PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling.

BACKGROUND: Mounting evidences shows that the ubiquitin‒proteasome pathway plays a pivotal role in tumor progression. The expression of 26S proteasome non-ATPase regulatory subunit 9 (PSMD9) is correlated with recurrence and radiotherapy resistance in several tumor types. However, the role and mechanism of PSMD9 in hepatocellular carcinoma (HCC) progression remain largely unclear. METHODS: PSMD9 was identified as a prognosis-related biomarker for HCC based on analysis of clinical characteristics and RNA-seq data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and the JP Project of the International Cancer Genome Consortium (ICGC-LIRI-JP). PSMD9 expression was analyzed in cancer tissues and adjacent noncancerous tissues via immunohistochemistry and Western blotting. Multiple in vivo and in vitro experimental techniques (such as CCK-8, colony formation, EdU, and Transwell assays; flow cytometry; Western blotting; quantitative RT-PCR; Coimmunoprecipitation assay and immunofluorescence confocal imaging) were used to assess the functions of PSMD9 in the pathogenesis of HCC. RESULTS: We found that the expression of PSMD9 was upregulated and associated with a poor prognosis in HCC patients. PSMD9 promoted HCC cell proliferation, migration, invasion and metastasis. Knockdown of PSMD9 significantly inhibited HCC cell proliferation by inducing G1/S cell cycle arrest and apoptosis. Mechanistically, we demonstrated that PSMD9 promoted HCC cell proliferation and metastasis via direct interaction with the E3 ubiquitin ligase c-Cbl, suppresses EGFR ubiquitination, influenced EGFR endosomal trafficking and degradation and subsequently activated ERK1/2 and Akt signaling. In addition, we showed that PSMD9 knockdown sensitized HCC cells to the tyrosine kinase inhibitor erlotinib in vitro and in vivo. CONCLUSIONS: Collectively, our results indicate that PSMD9 drives HCC progression and erlotinib resistance by suppressing c-Cbl mediated EGFR ubiquitination and therefore can be a potential therapeutic target for HCC.

Development of Cu(II) 4-hydroxybenzoylhydrazone complexes that induce mitochondrial DNA damage and mitochondria-mediated apoptosis in liver cancer.

Cisplatin remains the most widely used chemotherapeutic agent in cancer treatment; however, its inherent drawbacks have fueled the development of novel metalloanticancer drugs. In this study, two novel Cu(II) complexes (Cu1 and Cu2) were designed and synthesized. Notably, these Cu(II) complexes showed higher cytotoxicity against HL-7402 cells than cisplatin. Moreover, Cu(II) complexes significantly inhibited liver cancer growth in a xenograft model. A mechanism study revealed that the Cu(II) complexes reduced the mitochondrial membrane potential of cancer cells, produced excessive reactive oxygen species (ROS), induced mitochondrial DNA (mtDNA) damage, and ultimately facilitated cancer cell apoptosis.

m6A reader YTHDF3 is associated with clinical prognosis, related RNA signatures and immunosuppression in gastric cancer.

