TGF-ß activates pericytes via induction of the epithelial-to-mesenchymal transition protein SLUG in glioblastoma.

AIMS: In primary central nervous system tumours, epithelial-to-mesenchymal transition (EMT) gene expression is associated with increased malignancy. However, it has also been shown that EMT factors in gliomas are almost exclusively expressed by glioma vessel-associated pericytes (GA-Peris). In this study, we aimed to identify the mechanism of EMT in GA-Peris and its impact on angiogenic processes. METHODS: In glioma patients, vascular density and the expression of the pericytic markers platelet derived growth factor receptor (PDGFR)-ß and smooth muscle actin (αSMA) were examined in relation to the expression of the EMT transcription factor SLUG and were correlated with survival of patients with glioblastoma (GBM). Functional mechanisms of SLUG regulation and the effects on primary human brain vascular pericytes (HBVP) were studied in vitro by measuring proliferation, cell motility and growth characteristics. RESULTS: The number of PDGFR-ß- and αSMA-positive pericytes did not change with increased malignancy nor showed an association with the survival of GBM patients. However, SLUG-expressing pericytes displayed considerable morphological changes in GBM-associated vessels, and TGF-ß induced SLUG upregulation led to enhanced proliferation, motility and altered growth patterns in HBVP. Downregulation of SLUG or addition of a TGF-ß antagonising antibody abolished these effects. CONCLUSIONS: We provide evidence that in GA-Peris, elevated SLUG expression is mediated by TGF-ß, a cytokine secreted by most glioma cells, indicating that the latter actively modulate neovascularisation not only by modulating endothelial cells, but also by influencing pericytes. This process might be responsible for the formation of an unstructured tumour vasculature as well as for the breakdown of the blood-brain barrier in GBM.

Is (Disordered) Social Networking Sites Usage a Risk Factor for Dysfunctional Eating and Exercise Behavior?

BACKGROUND: Research over the past years has shown that exposure to thin and beauty ideals in the media can be associated with disordered eating and related variables. Nowadays, interactive media, such as social networking sites, have gained growing popularity and represent a major part of people's lives. It is therefore crucial to investigate how far users might be negatively influenced by social networking sites regarding eating pathology or excessive exercise behavior and if there are particular links to social media use disorder. METHODS: Data were collected by an online-survey encompassing questions on regular social networking site use, eating disorders, and excessive exercise behavior. RESULTS: Analyses showed that disordered social networking sites use was significantly related to eating pathology and a poorer body image in men and women. The frequency of active or passive social networking sites usage however was not associated with exercise behavior. CONCLUSIONS: Our results confirm that disordered social networking sites use represents a risk factor for body image dissatisfaction and associated eating disorders.

Nosological Characteristics in Women with Social Media Disorder: The Role of Social Functional Impairment and Agreeableness.

Social media disorder (SMD) is a frequently occurring subtype of Internet-related disorders (IRD), which has recently become a focus of research. It is noticeable that women are among those affected, whose nosological characteristics need to be examined. A clinical sample of n = 294 women (14-68 years, M = 36.88 years) was generated. The questionnaire included questions about demography, IRD, SMD, personality traits, psychopathological distress, functional impairment and comorbid mental illnesses. IRD was found in 17.5 percent and SMD in 12.5 percent of women. Compared to women with global IRD Women with SMD reported lower scores on the personality traits neuroticism and agreeableness. They are more frequently functionally impaired in the social dimension, more often reported comorbid substance-dependency and less eating disorders. The results suggest that although have similar characteristics to the comparison group, women with SMD differ in their nosological characteristics from women with global IRD.

[Undiagnosed Internet-Related Disorder in the Psychotherapeutic Care System: Prevalence and Gender-Specific Characteristics]. / Nicht diagnostizierte internetbezogene Störungen im psychotherapeutischen Versorgungssystem: Prävalenz und geschlechtsspezifische Besonderheiten.

