Viability of Glioblastoma Cells and Fibroblasts in the Presence of Imidazole-Containing Compounds.

The naturally occurring dipeptide carnosine (ß-alanyl-L-histidine) specifically attenuates tumor growth. Here, we ask whether other small imidazole-containing compounds also affect the viability of tumor cells without affecting non-malignant cells and whether the formation of histamine is involved. Patient-derived fibroblasts and glioblastoma cells were treated with carnosine, L-alanyl-L-histidine (LA-LH), ß-alanyl-L-alanine, L-histidine, histamine, imidazole, ß-alanine, and L-alanine. Cell viability was assessed by cell-based assays and microscopy. The intracellular release of L-histidine and formation of histamine was investigated by high-performance liquid chromatography coupled to mass spectrometry. Carnosine and LA-LH inhibited tumor cell growth with minor effects on fibroblasts, and L-histidine, histamine, and imidazole affected viability in both cell types. Compounds without the imidazole moiety did not diminish viability. In the presence of LA-LH but not in the presence of carnosine, a significant rise in intracellular amounts of histidine was detected in all cells. The formation of histamine was not detectable in the presence of carnosine, LA-LH, or histidine. In conclusion, the imidazole moiety of carnosine contributes to its anti-neoplastic effect, which is also seen in the presence of histidine and LA-LH. Despite the fact that histamine has a strong effect on cell viability, the formation of histamine is not responsible for the effects on the cell viability of carnosine, LA-LH, and histidine.

Magnetoimpedance spectroscopy of phase-separated La0.5Ca0.5MnO3 polycrystalline manganites.

Magnetoimpedance spectroscopy was carried out on phase-separated La0.5Ca0.5MnO3 polycrystalline manganites. The La0.5Ca0.5MnO3 powder was synthesized following an adapted sol-gel route. Structural and magnetic data showed the signs of phase coexistence of ferromagnetic (FM) Pnma and charge-ordered antiferromagnetic (CO-AFM) P21/m phases. Magnetization vs. temperature (M vs. T) measurements revealed several magnetic transitions from the high temperature paramagnetic (PM) to an FM phase upon cooling (PM-FM) at ≈240 K, FM-AFM (≈170 K) and AFM-FM (≈100 K). Magnetic field (H)-dependent impedance spectroscopy data were collected from sintered pellets and fitted with an equivalent circuit model to separately analyze the different dielectric contributions from the grain boundary (GB) and the grain interior bulk areas. This allowed separating the GB and bulk magnetoresistance (MR), which was shown to amount to a maximum of ≈80% for both GB and bulk at H = 10 T near the metal-insulator transition (MIT) at ≈100 K. The GB resistance was found to be larger than the bulk resistance by a factor of ≈3, which implies that the direct current (DC) resistance and DC MR are dominated by contributions from the GBs. The magnetocapacitance (MC) effects detected were all found to be small below ≈3%, including in the presence of a CO phase.

Carnosine's inhibitory effect on glioblastoma cell growth is independent of its cleavage.

The naturally occurring dipeptide carnosine (ß-alanyl-L-histidine) inhibits the growth of tumor cells. As its component L-histidine mimics the effect, we investigated whether cleavage of carnosine is required for its antineoplastic effect. Using ten glioblastoma cell lines and cell cultures derived from 21 patients suffering from this malignant brain tumor, we determined cell viability under the influence of carnosine and L-histidine. Moreover, we determined expression of carnosinases, the intracellular release of L-histidine from carnosine, and whether inhibition of carnosine cleavage attenuates carnosine's antineoplastic effect. We observed a significantly higher response of the cells to L-histidine than to carnosine with regard to cell viability in all cultures. In addition, we detected protein and mRNA expression of carnosinases and a low but significant release of L-histidine in cells incubated in the presence of 50 mM carnosine (p < 0.05), which did not correlate with carnosine's effect on viability. Furthermore, the carnosinase 2 inhibitor bestatin did not attenuate carnosine's effect on viability. Interestingly, we measured a ~ 40-fold higher intracellular abundance of L-histidine in the presence of 25 mM extracellular L-histidine compared to the amount of L-histidine in the presence of 50 mM carnosine, both resulting in a comparable decrease in viability. In addition, we also examined the expression of pyruvate dehydrogenase kinase 4 mRNA, which was comparably influenced by L-histidine and carnosine, but did not correlate with effects on viability. In conclusion, we demonstrate that the antineoplastic effect of carnosine is independent of its cleavage.

