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Sirotkina M.A.,Institute of Biomedical Technologies | Sirotkina M.A.,Nizhny Novgorod State Medical Academy | Buyanova N.L.,Institute of Biomedical Technologies | Buyanova N.L.,Nizhny Novgorod State Medical Academy | And 18 more authors.
Sovremennye Tehnologii v Medicine | Year: 2015

The objective of the research was to study the features of transplantation, growth and visualization of experimental tumors of animals, using multimodal optical coherence tomography (OCT) to develop the methodology of evaluation of individual tumor response to anti-cancer therapy. Materials and Methods. The research was carried out using an experimental high-speed spectral-domain multimodal OCT system developed at the Institute of Applied Physics of the Russian Academy of Sciences (Russia). The technical characteristics of the system are the following: speed of information acquisition, 20,000 А-scans per second; 1.3 μm wavelength; frame size, approximately 4×2 mm; lateral resolution, 25 μm; and depth resolution, 10 μm. We evaluated cross-polarized (CP) and microangiopathic (МА) OCT images. We performed an OCT study of the experimental tumor model of colon adenocarcinoma of mice Colo-26 on BALB/с mice (transplanted by suspension of tumor cells culture) inoculated subcutaneously into the thigh, intradermally into auricle, and in a dorsal skinfold window chamber. In the case of a deep subcutaneous location of a nodule, skin flap over the tumor was surgically opened. CP OCT images were compared with histological preparations (stained using hematoxylin and eosine). Results. It was established that a Colo-26 tumor growing subcutaneously is not suitable with OCT monitoring investigations. Applying of tumor model with opened skin flap made it possible considerably to increase the visualization depth; however, it is not feasible to use this method for everyday OCT monitoring. The tumor grown within a dorsal window chamber is optimal for the visualization of blood vessels by means the OCT. Nevertheless, the inflammation and edema sometimes observed at the tumor site impeded the МА OCT study. Superficial tumors on the auricle are available for OCT investigation throughout their entire depth if the size of nodule does not exceed 1.5 mm. The tumor model on the auricle is convenient for physiological studies of the state of the vessels during the tumor growth. Conclusions. The optimal tumor model for dynamic multimodal OCT observation is a tumor on the auricle. Unlike a tumor located on the thigh it is characterized by a subcutaneous location of the nodule yet one which still remains accessible for visualization. The tumor evolving in the ear can be studied using dynamics which would be impossible for the tumor with opened skin flap. Tumors in the dorsal skin window can also be used for research, but the monitoring of their growth is limited to those that are no larger than 5–7 mm, as the nodule goes beyond the window due to the decreased elasticity of the skin, typical of these mice. © 2015, Sovremennye Tehnologii v Medicine. All rights reserved.


Cherkasova E.I.,Laboratory | Cherkasova E.I.,Lobachevsky State University of Nizhni Novgorod | Murtazaliyeva M.S.,Volga District Medical Center under Federal Medical and Biological Agency of Russia | Gorshkova T.N.,Volga District Medical Center under Federal Medical and Biological Agency of Russia | And 5 more authors.
Sovremennye Tehnologii v Medicine | Year: 2015

