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Neutrophils are the most abundant circulating leukocytes and the first line of defense against invading pathogens. They are key components of the innate immune system. Neutrophils also cause tissue damage in various autoimmune and inflammatory diseases and play an important role in cancer progression. Due to the complex relationship between various diseases and neutrophils, these cells have become potentially important targets for therapeutic interventions. Monitoring neutrophils in the tumor microenvironment is critical for tumor treatment and prognostic analysis but remains challenging. Molecular imaging technology has made great progress as a valuable tool for noninvasively visualizing biological events and establishing effective cancer diagnoses and treatment methods. Molecular probes designed based on the characteristics of neutrophils, such as their flexible morphology, the abundance of surface receptors, and the absence of immunogenicity, have shown great potential. This has created an opportunity for novel ideas and research methods for the diagnosis and targeted therapy of inflammatory diseases and tumors, with the goal of integrated diagnosis and treatment. This review discusses the diverse tumor detection and diagnostic imaging strategies based on neutrophils. It is anticipated that neutrophil-based imaging will soon be gradually integrated into clinical applications.Neutrophils play a role in promoting/inhibiting tumor growth in the tumor microenvironment.To be more conducive to discovering neutrophils in tumors and guiding treatment, medical imaging technology has developed stepwise.In the context of the intersection of imaging technology, great breakthroughs have been made in the individualized research of tumor diagnosis.This article contributes to the promotion of new multimodal molecular imaging technology and the application of rapid diagnosis individualization.

Background Increasing studies have reported that oncogenes regulate components of the immune system, suggesting that this is a mechanism for tumorigenesis. Aurora kinase A (AURKA), a serine/threonine kinase, is involved in cell mitosis and is essential for tumor cell proliferation, metastasis, and drug resistance. However, the mechanism by which AURKA is involved in immune response regulation is unclear. Therefore, this study aimed to investigate the role of AURKA in immune regulation in triple‐negative breast cancer (TNBC). Methods Peripheral blood mononuclear cells (PBMCs) were co‐cultured with TNBC cells. The xCELLigence Real‐Time Cell Analyzer‐MP system was used to detect the killing efficiency of immune cells on TNBC cells. The expression of immune effector molecules was tested by quantitative real‐time polymerase chain reaction (qRT‐PCR) to evaluate immune function. Furthermore, to validate AURKA‐regulated immune response in vivo, 4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice. The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry. Results Downregulation of AURKA in TNBC cells increased immune response by activating CD8+ T cell proliferation and activity. Nuclear rather than cytoplasmic AURKA‐derived programmed death‐ligand 1 (PD‐L1) expression was independent of its kinase activity. Mechanistic investigations showed that nuclear AURKA increased PD‐L1 expression via an MYC‐dependent pathway. PD‐L1 overexpression mostly reversed AURKA silencing‐induced expression of immune effector molecules, including interleukin‐ (IL‐2), interferon‐γ (IFN‐γ), and perforin. Moreover, AURKA expression was negatively correlated with the enrichment and activity of tumor‐infiltrating CD8+ T cells in 4T1 engrafted BALB/c mouse model. Conclusions Nuclear AURKA elevated PD‐L1 expression via an MYC‐dependent pathway and contributed to immune evasion in TNBC. Therapies targeting nuclear AURKA may restore immune responses against tumors., The present study showed that nuclear AURKA rather than its kinase activity induced PD‐L1 expression via a MYC‐dependent pathway. In addition, downregulation of AURKA led to increased CD8+ T cell infiltration and activation in vivo. Thus, our data provided evidences for the involvement of AURKA in immune evasion of triple‐negative breast cancer.

Small extracellular vesicles (SEVs) are extracellular vesicles containing DNA, RNA, and proteins and are involved in intercellular communication and function, playing an essential role in the growth and metastasis of tumors. SEVs are present in various body fluids and can be isolated and extracted from blood, urine, and cerebrospinal fluid. Under both physiological and pathological conditions, SEVs can be released by some cells, such as immune, stem, and tumor cells, in a cytosolic manner. SEVs secreted by tumor cells are called tumor-derived exosomes (TEXs) because of their origin in the corresponding parent cells. Glioma is the most common intracranial tumor, accounting for approximately half of the primary intracranial tumors, and is characterized by insidious onset, high morbidity, and high mortality rate. Complete removal of tumor tissues by surgery is difficult. Chemotherapy can improve the survival quality of patients to a certain extent; however, gliomas are prone to chemoresistance, which seriously affects the prognosis of patients. In recent years, TEXs have played a vital role in the occurrence, development, associated immune response, chemotherapy resistance, radiation therapy resistance, and metastasis of glioma. This article reviews the role of TEXs in glioma progression, drug resistance, and clinical diagnosis.

