Direct Costs of Healthcare for Children with Type 1 Diabetes Using a CGM System: A Health Economic Analysis of the VIDIKI Telemedicine Study in a German Setting.

AIMS: The Virtual Diabetes Outpatient Clinic for Children and Adolescents (VIDIKI) study was a 6-month quasi-randomized, multicentre study followed by an extension phase to evaluate the effects of monthly video consultations in addition to regular care. A health economic analysis was conducted to assess the direct costs. METHODS: The cost data of 240 study participants (1-16 years of age) with type 1 diabetes who were already using a continuous glucose monitoring system were collected in the first 6 months of the study. The intervention group (IG) received monthly video consultations plus regular care, and the waiting control group (WG) received only regular care. Cost data were collected for a comparable anonymized group of children from the participating health insurance companies during the 6-month period before the study started (aggregated data group [AG]). RESULTS: Cost data were analysed for the AG (N=840) 6 months before study initiation and those for the study participants (N=225/240). Hospital treatment was the highest cost category in the AG. There was a cost shift and cost increase in the IG and WG, whereby diabetes supplies were the highest cost category. The mean direct diabetes-associated 6-month costs were € 4,702 (IG) and € 4,936 (WG). CONCLUSION: The cost development within the cost collection period over two years possibly reflects the switch to higher-priced medical supplies. Video consultation as an add-on service resulted in a small but nonsignificant reduction in the overall costs.

Interaction of Hydrogen with Ceria: Hydroxylation, Reduction, and Hydride Formation on the Surface and in the Bulk.

The study reports the first attempt to address the interplay between surface and bulk in hydride formation in ceria (CeO2 ) by combining experiment, using surface sensitive and bulk sensitive spectroscopic techniques on the two sample systems, i.e., CeO2 (111) thin films and CeO2 powders, and theoretical calculations of CeO2 (111) surfaces with oxygen vacancies (Ov ) at the surface and in the bulk. We show that, on a stoichiometric CeO2 (111) surface, H2 dissociates and forms surface hydroxyls (OH). On the pre-reduced CeO2-x samples, both films and powders, hydroxyls and hydrides (Ce-H) are formed on the surface as well as in the bulk, accompanied by the Ce3+ ↔ Ce4+ redox reaction. As the Ov concentration increases, hydroxyl is destabilized and hydride becomes more stable. Surface hydroxyl is more stable than bulk hydroxyl, whereas bulk hydride is more stable than surface hydride. The surface hydride formation is the kinetically favorable process at relatively low temperatures, and the resulting surface hydride may diffuse into the bulk region and be stabilized therein. At higher temperatures, surface hydroxyls can react to produce water and create additional oxygen vacancies, increasing its concentration, which controls the H2 /CeO2 interaction. The results demonstrate a large diversity of reaction pathways, which have to be taken into account for better understanding of reactivity of ceria-based catalysts in a hydrogen-rich atmosphere.

Water-Assisted Homolytic Dissociation of Propyne on a Reduced Ceria Surface.

The emergence of ceria (CeO2 ) as an efficient catalyst for the selective hydrogenation of alkynes has attracted great attention. Intensive research effort has been devoted to understanding the underlying catalytic mechanism, in particular the H2 -CeO2 interaction. Herein, we show that the adsorption of propyne (C3 H4 ) on ceria, another key aspect in the hydrogenation of propyne to propene, strongly depends on the degree of reduction of the ceria surface and hydroxylation of the surface, as well as the presence of water. The dissociation of propyne and the formation of methylacetylide (CH3 CC-) have been identified through the combination of infrared reflection absorption spectroscopy (IRAS) and DFT calculations. We demonstrate that propyne undergoes heterolytic dissociation on the reduced ceria surface by forming a methylacetylide ion on the oxygen vacancy site and transferring a proton to the nearby oxygen site (OH group), while a water molecule that competes with the chemisorbed methylacetylide at the vacancy site assists the homolytic dissociation pathway by rebounding the methylacetylide to the nearby oxygen site.

Oxidation of Reduced Ceria by Incorporation of Hydrogen.

