CcPTGS2a-like gene-mediated NF-κB/ERK signaling regulation in the common carp (Cyprinus carpio).

Prostaglandin-endoperoxide synthase 2 (PTGS2), a common biological macromolecule, is pivotal for innate immunity and pathogen recognition. In this study, we identified and characterized a CcPTGS2a-like gene in the common carp (Cyprinus carpio) with an open reading frame (ORF) of 1821 bp and epidermal growth factor and peroxidase domains. Our multiple sequence analysis revealed high homology between the amino acid sequence of CcPTGS2a-like and those of its homologs in other fish. CcPTGS2a-like mRNA and protein expressions were significantly upregulated in the spleen, head kidney, liver, and gill tissues upon exposure to Aeromonas hydrophila stimulation. CcPTGS2a-like protein recognized the conserved bacterial surface components and exhibited detectable bacterial binding activity. CcPTGS2a-like overexpression before exposure to A. hydrophila notably enhanced the survival rate of common carp, concomitant with decreased bacterial burden. The NF-κB/ERK signaling pathway initiated the immune response in common carp upon infection with A. hydrophila. CcPTGS2a-like overexpression or interference in the head kidney and Epithelioma papulosum cyprinid cells could modulate the p-NF-κB (p-p-65), p-IκBα, and p-ERK1/2 levels as well as the IL-1ß and IL-6 mRNA expression. These results indicated potential CcPTGS2a-like involvement in the immune response of the common carp to bacterial infections through the NF-κB/ERK signaling pathway.

PCBP1 protects bladder cancer cells from mitochondria injury and ferroptosis by inducing LACTB mRNA degradation.

Although Poly C Binding Protein 1 (PCBP1) affects cellular ferroptosis and mitochondrial dysfunction, the mechanisms by which PCBP1 regulates bladder cancer (BC) cell functions are unknown. In this study, two BC cell lines (T24 and UMUC3) were treated with different doses of ferroptosis inducer erastin to analyze the effect of PCBP1. Online databases (RPISeq and CatRAPID) were used to predict the possible direct interaction between PCBP1 protein and serine ß-lactamase-like protein (LACTB) mRNA, which was further validated via RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays. Mitochondria injury and ferroptosis were evaluated using CCK-8 assay, TUNEL staining, flow cytometry, corresponding kits, and JC-1 staining. In vivo experiments were conducted using tumor xenograft models. Quantitative reverse-transcription polymerase chain reaction was used to detect transcript expression levels, while protein levels were analyzed using western blot and immunohistochemistry. PCBP1 expression was significantly upregulated in BC tissues and cell lines. Also, PCBP1 knockdown increased erastin-mediated ferroptosis in T24 and UMUC3 cells, while PCBP1 overexpression decreased erastin-mediated ferroptosis in T24 and UMUC3 cells. Mechanistic results showed that LACTB mRNA is a novel PCBP1-binding transcript. LACTB upregulation promoted erastin-induced ferroptosis and mitochondrial dysfunction. Furthermore, LACTB overexpression reversed PCBP1-mediated ferroptosis protection, including decreased ROS and enhanced mitochondrial function, which were further alleviated after phosphatidylserine decarboxylase (PISD) overexpression. Moreover, PCBP1 silencing significantly enhanced tumor inhibition effect of sulfasalazine in xenograft mice transplanted with T24 and UMUC3 cells, leading to LACTB upregulation and PISD downregulation. In conclusion, PCBP1 protects BC cells against mitochondria injury and ferroptosis via LACTB/PISD axis.

Endovascular treatment versus medical management for mild stroke with acute anterior circulation large vessel occlusion: a meta-analysis.

