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.

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.

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.

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.