[A nested case-control study on the association of neonatal cord blood selenium, iron and copper with congenital heart disease].

Objective: To investigate the relationship between the levels of selenium, iron and copper in cord blood of neonates and the risk of congenital heart disease (CHD), and analyze their interaction effects. Methods: The subjects were obtained from the birth cohort in Lanzhou area established from 2010 to 2012. A baseline survey was conducted in the first trimester, and the follow-up was conducted in the second trimester, third trimester and 42 days after delivery. The umbilical vein blood was collected from newborns at delivery, and information on their birth outcomes was extracted from medical records. A nested case-control study was used to select 97 neonates with CHD newly diagnosed by echocardiography as the case group, and 194 neonates were selected as the control group by 1∶2 matching according to their mother's age, block and CHD onset time. Inductively coupled ion mass spectrometry was used to detect the concentrations of selenium, iron and copper in neonatal cord blood. The element exposure was categorized into three groups, the low, medium and high concentrations, according to the quartiles Q1 and Q3 of selenium, iron and copper concentrations in the control group. The association between cord blood selenium, iron and copper concentrations and CHD was analyzed by conditional logistic regression model using medium concentration as the reference standard. The association of their interactions with CHD was analyzed by a phase multiplication model. Results: The M (Q1, Q3) concentration of neonatal cord blood copper was 746.12 (467.48, 759.74) µg/L in the case group and 535.69 (425.21, 587.79) µg/L in the control group, with a statistically significant difference between the two groups (P<0.05). After adjustment for confounders, logistic regression models showed that the risk of CHD development was increased in neonates with either high copper in cord blood (OR=4.062, 95%CI: 2.013-8.199) or high copper combined with high iron (OR=3.226, 95%CI: 1.343-7.750). No correlation was observed between selenium and iron concentrations and the development of CHD in neonates. There was a multiplicative interaction between copper and iron in cord blood on the risk of developing CHD (OR=1.303, 95%CI: 1.056-1.608). Conclusion: There is a multiplicative interaction between iron and copper elements. The high copper and the high copper combined with high iron in umbilical cord blood are risk factors for neonatal CHD.

[The related factors of postoperative recurrence in trigeminalneuralgia patients undergoing fully neuroendoscopic microvascular decompression].

Objective: To evaluate the related factors of postoperative recurrence intrigeminal neuralgia (TN) patients treated with fully neuroendoscopic microvascular decompression (MVD). Methods: The clinical baseline data and preoperative MRI imaging data of 112 patients with TN treated by neuroendoscopic MVD from December 2008 to December 2020 in the Department of Neurosurgery, Beijing Shijitan Hospital Affiliated to Capital Medical University were retrospectively analyzed, including: area ratio of cerebellopontine area (CPA)(healthy side/affected side), trigeminal nerve(TGN)length ratio(healthy side/affected side), TGN angle ratio(healthy side/affected side), and criminal vessel type. Multivariate Cox proportional hazards model was used to analyze the factors affecting postoperative recurrence. Results: Among the 112 patients in this group, there were 49 males and 63 females. The age ranged from 20 to 82 (59±9) years, and the course of disease was 0.05 to 30.00 (5.60±5.15) years. Pain was located on the left side in 43 cases (38.39%) and on the right side in 69 cases (61.61%), respectively. All patients were followed up for more than 1 year, with an average follow-up time of 21.5 months, and 11 cases recurred. Multivariate Cox regression analysis revealed that disease duration≥3 years(HR=9.34, 95%CI:1.12-39.07), CPA area ratio(healthy side/affected side)>1 (HR=27.47, 95%CI:1.69-44.20), criminal vessel type with vein(HR=35.39, 95%CI:1.26-18.60) and criminal vessel type with arteriovenous (HR=46.07, 95%CI: 2.74-27.75) were the main factors influencing recurrence of MVD surgery (all P<0.05). Conclusion: The disease duration≥3 years, CPA area ratio(healthy side/affected side)>1, and criminal vessel type with vein/arteriovenous are the relevant factors that affect the recurrence rate after the fully neuroendoscopic MVD treatment for trigeminal neuralgia.

