The generation of glioma organoids and the comparison of two culture methods.

BACKGROUND: The intra- and inter-tumoral heterogeneity of gliomas and the complex tumor microenvironment make accurate treatment of gliomas challenging. At present, research on gliomas mainly relies on cell lines, stem cell tumor spheres, and xenotransplantation models. The similarity between traditional tumor models and patients with glioma is very low. AIMS: In this study, we aimed to address the limitations of traditional tumor models by generating patient-derived glioma organoids using two methods that summarized the cell diversity, histological features, gene expression, and mutant profiles of their respective parent tumors and assess the feasibility of organoids for personalized treatment. MATERIALS AND METHODS: We compared the organoids generated using two methods through growth analysis, immunohistological analysis, genetic testing, and the establishment of xenograft models. RESULTS: Both types of organoids exhibited rapid infiltration when transplanted into the brains of adult immunodeficient mice. However, organoids formed using the microtumor method demonstrated more similar cellular characteristics and tissue structures to the parent tumors. Furthermore, the microtumor method allowed for faster culture times and more convenient operational procedures compared to the Matrigel method. DISCUSSION: Patient-derived glioma organoids, especially those generated through the microtumor method, present a promising avenue for personalized treatment strategies. Their capacity to faithfully mimic the cellular and molecular characteristics of gliomas provides a valuable platform for elucidating tumor biology and evaluating therapeutic modalities. CONCLUSION: The success rates of the Matrigel and microtumor methods were 45.5% and 60.5%, respectively. The microtumor method had a higher success rate, shorter establishment time, more convenient passage and cryopreservation methods, better simulation of the cellular and histological characteristics of the parent tumor, and a high genetic guarantee.

Integrating intrapreneurial self-capital, cultural intelligence, and gender in Chinese international education: pathways to flourishing.

Background: This study investigates the complex interplay between Intrapreneurial Self Capital, Cultural Intelligence, and gender, and their collective influence on the flourishing of Chinese international students in foreign academic settings. As global interconnectivity intensifies, the increasing number of Chinese students seeking education abroad presents a unique opportunity to examine the psychological and sociocultural dynamics of this demographic. Aim: Central to our investigation is the role of Cultural Intelligence, a crucial competency for navigating diverse environments, and Intrapreneurial Self Capital, a composite of psychological resources instrumental in educational and career success. The study also explores the mediating role of Cultural Intelligence in the relationship between Intrapreneurial Self Capital and student flourishing, and examines how gender moderates this dynamic. Method: The research engaged 508 Chinese international students, utilizing a variety of social networks for participant recruitment. The survey, conducted via Qualtrics, focused on a diverse range of students across different educational levels and disciplines. A moderated mediation model was tested to examine the mediation effect of cultural intelligence on the relationship between intrapreneurial self-capital and flourishing, with gender serving as a moderating variable. Results: Our findings reveal significant insights into how Intrapreneurial Self Capital and Cultural Intelligence contribute to the personal and professional development of Chinese international students. Overall, the results suggest that the impact of Intrapreneurial Self Capital on various cognitive qualities (Metacognitive Cultural Intelligence, Cognitive Cultural Intelligence, Motivational Cultural Intelligence and Behavioral Cultural Intelligence) is moderated by gender, highlighting the importance of considering gender differences in this context. Related to the prediction of Flourishing, the direct effect of Intrapreneurial Self Capital on flourishing is notably strong. However, the mediating roles of Metacognitive, Cognitive, and Behavioral aspects of Cultural Intelligence show different levels of influence. Implications: The study underscores the need for educational institutions to adopt holistic approaches in fostering student well-being and success, accounting for the nuanced effects of cultural and gender dynamics. These results have significant implications for the development of targeted educational programs and training, aimed at enhancing the international educational experience for students and professionals.

Borneol-Modified Schisandrin B Micelles Cross the Blood-Brain Barrier To Treat Alzheimer's Disease in Aged Mice.

