The Interleukin-11/IL-11 Receptor Promotes Glioblastoma Survival and Invasion under Glucose-Starved Conditions through Enhanced Glutaminolysis.

Glioblastoma cells adapt to changes in glucose availability through metabolic plasticity allowing for cell survival and continued progression in low-glucose concentrations. However, the regulatory cytokine networks that govern the ability to survive in glucose-starved conditions are not fully defined. In the present study, we define a critical role for the IL-11/IL-11Rα signalling axis in glioblastoma survival, proliferation and invasion when cells are starved of glucose. We identified enhanced IL-11/IL-11Rα expression correlated with reduced overall survival in glioblastoma patients. Glioblastoma cell lines over-expressing IL-11Rα displayed greater survival, proliferation, migration and invasion in glucose-free conditions compared to their low-IL-11Rα-expressing counterparts, while knockdown of IL-11Rα reversed these pro-tumorigenic characteristics. In addition, these IL-11Rα-over-expressing cells displayed enhanced glutamine oxidation and glutamate production compared to their low-IL-11Rα-expressing counterparts, while knockdown of IL-11Rα or the pharmacological inhibition of several members of the glutaminolysis pathway resulted in reduced survival (enhanced apoptosis) and reduced migration and invasion. Furthermore, IL-11Rα expression in glioblastoma patient samples correlated with enhanced gene expression of the glutaminolysis pathway genes GLUD1, GSS and c-Myc. Overall, our study identified that the IL-11/IL-11Rα pathway promotes glioblastoma cell survival and enhances cell migration and invasion in environments of glucose starvation via glutaminolysis.

Cortical tension initiates the positive feedback loop between cadherin and F-actin.

Adherens junctions physically link two cells at their contact interface via extracellular binding between cadherin molecules and intracellular interactions between cadherins and the actin cytoskeleton. Cadherin and actomyosin cytoskeletal dynamics are regulated reciprocally by mechanical and chemical signals, which subsequently determine the strength of cell-cell adhesions and the emergent organization and stiffness of the tissues they form. However, an understanding of the integrated system is lacking. We present a new mechanistic computational model of intercellular junction maturation in a cell doublet to investigate the mechanochemical cross talk that regulates adherens junction formation and homeostasis. The model couples a two-dimensional lattice-based simulation of cadherin dynamics with a reaction-diffusion representation of the reorganising actomyosin network through its regulation by Rho signalling at the intracellular junction. We demonstrate that local immobilization of cadherin induces cluster formation in a cis-less-dependent manner. We then recapitulate the process of cell-cell contact formation. Our model suggests that cortical tension applied on the contact rim can explain the ring distribution of cadherin and actin filaments (F-actin) on the cell-cell contact of the cell doublet. Furthermore, we propose and test the hypothesis that cadherin and F-actin interact like a positive feedback loop, which is necessary for formation of the ring structure. Different patterns of cadherin distribution were observed as an emergent property of disturbances of this positive feedback loop. We discuss these findings in light of available experimental observations on underlying mechanisms related to cadherin/F-actin binding and the mechanical environment.

Extracellular Vesicles Secreted by Glioma Stem Cells Are Involved in Radiation Resistance and Glioma Progression.

