Apatinib in the treatment of gastric cancer in Henan Province: a multicenter prospective real-world observational study (Ahead-HAP01).

Background: Apatinib is approved in China for the treatment of advanced gastric adenocarcinoma that had progressed or relapsed after standard systemic chemotherapy treatments. However, the effectiveness of Apatinib under real-world condition has not been evaluated and the drug performance under ideal and controlled circumstances has not been validated. In fact, genetic factors, poor healthcare access, social economic status, comorbidities compliance and other factors play significant role in drug performance under "real-world" conditions. Real-world experience can help validate the safety and efficacy of apatinib. Methods: In this observational, prospective study we evaluated the safety and efficacy of Apatinib in patient treated in China. Between March 2018 and March 2019, a total of 943 patients with gastric cancer treated with Apatinib were enrolled. Response Evaluation Criteria in Solid Tumors, version 1.1 and Common Terminology Criteria for Adverse Events, version 4.0 were used to evaluate efficacy and adverse effects. Results: The median progression-free survival (PFS) was 5.65 months (5.22-6.05 months), and the median overall survival (OS) was 11.47 months (10.41-12.52 months). Apatinib in combination with more than two agents was superior to single agent apatinib in overall response rate (ORR) [18.18% vs. 9.43%, 95% confidence interval (CI): 1.03-5.90] and disease control rate (DCR) (82.82% vs. 77.87%, 95% CI: 1.21-2.59). Apatinib in combination with single agent chemotherapy was also superior to apatinib alone with DCR (86.29% vs. 77.87%, 95% CI: 1.47-2.99) irrespective of the dose (250 or 500 mg). In the patient cohort who received a starting dose of 250 mg, the DCRs of the combined treatment and monotherapy groups were 86.22% vs. 80.00% (95% CI: 1.18-3.09), respectively. The most common treatment-emergent adverse events were anemia, anorexia and thrombocytopenia (66.28%, 37.75%, 36.06%, respectively). Conclusions: Efficacy of Apatinib in this observational study is promising and toxicities are manageable. Combination of Apatinib with chemotherapy agents has a higher response rate and better disease control at the expense of increased serious adverse events. Better OS can be achieved by receiving apatinib treatment earlier. As a supplement and further validation of explanatory randomized controlled trials, the real-world study reflects the real efficacy of apatinib in practical application.

Apatinib with etoposide capsules as a third- or further-line therapy for extensive-stage small cell lung cancer: an open-label, multicenter, single-arm phase II trial.

BACKGROUND: Patients with extensive-stage small-cell lung cancer (ES-SCLC) have a particularly poor prognosis. And the treatment options for patients with relapsed or refractory ES-SCLC are limited. Thus, we conducted an open-label, multicenter, single-arm phase II clinical trial to assess the efficacy and safety of apatinib plus etoposide capsules as the third- or further-line treatment in ES-SCLC patients. METHODS: Patients with ES-SCLC who experienced disease progression following 2 to 3 previous therapies from 11 medical centers in China were enrolled to receive apatinib (250 mg/d, continuously) and etoposide capsules (50 mg/d, on day 1-21, per 28 days). The treatment continued until disease progression, treatment intolerance, or death. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. RESULTS: Fifty-six patients with relapsed or refractory ES-SCLC were enrolled from January 2018 to February 2020 and 53 of them were eventually included in the evaluation population. The median follow-up was 9.8 months. At the data cut-off time (March 5, 2020), 39 patients (74%) had died and 44 (83%) had progressed. The median PFS was 3.0 months (95% CI, 2.1-3.9) and the median OS was 5.0 months (95% CI, 3.6-6.4). No complete responses were seen. Eleven patients (21%) showed a best response of partial response and 37 (70%) patients achieved stable disease. The ORR was 20.8% (11/53), and the disease control rate (DCR) was 90.6% (48/53). The 6-month OS rate was 40.1% (95% CI, 26.2-54). After 12 months, the OS rate was 18.4% (95% CI, 4.7-32.1). Possible treatment-related grade III/IV adverse events included leukopenia [8 (15.1%)], neutropenia [7 (13.2%)], anemia [4 (7.4%)], and hand-foot syndrome [2 (3.8%)]. During the study, no mortality occurred as a consequence of treatment. CONCLUSIONS: Apatinib combined with etoposide capsules exhibits efficacy and has an acceptable safety profile. It could be used as a later-line treatment for ES-SCLC patients who have been heavily pretreated with standard therapies. Further exploration of apatinib combined with etoposide capsules in phase III trials is warranted.

