Efficacy and safety of zimberelimab (GLS-010) monotherapy in patients with recurrent or metastatic cervical cancer: a multicenter, single-arm, phase II study.

OBJECTIVE: There is an unmet need to improve clinical outcomes for patients with recurrent/metastatic cervical cancer. Checkpoint inhibitors represent a promising treatment strategy. We evaluated the safety and anti-tumor activity of zimberelimab, an anti-programmed cell death protein-1 antibody, in patients with previously treated, recurrent, metastatic cervical cancer. METHODS: This phase II, single-arm, open-label study used a Simon two-stage minimax design. Eligible patients were women aged 18-75 years with programmed death ligand-1-positive recurrent or metastatic cervical cancer that had progressed after first- or subsequent-line chemotherapy (Eastern Cooperative Oncology Group (ECOG) performance status 0-1). Patients received intravenous zimberelimab (240 mg every 2 weeks) for 2 years until disease progression, intolerable adverse effects, or withdrawal from the study. The primary endpoint was objective response rate assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, by an independent review committee. RESULTS: A total of 105 patients were enrolled. Median age was 51 (range, 31-75) years; 63.8% had an ECOG performance status of 1. The median number of previous treatment lines was 1 (range, 1-4). Median follow-up was 16.9 (range, 16.3-18.4) months. The objective response rate was 27.6%, and the disease control rate was 55.2%. Median duration of response was not reached. Median overall survival was 16.8 months, and median progression-free survival was 3.7 months. The incidence of treatment-related adverse events of any grade was 78.1%, of which the most common were hypothyroidism (26.7%) and anemia (19.0%). CONCLUSION: Zimberelimab monotherapy demonstrated durable anti-tumor activity and an acceptable safety profile in patients with cervical cancer. CLINICAL TRIAL REGISTRATION: NCT03972722.

Alternate-day fasting for the protection of cognitive impairment in c57BL/6J mice following whole-brain radiotherapy.

NLRP3 inflammasome activation is implicated in irradiation-induced cognitive dysfunction. Alternate-day fasting (ADF) has been demonstrated to improve neuroinflammation as a non-pharmacological intervention. However, the exact mechanism and the anti-inflammatory effect in irradiation-induced cognitive dysfunction still need further in-depth study. The present study examined the effects of eight-week ADF on the cognitive functions of mice as well as inflammasome-mediated hippocampal neuronal loss following irradiation in mouse models of irradiation-induced cognitive deficits using seven-week-old male C57BL/6J mice. The behavioral results of novel place recognition and object recognition tasks revealed that ADF ameliorated cognitive functions in irradiation-induced cognitive dysfunction mice. ADF inhibited the expression of components of the NLRP3 inflammasome (NLRP3, ASC, and Cl.caspase-1), the downstream inflammatory factor (IL-1ß and IL-18), and apoptosis-related proteins (caspase-3) via western blotting. Furthermore, an increased number of neurons and activated astrocytes were observed in the hippocampus using immunohistochemistry and Sholl analysis, which was jointly confirmed by western blotting. According to our study, this is the first time we found that ADF improved cognitive dysfunction induced by irradiation, and the anti-inflammatory effect of ADF could be due to inhibition in NLRP3-mediated hippocampal neuronal loss by suppressing astrocyte activation.

ALDH1B1 predicts poor survival for locally advanced nasopharyngeal carcinoma patients.

