Glioma Cancer Research Articles

Discovery of novel antibody-drug conjugates bearing tissue protease specific linker with both anti-angiogenic and strong cytotoxic effects

Bevacizumab is an FDA-approved class of monoclonal antibodies used to inhibit angiogenesis and promote normalization of blood vessels. It is usually combined with chemotherapeutic agents to treat a variety of solid tumors. However, the whole-body toxicities and toxicity associated with chemotherapy greatly limit the clinical use of this combination therapy. Antibody-drug conjugates (ADCs) couple monoclonal antibodies to cytotoxic molecules via a linker, utilizing the high specificity of monoclonal antibodies to tumor surface antigens to act as a “biological missile” to deliver chemotherapeutic drugs to the tumor site. Herein, we designed a bevacizumab-based ADC, Bevacizumab Vedotin, conjugating bevacizumab to the microtubulin inhibitor MMAE via a tissue protease-specific linker. Biological studies showed strong stability and good tumor cell targeting of our constructed ADCs; rapid drug release was achieved in the presence of exogenous histone protease B. In addition, Bevacizumab Vedotin exhibited good anti-proliferative, apoptosis-promoting and cell cycle-stalling effects on glioma (U87), hepatocellular carcinoma (HepG2), and breast cancer (MCF-7) cell lines. Further in vitro assays demonstrated the enhanced anti-migration activity against MCF-7, potent anti-angiogenic effects, and blockade of the VEGF/VEGFR pathway of Bevacizumab Vedotin.

Magnetohyperthermia-synergistic glioma cancer therapy enabled by magnetic graphene oxide nanoheaters: promising nanostructure for in vitro and in vivo applications

In the present study, a magnetohyperthermia (MH)-based therapy is introduced as an effective treatment for deep-seated tumors especially glioma, which combines the magnetothermal effect and the reactive oxygen species (ROS) induced with magnetic graphene oxide (GOMNPs) nanoheaters to overcome the issue of limited therapeutic efficacy in the current magnetothermal therapeutic strategy. Magnetic graphene oxide nanoheaters with a size of 34 nm and a surface charge of − 35 mV showed very little toxicity under in vitro and ex vivo circumstances based on MTT and hemolysis assay, respectively. The application of GOMNPs under an alternating magnetic coil (AMC) showed that they had high specific absorption rate (SAR, P < 0.01), with enhanced level of ROS production within the tumor microenvironment. The results confirmed a significant increase in the SAR in blood compared to culture media (P < 0.01), which indicates the improvement of magnetohyperthermia performance in in vivo conditions compared to in vitro. A significant therapeutic efficacy was achieved with a dosage of 30 mg/kg of GOMNPs following 3 therapeutic courses under alternating magnetic field (AMF) compared to AMF alone (P < 0.05). GOMNPs exhibited a strong anti-glioma effect by inhibiting tumor growth, and increasing the survival ratio by inducing apoptotic cell death (P < 0.05). The Bax/Bcl2 protein and gene ratio confirmed a higher rate of apoptotic death in the MH-treated group (P < 0.05). Combination of magnetohyperthermia with conventional modalities may offer tremendous clinical advantages compared to the currently available methods.Graphical

FAM129A promotes self-renewal and maintains invasive status via stabilizing the Notch intracellular domain in glioma stem cells.

Glioma stem cells (GSCs) are a subpopulation of tumor cells with self-renewal and tumorigenic capabilities in glioblastomas (GBMs). Diffuse infiltration of GSCs facilitates tumor progression and frustrates efforts at effective treatment. Further compounding this situation is the currently limited understanding of what drives GSC invasion. Here we comprehensively evaluated the significance of a novel invasion-related protein, Family with Sequence Similarity 129 Member A (FAM129A), in infiltrative GSCs. Western blotting, immunohistochemistry, and gene expression analysis were used to quantify FAM129A in glioma specimens and cancer datasets. Overexpression and knockdown of FAM129A in glioma stem cells were used to investigate its effects on tumor growth and invasion. RNA-seq, qRT-PCR, western blotting, and co-precipitation assays were used to investigate FAM129A signaling mechanisms. FAM129A is preferentially expressed in invasive frontiers. Targeting FAM129A impairs GSC invasion and self-renewal. Mechanistically, FAM129A acted as a positive regulator of Notch signaling by binding with the Notch1 intracellular domain (NICD1) and preventing its degradation. FAM129A and NICD1 provide a precise indicator for identifying tumor margins and aiding prognosis. Targeting them may provide a significantly therapeutic strategy for GSCs.