Is Online Video-Based Education an Effective Method to Teach Basic Surgical Skills to Students and Surgical Trainees? A Systematic Review and Meta-analysis.

BACKGROUND: Online education has been increasingly utilized over the past decades. The COVID-19 pandemic accelerated the transition of conventional face-to-face curricula to online platforms, with limited evidence for its teaching efficacy. This systematic review aims to assess the effectiveness of online video-based education compared with standard conventional education in teaching basic surgical skills to surgical trainees and students undergoing medical training. METHODS: We performed a literature search in Embase, Medline, Cochrane CENTRAL and Scopus from inception until February 2022. Studies included were randomised controlled trials (RCTs) and observational studies. We included randomised controlled trials only for meta-analysis. The primary outcome was surgical skill proficiency. The secondary outcomes were participant perception, confidence and satisfaction. Two authors independently assessed the search results for eligibility, extracted the data and assessed the risk of bias using the Cochrane Risk of Bias tool 2. Where appropriate, we performed random effects meta-analyses of the pooled study data to calculate a standardized mean difference. RESULTS: A total of 11 studies met the inclusion criteria totaling 715 participants; 603 were included in qualitative analysis and 380 in meta-analysis. All included studies were assessed as having a low risk of bias. The majority of studies found no significant difference between conventional and video-based education in teaching basic surgical skills, three studies found video-based education was superior and one study found conventional education was superior. There was no statistically significant difference in skill proficiency between the two groups (standardized mean difference of -0.02 (95% CI: -0.34, 0.30); p=0.90). Video-based education results in an equivalent improvement in confidence and satisfaction rates. Additional benefits of video-based education include convenience, accessibility and efficiency. CONCLUSIONS: Basic surgical skills can be taught as effectively through online video-based education as conventional teaching methods. Online education should be utilized as an adjunct to medical curricula beyond the COVID-19 era.

[Efficacy analysis of fully endoscopic microvascular decompression in primary trigeminal neuralgia via keyhole approach].

Objective: To explore the efficacy and technical features of fully endoscopic microvascular decompression(MVD) in primary trigeminal neuralgia(PTN) via keyhole approach. Methods: The clinical data of 97 patients with PTN underwent fully endoscopic MVD via keyhole approach in the Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University from December 2014 to February 2019 was collected. During fully endoscopic MVD in PTN via keyhole approach, performer use natural clearance without grinding except developed rock bone crest or excessive retraction of the brain tissue, visually and panoramically observe and evaluate the CPA area, accurately identify the responsible vessels, to avoid the omission of responsible vessels or insufficient decompression. And the use of preplaced technology, bridging technology and submersible technology, ensure the efficacy of surgery and reduce the surgical side injuries.Barrow Neurological Institute (BNI) pain score was used to evaluate the efficacy and identify the recurrence. The surgical efficacy was analyzed. Results: The offending vessels were identified under endoscope in 96 cases. Among them, arterial compression was found in 77 cases, venous compression in 6 cases, and both arterial and venous compression in 13 cases. About the pain outcomes, 87 cases had immediate and complete relief of pain, 5 cases had almost relief of pain, 4 cases had partial relief of pain, and still needed medication control, but the dose was lower than that before operation, and 1 case had no obvious relief of pain. About complications, there were 4 cases of temporary facial numbness, 1 case of temporary hearing loss, both of them recovered after symptomatic treatment. There was no cerebral infarction or hemorrhage, intracranial or incision infection. All cases were followed up for 3.0-38.0 months with a median period of(22.4±2.2) months. During the follow-up periods, postoperative recurrence occurred in 3 cases. Conclusion: Fully endoscopic MVD for PTN through keyhole approach, provides panoramic view to avoid omission of offending vessels and reduce complications, seemed to be a safe and effective surgical method.