Glioblastoma is the most aggressive brain tumour with short survival, partly due to resistance to conventional therapy. Glioma stem cells (GSC) are likely to be involved in treatment resistance, by releasing extracellular vesicles (EVs) containing specific molecular cargoes. Here, we studied the EVs secreted by glioma stem cells (GSC-EVs) and their effects on radiation resistance and glioma progression. EVs were isolated from 3 GSCs by serial centrifugation. NanoSight measurement, cryo-electron microscopy and live imaging were used to study the EVs size, morphology and uptake, respectively. The non-GSC glioma cell lines LN229 and U118 were utilised as a recipient cell model. Wound healing assays were performed to detect cell migration. Colony formation, cell viability and invadopodium assays were conducted to detect cell survival of irradiated recipient cells and cell invasion post GSC-EV treatment. NanoString miRNA global profiling was used to select for the GSC-EVs' specific miRNAs. All three GSC cell lines secreted different amounts of EVs, and all expressed consistent levels of CD9 but different level of Alix, TSG101 and CD81. EVs were taken up by both LN229 and U118 recipient cells. In the presence of GSC-EVs, these recipient cells survived radiation exposure and initiated colony formation. After GSC-EVs exposure, LN229 and U118 cells exhibited an invasive phenotype, as indicated by an increase in cell migration. We also identified 25 highly expressed miRNAs in the GSC-EVs examined, and 8 of these miRNAs can target PTEN. It is likely that GSC-EVs and their specific miRNAs induced the phenotypic changes in the recipient cells due to the activation of the PTEN/Akt pathway. This study demonstrated that GSC-EVs have the potential to induce radiation resistance and modulate the tumour microenvironment to promote glioma progression. Future therapeutic studies should be designed to interfere with these GSC-EVs and their specific miRNAs.

Carfilzomib Promotes the Unfolded Protein Response and Apoptosis in Cetuximab-Resistant Colorectal Cancer.

Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer.

Antitumor and Antiangiogenic Properties of Gold(III) Complexes Containing Cycloaurated Triphenylphosphine Sulfide Ligands.

A family of stable anticancer gold(III)-based therapeutic complexes containing cyclometalated triphenylphosphine sulfide ligands have been prepared. The anticancer properties of the newly developed complexes [AuCl2{κ2-2-C6H4P(S)Ph2}] (1), [Au(κ2-S2CNEt2){κ2-2-C6H4P(S)Ph2}]PF6 (2), [AuCl(dppe){κC-2-C6H4P(S)Ph2}]Cl (3), and [Au(dppe){κ2-2-C6H4P(S)Ph2}][PF6]2 (4) were investigated toward five human cancer cell lines [cervical (HeLa), lung (A549), prostate (PC3), fibrosarcoma (HT1080), and breast (MDA-MB-231)]. In vitro cytotoxicity studies revealed that compounds 2-4 displayed potent cell growth inhibition (IC50 values in the range of 0.17-2.50 µM), comparable to, or better than, clinically used cisplatin (0.63-6.35 µM). Preliminary mechanistic studies using HeLa cells indicate that the cytotoxic effects of the compounds involve apoptosis induction through ROS accumulation. Compound 2 also demonstrated significant inhibition of endothelial cell migration and tube formation in the angiogenesis process. Evaluation of the in vivo antitumor activity of compound 2 in nude mice bearing cervical cancer cell (HeLa) xenografts indicated significant tumor growth inhibition (55%) with 1 mg/kg dose (every 3 days) compared with the same dose of cisplatin (28%). These results demonstrate the potential of gold(III) complexes containing cyclometalated triphenylphosphine sulfide ligands as novel metal-based anticancer agents.

Cell quiescence correlates with enhanced glioblastoma cell invasion and cytotoxic resistance.

Glioblastoma (GBM) tumor cells exhibit drug resistance and are highly infiltrative. GBM stem cells (GSCs), which have low proliferative capacity are thought to be one of the sources of resistant cells which result in relapse/recurrence. However, the molecular mechanisms regulating quiescent-specific tumor cell biology are not well understood. Using human GBM cell lines and patient-derived GBM cells, Oregon Green dye retention was used to identify and isolate the slow-cycling, quiescent-like cell subpopulation from the more proliferative cells in culture. Sensitivity of cell subpopulations to temozolomide and radiation, as well as the migration and invasive potential were measured. Differential expression analysis following RNAseq identified genes enriched in the quiescent cell subpopulation. Orthotopic transplantation of cells into mice was used to compare the in vivo malignancy and invasive capacity of the cells. Proliferative quiescence correlated with better TMZ resistance and enhanced cell invasion, in vitro and in vivo. RNAseq expression analysis identified genes involved in the regulation cell invasion/migration and a three-gene signature, TGFBI, IGFBP3, CHI3L1, overexpressed in quiescent cells which correlates with poor GBM patient survival.