Background: Distant metastasis and local recurrence remain the major reasons of treatment failure in locally advanced nasopharyngeal carcinoma (NPC). Therefore, exploring novel biomarkers for prognosis and sensitivity of radiotherapy in locally advanced NPC is crucial. This retrospective study evaluates the expression and prognostic value of aldehyde dehydrogenase 1B1 (ALDH1B1) for locally advanced NPC patients. Methods: Sixty-seven locally advanced NPC patients and 22 chronic nasopharyngitis patients between September 2012 to November 2016 at The First Affiliated Hospital of University of South China were enrolled in this study. The expression of ALDH1B1 in tumor tissues were detected by using immunohistochemistry (IHC). Results: Significant difference was observed between NPC groups and Pharyngitis tissues groups, and NPC groups has a higher ratio of high ALDH1B1 expression. ALDH1B1 expression were significantly associated with age and radiotherapy response. The Kaplan-Meier analysis indicated that patients with high ALDH1B1 expression had a poor prognosis both in overall survival (OS) and progression-free survival (PFS). Univariate analysis found that age, radiotherapy response and ALDH1B1 expression were correlated with OS. Besides, factors affecting PFS are radiotherapy response and ALDH1B1 expression. Multivariate analysis revealed that radiotherapy response and ALDH1B1 expression were the independent prognostic factors for OS, whereas radiotherapy response was for PFS. Conclusions: The expression of ALDH1B1 was correlated with age and radiotherapy response. Patients with high ALDH1B1 expression show a poor prognosis both in OS and DFS. ALDH1B1 expression were the independent prognostic factors for OS.

DPYSL2 as potential diagnostic and prognostic biomarker linked to immune infiltration in lung adenocarcinoma.

BACKGROUND: Dihydropyrimidinase like 2 (DPYSL2) has been linked to tumor metastasis. However, the function of DPSY2L in lung adenocarcinoma (LUAD) is yet to be explored. METHODS: Herein, we assessed DPYSL2 expression in various tumor types via online databases such as Oncomine and Tumor Immune Estimation Resource (TIMER). Further, we verified the low protein and mRNA expressions of DPYSL2 in LUAD via the ULCAN, The TCGA and GEPIA databases. We applied the ROC curve to examine the role of DPYSL2 in diagnosis. The prognostic significance of DPYSL2 was established through the Kaplan-Meier plotter and the Cox analyses (univariate and multivariate). TIMER was used to explore DPYSL2 expression and its connection to immune infiltrated cells. Through Gene Set Enrichment Analysis, the possible mechanism of DPYSL2 in LUAD was investigated. RESULTS: In this study, database analysis revealed lower DPYSL2 expression in LUAD than in normal tissues. The ROC curve suggested that expression of DPYSL2 had high diagnostic efficiency in LUAD. The DPYSL2 expression had an association with the survival time of LUAD patients in the Kaplan-Meier plotter and the Cox analyses. The results from TIMER depicted a markedly positive correlation of DPYSL2 expression with immune cells infiltrated in LUAD, such as macrophages, dendritic cells, CD4+ T cells, and neutrophils. Additionally, many gene markers for the immune system had similar positive correlations in the TIMER analysis. In Gene Set Enrichment Analysis, six immune-related signaling pathways were associated with DPYSL2. CONCLUSIONS: In summary, DPYSL2 is a novel biomarker with diagnostic and prognostic potential for LUAD as well as an immunotherapy target. HIGHLIGHTS: 1. Expression of DPYSL2 was considerably lower in LUAD than in normal tissues. 2. Investigation of multiple databases showed a high diagnostic value of DPYSL2 in LUAD. 3. DPYSL2 can independently predict the LUAD outcomes. 4. Immune-related mechanisms may be potential ways for DPYSL2 to play a role in LUAD.

Increased CDCA2 Level Was Related to Poor Prognosis in Hepatocellular Carcinoma and Associated With Up-Regulation of Immune Checkpoints.