Microwave-Assisted Synthesis, Microstructure, and Magnetic Properties of Rare-Earth Cobaltites.

The series of perovskite rare-earth (RE) doped cobaltites (RE)CoO3 (RE = La-Dy) was prepared by microwave-assisted synthesis. The crystal structure undergoes a change of symmetry depending on the size of the RE cation. LaCoO3 is rhombohedral, S.G. R3̅c (No. 167), while, for the rest of the RE series (Pr-Dy), the symmetry is orthorhombic, S.G. Pnma (No. 62). The crystal structure obtained by X-ray diffraction was confirmed by high-resolution transmission electron microscopy, which yielded a good match between experimental and simulated images. It is further shown that the well-known magnetism in LaCoO3, which involves a thermally induced Co3+ (d6) low spin to intermediate or high spin state transition, is strongly modified by the RE cation, and a rich variety of magnetic order has been detected across the series.

Large Magnetoelectric Coupling Near Room Temperature in Synthetic Melanostibite Mn2 FeSbO6.

Multiferroic materials exhibit two or more ferroic orders and have potential applications as multifunctional materials in the electronics industry. A coupling of ferroelectricity and ferromagnetism is hereby particularly promising. We show that the synthetic melanostibite mineral Mn2 FeSbO6 (R3‾ space group) with ilmenite-type structure exhibits cation off-centering that results in alternating modulated displacements, thus allowing antiferroelectricity to occur. Massive magnetoelectric coupling (MEC) and magnetocapacitance effect of up to 4000 % was detected at a record high temperature of 260 K. The multiferroic behavior is based on the imbalance of cationic displacements caused by a magnetostrictive mechanism, which sets up an unprecedented example to pave the way for the development of highly effective MEC devices operational at or near room temperature.

Water-Free Proton Conduction in Discotic Pyridylpyrazolate-based Pt(II) and Pd(II) Metallomesogens.

In this work we report on water-free proton conductivity in liquid-crystal pyridylpyrazolate-based Pt(II) and Pd(II) complexes [M(pz(R(n,n)py))2] (pz(R(n,n)py) = 3-(3,5-dialkyloxyphenyl)-5-(pyridin-2-yl)pyrazolate, R(n,n) = C6H3(OCnH2n+1)2; n = 4, 12, 16, M = Pd; n = 12, M = Pt) with potential application as electrolyte materials in proton exchange membrane fuel cells. The columnar ordering of the complexes in the liquid-crystalline phase opens nanochannels, which are used for fast proton exchange as detected by impedance spectroscopy and NMR. The NMR spectra indicate that the proton conduction mechanism is associated with a novel C-H···N proton transfer, which persists above the clearing point of the material. The highest conductivity of ∼0.5 µS cm(-1) at 180 °C with an activation energy of 1.2 eV is found for the Pt(II) compound in the mesophase. The Pd(II) complexes with different chain length (n = 4, 12, and 16) show lower conductivity but smaller activation energies, in the range of 0.74-0.93 eV.

The 532-nm 180-W (GreenLight®) laser vaporization of the prostate for the treatment of lower urinary tract symptoms: how durable is the new side-fire fiber with integrated cooling system?

