To address efficacy issues of cancer diagnosis and chemotherapy, we have developed a magnetic nanoparticle (MNP) formulation with combined drug delivery and imaging properties that can potentially be ...used in image-guided drug therapy. Our MNP consists of an iron-oxide magnetic core coated with oleic acid (OA) and stabilized with an amphiphilic block copolymer. Previously, we reported that our MNP formulation can provide prolonged contrast for tumor magnetic resonance imaging and can be loaded with hydrophobic anticancer agents for sustained drug delivery. In this study, we developed MNPs with optical imaging properties using new near-infrared dyes to quantitatively determine their long-term biodistribution and tumor localization with and without an external magnetic field in mice with xenograft breast tumors. MNPs localized slowly in the tumor, reaching a peak 48 h post-injection before slowly declining over the next 11 days. One hour exposure of the tumor to a magnetic field further enhanced MNP localization to tumors. Our MNPs can be developed with combined drug delivery and multimodal imaging properties to improve cancer diagnosis, provide sustained treatment, and monitor therapeutic effects in tumors over time.
Abstract We are investigating the magnetic resonance imaging characteristics of magnetic nanoparticles (MNPs) that consist of an iron-oxide magnetic core coated with oleic acid (OA), then stabilized ...with a pluronic or tetronic block copolymer. Since pluronics and tetronics vary structurally, and also in the ratio of hydrophobic (polypropylene oxide) and hydrophilic (polyethylene oxide) segments in the polymer chain and in molecular weight, it was hypothesized that their anchoring to the OA coating around the magnetic core could significantly influence the physical properties of MNPs, their interactions with biological environment following intravenous administration, and ability to localize to tumors. The amount of block copolymer associated with MNPs was seen to depend upon their molecular structures and influence the characteristics of MNPs. Pluronic F127-modified MNPs demonstrated sustained and enhanced contrast in the whole tumor, whereas that of Feridex IV was transient and confined to the tumor periphery. In conclusion, our pluronic F127-coated MNPs, which can also be loaded with anticancer agents for drug delivery, can be developed as an effective cancer theranostic agent, i.e. an agent with combined drug delivery and imaging properties.
Introduction: Febrile seizures (FS) are the most common neurological disease in childhood. The etiology of FS is the subject of numerous studies including studies regarding genetic predisposition. ...Aim: The aim of the study was to analyze the association of TRPV1 rs222747 and KCC2 rs2297201 gene polymorphisms with the occurrence of FS. Materials and Methods: The study included 112 patients diagnosed with FS classified as simple febrile seizures (SFS) or complex febrile seizures (CFS). We analyzed selected polymorphisms of KCC2 and TRPV1 genes using the Real-time PCR method. Results: The CT and TT genotypes of the rs2297201 polymorphism of the KCC2 gene are significantly more common in the group of children with FS than the control group (p = .002) as well as the allele T of this polymorphism (p = .045). Additionally, genotypes CT and TT of the rs2297201 polymorphism of the KCC2 gene were more frequent in the group of children with CFS compared to the control group (p < .001). Different genotypes and alleles of the rs222747 TRPV1 gene polymorphism were not associated with the occurrence of febrile seizures or epilepsy, nor were associated with the occurrence of a particular type of febrile seizure (p = .252). Conclusion: These results indicate that the CT and TT genotypes, as well as the T allele of rs2297201 polymorphism of the KCC2 gene, could be a predisposing factor for the FS, as well as the occurrence of CFS.
Beside the importance of implementing physical activity in treatment of patients with osteoporosis, the multicomponent exercise program and assessment of its functional outcomes performed by five ...performance-based measures, have not been explored yet.
The present study evaluated the effect of the 12 weeks exercise program on functional outcomes of postmenopausal patients with densitometric diagnosed osteoporosis.
The study was designed as randomized control study.
Female outpatients with diagnosed postmenopausal osteoporosis were included in the study.
The study included women from urban area.
Patients were randomized in two groups: exercise group (EG) and control group (CG). Patients in the exercise group (N.=47) participated in a 12 weeks exercise program, which consisted of resistance training, balance exercise and aerobic exercise, while patients from control group (N.=49) had not participated in any exercise program during the intervention period. Functional outcomes determined by Time Up and Go Test (TUG), Sit To Stand test (STS) and One Leg Stance Test (OLST) were evaluated at baseline and 4 and 12 weeks after treatment, while Fall Efficacy Scale (FES-I) and Knowledge About Osteoporosis Questionnaire (OKAT-S) were assessed at baseline and after 12 weeks, respectively.
