Multimechanism biological profiling of tetrahydro-ß-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease.

With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-ß-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD.

Associations of sleep disorders with all-cause and cause-specific mortality in cancer survivors: a cross-sectional analysis of the NHANES 2005-2016.

BACKGROUND: The circadian clock and endoplasmic reticulum stress signaling play important roles in oncogenesis and development of cancer. Sleep disorders have been linked to an elevated risk of mortality in general populations. Nonetheless, the evidence for the sleep disorders-mortality association among cancer patients is limited. We aimed to prospectively investigate the association of sleep disorders with all-cause, cancer, and cardiovascular disease (CVD) mortality among cancer individuals. METHODS: We assessed 3187 participants with cancer from the National Health and Nutrition Examination Survey 2005-2016 cohorts with a median follow-up time of 83.0 months. Multivariable Cox proportional hazards models estimated the adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Multivariable Cox proportional hazards models showed that sleep disorders were associated with a higher risk of all-cause mortality (HR 1.23, 95%CI: 1.06,1.42), cancer mortality (HR 1.30, 95%CI: 1.02, 1.66), and cardiovascular disease mortality (HR 1.35, 95%CI: 1.02, 1.80). After the total group was stratified by gender, the high HRs were observed in men (P < 0.05), not in women. The correlation between sleep disorders and higher long-term mortality was also significant after individuals who died within 2 years of follow-up were excluded, with HR 1.24 (95%CI: 1.07, 1.45) in model I, HR 1.20 (95%CI: 1.02, 1.42) in model II for long-term all-cause mortality, HR (95%CI: 1.00, 1.74) in model I for long-term cancer mortality, and HR 1.5 (95%CI:1.12, 2.02) in model I, HR 1.45 (95%CI: 1.06, 1.99) in model II for long-term CVD mortality. CONCLUSIONS: Sleep disorders were associated with a higher risk of all-cause mortality, cancer mortality, and CVD mortality, as well as long-term mortality in cancer patients. Our finding underlies the importance of screening for sleep disorders for all cancer survivors and the urge to integrate sleep health as an important part of cancer care more effectively. Male individuals may be particularly vulnerable and could benefit from more frequent screening.

Postoperative ctDNA in indicating the recurrence risk and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a potential novel biomarker to predict molecular residual disease (MRD) in lung cancer after definitive treatment. Herein, we investigated the value of ctDNA in prognosing risk of relapse and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer (NSCLC). METHODS: We enrolled 58 NSCLC patients in a real-world setting, and 58 tumor tissues and 325 plasma samples were analyzed. Tumor tissues and plasma samples were subjected to targeted next-generation sequencing (NGS) of 1021 cancer-related and ultra-deep targeted NGS covering 338 genes, respectively. RESULTS: ctDNA was detected in 31.0% of cases at the first postoperative time, which was associated with advanced tumor stage, T stage and KEAP1 or GRIN2A mutations in tissues. ctDNA positivity at landmark and longitudinal indicated the shorter disease-free survival. For patients with ctDNA positivity at the first postoperative time, regardless of adjuvant therapy, all patients who were persistently ctDNA positive during postoperative surveillance had disease recurrence. Among the patients who were ctDNA negative, only two patients (15.4%, 2/13) receiving adjuvant therapy relapsed, while one patient (50.0%, 1/2) without adjuvant therapy relapsed. For the first postoperative ctDNA negative patients, the recurrence rate of patients with adjuvant therapy was and higher than without adjuvant therapy (22.6% [7/31] vs. 11.1% [1/9]). The patients who became ctDNA positive may also benefit from intervention therapy. CONCLUSION: Postoperative ctDNA is a prognostic marker, and ctDNA-detection may facilitate personalized adjuvant therapy, and applying adjuvant therapy to the patients with detectable ctDNA could bring clinical benefits for them.

Impact of cytotoxic T lymphocytes immunotherapy on prognosis of colorectal cancer patients.

