Elongin B promotes breast cancer progression by ubiquitinating tumor suppressor p14/ARF.

Elongin B (ELOB), a pivotal element in the ELOB/c-Cullin2/5-SOCS-box E3 ubiquitin-protein ligase complex, plays a significant role in catalyzing the ubiquitination and subsequent degradation of a broad spectrum of target proteins. Notably, it is documented to facilitate these processes. However, the regulatory role of ELOB in breast cancer remains ambiguous. In this study, through bio-informatic analysis of The Cancer Genome Atlas and Fudan University Shanghai Cancer Center database, we demonstrated that ELOB was over-expressed in breast cancer tissues and was related to unfavorable prognosis. Additionally, pathway enrichment analysis illustrated that high expression of ELOB was associated with multiple cancer promoting pathways, like cell cycle, DNA replication, proteasome and PI3K - Akt signaling pathway, indicating ELOB as a potential anticancer target. Then, we confirmed that both in vivo and in vitro, the proliferation of breast cancer cells could be significantly suppressed by the down-regulation of ELOB. Mechanically, immunoprecipitation and in vivo ubiquitination assays prompted that, as the core element of Cullin2-RBX1-ELOB E3 ligase (CRL2) complex, ELOB regulated the ubiquitination and the subsequent degradation of oncoprotein p14/ARF. Moreover, the anticancer efficacy of erasing ELOB could be rescued by simultaneous knockdown of p14/ARF. Finally, through analyzing breast cancer tissue microarrays and western blot of patient samples, we demonstrated that the expression of ELOB in tumor tissues was elevated in compared to adjacent normal tissues. In conclusion, ELOB is identified to be a promising innovative target for the drug development of breast cancer by promoting the ubiquitination and degradation of oncoprotein p14/ARF.

Theory and application of TTFields in newly diagnosed glioblastoma.

BACKGROUND: Glioblastoma is the most common primary malignant brain tumor in adults. TTFields is a therapy that use intermediate-frequency and low-intensity alternating electric fields to treat tumors. For patients with ndGBM, the addition of TTFields after the concurrent chemoradiotherapy phase of the Stupp regimen can improve prognosis. However, TTFields still has the potential to further prolong the survival of ndGBM patients. AIM: By summarizing the mechanism and application status of TTFields in the treatment of ndGBM, the application prospect of TTFields in ndbm treatment is prospected. METHODS: We review the recent literature and included 76 articles to summarize the mechanism of TTfields in the treatment of ndGBM. The current clinical application status and potential health benefits of TTFields in the treatment of ndGBM are also discussed. RESULTS: TTFields can interfere with tumor cell mitosis, lead to tumor cell apoptosis and increased autophagy, hinder DNA damage repair, induce ICD, activate tumor immune microenvironment, reduce cancer cell metastasis and invasion, and increase BBB permeability. TTFields combines with chemoradiotherapy has made progress, its optimal application time is being explored and the problems that need to be considered when retaining the electrode patches for radiotherapy are further discussed. TTFields shows potential in combination with immunotherapy, antimitotic agents, and PARP inhibitors, as well as in patients with subtentorial gliomas. CONCLUSION: This review summarizes mechanisms of TTFields in the treatment of ndGBM, and describes the current clinical application of TTFields in ndGBM. Through the understanding of its principle and application status, we believe that TTFields still has the potential to further prolong the survival of ndGBM patients. Thus,research is still needed to explore new ways to combine TTFields with other therapies and optimize the use of TTFields to realize its full potential in ndGBM patients.

Thrombin receptor activating peptide-6 decreases acute graft-versus-host disease through activating GPR15.