[Impacts of incomplete revascularization following off-pump coronary artery bypass grafting on perioperative outcomes in octogenarians].

Objective: To assess the impacts of incomplete revascularization following off-pump coronary artery bypass grafting (OPCABG) on perioperative outcomes in octogenarians. Methods: A retrospective analysis of 242 octogenarian patients with coronary artery disease (CAD) hospitalized in Beijing Anzhen Hospital from June 2008 to July 2016 was performed. These patients were divided into the complete revascularization group (n=181) and the incomplete revascularization group (n=61) depending on whether they underwent complete revascularization. The impacts of incomplete revascularization following OPCABG on perioperative outcomes were summarized and compared between the two groups. Results: Among the 242 patients over 80 years who received OPCABG, there were 198 males (81.8%). Compared to the complete revascularization group, those in the incomplete revascularization group were older [(83.2±1.5) vs (81.5±1.1) years old, P=0.03], with more carotid stenosis (44.3% vs 25.4%, P=0.01), more involved in the diagonal and circumflex branch of coronary artery (49.2% vs 17.1%, P=0.01; 83.6% vs 70.2%, P=0.03), shorter operative time [(4.1±1.7) h vs (4.7±1.2) h, P=0.03), longer preoperative [(7.1±2.3) d vs (5.2±2.0) d, P=0.01] and total hospitalization time [(16.3±6.8) d vs (12.5±4.2) d, P=0.01], however, the differences of the in-hospital mortality and incidence of other perioperative complications were not statistically significant between the two groups (all P>0.05). Conclusion: Compared with complete revascularization, incomplete revascularization following OPCABG in CAD patients over 80 years old does not increase the perioperative mortality and the incidence of other complications, and it reduces the operative time. However, it increases the time of preoperative and total hospital stay.

Molecular genetic analysis in 21 Chinese families with congenital insensitivity to pain with or without anhidrosis.

BACKGROUND AND PURPOSE: Hereditary sensory and autonomic neuropathies (HSANs) are a group of clinically and genetically heterogeneous neurological disorders characterized by sensory dysfunctions. Here, 21 affected Chinese families are reported, including 19 with congenital insensitivity to pain with anhidrosis (CIPA; namely HSAN IV) and two with congenital insensitivity to pain (CIP; namely HSAN IID) caused by biallelic variations in NTRK1 and SCN9A, respectively, aiming to identify causative variants in these families and compare how different variants in NTRK1 affect the function of tropomyosin receptor kinase A (TrkA). METHODS: Recombinant plasmids harboring the wild-type and six mutant alleles (p.Gln216*, p.Glu584Lys, p.Leu595Arg, p.Pro684Leu, p.Val709Leu and p.Arg765Cys) of NTRK1 cDNA were constructed and transfected into HEK293 cells. RESULTS: The results suggested that the five missense variants only presented a subtle influence on the expression level and glycosylation of TrkA but compromised the receptor phosphorylation. Our findings also suggested that a synonymous variant c.219C>T in NTRK1 may cause aberrant splicing, indicating a potential novel pathogenic mechanism of CIPA. Furthermore, gross deletion of SCN9A was first associated with CIP. CONCLUSIONS: This study identified multiple forms of variants responsible for CIPA/CIP in the Chinese population and might provide new insights into the pathogenesis of CIPA.

[A comparative analysis of quality of life between surgical and interventional treatment in patients with complex coronary heart disease].