The 532-nm side-fire laser vaporization is established for the treatment of symptomatic benign prostate hyperplasia. Meanwhile, the third generation of this system is offered by American Medical Systems, Inc. The laser power increased from 80 and 120 to 180 W from the first to the third generation. Despite good functional results, with the 80- and 120-W systems, the removal of prostate tissue is limited because of fiber degradation. To overcome this problem, the fiber was designed newly with an integrated cooling system and a sensor for decreasing the laser energy in case of overheating. We evaluate whether the new fiber still suffers from degradation with consecutive drop of power transmission during the procedure. The power output of the cooled fiber was measured in vitro and during prostate vaporization in ten patients. Laser beam power was measured at baseline and after the application each of 50 kJ during laser vaporization. Power emission of the fiber remains constant at 20, 80, and 180 W of power settings over the whole 40-kJ lifespan. During the transurethral procedure, a median total energy of 276 kJ (standard deviation 153 kJ) was applied for vaporization. Median power output from the fiber at the end of the procedure was 97% from the baseline value. There were no fiber malfunctions observed. In contrast to former generations, the third-generation laser fiber is durable without significant power loss during prostate vaporization.

Microwave-assisted synthesis, microstructure, and physical properties of rare-earth chromites.

The full rare-earth (RE) chromites series (RE)CrO(3) with an orthorhombic distorted (Pnma) perovskite structure and the isostructural compound YCrO(3) can be synthesized through a simple microwave-assisted technique, yielding high-quality materials. Magnetization measurements evidence that the Néel temperature for antiferromagnetic Cr(3+)-Cr(3+) ordering strongly depends on the RE(3+) ionic radius (IOR), and a rich variety of different magnetic spin interactions exists. Dielectric spectroscopy on sintered pellets indicates electronic inhomogeneity in all samples as manifested by the presence of at least two dielectric relaxation processes associated with grain boundary and grain interior bulk contributions. X-ray diffraction, Raman spectroscopy, and temperature-dependent dielectric permittivity data do not indicate potential noncentrosymmetry in the crystal or concomitant ferroelectricity. Strong correlations between the magnetic and dielectric properties were not encountered, and microwave-synthesized (RE)CrO(3) may not be classified as magnetoelectric or multiferroic materials.

Improving the mesomorphism in bispyrazolate Pd(II) metallomesogens: an efficient platform for ionic conduction.

The introduction of structural asymmetry in metallomesogens is an established strategy to improve their mesomorphic behaviour in terms of lower melting temperatures and higher stability ranges of the mesophase, which is particularly important for metallomesogens that have potential application as electrolytes that require wide operational temperature ranges. Here in this work, a novel series of unsymmetrical bis(isoquinolinylpyrazolate)palladium(II) compounds bearing four alkyl side-chains with different lengths are described. Rectangular and hexagonal columnar mesophases were formed with low melting temperatures of 42-45 °C in most cases, whereas the clearing temperatures reached values up to 412 °C. The charge transport properties have been studied by complex impedance spectroscopy, showing that the mesophase favours proton conduction in the absence of water or humidity. The exceptional thermal stability of these species makes them promising candidates to act as a platform for ionic conduction via the nanochannels originated in the columnar mesophases. The results presented confirm that introducing structural asymmetry in the Pd(II) metallomesogens studied is a valid strategy to enhance the liquid crystalline properties, which opens new ways to develop water-free electrolytes based on unsymmetrical bis(isoquinolinylpyrazolate) Pd(II) compounds for potential applications such as proton exchange membranes (PEMs).

Tissue-based Alzheimer gene expression markers-comparison of multiple machine learning approaches and investigation of redundancy in small biomarker sets.

BACKGROUND: Alzheimer's disease has been known for more than 100 years and the underlying molecular mechanisms are not yet completely understood. The identification of genes involved in the processes in Alzheimer affected brain is an important step towards such an understanding. Genes differentially expressed in diseased and healthy brains are promising candidates. RESULTS: Based on microarray data we identify potential biomarkers as well as biomarker combinations using three feature selection methods: information gain, mean decrease accuracy of random forest and a wrapper of genetic algorithm and support vector machine (GA/SVM). Information gain and random forest are two commonly used methods. We compare their output to the results obtained from GA/SVM. GA/SVM is rarely used for the analysis of microarray data, but it is able to identify genes capable of classifying tissues into different classes at least as well as the two reference methods. CONCLUSION: Compared to the other methods, GA/SVM has the advantage of finding small, less redundant sets of genes that, in combination, show superior classification characteristics. The biological significance of the genes and gene pairs is discussed.