BACKGROUND: The effectiveness of endovascular treatment (EVT) in patients with mild stroke (National Institutes of Health Stroke Scale score ≤5) and acute anterior circulation large vessel occlusion (AACLVO) remains unknown. OBJECTIVE: To conduct a meta-analysis to compare the efficacy and safety of EVT in patients with mild stroke and AACLVO. METHODS: EMBASE, Cochrane Library, PubMed, and Clinicaltrials.gov databases were searched until October 2022. Both retrospective and prospective studies which compared the clinical outcomes between EVT and medical treatment were included. ORs and 95% confidence intervals (CIs) for excellent and favorable functional outcomes, symptomatic intracranial hemorrhage (ICH), and mortality were pooled using a random-effects model. A propensity score (PS)-based methods adjusted analysis was also performed. RESULTS: 4335 patients from 14 studies were included. In patients with mild stroke and AACLVO, EVT presented no marked differences in excellent and favorable functional outcomes and mortality compared with medical treatment. A higher risk of symptomatic ICH (OR=2.79; 95% CI 1.49 to 5.24; P=0.001) was observed with EVT. Subgroup analysis revealed that EVT had potential benefit for proximal occlusions with excellent functional outcomes (OR=1.68; 95% CI 1.01 to 2.82; P=0.05). Similar results were observed when PS-based methods adjusted analysis was used. CONCLUSION: EVT did not significantly benefit clinical functional outcomes in comparison with medical treatment in patients with mild stroke and AACLVO. However, it may improve functional outcomes when treating patients with proximal occlusion, despite being associated with an increased risk of symptomatic ICH. Stronger evidence from ongoing randomized controlled trials is required.

Growth differentiation factor 15 is required for triple-negative breast cancer cell growth and chemoresistance.

Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine, which is involved in the cellular stress response following acute damage. However, the functional role of GDF15 in triple-negative breast cancer (TNBC) has not been fully elucidated. ELISA, Western blot, and PCR assays as well as bioinformatics analyses were conducted to observe the expression of GDF15. Cell Counting Kit-8, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet staining assays were conducted to evaluate paclitaxel resistance and cell viability. Cell apoptosis was analyzed by Western blotting. Murine xenograft model assay was employed to evaluate tumor growth in vivo . Our data indicate that GDF15 is markedly elevated in paclitaxel-resistant TNBC cells, which is significantly associated with unfavorable prognosis. Silencing of GDF15 robustly inhibits the proliferation of tumor cells and increases their sensitivity to paclitaxel in vitro and in vivo , whereas the treatment of purified GDF15 protein confers breast cancer cells with chemoresistance ability. Moreover, GDF15 activates protein kinase B (AKT) /mammalian target of rapamycin (mTOR) signaling, inhibition of AKT or mTOR reverses the prosurvival effect of GDF15 and enhances the antitumor efficacy of paclitaxel in TNBC cells. Altogether, our study uncovers the role of GDF15 in tumor growth and paclitaxel resistance, implicating a potential therapeutic target for TNBC.

Identification of serum glycobiomarkers for Hepatocellular Carcinoma using lectin microarrays.

Objective: Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer and ranks third in mortality among all malignant tumors; as a result, HCC represents a major human health issue. Although aberrant glycosylation is clearly implicated in HCC, changes in serum immunoglobulin (Ig)G and IgM glycosylation have not been comprehensively characterized. In this study, we used lectin microarrays to evaluate differences in serum IgG and IgM glycosylation among patients with HCC, hepatitis B cirrhosis (HBC), or chronic hepatitis B (CHB), and healthy normal controls (NC) and aimed to establish a model to improve the diagnostic accuracy of HCC. Methods: In total, 207 serum samples collected in 2019-2020 were used for lectin microarray analyses, including 97 cases of HCC, 50 cases of HBC, 30 cases of CHB, and 30 cases of NC. Samples were randomly divided into training and validation groups at a 2:1 ratio. Training group data were used to investigate the diagnostic value of the relative signal intensity for the lectin probe combined with alpha-fetoprotein (AFP). The efficacy of models for HCC diagnosis were analyzed by receiver operating characteristic (ROC) curves. Results: In terms of IgG, a model combining three lectins and AFP had good diagnostic accuracy for HCC. The area under the ROC curve was 0.96 (P < 0.05), the sensitivity was 82.54%, and the specificity was 100%. In terms of IgM, a model including one lectin combined with AFP had an area under the curve of 0.90 (P < 0.05), sensitivity of 75.41%, and specificity of 100%. Conclusion: Estimation of serum IgG and IgM glycosylation could act as complementary techniques to improve diagnosis and shed light on the occurrence and development of the HCC.