Background: Cell division cycle-associated protein 2 (CDCA2) is a member of cell cycle-related proteins. CDCA2 plays a role in the regulation of protein phosphatase 1(PP1) γ-dependent DNA damage response (DDR) and H3 phosphorylation. CDCA2 promotes the tumorigenesis and development of several types of cancers by promoting the proliferation of tumor cells. However, the relationship between CDCA2 expression and the clinicopathological characteristics of hepatocellular carcinoma (HCC) is unknown. Methods: Gene expression information and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. The expression of CDCA2 and its correlation to clinical characteristics in HCC were analyzed. The expression level of CDCA2 was validated in HCC cell lines. The relationship between CDCA2 expression and the survival of patients with HCC was analyzed by using Kaplan-Meier method. The prognostic value of CDCA2 in HCC was estimated by Cox regression analysis. The expression difference of CDCA2 between HCC and normal tissues and its correlation to survival were verified in independent datasets. Gene set enrichment analysis (GSEA) was used to screen the CDCA2-related signaling pathways. Results: Cell division cycle-associated protein 2 expression was upregulated in HCC tissues (p < 0.001) and increased CDCA2 was correlated to increased T stage, pathologic stage, histologic grade, and alpha-fetoprotein (AFP) level (p < 0.001). In addition, CDCA2 was overexpressed in HCC cell lines HepG2 and LM3. High CDCA2 expression level was associated with poor overall survival [hazard ratio (HR) = 1.69; 95% CI, 1.20-1.40, p = 0.003], disease specific survival (HR = 1.73; 95% CI, 1.11-2.71, p = 0.016), and progress free interval (HR = 1.74; 95% CI, 1.30-2.34, p < 0.001). Overexpression of CDCA2 and its correlation to poor survival in HCC were verified in Gene Expression Omnibus (GEO) datasets and Kaplan-Meier plotter database. Increased CDCA2 expression was associated with upregulation of PD-L1 (Spearman's coefficient = 0.207, p < 0.001), PD-L2 (Spearman coefficient's = 0.118, p < 0.05), and CTLA4 (Spearman's coefficient = 0.355, p < 0.001). GSEA showed that homologous recombination pathway, insulin signaling pathway, mitogen-activated protein kinase (MAPK) pathway, mismatch repair pathway, mechanistic target of rapamycin (mTOR) pathway, Notch pathway, T cell receptor pathway, toll like receptor pathway, and WNT pathway were enriched in CDCA2 high expression phenotype. Conclusion: Cell division cycle-associated protein 2 may serve as an independent biomarker for poor prognosis in HCC and increased CDCA2 expression was associated with upregulation of immune checkpoints.

MiR-185-3p regulates epithelial mesenchymal transition via PI3K/Akt signaling pathway by targeting cathepsin D in gastric cancer cells.

BACKGROUND: Recently research reported that miR-185-3p could serve as an independent prognosis factor in gastric cancer (GC). However, the functional role and underlying mechanism of miR-185-3p in GC and epithelial-mesenchymal transition (EMT) progression remains largely elusive. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to analyze the expression of miR-185-3p and cathepsin D in patient-derived GC samples and various GC cell lines. Scratch assay and Transwell assay were used to evaluate the migration ability. The influence of miR-185-3p on the cell cycle distribution and cell apoptosis was evaluated using flow cytometry. Western blotting assay was performed to detect the expression of EMT associated proteins and the activity of PI3K/Akt signaling pathway. Furthermore, the interaction between miR-185-3p and cathepsin D was explored by dual-luciferase reporter assay. RESULTS: Our data revealed that miR-185-3p was down-regulated, while cathepsin D was up-regulated in both patient-derived GC samples and GC cells. Apart from inducing apoptosis, overexpression of miR-185-3p also inhibited EMT process and migration of GC cells. Mechanically, we firstly verified that miR-185-3p directly targeted the cathepsin D. Furthermore, miR-185-3p exerted its function on EMT process and migration via inhibiting cathepsin D to mediated PI3K/Akt signaling pathway. CONCLUSIONS: Our findings suggested that miR-185-3p targeted cathepsin D inhibiting EMT process via PI3K/Akt signaling, which may serve as a potential prognosis factor and therapeutic target to reduce the malignancy of GCs.

Prolactin (PRL), placenta growth factor (PIGF) and nerve growth factor receptor (NGFR) as biomarkers for early diagnosis and prognosis in patients with esophageal squamous cell carcinoma (ESCC).

