Control of the charge state of metal atoms on thin MgO films

The arrangement of single gold and palladium atoms deposited on the surface of a 3 monolayer thin film of MgO was investigated using low-temperature scanning tunneling microscopy. While Pd atoms are arranged in a random fashion, Au forms an ordered array on the surface. The long-range ordering as well as the scanning tunneling microscopy appearance of single Au atoms on a 3 monolayer thin MgO film can be explained by partial charge transfer from the substrate to Au atoms as predicted recently by density functional theory calculations [Phys. Rev. Lett. 94, 226104 (2005)10.1103/PhysRevLett.94.226104]. In contrast with that, Au atoms on a thick film were found to be essentially neutral.     

Prediction of uncompensated polarity in ultrathin films

Relying on first principles simulations of stoichiometric MgO, ZnO, and NaCl (1x1) ultrathin (111) films, we demonstrate the existence of a critical thickness below which polarity is uncompensated: the surface charges are bulklike, and the total dipole moment and the formation energy grow linearly with thickness. This study reveals novel facets of the problematics of polarity akin to the nanoscopic size of the objects and opens stimulating perspectives on polar nanostructures with surface properties and reactivity unaffected by charge compensation as in macroscopic samples.     

Spectrally and Time-Resolved Fluorescence Imaging of 22-NBD-Cholesterol in Human Peripheral Blood Mononuclear Cells in Chronic Kidney Disease Patients

The interaction of the fluorescent probe 22-NBD-cholesterol with membranes of human peripheral blood mononuclear cells (PBMC) was tested by time- and spectrally resolved fluorescence imaging to monitor the disturbance of lipid metabolism in chronic kidney disease (CKD) and its treatment with statins. Blood samples from healthy volunteers (HV) and CKD patients, either treated or untreated with statins, were compared. Spectral imaging was done using confocal microscopy at 16 spectral channels in response to 458 nm excitation. Time-resolved imaging was achieved by time-correlated single photon counting (TCSPC) following excitation at 475 nm. The fluorescence of 22-NBD-cholesterol was mostly integrated into plasmatic membrane and/or intracellular membrane but was missing from the nuclear region. The presence of two distinct spectral forms of 22-NBD-cholesterol was uncovered, with significant variations between studied groups. In addition, two fluorescence lifetime components were unmasked, changing in CKD patients treated with statins. The gathered results indicate that 22-NBD-cholesterol may serve as a tool to study changes in the lipid metabolism of patients with CKD to monitor the effect of statin treatment.     

Development and Validation of an Analytical HPLC Method to Assess Chemical and Radiochemical Purity of [68Ga]Ga-NODAGA-Exendin-4 Produced by a Fully Automated Method

Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in pancreatic islets, especially in β-cells, and highly expressed in human insulinomas and gastrinomas. In recent years several GLP-1R–avid radioligands have been developed to image insulin-secreting tumors or to provide a tentative quantitative in vivo biomarker of pancreatic β-cell mass. Exendin-4, a 39-amino acid peptide with high binding affinity to GLP-1R, has been labeled with Ga-68 for imaging with positron emission tomography (PET). Preparation conditions may influence the quality and in vivo behavior of tracers. Starting from a published synthesis and quality controls (QCs) procedure, we have developed and validated a new rapid and simple UV-Radio-HPLC method to test the chemical and radiochemical purity of [⁶⁸Ga]Ga-NODAGA-exendin-4, to be used in the clinical routine. Methods: Ga-68 was obtained from a ⁶⁸Ge/⁶⁸Ga Generator (GalliaPharma^®) and purified using a cationic-exchange cartridge on an automated synthesis module (Scintomics GRP^®). NODAGA-exendin-4 contained in the reactor (10 µg) was reconstituted with HEPES and ascorbic acid. The reaction mixture was incubated at 100 °C. The product was purified through HLB cartridge, diluted, and sterilized. To validate the proposed UV-Radio-HPLC method, a stepwise approach was used, as defined in the guidance document released by the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH), adopted by the European Medicines Agency (CMP/ICH/381/95 2014). The assessed parameters are specificity, linearity, precision (repeatability), accuracy, and limit of quantification. Therefore, a range of concentrations of Ga-NODAGA-exendin-4, NODAGA-exendin-4 (5, 4, 3.125, 1.25, 1, and 0.75 μg/mL) and [⁶⁸Ga]Ga-NODAGA-exendin-4 were analyzed. To validate the entire production process, three consecutive batches of [⁶⁸Ga]Ga-NODAGA-exendin-4 were tested. Results: Excellent linearity was found between 5–0.75 μg/mL for both the analytes (NODAGA-exendin-4 and ⁶⁸Ga-NODAGA-exendin-4), with a correlation coefficient (R²) for calibration curves equal to 0.999, average coefficients of variation (CV%) < 2% (0.45% and 0.39%) and average per cent deviation value of bias from 100%, of 0.06% and 0.04%, respectively. The calibration curve for the determination of [⁶⁸Ga]Ga-NODAGA-exendin-4 was linear with a R² of 0.993 and CV% < 2% (1.97%), in accordance to acceptance criteria. The intra-day and inter-day precision of our method was statistically confirmed using 10 μg of peptide. The mean radiochemical yield was 45 ± 2.4% in all the three validation batches of [⁶⁸Ga]Ga-NODAGA-exendin-4. The radiochemical purity of [⁶⁸Ga]Ga-NODAGA-exendin-4 was >95% (97.05%, 95.75% and 96.15%) in all the three batches. Conclusions: The developed UV-Radio-HPLC method to assess the radiochemical and chemical purity of [⁶⁸Ga]Ga-NODAGA-exendin-4 is rapid, accurate and reproducible like its fully automated production. It allows the routine use of this PET tracer as a diagnostic tool for PET imaging of GLP-1R expression in vivo, ensuring patient safety.     

