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Introduction: Evidence summaries on the benefits and harms of treatment options support informed decisions under controlled conditions. However, few studies have investigated how such formats support decision-making across different social groups. There is a risk that only disadvantaged people will be able to make informed health decisions-possibly increasing the health equity gap. It is also unclear whether they support decision-making in the field at all. The aim of our study is to assess whether evidence summaries based on the fact box format can help people from different social groups make informed decisions about COVID-19 and influenza vaccinations, and thus reduce inequity in health communication., Methods and Analysis: In a multi-centre, cluster-randomised, controlled trial, health educators from usual care and outreach work in Germany will be randomised in a 1:1 ratio to provide either usual health communication plus an evidence summary ('fact box') or usual health communication. Health educators provide a flyer about COVID-19 or influenza vaccination which contains a link to an online study either with (intervention) or without (control) fact box on the reverse side. Flyer and online study will be available in Arabic, German, Turkish and Russian language. The primary outcome is informed vaccination intention, based on vaccination knowledge, attitudes, intentions and behaviour. Secondary outcomes include risk perception, decisional conflict and shared decision-making. We will use linear mixed models to analyse the influence of both individual (eg, education status) and cluster level factors and account for the expected cluster variability in realising usual health communication or the intervention. The statistical analysis plan includes the selection of appropriate measures of effect size and power calculation, assuming a sample size of 800 patients., Ethics and Dissemination: The trial has been approved by the Ethics Committee of the University of Potsdam, Germany (application numbers: 34/2021 and 57/2022).Results will be disseminated through peer-reviewed journals, conferences and to relevant stakeholders., Protocol Version: Version 6 (4 October 2024); Preprint available on Research Square: https://doi.org/10.21203/rs.3.rs-3401234/v3 TRIAL REGISTRATION NUMBER: NCT06076421., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID-19 pandemic has affected various urban population groups in different ways. Earlier studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disproportionally impacts nursing home residents by increasing morbidity and mortality following viral exposure. However, little is known about the epidemiology of this disease in detail. Therefore, the objective of this study is to analyze the development of the COVID-19 pandemic in 14 nursing homes across Berlin-Neukölln, Germany, during pandemic waves 1 to 5 (Feb 2020 - May 2022)., Methods: Reporting data to the Neukölln Department of Public Health on COVID-19 cases in connection with nursing homes were extracted from the SORMAS database. The case fatality rates (CFRs) and odds ratios (ORs) of demographic parameters, prevalent variants of concern (VOCs) and vaccine availability were calculated. In addition, the temporal course in waves 1-5 in Neukölln and the relevant government measures were examined., Results: Data collected from nursing homes providing age-dependent physical care revealed that 1.9 % of the total 108,600 cases registered in Berlin-Neukölln during the study period were related one of the 14 facilities. Compared to the general population in Neukölln, nursing homes exhibited a 20-fold increase in the CFR. Notably, nursing homes with higher bed capacities displayed a greater CFR than did smaller nursing homes. Similarly, elderly residents living in nursing homes faced a much greater mortality rate than did their counterparts living outside of medical settings (OR = 3.5). The original wild-type SARS-CoV-2 strain had the most severe direct impact, with a CFR of 16.7 %, compared to the alpha (CFR = 6.9 %), delta (CFR = 10.2 %) and omicron (CFR = 2.8 %) variants in nursing homes. Interestingly, the number of infections increased following vaccination campaigns, but this trend was accompanied by a decrease in the number of deaths from 2.6 to 1.1 per week. As a result, the CFR significantly decreased from 18.4 to 5.5, while still exceeding the mean CFR compared to that of the general population of Neukölln., Conclusions: Our findings reveal the changing patterns of outbreak frequency and severity across the five pandemic waves. They highlight the crucial role of rapid vaccination programs for residents, staff, visitors, and third-party services in safeguarding nursing homes. Additionally, improvements in containment and cluster strategies are essential in prevaccination scenarios to prevent future infection traps for elderly individuals in long-term care facilities. The presented data highlight the importance of tailored protection measures for one of the most vulnerable populations in our society., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The data-related desolate state of the health authorities became evident at the latest with the onset of the Covid-19 pandemic. The lack of interoperability and networking among health authorities quickly developed into blockages in contact tracing and pandemic control., Methodology: As a basis for the study, key figures and funding volumes from the Pact-Public Health Service (Pakt-ÖGD) were evaluated and analyzed using descriptive parameters. In addition, a literature review on the Pakt-ÖGD and related terms was carried out., Results: The Pakt-ÖGD represents the largest financing offensive for the Public Health Service to date. Despite the digitalization pact and the first distributions of funds, there is no consensus on the goals of digitalization such as the ISCODE, Findability, Accessibility, Interoperability und Reuse (FAIR concept). The RKI is currently presenting a new electronic reporting and information system for health authorities (EMIGA), which is to be introduced parallel to DEMIS as a nationwide core application for infection protection., Conclusion: In analogy to health literacy, the public health service needs increased digital literacy to strengthen competence in order to agree on common goals of ISCODE and the FAIR concept, i.e. what digitalization should create or not. A sustainable public health service requires an open and connectable network that goes beyond infection protection (pandemic prevention, preparedness and response - PPPR) to a global One-Health platform., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