Finite sample and asymptotic distributions of a statistic for sufficient follow‐up in cure models

AbstractThe existence of immune or cured individuals in a population and whether there is sufficient follow‐up in a sample of censored observations on their lifetimes to be confident of their presence are questions of major importance in medical survival analysis. Here we give a detailed analysis of a statistic designed to test for sufficient follow‐up in a sample. Assuming an i.i.d. censoring model, we obtain exact finite‐sample and asymptotic distributions for the statistic, and use these to calculate the power of a test based on it. A particularly useful finding is that the asymptotic distribution of the test statistic is parameter‐free in the null case when follow‐up is insufficient. The methods are illustrated with application to a glioma cancer dataset.

Flavonoids as Strong Inhibitors of MAPK3: A Computational Drug Discovery Approach.

Mitogen-activated protein kinase 3 (MAPK3) mediates the onset, progression, metastasis, drug resistance, and poor prognosis in various malignancies, including glioma, liver, ovarian, thyroid, lung, breast, gastric, and oral cancers. Negative regulation of MAPK3 expression using miRNAs has led to therapeutic effects in cancer. The present study performed molecular docking and dynamics simulation to identify potential MAPK3 inhibitors from natural flavonoids, possibly leading to drug development in cancer therapy. A computational drug discovery approach was performed using the AutoDock tool to identify potential MAPK3 inhibitors from 46 plant-based flavonoids. A cross-validation study was executed using the Schrödinger Maestro docking tool. Molecular dynamics (MD) was executed to evaluate the stability of docked poses between the top-ranked compounds and the MAPK3 catalytic domain. Interactions among the most potent MAPK3 inhibitors and residues within the receptor's active site were studied using the BIOVIA Discovery Studio Visualizer before and after 100 ns MD simulations. Kaempferol 3-rutinoside-4'-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 exhibited a magnificent binding affinity to the receptor's active site. In addition, the stability of the docked poses of these compounds seemed to be stable after ∼45 ns computer simulations. The present study suggests that kaempferol 3-rutinoside-4'-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 could strongly bind to the MAPK3 catalytic site and could be assigned as a potent inhibitor for MAPK3. These findings may be helpful in the treatment of various cancers. However, further validation experiments are needed.

Cancer Cell-Specific Fluorescent Prodrug Delivery Platforms.

Targeting cancer cells with high specificity is one of the most essential yet challenging goals of tumor therapy. Because different surface receptors, transporters, and integrins are overexpressed specifically on tumor cells, using these tumor cell-specific properties to improve drug targeting efficacy holds particular promise. Targeted fluorescent prodrugs not only improve intracellular accumulation and bioavailability but also report their own localization and activation through real-time changes in fluorescence. In this review, efforts are highlighted to develop innovative targeted fluorescent prodrugs that efficiently accumulate in tumor cells in different organs, including lung cancer, liver cancer, cervical cancer, breast cancer, glioma, and colorectal cancer. The latest progress and advances in chemical design and synthetic considerations in fluorescence prodrug conjugates and how their therapeutic efficacy and fluorescence can be activated by tumor-specific stimuli are reviewed. Additionally, novel perspectives are provided on strategies behind engineered nanoparticle platforms self-assembled from targeted fluorescence prodrugs, and how fluorescence readouts can be used to monitor the position and action of the nanoparticle-mediated delivery of therapeutic agents in preclinical models. Finally, future opportunities for fluorescent prodrug-based strategies and solutions to the challenges of accelerating clinical translation for the treatment of organ-specific tumors are proposed.