The interaction of hydrogen with reduced ceria (CeO2-x ) powders and CeO2-x (111) thin films was studied using several characterization techniques including TEM, XRD, LEED, XPS, RPES, EELS, ESR, and TDS. The results clearly indicate that both in reduced ceria powders as well as in reduced single crystal ceria films hydrogen may form hydroxyls at the surface and hydride species below the surface. The formation of hydrides is clearly linked to the presence of oxygen vacancies and is accompanied by the transfer of an electron from a Ce3+ species to hydrogen, which results in the formation of Ce4+ , and thus in oxidation of ceria.

CFTR Expression Analysis for Subtyping of Human Pancreatic Cancer Organoids.

BACKGROUND: Organoid cultures of human pancreatic ductal adenocarcinoma (PDAC) have become a promising tool for tumor subtyping and individualized chemosensitivity testing. PDACs have recently been grouped into different molecular subtypes with clinical impact based on cytokeratin-81 (KRT81) and hepatocyte nuclear factor 1A (HNF1A). However, a suitable antibody for HNF1A is currently unavailable. The present study is aimed at establishing subtyping in PDAC organoids using an alternative marker. METHODS: A PDAC organoid biobank was generated from human primary tumor samples containing 22 lines. Immunofluorescence staining was established and done for 10 organoid lines for cystic fibrosis transmembrane conductance regulator (CFTR) and KRT81. Quantitative real-time PCR (qPCR) was performed for CFTR and HNF1A. A chemotherapeutic drug response analysis was done using gemcitabine, 5-FU, oxaliplatin, and irinotecan. RESULTS: A biobank of patient-derived PDAC organoids was established. The efficiency was 71% (22/31) with 68% for surgical resections and 83% for fine needle aspirations. Organoids could be categorized into the established quasimesenchymal, exocrine-like, and classical subtypes based on KRT81 and CFTR immunoreactivity. CFTR protein expression was confirmed on the transcript level. CFTR and HNF1A transcript expression levels positively correlated (n = 10; r = 0.927; p = 0.001). PDAC subtypes of the primary tumors and the corresponding organoid lines were identical for most of the cases analyzed (6/7). Treatment with chemotherapeutic drugs revealed tendencies but no significant differences regarding drug responses. CONCLUSIONS: Human PDAC organoids can be classified into known subtypes based on KRT81 and CFTR immunoreactivity. CFTR and HNF1A mRNA levels correlated well. Furthermore, subtype-specific immunoreactivity matched well between PDAC organoids and the respective primary tumor tissue. Subtyping of human PDACs using CFTR might constitute an alternative to HNF1A and should be further investigated.

Water on Oxide Surfaces: A Triaqua Surface Coordination Complex on Co3O4(111).

The interaction of water with metal oxides controls their activity and stability in heterogeneous catalysis and electrocatalysis. In this work, we combine density functional theory calculations and infrared reflection absorption spectroscopy (IRAS) to identify the structural motifs formed upon interaction of water with an atomically defined Co3O4(111) surface. Three principal structures are observed: (i) strongly bound isolated OD, (ii) extended hydrogen-bonded OD/D2O structures, and (iii) a third structure which has not been reported to our knowledge. In this structure, surface Co2+ ions bind to three D2O molecules to form an octahedrally coordinated Co2+ with a "half hydration shell". We propose that this hydration structure represents an important intermediate in reorganization and dissolution on oxide surfaces which expose highly unsaturated surface cations.

Erratum to "CFTR Expression Analysis for Subtyping of Human Pancreatic Cancer Organoids".

[This corrects the article DOI: 10.1155/2019/1024614.].

A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV Infection.

