Health Technology Assessment: Evaluation of 7 Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus.

Purpose: This study provides a reference for healthcare organizations in the selection and rational use of glucagon-like peptide-1 receptor agonists (GLP-1RAs), based on the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition). Methods: According to the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition) released in 2023, relevant databases such as PubMed, Cochrane, and Embase, drug labels, and clinical guidelines were searched for drug information. We systematically evaluated 7 GLP-1RAs marketed in China for safety, efficacy, economy, pharmacological properties, and other attributes using a percentage scoring method. Results: The final assessment result scores from highest to lowest were semaglutide (71.5 points), dulaglutide (68.9 points), liraglutide (68.7 points), exenatide (62.5 points), lixisenatide (59.9 points), polyethylene glycol loxenatide (55.9 points), and benaglutide (45.1 points). Conclusion: When a healthcare organization introduces GLP-1RAs to their hospital, they can refer to the assessment results and use the top three recommended medications: semaglutide, dulaglutide, and liraglutide.

CDK4/6 inhibitors for hormone receptor-positive/human epidermal growth factor receptor 2 negative advanced breast cancer: A rapid health technology assessment.

OBJECT: Based on the best available evidence, rapid health technology was used to assess 4 CDK4/6 inhibitors approved for marketing in China. This assessment aims to provide a reference basis for the selection of drugs by medical institutions in China and to promote the rational use of drugs in the clinic. METHODS: Depending on the Rapid Guidelines for Drug Evaluation and Selection in Chinese Medical Institutions (the Second Edition), a percentage quantitative scoring approach was used to objectively score the pharmacological properties, efficacy, safety, economy, and other attributes of CDK4/6 inhibitors. RESULTS: The composite score rankings were, in descending order, 78.09 points for abemaciclib, 78.04 points for palbociclib, 72.15 points for dalpiciclib, and 69.24 points for ribociclib by integrating the result of the 5 dimensions. CONCLUSION: Until the clinical studies, guideline recommendations, prices, and many other aspects of this assessment are updated, abemaciclib and palbociclib, which have the top 2 scores, can be used as a priority recommendation for Chinese medical institutions to select CDK4/6 inhibitors and optimize the use of the drug catalog based on the scoring results of this assessment.

Comparison of the efficacy and safety of 10 glucagon-like peptide-1 receptor agonists as add-on to metformin in patients with type 2 diabetes: a systematic review.

Purpose: This study aimed to perform a network meta-analysis to objectively evaluate the efficacy and safety of 10 Glucagon-like peptide-1 receptor agonists (GLP-1RAs) in combination with metformin that is approved for use worldwide in patients with type 2 diabetes and to provide evidence-based support and reference for the selection of clinical treatment. Methods: Three databases (PubMed, Embase, and Cochrane Library) were searched from their respective inception until September 30, 2022. Only randomized controlled trials comparing the efficacy and safety of GLP-1RAs for treating type 2 diabetes (T2D) were included. The 10 GLP-1RAs are exenatide (including exenatide twice daily and once weekly), liraglutide, lixisenatide, dulaglutide, PEX168, semaglutide (subcutaneous and oral semaglutide), tirzepatide and albiglutide. Results: 34 RCTs with 10 GLP-1RAs and 12993 patients were included in the Network Meta-Analysis (NMA). According to the NMA, tirzepatide 15 mg, semaglutide 1.0 mg, PEX168-200µg, oral semaglutide 14 and dulaglutide 1.5 mg reduced HbA1c by -2.23%, -1.57%, -1.12%, -1.10%, -1.09% and body weight by -11.33 kg, -5.99 kg, +0.40 kg, -3.95 kg, -1.87 kg, respectively. There was no significant difference in the rate of adverse events for tirzepatide 15 mg, oral-semaglutide 14 mg, and semaglutide 1.0 mg. PEX168-200µg, tirzepatide 15mg, and oral semaglutide 14mg had Surface Under the Cumulative Ranking (SUCRA) values greater than placebo, and only tirzepatide 15mg and oral semaglutide 14mg were significantly different from placebo in the rate of serious adverse events. All GLP-1RA did not lead to increased incidence of hypoglycemia. Albiglutide 30mg and semaglutide 1.0mg significantly differed from placebo in Adverse Event (AE) withdrawal. Finally, the sensitivity analysis and publication bias analysis results indicate that the study results are reliable. Conclusion: This study's results showed that GLP-1RAs were effective in lowering HbA1c and reducing body weight without increased incidence of hypoglycemic reactions. In addition, this study may provide reference and evidence-based medical evidence for clinicians to select GLP-1RAs in patients with T2D and high body mass index (BMI). Based on the NMA results, tirzepatide 15mg and semaglutide 1.0mg may be preferred.