BACKGROUND: The purpose of this study was to investigate the expression and clinical significance of prolactin (PRL), placenta growth factor (PIGF) and nerve growth factor receptor (NGFR) in esophageal squamous cell carcinoma (ESCC). METHODS: PRL, PIGF and NGFR were selected through being screened normal human and esophageal cancer (EC) plasma by high-throughput protein chips. Subsequently, enzyme linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were used to detect the expression in ESCC and control group. Then, its clinical significance was statistically evaluated. RESULTS: The expression of PRL, PIGF and NGFR in plasma and tissue of patients with EC was higher than healthy controls and adjacent tissue, respectively. Among the clinical parameters, the expression of PRL and NGFR protein was correlated with the tumor classification of ESCC (P<0.05), while PIGF protein was correlated with the clinical stage of ESCC (P<0.05). The area under the ROC (AUC) of PRL, PIGF, and NGFR in plasma was 0.69, 0.72, and 0.66 in separately. Furthermore, the combined detection of three proteins had a better AUC of 0.74 with a sensitivity of 66.7% and a specificity of 72.4%. Kaplan-Meier survival analysis revealed that positive expression of PRL, PIGF and NGFR in histological predicted significantly worse overall survival (OS) than negative expression (P<0.05). CONCLUSIONS: PRL, PIGF and NGFR are promising biomarkers for diagnosis and prognosis prediction of ESCC.

The novel non-immunological role and underlying mechanisms of B7-H3 in tumorigenesis.

B7 homolog 3 (B7-H3) has been proven to be involved in tumorigenesis. An elucidation of its role and underlying mechanisms is essential to an understanding of tumorigenesis and the development of effective clinical applications. B7-H3 is abnormally overexpressed in many types of cancer and is generally associated with a poor clinical prognosis. B7-H3 inhibits the initiation of the "caspase cascade" by the Janus kinase/signal transducers and activators of transcription pathway to resist tumor cell apoptosis. B7-H3 accelerates malignant proliferation by attacking the checkpoint mechanism of the tumor cell cycle through the phosphatidylinositol 3-kinase and protein kinase B pathway. B7-H3 reprograms the metabolism of glucose and lipids and transforms the metabolic flux of tumor cells to promote tumorigenesis. B7-H3 induces abnormal angiogenesis by recruiting vascular endothelial growth factor and matrix metalloproteinase to tumor lesions. B7-H3 strongly promotes tumorigenesis through antiapoptotic, pro-proliferation, metabolism reprogramming, and pro-angiogenesis.

miR-124-3p acts as a potential marker and suppresses tumor growth in gastric cancer.

miR-124-3p has been implicated in a variety of cancers. The purpose of the present study was to investigate the expression, prognostic roles and functions of miR-124-3p in gastric cancer. Functional studies indicated that ectopic overexpression of miR-124-3p in gastric cancer cells suppressed cell viability and plate colony formation in vitro and tumor growth in vivo. In situ hybridization analysis demonstrated that decreased expression of miR-124-3p was associated with clinical stage and lymph node metastasis, as well as shorter overall survival and disease-free survival rates. Furthermore, it was observed that miR-124-3p repressed the carcinogenesis of gastric cancer by targeting Ras-related C3 botulinum toxin substrate 1 (Rac1) and specificity protein 1 (SP1). Collectively, these results indicate a potential underlying mechanism for the regulation of gastric cancer by miR-124-3p involving targeting of Rac1 and SP1. Thus, miR-124-3p may be an independent indicator of survival and treatment strategy for patients with gastric cancer.

Diallyl disulfide inhibits TGF­ß1­induced upregulation of Rac1 and ß­catenin in epithelial­mesenchymal transition and tumor growth of gastric cancer.

