Glioblastoma (GBM) is the most common malignant brain tumor in adults. Despite advancements in treatment, the prognosis for patients with GBM remains poor due to its aggressive nature and resistance to therapy. CRISPR-based genetic screening has emerged as a powerful tool for identifying genes crucial for tumor progression and treatment resistance, offering promising targets for tumor therapy. In this review, we provide an overview of the recent advancements in CRISPR-based genetic screening approaches and their applications in GBM. We highlight how these approaches have been used to uncover genetic determinants of GBM progression and susceptibility to various therapies. Furthermore, we discuss ongoing challenges and future directions of CRISPR-based screening methods in advancing GBM research.

Refractory materials are used worldwide in process equipment. However, gaseous and liquid process products penetrate the surface layer, and deep into the volume of refractories destructing rather expensive constructions complicated to repair. To address this challenge, there is a need to develop protective coatings for refractory that can limit the penetration of working media and extend their operational lifespan. In this work, the application of gas-dynamic cold spraying (CGDS) to produce a coating on the refractory using fine titanium dioxide (TiO2) particles is explored. These particles are accelerated within a nitrogen flow, passing through a Laval nozzle, and then sprayed onto a fireclay surface. The mechanisms of particle deposition and layer formation on porous surfaces through experiments and numerical simulations were investigated. The geometry of a typical refractory pore was determined, which was then incorporated into Computational Fluid Dynamics (CFD) simulations to model the cold spraying process of porous substrates. As a result, the influence of the particle size on its velocity and angle of penetration into pores was established. Experimental findings demonstrate the effective closure of pores and the formation of a particle layer on the refractory surface. Furthermore, the nanoindentation tests for the refractory samples showcase capabilities for checking coating thickness for porous materials.

Glioblastoma is the most common and malignant primary brain tumor. Despite a century of research efforts, the survival of patients has not significantly improved. Currently, diagnosis is based on neuroimaging techniques followed by histopathological and molecular analysis of resected or biopsied tissue. A recent paradigm shift in diagnostics ranks the molecular analysis of tissue samples as the new gold standard over classical histopathology, thus correlating better with the biological behavior of glioblastoma and clinical prediction, especially when a tumor lacks the typical hallmarks for glioblastoma. Liquid biopsy aims to detect and quantify tumor-derived content, such as nucleic acids (DNA/RNA), circulating tumor cells (CTC), or extracellular vesicles (EV) in biofluids, mainly blood, cerebrospinal fluid (CSF), or urine. Liquid biopsy has the potential to overcome the limitations of both neuroimaging and tissue-based methods to identify early recurrence and to differentiate tumor progression from pseudoprogression, without the risks of repeated surgical biopsies. This review highlights the origins and time-frame of liquid biopsy in glioblastoma and points to recent developments, limitations and challenges of adding liquid biopsy to support the clinical management of glioblastoma patients.

Glioblastoma (GBM) is the most common malignant primary brain tumor, with a median survival rate of less than two years. Currently, there is no cure for GBM, underscoring the urgent need for innovative treatment approaches. Vaccine design emerges as a crucial strategy, offering a safe and effective means for both preventive and therapeutic interventions against GBM. In this study, we targeted four GBM-associated mutated surface proteins—urokinase plasminogen activator sur-face receptor (PLAUR), integrin beta-3 (ITGB3), and the B-41 alpha chain (HLA-B) and A-24 alpha chain (HLA-A) of the HLA class I histocompatibility antigens—to design a peptide-based vaccine. The vaccine construct includes cytotoxic T lymphocyte (CTL) and T helper cell (Th cell) epitopes, and was meticulously evaluated for antigenicity, allergenicity, and toxicity. The results indicate that the vaccine is antigenic and non-allergenic, making it a promising candidate. Additionally, the physico-chemical properties of the vaccine suggest stability and suitability for further de-velopment. Immune simulation studies predict efficient immune responses upon vaccine ad-ministration. Our vaccine shows promise as a potential tool in the fight against GBM, offering new hope for patients facing this devastating disease.

Glioblastoma (GB) is the most aggressive and prevalent glioma within the Central Nervous System. GB exhibit a dismal 5-year survival rate (~6%) due to unfavorable prognosis and lack of viable treatment options. Therefore, novel therapies with plant-derived compounds emerge as very promising. This study aims to investigate the antitumor activity of 7α-acetoxy-6β-hydroxyroyleanone (Roy) in GB cell lines. Roy was isolated from Plectranthus hadiensis Schweinf. and its antitumor mechanism was assessed in a panel of five GB cell lines to mimic tumor heterogeneity. Metabolic activity was evaluated by Alamar Blue® assay, while cell death, cell cycle regulation, mitochondrial membrane potential, and activated caspase-3 were evaluated by flow cytometry. mRNA levels of target genes were measured by qPCR and protein expression was assessed by Western blotting. Cell uptake and impact on mitochondrial morphology were evaluated by confocal microscopy. Roy induced G2/M cell cycle arrest, mitochondrial fragmentation, and apoptosis by inhibiting the expression of anti-apoptotic proteins and increasing activated caspase-3 levels with concentration 6-9 fold lower than those of temozolomide, the first-line treatment. Roy demonstrated a robust antitumor activity against GB cells, without affecting non tumoral cells (microglia and astrocytes), being a promising natural lead compound for the development of novel chemotherapeutic approaches.

To elucidate mesenchymal stromal cells (MSC)-tumor intricate and ambiguous interactions, the reliable cell labeling and tracking techniques are imperative. Traditional methods of cell labelling have limitations mostly relevant to need for genetic modification what demands the exploration for alternative strategies. Here, we propose using fluorescent photoconvertible microcapsules containing Rhodamine B (RhB) to study mMSC migration in brain tumors. These 3 μm sized microcapsules are readily internalised by cells and undergo photoconversion under 561 nm laser exposure with fluorescence blue shift on demand. Optimal photoconversion was achieved with a laser irradiation duration of 0.4 ms, which provide a maximal brightness of photoconverted label without an excessive laser exposure on cells. Capsules modified with polyallylamine hydrochloride demonstrated the best potential for intracellular uptake without significantly affecting cell viability, motility, or proliferation. The optimal ratio of 20 capsules per mMSC was determined for labeling. Moreover, migration of individual mMSCs within 2D and 3D glioblastoma cell (EPNT-5) colonies over 2 days and in vivo tumor settings over 7 days was tracked. Our study unveils a robust platform for investigating MSC-tumor dynamics, offering insights into therapeutic strategies. Photoconvertible microcapsules could also become an indispensable tool for studying complex fundamental processes of cell-cell interactions for a wide range of problems in biology and medicine.

Cohesion in the refractory metals Cr, Mo, and W is phenomenologically described in this work via a n-body energy functional with a set of physically motivated parameters that were optimized to reproduce selected experimental properties characteristic of perfect and defective crystals. The functional contains four terms accounting for the hard-core repulsion, the Thomas-Fermi kinetic energy repulsion and for contributions to the binding energy of s and d valence electrons. Lattice dynamics, molecular statics, and molecular dynamics calculations show that this model describes satisfactorily thermodynamic properties of the studied metals whereas, unlike other empirical approaches from the literature, predictions of phonon dispersion relations and of surface and point defect energetics reveal in fair good agreement with experiments. These results suggest that the present model is well adapted to large-scale simulations and whenever total energy calculations of thermodynamic properties are unfeasible

Glioblastoma multiforme (GBM) is one of the deadliest human cancers with very lim-ited treatment options available. The malignant behavior of GBM is manifest in a tu-mor which is highly invasive, resistant to standard cytotoxic chemotherapy and is strongly immunosuppressive. Immune checkpoint inhibitors have recently been in-troduced in the clinic and have yielded promising results in certain cancers. GBM however is largely refractory to these treatments. The immune checkpoint CD47 has recently gained attention as potential target for intervention as it conveys a “don’t eat me” signal to tumor associated macrophages via the inhibitory SIRP alpha protein. In preclinical models, administration of anti-CD47 monoclonal antibodies have shown impressive results with GBM and other tumor models. Several well characterized on-cogenic pathways have recently been shown to regulate CD47 expression in GBM cells and Glioma Stem cells (GSCs) include EGFR, beta catenin and LRIG2. Other macro-phage pathways involved in regulating phagocytosis including TREM2 and glycan binding proteins are discussed as well. Finally, Chimeric Antigen Receptor Macro-phages (CAR)-M could be leveraged for greatly enhancing phagocytosis of GBM and repolarization of the microenvironment in general. Here we comprehensively review the mechanisms that regulate about macrophage phagocytosis of GBM cells.

The early 2-factor (E2F) family of transcription factors, including E2F1-8, plays a critical role in apoptosis, metabolism, proliferation, and angiogenesis within glioblastoma (GBM). However, the specific functions of E2F transcription factors (E2Fs) and their impact on the malignancy of Bevacizumab (BVZ)-responsive GBM subtypes remain unclear. This study used data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to explore the impact of eight E2F family members on the clinical characteristics of BVZ-responsive GBM subtypes and possible mechanisms of recurrence after BVZ treatment.To predict the possibility of GBM patient survival and progression, we classified and comparedthe expression of E2Fs according to BVZ-responsive subtypes and employed a machine learning method-TreeBagger, one random forest algorithm. Multiple bioinformatics analyses have shown that the significant increased E2F8 post BVZ treatment may enhance the function of angiogenesis and stem cell proliferation, indicating one of the mechanisms of GBM recurrence after treatment. In addition, BVZ treatment in unresponsive GBM patients may potentially worsen disease progression. Our findings suggest that E2F family members play important roles in GBM malignancy and BVZ treatment response, highlighting their potential as prognostic biomarkers and therapeutic targets and recommending precise BVZ treatment for GBM patients.

Purpose Immune responses for cancer cells can be altered according to genetic variation of human leukocyte antigen (HLA). Association of HLA polymorphism with risk of various cancer types is well known. However, the association between HLA and glioblastoma (GBM) remains uncertain. We sought to evaluate the association of HLA polymorphism with risk of GBM development in Koreans. Materials and Methods A case-control study was performed to identify the odds ratios (OR) of HLA class I and II genes for GBM. The control group consisted of 142 healthy Korean volunteers, and the GBM group was 80 patients with newly diagnosed GBM at our institution. HLA class I (-A, -B, and –C) and class II (-DR, -DQ, and –DP) genotyping was performed by high-resolution polymerase chain reaction (PCR)-sequence-based typing (PCR-SBT) methods. Results There were significantly decreased frequencies of HLA-A*26:02 (OR 0.22 CI 0.05-0.98), HLA-C*08:01 (OR 0.29 CI 0.10-0.87), and HLA-DRB1*08:03 (OR 0.32 CI 0.11-0.98), while there was significantly increased frequency of HLA-C*04:01 (OR 2.29 CI 1.05-4.97). In analysis of haplotypes, the frequency of DRB1*14:05-DQB1*05:03 was significantly decreased (OR 0.22 CI 0.05-0.98). Conclusion This study suggests that genetic variations of HLA may affect GBM development in Koreans. Further investigations with larger sample sizes are needed to delineate any potential role of the HLA polymorphisms in the pathogenesis of GBM development.

Glioblastoma (GBL) is one of the more malignant primary brain tumors, currently treated by a multimodality strategy including surgery, radio- and chemotherapy, mainly consisting of Temozolomide(TMZ)-based chemotherapy. Tumor relapse often occurs due to the establishment of TMZ resistance, with a patient median survival <2 years. The identification of natural molecules having strong anti-tumor activity, led to combine these compounds with conventional chemotherapeutic agents, developing protocols of integrated anticancer therapies. Curcumin (CUR), Resveratrol (RES), and its glucoside Polydatin (PLD) are widely employed in the pharmaceutical and nutraceutical fields, and several studies demonstrated that the combination of these natural products was more cytotoxic than the single compound alone in different cancers. Some of us recently demonstrated the synergistic efficacy of the sublingual administration of a new nutraceutical formulation of CUR+PLD in reducing tumor size and improving GBL patient survival. To deepen some mechanistic aspects of these results, we investigated if the pretreatment with a combination of CUR+PLD, can improve TMZ cytotoxicity on GBL cells, by analyzing the effects on cell cycle, viability and morphology, on proteins related to cell proliferation, differentiation, apoptosis or autophagy, and on actin network. Cell viability was assessed by MTT or by the cell counter CytoSmart. CalcuSyn software was used to study the CUR+PLD synergism. Morphology was evaluated by optical and scanning electron microscopy, and protein expression was analyzed by Western Blot. Flow cytometry was used for cell cycle, autophagic flux, and apoptosis analyses. The results obtained provide evidence that CUR and PLD, acting in synergy with each other, strongly improve the efficacy of alkylating antitumor agents such as TMZ, also in drug-resistant GBL cells, through their abilities to affect survival, differentiation, and tumor invasiveness.

Background: Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine therapy is a cornerstone in DTC management, but sometimes it became useless when cancer cells develop refractoriness. Radioactive Iodine Refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. 18F-FDG PET/CT has been widely used, it has a demonstrated prognostic value, but 18F-FDG DTC avidity may remain low. FA-Pi, PSMA, SSTR tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed to re-induce RAI accumulation in DTC cells. Results appeared promising, despite not excellent. Conclusions: RAIR-DTC yet represent a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation with post-therapy whole body scan (PT-WBS) is the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents oblige physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice.

Antler is the fastest growing tissue. Because is based on proto-oncogenes, to avoid the risk of cancer, antlers evolved strong anticancer mechanisms, and thus its extract (DVA) is effective also against the few human tumours studied so far. We assessed whether DVA is a general anticancer compound testing direct effects in cells of different tumours: glioblastoma (GBM), colorectal and breast cancer, and leukaemia. DVA reduced viability of tumour but not healthy cells. Mobility decreased at least at the longest test (72 h). Intraperitoneal/oral 200 mg DVA/kg administration in GBM xenograft mice for 28 d reduced tumour weight 66.3% and 61.4% respectively, and also spleen weight. In addition, tumours treated with DVA showed symptoms of liquefactive necrosis. Serum cytokines showed DVA up-regulated factors related with tumour fighting and down-regulated those related with inducing immune tolerance to the tumour. DVA shows general anticancer effects in the lines tested and, in GBM mice, also strong indirect effects apparently mediated by the immune system.

Background The metabolic syndrome increases the risk of developing various systemic cancers. The prevalence of the metabolic syndrome in newly diagnosed glioblastoma patients is unknown. Further, there have been contradictory reports about how the metabolic syndrome affects clinical outcomes. Therefore, the purpose of this study is to test the hypothesis that the metabolic syndrome is associ-ated with increased prevalence of glioblastoma and worsened survival outcomes. Methods This retrospective cohort study examines seventy-three patients with isocitrate dehydrogenase (IDH)-wild type glioblastoma as it provides for a relatively homogeneous population to examine. Patient characteristics, vital signs, lab results, tumor molecular markers, and overall survival were analyzed. Patients with the metabolic syndrome and individual risk factors were identified and survival outcomes were examined. Results Our results demonstrate that there is a higher prevalence of the metabolic syndrome in our cohort of patients with glioblastoma than the general population (41% vs 33%). We also demonstrate that after correction for confounding variables, the metabolic syndrome is not significantly asso-ciated with overall survival (p = 0.1). When analyzing individual metabolic risk factors, we demonstrate that there is a significant association between the accumulation of metabolic risk factors and decreased survival (p = 0.03), and hyperglycemia emerges as a significant independent risk factor for decreased survival (p = 0.05). Conclusion These results suggest that metabolic risk factors can affect survival in patients with glioblastoma, which can have significant implications for clinical practice. These findings need to be further ex-plored through further clinical and mechanistic studies.

