Intrinsic and extrinsic conduction contributions at nominally neutral domain walls in hexagonal manganites

Conductive and electrostatic atomic force microscopy (cAFM and EFM) are used to investigate the electric conduction at nominally neutral domain walls in hexagonal manganites. The EFM measurements reveal a propensity of mobile charge carriers to accumulate at the nominally neutral domain walls in ErMnO3, which is corroborated by cAFM scans showing locally enhanced d.c. conductance. Our findings are explained based on established segregation enthalpy profiles for oxygen vacancies and interstitials, providing a microscopic model for previous, seemingly disconnected observations ranging from insulating to conducting domain wall behavior. In addition, we observe variations in conductance between different nominally neutral walls that we attribute to deviations from the ideal charge-neutral structure within the bulk, leading to a superposition of extrinsic and intrinsic contributions. Our study clarifies the complex transport properties at nominally neutral domain walls in hexagonal manganites and establishes new possibilities for tuning their electronic response based on oxidation conditions, opening the door for domain-wall based sensor technology.Comment: 5 pages, 3 figure

Insulating improper ferroelectric domain walls as robust barrier layer capacitors

We report the dielectric properties of improper ferroelectric h-ErMnO$_3$. From the bulk characterisation we observe a temperature and frequency range with two distinct relaxation-like features, leading to high and even 'colossal' values for the dielectric permittivity. One feature trivially originates from the formation of a Schottky barrier at the electrode-sample interface, whereas the second one relates to an internal barrier layer capacitance (BLC). The calculated volume fraction of the internal BLC (of 8 %) is in good agreement with the observed volume fraction of insulating domain walls (DWs). While it is established that insulating DWs can give rise to high dielectric constants, studies typically focused on proper ferroelectrics where electric fields can remove the DWs. In h-ErMnO$_3$, by contrast, the insulating DWs are topologically protected, facilitating operation under substantially higher electric fields. Our findings provide the basis for a conceptually new approach to engineer materials exhibiting colossal dielectric permittivities using domain walls in improper ferroelecctrics with potential applications in electroceramic capacitors.Comment: 7 pages, 4 figure

Hepatocellular Carcinoma and Nuclear Paraspeckles: Induction in Chemoresistance and Prediction for Poor Survival

Background/Aims: Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related deaths worldwide, not least due to its high chemoresistance. The long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1), localised in nuclear paraspeckles, has been shown to enhance chemoresistance in several cancer types. Since data on NEAT1 in HCC chemosensitivity are completely lacking and chemoresistance is linked to poor prognosis, we aimed to study NEAT1 expression in HCC chemoresistance and its link to HCC prognosis. Methods: NEAT1 expression was determined in either sensitive, or sorafenib, or doxorubicin resistant HepG2, PLC/PRF/5, and Huh7 cells by qPCR. Paraspeckles were detected by immunostaining of paraspeckle component 1 (PSPC1) in cell culture and in a cohort of HCC patients. PSPC1 expression was correlated with clinical data. The expression of transcript variants of NEAT1 and transcripts encoding the paraspeckle-associated proteins was analysed in the TCGA liver cancer data set. Results: NEAT1 was overexpressed in all three sorafenib and doxorubicin resistant cell lines. Paraspeckles were present in all chemoresistant cells, whereas no signal was detected in the sensitive cells. Expression of NEAT1 transcripts as well as transcripts encoding PSPC1, NONO, and RBM14 was increased in tumour tissue. Expression of PSPC1, NONO, and RBM14 transcripts was significantly associated with poor survival, whereas NEAT1 expression was not. Immunohistochemical analysis revealed that nuclear and cytoplasmic PSPC1-positivity was significantly associated with shorter overall survival of HCC patients. Conclusion: Our data show an induction of NEAT1 in HCC chemoresistance and a high correlation of transcripts encoding paraspeckle-associated proteins with poor survival in HCC. Therefore, NEAT1, PSPC1, NONO, and RBM14 might be promising targets for novel HCC therapies, and the paraspeckle-associated proteins might be clinical markers and predictors for poor survival in HCC

Cytotoxicity, chemical stability, and surface properties of ferroelectric ceramics for biomaterials

© 2017 The American Ceramic Society Surface chemistry and topo-physical properties determine the interactions of biomaterials with their physiological environment. Ferroelectrics hold great promise as the next generation of scaffolds for tissue repair since they feature tunable surface electrical charges, piezoelectricity, and sensing capabilities. We investigate the topography, wettability, chemical stability, and cytotoxicity in salient ferroelectric systems such as (1−x) (Na1/2Bi1/2)TiO3–xBaTiO3, (1−x)Ba(Zr0.2Ti0.8)O3−x(Ba0.7Ca0.3)TiO3, and Pb(Zr,Ti)O3 to test their suitability as biomaterials. The lead-free ferroelectrics promote in vitro cell viability and proliferation to a considerably high extent. 0.94 mol % (Na1/2Bi1/2)TiO3–0.06 mol% BaTiO3 showed the greatest potential leading to a cell viability of (149 ± 30)% and DNA synthesis of (299 ± 85)% in comparison to the reference. Lead leaching from Pb(Zr,Ti)O3 negatively affected the cultured cells. Wettability and chemical stability are key factors that determine the cytotoxicity of ferroelectrics. These variables have to be considered in the design of novel electroactive scaffolds based on ferroelectric ceramics