Novel additive for sperm cryopreservation media: Holotheria parva coelomic cavity extract protects human spermatozoa against oxidative stress-A pilot study.

Cryopreservation is the most effective method for preserving semen for a long period of time. However, during the freeze-thaw process, production of reactive oxygen species (ROS) leads to a steep reduction in sperm fertility indices. In this study, we tested the effects of the extract of the coelomic cavity of five Holotheria parva, a marine organism rich in antioxidants, for its ROS-scavenging activity and cryoprotective effects on oxidative stress. Using a total of 50 semen samples, our results demonstrated that doses of 250 and 500 µg/ml of H. parva coelomic cavity extract significantly increased sperm vitality as compared to the control (p < .05). The addition of 250 µg/ml of the extract exerted a significant positive effect on sperm motility. Moreover, sperm DNA damage and ROS production were significantly reduced at extract concentrations of 250 and 500 µg/ml (p < .05). To the best of our knowledge, the results of this study represent the first demonstration of the possibility of improving sperm parameters and reducing ROS production and DNA damage by supplementing sperm freezing media with H. parva coelomic extract. Our results suggested that H. parva coelomic extract could be useful for improving the fertilising ability of frozen-thawed human semen.

Potent and Selective Cytotoxic and Anti-inflammatory Gold(III) Compounds Containing Cyclometalated Phosphine Sulfide Ligands.

Four cycloaurated phosphine sulfide complexes, [Au{κ2 -2-C6 H4 P(S)Ph2 }2 ][AuX2 ] [X=Cl (2), Br (3), I (4)] and [Au{κ2 -2-C6 H4 P(S)Ph2 }2 ]PF6 (5), have been prepared and thoroughly characterized. The compounds were found to be stable under physiological-like conditions and showed excellent cytotoxicity against a broad range of cancer cell lines and remarkable cytotoxicity in 3D tumor spheroids. Mechanistic studies with cervical cancer (HeLa) cells indicated that the cytotoxic effects of the compounds involve the inhibition of thioredoxin reductase and induction of apoptosis through mitochondrial disruption. In vivo experiments in nude mice bearing HeLa xenografts showed that treatment with compounds 4 and 5 resulted in significant inhibition of tumor growth (35.8 and 46.9 %, respectively), better than that of cisplatin (29 %). The newly synthesized gold complexes were also evaluated for their in vitro and in vivo anti-inflammatory activity through the study of lipopolysaccharide (LPS)-activated macrophages and carrageenan-induced hind paw edema in rats, respectively.

Epidermal growth factor receptor: Structure-function informing the design of anticancer therapeutics.

Research on the epidermal growth factor (EGF) family and the family of receptors (EGFR) has progressed rapidly in recent times. New crystal structures of the ectodomains with different ligands, the activation of the kinase domain through oligomerisation and the use of fluorescence techniques have revealed profound conformational changes on ligand binding. The control of cell signaling from the EGFR-family is complex, with heterodimerisation, ligand affinity and signaling cross-talk influencing cellular outcomes. Analysis of tissue homeostasis indicates that the control of pro-ligand processing is likely to be as important as receptor activation events. Several members of the EGFR-family are overexpressed and/or mutated in cancer cells. The perturbation of EGFR-family signaling drives the malignant phenotype of many cancers and both inhibitors and antagonists of signaling from these receptors have already produced therapeutic benefits for patients. The design of affibodies, antibodies, small molecule inhibitors and even immunotherapeutic drugs targeting the EGFR-family has yielded promising new approaches to improving outcomes for cancer patients. In this review, we describe recent discoveries which have increased our understanding of the structure and dynamics of signaling from the EGFR-family, the roles of ligand processing and receptor cross-talk. We discuss the relevance of these studies to the development of strategies for designing more effective targeted treatments for cancer patients.

