Exosomes derived from mesenchymal stromal cells exert a therapeutic effect on hypoxia-induced pulmonary hypertension by modulating the YAP1/SPP1 signaling pathway.

OBJECTIVE: Hypoxic pulmonary hypertension (HPH) is a progressive and life-threatening disease characterized by perivascular inflammation, pulmonary vascular remodeling, and occlusion. Mesenchymal stromal cell-derived exosomes (MSC-exo) have emerged as potential therapeutic agents due to their role in cell communication and the transportation of bioactive molecules. In this study, we aimed to investigate the therapeutic effects of MSC-exo against HPH and elucidate the underlying molecular mechanism. METHODS: Exosomes were isolated from conditioned media of human bone mesenchymal stromal cells using ultracentrifugation and characterized through western blotting, transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). An HPH animal model was established in male SD rats, and MSC-exo or phosphate-buffered saline (PBS) were administered via the tail vein for three weeks. Subsequently, right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and pulmonary vascular remodeling were evaluated. Lung tissues from HPH rats and normal rats underwent high-throughput sequencing and transcriptomic analysis. Gene Ontology (GO) analysis was employed to identify upregulated differentially expressed genes. Additionally, rat pulmonary artery smooth muscle cells (PASMC) exposed to platelet-derived growth factor-BB (PDGF-BB) were used to simulate HPH-related pathological behavior. In vitro cellular models were established to examine the molecular mechanism of MSC-exo in HPH. RESULTS: MSC-exo administration protected rats from hypoxia-induced increases in RVSP, RVHI, and pulmonary vascular remodeling. Additionally, MSC-exo alleviated PDGF-BB-induced proliferation and migration of PASMC. Transcriptomic analysis revealed 267 upregulated genes in lung tissues of HPH rats compared to control rats. Gene Ontology analysis indicated significant differences in pathways associated with Yes Associated Protein 1 (YAP1), a key regulator of cell proliferation and organ size. RT-qPCR and western blot analysis confirmed significantly increased expression of YAP1 in HPH lung tissues and PASMC, which was inhibited by MSC-exo treatment. Furthermore, analysis of datasets demonstrated that Secreted Phosphoprotein 1 (SPP1), also known as Osteopontin (OPN), is a downstream binding protein of YAP1 and can be upregulated by PDGF-BB. MSC-exo treatment reduced the expression of both YAP1 and SPP1. Lentivirus-mediated knockdown of YAP1 inhibited PDGF-BB-induced PASMC proliferation, migration, and SPP1 protein levels. CONCLUSION: Our findings demonstrate that MSC-exo exert a therapeutic effect against hypoxia-induced pulmonary hypertension by modulating the YAP1/SPP1 signaling pathway. The inhibition of YAP1 and downstream SPP1 expression by MSC-exo may contribute to the attenuation of pulmonary vascular remodeling and PASMC proliferation and migration. These results suggest that MSC-exo could serve as a potential therapeutic strategy for the treatment of HPH. Further investigations are warranted to explore the clinical applicability of MSC-exo-based therapies in HPH patients.

Circular RNA AGFG1 motivates breast cancer cell proliferation, invasion, migration, and glycolysis by controlling microRNA-653-5p/14-3-3 protein epsilon.

A recent Pairwise meta-analysis confirmed that circular RNA AGFG1 (circAGFG1) is abnormally highly expressed in breast cancer (BC) and may be associated with death risk. The purpose of this study was to elucidate the biological role of circAGFG1 in BC and to explore its potential downstream molecular mechanisms. CircAGFG1, miR-653-5p and YWHAE expression in BC tissues and cells were analyzed by RT-qPCR or western blot. Gene expression was regulated by transfection of plasmids or oligonucleotides and the biological behaviors of BC cells were analyzed by a series of assays. The ring structure of circAGFG1 was analyzed by RNase R and actinomycin D treatment. Dual luciferase reporter assay and RNA-pull down were used to verify the targeting relationship of circAGFG1 and downstream factors. A nude mouse xenograft experiment was performed to verify the effect of circAGFG1 on cancer cells in vivo. The results showed that circAGFG1 and YWHAE were highly expressed in BC while miR-653-5p was lowly expressed. Both circAGFG1 and YWHAE had a targeting relationship with miR-653-5p. Knockdown of circAGFG1 inhibited BC cell proliferation, invasion, migration, and glycolysis. The inhibitory effect of circAGFG1 knockdown on BC was reversed by silencing miR-653-5p. The inhibitory effect of overexpression of miR-653-5p on malignant behaviors of BC cells was reversed by overexpression of YWHAE. Knockdown of circAGFG1 inhibited tumor growth in vivo. Taken together, these data suggest that circAGFG1 acts as a sponge for miR-653-5p to mediate YWHAE expression to promote the malignant behaviors of BC.