Objective: Schisandrin B (Sch B) is a bioactive dibenzocyclooctadiene derizative that is prevalent in the fruit of Schisandra chinensis. Numerous studies have demonstrated that Sch B has a neuroprotective action by reducing oxidative stress and effectively preventing inflammation. It follows that Sch B is a potential treatment for Alzheimer's disease (AD). However, the drug's solubility, bioavailability, and lower permeability of the blood-brain barrier (BBB) can all reduce its efficacy during the therapy process. Therefore, this study constructed borneol-modified schisandrin B micelles (Bor-Sch B-Ms), which increase brain targeting by accurately delivering medications to the brain, effectively improving bioavailability. High therapeutic efficacy has been achieved at the pathological site. Methods: Bor-Sch B-Ms were prepared using the thin film dispersion approach in this article. On the one hand, to observe the targeting effect of borneol, we constructed a blood-brain barrier (BBB) model in vitro and studied the ability of micelles to cross the BBB. On the other hand, the distribution of micelle drugs and their related pharmacological effects on neuroinflammation, oxidative stress, and neuronal damage were studied through in vivo administration in mice. Results: In vitro studies have demonstrated that the drug uptake of bEnd.3 cells was increased by the borneol alteration on the surface of the nano micelles, implying that Bor-Sch B-Ms can promote the therapeutic effect of N2a cells. This could result in more medicines entering the BBB. In addition, in vivo studies revealed that the distribution and circulation time of medications in the brain tissue were significantly higher than those in other groups, making it more suitable for the treatment of central nervous system diseases. Conclusion: As a novel nanodrug delivery system, borneol modified schisandrin B micelles have promising research prospects in the treatment of Alzheimer's disease.

Borneol-modified docetaxel plus tetrandrine micelles for treatment of drug-resistant brain glioma.

OBJECTIVE: Glioma is the most common and deadly primary malignant tumor in adults. Treatment outcomes are ungratified due to the presence of blood-brain barrier (BBB), glioma stem cells (GSCs) and multidrug resistance (MDR). Docetaxel (DTX) is considered as a potential drug for the treatment of brain tumor, but its effectiveness is limited by its low bioavailability and drug resistance. Tetrandrine (TET) reverses the resistance of tumor cells to chemotherapy drugs. Borneol (BO) modified in micelles has been shown to promote DTX plus TET to cross the BBB, allowing the drug to better act on tumors. Therefore, we constructed BO-modified DTX plus TET micelles to inhibit chemotherapeutic drug resistance. SIGNIFICANCE: Provide a new treatment method for drug-resistant brain gliomas. METHODS: In this study, BO-modified DTX plus TET micelles were prepared by thin film dispersion method, their physicochemical properties were characterized. Its targeting ability was investigated. The therapeutic effect on GSCs was investigated by in vivo and in vitro experiments. RESULTS: The BO-modified DTX plus TET micelles were successfully constructed by thin film dispersion method, and the micelles showed good stability. The results showed that targeting micelles increased bEnd.3 uptake and helped drugs cross the BBB in vitro. And we also found that targeting micelles could inhibit cell proliferation, promote cell apoptosis and inhibit the expression of drug-resistant protein, thus provide a new treatment method for GSCs in vitro and in vivo. CONCLUSIONS: BO-modified DTX plus TET micelles may provide a new treatment method for drug-resistant brain gliomas.

KCNA1 promotes the growth and invasion of glioblastoma cells through ferroptosis inhibition via upregulating SLC7A11.

BACKGROUND: The high invasiveness and infiltrative nature of Glioblastoma (GBM) pose significant challenges for surgical removal. This study aimed to investigate the role of KCNA1 in GBM progression. METHODS: CCK8, colony formation assay, scratch assay, transwell assay, and 3D tumor spheroid invasion assays were to determine how KCNA1 affects the growth and invasion of GBM cells. Subsequently, to confirm the impact of KCNA1 in ferroptosis, western blot, transmission electron microscopy and flow cytometry were conducted. To ascertain the impact of KCNA1 in vivo, patient-derived orthotopic xenograft models were established. RESULTS: In functional assays, KCNA1 promotes the growth and invasion of GBM cells. Besides, KCNA1 can increase the expression of SLC7A11 and protect cells from ferroptosis. The vivo experiments demonstrated that knocking down KCNA1 inhibited the growth and infiltration of primary tumors in mice and extended survival time. CONCLUSION: Therefore, our research suggests that KCNA1 may promote tumor growth and invasion by upregulating the expression of SLC7A11 and inhibiting ferroptosis, making it a promising therapeutic target for GBM.

