[Primary cardiac angiosarcoma: a clinicopathological and molecular genetic analysis of thirteen cases].

Objective: To investigate the clinicopathological and molecular features of primary cardiac angiosarcoma (PCAS), and to analyze the correlation between KDR mutation and the clinicopathological features of PCAS. Methods: Thirteen cases of PCAS were collected at Beijing Anzhen Hospital, Capital Medical University from January 2007 to December 2021. The clinicopathological features, diagnosis, differential diagnosis and outcome were retrospectively analyzed. KDR mutation was detected by next-generation sequencing (NGS) and then the expression of KDR (VEGFR2) was determined by immunohistochemistry (IHC), with review of relevant literatures. Results: There were eight males and five females with a mean age of 45 years. The primary tumor was in the right atrium in 10 cases, left atrium in two cases and right ventricle in one case. The histomorphology was mainly poorly differentiated angiosarcoma (11 cases), with highly pleomorphic spindle or round cells in solid sheets, brisk mitotic activity and extensive necrosis. Vascular lumen formation was observed in two cases of high to moderate differentiation, and biphenotypic differentiation was seen in five cases. IHC staining showed CD34, CD31, Fli1, ERG and vimentin were diffusely positive, pan-cytokeratin was positive, Ki-67 index ranged from 3% to 90%, which was positively correlated with the differentiation degree and grade of the PCASs (P<0.05). At the end of follow-up period, one patient was alive, two patients were lost to follow-up, and the remaining 10 patients had an average survival time of 4.6 months. Finally, NGS sequencing was performed on seven samples after screening, and the results showed that KDR and NF1 mutations were both present in three cases. VEGFR2 expression had no significant correlation with the differentiation degree and grade of PCAS (P>0.05), and it was not related to KDR mutation. Conclusions: PCASs mainly occur in the right atrium, and are mainly poorly differentiated. Ki-67 index is helpful to assess the degree and grade of tumor differentiation. The occurrence and development of PCAS may be related to the pathway involved in KDR mutation, but KDR mutation has no clear correlation with clinicopathological characteristics of PCAS, and immunohistochemical staining can not replace gene detection to determine whether the tumor had KDR mutation.

Targeting the BRAF pathway in haematological diseases.

Since the recognition of BRAF V600E mutations in the majority of cases of hairy cell leukaemia, Erdheim-Chester disease and Langerhans cell histiocytosis, the targeted oral kinase inhibitors dabrafenib and vemurafenib have been adapted for their treatment. Like other targeted agents, these drugs produce high response rates and predictable but unique side effects. Physician familiarity is essential for the effective use of these agents. We review the Australian experience of BRAF/MEK inhibitor therapy in these rare haematological cancers.

[Acute respiratory distress syndrome caused by quetiapine poisoning: a case report].

Quetiapine is a psychotropic drug. Excessive use of quetiapine may lead to drowsiness, blurred vision, respiratory depression, hypotension and extrapyramidal reactions. Acute respiratory distress syndrome (ARDS) is rare due to overdose of quetiapine. On 14 February 2020, a patients with coma, respiratory arrest and hypotension due to overdose of quetiapine were admitted to our hospital. After receiving mechanical ventilation、plasma adsorption and anti-inflammatory treatment, the patient's consciousness turned clear, the machine was successfully removed and extubated, and the patient's condition was improved and discharged from hospital. We analyzed the clinical data of the patient with quetiapine poisoning, and discussed the clinical symptoms and chest CT characteristics of ARDS caused by quetiapine poisoning, in order to improve the understanding of quetiapine poisoning and improve the success rate of rescue.

[Four cases of acute diquat poisoning with prominent epileptoid seizure and literature review].