Effects of dexmedetomidine administration on outcomes in critically ill patients with acute kidney injury: A propensity score-matching analysis.

PURPOSE: To evaluate the effects of dexmedetomidine (DEX) on outcomes of critically ill patients with acute kidney injury (AKI). MATERIALS AND METHODS: Data were extracted from the Medical Information Mart for Intensive Care III database (MIMIC III). Propensity score matching (PSM) analysis (1 : 3), Cox proportional hazards model, linear regression and logistic regression model were used to assess the effect of DEX on clinical outcomes. RESULTS: After PSM, 324 pairs of patients were matched between the patients with DEX administration and those without. DEX administration was associated with decreased in-hospital mortality (hazard ratio (HR) 0.287; 95% CI 0.151 - 0.542; p < 0.001) and 90-day mortality (HR 0.344; 95% CI 0.221 - 0.534; p < 0.001), and it was also associated with reduced length of stay (LOS) in ICU (4.54 (3.13,7.72) vs. 5.24 (3.15,10.91), p < 0.001) and LOS in hospital (11.63 (8.02,16.79) vs 12.09 (7.83,20.44), p = 0.002). Subgroup analysis showed that the above associations existed only in the mild and moderate AKI subgroups, but not in the severe AKI subgroup. Nevertheless, DEX administration was not associated with recovery of renal function (HR 1.199; 95% CI 0.851 - 1.688; p = 0.300). CONCLUSION: DEX administration improved outcomes in critically ill patients with mild and moderate AKI and could be a good choice of sedation.

Destabilization of microrchidia family CW-type zinc finger 2 via the cyclin-dependent kinase 1-chaperone-mediated autophagy pathway promotes mitotic arrest and enhances cancer cellular sensitivity to microtubule-targeting agents.

BACKGROUND: Microtubule-targeing agents (MTAs), such as paclitaxel (PTX) and vincristine (VCR), kill cancer cells through activtion of the spindle assembly checkpoint (SAC) and induction of mitotic arrest, but the development of resistance poses significant clinical challenges. METHODS: Immunoblotting and RT-qPCR were used to investigate potential function and related mechanism of MORC2. Flow cytometry analyses were carried out to determine cell cycle distribution and apoptosis. The effect of MORC2 on cellular sensitivity to PTX and VCR was determined by immunoblotting, flow cytometry, and colony formation assays. Immunoprecipitation assays and immunofluorescent staining were utilized to investigate protein-protein interaction and protein co-localization. RESULTS: Here, we identified microrchidia family CW-type zinc finger 2 (MORC2), a poorly characterized oncoprotein, as a novel regulator of SAC activation, mitotic progression, and resistance of cancer cells to PTX and VCR. Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation. Degradation of MORC2 during mitosis leads to SAC activation through stabilizing anaphase promoting complex/cyclosome activator protein Cdc20 and facilitating mitotic checkpoint complex assembly, thus contributing to mitotic arrest induced by PTX and VCR. Notably, knockdown of MORC2 promotes mitotic arrest induced by PTX and VCR and enhances the sensitivity of cancer cells to PTX and VCR. CONCLUSIONS: Collectively, these findings unveil a previously unrecognized function and regulatory mechanism of MORC2 in mitotic progression and resistance of cancer cells to MTAs. These results also provide a new clue for developing combined treatmentstrategy by targeting MORC2 in combination with MTAs against human cancer.

Overexpression and diagnostic significance of INTS7 in lung adenocarcinoma and its effects on tumor microenvironment.

BACKGROUND: Lung cancer is the leading cause of death worldwide, and lung adenocarcinoma (LUAD) is the most common histological subtype. INTS7, one of the subunits of the integrator complex, is upregulated in several tumors. Thus, we aimed to investigate the expression profile and clinical significance of INTS7 in LUAD. METHODS: The expression profile of INTS7 was tested in TCGA database and clinical specimens. ROC curve was used to detect the diagnostic value of INTS7, CEA and INTS7 combined with CEA. Kaplan-Meier analysis was used to analyze the prognostic value of INTS7. Differentially expressed genes (DEGs) related to INTS7 were analyzed, and functional enrichment analysis was used to explore the potential mechanisms related to DEGs. The correlations between INTS7 and tumor-infiltrating immune cells, immune scores, stromal scores, and immune checkpoints were explored. Finally, the relationship between INTS7 expression and sensitivity to molecular-targeted therapy was examined. RESULTS: Data from TCGA database showed that INTS7 mRNA expression was substantially upregulated in LUAD, the AUC values of INTS7 for diagnosing LUAD were >0.8, combined detection of INTS7 and CEA could improve the diagnostic efficiency and early stage patients with high expression of INTS7 showed shorter overall survival. IHC analysis of clinical samples further verified the overexpression of INTS7 protein and confirmed the diagnostic value of INTS7 in LUAD, especially for patients at advanced stages with the AUC >0.8. A total of 192 DEGs were identified and DEGs were primarily involved in cell cycle, inflammatory response, and immune response. Moreover, INTS7 expression was negatively correlated with memory B cells, regulatory T cells (Treg), monocytes, resting myeloid dentritic cells and activated mast cells infiltration, and positively correlated with naive B cells, T follicular helper cells (Tfh), activated myeloid dentritic cells and neutrophils infiltration. In addition, patients with high expression of INTS7 showed less expression of immune checkpoints and exhibited less sensitivity to molecular-targeted drugs. CONCLUSION: INTS7 is a potential diagnostic biomarker for LUAD. And its expression level may correlate with tumor microenvireoment, immunotherapy responsiveness, and molecular-targeted therapy responsiveness in LUAD.

Sodium Tanshinone II Sulfonate A Ameliorates Hypoxia-Induced Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) remains a prevalent disease globally. Sodium tanshinone II sulfonate A (STS) has been used in clinical treatment of PH. AIMS: The aim of the present study was to investigate the effect of sodium STS treatment on hypoxia-induced PH and related mechanisms. METHODS: Male Sprague-Dawley rats were housed in a hypoxic chamber with an oxygen concentration of 10 ± 1% for 8 h a day over 21 days. Rats were treated with either STS (low-dose: 10 mg/kg or high-dose: 30 mg/kg) or LY294002 (which is an inhibitor of PI3K). Pulmonary arterial pressure (PAP) was measured, right ventricular hypertrophy parameters were monitored, lung edema parameters were measured, and pathological changes were observed by hematoxylin-eosin (HE) staining. Protein expressions of apoptosis, and PI3K/AKT/mTOR/autophagy pathways in rat lung tissue were examined by western blot. Levels of the pro-inflammatory factors IL-6, IL-8, TNF-α in lung tissues of rats were measured using an enzyme linked immunosorbent assay (ELISA). RESULTS: Results of our study demonstrate that persistent exposure to hypoxic conditions increased PAP, right ventricular hypertrophy, lung edema, parameters of lung vascular proliferation and decreased the ratio of Bax/Bcl-2. Furthermore, hypoxic conditions activated the PI3K/Akt/mTOR pathway, inhibited autophagy, and elevated abundance of inflammatory factors in rat lung tissue. Treatment with STS resulted in a dose-dependent decrease in PAP, right ventricular hypertrophy, lung edema, lung vascular proliferation and reversed hypoxia induced lung tissue protein expression and pro-inflammatory factors in rat lung tissue. In addition, hypoxia-induced increases in PAP, cardiac hypertrophy, and lung expression of the proteins PI3K/Akt/mTOR/autophagy pathway were partially reversed by treatment with LY294002. CONCLUSIONS: STS alleviates hypoxia-induced PH by promoting apoptosis, inhibiting PI3K/AKT/mTOR pathway, up-regulating autophagy, and inhibiting inflammatory responses.