Objective: To compare the improvement of quality of life in the patients with left main coronary artery disease and multi-vessel disease between off-pump coronary artery bypass grafting (OPCABG) and percutaneous coronary intervention (PCI) within one year after revascularization. Methods: This study was a prospective study. Between January and July 2018, 840 patients with complex coronary heart disease accepted revascularization therapy, 420 of whom underwent OPCABG and 420 for PCI, with a mean age of 61 years and a male rate of 74% (622/840). European Quality of Life-5 Dimensions (EQ-5D) and Seattle Angina Questionnaire (SAQ) were employed to assess the quality of life and health status of patients. Inverse probability weighting (IPW) was used to adjust treatment selection bias. Results: All-cause mortality (3.6% vs 1.3%, P=0.045), major adverse cardiac and cerebrovascular events (MACCE) (11.3% vs 4.1%, P<0.001) and target lesion revascularization (8.3% vs 1.2%, P<0.001) were higher in PCI group than those in OPCABG group. EQ-5D scores in PCI group were significantly higher than those in OPCABG group at 1 month after operation (P<0.001), but there was no significant difference between the two groups at 12 months after operation (P=0.210). In SAQ scale, the frequency score of angina pectoris in OPCABG group was higher than that in PCI group in 1 month, 6 months and 12 months after operation (all P<0.05). The physical activity limitation score in PCI group was significantly higher than that in OPCABG group at one month after operation (P<0.01). There was no significant difference between OPCABG group and PCI group in terms of stable state of angina pectoris, satisfaction of treatment and the knowledge of disease. Conclusions: In the short term, the quality of life of patients with left main coronary artery disease and multi-vessel disease treated with OPCABG is better than PCI. However, the improvement of quality of life in the medium and long term still needs to be identified in future follow-up study.

[Application of complete endoscopic technique in microvascular decompression related tovertebrobasilar artery compression].

Objective: To study the operative method, special technique and curative effect of complete neuroendoscopic microvascular decompression(MVD) related to vertebrobasilar artery compression. Methods: Thirteen patients with functional cranial nerve disease caused by vertebrobasilar artery as direct or indirect responsible vessel accepted complete endoscopic MVD, including 11 patients with hemifacial spasm and 2 patients with trigeminal neuralgia. The procedure and curative effect of endoscopic surgery were analyzed retrospectively. Results: All procedures of complete neuroendoscopic MVD were successfully completed.Intraoperative observation by endoscope showed that 6 cases were oppressed directly by vertebral artery, 2 cases were oppressed directly by basilar artery, 5 cases were combined oppressed by displaced basilar artery and other vessels (1 case was superior cerebellar artery and 4 cases were anterior inferior cerebellar artery). During the operation, Teflon sheets was placed directly into the compression point in 2 cases, the "Pre-placed" technique was used to place Teflon sheets in 7 cases, and the "Set up bridge" technique was used to place Teflon sheets in 4 cases. Follow-up for 8-38 months,the symptoms disappeared completely in 12 cases and improved in 1 case. No deaths and severe complications occurred, such as postoperative bleeding, cerebellar infarction and intracranial infection. Conclusion: MVD related to vertebrobasilar artery compression can be performed by complete neuroendoscopic technique, which can achieve sufficient decompression effect and curative effect.Flexible use of the special technology of placing Teflon sheets by single-hand under endoscope, such as the "Pre-placed" and "Set up bridge" technique, is an important technical guarantee for the successful completion of endoscopic MVD.

Comparing the efficacy of targeted next-generation sequencing in the identification of somatic mutations in circulating tumor DNA from different stages of lung cancer.

This study aims to assess the potential clinical application of targeted next generation sequencing (NGS)-based deep sequencing for the detection of clinically relevant mutations in circulating tumor DNA (ctDNA) obtained from non-small cell lung cancer (NSCLC) patients. Targeted deep sequencing was performed to identify High Confidence Somatic Variants (HCSVs) in matched tumor tissue DNA (tDNA) and ctDNA in 50 NSCLC patients. Our results demonstrated that NSCLC patients with Stage IV (61.5%) exhibited a higher concordance rate at the mutation level between plasma ctDNA and tDNA samples than those with Stage I-III (14.5%). Moreover, it is noteworthy that the allele frequency of these detected HCSVs in ctDNA increased with the advance in tumor stage. Besides, using tDNA as a reference, the sensitivity of plasma ctDNA analyzed by deep NGS for actionable EGFR was much higher in patients with Stage IV (66.6%) than those with Stage I-III (7.7%). In conclusion, it appears that ctDNA NGS-based deep sequencing is a feasible approach to identify mutations in patients with Stage IV NSCLC. However, additional methods with higher sensitivity and specificity are needed to improve the successful application of this platform in the earlier stages of NSCLC.