PURPOSE: Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is associated with unfavorable prognosis, while independent prognostic markers remain to be defined. EXPERIMENTAL DESIGN: We retrospectively performed miRNA expression profiling. Patients were operated for locally advanced HPV-negative HNSCC and had received radiochemotherapy in eight different hospitals (DKTK-ROG; n = 85). Selection fulfilled comparable demographic, treatment, and follow-up characteristics. Findings were validated in an independent single-center patient sample (LMU-KKG; n = 77). A prognostic miRNA signature was developed for freedom from recurrence and tested for other endpoints. Recursive-partitioning analysis was performed on the miRNA signature, tumor and nodal stage, and extracapsular nodal spread. Technical validation used qRT-PCR. An miRNA-mRNA target network was generated and analyzed. RESULTS: For DKTK-ROG and LMU-KKG patients, the median follow-up was 5.1 and 5.3 years, and the 5-year freedom from recurrence rate was 63.5% and 75.3%, respectively. A five-miRNA signature (hsa-let-7g-3p, hsa-miR-6508-5p, hsa-miR-210-5p, hsa-miR-4306, and hsa-miR-7161-3p) predicted freedom from recurrence in DKTK-ROG [hazard ratio (HR) 4.42; 95% confidence interval (CI), 1.98-9.88, P < 0.001], which was confirmed in LMU-KKG (HR 4.24; 95% CI, 1.40-12.81, P = 0.005). The signature also predicted overall survival (HR 3.03; 95% CI, 1.50-6.12, P = 0.001), recurrence-free survival (HR 3.16; 95% CI, 1.65-6.04, P < 0.001), and disease-specific survival (HR 5.12; 95% CI, 1.88-13.92, P < 0.001), all confirmed in LMU-KKG data. Adjustment for relevant covariates maintained the miRNA signature predicting all endpoints. Recursive-partitioning analysis of both samples combined classified patients into low (n = 17), low-intermediate (n = 80), high-intermediate (n = 48), or high risk (n = 17) for recurrence (P < 0.001). CONCLUSIONS: The five-miRNA signature is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative HNSCC.See related commentary by Clump et al., p. 1441.

Human gastric cancer modelling using organoids.

OBJECTIVE: Gastric cancer is the second leading cause of cancer-related deaths and the fifth most common malignancy worldwide. In this study, human and mouse gastric cancer organoids were generated to model the disease and perform drug testing to delineate treatment strategies. DESIGN: Human gastric cancer organoid cultures were established, samples classified according to their molecular profile and their response to conventional chemotherapeutics tested. Targeted treatment was performed according to specific druggable mutations. Mouse gastric cancer organoid cultures were generated carrying molecular subtype-specific alterations. RESULTS: Twenty human gastric cancer organoid cultures were established and four selected for a comprehensive in-depth analysis. Organoids demonstrated divergent growth characteristics and morphologies. Immunohistochemistry showed similar characteristics to the corresponding primary tissue. A divergent response to 5-fluoruracil, oxaliplatin, irinotecan, epirubicin and docetaxel treatment was observed. Whole genome sequencing revealed a mutational spectrum that corresponded to the previously identified microsatellite instable, genomic stable and chromosomal instable subtypes of gastric cancer. The mutational landscape allowed targeted therapy with trastuzumab for ERBB2 alterations and palbociclib for CDKN2A loss. Mouse cancer organoids carrying Kras and Tp53 or Apc and Cdh1 mutations were characterised and serve as model system to study the signalling of induced pathways. CONCLUSION: We generated human and mouse gastric cancer organoids modelling typical characteristics and altered pathways of human gastric cancer. Successful interference with activated pathways demonstrates their potential usefulness as living biomarkers for therapy response testing.

Structure-Dependent Dissociation of Water on Cobalt Oxide.

Understanding the correlation between structure and reactivity of oxide surfaces is vital for the rational design of catalytic materials. In this work, we demonstrate the exceptional degree of structure sensitivity of the water dissociation reaction for one of the most important materials in catalysis and electrocatalysis. We studied H2O on two atomically defined cobalt oxide surfaces, CoO(100) and Co3O4(111). Both surfaces are terminated by O2- and Co2+ in different coordination. By infrared reflection absorption spectroscopy and synchrotron radiation photoelectron spectroscopy we show that H2O adsorbs molecularly on CoO(100), while it dissociates and forms very strongly bound OH and partially dissociated (H2O) n(OH) m clusters on Co3O4(111). We rationalize this structure dependence by the coordination number of surface Co2+. Our results show that specific well-ordered cobalt oxide surfaces interact very strongly with H2O whereas others do not. We propose that this structure dependence plays a key role in catalysis with cobalt oxide nanomaterials.

Modulation of leucocytic angiotensin-converting enzymes expression in patients maintained on high-permeable haemodialysis.