A multicenter real-world study comparing the clinical equivalence of trastuzumab biosimilar HLX02 and reference trastuzumab in the treatment of HER-2-positive breast cancer.

As the first trastuzumab biosimilar introduced in China, there are few studies on the clinical application of HLX02, especially in combination with other antitumour drugs, for the treatment of HER-2-positive breast cancer. A multicenter retrospective study was conducted in three hospitals in China to select patients with HER-2-positive breast cancer who met the inclusion criteria and received HLX02 or the reference trastuzumab. Ninety-six patients diagnosed with HER-2-positive breast cancer were finally included and divided into two groups and treated with HLX02 or the reference trastuzumab. The results showed no significant differences in pathological complete response (70.0% vs. 76.2%; P=1.000) and overall response rate (91.9% vs. 94.9%; P=0.673) between the two groups. Kaplan-Meier survival curves also showed no significant difference in time-to-event variables between the two groups (log-rank P=0.48). Safety was also comparable in both groups. In conclusion, among patients with HER2-positive breast cancer, HLX02 demonstrated equivalent efficacy and safety to its reference trastuzumab, both in neoadjuvant chemotherapy and in postoperative adjuvant therapy. However, clinical equivalence studies between HLX02 and the original trastuzumab drug remain challenging. Future research should focus on the clinical exchange between biosimilars and original drugs, as well as the extrapolation of biosimilars' indications.

[Anti-pyroptosis effect of Albiziae Cortex-Tribuli Fructus combination on hepatic stellate cell line LX2: based on network pharmacology].

Based on network pharmacology, molecular docking, and in vitro experimental verification, this study aims to explore the effect of Albiziae Cortex-Tribuli Fructus combination on HSC-LX2 pyroptosis. Specifically, the targets of Albiziae Cortex, Tribuli Fructus, and hepatic fibrosis were retrieved from an online database and CNKI, and "drug-component-target" network and "drug-component-target-disease" network were constructed. Protein-protein interaction(PPI) network was established based on STRING. Metascape was employed for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and the mechanism of Albiziae Cortex-Tribuli Fructus combination against liver fibrosis was predicted. Molecular docking was used to verify some of the results of network pharmacology, and in vitro experiment was carried out to further verify the above conclusions. According to the results of network pharmacological analysis, 25 active components and 439 targets of Albiziae Cortex-Tribuli Fructus combination and 152 anti-liver fibrosis targets were screened out, including nucleotide-binding oligomerization domain and leucine-rich-repeat-and pyrin-domain-containing 3(NLRP3) and caspase-1. The key targets were involved in 194 KEGG pathways in which the NOD-like receptor signaling pathway topped. The binding common targets were related to pyroptosis. The results of in vitro experiment showed that the pair-containing serum reduced the proliferation rate of HSC-LX2 and the content of reactive oxygen species(ROS), interleukin-18(IL-18), and interleukin-1ß(IL-1ß)(P<0.05). Western blot and qRT-PCR suggested that the protein and gene expression of NLRP3, caspase-1, α-smooth muscle actin(α-SMA), and gasdermin D(GSDMD) in HSC-LX2 increased after AngⅡ stimulation, and the expression decreased after the intervention of pair-containing serum(P<0.05). In summary, the pair-containing serum can inhibit the classic pathway of pyroptosis, which may be the anti-liver fibrosis mechanism. This is consistent with the predicted results of network pharmacology.

