[Physical activity and its influencing factors in patients with diabetes mellitus: a comparative study between China and the United Kingdom].

Objective: To compare the differences in low-level physical activity (PA) and related influencing factors in patients with diabetes mellitus in China and the United Kingdom (UK). Methods: Using baseline survey data from the China Kadoorie Biobank and the UK Biobank, we analyzed the association between diabetes mellitus and low-level PA using logistic regression, with the participants' self-reported whether they had diabetes mellitus as the independent variable, and low-level PA as the dependent variable. Results: We included 509 254 Chinese adults and 359 763 British adults in the analysis. After adjusting for multiple factors, we found that both Chinese and British patients with diabetes mellitus were at elevated risk for low-level PA, with corresponding ORs (95%CIs) of 1.15 (1.12-1.19) and 1.37 (1.32-1.41), respectively. Patients with diabetes mellitus with longer disease duration and poorer glycemic control were at greater risk of having low-level of PA. Female, rural-distributed, employed, never-smoking Chinese diabetics, and male, urban-distributed, retired/unemployed, quit-smoking British diabetics were more likely to have low-level PA. Conclusions: Chinese and British patients with diabetes mellitus were more likely to have low-level PA compared with the general population, but the risk of low-level PA for patients in both countries varied by population characteristics. Therefore, PA guidelines and intervention measures should be based on the characteristics of individuals in the target countries and regions, which could improve PA levels among patients with diabetes mellitus.

Anthropogenic, biogenic, and photochemical influences on surface formaldehyde and its significant decadal (2006-2017) decrease in the Lewiston-Clarkston valley of the northwestern United States.

Formaldehyde (HCHO) is a key carcinogen and plays an important role in atmospheric chemistry. Both field measurements and Positive Matrix Factorization (PMF) modeling have been employed to investigate the concentrations and sources of HCHO in the Lewiston-Clarkston (LC) valley of the mountainous northwestern U.S. Different instruments were deployed to measure surface formaldehyde and other related compounds in July of 2016 and 2017. The measurements reveal that the average HCHO concentrations have significantly decreased to 2-5 ppb in the LC valley in comparison to its levels (10-20 ppb) observed in July 2006. This discovery with surface measurements deserves attention given that satellite retrievals showed an increasing long-term trend from 2005 to 2014 in total vertical column density of HCHO in the region, suggesting that satellite instruments may not adequately resolve small valleys in the mountainous region. Our PMF modeling identified four major sources of HCHO in the valley: (1) emissions from a local paper mill, (2) secondary formation and background, (3) biogenic sources, and (4) traffic. This study reveals that the emissions from the paper mill cause high HCHO spikes (6-19 ppb) in the early morning. It is found that biogenic volatile organic compounds (VOCs) in the area are influenced by national forests surrounding the region (e.g., Nez Perce-Clearwater, Umatilla, Wallowa-Whitman, and Idaho Panhandle National Forests). The results provide useful information for developing strategies to control HCHO levels and have implications for future HCHO studies in atmospheric chemistry, which affects secondary aerosols and ozone formation.

Harnessing a real-time location system for contact tracing in a busy emergency department.

BACKGROUND: With the persistent threat of emerging infectious diseases (EIDs), digital contact tracing (CT) tools can augment conventional CT for the prevention of healthcare-associated infectious disease transmission. However, their performance has yet to be evaluated comprehensively in the fast-paced emergency department (ED) setting. OBJECTIVE: This study compared the CT performance of a radiofrequency identification (RFID)-based real-time location system (RTLS) with conventional electronic medical record (EMR) review against continuous direct observation of close contacts ('gold standard') in a busy ED during the coronavirus disease 2019 pandemic period. METHODS: This cross-sectional study was conducted at the ED of a large tertiary care hospital in Singapore from December 2020 to April 2021. CT performance [sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and kappa] of the RTLS, EMR review and a combination of the two approaches (hybrid CT) was compared with direct observation. Finally, the mean absolute error (MAE) in the duration of each contact episode found via the RTLS and direct observation was calculated. RESULTS: In comparison with EMR review, both the RTLS and the hybrid CT approach had higher sensitivity (0.955 vs 0.455 for EMR review) and a higher NPV (0.997 vs 0.968 for EMR review). The RTLS had the highest PPV (0.777 vs 0.714 for EMR review vs 0.712 for hybrid CT). The RTLS had the strongest agreement with direct observation (kappa=0.848). The MAE between contact durations of 80 direct observations and their respective RTLS contact times was 1.81 min. CONCLUSION: The RTLS was validated to be a high-performing CT tool, with significantly higher sensitivity than conventional CT via EMR review. The RTLS can be used with confidence in time-strapped EDs for time-sensitive CT for the prevention of healthcare-associated transmission of EIDs.

