Positive progress for non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations: A novel targeted therapy option.

Epidermal growth factor receptor gene exon 20 insertion mutations are seen in ∼4-12% of patients with epidermal growth factor receptor-mutant non-small cell lung cancer. However, there is no targeted therapy approved for the treatment of non-small cell lung cancer patients with these rare epidermal growth factor receptor mutations. Previous studies revealed that epidermal growth factor receptor gene exon 20 insertion mutations are unique in their ability to activate epidermal growth factor receptor without the typical structural changes associated with the common epidermal growth factor receptor mutations, reducing the clinical efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors currently approved for non-small cell lung cancer. Therefore, there is an urgent need to identify active epidermal growth factor receptor-tyrosine kinase inhibitors and other effective treatment strategies for non-small cell lung cancer patients with epidermal growth factor receptor gene exon 20 insertion mutations. Mobocertinib is a novel irreversible epidermal growth factor receptor-tyrosine kinase inhibitor that selectively targets epidermal growth factor receptor gene exon 20 insertion mutations. Preclinical study revealed that mobocertinib inhibited the viability of epidermal growth factor receptor gene exon 20 insertion mutations-driven patient-derived xenografts and murine orthotopic tumors more potently than traditional epidermal growth factor receptor-tyrosine kinase inhibitors. In a study recently published in Cancer Discovery, Gonzalvez et al. assessed the safety, tolerability, and antitumor efficacy of mobocertinib in metastatic non-small cell lung cancer patients with epidermal growth factor receptor gene exon 20 insertion mutations. They found that non-small cell lung cancer patients with epidermal growth factor receptor gene exon 20 insertion mutations can benefit from mobocertinib treatment. Additionally, the treatment-related toxicity of mobocertinib was manageable. These findings lay the foundation for the application of mobocertinib in epidermal growth factor receptor gene exon 20 insertion-mutated non-small cell lung cancer.

Poly r(C) binding protein (PCBP) 1 expression is regulated by the E3 ligase UBE4A in thyroid carcinoma.

Thyroid cancer patients with high miR-490-3p inhibit translation of PCBP1 mRNA, whereas in patients with low miR-490-3p PCBP1 mRNA expression is high; however, the resultant protein is targeted for degradation through the proteasome. The objective of the present study was to evaluate the molecular mechanism that regulates post-translation degradation of poly r(C) binding protein (PCBP) 1 expression in thyroid cancer cells. Mass spectrometric analysis of PCBP1 immunoprecipitates from MG-132 treated TPC1 cells revealed a list of ubiquitin ligases associated with PCBP1. RNAi-mediated silencing of the candidate ubiquitin ligases revealed that knockdown of the ubiquitin ligase UBE4A stabilized PCBP1 in TPC1 cells. Concurrent overexpression of the candidate ubiquitin ligases in the normal thyroid epithelial cell line Nthy-ori 3-1 confirmed that ubiquitin conjugation factor E4 A (UBE4A) is the ubiquitin ligase that is degrading PCBP1. Coimmunoprecipitation of HA-tagged PCBP1 in TPC1 cells cotransfected with FLAG-UBE4A revealed robust polyubiquitinated smear of PCBP1, thus confirming UBE4A as the ubiquitin ligase of PCBP1. UBE4A expression mimicked PCBP1 mRNA expression in thyroid cancer patients and was inversely correlated to PCBP1 protein expression. Low UBE4A expression level was associated with a better prognosis in thyroid cancer patients. Our data reveal a post-translational regulatory mechanism of regulating PCBP1 expression in thyroid cancer cells.

Tripterygium wilfordii Inhibiting Angiogenesis for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with a serious pre-vascular inflammatory phase, followed by significant increase in vessel growth. Inhibition of angiogenesis is a novel therapeutic strategy against RA. The Chinese herbal remedy Tripterygium wilfordii, Hook. f. (TwHf) has been reported to be therapeutically efficacious in the treatment of RA. Recent studies have revealed that treatment with TwHf extracts inhibit angiogenesis of RA, thereby elaborately attenuation RA symptom. This review mainly addresses the anti-angiogenesis effect of TwHf in treatment of RA.

