Toxicity and fate of cadmium in hydroponically cultivated lettuce (Lactuca sativa L.) influenced by microplastics.

Although more attention has been paid to microplastics (MPs) pollution in environment, research on the synthetic influence of microplastic and heavy metals remains limited. To help fill this information gap, we investigated the adsorption behavior of virgin polyvinyl chloride microplastics (PVCMPs) (≤450 µm white spherical powder) on cadmium (II). The effects on seed germination, seedling growth, photosynthetic system, oxidative stress indicators of lettuce, and changes in Cd bioavailability were evaluated under Cd2+ (25 µmol/L), PVCMPs (200 mg/L), and PVCMP-Cd combined (200 mg/L + 25 µmol/L) exposures in hydroponic system. The results demonstrated that the PVCMPs effectively adsorbed Cd ions, which validated by the pseudo-second-order kinetic and the Langmuir isotherm models, indicating the sorption of Cd2+ on the PVCMPs was primary chemisorption and approximates monomolecular layer sorption. Compared to MPs, Cd significantly inhibits plant seed germination and seedling growth and development. However, Surprising improvement in seed germination under PVCMPs-Cd exposure was observed. Moreover, Cd2+ and MPs alone or combined stress caused oxidative stress with reactive oxygen species (ROS) including H2O2, O2- and Malondialdehyde (MDA) accumulation in plants, and substantially damaged to photosynthesis. With the addition of PVCMPs, the content of Cd in the leaves significantly (P<0.01) decreased by 1.76-fold, and the translocation factor and Cd2+removal rate in the water substantially (P<0.01) decreased by 6.73-fold and 1.67-fold, respectively in contrast to Cd2+ stress alone. Therefore, it is concluded the PVCMP was capable of reducing Cd contents in leaves, alleviating Cd toxicity in lettuce. Notably, this study provides a scientific foundation and reference for comprehending the toxicological interactions between microplastics and heavy metals in the environment.

Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence.

Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

A case of iatrogenic acute spinal cord injury with tetraplegia following thyroid surgery.

AIM: Iatrogenic acute spinal cord injury with tetraplegia is a serious consequence of non-spinal surgery.We report a case of acute spinal cord injury with tetraplegia after thyroid surgery. METHOD: The patient was pathologically diagnosed with papillary carcinoma, underwent left thyroidectomy, and developed tetraplegia after surgery. RESULT: The patient was diagnosed with acute spinal cord injury with tetraplegia and cured after anti-inflammatory and dehydrating treatment. CONCLUSION: Iatrogenic spinal cord injuries after elective non-spinal surgery can have catastrophic consequences, and clinicians must be alert to this possibility in clinical practice.

Photosynthetic Responses of Racomitrium japonicum L. to Strontium Stress Evaluated through Chlorophyll a Fluorescence OJIP Transient Analysis.

Nuclides pollution and its biological effects are of great concern, especially for bryophytes during their terrestrial adaptation. Understanding PSII activity and electron transport response is vital for comprehending moss abiotic stress reactions. However, little is known about the photosynthetic performance of moss under nuclide treatment. Therefore, this study aimed to evaluate the chlorophyll fluorescence of Racomitrium japonicum L. The moss was subjected to Sr2+ solutions at concentrations of 5, 50, and 500 mg/L to evaluate chlorophyll a fluorescence using the OJIP test. Moderate and high Sr2+ stress led to inner cell membrane dissolution and reduced chlorophyll content, indicating impaired light energy absorption. At 5 mg/L Sr2+, fluorescence kinetics showed increased light energy capture, energy dissipation, and total photosynthetic driving force, thus stimulating transient photosynthetic activity of PSII and improving PSI reduction. Linear electron transfer and PSII stability significantly decreased under moderate and high Sr2+ stress, indicating potential photosynthetic center damage. Cyclic electron transfer (CEF) alleviated photosynthetic stress at 5 mg/L Sr2+. Thus, low Sr2+ levels stimulated CEF, adjusting energy flux and partitioning to protect the photosynthetic apparatus. Nevertheless, significant damage occurred due to inefficient protection under high Sr2+ stress.