ObjectiveIn this prospective study of an in-vivo cervical examination using optical coherence tomography (OCT), we evaluated the diagnostic value of non-invasive and real-time OCT in cervical precancerous lesions and cancer diagnosis, and determined the characteristics of OCT images.Methods733 patients from 5 Chinese hospitals were inspected with OCT and colposcopy-directed biopsy. The OCT images were compared with the histological sections to find out the characteristics of various categories of lesions. The OCT images were also interpreted by 3 investigators to make a 2-class classification, and the results were compared against the pathological results.ResultsVarious structures of the cervical tissue were clearly observed in OCT images, which matched well with the corresponding histological sections. The OCT diagnosis results delivered a sensitivity of 87.0% (95% confidence interval, CI, 82.2%-90.7%), a specificity of 84.1% (95% CI, 80.3%-87.2%), and an overall accuracy of 85.1%.ConclusionBoth good consistency of OCT images and histological images and satisfactory diagnosis results were provided by OCT. Due to its features of non-invasion, real-time, and accuracy, OCT is valuable for the in-vivo evaluation of cervical lesions and has the potential to be one of the routine cervical diagnosis methods.

ObjectiveCervical cancer screening is very important in the prevention and treatment of cervical cancer. In China, the cervical screening strategy needs to be improved. To explore a suitable cervical screening strategy in China, we evaluated the performance of the human papillomavirus (HPV) E6/E7 mRNA (Aptima HPV (AHPV)) assay in primary screening and different triage strategies for women undergoing routine cervical screening.MethodsA total of 10,002 women aged 35 to 65 years of age were recruited in Liaoning Province and Qingdao City, China. Specimens were tested by liquid-based cytology (LBC) and the AHPV assay, and women who tested positive on any test were referred for colposcopy. Genotyping was performed on all high-risk HPV (HR-HPV)-positive samples. Test characteristics were calculated based on histological review.ResultsWe identified 109 women with high-grade squamous intraepithelial lesion or worse (HSIL+), including six with cervical cancer. The sensitivity of AHPV was clearly higher than that of LBC (92.7 [95% CI: 87.2, 97.2] vs. 67.9 [95% CI: 59.6, 76.1], p < 0.001). The specificity of AHPV was 93.0 (95% CI: 92.5, 93.5), which was lower than that of LBC (95.2 [95% CI: 94.8, 95.6], p < 0.001). There was no statistical difference between the positive predictive value of AHPV and LBC (13.5 [95% CI: 11.2, 16.2] vs. 14.3 [95% CI: 11.4, 17.6], p = 0.695). The difference of area under the curve (AUC) values between the AHPV test (0.928 [95% CI: 0.904, 0.953]) and LBC test (0.815 [95% CI: 0.771, 0.860]) in detecting HSIL+ was statistically significant (p < 0.001). Finally, among the three triage strategies, both the sensitivity (73.4 [95% CI: 65.1, 81.7]) and AUC (0.851 [95% CI: 0.809, 0.892]) of AHPV genotyping with reflex LBC triage were the greatest.ConclusionIn summary, the AHPV assay is both specific and sensitive for detecting HSIL+ and may be suitable for use in primary cervical cancer screening in China. AHPV genotyping with reflex LBC triage may be a feasible triage strategy.

A meta-analysis was conducted to investigate the correlation between calcium intake and the risk of brain tumors (especially glioma).The PubMed, Web of Science, and Embase databases were searched for relevant papers on the association between calcium intake and glioma as of August 22, 2021. The odds ratio (OR) with a 95% confidence interval (CI) was calculated using a random-effects model. Egger's test was conducted to assess publication bias.The meta-analysis includes four studies. The meta-analysis showed that calcium intake and the risk of brain tumors have a significant negative relationship (OR = 0.28; 95% CI: 0.11 to 0.72;There is a significant negative association between calcium intake and brain tumors (especially gliomas), but more high-quality studies are needed to verify these results.

Epidermal growth factor receptor (EGFR) amplification and EGFRvIII mutation drive glioblastoma (GBM) pathogenesis, but their regulation remains elusive. Here we characterized the EGFR/EGFRvIII “interactome” in GBM and identified thyroid receptor-interacting protein 13 (TRIP13), an AAA + ATPase, as an EGFR/EGFRvIII-associated protein independent of its ATPase activity. Functionally, TRIP13 augmented EGFR pathway activation and contributed to EGFR/EGFRvIII-driven GBM growth in GBM spheroids and orthotopic GBM xenograft models. Mechanistically, TRIP13 enhanced EGFR protein abundance in part by preventing Cbl-mediated ubiquitination and proteasomal degradation. Reciprocally, TRIP13 was phosphorylated at tyrosine(Y) 56 by EGFRvIII and EGF-activated EGFR. Abrogating TRIP13 Y56 phosphorylation dramatically attenuated TRIP13 expression-enhanced EGFR signaling and GBM cell growth. Clinically, TRIP13 expression was upregulated in GBM specimens and associated with poor patient outcome. In GBM, TRIP13 localized to cell membrane and cytoplasma and exhibited oncogenic effects in vitro and in vivo, depending on EGFR signaling but not the TRIP13 ATPase activity. Collectively, our findings uncover that TRIP13 and EGFR form a feedforward loop to potentiate EGFR signaling in GBM growth and identify a previously unrecognized ATPase activity-independent mode of action of TRIP13 in GBM biology.

