TGF-β Superfamily Receptors—Targets for Antiangiogenic Therapy?

The TGF-β pathway controls a broad range of cellular behavior including cell proliferation, differentiation, and apoptosis of various cell types including tumor cells, endothelial cells, immune cells, and fibroblasts. Besides TGF-β's direct effects on tumor growth and its involvement in neoangiogenesis have received recent attention. Germline mutations in TGF-β receptors or coreceptors causing Hereditary Hemorrhagic Teleangiectasia and the Loeys-Dietz syndrome underline the involvement of TGF-β in vessel formation and maturation. Several therapeutic approaches are evaluated at present targeting the TGF-β pathway including utilization of antisense oligonucleotides against TGF-β itself or antibodies or small molecule inhibitors of TGF-β receptors. Some of these therapeutic agents have already entered the clinical arena including an antibody against the endothelium specific TGF-β class I receptor ALK-1 targeting tumor vasculature. In conclusion, therapeutic manipulation of the TGF-β pathway opens great opportunities in future cancer therapy

Dexamethasone-Induced Expression of Endothelial Mitogen-Activated Protein Kinase Phosphatase-1 Involves Activation of the Transcription Factors Activator Protein-1 and 3',5'-Cyclic Adenosine 5'-Monophosphate Response Element-Binding Protein and the Generation of Reactive Oxygen Species

We have recently identified the MAPK phosphatase (MKP)-1 as a novel mediator of the antiinflammatory properties of glucocorticoids (dexamethasone) in the human endothelium. However, nothing is as yet known about the signaling pathways responsible for the up-regulation of MKP-1 by dexamethasone in endothelial cells. Knowledge of the molecular basis of this new alternative way of glucocorticoid action could facilitate the identification of new antiinflammatory drug targets. Thus, the aim of our study was to elucidate the underlying molecular mechanisms. Using Western blot analysis, we found that dexamethasone rapidly activates ERK, c-jun Nterminal kinase (JNK), and p38 MAPK in human umbilical vein endothelial cells. By applying the kinase inhibitors PD98059 (MAPK kinase-1) and SP600125 (JNK), ERK and JNK were shown to be crucial for the induction of MKP-1. Using EMSA and a decoy oligonucleotide approach, the transcription factors activator protein-1 (activated by ERK and JNK) and cAMP response element-binding protein (activated by ERK) were found to be involved in the up-regulation of MKP-1 by dexamethasone. Interestingly, dexamethasone induces the generation of reactive oxygen species (measured by dihydrofluorescein assay), which participate in the signaling process by triggering JNK activation. Our work elucidates a novel alternative mechanism for transducing antiinflammatory effects of glucocorticoids in the human endothelium. Thus, our study adds valuable information to the efforts made to find new antiinflammatory principles utilized by glucocorticoids. This might help to gain new therapeutic options to limit glucocorticoid side effects and to overcome resistance

Skap2 is required for β2 integrin-mediated neutrophil recruitment and functions.

Integrin activation is required for neutrophil functions. Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency (LAD) syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. The Src kinase-associated phosphoprotein 2 (Skap2) is involved in integrin functions in different leukocyte subtypes. However, the role of Skap2 in β2 integrin activation and neutrophil recruitment is unknown. In this study, we demonstrate the crucial role of Skap2 in regulating actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin cytoplasmic domain, thereby being indispensable for β2 integrin activation and neutrophil recruitment. The direct interaction of Skap2 with the Wiskott-Aldrich syndrome protein via its SH3 domain is critical for integrin activation and neutrophil recruitment in vivo. Furthermore, Skap2 regulates integrin-mediated outside-in signaling events and neutrophil functions. Thus, Skap2 is essential to activate the β2 integrins, and loss of Skap2 function is sufficient to cause a LAD-like phenotype in mice

Perceived Positive and Negative Life Changes in Testicular Cancer Survivors

Background and objectives: Despite a generally good prognosis, testicular cancer can be a life-altering event. We explored perceived positive and negative life changes after testicular cancer in terms of frequency, demographic and disease-related predictors, and associations with depression and anxiety. Materials and methods: All testicular cancer survivors receiving follow-up care at two specialized outpatient treatment facilities were approached at follow-up visits or via mail. We assessed a total of N = 164 patients (66% participation rate, mean time since diagnosis: 11.6 years, SD = 7.4) by the Posttraumatic Growth Inventory (PTGI, modified version assessing positive and negative changes for each of 21 items), Patient-Health-Questionnaire-9 (PHQ-9), and Generalized-Anxiety- Disorder-Scale-7 (GAD-7). We conducted controlled multivariate regression analyses. Results: Most survivors (87%) reported at least one positive change (mean number: 7.2, SD = 5.0, possible range: 0–21). The most frequent perceived positive changes were greater appreciation of life (62%), changed priorities in life (62%), and ability rely on others (51%). At least one negative change was perceived by 33% (mean number of changes: 1.1, SD = 2.5). Negative changes were most frequent for decreases in self-reliance (14%), personal strength (11%), and ability to express emotions (9%). A higher socioeconomic status was associated with more positive changes ( = 0.25, 95% CI 0.08 to 0.42); no other association with demographic and disease-related predictors emerged. While positive life changes were not associated with depression ( = 0.05, 95% CI 0.17 to 0.07) and anxiety ( = 0.00, 95% CI 0.13 to 0.13), more negative life changes were significantly associated with higher depression ( = 0.15, 95% CI 0.03 to 0.27) and anxiety ( = 0.23, 95% CI 0.11 to 0.36). There was no significant interaction of positive and negative changes on depression or anxiety. Conclusions: Although positive life changes after testicular cancer are common, a significant number of survivors perceive negative changes in life domains that have been primarily investigated in terms of personal growth. Early identification of and psychosocial support for patients who perceive predominantly negative changes may contribute to prevention of prolonged symptoms of anxiety and depression