In the aftermath of the COVID-19 pandemic, the German federal government recently orchestrated a fundamental change to its public health infrastructure. This reconstruction centers around the founding of a National Institute for Prevention and Education in Medicine (Bundesinstitut für Prävention und Aufklärung in der Medizin, BIPAM) at the cost of two federal institutions, the Robert Koch-Institute (RKI) and the Federal Center for Health Education (Bundeszentrale für gesundheitliche Aufklärung, BzGA). Thus, the Federal Ministry of Health (Bundesministerium für Gesundheit, BMG) plans to dissolve the BzGA and integrate its personnel into the future BIPAM. Further, all RKI research and surveillance activities related to non-communicable diseases, including AI methods development will be transferred into the BIPAM. The RKI responsibilities will solely focus on infectious diseases. According to announced plans of the BMG the primary objective for establishing the BIPAM is to address non-communicable diseases and enhance overall population health. However, the medical specialist training for public health remains non-academic at a state institution. Simultaneously the BMG already replaced two thirds of experts of the permanent commission on vaccination (Ständige Impfkommission, STIKO) and determined new procedures for appointing future expert commissioners. With these changes, Germany embarks on an extraordinary reshuffling of its national public health organizations and responsibilities, by fundamentally separating all issues around non-communicable diseases from those of infectious diseases. Germany's unraveled research tasks of public health authorities however remains unmet. Thus, 2024 marks a pivotal caesura for public health in the modern history of Germany., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Human malignant brain tumors such as gliomas are devastating due to the induction of cerebral edema and neurodegeneration. A major contributor to glioma-induced neurodegeneration has been identified as glutamate. Glutamate promotes cell growth and proliferation in variety of tumor types. Intriguently, glutamate is also an excitatory neurotransmitter and evokes neuronal cell death at high concentrations. Even though glutamate signaling at the receptor and its downstream effectors has been extensively investigated at the molecular level, there has been little insight into how glutamate enters the tumor microenvironment and impacts on metabolic equilibration until recently. Surprisingly, the 12 transmembrane spanning tranporter xCT (SLC7A11) appeared to be a major player in this process, mediating glutamate secretion and ferroptosis. Also, PPARγ is associated with ferroptosis in neurodegeneration, thereby destroying neurons and causing brain swelling. Although these data are intriguing, tumor-associated edema has so far been quoted as of vasogenic origin. Hence, glutamate and PPARγ biology in the process of glioma-induced brain swelling is conceptually challenging. By inhibiting xCT transporter or AMPA receptors in vivo, brain swelling and peritumoral alterations can be mitigated. This review sheds light on the role of glutamate in brain tumors presenting the conceptual challenge that xCT disruption causes ferroptosis activation in malignant brain tumors. Thus, interfering with glutamate takes center stage in forming the basis of a metabolic equilibration approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yakubov, Schmid, Hammer, Chen, Dahlmanns, Mitrovic, Zurabashvili, Savaskan, Steiner and Dahlmanns.)

Identifying areas with high and low infection rates can provide important etiological clues. Usually, areas with high and low infection rates are identified by aggregating epidemiological data into geographical units, such as administrative areas. This assumes that the distribution of population numbers, infection rates, and resulting risks is constant across space. This assumption is, however, often false and is commonly known as the modifiable area unit problem. This article develops a spatial relative risk surface by using kernel density estimation to identify statistically significant areas of high risk by comparing the spatial distribution of address-level COVID-19 cases and the underlying population at risk in Berlin-Neukölln. Our findings show that there are varying areas of statistically significant high and low risk that straddle administrative boundaries. The findings of this exploratory analysis further highlight topics such as, e.g., Why were mostly affluent areas affected during the first wave? What lessons can be learned from areas with low infection rates? How important are built structures as drivers of COVID-19? How large is the effect of the socio-economic situation on COVID-19 infections? We conclude that it is of great importance to provide access to and analyse fine-resolution data to be able to understand the spread of the disease and address tailored health measures in urban settings.

The COVID-19 pandemic represents a worldwide threat to health. Since its onset in 2019, the pandemic has proceeded in different phases, which have been shaped by a complex set of influencing factors, including public health and social measures, the emergence of new virus variants, and seasonality. Understanding the development of COVID-19 incidence and its spatiotemporal patterns at a neighborhood level is crucial for local health authorities to identify high-risk areas and develop tailored mitigation strategies. However, analyses at the neighborhood level are scarce and mostly limited to specific phases of the pandemic. The aim of this study was to explore the development of COVID-19 incidence and spatiotemporal patterns of incidence at a neighborhood scale in an intra-urban setting over several pandemic phases (March 2020-December 2021). We used reported COVID-19 case data from the health department of the district Berlin-Neukölln, Germany, additional socio-demographic data, and text documents and materials on implemented public health and social measures. We examined incidence over time in the context of the measures and other influencing factors, with a particular focus on age groups. We used incidence maps and spatial scan statistics to reveal changing spatiotemporal patterns. Our results show that several factors may have influenced the development of COVID-19 incidence. In particular, the far-reaching measures for contact reduction showed a substantial impact on incidence in Neukölln. We observed several age group-specific effects: school closures had an effect on incidence in the younger population (< 18 years), whereas the start of the vaccination campaign had an impact primarily on incidence among the elderly (> 65  years). The spatial analysis revealed that high-risk areas were heterogeneously distributed across the district. The location of high-risk areas also changed across the pandemic phases. In this study, existing intra-urban studies were supplemented by our investigation of the course of the pandemic and the underlying processes at a small scale over a long period of time. Our findings provide new insights for public health authorities, community planners, and policymakers about the spatiotemporal development of the COVID-19 pandemic at the neighborhood level. These insights are crucial for guiding decision-makers in implementing mitigation strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schmitz, Lakes, Manafa, Lambio, Butler, Roth and Savaskan.)