Efficacy and Safety of Liraglutide and Semaglutide on Weight Loss in People with Obesity or Overweight: A Systematic Review.

Purpose: The effect and safety of Semaglutide and Liraglutide on weight loss in people with obesity or overweight were evaluated by a Network Meta-Analysis system to provide an evidence-based reference for clinical treatment. Methods: Computer searched PubMed, Embase, and Cochrane Library databases to collect Liraglutide and Semaglutide injection monotherapy RCTs until April 2022, using Stata 16 software for Network Meta-Analysis. Results: Twenty-three RCTs study with 11,545 patients and 4 interventions (semaglutide 2.4mg, semaglutide 1.0mg, liraglutide 3.0mg and liraglutide 1.8 mg) were finally included. In terms of efficacy, semaglutide 2.4mg (-12.47 kg) had the best weight loss, followed by liraglutide 3.0mg (-5.24 kg), semaglutide 1.0mg (-3.74 kg) and liraglutide 1.8mg (-3.29 kg). In terms of decreased HbA1c, semaglutide 2.4mg (MD=-1.48%, 95% CI [-1.93, -1.04]), semaglutide 1.0mg (MD=-1.36%, 95% CI [-1.72, -1.01]), liraglutide 1.8mg (MD=-1.23%, 95%Cl [-1.66, -0.80]) more effective than placebo. In terms of safety, the total incidence of adverse events was semaglutide 2.4mg > liraglutide 3.0mg > liraglutide 1.8mg > semaglutide 1.0mg compare to placebo, the incidence of serious adverse events was liraglutide 3.0mg > liraglutide 1.8mg > semaglutide 2.4mg > semaglutide 1.0mg, the incidence of hypoglycemic events was semaglutide 2.4mg > liraglutide 3.0mg > semaglutide 1.0mg > liraglutide 1.8mg. Conclusion: This meta-analysis indicates that all GLP-1RAs were more efficacious than placebo in people with obesity or overweight on efficacy. Semaglutide 2.4mg has an absolute advantage in weight loss and decreased HbA1c, but the incidence of total adverse events is also the highest and can cause hypoglycemia. In addition, although liraglutide 3.0mg was less effective than semaglutide 2.4mg, serious adverse events were still the most elevated.

Graphene Oxide-Modified Concentric Microgrooved Titanium Surfaces for the Dual Effects of Osteogenesis and Antiosteoclastogenesis.

Surface modification is an effective method to resolve the biocompatibility, mechanical, and functional issues of various titanium implant materials. Therefore, many researchers have modified the implant surface to promote the osseointegration of the implant and improve the implant survival rate. In this study, we used photolithography to construct concentric microgrooves with widths of 10 µm and depths of 10 µm, to produce an osteon-mimetic concentric microgrooved titanium surface that was further modified with graphene oxide by silanization (GO-CMS). The modified surface had great biocompatibility and promoted the proliferation of bone marrow-derived mesenchymal stem cells (BMSCs) and RAW264.7 macrophages. The concentric microgrooves on the titanium surface guided cell migration, altered actin cytoskeleton, and caused the cells to arrange in concentric circles. The titanium surface of the GO-modified osteon-mimetic concentric microgrooves promoted the osteogenic differentiation of BMSCs and inhibited the osteoclastogenic differentiation of RAW264.7 cells. Subsequently, we constructed an indirect coculture system and found that RAW264.7 cells cultured on a GO-CMS material surface in a BMSC-conditioned medium (BCM) decreased receptor activator of nuclear factor-κB ligand (RANKL) secretion and increased OPG secretion and also that the BCM inhibited osteoclastogenic differentiation. Additionally, the secretion of OSM increased in BMSCs cultured in RAW264.7-conditioned medium (RCM) in the GO-CMS group, which in turn promoted the osteogenic differentiation of BMSCs. In conclusion, the titanium surface of GO-modified osteon-mimetic concentric microgrooves had dual effects of osteogenesis and antiosteoclastogenesis under single and coculture conditions, which is beneficial for implant osseointegration and is a promising method for the future direction of surface modifications of implants.