Periacetabular cortical and cancellous bone mineral density loss after press-fit cup fixation: a prospective 7-year follow-up.

The impact of total hip arthroplasty on strain adaptive bone remodeling has been extensively analyzed by dual-energy x-ray absorptiometry. In this study, we present a prospective computed tomography-assisted study of periacetabular cortical and cancellous bone mineral density (in milligrams of calcium hydroxyapatite [CaHA] per milliliter, or mgCaHA/mL) changes 10 days and 1, 3, and 7 years after press-fit cup implantation for 38 hips in vivo. Cancellous bone mineral density decreased by Ø -63% ventral and Ø -85% dorsal to the cup; cortical bone mineral density, by Ø -22% ventral and Ø -18% dorsal to the cup. The presented periacetabular strain adaptive bone mineral density data are the most extensive of the current literature. Even the measured extensive cancellous bone mineral density loss was thus far of no clinical relevance because all cups showed radiographic signs of stable ingrowth.

Stress-related femoral cortical and cancellous bone density loss after collum femoris preserving uncemented total hip arthroplasty: a prospective 7-year follow-up with quantitative computed tomography.

PURPOSE: Bone loss around uncemented femoral components is suspected to precede implant loosening and contribute to problems in revision surgery. Short-stemmed cementless femoral components are designed to preserve proximal femoral bone stock and ultimately the longevity of the prosthesis. METHODS: With quantitative computed tomography-assisted osteodensitometry, we prospectively analyzed femoral cortical and cancellous bone density (BD) and contact area changes of an uncemented collum femoris preserving stem (n = 38) 10 days, 1, 3 and 7 years post-operatively. RESULTS: Seven years post-operatively, cancellous BD (mg CaHA/mL) had decreased by as much as -66 % and cortical BD by up to -27 % at the metaphyseal portion of the femur; the decrease was progressive between the 1- and 3-year examinations and halted thereafter. Contact area (in % out of a possible 100 %) decreased proximally between the 1- and 3-year follow-up. CONCLUSION: Proximal cortical and cancellous bone density loss and decrease of contact area indicate that metaphyseal fixation cannot be achieved. The lack of cortical BD loss and increase of contact area values below the trochanter minor suggest diaphyseal fixation.

Pluripotent stem cells in mice.

Pluripotent stem cells are able to self-renew and to differentiate into all adult cell types. Many studies report data describing these cells and characterize them in molecular terms. Gene expression data of pluripotent and non-pluripotent cells from mouse were assembled. Machine learning was applied to classify samples into pluripotent and non-pluripotent cells. To identify minimal sets of best biomarkers, three methods were used: information gain, random forests, and genetic algorithm.

Impedance Spectroscopy of Encapsulated Single Graphene Layers.

In this work, we demonstrate the use of electrical impedance spectroscopy (EIS) for the disentanglement of several dielectric contributions in encapsulated single graphene layers. The dielectric data strongly vary qualitatively with the nominal graphene resistance. In the case of sufficiently low resistance of the graphene layers, the dielectric spectra are dominated by inductive contributions, which allow for disentanglement of the electrode/graphene interface resistance from the intrinsic graphene resistance by the application of an adequate equivalent circuit model. Higher resistance of the graphene layers leads to predominantly capacitive dielectric contributions, and the deconvolution is not feasible due to the experimental high frequency limit of the EIS technique.

Radiosensitization of head and neck cancer cells by the phytochemical agent sulforaphane.