Background Lung adenocarcinoma accounts for approximately 40% of all primary lung cancers; however, the mortality rates remain high. Successfully predicting progression and overall (OS) time will provide clinicians with more options to manage this disease. Methods We analyzed RNA sequencing data from 510 cases of lung adenocarcinoma from The Cancer Genome Atlas database using CIBERSORT, ImmuCellAI, and ESTIMATE algorithms. Through these data we constructed 6 immune subtypes and then compared the difference of OS, immune infiltration level and gene expression between these immune subtypes. Also, all the subtypes and immune cells infiltration level were used to evaluate the relationship with prognosis and we introduced lasso-cox method to constructe an immune-related prognosis model. Finally we validated this model in another independent cohort. Results The C3 immune subtype of lung adenocarcinoma exhibited longer survival, whereas the C1 subtype was associated with a higher mutation rate of MUC17 and FLG genes compared with other subtypes. A multifactorial correlation analysis revealed that immune cell infiltration was closely associated with overall survival. Using data from 510 cases, we constructed a nomogram prediction model composed of clinicopathologic factors and immune signatures. This model produced a C-index of 0.73 and achieved a C-index of 0.844 using a validation set. Conclusions Through this study we constructed an immune related prognosis model to instruct lung adenocarcinoma’s OS and validated its value in another independent cohost. These results will be useful in guiding treatment for lung adenocarcinoma based on tumor immune profiles.

Mps one binder 2 (MOB2) regulates the NDR kinase family, however, whether and how it is implicated in cancer remain unknown. Here we show that MOB2 functions as a tumor suppressor in glioblastoma (GBM). Analysis of MOB2 expression in glioma patient specimens and bioinformatic analyses of public datasets revealed that MOB2 was downregulated at both mRNA and protein levels in GBM. Ectopic MOB2 expression suppressed, while depletion of MOB2 enhanced, the malignant phenotypes of GBM cells, such as clonogenic growth, anoikis resistance, and formation of focal adhesions, migration, and invasion. Moreover, depletion of MOB2 increased, while overexpression of MOB2 decreased, GBM cell metastasis in a chick chorioallantoic membrane model. Overexpression of MOB2-mediated antitumor effects were further confirmed in mouse xenograft models. Mechanistically, MOB2 negatively regulated the FAK/Akt pathway involving integrin. Notably, MOB2 interacted with and promoted PKA signaling in a cAMP-dependent manner. Furthermore, the cAMP activator Forskolin increased, while the PKA inhibitor H89 decreased, MOB2 expression in GBM cells. Functionally, MOB2 contributed to the cAMP/PKA signaling-regulated inactivation of FAK/Akt pathway and inhibition of GBM cell migration and invasion. Collectively, these findings suggest a role of MOB2 as a tumor suppressor in GBM via regulation of FAK/Akt signaling. Additionally, we uncover MOB2 as a novel regulator in cAMP/PKA signaling. Given that small compounds targeting FAK and cAMP pathway have been tested in clinical trials, we suggest that interference with MOB2 expression and function may support a theoretical and therapeutic basis for applications of these compounds.

Background FK506-binding protein 9 (FKBP9) is amplified in high-grade gliomas (HGGs). However, the roles and mechanism(s) of FKBP9 in glioma are unknown. Methods The expression of FKBP9 in clinical glioma tissues was detected by immunohistochemistry (IHC). The correlation between FKBP9 expression levels and the clinical prognosis of glioma patients was examined by bioinformatic analysis. Glioblastoma (GBM) cell lines stably depleted of FKBP9 were established using lentiviruses expressing shRNAs against FKBP9. The effects of FKBP9 on GBM cells were determined by cell-based analyses, including anchorage-independent growth, spheroid formation, transwell invasion assay, confocal microscopy, immunoblot (IB) and coimmunoprecipitation assays. In vivo tumor growth was determined in both chick chorioallantoic membrane (CAM) and mouse xenograft models. Results High FKBP9 expression correlated with poor prognosis in glioma patients. Knockdown of FKBP9 markedly suppressed the malignant phenotype of GBM cells in vitro and inhibited tumor growth in vivo. Mechanistically, FKBP9 expression induced the activation of p38MAPK signaling via ASK1. Furthermore, ASK1-p38 signaling contributed to the FKBP9-mediated effects on GBM cell clonogenic growth. In addition, depletion of FKBP9 activated the IRE1α-XBP1 pathway, which played a role in the FKBP9-mediated oncogenic effects. Importantly, FKBP9 expression conferred GBM cell resistance to endoplasmic reticulum (ER) stress inducers that caused FKBP9 ubiquitination and degradation. Conclusions Our findings suggest an oncogenic role for FKBP9 in GBM and reveal FKBP9 as a novel mediator in the IRE1α-XBP1 pathway.

