Prodigiosin inhibits the proliferation of glioblastoma by regulating the KIAA1524/PP2A signaling pathway.

Prodigiosin (PG), a member of a family of natural red pigments produced by a variety of bacteria, was first discovered in Serratia marcescens. PG has been reported to have an apoptosis-inducing effect in many cancers, such as lymphoma, colon cancer and nasopharyngeal carcinoma. For this study, we used three glioblastoma (GBM) cell lines (LN229, U251 and A172) to explore the effect of prodigiosin on GBM cells. A CCK8 assay was used to evaluate cell viability. We determinedthe cell cycle distribution by flow cytometry and measured proliferation by an EdU incorporation assay. The expression of different molecules was investigated by western blotting and RT-PCR. We further confirmed our results by plasmid transfection and lentiviral transduction. The LN229 xenograft model was used to study the effect of prodigiosin in vivo. We confirmed that prodigiosin played an anticancer role in several GBM cell lines through the KIAA1524/PP2A/Akt signalling pathway. Prodigiosin inhibited the protein expression of KIAA1524 by suppressing its transcription, which led to activation of PP2A. Afterward, PP2A inhibited the phosphorylation of Akt, thereby inducing increased expression of p53/p21. Furthermore, it was verified that prodigiosin inhibited the KIAA1524/PP2A/Akt axis in vivo in the LN229 xenograft model. These data improve the understanding of the anticancer effects of prodigiosin and further highlight the potential of prodigiosin for the development of anti-glioma drugs.

Comprehensive Oncogenic Features of Coronavirus Receptors in Glioblastoma Multiforme.

The COVID-19 pandemic caused by SARS-CoV-2 infection has placed health systems under excessive pressure and especially elderly people with cancer. Glioblastoma multiforme (GBM) is a malignant brain tumor with an increasing incidence in elderly individuals, and thereby GBM patients are a vulnerable population during the COVID-19 outbreak. Accumulating studies have implied that SARS-CoV-2 might invade the brain directly via coronavirus receptors. However, little is known about SARS-CoV-2 infection in the clinical development of GBM. Here, we explored the oncogenic roles of six coronavirus receptors (ACE2, DPP4, ANPEP, AXL, TMPRSS2, and ENPEP) in GBM using bioinformatics and experimental approaches. We found that ANPEP and ENPEP were significantly increased at both the mRNA and protein levels in GBM compared with normal brain tissue. Kaplan-Meier survival curves and Cox regression analysis demonstrated that high expressions of ANPEP and ENPEP are associated with poor prognosis and survival. Moreover, all receptors are positively correlated with the immune infiltration levels of monocyte. Furthermore, we identified 245 genes between COVID-19 and coronavirus receptors-correlated genes in GBM and performed a thorough analysis of their protein-protein interaction network, functional signaling pathway and molecular process. Our work explores for the first time the association of coronavirus receptors with GBM and suggests ANPEP and ENPEP as potential therapeutic targets of GBM irrespective of COVID-19.

2,5-Dimethyl Celecoxib Inhibits Proliferation and Cell Cycle and Induces Apoptosis in Glioblastoma by Suppressing CIP2A/PP2A/Akt Signaling Axis.

2,5-Dimethyl-celecoxib (DMC) is a close structural analog of the selective COX-2 inhibitor celecoxib that lacks COX-2-inhibitory function. Thus, DMC is a promising drug for anti-tumor. In this study, we evaluated the efficacy and the molecular basis of DMC in the treatment of human glioblastoma multiforme (GBM). DMC inhibited the growth and proliferation of GBM cell lines (LN229, A172, U251, and U87MG) in a dose-dependent manner (P < 0.001). In GBM cells treated with DMC, detection by flow cytometry showed cell cycle arrest, and proteins involved in cell cycle such as P21 were increased. Compared with control group, Annexin-V/PI-staining in DMC-treatment group was increased, indicating that DMC could induce apoptosis in GBM cells. Also, associated proteins including cleaved caspase 3 and cleaved PARP-1 were increased. It was further explored whether DMC blocked cell cycle and induced apoptosis in GBM cells through CIP2A/PP2A/AKT signaling pathway. After treatment of DMC, the phosphorylation of Akt was reduced while the total Akt level was not affected. DMC suppressed the expression of CIP2A in a time-dependent manner, while the CIP2A overexpression group reversed cell cycle and apoptotic protein expression led by DMC. Finally, in a xenograft model in nude mice using LN229 cells, DMC suppressed tumor growth. These findings proved that DMC could block cell cycle and induce apoptosis in GBM cells by suppressing CIP2A/PP2A/Akt signaling axis, which indicated that DMC could be an effective option for GBM treatment.