LED-pumped eye-safe pulse laser with an extracavity optical parametric oscillator.

An LED-side-pumped Nd:YAG/Cr4+:YAG passively Q-switched (PQS) laser containing an extracavity optical parametric oscillator (EOPO) is demonstrated. As far as we know, it is the first LED-pumped eye-safe laser. The Nd:YAG pump module is optimized to increase the PQS pulse energy to 24 mJ at 1064 nm. By using a single-pass EOPO design, the output energy of the signal pulse at 1573 nm is 7.44 mJ with a pulse width of 16 ns, the peak power is 434 kW, and the pump-to-signal conversion efficiency is 31%. For double-pass EOPO operation, the pump-to-signal conversion efficiency increases to 45.8%, the output energy of signal pulse is up to 10.98 mJ with a pulse width of 23.5 ns, and the peak power is 459 kW.

[Pre-operative prognostic nutritional index as a predictive factor for prognosis in non-metastatic renal cell carcinoma treated with surgery].

OBJECTIVE: To evaluate the implications of the prognostic nutrition index (PNI) in non-metastatic renal cell carcinoma (RCC) patients treated with surgery and to compare it with other hematological biomarkers, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune inflammation index (SII). METHODS: A cohort of 328 non-metastatic RCC patients who received surgical treatment between 2010 and 2012 at Peking University First Hospital was analyzed retrospectively. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff values of the hematological biomarkers. The Youden index was maximum for PNI was value of 47.3. So we divided the patients into two groups (PNI≤ 47. 3 and >47. 3) for further analysis. Categorical variables [age, gender, body mass index (BMI), surgery type, histological subtype, necrosis, pathological T stage and tumor grade] were compared using the Chi-square test and Student' s t test. The association of the biomarkers with overall survival (OS) and disease-free survival (DFS) was analyzed using Kaplan-Meier methods with log-rank test, followed by multivariate Cox proportional hazards model. RESULTS: According to the maximum Youden index of ROC curve, the best cut-off value of PNI is 47. 3. Low level of PNI was significantly associated with older age, lower BMI and higher tumor pathological T stage (P < 0.05). Kaplan-Meier univariate analysis showed that lower PNI was significantly correlated with poor OS and DFS (P < 0.05). In addition, older age, lower BMI, tumor necrosis, higher tumor pathological T stage and Fuhrman grade were significantly correlated with poor OS (P < 0.05). Cox multivariate analysis showed that among the four hematological indexes, only PNI was an independent factor significantly associated with OS, whether as a continuous variable (HR=0.9, 95%CI=0.828-0.978, P=0.013) or a classified variable (HR=2.397, 95%CI=1.061-5.418, P=0.036). CONCLUSION: Low PNI was a significant predictor for advanced pathological T stage, decreased OS, or DFS in non-metastatic RCC patients treated with surgery. In addition, PNI was superior to the other hematological biomar-kers as a useful tool for predicting prognosis of RCC in our study. It should be externally validated in future research before the PNI can be used widely as a predictor of RCC patients undergoing nephrectomy.

Analysis of altered miRNA profiling in the colon of a mouse model with ß-lactoglobulin allergy.

