.01, OR = 0.417) was negatively, while of SMAD4 (p = 0.03, OR = 4.957) was positively correlated with brain metastasis of NSCLC. Additionally, smoking history (p = 0.004, OR = 0.004) was negatively correlated with pleural dissemination of NSCLC. Furthermore, models for prediction of lung metastasis (AUC = 0.706), pleural dissemination (AUC = 0.651), and brane metastasis (AUC = 0.629) were established. CONCLUSION: Taken together, this study revealed nine mutant genes and smoking history associated with organ tropism metastases of NSCLC and provided three models for the prediction of metastatic organs. This study enables us to predict the organs to which non-small cell lung cancer metastasizes before it does develop.

An Integrated Intelligent Approach for Monitoring and Management of a Deep Foundation Pit in a Subway Station.

As the scale of foundation pit projects of subway stations in Shenzhen becomes larger, and the construction constraints become more and more complex, there is an urgent need for intelligent monitoring and safety management of foundation pits. In this study, an integrated intelligent approach for monitoring and management of a deep foundation pit in a subway station was proposed and a case study based on the Waterlands Resort East Station Project of Shenzhen Metro Line 12 was used for validation. The present study first proposed the path of intelligent foundation pit engineering. Based on geotechnical survey and building information modeling, a three-dimensional transparent geological model of foundation pit was constructed. Multi-source sensing technologies were integrated, including micro electromechanical system sensing technology, Brillouin optical frequency domain analysis sensing technology, an unmanned aerial vehicle and machine vision for real-time high-precision wireless monitoring of the foundation pit. Moreover, machine learning models were developed for predicting key parameters of foundation pits. Finally, a digital twin integrated platform was developed for the management of the subway foundation pit in both construction and maintenance phases. This typical case study is expected to improve the construction, maintenance and management level of foundation pits in subway stations.

Molecular and clinical characteristics of IDH mutations in Chinese NSCLC patients and potential treatment strategies.

BACKGROUND: Isocitrate dehydrogenase (IDH) is an appealing target for anticancer therapy, and IDH (IDH1/2) inhibitors have been approved for targeted therapy of acute myeloid leukemia (AML) and Cholangiocarcinoma. The therapeutic potential of IDH inhibitors for non-small-cell lung cancer (NSCLC) patients is under active clinical investigation. Thus, it would be necessary and meaningful to study the molecular and clinical characteristics of IDH mutation in NSCLC patients, especially in the Chinese population. METHODS: A total of 17,978 Chinese patients with NSCLC who underwent next -generation sequencing (NGS) testing were retrospectively reviewed. RESULTS: We identified 161 unique IDH mutations in 361 of 17,978 patients (2.01%). Common active-site mutations, including IDH1R100 , IDH1R132 , IDH2R140 , and IDH2R172 , were detected in 154 patients (0.86%) and were associated with male sex (p = 0.004) and older age (p = 0.02). The IDH mutation spectra observed in NSCLC were quite different from those in glioma or AML. Patients with IDH active-site mutations exhibited significantly higher coalterations in KRAS (p. G12/13/61, 22.1% vs. 8.2%, p < 0.001) or BRAF (p. V600E, 6.5% vs. 1.0%, p < 0.001), but significantly lower coalterations in activating EGFR (e18-e20, 22.7 vs. 37.9%, p < 0.001) than IDH wild-type patients. Furthermore, we found that active-site IDH mutations were correlated with a short PFS (2-5.6 months) and short OS (2-9.5 months), which may arise as a resistance mechanism against common targeted drugs. In vitro, we experimentally observed that the combination of an IDH inhibitor and EGFR TKI could better inhibit lung cancer cell proliferation than an EGFR TKI alone. CONCLUSIONS: Taken together, this study reveals the molecular and clinical characteristics of IDH mutations in Chinese NSCLC patients and provides a theoretical basis for IDH-directed treatment. The potential of IDH mutations as response markers for targeted therapy warrants further investigation.

Temperature abetted synthesis of novel magnesium stannate nanoparticles assisted for nanomolar level detection of hazardous flavonoid in biological samples.

Fabrication of temperature-influenced nanoparticles over the superficial region of glassy carbon electrode (GCE) stimulates the electrocatalytic activity owing to their morphology, defective sites, and higher active surface area, etc. In this regard, we have fabricated annealed magnesium stannate nanoparticles (Mg2SnO4 NPs) on GCE for nanomolar level detection of hazardous flavoring and pharmaceutical compound Rutin (RT). To analyze the impact of temperature, we have compared annealed Mg2SnO4 NPs with unannealed magnesium stannate hydrate (MgSnO3·3H2O) particles. The physicochemical properties of synthesized materials were characterized with different microscopic and spectroscopic techniques. From these studies, annealed Mg2SnO4 NPs formed purely without any flith and existence of water molecules as compared to unannealed MgSnO3·3H2O. Moreover as fabricated, Mg2SnO4 NPs/GCE outcomes with higher redox behavior compared to other electrodes in presence of RT at optimized working buffer (pH = 7.0). Interestingly, the electrode successfully established a dual wider linear response (0.062-34.8 & 34.8-346.8 µM) with a nanomolar detection limit (1 nM) and higher sensitivity. The practicability analysis of the proposed sensor also affords excellent selectivity, reproducibility, repeatability, reversibility, and storage stability. Furthermore, the real sample analysis was carried out in blood and orange samples fallout with better recovery results.