Objective: To further improve the awareness of the clinical feature of acute diquat poisoning. Methods: A retrospective analysis was performed on 4 cases of acute diquat poisoning with epileptoid seizure as the main clinical manifestation, which were admitted and diagnosed by the Characteristic Medical Center of Chinese People's Armed Police Force from January 1, 2017 to December 31, 2019. Take "Diquat" or "Deiquat" or "Reward" as keyword search for CNKI, Pubmed, and EMbase in both Chinese and English. The date of literature retrieval was from the database founding to December 31, 2019. Results: Of the 4 patients, 3 were male and 1 female, with an average age of 28 years (22-33 years) . The estimated dose was 8-20 g. All patients were treated with gastric lavage, catharsis, fluid replacement, blood perfusion, and in the early stage of treatment of epileptic seizures, the initial routine antiepileptic drugs had poor effect. Then propofol and midazolam were injected into the treatment. The epilepsy was relieved, but the condition deteriorated rapidly, and the patients died eventually. The literature search retrieved 3 patients in the 3 literatures included in the study were analyzed, and their clinical course was similar to that of 4 cases in the center. Necropsy was performedon all 3 patients, and the results were cerebral edema, diffuse cerebral edema, and hemorrhage around the basal ganglia. Conclusion: Acute diquat poisoning can cause epileptic seizures. Once it occurs, the disease progresses rapidly and the prognosis is poor. The combination of large dose of sedative drugs can be used to treat epilepsy in order to improve the prognosis.

[Absence of arterial duct in fetus: an autopsy analysis].

Objective: To analyze the absence of congenital arterial duct in fetus and to improve the diagnostic accuracy. Methods: Four hundred cases of congenital heart disease diagnosed by echocardiography during pregnancy were examined the fetal cardiovascular malformation and visceral malformation, and the absence of arterial duct was analyzed. Results: There were 24(6%)cases of absence of arterial duct, including 19 cases of left aortic arch and five cases of right aortic arch. There were 21 cases with main pulmonary arteries and 3 cases without main pulmonary arteries and branches. There were 15 cases of pulmonary artery stenosis with absence of arterial duct and the major cardiovascular malformations included six cases of single ventricle, six cases of atrial septal defect, four cases of single atrium, four cases of right atrium isomerism, four cases of double outlet right ventricle, four cases of anomalous pulmonary venous drainage, three cases of tetralogy of Fallot, and three cases of persistent left superior vena cava. There were seven cases of pulmonary atresia with absence of arterial duct and with systemic-pulmonary collateral circulation. There was one case of tetralogy of Fallot with absent pulmonary valve and absent arterial duct and the pulmonary artery was dilated. There was one case of aortopulmonary septal defect with absent arterial duct, with normal pulmonary artery. There were also seven cases of asplenia, seven cases of pulmonary abnormality and seven cases of visceral inversion. Conclusions: The absence of arterial duct is often associated with congenital heart disease. Pulmonary atresia is often associated with systemic-pulmonary collateral circulation. The visceral malformations are related to the accompanying congenital cardiovascular malformations.

Long noncoding RNA MAFG-AS1 facilitates the progression of hepatocellular carcinoma via targeting miR-3196/OTX1 axis.

OBJECTIVE: Hepatocellular carcinoma (HCC) is an invasive malignant tumor with high mortality rate. Long non-coding RNA (lncRNA) MAFG-AS1 has been showed to play an oncogenic role in several malignant tumors. Nonetheless, the exact role of MAFG-AS1 in the progression of HCC has not been fully elucidated. PATIENTS AND METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect the mRNA and protein expression of MAFG-AS1 in HCC tissues and cells. Cell counting kit-8 (CCK-8), transwell and tubule formation assays were applied to uncover the proliferation, migration, invasion and tumor angiogenesis of HCC cells, respectively. RNA binding protein immunoprecipitation (RIP) assay and Luciferase reporter gene assay were employed to explore the molecular mechanism. In addition, Xenograft assay was used to investigate the effect of MAFG-AS1 in vivo. RESULTS: MAFG-AS1 was highly expressed in HCC tissues and cells. Attenuation of MAFG-AS1 evidently suppressed the proliferation, migration, invasion and tumor angiogenesis of HCC cells, suggesting that MAFG-AS1 played an oncogenic role in HCC. MiR-3196 was sponged by MAFG-AS1, and OTX1 was a downstream target of miR-3196 in HCC. In addition, OTX1 expression was negatively associated with miR-3196 but positively associated with MAFG-AS1 in HCC tissues. Overexpression of OTX1 could abolish the repressive influence of MAFG-AS1 inhibition on the proliferation, migration, invasion and tumor angiogenesis of HCC cells. CONCLUSIONS: MAFG-AS1 facilitated the progression of HCC via targeting miR-3196/OTX1 axis, which might be used as a new insight for HCC treatment.

