TAK-242 inhibits glioblastoma invasion, migration, and proneural-mesenchymal transition by inhibiting TLR4 signaling.

Resatorvid (TAK-242), a small-molecule inhibitor of Toll-like receptor 4 (TLR4), has the ability to cross the blood-brain barrier (BBB). In this study, we explored the role of TAK-242 on glioblastoma (GBM) invasion, migration, and proneural-mesenchymal transition (PMT). RNA sequencing (RNA-Seq) data and full clinical information of glioma patients were downloaded from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) cohorts and then analyzed using R language; patients were grouped based on proneural (PN) and mesenchymal (MES) subtypes. Bioinformatics analysis was used to detect the difference in survival and TLR4-pathway expression between these groups. Cell viability assay, wound-healing test, and transwell assay, as well as an intracranial xenotransplantation mice model, were used to assess the functional role of TAK-242 in GBM in vitro and in vivo. RNA-Seq, Western blot, and immunofluorescence were employed to investigate the possible mechanism. TLR4 expression in GBM was significantly higher than in normal brain tissue and upregulated the expression of MES marker genes. Moreover, TAK-242 inhibited GBM progression in vitro and in vivo via linking with PMT, which could be a novel treatment strategy for inhibiting GBM recurrence.

Engineering Water-Lotus-like Iridium-Cobalt Carbonate Hydroxides on Plasma-Treated Carbon Fibers for Enhanced Electrocatalytic Oxygen Evolution.

The sluggish kinetics of the oxygen evolution reaction (OER) in alkaline water electrolysis remains a significant challenge for developing high-efficiency electrocatalytic systems. In this study, we present a three-dimensional, micrometer-sized iridium oxide (IrO2)-decorated cobalt carbonate hydroxide (IrO2-P-CoCH) electrocatalyst, which is engineered in situ on a carbon cloth (CC) substrate pretreated with atmospheric-pressure dielectric barrier discharge (DBD) plasma (PCC). The electrocatalyst features petal-like structures composed of nanosized rods, providing abundant reactive areas and sites, including the oxygen vacancy caused by the air-DBD plasma. As a result, the IrO2-P-CoCH/PCC electrocatalyst demonstrates an outstanding OER performance, with overpotentials of only 190 and 300 mV required to achieve current densities of 10 mA cm-2 (j10) and 300 mA cm-2 (j300), respectively, along with a low Tafel slope of 48.1 mV dec-1 in 1.0 M KOH. Remarkably, benefiting from rich active sites exposed on the IrO2-P-CoCH (Ir) heterostructure, the synergistic effect between IrO2 and CoCH enhances the charge delivery rates, and the IrO2-P-CoCH/PCC exhibits a superior electrocatalytic activity at a high current density (300 mV/j300) compared to the commercial benchmarked RuO2/PCC (470 mV/j300). Furthermore, the IrO2-P-CoCH/PCC electrocatalyst shows exceptional OER stability, with a mere 1.3% decrease with a current density of j10 for 100 h testing, surpassing most OER catalysts based on CC substrates. This work introduces a novel approach for designing high-performance OER electrocatalysts on flexible electrode substrates.

[Mechanism of Huangqin Qingre Chubi Capsules in improving rheumatoid arthritis based on METTL3-SFRP4/Wnt/ß-catenin pathway].