OBJECTIVES: The differences in the expression profiles of colonic miRNAs between ß-lactoglobulin (ß-Lg) allergic mice and normal mice were analyzed to investigate the important role of the miRNA regulation mechanism in the pathogenesis of cow's milk allergy. METHODS: The present study performed Illumina sequencing to characterize the miRNA profile changes in mouse colon responding to ß-Lg challenge. Target genes were predicted by TargetScan 50 and miRanda 3.3a algorithms and assessed by GO and KEGG analysis. The expression levels of selected miRNAs and cytokine production were verified by cell transfection and quantitative RT-PCR. RESULTS: A total of 15 miRNAs were diversely expressed between the colon of the normal and ß-Lg-sensitized mice (P < 0.05, fold change of >1.50 or <0.67), including six up-regulated miRNAs and nine down-regulated miRNAs, among which seven miRNAs were validated using qRT-PCR. GO enrichment and KEGG pathway analyses further revealed that biological process, protein binding, cytoplasm and the pathways of cancer were significantly enriched, which were closely connected to the allergic inflammation development. Additionally, six key functional interaction pairs in ß-Lg allergy were identified in miRNA prediction algorithms and verified using qRT-PCR. CONCLUSIONS: We can conclude that our results suggested that the miRNAs regulation network participated in the pathogenesis of cow's milk allergy.

[Detection of right-to-left shunt with transthoracic contrast echocardiography in patients with pulmonary hypertension].

Objective: To explore the value of right heart contrast echocardiography in etiological diagnosis and severity assessment of pulmonary hypertension (PH). Methods: A retrospective analysis was conducted on 74 patients who underwent transthoracic contrast echocardiography in China-Japan Friendship Hospital from May 2015 to July 2018, all of whom were diagnosed as PH by right heart catheterization. Patients were divided into three groups according to contrast echocardiography: the intra-cardiac shunt group (<4 cardiac cycles with microbubbles in the left heart); Intrapulmonary shunt group (>4 cardiac cycles with microbubbles in the left heart); non-shunt group. The etiology, partial arterial oxygen pressure (PO(2)), N-terminal pro-brain natriuretic peptide (NT-proBNP), mean pulmonary artery pressure (mPAP), right atrial pressure (RAP), pulmonary vascular resistance (PVR) and cardiac output (CO) were analyzed. Central nervous system complications were also compared among the three groups. Results: Among the 74 patients, right-to-left shunt was found in 28 cases (37.8%) by contrast echocardiography, including 11 cases (14.9%) of intra-cardiac shunt and 17 cases (23.0%) of intrapulmonary shunt. In the 11 cases of intra-cardiac shunt, 7 were diagnosed with congenital heart disease and 4 were patent foramen. Two with hereditary hemorrhagic telangiectasia (HHT) and 1 with pulmonary arteriovenous malformation (PAVM) were included in the 16 cases of intrapulmonary shunt. There was no statistical difference in PO(2), mPAP, PVR, NT-proBNP, RAP, CO and functional class among the three groups (all P>0.05). A total of 5 cases (6.8%) were found with nervous system comorbidities, 4 cases (5.4%) with cerebral infarction and 1 cases epilepsy, and 2 cases of cerebral infarction were diagnosed as paradoxical embolism. Nervous system complications were more common in patients with intra-cardiac shunt than in other groups. Conclusion: While right-to-left shunt detected by contrast echocardiography has no relationship with disease severity, it has complementary value in the etiological diagnosis of PH, and intra-cardiac shunt may increase the risk of nervous system complications.

Modulation effect of Lactobacillus acidophilus KLDS 1.0738 on gut microbiota and TLR4 expression in ß-lactoglobulin-induced allergic mice model.

OBJECTIVES: ß-lactoglobulin (ß-Lg)-sensitized mice model was employed to investigate the correlation between Lactobacillus acidophilus KLDS 1.0738 (Lap KLDS 1.0738) modulating gut microbiota and inducting Toll-like receptors (TLRs) expression. METHODS: The alterations of mice fecal microbiota were analyzed by 16S rRNA gene sequencing. The serum cytokines production and TLR4/NF-κB mRNA expression in the colon tissues were measured by ELISA kit and quantitative RT-PCR, respectively. RESULTS: The results showed that Lap KLDS 1.0738 pretreatment attenuated ß-Lg-induced hypersensitivity, accompanied with a diminished expression of TLR4/NF-κB signaling. Moreover, oral administration of Lap KLDS 1.0738 improved the richness and diversity of fecal microbiota, which was characterized by fewer Proteobacteria phylum and Helicobacteraceae family, and higher Firmicutes phylum and Lachnospiraceae family than allergic group. Notably, TLR4/NF-κB expression was positively correlated with the family of Helicobacteraceae in allergic group, but negatively correlated with the family of Lachnospiraceae, Ruminococcaceae and anti-inflammatory cytokines level. A significant positive correlation was observed between TLR4/NF-κB expression and the production of histamine, total IgE and pro-inflammatory cytokines. CONCLUSIONS: Intake of Lap KLDS 1.0738 can influence the gut bacterial composition, which might result in recognizing TLRs signaling so as to inhibit allergic response.