Abstract 2967: Preclinical development of a B7-H3-targeting ADC with a novel DNA topoisomerase I inhibitor for solid tumors

Abstract Introduction: B7-H3 (CD276) is an immunomodulatory protein of the B7 superfamily molecules, it is overexpressed in a wide range of solid tumors. B7-H3 overexpression often correlates with poor survival and higher tumor grade, it has become an attractive target for the development of novel cancer therapies recently. B7-H3 targeting antibody-drug conjugates (ADCs), such as MGC018 and DS7300a, have shown preliminary clinical efficacy. DB-1311 is a B7-H3 targeting ADC comprised of a humanized B7-H3 antibody conjugated to a novel DNA topoisomerase I inhibitor P1021 via a cleavable linker. We herein report preclinical efficacy and safety data of DB-1311 and its differentiation from DS7300a. Methods: The binding of anti-B7-H3 to other B7 family members were evaluated via ELISA and SPR. Anti-B7-H3 antibody was conjugated to P1021 with different Drug-Antibody-Ratio (DAR) values. The efficacy of B7-H3 ADCs with different DAR values was tested in vivo, pharmacokinetics and safety profile were evaluated in cynomolgus monkeys. Based on potency and toxicity analysis, DB-1311, an ADC with DAR6, was selected for preclinical development. In vitro and in vivo studies were then conducted with DB-1311 to further investigate its pharmacological effects. Results: B7-H3 antibody with DAR6 demonstrated higher efficacy than its DAR4 counterpart in lung cancer (Calu6), glioma(U87MG) and prostate cancer (PC-3) models. In monkeys, the DAR6 ADC showed good stability and dose-proportionally increased exposure. Additionally, it was well tolerated with repeat dose administration up to 80 mg/kg and didn’t show significantly worse toxicities than DAR4 counterpart. In preclinical study, DB-1311 demonstrated specific, dose-dependent cytotoxicity toward B7-H3-positive tumor cell lines in vitro and potent antitumor activity in vivo but minimum tumor growth inhibition activity in a B7-H3 negative xenograft model. Moreover, DB-1311 showed more potent antitumor activity than DS7300a analogue in vitro and in vivo. Conclusions: DB-1311, a preclinical B7-H3 ADC candidate, with a DAR value of approximately 6, exhibited potent cytotoxicity in vitro and antitumor activity in vivo toward a range of B7-H3-expressing tumor cell lines representing several cancer types and was well tolerated in cynomolgus monkeys with promising pharmacokinetics characteristics. The preclinical antitumor activity and safety profile warrants further development of DB-1311 to evaluate its efficacy and safety in clinical studies. Citation Format: Chenggang Li, Jun Yao, Chen Qu, Bing Li, Yu Zhang, Rong Shi, Yang Qiu, Haiqing Hua. Preclinical development of a B7-H3-targeting ADC with a novel DNA topoisomerase I inhibitor for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2967.

Abstract 4789: Spin oscillating magnetic field sOMF of oncomagnetic device selectively kills glioma cancer cells by inducing oxidative stress and DNA damage