Hypoxia is one of the prominent features of solid tumors. Hypoxia activated prodrugs (HAPs), selectively killing hypoxic cells, possess the potential to transform hypoxia from a nuisance to an advantage in precision therapy. Exhibiting a more significant hypoxic microenvironment, gliomas, as the most frequent and incurable neurological tumors, provide HAPs a more attractive therapeutic prospect. However, the insufficient hypoxia and the obstruction of the blood-brain barrier (BBB) severely limit the activation and bio-availability of HAPs. Herein, a novel nanoparticle iRGD@ZnPc + TPZ was designed and synthesized to achieve gliomas inhibition by encapsulating tirapazamine (TPZ) as a HAP and zinc phthalocyanine (ZnPc) as a photosensitizer to enhance hypoxia. iRGD@ZnPc + TPZ can realize breakthrough BBB, deep penetration, and significant retention in gliomas, which is attributed to the iRGD-mediated receptor targeting and active transport. After being internalized by tumor cells and radiated, ZnPc efficiently consumes intratumoral Osub2/subto produce reactive oxygen species, which not only implements tumor suppression, but also intensify hypoxia to activate TPZ for amplifying chemotherapy. The photosensitizer-enhanced activation of HAPs inhibits gliomas growth. This study provides a new strategy with sensitizing and activating HAPs for gliomas treatment in clinical.

Background: Despite their great disease burden, there have been few studies on the epidemiology of central nervous system tumours (CNSTs) in China. We used the latest data updated by GBD to analyse the trends of incidence, mortality, and disability-adjusted life years (DALYs) for CNSTs in China versus globally. Methods: Epidemiological data on CNSTs were extracted from GBD 2019. We used Joinpoint regression analysis to calculate the magnitude and direction of the trends and the age-period-cohort method to analyse the age, period, and cohort effects of the trend. Results: From 1990 to 2019, the 106.52% increase in Chinese incident cases was higher than the global increase (94.35%). The 67.32% increase in cancer deaths and 16.03% increase in DALYs were lower than the global increases (cancer death: 76.36%; DALYs: 40.06%). The age-standardized incidence rates (ASIRs) in China were higher than the global ASIRs, and the increase in China was higher than that globally. Although the age-standardized mortality rates and age-standardized DALY rates in China were higher, their increases in China were less than those globally. Both in China and globally, the number and incidence, mortality, and DALYs by age group showed a bimodal distribution (younger than 5 years and older), and the peak in the older age group showed a backwards trend. The proportion of incident cases, cancer deaths, and DALYs also increased in the older age group. In the age-period-cohort model, the local drifts in the older age group were above zero. Conclusions: The burden of CNSTs is very serious in China, and we should pay attention to the key populations, early diagnosis technology, improvements in medical technology, and ways to reduce medical costs. We believe our results could help policymakers allocate resources efficiently to reduce the burden of CNSTs.

LIM homeobox transcription factor 1‐beta (LMX1B) has recently been found to be highly expressed in advanced gliomas and is associated with poor survival. However, the regulatory molecular mechanism of LMX1B expression in gliomas remains unclear. In this study, bioinformatics analysis showed that miR‐485‐5p may be the potential upstream regulator of LMX1B, and long noncoding RNA (lncRNA) small nucleolar RNA host gene 3 (SNHG3) may function as a competitive endogenous RNA to sponge miR‐485‐5p. In addition, the expression of SNHG3 and LMX1B in advanced glioma tissues was significantly upregulated, while the expression of miR‐485‐5p was significantly downregulated. SNHG3 overexpression reduced the expression of miR‐485‐5p; increased the expression of LMX1B; and promoted the proliferation, migration, and invasion of glioma cells. In contrast, miR‐485‐5p overexpression reduced the expression of LMX1B and inhibited cell proliferation, migration, and invasion. The luciferase reporter assay and RNA immunoprecipitation assay further confirmed the interaction between SNHG3 and miR‐485‐5p and between miR‐485‐5p and LMX1B. In addition, subcutaneous and orthotropic xenograft models confirmed that lncRNA SNHG3 silencing or miR‐485‐5p overexpression significantly reduced the growth of glioma xenografts and prolonged survival time. These results indicate that lncRNA SNHG3 can regulate the expression of LMX1B by sponging miR‐485‐5p, thereby promoting the proliferation, migration, and invasion of glioma cells. This study provides the first evidence that the SNHG3/miR‐485‐5p/LMX1B axis is involved in glioma tumorigenesis and highlights the potential of SNHG3 and miR‐485‐5p as therapeutic targets for glioma.

Gliomas are the most invasive and fatal primary malignancy of the central nervous system that have poor prognosis, with maximal safe resection representing the gold standard for surgical treatment. To achieve gross total resection (GTR), neurosurgery relies heavily on generating continuous, real-time, intraoperative glioma descriptions based on image guidance. Given the limitations of currently available equipment, developing a real-time image-guided resection technique that provides reliable functional and anatomical information during intraoperative settings is imperative. Nowadays, the application of intraoperative ultrasound (IOUS) has been shown to improve resection rates and maximize brain function preservation. IOUS, which presents an attractive option due to its low cost, minimal operational flow interruptions, and lack of radiation exposure, is able to provide real-time localization and accurate tumor size and shape descriptions while helping distinguish residual tumors and addressing brain shift. Moreover, the application of new advancements in ultrasound technology, such as contrast-enhanced ultrasound, three-dimensional ultrasound, navigable ultrasound, ultrasound elastography, and functional ultrasound, could help to achieve GTR during glioma surgery. The current review describes current advancements in ultrasound technology and evaluates the role and limitation of IOUS in glioma surgery.