There were noticed statistically significant improvement in all observed measurements in EG after 4 and 12 weeks, respectively. Comparison between groups showed statistically significant difference in EG compared to CG in all functional outcomes in observed periods (P<0.001 for all). OLST significantly changed only in EG, not in CG, in both experimental periods. After 4 weeks, in CG there were no statistically significant changes in any of the monitored parameters, while after 12 weeks improvements were detected with TUG, STS, FES-I and OKAT-S.
Twelve weeks exercise program, as an effective, inexpensive and easily performed method, improved functional status in postmenopausal osteoporotic women.
In the present study we found that supervised exercise program in postmenopausal osteoporotic female patients significantly improved their muscle strength and balance and decreased fear of falling. Thus, it is proposed to be a part of clinical protocol for osteoporosis treatment.
Although the overall quality of medicine has improved in recent decades, the functional capacity in many hip fracture patients remains insufficient. The goal of the present study was to identify ...significant predictors of Instrumental Activities of Daily Living (IADL) measured by the Lawton-Brody scale at 3- and 6-month follow-up in patients with hip fractures admitted to a hospital.
This observational cohort study included 191 patients with acute hip fractures. IADL was measured at baseline and after 3 and 6 months using the Lawton-Brody scale. Multivariable logistic regression analysis was carried out using pre-fracture functional status, sociodemographic variables, hand grip strength (HGS), surgical procedure, complications, and length of hospital stay, Short Physical Performance Battery, and Barthel Index (BI) on the fifth postoperative day as potential predictors for IADL after a hip fracture surgery.
The mean age of the participants was 80.3 ± 6.8 years, and 77.0% of our cohort were women. Multivariate regression analysis revealed that pre-fracture functional status and early functional recovery were independent predictors of IADL after hip fracture surgery.
Clinicians should take steps to improve functional outcomes by changing how patients are rehabilitated in the first days after hip fracture surgery, especially for the group of patients with a lower functional status before the fracture.
The p53 tumor suppressor gene is mutated in 50% of human cancers, resulting in more aggressive disease with greater resistance to chemotherapy and radiation therapy. Advances in gene therapy ...technologies offer a promising approach to restoring p53 function. We have developed polymeric nanoparticles (NPs), based on poly(lactic-
co
-glycolic acid), that provide sustained intracellular delivery of plasmid DNA, resulting in sustained gene expression without vector-associated toxicity. Our previous studies with p53 gene-loaded NPs (p53NPs) demonstrated sustained antiproliferative effects in cancer cells in vitro. The objective of this study was to evaluate the efficacy of p53NPs in vivo. Tumor xenografts in mice were established with human p53-null prostate cancer cells. Animals were treated with p53NPs by either local (intratumoral injection) or systemic (intravenous) administration. Controls included saline, p53 DNA alone, and control NPs. Mice treated with local injections of p53NPs demonstrated significant tumor inhibition and improved animal survival compared with controls. Tumor inhibition corresponded to sustained and greater p53 gene and protein expression in tumors treated with p53NPs than with p53 DNA alone. A single intravenous dose of p53NPs was successful in reducing tumor growth and improving animal survival, although not to the same extent as with local injections. Imaging studies showed that NPs accumulate in tumor tissue after intravenous injection; however, further improvement in tumor targeting efficiency of p53NPs may be needed for better outcome. In conclusion, the NP-mediated p53 gene therapy is effective in tumor growth inhibition. NPs may be developed as nonviral vectors for cancer and other genetic diseases.
Background. Osteoporosis is a disease characterized by decreased bone density and destruction of bone microarchitecture. Indicators for altered bone homeostasis are changes in the serum level of ...matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). The purpose of the current study was to evaluate the effect of a 12-week exercise program on enzyme activity of serum MMP-9 and TIMP-1 in postmenopausal osteoporotic patients. Materials and methods. Participants were randomized in two groups: exercise (EG) (N = 37) and control (CG) (N = 31). The exercise group completed a 12-week supervised exercise program, while the control group did not take part in any physical activity. Enzyme activities of serum MMP-9 and TIMP-1 were detected by gelatin zymography and ELISA in both groups, respectively. Results. Significant differences between pretreatment and posttreatment enzyme activities of serum MMP-9 (p=0.009), TIMP-1 (p≤0.001), and MMP-9/TIMP-1 ratio (p≤0.001) were detected in the exercise group. Exercises decreased the activity of serum MMP-9 and increased the activity of TIMP-1, while the enzyme activities of MMP-9 (0.583) and TIMP-1 (0.210) have not been significantly changed in CG. Patients from the exercise group had better treatment. Conclusion. Our results suggest that a 12-week exercise program has an influence on enzyme activity of serum MMP-9, revealing a possible role of MMPs in initiating training-specific adaptation. Although measurements of circulating MMP-9 and TIMP-1 allowed us to detect effects of exercise, as of today, they have no real role in the diagnosis of osteoporosis and/or follow-up of osteoporotic patient’s response to treatment. MMP-9 might be used as an important prognostic marker for the evaluation of patient’s response to exercise. Larger-randomized controlled studies need to be performed to expand this area of knowledge. This trial is registered with trial registration number: NCT03816449).