The effect and mechanism of Huangqin Qingre Chubi Capsules(HQC) on rheumatoid arthritis(RA) were studied.Seventy male SPF rats were randomly divided into normal group, model group, low-(0. 18 g·kg~(-1)), middle-(0. 36 g·kg~(-1)), and high-(0. 72 g·kg~(-1)) dose groups of HQC, methotrexate group(MTX, 0. 75 mg·kg~(-1)), and negative control group(NC group, model +saline). Adjuvant arthritis fibroblast-like synoviocytes(AA-FLS) were divided into normal group, model group, low-, middle-, and high-dose groups of HQC, and negative control group. RT-qPCR and Western blot were used to detect the m RNA and protein expressions of METTL3, SFRP4, ß-catenin, CCND1, c-Myc, MMP3, and fibronectin. The protein expression of MMP3 and ß-catenin was detected by immunofluorescence. The gene expression level of METTL3 on AA-FLS was knocked down to further examine the expression of each gene. ELISA measured the levels of IL-1ß, IL-6, and IL-8. The results showed that compared with the normal group, rats in the model group found redness and swelling in their limbs and significantly increased joint swelling. Compared with the model group, the joint swelling degree of each treatment group significantly decreased(P<0. 05). The paw retraction threshold and body weight mass index both significantly increased(P<0. 05). METTL3 was highly expressed on AA and negatively correlated with the expression of SFRP4. After treatment, the m RNA and protein expression of METTL3, ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 were significantly decreased on AA-FLS(P< 0. 05). Compared with the model group, knocking down METTL3 resulted in reduced m RNA and protein expression of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3(P< 0. 05). At the same time, the m RNA and protein expressions of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 in the HQC+METTL3 knockdown group were significantly lower than those in the METTL3 knockdown group(P<0. 05). HQC could reduce the levels of IL-1ß, IL-6, and IL-8 to varying degrees(P<0. 05). The results indicate that HQC has a significant improvement effect on arthritis in AA rats. The expression of METTL3 is significantly increased in synovial tissue and AA-FLS of AA rats, which may be a potential target for the diagnosis and treatment of RA. HQC improves RA through the METTL3-SFRP4/Wnt/ß-catenin signaling pathway and has significant antiinflammatory and anti-rheumatic effects.

Heat shock protein 27 deficiency promotes ferrous ion absorption and enhances acyl-Coenzyme A synthetase long-chain family member 4 stability to promote glioblastoma cell ferroptosis.

BACKGROUND: Glioblastoma is one of the malignant tumors of the central nervous system with high lethality, high disability and low survival rate. Effective induction of its death is one of the existing challenges. In recent studies, heat shock protein 27 (HSP27) has been shown to be associated with ferroptosis; therefore, targeting HSP27 may be a potential therapeutic approach for GBM. METHODS: Immunohistochemistry and western blot analysis were used to detect the expression of HSP27 in GBM tissues. CCK8, plate clone formation assay, EdU proliferation assay for cell proliferation ability, PI, LDH release assay for cell viability. Reactive oxygen, iron levels, and mitochondrial potential for HSP27 silencing were assayed for ferrotosis in vitro. Western blotting and IP were used to verify the relationship between HSP27 and ACSL4. The effect of knockdown of HSP27 on tumor growth capacity was assessed in an intracranial xenograft model. RESULTS: HSP27 was significantly highly expressed in GBM. In vitro experiments, knockdown of HSP27 significantly induced ferroptosis in GBM cells. IP and western blot demonstrated a sumo-ization link between HSP27 and ACSL4. In vivo experiments, HSP27 deficiency retarded tumor growth rate by promoting ferroptosis. CONCLUSIONS: HSP27 deficiency promotes GBM ferroptosis. Targeting HSP27 may serve as a new direction for GBM treatment.

White Matter Hyperintensities on Post-Stroke Balance and Gait Recovery: A Prospective Cohort Study Protocol.

INTRODUCTION: White matter hyperintensities (WMH) are commonly associated with balance and gait disturbances. Little is known whether WMH may affect post-stroke balance and gait recovery. We aim to investigate the association of post-stroke balance and gait recovery with imaging marker of WMH on magnetic resonance imaging (MRI). METHODS: This prospective cohort study will enroll consecutive patients with first-ever ischemic hemisphere stroke, between September 2023 and December 2024. Clinical data will be collected on day 30±3 and at 3-month after stroke onset. WMH on FLAIR are graded according to the modified Fazekas scale. Resting-state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) will be acquired to evaluate functional and structural connectivity. The primary endpoint is balance recovery, defined as a Postural Assessment Scale for Stroke score of 32 or higher at 3-month. The secondary endpoint is gait recovery, assessed using the modified Fugl-Meyer Gait Assessment at 3-month. We will investigate the association of post-stroke balance and gait recovery with WMH severity as well as WMH-related functional and structural connectivity. CONCLUSION: The study may contribute to clarify the effect of WMH on post-stroke balance and gait disorder recovery.