Effect of inoculation with arbuscular mycorrhizal fungi on the energy metabolism of selenite-rich amaranth.

A series of pot trials were undertaken to examine the impact of four arbuscular mycorrhizal fungi (AMF), namely Glomus mosseae (G.m), Glomus etunicatum (G.e), Corymbiglomus tortuosum (C.t), and the combined application of Glomus etunicatum and Corymbiglomus tortuosum (G.e + C.t), on the energy metabolism of amaranth plants grown in soil enriched with selenite at a concentration of 0.5 mg kg-1 . The inoculation of four AMFs resulted in an increase in both amaranth biomass and selenium (Se) content in leaves. The activities of phosphoglucose isomerase (PGI) and glucose-6-phosphate dehydrogenase + 6-phosphogluconate dehydrogenase were observed to decrease when AMFs were inoculated, as compared with the absence of AMF inoculation. The inoculation with G.m, C.t, and G.e + C.t resulted in an increase in succinate dehydrogenase activity; however, the inoculation with G.m, G.e, and G.e + C.t led to an increase in ascorbate oxidase activity. Furthermore, the inoculation of all four AMFs resulted in an increase in cytochrome c oxidase activity and the concentrations of oxidized coenzyme I (NAD) and reduced coenzyme I (NADH). The polyphenol oxidase activity of amaranth plants increased when inoculated with G.m and G.e, whereas it decreased when inoculated with C.t and G.e + C.t. Furthermore, the application of all four AMF treatments resulted in a reduction in adenosine triphosphate (ATP) levels and energy charge. It was worth mentioning that there was a clear inverse relationship between the energy charge and the biomass, Se concentration in the leaves. The findings presented in this research indicated that AMF may have an impact on energy metabolism and ultimately the biomass of amaranth by influencing the uptake of Se.

Immune characteristics and prognostic implications of mucosal-associated invariant T cells in acute myeloid leukemia.

Increasing evidence suggests that mucosal-associated invariant T cells (MAITs) play a crucial role in anti-tumor responses against various cancers. In this study, we investigated the immune characteristics of MAIT cells in patients with acute myeloid leukemia (AML). Using multi-parameter flow cytometry, we performed phenotypic and functional analysis of MAITs in peripheral blood or bone marrow samples collected from 131 patients with AML including 99 newly diagnosed, 18 remission, and 14 relapsed cases, as well as 69 healthy controls. We found that MAITs exhibit signs of aging and exhaustion, particularly in CD8+ MAITs subset, at newly diagnosis. MAITs exhibit an effector memory or terminally differentiated phenotype. Frequency and number of MAITs reflect AML cell genetic features, tumor burden, disease status, and treatment responsiveness. Moreover, MAITs exhibit a highly activated or even exhausted state, as indicated by upregulation of PD-1. Furthermore, impaired production of Th1-type cytokines and increased secretion of Th17-type cytokines, granzyme B, and perforin were observed in MAITs from AML patients. Additionally, MAITs shifted toward producing cytokines that promote tumor progression, such as IL-8. Lower frequency of MAITs was associated with poorer overall survival (OS), and multivariate analysis revealed that MAITs frequency < 2.12% was an independent prognostic factor affecting OS. Collectively, our findings suggest that MAITs may play a role in immune deficiency in AML, emphasizing their potential importance in AML pathogenesis and treatment. These discoveries provide a theoretical basis for the development of novel immunotherapeutic strategies in AML.

Construction of an Ultra-Large Phage Display Library by Kunkel Mutagenesis and Rolling Circle Amplification.

An important contributor to the successful generation of recombinant affinity reagents via phage display is a large and diverse library. We describe, herein, the application of Kunkel mutagenesis and rolling circle amplification (RCA) to the construction of a 1.1 × 1011 member library, with only 26 electroporations, and isolation of low- to sub-nanomolar monobodies to a number of protein targets, including human COP9 signalosome subunit 5 (COPS5), HIV-1 Rev. binding protein-like protein (HRBL), X-ray repair cross-complementing 5/6 (Ku70/80) heterodimer, the receptor-binding domain (RBD) of SARS-CoV-2, and transforming growth factor beta 1 (TGF-ß1).

