Temperature-controlled power modulation compensates for heterogeneous nanoparticle distributions: a computational optimization analysis for magnetic hyperthermia

Purpose: To study, with computational models, the utility of power modulation to reduce tissue temperature heterogeneity for variable nanoparticle distributions in magnetic nanoparticle hyperthermia.

Methods: Tumour and surrounding tissue were modeled by elliptical two- and three-dimensional computational phantoms having six different nanoparticle distributions. Nanoparticles were modeled as point heat sources having amplitude-dependent loss power. The total number of nanoparticles was fixed, and their spatial distribution and heat output were varied. Heat transfer was computed by solving the Pennes’ bioheat equation using finite element methods (FEM) with temperature-dependent blood perfusion. Local temperature was regulated using a proportional-integral-derivative (PID) controller. Tissue temperature, thermal dose and tissue damage were calculated. The required minimum thermal dose delivered to the tumor was kept constant, and heating power was adjusted for comparison of both the heating methods.

Results: Modulated power heating produced lower and more homogeneous temperature distributions than did constant power heating for all studied nanoparticle distributions. For a concentrated nanoparticle distribution, located off-center within the tumor, the maximum temperatures inside the tumor were 16% lower for modulated power heating when compared to constant power heating. This resulted in less damage to surrounding normal tissue. Modulated power heating reached target thermal doses up to nine-fold more rapidly when compared to constant power heating.

Conclusions: Controlling the temperature at the tumor-healthy tissue boundary by modulating the heating power of magnetic nanoparticles demonstrably compensates for a variable nanoparticle distribution to deliver effective treatment.     

Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

Several prior reports have suggested that chromosomal region 13q32 may harbor a schizophrenia susceptibility gene. In an attempt to replicate this finding, we assessed linkage between chromosome 13 markers and schizophrenia in 166 families, each with two or more affected members. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Studies Program, included 392 sampled affected subjects and 216 affected sib pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizoaffective disorder, depressed. The families had mixed ethnic backgrounds. The majority were northern European-American families (n = 62, 37%), but a substantial proportion were African-American kindreds (n = 60, 36%). Chromosome 13 markers, spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the 13q32 region were genotyped and the data analyzed using semi-parametric affected only linkage analysis. For the combined sample (with race broadly defined and schizophrenia narrowly defined) the maximum LOD score was 1.43 (Z-score of 2.57; P = 0.01) at 79.0 cM between markers D13S1241 (76.3 cM) and D13S159 (79.5 cM). Both ethnic groups showed a peak in this region. The peak is within 3 cM of the peak reported by Brzustowicz et al. [1999: Am J Hum Genet 65:1096-1103].     

In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens

Cytotoxic T lymphocytes (CTL) respond to antigenic peptides presented on MHC class I molecules. On most cells, these peptides are exclusively of endogenous, cytosolic origin. Bone marrow-derived antigen-presenting cells, however, harbor a unique pathway for MHC I presentation of exogenous antigens. This mechanism permits cross-presentation of pathogen-infected cells and the priming of CTL responses against intracellular microbial infections. Here, we report a novel diphtheria toxin-based system that allows the inducible, short-term ablation of dendritic cells (DC) in vivo. We show that in vivo DC are required to cross-prime CTL precursors. Our results thus define a unique in vivo role of DC, i.e., the sensitization of the immune system for cell-associated antigens. DC-depleted mice fail to mount CTL responses to infection with the intracellular bacterium Listeria monocytogenes and the rodent malaria parasite Plasmodium yoelii.     

The effects of feeding an Asian or Western diet on sperm numbers, sperm quality and serum hormone levels in cynomolgus monkeys (Macaca fascicularis) injected with testosterone enanthate (TE) plus depot medroxyprogesterone acetate (DMPA)