Efficacy and safety of proton pump inhibitors versus vonoprazan in treatment of erosive esophagitis: A PRISMA-compliant systematic review and network meta-analysis.

BACKGROUND: Proton-pump inhibitors (PPIs) and vonoprazan are recommended as first-line therapies for erosive esophagitis (EE). However, it is uncertain how the magnitude of efficacy and safety of first-line therapy, the choice of individual PPIs or vonoprazan in the treatment of EE remains controversial. This study aimed to evaluate the efficacy and safety of vonoprazan and PPIs in healing esophageal mucosal injury in patients with EE. METHODS: Relevant databases were searched to collect randomized controlled trials of proton pump inhibitors and vonoprazan in the treatment of reflux esophagitis up to December 2021. Studies on standard-dose PPIs or vonoprazan that were published in Chinese or English and assessed healing effects in EE were included in the analysis. Stata16.0 was used to conduct a network Meta-analysis to evaluate the efficacy and safety of the treatment. RESULTS: A total of 41 literatures were included with 11,592 enrolled patients. For the endoscopic cure rate, all the PPIs and vonoprazan significantly improve compared to Placebo; Based on the surface under the cumulative ranking curve, Ilaprazole ranked first, followed by esomeprazole, vonoprazan, pantoprazole, lansoprazole, omeprazole, rabeprazole and placebo therapy ranked the last. For the rate of adverse events, there was no significant difference among all the PPIs, vonoprazan, and placebo. CONCLUSIONS: Ilaprazole, esomeprazole and vonoprazan have more advantages in mucosal erosion healing, there was no significant difference in the comparative safety among all interventions.

A Health Technology Assessment Based on Chinese Guidelines: Glucagon-Like Peptide-1 Receptor Agonist in the Treatment of Type 2 Diabetes Complicated with Cardiovascular Disease.

Purpose: According to the requirements of the "Quick Guide for Drug Evaluation and Selection in Chinese Medical Institutions", this health technology assessment provides an evidence-based basis for drug selection and rational clinical use of glucagon-like peptide-1 receptor agonist drugs in medical institutions. Methods: We consult the drug instructions, clinical treatment guidelines and search relevant documents in databases such as China national knowledge infrastructure, Wanfang, PubMed, and government websites such as National Medical Products Administration, Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency to collect and sort out the relevant information of the indications, pharmacological effects, guideline recommendations, drug prices and other information of glucagon-like peptide-1 receptor agonists, using a percentile system systematically evaluate the five dimensions of glucagon-like peptide-1 receptor agonists in terms of pharmaceutical properties, efficacy, safety, economy, and other attributes. Results: The final scores of the evaluation results from high to low are semaglutide (71.00 points), dulaglutide (68.75 points), liraglutide (67.50 points), exenatide (67.00 points), lixisenatide (63.50 points), polyethylene glycol loxenatide (58.00 points) and benaglutide (49.00 points). Conclusion: In clinical practice, semaglutide and dulaglutide are the top two drugs that can be used as recommended drugs. This health technology assessment can provide an evidence-based basis for hospital selection and rational use of glucagon-like peptide-1 receptor agonists. Clinicians can rationally choose and use drugs according to the patient's conditions and needs.

Angiotensin II can trigger HSC-LX2 pyroptosis through both classical and non-classical pathways.