Pyridine-2,6-dicarboxaldehyde-Enabled N-Terminal In Situ Growth of Polymer-Interferon α Conjugates with Significantly Improved Pharmacokinetics and In Vivo Bioactivity.

Polymer-protein conjugates are a class of biohybrids with unique properties that are highly useful in biomedicine ranging from protein therapeutics to biomedical imaging; however, it remains a considerable challenge to conjugate polymers to proteins in a site-specific, mild, and efficient way to form polymer-protein conjugates with uniform structures and properties and optimal functions. Herein we report pyridine-2,6-dicarboxaldehyde (PDA)-enabled N-terminal modification of proteins with polymerization initiators for in situ growth of poly(oligo(ethylene glycol)methyl ether methacrylate) (POEGMA) conjugates uniquely at the N-termini of a range of natural and recombinant proteins in a mild and efficient fashion. The formed POEGMA-protein conjugates showed highly retained in vitro bioactivity as compared with free proteins. Notably, the in vitro bioactivity of a POEGMA-interferon α (IFN) conjugate synthesized by this new chemistry is 8.1-fold higher than that of PEGASYS that is a commercially available and Food and Drug Administration (FDA) approved PEGylated IFN. The circulation half-life of the conjugate is similar to that of PEGASYS but is 46.2 times longer than that of free IFN. Consequently, the conjugate exhibits considerably improved antiviral bioactivity over free IFN and even PEGASYS in a mouse model. These results indicate that the PDA-enabled N-terminal grafting-from method is applicable to a number of proteins whose active sites are far away from the N-terminus for the synthesis of N-terminal polymer-protein conjugates with high yield, well-retained activity, and considerably improved pharmacology for biomedical applications.

Gorham's disease: treatment with an autologous iliac bone graft and a reverse total shoulder arthroplasty.

BACKGROUND: Gorham's disease (GSD) is a rare osteolytic disease with unclear etiology, and no known prevention or effective treatment. Here we report a new surgical treatment for a case of GSD in September 2017. CASE PRESENTATION: We report GSD in a 52-year-old woman. She had disappearance of her humeral head and a defect of the glenoid bone in her left shoulder joint, which were serious obstacles to joint function. We used an autologous iliac bone graft to repair the glenoid bone defect and a reverse total shoulder arthroplasty. After surgery, humeral osteolysis did not continue, and her shoulder function recovered well. CONCLUSIONS: This case suggests that autologous bone grafting can still be used to treat GSD despite it being an osteolytic disease. The successful treatment suggests that this method could be used for GSD in other bones.

Site-Selective in Situ Growth-Induced Self-Assembly of Protein-Polymer Conjugates into pH-Responsive Micelles for Tumor Microenvironment Triggered Fluorescence Imaging.

Self-assembly of site-selective protein-polymer conjugates into stimuli-responsive micelles is interesting owing to their potential biomedical applications, ranging from molecular imaging to drug delivery, but remains a significant challenge. Herein we report a method of site-selective in situ growth-induced self-assembly (SIGS) to synthesize site-specific human serum albumin-poly(2-(diisopropylamino)ethyl methacrylate) (HSA-PDPA) conjugates that can in situ self-assemble into pH-responsive micelles with tunable morphologies. Indocyanine green (ICG) was selectively loaded into the core of sphere-like HSA-PDPA micelles to form pH-responsive fluorescence nanoprobes. The nanoprobes rapidly dissociated into protonated individual unimers at a transition pH of around 6.5, that is the extracellular pH of tumors, which resulted in a sharp fluorescence increase and markedly enhanced cellular uptake. In a tumor-bearing mouse model, they exhibited greatly enhanced tumor fluorescence imaging as compared to ICG alone and pH-nonresponsive nanoprobes. These findings suggest that pH-responsive and site-selective protein-polymer conjugate micelles synthesized by SIGS are promising as a new class of tumor microenvironment-responsive nanocarriers for enhanced tumor imaging and therapy.