G-protein coupled receptor 15 (GPR15) is expressed on T-cells. We previously reported knockout of GPR15 increased acute graft-versus-host disease (GvHD) in mice. In this study, we identified thrombin receptor activating peptide-6 (TRAP-6, peptide sequence: SFLLRN) as an activator of GPR15. GRP15 and ß-arrestin2 were needed for TRAP-6-mediated inhibition of mixed lymphocyte reactions. TRAP-6 decreased acute GvHD in allotransplant models in mice, an effect dependent on GPR15-expression in donor T-cells. RNA-seq and protein analyses indicated TRAP-6 increased binding of ß-arrestin2/TAB1 and inhibited phosphorylation of TAK1 and NF-κB-P65. GPR15 is expressed differently on CD4+ T-cells and CD8+ T-cells. TRAP-6 inhibited phosphorylation of NF-κB-P65 in CD4+ T-cells but increased granzyme B expression in CD8+ T-cells. TRAP-6 decreased acute GvHD without inhibiting graft-versus-tumor (GvT) efficacy against A20 lymphoma cells. SALLRN, a mutant of TRAP-6, preserved the anti-acute GvHD effect but avoided the adverse effects of TRAP-6. TRAP-6 and SALLRN also decreased allogeneic and xenogeneic reactions induced by human blood mononuclear cells. In conclusion, TRAP-6 activated GPR15 on T-cells and decreased acute GvHD in mice without impairing GvT efficacy.

High SERS performance of functionalized carbon dots in the detection of dye contaminants.

INTRODUCTION: The long-term overuse of malachite green (MG) has potential carcinogenic, teratogenic, and mutagenic effects. The functional nanocomposite is novel and challenging to construct and implement through surface enhanced Raman scattering (SERS) strategy to reveal the contributions in application. OBJECTIVES: The novel Ag-CDs (carbon dots)-PBA (phenyl boric acid) nanocomposite was constructed by a facile route to detect toxic MG molecule with high SERS sensitivity and good uniformity. METHODS: The enhanced substrate used for the detection of MG has been successfully constructed using PBA modulated Ag-CDs on a structured surface with rich binding sites. RESULTS: The fabricated Ag-CDs-PBA substrate can be used to analyze various probe molecules exhibiting high sensitivity, good signal reproducibility, and excellent stability. The mechanism between components has been proved by calculations originating from the plasmonic Ag and active electronic transmission among the bridging CDs and PBA via the close spatial π-π effect. In addition, the accelerated separation of electron-hole pairs was triggered to further improve the SERS activity of the hybrid via a bidirectional charge transfer (CT) process. Significantly, the Ag-CDs-PBA system shows distinctive selectivity, in which PBA can hinder the interference of other species without specific hydroxyl groups. CONCLUSION: Based on this deeper insight on plasmon-mediated mechanism, the SERS substrate was successfully practiced for quantitative determination in real water and fish samples. The strategy developed promises to be a new sensor technology and has great potential for environmental and food safety applications.

Epigenetic Reprogramming Drives Epithelial Disruption in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the CDH1 gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of CDH1 in COPD is due to increased DNA methylation site at the CDH1 enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme TET1. Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-2'-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.

Electro-catalytic adsorption mechanism of acetonitrile in water using a ME-ACFs system.

Acetonitrile wastewater is difficult to treat due to its high salinity and toxicity to microorganisms. In this paper, a micro electro-activated carbon fiber coupled system (ME-ACF) was established to treat simulated acetonitrile wastewater. In the 200 ml system, the concentration of acetonitrile adsorbed by ACF was 91.3 mg/L, while that of acetonitrile adsorbed by ME-ACF was 150.6 mg/L, and the removal efficiency was increased by 65 % in comparison. The activated carbon fibers before and after the reaction were subjected to a series of characterization, and it was found that the SABET decreased from 1393.48 m2/g to 1114.93 m2/g and 900.23 m2/g, respectively, but the oxygen on the surface of the activated carbon fibers was increased, and the effect of the micro electrolytic system on the activated carbon fibers was then analyzed. The possible reasons for the formation of acetic acid contained in the products were also discussed using DFT simulations. The removal mechanism of acetonitrile by ME-ACF was considered to be electrically enhanced adsorption and electro-catalytic hydrolysis.

Effects of neoadjuvant stereotactic body radiotherapy plus adebrelimab and chemotherapy for triple-negative breast cancer: A pilot study.