COVID-19 with cystic features on computed tomography: A case report.

RATIONALE: The cystic features of the novel coronavirus disease 2019 (COVID-19) found on computed tomography (CT) have not yet been reported in the published literature. We report the cystic chest CT findings of 2 patients confirmed to have COVID-19-related pneumonia. PATIENT CONCERNS: A 38-year-old man and a 35-year-old man diagnosed with severe COVID-19 pneumonia were admitted to the intensive care unit. DIAGNOSES: Chest CT findings showed multiple cysts in ground-glass opacities (bilaterally) with/without pneumothorax. The cysts had a smooth inner wall. INTERVENTIONS: The patients continued to be given oxygen by mask and received antitussive, phlegm-dispelling treatment. OUTCOMES: At follow up, there was a reduction in the number of multiple cystic lesions on CT. To date, 1 patient was discharged from hospital, while the other had been transferred to the rehabilitation department. LESSONS: COVID-19 may independently result in pulmonary cyst formation and pneumothorax; the application of a ventilator may be another causative factor.

A 17-gene expression-based prognostic signature associated with the prognosis of patients with breast cancer: A STROBE-compliant study.

Identification of reliable predictive biomarkers for patients with breast cancer (BC).Univariate Cox proportional hazards regression model was conducted to identify genes correlated with the overall survival (OS) of patients in the TCGA-BRCA cohort. Functional enrichment analysis was conducted to investigate the biological meaning of these survival related genes. Then, patients in TCGA-BCRA were randomly divided into training set and test. Least absolute shrinkage and selection operator (LASSO) penalized Cox regression model was performed and the risk score of BC patients in this model was used to build a prognostic signature. The prognostic performance of the signature was evaluated in the training set, test set, and an independent validation set GSE7390.2519 genes were demonstrated to be significantly associated with the OS of BC patients. Functional annotation of the 2519 genes suggested that these genes were associated with immune response and protein synthesis related gene ontology terms and pathways. 17 genes were identified in the LASSO Cox regression model and used to construct a 17-gene signature. Patients in the 17-gene signature low risk group have better OS and event-free survival compared with those in the 17-gene signature high risk group in the TCGA-BRCA cohort. The prognostic role of the 17-gene signature has been confirmed in the validation cohort. Multivariable Cox proportional hazards regression model suggested the 17-gene signature was an independent prognostic factor in BC.The 17-gene signature we developed could successfully classify patients into high- and low-risk groups, indicating that it might serve as candidate biomarker in BC.

R-spondin family members as novel biomarkers and prognostic factors in lung cancer.

The R-spondin (RSPO) family of secreted proteins consists of four members that have critical roles in embryonic development and organogenesis. However, the expression patterns and the exact roles of the individual RSPO family members in tumorigenesis and progression of lung cancer are unknown, particularly in non-small cell lung cancer, which accounts for 85% of all lung cancer cases. In the present study, data from the ONCOMINE database was used to compare the RNA expression levels of RSPOs in multiple different types of cancer with normal controls. The expression profiles of RSPOs in various types of cancer cell lines were subsequently compared based on data from the Broad Institute Cancer Cell Line Encyclopedia. Using the Kaplan-Meier plotter, the prognostic value of expression of the different RSPOs members was determined for different pathological subtypes of lung cancer. When compared with normal tissues, expression of RSPO1, RSPO2 and RSPO3 was significantly lower in patients with lung cancer. In the survival analysis, increased mRNA expression levels of RSPO1, RSPO2 and RSPO3 were associated with increased survival in patients with lung adenocarcinomas. These results suggest that RSPO1, RSPO2 and RSPO3 may serve as distinct biomarkers and prognostic factors in patients with lung cancer.

FBXO22 Possesses Both Protumorigenic and Antimetastatic Roles in Breast Cancer Progression.

