Revolutionizing Glioblastoma Treatment: A Comprehensive Overview of Modern Therapeutic Approaches.

Glioblastoma is the most common malignant primary brain tumor in the adult population, with an average survival of 12.1 to 14.6 months. The standard treatment, combining surgery, radiotherapy, and chemotherapy, is not as efficient as we would like. However, the current possibilities are no longer limited to the standard therapies due to rapid advancements in biotechnology. New methods enable a more precise approach by targeting individual cells and antigens to overcome cancer. For the treatment of glioblastoma, these are gamma knife therapy, proton beam therapy, tumor-treating fields, EGFR and VEGF inhibitors, multiple RTKs inhibitors, and PI3K pathway inhibitors. In addition, the increasing understanding of the role of the immune system in tumorigenesis and the ability to identify tumor-specific antigens helped to develop immunotherapies targeting GBM and immune cells, including CAR-T, CAR-NK cells, dendritic cells, and immune checkpoint inhibitors. Each of the described methods has its advantages and disadvantages and faces problems, such as the inefficient crossing of the blood-brain barrier, various neurological and systemic side effects, and the escape mechanism of the tumor. This work aims to present the current modern treatments of glioblastoma.

Cellular Distribution and Ultrastructural Changes in HaCaT Cells, Induced by Podophyllotoxin and Its Novel Fluorescent Derivative, Supported by the Molecular Docking Studies.

Podophyllotoxin (PPT) is an active pharmaceutical ingredient (API) with established antitumor potential. However, due to its systemic toxicity, its use is restricted to topical treatment of anogenital warts. Less toxic PPT derivatives (e.g., etoposide and teniposide) are used intravenously as anticancer agents. PPT has been exploited as a scaffold of new potential therapeutic agents; however, fewer studies have been conducted on the parent molecule than on its derivatives. We have undertaken a study of ultrastructural changes induced by PPT on HaCaT keratinocytes. We have also tracked the intracellular localization of PPT using its fluorescent derivative (PPT-FL). Moreover, we performed molecular docking of both PPT and PPT-FL to compare their affinity to various binding sites of tubulin. Using the Presto blue viability assay, we established working concentrations of PPT in HaCaT cells. Subsequently, we have used selected concentrations to determine PPT effects at the ultrastructural level. Dynamics of PPT distribution by confocal microscopy was performed using PPT-FL. Molecular docking calculations were conducted using Glide. PPT induces a time-dependent cytotoxic effect on HaCaT cells. Within 24 h, we observed the elongation of cytoplasmic processes, formation of cytoplasmic vacuoles, progressive ER stress, and shortening of the mitochondrial long axis. After 48 h, we noticed disintegration of the cell membrane, progressive vacuolization, apoptotic/necrotic vesicles, and a change in the cell nucleus's appearance. PPT-FL was detected within HaCaT cells after ~10 min of incubation and remained within cells in the following measurements. Molecular docking confirmed the formation of a stable complex between tubulin and both PPT and PPT-FL. However, it was formed at different binding sites. PPT is highly toxic to normal human keratinocytes, even at low concentrations. It promptly enters the cells, probably via endocytosis. At lower concentrations, PPT causes disruptions in both ER and mitochondria, while at higher concentrations, it leads to massive vacuolization with subsequent cell death. The novel derivative of PPT, PPT-FL, forms a stable complex with tubulin, and therefore, it is a useful tracker of intracellular PPT binding and trafficking.

Validation of Polish version of Gastrointestinal Dysfunction Scale for Parkinson's Disease.