E3 ubiquitin-ligase RNF138 may regulate p53 protein expression to regulate the self-renewal and tumorigenicity of glioma stem cells.

BACKGROUND: Glioblastoma multiforme (GBM), the most malignant tumor of the central nervous system, is characterized by poor survival and high recurrence. Glioma stem cells (GSCs) are key to treating GBM and are regulated by various signaling pathways. Ubiquitination, a post-translational modification, plays an important regulatory role in many biological processes. Ring finger protein 138 (RNF138) is an E3 ubiquitin-protein ligase that is highly expressed in several tumors; however, its role in GBM is unclear. This study investigated whether RNF138 regulates the self-renewal ability of glioma stem GSCs to treat GBM. MATERIALS AND METHODS: The expression of RNF138 in glioma tissues and its correlation with GSCs were analyzed using bioinformatics. Short hairpin ribonucleic acid (RNA) was designed to downregulate the expression of RNF138 in GSCs, and immunofluorescence, secondary pellet formation, and western blotting were used to detect changes in GSC markers and self-renewal ability. The effects of RNF138 on p53 protein expression were determined by immunofluorescence and western blotting. The effects of RNF138 on the self-renewal and tumorigenic abilities of GSCs were evaluated in vivo. RESULTS: RNF138 expression was higher in glioma tissues than in normal brain tissues, and was highly expressed in GSCs. RNF138 downregulation significantly decreased the expression of the GSC markers cluster of differentiation 133 (CD133) and nestin. Mechanistically, RNF138 may interfere with the self-renewal ability of GSCs by regulating the expression of p53. RNF138 downregulation in vivo prolonged survival time and regulated the expression of p53 protein in tumor-bearing mice. CONCLUSION: RNF138 may regulate the expression of p53 protein through ubiquitination, thereby affecting the self-renewal and tumorigenic ability of GSCs. This study provides a scientific basis for the treatment of glioblastoma by targeting RNF138 to inhibit GSCs.

Inhibition of TGF-ß1-induced epithelial-mesenchymal transition in gliomas by DMC-HA.

DMC-HA, a novel HDAC inhibitor, has previously demonstrated antiproliferative activity against various cancers, including gliomas. However, the role of DMC-HA in the regulation of EMT and its underlying mechanisms remain unknown. This study aimed to explore the effects of DMC-HA on TGF-ß1-induced EMT in human gliomas and the underlying mechanisms involved. Our results showed that TGF-ß1 induced EMT of U87 and U251 cells, leading to a decrease in epithelial marker ZO-1 and an increase in mesenchymal markers N-cadherin and Vimentin. Moreover, TGF-ß1 treatment resulted in a significant increase in the migratory and invasive abilities of the cells. However, treatment with DMC-HA effectively inhibited the augmented migration and invasion of glioma cells induced by TGF-ß1. Additionally, DMC-HA inhibits TGF-ß1-induced EMT by suppressing canonical Smad pathway and non-canonical TGF-ß/Akt and Erk signalling pathways. These findings suggest that DMC-HA has potential therapeutic implications for gliomas by inhibiting EMT progression.

Development of a Brain-Targeted Nano Drug Delivery System to Enhance the Treatment of Neurodegenerative Effects of Resveratrol.

As the aging population continues to increase, aging-related inflammation, oxidative stress, and neurodegenerative diseases have become serious global health threats. Resveratrol, a star molecule in natural polyphenols, has been widely reported to have physiological activities such as anti-aging, anti-inflammatory, antioxidant, and neuroprotection. However, its poor water solubility, rapid metabolism, low bioavailability and poor targeting ability, which limits its application. Accordingly, a brain-targeted resveratrol liposome (ANG-RES-LIP) was developed to solve these issues. Experimental results showed that ANG-RES-LIP has a uniform size distribution, good biocompatibility, and a drug encapsulation rate of over 90%. Furthermore, in vitro cell experiments showed that the modification of the targeting ligand ANG significantly increased the capability of RES to cross the BBB and neuronal uptake. Compared with free RES, ANG-RES-LIP demonstrated stronger antioxidant activity and the ability to rescue oxidatively damaged cells from apoptosis. Additionally, ANG-RES-LIP showed the ability to repair damaged neuronal mitochondrial membrane potential. In vivo experiments further demonstrated that ANG-RES-LIP improved cognitive function by reducing oxidative stress and inflammation levels in the brains of aging model mice, repairing damaged neurons and glial cells, and increasing brain-derived neurotrophic factor. In summary, this study not only provides a new method for further development and application of resveratrol but also a promising strategy for preventing and treating age-related neurodegenerative diseases.