Abstract A new noninvasive therapeutic device developed in our laboratory called the Oncomagnetic device provides a novel approach to glioblastoma (GBM) treatment. It involves repeated stimulation with oscillating magnetic fields (sOMF) produced by spinning permanent magnets. It is technologically and mechanistically distinct from the Optune® device approved by the FDA for the treatment of newly diagnosed and recurrent GBM. Use of this device in end-stage GBM patients reversed the progression of their recurrent tumor causing &amp;gt;30% reduction in its contrast-enhanced volume within 4-6 weeks of treatment. Mice with implanted mouse glioma cells in their brains also showed marked reduction in tumor size, increased survival (p&amp;lt; 0.05, n = 10) and higher DNA damage (γ-H2AX foci) after sOMF treatment with a whole-body stimulation method developed by us. Normal mice exposed to sOMF for 4 months had no adverse effects on the brain and other organs. In-vitro, sOMF markedly increased reactive oxygen species (ROS) levels in cancer cells leading to the selective death of these cells, while sparing normal neurons and astrocytes. Detection of γ-H2AX and 53BP1 foci showed that sOMF caused significant DNA damage in GBM cells and diffuse intrinsic pontine glioma (DIPG) cells but not in normal astroglial SVGp12 cells. Furthermore, sOMF exposure for just 2 h resulted in &amp;gt;40% loss of surviving GBM and DIPG cell colonies detected by clonogenic cell survival assay, similar to that produced by 2 Gy radiation dose. This loss was rescued by the antioxidant Trolox. These results indicate that sOMF stimulation has high anticancer potency comparable to low dose radiation therapy at the cellular level with an underlying mechanism of action that is substantially different from that proposed for Optune® TTF. Citation Format: Shashank Hambarde, Arvind Pandey, David S. Baskin, Santosh A. Helekar. Spin oscillating magnetic field sOMF of oncomagnetic device selectively kills glioma cancer cells by inducing oxidative stress and DNA damage. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4789.

466 Robust Model of Microglia Replacement With Circulation-Derived Microglia-Like Cells (CDMCs) in CNS Malignancies

INTRODUCTION: Tumor-associated microglia and macrophages (TAMs) represent a main cell type of brain malignancies and demonstrate complex interactions with cancerous cells and the tumor microenvironment. These interactions have important implications for the progression and treatment of malignant central nervous system (CNS) tumors. TAMs have therefore emerged as therapeutic targets, though their potential to date has been unfulfilled. METHODS: C57BL/6 mice were preconditioned for BMT with retroorbital busulfan injections (25 mg/kg), and native microglia were depleted via PLX5622 (1200 mg/kg, chow). Following transplantation, animals underwent intracranial stereotactic injection of syngeneic cell lines of either high-grade glioma (GL261) or breast cancer metastasis (E0771). Following animal sacrifice, we used single cell RNA sequencing of CD45-positive cells to profile the transcriptomic identity of glioma tumor-associated CDMCs (TA-CDMCs). RESULTS: Lineage tracing proved high intra- and peri-tumoral chimerism of BMT-graft derived cells among CNS myeloid cells in both models two weeks after tumor cell injection, demonstrating a robust ability to modify the tumor-immune microenvironment in animal models. TA-CDMCs showed a similarly activated morphology as naÏve TAMs under immunohistochemistry. Pathway enrichment analysis revealed an upregulation of immune response pathways in TA-CDMCs compared to regular TAMs, including the overexpression of genes relevant for the regulation of T cell activation, suggesting possible modification of the glioma immune-environment following CDMC repopulation. CONCLUSIONS: The present study offered a robust proof-of-concept that highly efficient TAM replacement could be achieved in orthotopic murine brain tumor models. Additionally, it appears that replaced CDMCs retain unique transcriptional patterns in the tumor-immune microenvironment, with the upregulation of several key immune response pathways. These efforts may represent a novel route of tumor-directed immunotherapy and offer exciting opportunities for ex-vivo CDMC manipulation to specifically target neoplastic cells.

Deciphering the role of QPCTL in glioma progression and cancer immunotherapy.