MicroRNA-32 and MicroRNA-548a Promote the Drug Sensitivity of Non-Small Cell Lung Cancer Cells to Cisplatin by Targeting ROBO1 and Inhibiting the Activation of Wnt/ß-Catenin Axis.

BACKGROUND: The roles of microRNA (miR)-32 and miR-548a in non-small cell lung cancer (NSCLC) have been studied. But their influences on NSCLC cells to cisplatin (DDP) resistance remain elusive. This study estimated the mechanisms of miR-32 and miR-548a in NSCLC cells to DDP. METHODS: Differentially expressed miRs in DDP-sensitive and resistant tissues were screened out using a GSE56036 chip. Then the predictive efficacies of miR-32 and miR-548a on DDP resistance were analyzed in NSCLC patients. The target mRNAs of miR-548a and miR-32 were predicted. miR-548a and miR-32 were knocked down to assess the influences of miR-32 and miR-548a on NSCLC growth. DDP-resistant cells were constructed and miR-32 and miR-548a expression was detected in resistant cells. After miR-32 and miR-548a knockdown, the IC50 value of DDP was detected. Then, the activation level of Wnt/ß-catenin pathway was detected. The roles of miR-32 and miR-548a in NSCLC growth in vivo were detected by tumorigenesis experiment. RESULTS: miR-32 and miR-548a were poorly expressed in DDP-resistant NSCLC. miR-32 and miR-548a mimic enhanced the DDP sensitivity of NSCLC cells. Both miR-32 and miR-548a targeted ROBO1, and overexpression of ROBO1 inhibited the promotion of miR-32 and miR-548a mimic on DDP sensitivity. ROBO1 activated the Wnt/ß-catenin pathway, thus enhancing the DDP resistance. CONCLUSION: miR-32 and miR-548a target ROBO1 and inhibit Wnt/ß-catenin activation, thus promoting the drug sensitivity of NSCLC cells to DDP.

Inhibition of GOT1 sensitizes colorectal cancer cells to 5-fluorouracil.

PURPOSE: Almost all colorectal cancer (CRC) cell lines are known to overexpress aspartate aminotransferase (GOT1), which potentially regulates the intracellular levels of reactive oxygen species (ROS) via the production of NADPH, and supports tumor growth. In our study, the role of GOT1 in the anticancer efficacy of 5-fluorouracil (5-FU) was examined. METHODS: HCT116, SW480, and HT-29 cells were transfected with lentiviral vectors expressing short hairpin RNA (shRNA) against GOT1. Following 5-FU treatment, cellular proliferation was evaluated, the NADP+/NADPH ratio was monitored, ROS was measured, and intracellular levels of glutamine (Gln), Aspartate (Asp), oxaloacetate (OAA), malate, and pyruvate were investigated using liquid chromatography-mass spectrometry (LC-MS). A CRC subcutaneous tumor model was performed to determine the impact of GOT1 inhibition on 5-FU efficacy in vivo. RESULTS: In response to 5-FU administration, CRC cells undergo metabolic adaptation, resulting in increased glutamine flux for the synthesis of aspartate. GOT1 is responsible for the conversion of glutamine-derived aspartate into OAA, which subsequently can be converted into malate and pyruvate. The GOT1-mediated metabolic process is able to maintain the NADP+/NADPH ratio, which counteracts 5-FU-induced oxidative stress. Inhibition of GOT1 impaired the defense against 5-FU-induced ROS, thereby sensitizing cells to 5-FU. The importance of GOT1 in supporting tumor growth during 5-FU treatment was also indicated in an in vivo tumor model of CRC. CONCLUSION: These findings show that GOT1 could serve as a promising target for increasing the anticancer efficacy of the conventional therapy in patients with CRC.

Meta-analysis of the incidence and risk of arterial and venous thromboembolic events associated with anti-EGFR agents in non-small-cell lung cancer patients.

