Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential.

Anticancer effects of a common lipid-lowering drug, fenofibrate, have been described in the literature for a quite some time; however, fenofibrate has not been used as a direct anticancer therapy. We have previously reported that fenofibrate in its unprocessed form (ester) accumulates in the mitochondria, inhibits mitochondrial respiration, and triggers a severe energy deficit and extensive glioblastoma cell death. However, fenofibrate does not cross the blood brain barrier and is quickly processed by blood and tissue esterases to form the PPARα agonist fenofibric acid, which is practically ineffective effective in triggering cancer cell death. To address these issues, we have made several chemical modifications in fenofibrate structure to increase its stability, water solubility, tissue penetration, and ultimately anticancer potential. Our data show that, in comparison to fenofibrate, four new compounds designated here as PP1, PP2, PP3, and PP4 have improved anticancer activity in vitro. Like fenofibrate, the compounds block mitochondrial respiration and trigger massive glioblastoma cell death in vitro. In addition, one of the lead compounds, PP1, has improved water solubility and is significantly more stable when exposed to human blood in comparison to fenofibrate. Importantly, mice bearing large intracranial glioblastoma tumors demonstrated extensive areas of tumor cell death within the tumor mass following oral administration of PP1, and the treated mice did not show any major signs of distress, and accumulated PP1 at therapeutically relevant concentrations in several tissues, including brain and intracranial tumors.

THE COMPARATIVE ANALYSIS OF DIFFERENT TECHNIQUES OF LASER POLARIMETRY FOR DETERMINATION OF TIME OF DEATH IN THE STUDY OF POLYCRYSTALLINE FILMS OF CEREBROSPINAL FLUID.

The estimation of death coming prescription (DCP) is one of the most important issues that confronts a medical examiner during the corpse examination right at the scene of death. The most promising biological object for the DCP estimation is cerebrospinal fluid. Aim - to compare the effectiveness of methods being used: stokes-polarimetry, stokes-colorimetry, autofluorescence polarimetry in order to improve the accuracy of DCP for the long - and short-term time intervals. The object of the study - cerebrospinal fluid from 75 cadavers (study group) and 20 live individuals (control group). Methods used: stokes polarimetry, stokes-colorimetry, autofluorescence polarimetry. When analyzing the image of the biological sample within the statistical analysis using the stokes polarimetry it is possible to obtain some quantitative characteristics about the amount of the statistical moments of the 1st - 4th orders, which can be used to find the relationship between them and the DCP. However, the coordinate and morphological structure of biological samples are ignored when using this approach. A correlation method in this context is more functional and sensitive. Due to this a higher accuracy of DCP is achieved in a short period. The analysis revealed that the spatial-frequency filtration of polarization-inhomogeneous images of polycrystal films of cerebrospinal fluid improves the time monitoring sensitivity of biochemical changes in optically active molecular compounds. Speaking about fluorescence microscopy - it carries the information about the concentration of molecular complexes of proteins, NADH, flavins, porphyrins, etc. As in the postmortem period the changes in the cerebrospinal fluid begin with the changes in the concentration of biochemical compounds, and crystalline changes are secondary, this method is the most effective for diagnosing the death coming prescription in the first 8 hours. The fluorescent methods of laser polarimetric are precise at a short interval of DCP estimation, and the polarization ones allow us to estimate this parameter at the long-term time intervals, though with less accuracy.

Anomalous density fluctuations in a strange metal.

A central mystery in high-temperature superconductivity is the origin of the so-called strange metal (i.e., the anomalous conductor from which superconductivity emerges at low temperature). Measuring the dynamic charge response of the copper oxides, [Formula: see text], would directly reveal the collective properties of the strange metal, but it has never been possible to measure this quantity with millielectronvolt resolution. Here, we present a measurement of [Formula: see text] for a cuprate, optimally doped Bi2.1Sr1.9CaCu2O8+x (Tc = 91 K), using momentum-resolved inelastic electron scattering. In the medium energy range 0.1-2 eV relevant to the strange metal, the spectra are dominated by a featureless, temperature- and momentum-independent continuum persisting to the electronvolt energy scale. This continuum displays a simple power-law form, exhibiting q2 behavior at low energy and q2/ω2 behavior at high energy. Measurements of an overdoped crystal (Tc = 50 K) showed the emergence of a gap-like feature at low temperature, indicating deviation from power law form outside the strange-metal regime. Our study suggests the strange metal exhibits a new type of charge dynamics in which excitations are local to such a degree that space and time axes are decoupled.

Efficacy and safety of electrochemotherapy combined with peritumoral IL-12 gene electrotransfer of canine mast cell tumours.

Electrochemotherapy combined with peritumoral interleukin-12 (IL-12) gene electrotransfer was used for treatment of mast cell tumours in 18 client-owned dogs. Local tumour control, recurrence rate, as well as safety of combined therapy were evaluated. One month after the therapy, no side effects were recorded and good local tumour control was observed with high complete responses rate which even increased during the observation period to 72%. IL-12 gene electrotransfer resulted in 78% of patients with detectable serum IFN-γ and/or IL-12 levels. In the treated tumours vascular changes as well as minimal T-lymphocytes infiltration was observed. After 1 week, the plasmid DNA was not detected intra- or peritumorally and no horizontal gene transfer was observed. In summary, our study demonstrates high antitumour efficacy of electrochemotherapy combined with IL-12 electrotransfer, which also prevented recurrences or distant metastases, as well as its safety and feasibility in treatment of canine mast cell tumours.