BACKGROUND: Current evidence suggests that liver fibrosis is reversible even at late stages. Pyroptosis is reportedly regulated by classical and non-classical pathways and is also involved in the activation of the human hepatic stellate cell line LX2. This study sought to identify regulatory pathways that pyroptosis of HSC during AngII-ROS-induced HSC activation and provides novel insights for anti-fibrosis therapy by targeting HSC. MATERIALS AND METHODS: All experiments were conducted in HSC-LX2. The expressions of α-SMA, NLRP3, Caspases-1, -4, -5, ASC and GSDMD-N were detected in HSC-LX2 cells induced with AngII by Western blot and qRT-PCR. CCK8 was used to detect cell proliferation and activity. 2'-7'dichlorofluorescin diacetate (DCFH-DA) was used to measure ROS generation. An LDH assay kit was used to detect LDH released from damaged cells, and ELISA was used to quantify IL-18 and IL-1ß levels. RESULTS: After AngII stimulation, HSC-LX2 cell viability, ROS, LDH, IL-18, and IL-1ß were increased compared with Control group. At the same time, the protein and mRNA levels of α-SMA, NLRP3, Caspases-1, -4, -5, ASC and GSDMD-N were increased. In addition, after NAC and NSA treatment, LDH, IL-18 and IL-1ß levels and the protein and mRNA expression of α-SMA, Caspases-4 and -5, and GSDMD-N were decreased. CONCLUSION: HSC-LX2 pyroptosis induced by AngII-ROS is mediated by the classical pathway involving NLRP3/Caspase-1 and the non-classical pathway involving Caspases-4 and -5. Our results provide compelling evidence that AngII could activate Caspases-4 and -5 by producing ROS.

Trastuzumab biosimilar HLX02 versus reference trastuzumab in patients with recurrent or metastatic HER2-positive breast cancer: a model-based economic evaluation for China.

BACKGROUND: HLX02 is a newly marketed trastuzumab biosimilar in China, but whether its price reflects a potential benefit in terms of its value remains unclear. In addition, the development of biosimilars in China is just beginning, and the state encourages health economic evaluation of newly marketed biosimilars. METHODS: Based on the previously published randomized controlled trial data, a Markov model was used to perform health economic evaluation of HLX02 and trastuzumab in the treatment of HER2-positive recurrent or metastatic breast cancer, calculate quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER), and evaluate the robustness of the model with sensitivity analysis. RESULTS: The model results showed that the 5-year mortality rate was 84.4% in the HLX02 group, while the mortality rate was 91.2% in the trastuzumab group. When without accounting for the cost of second-line treatment, patients treated with HLX02 had an increased life expectancy of 0.138 QALYs and a $421.11 lower cost compared with patients in the trastuzumab group, with an ICER value of -$3,051.52/QALY. CONCLUSIONS: At the willingness-to-pay threshold of $37,653/QALY in China, HLX02 is more cost-effective than trastuzumab. However, the relevant systems for the regulation of biosimilars still need to be improved.

Metastatic HER-2 positive breast cancer poses a considerable cost to society due to limitations in health care resources. HLX02 is the first trastuzumab biosimilar produced in China and evaluated worldwide, and its emergence has opened the door to trastuzumab biosimilars in China. Although HLX02 has been shown to be clinically equivalent to the original drug in the treatment of metastatic HER2-positive breast cancer, it remains unclear whether its price reflects the potential benefit in terms of its value. In addition, the development of biosimilars in China is just beginning, and the state encourages health economic evaluation of newly marketed biosimilars. Based on the results of Markov model, at the willingness-to-pay threshold of $37,653/QALY in China, HLX02 is more cost-effective than trastuzumab under the condition of equivalent efficacy and safety. However, it remains challenging to adjust the development of the regulation of biosimilars, such as the price difference between biosimilars and original drugs.

Cobalt-Catalyzed Regioselective para-Amination of Azobenzenes via Nucleophilic Aromatic Substitution of Hydrogen.

