Bone Mineral Density and Secondary Hyperparathyroidism in Pulmonary Hypertension

BACKGROUND: Low bone mineral density (BMD) is common in chronic lung diseases and associated with reduced quality of life. Little is known about BMD in pulmonary hypertension (PH). METHODS: Steroid-naïve patients with PH (n=34; 19 idiopathic, 15 chronic thromboembolic) had BMD measured by DXA at the time of diagnostic right heart catheterization. Exercise capacity, quality of life and various parameters related to PH severity and bone metabolism were also assessed. 24 patients with left heart failure (LHF) were similarly assessed as controls. RESULTS: The prevalence of osteopenia was high both in PH (80%) and in controls with LHF (75%). Low BMD was associated with lean body mass, age, lower BMI, impaired exercise capacity and in PH with higher pulmonary vascular resistance. Serum parathyroid hormone (PTH) was elevated and considerably higher in PH than in LHF (above normal, in 55 vs 29%). Secondary hyperparathyroidism was not related to impaired renal function but possibly to low vitamin D status. CONCLUSIONS: Osteopenia is common in PH and in chronically ill patients with LHF. Osteopenia is associated with known risk factors but in PH also with disease severity. Preventive measures in an increasingly chronic ill PH population should be considered. Secondary hyperparathyroidism is highly prevalent in PH and might contribute to bone and possibly pulmonary vascular disease. Whether adequate vitamin D substitution could prevent low BMD in PH remains to be determined

Differences in the Visual Perception of Symmetric Patterns in Orangutans (Pongo pygmaeus abelii) and Two Human Cultural Groups: A Comparative Eye- Tracking Study

Symmetric structures are of importance in relation to aesthetic preference. To investigate whether the preference for symmetric patterns is unique to humans, independent of their cultural background, we compared two human populations with distinct cultural backgrounds (Namibian hunter-gatherers and German town dwellers) with one species of non-human great apes (Orangutans) in their viewing behavior regarding symmetric and asymmetric patterns in two levels of complexity. In addition, the human participants were asked to give their aesthetic evaluation of a subset of the presented patterns. The results showed that humans of both cultural groups fixated on symmetric patterns for a longer period of time, regardless of the pattern’s complexity. On the contrary, Orangutans did not clearly differentiate between symmetric and asymmetric patterns, but were much faster in processing the presented stimuli and scanned the complete screen, while both human groups rested on the symmetric pattern after a short scanning time. The aesthetic evaluation test revealed that the fixation preference for symmetric patterns did not match with the aesthetic evaluation in the Hai//om group, whereas in the German group aesthetic evaluation was in accordance with the fixation preference in 60 percent of the cases. It can be concluded that humans prefer well-ordered structures in visual processing tasks, most likely because of a positive processing bias for symmetry, which Orangutans did not show in this task, and that, in humans, an aesthetic preference does not necessarily accompany the fixation preference

Silver clusters of five atoms as highly selective antitumoral agents through irreversible oxidation of thiols

Low atomicity clusters present properties dependent on the size, due to the quantum confinement, with well-defined electronic structures and high stability. Here it is shown that Ag5 clusters catalyze the complete oxidation of sulfur to S+6. Ag5 catalytic activity increases with different oxidant species in the order O2 ≪ H2O2 < OH•. Selective oxidation of thiols on the cysteine residues of glutathione and thioredoxin is the primary mechanism human cells have to maintain redox homeostasis. Contingent upon oxidant concentration, Ag5 catalyzes the irreversible oxidation of glutathione and thioredoxin, triggering apoptosis. Modification of the intracellular environment to a more oxidized state to mimic conditions within cancer cells through the expression of an activated oncogene (HRASG12V) or through ARID1A mutation, sensitizes cells to Ag5 mediated apoptosis. While cancers evolve to evade treatments designed to target pathways or genetic mutations that drive them, they cannot evade a treatment that takes advantage of aberrant redox homeostasis, which is essential for tumor progression and metastasis. Ag5 has antitumor activity in mice with orthotopic lung tumors reducing primary tumor size, and the burden of affected lymphatic nodes. The findings suggest the unique intracellular redox chemistry of Ag5 may lead to new redox-based approaches to cancer therapyThis research was partially supported by 1) “la Caixa” Foundation, Ref. LCF/PR/PR12/11070003 to F.D. and M.A.L.Q.; 2) Ministerio de Ciencia, Innovación y Universidades (MAT2017-89678-R, AEI/FEDER, UE) to F.D. and A.V.; 3) the Consellería de Educación (Xunta de Galicia), Grants No. Grupos Ref. Comp. ED431C 2017/22, ED431C 2019/13 and AEMAT-ED431E2018/08 to M.A.L.Q.; and ED431C 2019/13 to A.V. This project has received funding from the European Union's Horizon 2020 Research and Innovation Programme (Bac-To-Fuel) under Grant Agreement No. 825999 (M.A.L.Q.). J.C.H. acknowledge financial support from European Union's Horizon 2020 research and innovation programme under grant agreement no. 823717-ESTEEM3, and the MICIIN (projects PID2019-107578GA-100 and PID-110018GA-100). J.M.D, L.J.G., and F.G.R. thank to the ANPCyT (PICT 2015-2285 and 2017-3944), UNLP (Project 11/X790) and the partial support by the Laboratório Nacional de Luz Síncrotron (LNLS, Brazil) under proposal SXS-20180280. G.B. acknowledges the CINECA Award N. IsC51, year 2017, under the ISCRA initiative, for the availability of high-performance computing resources and support. D.B. expresses gratitude for a postdoctoral grant from Xunta de Galicia, Spain (POS-A/2013/018). B.D. expresses gratitude for a predoctoral grant from MICINN, Spain (BES-2016-076765). F.D. and A.V. also acknowledged Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019-2022 ref ED431G 2019/02) and the European Union (European Regional Development Fund – ERDF). Work in M.P.M.'s lab was supported by the Medical Research Council UK (MC_U105663142). T.G.C. gratefully acknowledges the technical assistance of María José Otero-Fraga (FIDIS)S