Chimeric antibody targeting SRPK-1 in the treatment of non-small cell lung cancer by inhibiting growth, migration and invasion.

Non-small cell lung cancer (NSCLC) is one of the most common types of cancer in humans, and is characterized by rapid growth, migration, invasion and reoccurrence. Evidence has indicated that the protein and mRNA levels of serine­arginine protein kinase­1 (SRPK­1) are upregulated in NSCLC tissues. However, the functions of SRPK1 and targeted therapy for SRPK1 in the progression and treatment of NSCLC remain to be fully elucidated. In the present study, the mRNA and protein expression levels of SRPK­1 in NSCLC cells and tissues were analyzed using reverse transcription­quantitative polymerase chain reaction analysis and SDS­PAGE, and the role of SRPK1 in the progression of NSCLC was investigated. In addition, a chimeric antibody target for SRPK­1 (ChanSRPK­1) was constructed, and the therapeutic effects of ChanSRPK­1 were investigated in H358­bearing mice. The curative effects of ChanSRPK­1 on the inhibition of growth, migration and invasion of NSCLC were also examined in vitro and in vivo. The results revealed that the mRNA and protein levels of SRPK­1 were upregulated in NSCLC cells and tumor tissues. Higher expression of SRPK1 promoted NSCLC cell growth, migration and invasion, whereas lower expression of SRPK­1 suppressed growth, migration and invasion of the NSCLC cells. Animal experiments demonstrated that ChanSRPK­1 inhibited the ß­catenin/T­cell factor complex. ChanSRPK­1 treatment also downregulated the phosphorylation levels of glycogen synthase kinase 3-ß and prolonged the survival of tumor­bearing mice. Taken together, SRPK­1 may offer potential as a therapeutic target oncogenic molecular in NSCLC, and ChanSRPK­1 may be a therapeutic agent with functions as a target and for oncolytic therapy in the treatment of NSCLC.

Long non­coding RNA AB019562 promotes cell proliferation and metastasis in human hepatocellular carcinoma.

Increasing evidence has supported the prognostic and therapeutic values of long non-coding RNAs (LncRNAs) in human tumorigenesis. Hepatocellular carcinoma (HCC), as one of the most refractory diseases, continues to warrant investigation for novel clues to enable early diagnosis. In the present study, the role of LncRNA AB019562 in cell proliferation and metastasis was investigated in HCC. Reverse transcription­quantitative polymerase chain reaction analysis was performed to determine the expression of AB019562 in clinical HCC samples and cultured HCC cells. In addition, a specific small interfering RNA against AB019562 was designed and transfected into HCC cells. A3­(4,5­ dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide assay and a transwell assay were used to assess the effects of AB019562 knockdown on cell proliferation and metastasis, respectively. The results revealed that the expression of AB019562 was increased 4­fold in the clinical HCC tissues, compared with adjacent non­cancerous tissue counterparts. AB019562 was differentially expressed in the HCC cell lines. The knockdown of AB019562 reduced the rate of cell proliferation by 28.6% in HepG2 cells and by 24% in SMMC­7721 cells. Cell cycle assays revealed that the proportion of cells in the G0/G1 phase was significantly increased, whereas those in the S and G2/M phases were decreased in the AB019562­knockdowncells. The results of the transwell assay showed that the knockdown of AB019562 inhibited cell migration abilities by up to 67% in the HepG2 cells and 63% in the SMMC­7721 cells, and significantly suppressed invasive abilities by up to 75% in the HepG2 cells and 60% in the SMMC­7721 cells. Furthermore, AB019562 knockdown increased the apoptotic rates of the two cell lines and activated the expression of caspase­3, but not caspase­8. These data demonstrated the pro­oncogenic properties of AB019562 and suggested that AB019562 may serve as a novel biomarker for the diagnosis and treatment of patients with HCC.

