Pazopanib, Cabozantinib, and Vandetanib in the Treatment of Progressive Medullary Thyroid Cancer with a Special Focus on the Adverse Effects on Hypertension

Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form of cancer is often insensitive to conventional chemotherapy, but the use of tyrosine kinase inhibitors (TKIs), such as pazopanib, cabozantinib, and vandetanib, has shown promising results with an increase in progression-free survival and prolonged lifetime. Therefore, we focused on the pharmacological characteristics of TKIs, their mechanism of action, their application as a secondary treatment option for MTC, their efficacy as a cancer drug treatment, and reviewed the ongoing clinical trials. TKIs also act systemically causing various adverse events (AEs). One common AE of this treatment is hypertension, known to be associated with cardiovascular disease and can therefore potentially worsen the well-being of the treated patients. The available treatment strategies of drug-induced hypertension were discussed. The mechanism behind the development of hypertension is still unclear. Therefore, the treatment of this AE remains symptomatic. Thus, future studies are necessary to investigate the link between tumor growth inhibition and hypertension. In addition, optimized, individual treatment strategies should be implemented

Translation from Microgravity Research to Earth Application

The topic Translation from Microgravity Research to Earth Application comprises publications focusing on space life sciences, gravitational biology and space medicine. It covers publications reporting the impact of altered environmental conditions, such as microgravity (µg), cosmic radiation and isolation on organisms down to the level of cells. In addition, the topic collects studies validating causal diagrams of human health risks for spaceflight, hypergravity studies and investigations about the impact of extreme isolation in the Antarctica on the human body. µg provides a unique research environment and an opportunity to identify the mechanism of gravity-sensing and related signaling pathways, regulation and adaptation responses at the cellular, tissue and organism level, covering animals, plants and humans. µg-research is supported and validated by ground-based studies in µg-analogues and simulations, as well as under increased gravitational (hypergravity) conditions, providing comprehensive and new knowledge on the regulation of cellular and subcellular functioning

{W\cal W}-Gauge Structures and their Anomalies:An Algebraic Approach

Starting from flat two-dimensional gauge potentials we propose the notion of ${\cal W}$-gauge structure in terms of a nilpotent BRS differential algebra. The decomposition of the underlying Lie algebra with respect to an $SL(2)$ subalgebra is crucial for the discussion conformal covariance, in particular the appearance of a projective connection. Different $SL(2)$ embeddings lead to various ${\cal W}$-gauge structures. We present a general soldering procedure which allows to express zero curvature conditions for the ${\cal W}$-currents in terms of conformally covariant differential operators acting on the ${\cal W}$ gauge fields and to obtain, at the same time, the complete nilpotent BRS differential algebra generated by ${\cal W}$-currents, gauge fields and the ghost fields corresponding to ${\cal W}$-diffeomorphisms. As illustrations we treat the cases of $SL(2)$ itself and to the two different $SL(2)$ embeddings in $SL(3)$, {\it viz.} the ${\cal W}_3^{(1)}$- and ${\cal W}_3^{(2)}$-gauge structures, in some detail. In these cases we determine algebraically ${\cal W}$-anomalies as solutions of the consistency conditions and discuss their Chern-Simons origin.Comment: 46 pages,LaTe

729-1 Modulation of Cardiac Hypertrophy by Blockade of the Renin Angiotensin System: Effects on LVH Regression, Gene Expression, and Survival

The aim of the present study was to investigate the contribution of the renin angiotensin system to maintenance of pressure overload left ventricular hypertrophy (LVH). Rats with fixed ascending aortic stenosis were treated with either vehicle (VEH, n=36), hydralazine (HYD, 20mg/kg/d, n=35). ramipril (RAM, 10mg/kg/d, n=35), or losartan (LOS, 40mg/kg/d, n=16) during weeks 6–12 after banding. We have previously demonstrated that compared to sham (n=36), VEH and HYD rats were characterized by a 1.8–1.9-fold increase of left ventricular to body weight ratios (LV/BW). whereas those aortic stenosis rats treated with RAM or LOS displayed a blunted increase of LV/BW (14-fold; p<0.05, each vs. HYD). We now extend these observations demonstrating that myocyte cross sectional widths were increased by 150% in VEH and HYD rats (p<0.001, vs. sham), whereas ramipril and losartan treatment resulted in myocyte widths that were only mildly elevated (53% and 28%, respectively). Furthermore, VEH and HYD displayed a 14–15 fold increase of LV atrial natriuretic peptide (ANP) mRNA as well as a 44% decrease of sarcoplasmatic reticulum (SR) Ca2+-ATPase (p<0.001, vs. sham). In contrast, alterations of ANP and SR-Ca2+-ATPase mRNA levels were significantly blunted by both RAM and LOS. The attenuation of LVH by RAM or LOS was not explained by blood pressure reduction that was similar in the HYD group. Finally, RAM and LOS decreased mortality (6 out of 51 animals; 11%)as compared to 20% in HYD and 31% in VEH groups (p<0.05).In summary, blockade of the renin angiotensin system may promote regression of pressure overload LVH on the macro-, and microscopical, as well as the molecular level by mechanisms that are, in part, independent of hemodynamic drug effects. LVH regression may improve survival despite persisting pressure overload