AIM OF STUDY: The Gastrointestinal Dysfunction Scale for Parkinson's Disease (GIDS-PD) is a novel, disease-specific self-report questionnaire used to quantitatively assess features of gastrointestinal dysfunction symptoms in patients with Parkinson's Disease. The aim of this paper was to validate the Polish translation of the scale, to summarise its consistency with the English language version, and to assess its clinimetric properties. CLINICAL RATIONALE FOR STUDY: Gastrointestinal dysfunction is a common and often debilitating manifestation of Parkinson's Disease (PD). Gastrointestinal symptoms are also considered to be prodromal features of this disease. To date, there has been no scale in Polish that has precisely assessed gastrointestinal symptoms in patients with PD. MATERIAL AND METHODS: The GIDS-PD was translated into Polish by two investigators (M.K. and J.N.). A back-translation was completed by two separate investigators (M.F. and A.A.) who were not involved in the original translation. Afterwards, 10 Polish PD patients underwent cognitive pre-testing. After the final translation was officially approved by the Movement Disorder Society, it was tested on 64 individuals with PD during field testing. For the purpose of testing scale reliability, 20 of the patients recruited for field testing underwent the GIDS-PD for a second time after 8-12 weeks. RESULTS: The GIDS-PD demonstrated overall good consistency (Cronbach's alpha of 0.74, ICC of 0.74). Regarding the individual domains, the constipation subscore demonstrated good reliability, the bowel irritability subscore demonstrated moderate reliability, and the upper GI subscore demonstrated poor reliability. Upper GI symptoms seem to be less pronounced, and also more varied, in the Polish PD population than in its English language counterpart. CONCLUSIONS AND CLINICAL IMPLICATIONS: This paper provides a validated Polish translation of the GIDS-PD questionnaire. We highly recommend using the GIDS-PD for research purposes, as well as everyday clinical practice in the Polish PD population.

Unilateral gamma knife thalamotomy for tremor safety and efficacy in multimodal assessment: a prospective case-control study with two-year follow-up.

INTRODUCTION: Unilateral gamma knife thalamotomy (GKT) is a treatment option for pharmacoresistant tremor of various aetiologies. There have been to date no randomised controlled trials performed to assess its safety and efficacy. Our aim was to summarise a two-year multimodal observation of patients with tremor caused by Parkinson's Disease (PD) or essential tremor (ET). MATERIAL AND METHODS: 23 patients with PD (n = 12) or ET (n = 11) were included. They underwent assessments before, V0 (n = 23), and 12 months, V12 (n = 23), and 24 months, V24 (n = 15), after unilateral GKT. Patients were assessed with psychological tests and acoustic voice analysis. Tremor assessment was performed with a digitising table using the Fahn-Tolosa-Marin rating scale (FTMRS). The Unified Parkinson's Disease rating scale part III (UPDRS-III) was also used in the PD group. Gait and balance was assessed using clinical tests, stabilometric platform, and treadmill. RESULTS: No side effects were observed in a two-year follow-up. There was no notable deterioration observed in the patients' psychological evaluation, speech, or assessment of gait and balance. The scores were significantly lower (p = 0.01) in parts A and B of FTMRS one year after GKT. In post hoc analysis, the scores did not differ significantly between V0 and V24. In FTMRS part C (activities of daily living), no significant change was observed. There was no significant difference in total UPDRS part III score or in score of UPDRS part III domains 3 and 4 ('tremor at rest' and 'action and postural tremor of hands') between measurements. CONCLUSIONS: UGKT may be a safe treatment modality if performed in an experienced centre. Tremor reduction may diminish over time, and UGKT did not lead to cognitive, gait or speech deterioration in a long-term observation.

Chemokine Fractalkine and Non-Obstructive Coronary Artery Disease-Is There a Link?

Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major coronary artery with a fractional flow reserve (FFR) of ≤0.80 observed in coronary angiography. The pathogenesis and progression of NO-CAD are still not fully understood, however, inflammatory processes, particularly atherosclerosis and microvascular dysfunction are known to play a major role in it. Chemokine fractalkine (FKN/CX3CL1) is inherently linked to these processes. FKN/CX3CL1 functions predominantly as a chemoattractant for immune cells, facilitating their transmigration through the vessel wall and inhibiting their apoptosis. Its concentrations correlate positively with major cardiovascular risk factors. Moreover, promising preliminary results have shown that FKN/CX3CL1 receptor inhibitor (KAND567) administered in the population of patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), inhibits the adverse reaction of the immune system that causes hyperinflammation. Whereas the link between FKN/CX3CL1 and NO-CAD appears evident, further studies are necessary to unveil this complex relationship. In this review, we critically overview the current data on FKN/CX3CL1 in the context of NO-CAD and present the novel clinical implications of the unique structure and function of FKN/CX3CL1 as a compound which distinctively contributes to the pathomechanism of this condition.