Background The quantity of metastases lesions is an important reference when it comes to making a more informed treatment decision for patients with colorectal cancer liver metastases. However, the molecular alterations in patients with different numbers of lesions have not been systematically studied. Methods We investigated somatic alterations and microsatellite instability (MSI) of liver metastases from patients with single, multiple or diffuse metastasis lesions. A new algorithm “Pathway Damage Score” was developed to comprehensively assess the functional impact of somatic alterations at the pathway level. Pathogenic pathways of different metastasis were identified and their prognosis effects were evaluated. Furthermore, the subnetworks and affected phenotypes of the altered genes in each pathogenic pathway were analyzed. Results Somatic alterations and altered genes occurred sporadically as well as in MSI state in different metastasis types, although MSS patients had more metastatic lesions than that of the MSI patients. Every metastasis group has their own pathogenic pathways and damaged “Cargo recognition for clathrin‐mediated endocytosis” is significantly associated with poor prognosis (P

This study is carried out to elucidate the role of long noncoding RNAs (lncRNAs) MT1JP in proliferation, invasion, migration, and apoptosis of glioma cells through the regulation of PTEN/Akt signaling pathway. The expression of MT1JP in 80 normal brain tissues and 138 glioma tissues, as well as glioma cell lines, was detected by quantitative reverse-transcription polymerase chain reaction. Besides, glioma cells with overexpression and low expression of MT1JP were constructed to confirm the role of MT1JP in proliferation, invasion, migration, and apoptosis of glioma cells and the growth of glioma cells in vivo through the regulation of PTEN/Akt signaling pathway. MT1JP expression was downregulated in glioma tissues and cells. The low expression of MT1JP was considered as an independent risk factor for predicting overall survival in gliomas. After transfection of MT1JP overexpression plasmid, glioma cells showed decreased proliferation, migration and invasion ability, increased apoptosis rate, and decreased the tumorigenic ability of nude mice. The trends were opposite in glioma cells transfected with MT1JP poor expression plasmid. Collectively, our study suggests that lncRNA MT1JP is responsible for inhibiting proliferation, invasion, and migration while promoting apoptosis of glioma cells through the activation of PTEN/Akt signaling pathway.

Glioma is the most common malignant tumor of the central nervous system, and it is characterized by high relapse and fatality rates and poor prognosis. Bufalin is one of the main ingredients of Chan-su, a traditional Chinese medicine (TCM) extracted from toad venom. Previous studies revealed that bufalin exerted inhibitory effects on a variety of tumor cells. To demonstrate the inhibitory effect of bufalin on glioma cells and glioma stem-like cells (GSCs) and discuss the underlying mechanism, the proliferation of glioma cells was detected by MTT and colony formation assays following treatment with bufalin. In addition, we investigated whether bufalin inhibits or kills GSCs using flow cytometry, Western blotting, and reverse transcription polymerase chain reaction analysis (RT-PCR). Finally, we investigated whether bufalin could improve the therapeutic effect of temozolomide (TMZ) and discussed the underlying mechanism. Taken together, our data demonstrated that bufalin inhibits glioma cell growth and proliferation, inhibits GSC proliferation, and kills GSCs. Bufalin was found to induce the apoptosis of GSCs by upregulating the expression of the apoptotic proteins cleaved caspase 3 and poly(ADP-ribose) polymerase (PARP) and by downregulating the expression of human telomerase reverse transcriptase, which is a marker of telomerase activity. Bufalin also improved the inhibitory effect of TMZ on GSCs by activating the mitochondrial apoptotic pathway. These results suggest that bufalin damages GSCs, induces apoptosis, and enhances the sensitivity of GSCs to TMZ.

Gliomas are the most common primary malignant brain tumors associated with a low survival rate. Even after surgery, radiotherapy, and chemotherapy, gliomas still have a poor prognosis. Extracellular vesicles are a heterogeneous group of cell-derived membranous structures. Exosomes are a type of extracellular vesicles, their size ranges from 30 nm to 100 nm. Recent studies have proved that glioma cells could release numerous exosomes; therefore, exosomes have gained increasing attention in glioma-related research. Recent studies have confirmed the importance of extracellular vesicles, particularly exosomes, in the development of brain tumors, including gliomas. Exosomes mediate intercellular communication in the tumor microenvironment by transporting biomolecules (proteins, lipids, deoxyribonucleic acid, and ribonucleic acid); thereby playing a prominent role in tumor proliferation, differentiation, metastasis, and resistance to chemotherapy or radiation. Given their nanoscale size, exosomes can traverse the blood-brain barrier and promote tumor progression by modifying the tumor microenvironment. Based on their structural and functional characteristics, exosomes are demonstrating their value not only as diagnostic and prognostic markers, but also as tools in therapies specifically targeting glioma cells. Therefore, exosomes are a promising therapeutic target for the diagnosis, prognosis, and treatment of malignant gliomas. More research will be needed before exosomes can be used in clinical applications. Here, we describe the exosomes, their morphology, and their roles in the diagnosis and progression of gliomas. In addition, we discuss the potential of exosomes as a therapeutic target/drug delivery system for patients with gliomas.