BACKGROUND AND PURPOSE: Sulforaphane is a naturally occurring compound found in broccoli and other cruciferous vegetables. Recently it gained attention because of its antiproliferative properties in many cancer cell lines. The aim of this study was to investigate whether sulforaphane could act as a radiosensitizer in head and neck squamous cell carcinoma cell lines. MATERIALS AND METHODS: Four head and neck squamous cell carcinoma cell lines (i.e., (HNSCC) SCC9, SCC25, CAL27, and FADU) were treated with sulforaphane and subsequently irradiated. Then proliferation and clonogenic assays were performed. Apoptosis was detected by flow cytometry. Possible regulation of Akt and Mcl-1 was investigated by western blotting. RESULTS: Sulforaphane and radiation in combination leads to stronger inhibition of cell proliferation and of clonogenic survival than each treatment method alone. Western blot analysis of Akt and Mcl-1 showed no changed expression. CONCLUSION: Sulforaphane is a promising agent in the treatment of head and neck cancer due to its antiproliferative and radio-sensitizing properties. A combination of sulforaphane and radiation decreases clonogenic survival. Apoptosis is not regulated through Akt or the Mcl-1 protein.

Excellent results with cementless total hip arthroplasty and alumina-on-alumina pairing: minimum ten-year follow-up.

Ceramic-on-ceramic coupling is thought to be a durable alternative to metal- or alumina-on-polyethylene pairing. No evidence exists suggesting superior clinical and radiological results for hydroxyapatite-coated stems versus uncoated stems. The aim of this study is to report the performance of an alumina-on-alumina bearing cementless total hip arthroplasty and to compare stems with a tapered design with and without hydroxyapatite coating. We prospectively analysed the results of cementless tapered femoral stems (40 hydroxyapatite-coated versus 22 uncoated stems), a metal-backed fibre mesh hydroxyapatite-coated socket and alumina-on-alumina pairing. Of 75 hips studied, 62 were available for follow-up (mean of 10.5 years after surgery). The average Harris hip score was 90. Only one hydroxyapatite-coated stem was revised for aseptic loosening. One instance of non-progressive osteolysis was detected around a screw of a cup. All other components showed radiographic signs of stable ingrowth. Hydroxyapatite coating of the stem had no significant impact on the clinical or radiological results. Total hip arthroplasty with the presented implant and pairing provides a durable standard for all patients requiring hip joint replacement against which all newer generations of cementless implants should be judged.

Prospective study of a cementless total hip arthroplasty with a collum femoris preserving stem and a trabeculae oriented pressfit cup: minimun 6-year follow-up.

AIM: Tissue sparing hip prostheses are becoming more and more popular especially for the treatment of younger patients. The objective of this study was to evaluate the clinical and radiological results after insertion of a tissue sparing hip prosthesis. METHOD: In 47 consecutive non-selected patients (50 hips), the clinical and radiographic results of cementless total hip arthroplasty using a collum femoris preserving stem, a pressfit cup and an alumina-polyethylene pairing were prospectively evaluated. The mean age at index-surgery was 58 (36-82) years, there were 38 women and 9 men. After a mean follow-up of 6.8 years (minimum 6.1 years), two patients had died and one patient underwent revision surgery due to aseptic loosening of the stem. RESULTS: The overall survival rate of the acetabular component was 100% and of the femoral component 98%. The mean Harris hip score at follow-up was 94 points. CONCLUSION: The mid-term survival with this type of total hip arthroplasty is excellent and compares equal with uncemented straight stems in this age group.

Progressive femoral cortical and cancellous bone density loss after uncemented tapered-design stem fixation.