Background: Expansion and activation of cytotoxic T lymphocytes (CTLs) in vitro represents a promising immunotherapeutic strategy, and CTLs can be primed by dendritic cells (DCs) loaded with tumor-associated antigens (TAAs) transformed by recombinant adeno-associated virus (rAAV). This study aimed to explore the impact of rAAV-DC-induced CTLs on prognosis of CRC and to explore factors associated with prognosis. Methods: This prospective observational study included patients operated for CRC at Yan'an Hospital Affiliated to Kunming Medical University between 2016 and 2019. The primary outcome was progression-free survival (PFS), secondary outcomes were overall survival (OS) and adverse events. Totally 49 cases were included, with 29 and 20 administered rAAV-DC-induced CTL and chemotherapy, respectively. Results: After 37-69 months of follow-up (median, 54 months), OS (P=0.0596) and PFS (P=0.0788) were comparable between two groups. Mild fever occurred in 2 (6.9%) patients administered CTL infusion. All the chemotherapy group experienced mild-to-moderate adverse effects, including vasculitis (n=20, 100%), vomiting (n=5, 25%), nausea (n=17, 85%) and fatigue (n=17, 85%). Conclusions: Lymphatic metastasis (hazard ratio [HR]=4.498, 95% confidence interval [CI]: 1.290-15.676; P=0.018) and lower HLA-I expression (HR=0.294, 95%CI: 0.089-0.965; P=0.044) were associated with poor OS in the CTL group. CTLs induced by rAAV-DCs might achieve comparable effectiveness in CRC patients compare to chemotherapy, cases with high tumor-associated HLA-I expression and no lymphatic metastasis were more likely to benefit from CTLs.

Clinical and radiomic factors for predicting invasiveness in pulmonary ground­glass opacity.

Patients with preinvasive or invasive pulmonary ground-glass opacity (GGO) often face different clinical treatments and prognoses. The present study aimed to identify the invasiveness of pulmonary GGO by analysing clinical and radiomic features. Patients with pulmonary GGOs who were treated between January 2014 and February 2019 were included. Clinical features were collected, while radiomic features were extracted from computed tomography records using the three-dimensional Slicer software. Predictors of GGO invasiveness were selected by least absolute shrinkage and selection operator logistic regression analysis, and receiver operating characteristic (ROC) curves were drawn for each prediction model. A total of 194 patients with pulmonary GGOs were included in the present study. The maximum diameter of the solid component, waveletHLL_ngtdm_Coarseness (P=0.03), waveletLHH_firstorder_Maximum (P<0.01) and waveletLLH_glrlm_LongRunEmphasis (P<0.01) were significant predictors of invasive lung GGOs. The area under the ROC curve (AUC) for the prediction models of clinical features and radiomic features was 0.755 and 0.719, respectively, whereas the AUC for the combined prediction model was 0.864 (95% CI, 0.802-0.926). Finally, a nomogram was established for individualized prediction of invasiveness. The combination of radiomic and clinical features can enable the differentiation between preinvasive and invasive GGOs. The present results can provide some basis for the best choice of treatment in patients with lung GGOs.

EPHX2 Inhibits Colon Cancer Progression by Promoting Fatty Acid Degradation.

Tumor cells use metabolic reprogramming to keep up with the need for bioenergy, biosynthesis, and oxidation balance needed for rapid tumor division. This phenomenon is considered a marker of tumors, including colon cancer (CRC). As an important pathway of cellular energy metabolism, fatty acid metabolism plays an important role in cellular energy supply and oxidation balance, but presently, our understanding of the exact role of fatty acid metabolism in CRC is limited. Currently, no lipid metabolism therapy is available for the treatment of CRC. The establishment of a lipidmetabolism model regulated by oncogenes/tumor suppressor genes and associated with the clinical characteristics of CRC is necessary to further understand the mechanism of fatty acid metabolism in CRC. In this study, through multi-data combined with bioinformatic analysis and basic experiments, we introduced a tumor suppressor gene, EPHX2, which is rarely reported in CRC, and confirmed that its inhibitory effect on CRC is related to fatty acid degradation.