Abstract: Background: Vasoplegic shock syndrome(VSS) after an off-pump coronary artery bypass graft (OPCABG) is an extremely rare condition. Inotropic support is usually the first-line therapy though it can precipitate several complications or be ineffective. We report the first case of severe refractory VSS after OPCABG successfully treated with hydroxycobalamin. Methods: A 77-year-old gentleman underwent OPCABG for three vessels coronary artery disease. Preoperative LV ejection fraction was 28%, and the patient before surgery started sacubi-tril/valsartan titrated, then, to the highest dose. Surgery was uneventful and, by the end of the procedure, TEE showed improved biventricular contractility. Results: The patient was transferred to the ICU without inotropic support but he developed soon hypotension. TEE ruled out pericardial tamponade and confirmed fair contractility. Norepineph-rine was titrated to a medium-high dose, vasopressin was started and a Swan-Ganz catheter was placed. SVR was 480 dyn·s·cm−5. Despite aggressive pharmacologic treatment (including Methylprednisolone and Methylene blue), no improvements were noticed. 10 g of hydroxycobalamin were administered. One hour later hemodynamic status re-assessment showed SVR > 800 dyn·s·cm−5. Afterward, vasopressors were gradually reduced. Conclusions: Our case demonstrated the importance of adequate early treatment in VSS after OPCABG. For the first time, hydroxycobalamin was effectively used to restore homeostasis.

Taxanes have been shown to be the most effective treatment for recurrent or metastatic breast cancer. However, for patients pretreated with taxanes, more active and possibly less toxic drugs are needed. In this retrospective study, we investigated on the effectiveness and safety of eribulin mesylate in 91 taxane-refractory subjects, extracted from the ESEMPIO database, which included 497 metastatic breast cancer patients treated with eribulin allover the Italy. This analysis included only those patients who have shown disease progression while receiving taxane therapy (primary refractory), or those who achieved a response followed by progression while still on therapy (taxane failure). Overall, 41/91 patients (45.2%) showed a clinical benefit; 1 complete response (2.2%) and 16 partial responses (17.6%) were observed. The median progression free survival was 3.1 months (95% CI: 2.8–3.5) and the median overall survival was 11.6 months (95% CI: 8.7–16.7). With regard to toxicity, 53 patients (58%) experienced asthenia/fatigue, 23 (25%) showed peripheral neurotoxicity, 18 (20%) alopecia, 12 (13%) mild constipation and 27 (30%) neutropenia. The toxicity related to the treatment led to eribulin dose reduction in 19 (21%) and discontinuation in 9 (10%) patients, respectively. In conclusion, this study suggests that eribulin is effective and well tolerated also in taxane-refractory patient.

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor. GBM is formed by a very heterogeneous astrocyte population, neurons, neovascularization and infiltrating myeloid cells (microglia and monocyte derived macrophages). The IQGAP1 scaffold protein interacts with components of the cytoskeleton, cell adhesion molecules, and several signaling molecules to regulate cell morphology and motility, cell cycle and other cellular functions. IQGAP1 overexpression and delocalization has been observed in several tumors, suggesting a role for this protein in cell proliferation, transformation and invasion. IQGAP1 has been identified as a marker of amplifying cancer cells in GBMs. To determine the involvement of IQGAP1 in the onco-biology of GBM, we performed immunohistochemical confocal microscopic analysis of the IQGAP1 protein in human GBM tissue samples using cell type-specific markers. IQGAP1 immunostaining and subcellular localization was heterogeneous; the protein was located in the plasma membrane and, at variable levels, in nucleus and/or cytosol. Moreover, IQGAP1 positive staining was found in podosome/invadopodia-like structures. IQGAP1⁺ staining was observed in neurons (Map2⁺ cells), in cancer stem cells (CSC; nestin⁺) and in several macrophages (CD31⁺ or Iba1⁺). Our results indicate that the IQGAP1 protein is involved in normal cell physiology as well as oncologic processes.

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), and nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres, 100-300 nm in size, loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than nonspecific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study shows the potential for anticancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labelling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier for precisely targeting tumors. This combination has the potential to produce anti-tumor effects in active targeted therapy of GBM.

Glioblastoma (GB), even though not frequent, is an extremely aggressive brain tumor, with a strong impact on patient outcomes, in terms of both length and quality of life. The protocol estab-lished by Stupp and coworkers in 2005, based on radiotherapy and temozolomide chemotherapy, after maximum safe surgical resection, remains the gold standard for GB treatment. However, it is evident nowadays that the extreme GB intratumoral and intertumoral heterogeneity, invasive-ness and recurrence are not compatible with a routinary and unfortunately uneffective treatment. In this review article, we summarize the principal challenging issues in finding new valuable therapies for GB and focus on the impact that extracellular vesicle (EV) research and exploitation can have in the field. EVs are natural particles delimited by a lipidic bilayer and full of functional cellular content, released and uptaken by cells as key means of cell communications. Moreover, being stable in body fluids, well-immunotolerated, able to cross physiological, inter-species, and inter-kingdom barriers, and to target specific cells, releasing inherent or externally loaded functionally active molecules, EVs can be potentially ideal allies in fighting GB and assuring to GB patients a better prognosis. Here we report the main results obtained until now, focusing on both EV sources and molecular cargo used in the different functional studies, mainly in vivo. Finally, we perform a SWOT analysis reporting both the main advantages and the pitfalls of developing EV-based GB therapeutic strategies to highlight the main directions to explore for realizing the promise of EV exploitation for GB treatment.

This study examines the impact of the impregnation of fireclay-based conventional (CC) and medium cement castables (MCC) with liquid sodium silicate glass under vacuum conditions. The goal is to assess how this treatment affects physical, mechanical properties, and durability (alkali and thermal shock resistance) of these castables used in biomass combustion boilers, where they are exposed to temperatures up to 1100°C. The research work employs standard test methods to evaluate physical and mechanical properties. Additionally, advanced techniques such as scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and specific tests for alkali resistance and thermal shock resistance are used. The research findings suggest that impregnation with sodium silicate glass under vacuum significantly enhances the alkali resistance of both CC and MCC castables. This improvement is primarily due to the reduction in porosity and the increase in density. SEM images reveal that impregnated samples are coated with a glassy layer and the pores are partially filled with sodium silicate. Tests for alkali resistance demonstrate the formation of a protective glassy layer (with a thickness of 0.9-1.5 mm) on the castables surfaces, thereby reducing further penetration of alkali into deeper layers of the samples. However, it is important to mention that impregnated refractory castables have reduced resistance to thermal shock cycles.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and biologically heterogeneous disease. Approximately 40% of patients with DLBCL will experience disease relapse or will be refractory to first line chemoimmunotherapy. In recent years there have been several new therapeutic agents approved for the treatment of relapsed/refractory (R/R) DLBCL. These agents include anti-CD19 chimeric antigen receptor T-cell therapies (CAR T-cells) and monoclonal antibodies as polatuzumab and tafasitamab. Nevertheless, despite the high efficacy of all these new therapies, there are still patients who do not respond or relapse, representing an unmet clinical need. This review describes new promising therapies that are under investigation to treat R/R DLBCL.

Cisplatin (CDDP) is a platinum-based drug effective against various cancers, including lung, bladder, prostate, ovarian, esophageal, stomach, and cervical cancer and malignant lymphoma. It plays a central role as the first choice in current anticancer therapy. However, CDDP causes serious side effects, such as neurological disorders, myelosuppression, and renal damage, because it is a small molecule indiscriminately distributed in normal tissues. Therefore, it is very important to prevent or attenuate CDDP toxicity. We hypothesized that liposomalization of CDDP could alleviate serious side effects. Therefore, this study aimed to evaluate the safety and efficacy of CDDP liposomes. A patient with multiple recurrent liver metastases from metastatic nasal carcinoma was administered CDDP liposomes with consent. Magnetic resonance imaging showed that the patient remained stable-diseased; however, no apparent side effects were observed, and blood draw data showed no worsening of renal function. Patients undergoing partial pancreatectomy and jejunoileal biliary anastomosis for biliary tract cancer who consented to receive CDDP liposomes demonstrated a partial response on angiographic computed tomography; however, they showed slight fatigue. To our knowledge, the present study is the first in Japan to suggest that liposomalization of CDDP may have anticancer effects while alleviating renal damage and bone marrow suppression.

The most common type of non-Hodgkin lymphoma in adults is diffuse large B-cell (DLBCL). There is a historical unmet need for more effective therapies in the 2nd and 3rd line setting. Emerging immunochemotherapies have shown activity in small studies of heavily pre-treated patients with prolonged remissions achieved in some patients. Anti-CD19 CAR (chimeric antigen receptor) T cells are potentially curative in the 3rd line and beyond setting and are under investigation in earlier lines of therapy.1 Antibody-drug conjugates (ADC’s) such as polatuzumab vedotin targeting the pan-B-cell marker CD79b has proven effectiveness in multiply-relapsed DLBCL patients. Tafasitamab (MOR208) is an anti-CD19 monoclonal antibody producing prolonged remissions when combined with Lenalidomide in patients who were not candidates for salvage chemotherapy or autologous stem cell transplant. Selinexor, an oral, small-molecule selective inhibitor of XPO1-mediated nuclear export (SINE), demonstrated prolonged activity against heavily-pretreated DLBCL without cumulative toxicity and is being investigated as part of an oral, chemotherapy-free regimen for relapsed aggressive lymphoma. This article reviews current strategies and novel therapies for relapsed/refractory DLBCL.

Background: Glioblastoma is the deadliest, yet most common, brain tumor in adults, with poor survival and response to aggressive therapy. Therapeutic failure results from a number of causes inherent to these tumors. Imaging, computational, and drug delivery approaches can aid in the quest to access and kill each tumor cell in patients. One factor, interstitial fluid flow, is a driving force therapeutic delivery. However, convective and diffusive transport mechanisms are un-der-studied. In this study, we examine the application of a novel image analysis method to meas-ure fluid flow and diffusion in glioblastoma patients with MRI and compare to patient outcomes. Methods: Building on a prior imaging methodology tested and validated in vitro, in silico and in preclinical models of disease, here we apply our analysis method to archival patient data from the Ivy GAP dataset. Results: We characterize interstitial fluid flow and diffusion patterns in patients. We find strong correlations between flow rates measured within tumors and in the surrounding parenchymal space, where we hypothesized that velocities would be higher. Looking at overall magnitudes, there is significant correlation with both age and survival in this patient cohort. Additionally, we find that tumor size nor resection significantly alter the velocity magnitude. Last, we map the flow pathways in patient tumors and find variability in degree of directionality that we hypothesize in future studies may lead to information concerning treatment, invasive spread, and progression. Conclusions: Analysis of standard DCE-MRI in patients with glioblastoma offers more infor-mation regarding transport within and around tumor, can be measured post-resection and mag-nitudes correlate with patient prognosis.

In this paper, we introduce a new causal formula to distinguish Gliosarcoma (GSM) from Glioblastoma (GBM). Our formula combines Probabilistic Easy Variational Causal Effect (PEACE) with XGBoost, or eXtreme Gradient Boosting algorithm. Unlike prior research, which often relied on statistical models to reduce dataset dimensions before causal analysis, our approach uses the complete dataset with PEACE and XGBoost algorithm. PEACE provides a comprehensive measurement of direct causal effects, applicable to both continuous and discrete variables. It offers a spectrum of both positive and negative causal effects of the events causal effect values based on the degree ?, reflecting the rarity and frequency of the events. By using PEACE with XGBoost, we achieve a detailed and nuanced understanding of the causal relationships within the dataset features, facilitating accurate differentiation between GSM and GBM.

Glioblastoma (GBM) is the most aggressive brain cancer. To model GBM in research, orthotopic brain tumor models, including syngeneic models like GL261 and genetically engineered mouse models like TRP, are used. In longitudinal studies, tumor growth and treatment response are typ-ically tracked with in vivo imaging, including bioluminescence imaging (BLI), which is quick, cost-effective, and easily quantifiable. However, BLI requires luciferase-tagged cells, and recent studies indicate that the luciferase gene can elicit an immune response, leading to tumor rejection and experimental variation. We sought to optimize the engraftment of two luciferase-expressing GBM models, GL261 Red-FLuc and TRP-mCherry-FLuc, showing differences in tumor take, with GL261 Red-FLuc cells requiring immunocompromised mice for 100% engraftment. Immuno-histochemistry and MRI revealed distinct tumor characteristics: GL261 Red-FLuc tumors were well-demarcated with densely packed cells, high mitotic activity, and vascularization. In con-trast, TRP-mCherry-FLuc tumors were large, invasive, and necrotic, with perivascular invasion. Quantifying tumor volume using the HALO® AI analysis platform yielded results comparable to manual measurements, providing a standardized and efficient approach for reliable high-throughput analysis of luciferase-expressing tumors. Our study highlights the importance of considering tumor engraftment when using luciferase-expressing GBM models, providing in-sights for preclinical research design.

High-grade gliomas are the most common and aggressive adult primary brain tumors with a median survival of only 12-15 months. Current standard therapy consists of maximal safe surgical resection followed by DNA-damaging agents, such as irradiation and chemotherapy that can delay but not prevent inevitable recurrence. Some have interpreted glioma recurrence as evidence of glioma stem cells which persist in a relatively quiescent state after irradiation and chemotherapy, before the ultimate cell cycle re-entry and glioma recurrence. Conversely, latent cancer cells with a therapy-induced senescent phenotype have been shown to escape senescence, giving rise to more aggressive stem-like tumor cells than those present in the original tumor. Therefore, approaches are needed to either eliminate or keep these glioma-initiating cells in a senescent state for a longer time to prolong survival. In our current study, we demonstrate that the radiation-induced cell cycle inhibitor P21 can provide a powerful route to induce cell death in short-term explants of PDXs derived from three molecularly diverse human gliomas. Additionally, cells not killed by P21 overexpression were maintained in a stable senescent state for longer than control cells. Collectively, these data suggest that P21 activation may provide an attractive therapeutic target to improve therapeutic outcomes.

Bacterial vaginosis (BV), the most common cause of vaginal discharge, is characterized by a shift in the vaginal microbiota from lactobacillus dominance to a diverse array of facultative and strict anaerobic bacteria which form a multi-species biofilm on vaginal epithelial cells. The rate of recurrence after therapy is high, often >60%. While the BV biofilm itself likely contributes to recurrent and/or refractory disease after treatment by reducing antimicrobial penetration, antimicrobial resistance in BV-associated bacteria including those, both within the biofilm and the vaginal canal, may be the result of independent, unrelated bacterial properties which are discussed in this paper. Our current recommendations for the treatment of refractory and recurrent BV are also provided.