Continuous venovenous hemodiafiltration with a low citrate dose regional anticoagulation protocol and a phosphate-containing solution: effects on acid–base status and phosphate supplementation needs

BACKGROUND: Recent guidelines suggest the adoption of regional citrate anticoagulation (RCA) as first choice CRRT anticoagulation modality in patients without contraindications for citrate. Regardless of the anticoagulation protocol, hypophosphatemia represents a potential drawback of CRRT which could be prevented by the adoption of phosphate-containing CRRT solutions. The aim was to evaluate the effects on acid--base status and phosphate supplementation needs of a new RCA protocol for Continuous Venovenous Hemodiafiltration (CVVHDF) combining the use of citrate with a phosphate-containing CRRT solution. METHODS: To refine our routine RCA-CVVH protocol (12 mmol/l citrate, HCO3- 32 mmol/l replacement fluid) (protocol A) and to prevent CRRT-related hypophosphatemia, we introduced a new RCA-CVVHDF protocol (protocol B) combining an 18 mmol/l citrate solution with a phosphate-containing dialysate/replacement fluid (HCO3- 30 mmol/l, Phosphate 1.2). A low citrate dose (2.5--3 mmol/l) and a higher than usual target circuit-Ca2+ (<=0.5 mmol/l) have been adopted. RESULTS: Two historical groups of heart surgery patients (n = 40) underwent RCA-CRRT with protocol A (n = 20, 102 circuits, total running time 5283 hours) or protocol B (n = 20, 138 circuits, total running time 7308 hours). Despite higher circuit-Ca2+ in protocol B (0.37 vs 0.42 mmol/l, p < 0.001), circuit life was comparable (51.8 +/- 36.5 vs 53 +/- 32.6 hours). Protocol A required additional bicarbonate supplementation (6 +/- 6.4 mmol/h) in 90% of patients while protocol B ensured appropriate acid--base balance without additional interventions: pH 7.43 (7.40--7.46), Bicarbonate 25.3 (23.8--26.6) mmol/l, BE 0.9 (-0.8 to +2.4); median (IQR). No episodes of clinically relevant metabolic alkalosis, requiring modifications of RCA-CRRT settings, were observed. Phosphate supplementation was needed in all group A patients (3.4 +/- 2.4 g/day) and in only 30% of group B patients (0.5 +/- 1.5 g/day). Hypophosphatemia developed in 75% and 30% of group A and group B patients, respectively. Serum phosphate was significantly higher in protocol B patients (P < 0.001) and, differently to protocol A, appeared to be steadily maintained in near normal range (0.97--1.45 mmol/l, IQR)

Cabozantinib in Advanced Hepatocellular Carcinoma: Efficacy and Safety Data from an International Multicenter Real-Life Cohort

Background and Aims: The multikinase inhibitor cabozantinib has been approved for hepatocellular carcinoma (HCC) previously treated with sorafenib. We report safety and efficacy data of an international, multicenter, real-life cohort of patients with advanced HCC treated with cabozantinib. Methods: Patients with HCC who were treated with cabozantinib were retrospectively identified across 11 centers in Austria, Switzerland, and Germany. Patients’ characteristics, adverse events, duration of treatment and overall survival (OS) data were analyzed until April 1, 2020. Results: Eighty-eight patients from 11 centers were included. The predominant underlying liver diseases were NAFLD/NASH in 26 (30%) and hepatitis C infection in 21 (24%) patients. Seventy-eight patients (89%) were classified as Barcelona clinic liver cancer (BCLC) stage C. Sixty patients (68%) were Child-Pugh A, whereas 22 (25%) were Child-Pugh B, respectively. Cabozantinib was used as systemic second- and third-line or later treatment in 41 (47%) and 46 (52%) patients, respectively. The following best responses under cabozantinib were documented: partial response in 6 (7%), stable disease in 28 (32%), and progressive disease in 28 (32%) patients, respectively. Fifty-two patients (59%) died during follow-up. The median OS from start of cabozantinib treatment was 7.0 months in the entire cohort and 9.7 months in Child-Pugh A patients, while Child-Pugh B patients had a median OS of 3.4 months, respectively. Thirty-seven (42%) patients fulfilled the CELESTIAL inclusion and exclusion criteria, showing a median OS of 11.1 months. Most common adverse events were fatigue (15.6%) and diarrhea (15.6%). Conclusion: Cabozantinib treatment was effective, safe, and feasible in patients with advanced HCC in patients with compensated cirrhosis. Patients in the real-life setting had more advanced liver disease – in which 25% of patients were Child-Pugh B. However, OS in patients with Child-Pugh A cirrhosis was similar to that reported in the phase 3 trial (CELESTIAL)