Rapid biodiagnostic ex vivo imaging at 1 µm pixel resolution with thermal source FTIR FPA.

A recent upgrade to the optics configuration of a thermal source FTIR microscope equipped with a focal plane array detector has enabled rapid acquisition of high magnification spectrochemical images, in transmission, with an effective geometric pixel size of ∼1 × 1 µm(2) at the sample plane. Examples, including standard imaging targets for scale and accuracy, as well as biomedical tissues and microorganisms, have been imaged with the new system and contrasted with data acquired at normal magnification and with a high magnification multi-beam synchrotron instrument. With this optics upgrade, one can now conduct rapid biodiagnostic ex vivo tissue imaging in-house, with images collected over larger areas, in less time (minutes) and with comparable quality and resolution to the best synchrotron source FTIR imaging capabilities.

Biochemical label-free tissue imaging with subcellular-resolution synchrotron FTIR with focal plane array detector.

The critical questions into the cause of neural degeneration, in Alzheimer disease and other neurodegenerative disorders, are closely related to the question of why certain neurons survive. Answers require detailed understanding of biochemical changes in single cells. Fourier transform infrared microspectroscopy is an excellent tool for biomolecular imaging in situ, but resolution is limited. The mid-infrared beamline IRENI (InfraRed ENvironmental Imaging) at the Synchrotron Radiation Center, University of Wisconsin-Madison, enables label-free subcellular imaging and biochemical analysis of neurons with an increase of two orders of magnitude in pixel spacing over current systems. With IRENI's capabilities, it is now possible to study changes in individual neurons in situ, and to characterize their surroundings, using only the biochemical signatures of naturally-occurring components in unstained, unfixed tissue. We present examples of analyses of brain from two transgenic mouse models of Alzheimer disease (TgCRND8 and 3xTg) that exhibit different features of pathogenesis. Data processing on spectral features for nuclei reveals individual hippocampal neurons, and neurons located in the proximity of amyloid plaque in TgCRND8 mouse. Elevated lipids are detected surrounding and, for the first time, within the dense core of amyloid plaques, offering support for inflammatory and aggregation roles. Analysis of saturated and unsaturated fatty acid ester content in retina allows characterization of neuronal layers. IRENI images also reveal spatially-resolved data with unprecedented clarity and distinct spectral variation, from sub-regions including photoreceptors, neuronal cell bodies and synapses in sections of mouse retina. Biochemical composition of retinal layers can be used to study changes related to disease processes and dietary modification.

Validation of a German version of the P-QOL Questionnaire.

OBJECTIVE: The objective of this study was to validate the German version of the prolapse quality-of-life questionnaire (P-QOL). METHODS: The P-QOL questionnaire was translated into German and administered to women recruited from two gynecological outpatient clinics and seven gynecological practices. All women were examined in supine position using the Pelvic Organ Prolapse Quantification System of the International Continence Society. The validity was assessed by comparing symptom scores and quality-of-life scores between symptomatic and asymptomatic women. RESULTS: According to the English study, 140 symptomatic and 75 asymptomatic women were included. The total scores for each P-QOL domain were significantly different between symptomatic and asymptomatic women (p < 0.001). Seven symptom regarding questions showed significant differences (p < 0.05). CONCLUSION: The German version of P-QOL is a valid, reliable, and easily comprehensible instrument to assess quality of life and symptoms in German-speaking patients with urogenital prolapse.

Therapeutic impact of intra-operative transoesophageal echocardiography during noncardiac surgery.

The impact of transoesophageal echocardiography on haemodynamic management during elective noncardiac surgery was assessed during this observational prospective database analysis. Ninety-nine consecutive patients were studied, who were at risk of intra-operative myocardial ischaemia or haemodynamic instability (Class II indications) and were undergoing vascular, visceral or chest surgery. A total of 165 new echocardiographic findings were recorded. Based on these findings changes in drug therapy were made in 47% and changes in fluid therapy in 24% of patients. Left ventricular wall motion abnormalities were seen in 32% and other relevant diagnoses made in 10%. Echocardiography showed a significant impact on drug therapy in patients with pre-operative systolic wall motion abnormalities (vasodilators: OR = 7.1, CI 95% = 2.1/24.0; vasopressors: OR = 3.3, CI 95% = 1.2/9.1) and patients with a history of left heart failure (vasodilators: OR = 5.2, CI 95% = 1.0/31.4). Fluid therapy was significantly influenced by echocardiographic findings during liver and lung transplantation (50% compared with 24% during other surgical interventions, p < 0.05).

The sensitivity of the respiratory center and some circulatory and subjective responses after nalorphine and naloxone injections.

In five volunteers the sensitivity of the respiratory centre to carbon dioxide after naloxone and nalorphine injections was studied using "double blind" method and increments of doses. Alterations in the respiratory centre sensitivity were reflected by changes in respiratory minute volume, which was measured before and after drug injections, as well as after carbon dioxide stimulation. Comparison of results and their statistical verification showed that nalorphine alone causes respiratory depression and carbon dioxide stimulation is, beside the weak initial action, almost ineffective. Naloxone causes very small, if at all, respiratory depression and the respiratory centre answers efficiently to carbon dioxide stimulation.