The Acidic Brain-Glycolytic Switch in the Microenvironment of Malignant Glioma.

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.

Sunitinib impedes brain tumor progression and reduces tumor-induced neurodegeneration in the microenvironment.

Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on the brain tumor microenvironment, revealing novel aspects for adjuvant approaches and new clinical assessment criteria when applied to brain tumor patients.

Germany's national public health gets reorganized: A new institute shall take center stage.

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.

Glial Glutamate Transporter-Mediated Plasticity: System xc-/xCT/SLC7A11 and EAAT1/2 in Brain Diseases.

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.

Exploration of the COVID-19 pandemic at the neighborhood level in an intra-urban setting.

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.

Exploring the Spatial Relative Risk of COVID-19 in Berlin-Neukölln.

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.

Ferroptosis and PPAR-gamma in the limelight of brain tumors and edema.

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.

Rac controls PIP5K localisation and PtdIns(4,5)P2 synthesis, which modulates vinculin localisation and neurite dynamics.

In N1E-115 cells, neurite retraction induced by neurite remodelling factors such as lysophosphatidic acid, sphingosine 1-phosphate and semaphorin 3A require the activity of phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks). PIP5Ks synthesise the phosphoinositide lipid second messenger phosphatidylinositol(4,5)bisphosphate [PtdIns(4,5)P2], and overexpression of active PIP5K is sufficient to induce neurite retraction in both N1E-115 cells and cerebellar granule neurones. However, how PIP5Ks are regulated or how they induce neurite retraction is not well defined. Here, we show that neurite retraction induced by PIP5Kß is dependent on its interaction with the low molecular weight G protein Rac. We identified the interaction site between PIP5Kß and Rac1 and generated a point mutant of PIP5Kß that no longer interacts with endogenous Rac. Using this mutant, we show that Rac controls the plasma membrane localisation of PIP5Kß and thereby the localised synthesis of PtdIns(4,5)P2 required to induce neurite retraction. Mutation of this residue in other PIP5K isoforms also attenuates their ability to induce neurite retraction and to localise at the membrane. To clarify how increased levels of PtdIns(4,5)P2 induce neurite retraction, we show that mutants of vinculin that are unable to interact with PtdIns(4,5)P2, attenuate PIP5K- and LPA-induced neurite retraction. Our findings support a role for PtdIns(4,5)P2 synthesis in the regulation of vinculin localisation at focal complexes and ultimately in the regulation of neurite dynamics.

Experimental evidence on improving COVID-19 vaccine outreach among migrant communities on social media.

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.

Chemical hybridization of sulfasalazine and dihydroartemisinin promotes brain tumor cell death.

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.

MCT4 Promotes Tumor Malignancy in F98 Glioma Cells.

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.

Therapeutic Potential of Selenium in Glioblastoma.

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.

Characterization of COVID-19 outbreaks in three nursing homes during the first wave in Berlin, Germany.

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.

A new phospholipid phosphatase, PRG-1, is involved in axon growth and regenerative sprouting.

Outgrowth of axons in the central nervous system is governed by specific molecular cues. Molecules detected so far act as ligands that bind to specific receptors. Here, we report a new membrane-associated lipid phosphate phosphatase that we have named plasticity-related gene 1 (PRG-1), which facilitates axonal outgrowth during development and regenerative sprouting. PRG-1 is specifically expressed in neurons and is located in the membranes of outgrowing axons. There, it acts as an ecto-enzyme and attenuates phospholipid-induced axon collapse in neurons and facilitates outgrowth in the hippocampus. Thus, we propose a novel mechanism by which axons are able to control phospholipid-mediated signaling and overcome the growth-inhibiting, phospholipid-rich environment of the extracellular space.

Role for glutathione peroxidase-4 in brain development and neuronal apoptosis: specific induction of enzyme expression in reactive astrocytes following brain injury.

Glutathione peroxidase-4 (GPx4) is a multifunctional selenoprotein expressed as mitochondrial, cytosolic, or nuclear isoforms. As a catalytically active enzyme it has been implicated in antioxidative defense, but during sperm development it functions as a structural protein. GPx4 null mice die in utero at midgestation and knockdown of GPx4 during embryogenesis disturbs brain development. To explore the cerebral function of GPx4 we profiled cell-specific enzyme expression at various stages of perinatal brain maturation and investigated its regulation following brain injury by immunohistochemistry, in situ hybridization, and quantitative RT-PCR. Large amounts of GPx4 mRNA were detected in all neuronal layers during perinatal brain development but expression became restricted during postnatal maturation. In adult brain mitochondrial and cytosolic GPx4 isoforms were detected in neurons of cerebral cortex, hippocampus, and cerebellum whereas glial cells were devoid of GPx4. Following selective brain injury expression of the enzyme was upregulated in reactive astrocytes of lesioned areas and deafferented regions but not in neurons. Selective knockdown of GPx4 by small interfering RNA induced depletion of phosphatidylinositol-(4,5)-bisphosphate in the neuronal plasma membrane and subsequently apoptosis as indicated by caspase-3 activation. We hypothesize that astrocytic upregulation of GPx4 in response to injury is part of a protective cascade counteracting further cell damage.

The role of selenite on microglial migration.

Oxidative brain damage, such as excitotoxicity and stroke, leads to primary neuronal destruction. The primary damage is further potentiated by macrophages and microglial cells, which are attracted and invade into the zone of damage resulting in secondary neuronal death. Since the essential trace element selenium has anti-inflammatory properties, we analyzed the effects of selenium on these inflammatory cells. Here, we show that the essential trace element selenium abrogates the stress-induced migration of microglial cells. Thus, the antimigratory effects of selenium may attenuate the secondary cell death cascade by preventing microglial invasion.

Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275.

Inhibitors of histone deacetylases are promising compounds for the treatment of cancer but have not been systematically explored in malignant brain tumors. Here, we characterize the benzamide MS-275, a class I histone deacetylase inhibitor, as potent drug for experimental therapy of glioblastomas. Treatment of four glioma cell lines (U87MG, C6, F98, and SMA-560) with MS-275 significantly reduced cell growth in a concentration-dependent manner (IC(90), 3.75 micromol/L). Its antiproliferative effect was corroborated using a bromodeoxyuridine proliferation assay and was mediated by G(0)-G(1) cell cycle arrest (i.e., up-regulation of p21/WAF) and apoptotic cell death. Implantation of enhanced green fluorescent protein-transfected F98 glioma cells into slice cultures of rat brain confirmed the cytostatic effect of MS-275 without neurotoxic damage to the organotypic neuronal environment in a dose escalation up to 20 micromol/L. A single intratumoral injection of MS-275 7 days after orthotopic implantation of glioma cells in syngeneic rats confirmed the chemotherapeutic efficacy of MS-275 in vivo. Furthermore, its propensity to pass the blood-brain barrier and to increase the protein level of acetylated histone H3 in brain tissue identifies MS-275 as a promising candidate drug in the treatment of malignant gliomas.