Multimodality OCT, IVUS and FFR evaluation of coronary intermediate grade lesions in women vs. men.

Background: The pathophysiology of atherosclerotic plaque formation and its vulnerability seem to differ between genders due to contrasting risk profiles and sex hormones, however this process is still insufficiently understood. The aim of the study was to compare the differences between sexes regarding the optical coherence tomography (OCT), intravascular ultrasound (IVUS) and fractional flow reserve (FFR)-derived coronary plaque indices. Methods: In this single-center multimodality imaging study patients with intermediate grade coronary stenoses identified in coronary angiogram (CAG) were evaluated using OCT, IVUS and FFR. Stenoses were considered significant when the FFR value was ≤0.8. Minimal lumen area (MLA), was analyzed by OCT in addition to plaque stratification into fibrotic, calcific, lipidic and thin-cap fibroatheroma (TCFA). IVUS was used for evaluation of lumen-, plaque- and vessel volume, as well as plaque burden. Results: A total of 112 patients (88 men and 24 women) with chronic coronary syndromes (CCS), who underwent CAG were enrolled. No significant differences in baseline characteristics were present between the study groups. The mean FFR was 0.76 (0.73-0.86) in women and 0.78 ± 0.12 in men (p = 0.695). OCT evaluation showed a higher prevalence of calcific plaques among women than men p = 0.002 whereas lipid plaques were more frequent in men (p = 0.04). No significant differences regarding minimal lumen diameter and minimal lumen area were found between the sexes. In IVUS analysis women presented with significantly smaller vessel area, plaque area, plaque volume, vessel volume (11.1 ± 3.3 mm2 vs. 15.0 ± 4.6 mm2 p = 0.001, 6.04 ± 1.7 mm2 vs. 9.24 ± 2.89 mm2 p < 0.001, 59.8 ± 35.2 mm3 vs. 96.3 (52.5-159.1) mm3 p = 0.005, 106.9 ± 59.8 mm3 vs. 153.3 (103-253.4) mm3 p = 0.015 respectively). At MLA site plaque burden was significantly greater for men than women (61.50 ± 7.7% vs. 55.5 ± 8.0% p = 0.005). Survival did not differ significantly between women and men (94.6 ± 41.9 months and 103.51 ± 36.7 months respectively; p = 0.187). Conclusion: The presented study did not demonstrate significant differences in FFR values between women and men, yet a higher prevalence of calcific plaques by OCT and lower plaque burden at the MLA site by IVUS was found in women vs. men.

The relationship between chronotype, dispositional mindfulness and suicidal ideation among medical students: mediating role of anxiety, insomnia and social dysfunction.

The aim of the study was to assess whether chronotype and subjective amplitude may predict suicidal ideation independently of mindfulness, and whether anxiety/insomnia and social dysfunction may be mediators of the relationship between chronotype and suicidal thoughts among medical students. The study group comprised 600 students of the medical faculties (191 men and 409 women), with a mean (SD, range) age of 21.94 (1.81, 18-31) years. The participants completed the Chronotype Questionnaire, the Five Facet Mindfulness Questionnaire (FFMQ) and the General Health Questionnaire (GHQ-28). Two items from GHQ-28 depression scale were extracted to measure suicidal ideation. The FFMQ score correlated negatively with the suicidal ideation score. The total effect of chronotype was insignificant when controlled for FFMQ. In the case of indirect effects, subjective amplitude score predicted suicidal ideation via both anxiety/insomnia and social dysfunction scores. The FFMQ score predicted suicidal ideation only via the social dysfunction scale. The direct effect of subjective amplitude was insignificant. Our findings indicate that the flexibility (or rigidity) of circadian rhythm may be linked to the intensity of experienced suicidal ideation, but only via anxiety/insomnia and social dysfunction, independently of mindfulness and morningness-eveningness.