Glioblastoma (GBM) is a very aggressive malignant brain tumor with the vast majority of patients surviving less than 12 months (Short-term survivors [STS]). Only around 2% of patients survive more than 36 months (Long-term survivors [LTS]). Studying these extreme survival groups might help in better understanding GBM biology. This work aims at exploring application of machine learning methods in predicting survival groups(STS, LTS). We used age and gene expression profiles belonging to 249 samples from publicly available datasets. 10 Machine learning methods have been implemented and compared for their performances. Hyperparameter tuned random forest model performed best with accuracy of 80% (AUC of 74% and F1_score of 85%). The performance of this model is validated on external test data of 16 samples. The model predicted the true survival group for 15 samples achieving an accuracy of 93.75%. This classification model is deployed as a web tool GlioSurvML. The top 1500 features which retained classification efficiency (Accuracy of 80%, AUC of 74%) were studied for enriched pathways and disease-causal biomarker associations using the HumanPSD^TM database. We identified 199 genes as possible biomarkers of GBM and/or similar diseases (like Glioma, astrocytoma, and others). 57 of these genes are shown to be differentially expressed across survival groups and/or have impact on survival. This work demonstrates the application of machine learning methods in predicting survival groups of GBM.

The paper provides and comments on the results of studies of the effect of sandstone-based abrasives and quartz sand alone on the wear of martensitic surfaces of wear-resistant steels. The wear process was examined on a ring-on-ring test rig seeking to determine the mass decrement parameter which characterised wear. The tests were conducted for three sandstone varieties: Carboniferous, Permian, and Cretaceous, and they made it possible to determine that the most intense process of deterioration of wear-resistant steels took place in the presence of quartz sand grain, while less intense wear was observed in the case of sandstone-based abrasives. The mass decrement values established in the presence of the sandstones in question did not differ significantly between individual sandstone varieties. Based on a surface damage analysis, the basic damage mechanism was found to be micro-scratching, however, with regard to the sandstones examined, it was also determined that individual grains could be pressed into surface irregularities, as well as that films of soft hematite cement developed in the Permian sandstone and that inclusions of carbonaceous matter were formed in the Carboniferous sandstone. With reference to the wear process observations, a wear model was described for the surface of the steels examined in the presence of sandstone-based abrasives.

As hematite ores become lower in grade, finer in grain size, and more complex in compositions, their beneficiation by froth flotation to produce the high Fe grade concentrate has become increasingly more difficult. A systematic and in-depth process mineralogy study based on the multi-element chemical and MLA analysis combined with other characterization techniques was conducted to explore the fundamental reasons for difficulties in refractory hematite flotation separation. The results show that the valuable mineral in the sample was mainly hematite and gangue mineral was primarily quartz. Hematite had a fine particle size distributed over a range of 0~45 μm with a degree of mineral liberation of 90.19%. The particle size of quartz was relatively coarse and was mainly distributed in the range of 20~150 μm with a liberation degree of only 67.72%. Unliberated quartz was mainly associated with hematite and the composite particle content was 36.44%. The rougher flotation tests produced a flotation concentrate of 66.71% TFe grade at a recovery of 65.47%. The screening analysis results with rougher flotation products indicated that the main reasons for the poor performance of rougher flotation were the serious entrainment of fine hematite particles and the difficulty in effective collection of coarse low-grade composite particles. Possible approaches for improving hematite flotation performance have been proposed based on the results from this study.

Background and objectives: Refractory ascites markedly worsens prognosis in cirrhosis. Large volume paracentesis (LVP) is standard treatment, but complications are common. In a randomized controlled case-series, we assessed a permanent tunneled peritoneal catheter versus LVP in patients with cirrhosis and ascites. Materials and Methods: Random allocation was computer-generated, and concealment used opaque envelopes. Patients were included from 01-2017 to 12-2018. Inclusion criteria were cirrhosis and recurrent ascites and expected survival of more than 3 months. Results: Thirteen patients were enrolled (PleurX =6 versus LVP =7). Seven were female, age range 51 to 80 years. No procedure-related complications occurred. Two patients died due to variceal bleeding (PleurX-group) and sepsis (LVP-group). One patient was withdrawn due to hyponatremia (PleurX-group). Two patients were withdrawn due to bacterial peritonitis and infection of unknown origin (Control-group). In the PleurX-group, all patients colonized the catheter, two developed bacterial peritonitis. The most common bacterial colonization was Staph. Epidermidis (n=4). Conclusions: In selected patients, the PleurX catheter mobilizes ascites and may be an alternative to LVP. The risk of infection should be considered in each case. The impact of colonization and risk of infections needs further investigation. Trial Registration: EudraCT: CIV-16-10-017324; clinicaltrials.gov: NCT 03027635; Scientific Ethics Committee journal no: H-1604179

Influence of particle size on the mechanical strength of alkali activated material from waste refractory monolithic was investigated in this study. Precursor was chemically and mineralogically analysed, separated on 4 fractions and alkali activated with Na-water glass. Alkali activated materials were thoroughly investigated under SEM and XRD to evaluate the not predicted differences in mechanical strength. Time dependence of curing temperature on mechanical strength was investigated in the sample prepared from a fraction that caused the highest compressive strength.

Objectives: To demonstrate the efficacy of Gemtuzumab ozogamicin in refractory AML patients with organ dysfunctions and poor performance status. Three refractory AML patients with are described. One of them was pretreated by intensive chemotherapy, two other patients progressed during Azacitidine treatment. WHO performance status III . Two patients had respiratory failure grade 2, the other one suffered from acute kidney insufficiency. Two patients were highly febrile with elevated CRP level. Gemtuzumab ozogamicin administration was performed in three patients followed by further switch to Gemtuzumab ozogamicin + Azacitidine or “7+3” treatment. Results: Gemtuzumab ozogamicin administration resulted in abrupt fever cessation in two febrile patients simultaneously with CRP level decrease and fast gradual resolution of respiratory failure. Recovery of kidney function was noticed in patient with renal insufficiency. WHO performance status have elevated in all three patients. No adverse effects grade II-III were noticed. Further treatment made two patients eligible for intensive chemotherapy, one patient was transplanted, patient with kidney failure obtained complete remission. Conclusions: Gemtuzumab ozogamicin therapy appeared to be safe and highly efficacious in relapsed/refractory AML patients with organ dysfunctions and poor performance status.

Glioblastoma (GBM) is a prevalent type of malignancy within the central nervous system (CNS), associated with a poor prognosis. The standard treatment for GBM includes surgical resection of the tumor, followed by radiotherapy and chemotherapy; yet despite these interventions, overall treatment outcomes remain suboptimal. The blood-brain barrier (BBB), which plays a crucial role in maintaining the stability of brain tissue under normal physiological conditions of the CNS,also poses a significant obstacle to the effective delivery of therapeutic agents to GBM. Recent preclinical studies have demonstrated that nanomedicine delivery systems (NDDS) offer promising results, demonstrating both effective GBM targeting and safety, thereby presenting a potential solution for targeted drug delivery. This review explores the various strategies employed in preclinical studies to overcome the BBB for drug delivery. Subsequently, the results of clinical translation of NDDS has been summarized, highlighting the progress made. Finally, we discuss potential strategies for advancing NDDS development and accelerating their translational research through well-designed clinical trials in GBM therapy.

Cancer cell lines are widely used as in vitro models of tumorigenesis, facilitating fundamental discoveries in cancer biology and translational medicine. Currently, there are few options for glioblastoma (GBM) treatment and limited in vitro models with accurate genomic and transcriptomic characterization. Here, a detailed characterization of a new GBM cell line, namely AHOL1, was conducted in order to fully characterize its molecular composition based on its copy number alteration (CNA) and transcriptome profiling, followed by the validation of key elements associated with GBM tumorigenesis. Large numbers of CNAs and differentially expressed genes (DEGs) were identified. CNAs were distributed throughout the genome, including gains at Xq11.1-q28, Xp22.33-p11.1, Xq21.1-q21.33, 4p15.1-p14, 8q23.2-q23.3 and losses at Yq11.21-q12, Yp11.31-p11.2 and 12p13.31 positions. Nine druggable genes were identified, including HCRTR2, ETV1, PTPRD, PRKX, STS, RPS6KA6, ZFY, USP9Y and KDM5D. By integrating DEGs and CNAs, we identified 57 overlapping genes enriched in fourteen pathways. Altered expression of several cancer-related candidates found in the DEGs-CNA dataset was confirmed by RT-qPCR. Taken together, this first comprehensive genomic and transcriptomic landscape of AHOL1 provides unique resources for further studies and identifies several druggable targets that may be useful for therapeutics and biologic and molecular investigation of GBM.

Molten LiCl-KCl salt and liquid cadmium are proposed as the electrolyte and the reactive cathode for the electrorefining of spent nuclear fuels. Corrosion testing of existing alloys is mandatory to ensure the service life of the electrorefiner vessel and electrode assemblies. Haynes C276, Inconel 600, AISI 316L stainless steel, and 42CrMo low alloy steel were exposed to LiCl-KCl melt at 500°C for 500 h in an argon atmosphere. All alloys suffered from dissolution attacks with the presence of oxide islands or porous oxide layer on the surface. AISI 316L, T91 steel and tungsten specimens were also submitted to corrosion tests in liquid cadmium at 500°C for 120 h. Corrosion of AISI 316L and T91 stainless steel were predominated by chemical oxidation with additional severe Ni dealloying occurred on AISI 316L. Tungsten only suffered from dissolution attack in comparison.

The aim of this study was to analyze surgical and refractive outcomes of XEN glaucoma implant (Allergan, an Abbvie company, Irvine, CA, USA), a minimally invasive surgical device for the treatment of refractory glaucoma. A retrospective chart review of eyes that received XEN Gel Stent placement from December 2014 to October 2019 was conducted. Intraocular pressure (IOP) change, best corrected visual acuity (BCVA), change in glaucoma medications, frequency of slit lamp revision procedures, and frequency of secondary glaucoma surgeries were the primary outcomes. Seventy-two subjects were included in the study: 32 (44%) males and 40 (56%) females. The mean follow-up time was 26.87 ± 15.33 months. The mean IOP before surgery was 24.82 ± 8.03 mmHg and decreased to 17.45 ± 5.84 mmHg at the end of the study, MD = -7.48, CI95 [-10.04; -4.93], p < 0.001. The mean decrease from baseline was 23%. Before surgery BCVA was 0.38±0.30 and at the end of the follow-up period it had improved to 0.47±0.37, MD = 0.09, CI95 [0.04; 0.13], p < 0.001. Additional procedures (fluorouracil injection, Bleb needling) were performed in 11/72 patients (15%). Further glaucoma surgery was necessary for 23.9%% of the patients. Implantation of XEN Gel Stent is both safe and effective for lowering IOP in refractory glaucoma patients.

We have previously shown that the transmembrane protein ODZ1 promotes cytoskeletal remodelling of glioblastoma (GBM) cells and invasion of the surrounding parenchyma through activation of a RhoA-ROCK pathway. We also described that GBM cells can control the expression of ODZ1 through transcriptional mechanisms triggered by binding of IL-6 to its receptor and a hypoxic environment. Epidermal growth factor (EGF) plays a key role in the invasive capacity of GBM. However, the molecular mechanisms that enable tumor cells to acquire the morphological changes to migrate out from the tumor core have not been fully characterized. Here we show that EGF is able to induce the expression of ODZ1 in primary GBM cells. We analysed the levels of EGF receptor (EGFR) in 20 GBM primary cell lines and found expression in 19 of them by flow cytometry. We selected two cell lines that do or do not express EGFR and found that EGFR-expressing cells responded to EGF ligand by increasing ODZ1 at the mRNA and protein level. Moreover, blockade of EGF-EGFR binding by Cetuximab, inhibition of the p38 MAPK pathway or siRNA-mediated knockdown of MAPK11 (p38 MAPK) reduced the induction of ODZ1 in response to EGF. Overall, we show that EGF may activate an EGFR-mediated signalling pathway through p38 MAPK, to upregulate the invasion factor ODZ1, which may initiate morphological changes for tumor cells to invade the surrounding parenchyma. These data identify a new candidate of the EGF-EGFR pathway for novel therapeutic approaches.

Aim: Glioblastoma multiform (GBM) is a prevalent brain cancer which accounts for 80% of cases globally with a noticeably short life expectancy subsequent diagnosis. There are several factors associated with GBM including alterations and over expressions of oncoproteins. Analysis of SEC61G expression in GBM patient’s favor tumour progression, which promotes an environment of oxidative stress, while preventing apoptosis. Methods: In this article using in silico tools including GEPIA2, ULCAN, LinkedOmics, Gene MANIA and mirTEd, we observed the role of SEC61G gene in GBM progression by analyzing the expression, positive correlation associated with metabolic, mitochondrial gene, immune cell infiltration level, gene interaction networks, miRNA association as well as survival analysis. Results: The expression of the mitochondrial, metabolic genes PGLS, PGK1, EIF6, and EIF3K which are involved in redox metabolism and CD63 immunoregulation, as well as other genes that promote tumour progression and invasion, including EGFR, LANCL2, BCL2L12, SEC61G-DT, KDELR1, CDKN2A, IFNA16, IFNA10, and BCL7C were positively correlated with the increased/high expression of SEC61G.We also found hsa-mir-380-5p to be unregulated in glioblastoma phenotypes. Conclusion: Our findings suggest that SEC61G associated redox metabolism, complement system and immunoregulation, as well as miRNA expression can be targeted to develop a potential therapeutic approach for GBM patients.

BACKGROUND: Glioblastoma (GBM) is driven by various genomic alterations. Next generation sequencing (NGS) could yield targetable alterations that may impact outcomes. The goal of this study was to describe how NGS can inform targeted therapy (TT) in this patient population. METHODS: The medical records of patients (pts) with a diagnosis of GBM from 2017-2019 were reviewed. Records of patients with recurrent GBM and genomic alterations were evaluated. Objective response rates and disease control rates were deter-mined. RESULTS: A total of 87 pts with GBM underwent NGS. Forty percent (n = 35) were considered to have actionable alterations. Of the 35, 40% (n=14) pts had their treatment changed due to an alteration. The objective response rate (ORR) of this population was 43%. The disease control rate (DCR) was 100%. The absolute mean decrease in contrast enhancing disease was 50.7% (95% CI 34.8 – 66.6). CONCLUSION: NGS for GBM, particularly in the recurrent setting, yields a high rate of actionable alterations. We observed a high ORR and DCR, reflecting the value of NGS in deciding on TT to match alterations that are likely to respond. In conclusion, patient selection and availability of NGS may impact outcomes in select pts with recurrent GBM.