[Efficacy analysis of soft neuroendoscopic techniques in the treatment of chronic subdural hematoma].

Objective: To investigate the efficacy of soft neuroendoscopic techniques in the treatment of chronic subdural hematoma (CSDH). Methods: A retrospective analysis of 201 cases of CSDH diagnosed and treated at Beijing Shijitan Hospital (CMU) from January 2006 to December 2017 was conducted. From January 2006 to December 2010, 126 cases of CSDH were treated with skull drilling and drainage (non-endoscopic group). From January 2011 to December 2017, 75 cases of CSDH were treated with soft neuroendoscopy (endoscopic group). The operation time of the non-endoscopic and endoscopic groups, the hematoma clearance rate on the first day after surgery, the time of the drainage tube, the length of hospital stay, the incidence of complications, mortality and recurrence rate were compared. Results: There were no deaths in both groups. The average operation time of the non-endoscopic group was 43 min, compared with the average operation time of the endoscopy group of 50 min, there was no significant difference (P>0.05). The average hematoma clearance rate on the first day after surgery in the endoscopy group (98.2%) was significantly higher than that in non-endoscopic group (87.3%) (P<0.01). The average time of drainage tube in the endoscopy group (23 h) was significantly shorter than that in the non-endoscopic group (50 h) (P<0.01). On the first postoperative day, the proportion of patients with mRS≤3 in the endoscopic group was significantly higher than that in the non-endoscopic group (P<0.01). At the time of discharge, the proportion of patients with mRS≤3 in the endoscopy group was also significantly higher than that in the non-endoscopic group, P<0.05. There was no significant difference in the average hospital stay between endoscopy group (7 d) and non-endoscopic group (8 d) (P>0.05). The postoperative complication rate in the endoscopy group was significantly lower than that in the non-endoscopic group (P<0.01). During 0.5-8 years of follow-up, the recurrence rate of CSDH in the endoscopic group (5.33%) was significantly lower than that in the non-endoscopic group (15.07%) (P<0.01). Conclusion: The application of visualization features of soft neuroendoscopy in the treatment of CSDH can significantly improve hematoma clearance, shorten the time of drainage tube, reduce postoperative complications and recurrence rate, and improve surgical outcomes.

Presence of pldA and exoU in mucoid Pseudomonas aeruginosa is associated with high risk of exacerbations in non-cystic fibrosis bronchiectasis patients.

OBJECTIVES: To explore the association between the virulence genes exoU and pldA in isolated mucoid Pseudomonas aeruginosa and the clinical outcomes of patients with non-cystic fibrosis (CF) bronchiectasis. METHODS: A prospective observational cohort study was performed in the Shanghai Pulmonary Hospital from October 2012 to January 2015. We consecutively enrolled all non-CF bronchiectasis patients with mucoid P. aeruginosa isolates obtained from bronchoalveolar lavage fluid or sputum. The exposure variable was the presence of virulence gene, exoU or pldA, in the strains. The primary outcome was exacerbation of bronchiectasis. Logistic regression analysis was performed to evaluate the association between virulence genes and exacerbation. RESULTS: The final analysis included 147 patients (mean (SD) age, 57.86 (11.43) years, 101 female subjects) with median (interquartile range) follow-up of 18 (13-26) months. The following factors were relative to exacerbations: body mass index ≤18.5 kg/m2 (odds ratio (OR) = 5.05; 95% confidence interval (CI), 1.37-18.57), length of stay ≥8 days (OR = 2.65; 95% CI, 1.14-6.19) and positive for either virulence gene (OR = 6.80; 95% CI, 1.47-31.37). The gene-positive group had more exacerbations per year (mean 2.37, SD 2.10, n = 33 vs. mean 0.79, SD 0.83, n = 114) and a higher proportion of patients with exacerbation (31/33, 93.94% vs. 74/114, 64.91%). The proportion of patients being exoU or pldA positive increased as the exacerbation frequency of bronchiectasis increased. CONCLUSIONS: The virulence genes exoU and pldA in mucoid P. aeruginosa are significant risk factors for exacerbations in patients with non-CF bronchiectasis.