Transforming growth factor­ß1 (TGF­ß1) has been demonstrated to promote epithelial­mesenchymal transition (EMT), invasion and proliferation in tumors via the activation of Rac1 and ß­catenin signaling pathways. The present study investigated the effects of diallyl disulfide (DADS) on TGF­ß1­induced EMT, invasion and growth of gastric cancer cells. TGF­ß1 treatment augmented EMT and invasion, concomitantly with increased expression of TGF­ß1, Rac1 and ß­catenin in gastric cancer cells. DADS downregulated the expression levels of TGF­ß1, Rac1 and ß­catenin. DADS, TGF­ß1 receptor inhibitor as well as Rac1 inhibitor antagonized the upregulation of the TGF­ß1­induced expression of these genes, abolishing the enhanced effects of TGF­ß1 on EMT and invasion. Blocking the TGF­ß1 receptor through inhibition resulted in the decreased expression of Rac1 and ß­catenin. Rac1 inhibitor reduced the TGF­ß1­induced ß­catenin expression. In addition, DADS and the aforementioned inhibitors attenuated the TGF­ß1­induced tumor growth and the expression changes of E­cadherin, vimentin, Ki­67 and CD34 in nude mice. These data indicated that the blockage of TGF­ß1/Rac1 signaling by DADS may be responsible for the suppression of EMT, invasion and tumor growth in gastric cancer.

MiR-99a suppresses cell invasion and metastasis in nasopharyngeal carcinoma through targeting HOXA1.

BACKGROUND: Recent studies reported that miRNAs play important roles in the carcinogenesis and progression of nasopharyngeal carcinoma (NPC). Therefore, further studies are warranted to better elucidate the function and mechanism of miRNAs in NPC. METHODS: Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the miR-99a expression in NPC cell lines and tissue samples. Wound healing, transwell migration and invasion, and lung metastatic colonization assays were performed to determine NPC cell migratory, invasive and metastatic abilities of NPC cells. Luciferase reporter assays, quantitative RT-PCR and Western blotting were used to validate the target of miR-99a. RESULTS: We found that miR-99a was significantly downregulated in NPC cell lines and tissue samples. Ectopic overexpression of miR-99a significantly inhibited NPC cell migration and invasion in vitro, and suppressed lung macroscopic and microscopic metastatic colonization in vivo. Conversely, silencing of miR-99a significantly promoted the migratory and invasive abilities of NPC cells. Furthermore, HOXA1 was validated as a direct target of miR-99a, and ectopic expression of HOXA1 could rescue the suppressive effect of miR-99a overexpression on NPC cell migration and invasion. CONCLUSION: Together, these results indicated that miR-99a could inhibit NPC invasion and metastasis by targeting HOXA1, thus providing a novel potential target for miRNA-based treatment for NPC patients in the future.

Identification of potential targets for differentiation in human leukemia cells induced by diallyl disulfide.

Diallyl disulfide (DADS) is a primary component of garlic, which has chemopreventive potential. We previously found that moderate doses (15-120 µM) of DADS induced apoptosis and G2/M phase cell cycle arrest. In this study, we observed the effect of low doses (8 µM) of DADS on human leukemia HL-60 cells. We found that DADS could inhibit proliferation, migration and invasion in HL-60 cells, and arrested cells at G0/G1 stage. Then, cell differentiation was displayed by morphologic observation, NBT reduction activity and CD11b evaluation of cytometric flow. It showed that DADS induced differentiation, reduced the ability of NBT and increased CD11b expression. Likewise, DADS inhibited xenograft tumor growth and induced differentiation in vivo. In order to make sure how DADS induced differentiation, we compared the protein expression profile of DADS-treated cells with that of untreated control. Using high resolution mass spectrometry, we identified 18 differentially expressed proteins after treatment with DADS, including four upregulated and 14 downregulated proteins. RT-PCR and western blot assay showed that DJ-1, cofilin 1, RhoGDP dissociation inhibitor 2 (RhoGDI2), Calreticulin (CTR) and PCNA were decreased by DADS. These data suggest that the effects of DADS on leukemia may be due to multiple targets for intervention.

Overexpression of CXCR4 promotes invasion and migration of non-small cell lung cancer via EGFR and MMP-9.