In prostate cancer, p53 maximizes apoptosis in response to severe DNA damage, not DNA replication stress. Here, we examined the apoptotic response of two glioblastoma cells, p53-wild type U87 and a p53-mutated T98G cell, for the same stresses. We ascertained that p53 intensified apoptosis in response to severe DNA damage, not DNA replication stress in glioblastoma. We further asked if p53-mediated apoptosis can be induced by cellular stress other than severe DNA damage. We analyzed two compounds, bortezomib and vorinostat, respective inhibitors of 26S proteasome and histone deacetylase, to evaluate their capacity to activate p53-mediated apoptosis. The cellular stress incited by bortezomib, not vorinostat, activated p53-mediated apoptosis. Next, we asked if the cellular stress generated by combining the two compounds had a synergistic effect on apoptosis. Our results demonstrated that doxorubicin with bortezomib or CFS-1686, or bortezomib with vorinostat have a significant synergistic effect on apoptosis only in p53-wild type cell. Under high stress, p53 translocates from cytosol into the nucleus to cause apoptosis possibly. Together, p53 maximizes apoptosis for cellular stress caused by severe DNA damage, disruption of protein turnover, and for the stress induced by drug combination including doxorubicin with bortezomib or CFS-1686, and bortezomib with vorinostat.

Brain cancer is the tenth leading cause of death in the U.S. Glioblastoma multiforme (GBM) is the most lethal primary malignant central nervous system tumor in adults. The present study employed samples from 1985-2014 to discover the difference in prognosis among glioblastoma subtypes after the evolution of treatment modalities over the past few years. The current study aims to find the differences between Glioblastoma multiforme (GBM) and giant cell glioblastoma (GCG) in terms of prognosis among adults and elderly patients in the U.S. This study is a historical cohort type of study and is conducted on adults and elderly individuals with GBM or GCG from the years 1985-2014 in the U.S. Data were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database. The study exposure was GBM or GCG and the outcome was mortality. The potential confounders were age, sex, race, ethnicity, year of diagnosis, primary site, and surgery. A chi-square test was used for categorical data. A univariate analysis was used for variables having a p-value < 0.05. Potential confounders were selected and evaluated using multivariate logistic regression models to calculate the odds ratio with stepwise selection. The study sample was 25,117. The incidences of GBM and GCG were not similar in relation to age group. Also, Spanish-Hispanic ethnicity was independently protective of GBM and GCG as compared to Non-Spanish-Hispanic ethnicity patients with GBM have a higher mortality rate than do GCG patients. The mortality rate was higher among patients diagnosed before 2010. In conclusion, GCG was not statistically significant in association to reduced mortality. Non-Spanish-Hispanics with GBM or GCG had a higher mortality rate than did Spanish-Hispanics. Factors such as being female, being age >59, and having a year of diagnosis before 2010 were independently associated with increased mortality.

Most patients with classic Hodgkin lymphoma (cHL) are cured with combination chemotherapy, but approximately 10-20% will relapse and another 5-10% will have primary refractory disease. The treatment landscape of relapsed/refractory (R/R) cHL has evolved significantly over the past decade following the approval of brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, and the PD-1 inhibitors, nivolumab and pembrolizumab. These agents have significantly expanded options for salvage therapy prior to autologous hematopoietic cell transplantation (AHCT), post-transplant maintenance, and treatment of relapse after AHCT, which have led to improved survival in the modern era. In this review, we highlight our approach to management of R/R cHL in 2023 with a focus on choosing first salvage therapy, post-transplant maintenance, and treatment of relapse after AHCT. We also discuss management of older adults and transplant-ineligible patients who require a separate approach. Finally, we review novel immunotherapy approaches in clinical trials, including combinations of PD-1 inhibitors with other immune-activating agents as well as novel antibody-drug conjugates, bispecific antibodies, and cellular immunotherapies. Ongoing studies assessing biomarkers of response to immunotherapy and dynamic biomarkers such as circulating tumor DNA may further inform treatment decisions and enable a more personalized approach in the future.

Mortarless refractory masonry structures are widely used in the steel industry for the linings of many high-temperature industrial applications including steel ladle. The design and the optimization of these components require accurate numerical models that consider the presence of joints as well as joints closure and opening due to cyclic heating and cooling. The present work reports on the formulation, numerical implementation, validation, and application of homogenized numerical models for simulation of refractory masonry structures with dry joints. The validated constitutive model has been used to simulate a steel ladle and to analyze its transient thermomechanical behavior during a typical thermal cycle of steel ladle. 3D solution domain, enhanced thermal and mechanical boundary conditions have been used. Parametric studies to investigate the impact of joints thickness on the thermomechanical response of the ladle have been carried out. The results clearly demonstrate that the thermomechanical behavior of mortarless masonry is orthotropic nonlinear due to gradual closure and reopening of joints with the increase and decrease of temperature. Also, resulting thermal stresses increase with the increase of temperature and decrease with the increase of joints thickness.

K+ channels do play a role in cell shape changes observed during cell proliferation and apoptosis. Research suggested that the dynamics of aggregation of Aquaporin-4 (AQP4) into AQP4-OAPs isoforms can trigger cell shape changes in malignant glioma cells. Here, we investigated the relationship between AQP4 and some K+ channels in the malignant glioma U87 line. The U87 cells transfected with the human M1-AQP4 and M23-AQP4 isoforms were investigated for morphology, gene expression of KCNJ8, KCNJ11, ABCC8, ABCC9, KCNMA1, and Cyclin genes by RT-PCR, recording the whole-cell K+ ions currents by patch-clamp experiments. AQP4 aggregation into OAPs increases the plasma membrane functional expression of the Kir6.2 and SUR2 subunits of the KATP channels, and of the KCNMA1 of the BK channels in U87 cells leading to a large increase in inward and outward K+ ion currents. These changes were associated with changes in morphology with a decrease in cell volume in the U87 cells and an increase in the ER density. These U87 cells accumulate in the mitotic and G2 cell cycle. The KATP channel blocker zoledronic acid reduced cell proliferation in either M23 AQP4-OAPs and M1 AQP4-tetramers transfected cells leading to early and late apoptosis, respectively. BK channel sustains the efflux of K+ ions associated with the M23 AQP4-OAPs expression in the U87 cells, but it is downregulated in the M1 AQP4-tetramers cells; KATP channels are effective in the M1 AQP4-tetramers and M23 AQP4-OAPs cells. Zoledronic acid can be effective in targeting pathogenic M1 AQP4-tetramers cell phenotype inhibiting KATP channels and inducing early apoptosis.

Glioblastoma is a central nervous system cancer type with a poor prognosis. One of its main features is the constant change of metabolism phenotype to support its development and progression. Mitochondria play a critical role in cellular metabolism. Acetylation on lysine residues of mitochondrial enzymes is a mechanism for regulating protein function. This modification negatively affects the mitochondrial proteome function and is counteracted by the enzyme sirtuin 3 (SIRT3). To better understand how SIRT3 regulates mitochondrial metabolism, we inhibited SIRT3 and examined by high-resolution mass spectrometry analysis the proteome and acetylome of two glioblastoma cell lines with different metabolic preferences. Our results indicate that protein synthesis machinery is regulated by lysine acetylation and plays a role in the metabolic phenotype. We also identified new SIRT3 targets not previously associated with specific functions, highlighting their potential as future targets for further study. This study shed light on the role of SIRT3 in mitochondria and its implication for cellular metabolism. We have generated knowledge at the proteome and acetylome levels on the dynamics between two glioblastoma cell lines with opposing metabolic phenotypes. Our results might guide in searching for biomarkers at both proteome and acetylome levels in glioblastoma.

The naturally occurring dipeptide carnosine (β alanyl L histidine) specifically attenuates tumor growth. Here, we asked whether other small imidazole containing compounds also affect viability of tumor cells without affecting non-malignant cells, and whether formation of histamine is involved. Patient-derived fibroblasts and glioblastoma cells were treated with carnosine, L alanyl L histidine (LA-LH), ß alanyl L alanine, L histidine, histamine, imidazole, β alanine and L alanine. Cell viability was assessed by cell-based assays and microscopy. The intracellular release of L histidine and formation of histamine was investigated by High Performance Liquid Chromatography coupled Mass Spectrometry. Whereas carnosine and LA LH inhibited tumor cell growth with minor effects on fibroblasts, L-histidine, histamine and imidazole affected viability in both cell types. Compounds without imidazole moiety did not diminish viability. In the presence of LA LH but not in the presence of carnosine a significant rise of intracellular amounts of histidine was detected in all cells. Formation of histamine was not detectable in the presence of carnosine, LA LH or histidine. In conclusion, the imidazole moiety of carnosine contributes to its anti-neoplastic effect, which is also seen in the presence of histidine and LA LH. Despite histamine had a strong effect on cell viability, formation of histamine is not responsible for the effects on cell viability of carnosine, LA LH and histidine.

P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs in glioblastoma multiforme (GB) because it is highly expressed in GB stem cells and in brain-blood barrier (BBB), the peculiar endothelium surrounding brain. Inhibiting Pgp activity in BBB and GB is still an open challenge. Here, we tested the efficacy of a small library of tetrahydroisoquinoline derivatives with an EC₅₀ for Pgp < 50 nM, in primary human BBB cells and in patients-derived GB, from which we isolated differentiated/adherent cells (AC, i.e. Pgp-negative/doxorubicin-sensitive cells) and stem cells (neurospheres, NS, i.e. Pgp-positive/doxorubicin-resistant cells). At 1 nM, 3 compounds increased the delivery of doxorubicin, a typical substrate of Pgp, across BBB monolayer, without altering expression and activity of other transporters. The compounds increased the drug accumulation within NS, restoring necrosis, apoptosis and reduction in cell viability induced by doxorubicin. In co-culture systems, the compounds added to the luminal face of BBB increased the delivery of doxorubicin to NS growing under BBB and rescued the drug’s cytotoxicity. Our work identified new ligands of Pgp active at low nanomolar concentrations, that effectively reduce Pgp activity in BBB and GB, and can improve chemotherapy efficacy in this tumor.

Abstract: Five patients with standard medical treatment-resistant symptoms of skin lesions, ear infections, allergic rhinitis, nasal congestion, asthma, heartburn, and failure to thrive were success- fully treated with an integrative medicine assessment and integrative medicine treatment approach. The integrative medicine assessment method of autonomic response testing enabled the identifica- tion of nickel sensitivity as a common element in these patients. It guided the use of the integrative medicine therapies of low dose immunotherapy, gamma linoleic acid supplementation, chelation, dietary nickel restriction, and removal of nickel containing dental and cosmetic appliances. A chart review of 151 patients indicated a strong association of nickel and the simultaneous presence of skin lesions.

In recent years, new treatments have been studied for relapsed-refractory multiple myeloma (RRMM), including two CAR-T products and a variety of non CAR-T agents. Since direct comparisons between these innovative treatments are not available, indirect comparisons can be of interest. Reconstruction of individual patient data from Kaplan-Meier graphs (Shiny method) has been employed in numerous reports that have validated its performance. In the present review, we evaluated six treatments proposed for RRMM including two CAR-T products (ciltacabtagene autoleucel and idecabtagene vicleucel) and four treatments not based on a CAR-T (melflufen plus dexamethasone, isatuximab plus dexamethasone, selinexor, and belantamab). The end-point was overall survival (OS); the Shiny method was used to generate reconstructed survival curves. Our results showed statistically significant differences in OS across these treatments. Compared with pharmacological treatments, CAR-T products significantly prolonged OS with an improvement of remarkable clinical relevance. In particular, ciltacabtagene autoleucel showed better OS than idecabtagene vicleucel. As regards non CAR-T treatments, the ranking in OS was headed by isatuximab plus dexamethasone, followed by belantamab, selinexor, and melflufen plus dexamethasone. In conclusion, while the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons have offered some original clues to better interpret the information on OS published in these studies.

Glioblastoma is a highly aggressive brain tumor and is considered to be the most common primary one. Recurrence after treatment is a major problem. The recurrence of GBM is related to different cellular mechanisms and molecular signaling. Therapies to prolong survival are not completely effective. Epigenetics and non-coding genetic elements play a crucial role in gliomagenesis. Non-coding RNAs are novel regulatory RNAs that play key roles in different physiological processes such as gene regulation, cell differentiation, and proliferation. Interestingly, some LncRNAs have a tumor suppressor role while others are oncogenic. In this review article, we are going to illustrate the role of a well-known lncRNA HOX transcript antisense intergenic RNA (HOTAIR) in glioma and highlight the possible functions in glioma in both pre-clinical and clinically evident studies.

ABSTRACT: Recurrent glioblastoma (rGBM) is a highly aggressive form of brain cancer that poses a significant challenge for treatment in neurooncology, and the survival status of patients after relapse usually means rapid deterioration, and also the leading cause of death among patients. In recent years, immunotherapy has emerged as a promising strategy for the treatment of recurrent glioblastoma by stimulate the body's immune system to recognize and attack cancer cells , which could be used as a in combination with other treatments such as surgery, radiation, and chemotherapy to improve outcomes for patients with recurrent glioblastoma, This therapy combines several key methods such as the use of monoclonal antibodies, chimeric antigen receptor T cell (CAR-T) therapy, checkpoint inhibitors, oncolytic viral therapy cancer vaccines, and combination strategies. In this review, we mainly document the latest immunotherapies for the treatment of glioblastoma and focus on the rGBM especially.

Pericyte and their tunnelling nanotubes (P-TNTs) have been described as involved in the early phases of angiogenesis in the human normal developing brain and glioblastoma, being a common feature of combined endothelium/pericyte vessel sprouts. Based on the few data available so far about this ‘alternative’ pericyte-TNT-driven mode of angiogenesis, whose precise function in vessel growth through vascular cells communication, has still to be determined, this study aims to cast light on the regulative molecules involved in this process, governed by intimate pericyte-endothelial interactions. After considering the existence of the sprout guiding pericyte and P-TNT, as shown by pioneering ultrastructural studies as well as by more recent observations with NG2/CD146 pericyte markers and basal lamina molecules, a step-by-step profile of the process has been suggested and an investigation undertaken on ‘unconventional’, pro-angiogenic ligand/receptor systems, that may have a role aside from the canonical pathways. In this context, a possible candidate worthy of investigation is the c-KIT receptor, a member of the tyrosine kinase family of proteins, which also includes the well-known VEGFR and PDGFR. According to the obtained results showing a primary localization of c-KIT on endothelial cells and pointing out a differential distribution of the receptor on normal vs glioblastoma vessels, it seems conceivable to propose the stem cell factor/c-KIT signaling as a key factor in pericyte-TNT-driven angiogenesis, advancing this alternative mode of angiogenesis and the c- KIT pathway as possible targets for devising effective antiangiogenic therapeutic strategies.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia caused by both immune-mediated platelet destruction and impaired platelet production in the bone mar-row, in the absence of any other identifiable cause of low platelets count. ITP in adult patients is a disease that frequently relapses and/or becomes refractory to multiple treatments during its course, with only a small minority of adult patients attaining a sustained complete remission off-therapy. Treatment of refrac-tory ITP can be challenging, due to the unlikeliness of attaining complete response over time. On the other hand, isolated thrombocytopenia may be due to a misdiagnosed clonal myeloid disorder, such as myelodys-plastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), thus mimicking ITP. We here per-form a narrative review on the association between ITP and MDS/CMML and the possibility of overlap and misdiagnosis between these conditions, while we report also the case a patient treated for a severe re-fractory thrombocytopenia which bone marrow examination led to suspect an overlap of MDS and ITP. Our clinical case describes ITP which is refractory to glucocorticoids, high-dose immunoglobulins, Rituxi-mab, splenectomy, thrombopoietin receptor agonists and Fostamatinib, that ultimately attained a short-lived response to a hypometylating agent that was initiated due to bone marrow examination that aroused the suspect of MDS.

