Impact of KRAS variant rs61764370 on breast cancer morbidity

Low-penetrance gene variants and their combinations are topical study objects in breast cancer pathogenesis. Single nucleotide polymorphism rs61764370, localized in 3՛ UTR of KRAS gene, plays an important role in the development and progression of seve­ral cancers. The aim of our study was to determine the KRAS variant impact on breast cancer morbidity. Patients and Methods: 2214 patients diagnosed with breast cancer and 861 healthy controls were screened for KRAS variant by RFLP method. Available clinical data were collected and processed using statistical analysis methods. Results of present study suggest the KRAS variant impact on breast cancer development risk in premenopausal women, but it has no effect on breast cancer prognosis. We did not observe any KRAS variant effect on breast cancer patient 10-year disease-specific survival rates. Key Words: breast cancer, rs61764370, KRAS variant, predisposing factor

The Role of TLR4 in the Paclitaxel Effects on Neuronal Growth In Vitro

Paclitaxel (Pac) is an antitumor agent that is widely used for treatment of solid cancers. While being effective as a chemotherapeutic agent, Pac in high doses is neurotoxic, specifically targeting sensory innervations. In view of these toxic effects associated with conventional chemotherapy, decreasing the dose of Pac has been recently suggested as an alternative approach, which might limit neurotoxicity and immunosuppression. However, it remains unclear if low doses of Pac retain its neurotoxic properties or might exhibit unusual effects on neuronal cells. The goal of this study was to analyze the concentration-dependent effect of Pac on isolated and cultured DRG neuronal cells from wild-type and TLR4 knockout mice. Three different morphological parameters were analyzed: the number of neurons which developed neurites, the number of neurites per cell and the total length of neurites per cell. Our data demonstrate that low concentrations of Pac (0.1 nM and 0.5 nM) do not influence the neuronal growth in cultures in both wild type and TLR4 knockout mice. Higher concentrations of Pac (1-100 nM) had a significant effect on DRG neurons from wild type mice, affecting the number of neurons which developed neurites, number of neurites per cell, and the length of neurites. In DRG from TLR4 knockout mice high concentrations of Pac showed a similar effect on the number of neurons which developed neurites and the length of neurites. At the same time, the number of neurites per cell, indicating the process of growth cone initiation, was not affected by high concentrations of Pac. Thus, our data showed that Pac in high concentrations has a significant damaging effect on axonal growth and that this effect is partially mediated through TLR4 pathways. Low doses of Pac are devoid of neuronal toxicity and thus can be safely used in a chemomodulation mode. © 2013 Ustinova et al

Up-regulation of brain-derived neurotrophic factor in primary afferent pathway regulates colon-to-bladder cross-sensitization in rat

Background In humans, inflammation of either the urinary bladder or the distal colon often results in sensory cross-sensitization between these organs. Limited information is known about the mechanisms underlying this clinical syndrome. Studies with animal models have demonstrated that activation of primary afferent pathways may have a role in mediating viscero-visceral cross-organ sensitization. Methods Colonic inflammation was induced by a single dose of tri-nitrobenzene sulfonic acid (TNBS) instilled intracolonically. The histology of the colon and the urinary bladder was examined by hematoxylin and eosin (H&E) stain. The protein expression of transient receptor potential (TRP) ion channel of the vanilloid type 1 (TRPV1) and brain-derived neurotrophic factor (BDNF) were examined by immunohistochemistry and/or western blot. The inter-micturition intervals and the quantity of urine voided were obtained from analysis of cystometrograms. Results At 3 days post TNBS treatment, the protein level of TRPV1 was increased by 2-fold (p \u3c 0.05) in the inflamed distal colon when examined with western blot. TRPV1 was mainly expressed in the axonal terminals in submucosal area of the distal colon, and was co-localized with the neural marker PGP9.5. In sensory neurons in the dorsal root ganglia (DRG), BDNF expression was augmented by colonic inflammation examined in the L1 DRG, and was expressed in TRPV1 positive neurons. The elevated level of BDNF in L1 DRG by colonic inflammation was blunted by prolonged pre-treatment of the animals with the neurotoxin resiniferatoxin (RTX). Colonic inflammation did not alter either the morphology of the urinary bladder or the expression level of TRPV1 in this viscus. However, colonic inflammation decreased the inter-micturition intervals and decreased the quantities of urine voided. The increased bladder activity by colonic inflammation was attenuated by prolonged intraluminal treatment with RTX or treatment with intrathecal BDNF neutralizing antibody. Conclusion Acute colonic inflammation increases bladder activity without affecting bladder morphology. Primary afferent-mediated BDNF up-regulation in the sensory neurons regulates, at least in part, the bladder activity during colonic inflammation