[Application of damage control orthopedics for the treatment of severe multiple fractures].

OBJECTIVE: To investigate the application effect of damage control orthopedics for the treatment of severe multiple fractures. METHODS: From January 2014 to December 2016, 23 patients with severe multiple fractures were treated with the damage control orthopedics (DCO), included 14 males and 9 females with an average age of (41.57±8.29) years old ranging from 28 to 60 years old; the NISS averaged(27.70±5.44) points ranging from 18 to 40 points. As the control group, 27 patients with severe multiple fractures were treated by the early total care(ETC) technology from Jan. 2007 to Dec. 2019, included 16 males and 11 females with an average age of (38.33±9.99) years old ranging from 19 to 55 years old, the NISS averaged (31.07±6.46) points ranging from 20 to 43 points. The ICU recovery time, blood transfusion, total operation time, mortality, complication and length of hospital stay were observed and compared between two groups. RESULTS: In the DCO group, there were 22 cases surviving and 1 case death, 3 cases of postoperative complication contained 2 cases of adult respiratory distress syndrome, 1 case pin of infection in external fixation. In ETC group, there were 25 cases surviving and 2 cases death, 10 cases of postoperative complication contained 4 cases of adult respiratory distress syndrome and 3 cases of pin infection in external fixation, 1 case of wound infection and 2 cases of multiple organ failure. There was statistically significant difference between two groups in blood transfusion in operation, the ICU recovery time, and complications(P<0.05). There was no statistically significant difference in total operation time, length of hospital stay and mortality between two groups(P>0.05). CONCLUSIONS: For patients with severe multiple fractures, application of damage control orthopedics can significantly reduce the postoperative complications, ICU recovery time and intraoperative blood transfusion, provide a certain basis for clinical treatment of such patients.

The duration perception of loading applications in smartphone: Effects of different loading types.

The loading time of a smartphone application is an important issue, which affects the satisfaction of phone users. This study evaluated the effects of black loading screen (BLS) and animation loading screen (ALS) during application loading on users' duration perception and satisfaction. A total of 43 volunteers were enrolled. They were asked to complete several tasks by clicking the icons of each application, such as camera or message. The duration of loading time for each application was manipulated. The participants were asked to estimate the duration, evaluate the loading speed and their satisfaction. The results showed that the estimated duration increased and the satisfaction for loading period declined along with the loading time increased. Compared with the BLS, the ALS prolonged the estimated duration, and lowered the evaluation of speed and satisfaction. We also discussed the tendency and key inflection points of the curves involving the estimated duration, speed evaluation and satisfaction with the loading time.

Tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates overcome doxorubicin resistance in cancer therapy.

Nanomedicines hold promise in overcoming drug resistance in cancer therapy, but the in vivo therapeutic efficacy is limited by their inefficient tumor targeting, poor tumor penetration, low cellular uptake and insufficient drug release. Here we report tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates for overcoming doxorubicin resistance. These nanoconjugates show accelerated cellular uptake and doxorubicin release and thus enhanced cytotoxicity to doxorubicin-resistant cancer cells when exposed to ultrasound. In a doxorubicin-resistant breast cancer mouse model, they exhibited improved tumor accumulation and penetration following exposure to ultrasound. More importantly, they displayed significantly improved in vivo anticancer efficacy without appreciable side effects post ultrasound irradiation. These findings suggest that these nanoconjugates are promising as a new class of intelligent nanomedicines for overcoming drug resistance in cancer therapy.

Glucose Oxidase-Polymer Nanogels for Synergistic Cancer-Starving and Oxidation Therapy.