Glioblastoma (GBM) presents a significant public health challenge as the deadliest and most common malignant brain tumor in adults. Despite standard-of-care treatment, which includes surgery, radiation, and chemotherapy, mortality rates are high, underscoring the critical need for advancing GBM therapy. Over the past two decades, numerous clinical trials have been performed, yet only a small fraction demonstrated benefit, raising concerns about the predictability of current preclinical models. Traditionally, preclinical studies utilize treatment-naïve tumors, failing to model the clinical scenario where patients undergo standard-of-care treatment prior to recurrence. Recurrent GBM generally exhibits distinct molecular alterations influenced by treatment selection pressures. In this review, we discuss the impact of treatment - surgery, radiation, and chemotherapy - on GBM. We also provide a summary of treatments used in preclinical models, advocating for their integration to enhance the translation of novel strategies to improve therapeutic outcomes in GBM.

Glioblastoma (GBM) is one of the most aggressive and intricate forms of brain cancer, demanding novel therapeutic interventions. The role of transcription factors in epigenetic regulation has emerged as a promising avenue for targeting GBM. This comprehensive review seeks to explore the complex interplay between specific transcription factors such as SNAI2, FOXA1, YAP1, TWIST1, ZEB1, and NF-kB, and their role in GBM progression and therapy. The focus extends to innovative therapeutic strategies, including epigenetic modifiers, targeted therapies, and CRISPR/Cas9 technology. A unique aspect of this review highlights the connection between transcription factors, neoantigen presentation, and personalized immunotherapy in GBM. By delving into current research, clinical trials, and immunological data, this review emphasizes the significant potential of targeting transcription factors for personalized immunotherapy in GBM. The challenges, future perspectives, and ethical considerations are also critically discussed, offering a complete and thought-provoking insight into a vital and rapidly evolving field.

Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ERBB4 is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM. Using RT-qPCR, we quantified mRNA encoding total ERBB4 and known ERBB4 variants in GBM and non-neoplastic normal brain (NNB) samples. Using immunohistochemistry, we characterized the localization of total and phosphorylated ERBB4 (p-ERBB4) and EGFR protein in archived GBM samples and assessed their association with patient survival. Furthermore, we evaluated the effect of ERBB4 phosphorylation on angiogenesis and tumorigenicity in GBM xenograft models. Total ERBB4 mRNA was significantly lower in GBM than NNB samples, with the JM-a and CYT-2 variants predominating. ERBB4 protein was ubiquitously expressed in GBM but was not associated with patient survival. However, high p-ERBB4 in 11% of archived GBM samples, independent of p-EGFR, was associated with shorter patient survival (12.0±3.2 months) than was no p-ERBB4 (22.5±9.5 months). Increased ERBB4 activation was also associated with increased proliferation, angiogenesis, tumorigenicity and reduced sensitivity to anti-EGFR treatment in xenograft models. Despite low ERBB4 mRNA in GBM, the functional effects of increased ERBB4 activation identify ERBB4 as a potential prognostic and therapeutic target.

The high Nb-containing TiAl-based alloy ingot beyond laboratory scale with a composition of Ti-46Al-8Nb (at. %) was prepared by a vacuum induction melting process based on BaZrO3 refractory. An ingot without macroscopic casting defects (such as pipe shrinkage and center line porosity) was finally obtained, and the chemical composition, solidification path, microstructure and tensile properties of the ingots were investigated. The results show that the deviations of Al and Nb content along a 430 mm long central part of the ingot are approximately \mathrm{\pm}0.39 at. % and \mathrm{\pm}0.14 at. %, and the oxygen content in the ingot can be controlled at around 1000 ppm. During the solidification process, the alloy suffered from peritectic reaction and formed columnar grains with anisotropy. In addition to Al segregation and Nb segregation, β-phase particles associated with γ phase at the triple junction of the colonies were observed. Moreover, the mechanical properties of the ingot in the transverse direction are significantly better than those in the longitudinal direction, with a tensile strength of up to high as 700 MPa and a corresponding fracture elongation of 1.1 %.

Background: Glioblastoma remains a challenging brain tumor to treat due to its infiltrative nature. Accurately identifying tumor boundaries during surgery is crucial for successful tumor resection. This study introduces an innovative intraoperative visualization method utilizing a surgical fluorescence microscope to precisely locate tumor cells. The focus of the study is on IR-Glint, a novel preparation comprising Cy7.5-labeled aptamers Gli-233nt and Gli-55_3L specific to human glioblastoma. Methods: The aptamers were modified using molecular modeling and quantum chemical techniques. The effectiveness of the preparation was assessed using flow cytometry and microscopy on primary cultures of human glioblastoma. In vivo studies were conducted on mouse and rabbit models, employing orthotopic xenotransplantation of human brain glioblastoma with various imaging techniques, including PET/CT, in vivo fluorescence visualization, confocal laser scanning, and surgical microscopy. Results: The experiments validated the potential of IR-Glint for intraoperative visualization of glioblastoma using infrared imaging. Surface application of the aptamer-based formulation on the brain allowed clear visualization of the tumor, aiding surgeons in tumor resection. This approach also reduces the dosage required and mitigates potential toxic effects on the patient. Conclusions: This study demonstrates the promising potential of using in-frared dye-labeled aptamers for intraoperative visualization of glioblastoma. By improving surgical treatment outcomes in neurosurgery, this novel approach may pave the way for future advancements in the field.

Glioblastoma is considered the most aggressive primary brain tumor. Recurrence after treatment is a significant problem with a failed response to optimal therapies. The recurrence of GBM is linked to different cellular pathways and molecular pathways. Not only genetics are involved in gliomagenesis, but also epigenetics. Epigenetic mechanisms are highly involved in the pathogenesis of GBM. Histone modulation through acetylation, phosphorylation, ubiquitination, and methylation can regulate gene expression and may play a role in the pathogenesis of GBM. Preclinical and clinical studies currently target epigenetic enzymes in gliomas, including a new generation of histone deacetylase (HDAC) inhibitors. Herein, I tried to highlight the current research in glioma epigenetics, focusing on the culprit of histone modifications and the use of HDAC target therapies as a possible treatment line for glioblastoma.

Glioblastoma (GB) is the most frequent malignant brain tumor among adults and currently there is no effective treatment. It is a very aggressive tumor that grows fast and spreads through the brain causing the death of patients in 15 months. GB cells mutate frequently and generate a heterogeneous population of tumoral cells genetically distinct. Thus, the contribution of genes and signaling pathways relevant for GB progression is of great relevance. We use a Drosophila model of GB that reproduces the features of human GB, and describe the upregulation of the circadian gene cry in GB patients and in a Drosophila GB model. We study the contribution of cry to the expansion of GB cells, to the neurodegeneration caused by GB, and to premature death and determine that cry is required for GB progression. Moreover, we analyze the mechanisms that regulate cry expression by the PI3K pathway. Finally, we conclude that cry is necessary and sufficient to regulate myc expression in GB. These results contribute to the understanding of the signals that impulse GB malignancy and lethality and open novel opportunities for the treatment of GB patients.

Glioblastoma is a highly aggressive brain tumor characterized by rapid growth, extensive infiltration, and poor prognosis. Understanding the complex interplay of biological processes driving glioblastoma progression is crucial for developing effective therapeutic strategies. In this study, we present a comprehensive mathematical model that incorporates key aspects of glioblastoma growth and dissemination, including tumor cell diffusion, angiogenesis, nutrient availability, molecular signaling pathways, and blood-brain barrier (BBB) interactions. The model is based on a system of coupled partial differential equations (PDEs) and ordinary differential equations (ODEs) that capture the spatiotemporal dynamics of tumor cell density, nutrient concentration, signaling molecule concentrations, and BBB integrity. We employ numerical simulation techniques, such as the finite difference method and the Runge-Kutta method, to solve the model equations and visualize the evolution of tumor growth and its associated biological processes. The model parameters are estimated using experimental data from the literature, and the model is validated against clinical observations. Furthermore, we perform a comprehensive sensitivity analysis to identify the key parameters that significantly influence tumor growth, diffusion, and dissemination. The sensitivity analysis reveals the relative importance of each parameter in driving glioblastoma progression and highlights potential targets for therapeutic interventions. Our computational framework provides a powerful tool for understanding the complex dynamics of glioblastoma growth and offers valuable insights into the underlying biological mechanisms. The model can be used to test hypotheses, predict tumor response to various treatment strategies, and guide the design of targeted therapies. The findings from this study contribute to the ongoing efforts in developing personalized treatment approaches for glioblastoma patients and improving their clinical outcomes.

Gliomas are one of the most aggressive and treatment-resistant types of human cancer. One of the most promising field in gliomas cancer therapy is identification and evaluation of anticancer properties of compounds found in plants i.a. naringenin (N) and 8-prenylnaringenin (8PN). The prenyl group seem to be crucial to the anticancer activity of flavones, which may lead to enhanced cell membrane targeting and thus increased intracellular activity. Unfortunately, 8PN content in hop cones is from 10 to 100 times lower compared to other flavonoids i.e. xanthohumol. In this study we used a simple method for the synthesis of 8PN from isoxanthohumol, via O-demethylation with high, 97% of the isolated yield. Cellular accumulation and cytotoxicity of naringenin and 8-prenylnaringenin in normal (BJ) and cancer cells (U-118 MG) were also examined. Obtained data indicated that 8-prenylnaringenin exhibited higher toxicity against used cell lines than naringenin and both flavones inhibited stronger glioblastoma U-118 MG cells than normal fibroblasts. The anticancer properties of 8PN correlated with its significantly greater (37%), accumulation in glioblastoma cells than in normal fibroblasts. Additionally, naringenin indicated higher selectivity for glioblastoma as it was over 6 times more toxic for cancer than normal cells. Our results provide evidence that examined prenylated and non-prenylated flavanones have different biological activity against normal and cancer cell lines and this phenomenon may be useful in clinical practice to construct new, anticancer drugs for glioblastoma.

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, have approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

Glioblastoma (GBM) is an incurable primary brain cancer characterized by increased reactive oxygen species (ROS) production. The redox-sensitive tumor suppressor gene TP53, wildtype (wt) for 70% of patients, regulates redox homeostasis. Glioblastoma stem cells (GSCs) increase thioredoxin (Trx) and glutathione (GSH) antioxidant systems as survival redox-adaptive mechanisms to maintain ROS below the cytotoxic threshold. Auranofin, an FDA-approved anti-rheumatoid drug, inhibits thioredoxin reductase 1 (TrxR1). L-buthionine sulfoximine (L-BSO) and the natural product piperlongumine (PPL) inhibit the GSH system. We evaluated the cytotoxic effects of Auranofin alone and in combination with L-BSO or PPL in GBM cell lines and GSCs with known TP53 status. The Cancer Genome Atlas/GBM analysis revealed a significant positive correlation between wtp53 and TrxR1 expression in GBM. Auranofin induced ROS-dependent cytotoxicity within a micromolar range in GSCs. Auranofin decreased TrxR1 expression, AKT(Ser-473) phosphorylation, increased p53, p21 and PARP-1 apoptotic cleavage in wtp53-GSCs, while mutant-p53 was decreased in a mutant-p53 GSC line. p53-knockdown in a wtp53-GSC line decreased TrxR1 expression and significantly increased sensitivity to auranofin, suggesting the role of wtp53 as a negative redox-sensitive mechanism in response to auranofin in GSCs. Auranofin and L-BSO combination synergistically increased ROS, decreased IC50s and induced long-term cytotoxicity irrespective of p53 in GBM cell lines and GSCs. Intriguingly, Auranofin increased expression of glutathione S-transferase pi-1 (GSTP-1), a target of PPL. Combination of auranofin with PPL synergistically decreased IC50s to a nanomolar range in GSCs, supporting the potential to repurpose auranofin and PPL in GBM.

Glioblastomas (GBMs) are aggressive and invasive cancers of the brain, associated with high rates of tumor recurrence and poor patient outcomes despite initial treatment. Targeting cell migration is therefore of interest in highly invasive cancers such as GBMs, to prevent tumor dissemination and regrowth. One current aim of GBM research focusses on assessing anti-migratory properties of novel or repurposed inhibitors, including plant-based drugs which display anti-cancer properties. We investigated the potential anti-migratory activity of plant-based products with known cytotoxic effects in cancers, using a range of two-dimensional (2D) and three-dimensional (3D) migration and invasion assays as well as immunofluorescence microscopy to determine specific anti-migratory and phenotypic effects of three plant-derived compounds, Turmeric, Indigo and Magnolia bark, on established glioma cell lines. Migrastatic activity was observed in all three drugs, with Turmeric exerting the most inhibitory effect on GBM cell migration into scratches and from the spheroid edge at all timepoints investigated (p < 0.001). We also observed novel cytoskeletal phenotypes affecting actin and focal adhesion dynamics. By determining the migrastatic activity of Turmeric, Indigo and Magnolia on GBM cell migration, we demonstrate a potential role for Turmeric as a novel GBM anti-migratory therapeutic, in combination with the current standard of care, to prevent tumor recurrence and promote patient survival.

Glioblastoma multiforme (GBM), the most prevalent primary malignant brain tumor in adults, exhibits a dismal 6.9% five-year survival rate post-diagnosis. Thymoquinone (TQ), the most abundant bioactive compound in Nigella Sativa, has been extensively researched for its anti-cancer properties across various human cancers. Yet, its specific anticancer mechanisms and pathways in glioblastoma remain to be elucidated. In this study, we assessed the impact of different TQ concentrations on the viability of A172 cells using WST-8 and Toluidine blue assays, followed by RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs). We confirmed their expression levels through quantitative RT-PCR and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for these DEGs. RNA-seq revealed no significant gene expression changes at 2.5 µM and 5 µM TQ concentrations. However, at 25 µM and 50 µM, TQ significantly reduced cell viability in a dose-dependent manner. We identified 1548 DEGs at 25 µM TQ (684 upregulated, 864 downregulated) and 2797 DEGs at 50 µM TQ (1528 upregulated, 1269 downregulated), with 1202 DEGs common to both concentrations. TQ inhibited key pathways such as PI3K-Akt signaling, calcium signaling, focal adhesion, and ECM-receptor interaction in A172 cells. It downregulated several potential oncogenes (e.g., AEBP1, MIAT) and genes linked to GBM proliferation and migration (e.g., SOCS2, HCP5), while modulating Wnt signaling and upregulating tumor suppressor genes (e.g., SPRY4, BEX2). TQ also affected p53 downstream targets, maintaining p53 levels. This study elucidates the anticancer mechanisms of TQ in A172 GBM cells, underscoring its effects on multiple signaling pathways and positioning TQ as a promising candidate for innovative glioblastoma treatment strategies.