Targeting EZH2 regulates the biological characteristics of glioma stem cells via the Notch1 pathway.

Glioma is the most common malignant brain tumor, and its behavior is closely related to the presence of glioma stem cells (GSCs). We found that the enhancer of zeste homolog 2 (EZH2) is highly expressed in glioma and that its expression is correlated with the prognosis of glioblastoma multiforme (GBM) in two databases: The Cancer Genome Atlas and the Chinese Glioma Genome Atlas. Additionally, EZH2 is known to regulate the stemness-associated gene expression, proliferation, and invasion ability of GSCs, which may be achieved through the activation of the STAT3 and Notch1 pathways. Furthermore, we demonstrated the effect of the EZH2-specific inhibitor GSK126 on GSCs; these results not only corroborate our hypothesis, but also provide a potential novel treatment approach for glioma.

Anti-VEGFR2 monoclonal antibody(MSB0254) inhibits angiogenesis and tumor growth by blocking the signaling pathway mediated by VEGFR2 in glioblastoma.

Angiogenesis is a key physiological process that plays a key role in glioblastoma (GBM) progression and displays therapeutic resistance to antiangiogenic therapies. In this study, we aimed to identify whether vascular endothelial growth factor receptor 2(VEGFR2)monoclonal antibodies(mab)could inhibit tumorigenicity and the formation of vascular mimicry (VM) in GBM. The bioinformatic analysis from TCGA, CGGA, and TCPA databases and Immunohistochemistry (IHC) revealed that VEGFR2 is highly expressed in glioma tissues and results in a poor prognosis and is positively associated with VM markers (CD34 and PAS). The anti-VEGFR2 monoclonal antibodies(MSB0254)could inhibit the invasion, migration, and VM formation of U251 and primary glioma cells in vitro. In vivo, MSB0254 (m) could not only inhibit the growth of transplanted tumors of U251 and GL261 cells, but also significantly inhibit the expression of CD34, VEGFR2, Ki67, MMP2, MMP9 and reduce the expression of CD34/PAS and inhibit VM formation. The VEGFR2 monoclonal antibody could inhibit the angiogenesis and tumor growth of GBM by blocking the signaling pathway mediated by VEGFR2. It may become a new supplementary treatment for GBM.

The Effect of Cerebellar Repetitive Transcranial Magnetic Stimulation on Dysphagia due to Posterior Circulation Stroke, a Randomized Controlled Trial Protocol.

INTRODUCTION: Cerebellum might be active during the task of swallowing. Little is known whether cerebellar repetitive transcranial magnetic stimulation (rTMS) could improve post-stroke dysphagia (PSD) due to occlusion in the posterior circulation. This paper describes the rationale and design of a randomized controlled trial that aims to determine the effect of cerebellar rTMS on dysphagia due to posterior circulation stroke. METHODS AND ANALYSIS: Thirty patients with PSD due to occlusion in the posterior circulation will be randomly divided to receive real (n = 20) or sham (n = 10) cerebellar rTMS. Patients in the real rTMS group will receive 250 pulses rTMS at a low intensity with 10 Hz frequency for 10 days (five consecutive days per week). The severity of dysphagia will be assessed with videofluoroscopic swallowing study (VFSS) using the Rosenbek penetration aspiration scale (PAS), the pharyngeal constriction ratio (PCR), and the dysphagia outcome and severity scale (DOSS) before and immediately after the last session and then again after 1 and 3 months. The functional magnetic resonance imaging (fMRI) will be assessed before and after the last session and then again after 1 month and 3 months. The primary outcome is the improvement of swallowing function determined by PAS, PCR, and DOSS. The secondary outcomes include changes in brain connectivity network detected using fMRI. DISCUSSION: This study will determine whether cerebellar rTMS improves dysphagia due to posterior circulation stroke in Chinese patients. Our findings will contribute to a new approach for swallowing function recovery after posterior circulation stroke.

Determinants for a low dose of alteplase and its relationship to a lower intracerebral bleeding risk in acute ischemic stroke.