Photosynthetic regulation in response to strontium stress in moss Racomitrium japonicum L.

Strontium (Sr2+) pollution and its biological effects are of great concern including photosynthetic regulation, which is fundamental to environmental responses, especially for bryophytes during their terrestrial adaptation. Alternative electron flows mediated by flavodiiron proteins (FLVs) and cyclic electron flow (CEF) in photosystem I (PSI) are crucial to abiotic stresses moss responses; however, little is known about the moss photosynthesis regulation under nuclide treatment. We measured chlorophyll fluorescence parameters in PSI, photosystem II (PSII) and the P700 redox state, oxidative stress in the moss Racomitrium japonicum under low (5 mg/L), moderate (50 mg/L) and high (500 mg/L) Sr2+ stress level. Moderate and high Sr2+ stress triggered H2O2 and malondialdehyde (MDA) generation, and catalase (CAT) activity increases, which are involved in reactive oxygen species regulation. The significant PSII photochemistry (Fv/Fm), Chla/chlb, Y(I)/Y(II), Y(NA), Y(ND) and ETRI-ETRII decreases at moderate and high Sr2+, and the Y(I), Y(II) decreases at high Sr2+ revealed the photo-inhibition and photo-damage in PSI and PSII by moderate and high Sr2+ stress. The nonphotochemical quenching (NPQ) increased significantly at moderate and high Sr2+ stress, reflecting a heat-dissipation-related photo-protective mechanism in antenna system and reaction centers. Moreover, rapid re-oxidation of P700 indicated that FLV-dependent flows significantly regulated PSI redox state under moderate and high Sr2+ stress. and CEF upregulation was found at low Sr2+. Finally, photosynthetic acclimation to Sr2+ stress in R. japonicum was linked to FLVs and CEF adjustments.

MRI Extraprostatic Extension Grade: Accuracy and Clinical Incremental Value in the Assessment of Extraprostatic Cancer.

Objective: The purpose was to compare the accuracy of extraprostatic extension (EPE) grade on MRI predicting EPE with Partin tables, Memorial Sloan Kettering Cancer Center nomogram (MSKCCn), and combined models and to analyze the clinical incremental value of EPE grade. Materials and Methods: 105 prostate cancer patients confirmed by pathology after radical prostatectomy in our hospital from 2017 to 2021 were selected. The clinical stage, PSA, Gleason score, number of positive biopsy cores, and percentage of positive biopsy cores were recorded. Evaluate EPE grade according to EPE grade criteria, and calculate the probability of predicting EPE with Partin tables and MSKCCn. EPE grade is combined with Partin tables and MSKCCn to construct EPE grade+Partin tables and EPE grade+MSKCCn models. Calculate the area under the curve (AUC), sensitivity, and specificity of EPE grade, Partin tables, MSKCCn, EPE grade+Partin tables, and EPE grade+MSKCCn and compare their diagnostic efficacy. The clinical decision curve was used to analyze the clinical net income of each prediction scheme. Results: The AUC of EPE grade was 0.79, Partin tables was 0.50, MSKCCn was 0.78, the EPE grade+Partin table model was 0.79, and the EPE grade+MSKCCn model was 0.83. After EPE grade was combined with Partin tables and MSKCCn, the diagnostic efficiency of clinical model was significantly improved (P < 0.05). There was no significant difference in the diagnostic efficacy of the combined model compared with the single EPE grade (P > 0.05). The calibration curve of the combined model shows that it has a good calibration degree for EPE. In the analysis of the decision curve, the net income of the EPE grade is higher than that of Partin tables and MSKCCn and is equal to the EPE grade+Partin tables and is slightly lower than that of EPE grade+MSKCCn. The clinical net income of the combined model is obviously higher than that of individual clinical models. Conclusion: The accuracy of EPE classification in predicting prostate cancer EPE is high, and combined with the clinical model, it can significantly improve the diagnostic efficiency of the clinical model and increase the clinical benefit.

