MicroRNA­1224 inhibits cell proliferation by downregulating CBX3 expression in chordoma.

MicroRNAs (miRNAs/miRs) have abnormal expression in numerous tumors and are closely related to tumor development and resistance to radiotherapy and chemotherapy. However, there are few studies assessing the role and mechanism of miRNA in chordoma. The sequencing data of three pairs of chordoma and notochord tissues from the GSE56183 dataset were analyzed in the present study. Cell proliferation was assessed in vitro using Cell Counting Kit-8. Bioinformatics analysis and the dual luciferase reporter assay were used to evaluate the regulatory relationship between miR-1224 and chromobox 3 (CBX3) in chordoma. The results demonstrated that miR-1224 had a significantly lower expression level in chordoma tissues and cell lines. Overexpression of miR-1224 inhibited proliferation in the chordoma cells, while the knockdown of miR-1224 promoted proliferation of the chordoma cells. Bioinformatics analysis and the dual luciferase reporter assay confirmed that CBX3 was a direct target gene of miR-1224 and that miR-1224 induced the proliferation of chordoma cells through the inhibition of CBX3. In summary, miR-1224 reduced the proliferation of chordoma cells through inhibition of CBX3, which provides a theoretical basis for selecting a novel therapeutic target for chordoma.

A Comprehensive Review of Interventional Clinical Trials in Patients with Bone Metastases.

Bone metastasis is one of the most important factors associated with poor prognosis for patients with prostate, breast, thyroid, and lung cancer. In the past two decades, 651 clinical trials, including 554 interventional trials, were being registered in ClinicalTrials.gov and pharma.id.informa.com to combat bone metastases from different perspectives. In this review, we comprehensively analyzed, regrouped, and discussed all the interventional trials on bone metastases. Clinical trials were re-grouped into bone-targeting agents, radiotherapy, small molecule targeted therapy, combination therapy, and others, based on the different mechanisms of action including modifying the bone microenvironment and preventing the growth of cancer cells. We also discussed the potential strategies that might improve overall survival and progression-free survival of patients with bone metastases in the future.

Corilagin alleviates intestinal ischemia/reperfusion-induced intestinal and lung injury in mice via inhibiting NLRP3 inflammasome activation and pyroptosis.

Intestinal ischemia reperfusion (II/R) is a clinical emergency that frequently occurs in a variety of clinical conditions. Severe intestinal injury results in the release of cytotoxic substances and inflammatory mediators which can activate local inflammatory response and bacterial translocation. This triggers multi-organ failure, including lung injury, which is a common complication of II/R injury and contributes to the high mortality rate. Corilagin (Cor) is a natural ellagitannin found in a variety of plants. It has many biological and pharmacological properties, including antioxidant, anti-inflammatory and anti-apoptosis activities. However, no studies have evaluated the effects and molecular mechanisms of Cor in alleviating II/R-induced intestinal and lung damage. In this study, Cor was found to significantly alleviate II/R-induced pathological damage, inflammatory response, oxidative stress, NLRP3 inflammasome activation, and pyroptosis in intestinal and lung tissues both in vivo and in vitro. Further, Cor inhibited the NLRP3 inflammasome activation and pyroptosis in RAW264.7 and MLE-12 cells induced by LPS/nigericin and that in IEC-6 cells induced by nigericin, indicating an amelioration of Cor in II/R-induced intestinal and lung injury via inhibiting NLRP3 inflammasome activation and pyroptosis. Thus, Cor might be a potential therapeutic agent for II/R-induced inflammation and tissue injury.

Inflammatory bowel disease and celiac disease: A bidirectional Mendelian randomization study.

Objective: Although previous epidemiological studies have reported substantial links between inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), and celiac disease (CeD), the causal relationship between the two remains unknown. The purpose of the current study was to evaluate the bidirectional causation between IBD and CeD using Mendelian randomization (MR). Method: We obtained genome-wide association study (GWAS) summary data of IBD (CD and UC) and CeD of thoroughly European ancestry from the IEU GWAS database. We screened eligible instrumental variables (IVs) according to the three assumptions of MR. MR was performed using MR-Egger, weighted median (WM), and inverse variance weighted (IVW) methods. The MR-Egger intercept and MR-PRESSO method investigated the horizontal pleiotropy effect. A leave-one-out analysis was performed to prevent bias caused by a single SNP. Results: The study assessed a bidirectional causal effect between CD and CeD; CD increased the risk of CeD (IVW odds ratio (OR) = 1.27, 95% confidence interval (CI) = 1.19-1.35, p = 3.75E-13) and vice-a-versa (IVW OR = 1.09, 95% CI = 1.05-1.13, p = 1.39E-05). Additionally, CeD was influenced by IBD (IVW OR = 1.24, 95% CI = 1.16-1.34, p = 9.42E-10) and UC (IVW OR = 0.90, 95% CI = 0.83-0.98, p = 0.017). However, we observed no evidence of a causal relationship between CeD and IBD (IVW OR = 1.00, 95% CI = 0.97-1.04, p = 0.900) or UC (IVW OR = 0.96, 95% CI = 0.92-1.02, p = 0.172). Conclusion: The present study revealed that IBD and CeD have a bidirectional causal relationship. However, it is slightly different from the results of previous observational studies, recommending that future studies focus on the mechanisms of interaction between CD and CeD.

