Value of tumor size as a prognostic factor in metastatic colorectal cancer patients after chemotherapy: a population-based study.

Aim: To evaluate the relationship between tumor size and survival in metastatic colorectal cancer (mCRC) patients who received chemotherapy. Materials & methods: SEER database was accessed for eligible patients. Multivariate Cox regression analysis was performed to compare the effect of tumor size on overall survival (OS) and CRC-specific survival (CCSS). Results: Tumor size ≥5 cm was an independent risk factor for OS and CCSS in mCRC patients treated with chemotherapy. Tumor size <5 cm did not show a survival advantage in patients whose primary tumor site was rectosigmoid junction, while tumor size ≥5 cm was associated with poor OS and CCSS in left-and right-sided colorectal cancer. Conclusion: Tumor size ≥5 cm was associated with poor prognosis after receiving chemotherapy treatment and a risk factor for survival of mCRC.

Expression of Protein 4.1 Family in Breast Cancer: Database Mining for 4.1 Family Members in Malignancies.

BACKGROUND The protein 4.1 family is a family of cytoskeletal proteins that play an important role in maintaining normal cell morphology and cell adhesion, migration, division, and intercellular signaling. The main aim of this study was to explore the prognostic significance of the protein 4.1 family in breast cancer (BC) patients and to provide new biomarkers and therapeutic targets for the diagnosis and treatment of BC. MATERIAL AND METHODS The expression of 4.1 family members in various tumor types was compared to normal controls using the ONCOMINE and GOBO databases. The prognostic significance of the 4.1 family in BC patients was determined by Kaplan-Meier Plotter. RESULTS EPB41L2 (4.1G) was expressed at higher levels in normal tissues compared with BC patients for all 4.1 family members. In survival analysis, 4.1G and EPB41 (4.1R) mRNA high expressions were associated with better survival in BC patients. Moreover, 4.1G high expression was significantly associated with longer overall survival (OS) in luminal A and protracted relapse-free survival (RFS) in luminal B subtype BC patients who received Tamoxifen treatment. In addition, high expression of each 4.1 family member also showed better prognostic value in different molecular subtypes of BC. CONCLUSIONS These results indicate that the protein 4.1 family can be regarded as novel biomarkers and potential therapeutic targets for BC. Further research is needed to explore the detailed biological functions.

Effects of saponins of patrinia villosa against invasion and metastasis in colorectal cancer cell through NF-κB signaling pathway and EMT.

BACKGROUND: Research has indicated that Herba Patriniae can suppress the growth of Several kinds of tumor cells in vitro and in vivo, thus displaying favorable antitumor activity. However, research regarding the effect of saponins of Patrinia villosa against CRC cell has not been reported. In the current study, We have revealed that the effects of saponins of patrinia villosa on colorectal cancer (CRC) cell invasion and epithelial-mesenchymal transition (EMT) as well as its underlying mechanism. METHODS: The CRC EMT model was induced through repeated TGF-ß1 stimulations on human CRC cell line SW480. Effects of saponins of patrinia villosa at various concentrations on CRC SW480 cell and EMT model cell proliferation were detected using MTT method, so as to select the optimal action concentration. Meanwhile, effects on SW480 cell and EMT model cell invasion were determined through Scratch assay and Transwell assay. Moreover, changes in expression of EMT-related proteins E-cadherin, N-cadherin and NF-ΚBp65 in each group were detected through Western blotting. RESULTS: Saponins of patrinia villosa at various concentrations could markedly inhibit the proliferation rate of CRC cell in an obvious concentration-dependent manner. Meanwhile, saponins of patrinia villosa at various concentrations could also remarkably suppress migration of cell developing EMT. In addition, the protein expression of E-cadherin and N-cadherin was down-regulated with the increase in saponins of patrinia villosa concentration, while that of NF-KBp65 was notably down-regulated. CONCLUSION: Saponins of patrinia villosa can act against tumor invasion and metastasis through inhibiting EMT in human CRC cell line, which may be achieved through down-regulating the NF-κB signaling pathway.