Extracellular Vesicles in Atherosclerosis: State of the Art.

Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation in the arteries, leading to narrowing and thrombosis that causes mortality. Emerging evidence has confirmed that atherosclerosis affects younger people and is involved in the majority of deaths worldwide. EVs are associated with critical steps in atherosclerosis, cholesterol metabolism, immune response, endothelial dysfunction, vascular inflammation, and remodeling. Endothelial cell-derived EVs can interact with platelets and monocytes, thereby influencing endothelial dysfunction, atherosclerotic plaque destabilization, and the formation of thrombus. EVs are potential diagnostic and prognostic biomarkers in atherosclerosis (AS) and cardiovascular disease (CVD). Importantly, EVs derived from stem/progenitor cells are essential mediators of cardiogenesis and cardioprotection and may be used in regenerative medicine and tissue engineering.

Modern Advances in CARs Therapy and Creating a New Approach to Future Treatment.

Genetically engineered T and NK cells expressing a chimeric antigen receptor (CAR) are promising cytotoxic cells for the treatment of hematological malignancies and solid tumors. Despite the successful therapies using CAR-T cells, they have some disadvantages, such as cytokine release syndrome (CRS), neurotoxicity, or graft-versus-host-disease (GVHD). CAR-NK cells have lack or minimal cytokine release syndrome and neurotoxicity, but also multiple mechanisms of cytotoxic activity. NK cells are suitable for developing an "off the shelf" therapeutic product that causes little or no graft versus host disease (GvHD), but they are more sensitive to apoptosis and have low levels of gene expression compared to CAR-T cells. To avoid these adverse effects, further developments need to be considered to enhance the effectiveness of adoptive cellular immunotherapy. A promising approach to enhance the effectiveness of adoptive cellular immunotherapy is overcoming terminal differentiation or senescence and exhaustion of T cells. In this case, EVs derived from immune cells in combination therapy with drugs may be considered in the treatment of cancer patients, especially effector T and NK cells-derived exosomes with the cytotoxic activity of their original cells.

Incorporation of Sulfonamide Moiety into Biguanide Scaffold Results in Apoptosis Induction and Cell Cycle Arrest in MCF-7 Breast Cancer Cells.

Metformin, apart from its glucose-lowering properties, has also been found to demonstrate anti-cancer properties. Anti-cancer efficacy of metformin depends on its uptake in cancer cells, which is mediated by plasma membrane monoamine transporters (PMAT) and organic cation transporters (OCTs). This study presents an analysis of transporter mediated cellular uptake of ten sulfonamide-based derivatives of metformin in two breast cancer cell lines (MCF-7 and MDA-MB-231). Effects of these compounds on cancer cell growth inhibition were also determined. All examined sulfonamide-based analogues of metformin were characterized by greater cellular uptake in both MCF-7 and MDA-MB-231 cells, and stronger cytotoxic properties than those of metformin. Effective intracellular transport of the examined compounds in MCF-7 cells was accompanied by high cytotoxic activity. For instance, compound 2 with meta-methyl group in the benzene ring inhibited MCF-7 growth at micromolar range (IC50 = 87.7 ± 1.18 µmol/L). Further studies showed that cytotoxicity of sulfonamide-based derivatives of metformin partially results from their ability to induce apoptosis in MCF-7 and MDA-MB-231 cells and arrest cell cycle in the G0/G1 phase. In addition, these compounds were found to inhibit cellular migration in wound healing assay. Importantly, the tested biguanides are more effective in MCF-7 cells at relatively lower concentrations than in MDA-MB-231 cells, which proves that the effectiveness of transporter-mediated accumulation in MCF-7 cells is related to biological effects, including MCF-7 cell growth inhibition, apoptosis induction and cell cycle arrest. In summary, this study supports the hypothesis that effective transporter-mediated cellular uptake of a chemical molecule determines its cytotoxic properties. These results warrant a further investigation of biguanides as putative anti-cancer agents.