The molecular underpinnings behind malignant progression of breast cancer from a localized lesion to an invasive and ultimately metastatic disease are incompletely understood. Here, we report that F-box only protein 22 (FBXO22) plays a dual role in mammary tumorigenesis and metastasis. FBXO22 was upregulated in primary breast tumors and promoted cell proliferation and colony formation in vitro and xenograft tumorigenicity in vivo Surprisingly, FBXO22 suppressed epithelial-mesenchymal transition (EMT), cell motility, and invasiveness in vitro and metastatic lung colonization in vivo Clinical data showed that expression levels of FBXO22 were associated with favorable clinical outcomes, supporting the notion that metastasis, rather than primary cancer, is the major determinant of the mortality of patients with breast cancer. Mechanistic investigations further revealed that FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3ß phosphorylation-dependent manner. Importantly, expression of SNAIL rescued FBXO22-mediated suppression of EMT, cell migration, and invasion. A patient-derived tryptophan-to-arginine mutation at residue 52 (W52R) within the F-box domain impaired FBXO22 binding to the SKP1-Cullin1 complex and blocked FBXO22-mediated SNAIL degradation, thus abrogating the ability of FBXO22 to suppress cell migration, invasion, and metastasis. Collectively, these findings uncover an unexpected dual role for FBXO22 in mammary tumorigenesis and metastatic progression and delineate the mechanism of an oncogenic mutation of FBXO22 in breast cancer progression.Significance: These findings highlight the paradoxical roles of FBXO22 in breast cancer, as it promotes breast tumor cell proliferation but prevents EMT and metastasis. Cancer Res; 78(18); 5274-86. ©2018 AACR.

Tanshinone IIA Sodium Sulfonate Attenuates LPS-Induced Intestinal Injury in Mice.

BACKGROUND: Tanshinone IIA sodium sulfonate (TSS) is known to possess anti-inflammatory effects and has exhibited protective effects in various inflammatory conditions; however, its role in lipopolysaccharide- (LPS-) induced intestinal injury is still unknown. OBJECTIVE: The present study is designed to explore the role and possible mechanism of TSS in LPS-induced intestinal injury. METHODS: Male C57BL/6J mice, challenged with intraperitoneal LPS injection, were treated with or without TSS 0.5 h prior to LPS exposure. At 1, 6, and 12 h after LPS injection, mice were sacrificed, and the small intestine was excised. The intestinal tissue injury was analyzed by HE staining. Inflammatory factors (TNF-α, IL-1ß, and IL-6) in the intestinal tissue were examined by ELISA and RT-PCR. In addition, expressions of autophagy markers (microtubule-associated light chain 3 (LC3) and Beclin-1) were detected by western blot and RT-PCR. A number of autophagosomes were also observed under electron microscopy. RESULTS: TSS treatment significantly attenuated small intestinal epithelium injury induced by LPS. LPS-induced release of inflammatory mediators, including TNF-α, IL-1ß, and IL-6, were markedly inhibited by TSS. Furthermore, TSS treatment could effectively upregulate LPS-induced decrease of autophagy levels, as evidenced by the increased expression of LC3 and Beclin-1, and more autophagosomes. CONCLUSION: The protective effect of TSS on LPS-induced small intestinal injury may be attributed to the inhibition of inflammatory factors and promotion of autophagy levels. The present study may provide novel insight into the molecular mechanisms of TSS on the treatment of intestinal injury.

Protective effects of tanshinone IIA sodium sulfonate on ischemia-reperfusion-induced myocardial injury in rats.

OBJECTIVES: This study investigated the protective effect of tanshinone IIA sodium sulfonate (TSS) on ischemia-reperfusion (I/R) induced cardiac injury, and the underlying mechanism of action. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to a 30-min coronary arterial occlusion followed by 24 hours' reperfusion. Half an hour before the left coronary artery ligation, rats were pretreated with TSS in three different dosages (15, 30, 70 mg/kg, IP). Twenty-four hours later, cardiac function was measured and the ratio of infarct size to area at risk (AAR) was calculated. Western blotting examined the expression of the inflammatory mediator high-mobility group box1 (HMGB-1), anti-apoptotic protein Bcl-2, pro-apoptotic mediators such as Bax and Caspase-3, markers of autophagy such as ratio of LC3B/LC3A and Beclin-1 expression. RESULTS: Our results showed that TSS dose-dependently improves cardiac function, accompanied with decrease of HMGB1 level, increase of LC3B/LC3A ratio and increase of Beclin-1 expression. TSS treatment down-regulates Bax and Caspase-3 expression, while up-regulating Bcl-2 levels. CONCLUSION: TSS ameliorates I/R induced myocardial injury and improves cardiac function via reducing inflammation and apoptosis, while enhancing autophagy.

