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Background Gastric cancer (GC) is an aggressive malignancy with high lethality. Systematic chemotherapy is the main therapeutic strategy for advanced GC patients. The overexpression of Axl is associated with poor prognosis and regulates tumor growth and metastasis in many types of cancer. However, the role of Axl in GC progression remains elusive. Materials and methods Western blot and quantitative real-time PCR assay (RT-PCR) assays were used to detect the expression of Gas6, Axl, ZEB1 and epithelial-mesenchymal transition (EMT)-related markers in GC cells. Cell proliferation was determined by EdU cell proliferation assay and CCK-8 assay. Transwell invasion assay was performed to explore the effect of Axl and ZEB1 on cell invasion. Tumor xenografts and lung metastasis models were conducted to examine the effect of Axl on the growth and lung metastasis of GC cells. Results In our study, we found that high levels of Gas6 and Axl expression were associated with reduced overall survival (OS) in GC patients and the expression of Gas6 and Axl was upregulated in GC cell lines. Ectopic expression of Axl induced EMT and promoted GC cell invasion and proliferation. The knockdown of Axl inhibited EMT and suppressed the proliferation and invasion of GC cell. In vivo study showed that inhibition of Axl impaired tumor growth and lung metastasis of GC cells. Mechanistic investigations revealed that Axl promoted EMT, invasion, and proliferation via upregulating ZEB1 expression in GC cells. Conclusion Our results demonstrated that the Gas6/Axl/ZEB1 signaling pathway regulated EMT, invasion, and proliferation in GC cells and might represent a potential therapeutic target for GC treatment.

Background The aim of this study was to evaluate the efficacy and safety of trastuzumab, combined with the FLOT regimen, in the perioperative treatment of resectable HER-2-positive advanced gastric cancer. Methods Overall, 45 patients were divided into two groups; 29 patients in the experimental group were treated with trastuzumab combined with FLOT and 16 patients in the control group were treated with FLOT alone. The primary endpoint was objective response rate (ORR), and the secondary endpoints were disease control rate (DCR), tumor regression grade (TRG), surgical margin, side effects, and overall survival. Results In the experimental and control groups, ORR was 72.4% and 43.8% (p=0.226), DCR was 89.7% and 87.5%, R0 resection rate was 96.5% and 93.7%, total/subtotal tumor regression grade was 17.2% and 6.3%, partial tumor regression grade was 27.6% and 18.7% (p=0.468), and 2-year survival rate was 78.1% and 73.9% (p=0.932), respectively. The common side effects were agranulocytosis and vomiting. There was no significant difference between the two groups. Conclusion Trastuzumab combined with FLOT has a good curative effect and safety profile in the perioperative treatment of patients with resectable HER-2-positive advanced gastric cancer. In addition, trastuzumab + FLOT had the same result as FLOT alone, as there was no significant benefit with the addition of T in the group studied.

Background Gastrointestinal stromal tumors rarely occur in children, but when they do, their biological behavior and histopathological patterns differ from those of adults. Case presentation A 13-year-old boy with a gastrointestinal stromal tumor was characterized by a rare genetic mutation. The patient complained of “fatigue with intermittent abdominal pain for 1 month”. According to the preoperative imaging examination, gastroscopy, and gastroscopic biopsy, the patient was diagnosed with a gastric stromal tumor. Postoperative pathology showed that the tumor cells were fusiform and ovoid, and mitotic figures were easily seen. Immunohistochemistry revealed that the tumor was S-100(+), SOX10(−), CD34(+), SMA(partially+), DOG-1(+), CD117(+), KI-67 (positive for 20% + of the subjects and 40% + of the hotspots), and SDHB(−). Genetic tests showed missense mutations in ALK and TSC1. With surgical treatment, the tumor was completely removed. The patient recovered well and was discharged on the ninth day after the operation. He is currently under follow-up. Conclusions In this case involving a patient with a gastrointestinal stromal tumor, immunohistochemistry indicated that the tumor was an "SDH-deficient type", and gene detection showed no KIT or PDGFRA mutation but rare ALK and TSC1 mutations, which adds to the knowledge of the types of gene mutations in children with gastrointestinal stromal tumors.

Endoplasmic reticulum (ER) stress is a significant mechanism for chemoresistance to colorectal cancer (CRC) treatment. The RNA-like endoplasmic reticulum kinase (PERK) is critical for ER stress induction. In the present study, we attempted to explore whether PERK activator CCT020312 (CCT) could be effective for CRC treatment, and reveal the underlying mechanisms. We first found that CCT dose- and time-dependently reduced CRC cell proliferation. Importantly, it markedly improved the chemosensitivity of CRC cells that were drug-sensitive or -resistant to taxol treatment, as evidenced by the significantly decreased cell viability. Moreover, CCT at the non-toxic concentration exhibited obviously synergistic effects with taxol to induce apoptosis and cell cycle arrest in G2/M phase in vitro. In addition, we showed that CCT alone considerably induced ER stress in CRC cells through a dose- and time-dependent fashion. Meanwhile, CCT combined with taxol caused significant ER stress through improving phosphorylated PERK, eukaryotic translation initiation factor 2α (eIF2ɑ), C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78). More studies showed that the interaction between PERK and GRP78 was a potential target for CCT to perform its regulatory events. Intriguingly, PERK knockdown markedly abolished the regulatory role of CCT and taxol cotreatments in cell proliferation suppression and apoptosis induction, indicating the importance of PERK for CCT to perform its anti-cancer bioactivity. Our in vivo experiments confirmed that CCT plus taxol dramatically reduced tumor growth in CRC xenografts. Together, all these results suggested that promoting PERK activation by CCT may be an effective therapeutic strategy to improve CRC to taxol treatment.