The efficacy of potential anticancer drugs during preclinical development is generally tested in vitro using cancer cells grown in monolayer; however, a significant discrepancy in their efficacy is ...observed when these drugs are evaluated in vivo. This discrepancy, in part, could be due to the three-dimensional (3-D) nature of tumors as compared to the two-dimensional (2-D) nature of monolayer cultures. Therefore, there is a need for an in vitro model that would mimic the 3-D nature of tumors. With this objective, we have developed surface-engineered, large and porous biodegradable polymeric microparticles as a scaffold for 3-D growth of cancer cells. Using the MCF-7 cell line as model breast cancer cells, we evaluated the antiproliferative effect of three anticancer drugs: doxorubicin, paclitaxel and tamoxifen in 3-D model vs in 2-D monolayer. With optimized composition of microparticles and cell culture conditions, a density of 4.5 × 106 MCF-7 cells/mg of microparticles, which is an 18-fold increase from the seeding density, was achieved in six days of culture. Cells were observed to have grown in clumps on the microparticle surface as well as in their interior matrix structure. The antiproliferative effect of the drugs in 3-D model was significantly lower than in 2-D monolayer, which was evident from the 12- to 23-fold differences in their IC50 values. Using doxorubicin, the flow cytometry data demonstrated ∼2.6-fold lower drug accumulation in the cells grown in 3-D model than in the cells grown as 2-D monolayer. Further, only 26% of the cells in 3-D model had the same concentration of drug as the cells in monolayer, thus explaining the reduced activity of the drugs in 3-D model. The collagen content of the cells grown in 3-D model was 2-fold greater than that of the cells grown in 2-D, suggesting greater synthesis of extracellular matrix in 3-D model, which acted as a barrier to drug diffusion. The microarray analysis showed changes in several genes in cells grown in 3-D, which could also influence the drug effect. In conclusion, the cells grown in 3-D are more resistant to chemotherapy than those grown in 2-D culture, suggesting the significant roles of cellular architecture, phenotypic variations, and extracellular matrix barrier to drug transport in drug efficacy. We propose that our model provides a better assessment of drug efficacy than the currently used 2-D monolayer as many of its characteristic features are similar to an actual tumor. A well-characterized 3-D model can particularly be useful for rapid screening of a large number of therapeutics for their efficacy during the drug discovery phase.
Febrile seizures (FS) are the most common neurological disorder in childhood and are a great stress for parents due to their dramatic clinical appearance. Using test for determination of homozygously ...recessive characteristics in humans (HRC test) we analyzed presence, distribution, and individual combination of 20 selected genetically controlled morphophysiological traits among FS patients (N=121) and control (N=121) to determine a possible deviation in the homozygosity level and genetic loads in the group of affected children and whether there is a predisposition to the occurrence of FS. The results of our study show a statistically significant difference in the mean values of the HRC tested (x¯HRC/20 CN = 3.2 ± 0.2; x¯HRC/20 FS = 4.6 ± 0.2, t= 5.74 , p< 0.0001), as well as in the distribution and variability of two studied samples (VC=55,3%, VFS= 39,6%), which indicates a complex polygenic difference among the tested groups of subjects. The differences in the degree of genetic homozygosity and variability are also present between the genders (t Cf/FSf = 4.12; t Cm/FSm = 3.98; p <0.0001) (VCf=56.9%, VFSf= 39.3%; VCm=54.1%, VFSm=40.1%). Obtained results indicate the enlargement of recessively homozygous genetic loads in the group of children with FS which may represent some kind of predisposition for expressivity of this type of seizures.
Botulinum toxin (BTX) is a neurotoxin derived from the Clostridium botulinum bacterium that inhibits the release of acetylcholine at the neuromuscular junction level whose effects has been used for ...many years to treat a variety of muscular/neuromuscular conditions and more recently also for cosmetic use. BTX has experimented in some dermatological conditions, which include Rosacea and facial flushing treatment with good results. The complex mechanism underlying those results is not completely understood but was proposed a release inhibition of acetylcholine from peripheral autonomic nerves of the cutaneous vasodilatory system combined with the blockade substance P and calcitonin gene-related peptide (CGRP) thus modulating blood vessel dilatation. We analysed the published data on BTX off label applications rosacea and flushing retrieved from PubMed.
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