Extracorporeal membrane oxygenation combined with continuous renal replacement therapy in cutaneous burn and inhalation injury caused by hydrofluoric acid and nitric acid.

RATIONALE: Hydrofluoric acid (HF) is a highly corrosive agent and can cause corrosive burns. HF can penetrate deeply into tissues through intact skin and the lipid barrier, leading to painful liquefactive necrosis, and inducing hypocalcemia and hypomagnesemia. In this study, we hypothesize that continuous renal replacement therapy (CRRT) may be beneficial in addressing hemodynamic instability in cases of HF poisoning. PATIENT CONCERNS: A 25-year-old man fell into an electroplating pool containing 10% HF and 50% nitric acid. DIAGNOSES: He had severe cutaneous injuries involving approximately 60% of his total body surface area including the head, face, neck, right upper arm, right hand, trunk, perineum, and both lower limbs and feet. Examination at admission showed the following electrolyte concentrations: ionic calcium 0.192 mmol/L, total calcium 0.72 mmol/L, magnesium 0.4 mmol/L, potassium 5.49 mmol/L, and sodium 136.8 mmol/L. INTERVENTIONS: An initial 20 mL intravenous bolus of 10% calcium gluconate was followed by a continuous infusion at 6 g/h plus continuous intravenous drip 25% magnesium sulfate at 1.5 g/h. Continuous cardiac monitoring was performed in the intensive care unit. Extracorporeal membrane oxygenation (ECMO) was used to improve oxygenation function at 38 hours post exposure. Antibiotic therapy using imipenem/cilastin plus vancomycin was required. OUTCOMES: After treatment for 12 hours, electrolyte concentrations returned to normal. On day 11, the hemodynamic parameters were stable and oxygenation function had improved. On day 26, the patient was weaned off CRRT. One month later, the patient twice received skin grafting, then was discharged from the hospital without pulmonary, cardiac, or neurological complications 3 months later. LESSONS: The present case study demonstrates that CRRT may be an effective and potentially lifesaving therapy after severe exposure to HF. Prolonged hemodialysis is recommended to remove delayed release fluoride ions to avoid delayed systemic injury. When conventional therapy can not improve oxygenation and/or carbon dioxide retention, ECMO should be performed as soon as possible.

The prognostic value of long noncoding RNA HOTTIP on clinical outcomes in breast cancer.

Although a few studies have assessed the prognostic value of long noncoding RNA HOTTIP in patients with malignant tumors, the relationship between HOTTIP and clinical outcome of breast cancer remains elusive. The aim of this study is to explore the prognostic significance of HOTTIP in breast cancer patients. A meta-analysis was performed to involve the eligible studies to investigate the association of HOTTIP expression level with outcome in cancer patients. Pooled hazard ratios (HRs) and 95% confidence interval (CI) of HOTTIP for cancer survival were calculated. Five relevant articles involving 460 patients with various solid carcinomas were included in this meta-analysis. For overall survival, high HOTTIP expression could significantly predict worse outcome with the pooled HR of 2.29 (95 % CI 1.72-3.03, P < 0.00001). Furthermore, Gene Expression Omnibus was performed to evaluate the association of HOTTIP expression with the prognosis in breast cancer patients. It was also found an indication that high HOTTIP expression was associated with worse survival in breast cancer patients by microarray analysis (GSE20711, GSE16446 and GSE9195). Finally, association between HOTTIP levels and clinicopathological factors and prognosis was also analyzed in an independent validation cohort including 100 breast cancer cases. HOTTIP expression was correlated with tumor size (P=0.025), lymph node status (P=0.009) and TNM stage (P=0.0001) in the breast cancer validation cohort. The Kaplan-Meier survival curves indicated that breast cancer patients with high HOTTIP expression had worse overall survival (P=0.0139) and disease-free survival (P=0.0003). Multivariate survival analysis based on the Cox proportional hazards model showed that HOTTP is considered as an independent prognostic factor in breast cancer patients. Together, our combined results suggest that high HOTTIP expression may be serving as an unfavorable prognosis predictor for breast cancer patients.