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.

ApoE-modified liposomes encapsulating resveratrol and salidroside alleviate manifestations of Alzheimer's disease in APP/PS-1 mice.

OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disease that is associated with aging and is influenced by both genetic and environmental factors. Several studies and clinical trials have demonstrated that resveratrol (Res) and salidroside (Sal) are not only biologically safe but also influence AD biomarker trajectories. However, their clinical applications have been quite limited due to poor specificity, low solubility, and insufficient blood-brain barrier (BBB) penetration. Therefore, we developed a nano-drug delivery system in which Res and Sal were encapsulated in liposomes, which were surface-modified with ApoE (ApoE-Res/Sal-Lips) to compensate for these deficiencies. METHOD: In this study, ApoE-Res/Sal-Lips were prepared using a standard thin-film hydration method for liposomes. Then, cellular uptake of the loaded liposomes was assessed in vitro using fluorescent staining assays. A BBB model was constructed to investigate the capacity of the liposomes to cross the BBB in vitro, and the ability of liposomes to target the brain was observed by in vivo imaging. In addition, the neuroprotective effects of the different liposome formulations in APP/PS-1 mice were evaluated by measuring the changes in levels of oxidative, anti-inflammatory, and anti-apoptotic factors in the mice brains. RESULTS: In vitro, ApoE-Res/Sal-Lips increased the uptake of Res and Sal by bEnd.3 and N2a cells, enhanced BBB penetration, and improved transport efficiency. In vivo, the ApoE-Res/Sal-Lips were found to alleviate AD pathological symptoms, reduce learning and memory impairments, and improve brain function. CONCLUSION: ApoE-Res/Sal-Lips provide a new method for the treatment of AD.

Quantity and location of aortic valve calcification predicts paravalvular leakage after transcatheter aortic valve replacement: a systematic review and meta-analysis.

Introduction: Transcatheter aortic valve replacement (TAVR) is the first-line treatment for patients with moderate-to-high surgical risk of severe aortic stenosis. Paravalvular leakage (PVL) is a serious complication of TAVR, and aortic valve calcification contributes to the occurrence of PVL. This study aimed to investigate the effect of location and quantity of calcification in the aortic valve complex (AVC) and left ventricular outflow tract (LVOT) on PVL after TAVR. Method: We performed a systematic review and meta-analysis to evaluate the effect of quantity and location of aortic valve calcification on PVL after TAVR using observational studies from PubMed and EMBASE databases from inception to February 16, 2022. Results: Twenty-four observational studies with 6,846 patients were included in the analysis. A high quantity of calcium was observed in 29.6% of the patients; they showed a higher risk of significant PVL. There was heterogeneity between studies (I2 = 15%). In the subgroup analysis, PVL after TAVR was associated with the quantity of aortic valve calcification, especially those located in the LVOT, valve leaflets, and the device landing zone. A high quantity of calcium was associated with PVL, regardless of expandable types or MDCT thresholds used. However, for valves with sealing skirt, the amount of calcium has no significant effect on the incidence of PVL. Conclusion: Our study elucidated the effect of aortic valve calcification on PVL and showed that the quantity and location of aortic valve calcification can help predict PVL. Furthermore, our results provide a reference for the selection of MDCT thresholds before TAVR. We also showed that balloon-expandable valves may not be effective in patients with high calcification, and valves with sealing skirts instead of those without sealing skirts should be applied more to prevent PVL from happening. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=354630, identifier: CRD42022354630.