BACKGROUND: YTHDF3 as a N6-methyladenosine (m6A) reader participates in the development and progression of multiple cancer types, however, the prognosis, molecular biology and immune infiltration of YTHDF3 in gastric cancer (GC) have not been investigated. METHODS: The YTHDF3 expression profile and clinicopathological parameters of stomach adenocarcinoma (STAD) were downloaded from TCGA. The online websites and databases such as GEPIA2, cBioPortal, UALCAN, ImmuCellAl, xCell, TISIDB, GSCA were utilized for analysis of the association of YTHDF3 with STAD, including clinical prognosis, WGCNA and LASSO Cox regression analysis. Further functional assays such as RT-qPCR, Western blot, immunohistochemistry (IHC), immunofluorescence (IF), CCK-8, colony formation, EdU and Transwell assays were performed to determine the role of YTHDF3 in GC. RESULTS: We found that YTHDF3 was upregulated in STAD tissue samples ascribed to its copy number amplification and associated with poor prognosis in patients with STAD. GO and KEGG analyses showed that YTHDF3-related differential genes were predominantly enriched in the proliferation, metabolism and immune signaling pathways. Knockdown of YTHDF3 repressed the growth and invasion of GC cells by inhibition of PI3K/AKT signaling. We then identified YTHDF3-related lncRNAs, miRNAs and mRNAs, and constructed their prognostic signatures in patients with STAD. Moreover, YTHDF3 associated with tumor immune infiltration such as CD8+ T cells, macrophages, Tregs, MHC molecules and chemokines, upregulated PD-L1 and CXCL1 and exerted a response to the immunotherapy in GC. CONCLUSIONS: YTHDF3 upregulation indicates poor prognosis and promotes GC cell growth and invasion by activating PI3K/AKT pathway and regulating immune microenvironment. The established YTHDF3-related signatures highlight the association of YTHDF3 with the clinical prognosis and immune cell infiltration in GC.

Postoperative psychological stress and expression of stress-related factors HSP70 and IFN-γ in patients with early lung cancer.

BACKGROUND: To explore the status of postoperative psychological stress and the expression of stress-related factors heat stress protein 70 (HSP70) and interferon γ (IFN-γ) in patients with early lung cancer, and to provide scientific basis for psychological rehabilitation and index detection of patients with lung cancer. METHODS: Patients with early lung cancer hospitalized in People's Hospital of Rizhao from April 2014 to March 2017 were selected as the research subjects, and a cross-sectional survey research method was used to conduct a questionnaire survey on the research subjects. The questionnaire included General Data Questionnaire and the SCL-90 Self-Assessment Scale for Health Symptoms, which were used to research the postoperative psychological stress of patients with early lung cancer. The enzyme-linked immunosorbent assay was used to detect the serum levels of HSP70 and IFN-γ. RESULTS: A total of 178 patients with early lung cancer were investigated, including 126 males (70.8%) and 52 females (29.2%). There were 52.6% of the patients with mild discomfort, 29.9% with moderate discomfort and 4.8% with severe discomfort, and the positive detection rate of psychological problems was 44.2%. The SCL-90 factors of the patients were higher than the norm, and the average scores of factors including anxiety, horror, somatization, depression, and interpersonal sensitivity were higher (P<0.05). Serum HSP70 expression level was the highest in patients with moderate discomfort of early lung cancer (P<0.05), and the serum IFN-γ expression level decreased with the increased stress level (P<0.05). HSP70 was positively correlated with somatization factors, and negatively correlated with fear factors, and IFN-γ was negatively correlated with the fear factor. CONCLUSIONS: Patients with early lung cancer have extensive postoperative psychological problems, and the timely postoperative psychological intervention is significant. There are differences in the expression levels of stress related factors HSP70 and IFN-γ in patients with different levels of psychological stress, which are of certain clinical value as the monitoring index of response psychological stress.

DDX54 Plays a Cancerous Role Through Activating P65 and AKT Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most malignant cancers, and its incidence is still steadily increasing. The DDX RNA helicase family members have been found to play a role in various cancers; however, the role of DDX54 in colorectal cancer is still unclear and needed to be defined. Here, we found DDX54 was overexpressed in CRC tissues by the label-free mass spectrum, which was also verified in tissue microarray of colon cancer, as well as the CRC cell lines and TCGA database. High DDX54 level was correlated with tumor stage and distant metastasis, which always indicated a poor prognosis to the CRC patients. DDX54 could promote the proliferation and mobility of CRC cells through increasing the phosphorylation level p65 and AKT leading to the tumorigenesis. Here, we have preliminarily studied the function of DDX54 in CRC, which would improve our understanding of the underlying biology of CRC and provide the new insight that could be translated into novel therapeutic approaches.

DNA methylation patterns of SOCS1 gene in peripheral blood identifies risk loci associated with bladder cancer based on principal component analysis.