circCCT3 Enhances Invasion and Epithelial-Mesenchymal Transition (EMT) of Non-Small-Cell Lung Cancer (NSCLC) via the miR-107/Wnt/FGF7 Axis.

Background: CircRNAs play a role in a variety of biological processes, including tumorigenesis. circCCT3 has been shown to regulate cancer initiation and progression. Unfortunately, whether circCCT3 is involved in non-small-cell lung cancer (NSCLC) metastasis remains unclear. Methods: Our study utilized RT-qPCR to examine gene expression levels. A transwell assay was used to measure invasion ability of cells. Starbase software and TargetScan software were used to predict target genes. Results: circCCT3 knockdown attenuated invasion and epithelial-mesenchymal transition (EMT) of A549 and Calu-1 cells. miR-107 mimics could rescue circCCT3-induced invasion and EMT. Next, miR-107 mimics and circCCT3 knockdown suppressed Wnt3a and FGF7 expression. An miR-107 inhibitor promoted Wnt3a and FGF7 expressions. Finally, FGF7 greatly restored miR-107-inhibited invasion and EMT of A549 cells. Conclusion: Here, we reveal a molecular mechanism circCCT3/miR-107/Wnt/FGF7 responsible for NSCLC metastasis.

Exosomal circDNER enhances paclitaxel resistance and tumorigenicity of lung cancer via targeting miR-139-5p/ITGB8.

BACKGROUND: Circular RNAs (circRNAs) are regarded as vital regulatory factors in various cancers. However, the biological functions of circDNER in the paclitaxel (PTX) resistance of lung cancer remain largely unexplored. METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze circDNER, miR-139-5p, and ITGB8. Cell proliferation was assessed via colony formation and MTT assays. Cell apoptosis was evaluated by flow cytometry. Western blot was performed to assess protein expression. The targeted interaction among circDNER, miR-139-5p, and ITGB8 were validated using dual-luciferase reporter or RNA immunoprecipitation assays. RESULTS: Inhibition of circDNER reduced IC50 of PTX, inhibited cell proliferation, invasion and migration, as well as promoted cell apoptosis in PTX-resistant lung cancer cells. Mechanistically, circDNER sponged miR-139-5p to upregulate ITGB8 expression. Overexpression of miR-139-5p reversed the biological functions mediated by circDNER in PTX-resistant lung cancer cells. MiR-139-5p overexpression suppressed PTX resistance and malignant behaviors of PTX-resistant lung cancer cells, with ITGB8 elevation rescued the impacts. Moreover, we demonstrated that circDNER was upregulated in plasma exosomes from lung cancer patients. The plasma exosomes derived from these patients are the key factors enhancing the migration and invasion potential of lung cancer cells. CONCLUSION: The circDNER mediated miR-139-5p/ITGB8 axis suppresses lung cancer progression. Our findings suggest that circDNER might act as a potential prognostic biomarker and therapeutic target for lung cancer treatment.

Evolution and Features of China's Central Government Funding System for Basic Research.

Basic research is believed to be a crucial factor for building national innovation capacity and therefore was perceived as a key battleground for national technological and economic competition. Since the economic reform and opening up in the late 1970s, China has made great achievements in building up its national research system. However, the lacking capabilities to conduct ground-breaking scientific work remain one of the daunting challenges for the country. How to restructure its funding system for basic research so to reinvigorate its indigenous innovation capacity has been one of the main concerns for the Chinese government in recent years. To address this, the paper proposes a conceptual framework to analyze how China's central government funding system for basic research has evolved since 1985. The paper concludes with a discussion of the identified problems and challenges that China is facing in its current funding system for basic research.

Potential Value of miR-221/222 as Diagnostic, Prognostic, and Therapeutic Biomarkers for Diseases.

microRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by base pairing with their target messenger RNAs. Dysregulation of miRNAs is involved in the pathological initiation and progression of many human diseases. miR-221 and miR-222 (miR-221/222) are two highly homologous miRNAs, and they are significantly overexpressed in several types of human diseases. Silencing miR-221/222 could represent a promising approach for therapeutic studies. In the present review, we will describe the potential value of miR-221/222 as diagnostic, prognostic, and therapeutic biomarkers in various diseases including cancer and inflammatory diseases.