Glioma is the most lethal and most aggressive brain cancer, and currently there is no effective treatment. Cancer immunotherapy is an advanced therapy by manipulating immune cells to attack cancer cells and it has been studied a lot in glioma treatment. Targeting the immune checkpoint CD47 or blocking the CD47-SIRPα axis can effectively eliminate glioma cancer cells but also brings side effects such as anemia. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the pyroglutamylation of CD47 and is crucial for the binding between CD47 and SIRPα. Further study found that loss of intracellular QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. However, the role of QPCTL in glioma and the relationship between its expression and clinical outcomes remains unclear. Deciphering the role of QPCTL in glioma will provide a promising therapy for glioma cancer immunotherapy. QPCTL expression in glioma tissues and normal adjacent tissues was primarily analyzed in The Cancer Genome Atlas (TCGA) database, and further validated in another independent cohort from the Gene Expression Omnibus (GEO) database, Chinese Glioma Genome Atlas (CGGA), and Human Protein Atlas (HPA). The relationships between QPCTL expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which QPCTL interacted was built using the online STRING website. Meanwhile, we use Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to investigate the relationships between QPCTL expression and infiltrated immune cells and their corresponding gene marker sets. We analyzed the Differentially Expressed Genes (DEGs) including GO/KEGG and Gene Set Enrichment Analysis (GSEA) based on QPCTL-high and -low expression tumors. In contrast to normal tissue, QPCTL expression was higher in glioma tumor tissue (p < 0.05). Higher QPCTL expression was closely associated with high-grade malignancy and advanced tumor stage. Univariate and multivariate analysis indicated the overall survival of glioma patients with higher QPCTL expression is shorter than those with lower QPCTL expression (p < 0.05). Glioma with QPCTL deficiency presented the paucity of infiltrated immune cells and their matching marker sets. Moreover, QPCTL is essential for glioma cell proliferation and tumor growth and is a positive correlation with glioma cell stemness. High QPCTL expression predicts high grades of gliomas and poor prognosis with impaired infiltration of adaptive immune cells in the tumor microenvironment as well as higher cancer stemness. Moreover, targeting QPCTL will be a promising immunotherapy in glioma cancer treatment.

Preclinical Activity of 4-Demethyl-4-cholesteryloxycarbonylpenclomedine in Melanoma.

Temozolomide plays a role in treating melanoma refractory to immunomodulatory and mitogen-activated protein kinase-targeted approaches, but its efficacy is limited. 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a polychlorinated pyridine cholesteryl carbonate. Its mechanism of action is considered to be via alkylation/adduct formation with N7-guanine. It demonstrated activity in intracranial implanted human glioma and breast cancer xenograft mouse models. The activity of DM-CHOC-PEN in melanoma models was assessed. B-16 melanoma cells were exposed to DM-CHOC-PEN at different concentrations to assess proliferation and survival. B-16 cells were implanted subcutaneously into the flank of adult female C57BL mice which were then were treated with 200 mg/kg DM-CHOC-PEN intraperitoneally daily for 5 days in the setting of palpable subcutaneous tumor. Survival was compared to mice treated with temozolomide or saline. Five mice were treated per group. In vitro, the respective half-maximal inhibitory concentrations of DM-CHOC-PEN and temozolomide were 0.5 and ≥3.0 μg/ml. Floating, heavily melanotic cells formed and these cells were separated, analyzed, and contained 10-90 ng DM-CHOC-PEN per 105 cells. The improvement in survival of mice treated with DM-CHOC-PEN or temozolomide relative to saline controls was 142% and 78%, respectively. Longer survival was seen with DM-CHOC-PEN in a C57BL murine model relative to temozolomide and saline-treated controls, supporting the development of clinical trials assessing the efficacy of DM-CHOC-PEN as treatment for metastatic melanoma.

Study of MDM2 as Prognostic Biomarker in Brain-LGG Cancer and Bioactive Phytochemicals Inhibit the p53-MDM2 Pathway: A Computational Drug Development Approach.

An evaluation of the expression and predictive significance of the MDM2 gene in brain lower-grade glioma (LGG) cancer was carried out using onco-informatics pipelines. Several transcriptome servers were used to measure the differential expression of the targeted MDM2 gene and search mutations and copy number variations. GENT2, Gene Expression Profiling Interactive Analysis, Onco-Lnc, and PrognoScan were used to figure out the survival rate of LGG cancer patients. The protein-protein interaction networks between MDM2 gene and its co-expressed genes were constructed by Gene-MANIA tool. Identified bioactive phytochemicals were evaluated through molecular docking using Schrödinger Suite Software, with the MDM2 (PDB ID: 1RV1) target. Protein-ligand interactions were observed with key residues of the macromolecular target. A molecular dynamics simulation of the novel bioactive compounds with the targeted protein was performed. Phytochemicals targeting MDM2 protein, such as Taxifolin and (-)-Epicatechin, have been shown with more highly stable results as compared to the control drug, and hence, concluded that phytochemicals with bioactive potential might be alternative therapeutic options for the management of LGG patients. Our once informatics-based designed pipeline has indicated that the MDM2 gene may have been a predictive biomarker for LGG cancer and selected phytochemicals possessed outstanding interaction results within the macromolecular target's active site after utilizing in silico approaches. In vitro and in vivo experiments are recommended to confirm these outcomes.