Objective To explore the potential of the transcription factor LMX1B and downstream gankyrin as prognostic biomarkers of glioma. Methods The expression levels of gankyrin and LMX1B were detected in 52 normal brain specimens and 339 glioma specimens. Correlations of gankyrin and LMX1B expression levels with pathological stages and clinical characteristics were statistically analyzed. Furthermore, the binding of LMX1B to the gankyrin promoter was evaluated using ALGGEN PROMO. Results Levels of LMX1B and gankyrin were significantly increased in tumor tissue, and were significantly associated with advanced glioma grade and poor survival. Compared with gankyrin- and LMX1B-negative glioma, the mean survival of patients with higher gankyrin and LMX1B expression was significantly reduced, from 83.46 to 18.87 months and from 63.79 to 18.29 months, respectively. Furthermore, LMX1B had a moderate positive correlation with gankyrin expression (Pearson’s r = 0.650), and it was also found to act as a transcription factor with NF-κB and E47 on the gankyrin promoter. Conclusions Increased expression of LMX1B and gankyrin has independent prognostic value in glioma patients. The transcription factor LMX1B may have an upstream role in the mechanism of action.

Glioblastoma multiforme (GBM) is a highly invasive cancer with a high recurrence rate. The prognosis of GBM patients remains poor, even after standard surgical resection combined with chemoradiotherapy. Thus, there is an urgent need for new therapeutic targets in GBM. In recent years, microRNAs have received considerable attention due to their important role in tumor development and progression. In this study, we investigated the role of miR-129-5p and miR-129-5p/ZFP36L1 axis in GBM tumorigenesis. Analysis of GSE103228 microarray data from the GEO database showed that miR-129-5p was significantly downregulated in GBM vs. normal brain tissues. Quantitative reverse transcription PCR analysis of miR-129-5p expression in seven GBM cell lines (LN229, A172, U87, T98G, U251, H4, and LN118) vs. normal human astrocytes (NHA) showed miR-129-5p was significantly downregulated in GBM cells. Overexpression of miR-129-5p in LN229 and A172 cells significantly suppressed cell proliferation, migration, invasion, and colony-forming ability. Target Scan analysis identified ZFP36L1 as the target of miR-129-5p. UALCAN dataset analysis found that ZFP36L1 was significantly upregulated in GBM vs. normal brain tissues, and high ZFP36L1 expression was positively associated with the poor survival of GBM patients. Western blot analysis demonstrated that ZFP36L1 was significantly upregulated in seven GBM cell lines vs. NHA. Overexpression of miR-129-5p in LN229 and A172 cells significantly inhibited ZFP36L1 mRNA and protein expression, while overexpression of ZFP36L1 in LN229 and A172 cells reversed miR-129-5p-mediated inhibition on GBM tumorigenesis. Our results revealed an important role of miR-129-5p in the negative regulation of ZFP36L1 expression in GBM, suggesting new candidates for targeted therapy in GBM patients.

Cancer immunotherapy, due to its high anti-tumor efficacy, has attracted considerable attention globally from experts in various fields. However, immunotherapy could be severely toxic; not all patients may respond, thus requiring combination therapy. Therefore, a reasonable selection strategy for early treatment is urgently needed. It is vital to capture the dynamic, heterogeneous, and complex tumor behavior considering the absence of ideal companion biomarkers. Since tumor immune response involves tumor cells, several other cell types, and molecules in the tumor microenvironment, detection is very complex and variable. However, molecular imaging technology, namely the non-invasive whole-body molecular imaging by positron emission tomography and single-photon emission computed tomography, has shown considerable promise in tumor detection and cancer immunotherapy response. Identification of potential novel imaging biomarkers will allow a personalized treatment plan for every patient. Future imaging strategies for these molecules used alone or in combination or continuously, might help stratify patients before or during the early stages of immunotherapy, and might address the immunotherapy challenges encountered by the oncologists.

Background Glioblastoma (GBM) is an extremely deadly form of brain cancer with limited treatment options and thus novel therapeutic modalities are necessary. Histone deacetylase inhibitors (HDACi) have demonstrated clinical and preclinical activities against GBM. (Silent mating type information regulation 2 homolog, Sirt1) abbreviated as Sirtuin 1, has been implicated in GBM. We explored the activity of the Sirt1 activator SRT2183 in glioma cell lines in terms of biological response. Methods The effects of SRT2183 on glioma cell growth and neurosphere survival were evaluated in vitro using the CCK-8, clonogenic and neurosphere assays, respectively. Glioma cell cycle arrest and apoptosis were determined by flow cytometry. SRT2183-induced autophagy was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). Acetylation of STAT3 and NF-κB in SRT2183-treated glioma cells was examined using immunoprecipitation. The expression levels of anti-apoptotic proteins were assayed by immunoblotting. Results SRT2183 suppressed glioma cell growth and destroyed neurospheres in vitro. Furthermore, SRT2183 induced glioma cell cycle arrest and apoptosis, accompanying by upregulation of the pro-apoptotic Bim and downregulation of Bcl-2 and Bcl-xL. Notably, ER stress was triggered in glioma cells upon exposure to SRT2183 while the pre-exposure to 4-PBA, an ER stress inhibitor, significantly antagonized SRT2183-mediated growth inhibition in glioma cells. In addition, SRT2183 induced autophagy in glioma cells and pharmacological modulation of autophagy appeared not to affect SRT2183-inhibited cell growth. Of interest, the acetylation and phosphorylation of p65 NF-κB and STAT3 in glioma cells were differentially affected by SRT2183. Conclusions Our data suggest the ER stress pathway is involved in SRT2183-mediated growth inhibition in glioma. Further investigation in vivo is needed to consolidate the data.