[Brain protection strategy and effectivity in pulmonary thromboendarterectomy].

Objective: To summarize the experience and effectivity of brain protection in 25 patients who suffered from chronic thromboembolic pulmonary hypertension (CTEPH) and received pulmonary thromboendarterectomy (PTE) under deep hypothermic circulatory arrest. Methods: Retrospective analysis of 25 PTE surgeries in our center from December 2016 to August 2018. All cases were completed underdeep hypothermic circulatory arrest. Standard brain protections were strictly executed, including: balanced and controlled extracorporeal circulation cooling, cerebral oxygen saturation (rSO(2)) monitoring, strictly control of circulatory arrest time, and etc. The neurological adverse events during the perioperative period were recorded and statistically analyzed, and the intelligence level and cognitive function of the patients were evaluated by MMSE scale and MoCA scale before surgery and discharge. Results: All the 25 patients successfully completed the surgery, and 1 patient (4%) died of postoperative infection. The mean pulmonary arterial pressure decreased from (52.9±16.7) mmHg before surgery to (23.6±8.1) mmHg immediately after surgery (t=10.01, P<0.01), and(20.7±7.9) mmHg at 3 months follow-up (t=10.73, P<0.01). Pulmonary vascular resistance decreased from 975.4 (788.6-1 292.8) dyn·s·cm(-5) to 376.1 (283.6-565.5) dyn·s·cm(-5) (Z=5.34, P<0.01). Neurological complications occurred in 3 patients during the perioperative period, including 2 patients with hypoxic encephalopathy, and 1 patient with cerebral hemorrhage. All 3 patients fully recovered before discharge. Univariate analysis showed that the duration of rSO(2)<40% and the maximum decrease rate of rSO(2) from baseline were significantly correlated with postoperative neurological damage. Multivariate analysis showed only time of rSO(2)<40% was significantly correlated with postoperative neurological damage. There was no significant difference in MMSE and MoCA score before and after surgery (P>0.05). Conclusions: Adequate brain protection measures are essential to reduce the neurological complications of PTE surgery. Real-time intraoperative monitoring of rSO(2) and strict control of circulatory arrest time can further reduce the occurrence of neurological damage.

[Treating of 20 cases of uterine scar pregnancy by laparoscopic folding and suture of the lower segment of the uterus].

Objective: To explore a new surgical method to treat cesarean scar pregnancy (CSP) by laparoscopic surgery. Method: The clinical data of 20 patients with CSP treated by laparoscopic subsegmental muscle folding and suture between January 2015 and June 2018 in our hospital were retrospectively analyzed. Results: Abortion was performed in 20 patients with CSP after laparoscopic suture of the lower segment of the uterus, the results was satisfying.Operation time was short, average (47±11) minutes.Bleeding was less, average (40±17) ml.Human chorionic gonadotropin (HCG) decreased well after operation.Color ultrasound examination was performed 3 months after the operation.The subuterine muscle layer healed well and the thickness was normal, average (3.9±0.3) mm. Conclusion: The operation is easy to be grasped.While repairing the muscular layer of the lower segment of the uterus, the pregnancy capsules between the muscle walls were pushed back into the uterine cavity and induced abortion was performed.Both approaches repair the weak myometrium and it can be routinely performed artificial abortion surgery.The operation time is short, the wound of the patient is small, the postoperative recovery is quick, and the lower segment of the uterus is not damaged again.The laparoscopic suture of the lower segment of the uterus and induced abortion are easy to be popularized in the primary surgery.

MiR-181a mediates Ang II-induced myocardial hypertrophy by mediating autophagy.

