High Intensity Focused Ultrasound Optimal Device Design for Targeted Prostate Cancer Treatment: A Numerical Study

A parametric study was performed to design a device capable of treating small targeted regions within the prostate using high intensity focused ultrasound, while sparing the surrounding organs and minimizing the number of elements. The optimal focal length (L), operating frequency (f), element size (a) and central opening radius for lodging an imaging probe (r) of a device that would safely treat tissue within the prostate were obtained. Images from the Visible Human Project were used to determine simulated organ sizes and treatment locations. Elliptical tumors were placed throughout the simulated prostate and their lateral and axial limits were selected as test locations. Using graphics processors, the acoustic field and Bio-Heat Transfer Equation were solved to calculate the heating produced during a simulated treatment. L, f, a and r were varied from 45 to 75 mm, 2.25 to 3 MHz, 1.5 to 8 times the wavelength and 9 to 12.5 mm, respectively. The resulting optimal device was a 761-element concentric-ring transducer with L = 68 mm, f = 2.75 MHz, a = 2.05λ and r = 9 mm. Simulated thermal lesions showed that it was possible to treat target tumors consistent with reported locations and sizes for prostate cancer.

Unfolded annealing molecular dynamics conformers for wild-type and disease-associated variants of alpha-synuclein show no propensity for beta-sheetformation

Aggregation of alpha-synuclein leads to the formation of Lewy bodies in the brains of patients affected by Parkinson's disease (PD). Native human alpha-synuclein is unfolded in solution but assumes a partial alpha-helical conformation upon transient binding to lipid membranes. Annealing Molecular Dynamics (AMD) was used to generate a diverse set of unfolded conformers of free monomeric wild-type alpha-synuclein and PD-associated mutants A30P and A53T. The AMD conformers were compared in terms of secondary structure, hydrogen bond network, solvent-accessible surface per residue, and molecular volume. The objective of these simulations was to identify structural properties near mutation sites and the non-amyloid component (NAC) region that differ between wild- type and disease-associated variants and may be associated to aggregation of alpha- synuclein. Based on experimental evidence, a hypothesis exists that aggregation involves the formation of intermolecular beta sheets. According to our results, disease-associated mutants of alpha-synuclein are no more propense to contain extended beta regions than wild-type alpha-synuclein. Moreover, extended beta structures (necessary for beta sheet formation) were not found at or around positions 30 and 53, or the NAC region in any unfolded conformer of wild-type, A30P or A53T alpha-synuclein, under the conditions of the simulations. These results do not support the hypothesis that the mutant's higher propensity to aggregation results solely from changes in amino acid sequence leading to changes in secondary structure folding propensity.

Contrast Optimization for an Animal Model of Prostate Cancer MRI at 3T

Purpose: To optimize contrast to noise ratio (CNR) in magnetic resonance imaging (MRI) of prostate cancer using at 3T. Methods: CNR was expressed as a difference in MR signals of two samples. Amulti-echo spin-echo (MESE) pulse sequence was used. The theoretical value of the maximum CNR was obtained using the derivative of CNR with echo time (TE) as a variable. The T1 relaxation time was ignored as repetition time (TR) was assumed to be very long (TR >> T1). The theoretical calculations were confirmed with in vitro and in vivo experiments. For in vitro experiments we used samples with different T2 values using various concentrations of super paramagnetic iron oxide (SPIO) and for in vivo experiments we used an animal model of prostate cancer. Results: CNR was maximized by selecting the optimum TE for a multi-echo spin-echo (MESE) pulse sequence based on theoretical predictions. MR images of prostate cancer at 3T were obtained and showed maximum CNR at the predicted TE. Conclusions: It was possible to maximize CNR of prostate tumour by selecting the optimal TE based on simple theoretical calculations. The proposed method can be applied to other pulse sequences and tissues. It can be applied to any MRI system at any magnetic field. However the method requires knowledge of T2 relaxation times.

Exposure to Long Magnetic Resonance Imaging Thermometry Does Not Cause Significant DNA Double-Strand Breaks on CF-1 Mice

The purpose of the study was to investigate if the high gradient strength and slew rate used for long MRI-thermometry monitoring could cause DNA double-stranded breaks (DSBs). To this end, an enzyme-linked immunosorbent assay (ELISA) was used to quantify γH2AX, a molecular marker for DSBs, in the blood of mice after a 6-hour exposure to magnetic resonance imaging (MRI). Fourteen CF-1 female mice were separated into 4 experimental groups: Untreated negative control, MRI-treated, MRI-Control, and exposed to ionizing radiation positive control. Untreated negative control was used as a baseline for ELISA to quantify γH2AX. MRI-treated consisted of a 6-hour continuous magnetic resonance imaging (MRI) echo planar imaging (EPI) sequence with a slew rate of 192 mT/m/s constituting a significantly longer imaging time than routine clinical imaging. MRI-control mice were maintained under the same conditions outside the MRI scanner for 6-hours. Mice in the irradiation group served as a positive control of DSBs and were exposed to either 2 Gy, 5 Gy or 10 Gy of ionizing radiation. DSBs in the blood lymphocytes from the treatment groups were analyzed using the γH2AX ELISA and compared. Total protein concentration in lysates was determined for each blood sample and averaged 1 ± 0.35 mg/mL. Irradiated positive controls were used to test radiation dose-dependency of the γH2AX ELISA assay where a linear dependency on radiation exposure was observed (r2 = 0.93) between untreated and irradiated samples. Mean and standard error mean of γH2AX formation were calculated and compared between each treatment group. Repeated measures 1-way ANOVA showed statistically significant differences between the means of irradiated controls and both the MRI-control and MRI-treated groups. There was no statistically significant difference between the MRI-treated samples and the MRI-control groups. Our results show that long MRI exposure at a high slew rate did not cause increased levels of γH2AX when compared to control mice, suggesting that no increase in DSBs was caused by the long MR thermometry imaging session. The novelty of this work contradicts other studies that have suggested MRI may cause DSBs;this work suggests an alternative cause of DNA damage.

Deficiency of cystathionine gamma-lyase and hepatic cholesterol accumulation during mouse fatty liver development

Abnormal hepatic lipid metabolism is a key component of fatty liver development with excess fat deposition in the liver through steatosis. Cystathionine gamma-lyase （CSE） is one of the enzymes that catalyze hydrogen sulfide （HAS） production in the liver. The aim of the present study was to investigate the role of CSE/H2S in hepatic regulation of cholesterol and fatty acid metabolism. Wild-type （WT） and CSE knockout （CSE-KO） mice fed with high-fat diet （HFD） were analyzed for liver morphological and biochemical changes. HFD feeding of CSE-KO mice, not WT mice, markedly increased cholesterol levels in plasma and livers, and the sizes of the liver and gall bladder. Typical histological and biochemical changes of fatty liver disease were found in CSE-KO mice with damaged liver functions. The levels of plasma and liver triglyceride were significantly lower in HFD-fed CSE-KO mice than in HFD-fed WT mice. Moreover, the expression of nuclear receptors transcriptional factors, especially LXRα, in the liver was decreased in both control diet-or HFD-fed CSE-KO mice. Decreased expression of CYP7A1, an LXRα targeted gene, halted catabolism of cholesterol into bile and subsequently led to cholesterol accumulation in the liver and gall bladder. Since deficiency in CSE/H2S pathway results in high susceptibility to HFD- induced fatty liver, targeting at CSE/H2S pathway in the liver may represent a novel strategy against the development of fatty liver damage.