Background: Factors for the utilization of intravenous thrombolysis with a low-dose of alteplase (0.6mg/kg) and whether the low-dose of alteplase could reduce the risk of intracerebral bleeding in acute ischemic stroke (AIS) remains uncertain. Aims: We aimed to investigate determinants for the utilization of intravenous thrombolysis with a low-dose of alteplase. We further assessed the association between the low-dose of alteplase and the intracerebral bleeding risk in AIS patients. Method: We included AIS patients who received intravenous thrombolysis using alteplase in this multicenter retrospective observational study. We investigated the association between baseline characteristics and the utilization of a low-dose of alteplase to identify determinants. We assessed the association of the low-dose of alteplase with the risk of symptomatic intracranial hemorrhage (sICH) using a multivariable logistic regression model. We further compared the rate of sICH and any ICH in patients in the low-dose group to those in the standard-dose group, using propensity score-matching data. Results: A total of 506 AIS patients were included in this study. The mean age was 67 (interquartile range [IQR] 59-75), and 178 (35.2%) were women. A total of 96 patients were treated with the low-dose. Age (adjusted odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00 -1.04, p = 0.042), having a previous ischemic stroke (adjusted OR 2.01, 95%CI 1.11 - 3.64 p = 0.021) and increasing baseline systolic blood pressure (adjusted OR 1.12, 95%CI 1.00 - 1.26, p = 0.049) were determinants for the utilization of the low-dose. Multivariable logistic regression analysis showed that the low-dose was significantly associated with a reduced risk of sICH (adjusted OR 0.13, 95%CI 0.03 - 0.62, p = 0.01). Propensity score analysis showed that the rate of sICH was significantly lower in the low-dose group compared to standard-dose group (2 [2.3%] vs 10 [11.4%], p = 0.032). There was no significant difference in the rate of any ICH between two groups (14 [15.9%] vs 18 [20.5%], p = 0.434). Conclusions: Patients with increasing age, a higher baseline systolic blood pressure, and previous ischemic stroke were at a higher odd of receiving a low-dose of alteplase. The low-dose was associated with a lower risk of developing symptomatic intracranial hemorrhage.

MRI diagnose post-operative anastomotic leak in patients with rectal cancer: preliminary experience.

BACKGROUND: Anastomotic leakage (AL) is one of the most serious postoperative complications after colorectal anastomosis. This study aims to evaluate the feasibility and diagnostic accuracy of magnetic resonance imaging (MRI) in the early detection of AL in patients with clinically suspected AL after rectal anterior resection. METHODS: This was a prospective study including patients who underwent anterior resection and postoperative MRI examination. AL was diagnosed by comprehensive indictors, which were mainly confirmed by clinical signs, symptoms, and retrograde contrast enema (RCE) radiography. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of diagnosing AL with MRI were calculated. RESULTS: In total, 347 patients received anterior resection for rectal cancer, and 28 patients were suspected to have AL. Finally, 23 patients were included and received MRI examination. The median time interval from surgery to MRI was 10 days (3-21 days). The median distance from anastomosis to anal verge was 4.0 cm (2.0-10 cm), and 11 patients underwent diverted ileostomy. Eighteen patients had an anastomotic leak, including one patient who had a pelvic abscess and five patients who had no evidence of AL in the MRI examination. The overall sensitivity and specificity were 94.4% (95% CI 70.6% to 99.7%) and 80% (95% CI 29.8% to 98.9%), respectively. The PPV was 0.94 (95% CI 0.71 to 0.99) and the NPV was 0.80 (95% CI 0.29 to 0.99). For patients who had anastomosis less than 5 cm, the diagnostic accuracy of MRI was 93.7% (15/16). T2-weighted imaging with fat suppression can effectively reveal the leak track. CONCLUSIONS: The accuracy of plain MRI examination in diagnosing AL was favorable for patients with a suspected AL. T2-weighted imaging with fat suppression was the best imaging modality to diagnose AL. A multicenter prospective study with more samples is needed to further determine the safety and feasibility of MRI in the diagnosis of AL.

[Di'ao Xinxuekang alleviates non-alcoholic steatohepatitis in mice by up-regulating Nrf2/HO-1 signaling pathway].

The present study investigated the therapeutic effect and mechanism of Di'ao Xinxuekang(DXXK) on non-alcoholic steatohepatitis(NASH) in mice. Sixty-five C57 BL/6 J mice were randomly divided into a normal group and an experimental group for model induction with the high-fat diet for 16 weeks. Then the mice in the experimental group were randomly divided into a model group, an atorvastatin group(4 mg·kg~(-1)·d~(-1)), and high-(200 mg·kg~(-1)·d~(-1)), medium-(60 mg·kg~(-1)·d~(-1)), and low-dose(20 mg·kg~(-1)·d~(-1)) DXXK groups, with 10 mice in each group. Drugs were administered by gavage for eight weeks. Serum lipid, liver lipid, serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), malondialdehyde(MDA), superoxide dismutase(SOD), and glutathione reductase(GSH-Px) were determined. Interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) were measured by enzyme-linked immunosorbent assay(ELISA). The liver index was calculated. The liver pathological change and lipid accumulation were observed by HE and oil red O staining. The liver ultrastructure was observed by the transmission electron microscope. The mRNA and protein expression of nuclear factor-erythroid 2 related factor 2(Nrf2) and heme oxygenase-1(HO-1) was detected by real-time fluorescence-based quantitative PCR and Western blot, respectively. The results showed that compared with the normal group, the model group displayed serum lipid and liver lipid metabolism disorders, elevated transaminase, lipid deposition, steatosis, and inflammation, suggesting that the NASH model in mice was properly induced. Compared with the model group, the DXXK groups showed decreased serum lipid, liver lipid, ALT, AST, MDA, IL-1ß, and TNF-α, increased SOD and GSH-Px, alleviated hepatic steatosis, ballooning, and inflammation, and up-regulated Nrf2 and HO-1 gene and protein expression. In conclusion, DXXK can significantly alleviate NASH in mice, which is related to the inhibition of oxidative stress and inflammatory damage by up-regulating the Nrf2/HO-1 signaling pathway.

Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma.

BACKGROUND: Xanthine dehydrogenase (XDH) is a critical enzyme involved in the oxidative metabolism of purines, pterin and aldehydes and a central component of the innate immune system. However, the prognostic value of XDH in predicting tumor-infiltrating lymphocyte abundance, the immune response, and survival in different cancers, including hepatocellular carcinoma (HCC), is still unclear. METHODS: XDH expression was analyzed in multiple databases, including Oncomine, the Tumor Immune Estimation Resource (TIMER), the Kaplan-Meier plotter database, the Gene Expression Profiling Interactive Analysis (GEPIA) database, and The Cancer Genome Atlas (TCGA). XDH-associated transcriptional profiles were detected with an mRNA array, and the levels of infiltrating immune cells were validated by immunohistochemistry (IHC) of HCC tissues. A predictive signature containing multiple XDH-associated immune genes was established using the Cox regression model. RESULTS: Decreased XDH mRNA expression was detected in human cancers originating from the liver, bladder, breast, colon, bile duct, kidney, and hematolymphoid system. The prognostic potential of XDH mRNA expression was also significant in certain other cancers, including HCC, breast cancer, kidney or bladder carcinoma, gastric cancer, mesothelioma, lung cancer, and ovarian cancer. In HCC, a low XDH mRNA level predicted poorer overall survival, disease-specific survival, disease-free survival, and progression-free survival. The prognostic value of XDH was independent of the clinical features of HCC patients. Indeed, XDH expression in HCC activated several immune-related pathways, including the T cell receptor, PI3K-AKT, and MAPK signaling pathways, which induced a cytotoxic immune response. Importantly, the microenvironment of XDHhigh HCC tumors contained abundant infiltrating CD8 + T cells but not exhausted T cells. A risk prediction signature based on multiple XDH-associated immune genes was revealed as an independent predictor in the TCGA liver cancer cohort. CONCLUSION: These findings suggest that XDH is a valuable prognostic biomarker in HCC and other cancers and indicate that it may function in tumor immunology. Loss of XDH expression may be an immune evasion mechanism for HCC.

USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4.

BACKGROUND: Glioblastomas (GBMs) are grade IV central nervous system tumors characterized by a poor prognosis and a short median overall survival. Effective induction of GBM cell death is difficult because the GBM cell population is genetically unstable, resistant to chemotherapy and highly angiogenic. In recent studies, ubiquitin-specific protease 7 (USP7) is shown to scavenge ubiquitin from oncogenic protein substrates, so effective inhibition of USP7 may be a potential key treatment for GBM. METHODS: Immunohistochemistry and western blotting were used to detect the expression of USP7 in GBM tissues. In vitro apoptosis assay of USP7 inhibition was performed by western blotting, immunofluorescence, and flow cytometry. Anti-apoptotic substrates of USP7 were defined by Co-IP and TMT proteomics. Western blotting and IP were used to verify the relationship between USP7 and its substrate. In an in vivo experiment using an intracranial xenograft model in nude mice was constructed to assess the therapeutic effect of target USP7. RESULTS: Immunohistochemistry and western blotting confirmed that USP7 was significantly upregulated in glioblastoma samples. In in vitro experiments, inhibition of USP7 in GBM induced significant apoptosis. Co-IP and TMT proteomics identified a key anti-apoptotic substrate of USP7, ADP-ribosylation factor 4 (ARF4). Western blotting and IP confirmed that USP7 interacted directly with ARF4 and catalyzed the removal of the K48-linked polyubiquitinated chain that binded to ARF4. In addition, in vivo experiments revealed that USP7 inhibition significantly suppressed tumor growth and promoted the expression of apoptotic genes. CONCLUSIONS: Targeted inhibition of USP7 enhances the ubiquitination of ARF4 and ultimately mediates the apoptosis of GBM cells. In a clinical sense, P5091 as a novel specific inhibitor of USP7 may be an effective approach for the treatment of GBM.

Cancer risk in tuberculosis patients in a high endemic area.

BACKGROUND: Tuberculosis (TB) may facilitate carcinogenesis. We performed a case-control study of the association between TB and cancer in Xinjiang, a high TB endemic area of China. METHODS: From January 2016 to December 2018, a total of 45,455 patients hospitalized in Xinjiang Cancer Hospital were consecutively enrolled and divided into a malignant tumor group (n = 32,539) and a benign tumor group (n = 12,916). Patients with active and previous TB before the diagnosis of cancer were retrospectively identified in the two groups. RESULTS: A significantly higher proportion of TB was found in the malignant tumor group (n = 1776, 5.46%) than in the control (benign tumor) group (n = 175, 1.35%) (p < 0.0001). The highest and lowest proportions of TB in the malignant group were in patients with non-Hodgkin's lymphoma (16.74%) and thyroid cancer (0.77%), respectively. In multivariate analysis adjusting for age, sex, and ethnicity, TB remained an independent risk factor for all cancers (odds ratio (OR) 1.68; 95% confidence interval (CI) 1.43-1.97). Furthermore, TB was associated with a significantly higher risk of non-Hodgkin's lymphoma, cervical cancer, esophageal cancer, "other" cancers, ovarian cancer, and breast cancer. Moreover, females with TB were more likely to develop cancer than males (p < 0.0001), except for esophageal cancer and lymphoma. CONCLUSION: TB patients have an elevated cancer risk. A screening strategy for TB should be taken into consideration before treatment in patients with some cancer types that are associated with a high proportion of TB.

Dual PLK1 and STAT3 inhibition promotes glioblastoma cells apoptosis through MYC.