Background: Emerging data have supported the immunostimulatory role of radiotherapy, which could exert a synergistic effect with immune checkpoint inhibitors (ICIs). With proven effective but suboptimal effect of ICI and chemotherapy in triple-negative breast cancer (TNBC), we designed a pilot study to explore the efficacy and safety of neoadjuvant stereotactic body radiotherapy (SBRT) plus adebrelimab and chemotherapy in TNBC patients. Methods: Treatment-naïve TNBC patients received two cycles of intravenous adebrelimab (20 mg/kg, every 3 weeks), and SBRT (24 Gy/3 f, every other day) started at the second cycle, then followed by six cycles of adebrelimab plus nab-paclitaxel (125 mg/m² on days 1 and 8) and carboplatin (area under the curve 6 mg/mL per min on day 1) every 3 weeks. The surgery was performed within 3-5 weeks after the end of neoadjuvant therapy. Primary endpoint was pathological complete response (pCR, ypT0/is ypN0). Secondary endpoints included objective response rate (ORR), residual cancer burden (RCB) 0-I, and safety. Results: 13 patients were enrolled and received at least one dose of therapy. 10 (76.9%) patients completed SBRT and were included in efficacy analysis. 90% (9/10) of patients achieved pCR, both RCB 0-I and ORR reached 100% with three patients achieved complete remission. Adverse events (AEs) of all-grade and grade 3-4 occurred in 92.3% and 53.8%, respectively. One (7.7%) patient had treatment-related serious AEs. No radiation-related dermatitis or death occurred. Conclusions: Adding SBRT to adebrelimab and neoadjuvant chemotherapy led to a substantial proportion of pCR with acceptable toxicities, supporting further exploration of this combination in TNBC patients. Funding: None. Clinical trial number: NCT05132790.

Aryl hydrocarbon receptor regulates IL-22 receptor expression on thymic epithelial cell and accelerates thymus regeneration.

Improving regeneration of damaged thymus is important for reconstituting T-cell immunity. Interleukin-22 (IL-22) was proved to improve thymus regeneration through recovering thymic epithelial cells (TECs). The IL-22 receptor IL-22RA1 is crucial for mediating IL-22 functions. Mechanism that regulates IL-22RA1 expression is unknown. Through using TECs-conditional knockout mice, we found aryl hydrocarbon receptor (AHR) is important for thymus regeneration, because Foxn1-cre-mediated AHR knockout (AhrKO) significantly blocks recovery of thymus cells. Giving mice the AHR inhibitor CH-223191 or the AHR agonist FICZ blocks or accelerates thymus regeneration, respectively. AhrKO-mediated blockade of thymus regeneration could not be rescued by giving exogenous IL-22. Mechanistically, AhrKO mice shows decreased IL-22RA1 expression. In the murine TECs cell line mTEC1 cells, targeting AHR shows an impact on IL-22RA1 mRNA levels. Using chromatin immunoprecipitation and luciferase reporter assays, we find AHR co-operates with STAT3, binds the promotor region of IL-22RA1 gene and transcriptionally increases IL-22RA1 expression in mTEC1 cells. Foxn1-cre-mediated IL-22RA1 knockout (Il22ra1KO) blocks thymus regeneration after irradiation. Furthermore, targeting AHR or IL-22RA1 has significant impacts on severity of murine chronic graft-versus-host disease (cGVHD), which is an autoimmune-like complication following allogeneic hematopoietic cell transplantation. Giving FICZ decreases cGVHD, whereas Il22ra1KO exacerbates cGVHD. The impacts on cGVHD are associated with thymus regeneration and T-cell immune reconstitution. In conclusion, we report an unrecognized function of TECs-expressed AHR in thymus regeneration and AHR transcriptionally regulates IL-22RA1 expression, which have implications for improving thymus regeneration and controlling cGVHD.

SUMOylation of RALY promotes vasculogenic mimicry in glioma cells via the FOXD1/DKK1 pathway.

Human malignant gliomas are the most common and aggressive primary malignant tumors of the human central nervous system. Vasculogenic mimicry (VM), which refers to the formation of a tumor blood supply system independently of endothelial cells, contributes to the malignant progression of glioma. Therefore, VM is considered a potential target for glioma therapy. Accumulated evidence indicates that alterations in SUMOylation, a reversible post-translational modification, are involved in tumorigenesis and progression. In the present study, we found that UBA2 and RALY were upregulated in glioma tissues and cell lines. Downregulation of UBA2 and RALY inhibited the migration, invasion, and VM of glioma cells. RALY can be SUMOylated by conjugation with SUMO1, which is facilitated by the overexpression of UBA2. The SUMOylation of RALY increases its stability, which in turn increases its expression as well as its promoting effect on FOXD1 mRNA. The overexpression of FOXD1 promotes DKK1 transcription by activating its promoter, thereby promoting glioma cell migration, invasion, and VM. Remarkably, the combined knockdown of UBA2, RALY, and FOXD1 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. UBA2/RALY/FOXD1/DKK1 axis may play crucial roles in regulating VM in glioma, which may contribute to the development of potential strategies for the treatment of gliomas.