Retrospective analysis of the efficacy of adjuvant cytokine-induced killer cell immunotherapy combined with chemotherapy in colorectal cancer patients after surgery.

OBJECTIVES: Even though postoperative chemotherapy can eliminate residual tumor cells in patients with colorectal cancer (CRC), severe adversity, weakened immunity and drug resistance are still problems. Adjuvant cytokine-induced killer (CIK) cell therapy is an alternative to CRC patients after surgery. The present study investigated the efficacy of adjuvant CIK cell therapy combined with chemotherapy in postoperative CRC patients. METHODS: This retrospective analysis included 137 postoperative CRC patients, including 71 who received adjuvant chemotherapy alone (control group) and 66 who received adjuvant immunotherapy based on CIK cells combined with chemotherapy (CIT group). RESULTS: Long-term follow-up study indicated that overall survival (OS) and progression-free survival (PFS) were significantly longer in the CIT group than in the control group. Subgroup analyses showed that CIT treatment significantly improved OS and PFS of CRC patients classified as stage II and N0 stage and in patients with primary tumors in the rectum. Increasing the number of CIK infusions resulted in better prognosis. CRC patients aged < 65 years were found to benefit more from CIT-based therapy than patients aged ≥ 65 years. A retrospective case-control study indicated that the primary tumor expression of signalling lymphocytes activating molecule family 7 (SLAMF7) was associated with increased efficacy of CIT treatment. CONCLUSIONS: Adjuvant CIT therapy was an effective therapeutic strategy for postoperative CRC patients prolonging OS and PFS. Patient age, tumor stage and expression of SLAMF7 may be potential indicators of the efficacy of CIT therapy.

[Efficacy of Osimertinib Combined with Bevacizumab in Advanced Non-small Cell 
Lung Cancer Patients with Acquired EGFR T790M Mutation].

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) capable of overcoming non-small cell lung cancer (NSCLC) with EGFR T790M mutation. Although the addition of bevacizumab to 1st generation EGFR-TKIs confers a significant improvement in progression-free survival (PFS) in treatment-naive EGFR mutant NSCLC patients, osimertinib plus bevacizumab combination failed to show prolongation in the phase 2 study WJOG8715L. Data of such combination in Chinese patients are still lacking. This study aimed to explore the efficacy of the addition of bevacizumab to osimertinib as second-line therapy in real-world data, and to evaluate the role of anti-angiogenesis plus osimertinib combination therapeutic strategies in pretreated Chinese NSCLC patients with acquired EGFR T790M mutation. METHODS: A total of 42 advanced NSCLC patients with acquired EGFR T790M mutation after prior EGFR-TKIs treatment were collected between January 2020 to August 2021, with 16 cases treated with osimertinib plus bevacizumab and 26 cases treated with osimertinib. The treatment effect of patients were analyzed. RESULTS: The objective response rate (ORR) in combination group and osimertinib group were 43.8% and 50.0% respectively (P=0.694). No statistically significant difference in median PFS (14.0 mon vs 13.0 mon, P=0.797) and overall survival (OS) (29.0 mon vs 26.0 mon, P=0.544) between the combination group and osimertinib group were observed. Prior history of bevacizumab was identified as an independent predictor of PFS (P=0.045) and OS (P=0.023). CONCLUSIONS: Our study demonstrated that adding bevacizumab to osimertinib could not show advantages in PFS and OS in pretreated NSCLC patients harboring EGFR T790M-mutation.

Clinical and radiological predictors of epidermal growth factor receptor mutation in nonsmall cell lung cancer.