MiR-448 downregulates CTTN to inhibit cell proliferation and promote apoptosis in glioma.

OBJECTIVE: miRNAs have been confirmed to be related to cell proliferation and apoptosis. In this study, we detected the potential effect of miR-448 on glioma cell proliferation and apoptosis. MATERIALS AND METHODS: miR-448 and CTTN expression levels were detected in glioma cell lines with quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Cells were transfected with miR-448 mimics and inhibitor by using lipofectamine 2000 respectively. The proliferative ability of transfected cells was detected via methyl thiazolyl tetrazolium (MTT) and cell counting kit-8 (CCK8) assays. Cell apoptosis and cell-cycle were tested using flow cytometry. The regulatory correlation between miR-448 and CTTN was explored by bioinformatics analysis and luciferase reporter assay. RESULTS: Lower expression of miR-448 and higher level of CTTN were detected in glioma cells. MiR-448 could regulate cell proliferation, cell apoptosis, and cell cycle. CTTN was negatively regulated by miR-448. CONCLUSIONS: miR-448 downregulates CTTN to inhibit cell proliferation and promote apoptosis in glioma, which indicates a potential therapeutic target of glioma.

TNFα-YAP/p65-HK2 axis mediates breast cancer cell migration.

Clinical and experimental evidence indicates that macrophages could promote solid-tumor progression and metastasis. However, the mechanisms underlying this process remain unclear. Here we show that yes-associated protein 1 (YAP1), a transcriptional regulator that controls tissue growth and regeneration, has an important role in tumor necrosis factor α (TNF α)-induced breast cancer migration. Mechanistically, macrophage conditioned medium (CM) or TNFα triggers IκB kinases (IKKs)-mediated YAP phosphorylation and activation in breast cancer cells. We further found that TNFα or macrophage CM treatment increases the interaction between p65 and YAP. Chromatin immunoprecipitation (ChIP) assay shows that YAP/TEAD (TEA domain family member) and p65 proteins synergistically regulate the transcription of hexokinase 2 (HK2), a speed-limiting enzyme in glycolysis, and promotes TNFα-induced or macrophage CM-induced cell migration. Together, our findings indicate an important role of TNFα-IKK-YAP/p65-HK2 signaling axis in the process of inflammation-driven migration in breast cancer cells, which reveals a new molecular link between inflammation and breast cancer metastasis.

Asthma-COPD overlap syndrome showed more exacerbations however lower mortality than COPD.

BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a new determinate syndrome whose exact characteristics remain unclear. AIM: The objective of this study is to find more difference between ACOS and COPD. DESIGN: A retrospective study of ACOS and COPD in Chinese. METHODS: Data from 65 patients with ACOS and 65 patients with COPD were retrospectively collected and analyzed. The basis of this study was to compare the two groups while ruling out differences in age, sex and smoking history. RESULTS: Patients with ACOS tended to have earlier ages of onset, longer durations of symptoms, better nutritional status, higher single-breath diffusing capacity of carbon monoxide (DLCO) %predicted and airway resistance %predicted, more exacerbations in the preceding 12 months and shorter lengths of hospitalization. DLCO %predicted, airway resistance %predicted, and length of hospitalization were the variables most significantly associated with the presence of ACOS in patients with COPD. ROC correlating airway resistance %predicted value and current ACOS showed an optimal cutoff of airway resistance %predicted of over 296.6. During follow-up (median: 45 months; interquartile range: 6-82 months), 16 patient deaths were recorded (3 patients with ACOS). The risk remained significantly higher in patients with COPD alone than in patients with ACOS (HR 3.932; 95% CI 1.083-19.755; P = 0.046). CONCLUSION: Patients with ACOS were more likely to have better prognoses and lower mortality than those with COPD alone, though with greater exacerbation frequency.