Glucose oxidase (GOX) can convert glucose into gluconic acid and hydrogen peroxide (H2O2), which is potentially useful for synergistic cancer-starving and oxidation therapy. Herein we demonstrate a glucose-responsive nanomedicine made of GOX-polymer nanogels to regulate H2O2 production for synergistic melanoma starving and oxidation therapy. GOX-polymer nanogels showed glucose-responsive H2O2-generating activity in vitro, improved stability, and considerably enhanced tumor retention as compared to native GOX. More importantly, they exhibited high antimelanoma efficacy and no obvious systemic toxicity, whereas native GOX was ineffective and systemically toxic at the same dose. This work paves the way for establishing an endogenous and noninvasive cancer treatment paradigm that is based on intratumoral glucose-responsive, H2O2-generating chemical reactions.

Effect of transplantation of olfactory ensheathing cell conditioned medium induced bone marrow stromal cells on rats with spinal cord injury.

Spinal cord injury is a serious threat to human health and various techniques have been deployed to ameliorate or cure its effects. Stem cells transplantation is one of the promising methods. The primary aim of the present study was to investigate the effect of the transplantation of olfactory ensheathing cell (OEC) conditioned medium­induced bone marrow stromal cells (BMSCs) on spinal cord injury. Rat spinal cord compression injury animal models were generated, and the rats divided into the following three groups: Group A, (control) Dulbecco's modified Eagle's medium­treated group; group B, normal BMSC­treated group; group C, OEC conditioned medium­induced BMSC­treated group. The animals were sacrificed at 2, 4 and 8 weeks following transplantation for hematoxylin and eosin staining, and fluorescence staining of neurofilament protein, growth associated protein­43 and neuron­specific nuclear protein. The cavity area of the spinal cord injury was significantly reduced at 2 and 4 weeks following transplantation in group C, and a significant difference between the Basso, Beattie and Bresnahan score in group C and groups A and B was observed. Regenerated nerve fibers were observed in groups B and C; however, a greater number of regenerated nerve fibers were observed in group C. BMSCs induced by OEC conditioned medium survived in vivo, significantly reduced the cavity area of spinal cord injury, promoted nerve fiber regeneration following spinal cord injury and facilitated recovery of motor function. The present study demonstrated a novel method to repair spinal cord injury by using induced BMSCs, with satisfactory results.

Effects of trait anger, driving anger, and driving experience on dangerous driving behavior: A moderated mediation analysis.

To explore the effect of anger behind the wheel on driving behavior and accident involvement has been the subject of many studies. However, few studies have explored the interaction between anger and driving experience on dangerous driving behavior. This study is a moderated mediation analysis of the effect of trait anger, driving anger, and driving experience on driving behavior. A sample of 303 drivers was tested using the Trait Anger Scale (TAS), the Driving Anger Scale (DAS), and the Dula Dangerous Driving Index (DDDI). The results showed that trait anger and driving anger were positively correlated with dangerous driving behavior. Driving anger partially mediated the effect of trait anger on dangerous driving behavior. Driving experience moderated the relationship between trait anger and driving anger. It also moderated the effect of driving anger on dangerous driving behavior. These results suggest that drivers with more driving experience may be safer as they are not easily irritated during driving.

In situ growth of a C-terminal interferon-alpha conjugate of a phospholipid polymer that outperforms PEGASYS in cancer therapy.

Conjugating therapeutic proteins and peptides to poly(ethylene glycol) (PEG) can improve their pharmacokinetics and therapeutic potential. However, PEGylation suffers from non-specific conjugation, low yield and immunogenicity. Herein we report a new and general methodology to synthesize a protein-polymer conjugate with site-specificity, high yield and activity, long circulation half-life and excellent therapeutic efficacy. A phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), was grown solely from the C-terminus of interferon-alpha to form a site-specific (C-terminal) and stoichiometric (1:1) PMPC conjugate of interferon-alpha in high yield. Notably, the PMPC conjugate showed 194- and 158-fold increases in systemic exposure and tumor uptake as compared with interferon-alpha, respectively. The in vitro antiproliferative bioactivity of the PMPC conjugate was 8.7-fold higher than that of PEGylated interferon-alpha (PEGASYS). In a murine cancer model, the PMPC conjugate completely inhibited tumor growth and cured 75% mice, whereas at the same dose, no mice treated with interferon-alpha or PEGASYS survived. We believe that this new approach to synthesize C-terminal protein conjugates of PMPC may be applicable to a large subset of protein and peptide drugs, thereby providing a general platform for the development of next-generation protein therapeutics.