Background Alpha lipoic acid (α -LA) is a naturally occurring antioxidant and metabolic enzyme co-factor. Recently, α -LA has been reported to inhibit the growth of various cancer cells, but the precise signaling pathways that mediate the effects of α -LA on non-small cell lung cancer (NSCLC) development remain unclear. Methods The CCK-8 assay was used to assess cell proliferation in NSCLC cell lines after α -LA treatment. The expression of growth factor receptor-bound protein 2 (Grb2), cyclin-dependent kinase (CDK)-2, CDK4, CDK6, Cyclin D3, Cyclin E1, Ras, c-Raf, epidermal growth factor receptor (EGFR), ERK1/2 and activated EGFR and ERK1/2 was evaluated by western blotting. Grb2 levels were restored in α-LA-treated cells by transfection of a plasmid carrying Grb2 and were reduced in NSCLC cells via specific siRNA-mediated knockdown. Results α -LA dramatically decreased NSCLC cell proliferation by downregulating Grb2; in contrast, Grb2 overexpression significantly prevented α-LA-induced decrease in cell growth in vitro. Western blot analysis indicated that α-LA decreased the levels of phospho-EGFR, CDK2/4/6, Cyclins D3 and E1, which are associated with the inhibition of G1/S-phase transition. Additional experiments indicated that Grb2 inhibition partially abolished EGF-induced phospho-EGFR and phospho-ERK1/2 activity. In addition, α-LA exerted greater inhibitory effects than gefitinib on NSCLC cells by preventing EGF-induced EGFR activation. Conclusion For the first time, these findings provide the first evidence that α-LA inhibits cell proliferation through Grb2 by suppressing EGFR phosphorylation and that MAPK/ERK is involved in this pathway.

We performed the multi-omic characterization of gastric cancer to detect key molecular features for neoadjuvant chemotherapy., Neoadjuvant chemotherapy is a common treatment for patients with gastric cancer. Although its benefits have been demonstrated, neoadjuvant chemotherapy is underutilized in gastric cancer management, because of the lack of biomarkers for patient selection and a limited understanding of resistance mechanisms. Here, we performed whole-genome, whole-exome, and RNA sequencing on 84 clinical samples (including matched pre- and posttreatment tumors) from 35 patients whose responses to neoadjuvant chemotherapy were rigorously defined. We observed increased microsatellite instability and mutation burden in nonresponse tumors. Through comparisons of response versus nonresponse tumors and pre- versus posttreatment samples, we found that C10orf71 mutations were associated with treatment resistance, which was supported by drug response data and potentially through inhibition of cell cycle, and that MYC amplification correlated with treatment sensitivity, whereas MDM2 amplification showed the opposite pattern. Neoadjuvant chemotherapy also reshapes tumor-immune signaling and microenvironment. Our study provides a critical basis for developing precision neoadjuvant regimens.

The present study aimed to investigate the mechanisms underlying microRNA (miRNA)-mediated regulation of chondrogenic differentiation. Mouse embryo-derived stem cells C3H10T1/2 were cultured and chondrogenic differentiation was induced using transforming growth factor-β3 (TGF-β3). In addition, miRNA expression profiles were detected via miRNA array analysis, and quantitative polymerase chain reaction was performed to verify the differentially expressed miRNAs. Furthermore, bioinformatics software was used to predict the putative targets and the prediction was validated by dual-luciferase reporter assays and western blot analysis. In addition, cell proliferation and glycosaminoglycans were measured by a direct cell count method and alcian blue staining, respectively. Compared with the control group, 86 miRNAs were identified as differentially expressed in TGF-β3-induced cells and the expression levels of 28 miRNAs were increased while the remaining 58 miRNAs exhibited a decline in expression. Amongst the differentially expressed miRNAs, miR-30b expression was observed to have significantly decreased during chondrogenic differentiation. SOX9 is a target gene of miR-30b, and miR-30b inhibits SOX9 expression during chondrogenic differentiation. Furthermore, the alcian blue staining results demonstrated that miR-30b inhibited early chondrogenic differentiation. However, the data of the present study indicated that miR-30b had no influence on C3H10T1/2 cell line proliferation. In conclusion, miR-30b is a key negative regulator of TGF-β3-induced C3H10T1/2 cell chondrogenic differentiation, which functions by directly targeting SOX9.

Robot-assisted minimally invasive surgery becomes more and more popular, but the lack of force sensing for surgical robots restricts the development of this technology. The traditional way to obtain tool-tissue interaction force is to integrate sensors at the end of surgical instruments, which is not well adopted in practical due to high-cost and sterilization problems. It is necessary to explore a sensorless force obtaining method. A model-based force estimation method is proposed in this paper. We studied the structure characteristics of a cable-driven surgical instrument, and built an experimental platform to investigate the friction phenomenon of it. The dynamic model of one jaw is established and the force estimation experiment is conducted. The result shows that the estimation value obtained using the proposed method followed the true value of force.