The aim of this study was to elucidate the effects of an Asian diet compared to a Western diet on sperm numbers and quality, and serum hormones in cynomolgus monkeys (Macaca fascicularis) injected with testosterone enanthate (TE) plus depot medroxyprogesterone acetate (DMPA). Thirty male monkeys were divided into three groups of ten animals each. The first group (control) was fed with standard diet 'monkey chow' (9% fat, 13% protein, 78% carbohydrate); the second group was fed an 'asian' diet (15% fat, 15% protein, 70% carbohydrate); the third group was fed a 'Western' diet (35% fat, 25% protein, 40% carbohydrate). These diets were administered from the beginning (adaptation) until the experiment was terminated. Three months after the adaptation period, all groups were injected with 20 mg TE (once per week) and 25 mg DMPA (once every 6 weeks) for 18 weeks, while TE injections were continued for another 6 weeks. There were no differences in sperm numbers and quality, or in hormone levels between the first and second groups. In both of these groups azoospermia was achieved in 100% of animals, while in the third group only 70% achieved azoospermia. In all 3 groups, spermatozoa were once again detectable by week 33. However, by the end of the study at week 39, sperm numbers in the first and second groups reached only severe oligozoospermia (two animals remained azoospermic in the first group) while in the third group, numbers had returned to normozoospermia. The quality of spermatozoa during and after the treatment in the third group was better than in the first and second groups. Hormone concentrations decreased more rapidly in both the first and second groups, compared to the third group, while the recovery period was slower in the first and second groups, compared to the third group. It is concluded that different formula diets result in differential decreases in sperm numbers and quality, and in hormone concentrations in M. fascicularis injected with TE in combination with DMPA. Animals fed with either monkey chow or an Asian diet exhibited more severe and prolonged decreases in these parameters than did animals fed with a Western diet.     

Stilbenoids from Gnetum macrostachyum Attenuate Human Platelet Aggregation and Adhesion

Platelets play a critical role in pathogenesis of cardiovascular disorders and strokes. The inhibition of platelet function is beneficial for the treatment and prevention of these diseases. The phytochemical investigation of stilbenoids from Gnetum macrostachyum Hook. f. led to the isolation of trans‐resveratrol (1), isorhapotigenin (2), gnetol (3), bisisorhapontigenin B (4), gnetin C (5), parvifolol A (6), latifolol (7) and gnetuhainin C (8). The isolated stilbenoids were evaluated for in vitro antiplatelet activities via agonist‐induced platelet aggregation and static platelet‐collagen adhesion assays using washed human platelets. Compounds 1, 2 and 3 were active in the inhibition of arachidonic acid (AA)‐induced platelet aggregation. Compound 2 and its dimer, compound 4, were the most active stilbenoids in thrombin‐induced platelet aggregation. Moreover, compounds 4, 5 and 6, tended to be more potent than monomeric and trimeric stilbenoids in a human platelet‐collagen adhesion assay under static conditions. This is the first report of the antiplatelet activity of stilbenoids isolated from G. macrostachyum. Copyright © 2012 John Wiley & Sons, Ltd.     

Cholesterol-conjugated poly(D,L-lactide)-based micelles as a nanocarrier system for effective delivery of curcumin in cancer therapy

Polymeric micelles have been widely explored preclinically as suitable delivery systems for poorly soluble chemotherapeutic drugs in cancer therapy. The present study reported the development of cholesterol (Ch)-conjugated poly(D,L-Lactide) (PLA)-based polymeric micelles (mPEG–PLA-Ch) for effective encapsulation and delivery of curcumin (CUR) at the tumor site. Cholesterol conjugation dramatically affected the particle size and improved drug loading (DL) and encapsulation efficiency (EE). mPEG–PLA-Ch-CUR showed bigger hydrodynamic diameter (104.6?±?2.1?nm, and 169.3?±?1.52?nm for mPEG–PLA and mPEG–PLA-Ch, respectively) due to increased size of the hydrophobic core. The newly developed polymer exhibited low critical micelles concentration (CMC) (25?μg/mL) which is close to lipid-based polymer, PEG-phosphatidyl ethanolamine (12.5?μg/mL) compared to mPEG–PLA (50?μg/mL). mPEG–PLA-Ch micelles exhibited relatively higher EE (93.74?±?1.6%) and DL (11.86?±?0.8%) compared to mPEG–PLA micelles (EE 91.89?±?1.2% and DL 11.06?±?0.8%). mPEG–PLA-Ch micelles were internalized by the cancer cells effectively and exhibited higher cytotoxicity compared to free CUR in both, murine melanoma (B16F10) and human breast cancer (MDA-MB-231) cells. mPEG–PLA-Ch exhibited satisfactory hemocompatibility indicating their potential for systemic application. Further, mPEG–PLA-Ch-CUR demonstrated higher rate of reduction of tumor volume in B16F10-xenografted tumor-bearing mice compared to free CUR. At the end of 22 days, the tumor reduced to 1.87-fold (627.72?±?0.9?mm³ versus 1174.68?±?1.64?mm³) compared to the treatment with free CUR. In conclusion, the experimental data in vitro and in vivo indicated that the newly developed CUR-mPEG–PLA-Ch micelles may have promising applications in solid tumors.     