OBJECTIVE: To investigate the relationship between miR-181a and cardiac hypertrophy and autophagy in rats with myocardial hypertrophy, and whether miR-181a regulates the autophagy through ATG5, thereby participating in the occurrence and development of myocardial hypertrophy. MATERIALS AND METHODS: The rat model of myocardial hypertrophy was established via the abdominal aortic coarctation. The expression of miR-181a in cardiac tissues was detected via reverse transcription-polymerase chain reaction (RT-PCR). The expressions of autophagy-related proteins, ATG5 and LC3II/LC3I, in cardiac tissues, were detected via Western blotting (WB). After the primary culture of myocardial cells in rats, they were stimulated via Angiotensin II (Ang II) to observe the effects of autophagy inhibitor 3-methyladenine (3-MA) and overexpression of ATG5 on the expression of hypertrophic genes in myocardial cells, respectively. The expressions of autophagy-related proteins ATG5 and LC3II/LC3I were detected via WB, the autophagic rate was observed via flow cytometry and the changes in autophagic vacuoles of myocardial cells were observed using the transmission electron microscope. The changes in mRNA and protein expressions of ATG in myocardial cells were observed after the overexpression of miR-181a or the inhibition of miR-181a activity. The changes in miR-181a and the expression of hypertrophic genes in myocardial cells after Ang II stimulation were observed via RT-PCR. RESULTS: In rats with myocardial hypertrophy, the cardiac autophagy was increased and the expression of miR-181a in hypertrophic myocardium was downregulated. 3-MA inhibited the ATG5-induced autophagy and improved the Ang II-induced myocardial hypertrophy, while the overexpression of ATG5 enhanced the myocardial autophagy and the expression of hypertrophic genes. MiR-181a regulated the ATG5-induced myocardial autophagy, and its downregulation mediated the Ang II-induced myocardial hypertrophy. CONCLUSIONS: The enhancement of ATG5-induced myocardial autophagy mediates the Ang II-induced myocardial hypertrophy. ATG5 is the target gene of miR-181a, it can regulate the myocardial autophagy via ATG5, thus mediating the Ang II-induced myocardial hypertrophy.

Relationship between levels of inflammatory cytokines in the peripheral blood and the severity of depression and anxiety in patients with Parkinson's disease.

OBJECTIVE: The present study aims to investigate the relationship between expression of inflammatory cytokines in the peripheral blood and the severity of depression and anxiety in patients with Parkinson's disease (PD). PATIENTS AND METHODS: Between January 2012 and December 2015, 62 PD patients admitted to our institution were included in the PD group, and 62 healthy subjects seeking health check-up at our institution during the same period of time were enrolled in the control group. Levels of inflammatory cytokines, including IL-1b, IL-6, interferon-g (INF-g), hypersensitive C-reactive protein (hsCRP) and soluble IL-2 receptor (sIL-2R), were measured by using Enzyme-linked immunosorbent assay (ELISA). Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) were used to assess the severity of depression and anxiety, respectively. RESULTS: A total of 124 subjects were included into PD group and control group, 62 for each. No significant differences were observed in the gender, age, body mass index (BMI), smoking history and alcohol history between two groups (p > 0.05). Levels of IL-1b, IL-6, TNF-a, hsCRP and sIL-2R were significantly higher in patients of PD group than those in the control group (p < 0.05). HAMD and HAMA scores in PD group were significantly higher than those in the control group [(22.74 ± 6.34), (20.90 ± 5.86) vs. (2.17±3.46), (3.79 ± 3.55), p < 0.05]. HAMD and HAMA scores were positively correlated with the levels of TNF-a, hsCRP and sIL-2R in the peripheral blood of PD patients (p < 0.05). CONCLUSIONS: Expression of inflammatory cytokines are elevated in the peripheral blood of PD patients, and the severity of depression and anxiety is correlated with levels of TNF-a, hsCRP and sIL-2R in the peripheral blood of these patients.

Expressions of serum inflammatory cytokines and their relationship with cerebral edema in patients with acute basal ganglia hemorrhage.