Expressing Anger Is More Dangerous than Feeling Angry when Driving.

Anger is an emotion that drivers often feel and express while driving, and it is believed by researchers to be an important cause of dangerous driving behavior. In this study, the relationships between driving trait anger, driving anger expression, and dangerous driving behaviors were analyzed. The Driving Anger Scale (DAS) was used to measure driving trait anger, whereas the Driving Anger Expression (DAX) Inventory was used to measure expressions of driving anger. A sample of 38 drivers completed the DAS, DAX, and a driving simulation session on a simulator where their driving behaviors were recorded. Correlation analysis showed that the higher scores on the DAS were associated with longer durations of speeding in the simulator. The more participants expressed their anger in verbal and physical ways, the more likely they were to crash the virtual vehicle during the simulation. Regression analyses illustrated the same pattern. The findings suggest that, although trait anger is related to speeding, the passive expression of anger is the real factor underling traffic accidents. This study extends findings about the predictive effects of self-report scales of driving behaviors to behaviors recorded on a simulator. Thus, if in traffic safety propaganda, guiding drivers to use positive ways to cope with driving anger is recommended by our findings.

Validation of the Driver's Angry Thoughts Questionnaire (DATQ) in a Chinese sample.

The relationship between driving anger and negative driving outcomes, such as dangerous driving behaviors and traffic violations, has been the topic of several studies, but few studies have explored drivers' angry thoughts when they encounter anger-provoking situations and the potential consequences of such thoughts. The purpose of this study was to investigate drivers' angry thoughts behind the wheel and their relationship with dangerous driving behaviors. A total of 303 Chinese drivers completed the Chinese version of the Driver's Angry Thoughts Questionnaire (DATQ), the Dula Dangerous Driving Index (DDDI) and the Driving Anger Scale (DAS). A confirmatory factor analysis (CFA) of the Chinese DATQ yielded a five-factor solution with 20 items that showed the best goodness of fit for the data. The brief DATQ also showed good reliability and validity. Three forms of aggressive thinking were positively correlated with dangerous driving behaviors, and coping self-instruction was negatively correlated with dangerous driving behaviors and traffic violations. More importantly, aggressive thinking mediated the effect of driving anger on dangerous driving behaviors, indicating the importance of thoughts behind the wheel. These results provide evidence supporting the development of strategies to reduce and prevent aggressive driving and accidents.

Modeling of Causes of Sina Weibo Continuance Intention with Mediation of Gender Effects.

Sina Weibo is a Twitter-like social networking site and one of the most popular microblogging services in China. This study aims to examine the factors that influence the intentions of users to continue using this site. This paper synthesizes the expectation confirmation model, constructs of habit and perceived critical mass, and the gender effect to construct a theoretical model to explain and predict these user intentions. The model is then tested via an online survey of 498 Sina Weibo users and partial least squares (PLS) modeling. The results indicate that the continuance intention of users is directly predicted by their perceived usefulness of the service (ß = 0.299), their satisfaction (ß = 0.208), and their habits (ß = 0.389), which jointly explain 65.9% of the variance in intention. In addition to the effects of these predictors on the continuance intentions of Sina Weibo users, an assessment of the moderating effect of gender suggests that habit plays a more important role for females than for males in continuance intention, but perceived usefulness seems to be more important for males than for females. The implications of these findings are then discussed.

Site-specific in situ growth of an interferon-polymer conjugate that outperforms PEGASYS in cancer therapy.

Conjugating poly(ethylene glycol) (PEG), PEGylation, to therapeutic proteins is widely used as a means to improve their pharmacokinetics and therapeutic potential. One prime example is PEGylated interferon-alpha (PEGASYS). However, PEGylation usually leads to a heterogeneous mixture of positional isomers with reduced bioactivity and low yield. Herein, we report site-specific in situ growth (SIG) of a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA), from the C-terminus of interferon-alpha to form a site-specific (C-terminal) and stoichiometric (1:1) POEGMA conjugate of interferon-alpha in high yield. The POEGMA conjugate showed significantly improved pharmacokinetics, tumor accumulation and anticancer efficacy as compared to interferon-alpha. Notably, the POEGMA conjugate possessed a 7.2-fold higher in vitro antiproliferative bioactivity than PEGASYS. More importantly, in a murine cancer model, the POEGMA conjugate completely inhibited tumor growth and eradicated tumors of 75% mice without appreciable systemic toxicity, whereas at the same dose, no mice treated with PEGASYS survived for over 58 days. The outperformance of a site-specific POEGMA conjugate prepared by SIG over PEGASYS that is the current gold standard for interferon-alpha delivery suggests that SIG is of interest for the development of next-generation protein therapeutics.