The molecular subtypes of triple negative breast cancer were defined and a ligand-receptor pair score model was constructed by comprehensive analysis of ligand-receptor pairs.

Background: Intercellular communication mediated by ligand-receptor interactions in tumor microenvironment (TME) has a profound impact on tumor progression. This study aimed to explore the molecular subtypes mediated by ligand-receptor (LR) pairs in triple negative breast cancer (TNBC), identify the most important LR pairs to construct a prognostic risk model, and study their effect on TNBC immunotherapy. Methods: LR pairs subclasses of TNBC were categorized by consensus clustering based on LR Pairs in METABRIC dataset. Least absolute shrinkage and selection operator (LASSO) Cox regression and stepwise Akaike information criterion (stepAIC) were conducted to build a LR pairs score model. The relationship between LR pairs score and immune cell infiltration, stromal score and immune score associated with TME was analyzed, and the prediction of drug therapy and immunotherapy efficacy by LR pairs score was evaluated. Results: According to the expression pattern of 145 TNBC prognostic LR pairs, the samples were divided into three subclasses with different survival outcomes, copy number variation (CNV), TME immune cell infiltration, stromal score and immune score. The LR pairs score model constructed in the METABRIC dataset was composed of four LR pairs, and its predictive significance for TNBC prognosis was verified in GSE58812 and GSE21653 cohorts. In addition, LR pairs score was negatively correlated with several immune pathways regulating immunity and immune score, and related to the sensitivity of anti-neoplastic drugs and the effect of anti-PD-L1 therapy. Conclusion: Our study confirmed the impact of LR pairs on the molecular heterogeneity of TNBC, characterized three LR pairs subtypes with different survival outcomes and TME patterns, and proposed a LR pairs score system with predictive significance for TNBC prognosis and anti-PD-L1 therapeutic effect, which provides a potential evaluation scheme for TNBC management.

Indeterminate results of QuantiFERON-TB Gold in-tube due to high nil concentration and methodological exploration and improvement.

BACKGROUND: The features of indeterminate results (ITRs) due to high interferon gamma (IFN-γ > 8.0 IU/mL) concentrations in Nil tubes of QuantiFERON-TB Gold in-Tube (QFT-GIT) have not been well studied. Therefore, this study aimed at investigating the features of ITRs and optimization alternatives for this method. METHODS: We used the plasma exchange method to reduce the ITR rate due to high Nil concentrations (Nil > 8.0 IU/mL) between March 2020 and September 2021 at Xiangya Hospital of Central South University in China. One hundred and eleven out of 28,193 patient samples were considered ITRs due to Nil > 8.0 IU/mL. Of these 111, blood was re-sampled from 82 patients (pretreated group) who received the plasma exchange. Moreover, 40 out of 82 (blood volume ≥ 5 mL) received pretreated QFT-GIT and standard QFT-GIT (untreated group) simultaneously, while the remaining 42 received pretreated QFT-GIT only. The statistical difference between groups was evaluated. Cohen's kappa coefficient was used to assess the level of agreement between the pretreated and untreated group. RESULTS: Of the 28,193 subjects, 1,083 (3.8%) had ITRs, and 111 (0.4%) had ITRs due to Nil > 8.0 IU/mL. The population studied had a mean age of 52.9 years, and 70.3% were men, which is a larger proportion than that in patients with ITR and the overall population. Significantly decreased IFN-γ levels in Nil tubes were detected using the pretreated QFT-GIT compared with standard QFT-GIT (p < 0.01). The determinate results rate in the pretreated group was significantly higher than that of the untreated group (80% (32/40) vs 57.5%, (23/40), p = 0.03). Further comparison revealed that the pretreated group was consistent with the untreated group in 17/20 (85%) positive tests, 3/3 (100%) negative tests, and 6/17 (35.3%) ITRs. The overall agreement rate was 26/40 (65%) among all 40 subjects, and the κ value was 0.39 (minimal agreement). The majority of results obtained after pretreatment were positive (71.2%, 59/82) and the agreement rate between clinical diagnosis and pretreated QFT-GIT was at least 61.0% (39/59). CONCLUSION: Plasma exchange pretreated QFT-GIT yields more reliable results than untreated QFT-GIT when processing high Nil concentrations.