BACKGROUND: To determine the risk of arterial and venous thromboembolic events (ATEs and VETs) associated with anti-epidermal growth factor receptor (EGFR) agents in non-small-cell lung cancer (NSCLC) patients. METHODS: Prospective randomized trials evaluating therapy with or without anti-EGFR agents in NSCLC patients. Data on VTEs and ATEs were extracted. RESULTS: A total of 8,410 patients from 12 trials were included for analysis. Anti-EGFR agents significantly increased the risk of all-grade and high-grade VTEs (Peto OR 1.50, 95%CI 1.16-1.95, P = 0.002; Peto OR 1.73, 95%CI: 1.32-2.26, p < 0.001, respectively), but not for all-grade and high-grade ATEs. CONCLUSION: The use of anti-EGFR agents significantly increased the risk of all-grade and high-grade VTEs but not for ATEs in NSCLC patients.

[Analysis of Clinical Prognosis of 50 Cases of Primary Gastrointestinal Non-Hodgkin's Lymphoma].

OBJECTIVE: To analyze the clinical pathologic characteristics, diagnosis, treatment and outcome of patients with primary gastrointestinal non-Hodgkin's lymphoma(PGI-NHL). METHODS: The clinical and pathological features of 50 cases of PGI-NHL were analyzed retrospectively, the Kaplan-Meier was applied to estimate the survival time of all the patients. RESULTS: The median age of patients was 58 years old, the cases of male patient were more than that of femal. The main clinical symptoms included pain and discomfort. The patients of Ⅰ-Ⅱstage accounted for 66%, DLBCL was most common. The clinical and pathological features were not significantly different between gastric and intestinal lymphoma. In 58% of the patients, surgery was the first choice for treatment. The median survival time was 74 months. The OS rates at 1-, 3- and 5-year were 78%, 65.9% and 61.8% respectively. Log-rank univariate analysis showed that age, sex, ECOG score, B symptoms, disease location and treatment methods all did not relate with OS, however, IPI, stage, LDH, cell phenotype and pathological type closely related with the OS. CONCLUSION: As lacking characteristic clinical manifestations of PGI-NHL, the DLBCL is the most common type. The prognosis of B cell lymphoma is significantly better than that of T cell lymphoma. The prognosis of PTCL is the worst.

XPC gene intron 11 C/A polymorphism is a predictive biomarker for the sensitivity to NP chemotherapy in patients with non-small cell lung cancer.

The fact that intron single nucleotide polymorphisms could regulate gene expression or even alter gene expression levels has been the focus of attention. To study the relationship between the intron 11 C/A single nucleotide polymorphism of XPC gene and the efficacy of vinorelbine and cisplatin (NP) chemotherapy, 164 patients with non-small cell lung cancer (NSCLC) taking NP chemotherapy drugs were evaluated according to the efficacy of the treatment. We used polymerase chain reaction restriction fragment length polymorphism to examine the C/A polymorphism in the XPC gene intron 11 of the DNA samples extracted from peripheral blood. It was found that the frequency of patients in the effective group with C/C+C/A genotype (37.6%) had significant difference to chemotherapy than that of patients with A/A homozygotes (27.7%) in the same group (P=0.043, odds ratio=2.366, 95% confidence interval=1.026-5.457). Therefore, NSCLC patients with the C/C+C/A genotype are more sensitive to NP treatment than those with the A/A genotype. The XPC gene intron 11 C/A polymorphism may be a predictive biomarker for sensitivity to NP chemotherapy in patients with NSCLC.

[Correlation of the sensitivity of NP chemotherapy in non-small lung cancer with DNA repair gene XRCC1 polymorphism].

BACKGROUND AND OBJECTIVE: The gene polymorphism is used to predict the sensitivity of chemotherapy, which is significant for the individualized treatment of tumor. This study was to explore the correlation of codon 194 and codon 399 polymorphisms of DNA repair gene X-ray repair cross complementing (XRCC1) with the sensitivity of non-small cell lung cancer (NSCLC) to NP (vinorebine and cisplatin) chemotherapy. METHODS: XRCC1 polymorphisms at codon 194 and codon 399 were detected in 164 patients with NSCLC using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The haplotype of XRCC1 gene was analyzed using SHEsis analysis software. Patients treated with NP chemotherapy were evaluated after two periods of treatment, then the correlation of the sensitivity of chemotherapy with polymorphisms was analyzed. RESULTS: The patients with the XRCC1 codon 194 C/T+T/T polymorphisms were 2.038 times as sensitive to the chemotherapy as the patients with C/C genotype (P=0.036, 95% CI:1.044-3.976). The effective rate to chemotherapy was no significant difference between the patients with XRCC1 codon 399 G/G, A/G, and A/A polymorhism. The effective rate of chemotherapy of the patients with T-A haplotype significantly increased compared with those with other haplotype (P=0.031), while that of the patients with C-A haplotype significantly decreased compared with others(P=0.035). CONCLUSIONS: The sensitivity to NP chemotherapy significantly increased in the NSCLC patients with XRCC1 194 CT and TT genotypes compared with those with CC genotype. XRCC1 codon 194 and codon 399 polymorphisms may be used to predict the sensitivity of NSCLC to NP chemotherapy.