Preparation, characterization and catalytic testing of GePt catalysts

Unsupported and SiO2 supported GePt bimetallic catalysts were prepared by depositing Ge on to Pt underpotentially. Surface-sensitive cyclic voltammetry of Pt black indicated that Ge covered ca. 40–45% of the Pt surface, whereas XPS showed just 96% Pt and 4% Ge (normalized to Pt+Ge=100%). High-resolution Ge map of GePt black obtained by Energy Filtered TEM (EFTEM) showed Ge scattered in the near-surface regions. Both catalysts were tested in hexane (nH) transformation reactions between 543 and 603 K and 60 to 480 Torr H2 pressure (with 10 Torr nH), and compared with the parent Pt catalysts. GePt/SiO2 catalyst was also tested with methylcyclopentane (MCP). Adding Ge to Pt/SiO2 lowered the activity; the opposite effect was observed with GePt black. The selectivities of saturated products on bimetallic catalysts decreased, while those of hydrogenolysis products, benzene and hexenes increased in nH transformations over supported catalyst. The reverse effects were observed over the black samples where addition of Ge prevented accumulation of adventitious carbon. Ring opening was the main reaction with MCP, together with some fragments, benzene and unsaturated hydrocarbons. Ring opening of MCP became more selective with decreasing temperature and increasing hydrogen pressure. Ge on GePt black blocked contiguous Pt sites favoring the formation of coke precursors. The different catalytic behavior of GePt/SiO2 indicated somewhat different Pt–Ge interaction(s)

Palladium-platinum powder catalysts manufactured by colloid synthesis II. Characterization and catalytic tests after oxidizing and reducing treatment

Unsupported Pd, Pt and PdPt bimetallic catalysts were prepared in different atomic ratios using methods of colloid chemistry. They were characterized by XPS, UPS and TEM. Four subsequent treatments with O2 and H2 up to T = 603K were applied in the preparation chamber of the electron spectrometer and before the catalytic runs. Platinum strongly hindered the oxidation of palladium in the bimetallic samples indicating an alloying of the two components. The H2 treatment after O2 led to rather clean metals. These treatments up to 603K decreased the Pt enrichment near to the surface found by XPS, destroying presumably the Pt islands on the surface of a Pd-rich matrix. The particle composition approached thus a homogeneous metal mixture. The catalytic behavior was tested in the hydrogenative ring opening reaction of cis- and trans-methyl-ethyl-cyclopropane (MECP) at 373 K. The product ratios 2-methylpentane/3-methylpentane (2MP/3MP) and 2-methylpentane/n-hexane (2MP/nH) were used to characterize the ring-opening pattern of the samples. The bimetallic catalysts revealed higher activity and completely different selectivities than the monometallic Pt and Pd. Moreover, the 2MP/3MP ratio from trans-MECP and 2MP/nH ratio from cis-MECP increased as the surface Pt enrichment decreased. PdPt catalysts were cleaner than Pd or Pt, their activity higher and selectivity closer to random C C rupture, due, very likely, to the presence of active Pd-Pt ensembles

Opposite prognostic roles of HIF1alpha and HIF2alpha expressions in bone metastatic clear cell renal cell cancer

BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1alpha/HIF2alpha and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2alpha was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1alpha was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2alpha and high HIF1alpha as well as CAIX, GAPDH and GLUT1 expressions correlated with adverse prognosis, while VEGFR2 and EPOR gene expressions were associated with favorable prognosis. Multivariate analysis confirmed high HIF2alpha protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1alpha gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2alpha and VEGFR2 expressions as favorable prognostic factors. HIF1alpha/HIF2alpha-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort. PATIENTS AND METHODS: Expressions of HIF1alpha and HIF2alpha as well as their 7 target genes were analysed on the mRNA and protein level in 59 non-metastatic ccRCCs (nmRCC), 40 bone metastatic primary ccRCCs (mRCC) and 55 corresponding bone metastases. Results were validated in 399 ccRCCs from the TCGA project. CONCLUSIONS: We identified HIF2alpha protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1alpha, increased HIF2alpha expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC

Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer

Background: A combination of entinostat, all-trans retinoic acid, and doxorubicin (EAD) induces cell death and differentiation and causes significant regression of xenografts of triple-negative breast cancer (TNBC). Methods: We investigated the mechanisms underlying the antitumor effects of each component of the EAD combination therapy by high-throughput gene expression profiling of drug-treated cells. Results: Microarray analysis showed that entinostat and doxorubicin (ED) altered expression of genes related to growth arrest, inflammation, and differentiation. ED downregulated MYC, E2F, and G2M cell cycle genes. Accordingly, entinostat sensitized the cells to doxorubicin-induced growth arrest at G2. ED induced interferon genes, which correlated with breast tumors containing a higher proportion of tumor-infiltrating lymphocytes. ED also increased the expression of immune checkpoint agonists and cancer testis antigens. Analysis of TNBC xenografts showed that EAD enhanced the inflammation score in nude mice. Among the genes differentially regulated between the EAD and ED groups, an all-trans retinoic acid (ATRA)-regulated gene, DHRS3, was induced in EAD-treated xenografts. DHRS3 was expressed at lower levels in human TNBC metastases compared to normal breast or primary tumors. High expression of ED-induced growth arrest and inflammatory genes was associated with better prognosis in TNBC patients. Conclusions: Entinostat potentiated doxorubicin-mediated cell death and the combination induced inflammatory signatures. The ED-induced immunomodulation may improve immunotherapy. Addition of ATRA to ED may potentiate inflammation and contribute to TNBC regression. © 2018 The Author(s)