Adjuvant SOX chemotherapy versus concurrent chemoradiotherapy after D2 radical resection of locally advanced esophagogastric junction (EGJ) adenocarcinoma: study protocol for a randomized phase III trial (ARTEG).

BACKGROUND: Survival benefit of adjuvant radiotherapy for locally advanced gastric cancer following gastrectomy plus D2 lymphadenectomy has always been controversial. Esophagogastric junction (EGJ) adenocarcinoma, which is usually classified as gastric cancer in East Asia, often has a higher locoregional recurrence rate after operation because of its special anatomical characteristics. The aim of this study is to determine whether adjuvant radiotherapy can improve survival of locally advanced EGJ adenocarcinoma after D2 radical resection. METHODS: In this phase III, randomized, open label, controlled trial, we plan to recruit 378 patients with Siewert type II and III adenocarcinoma of EGJ, who had undergone transabdominal radical surgery and D2 lymphadenectomy, and were divided into pathological stage IIB to IIIC. All patients will be randomized 1:1 to receive either adjuvant chemotherapy alone (control group) or adjuvant chemotherapy plus chemoradiotherapy (experimental group). Patients allocated to control group will receive eight cycles of S-1 plus oxaliplatin (SOX), while the experimental group will receive two cycles of SOX followed by 45-Gy RT combined with S-1 and four additional cycles of SOX. The primary endpoint is 3-year disease-free survival rate (DFS). The secondary endpoints are 3-year overall survival rate (OS), 3-year locoregional recurrence-free survival rate (LRFS), 3-year distant metastasis-free survival rate (DMFS), and quality of life (QoL). DISCUSSION: In the past, the adjuvant treatment of EGJ adenocarcinoma needs to draw on the experience of esophageal adenocarcinoma or gastric adenocarcinoma. In this study, EGJ adenocarcinoma is considered as an independent disease, and the conclusion will provide evidence for optimal adjuvant therapy of locally advanced EGJ adenocarcinoma after D2 radical resection. TRIAL REGISTRATION: ClinicalTrials.gov NCT03973008 . Registered on 1 June 2019 (retrospectively registered), URL: https://clinicaltrials.gov/ct2/show/NCT03973008?term=NCT03973008&draw=2&rank=1.

Adjuvant albumin-bound paclitaxel combined with S-1 vs. oxaliplatin combined with capecitabine after D2 gastrectomy in patients with stage III gastric adenocarcinoma: a phase III multicenter, open-label, randomized controlled clinical trial protocol.

BACKGROUND: Surgery is the only treatment option for operable gastric cancer. The CLASSIC and ACTS-GC studies showed that the 5-year overall survival (OS) of patients with stage III gastric cancer undergoing D2 gastrectomy is still very low. Whether adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) combined chemotherapy is more effective than the XELOX standard adjuvant chemotherapy in patients with stage III gastric cancer has not been confirmed. METHODS: This is a multicenter, open-label, phase III clinical study. In this trial, 616 patients with locally advanced stage III gastric cancer that underwent curative D2 radical surgery and achieved R0 are planned to be included. Patients will be randomized 1:1 to nab-paclitaxel combined with S-1 (AS) vs. oxaliplatin combined with capecitabine (XELOX). XELOX group: Patients assigned to the XELOX group received eight 3-week cycles of oral capecitabine (1000 mg/m2) twice daily on days 1-14 of each cycle plus intravenous oxaliplatin 130 mg/m2 on day 1 of each cycle. AS group: AS group received eight 3-week cycles of oral S-1 (80-120 mg) (< 1.25 m2, 40 mg; 1.25 to < 1.5 m2, 50 mg; and > 1.5 m2, 60 mg) twice daily on days 1-14 plus intravenous nab-paclitaxel 120 mg/m2 on days 1 and 8 of each cycle. The primary endpoint was the 3-year disease-free survival (3-year-DFS) defined as the time from randomisation to the time of recurrence of the original gastric cancer, development of a new gastric cancer, or death from any cause. The secondary endpoints were the overall survival, (defined as the time from the date of randomisation to date of death from any cause) and safety (any adverse event). DISCUSSION: Compared with previous studies, this study includes nab-paclitaxel based on S-1 adjuvant chemotherapy, which is expected to achieve better efficacy and lower toxicity than the standard treatment. This study is the first clinical study to evaluate the safety and efficacy of nab-paclitaxel combined with S-1 in patients with stage III gastric cancer after D2 radical resection. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov, registration number: NCT04135781 , on October 20th, 2019.