The van der Waals interaction and absorption and electron circular dichroism spectra of two-dimensional bilayer stacked structures.

van der Waals (vdW) heterojunctions based on two-dimensional (2D) materials, graphene and transition metal dichalcogenides (TMDs), are a research hotspot for future optoelectronic and exciton devices. Bond-free vdW interactions are key to 2D material heterojunction device reliability and stability. However, most of the current research on 2D stacked materials heterostructures mainly focuses on optical properties and electronic structure. Furthermore, vdW interaction in 2D heterostructures is studied and understood on the basis of qualitative description and energy ranges from the literature. There are few studies on the nature of vdW interaction based on practical calculations of the quantitative strength and microscopic mechanism of vdW interaction between 2D stacked materials. Therefore, this paper explores the vdW interaction between 2D material stacked bilayer structures, including bilayer graphene, graphene/MoS2 and graphene/WS2 heterostructures, focusing on quantitative analysis of the energy components of the vdW interaction. We first visually observed the weak interactions in the three stacked bilayer structures through noncovalent interaction (NCI) analysis, and found that the interactions are concentrated in the binding region between the two-layer structures. We mainly decomposed the weak interaction energy in the three 2D material bilayer heterostructures through energy decomposition analysis based on the force field (EDA-FF) method and obtained the energy values and proportions of the three components-electrostatic energy, exchange repulsion energy and dispersion energy of the total binding energy between the 2D stacked bilayer structures. The vdW interaction energy is the sum of the exchange repulsion energy and dispersion energy, and the dispersion energy of the vdW interaction accounts for more than 60% of the binding energy of the weak interaction between the 2D bilayer stacked structures. The vdW strengths in the bilayer structures are on the order of 177.07, 123.85, and 133.93 kJ/mol, approxmately 1-2 orders of magnitude larger than the classically defined vdW energies of 0.1-10 kJ/mol. Furthermore, we calculate the density of states of the three 2D stacked structures, and further obtained HOMO-LOMO information; to further understand the electronic structures of the graphene/MoS2 and graphene/WS2 heterostructures, we calculated their optical absorption spectra and electron circular dichroism (ECD) spectra. According to the calculation results, the two heterostructures have strong absorption peaks in the visible region, and the charge transfer forms at the strong absorption peak can be determined according to the charge transfer diagram. The ECD spectra indicate that the configurations of the graphene/MoS2 and graphene/WS2 heterostructures have large chirality. Our work contributes to a deeper understanding of the nature of the weak interactions and optical properties in 2D stacked materials, which plays a fundamental role in promoting the construction of stable 2D heterostructure configurations and the development of multifunctional 2D devices. The research is conducive to further promoting the basic research and practical development of strong optoelectronic and excitonic 2D heterojunctions devices.

Evaluation and Comparation of a Novel Surgical Technique and Hemivertebra Resection to the Correction of Congenital Cervical Scoliosis in Lower Cervical and Cervicothoracic Spine.

OBJECTIVE: To report concave-side distraction technique to treat congenital cervical scoliosis in lower cervical and cervicothoracic spine. To evaluate and compare clinical and radiographic results of this procedure with classic hemivertebra resection procedure. METHODS: This study reviewed 29 patients in last 13 years. These patients were divided into convex-side resection group (group R) and concave-side distraction group (group D). Radiographic assessment was based on parameter changes preoperatively, postoperatively and at last follow-up. Demographic data, surgical data and complications were also evaluated and compared between the 2 groups. RESULTS: In group R, mean age was 8.9 ± 3.3 years and follow-up was 46 ± 18 months. Operation time and blood loss averaged 500 ± 100 minutes, 703 ± 367 mL. In group D, mean age was 9.9 ± 2.8 years and follow-up was 34 ± 14 months. Operation time and blood loss averaged 501 ± 112 minutes, 374 ± 181 mL. Structural Cobb angle was corrected from 29.4° ± 12.5° to 5.3° (2.1°-18.1°) (p = 0.001) and 33.7° ± 14.1° to 12.8° ± 11.4° (p < 0.001) in groups R and D. Compensatory Cobb angle had a spontaneous correction rate of 59.6% (40.0%-80.8%) and 59.7% ± 23.0% in groups R and D. Mandibular incline, clavicle angle and spine coronal balance were significantly improved at last follow-up in both groups. All correction rates were not statistically different between groups. However, group D had significant less blood loss (p < 0.001) and operation time (p = 0.004) per vertebra than group R. Seven patients developed C5 nerve root palsy and recovered by 6 months of follow-up. CONCLUSION: Both surgical procedures are safe and effective in correcting congenital cervical scoliosis. But concave-side distraction technique has less blood loss and time-consuming during surgery, which provides a better option for the treatment of congenital cervical scoliosis.