OBJECTIVE: The aim of the present study is to investigate expressions of inflammatory cytokines and their relationship with cerebral edema in the patients with acute basal ganglia hemorrhage. PATIENTS AND METHODS: Between January 2015 and March 2016, 94 patients with acute basal ganglia hemorrhage admitted to our institution were included in the present study. Serum levels of interleukin (IL)-4, IL-6, IL-8 and IL-10 were measured using enzyme-linked immunosorbent assay (ELISA), and conditions of cerebral edema were evaluated using head CT upon admission, 1d after admission and 3d after admission, respectively. RESULTS: Serum levels of IL-4, IL-6 and IL-8 peaked 1d after admission and decreased 3d after admission with statistical significance (p <0.05); the IL-10 level was continuously increased after admission and peaked 3 days after admission with statistical significance (p<0.05). Cerebral edema was not observed in any of these patients upon admission, while occurred with a maximal edema volume 1 day after admission and the volume decreased 3 days after admission with statistical significance (p <0.05). Correlation analysis showed that levels of IL-4, IL-6 and IL-8 were positively correlated with severity of cerebral edema (r=0.324, 0286, 0.305, p <0.05 respectively), whereas IL-10 level was negatively correlated with severity of cerebral edema (r=-0.336, p <0.05). CONCLUSIONS: Serum levels of IL-4, IL-6 and IL-10 are positively correlated while the IL-10 level is negatively correlated with the severity of the cerebral edema in patients with acute basal ganglia hemorrhage.

XRCC3 T241M polymorphism and lung cancer risk in the Han Chinese population: a meta-analysis.

Numerous studies have evaluated the association between the X-ray repair cross-complementing group 3 (XRCC3) T241M polymorphism and lung cancer risk; however, the actual association is controversial. We examined whether the T241M polymorphism confers a lung cancer risk in China. We searched the PubMed, Google Scholar, and China National Knowledge Infrastructure databases to identify studies that examined the association between the XRCC3 T241M polymorphism and the risk of lung cancer. We estimated the pooled odds ratio with its 95% confidence interval to assess this association. A total of 3977 patients with lung cancer and 3761 controls from 8 comparative studies were included in this meta-analysis. The meta-analysis results revealed no significant association between the XRCC3 T241M polymorphism and lung cancer risk. In the subgroup analysis, 6 studies with sample sizes over 500 found that the T241M polymorphism had no association with lung cancer. The XRCC3 T241M polymorphism may not be a risk factor for lung cancer. However, larger studies involving a stratified case-control population and biological characterization are needed to validate this finding.

Quantitative analysis of P16 gene CpG methylation in Uyghur patients with cervical squamous cell carcinoma and its relationship with HPV16 infection.

The methylation of CpG sites in the promoter region of the P16 gene in Uyghur patients with cervical squamous cell carcinoma (CSCC) was quantitatively analyzed and its relationship with human papillomavirus 16 (HPV16) infection was explored. Cervical samples were collected from 20 Uyghur patients with CSCC and 20 Uyghur controls. Matrix-assisted laser desorption ionization-time of flight mass spectrometry was applied to detect methylation of CpG sites in the promoter region of the P16 gene; polymerase chain reaction was performed to assess HPV16 infection in the 2 groups. Among the 16 CpG sites in the P16 gene promoter region, the methylation level of the CpG1-2 and CpG 6 sites, as well as the HPV16 infection rate, was higher in the CSCC group than in the control group (P<0.05). There was no significant correlation between P16 CpG methylation and HPV16 infection in Uyghur patients with CSCC. The P16 gene CpG1-2 and CpG 6 hypermethylation and HPV16 infection, which are independent of each other, play an important role in cervical squamous cell carcinogenesis in Uyghur patients.

Effects of hypoxia on biofilms and subsequently larval settlement of benthic invertebrates.

Biofilms on submerged surfaces are important in determining larval settlement of most marine benthic invertebrates. We investigated if exposure of biofilms to hypoxia would alter the larval settlement pattern and result in a shift in benthic invertebrate community structure in the field. Biofilms were first exposed to hypoxia or normoxia in laboratory microcosms for 7 days, and then deployed in the field for another 7 days to allow for larval settlement and recruitment to occur. Using terminal-restriction fragment length polymorphism of the 16S rRNA gene, this study showed that hypoxia altered the biofilm bacterial community composition, and the difference between the hypoxic and normoxic treatments increased with the time of exposure period. This study also demonstrated significantly different benthic invertebrate community structures as a result of biofilm exposure to hypoxia and that the hypoxic and normoxic treatments were dominated by Hydroides sp. and Folliculina sp., respectively.