The aim of the present study was to verify whether overexpression of CXC receptor 4 (CXCR4) promotes the invasion and migration of non-small cell lung cancer (NSCLC) via epidermal growth factor receptor (EGFR) and matrix metallopeptidase-9 (MMP-9), and to detect the association between CXCR4, EGFR and MMP-9. The effects of overexpression of CXCR4 on lung cancer cell functions were investigated by migration and invasion assays. Western blotting and zymograph assays were used to analyze the protein expression levels of EGFR and the production of MMP-9, respectively. Immunohistochemistry was applied to analyze the expression of EGFR, CXCR4 and MMP-9 in NSCLC. Statistical analyses were used to detect the associations among EGFR, CXCR4 and MMP-9 in NSCLC. Finally, survival analyses were performed. CXCR4 overexpression enhanced cell motility and invasion. CXCR4 also promoted expression of EGFR and elevated MMP-9 production. CXCR4, EGFR and MMP-9 were highly expressed in NSCLC, and were not identified as associated with age and sex (P>0.05). However, they were associated with tumor differentiation and lymph node metastasis (P<0.05). CXCR4, EGFR and CXCR4 expression were positively associated with one another in NSCLC (P<0.05). In addition, patients with positive expression of CXCR4, EGFR or MMP-9 in tumors exhibited significantly shorter overall survival compared with those with negative expression (P<0.05). In conclusion, CXCR4 overexpression enhanced cell motility and invasion via EGFR and MMP-9. CXCR4, EGFR and MMP-9 were identified as highly expressed in NSCLC, and there was positive correlation among them.

Pre-treatment serum alkaline phosphatase and lactate dehydrogenase as prognostic factors in triple negative breast cancer.

Background: Serum parameters as prognostic parameters are studied widely. We aim to examine the prognostic significance of the serum alkaline phosphatase (ALP) level and lactate dehydrogenase (LDH) level in triple negative breast cancer (TNBC). Methods: Total of 253 TNBC patients from Sun Yat-sen University Cancer Center who underwent treatment between January 2004 and December 2009 was conducted in this retrospective study. Before treatment serum ALP and LDH levels were routinely measured. We use the receiver operating characteristic (ROC) curve analysis to estimate the cutoff value of serum ALP and LDH levels. The Kaplan-Meier method and multivariable Cox regression analysis were used for Disease free survival (DFS) and overall survival (OS) assessed. Results: The ROC curves determined that the optimum cutoff point for ALP and LDH were 66.5u/L and 160.5u/L, respectively. The elevated ALP and LDH were both significantly associated with decreased DFS and OS (both P < 0.001). In addition, the entire cohort was stratified into three subgroups basis of ALP levels and LDH levels. TNBC Patients who with ALP >66.5 u/L and LDH >160.5u/L had the worst DFS and OS (both P < 0.001). In TNBC patients, univariate and multivariate Cox regression analyses conformed ALP and LDH were independent unfavorable prognostic factors for DFS and OS. Conclusions: The serum levels of ALP and LDH before treatment are independent prognostic parameters and may serve as complement to help predict survival in TNBC.

Pretreatment Hematocrit Is Superior to Hemoglobin as a Prognostic Factor for Triple Negative Breast Cancer.

BACKGROUND: Anemia usually refers to low hemoglobin (Hb) levels. Previous studies indicated that anemia negatively influence the survival in various cancers. Hematocrit (HCT) is the volume percentage of red blood cells in blood, which could indicate anemia in both individuals and populations. This study compared the value of HCT with that of Hb for predicting outcomes of patients who underwent treatment for triple negative breast cancer (TNBC). METHODS: A retrospective study of 293 triple negative breast cancer patients, accepting treatment from January 2004 to December 2009 at Sun Yat-sen University Cancer Center, was conducted. Kaplan-Meier curves and multivariate Cox proportional models were used to calculate disease free survival (DFS) and overall survival (OS). RESULTS: The cut-off value of HCT was 35.9% determined by X-tile software analysis. The cut-off value of Hb was 12.0 g/dl based on the World Health Organization (WHO) criteria. In univariate analysis, low HCT and low Hb were both significantly associated with decreased DFS and OS. In multivariate analysis, HCT (HR: 0.570; 95% CI: 0.331-0.981, P = 0.042 for DFS; HR: 0.456; 95% CI: 0.256-0.813, P = 0.008 for OS) was still identified as independent predictor of outcome, but not Hb. CONCLUSION: Pretreatment low HCT is independently associated with poor prognosis in TNBC patients. However, HCT was found to be superior to Hb in terms of predicting breast cancer mortality. In the future, large-scale prospective studies or validation studies are needed to verify our findings.