Synthesis of BiPO4 by crystallization and hydroxylation with boosted photocatalytic removal of organic pollutants in air and water.

Environmental photocatlytsis has been considered as a promising alternative strategy to address the current environmental threats and pressures. Fabrication of the photocatalysts with high efficiency, stability and bio-safety is the core of photocatalytic applications. Herein, we report a facile approach to synthesize monazite BiPO4 (SHTW) with high crystallization and hydroxylation. The wide bandgap of the SHTW can provide strong redox abilities to produce reactive species and mineralize organic pollutants. Its high crystallinity and dipole moment can promote separation and transportation of the photoexcited electron-hole pairs effectively. In addition, the hydroxylation can produce more highly oxidizing hydroxyl radicals and further improve charge carrier separation. Notably, the hydroxylation can be reborn and the high crystallization can be maintained during photocatalysis. Thus, a virtuous cycle can be established and organic pollutants can be removed efficiently. The mineralization rate of 146.1 µmol g-1 h-1 can be obtained on the SHTW for photocatalytic degradation of benzene, which is about 8.5 times higher than that of the commercial TiO2 (P25). Various dyes, dyes mixture and bisphenol A can all be completely degraded over the SHTW. It shows the potential application and value in environmental governance.

Upregulation of lncRNA SUMO1P3 promotes proliferation, invasion and drug resistance in gastric cancer through interacting with the CNBP protein.

Gastric cancer (GC) is one type of the most common malignancies in the world. In the process of exploring the pathological mechanism of GC and searching for treatment methods, long non-coding RNAs (lncRNAs) display significant participation. Small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) is a newly identified lncRNA, of which the biological role and underlying mechanism in GC progression have not been elucidated. Here, through the comparisons between GC patients' tumor and normal tissue samples, as well as normal gastric mucosal and GC cell lines, we confirmed a significant upregulation of SUMO1P3 in GC tissues and cell lines. Meanwhile, significant upregulation of SUMO1P3 was observed in advanced GC patients, and patients with high level of SUMO1P3 displayed a poor survival rate. Next, gain- and loss-of-function experiments were performed in GC cells, and the results exhibited that SUMO1P3 positively regulated proliferation and invasion of GC cells. Then, we constructed drug-resistant GC cell strains and explore the role of SUMO1P3 in the resistance of GC cells to cisplatin (DDP) and 5-fluorouracil (5-Fu). Finally, bioinformatics analysis and RNA pull-down assay demonstrated that SUMO1P3 could directly interact with cellular nucleic acid binding protein (CNBP), thus positively regulating CNBP downstream oncogenes c-myc and cyclin D1 (CCND1). Our findings indicate that SUMO1P3 promotes proliferation, invasion and drug resistance of GC cells by interacting with CNBP, which reveals a potential prognostic biomarker and a novel therapeutic target for GC.

CASC15 promotes epithelial to mesenchymal transition and facilitates malignancy of hepatocellular carcinoma cells by increasing TWIST1 gene expression via miR-33a-5p sponging.

Long noncoding RNA cancer susceptibility candidate 15 (CASC15) facilitates progression of hepatocellular carcinoma (HCC) cells, but the molecular mechanisms remain unknown. CASC15 co-expressing genes were explored in the Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset. Putative co-expressing genes were analyzed by Gene Ontology and biological pathway enrichment analysis. CASC15 overexpression or knockdown and TWIST1 overexpression or knockdown in HCC cells was achieved by lentiviral transduction or plasmid transfection. Interaction between CASC15 and microRNA-33a-5p (miR-33a-5p) was verified by argonaute 2-RNA Immunoprecipitation (AGO2-RIP) and luciferase reporter assays. HCC cell malignancy was determined by cell proliferation, apoptosis, migration and invasion assays. Tumorigenicity was evaluated by xenograft assay. Epithelial-to-mesenchymal transition (EMT) of HCC cells was assessed by Western blot. TWIST1, sex-determining region Y-related high-mobility group box 4 (Sox4) and Versican were found as putative CASC15 co-expressing genes. CASC15 positively regulated TWIST1 gene expression as well as protein level of Sox4 and Versican in HCC cells. Positive correlation in expression between CASC15 and TWIST1 mRNA was verified in 42 pairs of HCC pathologic and adjacent tissue specimens. CASC15 upregulated TWIST1 gene expression in HCC cells by sponging miR-33a-5p. CASC15 promoted EMT in HCC cells by increasing N-cadherin and Vimentin protein level while decreasing that of E-cadherin through TWIST1. CASC15 facilitated HCC cell proliferation, migration and invasion while reducing cell apoptosis through TWIST1. CASC15 facilitated the tumorigenicity of HCC cells in vivo. a CASC15 could promote EMT and facilitate malignancy of HCC cells by increasing TWIST1 gene expression via miR-33a-5p sponging.