Bladder cancer (BCa) is a common carcinoma of the urinary tract, which occurs in the bladder mucosa. In recent years, people have recognized that epigenetic changes such as DNA methylation play important roles in the development of BCa but the specific mechanism is unclear. In this study, we detected the methylation rates in the SOCS1 gene of 490 subjects (including 247 patients with BCa and 243 healthy controls) using the MassARRAY EpiTYPER system. Principal component analysis (PCA) was conducted with the aim of identifying common underlying patterns that could explain the largest part of common variance in methylation across units. A logistic regression model was used to assess the relation of SOCS1 methylation patterns with factors related to BCa risk. The methylation rates varied for different CpG units and were significantly different in BCa patients compared to controls. Six principal component factors were extracted by combining initial eigenvalue, explanatory power, and Scree Plot. After adjusting for age, gender, family history of bladder cancer, smoking, and drinking, we observed that Factor 1 (OR=0.051, 95% CI: 0.015-0.178, p<0.001), Factor 2 (OR=0.146, 95% CI: 0.073-0.295, p<0.001), Factor 3 (OR=0.346, 95% CI: 0.198-0.606, p<0.001), and Factor 4 (OR=0.270, 95% CI: 0.135-0.537, p<0.001) were associated with BCa. Based on follow-up results, we found that the 1-, 3-, 5-year survival rates in the hypermethylated group were lower than in the hypomethylated group. We found that several CpG units in methylation patterns were associated with the incidence of BCa showing the important DNA methylation patterns for BCa pathogenesis. Our findings provided new insights into understanding this disease and new potential targets for therapeutic intervention for BCa patients in the future.

Protective effects of valsartan administration on doxorubicin­induced myocardial injury in rats and the role of oxidative stress and NOX2/NOX4 signaling.

Clinical application of doxorubicin (DOX) is hampered by its potential cardiotoxicity, however angiotensin receptor blockers could attenuate DOX­induced cardiomyopathy. The present study tested the hypothesis that simultaneous administration of valsartan (Val) with DOX could prevent DOX­induced myocardial injury by modulating myocardial NAD(P)H oxidase (NOX) expression in rats. Eight­week­old male Sprague­Dawley rats were randomly divided into control (CON), DOX, and DOX+Val groups. After 10 weeks, surviving rats underwent echocardiography examination, myocardial mRNA and protein expression detection of NOX1, NOX2 and NOX4. H9C2 cells were used to perform in vitro experiments, reactive oxygen species (ROS) production and apoptosis were observed under the conditions of down­ or upregulation of NOX2 and NOX4 in DOX­ and DOX+Val­treated H9C2 cells. Cardiac function was significantly improved, pathological lesion and collagen volume fraction were significantly reduced in the DOX+Val group compared with the DOX group (all P<0.05). Myocardial protein and mRNA expression of NOX2 and NOX4 was significantly downregulated in DOX+Val group compared with in the DOX group (all P<0.05). In vitro, ROS production and apoptosis in DOX­treated H9C2 cells was significantly reduced by NOX2­small interfering (si)RNA and NOX4­siRNA, and significantly increased by overexpressing NOX2 and NOX4. To conclude, Val applied simultaneously with DOX could prevent DOX­induced myocardial injury and reduce oxidative stress by downregulating the myocardial expression of NOX2 and NOX4 in rats.

Aberrant Methylation of Suppressor of Cytokine Signaling 1 (SOCS1) Gene as a Biomarker for Early Prediction and Diagnosis of Bladder Cancer.