Expression and Clinical Significance of Serum Dipeptidyl Peptidase IV Chronic Obstructive Pulmonary Disease.

OBJECTIVE: The purpose of this study is to explore the correlation between serum dipeptidyl peptidase IV (DPPIV) and chronic obstructive pulmonary disease (COPD) at its various disease states, analyze its applications in the prediction and diagnosis of COPD and test the possibility of DPPIV as the serologic marker for COPD screening. MATERIALS AND METHODS: Samples from 74 patients (42 cases with acute exacerbation of COPD or acute exacerbation COPD (AECOPD) and 32 cases with stable COPD) and 29 control subjects were collected in this study. Those patients with AECOPD were classified as COPD remission group if their clinical symptoms relieved after nonintravenous or oral hormone therapy for 7 ± 3 days. DPPIV concentration was measured by enzyme-linked immunosorbent assay, and the difference in serum concentration of DPPIV was compared among different groups. The correlation between DPPIV concentration and age, sex or smoking history was analyzed, and the diagnostic value of DPPIV was evaluated by receiver-operating characteristic (ROC) curve analysis. RESULTS: Serum DPPIV concentration was significantly lower in all COPD groups as compared with that in healthy control group (P < 0.001). Serum DPPIV concentration in AECOPD group was increased after treatment (P < 0.001). There was no significant correlation between DPPIV concentration and age, sex or smoking history (P > 0.05). ROC analysis indicated that serum DPPIV concentration in all groups showed a good diagnostic accuracy, especially in stable COPD and AECOPD groups. The area under the ROC curve values were 0.901 and 0.906, respectively, with a high specificity of 0.931 for both groups and a high sensitivity of 0.75 for stable COPD and 0.875 for AECOPD. CONCLUSIONS: Serum DPPIV concentration in patients with COPD is decreased significantly, and there is no correlation between serum DPPIV concentration and sex or age. Serum DPPIV not only is an independent predictive factor, but also of high value as a good serologic marker for the diagnosis of COPD.

Diallyl disulfide suppresses epithelial-mesenchymal transition, invasion and proliferation by downregulation of LIMK1 in gastric cancer.

Diallyl disulfide (DADS) has been shown to have multi-targeted antitumor activities. We have previously discovered that it has a repressive effect on LIM kinase-1 (LIMK1) expression in gastric cancer MGC803 cells. This suggests that DADS may inhibit epithelial-mesenchymal transition (EMT) by downregulating LIMK1, resulting in the inhibition of invasion and growth in gastric cancer. In this study, we reveal that LIMK1 expression is correlated with tumor differentiation, invasion depth, clinical stage, lymph node metastasis, and poor prognosis. DADS downregulated the Rac1-Pak1/Rock1-LIMK1 pathway in MGC803 cells, as shown by decreased p-LIMK1 and p-cofilin1 levels, and suppressed cell migration and invasion. Knockdown and overexpression experiments performed in vitro demonstrated that downregulating LIMK1 with DADS resulted in restrained EMT that was coupled with decreased matrix metalloproteinase-9 (MMP-9) and increased tissue inhibitor of metalloproteinase-3 (TIMP-3) expression. In in vitro and in vivo experiments, the DADS-induced suppression of cell proliferation was enhanced and antagonized by the knockdown and overexpression of LIMK1, respectively. Similar results were observed for DADS-induced changes in the expression of vimentin, CD34, Ki-67, and E-cadherin in xenografted tumors. These results indicate that downregulation of LIMK1 by DADS could explain the inhibition of EMT, invasion and proliferation in gastric cancer cells.

Identification of potential targets for diallyl disulfide in human gastric cancer MGC-803 cells using proteomics approaches.