Common cytokine polymorphisms and predisposition to polycystic ovary syndrome: a meta-analysis.

The results of studies on the relationship between cytokine polymorphisms and polycystic ovary syndrome (PCOS) have been controversial. This meta-analysis was thus designed to more precisely assess the relationship between TNF-α/IL-1/IL-6/IL-10 polymorphisms and PCOS by pooling the results of published studies. A search of PubMed, Embase, Web of Science, and CNKI databases turned up 23 studies that were pooled and analyzed in this meta-analysis. The overall results showed that the distributions of TNF-α -238 G/A, TNF-α -857 C/T, and IL-1B -51 C/T polymorphisms among patients and controls differed significantly. Additionally, the distributions of TNF-α -308 G/A and IL-1B -51 C/T polymorphisms among patients and controls from Asian populations differed significantly, whereas the distributions of IL-6 -174 G/C and IL-1A -889 C/T polymorphisms among patients and controls from Caucasian populations also differed significantly. In conclusion, our meta-analysis demonstrated that TNF-α -238 G/A, TNF-α -857 C/T, and IL-1B -51 C/T polymorphisms might influence susceptibility to PCOS in the overall pooled population. Moreover, TNF-α -308 G/A and IL-1B -51 C/T polymorphisms might influence susceptibility to PCOS in Asians, whereas IL-6 -174 G/C and IL-1A -889 C/T polymorphisms might influence susceptibility to PCOS in Caucasians.

Cdc42 subcellular relocation in response to VEGF/NRP1 engagement is associated with the poor prognosis of colorectal cancer.

Microscopic indications of malignancy and hallmark molecules of cancer are pivotal to determining cancer patient prognosis and subsequent medical intervention. Here, we found that compared to apical expression of Cdc42, which indicated that basal expression of Cdc42 occurred at the migrating cell front, glandular basal expression of Cdc42 (cell division cycle 42) in tissues indicated poorer prognoses for colorectal cancer (CRC) patients. The current study shows that activated Cdc42 was rapidly recruited to the migrating CRC cell front after VEGF stimulation through engagement of membrane-anchored neuropilin-1 (NRP1). When VEGF signalling was blocked with NRP1 knockdown or ATWLPPR (A7R, antagonist of VEGF/NRP1 interaction), Cdc42 activation and relocation to the cell front was attenuated, and filopodia and invadopodia formation was inhibited. The VEGF/NRP1 axis regulates directional migration, invasion, and metastasis through Cdc42 activation and relocation resulting from actin filament polymerisation of the extensions of membrane protrusions. Collectively, the immuno-micromorphological pattern of subcellular Cdc42 at the cell front indicated aggressive behaviours and predicted poor prognosis in CRC patients. Disruption of the intra- and extracellular interactions of the VEGF/NRP1 axis or Cdc42 relocation could be performed in clinical practice because it might inhibit cancer cell motility and metastasis.

Effects of miR-489 targeting on SOX4 gene on proliferation and apoptosis of human hepatocellular carcinoma cells.

