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Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304\(\pm\)0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of \(\pm\)0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies.
Background
The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO) stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort.
Methods
From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated.
Results
In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1–4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n = 213 pts.; 300 lesions) and breast cancer (n = 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1–13) and dose per fraction (median: 18.5 Gy; range 3–37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control.
Conclusion
After an initial learning curve with regards to total cumulative doses, consistently high biologically effective doses have been employed translating into high local tumor control at 1 and 2 years. The true impact of histology and motion management method on treated metastases control deserve deeper analysis. Overall survival is mainly influenced by histology and metastatic tumor burden.
Background
The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer.
Methods
The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS.
Results
Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC.
Conclusion
In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.
Twenty silanes of the type R\(^1\)R\(^2\)Si(H)CH\(_2\)OR\(^3\) (A) were syn- and entropy of activation) of these reactions were studied by thesized {R\(^1\), R\(^2\) = Me, Ph, 1-naphthyl, PhCH\(_2\), Me\(_3\)SiCH\(_2\); OR\(^3\) means of düferential scanning calorimetry (DSC). In addition, = OC(O)Me, OC(O)Ph, OC(O)CF\(_3\) , OS(0)\(_2\)CF\(_3\), OP(O)Ph\(_2\), the kinetics of all reactions were investigated by 1H-NMR OC(O)Cl, and studied for their thermal behaviour. The silanes spectroscopy. The transition state of the rearrangement was A undergo a thermally induced rearrangement to give the investigated by an ab initio study based on the model comcorresponding silanes R\(^1\)R\(^2\)Si(OR\(^3\))Me (B). For compounds with pound H\(_3\)SiCH\(_2\)OC(O)H (-> MeH\(_2\)SiOC(O)H]. The theoretical OR3 = OC(O)Cl, an additional decarboxylation takes place to data and the experimentally obtained energetic and kinetic yield the chlorosilanes R1R2Si(Cl)Me. Except for the deriva- data are discussed in terms of mechanistic aspects of the retives with OR\(^3\) = OC(O)Cl, the energetic (reaction enthalpy) arrangement reaction A -> B. and kinetic data (reaction order, frequency factor, enthalpy ...
Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote \(Tsc1^{+/-}\) mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (<P19). Seizures are generated intracortically in the granular layer of the neocortex. Slow kinetics of aberrant GluN2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in \(Tsc1^{+/-}\) mice in vivo and in vitro. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients.
BACKGROUND: In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data.
RESULTS: We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs.
CONCLUSIONS: Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas.
New resonant-mode infrared absorption lines have been observed in NaCl with high concentrations of fluorine impurities. The quadratic concentration dependence of the strength of these lines indicates that they are due to pairs of fluorine impurities. At the resonant frequencies, the motion of some host ions appears to be as important as the motion of the impurities themselves.
The selected area epitaxial overgrowth of narrow gap HgTe as well as wide gap CdTe and ZnTe on CdTe/GaAs substrates, which had been structured by dry etching techniques, has been investigated. A plasma etching process using a barrel reactor with CH\(_4\)-CH\(_2\) gases has been employed to prepare stripes with a width of about 1 μm with anisotropic as well as isotropic etching profiles. It has been found, that the selected area HgTe overgrowth takes place with a high local selectivity to the low index planes of the patterned surface. In contrast, the selected area overgrowth of the wide gap CdTe and ZnTe is controlled by anisotropic growth kinetics provided that the substrate temperature is not lower than 220°C and the starting surface consists of well developed low index crystallographic planes.
In einem Kollektiv von 130 MR-tomographisch untersuchten psychiatrischen Patienten (axiale T2-SE-Sequenz) wurden Zahl und räumliche Verteilung von hyperintensen Marklagerläsionen ("white matter lesions"; WM L) erfaßt und die Ventricle-to-brain-Ratio (VBR) bestimmt. Eine Konfigurationsfrequenzanalyse auf der Grundlage der räumlichen WMLVerteilung erlaubte die Abgrenzung von vier Patientengruppen: 1. keine WML (n = 35), 2. WML rechts frontotemporal (n = 23), 3. WML bifrontal (n = 12), 4. WML ubiquitär (n = 16). Die während 3 Jahren beobachteten psychopathologischen Symptome dieser Patienten wurden retrospektiv nach dem AMDP-Systemdokumentiert. In der Gruppe mit ubiquitären WML überwogen organisch-psychopathologische Ttems, die VER war größer als in den anderen Gruppen (ANOVA;p < 0,001). Die räumliche W M L- Verteilung erklärte 10,24 % der Gesamtvarianz psychopathologischer M erkmalsverteilung in den Gruppen. Das Patientenalter (MANCOVA; p < 0,021), nicht aber die VER hattesignifikanten Einfluß auf das psychopathologische Symptomprofil. Nach Ausblendung der Patientengruppe mit ubiquitären WMLblieb der Einfluß der WML-Verteilung auf die psychopathologische Symptomatiksignifikantc (p <0,05). Bifrontale WML waren mit Denkstörung, rechts frontotemporale WML mit affektiven Symptomen assoziiert. Die Befunde sprechen für einen Einfluß der räumlichen Verteilung unspezifischer Marklagerläsionen auf die psychopathologische Symptomatik.
46 Patienten mit affektiven Erkrankungen und pathologischem CT wurden untersucht (Infarkt: 22, Kontusion: 6, Leukoaraiose: 11, frühkindlicher Hirnschaden: 7). Monopolar Depressive (DSMIII- R; MD) zeigten oft Leukoaraiose, Infarkte waren mit MD, Kontusionen und frühkindliche Schäden mit bipolarer Erkrankung assoziiert (BP; ANCOV A, p< .1). Kortikale Läsionen waren bei BP häufiger, jedoch fehlten signifikante Effekte von Läsionsort oder -zeitpunkt auf die Polarität der Erkrankung (ANOV A). Bei einigen Infarktpatienten kam es zur Verlaufsänderung (Chronifizierung, Bipolarität) nach Infarkt, alle Post-Infarkt-Ersterkrankungen waren bipolar.
Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [\(^{11}\)C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [\(^{11}\)C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.