Aortic Root Dilation and Testosterone Use: Are They Associated?

Aortic root dilation and thoracic aortic aneurysms are relatively rare in young and healthy patient populations. However, a number of observed incidental cases regarding young males and testosterone use raises suspicion of a potential risk factor for aortic root dilation. The authors' patient, a healthy 40-year-old man with a significant history of testosterone use who developed a massively dilated aortic root, is sufficiently alarming to report. Notwithstanding anecdotal cases, there exists a well-known association between elite strength athletes and aortic root dilation. Nevertheless, very little clinical research exists on the relationship between testosterone use and aortic root dilation and/or thoracic aortic aneurysms. Furthermore, a small number of animal studies showed a relationship between testosterone and vascular dilation, particularly the aorta. Although testosterone may play a role in the development of aortic pathologies, further research is necessary to clarify the possible relationship if cases such as these are to be prevented.

The future is not always open.

We demonstrate the breakdown of several fundamentals of Lorentzian causality theory in low regularity. Most notably, chronological futures (defined naturally using locally Lipschitz curves) may be non-open and may differ from the corresponding sets defined via piecewise C 1 -curves. By refining the notion of a causal bubble from Chrusciel and Grant (Class Quantum Gravity 29(14):145001, 2012), we characterize spacetimes for which such phenomena can occur, and also relate these to the possibility of deforming causal curves of positive length into timelike curves (push-up). The phenomena described here are, in particular, relevant for recent synthetic approaches to low-regularity Lorentzian geometry where, in the absence of a differentiable structure, causality has to be based on locally Lipschitz curves.

Inextendibility of spacetimes and Lorentzian length spaces.

We study the low-regularity (in-)extendibility of spacetimes within the synthetic-geometric framework of Lorentzian length spaces developed in Kunzinger and Sämann (Ann Glob Anal Geom 54(3):399-447, 2018). To this end, we introduce appropriate notions of geodesics and timelike geodesic completeness and prove a general inextendibility result. Our results shed new light on recent analytic work in this direction and, for the first time, relate low-regularity inextendibility to (synthetic) curvature blow-up.

Fe(III)-salen and salphen complexes induce caspase activation and apoptosis in human cells.

To explore the apoptotic and antitumor activities of metallo-salens, the authors have synthesized several Fe(III)-salen and salphen complexes and analyzed their effects on human cancer and noncancer cells. Their results demonstrated that Fe(III)-salen and salphen complexes affect cell viability and induce nuclear fragmentation and apoptosis in breast cancer (MCF7) cells. The IC(50) values for the active metallo-salen complexes ranged between 0.3 and 22 µM in MCF7 cells. Biochemically active Fe(III)-salen and salphen complexes induced caspase-3/7 activation and release of cytochrome c from the mitochondria to cytosol, suggesting the involvement of the mitochondrial pathway of apoptosis. Comparison of IC(50) values toward 3 different cell lines demonstrated that selected Fe(III)-salen complexes induce tumor cell-selective apoptosis in cultured cells. Overall, the studies demonstrated that Fe(III)-salen and salphen complexes induced efficient apoptosis in cultured human cells. The nature of the substituents and the bridging spacer between diamino groups play critical roles in determining the apoptotic activities of Fe(III)-salen and salphen complexes.

Apoptosis and anti-tumour activities of manganese(III)-salen and -salphen complexes.

We analyzed the apoptosis and anti-tumour activities of several Mn(III)-salen and -salphen complexes (1-14) towards three different cultured human cancer and non-cancer cells. We demonstrated that most of the Mn(III)-salen and -salphen complexes affect cell viability and induce apoptosis in MCF7 cells. Biochemically active Mn(III)-salen and -salphen complexes induced nuclear fragmentation and release of cytochrome c from the mitochondria to cytosol indicating involvement of mitochondrial pathway of apoptosis. The nature and position of the substituents and the bridging group on the salen ligands play crucial roles in determining the apoptotic activities of Mn(III)-salen and -salphen complexes. The IC50 values for the active Mn(III)-salen complexes ranged between 12 and 55 microM. For Mn(III)-salen complexes with ethylenediamine bridges, methoxy substituted complexes were more active than the corresponding hydroxy derivatives. However, this correlation does not hold when the bridging group was changed from ethylenediamine to o-phenylenediamine. Importantly, several Mn(III)-salen and -salphen complexes showed about 2-3 fold selectivity toward cancer cells such as MCF7 (breast cancer), and CCL228 (colon cancer) over a normal non-malignant cell MCF10 (breast epithelial cells) indicating their potential application towards novel anti-tumour therapy.

Manganese(III)-salens induce tumor selective apoptosis in human cells.

In order to explore the apoptotic and anti-tumor activities of metallo-salens, we synthesized several Mn(III)-salen derivatives (compds. 1-9) and analyzed their effects on cultured human cancer and non-cancer cells. Our results demonstrated that Mn(III)-salen derivatives affect cell viability, induce nuclear condensation and fragmentation in breast cancer cells (MCF7). Mn(III)-salen derivatives also induced caspase-3/7 activation and release of cytochrome-c from the mitochondria to cytosol suggesting that Mn(III)-salen derivatives induce apoptosis in human cells via mitochondrial pathway. Importantly, the nature of the substituent and the bridging spacer between diimino groups on the salen ligand play critical roles in determining the apoptotic activities of Mn(III)-salen derivatives. The IC(50) values for the active Mn(III)-salen derivatives lie within the range of 11-40microM in MCF7 cells. Most importantly, several Mn(III)-salen derivatives showed preferential cytotoxicity (2- to 5-fold) toward malignant breast cells (MCF7) over a non-malignant breast epithelial cell line (MCF10). Notably, the level of cytotoxicity and selectivity of the Mn(III)-salen derivatives towards MCF7 and MCF10 cells are very similar to cisplatin which indicate that Mn(III)-salens are potential novel anti-tumor agent.

Iron(III)-salen complexes with less DNA cleavage activity exhibit more efficient apoptosis in MCF7 cells.

To understand the relationship between DNA damage potential and biochemical activities, we synthesized nine different Fe(III)-salen derivatives with varying substituents, and analyzed their in vitro DNA cleavage properties and biochemical effects on cultured human cells. Our results demonstrated that Fe(III)-salen complexes affect cell viability, induce nuclear fragmentation, and activate caspases and apoptosis in cultured human cells. The nature and the position of the substituents in the Fe(III)-salen complexes play critical roles in determining their apoptotic efficiencies. Most importantly, our results demonstrated that the in vitro DNA cleavage activities of Fe(III)-salen complexes are not essential for their apoptotic activities in human cells. Instead, the lesser their DNA cleavage activity the greater is their apoptotic efficiency.