Coalition of Oct4A and ß1 integrins in facilitating metastasis in ovarian cancer.

BACKGROUND: Ovarian cancer is a metastatic disease and one of the leading causes of gynaecology malignancy-related deaths in women. Cancer stem cells (CSCs) are key contributors of cancer metastasis and relapse. Integrins are a family of cell surface receptors which allow interactions between cells and their surrounding microenvironment and play a fundamental role in promoting metastasis. This study investigates the molecular mechanism which associates CSCs and integrins in ovarian cancer metastasis. METHODS: The expression of Oct4A in high-grade serous ovarian tumors and normal ovaries was determined by immunofluorescence analysis. The functional role of Oct4A was evaluated by generating stable knockdown (KD) of Oct4A clones in an established ovarian cancer cell line HEY using shRNA-mediated silencing. The expression of integrins in cell lines was evaluated by flow cytometry. Spheroid forming ability, adhesion and the activities of matrix metalloproteinases 9/2 (MMP-9/2) was measured by in vitro functional assays and gelatin zymography. These observations were further validated in in vivo mouse models using Balb/c nu/nu mice. RESULTS: We report significantly elevated expression of Oct4A in high-grade serous ovarian tumors compared to normal ovarian tissues. The expression of Oct4A in ovarian cancer cell lines correlated with their CSC-related sphere forming abilities. The suppression of Oct4A in HEY cells resulted in a significant diminution of integrin ß1 expression and associated α5 and α2 subunits compared to vector control cells. This was associated with a reduced adhesive ability on collagen and fibronectin and decreased secretion of pro-MMP2 in Oct4A KD cells compared to vector control cells. In vivo, Oct4A knock down (KD) cells produced tumors which were significantly smaller in size and weight compared to tumors derived from vector control cells. Immunohistochemical analyses of Oct4A KD tumor xenografts demonstrated a significant loss of cytokeratin 7 (CK7), Glut-1 as well as CD34 and CD31 compared to vector control cell-derived xenografts. CONCLUSION: The expression of Oct4A may be crucial to promote and sustain integrin-mediated extracellular matrix (ECM) remodeling requisite for tumor metastasis in ovarian cancer patients.

A critical role of Oct4A in mediating metastasis and disease-free survival in a mouse model of ovarian cancer.

BACKGROUND: High grade epithelial ovarian cancer (EOC) is commonly characterised by widespread peritoneal dissemination and ascites. Metastatic EOC tumour cells can attach directly to neighbouring organs or alternatively, maintain long term tumourigenicity and chemoresistance by forming cellular aggregates (spheroids). Cancer stem-like cells are proposed to facilitate this mechanism. This study aimed to investigate the role of Oct4A, an embryonic stem cell factor and known master regulator of pluripotency in EOC progression, metastasis and chemoresistance. METHODS: To investigate the expression of Oct4A in primary EOC tumours, IHC and qRT-PCR analyses were used. The expression of Oct4A in chemonaive and recurrent EOC patient ascites-derived tumour cells samples was investigated by qRT-PCR. The functional role of Oct4A in EOC was evaluated by generating stable knockdown Oct4A clones in the established EOC cell line HEY using shRNA-mediated silencing technology. Cellular proliferation, spheroid forming ability, migration and chemosensitivty following loss of Oct4A in HEY cells was measured by in vitro functional assays. These observations were further validated in an in vivo mouse model using intraperitoneal (IP) injection of established Oct4A KD clones into Balb/c nu/nu mice. RESULTS: We demonstrate that, compared to normal ovaries Oct4A expression significantly increases with tumour dedifferentiation. Oct4A expression was also significantly high in the ascites-derived tumour cells of recurrent EOC patients compared to chemonaive patients. Silencing of Oct4A in HEY cells resulted in decreased cellular proliferation, migration, spheroid formation and increased chemosensitivity to cisplatin in vitro. IP injection of Oct4A knockdown cells in vivo produced significantly reduced tumour burden, tumour size and invasiveness in mice, which overall resulted in significantly increased mouse survival rates compared to mice injected with control cells. CONCLUSIONS: This data highlights a crucial role for Oct4A in the progression and metastasis of EOC. Targeting Oct4A may prove to be an effective strategy in the treatment and management of epithelial ovarian tumours.