The changes of von willebrand factor/a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 balance in aneurysmal subarachnoid hemorrhage.

The aim of this study was to investigate the role of Von Willebrand Factor/thrombospondin type I repeats-13 (VWF/ADAMTS13) balance in aSAH. Fifty eight patients with aSAH at the First Affiliated hospital of Soochow University, Suzhou, China, between January 2012 and January 2014 were eligible for the study. They were divided into delayed cerebral ischemia group (DCI group) and non-delayed cerebral ischemia group (no DCI group), or cerebral vasospasm group (CVS group) and no spasm group (no CVS group), or good outcome group and poor outcome group. The control group consisted of twenty healthy people. All patients underwent CT, DSA, or (and) CTA diagnosed with intracranial subarachnoid hemorrhage which is caused by aneurysm rupture. Venous blood was drawn in tubes at 3 time points: 1 day after SAH (T1), (4±1) days after SAH (T2), and (9±1) days after SAH (T3) to determine plasma concentrations of ADAMTS13, VWF, P-selectin and IL-6 via enzyme-linked immunosorbent assay (ELISA). Transcranial doppler sonography (TCD) was used to measure mean blood flow velocity of the middle cerebral artery (VMCA). Glasgow Outcome Scale (GOS) was measured before discharge. Among 58 patients, 12 (20.7%) had DCI, 40 (68.9%) had TCD evidence of CVS, and 20 (34.5%) had poor outcome. The concentrations of VWF, P-selectin and IL-6 on T1, T2 and T3 after SAH were significantly higher in DCI, CVS and poor outcome groups compared with those of the control group (P < 0.05). The concentrations of VWF, P-selectin and IL-6 were significantly higher in DCI, CVS and poor outcome groups compared with those of the no DCI, no CVS and good outcome groups. The activity of ADAMTS13 was lower in DCI and poor outcome groups compared with those of the no DCI and good outcome groups (P < 0.05). The activity of ADAMTS13 showed no difference in CVS group and no CVS group (P > 0.05). The results of our study suggest that the increased VWF and decreased ADAMTS13 activity were associated with DCI and poor outcome. The balance of VWF/ADAMTS13 could be used to predict the clinical outcome. The deficiency of ADAMTS13 can not only induce DCI but also accelerate inflammatory reaction. Our results reported in this paper may provide new insights into the possible use of ADAMTS13 as a therapeutic agent in aneurysmal subarachnoid hemorrhage.

Prognostic role of circulating microRNA-21 in cancers: evidence from a meta-analysis.

Circulating microRNAs (miRNAs) exhibit altered expression in patients with cancer and could be considered as potential prognostic biomarker of cancer. Here, we performed a meta-analysis to summarize all the results from available studies, aiming to analyze the prognostic role of circulating microRNA-21 (miR-21) in human cancers. Eligible studies were identified from PubMed and EMBASE through multiple search strategies. We extracted and estimated the hazard ratios (HRs) for overall survival (OS), which compared the high and low expression levels of circulating miR-21 in patients with a variety of carcinomas. Pooled HRs and 95 % confidence intervals (CIs) were calculated. Eleven studies with a total of 1,224 patients with various carcinomas were included this meta-analysis. For OS, higher circulating miR-21 expression could significantly predict worse outcome with the pooled HR of 2.11 (95 % CI 1.36-3.26, P = 0.0009). The subgroup analysis suggested that the elevated circulating miR-21 expression was correlated with worse OS in Asian population with the pooled HR of 2.36 (95 % CI 1.61-3.48, P < 0.0001) and digestive system cancers with the pooled HR of 2.19 (95 % CI 1.01-4.75, P = 0.05). The present meta-analysis suggests that circulating miR-21 expression is associated with poor survival in patients with cancer and could be a prognostic biomarker for those patients.

Expression patterns of plasma von Willebrand factor and serum interleukin-8 in patients with early-stage severe pulmonary contusion.