Glial cells play an essential role in the complex function of the nervous system. In particular, astrocytes provide nutritive support for neuronal cells and are involved in regulating synaptic transmission. Oligodendrocytes ensheath axons and support information transfer over long distances. Microglial cells constitute part of the innate immune system in the brain. Glial cells are equipped with the glutamate-cystine-exchanger xCT (SLC7A11), the catalytic subunit of system xc-, and the excitatory amino acid transporter 1 (EAAT1, GLAST) and EAAT2 (GLT-1). Thereby, glial cells maintain balanced extracellular glutamate levels that enable synaptic transmission and prevent excitotoxic states. Expression levels of these transporters, however, are not fixed. Instead, expression of glial glutamate transporters are highly regulated in reaction to the external situations. Interestingly, such regulation and homeostasis is lost in diseases such as glioma, (tumor-associated) epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis. Upregulation of system xc- (xCT or SLC7A11) increases glutamate export from the cell, while a downregulation of EAATs decreases intracellular glutamate import. Occurring simultaneously, these reactions entail excitotoxicity and thus harm neuronal function. The release of glutamate via the antiporter system xc- is accompanied by the import of cystine-an amino acid essential in the antioxidant glutathione. This homeostasis between excitotoxicity and intracellular antioxidant response is plastic and off-balance in central nervous system (CNS) diseases. System xc- is highly expressed on glioma cells and sensitizes them to ferroptotic cell death. Hence, system xc- is a potential target for chemotherapeutic add-on therapy. Recent research reveals a pivotal role of system xc- and EAAT1/2 in tumor-associated and other types of epilepsy. Numerous studies show that in Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, these glutamate transporters are dysregulated-and disease mechanisms could be interposed by targeting system xc- and EAAT1/2. Interestingly, in neuroinflammatory diseases such as multiple sclerosis, there is growing evidence for glutamate transporter involvement. Here, we propose that the current knowledge strongly suggest a benefit from rebalancing glial transporters during treatment., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Studies from several countries suggest that COVID-19 vaccination rates are lower among migrants compared to the general population. Urgent calls have been made to improve vaccine outreach to migrants, however, there is limited evidence on effective approaches, especially using social media. We assessed a targeted, low-cost, Facebook campaign disseminating COVID-19 vaccine information among Arabic, Turkish and Russian speakers in Germany (N = 888,994). As part of the campaign, we conducted two randomized, online experiments to assess the impact of the advertisement (1) language and (2) depicted messenger (government authority, religious leader, doctor or family). Key outcomes included reach, click-through rates, conversion rates and cost-effectiveness. Within 29 days, the campaign reached 890 thousand Facebook users. On average, 2.3 individuals accessed the advertised COVID-19 vaccination appointment tool for every euro spent on the campaign. Migrants were 2.4 (Arabic), 1.8 (Russian) and 1.2 (Turkish) times more likely to click on advertisements translated to their native language compared to German-language advertisements. Furthermore, findings showed that government representatives can be more successful in engaging migrants online compared to other messengers, despite common claims of lower trust in government institutions among migrants. This study highlights the potential of tailored, and translated, vaccination campaigns on social media for reaching migrants who may be left out by traditional media campaigns., (© 2022. The Author(s).)

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) belongs to the coronavirus family and is characterized by its high transmission competence. Elderly COVID-19 patients are at significantly higher risk of severe course of disease and death. Therefore, outbreaks in nursing homes are particularly challenging for facility managers and health authorities. Here, we report three outbreaks of COVID-19 related to nursing homes (NH01.a, NH02 and NH03) with almost 1000 affected individuals during the first COVID-19 wave in Berlin, Germany. The occurrence of cases and the measures taken were analyzed retrospectively. In all three outbreaks, the index persons were nursing home employees or volunteers. Measures taken were quarantine of contacts, close-meshed tests, separation of the affected housing unit, suspension of admission, ban on visiting, and equipping staff with personal protective equipment, of which there was a shortage in Germany at the beginning of the pandemic. A court-ordered quarantine became necessary for three residents of NH01.a due to cognitive disabilities. In total, 61 persons were tested positive for SARS-CoV-2 in NH01.a, ten persons in NH02, and sixteen persons in NH03. Seventeen patients (27.9%) of NH01.a and three patients (18.8%) of NH03 were referred to hospital. Of all confirmed cases, thirteen (21.3%) related to NH01.a and four (25.0%) related to NH03 died as a result of the infection. Besides one 82 year old volunteer, all deceased persons were residents aged between 66 and 98. Our results emphasize the importance of a previously developed containment and cluster strategy for nursing homes. Due to the particular vulnerability of the residents, immediate action, close cooperation and communication between the facility management, residents, visitors and the health authorities are essential in the case of confirmed COVID-19 cases in healthcare facilities., (© 2021. The Author(s).)