BACKGROUND: SOCS1 protein, the negative regulatory protein of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway, may inhibit signaling of JAK-STAT pathway by several cytokines and has tumor suppressor activity. Methylation of CpG island in the promoter region of SOCS1 gene has often been shown to inactivate the SOCS1 gene in certain human cancers. However, the precise role of SOCS1 in bladder cancer is unclear. METHODS: Two hundred forty-seven patients with BCa and 243 healthy controls were enrolled from Tumour Hospital Affiliated to Harbin Medical University, Hongqi Hospital Affiliated to Mudanjiang Medical University, and Mudanjiang Tumour Hospital from September 2013 to March 2019. The methylation rate in the promoter region of the SOCS1 among all participants were detected using the MassARRAY EpiTYPER system. A ROC curve was set out to analyze SOCS1 gene promoter CpG island methylation for BCa diagnosis. RESULTS: There was a significantly higher methylation rate in BCa compared to controls. Then we assessed the methylation rate of different CpG islands in SOCS1 gene among BCa cases and normal controls. Methylation rate was shown to vary among different CpG islands. The methylation rates of CpG islands were shown to vary among different grades. We observed that the methylation rate of different CpG islands vary according to pathological grades. CONCLUSIONS: Our study demonstrates that aberrant methylation of CpG island in the promoter region of SOCS1 gene may be involved in occurrence, progression, and prognosis of BCa and, thus, may serve as an independent diagnosis and prognostic biomarker.

Biomineralized nanosilica-based organelles endow living yeast cells with non-inherent biological functions.

We propose a biomimetic strategy to construct engineered yeast cells (EYCs) by building intracellular silica nanoscaffolds as biomimetic organelles. These nanosilica-based organelles can coordinate with loaded drug and yeast as a shell could prevent drug leakage. In vivo results show that EYCs serve as a dually responsive drug delivery system, targeted with extracellular caps (folate) and triggered by intracellular SiO2 at the low pH of cancer tissue.

Activated hepatic stellate cells promote angiogenesis in hepatocellular carcinoma by secreting angiopoietin-1.

Angiogenesis is the central pathological process in hepatocellular carcinoma (HCC), and its progression is affected by tumor cells and the microenvironment. Activated hepatic stellate cells (aHSCs) are the most significant stromal cells involved in HCC. This study was aimed to explore the effects and mechanisms of aHSCs on angiogenesis in HCC. We isolated primary hepatoma cells, aHSCs, and hepatic vascular endothelial cells from human HCC samples. Then, we performed a novel in vitro assay and in vivo experiment in a nude mouse HCC model to investigate the functions of aHSCs on angiogenesis in HCC. Our results demonstrated that aHSCs are the primary sources of angiopoietin-1 (Ang-1) in human HCC in vitro, and aHSCs could promote hepatic vascular endothelial cell (HVEC) growth by secreting Ang-1. Furthermore, aHSCs could induce HVEC microtubule formation, and this ability was reduced when Ang-1 expression was silenced in aHSCs. In addition, CD34 expression in a nude mouse HCC model was downregulated when Ang-1 messenger RNA was silenced in aHSCs. Our data also indicated that HSC Ang-1 expression could be inhibited by overexpressing Raf kinase inhibitor protein. Therefore, we suggest that aHSCs promote angiogenesis through secreting Ang-1, potentially providing an interesting target for antiangiogenic therapies for HCC.

Association of upper airway surgery and improved cardiovascular biomarkers and risk in OSA.