Novel ß-carbolines against colorectal cancer cell growth via inhibition of Wnt/ß-catenin signaling.

Wnt signaling pathway is aberrantly activated in a variety of cancers, especially in colorectal cancer (CRC), because of mutations in the genes encoding adenomatous polyposis coli (APC), ß-catenin and Axin. Small-molecule antagonists of Wnt/ß-catenin signaling are attractive candidates for developing effective therapeutics for CRC. In this study, we have identified a novel Wnt signaling inhibitor, isopropyl 9-ethyl-1- (naphthalen-1-yl)-9H-pyrido[3,4-b]indole-3- carboxylate (Z86). Z86 inhibited Wnt reporter activities and the expression of endogenous Wnt signaling target genes in mammalian cells and antagonized the second axis formation of Xenopus embryos induced by Wnt8. We showed that Z86 treatment inhibits GSK3ß (Ser9) phosphorylation, leading to its overactivation and promoting the phosphorylation and degradation of ß-catenin. In vitro, Z86 selectively inhibited the growth of CRC cells with constitutive Wnt signaling and caused obvious G1-phase arrest of the cell cycle. Notably, in a nude mouse model, Z86 inhibited dramatically the xenografted tumor growth of CRC. Daily intraperitoneal injection of Z86 at 5 mg/kg resulted in >70% reduction in the tumor weight of HCT116 cell origin that was associated with decreased GSK3ß (Ser9) phosphorylation and increased ß-catenin phosphorylation. Taken together, our findings provide a novel promising chemotype for CRC therapeutics development targeting the canonical Wnt signaling.

SIRT1 regulates YAP2-mediated cell proliferation and chemoresistance in hepatocellular carcinoma.

The MST/YAP (mammalian Ste20-like kinase/Yes-associated protein 2) pathway plays an important role in hepatocellular carcinoma (HCC). Although post-translational modification-especially MST/Lats (large tumor suppressor)-mediated phosphorylation and PP1 (protein phosphatase-1)-mediated dephosphorylation-has been found to regulate the activity of YAP2, very little is known about its acetylation. In our experiments, we observed that the expression of SIRT1 is significantly upregulated in the tumor samples of the hepatocarcinoma patients, and SIRT1 mRNA level positively correlates with connective tissue growth factor (CTGF) mRNA level. We then found that SIRT1 deacetylates YAP2 protein in HCC cells and SIRT1-mediated deacetylation increases the YAP2/TEAD4 association, leading to YAP2/TEAD4 transcriptional activation and upregulated cell growth in HCC cells. Moreover, knockdown of SIRT1 blocks the cisplatin (CDDP)-induced nuclear translocation of YAP2 and enhances the chemosensitivity of HCC cells to CDDP treatment. Together, our findings reveal a new regulatory mechanism of YAP2 by the SIRT1-mediated deacetylation that may be involved in HCC tumorigenesis and drug resistance.

Plasmid encoding matrix protein of vesicular stomatitis viruses as an antitumor agent inhibiting rat glioma growth in situ.

AIM: Oncolytic effect of vesicular stomatitis virus (VSV) has been proved previously. Aim of the study is to investigate glioma inhibition effect of Matrix (M) protein of VSV in situ. MATERIALS AND METHODS: A recombinant plasmid encoding VSV M protein (PM) was genetically engineered, and then transfected into cultured C6 gliomas cells in vitro. C6 transfected with Liposome-encapsulated PM (LEPM) was implanted intracranially for tumorigenicity study. In treatment experiment, rats were sequentially established intracranial gliomas with wild-typed C6 cells, and accepted LEPM injection intravenously. Possible mechanism of M protein was studied by using Hoechst staining, PI-stained flow cytometric analysis, TUNEL staining and CD31 staining. RESULTS: M protein can induce generous gliomas lysis in vitro. None of the rats implanted with LEPM-treated cells developed any significant tumors, whereas all rats in control group developed tumors. In treatment experiment, smaller tumor volume and prolonged survival time was found in the LEPM-treated group. Histological studies revealed that possible mechanism were apoptosis and anti-angiogenesis. CONCLUSION: VSV-M protein can inhibit gliomas growth in vitro and in situ, which indicates such a potential novel biotherapeutic strategy for glioma treatment.