Effect of percutaneous minimally invasive pedicle screw internal fixation in the treatment of thoracolumbar vertebral fractures and its impact on quality of life.

OBJECTIVES: To investigate and analyze the effect of percutaneous minimally invasive pedicle screw internal fixation in the treatment of thoracolumbar vertebral fractures and its impact on quality of life. METHODS: Fifty patients with thoracolumbar vertebral fracture admitted to our hospital from January 2015 to December 2018 were selected and divided into two groups according to different treatment regimens. The observation group was treated with minimally invasive percutaneous pedicle screw internal fixation, while the control group was treated with traditional posterior approach open pedicle screw internal fixation. The surgery time, incision length, intraoperative blood loss, postoperative drainage, hospitalization time, ambulation time, fracture healing time and postoperative VAS scores were compared between the two groups. In addition, the cobb angle, the sagittal plane index, and the anterior vertebral height were compared between the two groups before and after surgery, as were the Oswestry Disability Index (ODI) at 1d, 3 months, and 6 months postoperatively. RESULTS: The surgery time, incision length, postoperative pain level, postoperative drainage and intraoperative blood loss of the observation group were less than those of the control group (P<0.05). The postoperative Cobb angle of the two groups decreased, the sagittal plane index as well as the anterior vertebral height increased (P<0.05). The Oswestry index of the observation group was better than that of the control group at one day and three months postoperatively, with a statistical significance between the two groups (P<0.05). The complication rate of the observation group was significantly lower than that of the control group (P<0.05). CONCLUSION: Percutaneous minimally invasive pedicle screw internal fixation is safer than the traditional open pedicle screw internal fixation, and it is more worthy of clinical promotion.

Derivation of Mouse Parthenogenetic Advanced Stem Cells.

Parthenogenetic embryos have been widely studied as an effective tool related to paternal and maternal imprinting genes and reproductive problems for a long time. In this study, we established a parthenogenetic epiblast-like stem cell line through culturing parthenogenetic diploid blastocysts in a chemically defined medium containing activin A and bFGF named paAFSCs. The paAFSCs expressed pluripotent marker genes and germ-layer-related genes, as well as being alkaline-phosphatase-positive, which is similar to epiblast stem cells (EpiSCs). We previously showed that advanced embryonic stem cells (ASCs) represent hypermethylated naive pluripotent embryonic stem cells (ESCs). Here, we converted paAFSCs to ASCs by replacing bFGF with bone morphogenetic protein 4 (BMP4), CHIR99021, and leukemia inhibitory factor (LIF) in a culture medium, and we obtained parthenogenetic advanced stem cells (paASCs). The paASCs showed similar morphology with ESCs and also displayed a stronger developmental potential than paAFSCs in vivo by producing chimaeras. Our study demonstrates that maternal genes could support parthenogenetic EpiSCs derived from blastocysts and also have the potential to convert primed state paAFSCs to naive state paASCs.

NCBP3/SNHG6 inhibits GBX2 transcription in a histone modification manner to facilitate the malignant biological behaviour of glioma cells.

RNA-binding proteins (RBPs) are significantly dysregulated in glioma. In this study, we demonstrated the upregulation of Nuclear cap-binding subunit 3 (NCBP3) in glioma tissues and cells. Further, knockdown of NCBP3 inhibited the malignant progression of glioma. NCBP3 directly bound to small nucleolar RNA host gene 6 (SNHG6) and stabilized SNHG6 expression. In contrast, the gastrulation brain homeobox 2 (GBX2) transcription factor was downregulated in glioma tissues and cells. SNHG6 inhibited GBX2 transcription by mediating the H3K27me3 modification induced by polycomb repressive complex 2 (PRC2). Moreover, GBX2 decreased the promoter activities and downregulated the expression of the flotillin protein family 1 (FLOT1) oncogene. In conclusion, NCBP3/SNHG6 inhibits GBX2 transcription in a PRC2-dependent manner to facilitate the malignant progression of gliomas.