Poly r(C) binding protein (PCBP) 1 expression is regulated at the post-translation level in thyroid carcinoma.

Poly r(C) binding protein (PCBP) 1 or heterogeneous ribonucleoprotein (hnRNP) E1 is a RNA binding protein that plays a vital role in a wide variety of biological processes. PCBP1 has been shown to function as a tumor suppressor by negatively regulating translation of pro-metastatic proteins in different cancers. Loss of PCBP1 expression or its Akt2-mediated phosphorylation at serine 43 residue has both been indicated to de-repress its regulation of EMT inducer proteins. Our previous work has established that PCBP1 functions as a tumor suppressor in thyroid cancer, where its translation is inhibited by microRNA-490-3p. Here we show that thyroid cancer patients can be divided into 2 cohorts based on miR-490-3p expression and PCBP1 mRNA expression-one cohort with high PCBP1 mRNA expression and basal miR-490-3p expression and a second cohort with low PCBP1 mRNA expression and high miR-490-3p expression. However, PCBP1 protein expression is also downregulated in the cohort with high PCBP1 mRNA expression, with expression levels similar to what is observed in patients with the low PCBP1 mRNA expression. Our analysis shows that PCBP1 mRNA is actively translated in patients with high PCBP1 mRNA expression, but that the protein is post translationally degraded by the proteasome machinery. Our results thus elucidate a novel mechanism responsible for down regulation of PCBP1 expression in thyroid cancer. It will be important in future to identify the mechanism that causes degradation of PCBP1 protein and to identify if similar mechanisms are active in other tumors characterized by low PCBP1 protein expression.

Poly r(C) binding protein (PCBP) 1 is a negative regulator of thyroid carcinoma.

Poly r(C) binding protein (PCBP) 1 or heterogeneous ribonucleoprotein (hnRNP) E1 is a RNA binding protein functional in multiple biological processes. PCBP1 has been shown to function as a tumor suppressor by negatively regulating translation of EMT inducer proteins in different cancers. Loss of PCBP1 expression or its Akt2-mediated phosphorylation at serine residue 43 has both been indicated to de-repress its regulation of EMT inducer proteins. However, its role in thyroid carcinoma has not been elucidated. Here we report that PCBP1 expression is significantly downregulated in thyroid carcinoma patients. In vitro kinase assay revealed that immunoprecipitated PCBP1 from transient or stably transfected thyroid carcinoma cells can be phosphorylated by recombinant Akt2 kinase. In situ analysis revealed that PCBP1 is a putative target of miR-490-3p, which was further confirmed by PCBP1 3'UTR-based reporter assays using the wild-type or a miR-490 seed mutant 3'UTR. The endogenous regulation of the PCBP1 3'UTR reporter by miR-490-3p could be rescued by transfection of miR-490 antagomir in WRO and BCPAP cells. Stably overexpressing PCBP1 BCPAP cells attenuated tumor formation completely as compared to empty vector overexpressing cells in xenograft assay. Cumulatively, our results indicate that PCBP1 functions as a tumor suppressor in thyroid carcinoma and that its expression is down regulated by high expression of the miR-490-3p observed in thyroid carcinoma patients.

Role of hypothyroidism in obstructive sleep apnea: a meta-analysis.

OBJECTIVE: This study evaluates the role of hypothyroidism in obstructive sleep apnea (OSA) by comparing the OSA indices in hypothyroid OSA (OSA-HYPOT) with euthyroid OSA (OSA-EUTHY) patients. METHODS: After literature search in several electronic databases and selection of studies by following eligibility criteria, meta-analyses of mean differences/standardized mean differences were performed to compare OSA indices at the time of diagnosis between OSA-HYPOT and OSA-EUTHY patients. Metaregression analyses were carried out to examine the relationship between age, BMI, sample size, and gender vs OSA indices in OSA-HYPOT patients. RESULTS: Twelve studies and five case reports recruiting 192 OSA-HYPOT and 1423 OSA-EUTHY patients were included in the meta-analysis. Prevalence (mean ± SD) of clinical hypothyroidism in OSA patients was 8.12 ± 7.13% and that of subclinical hypothyroidism 11.07 ± 8.49%. Apnea-Hypopnea Index, time of sleep with oxygen desaturation <90%, and Epworth Sleepiness Scale were significantly higher in the OSA-HYPOT patients at diagnosis, whereas there was no significant difference in arousal index, respiratory disturbance index and sleeping efficiency between OSA-HYPOT and OSA-EUTHY patients. Body mass index was positively associated with Apnea-Hypopnea Index in OSA-HYPOT patients. CONCLUSIONS: Hypothyroidism is found to be associated with severity of OSA. However, obesity can be a confounder in the outcomes observed herein.