Circular RNA hsa_circ_0051246 acts as a microRNA-375 sponge to promote the progression of gastric cancer stem cells via YAP1.

Background: Gastric cancer (GC) stem cells play an important role in GC progression. Circular RNAs (circRNAs) act as microRNA (miRNA) sponges and inhibit the biological function of miRNAs in GC cytoplasm. MiRNAs also participate in GC progress. circ_0051246 was shown to be associated with miR-375 after analyzing GC microarray data GSE78091 and GSE83521. The oncoprotein Yes-associated protein 1 (YAP1) is targeted by miR-375 and can be inactivated via the Hippo tumor suppressor pathway. Due to insufficient research on circ_0051246, this study aimed to investigate its relationship with miR-375 and YAP1 in cancer stem cells (CSCs). Methods: SGC-7901 CSCs were used to establish knockdown/overexpression models of circ_0051246, miR-375, and YAP1. Malignant phenotypes of CSCs were assessed using Cell Counting Kit 8, colony/sphere formation, 5-Ethynyl-2'-deoxyuridine assay, flow cytometry, Transwell, and wound healing assays. To detect the interactions between circ_0051246, miR-375, and YAP1 in CSCs, a dual-luciferase reporter assay and fluorescence in situ hybridization were performed. In addition, 24 BALB/c nude mice were used to establish orthotopic xenograft tumor models. Four groups of mice were injected with CSCs (1 × 106 cells/100 µL) with circ_0051246 knockdown, miR-375 overexpression, or their respective control cells, and tumor progression and gene expression were observed by hematoxylin-eosin staining, immunohistochemistry. Western blot and quantitative real-time PCR were utilized to examine protein and gene expression, respectively. Results: Circ_0051246 silencing reduced viability, promoted apoptosis, and inhibited proliferation, migration and invasion of CSCs. The functional effects of miR-375 mimics were comparable to those of circ_0051246 knockdown; however, the opposite was observed after miR-375 inhibitors treatment of CSCs. Furthermore, circ_0051246-overexpression antagonized the miR-375 mimics' effects on CSCs. Additionally, YAP1 overexpression promoted CSC features, such as self-renewal, migration, and invasion, inhibited apoptosis and E-cadherin levels, and upregulated the expression of N-cadherin, vimentin, YAP1, neurogenic locus notch homolog protein 1, and jagged canonical notch ligand 1. Conversely, YAP1-silenced produced the opposite effect. Moreover, miR-375 treatment antagonized the malignant effects of YAP1 overexpression in CSCs. Importantly, circ_0051246 knockdown and miR-375 activation suppressed CSC tumorigenicity in vivo. Conclusion: This study highlights the promotion of circ_0051246-miR-375-YAP1 axis activation in GC progression and provides a scientific basis for research on the molecular mechanism of CSCs.

Research of the Active Components and Potential Mechanisms of Qingfei Gujin Decoction in the Treatment of Osteosarcoma Based on Network Pharmacology and Molecular Docking Technology.

Aim: Qingfei Gujin Decoction (QGD) has been shown to be effective against osteosarcoma. This research was aimed at investigating the main active ingredients and potential mechanisms of QGD acting on osteosarcoma through network pharmacology and molecular docking techniques. Methods: The active ingredients and targets of QGD were screened from the TCMSP database, and the predicted targets were obtained from the PharmMapper database. Meanwhile, the targets of osteosarcoma were collected using OMIM, PharmGKB, and DisGeNET databases. Then, GO and KEGG enrichment analyses were performed by RStudio. PPI and drug-ingredient-target networks were constructed using Cytoscape 3.2.1 to screen the major active ingredients, key networks, and targets. Finally, molecular docking of key genes and their regulatory active ingredients was performed using AutoDockTools 1.5.6 software. Results: 38 active ingredients were collected, generating 89 cross-targets; quercetin, luteolin, ß-sitosterol, and kaempferol were the main active ingredients of QGD acting on osteosarcoma, and major signaling pathways such as PI3K-Akt signaling pathway, MAPK signaling pathway, and IL-17 signaling pathway were observed. TP53, SRC, and ESR1 were identified as key proteins that docked well with their regulated compounds. Conclusion: QGD is effective against osteosarcoma through multicomponent, multitarget, and multipathway. This study was helpful for finding effective targets and compounds for osteosarcoma treatment.