BACKGROUND: High mortality of haemodialysis patients is associated with systemic chronic inflammation and overactivation of the renin-angiotensin system (RAS). Insufficient elimination of pro-inflammatory immune mediators, especially in the molecular weight range of 15-45 kDa, may be one of the reasons for this. Employment of haemodialysis membranes with increased permeability was shown to ameliorate the inflammatory response and might modulate the effects of local RAS. In this study, we tested the impact of high cut-off (HCO), medium cut-off (MCO) and high-flux (HF) dialysis on leucocytic transcripts of angiotensin-converting enzymes (ACE and ACE2). Additionally, the impact of HCO, MCO and HF sera and dialysates on local ACEs and inflammation markers was tested in THP-1 monocytes. METHODS: Patients' leucocytes were obtained from our recent clinical studies comparing HCO and MCO dialysers with HF. The cells were subjected to quantitaive polymerase chain reaction (qPCR) analyses with TaqMan probes specific for ACE, ACE2 and angiotensin II (AngII) and Ang1-7 receptors. Sera and dialysates from the clinical trials as well as samples from in vitro dialysis were tested on THP-1 monocytic cells. The cells were subjected to qPCR analyses with TaqMan probes specific for ACE, ACE2, interleukin-6 and tumour necrosis factor α and immunocytochemistry with ACE and ACE2 antibodies. RESULTS: Leucocytes obtained from patients treated with HCO or MCO demonstrated decreased transcript expression of ACE, while ACE2 was significantly upregulated as compared with HF. Receptors for AngII and Ang1-7 remained unchanged. THP-1 monocytes preconditioned with HCO and MCO patients' or in vitro dialysis sera reflected the same expressional regulation of ACE and ACE2 as those observed in HCO and MCO leucocytes. As a complementary finding, treatment with HCO and MCO in vitro dialysates induced a pro-inflammatory response of the cells as demonstrated by elevated messenger RNA expression of tumour necrosis factor α and interleukin-6, as well as upregulation of ACE and decreased levels of ACE2. CONCLUSIONS: Taken together, these data demonstrate that employment of membranes with high permeability eliminates a spectrum of mediators from circulation that affect the RAS components in leucocytes, especially ACE/ACE2.

Toward an Understanding of Selective Alkyne Hydrogenation on Ceria: On the Impact of O Vacancies on H2 Interaction with CeO2(111).

Ceria (CeO2) has recently been found to be a promising catalyst in the selective hydrogenation of alkynes to alkenes. This reaction occurs primarily on highly dispersed metal catalysts, but rarely on oxide surfaces. The origin of the outstanding activity and selectivity observed on CeO2 remains unclear. In this work, we show that one key aspect of the hydrogenation reaction-the interaction of hydrogen with the oxide-depends strongly on the presence of O vacancies within CeO2. Through infrared reflection absorption spectroscopy on well-ordered CeO2(111) thin films and density functional theory (DFT) calculations, we show that the preferred heterolytic dissociation of molecular hydrogen on CeO2(111) requires H2 pressures in the mbar regime. Hydrogen depth profiling with nuclear reaction analysis indicates that H species stay on the surface of stoichiometric CeO2(111) films, whereas H incorporates as a volatile species into the volume of partially reduced CeO2-x(111) thin films (x ∼ 1.8-1.9). Complementary DFT calculations demonstrate that oxygen vacancies facilitate H incorporation below the surface and that they are the key to the stabilization of hydridic H species in the volume of reduced ceria.

Dietary supplementation with n-3-fatty acids in patients with pancreatic cancer and cachexia: marine phospholipids versus fish oil - a randomized controlled double-blind trial.

BACKGROUND: Like many other cancer patients, most pancreatic carcinoma patients suffer from severe weight loss. As shown in numerous studies with fish oil (FO) supplementation, a minimum daily intake of 1.5 g n-3-fatty acids (n-3-FA) contributes to weight stabilization and improvement of quality of life (QoL) of cancer patients. Given n-3-FA not as triglycerides (FO), but mainly bound to marine phospholipids (MPL), weight stabilization and improvement of QoL has already been seen at much lower doses of n-3-FA (0,3 g), and MPL were much better tolerated. The objective of this double-blind randomized controlled trial was to compare low dose MPL and FO formulations, which had the same n-3-FA amount and composition, on weight and appetite stabilization, global health enhancement (QoL), and plasma FA-profiles in patients suffering from pancreatic cancer. METHODS: Sixty pancreatic cancer patients were included into the study and randomized to take either FO- or MPL supplementation. Patients were treated with 0.3 g of n-3-fatty acids per day over six weeks. Since the n-3-FA content of FO is usually higher than that of MPL, FO was diluted with 40% of medium chain triglycerides (MCT) to achieve the same capsule size in both intervention groups and therefore assure blinding. Routine blood parameters, lipid profiles, body weight, and appetite were measured before and after intervention. Patient compliance was assessed through a patient diary. Quality of life and nutritional habits were assessed with validated questionnaires (EORTC-QLQ-C30, PAN26). Thirty one patients finalized the study protocol and were analyzed (per-protocol-analysis). RESULTS: Intervention with low dose n-3-FAs, either as FO or MPL supplementation, resulted in similar and promising weight and appetite stabilization in pancreatic cancer patients. MPL capsules were slightly better tolerated and showed fewer side effects, when compared to FO supplementation. CONCLUSION: The similar effects between both interventions were unexpected but reliable, since the MPL and FO formulations caused identical increases of n-3-FAs in plasma lipids of included patients after supplementation. The effects of FO with very low n-3-FA content might be explained by the addition of MCT. The results of this study suggest the need for further investigations of marine phospholipids for the improvement of QoL of cancer patients, optionally in combination with MCT.