OBJECTIVE: Internet-related disorders (IRD) are characterized by uncontrolled use of various Internet applications, which is associated with impairments in various sections and an increased rate of other forms of mental illness. The aim was to identify undiagnosed comorbid IRD and to examine gender-specific differences. METHODS: In 19 psychotherapeutic institutions 501 patients (65.3 % women) were recruited. RESULTS: Comorbid IRD was found in 20.7 % of men and 15.9 % of women. IBS was not identified by the practitioners in 94.6 % of women and 66.6 % of men. In particular affective disorders and substance-related addiction occurred very frequently and regardless of gender. Women were significantly more often affected by eating and personality disorders, men were significantly more often affected by pathological gambling. CONCLUSION: A high rate of IBS remains undetected in the psychotherapeutic care system. Women with IBS have other referral diagnoses and are more often affected by severe mental disorders than men.

Targeted Temperature Management for Subarachnoid Hemorrhage: Excellent Outcome After Severe Vasospasm-A Case Series.

Targeted temperature management (TTM) might improve outcome of patients with severe subarachnoid hemorrhage (SAH) in which vasospasm, delayed cerebral ischemia (DCI), and increased intracranial pressure (ICP) are frequent and severe complications. A series of patients (n = 3) with severe aneurysmatic SAH were treated by TTM if they developed ICP crisis and/or severe vasospasm diagnosed by angiography. Once these complications were detected, body core temperature (BCT) was rapidly decreased to 35°C or 33°C, if necessary. BCT induced and maintained by surface cooling remained at the desired level for at least 72 hours. Rewarming was performed by 1°C, only if the target parameters ICP and velocities in the serial Doppler sonography indicating macrovascular vasospasm improved to regular levels. In case of increase of ICP or middle cerebral arteries velocities BCT was decreased again to the last effective level. The patients developed vasospasm between days 6 and 12 after SAH. All aneurysms were treated by coiling. BCT was reduced between days 6 and 12 after SAH. Total duration of BCT <36.5°C was between 5.5 and 8 days. It remained <35°C for 4-6 days, and at 33°C for 3 days on average. ICP could be sufficiently controlled in all patients, because no ICP crisis was observed during TTM and after rewarming. Two patients developed minor DCI. Side effects of prolonged ventilation of 7-18 days included pneumonia for two patients that could be treated sufficiently. Other complications were one case of ventriculitis and two temporary deliriums. Outcome of the patients was good because no focal neurological symptoms could be detected after rehabilitation. TTM represents a promising treatment approach for severe SAH in which standard treatment is often limited and experimental. It deserves further clinical investigation in a larger cohort.

Pericytes/vessel-associated mural cells (VAMCs) are the major source of key epithelial-mesenchymal transition (EMT) factors SLUG and TWIST in human glioma.

Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas. We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed. Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis. In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.

Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, -2, and -3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas.

BACKGROUND: A major hallmark of malignant progression in human astrocytomas is the formation of new blood vessels. Antiangiogenic therapy using the anti-vascular endothelial growth factor (VEGF)-antibody bevacizumab leads to increased progression-free survival in glioblastoma patients but does not influence their overall survival. To date, it is unclear why antiangiogenic therapy fails in many glioblastoma patients, while a small subpopulation profits considerably from this treatment. METHODS: The aim of our study was to determine the expression of VEGF-A and its (co-) receptors by immunohistochemistry and to test the association with patient survival in 350 glioma patients. Additionally, VEGF-A expression was analyzed by in-situ hybridization. In 18 patients, the protein expression was compared with the bevacizumab response according to extended and modified RANO criteria. RESULTS: We found a heterogeneous expression pattern of VEGF and its receptors in glioblastoma patients with significantly lower levels in WHO grade II and III tumors and normal-appearing brain tissue (P < .001). Pilocytic astrocytomas (WHO grade I) showed significantly higher VEGFR-1, -2 and neuropilin-1 levels as compared to WHO grade II and III astrocytomas (P < .01) but at lower levels than glioblastomas. The expression of neuropilin-2 was low in all tumors. There was neither a significant correlation between protein expression and patient survival nor between protein levels and bevacizumab response after modified RANO criteria. CONCLUSION: Since our data indicate that beneficial response to bevacizumab treatment is independent of the expression of VEGF-A and its (co-) receptors, further investigation is needed to decipher the underlying mechanisms of antiangiogenic treatment response.

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma.

The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFß1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma.