Functional Characterization of Novel Mutations Affecting Survivin (BIRC5)‐Mediated Therapy Resistance in Head and Neck Cancer Patients

Survivin (BIRC5) is an acknowledged cancer therapy‐resistance factor and overexpressed in head and neck squamous cell carcinomas (HNSCC). Driven by its nuclear export signal (NES), Survivin shuttles between the nucleus and the cytoplasm, and is detectable in both cellular compartments in tumor biopsies. Although predominantly nuclear Survivin is considered a favorable prognostic disease marker for HNSCC patients, the underlying molecular mechanisms are not resolved. Hence, we performed immunohistochemical and mutational analyses using laser capture microdissection on HNSCC biopsies from patients displaying high levels of nuclear Survivin. We found somatic BIRC5 mutations, c.278T>C (p.Phe93Ser), c.292C>T (p.Leu98Phe), and c.288A>G (silent), in tumor cells, but not in corresponding normal tissues. Comprehensive functional characterization of the Survivin mutants by ectopic expression and microinjection experiments revealed that p.Phe93Ser, but not p.Leu98Phe inactivated Survivin's NES, resulted in a predominantly nuclear protein, and attenuated Survivin's dual cytoprotective activity against chemoradiation‐induced apoptosis. Notably, in xenotransplantation studies, HNSCC cells containing the p.Phe93Ser mutation responded significantly better to cisplatin‐based chemotherapy. Collectively, our results underline the disease relevance of Survivin's nucleocytoplasmic transport, and provide first evidence that genetic inactivation of Survivin's NES may account for predominantly nuclear Survivin and increased therapy response in cancer patients.     

Secretory products from human adipocytes impair endothelial function via nuclear factor kappaB

Hyperplasia and hypertrophy of fat cells can be found in obesity, and increased adiposity is associated with endothelial dysfunction as an early event of atherosclerosis. However, it is unclear whether human adipocytes directly influence endothelial function. To study the crosstalk between fat and endothelial cells, human umbilical venous endothelial cells (HUVECs), and human coronary artery endothelial cells (HCAECs) were cultured in infranatants (Adipo) of primary differentiated human adipocytes. Interestingly, incubation of HUVECs and HCAECs with Adipo significantly increased monocyte adhesion 7.3 and 2.2-fold, respectively. VCAM-1, ICAM-1, and E-selectin in HUVECs were upregulated 3.9, 3.0, and 9.5-fold, respectively, under these conditions. Furthermore, Adipo significantly stimulated NFkappaB activity 1.9-fold. The NFkappaB inhibitor MG-132 and heat inactivation significantly reversed Adipo-stimulated monocyte adhesion. TNFalpha-neutralizing antibodies partly reversed Adipo-induced monocyte adhesion. In contrast, thiazolidinedione-pretreatment of human adipocytes did not alter the effects of Adipo. Adipo did not show cytotoxic effects. Taken together, we demonstrate that endothelial dysfunction is induced by adipocyte-secreted factors via NFkappaB partly dependent on TNFalpha.     

The uniqueness of subjective ageing: convergent and discriminant validity

Although a large body of research has demonstrated the predictive power of subjective ageing for several decisive developmental outcomes, there remains some controversy about whether subjective ageing truly represents a unique construct. Thus, information about the convergent and discriminant validity of different approaches to measuring subjective ageing is still critically needed. Using data from the 2014 wave of the German Ageing Survey, we examined how three established subjective ageing measures (subjective age, global attitude toward own ageing, multidimensional ageing-related cognitions) were inter-related as well as distinct from general dispositions (optimism, self-efficacy) and well-being (negative affect, depressive symptoms, self-rated health). Using correlational and multivariate regression analysis, we found that the three subjective ageing measures were significantly inter-related (r = |.09| to |.30|), and that each measure was distinct from general dispositions and well-being. The overlap with dispositional and well-being measures was lowest for subjective age and highest for global attitudes towards own ageing. The correlation between global attitudes towards own ageing and optimism was particularly striking. Despite the high convergent validity of the different dimensions of ageing cognitions, we nevertheless observed stronger associations between specific dimensions of ageing cognitions with negative affect and self-rated health. We conclude that researchers should be aware of the multidimensional nature of subjective ageing. Furthermore, subjective age appears to be a highly aggregated construct and future work is needed to clarify its correlates and reference points.Electronic supplementary materialThe online version of this article (10.1007/s10433-019-00529-7) contains supplementary material, which is available to authorized users.