Immortalized cell culture of hepatocytes, Chang liver, is one of the candidates for the use in “bioartificial liver” systems. The aim of the investigation was to evaluate the possibility of using the Chang liver cell culture as a bioreactor cell kit making a complex study of biochemical parameters of its effect on the blood serum of patients with liver diseases of various etiology. Materials and Methods. Samples of blood serum from two groups of patients were investigated: patients with obstructive jaundice were included in group 1 “jaundice” (n=9), group 2 “cirrhosis” (n=10) comprised patients with hepatic cirrhosis and hepatocellular jaundice. To study the effect of the cultured Chang liver cells on the patients’ blood serum, confluent monolayer of the cells was incubated with serum samples at 37°C in a 5% CO2 atmosphere with the ratio of (2.0‒2.1)·105 cells per 0.105 ml of serum during 12 h. On completion of the process, the values of the main biochemical parameters of synthetic (albumin, urea, transthyretin) and detoxifying (total bilirubin fraction) functions were determined, as well as markers of cell destruction (hepatic transaminases, lactate dehydrogenases). Viability cell changes after exposure to the serum were defined by MTT test. Results. It was estimated, that complex assessment of biochemical parameters of synthetic and detoxifying functions of the Chang liver culture relative to the blood serum of the patients of both groups, is the most informative one. This cell culture is synthetically active to the most extent in respect to the serum of the patients in “cirrhosis” group, while in “jaundice” group the reduction of this biochemical parameter was observed. Detoxifying activity of the Chang liver culture, exhibited in the dynamics of bilirubin fractures, was noted in both groups, but in “cirrhosis” group it was most marked, as it occurred in half the cases. Biochemical components of the serum, in their turn, also influenced cell viability. Serum samples of both patient groups were found to inhibit the viability of the cells almost in 50% of cases for each group. Conclusion. The results of complex assessment can be used to determine the efficacy of applying various cell cultures as a model system in the development of “bioartificial liver” systems. Chang liver cell culture, according to the complex assessment results, is most active relative to the blood serum of the “cirrhosis” group of patients with impairments of synthetic and detoxifying liver functions. © 2015, Sovremennye Tehnologii v Medicine. All rights reserved.


Ijpma G.,Institute of Biomedical Technologies | Al-Jumaily A.M.,Institute of Biomedical Technologies | Cairns S.P.,Auckland University of Technology | Sieck G.C.,Mayo Medical School
Journal of Applied Physiology | Year: 2011

Length adaptation in airway smooth muscle (ASM) is attributed to reorganization of the cytoskeleton, and in particular the contractile elements. However, a constantly changing lung volume with tidal breathing (hence changing ASM length) is likely to restrict full adaptation of ASM for force generation. There is likely to be continuous length adaptation of ASM between states of incomplete or partial length adaption. We propose a new model that assimilates findings on myosin filament polymerization/ depolymerization, partial length adaptation, isometric force, and shortening velocity to describe this continuous length adaptation process. In this model, the ASM adapts to an optimal force-generating capacity in a repeating cycle of events. Initially the myosin filament, shortened by prior length changes, associates with two longer actin filaments. The actin filaments are located adjacent to the myosin filaments, such that all myosin heads overlap with actin to permit maximal cross-bridge cycling. Since in this model the actin filaments are usually longer than myosin filaments, the excess length of the actin filament is located randomly with respect to the myosin filament. Once activated, the myosin filament elongates by polymerization along the actin filaments, with the growth limited by the overlap of the actin filaments. During relaxation, the myosin filaments dissociate from the actin filaments, and then the cycle repeats. This process causes a gradual adaptation of force and instantaneous adaptation of shortening velocity. Good agreement is found between model simulations and the experimental data depicting the relationship between force development, myosin filament density, or shortening velocity and length. © 2011 by the American Physiological Society.


Lanari M.,Imola Hospital | Vandini S.,University of Bologna | Adorni F.,Institute of Biomedical Technologies | Prinelli F.,Institute of Biomedical Technologies | And 3 more authors.
Respiratory Research | Year: 2015

Background: Tobacco smoke exposure (TSE) is a worldwide health problem and it is considered a risk factor for pregnant women's and children's health, particularly for respiratory morbidity during the first year of life. Few significant birth cohort studies on the effect of prenatal TSE via passive and active maternal smoking on the development of severe bronchiolitis in early childhood have been carried out worldwide. Methods: From November 2009 to December 2012, newborns born at ≥33 weeks of gestational age (wGA) were recruited in a longitudinal multi-center cohort study in Italy to investigate the effects of prenatal and postnatal TSE, among other risk factors, on bronchiolitis hospitalization and/or death during the first year of life. Results: Two thousand two hundred ten newborns enrolled at birth were followed-up during their first year of life. Of these, 120 (5.4 %) were hospitalized for bronchiolitis. No enrolled infants died during the study period. Conclusions: These results confirm the detrimental effects of passive TSE and active heavy smoke during pregnancy for infants' respiratory health, since the exposure significantly increases the risk of hospitalization for bronchiolitis in the first year of life. © 2015 Lanari et al.


