Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells

Glioblastoma cells with stem-like properties control brain tumour growth and recurrence. Here, we show that endogenous neural precursor cells perform an anti-tumour response by specifically targeting stem-like brain tumour cells. In vitro, neural precursor cells predominantly express bone morphogenetic protein-7; bone morphogenetic protein-7 is constitutively released from neurospheres and induces canonical bone morphogenetic protein signalling in stem-like glioblastoma cells. Exposure of human and murine stem-like brain tumour cells to neurosphere-derived bone morphogenetic protein-7 induces tumour stem cell differentiation, attenuates stem-like marker expression and reduces self-renewal and the ability for tumour initiation. Neurosphere-derived or recombinant bone morphogenetic protein-7 reduces glioblastoma expansion from stem-like cells by down-regulating the transcription factor Olig2. In vivo, large numbers of bone morphogenetic protein-7-expressing neural precursors encircle brain tumours in young mice, induce canonical bone morphogenetic protein signalling in stem-like glioblastoma cells and can thereby attenuate tumour formation. This anti-tumour response is strongly reduced in older mice. Our results indicate that endogenous neural precursor cells protect the young brain from glioblastoma by releasing bone morphogenetic protein-7, which acts as a paracrine tumour suppressor that represses proliferation, self-renewal and tumour-initiation of stem-like glioblastoma cell

Localized Drug Delivery Systems in High‐Grade Glioma Therapy—From Construction to Application

High-grade gliomas are the most common and most malign primary brain tumors. Current therapy approaches only reach unsatisfactory results, still not providing a long-lasting time to relapse or a curative treatment. A novel approach to overcome the present challenges of medical attendance, as drug resistance, systemic side effects, and limited drug availability due to the blood-brain barrier, are localized drug delivery systems (DDSs), which are already used in clinical trials. Further development of this therapy regime may clearly improve patient's outcomes. In order to design compact, biocompatible, robust, and highly flexible systems which permit a prolonged drug release, a broad knowledge of the technical and medical field is required. Thus, this interdisciplinary article reviews different designs, testing, and validation models, and finally, clinical applications of localized DDSs, to utilize this available experience as a basis for the desperately needed reform of glioma treatment

Evaluation of a Brown Seaweed Extract from Dictyosiphon foeniculaceus as a Potential Therapeutic Agent for the Treatment of Glioblastoma and Uveal Melanoma

Ingredients of brown seaweed like fucoidans are often described for their beneficial biological effects, that might be interesting for a medical application. In this study, we tested an extract from Dictyosiphon foeniculaceus (DF) to evaluate the effects in glioblastoma and uveal melanoma, looking for a possible anti-cancer treatment. We investigated toxicity, VEGF (vascular endothelial growth factor) secretion and gene expression of tumor and non-tumor cells. SVGA (human fetal astrocytes), the human RPE (retinal pigment epithelium) cell line ARPE-19, the tumor cell line OMM-1 (human uveal melanoma), and two different human primary glioblastoma cultures (116-14 and 118-14) were used. Tests for cell viability were conducted with MTS-Assay (3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium), and the proliferation rate was determined with cell counting. VEGF secretion was assessed with ELISA (enzyme-linked immunosorbent assay). The gene expression of VEGF receptor 1 (VEGFR1), VEGF receptor 2 (VEGFR2) and VEGF-A was determined with real-time qPCR (quantitative polymerase chain reaction). DF lowered the cell viability of OMM-1. Proliferation rates of ARPE-19 and OMM-1 were decreased. The VEGF secretion was inhibited in ARPE-19 and OMM-1, whereas it was increased in SVGA and 116-14. The expression of VEGFR1 was absent and not influenced in OMM-1 and ARPE-19. VEGFR2 expression was lowered in 116-14 after 24 h, whereas VEGF-A was increased in 118-14 after 72 h. The extract lowered cell viability slightly and was anti-proliferative depending on the cell type investigated. VEGF was heterogeneously affected. The results in glioblastoma were not promising, but the anti-tumor properties in OMM-1 could make them interesting for further research concerning cancer diseases in the human eye

Riscurile și beneficiile înregistrării cu microelectrod în chirurgia bolii Parkinson