Perinatal risk factors for fecal antibiotic resistance gene patterns in pregnant women and their infants.

Perinatal factors can shape fecal microbiome patterns among pregnant women and their infants. However, there is scarce information about the effect of maternal demographics and perinatal exposures on antibiotic resistance genes (ARG) and mobile genetic element (MGE) patterns in pregnant women and infants. We examined fecal samples from pregnant women during their third trimester of pregnancy (n = 51) and 6-month-old infants (n = 40). Of the 91 participants, 72 represented 36 maternal-infant dyads, 15 were additional pregnant women, and 4 were additional infants. We assessed the effects of demographics, pre-pregnancy BMI, smoking and parity in the pregnancy resistome and the effects of demographics, delivery mode, feeding habits and prenatal antibiotic treatment on the infancy resistome. ARG and MGE richness and abundance were assessed using a SmartChip qPCR-array. Alpha diversity (Shannon and Inverse Simpson index) and beta diversity (Sorensen and Bray-Curtis index) were calculated. The Wilcoxon and the Kruskal non-parametric test were used for comparisons. There is a high variability in shared resistome patterns between pregnant women and their infants. An average of 29% of ARG and 24% of MGE were shared within dyads. Infants had significantly greater abundance and higher diversity of ARG and MGE compared to pregnant women. Pregnancy and infancy samples differed in ARG and MGE gene composition and structure. Composition of the fecal resistome was significantly associated with race in pregnant women, with non-white women having different patterns than white women, and, in infants, with extent of solid food consumption. Our data showed that the pregnancy and infancy resistome had different structure and composition patterns, with maternal race and infant solid food consumption as possible contributors to ARG. By characterizing resistome patterns, our results can inform the mechanism of antibiotic resistome development in pregnant women and their infants.

Tyrophagus putrescentiae group 4 allergen allergenicity and epitope prediction.

INTRODUCTION AND OBJECTIVES: Allergen-specific immunotherapy (ASIT) is the only allergic disease-modifying therapy available for children and adults, and recombinant allergens are an interesting approach to improve allergy diagnosis and ASIT. Tyrophagus putrescentiae is a common storage mite that produces potent allergens. The aim of this study was to express and characterize recombinant group 4 allergen protein of T. putrescentiae (Tyr p 4), and to further investigate allergenicity and potential epitopes of Tyr p 4. MATERIALS AND METHODS: The cDNA encoding Tyr p 4 was generated by RT-PCR and subcloned into pET-28a(+) plasmid. The plasmid was then transformed into E. coli cells for expression. After purification by nickel affinity chromatography and identification by SDS-PAGE, recombinant Tyr p 4 protein was used for a skin prick test and an ELISA to determine the allergic response. RESULTS: Study participants' allergic response rate to Tyr p 4 protein was 13.3% (16/120). Eight B-cell epitopes and three T-cell epitopes of Tyr p 4 were predicted. CONCLUSIONS: Similar to group 4 allergens of other species of mite, allergenicity of Tyr p 4 is weak. The expression, characterization and epitope prediction of recombinant Tyr p 4 protein provide a foundation for further study of this allergen in the diagnosis and ASIT of storage mite allergy.

[Expression and clinical significance of MIIP and PAK1 in endometrial carcinoma].

Objective: To investigate the expressions of migration and invasion inhibitory protein (MIIP) and p21-activated kinase 1 (PAK1) in endometrial carcinoma (EC) and their correlation with clinicopathological features. Methods: The protein levels of MIIP and PAK1 in 135 paraffin-embedded EC tissues, 55 atypical hyperplasia of endometrium (AHE) and 88 normal endometrium (NE) tissues were quantified by immunohistochemistry, the clincial significance and the relationship of these two proteins were also analyzed. Results: The positive rates of MIIP expression in NE, AHE and EC tissues were 52.3%(46/88), 41.8% (23/55) and 34.8% (47/135), respectively. The expression of MIIP in EC was significantly lower than that of MIIP in NE (P<0.05). The positive rates of PAK1 expression in NE, AHE and EC tissues were 45.5% (40/88), 50.9% (28/55) and 62.2% (84/135), respectively. The expression of PAK1 in EC tissues was significantly higher than that of PAK1 in NE tissues (P<0.05). The expression of MIIP in EC tissues was significantly associated with myometrial invasion, International Federation of Gynaecology and Obstetrics (FIGO) stage and lymph node metastasis (P<0.05). The expression of PAK1 in EC tissues was significantly related with differentiation, myometrial invasion, FIGO stage and lymph node metastasis (P<0.05). The expressions of MIIP and PAK1 in EC tissues were marginally related with the overall survival of patients (P=0.092, P=0.052). The expression of MIIP in EC was negatively correlated with PAK1 (r=-0.329, P<0.001). Conclusions: The down-regulation of MIIP and up-regualtion of PAK1 paticipate in the initiation and development of EC, which are correlated with the poor prognosis of EC. The protein expression of MIIP is inversely related with PAK1 in EC.

Berberine Improves Cognitive Deficiency and Muscular Dysfunction via Activation of the AMPK/SIRT1/PGC-1a Pathway in Skeletal Muscle from Naturally Aging Rats.

OBJECTIVE: The manifestations of aging include cognitive deficits and muscular dysfunction, which are closely linked to impairment of mitochondrial biogenesis. Berberine, an isoquinoline alkaloid, presents multiple anti-diabetic pharmacological effects. Evidence has indicated that insulin resistance and cognitive impairment share the same pathogenesis, and berberine could reverse glucose metabolism abnormalities and muscle mitochondrial dysfunction induced by a high-fat diet. This study was used to investigate whether berberine could be used as an anti-aging drug to prevent cognitive deficits and muscular dysfunction in natural aging. METHODS: Biochemical indicators and an intraperitoneal glucose tolerance test were tested in 5-month-old rats (5 mo group), 24-month-old rats (24 mo group) and 24-month-old rats that had undergone 6 months of berberine treatment (BBR group). A Morris water maze test was conducted to assess the cognitive ability of the rats. Insulin resistance in whole-body was evaluated by intraperitoneal glucose tolerance test (IPGTT). The morphology of the skeletal muscle tissue was observed by hematoxylin-eosin (HE) staining. The levels of total cholesterol, triglyceride, ATP and reactive oxygen species (ROS) were assessed with corresponding reagent kits. The protein expressions of GLUT4, AMPK, SIRT1 and PGC-1α in skeletal muscle were examined by Western blot. RESULTS: The results showed that administration of berberine for 6 months significantly improved cognitive deficits and insulin resistance in naturally aging rats (p<0.01). Furthermore, berberine treatment helped normalize the disordered alignment and the decreased number of muscle fibers (p<0.01) in the skeletal muscle of 24 mo rats. Berberine decreased the levels of ROS in both the serum and the skeletal muscle of 24 mo rats (p<0.01). Berberine increased the protein expression of p-AMPK, SIRT1 and PGC-1α and increased the production of ATP in the skeletal muscle of aging rats (p<0.01). CONCLUSIONS: Berberine markedly ameliorates aging-related reductions in cognitive ability and muscular function, and the activation of the AMPK/SIRT1/PGC-1α pathway in skeletal muscle may be the underlying protective mechanism of berberine on muscular function.