Medium Cut-Off (MCO) Membranes Reduce Inflammation in Chronic Dialysis Patients-A Randomized Controlled Clinical Trial.

BACKGROUND: To increase the removal of middle-sized uremic toxins a new membrane with enhanced permeability and selectivity, called Medium Cut-Off membrane (MCO-Ci) has been developed that at the same time ensures the retention of albumin. Because many middle-sized substances may contribute to micro-inflammation we hypothesized that the use of MCO-Ci influences the inflammatory state in hemodialysis patients. METHODS: The randomized crossover trial in 48 patients compared MCO-Ci dialysis to High-flux dialysis of 4 weeks duration each plus 8 weeks extension phase. Primary endpoint was the gene expression of TNF-α and IL-6 in peripheral blood mononuclear cells (PBMCs), secondary endpoints were plasma levels of specified inflammatory mediators and cytokines. RESULTS: After four weeks of MCO-Ci the expression of TNF-α mRNA (Relative quantification (RQ) from 0.92 ± 0.34 to 0.75 ± 0.31, -18.5%, p<0.001)-α and IL-6 mRNA (RQ from 0.78 ± 0.80 to 0.60 ± 0.43, -23.1%, p<0.01) was reduced to a significantly greater extent than with High-flux dialyzers (TNF mRNA-RQ: -14.3%; IL-6 mRNA-RQ: -3.5%). After retransformation of logarithmically transformed data, measurements after MCO were reduced to 82% of those after HF (95% CI 74%-91%). 4 weeks use of MCO-Ci resulted in long-lasting change in plasma levels of several cytokines and other substances with a significant decrease for sTNFR1, kappa and lambda free light chains, urea and an increase for Lp-PLA2 (PLA2G7) compared to High-flux. Albumin levels dropped significantly after 4 weeks of MCO dialysis but increased after additional 8 weeks of MCO dialysis. Twelve weeks treatment with MCO-Ci was well tolerated regarding the number of (S)AEs. In the extension period levels of CRP, TNF-α-mRNA and IL-6 mRNA remained stable in High-flux as well as in MCO-Ci. CONCLUSIONS: MCO-Ci dialyzers modulate inflammation in chronic HD patients to a greater extent compared to High-flux dialyzers. Transcription of pro-inflammatory cytokines in peripheral leukocytes is markedly reduced and removal of soluble mediators is enhanced with MCO dialysis. Serum albumin concentrations stabilize after an initial drop. These results encourage further trials with longer treatment periods and clinical endpoints.

Impact of serum and dialysates obtained from chronic hemodialysis patients maintained on high cut-off membranes on inflammation profile in human THP-1 monocytes.

INTRODUCTION: Patients with chronic kidney disease maintained on intermittent hemodialysis suffer from systemic chronic inflammation which is causally associated with high mortality. Inflammation mediators of 15-45 kDa range cannot be effectively removed by conventional dialysis membranes. In this study, we tested the influence of serum and dialysates obtained from patients maintained on High cut-off or High flux membranes on the inflammation profile of THP-1 monocytes. METHODS: THP-1 monocytes were treated with serum or dialysates obtained from patients maintained on High cut-off and High flux membranes within a randomized crossover pilot trial. Serum-treated cells were subjected to qPCR analyses with TaqMan probes specific for IL6, TNFa, osteopontin and osteocalcin, and transcriptional screening with Inflammatory Array. Apoptosis assay was performed flow cytometrically with 7-AAD and Annexin V staining. FINDINGS: Treatment of the cells with High cut-off serum led to significant reduction of TNFa and IL-6 expression as well as inflammation-related osteopontin and osteocalcin as compared to High flux membrane treatment. As a complementary finding, treatment with High cut-off dialysates induced a pro-apoptotic phenotype in the cells as demonstrated by a significantly increased percentage of 7-AAD and Annexin V positivity. Global screening of serum-treated cells revealed noticeably decreased inflammation profile under High cut-off serum as compared to High flux treatment. DISCUSSION: Taken together, these data demonstrate that High cut-off -membranes eliminate a spectrum of mediators from serum into the dialysate that possess proinflammatory properties and may impair cellular viability.