Comparison of regulatory networks of E74-like factor 1 and cold-shock domain-containing E1 in breast cancer cell lines using ChIP datasets.

In the present study, differences in the expression of target genes between chromatin immunoprecipitation sequencing (ChIP-seq) datasets of breast cancer MCF-7 cells treated with antibodies to E74-like factor 1 (ELF1) and cold-shock domain-containing E1 (CSDE1) were analyzed and gene regulatory networks were established. The datasets were downloaded from the Gene Expression Omnibus (GEO) database. ELF1-associated target genes and CSDE1-associated target genes were analyzed for functional prediction and protein-protein interaction (PPI) networks. The ELF1 ChIP-seq dataset contained 95 ELF1-associated target genes, while the CSDE1 ChIP-seq dataset contained 826 CSDE1-associated target genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the ELF1- and CSDE1-associated target genes had different potential functions and signaling pathways. The ELF1-associated target genes were mainly enriched in the GO terms of molecular transducer activity, catalytic activity, cellular processes and response to sensitivity, and in the KEGG pathways of olfactory transduction, the chemokine signaling pathway, carbohydrate digestion and absorption, and starch and sucrose metabolism. The CSDE1-associated target genes were mainly enriched in the GO terms of binding, transcription regulator activity, cellular processes and metabolic processes, and in the KEGG pathways of ribosome, metabolic pathways, endocytosis, oxidative phosphorylation and transcriptional misregulation in cancer. PPI network analysis revealed that the ELF1 regulatory network primarily regulated chemokine-mediated malignant tumor cells, while the CSDE1 regulatory network mainly regulated ribosomes, metabolic pathways and oxidative phosphorylation. Reverse transcription-quantitative PCR indicated that ELF1 overexpression led to significant downregulation of C-X-C motif chemokine-8 and -6 expression levels in MCF-7 cells, while overexpression of CSDE1 significantly induced the mRNA expression of CSDE1-associated target genes, which included mitochondrial ribosomal protein L4, NADH: ubiquinone oxidoreductase subunit B7, small nuclear ribonucleoprotein polypeptide E, ribosomal protein S26 (RPS26), RPS11 and RPS6, in the MCF-7 cells. In breast cancer MCF-7 cells, the target genes and regulatory pathways of ELF1 and CSDE1 were different. Understanding these regulatory pathways may help to develop strategies for personalized breast cancer treatment.

Lin28A promotes IRF6-regulated aerobic glycolysis in glioma cells by stabilizing SNHG14.

Warburg effect is a hallmark of cancer cells, wherein glycolysis is preferred over oxidative phosphorylation even in aerobic conditions. Reprogramming of glycometabolism is especially crucial for malignancy in glioma. RNA-binding proteins and long noncoding RNAs are important for aerobic glycolysis during malignant transformation. Thus, we determined the expression and function of RNA-binding protein Lin28A, long noncoding RNA SNHG14, and transcription factor IRF6 in human glioma cells to elucidate the mechanism(s) underlying their role in glycolysis. Quantitative real-time polymerase chain reaction and western blotting showed that Lin28A and SNHG14 were overexpressed and IRF6 was downregulated in glioma. Depleting Lin28A from cells decreased the stability and expression of SNHG14. Furthermore, depleting SNHG14 reduced IRF6 mRNA degradation by targeting its 3' untranslated region and inhibiting STAU1-mediated degradation, thereby increasing the expression of IRF6. PKM2 is an important enzyme in aerobic glycolysis, and GLUT1 is the primary transporter that facilitates glucose uptake. IRF6 inhibited the transcription of PKM2 and GLUT1, thereby impairing glycolysis and cell proliferation and inducing apoptosis in glioma. Notably, depleting Lin28A and SNHG14 and overexpressing IRF6 reduced the growth of xenograft tumors in vivo and prolonged the survival of nude mice. Taken together, our data revealed that the Lin28A/SNHG14/IRF6 axis is crucial for reprogramming glucose metabolism and stimulating tumorigenesis in glioma cells. Thus, targeting this axis might help in the development of a novel therapeutic strategy for glioma metabolism.