PCAT-1 contributes to cisplatin resistance in gastric cancer through miR-128/ZEB1 axis.

Increasing evidence suggests that dysregulation of long non-coding RNAs (lncRNAs) is implicated with chemoresistance in cancers. However, their function and molecular mechanisms in gastric cancer (GC) chemoresistance remain not well elucidated. In this study, we aimed to investigate the functional role and the underlying molecular mechanism of lncRNA prostate cancer-associated transcript 1 (PCAT-1) in cisplatin (DDP) resistance of GC. Our results revealed that PCAT-1 was up-regulated in DDP-resistant GC tissues and cells. GC patients with high PCAT-1 expression levels had a poor prognosis. Knockdown of PCAT-1 facilitated the sensitivity of DDP-resistant GC cells to DDP. Additionally, PCAT-1 functioned as a sponge of miR-128 in GC cells. Moreover, inhibition of miR-128 reversed the inductive effect of PCAT-1 knockdown on DDP sensitivity of GC cells. In addition, ZEB1 was identified as a target of miR-128, and overexpression of ZEB1 could block the inductive effect of PCAT-1 knockdown on DDP sensitivity of GC cells. Besides, PCAT-1 knockdown enhanced DDP sensitivity in tumors in vivo. In summary, PCAT-1 confers DDP resistance in GC cells through miR-128/ZEB1 axis, providing a promising therapeutic strategy for GC.

Panax notoginseng saponins radiosensitize colorectal cancer cells by regulating the SNHG6/miR-137 axis.

Panax notoginseng saponins (PNS) have recently attracted great attention for their anti-cancer activity in colorectal cancer (CRC). The aim of this study was to explore the functional role and underlying mechanisms of PNS on CRC radiosensitivity. Cell viability was assessed by a Cell Counting kit-8 assay. Cell survival and apoptosis were determined using colony formation assay and flow cytometry, respectively. Quantitative real-time PCR was used to quantify the levels of SNHG6 and miR-137. The targeted correlation between SNHG6 and miR-137 was validated by dual-luciferase reporter and RNA immunoprecipitation assays. Our data supported that PNS weakened the viability of CRC cells. Moreover, PNS promoted the radiosensitivity of CRC cells. Mechanistically, PNS enhanced CRC cell radiosensitivity by upregulating SNHG6. SNHG6 directly targeted miR-137 and inhibited miR-137 expression. MiR-137 was involved in the regulatory effect of SNHG6 on CRC cell radiosensitivity. Furthermore, PNS increased miR-137 expression through SNHG6 in CRC cells. Our study suggested that PNS promoted radiosensitivity in CRC cells at least partly through regulating the SNHG6/miR-137 axis, providing a novel understanding of the anti-cancer mechanism of PNS in CRC.

TUG1 confers cisplatin resistance in esophageal squamous cell carcinoma by epigenetically suppressing PDCD4 expression via EZH2.

BACKGROUND: Increasing evidence has suggested the involvement of long non-coding RNA taurine upregulated gene 1 (TUG1) in chemoresistance of cancer treatment. However, its function and molecular mechanisms in esophageal squamous cell carcinoma (ESCC) chemoresistance are still not well elucidated. In the present study, we investigate the functional role of TUG1 in cisplatin (DDP) resistance of ESCC and discover the underlying molecular mechanism. RESULTS: Our study revealed that TUG1 was up-regulated in DDP-resistant ESCC tissues and cells. High TUG1 expression was correlated with poor prognosis of ESCC patients. TUG1 knockdown improved the sensitivity of ECA109/DDP and EC9706/DDP cells to DDP. Moreover, TUG1 could epigenetically suppress PDCD4 expression via recruiting enhancer of zeste homolog 2. PDCD4 overexpression could mimic the functional role of down-regulated TUG1 in DDP resistance. PDCD4 knockdown counteracted the inductive effect of TUG1 inhibition on DDP sensitivity of ECA109/DDP and EC9706/DDP cells. Furthermore, TUG1 knockdown facilitated DDP sensitivity of DDP-resistant ESCC cells in vivo. CONCLUSION: TUG1 knockdown overcame DDP resistance of ESCC by epigenetically silencing PDCD4, providing a novel therapeutic target for ESCC.