BACKGROUND: Hepatocellular carcinoma is one of the most common malignant tumors found all over the globe. Despite advances in surgery and chemotherapy, the five-year survival rate of patients with hepatocellular carcinoma is still low. It is known that the proliferation of hepatocellular carcinoma cells is closely related to the occurrence, development and prognosis of hepatocellular carcinoma. The present work investigates the expression of microRNA-489 (miR-489) in human hepatocellular carcinoma cells and its effect on the biological behavior of human hepatocellular carcinoma cells. METHODS: The expression of miR-489 by fluorescence quantitative PCR detection in 30 patients with hepatoblastoma of liver cancer tissues and adjacent tissues was studied. Also, the determination of hepatoblastoma in four cell lines with different metastatic potential (HR8348, HCT116, HT29 and HEPG2) and the expression of miR-489 during miR-489 simulation process was studied. MTT assay, flow cytometry and Western blot analysis were performed to know the cell proliferation to detect the changes in cell cycle, apoptosis of cells, and SOX4 gene expression respectively. RESULTS: RT-PCR results showed that the cells compared with pre-cancerous tissue, the expression level of miR-489 in hepatocellular carcinoma tissues than in adjacent tissue significantly decreased (P<0.05), and with liver cancer cell metastasis increased (P<0.05); analogue transfection constructed miR-489 overexpressing HEPG2 cell line by microRNA. MTT results showed that miR-489 can inhibit the proliferation of HEPG2 cells, the differences were statistically significant (P<0.05); flow cytometry results showed that miR-489 mimics was transfected into HEPG2 cells at 48 hours had no significant effect on cell cycle distribution (P > 0.05); but miR-489 expression could induce apoptosis, compared with the control group, the apoptosis of miR-489 mimics was significantly increased and the difference was statistically significant (P < 0.05). CONCLUSION: In conclusion, miR-489 can significantly inhibit the occurrence and development of hepatocellular carcinoma cells. The mechanism may be down regulated by the expression of SOX4 and inhibit cell proliferation. Further this study showed that the tumor cells SOX4 gene as a regulatory factor target the genes of miR-489 in hepatocellular carcinoma.

Clostridium difficile toxin B recombinant protein inhibits tumor growth and induces apoptosis through inhibiting Bcl-2 expression, triggering inflammatory responses and activating C-erbB-2 and Cox-2 expression in breast cancer mouse model.

Clostridium difficile toxin B (cdtB) is a critical virulence factor characterized with potential cytotoxicity and pro-inflammatory activity. This study aims to investigate anti-tumor effects of cdtB on breast cancer development. Clostridium difficile strain was cultured and cdtB recombinant protein (rcdtB) was synthesized. Breast cancer cell line, MDA-MB-231, was divided into Normal control, rcdtB 50, 100, 200 and 400 ng/ml group in vitro. Mice were divided into Normal control and rcdtB treatment group (400 ng/ml) in vivo. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was performed to evaluate inhibitive effects of rcdtB on cell growth. Flow cytometry and transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) were employed to examine apoptosis in vitro and in vivo, respectively. Cell cycle distribution was analyzed by utilizing commercial kit. B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) were examined using western blot. Inflammatory response was detected using haematoxylin and eosin (HE). Erythroblastic leukemia viral oncogene homolog 2 (C-erbB-2) and cyclooxygenase-2 (Cox-2) were examined using immunohistochemical and immunofluorescence assay, respectively. The results indicated that rcdtB significantly induced MDA-MB-231 death, inhibited growth and decreased S-phase cells compared to Normal control group (P < 0.05). rcdtB significantly induced early and late apoptosis, and decreased Bcl-2 levels compared to Normal control group (P < 0.05). rcdtB significantly inhibited cell migration compared to Normal control group (P < 0.05). rcdtB significantly inhibited tumor growth and activated inflammation of breast cancer model compared to Normal control group (P < 0.01). rcdtB significantly reduced C-erbB-2 and Cox-2 in tumor tissues compared to Normal control group (P < 0.01). In conclusion, rcdtB treatment inhibited tumor growth and induced apoptosis through inhibiting Bcl-2 expression, inflammatory responses, and activating C-erbB-2 and Cox-2 expression in breast cancer mouse model.

Effective component of Salvia miltiorrhiza in promoting cardiomyogenic differentiation of human placenta­derived mesenchymal stem cells.