Gliomas are primary brain tumors with still poor prognosis for the patients despite a combination of cytoreduction via surgery followed by a radio-chemotherapy. One strategy to find effective treatment is to combine two different compounds in one hybrid molecule via linker to add to or at best potentiate their impact on malignant cells. Here, we report on the effects of a newly synthesized hybrid of sulfasalazine (SAS) and dihydroartemisinin (DHA), called AC254. In previous studies, both SAS and DHA have already proved to have anti-tumor properties themselves and to have sensitizing respectively potentiating effects on other treatments against malignant tumors. We investigated the impact of individual drugs SAS and DHA, their 1:1 combination and a novel SAS-DHA hybrid compound (AC254) on rodent and human glioma cells. In our study SAS alone showed no or only a mild effect on glioma, whereas DHA led to a significant reduction of cell viability in a dose-dependent manner. Next we compared the efficacy of the hybrid AC254 to the combinational treatment of its parent compounds SAS and DHA. The hybrid was highly efficient in combating glioma cells compared to single treatment strategies regarding cell viability and cell death. Interestingly, AC254 showed a remarkable advantage over the combinational treatment with both parent compounds in most used concentrations. In addition to its reduction of tumor cell viability and induction of cell death, the hybrid AC254 displayed changes in cell cycle and reduction of cell migration. Taken together, these results demonstrate that clinically established compounds such as SAS and DHA can be potentiated in their anti-cancer effects by chemical hybridization. Thus, this concept provides the opportunity to devise new effective chemotherapeutic agents., (© 2021. The Author(s).)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Little progress has been made in the long-term management of malignant brain tumors, leaving patients with glioblastoma, unfortunately, with a fatal prognosis. Glioblastoma remains the most aggressive primary brain cancer in adults. Similar to other cancers, glioblastoma undergoes a cellular metabolic reprogramming to form an oxidative tumor microenvironment, thereby fostering proliferation, angiogenesis and tumor cell survival. Latest investigations revealed that micronutrients, such as selenium, may have positive effects in glioblastoma treatment, providing promising chances regarding the current limitations in surgical treatment and radiochemotherapy outcomes. Selenium is an essential micronutrient with anti-oxidative and anti-cancer properties. There is additional evidence of Se deficiency in patients suffering from brain malignancies, which increases its importance as a therapeutic option for glioblastoma therapy. It is well known that selenium, through selenoproteins, modulates metabolic pathways and regulates redox homeostasis. Therefore, selenium impacts on the interaction in the tumor microenvironment between tumor cells, tumor-associated cells and immune cells. In this review we take a closer look at the current knowledge about the potential of selenium on glioblastoma, by focusing on brain edema, glioma-related angiogenesis, and cells in tumor microenvironment such as glioma-associated microglia/macrophages., Competing Interests: NS was employed by the company BiMECON Ent. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yakubov, Eibl, Hammer, Holtmannspötter, Savaskan and Steiner.)

Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between isocitrate dehydrogenase (IDH) mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma.

Monocarboxylate transporter 4 (MCT4, SLC16A3 ) is elevated under hypoxic conditions in many malignant tumors including gliomas. Moreover, MCT4 expression is associated with shorter overall survival. However, the functional consequences of MCT4 expression on the distinct hallmarks of cancer have not yet been explored at the cellular level. Here, we investigated the impact of MCT4 overexpression on proliferation, survival, cell death, migration, invasion, and angiogenesis in F98 glioma cells. Stable F98 glioma cell lines with MCT4 overexpression, normal expression, and knockdown were generated. Distinct hallmarks of cancer were examined using in silico analysis, various in vitro cell culture assays, and ex vivo organotypic rat brain slice culture model. Consistent with its function as lactate and proton exporter, MCT4 expression levels correlated inversely with extracellular pH and proportionally with extracellular lactate concentrations. Our results further indicate that MCT4 promotes proliferation and survival by altered cell cycle regulation and cell death mechanisms. Moreover, MCT4 overexpression enhances cell migration and invasiveness via reorganization of the actin cytoskeleton. Finally, MCT4 inhibition mitigates the induction of angiogenesis, suggesting that MCT4 also plays a crucial role in tumor-related angiogenesis. In summary, our data highlight MCT4 /SLC16A3 as a key gene for distinct hallmarks of tumor malignancy in glioma cells., Competing Interests: The authors declare that they have no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Anna Maria Reuss et al.)