Tubulin Maytansine Site Binding Ligands and their Applications as MTAs and ADCs for Cancer Therapy.

BACKGROUND: Microtubule Targeting Agents (MTAs) represent the most successful anticancer drugs for cancer chemotherapy. Through interfering with the tubulin polymerization and depolymerization dynamics, MTAs influence intracellular transport and cell signal pathways, inhibit cell mitosis and cell proliferation, and induce cell apoptosis and death. The tubulin maytansine site binding agents are natural or nature-derived products that represent one type of the MTAs that inhibit tubulin polymerization and exhibit potent antitumor activity both in vitro and in vivo. They are used as Antibody-Drug Conjugates (ADCs) in cancer chemotherapy. METHODS: Using SciFinder® as a tool, the publications about maytansine, its derivatives, maytansine binding site, maytansine site binding agents and their applications as MTAs for cancer therapy were surveyed with an exclusion on those published as patents. The latest progresses in clinical trials were obtained from the clinical trial web. RESULTS: This article presents an introduction about MTAs, maytansine, maytansine binding site and its ligands, the applications of these ligands as MTAs and ADCs in cancer therapy. CONCLUSION: The maytansine site binding agents are powerful MTAs for cancer chemotherapy. The maytansine site ligands-based ADCs are used in clinic or under clinical trials as cancer targeted therapy to improve their selectivity and to reduce their side effects. Further improvements in the delivery efficiency of the ADCs will benefit the patients in cancer targeted therapy.

Knockdown of LncRNA SCAMP1 suppressed malignant biological behaviours of glioma cells via modulating miR-499a-5p/LMX1A/NLRC5 pathway.

Dysregulation of long non-coding RNAs (lncRNAs) confirm that it plays a crucial role in tumourigenesis and malignant progression of glioma. The present study demonstrated that LncRNA secretory carrier membrane protein 1 (SCAMP1) was up-regulated and functioned as an oncogene in glioma cells. In addition, miR-499a-5p was down-regulated meanwhile exerted tumour-suppressive function in glioma cells. Subsequently, inhibition of SCAMP1 significantly restrained the cell proliferation, migration and invasion, as well as promoted apoptosis by acting as a molecular sponge of miR-499a-5p. Transcription factor LIM homeobox transcription factor 1, alpha (LMX1A) was overexpressed in glioma tissues and cells. Moreover, miR-499a-5p targeted LMX1A 3'-UTR in a sequence-specific manner. Hence, down-regulation of SCAMP1 remarkably reduced the expression level of LMX1A, indicating that LMX1A participated in miR-499a-5p-induced tumour-suppressive effects on glioma cells. Furthermore, knockdown of LMX1A decreased NLR family, CARD domain containing 5 (NLRC5) mRNA and protein expression levels through directly binding to the NLRC5 promoter region. Down-regulation of NLRC5 obviously inhibited malignant biological behaviours of glioma cells through attenuating the activity of Wnt/ß-catenin signalling pathway. In conclusion, our study clarifies that SCAMP1/miR-499a-5p/LMX1A/NLRC5 axis plays a critical role in modulating malignant progression of glioma cells, which provide a novel therapeutic strategy for glioma treatment.

The RNA N6-methyladenosine modification landscape of human fetal tissues.

A single genome gives rise to diverse tissues through complex epigenomic mechanisms, including N6-methyladenosine (m6A), a widespread RNA modification that is implicated in many biological processes. Here, to explore the global landscape of m6A in human tissues, we generated 21 whole-transcriptome m6A methylomes across major fetal tissues using m6A sequencing. These data reveal dynamic m6A methylation, identify large numbers of tissue differential m6A modifications and indicate that m6A is positively correlated with gene expression homeostasis. We also report m6A methylomes of long intergenic non-coding RNA (lincRNA), finding that enhancer lincRNAs are enriched for m6A. Tissue m6A regions are often enriched for single nucleotide polymorphisms that are associated with the expression of quantitative traits and complex traits including common diseases, which may potentially affect m6A modifications. Finally, we find that m6A modifications preferentially occupy genes with CpG-rich promoters, features of which regulate RNA transcript m6A. Our data indicate that m6A is widely regulated by human genetic variation and promoters, suggesting a broad involvement of m6A in human development and disease.