Single live cell TGF-ß signalling imaging: breast cancer cell motility and migration is driven by sub-populations of cells with dynamic TGF-ß-Smad3 activity.

BACKGROUND: Metastasis is a process where only a small subset of cells is capable of successfully migrating to and propagating at secondary sites. TGF-ß signalling is widely known for its role in cancer metastasis and is associated with cell migration in whole cell populations. FINDINGS: We extend these findings by investigating the role of TGF-ß signalling in promoting migration and motility by imaging the signalling activity in live, individual MDA-MB-231 cancer cells utilizing a novel Smad3 Td-Tomato reporter adenovirus. Here we find that not all MDA-MB-231 cancer cells have similar TGF-ß mediated Smad3 transcription activity and display at least two distinct migratory populations. Importantly, Smad3 activity was significantly higher within migratory cells compared to non-migrated cells in wound healing and transwell assays. Furthermore, time-lapse experiments showed that MDA-MB-231 cells displaying Smad3 activity moved faster and a greater distance compared to cells not displaying Smad3 reporter activity. Interestingly, despite being more motile than cells with undetectable levels of Smad3 activity, high Smad3 activity was detrimental to cell motility compared to low and medium level of Smad3 activity. CONCLUSIONS: We have developed a method enabling real-time visualization of TGF-ß signalling in single live cells. Breast cancer cell motility and migration is driven by sub-populations of cells with dynamic TGF-ß-Smad3 activity. Those sub-populations may be responsible for tumor invasion and metastasis.

MicroRNA as potential biomarkers in Glioblastoma.

Glioblastoma is the most aggressive and lethal tumour of the central nervous system and as such the identification of reliable prognostic and predictive biomarkers for patient survival and tumour recurrence is paramount. MicroRNA detection has rapidly emerged as potential biomarkers, in patients with glioblastoma. Over the last decade, analysis of miRNA in laboratory based studies have yielded several candidates as potential biomarkers however, the accepted use of these candidates in the clinic is yet to be validated. Here we will examine the use of miRNA signatures to improve glioblastoma stratification into subgroups and summarise recent advances made in miRNA examination as potential biomarkers for glioblastoma progression and recurrence.

Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden.

BACKGROUND: Current treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment. METHODS: The mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model. RESULTS: Treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 µM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated cell-derived xenografts compared to paclitaxel only-treated cell derived xenografts. CONCLUSIONS: This proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the 'stemness' profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These findings have important implications for ovarian cancer patients who are treated with taxane and/or platinum-based therapies.

Transforming growth factor-ß in tumor microenvironment: Understanding its impact on monocytes and macrophages for its targeting.

TGF-ß is a pivotal cytokine that orchestrates various aspects of cancer progression, including tumor growth, metastasis, and immune evasion. In this review, we present a comprehensive overview of the multifaceted role of transforming growth factor ß (TGF-ß) in cancer biology, focusing on its intricate interactions with monocytes and macrophages within the tumor microenvironment (TME). We specifically discuss how TGF-ß modulates monocyte and macrophage activities, leading to immunosuppression and tumor progression. We conclude with the current translational and clinical efforts targeting TGF-ß, recognizing the promising role of this strategy in immunooncology.