A Novel Nomogram for Predicting the Risk of Short-Term Recurrence After Surgery in Glioma Patients.

OBJECTIVE: The aim of this study was to establish a nomogram model for predicting the risk of short-term recurrence in glioma patients. METHODS: The clinical data of recurrent glioma patients were summarized and analyzed in this study. Univariate and multivariate logistic regression analyses were performed to analyze the correlation between clinical data and the risk of short-term recurrence after operation. A nomogram was established based on the multivariate logistic regression model results. RESULTS: A total of 175 patients with recurrent glioma were enrolled, with 53 patients in the short-term recurrence (STR) group (recurrent time ≤6 months) and 122 patients in the long-term recurrence (LTR) group (recurrent time ≥36 months). Univariate analysis revealed that age at diagnosis, Karnofsky performance scores (KPSs), tumor location, glioma grade, glioma type, extent of resection (EOR), adjuvant chemotherapy (ad-CT), concurrent chemotherapy (co-CT), and isocitrate dehydrogenase (IDH) status were significantly associated with the short-term glioma recurrence. Multivariate analyses revealed that age at diagnosis, KPS, glioma grade, EOR, and IDH were independent risk factors for short-term glioma recurrence. A risk nomogram for the short-term recurrence of glioma was established, with the concordance index (C-index) of 0.971. The findings of calibration and receiver operating characteristic (ROC) curves showed that our nomogram model had good performance and discrimination to estimate short-term recurrence probability. CONCLUSION: This nomogram model provides reliable information about the risk of short-term glioma recurrence for oncologists and neurosurgeons. This model can predict the short-term recurrence probability and give assistance to decide the interval of follow-up or formulate individualized treatment strategies based on the predicted results. A free online prediction risk tool for this nomogram is provided: https://rj2021.shinyapps.io/Nomogram_ recurrence-risk/.

Type discrimination and concentration prediction towards ethanol using a machine learning-enhanced gas sensor array with different morphology-tuning characteristics.

A simple microwave-assisted method was applied to synthesize zinc oxide (ZnO) with controllable hierarchical structures. In a surfactant-free solvent system, the hierarchical structure of the ZnO precursor can be regulated by the concentration of urea at normal temperature and pressure. Upon annealing, ZnO with different morphologies shows its unique response towards six kinds of gases. The response data were clustered and analyzed by principal component analysis (PCA) to provide a basis for feature extraction. The classification to six kinds of gases was conducted through a model based on linear ridge classification (LRC), support vector machine (SVM). The prediction of ethanol concentration was achieved using backpropagation (BP) neural network and extreme learning machine (ELM). The results indicate that the six confusing gases can be distinguished clearly using SVM with an accuracy more than 0.99. Furthermore, the prediction of ethanol concentration shows a prominent performance (R2 > 0.98) by the ELM-based regressor, despite the nearly saturated response of the sensor array. This study explores the possibility of pattern recognition analysis based on machine learning to further improve the detection performance of the gas sensor array with different response characteristics regulated by the morphology.

Circular RNA circLGMN facilitates glioblastoma progression by targeting miR-127-3p/LGMN axis.

Glioblastoma (GBM) is one of the most devastating cancers and is characterized by rapid cell proliferation and aggressive invasiveness. Legumain (LGMN), a substrate-specific protease, is associated with poor progression of GBM. Circular RNAs (circRNAs) are aberrantly expressed in various cancers and play crucial roles in tumor progression; however, the functional roles of circRNAs originating from LGMN remain largely unknown in GBM. Herein, we found that hsa_circ_0033009 (circLGMN) was the most abundantly expressed circRNA derived from LGMN. CircLGMN was upregulated in high-grade glioma (HGG), and high expression of circLGMN was associated with poor prognosis in patients with glioma. CircLGMN overexpression promoted GBM cell proliferation and enhanced cell invasion. Mechanistically, circLGMN acts as a sponge for miR-127-3p, and prevents miR-127-3p-mediated degradation of LGMN mRNA, ultimately leading to increased LGMN protein expression. Treatment with miR-127-3p mimic suppressed proliferation and reduced invasion of GBM cells overexpressing circLGMN. Moreover, circLGMN overexpression promoted GBM malignancy in vivo, while miR-127-3p overexpression alleviated this effect. Taken together, circLGMN is a novel tumor-promoting circRNA that acts by sponging miR-127-3p, which ultimately leads to LGMN upregulation. Thus, targeting the circLGMN/miR-127-3p/LGMN axis might be a promising strategy for GBM treatment. More importantly, the discovery of the self-regulatory mechanism of LGMN expression by circLGMN, will facilitate further research on LGMN.