Efficient and Non-Toxic Biological Response Carrier Delivering TNF-α shRNA for Gene Silencing in a Murine Model of Rheumatoid Arthritis.

Small interfering RNA (siRNA) is an effective and specific method for silencing genes. However, an efficient and non-toxic carrier is needed to deliver the siRNA into the target cells. Tumor necrosis factor α (TNF-α) plays a central role in the occurrence and progression of rheumatoid arthritis (RA). In this study, we pre-synthetized a degradable cationic polymer (PDAPEI) from 2,6-pyridinedicarboxaldehyde and low-molecular-weight polyethyleneimine (PEI, Mw = 1.8 kDa) as a gene vector for the delivery of TNF-α shRNA. The PDAPEI/pDNA complex showed a suitable particle size and stable zeta potential for transfection. In vitro study of the PDAPEI/pDNA complex revealed a lower cytotoxicity and higher transfection efficiency when transfecting TNF-α shRNA to macrophages by significantly down-regulating the expression of TNF-α. Moreover, the complex was extremely efficient in decreasing the severity of arthritis in mice with collagen-induced arthritis. PDAPEI delivered TNF-α shRNA has great potential in the treatment of RA.

p66Shc Couples Mechanical Signals to RhoA through Focal Adhesion Kinase-Dependent Recruitment of p115-RhoGEF and GEF-H1.

Tissue cells respond to changes in tensional forces with proliferation or death through the control of RhoA. However, the response coupling mechanisms that link force with RhoA activation are poorly understood. We found that tension applied to fibronectin-coated microbeads caused recruitment of all three isoforms of the Shc adapter (p66Shc, p52Shc, and p46Shc) to adhesion complexes. The Shc PTB domain was necessary and sufficient for this recruitment, and screening studies revealed the direct interactions with the FERM domain of focal adhesion kinase (FAK) that were required for Shc translocation to adhesion complexes. The FAK/p66Shc complex specifically bound and activated the Rho guanyl exchange factors (GEFs) p115-RhoGEF and GEF-H1, leading to tension-induced RhoA activation. In contrast, the FAK/p52Shc complex bound SOS1 but not the Rho GEFs to mediate tension-induced Ras activation. Nuclear translocation and activation of the YAP/TAZ transcription factors on firm substrates required the FAK/p66Shc/Rho GEF complex, and both proliferation on firm substrates and anoikis in suspension required signaling through p66Shc and its associated Rho GEFs. These studies reveal the binary and exclusive assignment of p66Shc and p52Shc to tension-induced Rho or Ras signals, respectively, and suggest an integrated role for the two Shc isoforms in coordinating the cellular response to mechanical stimuli.

High-Tg Thiol-Click Thermoset Networks via the Thiol-Maleimide Michael Addition.

Thiol-click reactions lead to polymeric materials with a wide range of interesting mechanical, electrical, and optical properties. However, this reaction mechanism typically results in bulk materials with a low glass transition temperature (Tg ) due to rotational flexibility around the thioether linkages found in networks such as thiol-ene, thiol-epoxy, and thiol-acrylate systems. This report explores the thiol-maleimide reaction utilized for the first time as a solvent-free reaction system to synthesize high-Tg thermosetting networks. Through thermomechanical characterization via dynamic mechanical analysis, the homogeneity and Tg s of thiol-maleimide networks are compared to similarly structured thiol-ene and thiol-epoxy networks. While preliminary data show more heterogeneous networks for thiol-maleimide systems, bulk materials exhibit Tg s 80 °C higher than other thiol-click systems explored herein. Finally, hollow tubes are synthesized using each thiol-click reaction mechanism and employed in low- and high-temperature environments, demonstrating the ability to withstand a compressive radial 100 N deformation at 100 °C wherein other thiol-click systems fail mechanically.

Ultraflexible, large-area, physiological temperature sensors for multipoint measurements.

We report a fabrication method for flexible and printable thermal sensors based on composites of semicrystalline acrylate polymers and graphite with a high sensitivity of 20 mK and a high-speed response time of less than 100 ms. These devices exhibit large resistance changes near body temperature under physiological conditions with high repeatability (1,800 times). Device performance is largely unaffected by bending to radii below 700 µm, which allows for conformal application to the surface of living tissue. The sensing temperature can be tuned between 25 °C and 50 °C, which covers all relevant physiological temperatures. Furthermore, we demonstrate flexible active-matrix thermal sensors which can resolve spatial temperature gradients over a large area. With this flexible ultrasensitive temperature sensor we succeeded in the in vivo measurement of cyclic temperatures changes of 0.1 °C in a rat lung during breathing, without interference from constant tissue motion. This result conclusively shows that the lung of a warm-blooded animal maintains surprising temperature stability despite the large difference between core temperature and inhaled air temperature.