OBJECTIVES: To evaluate the association between upper airway surgery and changes of cardiological metabolic biomarkers and the overall cardiovascular risk in obstructive sleep apnea (OSA), and to define factors associated with better cardiovascular outcomes. METHODS: A total of 161 patients with newly diagnosed OSA who underwent classical or modified uvulopalatopharyngoplasty with or without genioglossus advancement and hyoid suspension were included. The pre- and postoperative (at least 6 months later) assessments, including polysomnography, measurement of glucose and lipids, blood pressure, and overall cardiovascular risk (as estimated by Framingham Risk Scores), were compared. We accounted for multiple comparisons with the use of the Benjamini-Hochberg correction. RESULTS: The mean follow-up time was 2.5 ± 1.9 years. The apnea hypopnea index decreased significantly in the entire cohort (mean changes with 95% confidence intervals were [-25.3 (-29.5, -21.0) events/hour, P < 0.001]. We also noted decreases in the age-adjusted Framingham Risk Scores [-2.5% (-4.0%, -1.0%), P < 0.001] as well as single cardiometabolic biomarkers, including glucose [-0.50 (-0.70, -0.30) mmol/L, P < 0.001], total cholesterol [-0.46 (-0.65, -0.28) mmol/L, P < 0.001], triglycerides [-0.56, (-0.99, -0.14) mmol/L, P = 0.014], low-density lipoprotein cholesterol [-0.27, (-0.43, -0.11) mmol/L, P = 0.002], apolipoprotein B [-0.10 (-0.14, -0.07) g/L, P < 0.001], systolic blood pressure [-3.58 (-6.02, -1.14) mmHg, P = 0.007], and diastolic blood pressure [-3.25 (-5.47, -1.02) mmHg, P = 0.008] after surgery. Patients with preoperative metabolic abnormalities exhibited better postoperative risk profiles changes (P < 0.001). In addition, associations were found between Δapolipoprotein B, Δsystolic blood pressure, and improvements in nocturnal oxygen level after surgery. CONCLUSION: OSA-related upper airway surgery was associated with improvements in cardiological metabolic biomarker levels and the overall cardiovascular risk, especially in patients with both OSA and metabolic disorders. The changes in biomarker levels may be associated with improved oxygen saturation after surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:818-824, 2020.

Efficacy of Compounds Isolated from Streptomyces olivaceus against the Morphogenesis and Virulence of Candida albicans.

Candida albicans is a type of commensal fungi which causes serious infections in immunocompromised patients and contributes to high mortality. In the present study, we identified that the extract from Streptomyces olivaceus SCSIO T05 inhibited hypha and biofilm formation of C. albicans. Seven compounds were isolated and evaluated for their effects on the biological functions and virulence of C. albicans. Two leading compounds, compound 1 (sorbicillin) and compound 2 (3-methyl-N-(2'-phenethyl)-butyrylamide) were identified as exhibiting strong activity against C. albicans morphological transition, adhesion activity, cytotoxicity, and adhesion to human cells, in a dose-dependent manner. Notably, compound 2 inhibited C. albicans infection in mouse oral mucosal models. Transcriptomic analysis and real-time PCR results revealed that compound 2 most likely inhibited the biological functions of C. albicans cells by regulating the expression levels of HWP1, TEC1, ALS1, IFD6, and CSH1, which are associated with filament formation and cell adhesion. Our results suggest that the candidate compounds present excellent efficacy against C. albicans pathogenicity and that they can be developed as potential options for the clinical treatment of candidiasis.

The Relationship between Simple Snoring and Metabolic Syndrome: A Cross-Sectional Study.

PURPOSE: This cross-sectional study was performed to assess the relationship between simple snoring and metabolic syndrome (MetS). METHODS: A total of 5635 participants including 300 healthy volunteers without snoring allegedly were initially included from 2007 to 2016. Polysomnographic variables, anthropometric measurements, and biochemical indicators were collected. The polynomial linear trend test was used to assess the linear trend across snoring intensity for metabolic score, and logistic regression was used to evaluate the odds ratios (ORs) for MetS after controlling for age, sex, obesity, smoking status, and alcohol consumption. RESULTS: The final study population consisted of 866 participants. Simple snorers showed more severe metabolic disorders and higher prevalence of MetS than nonsnorers. A significant linear trend was observed between snoring intensity and metabolic score. Simple snoring was significantly associated with increased odds for MetS among all participants (OR = 2.328, 95% CI: 1.340-4.045) and female participants (OR = 2.382, 95% CI: 1.136-4.994) after multivariable adjustment. With regard to MetS components, simple snoring was significantly associated with increased odds for hypertension (OR = 1.730, 95% CI: 1.130-2.650), abdominal obesity (OR = 1.810, 95% CI: 1.063-3.083), and hyper-triglycerides (TG) (OR = 1.814, 95% CI: 1.097-2.998) among all participants, with hypertension (OR = 3.493, 95% CI: 1.748-6.979) among males and with abdominal obesity (OR = 2.306, 95% CI: 1.245-4.270) and hyper-TG (OR = 2.803, 95% CI: 1.146-6.856) among females after multivariable adjustment. CONCLUSIONS: After excluding the influence of repeated apnea and hypoxia, simple snoring was still significantly associated with MetS, especially in women. Furthermore, the associations were more obvious for hypertension among males and for abdominal obesity and hyper-TG among females. In addition to OSA, simple snoring also should be valued.