Role of TFEB-driven autophagy regulation in pancreatic cancer treatment.

Autophagy pathways promote the growth of pancreatic ductal adenocarcinoma (PDAC), but the critical role is yet to be determined. Transcription factor EB (TFEB) centrally controls lysosomal and autophagy biogenesis. This study aimed to explore the role of TFEB for autophagy regulation in PDAC. We found that TFEB expression was significantly elevated in human PDAC samples (n=45), and localized to the cytoplasm and nucleus in 11 of 15 cases. In primary PDAC cell lines, TFEB nuclear expression was evident even under basal conditions, and further nuclear enrichment was achieved by starvation. Transient RNA interference reduced TFEB expression to 11-23%, but starvation-induced accumulation of the lipidated, autophagosome-associated LC3-II and the autophago-to-lysosome route was maintained after TFEB silencing. Likewise, gemcitabine treatment of the cancer cells augmented apoptosis and LC3-II as an indicator of autophagy, regardless of the TFEB expression levels. Moreover, the interplay of oncogenic KRAS with TFEB and autophagy was investigated. KRAS silencing caused PDAC cell apoptosis and a reciprocal increase in TFEB expression. This inverse correlation could be confirmed in published data sets of genetically engineered mouse models and human PDAC samples using the the Pubmed GEO and BioPortal databases, and was independent of KRAS mutation status. In conclusion, the central autophagy regulator TFEB is expressed and active in PDAC, but autophagy is sustained after TFEB knockdown, suggesting alternative bypass signaling. TFEB is dispensable for gemcitabine-induced cell death, but inversely correlated with KRAS expression.

The surface structure matters: thermal stability of phthalic acid anchored to atomically-defined cobalt oxide films.

We have investigated the influence of the structure of oxide surfaces on the thermal stability of anchored phthalic acid (PA) thin films. Specifically, we have performed temperature programmed infrared reflection absorption spectroscopy (TP-IRAS) of PA films deposited by physical vapor deposition (PVD) in ultra-high vacuum (UVH) onto three well-ordered surfaces: Co3O4(111), CoO(111) and CoO(100), all grown on Ir(100). Restructuring and desorption of PA were monitored in situ by TP-IRAS. Upon annealing of PA multilayers, co-adsorbed phthalic anhydride (PAA) desorbs at 200 K and a structural transition to a flat-lying adsorption geometry occurs at 250 K, before the PA multilayer desorbs at 300 K. At temperatures up to 400 K co-adsorbed mono-carboxylates partially desorb and partially convert to bis-carboxylates. Pronounced structure dependencies are observed regarding the thermal stability of the anchored bis-carboxylate monolayers. From Co3O4(111) the anchored PA desorbs over a wide range of temperatures centered at around 540 K. Weaker binding is observed for CoO(111) with desorption temperatures centered around 490 K. The strongest binding occurs on CoO(100), where the anchored PA films are found to be perfectly stable up to 510 K, before desorption starts and centers at around 580 K. The differences in binding strength are rationalized based on the density and the accessibility of the surface Co(2+) ions. The findings show that the atomic structure of the oxide surface plays an important role in the stability of organic hybrid interfaces.

Structure-Dependent Anchoring of Organic Molecules to Atomically Defined Oxide Surfaces: Phthalic Acid on Co3O4(111), CoO(100), and CoO(111).