Glioblastoma (GBM) is the deadliest primary brain tumor that is highly resistant to current treatments. Polo-like kinase 1 (PLK1) and signal transducer and activator of transcription 3 (STAT3) are highly expressed in gliomas, especially GBM. Previous studies have shown reciprocal activation between PLK1 and STAT3 and that they regulate the same pools of MYC downstream. We have demonstrated that PLK1 and STAT3 levels are elevated in gliomas compared with those in normal brain tissues, and high expression of both PLK1 and STAT3 is associated with poor prognosis in TCGA. Moreover, there was direct or indirect reciprocal regulation between PLK1 and STAT3. Furthermore, we found that PLK1 and STAT3 can regulate the same pools of MYC downstream. Compared to monotherapy, combined treatment of glioma cells with PLK1 and STAT3 inhibitors, BI2536 and Stattic, respectively, showed lower expression of MYC, synergistic induction of cell invasion and apoptosis in vitro, and tumor inhibition in xenografts. PLK1 and STAT3 were able to directly regulate the expression of MYC and induce apoptosis of glioma cells through the regulation of MYC. These findings may help develop a therapeutic strategy for dual inhibition of PLK1 and STAT3 against the tumorigenesis of glioma.

Mulberry-Inspired Nickel-Niobium Phosphide on Plasma-Defect-Engineered Carbon Support for High-Performance Hydrogen Evolution.

Bimetallic phosphate electrocatalysts on carbon-cloth support are among the most promising industry-relevant solutions for electrocatalytic hydrogen production. To address the persistent issue of hetero-phase interfacing on carbon support while ensuring high activity and stability, a low-cost, high-performance hydrogen evolution reaction (HER) electrocatalyst is developed. Bi-phase Ni12 P5 -Ni4 Nb5 P4 nanocrystals with rich heterointerfaces and phase edges are successfully fabricated on carbon cloth (CC), which is enabled by intentional defect creation by atmospheric pressure dielectric barrier discharge (DBD) plasma (PCC). The obtained Ni12 P5 -Ni4 Nb5 P4 /PCC electrocatalyst exhibits excellent HER performance, heralded by the low overpotentials of 81 and 287 mV for delivering current densities of 10 (j10 ) and 500 (j500 ) mA cm-2 , respectively. Meanwhile, the Ni12 P5 -Ni4 Nb5 P4 /PCC maintains spectacular catalytic activity at high current density region (>j615 ), which outperformed the industry-relevant benchmark Pt/C/PCC catalyst. The catalyst grown on the plasma-treated support shows remarkably longer operation and ultra-stable electrocatalytic characteristics over 100 h continuous operation. Ab initio numerical simulations reveal that Ni atoms exposed in the heterointerfaces act as the main catalytically active centers for HER.

LC-MS/MS determination of buparlisib, a phosphoinositide 3 kinase inhibitor in rat plasma: Application to a pharmacokinetic study.

Buparlisib is a selective phosphoinositide 3 kinase inhibitor currently evaluated in clinical trials. We developed and validated an LC-MS/MS coupled with a one-step protein precipitation extraction method for the quantitation of buparlisib in rat plasma. After protein precipitation with acetonitrile, the plasma sample was analyzed using a Cortecs UPLC C18 column, with acetonitrile-0.1% formic acid as the mobile phase system. Mass spectrometric detection was conducted in positive ionization mode, with target quantitative ion pair of m/z 411.2 → 367.2 for buparlisib. The calibration curve showed good linearity (1.0-3000 ng/ml), with acceptable accuracy (RE ranging from -6.2 to 5.9%) and precision (RSD within 8.2%) values at quality control concentrations. Extraction recovery from plasma was 80.9-88.7% and the matrix effect was negligible (92.6-95.2%). The validated method presented a simple quantification method of buparlisib in detail and utilized it for a pharmacokinetic study at three dose concentrations after oral administration in Wistar rats.

[Regulatory effect of Di'ao Xinxuekang on TLR4/MyD88/NF-κB signaling pathway in atherosclerotic rats].