Analysis for the mechanism between the small cell lung cancer and non-small cell lung cancer combing the miRNA and mRNA expression profiles.

BACKGROUND: We investigated the relationship between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) based on micro ribonucleic acid (miRNA) and messenger (m)RNA expression profiles. METHODS: Utilizing the differentially expressed mRNAs and the targeting miRNAs, the mRNA-miRNA network for the two cancers was constructed. By integrating the miRNA expression profile, drug, and drug targets, miRNA-drug target-drug networks were established and the mechanisms in drug therapy efficacy were compared between SCLC and NSCLC. RESULTS: Drug targets of different expressed miRNAs of SCLC are mainly located in the organelle, act in the electron carrier activity, and consist of the synapse; while drug targets of NSCLC are the membrane-enclosed lumen, mainly distributed in the extracellular region and synapse, and function in the binding. Drug targets of miRNA expressed commonly in the two cancers are involved in the reproduction multi-organism process. In SCLC, the miR-16 in the miRNA-drug target-drug network is significant and follows the result of the mRNA-miRNA network. The pigmentation and rhythmic process of SCLC is different from NSCLC, while the process of cellular component biogenesis and cellular component organization are important for the occurrence of NSCLC. miR-16 in the miRNA-mRNA-drug network of SCLC is significant and we acquired 11 potential drugs, such as dexamethasone and budesonide. The miR-124 for NSCLC is important in the network and 17 potential drugs were screened, including dexamethasone and budesonide. CONCLUSIONS: These findings suggest that miR-16 and miR-124 might be novel diagnostic and prognostics markers for SCLC and NSCLC, respectively.

Meta-analysis of the diagnostic yield and safety of electromagnetic navigation bronchoscopy for lung nodules.

OBJECTIVE: This meta-analysis is to evaluate the overall diagnostic yield and accuracy of electromagnetic navigation bronchoscopy (ENB)-based targeted biopsies in detecting peripheral lesions. METHODS: A systematic search in PubMed was performed using "electromagnetic navigation bronchoscopy" crossed with "peripheral lesions" and "lung nodules". Test performance characteristics with the use of forest plots, summary receiver operating characteristic curves (SROCs) and bivariate random effects were summarized using Meta-Disc software. Adverse events and complications were recorded if reported. RESULTS: A total of 17 studies (1,106 patients with peripheral lung lesions) were included in this analysis. The pooled sensitivity, specificity, positive likelihood ratios (PLRs), negative likelihood ratios (NLRs), and diagnostic odds ratios (DORs) of ENB was 82%, 100%, 19.36, 0.23, and 97.62, respectively. The area under the curve (AUC) for the SROC was 0.9786. No procedure-related complication was found. CONCLUSIONS: ENB is an effective and safe procedure in diagnosing peripheral lung lesions.