Depletion of pre-mRNA splicing factor Cdc5L inhibits mitotic progression and triggers mitotic catastrophe.

Disturbing mitotic progression via targeted anti-mitotic therapy is an attractive strategy for cancer treatment. Therefore, the exploration and elucidation of molecular targets and pathways in mitosis are critical for the development of anti-mitotic drugs. Here, we show that cell division cycle 5-like (Cdc5L), a pre-mRNA splicing factor, is a regulator of mitotic progression. Depletion of Cdc5L causes dramatic mitotic arrest, chromosome misalignments and sustained activation of spindle assembly checkpoint, eventually leading to mitotic catastrophe. Moreover, these defects result from severe impairment of kinetochore-microtubule attachment and serious DNA damage. Genome-wide gene expression analysis reveals that Cdc5L modulates the expression of a set of genes involved in the mitosis and the DNA damage response. We further found that the pre-mRNA splicing efficiency of these genes were impaired when Cdc5L was knocked down. Interestingly, Cdc5L is highly expressed in cervical tumors and osteosarcoma. Finally, we demonstrate that downregulation of Cdc5L decreases the cell viability of related tumor cells. These results suggest that Cdc5L is a key regulator of mitotic progression and highlight the potential of Cdc5L as a target for cancer therapy.

Enhanced matrix metalloproteinases-2 activates aortic endothelial hypermeability, apoptosis and vascular rarefaction in spontaneously hypertensive rat.

Microvascular rarefaction with endothelial cells apoptosis is a common characteristic of various microvascular complications in the spontaneously hypertensive rat (SHR). Elevated levels of proteolytic (e.g. matrix metalloproteinase, MMPs) activity and apoptosis in aortic endothelial cells of SHR were found when compared to its normotensive control. However, the exact mechanisms of microvascular rarefaction and the role of MMPs in this process remain poorly understood. Besides cleavage of VEGFR2 via unbalanced MMPs, we hypothesize that selected cleavage of Beta-Catenin and VE-cadherin by MMPs could induce apoptosis of rat aortic endothelial cells (RAECs) and rarefaction. Primary RAECs were isolated, identified and used in a in-vitro model. Transwell system was used to analyze the permeability of Wistar RAECs, SHR RAECs and SHR RAECs with pretreatment by doxycycline. Qualitative and semi-quantitative analysis of major endothelial adhesion molecules were detected by immunofluorescence technique and Western blot, respectively. MMP-2 activity of SHR RAECs was increased significantly and doxycycline (50 µM) effectively reduced the level of MMP-2 and hyper-permeability in SHR RAECs. SHR RAECs showed enhanced cleavage of VEGFR2, VE-cadherin and B-catenin, which could be prevented by doxycycline (50 µM). Doxycycline (50 µM) attenuated hyper-permeability via decreased MMP-2 by protecting VEGFR2, VE-cadherin, Beta-catenin from cleavage and inhibited the reduction of mitochondrial transmembrane potential (MTP), thus prevented mitochondria-mediated apoptotic signaling and capillary rarefaction in the SHR. It might be a novel insight into the mechanisms of SHR microvascular rarefaction that is independent of pressure but relevant to MMP-2.

Tumor-targeted delivery of biologically active TRAIL protein.

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent inducer of tumor cell apoptosis, but concerns of considerable liver toxicity limit its uses in human cancer therapy. Here, we show that i.v. injected Escherichia coli DH5alpha (E. coli DH5alpha) specifically replicates in solid tumors and metastases in live animals. E. coli DH5alpha does not enter tumor cells and suits for being the vector for soluble TRAIL (sTRAIL), which induces apoptosis by activating cell-surface death receptors. With the high 'tumor-targeting' nature, we demonstrate that intratumoral (i.t.) and intravenous injection of sTRAIL-expressing E. coli DH5alpha results in the tumor-targeted release of biologically active molecules, which leads to a dramatic reduction in the tumor growth rate and the prolonged survival of tumor-bearing mice. TRAIL delivery by E. coli DH5alpha did not cause any detectable toxicity to any organs, suggesting that E. coli DH5alpha-delivered sTRAIL protein therapy may provide a feasible and effective form of treatment for solid tumors.