PURPOSE: To determine the prognostic factors of epidermal growth factor receptor (EGFR) mutation status in a group of patients with nonsmall cell lung cancer (NSCLC) by analyzing their clinical and radiological features. MATERIALS AND METHODS: Patients with NSCLC who underwent EGFR mutation detection between 2014 and 2017 were included. Clinical features and general imaging features were collected, and radiomic features were extracted from CT data by 3D Slicer software. Prognostic factors of EGFR mutation status were selected by least absolute shrinkage and selection operator (LASSO) logistic regression analysis, and receiver operating characteristic (ROC) curves were drawn for each prediction model of EGFR mutation. RESULTS: A total of 118 patients were enrolled in this study. The smoking index (P = 0.028), pleural retraction (P = 0.041), and three radiomic features were significantly associated with EGFR mutation status. The areas under the ROC curve (AUCs) for prediction models of clinical features, general imaging features, and radiomic features were 0.284, 0.703, and 0.815, respectively, and the AUC for the combined prediction model of the three models was 0.894. Finally, a nomogram was established for individualized EGFR mutation prediction. CONCLUSIONS: The combination of radiomic features with clinical features and general imaging features can enable discrimination of EGFR mutation status better than the use of any group of features alone. Our study may help develop a noninvasive biomarker to identify EGFR mutation status by using a combination of the three group features.

LINC00501 Inhibits the Growth and Metastasis of Lung Cancer by Mediating miR-129-5p/HMGB1.

BACKGROUND: The function of LINC00501, a long-non-coding RNA (lncRNA), is unclear at present. According to the Cancer Genome Atlas (TCGA), LINC00501 is highly expressed in lung cancer (LC), but whether it can be adopted as a potential therapy target for LC still needs further research. METHODS: The expression of LINC00501 in LC was analyzed based on the TCGA, and a real-time fluorescent quantitative PCR assay was carried out to quantify LINC00501 in non-small-cell lung cancer (NSCLC). Additionally, bioinformatics analysis, luciferase reporter gene technique, and RNA immunoprecipitation (RIP) were employed to analyze the direct interaction between LINC00501 and miR-129-5p, and CCK-8 and Transwell assays and flow cytometry were employed to analyze the effects of LINC00501 on cell proliferation, invasion, and apoptosis. Furthermore, a Western blot assay was carried out to determine the protein level of HMGB1. RESULTS: LINC00501 was highly expressed in LC according to the database, and it was found that LINC00501 was upregulated in NSCLC specimens and cells, and the up-regulation indicated an unfavorable prognosis. Besides, knockdown of LINC00501 hindered the proliferation and invasion of NSCLC cells and intensified their apoptosis, and LINC00501 could be adopted as competitive endogenous RNA to regulate HMGB1 and tumorigenesis through miR-129-5p. CONCLUSION: LINC00501 is overexpressed in LC and the overexpression indicates poor prognosis of patients. In addition, LINC00501 can inhibit the invasion and migration of LC by mediating miR-129-5p/HMGB1.

[Diagnostic Value of Transbronchial Ultrasound-guided Needle Aspiration Biopsy in the Diagnosis of Small Cell Lung Cancer and Non-small Cell Lung Cancer].