The metal-catalyzed nucleophilic aromatic substitution of hydrogen (SNArH) via coordination of the substituent on the aromatic ring to the metal catalyst, in terms of reactivity, substrate type, and reaction selectivity, complements the transition metal-catalyzed C-H functionalization that proceeds via C-H metalation but remains an elusive target. Described herein is the development of an unprecedented cobalt-catalyzed para-selective amination of azobenzenes, which is essentially a metal-promoted SNArH process as revealed by Hammett analysis, thus illustrating the concept that coordination of the substituent on the arene ring to the metal catalyst may result in electrophilic activation of the arene ring toward SNArH. This cobalt-catalyzed protocol allows the use of a variety of both aliphatic amines and anilines as aminating reagents, tolerates electronically diverse substituents of azobenzene, and furnishes the corresponding products in good yields with a regiospecific selectivity for para-amination.

Erianin suppresses proliferation and migration of cancer cells in a pyruvate carboxylase-dependent manner.

Erianin is a natural small molecule dibenzyl compound extracted from Dendrobium officinale or Dendrobium chrysotoxum. Studies show erianin has many pharmacological functions such as antioxidant, antibacterial, antiviral, improving diabetic nephropathy, relaxing bronchial smooth muscle and anti-tumor. However, the erianin-mediated molecular mechanism is elusive, and the target protein of erianin is not clear yet. Here, we screened and identified that the target protein of erianin in human hepatoma HepG2 cells is human pyruvate carboxylase, and explored the anti-tumor signal pathway regulated by erianin in several cell lines. Firstly, the interaction between human pyruvate carboxylase and erianin was studied by bioinformatics and biochemical methods. Secondly, in vitro, erianin can specifically inhibit the activity of human pyruvate carboxylase, and the purified human pyruvate carboxylase can specifically bind to the activity probe of erianin. Thirdly, human pyruvate carboxylase is highly expressed in a variety of malignant tumors, and the inhibitory effect of erianin on tumor cells is positively correlated with the expression of human pyruvate carboxylase, and erianin can selectively inhibit the activity of pyruvate carboxylase. Finally, erianin can regulate the pyruvate carboxylase-mediated Wnt/ ß- Catenin pathway. All of which provide important data for the further study of the anticancer mechanism of erianin, and lay a solid foundation for the further development and utilization of erianin.

Intuitionistic Fuzzy C-Means Algorithm Based on Membership Information Transfer-Ring and Similarity Measurement.

The fuzzy C-means clustering (FCM) algorithm is used widely in medical image segmentation and suitable for segmenting brain tumors. Therefore, an intuitionistic fuzzy C-means algorithm based on membership information transferring and similarity measurements (IFCM-MS) is proposed to segment brain tumor magnetic resonance images (MRI) in this paper. The original FCM lacks spatial information, which leads to a high noise sensitivity. To address this issue, the membership information transfer model is adopted to the IFCM-MS. Specifically, neighborhood information and the similarity of adjacent iterations are incorporated into the clustering process. Besides, FCM uses simple distance measurements to calculate the membership degree, which causes an unsatisfactory result. So, a similarity measurement method is designed in the IFCM-MS to improve the membership calculation, in which gray information and distance information are fused adaptively. In addition, the complex structure of the brain results in MRIs with uncertainty boundary tissues. To overcome this problem, an intuitive fuzzy attribute is embedded into the IFCM-MS. Experiments performed on real brain tumor images demonstrate that our IFCM-MS has low noise sensitivity and high segmentation accuracy.

Inactivation of Wnt-LRP5 signaling suppresses the proliferation and migration of ovarian cancer cells.