Angiopep-2 modified dual drug-loaded liposomes with brain targeting functionality mitigate Alzheimer's disease-related symptoms in APP/PS-1 mice.

The blood-brain barrier (BBB) is a barrier that maintains brain homeostasis, but it is also one of the major problems that must be overcome in the development of Alzheimer's disease (AD) drugs. To solve this problem, Salidroside (Sal) and Icariin (Ica), drugs with neuroprotective effects were loaded into liposomes, and the targeting molecule Angiopep-2 was modified on the surface of liposomes (Ang-Sal/Ica-Lip), so that the constructed nano-drug delivery system could effectively cross the BBB and exert anti-AD effects. The prepared liposomes exhibited ideal physicochemical properties. In vitro and in vivo targeting studies showed that Ang-Sal/Ica liposome could cross the BBB to increase drug accumulation in the brain, and increase the uptake of N2a cells and bEnd.3 cells. The pharmacodynamic analysis in vivo showed that Ang-Sal/Ica liposome could reverse neuronal and synaptic damage, inhibit neuroinflammation and oxidative stress and improve learning and cognitive function. Therefore, Ang-Sal/Ica liposome may be a promising therapeutic strategy for mitigating AD-related symptoms.

Multiple stimulus-response berberine plus baicalin micelles with particle size-charge-release triple variable properties for breast cancer therapy.

OBJECTIVE: The aim was to develop a nanoscale drug delivery system with enzyme responsive and acid sensitive particle size and intelligent degradation aiming to research the inhibitory effect on breast cancer. SIGNIFICANCE: The delivery system addressed the problems of tissue targeting, cellular internalization, and slow drug release at the target site, which could improve the efficiency of drug delivery and provide a feasible therapeutic approach for breast cancer. METHODS: The acid sensitive functional material DSPE-PEG2000-dyn-PEG-R9 was synthesized by Michael addition reaction. Then, the berberine plus baicalin intelligent micelles were prepared by thin-film hydration. Subsequently, we characterized the physical and chemical properties of berberine plus baicalin intelligent micelles, evaluated its anti-tumor effects in vivo and in vitro. RESULTS: The target molecule was successfully synthesized, and the intelligent micelles showed excellent chemical and physical properties, delayed drug release and high encapsulation efficiency. In vitro and in vivo experiments also confirmed that the intelligent micelles could effectively target tumor sites, penetrate tumor tissues, enrich in tumor cells, inhibit tumor cell proliferation, inhibit tumor cell invasion and migration, and induce tumor cell apoptosis. CONCLUSION: Berberine plus baicalin intelligent micelles have excellent anti-tumor effects and no toxicity to normal tissues, which provides a new potential drug delivery strategy for the treatment of breast cancer.

Sex-biased molecular differences in lung adenocarcinoma are ethnic and smoking specific.

BACKGROUND: Sex-related differences in cancer epidemiology, tumor biology, immune system activity, and pharmacogenomics have been suggested to be important considerations for precision cancer control. Here we elucidated systematically sex biases in genetic variants, gene expression profiles, and immunological landscapes of lung adenocarcinoma patients (LUADs) with different ancestry and smoking status. METHODS: Somatic mutation and mRNA expression data of Asian and Non-Asian LUADs were obtained from public databases. Sex-biased genetic mutations, gene expression, biological pathways, and immune infiltration were identified in the context of smoking status and race. RESULTS: Among nonsmokers, male-biased mutations were prevalent in Asian LUADs, while few sex-biased mutations were detected in Non-Asian LUADs. EGFR was the only mutation whose frequency was significantly higher in females than males in both Asian and Non-Asian nonsmokers. More genes exhibited sex-biased expression in Non-Asian LUADs compared to Asian LUADs. Moreover, genes distinctly expressed in females were mainly related to immune-related pathways, whereas those in males were more involved in activation of DNA repair, E2F_targets, and MYC_targets pathways. We also detected sex-specific immune infiltration in the context of genetic variation. In EGFR-mutant LUADs, males had a significantly increased infiltration of CD8 + T cells, whereas resting CD4 + memory T cells were more abundant in females. Additionally, in KRAS-mutant LUADs, CD8 + and CD4 + T cells were more abundant in females than males. In addition, we detected all female patients with high SCGB3A2 expression were exclusively sensitive to immunotherapy, while this phenomenon was not observed in male patients. CONCLUSIONS: Our findings provided evidence that sex-related molecular and cellular components are involved in shaping tumor distinct genetic and immune features, which might have important impact on personalized targeted and immune therapy.