BACKGROUND: As a new technique developed in recent years, endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) has the advantages of simple operation, minimal invasive, high accuracy, safety and repeatability. It has become a new standard for lung cancer diagnosis and mediastinal staging. Because small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) have different biological characteristics and treatment methods, it is very important to diagnose and differentiate the types of lung cancer in the early stage of lung cancer for the staging, treatment and prognosis of lung cancer. This article evaluated the accuracy and sensitivity of EBUS-TBNA in the diagnosis of SCLC and NSCLC. METHODS: From January 2012 to December 2018, the clinical data of 85 patients with SCLC and NSCLC who performed EBUS-TBNA in Xuan Wu Hospital CMU were retrospectively analyzed and the differences between the two groups were compared. RESULTS: 45 cases of SCLC were confirmed by immunohistochemistry and pathology. 42 cases of SCLC were diagnosed by EBUS-TBNA. The accuracy and sensitivity of diagnosis were 93.3% (42/45) and 100.0% (42/42), respectively. The positive rate of diagnosis was 48.9% (22/45) in 22 cases diagnosed by cytology, and 40 cases diagnosed by pathology, including 35 cases diagnosed by EBUS-TBNA. The accuracy and sensitivity of diagnosis were 87.5% (35/40) and 100.0% (35/35), respectively. The positive rate of diagnosis was 27.5% (11/40) in 11 cases diagnosed by cytology. The diagnostic sensitivity of EBUS-TBNA in SCLC group was significantly higher than that in NSCLC group (P<0.05). CONCLUSIONS: EBUS-TBNA is more sensitive in the diagnosis of SCLC than NSCLC. As a minimally invasive technique, EBUS-TBNA can assist SCLC in early diagnosis and timely treatment.

[Expression and Clinical Significance of Galcetin-3 in the Serum of Non-small Cell Lung Cancer Patients].

BACKGROUND: Lung cancer is one of the most dangerous diseases to human health, with high morbidity and mortality. It can be cured by surgery at early stage, therefore, the early detection and early treatment of lung cancer are especially important. Serum tumor markers play an important role in the detection and diagnosis of lung cancer. Galectin-3 is known to be expressed in a variety of malignant tumors. This study was to explore the serum levels of Galectin-3 and its clinical significance in non-small cell lung cancer (NSCLC) patients. METHODS: The serum levels of Galectin-3 in peripheral blood were detected by enzyme linked immunosorbent assay (ELISA) in 69 NSCLC patients and 77 cases of healthy control subjects, and compared between the two groups. Then we analyze the correlations between the serum levels of Galectin-3 and the clinical features of lung cancer. RESULTS: The serum levels of Galectin-3 in NSCLC patients were significantly higher than those of healthy control subjects (P<0.01). The serum levels of Galectin-3 with lymph node metastasis were significantly higher than those of patients without lymph node metastasis (P<0.01), and N2 lymph node metastasis had higher levels of serum Galectin-3 than those of N1 lymph node metastasis (P<0.01). Clinical stage III and stage IV patients had higher levels of serum Galectin-3 than those of clinical stage I and clinical stage II (P<0.05). CONCLUSIONS: Our study showed the serum levels of Galectin-3 are highly expressed in NSCLC patients and are significantly related to lymph node metastasis. It may be a potential tumor marker for lung cancer.

Real world study for the concordance between IBM Watson for Oncology and clinical practice in advanced non-small cell lung cancer patients at a lung cancer center in China.

BACKGROUND: IBM Watson for Oncology (WFO) provides physicians with evidence-based treatment options. This study was designed to explore the concordance of the suggested therapeutic regimen for advanced non-small cell lung (NSCLC) cancer patients between the updated version of WFO and physicians in our department, in order to reflect the differences of cancer treatment between China and the United States. METHODS: Retrospective data from 165 patients with advanced NSCLC from September 2014 to March 2018 were entered manually into WFO. WFO recommendations were provided in three categories: recommended, for consideration, and not recommended. Concordance was analyzed by comparing the treatment decisions proposed by WFO with the real treatment. Potential influenced factors were also analyzed. RESULTS: Overall, the treatment recommendations were concordant in 73.3% (121/165) of cases. When two alternative drugs such as icotinib and nedaplatin were included as "for consideration," the total consistency could be elevated from 73.3% to 90.3%(149/165). The logistic regression analysis showed that gender (P = 0.096), ECOG (P = 0.0.502), smoking (P = 0.455), and pathology (P = 0.633) had no effect on consistency, but stages (P = 0.019), including stage ≤III (77.8%, 21/27) and stage IV (93.5%, 129/138) had significant effects on consistency. CONCLUSIONS: In China, most of the treatment recommendations of WFO are consistent with the real world treatment. Factors such as patient preferences, prices, drug approval and medical insurance are also taken into consideration, and they ultimately affect the inconsistency. To be comprehensively and rapidly applied in China, localization needs to be accelerated by WFO.