Effect of the Interaction between Obstructive Sleep Apnea and Lipoprotein(a) on Insulin Resistance: A Large-Scale Cross-Sectional Study.

Both obstructive sleep apnea (OSA) and decreased serum lipoprotein(a) (Lp(a)) concentrations are associated with insulin resistance. However, their interaction effect on insulin resistance has never been investigated. Therefore, we performed a cross-sectional study on OSA-suspected Chinese Han participants. Laboratory-based polysomnographic variables, biochemical indicators, anthropometric measurements, and medical history were collected. Linear regression and binary logistic regression analyses with interaction terms were used to investigate the potential effects of the interaction between the severity of OSA (assessed by the apnea-hypopnea index (AHI)) and Lp(a) concentrations on insulin resistance (assessed by the homeostasis model assessment of insulin resistance (HOMA-IR)), after adjusting for potential confounders including age, gender, body mass index, waist-to-hip circumference ratio, mean arterial pressure, smoking status, drinking status, and lipid profiles. A total of 4,152 participants were enrolled. In the OSA-suspected population, AHI positively correlated with insulin resistance and serum Lp(a) concentrations independently and inversely correlated with insulin resistance. In addition, the interaction analysis showed that the linear association between lgAHI and lgHOMA-IR was much steeper and more significant in subjects with relatively low Lp(a) concentrations, suggesting a significant positive interaction between lgLp(a) and lgAHI on lgHOMA-IR (P = 0.013). Furthermore, the interaction on a multiplicative scale also demonstrated a significant positive interaction (P = 0.044). A stronger association between AHI quartiles and the presence of insulin resistance (defined as HOMA-IR > 3) could be observed for participants within lower Lp(a) quartiles. In conclusion, a significant positive interaction was observed between OSA and decreased Lp(a) with respect to insulin resistance. This association might be relevant to the assessment of metabolic or cardiovascular disease risk in OSA patients.

Inhibition of Yeast-to-Hypha Transition and Virulence of Candida albicans by 2-Alkylaminoquinoline Derivatives.

A rapid increase in Candida albicans infection and drug resistance has caused an emergent need for new clinical strategies against this fungal pathogen. In this study, we evaluated the inhibitory activity of a series of 2-alkylaminoquinoline derivatives against C. albicans isolates. A total of 28 compounds were assessed for their efficacy in inhibiting the yeast-to-hypha transition, which is considered one of the key virulence factors in C. albicans Several compounds showed strong activity to decrease the morphological transition and virulence of C. albicans cells. The two leading compounds, compound 1 (2-[piperidin-1-yl]quinolone) and compound 12 (6-methyl-2-[piperidin-1-yl]quinoline), remarkably attenuated C. albicans hyphal formation and cytotoxicity in a dose-dependent manner, but they showed no toxicity to either C. albicans cells or human cells. Intriguingly, compound 12 showed an excellent ability to inhibit C. albicans infection in the mouse oral mucosal infection model. This leading compound also interfered with the expression levels of hypha-specific genes in the cyclic AMP-protein kinase A and mitogen-activated protein kinase signaling pathways. Our findings suggest that 2-alkylaminoquinoline derivatives could potentially be developed as novel therapeutic agents against C. albicans infection due to their interference with the yeast-to-hypha transition.

Low serum gastrin associated with ER+ breast cancer development via inactivation of CCKBR/ERK/P65 signaling.