Development of resistance to endocrine therapy, such as tamoxifen, remains a tricky clinical problem during the treatment of breast cancer. Accumulating evidence suggested that dysregulation of long noncoding (lnc_RNAs contributes to the development of tamoxifen resistance. In the current study, via screening, cytoskeleton regulator RNA (CYTOR) was identified as the most significantly elevated lncRNA in the established tamoxifen resistant MCF7 cell lines (MCF7/TAM1 and MCF7/TAM2) compared with the parental MCF7 cells (MCF7‑P). The CCK‑8 assay indicated that silencing of CYTOR increased the sensitivity of MCF7/TAM1 and MCF7/TAM2 to tamoxifen treatment. Using bioinformatic analysis, it was predicted that microRNA (miR)‑125a‑5p might bind to CYTOR and the expression of miR‑125a‑5p was negatively correlated with CYTOR in the tumor tissues of breast cancer. In addition, RT‑qPCR and dual luciferase assays validated that CYTOR directly repressed miR‑125a‑5p expression in breast cancer cells. Through regulation of miR‑125a‑5p, CYTOR elevated serum response factor (SRF) expression and activated Hippo and mitogen associated protein kinase signaling pathways to promote breast cancer cell survival upon tamoxifen treatment. In the collected tumor tissues of breast cancer in the present study, high expression of CYTOR was detected in tissues from patients with no response to tamoxifen compared with those from patients who were not treated with tamoxifen. A positive correlation between CYTOR and SRF mRNA expression was observed in tissues collected from patients with breast cancer. In conclusion, the results of the present study demonstrated a pivotal role of CYTOR in mediating tamoxifen resistance in breast cancer.

Background Aberrant activation of β-catenin and Yes-associated protein (YAP) signaling pathways has been associated with hepatocellular carcinoma (HCC) progression. The LIM domain protein Ajuba regulates β-catenin and YAP signaling and is implicated in tumorigenesis. However, roles and mechanism of Ajuba expression in HCC cells remain unclear. The E3 ligase Hakai has been shown to interact with other Ajuba family members and whether Hakai interacts and regulates Ajuba is unknown. Methods HCC cell lines stably depleted of Ajuba or Hakai were established using lentiviruses expressing shRNAs against Ajuba or Hakai. The effects of Ajuba on HCC cells were determined by a number of cell-based analyses including anchorage-independent growth, three dimension cultures and trans-well invasion assay. In vivo tumor growth was determined in a xenograft model and Ajuba expression in tumor sections was examined by immunohistochemistry. Co-immunoprecipitation, confocal microscopy and immunoblot assay were used to examine the expression and interaction between Ajuba and Hakai. Results Depletion of Ajuba in HCC cells significantly enhanced anchorage-independent growth, invasion, the formation of spheroids and tumor growth in a xenograft model, suggesting a tumor suppressor function for Ajuba in HCC. Mechanistically, Ajuba depletion triggered E-cadherin loss and β-catenin translocation with increased Cyclin D1 levels. In addition, depletion of Ajuba upregulated the levels of YAP and its target gene CYR61. Furthermore, siRNA-mediated knockdown of either β-catenin or YAP attenuated the pro-tumor effects by Ajuba depletion on HCC cells. Notably, Ajuba stability in HCC cells was regulated by Hakai, an E3 ligase for E-cadherin. Hakai interacted with Ajuba via its HYB domain and induced Ajuba neddylation, which was antagonized by the neddylation inhibitor, MLN4924, but not MG132. We further show that overexpression of Hakai in HCC cells markedly increased anchorage-independent growth, spheroid-formation ability and tumor growth in xenografts whereas Hakai depletion resulted in these opposite effects, indicating an oncogenic role for Hakai in HCC. Hakai also induced β-catenin translocation with increased levels of Cyclin D1. Conclusions Our data suggest a role for Ajuba and Hakai in HCC, and uncover the mechanism underlying the regulation of Ajuba stability. Electronic supplementary material The online version of this article (10.1186/s13046-018-0806-3) contains supplementary material, which is available to authorized users.

Cell-based immunotherapy using natural killer (NK) cells, cytokine-induced killer (CIK) cells and dendritic cells (DCs) is emerging as a potential novel approach in the auxiliary treatment of a tumor. However, non-standard operation procedure, small-scale cell number, or human error may limit the clinical development of cell-based immunotherapy. To simplify clinical scale NK cells, CIK cells and DCs expansions, we investigated the use of the WAVE bioreactor, a closed system bioreactor that utilizes active perfusion to generate high cell numbers in minimal volumes. We developed an optimized rapid expansion protocol for the WAVE bioreactor that produces clinically relevant number of cells for our adoptive cell transfer clinical protocols. The high proliferative rate, surface phenotypes, and cytotoxicity of these immune cells, as well as the safety of cultivation were analyzed to illuminate the effect of WAVE bioreactor. The results demonstrated that the benefit of utilizing modern WAVE bioreactors in cancer immunotherapy was simple, safe, and flexible production.