Transforming growth factor ß (TGF-ß), a pivotal cytokine, plays a crucial role in maintaining homeostasis and influencing cancer development by affecting various cell types. In cancer, TGF-ß initially suppresses tumor cell growth but later contributes to tumor progression and metastasis, presenting challenges in developing therapeutics targeting this cytokine. Mechanistically, TGF-ß impacts diverse cellular processes through canonical Smad and non-Smad pathways, that explains its diverse regulation of different, sometimes opposing, cellular processes.In the context of immunity, exposure to TGF-ß renders immune cells immunosuppressive, hindering their ability to fight tumor development. This article explores the effects of TGF-ß on monocytes and macrophages, highlighting its role in creating an immunosuppressive tumor microenvironment (TME) required for tumor survival and growth. The article provides an update on recent studies that underscore the potential of TGF-ß inhibition in modulating the immune response within the TME, thereby enhancing the effectiveness of cancer immunotherapy.Overall, this review article delves into the multifaceted role of TGF-ß in cancer biology, with a specific focus on its interactions with monocytes and macrophages. It underscores the knowledge gaps and the importance of targeting TGF-ß signaling in tumor-associated monocytes and macrophages as a promising therapeutic approach in TGF-ß secreting tumors.

A New Systemic Disease Mouse Model for Glioblastoma Capable of Single-Tumour-Cell Detection.

BACKGROUND: Glioblastoma is characterised by extensive infiltration into the brain parenchyma, leading to inevitable tumor recurrence and therapeutic failure. Future treatments will need to target the specific biology of tumour recurrence, but our current understanding of the underlying mechanisms is limited. Significantly, there is a lack of available methods and models that are tailored to the examination of tumour recurrence. METHODS: NOD-SCID mice were orthotopically implanted with luciferase-labelled donor U87MG or MU20 glioblastoma cells. Four days later, an unlabelled recipient tumor was implanted on the contralateral side. The mice were euthanised at a humane end-point and tissue and blood samples were collected for ex vivo analyses. RESULTS: The ex vivo analyses of the firefly-labelled MU20 tumours displayed extensive invasion at the primary tumour margins, whereas the firefly-labelled U87MG tumours exhibited expansive phenotypes with no evident invasions at the tumour margins. Luciferase signals were detected in the contralateral unlabelled recipient tumours for both the U87MG and MU20 tumours compared to the non-implanted control brain. Remarkably, tumour cells were uniformly detected in all tissue samples of the supratentorial brain region compared to the control tissue, with single tumour cells detected in some tissue samples. Circulating tumour cells were also detected in the blood samples of most of the xenografted mice. Moreover, tumour cells were detected in the lungs of all of the mice, a probable event related to haematogenous dissemination. Similar results were obtained when the U87MG cells were alternatively labelled with gaussian luciferase. CONCLUSIONS: These findings describe a systemic disease model for glioblastoma which can be used to investigate recurrence biology and therapeutic efficacy towards recurrence.

The Prognostic Value of Preoperative Inflammatory Markers for Pathological Grading of Glioma Patients.

Introduction: The independent diagnostic value of inflammatory markers neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) and the diagnostic efficacy of NLR, derived neutrophil to lymphocyte ratio (dNLR), PLR, and lymphocyte-to-monocyte ratio (LMR) in glioma cases remain unclear. We investigated the correlation of preoperative peripheral blood inflammatory markers with pathological grade, Ki-67 Proliferation Index, and IDH-1 gene phenotype in patients with glioma, focusing on tumor grade and prognosis. Methods: We retrospectively analyzed the clinical, pathological, and laboratory data of 334 patients with glioma with varying grades and 345 with World Health Organization (WHO I) meningioma who underwent initial surgery at the Affiliated Hospital of Jining Medical University from December 2019 to December 2021. The diagnostic value of peripheral blood inflammatory markers for glioma was investigated. Results: The proportion of men smoking and drinking was significantly higher in the glioma group than in the meningioma group (P < .05); in contrast, the age and body mass index (Kg/m2) were significantly lower in the glioma group (P = .01). Significant differences were noted in the pathological grade (WHO II, III, and IV), Ki-67 Proliferation Index, and peripheral blood inflammatory markers such as lymphocyte median, NLR, dNLR, and PLR between the groups (P < .05). No significant correlation existed between peripheral blood inflammatory factors and IDH-1 gene mutation status or tumor location in patients with glioma (P > .05). LMR, NLR, dNLR, and PLR, varied significantly among different glioma types (P < .05). White blood cell (WBC) count, neutrophil, NLR, and dNLR correlated positively with glioma risk. Further, WBC, neutrophil, NLR, dNLR, and LMR had a high diagnostic efficiency. Conclusion: Peripheral blood inflammatory markers, serving as noninvasive biomarkers, offer high sensitivity and specificity for diagnosing glioma, differentiating it from meningioma, diagnosing GBM, and distinguishing GBM from low-grade glioma. These markers may be implemented as routine screening tools.