Identification of Key Genes Mutations Associated With the Radiosensitivity by Whole Exome Sequencing in Pancreatic Cancer.

BACKGROUND: Pancreatic cancer (PC) is one of the most lethal human cancers, and radiation therapy (RT) is an important treating option. Many patients diagnosed with PC do not achieve objective responses because of the existence of intrinsic and acquired radioresistance. Therefore, biomarkers, which predict radiotherapy benefit in PC, are eagerly needed to be identified. METHODS: Whole-exome sequencing of six pancreatic ductal adenocarcinoma patients (PDAC) (three with a good response and three with a poor response) who had received radical surgery and then radiotherapy has been performed as standard of care treatment. Somatic and germline variants and the mutational signatures were analyzed with bioinformatics tools and public databases. Functional enrichment and pathway-based protein-protein interaction analyses were utilized to address the possibly mechanism in radioresistance. MTT, LDH, and colony formation assay were applied to evaluate cell growth and colony formation ability. RESULTS: In the present study, somatic mutations located in 441 genes were detected to be radiosensitivity-related loci. Seventeen genes, including the Smad protein family members (SMAD3 and SMAD4), were identified to influence the radiosensitivity in PDAC. The SMAD3 and SMAD4 genes mutate differently between radiosensitive and radioresistant PDAC patients. Mutation of SMAD3 potentiates the effects of ionizing radiation (IR) on cell growth and colony formation in PDAC cells, whereas mutation of SMAD4 had the opposite effects. SMAD3 and SMAD4 regulate the radiosensitivity of PDAC, at least in part, by P21 and FOXO3a, respectively. CONCLUSIONS: These results indicate that mutations of SMAD3 and SMAD4 likely cause the difference of response to radiotherapy in PDAC, which might be considered as the biomarkers and potential targets for the radiotherapy of pancreatic cancer.

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication.

Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, which leads to improved potency of allosteric drugs. Epidermal growth factor receptor (EGFR), as one of the most critical anti-cancer targets belonging to the receptor tyrosine kinase family, represents a quintessential example. It was revealed that osimertinib, an ATP-competitive covalent EGFR inhibitor, remarkably enhanced the affinity of a recently developed allosteric inhibitor JBJ-04-125-02 for EGFRL858R/T790M. Here, we utilized extensive large-scale molecular dynamics simulations and the reversed allosteric communication to untangle the detailed molecular underpinning, in which occupation of osimertinib at the orthosteric site altered the overall conformational ensemble of EGFR mutant and reshaped the allosteric site via long-distance signaling. A unique intermediate state resembling the active conformation was identified, which was further stabilized by osimertinib loading. Based on the allosteric communication pathway, we predicted a novel allosteric site positioned around K867, E868, H893, and K960 within the intermediate state. Its correlation with the orthosteric site was validated by both structural and energetic analysis, and its low sequence conservation indicated the potential for selective targeting across the human kinome. Together, these findings not only provided a mechanistic basis for future clinical application of the dual-targeting therapeutics, but also explored an innovative perception of allosteric inhibition of tyrosine kinase signaling.

A retrospective analysis of the risk factors affecting recurrence time in patients with recurrent glioblastoma.