A meta-analysis comparing hyperfractionated vs. conventional fractionated radiotherapy in non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality. Non-small cell lung cancer (NSCLC) accounts for most lung cancer and carries a 5-year survival rate of 15%. The squamous cell carcinoma, large cell carcinoma, and adenocarcinoma are the most common types of NSCLC. The data on long term use of hyperfractionated radiotherapy (HRT) in NSCLC treatment is lacking. We performed a meta-analysis, based on published randomized trials to compare HRT [continuous hyperfractionated accelerated radiotherapy (CHART)/continuous hyperfractionated accelerated radiotherapy weekend less (CHARTWEL)] vs. conventional fractionated (CF) radiotherapy in the treatment of NSCLC. METHODS: A systematic search through the bibliographic databases, PubMed, Google Scholar and Cochrane Library was performed till December 2013. RESULTS: Of 63 studies identified, 3 studies were analyzed. All were randomized studies and included 1,005 patients in total. The pooled results of the studies showed that HRT did not improve overall survival (OS) of patients suffering from NSCLC compared to CF after 2 years (OR, 1.29; 95% CI, 0.98-1.71; P=0.16) and 3 years (OR, 0.55; 95% CI, 0.34-0.87; P=0.22) which was statistically significant. HRT was no better than CF in controlling tumour (OR, 1.40; 95% CI, 1.03-1.91). No significant difference in metastasis free survival (OR, 1.08; 95% CI, 0.83-1.39) and late dysphagia (OR, 1.48; 95% CI, 0.75-2.92) were observed between the two groups. CONCLUSIONS: The results of the present meta-analysis showed that HRT was not significantly better to conventional radiotherapy in NSCLC treatment.

Review on anti-tumor effect of triterpene acid compounds.

Recent studies have found that triterpene acid type compounds has many effects including antiinflammatory, regulating blood sugar level, antiviral and antitumor activity. More importantly, triterpene acid type compounds has become one of the most popular topics recently because its selective toxic effects on cancer cells and harmless to normal cells at the same time. This review summarized the antitumor activity and the mechanism of triterpene acid type compounds, providing guideline for further research and development of new antitumor natural products.

Role of traditional Chinese medicine and its chemical components in anti-tumor metastasis.

Tumor incidence has become higher and higher in recent years, and it has also become the first killer jeopardizing human health. Tumor metastasis is the major barrier for tumor treatment. Some metastases occur in 5 or 10 years and some even in 20 years after tumor is controlled, but the metastases are impossible to defend effectively till now. Therefore, controlling tumor metastasis is critical in determining tumor patients' outcomes. In consideration of the limitations, toxicity and side effects of chemotherapeutic drugs for antitumor metastasis at present stage, seeking for drugs among traditional Chinese medicines (TCM) that share high safety and can effectively prevent and control metastasis is being paid more and more attention. This article is to expound the mechanisms of tumor metastasis and summarize the researches on antitumor metastasis with TCM.

Risk factors for dementia in highly educated elderly people in Tianjin, China.

BACKGROUND: Low education level has been thought an important and specific risk factor for dementia. Therefore, we surveyed dementia in a highly educated population in Tianjin, China. METHODS: In total, 1324 old people (aged 55 years and over) in three cluster samples from university communities in Tianjin responded to our survey. Data from psychological tests and dementia questionnaires were analyzed. RESULTS: The prevalence of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) was 4.98%, 2.11%, and 2.27%, respectively. A history of stroke (OR=6.036), lack of fruit (OR=5.489), early parental death (OR=3.102), household financial management (OR=2.638), a history of cardiovascular disease (OR=2.434), a history of hypertension (OR=2.042), physical exercise (OR=2.556), were significantly associated with dementia in a single-factor analysis. Four independent variables were entered in a regression equation: early parental death (OR=6.417), lack of fruit in the diet (OR=3.919), personal stroke history (OR=3.901), and lack of physical exercise (OR=2.220). CONCLUSION: The prevalence of dementia was lower in highly educated elderly people in universities in Tianjin than in the general population. Risk factors for dementia included disease history, living habits, and early parental death, so corresponding interventions are required.

The new concepts on overcoming drug resistance in lung cancer.

Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.

A meta-analysis of the relationship between RARß gene promoter methylation and non-small cell lung cancer.