Anticancer potential of β-sitosterol and oleanolic acid as through inhibition of human estrogenic 17beta-hydroxysteroid dehydrogenase type-1 based on an in silico approach

The human estrogenic enzyme 17beta-hydroxysteroid dehydrogenase type-1 (HSD17B1) provides biosynthesis regulation of active estrogen in stimulating the development of breast cancer through cell proliferation. The β-sitosterol is classified as a steroid compound and is actually a type of triterpenoid compound that has a similar structure to a steroid. This similarity provides a great opportunity for the inhibitor candidate to bind to the HDS17B1 enzyme because of the template similarity on the active site. Several in silico approaches have been applied in this study to examine the potential of these two inhibitor candidates. Pharmacokinetic studies showed positive results by meeting several drug candidate criteria, such as drug-likeness, bioavailability, and ADMET properties. A combination of molecular docking and MD simulation showed good conformational interaction of the inhibitors and HSD17B1. Prediction of binding free energy (ΔG_bind) using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) approach shows ΔG_bind (kcal mol⁻¹) of C1–HSD17B1: −49.31 ± 0.23 and C2–HSD17B1: −33.54 ± 0.34. Meanwhile, decomposition energy analysis (ΔG^residue_bind) suggested several key residues that were also responsible for the interaction with inhibitors, such as C1–HSD17B1 (six residues: Leu96, Leu149, Pro187, Met193, Val225, and Phe226) and C2–HSD17B1 (four residues: Ile14, Gly94, Pro187, and Val188). Hopefully, the obtained results from this research could be considered for the mechanistic inhibition of the HSDS17B1 enzyme at molecular and atomistic levels.

We presented pharmacokinetic study, molecular docking, and MD simulation to study β-sitosterol and oleanolic acid compounds and potential HSD17B1 inhibitors.     

Hepatoprotective effect of Pandanus odoratissimus seed extracts on paracetamol-induced rats

ContextPandanus odoratissimus Linn. (Pandanaceae) seed extract is known to have antioxidant activities. However, the potential hepatoprotective effect is still unclear.ObjectiveTo investigate the hepatoprotection aspect of P. odoratissimus methanol extract towards paracetamol-induced rats.Materials and methodsThirty male Sprague–Dawley rats were randomly divided into six equal groups: one group served as the healthy control and five groups with hepatotoxicity (hepatotoxic control and 4 treatment groups). The oral treatment of paracetamol-induced hepatotoxicity of 3 g/kg using three different concentrations of P. odoratissimus (300, 600 and 900 mg/kg), and silymarin (200 mg/kg) groups were administered once a day for 14 days. Enzyme activities and protein levels in serum were determined in rats at the end of the treatments. The histopathology of rat livers was observed under an electron microscope with 10× magnification.ResultsPandanus odoratissimus significantly decreased the serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) activities in induced-paracetamol rat serum (p < 0.05). Moreover, P. odoratissimus significantly decreased total bilirubin and direct bilirubin levels (p < 0.05). It significantly blocked the decline of serum albumin and protein levels (p < 0.05). Histopathological changes amplified paracetamol-induced liver damage and the hepatoprotective effect of P. odoratissimus in the liver.Discussion and conclusionsPandanus odoratissimus improved the hepatoprotective effect in a concentration-dependent manner by reducing related hepatic enzyme and protein markers, suggesting as a useful agent in hepatotoxicity treatment, and it can be generalized to a broader study population in different hepatotoxic animal models.