Treatment options for pulmonary multifocal ground glass opacity type adenocarcinoma: Surgery combine thermal ablation?

OBJECTIVES: To retrospectively analyze the clinical results of the treatment of pulmonary multifocal adenocarcinoma presenting as ground glass opacity (GGO) by surgery and thermal ablation. METHODS: 87 GGO-type pulmonary adenocarcinomas of 48 patients (14 males and 34 females; mean age: 59.7 years old ±9.9, range: 33-79 years old) had been treated from March 2015 to March 2019. Treatment means included 43 wedge resections, 7 segmentectomy, 17 lobectomies, and 20 thermal ablations. The indication selected for treatment means, safety, and local tumor progression rate were evaluated. RESULTS: No operation-related death occurred in all patients. 42 times of surgery were performed and 67 carcinomas were resected in 42 patients. 23 times of single-port Video-assisted thoracoscopic surgery (VATS), 8 times of two-port VATS and 11 times of three-port VATS were performed in total. There were 2 cases of air leak (exceeding 1 week), 1 case of chylothorax and 1 case of massive pleural effusion. Time duration of surgery was between 60 and 300mins (mean: 167mins). Intra-operative blood loss was between 5 and 300 â€‹mL (mean: 44 â€‹mL). Time of chest drainage was between 2 and 23d (mean 4.9d). Chest drainage volume was between 14 and 4633 â€‹mL (mean: 872 â€‹mL). Post-operation LOS (length of stay) was between 3 and 25d (mean: 6.2d). 15 times of thermal ablation were performed (1 case of air leak) and 20 carcinomas were ablated in 14 patients. The ablation time was between 30 and 120min (mean: 43min); post-operation LOS was between 1 and 10d (mean: 3.5d). During the mean follow-up period (16 months â€‹± â€‹13) (range: 5-60 months), no local tumor progression occurred. CONCLUSIONS: Surgery and thermal ablation are safe and effective options for the treatment of pulmonary multifocal GGO-type adenocarcinoma.

[Prognostic and Predictive Value of Thyroid Transcription Factor-1, CD56, P40 and Other Clinical Characteristics in Small Cell Lung Cancer Patients].

BACKGROUND: The aim of this study is to explore roles of thyroid transcription factor-1 (TTF-1), CD56, P40 expression and other clinical characteristics predicting response and survival in patients with small cell lung cancer (SCLC). METHODS: Formalin-fixed, paraffin-embedded biopsy tissues were retrospectively obtained from 198 SCLC patients who were diagnosed first in Xuanwu Hospital. The expressions of TTF-1, CD56 and P40 were detected by immunohistochemistry. The clinical data including age, gender, cancer stage, Eastern Cooperative Oncology Group (ECOG) score, smoking or not, superior vena cava syndrome (SVCS) due to lung cancer or not were collected. Cox proportional hazard model was used to analyze the relationship between the overall survival (OS) and factors. RESULTS: Immunohistochemical staining results showed the positive rate of TTF-1, CD56, P40 were 73.2%, 88.4% and 7.1% respectively. TTF-1 expression (OR=0.665, 95%CI: 0.472-0.937), smoking index ≤400 (OR=1.72, 95%CI: 1.061-2.789) and ECOG=2 (OR=3.551, 95%CI: 2.133-5.914), extensive-stage (OR=2.487, 95%CI: 1.793-3.451) and SVCS due to lung cancer (OR=2.394, 95%CI: 1.49-3.846) were independent prognostic factors for SCLC patients. CONCLUSIONS: Prognosis of SCLC was related to TTF-1 expression independently after adjusting smoking, ECOG score, stage and SVCS due to lung cancer. Detection of TTF-1, CD56 and P40 expression level might be helpful for predict the prognosis of SCLC.
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microRNA-130a is an oncomir suppressing the expression of CRMP4 in gastric cancer.