BACKGROUND: Ovarian cancer (OCa) is the most lethal gynecological malignant tumor, with few or no specific symptoms in its early stage. There are many signaling pathways involved in the process of OCa progression, among which the highly complex Wnt signaling pathway plays a unique role in the occurrence and development of OCa because of its functions of regulating gene expression, cell proliferation, migration, and invasion. Lipoprotein associated receptor protein 5/6 (LRP5/6) binds to activate this key pathway. Therefore, it is very important to study the mechanism of Wnt-LRP5 signaling pathway in the proliferation and migration of OCa. METHODS: In the present study, we have investigated the role of Wnt-LRP5 signaling pathway in OCa proliferation and migration for the first time using the dominant negative plasmid of LRP5 (DN-LRP5) and human OCa cells HO8910PM plus in a mouse model. RESULTS: Our data showed inactivation of LRP5 resulted in shift of epithelial-mesenchymal transition (EMT), rearrangement of the cytoskeleton, lowered activity of pro-proliferation and pro-migration cancer signaling pathways including Akt, p38 and NF-κB, eventually decreased proliferation and migration of OCa cells HO8910PM in vitro. Moreover, in vivo OCa-DN-LRP5 mouse model developed significantly smaller tumors as determined by inoculation of HO8910PM-DN-LRP5 cells into nude mice. CONCLUSIONS: Collectively, our results demonstrate the dominant role of Wnt-LRP5 in OCa proliferation and migration and its potential as a valuable therapeutic target.

Time-resolved quantification of the dynamic extracellular space in the brain: study of cortical spreading depression.

Extracellular diffusion in the brain is customarily characterized by two parameters, the extracellular space (ECS) volume fraction α and the diffusion tortuosity λ. How these two parameters are temporarily modified and correlated in a physiological/pathological event remains unclear to date. Using tetramethylammonium (TMA+) as an ECS ion tracer in a newly updated iontophoretic sinusoidal method, we studied in this work the dynamic α(t) and λ(t) in rat somatosensory cortex during spreading depression (SD). Temporal variations of α(t) and λ(t), as evoked by SD, were obtained through analyses of the extracellular TMA+ diffusion waveform resulting from a sinusoidally modulated point source. Most of the time, cortical SD induced coordinated α(t) decreases and λ(t) increases. In rare occasions, SD induced sole decreases of α(t) with no changes in λ(t). The independent modulation of α(t) and λ(t) was neither associated with cortical anatomy nor with the specific shape of the SD field potential wave. Changes of α(t) and λ(t) often took place acutely at the onset of SD, followed by a more transient modulation. Compared with the prior iontophoretic methods of TMA+, the sinusoidal method provides time-resolved quantification of α(t) and λ(t) in relative terms but also raises a higher property requirement on the TMA+-selective microelectrode. The sinusoidal method could become a valuable tool in the studies of the dynamic ECS response in various brain events. NEW & NOTEWORTHY An iontophoretic sinusoidal method was applied to study the dynamic changes of two extracellular space parameters, the extracellular volume fraction α(t) and tortuosity λ(t), in the brain during cortical spreading depression. Both parameters showed coordinated (most often) and independent (rarely) modulations in spreading depression. The sinusoidal method is equally applicable to other acute pathological events and a valuable tool to study the functional role of extracellular space in brain events.

Synthesis and inhibitory effect of 10-chlorocanthin-6-one on ovarian cancer HO8910PM cells.

OBJECTIVE: To synthesize and determine the antitumor activity of 10-chlorocanthin-6-one in ovarian cancer HO8910PM cells. RESULTS: Among the synthesized canthin-6-one analogs, 10-chlorocanthin-6-one was the most cytotoxic (IC50 = 4.9 µM), as demonstrated by a dose-dependent cytotoxicity assay. Moreover, 10-chlorocanthin-6-one induced apoptosis through the activation of poly(ADP-ribose) polymerase and caspase-3 cleavage, upregulation of Bcl-2, and downregulation of Bim, x-linked inhibitor of apoptosis protein (XIAP), and survivin in HO8910PM cells. Furthermore, Bim RNA, upregulated in a concentration-dependent manner, and knockdown of Bim via short-hairpin RNAs attenuated the inhibitory effects of 10-chlorocanthin-6-one on HO8910PM cell growth. CONCLUSIONS: 10-Chlorocanthin-6-one inhibits cell proliferation and induces apoptosis in H08910PM cells. The underlying molecular mechanisms of 10-chlorocanthin-6-one include activation of the Bim-mediated mitochondrial apoptotic pathway via upregulation of Bim and downregulation of Bcl-2, XIAP, and survivin. These data suggest that Bim is a potential target of 10-chlorocanthin-6-one, further demonstrating its potential use in the prevention and treatment of ovarian cancer.