In the search for new potential chemotherapeutics, the compounds' toxicity to healthy cells is an important factor. The brain with its functional units, the neurons, is especially endangered during the radio- and chemotherapeutic treatment of brain tumors. The effect of the potential compounds not only on neuronal survival but also neuronal function needs to be taken into account. Therefore, in this study we aimed to comprehend the biological effects of chemotherapeutic xCT inhibition on healthy neuronal cells with our synaptic optogenetic function analysis tool (SOFA). We combined common approaches, such as investigation of morphological markers, neuronal function and cell metabolism. The glutamate-cystine exchanger xCT (SLC7A11, system X c - ) is the main glutamate exporter in malignant brain tumors and as such a relevant drug target for treating deadly glioblastomas (WHO grades III and IV). Recently, two small molecules termed sorafenib (Nexavar) and erastin have been found to efficiently block xCT function. We investigated neuronal morphology, metabolic secretome profiles, synaptic function and cell metabolism of primary hippocampal cultures (containing neurons and glial cells) treated with sorafenib and erastin in clinically relevant concentrations. We found that sorafenib severely damaged neurons already after 24 h of treatment. Noteworthy, also at a lower concentration, where no morphological damage or metabolic disturbance was monitored, sorafenib still interfered with synaptic and metabolic homeostasis. In contrast, erastin-treated neurons displayed mostly inconspicuous morphology and metabolic rates. Key parameters of proper neuronal function, such as synaptic vesicle pool sizes, were however disrupted following erastin application. In conclusion, our data revealed that while sorafenib and erastin effectively inhibited xCT function they also interfered with essential neuronal (synaptic) function. These findings highlight the particular importance of investigating the effects of potential neurooncological and general cancer chemotherapeutics also on healthy neuronal cells and their function as revealed by the SOFA tool., Competing Interests: The authors declare no conflict of interest.

Gliomas are brain-born tumors with devastating impact on their brain microenvironment. Novel approaches employ multiple combinations of chemical compounds in synthetic hybrid molecules to target malignant tumors. Here, we report on the chemical hybridization approach exemplified by artesunic acid (ARTA) and naturally occurring triterpene betulinic acid (BETA). Artemisinin derived semisynthetic compound artesunic acid (ARTA) and naturally occurring triterpene BETA were used to synthetically couple to the hybrid compound termed 212A. We investigated the impact of 212A and its parent compounds on glioma cells, astrocytes and neurons. ARTA and BETA showed cytotoxic effects on glioma cells at micromolar concentrations. ARTA was more effective on rodent glioma cells compared to BETA, whereas BETA exhibited higher toxic effects on human glioma cells compared to ARTA. We investigated these compounds on non-transformed glial cells and neurons as well. Noteworthy, ARTA showed almost no toxic effects on astrocytes and neurons, whereas BETA as well as 212A displayed neurotoxicity at higher concentrations. Hence we compared the efficacy of the hybrid 212A with the combinational treatment of its parent compounds ARTA and BETA. The hybrid 212A was efficient in killing glioma cells compared to single compound treatment strategies. Moreover, ARTA and the hybrid 212A displayed a significant cytotoxic impact on glioma cell migration. Taken together, these results demonstrate that both plant derived compounds ARTA and BETA operate gliomatoxic with minor neurotoxic side effects. Altogether, our proof-of-principle study demonstrates that the chemical hybrid synthesis is a valid approach for generating efficacious anti-cancer drugs out of virtually any given structure. Thus, synthetic hybrid therapeutics emerge as an innovative field for new chemotherapeutic developments with low neurotoxic profile., Competing Interests: CONFLICTS OF INTERESTS The authors declare no competing financial conflicts of interest.