Ion implantation in nanodiamonds: Size effect and energy dependence

Nanoparticles are ubiquitous in nature and are increasingly important for technology. They are subject to bombardment by ionizing radiation in a diverse range of environments. In particular, nanodiamonds represent a variety of nanoparticles of significant fundamental and applied interest. Here we present a combined experimental and computational study of the behaviour of nanodiamonds under irradiation by xenon ions. Unexpectedly, we observed a pronounced size effect on the radiation resistance of the nanodiamonds: particles larger than 8 nm behave similarly to macroscopic diamond (i.e. characterized by high radiation resistance) whereas smaller particles can be completely destroyed by a single impact from an ion in a defined energy range. This latter observation is explained by extreme heating of the nanodiamonds by the penetrating ion. The obtained results are not limited to nanodiamonds, making them of interest for several fields, putting constraints on processes for the controlled modification of nanodiamonds, on the survival of dust in astrophysical environments, and on the behaviour of actinides released from nuclear waste into the environment

Mast Cell-Derived Histamine Mediates Cystitis Pain

Background: Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC. Methods and Findings: Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology. Conclusions: These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, an

Integrative genetic map of repetitive DNA in the sole Solea senegalensis genome shows a Rex transposon located in a proto-sex chromosome

Repetitive sequences play an essential role in the structural and functional evolution of the genome, particularly in the sexual chromosomes. The Senegalese sole (Solea senegalensis) is a valuable flatfish in aquaculture albeit few studies have addressed the mapping and characterization of repetitive DNA families. Here we analyzed the Simple Sequence Repeats (SSRs) and Transposable elements (TEs) content from fifty-seven BAC clones (spanning 7.9 Mb) of this species, located in chromosomes by multiple fluorescence in situ hybridization (m-BAC-FISH) technique. The SSR analysis revealed an average density of 675.1 loci per Mb and a high abundance (59.69%) of dinucleotide coverage was observed, being 'AC' the most abundant. An SSR-FISH analysis using eleven probes was also carried out and seven of the 11 probes yielded positive signals. 'AC' probes were present as large clusters in almost all chromosomes, supporting the bioinformatic analysis. Regarding TEs, DNA transposons (Class II) were the most abundant. In Class I, LINE elements were the most abundant and the hAT family was the most represented in Class II. Rex/Babar subfamily, observed in two BAC clones mapping to chromosome pair 1, showed the longest match. This chromosome pair has been recently reported as a putative sexual proto-chromosome in this species, highlighting the possible role of the Rex element in the evolution of this chromosome. In the Rex1 phylogenetic tree, the Senegalese sole Rex1 retrotransposon could be associated with one of the four major ancient lineages in fish genomes, in which it is included O. latipes

Metformin strongly affects transcriptome of peripheral blood cells in healthy individuals

Funding Information: The study was supported by the European Regional Development Fund under the project ?Investigation of interplay between multiple determinants influencing response to metformin: search for reliable predictors for efficacy of type 2 diabetes therapy? (Project No.: 1.1.1.1/16/A/091, https://ec.europa.eu/regional_policy/en/funding/ erdf/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank all the volunteers for their participation and acknowledge the Genome Database of the Latvian Population for providing biological material and data. Publisher Copyright: © 2019 Ustinova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Metformin is a commonly used antihyperglycaemic agent for the treatment of type 2 diabetes mellitus. Nevertheless, the exact mechanisms of action, underlying the various therapeutic effects of metformin, remain elusive. The goal of this study was to evaluate the alterations in longitudinal whole-blood transcriptome profiles of healthy individuals after a one-week metformin intervention in order to identify the novel molecular targets and further prompt the discovery of predictive biomarkers of metformin response. Next generation sequencing-based transcriptome analysis revealed metformin-induced differential expression of genes involved in intestinal immune network for IgA production and cytokine-cytokine receptor interaction pathways. Significantly elevated faecal sIgA levels during administration of metformin, and its correlation with the expression of genes associated with immune response (CXCR4, HLA-DQA1, MAP3K14, TNFRSF21, CCL4, ACVR1B, PF4, EPOR, CXCL8) supports a novel hypothesis of strong association between metformin and intestinal immune system, and for the first time provide evidence for altered RNA expression as a contributing mechanism of metformin’s action. In addition to universal effects, 4 clusters of functionally related genes with a subject-specific differential expression were distinguished, including genes relevant to insulin production (HNF1B, HNF1A, HNF4A, GCK, INS, NEUROD1, PAX4, PDX1, ABCC8, KCNJ11) and cholesterol homeostasis (APOB, LDLR, PCSK9). This inter-individual variation of the metformin effect on the transcriptional regulation goes in line with well-known variability of the therapeutic response to the drug.publishersversionPeer reviewe

Biofeedback for training balance and mobility tasks in older populations: a systematic review