BACKGROUND: Aseptic implant loosening and periprosthetic bone loss are major problems after total hip arthroplasty (THA). We present an in vivo method of computed tomography (CT) assisted osteodensitometry after THA that differentiates between cortical and cancellous bone density (BD) and area around the femoral component. METHOD: Cortical and cancellous periprosthetic femoral BD (mg CaHA/mL), area (mm(2)) and contact area between the prothesis and cortical bone were determined prospectively in 31 patients 10 days, 1 year, and 6 years after uncemented THA (mean age at implantation: 55 years) using CT-osteodensitometry. RESULTS: 6 years postoperatively, cancellous BD had decreased by as much as 41% and cortical BD by up to 27% at the metaphyseal portion of the femur; this decrease was progressive between the 1-year and 6-year examinations. Mild cortical hypertrophy was observed along the entire length of the diaphysis. No statistically significant changes in cortical BD were observed along the diaphysis of the stem. INTERPRETATION: Periprosthetic CT-assisted osteodensitometry has the technical ability to discriminate between cortical and cancellous bone structures with respect to strain-adapted remodeling. Continuous loss of cortical and cancellous BD at the femoral metaphysis, a homeostatic cortical strain configuration, and mild cortical hypertrophy along the diaphysis suggest a diaphyseal fixation of the implanted stem. CT-assisted osteodensitometry has the potential to become an effective instrument for quality control in THA by means of in vivo determination of periprosthetic BD, which may be a causal factor in implant loosening after THA.

Patient-specific finite element modeling of respiratory lung motion using 4D CT image data.

Development and optimization of methods for adequately accounting for respiratory motion in radiation therapy of thoracic tumors require detailed knowledge of respiratory dynamics and its impact on corresponding dose distributions. Thus, computer aided modeling and simulation of respiratory motion have become increasingly important. In this article a biophysical approach for modeling respiratory lung motion is described: Major aspects of the process of lung ventilation are formulated as a contact problem of elasticity theory which is solved by finite element methods; lung tissue is assumed to be isotropic, homogeneous, and linearly elastic. A main focus of the article is to assess the impact of biomechanical parameters (values of elastic constants) on the modeling process and to evaluate modeling accuracy. Patient-specific models are generated based on 4D CT data of 12 lung tumor patients. Simulated motion patterns of inner lung landmarks are compared with corresponding motion patterns observed in the 4D CT data. Mean absolute differences between model-based predicted landmark motion and corresponding breathing-induced landmark displacements as observed in the CT data sets are in the order of 3 mm (end expiration to end inspiration) and 2 mm (end expiration to midrespiration). Modeling accuracy decreases with increasing tumor size both locally (landmarks close to tumor) and globally (landmarks in other parts of the lung). The impact of the values of the elastic constants appears to be small. Outcomes show that the modeling approach is an adequate strategy in predicting lung dynamics due to lung ventilation. Nevertheless, the decreased prediction quality in cases of large tumors demands further study of the influence of lung tumors on global and local lung elasticity properties.

D,L-Methadone does not improve radio- and chemotherapy in glioblastoma in vitro.

PURPOSE: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. Median survival of glioblastoma patients under standard therapy including radiotherapy and chemotherapy using temozolomide (TMZ) is 14.6 months. As cell culture experiments combining D,L-methadone with doxorubicin demonstrated an increased reduction of cell viability of glioblastoma cells, the opioid has been discussed as a drug for the treatment of GBM. Despite lack of clinical and experimental evidence that D,L-methadone in combination with standard therapy will be beneficial, an increasing number of tumor patients medicating themselves with D,L-methadone present to the hospitals in Germany. METHODS: As a first step towards understanding whether D,L-methadone may increase the efficacy of standard therapy, we used a cell culture model of primary GBM and fibroblast cell cultures derived from GBM patients. The cultures were treated with different concentrations of D,L-methadone in combination with X-irradiation, TMZ or both. Cell viability was determined by measuring ATP in cell lysates and dehydrogenase activity in living cells. RESULTS: When only treated with D,L-methadone, 1 µM of the opioid was sufficient to reduce viability of fibroblasts, whereas 10 µM was needed to significantly reduce glioblastoma cell viability. In addition, D,L-methadone did not improve the anti-neoplastic effects of X-irradiation, temozolomide or both. CONCLUSIONS: As D,L-methadone reduces glioblastoma cell viability only when concentrations are used that had been reported to be toxic to patients and as there were no interactions observable combining it with standard therapy, a recommendation for the use of D,L-methadone in glioblastoma therapy cannot be given.