Manunta P.,Vita-Salute San Raffaele University | Ferrandi M.,CVie Therapeutics Ltd | Cusi D.,Institute of Biomedical Technologies | Ferrari P.,CVie Therapeutics Ltd | And 3 more authors.
Current hypertension reports | Year: 2016

During the past 20 years, the studies on genetics or pharmacogenomics of primary hypertension provided interesting results supporting the role of genetics, but no actionable finding ready to be translated into personalized medicine. Two types of approaches have been applied: a "hypothesis-driven" approach on the candidate genes, coding for proteins involved in the biochemical machinery underlying the regulation of BP, and an "unbiased hypothesis-free" approach with GWAS, based on the randomness principles of frequentist statistics. During the past 10-15 years, the application of the latter has overtaken the application of the former leading to an enlargement of the number of previously unknown candidate loci or genes but without any actionable result for the therapy of hypertension. In the present review, we summarize the results of our hypothesis-driven approach based on studies carried out in rats with genetic hypertension and in humans with essential hypertension at the pre-hypertensive and early hypertensive stages. These studies led to the identification of mutant adducin and endogenous ouabain as candidate genetic-molecular mechanisms in both species. Rostafuroxin has been developed for its ability to selectively correct Na(+) pump abnormalities sustained by the two abovementioned mechanisms and to selectively reduce BP in rats and in humans carrying the gene variants underlying the mutant adducin and endogenous ouabain (EO) effects. A clinical trial is ongoing to substantiate these findings. Future studies should apply both the candidate gene and GWAS approaches to fully exploit the potential of genetics in optimizing the personalized therapy.


PubMed | University of Évry Val d'Essonne, Unita di Reumatologia, The Second University of Naples, University of Rome La Sapienza and 8 more.
Type: Journal Article | Journal: Clinical and experimental rheumatology | Year: 2016

Systemic sclerosis (SSc) is a rare autoimmune disease (AID) with a complex genetic etiology. Evidence for a shared pathogenesis across AIDs is given by the well-known pleiotropism of autoimmune genes. Recently, several unbiased approaches have identified an association between polymorphisms of the CD2 gene, and rheumatoid arthritis (RA) susceptibility. The objective of this study was to investigate whether CD2 polymorphisms are associated with SSc.Two SNPs of CD2, rs624988 and rs798036, were genotyped in a total of 1,786 SSc patients and 2,360 healthy individuals from two European populations (France and Italy). Meta-analyses were performed to assess whether an association exists between CD2 polymorphisms or haplotypes and SSc or its main subtypes.The combined analyses revealed an association between the rs624988 A allele and SSc susceptibility: padj=0.023, OR=1.14 (95%CI 1.04-1.25). Single marker analysis did not reveal any association between rs798036 and SSc. Haplotype analysis identified that the A-T haplotype, previously described in RA, was associated with higher susceptibility for SSc (padj=0.029, OR=1.14, 95%CI 1.04-1.25) and with the positive anti-centromere antibody sub-group of SSc patients (padj=0.009, OR=1.19 95%CI 1.07-1.32). Genotype-mRNA expression correlations revealed that the CD2 risk haplotype was associated with decreased CD2 mRNA expression in SSc patients.Our study establishes CD2 as a new susceptibility factor for SSc, in a European Caucasian population, confirming the sharing of autoimmune risk factors by SSc and RA.