Radiosensitivity Index is Not Fit to be Used for Dose Adjustments: A Pan-Cancer Analysis

AimsTo explore the preclinical and latest clinical evidence of the radiation sensitivity signature termed ‘radiosensitivity index’ (RSI), to assess its suitability as an input into dose-adjustment algorithms. Materials and methodsThe original preclinical test-set data from the publication where RSI was derived were collected and reanalysed by comparing the observed versus predicted survival fraction at 2 Gy (SF2). In addition, the predictive capability of RSI was also compared to random guessing. Clinical data were collected from a recently published dataset that included RSI values, overall survival outcomes, radiotherapy dose and tumour site for six cancers (glioma, triple-negative breast, endometrial, melanoma, pancreatic and lung cancer). Cox proportional hazards models were used to assess: (i) does adjusting for RSI elucidate a dose response and (ii) does an interaction between RSI and dose exist with good precision. ResultsPreclinically, RSI showed a negative correlation (Spearman's rho = –0.61) between observed and predicted SF2, which remained negative after removing leukaemia cell lines. Furthermore, random guesses showed better correlation to SF2 than RSI, 98% of the time on the full dataset and 80% after removing leukaemia cell lines. The preclinical data show that RSI does not explain the variance in SF2 better than random guessing. Clinically, a dose response was not seen after adjusting for RSI (hazard ratio = 1.00, 95% confidence interval 0.97–1.04; P = 0.876) and no evidence of an interaction between RSI and dose was found (P = 0.844). ConclusionsThese results suggest that RSI does not explain a sufficient amount of the outcome variance to be used within dose-adjustment algorithms.

The Investigation of the Chemical Composition and Applicability of Gold Nanoparticles Synthesized with Amygdalus communis (Almond) Leaf Aqueous Extract as Antimicrobial and Anticancer Agents

The current work's main objective was to determine the chemical composition of Amygdalus communis (AC) leaf extract and examine the antibacterial and cytotoxic properties of biosynthesized gold nanoparticles (AuNPs). The chemical composition of AC leaf extract was determined using LC-ESI/MS/MS to detect compounds that may be responsible for the reducing, stabilizing, and capping steps in the synthesis of nanoparticles and their biological activities. The AC-AuNPs were spherical, with a particle size lower than 100 nm and a face-centered cubic structure. The EDX spectrum confirmed the formation of AuNPs and a negative zeta potential value (-27.7 mV) suggested their physicochemical stability. The in vitro cytotoxic efficacy of the AC-AuNPs against colorectal adenocarcinoma (Caco-2), glioma (U118), and ovarian (Skov-3) cancer cell lines and human dermal fibroblasts (HDFs) was evaluated by MTT assay. CaCo-2 cell proliferation was effectively inhibited by the AC-AuNPs at concentrations between 25 and 100 g mL-1. The AC-AuNPs exerted preeminent antimicrobial activity against Bacillus subtilis with an MIC of 0.02 μg/mL, whilst good activity was shown against Staphylococcus aureus bacteria and Candida albicans yeast with an MIC of 0.12 μg/mL. Ultimately, the results support the high antibacterial and anticancer potential of biosynthesized AuNPs from AC leaf extract.

Hierarchical multimodal fusion framework based on noisy label learning and attention mechanism for cancer classification with pathology and genomic features.