BACKGROUND: Hypermethylation of CpG islands in tumor suppressor gene plays an important role in carcinogenesis. Many studies have demonstrated that hypermethylation in promoter region of RARß gene could be found with high prevalence in tumor tissue and autologous controls such as corresponding non-tumor lung tissue, sputum and plasma of the NSCLC patients. But with the small number subjects included in the individual studie, the statistical power is limited. Accordingly, we performed this meta-analysis to further asses the relationship of methylation prevalence between the cancer tissue and atuologous controls (corresponding non-tumor lung tissue, sputum and plasma). METHODS: The published articles about RARß gene promoter hypermethyltion were identified using a systematic search strategy in PubMed, EMBASE and CNKI databases. The pooled odds ratio (OR) of RARß promoter methylation in lung cancer tissue versus autologous controls were calculated. RESULTS: Finally, eleven articles, including 1347 tumor tissue samples and 1137 autologous controls were included in this meta-analysis. The pooled odds ratio of RARß promoter methylation in cancer tissue was 3.60 (95%CI: 2.46-5.27) compared to autologous controls with random-effect model. Strong and significant correlation between tumor tissue and autologous controls of RARß gene promoter hypermethylation prevalence across studies (Correlation coefficient 0.53) was found. CONCLUSION: RARß promoter methylation may play an important role in carcinogenesis of the NSCLC. With significant methylation prevalence correlation between tumor tissue and autologous of this gene, methylation detection may be a potential method for searching biomarker for NSCLC.

Network analysis in the identification of special mechanisms between small cell lung cancer and non-small cell lung cancer.

BACKGROUND: To explore the similar and different pathogenesis between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). METHODS: This study used bioinformatics methods, including functional enrichment analysis, compared the topological features of SCLC and NSCLC in the human protein interaction network in a system aspect, and analyzed the highly intense modules from an integrated network. RESULTS: This study included 5082 and 2781 significantly different expression genes for NSCLC and SCLC, respectively. The differently expressed genes of NSCLC are mainly distributed in the extracellular region and synapse. By contrast, the genes of SCLC are located in the organelle, macromolecular complex, membrane-enclosed lumen, cell part, envelope, and synapse. Compared with SCLC, the differently expressed genes of NSCLC act in the biological regulation, multicellular organismal process, and viral reproduction and locomotion, which show that NSCLC is more likely to cause a wide range of cancer cell proliferation and virus infection than SCLC. The network topological properties of SCLC and NSCLC are similar, except the average shortest path length, which indicates that most of the genes of the two lung cancers play a similar function in the entire body. The commonly expressed genes show that all of the genes in the module may also cause NSCLC and SCLC, simultaneously. CONCLUSIONS: The proteins in module will involve the same or similar biological functions and the interactions among them induce the occurrence of lung cancer. Moreover, a potential biomarker of SCLC is the interaction between APIP and apoptotic protease activating factor (APAF)1, which share a common module.

Protective effects of astragalus extract against intermittent hypoxia-induced hippocampal neurons impairment in rats.

BACKGROUND: Intermittent hypoxia is the main pathophysiological cause of the obstructive sleep apnea syndrome. Astragalus shows improvement of spatial learning and memory abilities under intermittent hypoxia. Our study aimed to investigate the protective effect of astragalus against intermittent hypoxia induced-hippocampal neurons impairment in rats and lay the theoretical foundation for the sleep apnea improvement in cognitive function by astragalus. METHODS: Male Wistar rats were divided into 4 groups: blank control group, normoxia group, intermittent hypoxia group and astragalus treated intermittent hypoxia group. After 6-week treatment, apoptosis of neurons was evaluated by terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL) assay. Furthermore, the expression of HIF-1a was detected by real-time reverse transcription polymerase chain reaction (RT-PCR) at the mRNA level as well as by immunohistochemistry (IHC) and Western blotting at the protein level. RESULTS: HPLC analysis indicated that astragaloside IV, astragaloside II and astragaloside I were the main compounds in astragals extract. Astragalus extract reduced the apoptosis of hippocampal neurons (P < 0.05) and decreased the expression of HIF-1a at both the mRNA and protein levels in hippocampus compared with non-treated groups (P < 0.05). CONCLUSION: Astragalus protects against intermittent hypoxia-induced hippocampal neurons impairment in rats.