BACKGROUND: Gastrin is an important gastrointestinal hormone produced primarily by G-cells in the antrum of the stomach. It normally regulates gastric acid secretion and is implicated in a number of human disease states, but how its function affects breast cancer (BC) development is not documented. The current study investigated the suppressive effects of gastrin on BC and its underlying mechanisms. METHODS: Serum levels of gastrin were measured by enzyme-linked immunosorbent assay (ELISA) and correlation between gastrin level and development of BC was analyzed by chi-square test. Inhibitory effects of gastrin on BC were investigated by CCK-8 assay and nude mice models. Expressions of CCKBR/ERK/P65 in BC patients were determined through immunohistochemistry (IHC) and Western blot. Survival analysis was performed using the log-rank test. RESULTS: The results indicated that the serum level of gastrin in BC patients was lower compared with normal control. Cellular and molecular experiments indicated that reduction of gastrin is associated with inactivation of cholecystokinin B receptor (CCKBR)/ERK/P65 signaling in BC cells which is corresponding to molecular type of estrogen receptor (ER) positive BC. Furthermore, we found that low expression of gastrin/CCKBR/ERK /P65 was correlated to worse prognosis in BC patients. Gastrin or ERK/P65 activators inhibited ER+ BC through CCKBR-mediated activation of ERK/P65. Moreover, combination treatment with gastrin and tamoxifen more efficiently inhibited ER+ BC than tamoxifen alone. CONCLUSIONS: We concluded that low serum gastrin is related to increased risk of ER+ BC development. The results also established that CCKBR/ERK/P65 signaling function is generally tumor suppressive in ER+ BC, indicating therapies should focus on restoring, not inhibiting, CCKBR/ERK/P65 pathway activity.

Overexpression of dedicator of cytokinesis 2 correlates with good prognosis in colorectal cancer associated with more prominent CD8+ lymphocytes infiltration: a colorectal cancer analysis.

Recently, dedicator of cytokinesis 2 (DOCK2) has been reportedly exhibited high mutation prevalence in the Asian colorectal cancer (CRC) cohort. However, the expression pattern of DOCK2 and its clinical significance in CRC were still unknown. To characterize the role of DOCK2, a tissue microarray (TMA) containing 481 archived paraffin-embedded CRC specimens was performed by immunohistochemistry. Among which, 54 primary CRC tissues showed high expression of DOCK2 protein, while others were negative. Moreover, DOCK2 expression was positively associated with invasion depth (P < .001) and tumor size (P = .016). Significantly, Kaplan-Meier survival analysis revealed that patients with higher DOCK2 expression had a longer overall survival time (P = .017). Furthermore, univariate and multivariate Cox regression analysis confirmed that DOCK2 is an independent prognostic marker in CRC (P = .049,; HR, 0.519; 95% CI, 0.270 to 0.997). In addition, we observed a strong correlation between the infiltration of CD8+ T lymphocytes and DOCK2 expression (P = .0119). Our findings demonstrated that overexpressed DOCK2 might involve in recruiting CD8+ T lymphocytes and serve as a novel prognostic indicator and indicated a potential therapeutic strategy by restoring DOCK2 for CRC.

Gastrin inhibits gastric cancer progression through activating the ERK-P65-miR23a/27a/24 axis.