<p>Abstract</p> <p>Context</p> <p>An effective application of biofeedback for interventions in older adults with balance and mobility disorders may be compromised due to co-morbidity.</p> <p>Objective</p> <p>To evaluate the feasibility and the effectiveness of biofeedback-based training of balance and/or mobility in older adults.</p> <p>Data Sources</p> <p>PubMed (1950-2009), EMBASE (1988-2009), Web of Science (1945-2009), the Cochrane Controlled Trials Register (1960-2009), CINAHL (1982-2009) and PsycINFO (1840-2009). The search strategy was composed of terms referring to biofeedback, balance or mobility, and older adults. Additional studies were identified by scanning reference lists.</p> <p>Study Selection</p> <p>For evaluating effectiveness, 2 reviewers independently screened papers and included controlled studies in older adults (i.e. mean age equal to or greater than 60 years) if they applied biofeedback during repeated practice sessions, and if they used at least one objective outcome measure of a balance or mobility task.</p> <p>Data Extraction</p> <p>Rating of study quality, with use of the Physiotherapy Evidence Database rating scale (PEDro scale), was performed independently by the 2 reviewers. Indications for (non)effectiveness were identified if 2 or more similar studies reported a (non)significant effect for the same type of outcome. Effect sizes were calculated.</p> <p>Results and Conclusions</p> <p>Although most available studies did not systematically evaluate feasibility aspects, reports of high participation rates, low drop-out rates, absence of adverse events and positive training experiences suggest that biofeedback methods can be applied in older adults. Effectiveness was evaluated based on 21 studies, mostly of moderate quality. An indication for effectiveness of visual feedback-based training of balance in (frail) older adults was identified for postural sway, weight-shifting and reaction time in standing, and for the Berg Balance Scale. Indications for added effectiveness of applying biofeedback during training of balance, gait, or sit-to-stand transfers in older patients post-stroke were identified for training-specific aspects. The same applies for auditory feedback-based training of gait in older patients with lower-limb surgery.</p> <p>Implications</p> <p>Further appropriate studies are needed in different populations of older adults to be able to make definitive statements regarding the (long-term) added effectiveness, particularly on measures of functioning.</p

Comparing unilateral and bilateral upper limb training: The ULTRA-stroke program design

<p>Abstract</p> <p>Background</p> <p>About 80% of all stroke survivors have an upper limb paresis immediately after stroke, only about a third of whom (30 to 40%) regain some dexterity within six months following conventional treatment programs. Of late, however, two recently developed interventions - constraint-induced movement therapy (CIMT) and bilateral arm training with rhythmic auditory cueing (BATRAC) - have shown promising results in the treatment of upper limb paresis in chronic stroke patients. The ULTRA-stroke (acronym for Upper Limb TRaining After stroke) program was conceived to assess the effectiveness of these interventions in subacute stroke patients and to examine how the observed changes in sensori-motor functioning relate to changes in stroke recovery mechanisms associated with peripheral stiffness, interlimb interactions, and cortical inter- and intrahemispheric networks. The present paper describes the design of this single-blinded randomized clinical trial (RCT), which has recently started and will take several years to complete.</p> <p>Methods/Design</p> <p>Sixty patients with a first ever stroke will be recruited. Patients will be stratified in terms of their remaining motor ability at the distal part of the arm (i.e., wrist and finger movements) and randomized over three intervention groups receiving modified CIMT, modified BATRAC, or an equally intensive (i.e., dose-matched) conventional treatment program for 6 weeks. Primary outcome variable is the score on the Action Research Arm test (ARAT), which will be assessed before, directly after, and 6 weeks after the intervention. During those test sessions all patients will also undergo measurements aimed at investigating the associated recovery mechanisms using haptic robots and magneto-encephalography (MEG).</p> <p>Discussion</p> <p>ULTRA-stroke is a 3-year translational research program which aims (1) to assess the relative effectiveness of the three interventions, on a group level but also as a function of patient characteristics, and (2) to delineate the functional and neurophysiological changes that are induced by those interventions.</p> <p>The outcome on the ARAT together with information about changes in the associated mechanisms will provide a better understanding of how specific therapies influence neurobiological changes, and which post-stroke conditions lend themselves to specific treatments.</p> <p>Trial Registration</p> <p>The ULTRA-stroke program is registered at the Netherlands Trial Register (NTR, <url>http://www.trialregister.nl</url>, number NTR1665).</p

Screen Position Preference Offers a New Direction for Action Observation Research: Preliminary Findings Using TMS

Action observation has been suggested to be an effective adjunct to physical practice in motor (re)learning settings. However, optimal viewing conditions for interventions are yet to be established. Single-pulse transcranial magnetic stimulation (TMS) was used to investigate the effect of two different screen positions and participants’ screen position viewing preference on the amplitude of motor evoked potentials (MEPs) during observation of a ball pinch action. Twenty-four participants observed four blocked conditions that contained either a dynamic index finger-thumb ball pinch or a static hand holding a ball in a similar position on a horizontally or vertically positioned screen. TMS was delivered to the hand representation of the left primary motor cortex and MEPs were recorded from the first dorsal interosseous muscle of the right hand. Initial analysis of the normalized MEP amplitude data showed no significant differences between conditions. In a follow-up procedure, participants engaged in individual semi-structured interviews and completed a questionnaire designed to assess viewing affect and screen position viewing preference. The MEP data were subsequently split by screen position preference and re-analyzed using a 2 × 2 repeated measures ANOVA. Main effects indicated that participants who preferred the horizontal screen position (n = 16) demonstrated significantly greater MEP amplitudes during observation of the ball-pinch action compared to the static hand condition irrespective of screen position, and during the horizontal compared to the vertical screen position irrespective of video type. These results suggest that ensuring anatomical and perceptual congruency with the physical task, alongside consideration of participants’ screen position viewing preferences, may be an important part of optimizing action observation interventions