Gastric cancer is one of the most common causes of death worldwide, although its incidence has steadily declined in recent years. There is strong evidence that aberrantly expressed microRNAs (miRNAs) are involved in gastric cancer tumorigenesis. Furthermore, CRMP4 is closely associated with the occurrence and development of gastric cancer, and our predictions suggest that miR-130a, which can promote gastric cancer tumorigenesis, is a potential CRMP4 regulator. In this study, we investigated the expression of CRMP4 and miR-130a in human gastric cancer cell lines by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB) examination and direct interactions between miR-130a and CRMP4 by dual-luciferase reporter assay. We also evaluated the biological roles of miR-130a and CRMP4 in gastric cancer cells by flow cytometry, MTT assay, soft agar colony formation assay, and Transwell tests and confirmed CRMP4 function in vivo, using a tumor xenograft model. Our results demonstrated that CRMP4 expression was significantly decreased at both the gene and protein levels, while miR-130a expression was notably increased, in five human gastric cancer cell lines compared with human gastric epithelial cells. Dual-luciferase reporter assays indicated that CRMP4 was the direct target of miR-130a. Moreover, an inverse regulatory relationship between miR-130a and CRMP4 was verified by qRT-PCR and WB, and overexpression of miR-130a in BGC823 cells enhanced apoptosis and cell proliferation, arrested the cell cycle in G0/G1, and facilitated cell colony formation, invasion, migration, and adhesion, while upregulation of CRMP4 had opposite effects. Finally, the growth and weight of transplanted tumors derived from BGC823 cells in which CRMP4 was knocked down were remarkably reduced. These data indicate that miR-130a is an oncomir targeting CRMP4 and could be developed as a potential prognostic factor and a novel therapeutic target in gastric cancer.

[Primary Application of Radiofrequency Ablation after Locally Progression of
EGFR-TKIs in Non-small Cell Lung Cancer].

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is one of the foundamental treatment for non-small cell lung cancer (NSCLC) with EGFR mutation, however some patients might develop locally progression in primary site. The aim of this study is to assess the clinical application of radiofrequency ablation after locally progression of NSCLC while receving EGFR-TKIs. METHODS: Twenty-eight eligible NSCLC patients were enrolled. Efficacy and Safety data of radiofrequency ablation followed by EGFR-TKIs or chemotherapy were collected. RESULTS: None of patients had died during peri-operation period. The average follow-up time was 17.25 months. Locally progression rate was 10.7% (3/28), and locally progression time was 16.6 months. The average progression-free survival was (24.55±5.36) (95%CI:14.04-35.05), and the average overall survival was (25.57±5.45)(95%CI:14.88-36.27). Patients were divided into EGFR-TKIs group and chemotherapy group after radiofrequency ablation. The average progression-free survival of the two groups were (27.82±7.58)(95%CI:12.97-42.68) and (17.88±3.76)(95%CI:10.52-25.25)(P>0.05) respectively. The average OS (overall survival) was (29.42±7.68)(95%CI:14.36-44.48) and (18.44±3.87)(95% CI:14.89-36.27)(P>0.05) in two groups. CONCLUSIONS: Radiofrequency ablation combined with EGFR-TKIs or chemotherapy could prolong progression-free survival and overall survival of EGFR mutant NSCLC patients who had developed locally progression in primary site during EGFR-TKIs treatment.

MiR-330-3p inhibits gastric cancer progression through targeting MSI1.