Classification of subtype and grade is imperative in the clinical diagnosis and prognosis of cancer. Many deep learning-based studies related to cancer classification are based on pathology and genomics. However, most of them are late fusion-based and require full supervision in pathology image analysis. To address these problems, we present an integrated framework for cancer classification with pathology and genomics data. This framework consists of two major parts, a weakly supervised model for extracting patch features from whole slide images (WSIs), and a hierarchical multimodal fusion model. The weakly supervised model can make full use of WSI labels, and mitigate the effects of label noises by the self-training strategy. The generic multimodal fusion model is capable of capturing deep interaction information through multi-level attention mechanisms and controlling the expressiveness of each modal representation. We validate our approach on glioma and lung cancer datasets from The Cancer Genome Atlas (TCGA). The results demonstrate that the proposed method achieves superior performance compared to state-of-the-art methods, with the competitive AUC of 0.872 and 0.977 on these two datasets respectively. This paper establishes insight on how to build deep networks on multimodal biomedical data and proposes a more general framework for pathology image analysis without pixel-level annotation.

Fabrication of Etoposide-loaded superparamagnetic iron oxide nanoparticles (SPIONs) induced apoptosis in glioma cancer cells

Recent research has shown that etoposide (ETP), an immunomodulatory medication, can have cytotoxic effects. When accompanied by nano-drug delivery, this possibility can lead to a more effective treatment for cancer. This study involved the delivery of ETP via PDA@SPIONs (termed as ETP-PDA@SPIONs), which are superparamagnetic iron oxide nanoparticles (SPIONs) that have been coated with polydopamine (PDA) and utilized to treat C6 and U87 glioma cancer cell lines. The particle diameter, polydispersive index (PDI), zeta potential, and shape of nanoparticles were determined. The fabricated nanoparticles had a mean particle size of 164 ± 7 nm and a − 37 ± 3 mv zeta potential. Cell lines were tested for sensitivity to PDA@SPIONs, free-ETP, and ETP-PDA@SPIONs. On the cell lines, we tested the proliferation of PDA@SPIONs, free-ETP, and PDA@SPIONs loaded with ETP. The cytotoxicity of ETP-PDA@SPIONs was substantially higher than that of free-ETP-treated cells. The cells' morphological changes were examined by dual staining (acridine orange/ethidium bromide, AO/EB) and nuclear staining methods. Interestingly, this inhibitory impact was not ascribed to the known cellular membrane destruction, cell membrane damage, and reactive oxygen species (ROS). Further tests demonstrated that the nanoparticles substantially impacted mitochondrial functioning, resulting in an aberrant mitochondrial shape, and reduced mitochondrial membrane potential (MMP). Future studies into glioma cancer therapy may want to investigate using the proposed ETP-loaded nanoparticles.

MGFFCNN: Two‐dimensional matrix spectroscopy combined with multi‐channel gradient feature fusion convolutional neural network means to diagnose glioma and esophageal cancer patients

AbstractCurrently, glioma and esophageal cancer are common malignant tumors worldwide with low cure rate and high mortality rate, and they endanger human health seriously. In this study, we analyzed the correlation and difference between glioma and esophageal cancer through serum mid‐infrared and Raman spectra and established a multi‐channel gradient feature fusion convolutional neural network to achieve rapid diagnosis of glioma and esophageal cancer patients. We transformed the spectra from one‐dimensional matrix to two‐dimensional matrix form separately as the input of the network and fused the features extracted from the Flatten layer of the network. First, we fused the features of mid‐infrared and Raman spectra and constructed a two‐channel gradient feature fusion idea. Then, in order to enrich the learning of features further, we took the first‐order derivative of mid‐infrared and Raman original spectra, respectively, and used the derivative spectra as two channels as well. The mid‐infrared and Raman spectra in two‐dimensional matrix form were fused with their derivative spectral features, respectively, and the fused features were fused again to construct a four‐channel gradient feature fusion network model. Finally, compared with the single original spectrum and the one‐dimensional matrix feature fusion spectrum, the two‐dimensional matrix feature fused spectrum was more advantageous, and the classification accuracy of the model was as high as 99.2% ± 0.7%. This study showed that two‐dimensional matrix spectra combined with multi‐channel gradient feature fusion technique had great potential for rapid and accurate identification of patients with glioma and esophageal cancer.