Integrated molecular analysis of Tamoxifen-resistant invasive lobular breast cancer cells identifies MAPK and GRM/mGluR signaling as therapeutic vulnerabilities

Invasive lobular breast cancer (ILC) is an understudied malignancy with distinct clinical, pathological, and molecular features that distinguish it from the more common invasive ductal carcinoma (IDC). Mounting evidence suggests that estrogen receptor-alpha positive (ER+) ILC has a poor response to Tamoxifen (TAM), but the mechanistic drivers of this are undefined. In the current work, we comprehensively characterize the SUM44/LCCTam ILC cell model system through integrated analysis of gene expression, copy number, and mutation, with the goal of identifying actionable alterations relevant to clinical ILC that can be co-targeted along with ER to improve treatment outcomes. We show that TAM has several distinct effects on the transcriptome of LCCTam cells, that this resistant cell model has acquired copy number alterations and mutations that impinge on MAPK and metabotropic glutamate receptor (GRM/mGluR) signaling networks, and that pharmacological inhibition of either improves or restores the growth-inhibitory actions of endocrine therapy

Reproductive health and burn-out among female physicians: nationwide, representative study from Hungary

BACKGROUND: There is a worldwide rising tendency of women deciding to become physicians; hence, one of the most remarkable fields of investigation is the wellbeing of female doctors. The aim of this study was to describe female physicians' reproductive health in Hungary and to explore the potential correlation between their reproductive disorders and burnout symptoms. Up to our present knowledge, there have not been any studies investigating the correlation between reproductive disorders and burnout of female physicians; therefore, our study represents a unique approach. METHODS: Data in this representative cross-sectional epidemiological study were obtained from online questionnaires completed by 3039 female physicians. Participants in a representative nationwide survey (Hungarostudy, 2013) served as controls (n = 1069). Differences between physicians and the control group were disclosed by chi-square test. Correlations between certain factors of reproductive health and the three dimensions of burnout were detected by Pearson correlations and X2 test. Binary logistic regression analysis was used to determine the association between burnout and reproductive health. RESULTS: Female physicians were more often characterised by time-to-pregnancy interval longer than one year (18.4% vs. 9.8%), were bearing more high-risk pregnancies (26.3% vs.16.3%), and were more likely to be undergoing infertility therapy (8.5% vs. 3.4%) and experiencing miscarriage (20.8% vs. 14.6%) during their reproductive years, compared with the general female population. With the exception of miscarriages, the difference remained significant in all comparisons with the professional control group. Both high-risk pregnancies and miscarriages of doctors were associated with depersonalisation (p = 0.028 and p = 0.012 respectively) and personal accomplishment (p = 0.016 and p = 0.008 respectively) dimensions of burnout. Results of the multivariate analysis showed that, beside traditional risk factors, depersonalisation acted as an important explanatory factor in case of high-risk pregnancies (OR = 1.086). CONCLUSIONS: There is a circulatory causality between burnout and the development of reproductive disorders. Burnout is an important risk factor for high-risk pregnancies and miscarriages, and it has a negative effect on the outcome of pregnancies. At the same time, women suffering from reproductive disorders are more likely to develop burnout syndrome. Improvement of working conditions and prevention of burnout in female doctors are equally important tasks

A network-based target overlap score for characterizing drug combinations: High correlation with cancer clinical trial results

Drug combinations are highly efficient in systemic treatment of complex multigene diseases such as cancer, diabetes, arthritis and hypertension. Most currently used combinations were found in empirical ways, which limits the speed of discovery for new and more effective combinations. Therefore, there is a substantial need for efficient and fast computational methods. Here, we present a principle that is based on the assumption that perturbations generated by multiple pharmaceutical agents propagate through an interaction network and can cause unexpected amplification at targets not immediately affected by the original drugs. In order to capture this phenomenon, we introduce a novel Target Overlap Score (TOS) that is defined for two pharmaceutical agents as the number of jointly perturbed targets divided by the number of all targets potentially affected by the two agents. We show that this measure is correlated with the known effects of beneficial and deleterious drug combinations taken from the DCDB, TTD and Drugs.com databases. We demonstrate the utility of TOS by correlating the score to the outcome of recent clinical trials evaluating trastuzumab, an effective anticancer agent utilized in combination with anthracycline- and taxane-based systemic chemotherapy in HER2-receptor (erb-b2 receptor tyrosine kinase 2) positive breast cancer. © 2015 Ligeti et al