Correction to: Synthesis and inhibitory effect of 10-chlorocanthin-6-one on ovarian cancer HO8910PM cells.

The addresses given for the authors of this paper were incorrect. The correct assignments of the authors are given in this erratum.

The expression of cytoglobin as a prognostic factor in gliomas: a retrospective analysis of 88 patients.

BACKGROUND: Evidence suggests that cytoglobin (Cygb) may function as a tumor suppressor gene. METHODS: We immunohistochemically evaluated the expression of Cygb, phosphatidylinositol-3 kinase (PI-3K), phosphorylated (p)-Akt, Interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) and vascular endothelial growth factor (VEGF) in 88 patients with 41 high-grade gliomas and 47 low-grade gliomas. Intratumoral microvessel density (IMD) was also determined and associated with clinicopathological factors. RESULTS: Low expression of Cygb was significantly associated with the higher histological grading and tumor recurrence. A significant negative correlation emerged between Cygb expression and PI3K, p-Akt, IL-6, TNFα or VEGF expression. Cygb expression was negatively correlated with IMD. There was a positive correlation between PI3K, p-Akt, IL-6, TNFα and VEGF expression with IMD.High histologic grade, tumor recurrence, decreased Cygb expression, increased PI3K expression, increased p-Akt expression and increased VEGF expression correlated with patients' overall survival in univariate analysis. However, only histological grading and Cygb expression exhibited a relationship with survival of patients as independent prognostic factors of glioma by multivariate analysis. CONCLUSIONS: Cygb loss may contribute to tumor recurrence and a worse prognosis in gliomas. Cygb may serve as an independent predictive factor for prognosis of glioma patients.

Comparison of manually shaped and computer-shaped titanium mesh for repairing large frontotemporoparietal skull defects after traumatic brain injury.

OBJECT: The object of this study was to compare the effects and complications of manual and computer-aided shaping of titanium meshes for repairing large frontotemporoparietal skull defects following traumatic brain injury. METHODS: From March 2005 to June 2011, 161 patients with frontotemporoparietal skull defects were observed. Patients were divided into 2 groups according to the repair materials used for cranioplasty: 83 cases used computer-aided shaping for the titanium mesh, whereas the remaining 78 cases used a manually shaped titanium mesh. The advantages and disadvantages of the 2 methods were compared. RESULTS: No case of titanium mesh loosening occurred in either group. Subcutaneous fluid collection, titanium mesh tilt, and temporal muscle pain were the most common complications. In the manually shaped group, there were 14 cases of effusion, 10 cases of titanium mesh tilt, and 15 cases of temporal muscle pain. In the computer-aided group, there were 6 cases of effusion, 3 cases of titanium mesh tilt, and 6 cases of temporal muscle pain. The differences were significant between the 2 groups (p < 0.05). Other common complications were scalp infection, exposure of titanium mesh, epidural hematoma, and seizures. In the computer-aided group, the operative time decreased (p < 0.01), the number of screws used was reduced (p < 0.01), and the satisfaction of patients was significantly increased (p < 0.05). CONCLUSIONS: Computer-aided shaping of titanium mesh for repairing large frontotemporoparietal skull defects decreases postoperative complications and the operative duration, reduces the number of screws used, increases the satisfaction of patients, and restores the appearance of the patient's head, making it an ideal choice for cranioplasty.