Background: Glioma is the most prevalent malignant tumor in human central nervous systems. Recently, the development of resistance to radiotherapy in glioma patients markedly vitiates the therapy outcome. MiR-153-3p has been reported to be closely correlated with tumor progression, but its effect and molecular mechanism underlying radioresistance remains unclear in glioma. Methods: The expression of miR-153-3p was determined in radioresistant glioma clinical specimens as well as glioma cell lines exposed to irradiation (IR) using quantitative real-time PCR. Cell viability, proliferation and apoptosis were then evaluated by MTT assay, colony formation assay, Flow cytometry analysis and caspase-3 activity assay in glioma cells (U87 and U251). Tumor forming was evaluated by nude mice model in vivo. TUNEL staining was used to detect cell apoptosis in nude mice model. The target genes of miR-153-3p were predicted and validated using integrated bioinformatics analysis and a luciferase reporter assay. Results: Here, we found that miR-153-3p was down-regulated in radioresistant glioma clinical specimens as well as glioma cell lines (U87 and U251) exposed to IR. Enhanced expression of miR-153-3p promoted the radiosensitivity, promoted apoptosis and elevated caspase-3 activity in glioma cells in vitro, as well as the radiosensitivity in U251 cell mouse xenografs in vivo. Mechanically, B cell lymphoma-2 gene (BCL2) was identified as the direct and functional target of miR-153-3p. Moreover, restoration of BCL2 expression reversed miR-153-3p-induced increase of radiosensitivity, apoptosis and caspase-3 activity in U251 cells in vitro. In addition, clinical data indicated that the expression of miR-153-3p was significantly negatively associated with BCL2 in radioresistance of glioma samples. Conclusions: Our findings suggest that miR-153-3p is a potential target to enhance the effect of radiosensitivity on glioma cells, thus representing a new potential therapeutic target for glioma.

Vacquinol‑1 (Vacq), a quinolone derivative, has recently been reported to display potent antitumor effects in glioblastomas by inducing cellular massive vacuolization and cell death. However, whether Vacq induces cytotoxicities in other types of cancers, and the potential underlying mechanism, remain to be investigated. In the present study, it was revealed that Vacq suppressed cell growth and colony formation in the hepatocellular carcinoma (HCC) cell lines BEL7402 and Huh7. In addition, treatment with Vacq increased the number of early and late apoptotic cells as assessed by flow cytometry with fluorescein isothiocyanate‑conjugated Annexin V and propidium iodide double staining. Notably, the effect by Vacq in the tested cells could be inhibited by pretreatment with a broad specificity caspase inhibitor Z‑VAD‑FMK, suggesting that Vacq may induce apoptosis in HCC cells. Morphologically, exposure to Vacq resulted in nuclear fragmentation and the apoptotic body formation in HCC cells. Furthermore, Vacq treatment increased the cleavage of caspase‑3, caspase‑9 and poly(adenosine diphosphate‑ribose) polymerase‑1. Mechanistic analysis revealed that Vacq upregulated the expressions of pro‑apoptotic proteins [B‑cell lymphoma 2 (bcl‑2)‑associated X protein (Bax) and Bcl‑2‑like protein 11] and downregulated the pro‑survival protein, Bcl‑2, expression in HCC cells. Furthermore, Vacq induced Bax translocation. Of note, Vacq displayed inhibitory effects on patient‑derived HCC cells in two‑dimensional (2D) and three-dimensional (3D) cultures. Taken together, the data suggested that Vacq induced intrinsic apoptosis and may be utilized as an effective reagent for HCC treatment.

Human glioma cell line KG-1C contains GM3 ganglioside as its sole glycolipid. The degree of M2590 antibody binding to GM3 was found to be regulated by the cell density; the percentage of positive cells in FACS analysis decreased from approximately 20% to close to none as the cells increased their density from sparse to confluent. The contents of GM3 with different cell densities were consistent, being more than 0.4 μmol/g of the cellular weight, which was high enough to be recognized by the antibody. Trypsin treatment of the cells did not increase antibody reactivity. The extracted GM3 retained its antigenicity, being intensely stained with M2590 on a TLC plate; there was no change in chromatographic mobility either, indicating no modification of its chemical structure. The fluorescent microscope disclosed scattered dot-like staining of GM3, particularly at the periphery of the cells. We were able to expose cryptic GM3 fully within 12 h by dispersion of the cells to a sparse density. Surface labeling of GM3 with the use of limited sodium periodate oxidation of sialylated residue equally labeled GM3 either from the confluent cells or the sparse cells. Disassembly of actin filaments with cytochalasin B (10 μM) partially exposed cryptic GM3 of confluent cells, indicating reversibility of the crypticity. All together, the results indicate that cryptic GM3 actually exists on the cell surface, hidden from the surface not by other molecules but by other mechanisms associated with the cellular architecture. We are beginning to explore the possibility of selective localization of GM3 in small caves or folds of the cell membrane produced upon cell-to-cell contact.