Erratum: Jiedu Sangen Decoction Reverses Epithelial-to-mesenchymal Transition and Inhibits Invasion and Metastasis of Colon Cancer via AKT/GSK-3ß Signaling Pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.32873.].

Inhibition to Epithelial-Mesenchymal Transition and Metastatic Potential In Colorectal Cancer Cell By Combination of Traditional Chinese Medicine Formulation Jiedu Sangen Decoction and PD-L1 Inhibitor.

BACKGROUND: Jiedu Sangen Decoction (JSD), a traditional Chinese medicine formula, has been widely applied in the treatment of gastrointestinal cancer, especially in colorectal cancer. Our study mainly aimed to assess the combined efficacy of Jiedu Sangen aqueous extract (JSAE) and a PD-L1 inhibitor (PI) in colon cancer cells migration and invasion, along with epithelial-mesenchymal transition, and then provide deep insights into the potential mechanism. METHODS: We explored the inhibitory effects on invasion and metastasis and the reverse effect on EMT process in CT-26 colon cancer cell via Transwell migration assay, Matrigel invasion assay and confocal laser scanning microscopy. Furthermore, regulation in expression of EMT-related proteins and molecular biomarkers and underlying signal pathway proteins were detected through Western blotting and IHC. RESULTS: The combination of JSD and PD-L1 inhibitor could inhibit migration, invasive ability and EMT of CT-26 cells in a concentration-dependent manner. Meanwhile, JSD combined with PD-L1 inhibitor could also remarkably reverse EMT and metastasis in vivo. In addition, the protein expression of N-cadherin, Slug, Snail, Vimentin was down-regulated along with E-cadherin s up-regulation with the combination of JSD and PD-L1 inhibitor, while that of PI3K/AKT was notably down-regulated. CONCLUSIONS: These findings indicated that JSAE and a PD-L1 inhibitor could drastically inhibit the migration and invasion of colorectal cancer by reversing EMT through the PI3K/AKT signaling pathway.

The Method of Activating Blood and Dredging Collaterals for Reducing Chemotherapy-Induced Peripheral Neuropathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) remains as a big unsolved challenge for cancer patients and oncologists. However, there is no effective treatment to prevent and cure it. This systematic review and meta-analysis chiefly aimed to assess the effectiveness and safety on the method of activating blood and dredging collaterals in traditional Chinese medicine (TCM) for reducing CIPN. METHODS: Two authors comprehensively searched all the randomized controlled trials (RCTs) via PubMed, Cochrane, China National Knowledge Infrastructure (CNKI), and Wanfang Database of China Science Periodical Database (CSPD). The Review Manager (RevMan) 5.0 was used to conduct the meta-analysis. RESULTS: 20 trials including 1481 participants were analyzed. 15 trials tested the incidence of all-grade CIPN which was significantly lower in intervention arm and 16 trails presented that the result of high-grade CIPN was the same. The total effective rate of the use of Chinese herbs was 77.19% versus 45.79% in the comparator group. Besides, the use of Chinese herbs statistically promoted the sensory nerve conduction velocity (SNCV) and the motor nerve conduction velocity (MNCV). Besides, the quality of life (QoL) in the intervention group was better than the comparator one. Herbs-related adverse events were skin allergy, skin chap, and scald, which could be managed well. CONCLUSIONS: The work involving studies of the effectiveness and safety on TCM for reducing CIPN proves to be encouraging. Herbs with the function of activating blood and dredging collaterals were found to potentially promote the curative effects as well as making improvements of SNCV and MNCV. However, in the future, more double-blind, multicenter, large-scale RCTs and more comprehensive researches are still required.