Malignant gliomas are devastating neoplasia with limited curative treatment options. Temozolomide (TMZ, Temcat ® , Temodal ® or Temodar ® ) is a first-line treatment for malignant gliomas but the development of drug resistance remains a major concern. Activating transcription factor 4 (ATF4) is a critical oxido-metabolic regulator in gliomas, and its role in the pathogenesis of TMZ-resistance remains elusive. We investigated the effect of TMZ on human glioma cells under conditions of enhanced ATF4 expression (ATF4 OE ) and ATF4 knock down (ATF4 KD ). We monitored cell survival, ATF4 mRNA expression of ATF4 and xCT (SLC7a11) regulation within human gliomas. TMZ treatment induces a transcriptional response with elevated expression of ATF4, xCT and Nrf2, as a sign of ER stress and toxic cell damage response. ATF4 overexpression (ATF4 OE ) fosters TMZ resistance in human gliomas and inhibits TMZ-induced autophagy. Conversely, ATF4 suppression by small interfering RNAs (ATF4 KD ) leads to increased TMZ susceptibility and autophagy in comparison to wild type gliomas. ATF4 OE gliomas show reduced cell cycle shift and apoptotic cell death, whereas ATF4 KD gliomas reveal higher susceptibility towards cell cycle rearrangements. Hence, the migration capacity of ATF4 OE glioma cells is almost not affected by TMZ treatment. In contrast, ATF4 KD gliomas show a migratory stop following TMZ application. Mechanistically, xCT elevation is a consequence of ATF4 activation and increased levels of xCT amplifies ATF4-induced TMZ resistance. Our data show that ATF4 operates as a chemo-resistance gene in gliomas, and the tumor promoting function of ATF4 is mainly determined by its transcriptional target xCT. Therefore, therapeutic inactivation of ATF4 can be a promising strategy to overcome chemo-resistance and promote drug efficacy in human gliomas., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial conflict of interests.

Cell death and its recently discovered regulated form ferroptosis are characterized by distinct morphological, electrophysiological, and pharmacological features. In particular ferroptosis can be induced by experimental compounds and clinical drugs (i.e., erastin, sulfasalazine, sorafenib, and artesunate) in various cell types and cancer cells. Pharmacologically, this cell death process can be inhibited by iron chelators and lipid peroxidation inhibitors. Relevance of this specific cell death form has been found in different pathological conditions such as cancer, neurotoxicity, neurodegeneration, and ischemia. Distinguishing cell viability and cell death is essential for experimental and clinical applications and a key component in flow cytometry experiments. Dead cells can compromise the integrity of the data by nonspecific binding of antibodies and dyes. Therefore it is essential that dead cells are robustly and reproducibly identified and characterized by means of cytometry application. Here we describe a procedure to detect and quantify cell death and its specific form ferroptosis based on standard flow cytometry techniques.

Cowden syndrome (CS) is clinically presented by multiple hamartomas, often with mucocutaneous lesions, goiter, breast cancer and gastrointestinal polyps. CS is a genetic disorder of autosomal dominant inheritance and is one distinct syndrome of the phosphatase and tensin homolog on chromosome 10 (PTEN) hamartoma tumor spectrum. Noteworthy, PTEN germline mutations are related to a wide range of brain tumors. We performed a systematic analysis and review of the medical literature for Cowden syndrome and meningioma and additionally present the case of a 29-year- old CS patient diagnosed with multiple meningiomas. We found strong evidence for high incidence of brain tumors in CS patients. In particular meningiomas and gangliocytomas/Lhermitte-Duclos disease were often associated with 8% and 9% respectively in CS patients. Since aberrations in chromosome 10q are associated with meningiomas, it is likely that the underlying mutations in CS drive to a certain extent neoplastic meningioma growth. We propose to include meningiomas and brain tumors in the major criteria spectrum of CS-related disorders. This could warrant early diagnosis of brain lesions and close therapy, as well as better monitoring of patients with CS.