The role of PTPα in mammary tumorigenesis

Ziel der vorliegenden Arbeit war es die Rolle der PTPα im Mammakarzinomsystem zu untersuchen, da eine mögliche Beteiligung dieser Phosphatase an der Förderung der neoplastischen Transformation oder der Fortschreitung der Brusttumoren nicht beschrieben wurde. In einem molekulardiagnostischen Teil konnte mittels cDNA-Arrays eine klare hoch-regulierte Expression der PTPα in primären Brusttumoren und in Brustkrebszellinien gezeigt werden. Eine starke Expressionskorrelation zwischen PTPα und c-src, sowie zwischen PTPα und einem positiven Östrogenrezeptorstatus konnte ebenfalls gezeigt werden. Die anschließenden cDNA-Array Validierungen mit Northern-, bzw. Westernblots bestätigten diese Erkenntnisse. Die Erkenntnisse aus dem molekulardiagnostischen Teil sollten mit einem funktionsanalytischen Teil mittels gezielter Manipulation von Brusttumorzellen überprüft werden. Tetrazylin-induzierte Genexpression der PTPα-wt und der PTPα-cc/ss katalytisch inaktiven Mutante wurde in einer Reihe von Brustzellinien etabliert. Ein für diesen Zweck modifiziertes retrovirales Zwei-Vektor System ermöglichte eine starke Induktion der Zielgene in einem erweiterten Zellspektrum ohne detektierbare Basalaktivität. Die Induktionsstärke der Transaktivatorklone führte zu spezifischen Genregulationen in den meisten Zellinien, und diese könnten einen potentiellen Zusammenhang zwischen dem beobachteten verringerten Zellwachstum der induzierten Zellinien und der induzierten Expression des Transaktivators herstellen. Weiterhin konnte durch die induzierte Genexpression der PTPα verringertes Zellwachstum aller untersuchten Brustkrebszellinien, vermehrte Zellzahlen in der G1-Phase der MCF10A und MCF7 Zellen, und Aktivierung von c-src in den MCF7 Zellen gezeigt werden. Erhöhte c-src Aktivität korrelierte mit einer verringerten c-src Expression, welche wahrscheinlich auf Herunterregulierung des Gens zurückzuführen ist. Die Hochregulation der PTPα in Primärtumoren und Brustkrebszellinien, die PTPα-vermittelte Wachstumsreduzierung und die Aktivierung von c-src in Brusttumorzellinien, sowie die Korrelation mit der c-src Expression und einem positiven Östrogenrezeptorstatus implizieren eine Beteiligung dieser Phosphatase in der Tumorigenese im Mammakarzinomsystem.The aim of this work was the investigation of the role of PTPα in mammary carcinoma, since a potential contributory role of this phosphatase in the initiation and progression of neoplastic transformation in mammary tumors hadn't been reported as yet. cDNA array diagnostic analysis of breast tumors and breast cancer cell lines revealed high expression of PTPα, and its expression correlated with that of c-src and the estrogen receptor alpha. These results were confirmed with northern- and western-blots. Functional analysis using improved tetracycline-inducible retroviral gene expression of the wildtype and the catalytically inactive mutant of PTPα in breast cancer cells was intended to validate the above results. The modified gene expression system allowed the induction of target genes in an expanded panel of cell lines without detectable basal expression. The induction of the transactivator led to specific gene regulation in most cell lines, and could potentially link reduced growth parameters of induced cell lines to induced expression of the transactivator protein. The induced expression of PTPα wildtype led to reduced cellular growth of all cell lines, a higher percentage of cells in G1-phase of the cell cycle of MCF10A and MCF7 cells, and activation of c-src in MCF7. Higher c-src activity correlated with reduced c-src expression, probably due to downregulation of gene activity. The upregulation of PTPα in primary tumors and cell lines, the PTPα-mediated growth reduction and the activation of c-src in breast cancer cell lines, as well as the correlated expression of c-src and the estrogen receptor imply a contributory role of this phosphatase in mammary tumorigenesis