Background. Microelectrode recording is believed to improve the outcome by enhancing the precision of electrodes used in deep brain stimulation in patients with Parkinson’s Disease. There is a trend that higher number of penetrations correlate with high rate of hemorrhagic complications. Objective of the study. Determine the clinical outcome of patients stimulated decentrally compared to those placed centrally. Additionally, to assess whether a higher number of penetrations correlate with higher rates of intracranial bleeding. Material and Methods. This monocentric study included 556 patients with bilateral STN-DBS and relies on a large prospectively established database. Data were available from 400 patients. The outcome parameter was the stimulation-induced improvement of the UPDRS for PD. We compared patients with both electrodes centrally to that bi-decentrally. Also, we determined the rate of surgical complications. Results. A decentral tract was chosen in 41% of the electrodes based on clinical grounds (central, n = 471 electrodes; decentral, n = 329). Motor symptom improvement was not different between patients with electrodes implanted bilaterally in the central (44.39% ± 22.71) or decentral (43,22% ± 17) trajectory bilaterally (p = 0.5571). Similar results were obtained for the hemibody score and subscores for akinesia, tremor, rigidity, postural instability and gait disorder. The overall bleeding rate was 2,78% and not depending on the number of penetrations. Conclusion. Outcomes between the groups with central or decentral electrode trajectories did not differ and, therefore, the use of mMER is likely to improve outcome quality. Comparison with other cohorts does not disclose a higher rate of bleeding complications in this cohort with mMER. Introducere. În chirurgia bolii Parkinson, înregistrarea cu microelectrod se utilizează pentru determinarea punctului optim pentru stimulare cerebrală profundă. Se consideră că numărul crescut de penetrații corelează cu rata mai mare a complicațiilor hemoragice postoperatorii. Scopul lucrării. De a determina efectul clinic al pacienților stimulați cu electrozi bicentral versus cei implantați decentral bilateral. De asemenea, de a evalua dacă numărul mai mare de penetrații corelează cu rata mai mare a sângerării intracraniene. Material și Metode. Acest studiu monocentric a inclus 556 de pacienți cu boala Parkinson, stimulați bilateral, bază pe o bază de date prospectivă. Datele complete au fost găsite la 400 de pacienți. Parametrul pentru comparație a fost scala UPDRS pentru BP. Studiul nostru a comparat pacienții cu ambii electrozi implantați bilateral central și decentral. De asemenea, s-a studiat rata sângerării postoperatorii. Rezultate. Traiectorie decentrală s-a ales în 41% din electrozi pe baza la rezultatul clinic (central - 471 electrozi, decentral - 329). Ameliorarea simptomelor motorii nu diferă între grupurile de pacienți cu electrozi implantați bilateral central (44.39% ± 22.71) sau decentral (43, 22% ± 17), p = 0.56. Aceleași rezultate s-au obținut pentru scorul hemibody și subscoruri ca: akinezia, tremorul, rigiditatea, tulburările de statică și mers. Incidența hemoragiei a fost de 2.78% și nu corelează cu numărul de penetrații cu microelectroade. Concluzii. Rezultatul clinic al pacienților cu ambii electrozi bilateral central și decentral nu diferă. Astfel, utilizarea MER poate ameliora rezultatul final. Totodată, incidența complicațiilor postoperatorii hemoragice în studiul nostru nu este mai mare decât în alte studii

Sequential Treatment with Temozolomide Plus Naturally Derived AT101 as an Alternative Therapeutic Strategy: Insights into Chemoresistance Mechanisms of Surviving Glioblastoma Cells

Glioblastoma (GBM) is a poorly treatable disease due to the fast development of tumor recurrences and high resistance to chemo- and radiotherapy. To overcome the highly adaptive behavior of GBMs, especially multimodal therapeutic approaches also including natural adjuvants have been investigated. However, despite increased efficiency, some GBM cells are still able to survive these advanced treatment regimens. Given this, the present study evaluates representative chemoresistance mechanisms of surviving human GBM primary cells in a complex in vitro co-culture model upon sequential application of temozolomide (TMZ) combined with AT101, the R(-) enantiomer of the naturally occurring cottonseed-derived gossypol. Treatment with TMZ+AT101/AT101, although highly efficient, yielded a predominance of phosphatidylserine-positive GBM cells over time. Analysis of the intracellular effects revealed phosphorylation of AKT, mTOR, and GSK3ß, resulting in the induction of various pro-tumorigenic genes in surviving GBM cells. A Torin2-mediated mTOR inhibition combined with TMZ+AT101/AT101 partly counteracted the observed TMZ+AT101/AT101-associated effects. Interestingly, treatment with TMZ+AT101/AT101 concomitantly changed the amount and composition of extracellular vesicles released from surviving GBM cells. Taken together, our analyses revealed that even when chemotherapeutic agents with different effector mechanisms are combined, a variety of chemoresistance mechanisms of surviving GBM cells must be taken into account

The role of microelectrode recording during Deep Brain Stimulation of Subthalamic Nucleus in patients with Parkinson’s disease