Diallyl disulfide (DADS) is characterized as an effective agent for the prevention and therapy of cancer, however, mechanisms regarding its anticancer effects are not fully clarified. In the present study, we compared the protein expression profile of gastric cancer MGC-803 cells subjected to DADS treatment with that of untreated control cells to explore potential molecules regulated by DADS. Using proteomic approaches, we identified 23 proteins showing statistically significant differences in expression, including 9 upregulated and 14 downregulated proteins. RT-PCR and western blot analysis confirmed that retinoid-related orphan nuclear receptor α (RORα) and nM23 were increased by DADS, whereas LIM kinase-1 (LIMK1), urokinase-type plasminogen activator receptor (uPAR) and cyclin-dependent kinase-1 (CDK1) were decreased. DADS treatment and knockdown of uPAR caused suppression of ERK/Fra-1 pathway, downregulation of urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9) and vimentin, and upregulation of tissue inhibitor of metalloproteinase-3 (TIMP-3) and E-cadherin, concomitant with inhibition of cell migration and invasion. Moreover, knockdown of uPAR potentiated the effects of DADS on MGC-803 cells. These data demonstrate that downregulation of uPAR may partially be responsible for DADS-induced inhibition of ERK/Fra-1 pathway, as well as cell migration and invasion. Thus, the discovery of DADS-induced differential expression proteins is conducive to reveal unknown mechanisms of DADS anti-gastric cancer.

Casticin inhibits self-renewal of liver cancer stem cells from the MHCC97 cell line.

Casticin exerts anticarcinogenic activity in several types of cancers, including human hepatocellular carcinoma (HCC). The aim of the present study was to investigate the effects of casticin, which is derived from Fructus Viticis Simplicifoliae, on the self-renewal capacity of liver cancer stem cells (LCSCs) derived from the HCC MHCC97 cell line. The present study demonstrated that casticin significantly inhibited the proliferation of LCSCs from the MHCC97 cell line in a dose-dependent manner (P<0.05), the half maximal inhibitory concentration of the parental cells and LCSCs was 17.9 and 0.5 µmol/l, respectively. Furthermore, casticin reduced the sphere-forming capacity of LCSCs and downregulated ß-catenin protein expression in a concentration-dependent manner. Lithium chloride, an agonist known to activate the Wnt/ß-catenin signaling pathway, attenuated the casticin-induced downregulation of ß-catenin protein expression and inhibited the self-renewal capacity. To the best of our knowledge, the present study is the first to demonstrate that casticin effectively eradicates LCSCs and ß-catenin was identified as the potential target. Thus, casticin may offer a novel therapeutic approach for the treatment of HCC.

Casticin inhibits epithelial-mesenchymal transition of liver cancer stem cells of the SMMC-7721 cell line through downregulating Twist.

The existence of cancer stem cells (CSCs) is central to the pathogenesis and therapeutic target of human hepatocellular carcinoma. The aim of this study was to investigate the effects of casticin on epithelial-mesenchymal transition (EMT) of liver cancer stem cells (LCSCs) derived from the SMMC-7721 cell line. Our results demonstrated that CD133+ sphere-forming cells (SFCs) sorted from the SMMC-7721 cell line not only possessed a higher capacity to form tumor spheroids in vitro, but also had a greater potential to form tumors when implanted in Balb/c-nu mice, indicating that CD133+ SFCs possessed similar traits to LCSCs. Casticin increased the expression levels of E-cadherin and decreased those of N-cadherin in LCSCs. Treatment of LCSCs with casticin for 48 h also decreased the levels of the EMT-associated transcription factor, Twist. Overexpression of Twist attenuated the casticin-induced regulation of E-cadherin and N-cadherin protein expression, as well as the EMT capacity of LCSCs. In conclusion, CD133+ SFCs of the SMMC-7721 cell line may represent a subpopulation of LCSCs with the characteristics of EMT. Furthermore, casticin targeted LCSCs through the inhibition of EMT by downregulating Twist.