CXCR4 and CXCR3 are two distinct prognostic biomarkers in breast cancer: Database mining for CXCR family members.

CXC chemokine receptors (CXCRs) and chemokines are involved in tissue development and homeostasis, including in cancer development and progression. To date, seven CXCRs have been identified. However, the expression of CXCRs and their influence on the occurrence and development of breast cancer (BC) requires further investigation. In the present study, mRNA expression levels of the seven CXCRs were compared between normal tissues and several cancer types using the Oncomine database. Highly expressed CXCRs were selected and the expression levels of these CXCRs were examined in different subtypes of BC using the Gene Expression­Based Outcome for Breast Cancer database. Finally, the prognostic value of these CXCRs was examined using Kaplan­Meier plotter. It was found that, compared with normal controls, transcripts of CXCR4 and CXCR3 were significantly overexpressed in BC samples compared with other CXCRs. Survival analysis showed that high expression of CXCR4 promoted the recurrence of BC but had no impact on overall survival (OS), while a high level of CXCR3 transcript expression was significantly associated with increased survival in patients with BC. With regards to different subtypes of BC, the present study revealed that high CXCR4 transcript expression was significantly associated with both longer relapse­free survival and OS only in basal­like BC. Furthermore, CXCR4 promoted chemosensitivity in patients with basal­like BC and induced resistance against endocrine therapy for patients with luminal A BC. Thus, CXCR4 and CXCR3 are two distinct prognostic biomarkers and further studies are required.

Jiedu Sangen Decoction Reverses Epithelial-to-mesenchymal Transition and Inhibits Invasion and Metastasis of Colon Cancer via AKT/GSK-3ß Signaling Pathway.

Ethnopharmacology relevance: Jiedu Sangen Decoction (JSD), an empirical prescription of Traditional Chinese Medicine (TCM), has been reported to inhibit invasion and metastasis of colon cancer in our previous study. The aim of this study was to investigate the mechanism of JSD-triggered inhibition of invasion and metastasis in colon cancer. Methods: In vitro, AKT1 knockdown (si-AKT1) or overexpression (oe-AKT1) cells were successfully constructed both in SW480 and SW620 cell lines. Si-AKT1 and oe-AKT1 cells were then treated with or without JSD. Cell invasion, metastasis potential and expression of epithelial-mesenchymal transformation (EMT)-related and AKT1/GSK-3ß proteins were then observed by wound healing, transwell, and western blot assays. In vivo, liver metastasis model mice were developed by inoculating SW480 cells. After JSD diet intervention, living fluorescence imaging and weight measurements were carried out to investigate JSD induced inhibition effects on liver metastasis of colon cancer. Immunohistochemistry and western blot assays were performed to observe tissue features and detect protein expression. Results: Invasion and metastasis potential, as well as EMT of colon cancer, can be markedly inhibited by JSD treatment or AKT1 knockdown, while enhanced by AKT1 overexpression. JSD-induced inhibition effects were significantly weakened when AKT1 was knocked down, while clearly enhanced when AKT1 was overexpressed. Additionally, JSD could lead to an increase in expression of E-cadherin, and a decrease in expression of N-cadherin, Vimentin, p-AKT1, AKT1, p- GSK-3ß, Snail, Slug, and Twist in colon cancer cells. Conclusion: JSD reverses EMT and inhibits invasion and metastasis of colon cancer through the AKT/GSK-3ß signaling pathway.

Association between the overexpression of Her3 and clinical pathology and prognosis of colorectal cancer: A meta-analysis.