Our previous study indicated that Salvia miltiorrhiza (SM) induced human placenta­derived mesenchymal stem cells (hPDMSCs) to differentiate into cardiomyocytes, however, the effective component of SM in promoting cardiomyogenic differentiation remained to be elucidated. In the present study, the most commonly examined components of SM, including danshensu, salvianolic acid B, protocatechuic aldehyde, tanshinone I (TS I), TS IIA and cryptotanshinone, were used to determine the effective components of SM in promoting cardiomyogenic differentiation. The above components of SM slowed cell growth rate and altered cell morphology with a spindle or irregular shape to different degrees. The cells treated with the above components of SM showed increasing of cardiac protein expression to differing degrees, including GATA­binding protein 4, atrial natriuretic factor, α­sarcomeric actin and cardiac troponin­I. Among the components of SM, TS IIA induced the most marked effects. In addition, the above components of SM increased the expression of phosphorylated glycogen synthase kinase­3ß, but decreased the expression of ß­catenin to different degrees, with TS IIA also having the most marked effects. In conclusion, the results of the present study suggested that TS IIA was the most effective active component of SM in inducing hPDMSCs to differentiate into cardiomyocytes, and that Wnt/ß­catenin signaling was important in the process of TS IIA promoting cardiomyogenic differentiation.

Knockdown of PHGDH potentiates 5-FU cytotoxicity in gastric cancer cells via the Bcl-2/Bax/caspase-3 signaling pathway.

Gastric cancer (GC) is one of the most common malignancies in the world. Fluorouracil (5-FU) is widely used in the treatment of cancers, but resistance to 5-FU results in the failure of chemotherapy. Phosphoglycerate dehydrogenase (PHGDH) has been reported to play a vital role in the development of 5-FU resistance in cancer cells. However, the exact role of PHGDH and the underlying mechanisms for 5-FU resistance in GC cells remain elusive. In this study, PHGDH expression was much higher in the GC tissues of 5-FU-resistant patients than that in the GC tissues of 5-FU-sensitive patients. Moreover, the expression of PHGDH was obviously increased in BGC823/5-FU cells compared with that in BGC823 cells. 5-FU treatment significantly reduced the viability of BGC823/5-FU cells, in a dose- and time-dependent manner. Furthermore, 5-FU treatment inhibited the proliferation of BGC823/5-FU cells, as evidenced by decreased cell viability and reduced colony-forming ability. The knockdown of PHGDH made possible the inhibitory effect of 5-FU on the proliferation of BGC823/5-FU cells. Furthermore, 5-FU treatment promoted apoptosis of BGC823/5-FU cells, as indicated by increased numbers of TUNEL-positive cells and increased rates of apoptosis. Notably, the promoting effect of 5-FU on the apoptosis of BGC823/5-FU cells was markedly enhanced by PHGDH knockdown. Additionally, 5-FU treatment downregulated Bcl-2 expression and upregulated the expression of Bax and caspase-3, and this effect was remarkably enhanced by PHGDH knockdown. In conclusion, knockdown of PHGDH potentiates 5-FU cytotoxicity in GC cells via the Bcl-2/Bax/caspase-3 signaling pathway.

An integrated approach of predicted miR-34a targets identifies a signature for gastric cancer.

microRNA-34a (miRNA/miR-34a) functions as a tumor suppressor gene in gastric cancer and may be involved in system-wide regulatory networks. To clarify the expression of all predicted target genes of this miRNA, a comprehensive and systematic analysis of miR-34a-target genes in gastric cancer was conducted in the present study. In the initial analysis, the potential functions, pathways and networks of gastric cancer-associated molecules and miR-34a targets were identified. In the final integrative analysis of gastric cancer-associated miR-34a targets, 30 hub genes were identified using overlap calculations, indicating that miR-34a may be significant in the development and progression of gastric cancer through the Smad signaling pathway, the cell cycle, the mitogen-activated protein kinase signaling pathway, apoptosis, the Notch signaling pathway and other pathways. The present study provides a bioinformatic analysis of miR-34a-targets in gastric cancer, describes numerous target genes and novel coregulatory networks, and may provide an opportunity to identify a critical regulatory network for predicting the molecular mechanisms of miR-34a in the development and progression of gastric cancer.