Effects of transcytolemmal water exchange on the assessment of myocardial extracellular volume with cardiovascular MRI.

Quantitative analysis of the myocardial interstitial space is gaining increased interest as a biomarker in the MRI and clinical cardiovascular communities. To investigate the effect of water exchange on the calculation of myocardial extracellular volume (ECV), we employed two tissue models: the standard ECV two-point model (SM) and the shutter speed model (SSM). Twenty individuals (18 men and two women; age 61.9 ± 10.3 years) underwent MRI at 1.5 T with pre-contrast and post-contrast dynamic T1 quantification. Means, standard deviations and ranges for SM and SSM model parameters were calculated. Infarct and viable myocardial model parameters as well as apparent ECV values calculated with the SM and SSM were statistically compared. Viable ECV(SM) remained temporally constant (27.3-28.0%: P = 0.5) and infarcted myocardial ECV(SM) changed significantly (49.3-58.8%; P < 0.001), reaching a steady-state value after 15 min. The intracellular lifetime of water was three times greater in infarcted myocardium when compared with viable myocardium (τi: 66.6 ± 115 versus 208.7 ± 72.7 ms) and accompanied a twofold increase in ECV (ECV(SSM) : 30.3 ± 11.1 versus 71.0 ± 13.1%; P < 0.001). There was a consistent significant difference in ECV values of infarcted myocardium at different timepoints between the SM and SSM, but not viable myocardium, presumably due to slower water exchange. In summary, we found a significant change in apparent ECV and water exchange in infarcted myocardium when compared with viable myocardium. This was visualized by changes in dynamic contrast enhanced curve shapes and quantified using the SSM as not only an increase in apparent ECV but also a decrease in water exchange.

Validation of the Driver Stress Inventory in China: Relationship with dangerous driving behaviors.

Perceived stress while driving may affect how critical driving events are handled. The current study validates a Chinese version of the Driver Stress Inventory (DSI) and explores its correlation with dangerous driving behaviors and gender. A sample of 246 drivers completed the Chinese version of the DSI and the Driver Behavior Questionnaire (DBQ). We also evaluated specific sociodemographic variables and traffic violations (including speeding, violating traffic signs or markings, driving while intoxicated, running a red light, and incurring penalty points). A confirmatory factor analysis (CFA) verified the DSI's internal structure. The DSI was also validated using questionnaires related to the DBQ, self-reported traffic accidents and violations, and sociodemographic characteristics. First, all of the DSI dimensions were moderately or weakly correlated with the DBQ subscales. Second, aggression, hazard monitoring and fatigue were weakly correlated with minor accidents. Third, drivers who had sped and violated traffic signs during the previous three years reported higher aggression and thrill seeking, while drivers who had violated traffic signs or markings during the previous three years reported decreased hazard monitoring compared with non-offenders. Finally, there were significant gender differences in driver stress. The Chinese version of the DSI will be useful for classifying and diagnosing drivers who may be at an increased risk for stress reactions.

Identifying risky drivers with simulated driving.

OBJECTIVE: The present study aimed to examine whether high-risk drivers differ from low-risk drivers in driving behavior in a simulated environment. METHOD: The 2 risk groups including 36 drivers (18 males and 18 females) performed driving tasks in a simulated environment. The simulated driving behaviors are compared between the 2 risk groups. RESULTS: The high-risk drivers drove much faster and exhibited larger offsets of the steering wheel than did the low-risk drivers in events without incidents. Additionally, the high-risk drivers used turn signals and horns less frequently than the low-risk drivers. CONCLUSIONS: The present study revealed that the high-risk group differed from the low-risk group in driving behavior in a simulated environment. These results also suggest that simulated driving tasks might be useful tools for the evaluation of drivers' potential risks.