[Triptolide reverses apatinib resistance in gastric cancer cell line MKN45 via inhibition of heat shock protein 70].

Objective: To investigate the effect of triptolide, a specific inhibitor of heat shock protein 70 (HSP70), on apatinib resistance in gastric cancer cells line MKN45. Methods: The apatinib-resistant cells (MKN45/AR) and MKN45 parental cells were treated with apatinib, triptolide and apatinib combined with triptolide, respectively. CCK-8 assay was performed to determine the half maximal inhibitory concentration (IC(50)) of MKN45/AR and MKN45 cells in the presence of different treatment. The mRNA expression of heat shock protein gene (HSPA1A and HSPA1B) was detected by RT-PCR, while the protein expression of heat shock protein 70 was analyzed using Western blot in MKN45/AR and MKN45 cells. Results: The IC(50) values of apatinib-sensitive and apatinib-resistant MKN45 cells were 10.411 µmol/L and 70.527 µmol/L, respectively, showing a significant difference (P<0.05). The mRNA expression of HSPA1A and HSPA1B in MKN45/AR cells was significantly higher than that in MKN45 cells (P<0.001). The protein expression of heat shock protein 70 was significantly decreased after 0.25 µmol/L triptolide treatment in MKN45/AR cells (P<0.01). When heat shock protein 70 was inhibited by triptolide, the IC(50) value of apatinib in MKN45/AR cells was reduced to 11.679 µmol/L, which was significantly lower than cells treated with apatinib alone (P<0.05). Conclusions: The apatinib-resistant MKN45 cells have high levels of heat shock protein 70. Low doses of triptolide can significantly inhibit heat shock protein 70, leading to reverse the resistance phenotype of MKN45/AR cells. Therefore, inhibition of heat shock protein 70 provides a new therapy strategy for patients with apatinib resistance.

Polydopamine deposition with anodic oxidation for better connective tissue attachment to transmucosal implants.

BACKGROUND AND OBJECTIVE: Nowadays, most designs for the transmucosal surface of implants are machined-smooth. However, connective tissue adhered to the smooth surface of an implant has poor mechanical resistance, which can render separation of tissue from the implant interface and induce epithelial downgrowth. Modification of the transmucosal surface of implants, which can help form a good seal of connective tissue, is therefore desired. We hypothesized that anodic oxidation (AO) and polydopamine (PD) deposition could be used to enhance the attachment between an implant and peri-implant connective tissue. We tested this hypothesis in the mandibles of Beagle dogs. MATERIAL AND METHODS: AO and PD were used to modify the transmucosal region of transmucosal implants (implant neck). The surface microstructure, surface roughness and elemental composition were investigated in vitro. L929 mouse fibroblasts were cultured to test the effect of PD on cell adhesion. Six Beagle dogs were used for the in vivo experiment (n = 6 dogs per group). Three months after building the edentulous animal model, four groups of implants (control, AO, PD and AO + PD) were inserted. After 4 months of healing, samples were harvested for histometric analyses. RESULTS: The surfaces of anodized implant necks were overlaid with densely distributed pores, 2-7 µm in size. On the PD-modified surfaces, N1s, the chemical bond of nitrogen in PD, was detected using X-ray photoelectron spectroscopy. L929 developed pseudopods more quickly on the PD-modified surfaces than on the surfaces of the control group. The in vivo experiment showed a longer connective tissue seal and a more coronally located peri-implant soft-tissue attachment in the AO + PD group than in the control group (P < .05). CONCLUSION: The modification of AO + PD on the implant neck yielded better attachment between the implant and peri-implant connective tissue.

[Clinical application of adult comorbidity evaluation-27 in endometrial cancer].