Increasing evidences demonstrated that microRNAs (miRNAs) play critical roles in the human tumor development and progression. In our study, we found that miR-330-3p expression was downregulated in gastric cancer cell lines and tissues. Ectopic expression of miR-330-3p suppressed the gastric cancer cell proliferation, colony formation and migration. Overexpression of miR-330-3p promoted E-cadherin expression and inhibited the expression of N-cadherin, vimentin and snail. We identified Musashi-1 (MSI1) as a direct target gene of miR-330-3p in gastric cancer cell. In addition, MSI1 was upregulated in gastric cancer cell lines and tissues and the MSI1 expression was inversely correlated with miR-330-3p expression in gastric cancer tissues. MiR-330-3p expression was increased in gastric cancer cells after treated with histone deacetylase inhibitor trichostatin A (TSA) and DNA methylation inhibitor 5-aza-CdR (AZA). These indicated that downregulated expression of miR-330-3p was partly mediated by gene promoter region hypermethylation. These results suggested that miR-330-3p acted as a tumor suppressor gene in GC.

Retrospective study of adjuvant icotinib in postoperative lung cancer patients harboring epidermal growth factor receptor mutations.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations occur in about 50% of Asian patients with non-small cell lung cancer (NSCLC). Patients with advanced NSCLC and EGFR mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). This study assessed the efficacy and safety of adjuvant icotinib without chemotherapy in EGFR-mutated NSCLC patients undergoing resection of stage IB-IIIA. METHODS: Our retrospective study enrolled 20 patients treated with icotinib as adjuvant therapy. Survival factors were evaluated by univariate and Cox regression analysis. RESULTS: The median follow-up time was 30 months (range 24-41). At the data cut-off, five patients (25%) had recurrence or metastasis and one patient had died of the disease. The two-year disease-free survival (DFS) rate was 85%. No recurrence occurred in the high-risk stage IB subgroup during the follow-up period. In univariate analysis, the micropapillary pattern had a statistically significant effect on DFS ( P = 0.040). Multivariate logistic regression analysis showed that there was no independent predictor. Drug related adverse events (AEs) occurred in nine patients (45.0%). The most common AEs were skin-related events and diarrhea, but were relatively mild. No grade 3 AEs or occurrences of intolerable toxicity were observed. CONCLUSIONS: Icotinib as adjuvant therapy is effective in patients harboring EGFR mutations after complete resection, with an acceptable AE profile. Further trials with larger sample sizes might confirm the efficiency of adjuvant TKI in selected patients.

LFC131 peptide-conjugated polymeric nanoparticles for the effective delivery of docetaxel in CXCR4 overexpressed lung cancer cells.

CXCR4 is a chemokine receptor which is over expressed in multiple cancers including lung cancers. LFC131 peptide (d-Tyr-Arg-Arg-2-Nal-Gly), an inhibitor of CXCR4-ligand binding, is a low molecular weight CXCR4 antagonist. In this study, we developed novel LFC131 peptide surface conjugated O-carboxymethyl chitosan nanoparticles (O-CMC NP) to target CXCR4 over expressed A549 lung cancer cells. CXCR4-targeted drug delivery system was characterized for its binding, uptake, targeting specificity, and in vitro antitumour effect. Our main goal was to increase the intracellular concentration of docetaxel (DTX) in the cancer cells via a targeted approach. We have reported a nanosized particle with spherical shape and showed a high loading capacity. The CMC NP showed a controlled release pattern and presence of LFC131 did not influence the release of DTX. The fluorescence analysis showed an enhanced cell uptake for targeted NP via CXCR4-LFC131 biological interactions. The receptor-mediated cellular internalization was further confirmed confocal microscopy. The cytotoxicity assays showed enhanced cancer cell death by targeted NPs due to the selective delivery of DTX. Consistent with the cellular uptake analysis, targeted NPs induced a greater caspase-3 activity in A549 cancer cells. LFC/CMC NP exhibited a remarkable cell apoptosis by inducing apoptotic and necrotic cell death. Together, targeted LFC/CMC NP significantly enhanced cancer cell death than compared to non-targeted and free drugs. This kind of targeted nanoplatform which is based on polymeric nanocarriers could further facilitate a treatment protocol for CXCR4 overexpressing A549 lung cancer cells.