Growing blood vessels in space : preparation studies of the SPHEROIDS project using related ground-based studies

Endothelial cells (ECs) grow as single layers on the bottom surface of cell culture flasks under normal (1g) culture conditions. In numerous experiments using simulated microgravity we noticed that the ECs formed three-dimensional, tube-like cell aggregates resembling the intima of small, rudimentary blood vessels. The SPHEROIDS project has now shown that similar processes occur in space. For the first time, we were able to observe scaffold-free growth of human ECs into multicellular spheroids and tubular structures during an experiment in real microgravity. With further investigation of the space samples we hope to understand endothelial 3D growth and to improve the in vitro engineering of biocompatible vessels which could be used in surgery

Interaction Network Provides Clues on the Role of BCAR1 in Cellular Response to Changes in Gravity

When culturing cells in space or under altered gravity conditions on Earth to investigate the impact of gravity, their adhesion and organoid formation capabilities change. In search of a target where the alteration of gravity force could have this impact, we investigated p130cas/BCAR1 and its interactions more thoroughly, particularly as its activity is sensitive to applied forces. This protein is well characterized regarding its role in growth stimulation and adhesion processes. To better understand BCAR1′s force-dependent scaffolding of other proteins, we studied its interactions with proteins we had detected by proteome analyses of MCF-7 breast cancer and FTC-133 thyroid cancer cells, which are both sensitive to exposure to microgravity and express BCAR1. Using linked open data resources and our experiments, we collected comprehensive information to establish a semantic knowledgebase and analyzed identified proteins belonging to signaling pathways and their networks. The results show that the force-dependent phosphorylation and scaffolding of BCAR1 influence the structure, function, and degradation of intracellular proteins as well as the growth, adhesion and apoptosis of cells similarly to exposure of whole cells to altered gravity. As BCAR1 evidently plays a significant role in cell responses to gravity changes, this study reveals a clear path to future research performing phosphorylation experiments on BCAR1

Towards human exploration of space: The THESEUS review series on immunology research priorities

Dysregulation of the immune system occurs during spaceflight and may represent a crew health risk during exploration missions because astronauts are challenged by many stressors. Therefore, it is crucial to understand the biology of immune modulation under spaceflight conditions in order to be able to maintain immune homeostasis under such challenges. In the framework of the THESEUS project whose aim was to develop an integrated life sciences research roadmap regarding human space exploration, experts working in the field of space immunology, and related disciplines, established a questionnaire sent to scientists around the world. From the review of collected answers, they deduced a list of key issues and provided several recommendations such as a maximal exploitation of currently available resources on Earth and in space, and to increase increments duration for some ISS crew members to 12 months or longer. These recommendations should contribute to improve our knowledge about spaceflight effects on the immune system and the development of countermeasures that, beyond astronauts, could have a societal impact

In Prostate Cancer Cells Cytokines are early Responders to Gravitational Changes occurring in Parabolic Flights

The high mortality in men with metastatic prostate cancer (PC) establishes the need for diagnostic optimization by new biomarkers. Mindful of the effect of real microgravity on metabolic pathways of carcinogenesis, we attended a parabolic flight (PF) mission to perform an experiment with the PC cell line PC-3, and submitted the resulting RNA to next generation sequencing (NGS) and quantitative real-time PCR (qPCR). After the first parabola, alterations of the F-actin cytoskeleton-like stress fibers and pseudopodia are visible. Moreover, numerous significant transcriptional changes are evident. We were able to identify a network of relevant PC cytokines and chemokines showing differential expression due to gravitational changes, particularly during the early flight phases. Together with differentially expressed regulatory lncRNAs and micro RNAs, we present a portfolio of 298 potential biomarkers. Via qPCR we identified IL6 and PIK3CB to be sensitive to vibration effects and hypergravity, respectively. Per NGS we detected five upregulated cytokines (CCL2, CXCL1, IL6, CXCL2, CCL20), one zink finger protein (TNFAIP3) and one glycoprotein (ICAM1) related to c-REL signaling and thus relevant for carcinogenesis as well as inflammatory aspects. We found regulated miR-221 and the co-localized lncRNA MIR222HG induced by PF maneuvers. miR-221 is related to the PC-3 growth rate and MIR222HG is a known risk factor for glioma susceptibility. These findings in real microgravity may further improve our understanding of PC and contribute to the development of new diagnostic tools