PLK1 inhibition promotes apoptosis and DNA damage in glioma stem cells by regulating the nuclear translocation of YBX1.

Glioma stem cells (GSCs) are the important cause of tumorigenesis, recurrence, and chemo(radio)resistance in glioma. Targeting GSCs helps improve the outcomes of glioma treatment. Polo-like kinase 1 (PLK1) is a member of the serine/threonine protein kinase family, which is highly conserved. In recent years, it has been suggested that increased levels of PLK1 and its activity are associated with tumor progression and poor prognosis. We aimed to identify whether PLK1 plays a critical role in stemness maintenance and apoptosis regulation in GSCs. Here we identify that PLK1 inhibition can induce apoptosis and DNA damage of GSCs, we have also delineat the possible underlying molecular mechanisms: PLK1 interacts with YBX1 and directly phosphorylates serine 174 and serine 176 of YBX1. Inhibition of PLK1 reduces the phosphorylation level of YBX1, and decreased phosphorylation of YBX1 prevents its nuclear translocation, thereby inducing apoptosis and DNA damage of GSCs. We confirmed that YBX1 knockdown resulted in the apoptosis and DNA damage of GSCs. These findings uncover that PLK1 inhibition induces cell apoptosis and DNA damage in GSCs through YBX1 phosphorylation, providing new insights into the mechanism by which PLK1 inhibition contributes to the apoptosis of and DNA damage in gliomas.

Immunogenicity of small-cell lung cancer associates with STING pathway activation and is enhanced by ATR and TOP1 inhibition.

INTRODUCTION: The activation of STING (stimulator of interferon genes) pathway enhances antitumor immunity in small-cell lung cancer (SCLC), while the DNA damage induced by non-cGAMP-based agonists is a potent inducer of STING activity. Here, we investigate the intrinsic expression of STING in cancer cells and evaluate the value of the combination of ATR and TOP1 inhibitors in enhancing antitumor immunity. METHODS: STING expression was assessed at mRNA and protein levels in SCLC and normal lung tissues. Transcriptomic subsets of SCLC were identified based on STING-related genes. Distinct mutation and immunogenomic profiles of these subsets were determined. The direct antitumor efficacy and the potential of enhancing antitumor immunity of the strategy using the ATR-TOP1-inhibitor combination were tested in SCLC cell lines. RESULTS: The intrinsic expression of STING was significantly reduced in SCLC compared to normal lung tissues (p < 0.0001). Three STING-related SCLC subtypes were identified in which the STING-high subtype was associated with (1) high immune infiltration, (2) high expression of genes related to MHC and immune checkpoints, and (3) high EMT and ferroptosis score. On the contrary, the STING-low subtype was enriched with pathways related to DNA damage response (DDR) and cell cycle progression. The association between the DDR pathway activity and the STING-IFN innate immune response was verified by in vitro experiments in which the inhibition of ATR and TOP1 triggered the expression of genes encoding type I IFN signaling and pro-inflammatory cytokines/chemokines in a STING-low SCLC cell line. CONCLUSION: Our study verifies that activation of the STING-IFN response by ATR and TOP1 inhibitors might be a therapeutic strategy to improve the response to immune checkpoint therapy in STING-low SCLC. Furthermore, the combinations of ATR and TOP1 inhibitors can augment tumor inflammation in STING-low SCLC.

Efficacy of epi-1 modified epirubicin and curcumin encapsulated liposomes targeting-EpCAM in the inhibition of epithelial ovarian cancer cells.

Treatment of epithelial ovarian cancer (EOC) is a challenge because it still leads to unsatisfactory clinical prognosis. This is due to the toxicity and poor targeting of chemotherapeutic agents, as well as metastasis of the tumor. In this study, we designed a targeted liposome with nanostructures to overcome these problems. In the liposomes, epirubicin and curcumin were encapsulated to achieve their synergistic antitumor efficacy, while Epi-1 was modified on the liposomal surface to target epithelial cell adhesion molecule (EpCAM). Epi-1, a macrocyclic peptide, exhibits active targeting for enhanced cellular uptake and potent cytotoxicity against tumor cells. The encapsulation of epirubicin and curcumin synergistically inhibited the formation of neovascularization and vasculogenic mimicry (VM) channels, thereby suppressing tumor metastasis on SKOV3 cells. The dual drug loaded Epi-1-liposomes also induced apoptosis and downregulated metastasis-related proteins for effective antitumor in vitro. In vivo studies showed that dual drug loaded Epi-1-liposomes prolonged circulation time in the blood and increased the selective accumulation of drug at the tumor site. H&E staining and immunohistochemistry with Ki-67 also showed that targeted liposomes elevated antitumor activity. Also, targeted liposomes downregulated angiogenesis-related proteins to inhibit angiogenesis and thus tumor metastasis. In conclusion, the production of dual drug loaded Epi-1-liposomes is an effective strategy for the treatment of EOC.

Granulomatous Inflammation of Greater Omentum Caused by a Migrating Fishbone.

Fishbone is the most common ingested gastrointestinal foreign matter and is less than 1% perforate. However, a fishbone penetrating the gastrointestinal tract and causing granulomatous inflammation of the greater omentum with local suppuration is not common. Because of the nonspecific clinical symptoms, gastrointestinal perforation may be manifested only as dull abdominal pain, which is often ignored and timely clinical treatment may be delayed. We report a case of a 61-year male who experienced intermittent right median ventral abdominal pain for half a year. These symptoms were the result of granulomatous inflammation of the greater omentum with local suppuration caused by a migrating fishbone (3.5 cm in length). Finally, the fishbone was removed by exploratory laparotomy. Key Words: Fishbone, Gastrointestinal perforation, Greater omentum, Granulomatous inflammation, Laparotomy.

[Retracted] miR­218­5p inhibits the stem cell properties and invasive ability of the A2B5+CD133­ subgroup of human glioma stem cells.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that Fig. 5 on p. 874 contained a series of DAPI panels within the figure that looked unexpectedly similar in appearance, with the similarities also evident in the second and 'Merge' data columns; moreover, of especial note, the similarities in the 'DAPI' panels for the Blank control experiments shown in Fig. 5C and D only affected a partial section of the data. In addition, the 'blank' and 'miR­control' panels in Fig. 6A also appeared to contain overlapping data. Independently of the issues that were raised by the interested reader, the authors themselves requested that their paper be retracted on account of having identified some problems with the presentation of various of the figures, and no longer being able to access their original data. The Editor of Oncology Reports has agreed that this paper should be retracted from the Journal, and apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 869­877, 2016; DOI: 10.3892/or.2015.4418].

Redeploy manure resources to enhance the agro-pastoral cycle.

Returning manure to the land is a critical link in the internal cycle of agricultural systems, but excess manure leads to water eutrophication. The traditional manure re-use method brings pathogenic microorganisms, heavy metals, antibiotic resistance genes (ARGs), insect eggs, and other contaminants into the soil, posing a great threat to the ecological environment and human health. Clarifying the spatial distribution patterns of manure nutrient supply and farmland nutrient demand can help guide a more efficient and harmless way to return manure to farmland. This work counted data on cultivation and breeding in 356 cities on the Chinese mainland from 2015 to 2019 and calculated the livestock breeding volume (LB), total environmental capacity (C), and remaining environmental capacity (RC) accordingly. The Spatial Autocorrelation Model (SAC) was used to analyze the distribution patterns of the three. Data results show that China currently has the potential to double LB, but most cities in the west have excess manure due to the mismatched distribution of LB and C. The hot spot analysis results demonstrate the priority/general areas of manure management and the export/import areas of manure resources. The results of the outlier analysis show that some cities located at the boundary of RC Cold/Hot spot areas (e.g., Chengdu City) can perform resource replacement nearby to relieve local environmental pressure. This study analyzes the potential and realistic resistance to utilizing manure as an organic nutrient resource and provides a reference for developing manure management links.