BACKGROUND: This study explored the related factors that influence the recurrence time of glioblastomas (GBM). METHODS: A retrospective study of recurrent GBM patients with surgical resection was performed. Recurrence time was analyzed using Kaplan-Meier survival curves. The Cox regression model was used to investigate the possible factors associated with recurrence time. RESULTS: A total of 176 patients (113 males and 63 females) were enrolled in the study, with a median age of 57 years (range, 19-76 years). From this cohort, 18 patients (10.2%) had gross total resection (GTR), 53 patients (30.1%) had subtotal resection (STR), and 105 patients (59.7%) had partial resection (PR). Postoperatively, all patients received radiotherapy (RT), with 55.1% administered concurrent chemotherapy (CTh) and 59.7% administered adjuvant CTh. The median recurrence time was 10.0 months (range, 1.0-75.0 months). Patients with PR (P=0.004), gliomas that contacted the subventricular zone (SVZ) (P=0.004), isocitrate dehydrogenase 1 (IDH1) wild-type (P=0.048), telomerase reverse transcriptase (TERT) C228T wild-type (P=0.012), and positive glial fibrillary acidic protein (GFAP) expression (P=0.044) had a shortened time to recurrence. Cox regression analysis revealed that PR (P=0.036), SVZ contact (P=0.008), and TERT C228T wild type (P=0.023) were significantly associated with a shortened recurrence time. CONCLUSIONS: PR, tumor contacting the SVZ, and TERT C228T wild type were independent risk factors for tumor recurrence in patients with GBM.

Microwave-Assisted Chitosan-Functionalized Graphene Oxide as Controlled Intracellular Drug Delivery Nanosystem for Synergistic Antitumour Activity.

To achieve better antitumour efficacy, it is urgent to improve anticancer drug delivery efficiency in targeting cancer cells. In this work, chitosan-functionalized graphene oxide (ChrGO) nanosheets were fabricated via microwave-assisted reduction, which were employed to the intracellular delivery nanosystem for anticancer drug agent in breast cancer cells. Drug loading and release research indicated that adriamycin can be efficiently loaded on and released from the ChrGO nanosheets. Less drug release during delivery and better biocompatibility of ChrGO/adriamycin significantly improve its safety and therapeutic efficacy in HER2-overexpressing BT-474 cells. Furthermore, ChrGO/adriamycin in combination with trastuzumab exhibited synergistic antitumour activity in BT-474 cells, which demonstrated superior therapeutic efficacy compared with each drug alone. Cells treated with trastuzumab (5 µg/mL) or equivalent ChrGO/adriamycin (5 µg/mL) each elicited 54.5% and 59.5% cell death, respectively, while the combination treatment with trastuzumab and ChrGO/adriamycin resulted in a dramatic 88.5% cell death. The dual-targeted therapy displayed higher apoptosis, indicating superior therapeutic efficacy due to the presence of different mechanisms of action. The combined treatment of ChrGO/adriamycin and trastuzumab in BT-474 cells induced cell cycle arrest and apoptosis, which ultimately led to the death of augmented cancer cells. This work has provided a facile microwave-assisted fabrication of ChrGO as a controlled and targeted intracellular drug delivery nanosystem, which is expected to be a novel promising therapy for treating HER2-overexpressing breast cancer cells.

The LGMN pseudogene promotes tumor progression by acting as a miR-495-3p sponge in glioblastoma.

Pseudogenes, which are long noncoding RNAs that originate from protein-coding genes, have been suggested to play important roles in disease. Although studies have revealed high expression of legumain (LGMN) in many types of tumors, the regulation of LGMN remains largely unknown. Here, we found that a novel LGMN pseudogene (LGMNP1) was upregulated in glioblastoma (GBM) tissues and high LGMNP1 expression in GBM cells enhanced proliferation and invasion. Biochemical analysis showed that cytoplasmic LGMNP1 functionally targeted miR-495-3p in a manner involving an RNA-induced silencing complex. Dual-luciferase reporter assays demonstrated that LGMN was a target of miR-495-3p, and LGMN was upregulated and positively correlated with LGMNP1 in GBM. Moreover, miR-495-3p was downregulated and negatively correlated with LGMNP1 in GBM tissues. Notably, the tumor-promoting effects of LGMNP1 upregulation could be alleviated by miR-495-3p mimics. Furthermore, GBM cells overexpressing LGMNP1 exhibited more aggressive tumor progression and elevated LGMN expression in vivo. Thus, our data illustrate that LGMNP1 exerts its oncogenic activity, at least in part, as a competitive endogenous RNA (ceRNA) that elevates LGMN expression by sponging miR-495-3p. CeRNA-mediated miRNA sequestration might be a novel therapeutic strategy in GBM.