Critical slope p-adic L-functions of CM modular forms

For ordinary modular forms, there are two constructions of a p-adic L-function attached to the non-unit root of the Hecke polynomial, which are conjectured but not known to coincide. We prove this conjecture for modular forms of CM type, by calculating the critical-slope L-function arising from Kato’s Euler system and comparing this with results of Bellaïche on the critical-slope L-function defined using overconvergent modular symbols.     

Magnetic Resonance Imaging (MRI) of hormone-induced breast changes in young premenopausal women

Objectives

We conducted a pilot study to identify whether MRI parameters are sensitive to hormone-induced changes in the breast during the natural menstrual cycle and whether changes could also be observed during an oral contraceptive (OC) cycle.

Materials and Methods

The New York University Langone Medical Center Institutional Review Board approved this HIPAA-compliant prospective study. All participants provided written informed consent. Participants were aged 24-31 years.We measured several non-contrast breast MRI parameters during each week of a single menstrual cycle (among 9 women) and OC cycle (among 8 women). Hormones were measured to confirm ovulation and classify menstrual cycle phase among naturally cycling women and to monitor OC compliance among OC users. We investigated how the non-contrast MRI parameters of breast fibroglandular tissue (FGT), apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR), and transverse relaxation time (T2) varied over the natural and the OC cycles.

Results

We observed significant increases in MRI FGT% and ADC in FGT, and longer T2 in FGT in the luteal vs. follicular phase of the menstrual cycle. We did not observe any consistent pattern of change for any of the MRI parameters among women using OCs.

Conclusions

MRI is sensitive to hormone-induced breast tissue changes during the menstrual cycle. Larger studies are needed to assess whether MRI is also sensitive to the effects of exogenous hormones, such as various OC formulations, on the breast tissue of young premenopausal women.     

Multivariate statistical differentiation of renal cell carcinomas based on lipidomic analysis by ambient ionization imaging mass spectrometry

Desorption electrospray ionization (DESI) mass spectrometry (MS) was used in an imaging mode to interrogate the lipid profiles of thin tissue sections of 11 sample pairs of human papillary renal cell carcinoma (RCC) and adjacent normal tissue and nine sample pairs of clear cell RCC and adjacent normal tissue. DESI-MS images showing the spatial distributions of particular glycerophospholipids (GPs) and free fatty acids in the negative ion mode were compared to serial tissue sections stained with hematoxylin and eosin (H&E). Increased absolute intensities as well as changes in relative abundance were seen for particular compounds in the tumor regions of the samples. Multivariate statistical analysis using orthogonal projection to latent structures treated partial least square discriminate analysis (PLS-DA) was used for visualization and classification of the tissue pairs using the full mass spectra as predictors. PLS-DA successfully distinguished tumor from normal tissue for both papillary and clear cell RCC with misclassification rates obtained from the validation set of 14.3% and 7.8%, respectively. It was also used to distinguish papillary and clear cell RCC from each other and from the combined normal tissues with a reasonable misclassification rate of 23%, as determined from the validation set. Overall DESI-MS imaging combined with multivariate statistical analysis shows promise as a molecular pathology technique for diagnosing cancerous and normal tissue on the basis of GP profiles.