BACKGROUND: To test the hypothesis that activated extracellular signal-regulated kinase (ERK) regulates P65-miR23a/27a/24 axis in gastric cancer (GC) and the ERK-P65-miR23a/27a/24 axis plays an important role in the development of GC, and to evaluate the role of gastrin in GC progression and ERK-P65-miR23a/27a/24 axis. METHODS: The component levels of the ERK-P65-miR23a/27a/24 axis in four fresh GC tissues, 101 paraffin-embedded GC tissues and four GC cell lines were determined by Western blotting, immunohistochemistry (IHC) or qRT-PCR. The effects of gastrin on GC were first evaluated by measuring gastrin serum levels in 30 healthy and 70 GC patients and performing a correlation analysis between gastrin levels and survival time in 27 GC patients after eight years of follow-up, then evaluated on GC cell lines, GC cell xenograft models, and patient-derived xenografts (PDX) mouse models. The roles of ERK-P65-miR23a/27a/24 axis in GC progression and in the effects of gastrin on GC were examined. RESULTS: ERK- P65-miR23a/27a/24 axis was proved to be present in GC cells. The levels of components of ERK-P65-miR23a/27a/24 axis were decreased in GC tissue samples and PGC cells. The decreased levels of components of ERK-P65-miR23a/27a/24 axis were associated with poor prognosis of GC, and ERK-P65-miR23a/27a/24 axis played a suppressive role in GC progression. Low blood gastrin was correlated with poor prognosis of the GC patients and decreased expression of p-ERK and p-P65 in GC tissues. Gastrin inhibited proliferation of poorly-differentiated GC (PGC) cells through activating the ERK-P65-miR23a/27a/24 axis. Gastrin inhibited GC growth and enhanced the suppression of GC by cisplatin in mice or PGC cell culture models through activating the ERK-P65-miR23a/27a/24 axis or its components. CONCLUSIONS: ERK-P65-miR23a/27a/24 axis is down-regulated, leading to excess GC growth and poor prognosis of GC. Low gastrin promoted excess GC growth and contributed to the poor prognosis of the GC patients by down-regulating ERK-P65-miR23a/27a/24 axis. Gastrin inhibits gastric cancer growth through activating the ERK-P65-miR23a/27a/24 axis.

Simultaneous transcatheter therapy for perimembranous ventricular septal defect combined with patent ductus arteriosus.

OBJECTIVE: This study aims to assess the clinical efficiency and safety of simultaneous transcatheter interventional treatment for perimembranous ventricular septal defect (pmVSD) combined with patent ductus arteriosus (PDA). METHODS: Twenty-five patients with pmVSD and PDA treated with simultaneous transcatheter interventions from April 2004 to December 2015 were included in this study. The mean age was 9.80 ± 8.14 years and the mean weight was 29.76 ± 14.82 Kg. Transthoracic echocardiography (TTE) and angiography were performed immediately after the procedure. Patients were re-examined by electrocardiogram, X-ray, and TTE at 2 days, 1 month, 3 months, and 6 months postoperatively. RESULTS: The interventional procedure was successfully performed in all 25 patients. No intraoperative complication was noted. TTE examination of the VSD and PDA immediately after the procedure showed no residual shunt and the occluder was well positioned. Among these patients, four patients showed electrocardiogram changes after the procedure that resolved after drug therapy. The cardiothoracic ratio, left atrial diameter, left ventricular end-systolic diameter, and left ventricular end-diastolic diameter recovered to normal in most patients at 6 months postoperatively. CONCLUSIONS: Simultaneously transcatheter interventional therapy is a safe and effective method for pmVSD combined with PDA.

An immunochromatographic assay for carcinoembryonic antigen on cotton thread using a composite of carbon nanotubes and gold nanoparticles as reporters.

This paper describes a low-cost, sensitive, visual and rapid immunochromatographic assay method on cotton thread for carcinoembryonic antigen (CEA) detection by using novel carbon nanotube/gold nanoparticles (CNT/GNPs) nanocomposite reporter probe. CEA, a lung cancer protein biomarker, was used as analyte to demonstrate the principle of the immunochromatographic assay on cotton thread biosensor. In the presence of target CEA, the decreasing aggregation amount of CNT/GNPs nanocomposite reporter probes on the test zone induced directly readout by naked eye. Meanwhile, quantitative detection could be performed conveniently with a commercial available scanner. The performance with respect to sensitivity of the method was greatly improved by 2-3 magnitudes comparing with traditional gold nanoparticles (GNPs) or carbon nanotubes (CNTs) as reporter probe. Under optimal conditions, the biosensor was capable of detecting 2.32 ng/mL CEA (S/N ≥ 3) which is sensitive enough for clinical diagnosis. These results indicated the novel CNT/GNPs nanocomposite reporter probe based immunochromatographic assay on cotton thread is particularly suitable for point-of-care (POC) diagnostics in resource-limited regions.