Advances in CRISPR/Cas systems-based cell and gene therapy.

Cell and gene therapy are innovative biomedical strategies aimed at addressing diseases at their genetic origins. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) systems have become a groundbreaking tool in cell and gene therapy, offering unprecedented precision and versatility in genome editing. This chapter explores the role of CRISPR in gene editing, tracing its historical development and discussing biomolecular formats such as plasmid, RNA, and protein-based approaches. Next, we discuss CRISPR delivery methods, including viral and non-viral vectors, followed by examining the various engineered CRISPR variants for their potential in gene therapy. Finally, we outline emerging clinical applications, highlighting the advancements in CRISPR for breakthrough medical treatments.

hERG channel agonist NS1643 strongly inhibits invasive astrocytoma cell line SMA-560.

Gliomas are highly malignant brain tumours that remain refractory to treatment. Treatment is typically surgical intervention followed by concomitant temozolomide and radiotherapy; however patient prognosis remains poor. Voltage gated ion channels have emerged as novel targets in cancer therapy and inhibition of a potassium selective subtype (hERG, Kv11.1) has demonstrated antitumour activity. Unfortunately blockade of hERG has been limited by cardiotoxicity, however hERG channel agonists have produced similar chemotherapeutic benefit without significant side effects. In this study, electrophysiological recordings suggest the presence of hERG channels in the anaplastic astrocytoma cell line SMA-560, and treatment with the hERG channel agonist NS1643, resulted in a significant reduction in the proliferation of SMA-560 cells. In addition, NS1643 treatment also resulted in a reduction of the secretion of matrix metalloproteinase-9 and SMA-560 cell migration. When combined with temozolomide, an additive impact was observed, suggesting that NS1643 may be a suitable adjuvant to temozolomide and limit the invasiveness of glioma.

Interleukin-11/IL-11 Receptor Promotes Glioblastoma Cell Proliferation, Epithelial-Mesenchymal Transition, and Invasion.

Glioblastoma is highly proliferative and invasive. However, the regulatory cytokine networks that promote glioblastoma cell proliferation and invasion into other areas of the brain are not fully defined. In the present study, we define a critical role for the IL-11/IL-11Rα signalling axis in glioblastoma proliferation, epithelial to mesenchymal transition, and invasion. We identified enhanced IL-11/IL-11Rα expression correlated with reduced overall survival in glioblastoma patients using TCGA datasets. Proteomic analysis of glioblastoma cell lines overexpressing IL-11Rα displayed a proteome that favoured enhanced proliferation and invasion. These cells also displayed greater proliferation and migration, while the knockdown of IL-11Rα reversed these tumourigenic characteristics. In addition, these IL-11Rα overexpressing cells displayed enhanced invasion in transwell invasion assays and in 3D spheroid invasion assays, while knockdown of IL-11Rα resulted in reduced invasion. Furthermore, IL-11Rα-overexpressing cells displayed a more mesenchymal-like phenotype compared to parental cells and expressed greater levels of the mesenchymal marker Vimentin. Overall, our study identified that the IL-11/IL-11Rα pathway promotes glioblastoma cell proliferation, EMT, and invasion.