Glioblastoma (GBM) is a representative malignant brain tumor characterized by a dismal prognosis, with survival rates of less than 2 years and high recurrence rates. Despite surgical resection and several alternative treatments, GBM remains a refractory disease due to its aggressive invasiveness and resistance to anticancer therapy. In this report, we explore the role of fibronectin type III domain containing 3B (FNDC3B) and its potential as a prognostic and therapeutic biomarker in GBM. GBM exhibited a significantly higher cancer-to-normal ratio compared to other organs, and patients with high FNDC3B expression had a poor prognosis (p < 0.01). In vitro studies revealed that silencing FNDC3B significantly reduced the expression of Survivin, an apoptosis inhibitor, and also reduced cell migration, invasion, extracellular matrix adhesion ability, and stem cell properties in GBM cells. Furthermore, we identified that FNDC3B regulates PTEN/PI3K/Akt signaling in GBM cells using MetaCore integrated pathway bioinformatics analysis and a proteome profiler phospho-kinase array with sequential western blot analysis. Collectively, our findings suggest FNDC3B as a potential biomarker for predicting GBM patient survival and for the development of treatment strategies for GBM.

The blood brain barrier (BBB) is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system (CNS). During the occurrence and development of glioblastoma (GBM), BBB is pathologically disrupted with markedly increased permeability. Due to the obstruction imposed by the BBB, strategies currently employed for GBM therapeutics still obtain a very low success rate and lead to systemic toxicity. Moreover, chemotherapy could promote pathological BBB functional restoration, accompanied with a prominent decrease of intracerebral therapeutics transportion during GBM multiple administration, resulting in chemotherapy failure for GBM treatment. The effective delivery of therapeutics into the brain still faces with severe challenges. Regulation of pathological BBB for enhanced transporting of therapeutics across the barrier may provide new opportunities for effective and safe treatment of GBM. This article reviews the structure and function of BBB in physiological state, the mechanisms underlying BBB pathological fenestration during the development of GBM, and the therapeutic strategies of GBM based on BBB intervention and therapeutic drugs transporting across the BBB.

Glioblastoma (GBM) is the most lethal form of brain tumor, characterized by rapid growth and surrounding tissue invasion. The current standard treatment is surgery followed by radiotherapy, and concurrent chemotherapy, typically with temozolomide. Although extensive research has been performed over the past years to develop an effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in the overall survival of patients with GBM. Thus, new therapeutic approaches are urgently needed. A major challenge in the development of therapies for central nervous system (CNS) disorders is overcoming the blood–brain barrier (BBB). In this context, the intranasal (IN) route of drug administration has been proposed as a non-invasive alternative route to directly targeting the CNS. In fact, this route of drug administration may bypass the blood-brain barrier and reduce systemic side effects. Recently, formulations have been developed to further enhance nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review will be on the strategies developed to deliver a number of anticancer compounds for the treatment of GBM using the nasal administration. In particular, the specific properties of nanomedicines proposed for the nose-to-brain delivery will be critically evaluated. The number of preclinical and clinical data reviewed support the idea that nasal delivery of anticancer drugs might represent a breakthrough advancement in the fight against GBM.

Important tumor biomarkers, therapeutic targets, and mechanisms of tumorigenesis were discovered in animal models. Mouse models of malignant gliomas were represented by transplantable, chemically-induced, and genetically-engineered cells. The aim of the study was to investigate the morphological, molecular, and immunological characteristics of two original glioblastoma (GB) strains, M2 and M6. These are new, chemically-induced, trans-plantable tissue models of malignant diffuse mouse glioma. Tissues from M2 GB and M6 GB were transplanted into immunocompetent C57BL/6 mice. The clinical manifestations of M2 GB and M6 GB growth in mice include motility disorders, cachexia, and priapism. Morphologically, M2 GB and M6 GB are characterized by diffuse proliferation, cellular and nuclear polymorphism, high mitotic activity, and pathological forms of mitosis due to the aggressive nature of these tumors. Flow cytometry showed that CD3+ T lymphocytes (~32%) and F4/80+ macrophages (~28-50%) highly infiltrated both tumors. M2 GB had higher levels of F4/80+ macrophages than M6 GB. Cdkn2a, S100b, Mki67, Pten, Vegfa, Hif1a, Sox2, Abcb1, and Gfap genes were overexpressed in both tumors. Cd133, Tp53, and Pdgfra expression was increased in M2 GB. High expression of Pi3k and Gdnf was observed in M6 GB. Expression of Cd44, Pi3k, Hif1a, Gdnf and Egfr was higher in the M6 GB tissues com-pared to M2 GB, while Cdkn2a, Tp53, Cd133 and Pdgfra were higher in the M2 GB tissue compared to M6 GB. The transplantable M2 GB and M6 GB tissue models have intratumor immune responses, clinical and morphological features similar to human GB, as well as gene expression patterns that are important for further studies on tumorigenesis. These models can be used to develop diagnostic and therapeutic procedures and study carcino-genesis.

In our study, we investigated the prognostic significance of hematological markers—NLR (Neutrophil-to-Lymphocyte Ratio), PLR (Platelet-to-Lymphocyte Ratio), and RDW-CV (Red Blood Cell Distribution Width - Coefficient of Variation)—in 117 glioblastoma patients. Data collected from January 2016 to December 2018 included demographics, clinical scores, and treatment regimens. Unlike previous research, which often examined these markers solely before surgery, our unique approach analyzed them at multiple stages: preoperative, postoperative, and before adjuvant therapies. We correlated these markers with overall survival (OS) and progression-free survival (PFS) using statistical tools, including ANOVA, Cox regression, and Kaplan-Meier survival analyses, employing SPSS version 29.0. Our findings revealed notable variations in NLR, PLR, and RDW-CV across different treatment stages. NLR and PLR decreased after surgery, with some stabilization post-STUPP phase (NLR: p=0.007, η2p=0.06; PLR: p=0.001, η2p=0.23), while RDW-CV increased post-surgery and during subsequent treatments (RDW-CV: p &lt; 0.001, η2p=0.67). Importantly, we observed significant differences between the preoperative phase and other treatment phases. Additionally, higher NLR and RDW-CV at the second-line treatment and disease progression were associated with an increased risk of death (NLR at 2nd line: HR=1.03, p=0.029; RDW-CV at progression: HR=1.14, p=0.004). We proposed specific marker cutoffs that demonstrated significant associations with survival outcomes when applied to Kaplan-Meier survival curves (NLR at 2nd line &lt; 5: p&lt;0.017; RDW-CV at progression &lt; 15: p=0.007). Elevated NLR and RDW-CV at later treatment stages correlated with poorer OS and PFS. No significant preoperative differences were detected. These biomarkers may serve as non-invasive tools for glioblastoma management.

In this paper, we introduce an innovative approach to distinguish Gliosarcoma (GSM) from Glioblastoma (GBM). Our method combines causal fuzzy logic rules with the Big Bird architecture, a Transformer-based Deep Learning algorithm. Unlike prior research, which often relied on statistical models to reduce dataset dimensions before causal analysis, our approach harnesses the complete dataset in tandem with our causal fuzzy Big Bird architecture. Additionally, we benchmark our results not only against previous Gliosarcoma/Glioblastoma studies but also against GPT-2 for a comprehensive evaluation.

Introduction: This study aims to characterize changes in biogenic amines patterns in glioblasto-ma patients undergoing surgery and concurrent chemoradiation to illustrate how this class of metabolites changes during different stages of standard care treatment protocol. Methods: We examined 138 plasma specimens (before surgery, 2 days after surgical resection, before starting concurrent chemoradiation, immediately after chemoradiation, and after adju-vant chemotherapy treatment) from 36 patients with isocitrate dehydrogenase (IDH) wildtype glioblastoma. Untargeted GC-TOF mass spectrometry-based metabolomics of biogenic amines was used given its superiority for identifying and quantitating small metabolites; this yielded 340 structurally identified metabolites. Results: Comparing post-surgery to pre-surgery showed increased level of 12 metabolites: Gly-codeoxycholic acid (P=7.79E-05), Betonicine (P=9.23E-05), Glycocholic acid (P=3.18E-03), 3-Cysteinylaectaminophen (P=4.95E-03), S-Methyl-3-thioacetaminophen (P=5.77E-03), Tau-rocholic acid (P=9.97E-03), N-glycine (P=0.0013), p-acetamidophenyl.beta.-D-glucuronide (P=0.0048), 2-Hydroxy-5-sulfopyridine-3-carboxylic acid (P=0.0074), Acetaminophen sulfate (P=0.0095), 2-Amino-3-methoxybenzoic acid (P=0.02), and Dehydrofelodipine (P=0.024). There were 11 compounds that were downregulated, which included Mannitol (P=1.96E-19), Sorbitol (P=2.75E-019), Linoleic acid (P=1.51E-10), 1-Methylnicotinamide (P=1.78E-09), Nudifloramide (P=2.81E-08), Hexadecanedioic acid (P=5.49E-05), 3-Hydroxybutyric acid (P=0.0002), Riluzole (0.0036), Bupivacaine (P=0.0041), Lactitol (P=0.008), and 1-hydroxymidazolam.beta.-D-glucuronide (P=0.0414). After chemoradiation, significant de-crease was uncovered in Famotidine (P=0.0074), N-Isovalerylglycine (P=0.012), and 3-Methylcrotonylglycine (P=0.0131). While significant increase was detected in N-Methylisoleucine (P=0.0011), 4-Methyl-5-thiazoleethanol (P=0.042), and 6-Hydroxycaproic acid (P=0.049). Ensemble learning models, specifically random forest (RF) and AdaBoost (AB), accurately classified treatment phases with high accuracy (RF: 0.81 ± 0.04, AB: 0.78 ± 0.05). One significant insight gleamed from these models were that the metabolites Sorbitol and N-methylisoleucine were identified as important predictive features and confirmed by SHAP analysis. Conclusion: To our knowledge, this is the first study to describe plasma biogenic amines signa-tures during different treatment phases in patients with glioblastoma. A larger study is needed to confirm the results and the potential application of this algorithm for classification of treatment responses.

Preoperative angiography in glioblastoma (GBM) often shows arteriovenous shunts and early venous filling (EVF). Here, we investigated the clinical implications of EVF in GBM as a prognostic and vascular mimicry biomarker. In this retrospective multicenter study, we consecutively enrolled patients who underwent angiography with a GBM diagnosis between April 1, 2013, and March 31, 2021. The primary and secondary endpoints were the differences in overall survival (OS) and progression-free survival (PFS), respectively, between cases with and without EVF. Of 133 initially enrolled patients, 91 newly diagnosed with GBM underwent preoperative angi-ography and became the study population. The 6-year OS and PFS were significantly worse in the EVF than in the non-EVF group. Moreover, 20 GBM cases (10 with EVF and 10 without EVF) were randomly selected and evaluated for histological vascular mimicry. Except for two cases that were difficult to evaluate, the EVF group had a significantly higher frequency of vascular mimicry than the non-EVF group (0/8 vs. 5/10, P = 0.04). EVF on preoperative angiography is a robust prognostic biomarker for GBM and may help detect cases with a high frequency of histological vascular mimicry.

Background: Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. Especially MGMT promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response. Methods: Lomeguatrib, a highly specific MGMT inhibitor was used to inhibit MGMT protein expression in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation. Results: Lomeguatrib significantly decreased MGMT protein expression and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM. Conclusion: Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect.

Glioblastoma multiforme (GBM) is the most common high-grade intracranial tumor in adults. It is characterized by uncontrolled proliferation, diffuse infiltration due to high invasive and migratory capacities, as well as intense resistance to chemo- and radiotherapy. With a five-year survival of less than 3% and an average survival rate of 12 months after diagnosis, GBM has become a focus of current research to urgently develop new therapeutic approaches in order to prolong survival of GBM patients. The methylation status of the promoter region of the O6-methylguanine–DNA methyltransferase (MGMT) is nowadays routinely analyzed, since a methylated promoter region is beneficial for an effective response to temozolomide-based chemotherapy. Furthermore, several miRNAs were identified regulating MGMT expression, apart from promoter methylation, by degrading MGMT mRNA before protein translation. These miRNAs could be a promising innovative treatment approach to enhance Temozolomide (TMZ) sensitivity in MGMT unmethylated patients and to increase progression-free survival as well as long-term survival. In this review, the relevant miRNAs are systematically reviewed.

Objective: To evaluate the effect of care bundles on treatment compliance and intestinal barrier function in patients with refractory septic shock in the intensive care units (ICUs). Methods: In this retrospective study, the clinical data of 94 patients with refractory septic shock admitted to our hospital between June 2020 and April 2022 were collected. Patients with routine nursing were included in the routine group, and those with care bundles were assigned to the care bundles group, with 47 cases in each group. Outcome measures included nursing efficiency, treatment compliance, sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation (APACHE II) score, intestinal barrier function, inflammation factor level, treatment outcome and complications. Results: Care bundles resulted in significantly higher nursing efficiency and treatment compliance versus routine care (P<0.05). Patients receiving care bundles showed significantly higher SOFA scores and APACHE II scores than those receiving routine care (P<0.05). Intestinal fatty-acid binding protein (I-FABP), diamine oxidase (DAO), lactate, endotoxin, and intestinal dysfunction scores in the care bundles group were significantly lower than those in the conventional group after treatment (P<0.05). Care bundles were associated with significantly lower levels of procalcitonin (PCT) and hypersensitive C-reactive protein (hsCRP), shorter time to symptom relief, ICU treatment time, and duration of mechanical ventilation, and lower 28-d morbidity and mortality versus routine care (P<0.05). Patients in the care bundles group had a significantly lower incidence of complications than those in the routine group (P<0.05). Conclusion: Care bundles effectively enhance treatment compliance, improve intestinal barrier function and treatment outcomes, reduce the inflammatory response, and decrease the risk of SOFA score, APACHE II score, and complications in patients with refractory septic shock.

Objective: To evaluate the effect of care bundles on treatment compliance and intestinal barrier function in patients with refractory septic shock in the intensive care units (ICUs). Methods: In this retrospective study, the clinical data of 94 patients with refractory septic shock admitted to our hospital between June 2020 and April 2022 were collected. Patients with routine nursing were included in the routine group, and those with care bundles were assigned to the care bundles group, with 47 cases in each group. Outcome measures included nursing efficiency, treatment compliance, sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation (APACHE II) score, intestinal barrier function, inflammation factor level, treatment outcome and complications. Results: Care bundles resulted in significantly higher nursing efficiency and treatment compliance versus routine care (P<0.05). Patients receiving care bundles showed significantly higher SOFA scores and APACHE II scores than those receiving routine care (P<0.05). Intestinal fatty-acid binding protein (I-FABP), diamine oxidase (DAO), lactate, endotoxin, and intestinal dysfunction scores in the care bundles group were significantly lower than those in the conventional group after treatment (P<0.05). Care bundles were associated with significantly lower levels of procalcitonin (PCT) and hypersensitive C-reactive protein (hsCRP), shorter time to symptom relief, ICU treatment time, and duration of mechanical ventilation, and lower 28-d morbidity and mortality versus routine care (P<0.05). Patients in the care bundles group had a significantly lower incidence of complications than those in the routine group (P<0.05). Conclusion: Care bundles effectively enhance treatment compliance, improve intestinal barrier function and treatment outcomes, reduce the inflammatory response, and decrease the risk of SOFA score, APACHE II score, and complications in patients with refractory septic shock.