Taxanes target microtubules and are clinically established chemotherapeutic agents with proven efficacy in human cancers. Cabazitaxel (XRP-6258, Jevtana®) is a second generation semisynthetic taxane with high chemotherapeutic potential in prostate cancer. There, cabazitaxel can overcome docetaxel-resistant prostate cancer. Here, we tested the effects of cabazitaxel on glioma cells, and non-transformed cells such as neurons and astrocytes. Cabazitaxel operates highly toxic in various human glioma cells at nanomolar concentrations. In contrast, primary astrocytes and neurons are not affected by this agent. Cabazitaxel disrupts cytoskeletal F-actin fibers and induces apoptotic cell death in gliomas. Moreover, cabazitaxel displayed highest efficacy in inhibiting glioma cell migration and invasion. Here we demonstrate that cabazitaxel inhibited tumor migration already at 1 nM. We also tested cabazitaxel in the ex vivo VOGiM assay. Cabazitaxel stalled glioma growth and at the same time inhibited tumor-induced angiogenesis. In summary, we found that cabazitaxel operates as an apoptosis-inducing gliomatoxic agent with strongest effects on migration and invasive growth. Thus, our report uncovered cabazitaxel actions on gliomas and on the brain tumor microenvironment. These data reveal novel aspects for adjuvant approaches when applied to brain tumor patients., Competing Interests: This study was in part supported by Sanofi-Aventis Deutschland GmbH (#019278). However, the funding body had no influence on data acquisition, evaluation or presentation.

The glutamate transporter xCT (SCL7a11, system Xc-, SXC) is an emerging key player in glutamate/cysteine/glutathione homeostasis in the brain and in cancer. xCT expression correlates with the grade of malignancy. Here, we report on the use of the U.S. Food and Drug Administration and EMA-approved xCT inhibitor, sulfasalazine (SAS) in gliomas. SAS does not affect cell viability in gliomas at concentrations below 200 µM. At higher concentrations SAS becomes gliomatoxic. Mechanistically SAS inhibits xCT and induces ferroptotic cell death in glioma cells. There is no evidence for impact on autophagic flux following SAS application. However, SAS can potentiate the efficacy of the standard chemotherapeutic and autophagy-inducing agent temozolomide (Temcat, Temodal or Temodar®). We also investigated SAS in non-transformed cellular constituents of the brain. Neurons and brain tissue are almost non-responding to SAS whereas isolated astrocytes are less sensitive towards SAS toxicity compared to gliomas. In vivo SAS treatment does not affect experimental tumor growth and treated animals revealed comparable tumor volume as untreated controls. However, SAS treatment resulted in reduced glioma-derived edema and, hence, total tumor volume burden as revealed by T2-weighted magnetic resonance imaging. Altogether, we show that SAS can be utilized for targeting the glutamate antiporter xCT activity as a tumor microenvironment-normalizing drug, while crucial cytotoxic effects in brain tumors are minor., Competing Interests: CONFLICTS OF INTERESTS The authors declare no competing financial conflict of interests.

Safe and complete resection represents the first step in the treatment of glioblastomas and is mandatory in increasing the effectiveness of adjuvant therapy to prolong overall survival. With gross total resection currently limited in extent to MRI contrast enhancing areas, the extent to which supra-complete resection beyond obvious contrast enhancement could have impact on overall survival remains unclear. DiVA (dual intraoperative visualization approach) redefines gross total resection as currently accepted by enabling for the first time supra-complete surgery without compromising patient safety. This approach exploits the advantages of two already accepted surgical techniques combining intraoperative MRI with integrated functional neuronavigation and 5-ALA by integrating them into a single surgical approach. We investigated whether this technique has impact on overall outcome in GBM patients. 105 patients with GBM were included. We achieved complete resection with intraoperative MRI alone according to current best-practice in glioma surgery in 75 patients. 30 patients received surgery with supra-complete resection. The control arm showed a median life expectancy of 14 months, reflecting current standards-of-care and outcome. In contrast, patients receiving supra-complete surgery displayed significant increase in median survival time to 18.5 months with overall survival time correlating directly with extent of supra-complete resection. This extension of overall survival did not come at the cost of neurological deterioration. We show for the first time that supra-complete glioma surgery leads to significant prolongation of overall survival time in GBM patients., Competing Interests: The authors declare no competing financial interests.