PubMed | University of Jyväskylä, Institute of Biomedical Technologies and University of Helsinki
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Cyclodextrins are cyclic oligosaccharides widely used in the pharmaceutical industry to improve drug delivery and to increase the solubility of hydrophobic compounds. Anabaenolysins are lipopeptides produced by cyanobacteria with potent lytic activity in cholesterol-containing membranes. Here, we identified the 23- to 24-kb gene clusters responsible for the production of the lipopeptide anabaenolysin. The hybrid nonribosomal peptide synthetase and polyketide synthase biosynthetic gene cluster is encoded in the genomes of three anabaenolysin-producing strains of Anabaena. We detected previously unidentified strains producing known anabaenolysins A and B and discovered the production of new variants of anabaenolysins C and D. Bioassays demonstrated that anabaenolysins have weak antifungal activity against Candida albicans. Surprisingly, addition of the hydrophilic fraction of the whole-cell extracts increased the antifungal activity of the hydrophobic anabaenolysins. The fraction contained compounds identified by NMR as -, -, and -cyclodextrins, which undergo acetylation. Cyclodextrins have been used for decades to improve the solubility and bioavailability of many drugs including antifungal compounds. This study shows a natural example of cyclodextrins improving the solubility and efficacy of an antifungal compound in an ancient lineage of photosynthetic bacteria.


PubMed | University of Michigan, French Institute of Health and Medical Research, Mayo Medical School, University of Paris 13 and 6 more.
Type: Journal Article | Journal: PLoS genetics | Year: 2016

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.410-10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.9710-4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.


PubMed | Institute of Biomedical Technologies
Type: Journal Article | Journal: European review for medical and pharmacological sciences | Year: 2010

Drug therapy for schizophrenia aims to both reduce symptoms in the acute phase and maintain long-term symptomatic remission during periods of stabilization. Atypical antipsychotic agents are the mainstay of schizophrenia therapy because of their improved tolerability, including a reduced likelihood of extrapyramidal symptoms, compared with conventional antipsychotics. However, responses to antipsychotic therapy are influenced by a wide range of factors, such as age, gender, race, comorbidities, genetics and social and environmental conditions, that make identifying the most appropriate antipsychotic treatment for each individual patients, an ongoing challenge for physicians. Tools that may be useful to assist clinicians in determining appropriate individual therapy include consideration of treatment moderators, which specify for whom or under what conditions a treatment works, treatment mediators, which are mechanisms by which a treatment achieves its effects, and cluster group analyses, which identify subsets of patients with similar characteristics. Further research is required to determine whether cluster groups of patients with schizophrenia can be identified based on treatment moderators and mediators, and whether antipsychotic prescribing based on consideration of these cluster groups leads to improved treatment outcomes.


PubMed | Institute of Biomedical Technologies
Type: | Journal: Current drug targets | Year: 2015

Allostery is a long-range macromolecular mechanism of internal regulation, in which the binding of a ligand in an allosteric site induces distant conformational changes in a distant portion of the protein, modifying its activity. From the drug design point of view, this mechanism can be exploited to achieve important therapeutic effects, since ligands able to bind allosteric sites may be designed to regulate target proteins. Computational tools are a valid support in this sense, since they allow the characterization of allosteric communications within proteins, which are essential to design modulator ligands. While considering long-range interactions in macromolecules, the principal drug design tool available to researcher is molecular dynamics, and related applications, since it allows the evaluation of conformational changes of a protein bound to a ligand. In particular, all-atoms molecular dynamics is suitable to verify the internal mechanisms that orchestrate allosteric communications, in order to identify key residues and internal pathways that modify the protein behaviour. The problem is that these techniques are heavily time-consuming and computationally intensive, thus high performance computing systems, including parallel computing and GPU-accelerated computations, are necessary to achieve results in a reasonable time. In this review, we will discuss how it is possible to exploit in silico approaches to characterize allosteric modulations and long-range interactions within proteins, describing the case study of the Heat Shock Proteins, a class of chaperons regulated by stress conditions, which is particular important since it is involved in many cancers and neurodegenerative diseases.

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