Glioblastoma, a deadly brain tumor, shows limited response to standard therapies like te-mozolomide (TMZ). Recent findings from the REGOMA trial underscore a significant survival improvement offered by regorafenib (REGO) in recurrent glioblastoma. Our study aimed to propose a 3D ex vivo drug response precision medicine approach to investigate recurrent glio-blastoma sensitivity to REGO and elucidate the underlying molecular mechanisms involved in tumor resistance or responsiveness to treatment. 3D glioblastoma organoids (GB-EXPs) obtained from 18 patients’ resected recurrent glioblastoma tumors were treated with TMZ and REGO. Drug responses were evaluated using NAD(P)H FLIM, stratifying tumors as responders (Resp) or non-responders (NR). Whole-exome sequencing was performed on 16 tissue samples, and whole-transcriptome analysis on 13 GB-EXPs treated and untreated. We found 35% (n=9) and 77% (n=20) of tumors responded to TMZ and REGO, respectively, with no instances of TMZ-Resp be-ing REGO-NR. Exome analysis revealed a unique mutational profile in REGO-Resp tumors compared to NR tumors. Transcriptome analysis identified distinct expression patterns in Resp and NR tumors, impacting Rho GTPase and NOTCH signaling, known to be involved in drug response. In conclusion, recurrent glioblastoma tumors were more responsive to REGO com-pared to TMZ treatment. Importantly, our approach enables a comprehensive longitudinal ex-ploration of the molecular changes induced by treatment, unveiling promising biomarkers in-dicative of drug response.

Neuroblastoma is the most common tumour in children under 1 year old, accounting for approximately 50% of infant cancer cases. Although current treatments are relatively efficacious against this cancer, associated adverse effects could be detrimental to growth and development. In contrast, glioblastoma accounts for 52% of brain tumours and has an extremely poor prognosis. Current chemotherapeutics include temozolomide, which has numerous negative side-effects and a low-effective rate. Previous studies have shown the manipulation of autophagy to be a promising method for targeting cancers, including glioblastoma. We sought to determine the effects of autophagic alterations in combination with current chemotherapies in both neuroblastoma and glioblastoma. Supplementing cisplatin or temozolomide with autophagy activator rapamycin stabilized cancer cell mitochondria, despite having little effect on apoptosis or oxidative stress. Autophagy inhibition via 3-methyladenine or hydroxychloroquine alongside standard chemotherapies enhanced apoptosis and oxidative stress, with 3-methyladenine also disrupting mitochondrial health. Importantly, combining hydroxychloroquine with 0.5 µM cisplatin or 50 µg/mL temozolomide was as or more effective than 2 µM cisplatin or 100 µg/mL temozolomide alone. Analyzing these interesting results, a combined treatment of autophagy inhibitor with a standard chemotherapeutic agent could help to improve patient prognosis and reduce chemotherapy doses and their associated side-effects.

The most aggressive primary malignant brain tumor in adults is glioblastoma (GBM), which has poor overall survival (OS). There is a high relapse rate among patients with GBM despite maxi-mally safe surgery, radiation therapy, temozolomide (TMZ), and aggressive treatment. Hence, there is an urgent and unmet clinical need for new approaches to managing GBM. The current study identified modules (MYC, EGFR, PIK3CA, SUZ12, and SPRK2) involved in GBM disease through the NeDRex plugin. Furthermore, hub genes were identified in a comprehensive interaction network containing 7,560 proteins related to GBM disease and 3,860 proteins associated with signaling pathways involved in GBM. By integrating the results of the aforementioned analyses and performing centrality analysis again, eleven key genes involved in GBM disease were identi-fied. ProteomicsDB or Gliovis databases were used for determining the gene expression in normal or tumor brain tissue. The NetworkAnalyst and the mGWAS-Explorer tools identified miRNAs, SNPs, and metabolites associated with these 11 genes. Moreover, a literature review of recent studies revealed other lists of metabolites related to GBM disease. The enrichment analysis of iden-tified genes, miRNAs, and metabolites associated with GBM disease was done using ExpressAna-lyst, miEAA, and MetaboAnalyst tools. Further investigation of metabolite roles in GBM was done through the pathway, joint pathway, and network analyses. The results of this study identified 11 genes (UBC, HDAC1, CTNNB1, TRIM28, CSNK2A1, RBBP4, TP53, APP, DAB1, PINK1, and RELN), five miRNAs (hsa-mir-221-3p, hsa-mir-30a-5p, hsa-mir-15a-5p, hsa-mir-130a-3p, hsa-let-7b-5p), six metabolites (HDL, N6-acetyl-L-lysine, cholesterol, formate, N, N-dimethylglycine/xylose and X2. piperidinone) and 15 distinct signaling pathways that play an indispensable role in the GBM disease development. To establish early diagnostic methods and plan personalized GBM treatment strategies, the identified top genes-miRNAs and metabolite signatures can be targeted.

The poor oxidation resistance of refractory high-entropy alloys (RHEAs) is a major obstacle for their use in high-temperature engineering applications. Anti-oxidation coating technology is an effective method for improving the oxidation resistance. In this paper, the Si-20Cr-20Fe coating was prepared on MoNbTaTiW RHEA by a fused slurry method. The microstructural evolution and compositions of the silicide coating under high-temperature oxidation environment were studied. The results show that the silicide coating could effectively prevent the oxidation of the MoNbTaTiW RHEA. The initial silicide coating had a double-layer structure; a high silicon-content layer mainly composed of MSi2 as the outer layer and a low silicon-content layer mainly contained M5Si3 as the inner layer. Under high-temperature oxidation conditions, the silicon element diffused from the silicide coating to the RHEA substrate while the oxidation of the coating occurred. After oxidation, the coating was composed of an outer oxide layer and an inner silicide layer. The silicide layer moved toward the inside of the substrate, led to the increase of its thickness. Compared with the initial silicified layer, its structure did not change significantly. The structure and compositions of the oxide layer on the outer surface strongly depended on the oxidation temperature. This paper provides a strategy for protecting RHEAs from oxidation at high-temperature environments.

Background: Glioblastoma (GBM) is a highly aggressive, invasive, and growth-factor-independent grade IV glioma. Survival following the diagnosis is generally poor, with a median survival of approximately 15 months, and it is considered the most aggressive and lethal central nervous system tumor. Conventional treatments based on surgery, chemotherapy, and radiation therapy only delay progression, and death is inevitable. Malignant glioma cells are resistant to traditional therapies, potentially due to a subpopulation of glioma stem cells that are invasive and capable of rapid regrowth. Methods: Systematic retrieval of information was performed on PubMed. Specified keywords were used in PubMed and the articles published in peer-reviewed scientific journals were associated with brain GBM cancer, sodium iodide symporter (NIS). Additionally, the words 'radionuclide therapy', 'radioiodine', 'iodine-131', 'molecular imaging', 'gene therapy', and 'translational imaging' were used. Other keywords such as ‘glioblastoma', 'targeted', 'theranostic', 'symporter', 'virus', 'solid tumor', 'combined therapy', 'pituitary', or 'plasmid' were also used in appropriate literature databases and search engines. 19 articles were found in this search on Mesenchymal Stem Cell Sodium Iodide Symporter and GBM. \ These articles were from the years 2000 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. Results: For as long as they express functional NIS, mesenchymal stem cells systemically repress T and B cells; however, after that, they are largely replaced by mesenchymal stem cells generated from embryonic stem cells that are functionally competent. As a result of their natural capacity to identify malignancies, MSC are employed as tumor therapy vehicles. Because MSCs may be transplanted in several methods, they have been proposed as ideal vehicles for NIS gene transfer. Conclusion: Non-invasive imaging-based detection of glioma stem cells presents an alternate means to monitor the tumor and diagnose and evaluate recurrence. The sodium iodine symporter gene is a specific gene in a variety of human thyroid disease that functions to move iodine into the cell. In recent years, an increasing number of studies related to the sodium iodide symporter gene have been reported in a variety of tumors and as therapeutic vectors for imaging and therapy. Gene therapy and nuclear medicine therapy for GBM provide a new direction.

Despite improved knowledge regarding diagnosis and treatment of osteomyelitis of the jaw (OMJ), it remains a clinical challenge for oral and maxillofacial surgeons. This study aimed to identify risk factors associated with severe forms of OMJ, i.e. related to the occurrence of major complications or the refractory course of the disease. A retrospective study was performed based on the medical records of all patients diagnosed with OMJ from the past 20 years. Collected data included demographic information, medical and dental history, clinical, radiological, and bacterial findings as well as treatment modalities. The main outcome variables were the onset of major complications and treatment results. Fifty-four patients were included. Our results showed that alcohol and smoking habits, as well as malnutrition, were significantly associated with the occurrence of major complications. We also established that dental implant–induced OMJ should be considered as an aggressive subtype of OMJ. Finally, clinical bone exposure was significantly associated with unfavorable outcomes, whereas dental causes or radiological evidence of periosteal reaction were predictive of successful outcomes. Identifying such factors could be useful in preventing serious complication and informing patients about the refractory course of the disease based on the presence of these factors.

Background: External beam radiation therapy requires a sophisticated and laborious planning procedure. To improve the efficiency and quality of the planning procedure, machine learning predictions of the dose distributions have been introduced to speed up the planning procedure and to serve as quality assurance. The most recent dose prediction models are based on deep learning U-Nets that give good approximations of the dose in 3D almost instantly. It is our purpose to train a 3D dose prediction for glioblastoma VMAT treatment and test its robustness and sensitivity for the purpose of quality assurance of automatic contouring. Methods: From a cohort of 125 glioblastoma (GBM) patients, VMAT plans were created according to a clinical protocol. The initial model was trained on a concatenated 3D U-Net. A total of 60 cases were used for training, 15 for validation and 20 for testing. The prediction model was tested for sensitivity to dose changes according to realistic contour variations. Additionally, the model was tested for robustness by exposing it to a worst-case test set containing out-of-distribution cases.Results: The initially trained prediction model had a dose score of 0.94 Gy and a mean DVH score for all structures of 1.95 Gy. In terms of sensitivity, the model was able to predict the dose changes that occurred due to the contour variations with a mean error of 1.38 Gy.Conclusions: We obtained a 3D VMAT dose prediction model for GBM with limited data, providing good sensitivity to realistic contour variations. We tested and improved the model's robustness, by targeted updating the training set, making it a useful technique for dose awareness in the contouring evaluation and quality assurance.

Aggressive mature T-cell lymphoma (TCL) is a disease that carries a poor prognosis. The mechanism, at the functional protein level, of the resistance to therapy of TCL has not yet been well clarified. To comprehensively clarify the mechanism, we first reviewed the literature, as mentioned in the Introduction section, on 22 types of representative functional proteins reported as being potentially associated with treatment resistance, mainly in hematologic tumors. Next, we retrospectively analyzed the tumor cell expressions of these 22 functional proteins in 16 randomly selected patients with TCL who had received CHOP (cyclophosphamide, hydroxyl doxorubicin, oncovin, and prednisolone) therapy as first-line treatment. As a result, we propose a new three-group prognostic classification of TCL (the TCL Urayasu Classification) based on the mechanism of resistance to treatment of these tumors. The study subjects included 7 patients (44%) with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 6 patients (38%) with angioimmunoblastic T-cell lymphoma (AITL), and 3 patients (19%) with anaplastic large T-cell lymphoma (ALCL). Immunohistochemistry was performed in paraffin-embedded tumor tissue sections prepared from these patients as antigens using antibodies against the 22 previously reported treatment-resistance-related proteins to determine the tumor cell expression statuses of these proteins. Log-rank test was performed to compare the overall survival (OS) after CHOP therapy of the patients showing positive and negative immunostaining for these proteins, as well as among patients grouped based on other factors. Overall, the median OS of the TCL patients was about 33.5 months. When compared by the disease type, the prognosis was found to be worse in the order of ALCL, AITL, and PTCL. A multivariate analysis showed that expression of glucose-regulated protein 94 (GRP94), a protein that serves as a pro-survival component under endoplasmic reticulum (ER) stress in the tumor microenvironment, was significantly associated with shortened survival. No significant difference was observed for the conventional poor prognostic factors: high-risk International Prognostic Index (IPI) and high-risk Prognostic Index for peripheral T-cell lymphoma, unspecified (PTCL-U) (PIT). However, when GRP94 was combined with six other factors, listed below, as survival-shortening factors, significant differences were observed. The 6 factors were 1) programmed cell death-ligand 1 (PD-L1) and 2) programmed cell death 1 (PD-1), which are involved in immune surveillance; 3) aldo-keto reductase family 1 member C3 (AKR1C3), which is an enzyme that inactivates HO (hydroxyl doxorubicin [H] and oncovin [O]) of CHOP; 4) P53, a tumor suppressor; 5) Glucose-regulated protein 78 (GRP78), an ER stress protein; 6) thymidine phosphorylase (TP), which is an enzyme involved in thymidine catabolism. Based on the combination of GRP94 and the six other factors expressed in the tumors, we propose a new prognostic classification system for TCL (TCL Urayasu classification). Group 1 (group with a relatively good prognosis): GRP94-negative (n = 6; median OS, 88 months; p < 0.01); Group 2 (group with a poor prognosis): GRP94-positive, plus expression of 2 of the 6 aforementioned factors (n = 5; median OS, 25 months; p > 0.05); and Group 3 (group with a very poor prognosis): GRP94-positive, plus expression of at least 3 of the 6 aforementioned factors (n = 5; median OS, 10 months; p < 0.01). Thus, the TCL Urayasu prognostic classification is a simple, useful, and innovative classification that also explains the mechanism of resistance to treatment for each functional protein. Accumulation of more cases and further analyses are expected in the future to enable clinical application, such as use of a stratified treatment approach and treatment using inhibitors.

Stem cell therapy in canines has increased considerably in recent years; however, there are few publications on the treatment of perianal fistulas (PF) in this species, and there is no agreed protocol for the number of cells per dose and their repetitions, nor for the in situ delivery methodology and follow-up period after cell therapy. The aim of this open-label clinical trial was to demonstrate the efficacy and safety of a new protocol for in situ administration of low-dose, expanded and cryopreserved allogeneic adipose-derived stem cells for the treatment of refractory spontaneous perianal fistula. The methodology consisted of intralesional application of 1 to 3 doses - depending on evidence of clinical signs of recurrence - of 5x106 cryopreserved allogeneic adipose-derived allogeneic stem cells in each fistula. The study was conducted in 14 dogs regardless of sex, breed or age with a clinical diagnosis of refractory PF presented between January 2019 and December 2023. Cells were diluted in 1 mL of phosphate-buffered saline and this volume was applied to five sites at the edge of the FP in an amount of 1x106 per application site. The evolution of the fistula was followed for 12 to 48 months. Efficacy was determined by complete healing as evidenced by complete closure of the fistula, which was observed in 100% of the cases studied one month after therapy, with a subsequent follow-up of 12 to 48 months after therapy. In addition, there were no local or systemic adverse effects assessed by clinical examination, complete blood count and blood biochemistry. In conclusion, the protocol used in this work demonstrates the efficacy without adverse effects of in situ application of allogeneic adipose-derived adipose stem cells in low doses and cell replicates to treat canine refractory PF, providing a simple, non-invasive, long-lasting and low-cost therapeutic option.