Psychosocial factors associated with workability after surgery in cancer survivors: An explorative study.

This study aimed to evaluate the work ability and its associated factors in patients with glioma (II, III) and breast cancer after 6 (T0) and 12 (T1) months from surgery. A total of 99 patients were evaluated with self-reported questionnaires at T0 and T1. Correlation and Mann-Whitney tests were used to investigate the association between work ability and sociodemographic, clinical, and psychosocial factors. The Wilcoxon test was used to investigate the longitudinal change in work ability. Our sample showed a decrease in work ability level between T0 and T1. Work ability was associated with emotional distress, disability, resilience, and social support in glioma III patients at T0, and with fatigue, disability, and clinical treatments in patients with breast cancer at T0 and T1. Work ability levels decreased in patients with glioma and breast cancer and were associated with different psychosocial factors after surgery. Their investigation is suggested to facilitate the return to work.

Bio-fabrication of gold nanoparticles from brown seaweeds for anticancer activity against glioblastoma through invitro and molecular docking approaches

This research aimed to investigate the mechanism of glioblastoma-killing action of brown seaweed Spatoglossum asperum fabricated gold nanoparticles (Sa-AuNPs) as a novel medication. UV spectroscopy revealed the surface plasmon resonance peak at 530 nm for the stability of bio-fabricated Sa-AuNPs. The XRD and SEM analysis affirmed the Sa-AuNPs were crystalline condition and cubic shapes with 20 nm size. The reducing and capping agents of organic compounds present in the Sa-AuNPs were identified by FTIR, NMR and Mass spectroscopic analysis. In addition, Sa-AuNPs showed excellent antioxidant activity through maximum inhibition of DPPH radicals (73.21%) and hydrogen peroxide radicals (68.9%). The biosynthesized Sa-AuNPs showed potent cytotoxic activity against LN-18 Glioblastoma cells (IC50 = 13.38 μg/mL). Furthermore, 11 genes involved in glioma cancer (as protein) and 10 compounds in the S. asperum (as Ligand) were picked for molecular docking. The docking result showed, among the 10 selected compounds, stigmast-5-en-3-ol has an effective binding affinity with 11 genes and effectively targeted EGFR, IDH and PTEN. This study concludes that Sa-AuNPs have potent antioxidant and anticancer activity due to the presence of bioactive molecules involved in the nanoparticle's reduction process. The research provides strong support for the prospective development of innovative treatments for glioblastoma.

Opportunities and Challenges for the Development of MRCK Kinases Inhibitors as Potential Cancer Chemotherapeutics.

Cytoskeleton organization and dynamics are rapidly regulated by post-translational modifications of key target proteins. Acting downstream of the Cdc42 GTPase, the myotonic dystrophy-related Cdc42-binding kinases MRCKα, MRCKβ, and MRCKγ have recently emerged as important players in cytoskeleton regulation through the phosphorylation of proteins such as the regulatory myosin light chain proteins. Compared with the closely related Rho-associated coiled-coil kinases 1 and 2 (ROCK1 and ROCK2), the contributions of the MRCK kinases are less well characterized, one reason for this being that the discovery of potent and selective MRCK pharmacological inhibitors occurred many years after the discovery of ROCK inhibitors. The disclosure of inhibitors, such as BDP5290 and BDP9066, that have marked selectivity for MRCK over ROCK, as well as the dual ROCK + MRCK inhibitor DJ4, has expanded the repertoire of chemical biology tools to study MRCK function in normal and pathological conditions. Recent research has used these novel inhibitors to establish the role of MRCK signalling in epithelial polarization, phagocytosis, cytoskeleton organization, cell motility, and cancer cell invasiveness. Furthermore, pharmacological MRCK inhibition has been shown to elicit therapeutically beneficial effects in cell-based and in vivo studies of glioma, skin, and ovarian cancers.