Surgical treatment of huge hepatocarcinoma with invasion or severe adhesion of diaphragm using the technique of orthotopic liver resection.

BACKGROUND/AIMS: To explore the clinical application and significance of the technique of orthotopic liver resection. METHODOLOGY: From January 2004 to December 2011, five patients with huge hepatocellular carcinoma with invasion or severe adhesion of diaphragm were undergone right semi-liver resection using the technique of orthotopic liver resection. The right hemi-liver was isolated from the first liver portal, second liver portal and third liver portal, then isolated from the normal liver, finally the tumor and the invaded diaphragm were resected or removed from the severe adhesion. The approach to hepatic resection involved routine use of Peng's multifunctional operative dissector, selective control of in and out-flow of liver, control of inferior vena cava (IVC) and liver hanging maneuver, anterior approach, etc. RESULTS: The operations were successfully performed in 5 patients. Operative time was 120, 180, 150, 150 and 160 min, respectively. The amount of blood loss were 350, 350, 400, 450, 600 ml, respectively. Postoperative complications were pleural effusion in 3 cases, and other 2 cases recovered without complications. CONCLUSIONS: Although the technique of orthotopic liver resection has a high technical requirement for surgeons, it provides a surgical method and operative opportunity for the patients whose tumor has invaded diaphragm or has been severe adhesion with diaphragm and conventional liver resection cannot be performed.

Icariin Acts as a Potential Agent for Preventing Cardiac Ischemia/Reperfusion Injury.

Myocardial infarction is a leading cause of mortality and morbidity worldwide. Although essential for successful recovery, myocardium reperfusion is associated with reperfusion injury. Icariin, a major flavonoid of Epimedium koreanum Nakai, has been proven to exert efficacy for improving cardiovascular function. We investigated the molecular effect and signal pathway of icariin on cardiac ischemia/reperfusion injury. In an in vivo model of infarct in rats, icariin (10 mg/kg) significantly attenuated myocardial infarct size induced by ischemia/reperfusion (I/R). From the TUNEL assay, icariin reduced the apoptotic cell induced by I/R and decreased blood indicators of creatine kinase, ischemia-modified albumin, and lactate dehydrogenase. All this effect was antagonized by the PI3K inhibitor LY294002. Meanwhile, icariin activated the PI3K/Akt/eNOS pathway. The PI3K inhibitor LY294002 suppressed icariin-mediated protective effect. These results suggest that icariin protects against myocardial ischemia reperfusion injury in rats by activating the PI3K/Akt/eNOS-dependent signal pathways and may be a useful drug for angiogenic therapy.

A new receptor tyrosine kinase inhibitor, icotinib, for patients with lung adenocarcinoma cancer without indication for chemotherapy.

Epidermal growth factor receptor (EGFR) is an important therapeutic target in lung cancer. Gefitinib and erlotinib, two reversible EGFR receptor tyrosine kinases inhibitors (TKIs), have been approved for the treatment of patients with metastatic non small-cell lung cancer. Icotinib, which is a selective EGFR-TKI, provides a similar efficacy to gefitinib. The present study aimed to investigate the survival and safety of icotinib in patients with lung adenocarcinoma with a poor performance status (PS). A total of 42 cases of lung adenocarcinoma, including 35 females and 7 males, were enrolled. Icotinib was used as the first-line of treatment due to poor PS of the patient or a more advanced age. Icotinib (125 mg) was orally administered three times per day. The overall response rate and disease control rates were 33.3 and 85.7%, respectively. The median survival time was 13.0 months (95% CI, 5.6-20.4), The median progression-free survival time was 7.0 months, and the 1-year survival rate was 71.4%. A total of 79% of patients had an improved PS following icotinib treatment. Grade 1 to 2 rashes and diarrhea were the most frequent side effects. One patient succumbed during the study due to interstitial pneumonia. In conclusion, this is the first study indicating that patients with lung adenocarcinoma and poor PS may benefit from first-line icotinib therapy, but should be cautious of the occurrence of interstitial lung disease.