To investigate factors associated with the success of switching to faricimab for type 1 macular neovascularization (MNV) refractory to intravitreal aflibercept (IVA). This retrospective cohort study included patients with type 1 MNV who were switched to faricimab because they were refractory to IVA at two centers. The main outcome was an extension of the treatment interval after 6 months, and factors related to the success or failure of the extension and visual and anatomical outcomes were assessed. The analysis included 43 eyes of 43 patients. Extended dosing intervals of more than 2 weeks were identified in 14 eyes (32.6%). A short dosing interval before the switch, the absence of polypoidal lesions, and a thin central choroidal thickness before the switch were identified as factors involved in successful extension. For patients with refractory type 1 MNV, switching to faricimab is a safe and potential option to extend from existing dosing intervals.

Glioblastoma (GBM) is an aggressive brain cancer characterized by significant molecular and cellular heterogeneity, complicating treatment efforts. Current standard therapies, including surgical resection, radiation, and temozolomide (TMZ) chemotherapy, often fail to achieve long-term remission due to tumor recurrence and resistance. A pro-oxidant environment is in-volved in glioma progression, with oxidative stress contributing to the genetic instability that leads to gliomagenesis. However, the generation of reactive oxygen species (ROS) results in the dysregulation of antioxidant defenses in GBM cells, creating a vulnerability that can be thera-peutically exploited. Evaluating pro-oxidant therapies in brain tumors is crucial due to their po-tential to selectively target and eradicate cancer cells by exploiting the elevated oxidative stress levels inherent in these malignant cells, thereby offering a novel and effective strategy for overcoming resistance to conventional therapies. This study investigates the therapeutic potential of doxorubicin (DOX) and photodynamic therapy (PDT) with Me-ALA, focusing on their effects on redox homeostasis. Basal ROS levels and antioxidant gene expression (NFE2L2, CAT, GSR) were quantitatively assessed across GBM cell lines, revealing significant variability probably linked to genetic differences. DOX and PDT treatments, both individually and in combination, were ana-lyzed for their efficacy in inducing oxidative stress and cytotoxicity. An in silico analysis further explored the relationship between gene mutations and oxidative stress in GBM patients, providing insights into the molecular mechanisms underlying treatment responses. Our findings suggest that pro-oxidant therapies, such as DOX and PDT in combination, could selectively target GBM cells, highlighting a promising avenue for improving therapeutic outcomes in GBM.

Background: Despite continuous improvements in revascularization techniques, refractory angina without potential revascularization options remains a relevant clinical issue with significant impact on patient’s quality of life. Recently, a novel device, the Coronary Sinus Reducer (CSR), has been introduced into clinical practice as a therapeutic option for patients with disabling angina pectoris. In this single-center, observational study, we evaluated the mid-term (3-month) safety and efficacy of the CSR in a real-world cohort. Methods: The study population consisted of 55 patients with refractory angina without potential revascularization options, predominantly men (87.3%) with a high cardiovascular risk factor burden and advanced angina (baseline CCS angina class 3.15 ± 0.6). In terms of procedure safety, all patients underwent successful device deployment with only one periprocedural complication. Results: At the 3-month follow-up we observed statistically significant improvement in angina control measured CCS class and SAQ-7 Total questionnaire along with increased abolition of physical limitation – 6-MWT (233.3 ± 107.1 vs 305.2 ± 126.8; p&lt;0.0001). Additionally, we observed significant improvement in terms of quality of life measurements SF-36, the EQ-5D-5L questionnaire, and the EQ-VAS. Conclusions: Our real-world data suggest that CSR implantation is a relatively safe procedure and appears to be particularly effective in relieving angina symptoms and improving quality of life in subjects with refractory angina.

The prognosis of patients with recurrent or metastatic of the head and neck squamous-cell carcinoma (HNSCC) refractory to platinum-based chemotherapy is severe and, consequently, the identification of therapeutic options for this category of patients is a priority. Nivolumab, an anti- programmed cell death protein 1 (anti-PD-1) monoclonal antibody, has been approved for the treatment of recurrent or metastatic HNSCC after platinum-based therapy progressing. We present the early experience of two academic center including diagnostic, clinical, biological, therapeutic and outcomes characteristics of head and neck cancer (HNC) patients treated with Nivolumab. The purpose of the study is to identify certain peculiarities and to report them compared to the data from the literature in order to generate some hypotheses that coud constitute criteria for the selection of cases with maximum benefit to immunotherapy. Analyzing the data obtained from 18 patients treated in Emergency County Hospital Craiova, "Saint Nectarie" Oncological Hospital Craiova and Euroclinic Oncological Center Iasi January 2020 and March 2023 it could be hypothesized that lower nadir values of neutrophil to lymphocyte ratio (<3.5) and the adition of intensive regimens of chemotherapy and radiotherapy could justify a favorable response in terms of progression free survival (PFS) during immunotherapy with Nivolumab. To our knowledge, the study included the first two cases of second primary malignancy (SPM) in the head neck region treated with Nivolumab. The reported data support a possible benefit of the sequential administration of radiotherapy, immunotherapy for SPM cases. Higher positive dynamic of neutrophil to lymphocyt ratio (NLR) could be associated with worst outcome during immunotherapy. All study observations including the role of infections and antibiotic treatment as well as the possible biomarker value of NLR variation during immunotherapy should be investigated in multicenter clinical trials.

This paper presents the rationale for using ultra low intensity transcranial light photodynamic treatment (LIT-PDT) for treating glioblastoma. Glioblastoma is currently treated with maximal safe resection, temozolomide and ionizing irradiation. Mortality in 2024 remains at over 80% within several years from diagnosis. 5-aminolevulinic acid (5-ALA) is a heme precursor that is selectively taken up preferentially by malignant cells, including glioblastoma. Photon energy can be transduced to molecular oxygen by a 5-ALA metabolite, PpIX, transforming oxygen to the singlet state, a reactive oxygen species (ROS) that destroys or damages vital glioblastoma cell structures. In PDT, light energy ~ 100 to 200 J / cm2, at 630 nm is delivered intraoperatively after resection and preoperative oral 5-ALA. This generates ROS cytotoxicity in residual glioblastoma cells within the resection cavity wall. 630 nm light poorly penetrates skin, skull, and brain tissue. That currently restricts PDT to a single intraoperative session using high flux light. LIT-PDT addresses some current shortcomings of 5-ALA PDT treatment. Part 1 analyzes published data indicating that continuous ultra low light flux, 17 μW / cm2, over 24 hours for a total delivery of 1.5 J / cm2, is effective for 5-ALA PDT treatment. That opens the way for repetitive, extracranial light to deliver enough energy for low flux, long duration PDT to any deep brain structure using less than 12 W total distributed over the entire scalp area. In Part 2, by analysis of 5-ALA and PpIX physiology, it became apparent that four non oncology drugs - ciprofloxacin, deferiprone, telmisartan and ziprasidone, will increase energy capture by GB cells, thereby increasing PDT treatment cytotoxicity. A phased pilot study of LIT-PDT treatment is being planned.

Background: Glioblastoma is the most common primary brain neoplasm in adults, with still a poor prognosis despite a constant effort to improve patients’ survival. Some neuroradiological volumetric parameters seem to play a predictive role on Overall Survival (OS) and Progression Free Survival (PFS). The aim of this study is to analyze the impact that the volumetric areas of contrast-enhancing tumor and perineoplastic edema have on survival of patients treated for glioblastoma; Methods: A series of 87 patients who underwent surgery was retrospectively analyzed; OS and PFS were considered as the end points of the study. For each patient a multidisciplinary revision was conducted in collaboration with the Neuroradiology and Neuro-Oncology board. A manual and semi-automatic measurement were adopted to perform the radiological evaluation: contrast Enhancement Preoperative (CE-PTV) and Postoperative Tumor Volume (CE-RTV), Edema/Infiltration Preoperative (T2/FLAIR-PV) and Postoperative Volume (T2/FLAIR-RV); necrosis volume inside the tumor (NV); total tumor volume, including necrosis (TV); Results: The median OS value was 9 months and the median PFS value was 4 m; the mean values were respectively 12,3 m and 6,9 m. Multivariate analysis showed that the OS related factors were: adjuvant chemo-radiotherapy (p &lt; 0,0001), CE-PTV &lt; 15 cm³ (p=0,03), surgical resection &gt; 95% (p=0,004) and the presence of a “pseudo-capsulated” radiological morphology (p=0,04); Conclusions: maximal safe resection is one of the most relevant predictive factors for patients’ survival. The semi-automatic pre-operative MRI evaluation could play a key role in prognostically categorizing these tumors.

Glioblastomas (GBM) are most common, primary brain tumors in adults. Despite advances in neurosurgery, radio- and chemotherapy, the median survival of GBM patients is 15 months. Recent large-scale genomic, transcriptomic and epigenetic analyses have shown the cellular and molecular heterogeneity of GBMs, which hampers the outcomes of standard therapies. We have established 13 GBM-derived cell cultures from fresh tumor specimens and characterized them molecularly using RNAseq, immunoblotting and immunocytochemistry. Evaluation of proneural (OLIG2, IDH1R132H, TP53 and PDGFRα), classical (EGFR) and mesenchymal markers (CHI3L1/YKL40, CD44 and phospho-STAT3), as well as expression of pluripotency (SOX2, OLIG2, NESTIN) and differentiation (GFAP, MAP2, β-Tubulin III) markers revealed the striking inter-tumor heterogeneity of primary GBM cell cultures. Upregulated expression of VIMENTIN, N-CADHERIN and CD44 at mRNA/protein levels suggested increased epithelial to mesenchymal transition (EMT) in most studied cell cultures. The effects of temozolomide (TMZ) or doxorubicin (DOX) were tested in three GBM-derived cell cultures with different methylation status of the MGMT promoter. Amongst TMZ- or DOX-treated cultures the strongest accumulation of apoptotic markers: caspase 7 and PARP were found in WG4 cells with methylated MGMT suggesting that its methylation status predicts vulnerability to both drugs. As many GBM-derived cells showed high EGFR levels, we tested the effects of AG1478, an EGFR inhibitor, on downstream signaling pathways. AG1478 caused decreased levels of phospho-STAT3, thus inhibition of active STAT3 augmented antitumor effects of DOX and TMZ in cells with methylated and intermediate status of MGMT. Altogether, our findings show that GBM-derived cell cultures mimic the considerable tumor heterogeneity and identifying patient-specific signaling vulnerabilities can assist in overcoming therapy resistance, by providing personalized combinatorial treatment recommendations.

Gold nanoparticles (GNPs) have demonstrated significant dose enhancement with kilovoltage (kV) X-rays however recent studies have shown inconsistent findings with megavoltage (MV) X-rays. We proposed to evaluate the radiosensitization effect in U87 glioblastoma (GBM) cells in the presence of 42 nm GNPs and irradiated with a clinical 6 MV photon beam. Cytotoxicity and radiosensitization was observed using MTS and clonogenic cellular radiation sensitivity assays respectively. Sensitization enhancement ratio was calculated for 2 Gy (SER2Gy) with GNP (100 μg/mL). Dark field and MTS assay revealed high co-localization and good biocompatibility of the GNPs with GBM cells. Significant sensitization enhancement of 1.45 (P = 0.001) was observed with GNP 100 μg/mL. Similarly, at 6 Gy there was significant difference in the survival fraction between GBM alone group (Mean (M) = 0.26, Standard Deviation (SD) = 0.008) and GBM plus GNP group (M = 0.07, SD = 0.05, P = 0.03). GNPs enable radiosensitization in U87 GBM cells at 2 Gy when irradiated using a clinical platform. In addition to the potential clinical utility of GNPs, these studies demonstrate the effectiveness of a robust and easy to standardise in-vitro model that can be employed for future studies involving metal nanoparticle plus irradiation.

During glioblastoma treatment, the pharmaceutical monoclonal antibody to VEGF, bevacizumab, has improved quality of life and delayed progression for several months but has not, or only marginally prolonged overall survival. In 2017 several dramatic research papers appeared that are crucial to our understanding of glioblastoma vis a vis the mode of action of bevacizumab. As a consequence of these papers, a new, potentially more effective, treatment protocol can be built around bevacizumab. This is the ADZT Regimen where four old drugs are added to bevacizumab. These four are apremilast, marketed to treat psoriasis, dapsone, marketed to treat Hansen’s disease, zonisamide, marketed to treat seizures, and telmisartan, marketed to treat hypertension. The ancillary attributes of each of these drugs has been shown to augment bevacizumab. This paper will detail the research data supporting that contention.

Glioblastoma multiforme (GBM) is a highly invasive brain malignancy originating from astrocytes, accounting for approximately 30% of central nervous system malignancies. Despite advancements in therapeutic strategies including surgery, chemotherapy, and radiopharmaceutical drugs, the prognosis for GBM patients remains dismal. The aggressive nature of GBM necessitates the identification of molecular targets and the exploration of effective treatments to inhibit its proliferation. The Notch signaling pathway, which plays a critical role in cellular homeostasis, becomes deregulated in GBM, leading to increased expression of pathway target genes such as MYC, Hes1, and Hey1, thereby promoting cellular proliferation and differentiation. Recent research has highlighted the regulatory role of non-coding RNAs (ncRNAs) in modulating Notch signaling by targeting critical mRNA expression at the post-transcriptional or transcriptional levels. Specifically, various types of ncRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been shown to control multiple target genes and significantly contribute to the carcinogenesis of GBM. Furthermore, these ncRNAs hold promise as prognostic and predictive markers for GBM. This review aims to summarize the latest studies investigating the regulatory effects of ncRNAs on the Notch signaling pathway in GBM.

Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options and a poor prognosis. Cancer stem cells (CSCs) have emerged as a critical factor in GBM resistance and management, contributing to tumor growth, heterogeneity, and immunosuppression. The transcription factor FOXM1 has been identified as a key player in the progression, spread, and therapy resistance of various cancers, including GBM. In this study, researchers conducted structure-based in silico screening to identify natural compounds that could target the DNA-binding domain (DBD) of the FOXM1 protein. Through molecular docking analyses, identified Silybin B as a potential inhibitor of FOXM1, exhibiting strong interaction with the protein. MD simulations were performed to validate the binding stability of the FOXM1-Silybin B complex. The study provides valuable insights into the potential of Silybin B as a FOXM1 inhibitor and its ability to induce senescence in GBM stem cells. These findings contribute to the development of structure-based design strategies for FOXM1 inhibitors and innovative therapeutic approaches for the treatment of Glioblastoma.