Objective: To investigate the significant role of the clinical application of adult comorbidity evaluation-27 (ACE-27) in endometrial cancer (EC). Methods: A total of 847 EC patients were included during Jan. 1985 to Dec. 2015 from Tianjin Medical University General Hospital. The clinical data of the patients were collected and analyzed retrospectively. All of the patients were received operation with no chemotherapy and radiotherapy before operation. The average age was 57.6 years old (range from 25 to 85 years old). The average follow-up period was 59.0 months (range from 2 to 312 months). The comorbidity of the patients was evaluated by ACE-27. EC patients survival was analyzed by Kaplan-Meier survival curve. The relationship between the prognosis of EC and ACE-27, age, body mass index (BMI) , pathological characteristic were showed by Cox modeling. Results: (1) The patient number of score 0, 1, 2 and 3 of ACE-27 in EC patients were respectively 311 (36.7%), 263 (31.1%), 132 (15.6%) and 141 (16.6%) cases. (2) Kaplan-Meier survival curve analysis showed that overall survival time of EC patients was gradually decreased as increased score of ACE-27 (χ2=19.003, P=0.000) . In the patients of BMI<25 kg/m2 and BMI 25-<30 kg/m2, International Federation of Gynecology and Obstetrics (FIGO) stage Ⅰ, endometrial adenocarcinoma type and the overall survival time of those EC patients were gradually decreased as increased score of ACE-27 (P<0.05) . However, there was no statistically significant difference in overall survival time for patients with BMI ≥30 kg/m2, FIGO stage with Ⅱ-Ⅳand non-endometrial adenocarcinoma type (P>0.05). Per unvariate logistic modeling showed that the risk of death in score 3 of ACE-27 was increased compared with score 0 of ACE-27 (OR=2.53, P=0.000) . The overall survival time in EC patients with aged 50-59, 60-69 and ≥70 years old, BMI 25-<30 kg/m2 and ≥ 30 kg/m2, G3, FIGO stage Ⅱ-Ⅳ and non-endometrial adenocarcinoma type were significantly decreased compared with those aged <50 years old, BMI < 25 kg/m2, G1, FIGO stage Ⅰ and endometrial adenocarcinoma type (all P<0.05) . Further we found that postoperative chemotherapy or radiotherapy rate were decreased for EC patients with FIGO staging Ⅲ or Ⅳ as the increase of ACE-27 score, but there was no statistically significant difference (P>0.05). (3) Per multivariate logistic modeling showed that the risks of death in score 3 of ACE-27 was increased compared with score 0 of ACE-27 among age-adjusted, BMI, histological grade, FIGO stage and pathologic type (OR=2.40, P=0.000) . Per multivariate logistic modeling showed that, the overall survival time in EC patients with aged 60-69 and ≥70 years old, BMI 25-<30 kg/m2 and ≥30 kg/m2, FIGO stage Ⅲ-Ⅳ and non- endometrial adenocarcinoma type remain significantly decreased compared with those aged <50 years old, BMI<25 kg/m2, FIGO stage Ⅰ and endometrial adenocarcinoma type (P<0.05) , but there was no statistically significant difference in histological grade (P>0.05). Conclusions: ACE-27 may become one of the factors of predictive therapy and the prognosis for EC patients. The detailed clinical data of comorbidity should be collected to evaluate prognosis and therapy plan.

Transcriptomic/proteomic identification of allergens in the mite Tyrophagus putrescentiae.

While a number of allergens from house dust mites have been described, much remains to be discovered about allergens from storage mites. Here, next-generation sequencing was combined with MS/MS shotgun proteomics to identify proteins, especially potential allergens from Tyrophagus putrescentiae, commonly found in stored food products, especially flour. cDNAs of suspected allergens were cloned and expressed from bacterial cells, and recombinant allergens were tested for binding to IgE in sera from T. putrescentiae-sensitive patients. These analyses identified three previously uncharacterized allergens, Tyr p 28, Tyr p 35, and Tyr p 36, which have been officially assigned by the WHO/IUIS Allergen Nomenclature Sub-committee. Recombinant proteins rTyr p 28, rTyr p 35, and rTyr p 36 bound with 47.1%, 82.4%, and 70.6% of T. putrescentiae-sensitive sera. We provide here a new method to identify allergens by the combination of transcriptomic and proteomic approaches.