Adaptive EGF expression sensitizes pancreatic cancer cells to ionizing radiation through activation of the cyclin D1/P53/PARP pathway.

It is well-known that the activation status of the P53, signal transducer and activator of transcription (Stat)3 and nuclear factor (NF)­κB signaling pathways determines the radiosensitivity of cancer cells. However, the function of these pathways in radiosensitive vs radioresistant cancer cells remains elusive. The present study demonstrated that adaptive expression of epidermal growth factor (EGF) following exposure to ionizing radiation (IR) may induce radiosensitization of pancreatic cancer (PC) cells through induction of the cyclin D1/P53/poly(ADP­ribose) polymerase pathway. By contrast, adaptively expressed interleukin (IL)­6 and insulin­like growth factor (IGF)­1 may promote radioresistance of PC cells, likely through activation of the Stat3 and NF­κB pathways. In addition, cyclin D1 and survivin, which are specifically expressed in the G1/S and G2/M phase of the cell cycle, respectively, are mutually exclusive in radiosensitive and radioresistant PC cells, while Bcl­2 and Bcl­xL expression does not differ between radiosensitive and radioresistant PC cells. Therefore, adaptively expressed EGF and IL­6/IGF­1 may alter these pathways to promote the radiosensitivity of PC cancers. The findings of the present study highlight potential makers for the evaluation of radiosensitivity and enable the development of effective regimens for cancer radiotherapy.

Upregulated AHIF-mediated radioresistance in glioblastoma.

Long non-coding RNAs (lncRNAs) play vital roles in the pathobiology of glioblastoma multiforme (GBM). Though radiotherapy remains the most effective component of multiple therapies for patients with GBM, lncRNAs conferring GBM radioresistance are less unknown. Here, the present study identified that the antisense transcript of hypoxia-inducible factor-1α (AHIF) was upregulated in GBM cells after radiotherapy. The deregulation of AHIF affected GBM cell clonogenic formation, DNA repair and apoptosis. Notably, knockdown of AHIF inhibited tumorigenesis after radiotherapy in vivo. Further biochemical analysis identified that AHIF regulated proteins associated with apoptosis after radiotherapy. Thus, the present data illustrate that suppression of AHIF increases radiosensitivity in GBM cells, which may be a potential diagnostic and therapeutic target for GBM patients.

AHIF promotes glioblastoma progression and radioresistance via exosomes.

Glioblastoma multiforme (GBM) has the highest mortality rate among patients with brain tumors, and radiotherapy forms an important part of its treatment. Thus, there is an urgent requirement to elucidate the mechanisms conferring GBM progression and radioresistance. In the present study, it was identified that antisense transcript of hypoxia­inducible factor­1α (AHIF) was significantly upregulated in GBM cancerous tissues, as well as in radioresistant GBM cells. The expression of AHIF was also upregulated in response to radiation. Knockdown of AHIF in GBM cells decreased viability and invasive capacities, and increased the proportion of apoptotic cells. By contrast, overexpression of AHIF in GBM cells increased viability and invasive capacities, and decreased the proportion of apoptotic cells. Furthermore, exosomes derived from AHIF­knockdown GBM cells inhibited viability, invasion and radioresistance, whereas exosomes derived from AHIF­overexpressing GBM cells promoted viability, invasion and radioresistance. Further biochemical analysis identified that AHIF regulates factors associated with migration and angiogenesis in exosomes. To the best of our knowledge, the present study is the first to establish that AHIF promotes glioblastoma progression and radioresistance via exosomes, which suggests that AHIF is a potential therapeutic target for GBM.