BACKGROUND: von Willebrand factor (vWF) is only released from endothelial cells and platelets and is an in vivo and in vitro marker of endothelial injury in septic patients with acute lung injury (ALI). Interleukin-8 (IL-8), as a proinflammatory mediator causing recruitment of inflammatory cells, induces an increase in oxidant stress mediators and makes it as a key parameter for localized inflammation. However, it has not been well established whether the level of serum IL-8 is associated with the severity of lung injury and whether it is a prognosis marker for severe lung contusion. This study was to investigate the expression of plasma vWF and IL-8 and their association with the severity and outcomes of severe pulmonary contusion. METHODS: A total of 63 patients were divided into a severe pulmonary contusion with acute respiratory distress syndrome (ARDS) group and a non-ARDS group, or a survivor group and a non-survivor group, or an injury severity score (ISS) <20 group and an ISS ≥20 group. Another 20 healthy volunteers served as controls. The levels of plasma vWF and serum IL-8 were measured by enzyme-linked immunosorbent assay (ELISA) at 1, 3, 5 and 7 days after injury. The expression patterns of the plasma vWF and serum IL-8 were compared between different groups. RESULTS: The concentrations of plasma vWF and serum IL-8 were significantly increased in all severe pulmonary contusion patients at all time points in comparison with the control group. The concentrations of plasma vWF in patients with ARDS increased during the whole study period, but vWF in patients with non-ARDS increased gradually until day 5 and then decreased at day 7. The concentration of serum IL-8 showed a similar expression pattern in both groups, but the expression increased more significantly in the ARDS group than in the non-ARDS group. Interestingly, both plasma vWF and serum IL-8 levels steadily increased in the non-survivor group. Furthermore, the level of plasma vWF was higher in the ISS≥20 group than in the ISS<20 group. The level of serum IL-8 in the ISS≥20 group was consistently high, while that in the ISS<20 group peaked at day 3 and decreased at day 5. In addition, the level of plasma vWF was positively correlated with platelet count, but negatively correlated with oxygen index. The level of serum IL-8 was positively correlated with white blood cell count and ISS score, and inversely correlated with oxygen index. CONCLUSION: The elevated levels of plasma vWF and serum IL-8 in severe pulmonary contusion patients reflect the severity of pulmonary injury and patients outcomes, suggesting that the plasma vWF and serum IL-8 are sensitive markers for clinical evaluation of the severity of pulmonary injury and predication of patient prognosis.

[Expression and clinical significance of MTA1 in non-small cell lung cancer.].

BACKGROUND: Metastasis-associated gene 1 (MTA1 ) has been studied deeply recently as a tumor infiltration and metastasis gene. It was expressed in many tumor cell line and was correlated with tumor infiltration and metastasis. The aim of this study is to investigate the relationship between the expression of MTA1 and invasion and metastasis of non-small cell lung cancer (NSCLC). METHODS: Optimal conditions of nested reverse transcription polymerase chain reaction (RT-PCR) were found out; then the expression of MTA1 mRNA in 42 samples of primary carcinoma tissues, paracancerous tissues, normal tissues and corresponding lymph nodes were compared with 20 lung innocence tissues at semi-quantitative level and the results were compared with clinical pathologic data. RESULTS: Average expression of the MTA1 gene in NSCLC primary carcinoma tissue (1.50+/-0.26) and lymph nodes with metastasis (1.88+/-0.35) was remarkably higher than that in normal tissue (1.02+/-0.17) and lung innocence tissue (0.90+/-0.15) (P <0.01). Average expression of the MTA1 gene in NSCLC primary carcinoma tissue (1.50+/-0.26) was significantly higher than that in paracancerous tissue (1.09+/-0.16). Average expression of the MTA1 gene in lymph nodes with metastasis (1.88+/-0.35) was significantly higher than that in those without metastasis (1.40+/-0.36) (P <0.01). The frequency of MTA1 overexpression in NSCLC tissue was closely correlated with clinical staging, T staging and N staging; the frequency of MTA1 overexpression was 45.2% (19/42) in NSCLC tissue. The frequency of MTA1 overexpression was 84.2% (16/19) in lymph nodes with metastasis. The expression level of MTA1 gene in cancer tissues was not related to age, gender of the patients and type of tumor. CONCLUSIONS: Our data suggests that the overexpression of the MTA1 gene correlates with invasion and metastasis of NSCLC. A high expression of MTA1 mRNA may be a potential indicator for assessing the malignancy and metastasis of NSCLC.