Background: Deep brain stimulation of the subthalamic nucleus improves symptoms of Parkinson’s disease. However, the clinical outcome depends on the accurate location of the final electrode. Multiple microelectrode recording is believed to improve the precision, although it prolongs the duration of surgery. We hypothesize that patients implanted in the central trajectory have the same outcome as patients implanted decentrally. Material and methods: This study was carried out in UKSH Kiel and included 556 patients treated from 1999 until 2018 with bilateral STN-DBS (safety population). Pre- and postoperative efficacy data were available from 400 patients. The outcome parameter was the stimulation-induced improvement of the UPDRS for PD. We compared patients with both electrodes centrally to that bi-decentrally. The rate of surgical complications was determined with postoperative imaging. Results: A decentral tract was chosen in 41% of the electrodes (central, n = 471 electrodes; decentral, n = 329). Motor improvement was not different between patients with electrodes implanted bicentral (44.39% ± 22.71) or decentral (43.22% ± 17) trajectory bilaterally (p = 0.5571). Similar results were obtained for the hemi body score and subscores for akinesia, tremor, rigidity, postural instability and gait disorder. The overall bleeding rate was 2.78% and not dependent on the number of penetrations. Conclusions: Outcomes between the groups did not differ and, therefore, the use of mMER is likely to improve the outcome. Comparison with other cohorts does not disclose a higher rate of bleeding complications in this cohort with mMER

Sustainability of large-scale implementation of shared decision making with the SHARE TO CARE program

Introduction SHARE TO CARE (S2C) is a comprehensive implementation program for shared decision making (SDM). It is run at the University Hospital Schleswig-Holstein (UKSH) in Kiel, Germany, and consists of four combined intervention modules addressing healthcare professionals and patients: (1) multimodal training of physicians (2) patient activation campaign including the ASK3 method, (3) online evidence-based patient decision aids (4) SDM support by nurses. This study examines the sustainability of the hospital wide SDM implementation by means of the Neuromedical Center comprising the Departments of Neurology and Neurosurgery. Methods Between 2018 and 2020, the S2C program was applied initially within the Neuromedical Center: We implemented the patient activation campaign, trained 89% of physicians ( N = 56), developed 12 patient decision aids and educated two decision coaches. Physicians adjusted the patients' pathways to facilitate the use of decision aids. To maintain the initial implementation, the departments took care that new staff members received training and decision aids were updated. The patient activation campaign was continued. To determine the sustainability of the initial intervention, the SDM level after a maintenance phase of 6–18 months was compared to the baseline level before implementation. Therefore, in- and outpatients received a questionnaire via mail after discharge. The primary endpoint was the “Patient Decision Making” subscale of the Perceived Involvement in Care Scale (PICS PDM ). Secondary endpoints were an additional scale measuring SDM (CollaboRATE), and the PrepDM scale, which determines patients' perceived health literacy while preparing for decision making. Mean scale scores were compared using t -tests. Results Patients reported a significantly increased SDM level (PICS PDM p = 0.02; Hedges' g = 0.33; CollaboRATE p = 0.05; Hedges' g = 0.26) and improved preparation for decision making (PrepDM p = 0.001; Hedges' g = 0.34) 6–18 months after initial implementation of S2C. Discussion The S2C program demonstrated its sustainability within the Neuromedical Center at UKSH Kiel in terms of increased SDM and health literacy. Maintaining the SDM implementation required a fraction of the initial intensity. The departments took on the responsibility for maintenance. Meanwhile, an additional health insurance-based reimbursement for S2C secures the continued application of the program. Conclusion SHARE TO CARE promises to be suitable for long-lasting implementation of SDM in hospitals

TAMEP are brain tumor parenchymal cells controlling neoplastic angiogenesis and progression

Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor parenchymal cells may promote specific phases of disease progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Notably, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell population, by conditional Sox2-knockout, drastically reduced glioblastoma vascularization and size. Hence, TAMEP emerge as a tumor parenchymal component with a strong impact on glioblastoma progression

Role of neurotransmitter receptors and neural progenitors in glioma brain parenchyma interaction

Hirneigene Tumor wie die Gruppe der Gliome sind bisher wenig in ihrer Interaktion mit dem Hirnparenchym untersucht. In dieser Arbeit werden sowohl zelluläre als auch humorale Mechamismen in der Interaktionen von Gliomen untersucht. Dabei kann die besondere Rolle der immunkompetenten Zelle des ZNS, der Mikroglia, als auch der endogener neuronaler Vorläuferzellen herausgearbeitet werden.Interaction of primary brain tumors like glioma with brain parenchyma are not investigated in detail yet. Here the cellular and humoral mechanisms of glioma-parenchyma-interaction are explored and the highlighted role of microglia and endogenous neural progenitors are delinated