BACKGROUND: This study aimed to investigate the association between the overexpression of human epidermal growth factor receptor-3 (Her3) and the clinicopathological parameters and survival of patients with colorectal cancer (CRC). METHODS: Relevant studies on the overexpression of Her3 (measured by immunohistochemistry) and overall survival (OS) in patients with CRC were searched for in PubMed, EMBASE, and Cochrane Library. Published data were extracted and computed into odds ratios (ORs) for assessing the association of Her3 overexpression with tumor differentiation, tumor node metastasis (TNM) stage, position of colon cancer, sex, and age. Prognostic data were computed into hazard ratios (HRs) for OS. RESULTS: Eight studies including 1716 patients with CRC were included in this meta-analysis. The results revealed a significant association between Her3 overexpression and tumor differentiation [OR = 2.38; 95% confidence interval (95% CI): 1.76-3.22; P < .001], TNM tumor stage (OR = 0.71; 95% CI: 0.53-0.96; P = .03), and position of colon cancer (OR = 1.71; 95% CI: 1.28-2.27; P < .001). While patients with Her3 overexpression demonstrated a worse tumor response (OR = 0.31; 95% CI: 0.16-0.60; P < .001) and OS after treatment with cetuximab (HR = 1.86; 95% CI: 1.24-2.79; P = .003), they demonstrated better OS after symptomatic treatment (HR = 0.65; 95% CI: 0.50-0.85; P = .002). Her3 overexpression was not associated with sex (OR = 1.03; 95% CI: 0.83-1.28; P = .79), age (OR = 0.96; 95% CI: 0.75-1.24; P = .77), colon or rectum site (OR = 0.79; 95% CI: 0.44-1.43; P = .44), and total OS (HR = 1.09; 95% CI: 0.69-1.72; P = .72). CONCLUSION: Her3 expression is associated with the clinical pathology and prognosis of CRC, which explains the nonefficacy of cetuximab treatment in patients with CRC.

Jiedu Sangen Decoction Inhibits Migration and Invasion of Colon Cancer SW480 Cells via Suppressing Epithelial Mesenchymal Transition.

Jiedu Sangen Decoction (JSD), a traditional Chinese medicine (TCM) formula, has been widely used in China to treat gastrointestinal cancer, especially as an adjuvant therapy in colorectal cancer (CRC) patients. This study aimed to evaluate the efficacy of JSD and Jiedu Sangen aqueous extract (JSAE) in colon cancer cells and explored the underlining mechanisms by cytotoxicity assay, scratch assay, transwell migration assay, matrigel invasion assay, confocal laser scanning microscopy, and western blot analysis. We demonstrated that JSAE inhibited the growth of colon cancer SW480 cells in a dose-dependent manner and JSAE repressed cancer cell migration and invasion. Furthermore, epithelial mesenchymal transition (EMT) was reversed by JSAE via enhancing E-cadherin expression and attenuating protein levels of EMT promoting factors such as N-cadherin, Slug, and ZEB1. These findings provided the first experimental evidence confirming the efficacy of JSAE in repressing invasion and metastasis of CRC and paving a way for the broader use of JSD in clinic.

[Determination of hydromorphone in Beagle dogs plasma by liquid chromatography-tandem mass spectrometry].

AIM: To establish a LC/MS/MS method for determination of hydromorphone (HYD) in Beagle dog plasma. METHODS: After incubation with beta-glucuronidase for 16 h, an aliquot of 0.1 mL plasma was treated by liquid-liquid extraction. The analytes of interest were separated on a Zorbax SB C8 column with the mobile phase consisting of methanol-water- formic acid (65: 35: 1). Atmospheric pressure chemical ionization source of MS was applied and operated in positive ion mode. RESULTS: The linear calibration curve was obtained in the concentration range of 0.80 - 200.0 microg x L(-1). The lower limit of quantification was 0.80 microg x L(-1). The inter-day and intra-day precision (RSD) was below 6.0%, and the accuracy (RE) was within 1% calculated from QC samples. The method was used to determine the pharmacokinetic parameters of HYD after a single oral administration of 4 mg HYD sustained release tablets to Beagle dogs. CONCLUSION: The method was proved to be specific, sensitive, and suitable for the pharmacokinetic study of HYD sustained release formulation.