The association of HOTAIR expression with clinicopathological features and prognosis in gastric cancer patients.

INTRODUCTION: A number of studies in gastric carcinoma have demonstrated that cancerous tissues have a significant higher HOTAIR level than that in noncancerous tissues. Overexpression of HOTAIR is associated with the development in gastric cancer. EVIDENCE ACQUISITION: We collected all relevant articles and explored the association of HOTAIR expression with clinicopathological features and prognosis in patients with gastric cancer. Literature collections were conducted by searching a number of electronic databases (up to November 15, 2015). The meta-analysis was conducted by using RevMan v.5.3 software and Stata SE 12.0. EVIDENCE SYNTHESIS: A total of 832 patients with gastric cancer based on 10 studies were included. The Meta-analysis results showed that high-expression of HOTAIR is significantly associated with clinicopathological features in gastric cancer patients, especially in the depth of tumor invasion, lymph node metastasis, vessel invasion, lymphatic vessel involvement and TNM stage, but there is no association between HOTAIR overexpression and other clinicopathological features. In addition, aberrant HOTAIR expression is also significantly associated with the prognosis in gastric cancer patients. CONCLUSIONS: There is an association between HOTAIR expression and clinicopathological features and prognosis in gastric cancer patients. High expression of HOTAIR in cancerous tissue could predict poor clinical outcome in gastric cancer, suggesting HOTAIR abundance may serve as a novel candidate biomarker for the clinical outcome in gastric cancers.

Long noncoding RNA PVT1, a novel promising biomarker to predict lymph node metastasis and prognosis: a meta-analysis.

BACKGROUND: Numerous studies have found that the expression levels of long noncoding RNA PVT1 (lncRNA PVT1) were elevated in cancerous tissue, which was significantly higher than those in adjacent noncancerous tissues or corresponding normal tissues. Overexpression of lncRNA PVT1 was correlated with lymph node metastasis and a poor prognosis in various cancers. METHODS: This quantitative meta-analysis collected all relevant articles and explored the association of lncRNA PVT1 expression levels with lymph node metastasis and prognosis. The systematic search was conducted through multiple electronic databases (up to December 1, 2015). The meta-analysis was performed by using RevMan5.3 software and Stata SE12.0. RESULTS: A total of 939 patients with cancer from 10 studies were included. The Meta-analysis results showed that cancer patients with high PVT1 have a strong trend for LNM (OR=2.05, 95%CI:0.97-4.30, P=0.06, random-effects model). Moreover, we found that cancer patients with high PVT1 expression had a poorer overall survival (HR=2.07, 95%CI:1.40-2.74, P=0.000, fixed-effects model), a shorter recurrence-free survival (HR=1.70, 95%CI:1.02-2.39, P=0.000, fixed-effects model), and a worse disease-free survival (HR:2.10, 95%CI:0.96-3.23, P=0.000, fixed-effects model). CONCLUSIONS: PVT-1 may serve as a novel molecular marker for lymph node metastasis and prognosis.

Galectin-9 in Combination With EX-527 Prolongs the Survival of Cardiac Allografts in Mice After Cardiac Transplantation.

Galectin-9 (Gal-9), a member of the galectin family, has a variety of biologic activities. However, its role in allografts is not fully clarified yet. The relationship between interleukin-17 (IL-17) and Gal-9 and the role of Gal-9 in T(H)17-cell differentiation also remain unclear. We built a murine cardiac transplantation model, which we treated with Gal-9 and/or EX-527, a specific Sirtuin-1 inhibitor. Afterwards, flow-cytometric analysis and reverse-transcription polymerase chain reaction were used to detect the number of T(H)17 cells and the expression of key factors involved in the differentiation of T(H)17 cells; in addition, the survival times of cardiac transplanted mice in different groups were recorded. The levels of circulating T(H)17 cells were found to increase in the peripheral blood of mice that exhibited acute rejection (AR) after heart transplantation, which was determined to be correlated with the rejection grade. Gal-9 or EX-527 can inhibit the activation and differentiation of T(H)17 cells and effectively suppress T(H)17-cell-mediated AR. These data provide new evidence for the potential regulatory effects of Gal-9 in alloimmune responses in a murine model of heart transplantation, and suggest the combined use of galectin-9 and EX-527 may be a powerful method to induce tolerance of fully mismatched murine cardiac allografts.