The aim of this paper was to observe the effect of Di'ao Xinxuekang(DXXK) on TLR4/MyD88/NF-κB signaling pathway in atherosclerotic rats, and to explore its anti-atherosclerotic mechanism. Sixty SD rats were randomly divided into normal group, model group, atorvastatin group(4.0 mg·kg~(-1)), and DXXK groups(100, 30, 10 mg·kg~(-1)), with 10 rats in each group. The atherosclerosis model was induced by high fat diet plus vitamin D_2. Experimental drugs were administered intragastrically once daily for 8 weeks starting from the 9 th week. Biochemical analyzers were used to detect levels of triglyceride(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C) and high-density lipoprotein cholesterol(HDL-C) in blood lipid. The levels of serum tumor necrosis factor(TNF)-α, interleukin(IL)-6 and IL-1ß were detected by ELISA. Pathological changes of aortic tissues were observed by using Sudan Ⅳ and HE staining. The mRNA and protein expressions of TLR4, MyD88 and NF-κB p65 in aortic tissues were detected by RT-PCR and Western blot, respectively. As compared with the model group, TC, TG, and LDL-C levels in serum were significantly decreased, HDL-C content was significantly increased, and levels of TNF-α, IL-6, and IL-1ß in serum were significantly decreased in atorvastatin group and DXXK high and middle dose groups. Aortic lesions in atorvastatin group and DXXK group were significantly improved, and the mRNA and protein expressions of TLR4, MyD88, NF-κB p65 in the aorta were decreased. DXXK has a preventive and therapeutic effect on atherosclerosis in rats, and its mechanism may be related to inhibiting inflammatory reaction by regulating TLR4/MyD88/NF-κB signal transduction, thereby inhibiting the progression of atherosclerosis.

Incidental pulmonary embolism in suspected stroke patients undergoing carotid CT angiography.

PURPOSE: The purpose of this study was to investigate the prevalence of incidental pulmonary embolism (IPE) in suspected stroke patients receiving carotid computed tomography angiography (CTA) and its characteristics. MATERIALS AND METHODS: A total of 4873 cases receiving carotid CTA between January 2013 and December 2016 were retrospectively reassessed by one radiologist. Patients with previous or suspected PE were excluded. The remaining prior contrast-enhanced carotid CTA studies were regarded as a "potentially incidental" IPE when a filling defect was found in one or more pulmonary arteries and subjected to the other two thoracic radiologists independently for reviewing and assessing for characteristics of the IPE and the image quality of the PE. The differences were noted between inpatients and outpatients in prevalence of IPE. Characteristics of the patients with IPE were also studied in terms of gender, age, as well as clinical indication. RESULTS: The prevalence of IPE among these suspected stroke patients was 0.8% on carotid CT angiography, and 24 (96%) of all IPEs had not been previously diagnosed by the original reporting radiologists. Most of the IPEs were at the lobar or segmental levels, single and in right upper lobe of pulmonary arteries. In most of the cases, the reviewing radiologists judged the contrast bolus as good. The outpatient group had a lower percentage of patients with IPE when compared with the inpatient counterpart (p = 0.024). The prevalence of IPE in patients with suspected stroke was higher with the increasing of age (p = 0.013). CONCLUSIONS: IPE can occur in suspected stroke patients on carotid CT angiography, and most of them have been previously neglected in clinical practice. Radiologists should check the higher pulmonary arterial vasculature carefully on the contrast-enhanced carotid CTA scans.

Adipogenic niches for melanoma cell colonization and growth in bone marrow.

Bone marrow (BM) adipocytes are abundant in BM and may be involved in the process of bone metastasis. However, their behaviors in metastatic BM niches during bone metastasis have not been fully explored. In this study, intracardiac transplantation of B16-F10 melanoma cells into immunocompetent C57BL/6 mice was performed. Tibial marrow sections were stained with hematoxylin and eosin, Masson's trichrome, tartrate-resistant acid phosphatase, and fatty acid-binding protein 4 (FABP4) and analyzed using a histomorphometric system. The results showed that the number of BM adipocytes rapidly increased in melanoma metastatic BM niches, which were in direct contact with metastasizing melanoma cells and acted as a tumor stromal population in the BM-melanoma niche. Melanoma cell-derived factors could enhance BM adipogenesis, which promotes melanoma cell proliferation and cell cycle transitions. Moreover, BM adipocytes might aid in the modification of the osteolytic BM microenvironment. These results indicate that an increase in the number of BM adipocytes in a metastatic BM niche may facilitate melanoma cell colonization and growth in BM. BM adipocytes might therefore support the development of bone metastases.