We have performed a model study to explore the influence of surface structure on the anchoring of organic molecules on oxide materials. Specifically, we have investigated the adsorption of phthalic acid (PA) on three different, well-ordered, and atomically defined cobalt oxide surfaces, namely 1) Co3O4(111), 2) CoO(111), and 3) CoO(100) on Ir(100). PA was deposited by physical vapor deposition (PVD). The formation of the PA films and interfacial reactions were monitored in situ during growth by isothermal time-resolved IR reflection absorption spectroscopy (TR-IRAS) under ultrahigh vacuum (UHV) conditions. We observed a pronounced structure dependence on the three surfaces with three distinctively different binding geometries and characteristic differences depending on the temperature and coverage. 1) PA initially binds to Co3O4(111) through the formation of a chelating bis-carboxylate with the molecular plane oriented perpendicularly to the surface. Similar species were observed both at low temperature (130 K) and at room temperature (300 K). With increasing exposure, chelating mono-carboxylates became more abundant and partially replaced the bis-carboxylate. 2) PA binds to CoO(100) in the form of a bridging bis-carboxylate for low coverage. Upon prolonged deposition of PA at low temperature, the bis-carboxylates were converted into mono-carboxylate species. In contrast, the bis-carboxylate layer was very stable at 300 K. 3) For CoO(111) we observed a temperature-dependent change in the adsorption mechanism. Although PA binds as a mono-carboxylate in a bridging bidentate fashion at low temperature (130 K), a strongly distorted bis-carboxylate was formed at 300 K, possibly as a result of temperature-dependent restructuring of the surface. The results show that the adsorption geometry of PA depends on the atomic structure of the oxide surface. The structure dependence can be rationalized by the different arrangements of cobalt ions at the three surfaces.

Functionalized Porphyrins on an Atomically Defined Oxide Surface: Anchoring and Coverage-Dependent Reorientation of MCTPP on Co3O4(111).

We have studied the adsorption of tetraphenylporphyrin (2HTPP) and its carboxylated counterpart mono-para-carboxyphenyltriphenylporphyrin (MCTPP) on an atomically defined Co3O4(111) film under ultrahigh vacuum (UHV) conditions. Using time-resolved infrared reflection absorption spectroscopy (TR-IRAS), we show that 2HTPP adsorbs molecularly in a flat-lying orientation, whereas MCTPP binds to the surface via formation of a chelating bidentate carboxylate upon deposition at 400 K. Combining TR-IRAS and density-functional theory (DFT), we determine the molecular tilting angle as a function of coverage. We show that the MCTPP adsorption geometry changes from a nearly flat-lying orientation (tilting angle <30°) at low coverage to a nearly perfectly upright-standing orientation (tilting angle of approximately 80°) in the full monolayer.

High constitutive Akt2 activity in U937 promonocytes: effective reduction of Akt2 phosphorylation by the histamine H2-receptor and the ß2-adrenergic receptor.

Histamine (HA) is approved for the treatment of acute myeloid leukemia (AML). Its antileukemic activity is related to histamine H2-receptor (H2R)-mediated inhibition of reactive oxygen species (ROS) production in myeloid cells facilitating survival of antineoplastic lymphocytes. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which plays a crucial role in cell survival and proliferation, is constitutively activated in leukemic cells of most AML patients resulting in poor survival prognosis. In a proof-of-principle experiment using a human phosphorylated mitogen-activated protein kinase (MAPK) array, we found high phosphorylation levels of Akt2 in U937 promonocytes that was abrogated by HA or selective H2R agonists. The H2R and the ß2-adrenergic receptor (ß2AR) are Gs-protein-coupled receptors. Stimulation results in adenylyl cyclase activation followed by generation of the second messenger adenosine 3',5'-cyclic monophosphate (cAMP). In our present study, we evaluated the pharmacological profile of the H2R and the ß2AR regarding Akt2 phosphorylation at Ser474 via western blot analysis and ELISA and cAMP accumulation via HPLC-MS/MS in U937 promonocytes. H2R and ß2AR agonists concentration-dependently decreased Akt2 phosphorylation at Ser474. Deviations of potencies and efficacies of agonists in Akt2 phosphorylation and cAMP accumulation assays indicated participation of cAMP-independent signaling in GPCR-induced reduction of Akt2 phosphorylation. Accordingly, our study supports the concept of functional selectivity of the H2R and the ß2AR in U937 promonocytes. In summary, we extended the antileukemic mechanism of HA via H2R and revealed the potential of ß2AR agonists, which are already approved in the treatment of bronchial asthma and chronic obstructive pulmonary disease, as antileukemic drugs.