[Inhibitory effects of phosphorothioate antisense oligonucleotides on gene expression controlled by HCV 5'NCR in nude mice xenograft].

OBJECTIVE: To evaluate the activity in vivo of 3 phosphorothioate antisense oligonucleotides, HCV363, HCV279 and HCV349 using nude mice xenograft models based on the establishment of HCV 5' NCR transgenic cellular model (HepG2.9706). METHODS: Female BALB/C nude mice, aged 4 to 6 weeks and weighing around 20g, were implanted s.c. with 100mul (106 cells) of the HepG2.9706 cells suspension in the lower-back region. In approximate 1 weeks, the animals were randomly grouped and intraperitoneally administrated the antisense drugs at 10 mg/kg body weight. RESULTS: HCV363, HCV279 and HCV349 had obvious sequence-specific inhibitory effects on luciferase expression controlled by HCV 5' NCR in xenograft cells with the inhibitory rates of 80.4%, 78.6% and 47.9%, respectively. The effects of three different concentrations (5, 10, 20 mg/kg body weight) of HCV363 indicated that HCV363 increased the inhibitory activities on luciferase expression following the concentration raise and its inhibitory rate was up to 82.7%. CONCLUSIONS: This study suggests that antisense oligonucleotides may provide a novel therapeutic approach to the treatment of HCV infection.

LDL-receptor-related protein 6 is a receptor for Dickkopf proteins.

Wnt glycoproteins have been implicated in diverse processes during embryonic patterning in metazoa. They signal through frizzled-type seven-transmembrane-domain receptors to stabilize beta-catenin. Wnt signalling is antagonized by the extracellular Wnt inhibitor dickkopf1 (dkk1), which is a member of a multigene family. dkk1 was initially identified as a head inducer in Xenopus embryos but the mechanism by which it blocks Wnt signalling is unknown. LDL-receptor-related protein 6 (LRP6) is required during Wnt/beta-catenin signalling in Drosophila, Xenopus and mouse, possibly acting as a co-receptor for Wnt. Here we show that LRP6 (ref. 7) is a specific, high-affinity receptor for Dkk1 and Dkk2. Dkk1 blocks LRP6-mediated Wnt/beta-catenin signalling by interacting with domains that are distinct from those required for Wnt/Frizzled interaction. dkk1 and LRP6 interact antagonistically during embryonic head induction in Xenopus where LRP6 promotes the posteriorizing role of Wnt/beta-catenin signalling. Thus, DKKs inhibit Wnt co-receptor function, exemplifying the modulation of LRP signalling by antagonists.

[Expression of C-myc and N-myc protein in adulthood and childhood medulloblastomas and prognostic analysis].

OBJECTIVE: To detect the expression of C-myc and N-myc in medulloblastomas, the difference between adults and children, and the relation between expression and prognosis. METHODS: ABC immunostaining was used to detect C-myc and N-myc protein expression in 21 cases of adulthood medulloblastomas and 14 childhood cases. Follow-up materials were obtained to perform survival curve analysis. RESULTS: Of these 35 cases, 5 (4 children, 1 adult) showed C-myc positive expression. No N-myc expression was found. There was no relationship between expression and survival. CONCLUSION: C-myc may play a role in the tumorgenesis of medulloblastoma, especially in children, but it is of no prognostic significance. N-myc antigen may be lost during the fixation of specimens.