Exendin-4 promotes endothelial barrier enhancement via PKA- and Epac1-dependent Rac1 activation.

Among emerging antidiabetic agents, glucagon-like peptide-1 (GLP-1)-based therapies carry special cardiovascular implications, exerting both direct and indirect effects. The control of vascular permeability is of pivotal importance in vascular pathologies. The objective of the present study was to determine the effect of GLP-1 on endothelial barrier function and assess the underlying mechanism(s). Here we show for the first time that the stable GLP-1 analog exendin-4 attenuated the leakage of subcutaneous blood vessels in mice indexed by dye extravasation caused by injections of thrombin. Moreover, in cultured endothelial cells, exendin-4 significantly prevented the thrombin-induced FITC-dextran permeability of endothelial monolayers via GLP-1 receptor. Immunofluorescence microscopy reveals that exendin-4 abrogates detrimental effects of thrombin on VE-cadherin and the F-actin cytoskeleton, with decreased stress fiber and gap formation. Importantly, exendin-4 reduced thrombin-induced tyrosine phosphorylation of VE-cadherin at Y731 and Y658. Moreover, small GTPase Rac1 was significantly activated as a result of exendin-4 treatment. The efficacy of exendin-4 to counteract the barrier-compromising effect of thrombin was blunted when Rac1 was inactivated by Rac1 inhibitor NSC-23766. Inhibition of PKA activity or small-interfering RNA for exchange protein directly activated by cAMP 1 (Epac1) decreased exendin-4-induced Rac1 activation and barrier enhancement, indicating the participation of both PKA and Epac1 in the barrier-stabilizing effect of exendin-4 elicited on thrombin-impaired barrier function. Thus, our findings have uncovered an unpredicted role for exendin-4 in the coordination of vascular permeability and clarified the molecular underpinnings that contribute to barrier restoration initiated by exendin-4.

Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway.

Vascular aging has been implicated in the progression of diabetes and age-related cardiovascular disorders. Glucagon-like peptide-1 (GLP-1) is an incretin hormone capable of cytoprotective actions in addition to its glucose-lowering effect. The present study was undertaken to examine whether Exendin-4, a specific ligand for the GLP-1 receptor, could prevent angiotensin (ANG) II-induced premature senescence in vascular smooth muscle cells (VSMCs) and to determine the underlying mechanism involved. Senescence-associated ß-galactosidase (SA ß-gal) assay showed that ANG II induced premature senescence of VSMCs. Pretreatment with Exendin-4 significantly attenuated ANG II-induced generation of H2O2 and the subsequent VSMC senescence. These effects were, however, reversed in the presence of exendin fragment 9-39, a GLP-1 receptor antagonist, or PKI14-22. Moreover, a marked increase in the levels of p53 and p21 induced by ANG II was blunted by the treatment with Exendin-4. Nevertheless, Exendin-4 failed to decrease ANG II-induced expression of NAD(P)H oxidase 1 (Nox1), NAD(P)H oxidase 4 (Nox4), p22(phox), or p47(phox) in VSMCs. Mechanistically, Exendin-4 blocked ANG II-induced Rac1 activation through the cAMP/PKA signaling cascade. Specifically, NSC23766, a Rac1 inhibitor, abrogated the suppressive effects of Exendin-4 on ANG II-induced premature senescence and H2O2 generation, respectively. Thus Exendin-4 confers resistance to ANG II-induced superoxide anion generation from NAD(P)H oxidase and the resultant VSMC senescence by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. These findings demonstrate that GLP-1 as well as its analogs (GLP-1-related reagents) may hold therapeutic potential in the treatment of diabetes with cardiovascular disease.