Search results for: phenotype switch of smooth muscle cells
4225 Modeling of Bioelectric Activity of Nerve Cells Using Bond Graph Method
Authors: M. Ghasemi, F. Eskandari, B. Hamzehei, A. R. Arshi
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Bioelectric activity of nervous cells might be changed causing by various factors. This alteration can lead to unforeseen circumstances in other organs of the body. Therefore, the purpose of this study was to model a single neuron and its behavior under an initial stimulation. This study was developed based on cable theory by means of the Bond Graph method. The numerical values of the parameters were derived from empirical studies of cellular electrophysiology experiments. Initial excitation was applied through square current functions, and the resulted action potential was estimated along the neuron. The results revealed that the model was developed in this research adapted with the results of experimental studies and demonstrated the electrical behavior of nervous cells properly.Keywords: bond graph, stimulation, nervous cells, modeling
Procedia PDF Downloads 4284224 Relationship between Body Composition and Balance in Young Adults
Authors: Ferruh Taspinar, Gulce K. Seyyar, Gamze Kurt, Eda O. Okur, Emrah Afsar, Ismail Saracoglu, Betul Taspinar
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Overweight and obesity has been associated with postural balance. The aim of this study was to investigate the relationship between body composition and balance. One hundred and thirty two young adults (58 male, 74 female) were included in the study. Mean age of participants were found as 21.21±1.51 years. Body composition (body mass index, total body fat ratio, total body muscle ratio) and balance (right anterior, right postero-medial, right postero-lateral, left anterior, left postero-medial, left postero-lateral) were evaluated by Tanita BC-418 and Y balance test, respectively. Pearson correlation analysis was used to evaluate the correlation between the parameters. Significance level in statistical analysis was accepted as 0.05. According to results, no correlation was found between body mass index and balance parameters. There was negative correlation between total body fat ratio and balance parameters (r=0.419-0.509, p˂0.05). On the other hand, positive correlation was found between total body muscle ratio and balance parameters (r=0.390-0.494, p˂0.05). This study demonstrated that body fat and muscle ratio affects the balance. Body composition should be considered in rehabilitation programs including postural balance training.Keywords: balance, body composition, body mass, young adults
Procedia PDF Downloads 3744223 Evaluation of a Method for the Virtual Design of a Software-based Approach for Electronic Fuse Protection in Automotive Applications
Authors: Dominic Huschke, Rudolf Keil
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New driving functionalities like highly automated driving have a major impact on the electrics/electronics architecture of future vehicles and inevitably lead to higher safety requirements. Partly due to these increased requirements, the vehicle industry is increasingly looking at semiconductor switches as an alternative to conventional melting fuses. The protective functionality of semiconductor switches can be implemented in hardware as well as in software. A current approach discussed in science and industry is the implementation of a model of the protected low voltage power cable on a microcontroller to calculate its temperature. Here, the information regarding the current is provided by the continuous current measurement of the semiconductor switch. The signal to open the semiconductor switch is provided by the microcontroller when a previously defined limit for the temperature of the low voltage power cable is exceeded. A setup for the testing of the described principle for electronic fuse protection of a low voltage power cable is built and successfullyvalidated with experiments afterwards. Here, the evaluation criterion is the deviation of the measured temperature of the low voltage power cable from the specified limit temperature when the semiconductor switch is opened. The analysis is carried out with an assumed ambient temperature as well as with a measured ambient temperature. Subsequently, the experimentally performed investigations are simulated in a virtual environment. The explicit focus is on the simulation of the behavior of the microcontroller with an implemented model of a low voltage power cable in a real-time environment. Subsequently, the generated results are compared with those of the experiments. Based on this, the completely virtual design of the described approach is assumed to be valid.Keywords: automotive wire harness, electronic fuse protection, low voltage power cable, semiconductor-based fuses, software-based validation
Procedia PDF Downloads 1054222 Evaluation of Bone and Body Mineral Profile in Association with Protein Content, Fat, Fat-Free, Skeletal Muscle Tissues According to Obesity Classification among Adult Men
Authors: Orkide Donma, Mustafa M. Donma
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Obesity is associated with increased fat mass as well as fat percentage. Minerals are the elements, which are of vital importance. In this study, the relationships between body as well as bone mineral profile and the percentage as well as mass values of fat, fat-free portion, protein, skeletal muscle were evaluated in adult men with normal body mass index (N-BMI), and those classified according to different stages of obesity. A total of 103 adult men classified into five groups participated in this study. Ages were within 19-79 years range. Groups were N-BMI (Group 1), overweight (OW) (Group 2), first level of obesity (FLO) (Group 3), second level of obesity (SLO) (Group 4) and third level of obesity (TLO) (Group 5). Anthropometric measurements were performed. BMI values were calculated. Obesity degree, total body fat mass, fat percentage, basal metabolic rate (BMR), visceral adiposity, body mineral mass, body mineral percentage, bone mineral mass, bone mineral percentage, fat-free mass, fat-free percentage, protein mass, protein percentage, skeletal muscle mass and skeletal muscle percentage were determined by TANITA body composition monitor using bioelectrical impedance analysis technology. Statistical package (SPSS) for Windows Version 16.0 was used for statistical evaluations. The values below 0.05 were accepted as statistically significant. All the groups were matched based upon age (p > 0.05). BMI values were calculated as 22.6 ± 1.7 kg/m2, 27.1 ± 1.4 kg/m2, 32.0 ± 1.2 kg/m2, 37.2 ± 1.8 kg/m2, and 47.1 ± 6.1 kg/m2 for groups 1, 2, 3, 4, and 5, respectively. Visceral adiposity and BMR values were also within an increasing trend. Percentage values of mineral, protein, fat-free portion and skeletal muscle masses were decreasing going from normal to TLO. Upon evaluation of the percentages of protein, fat-free portion and skeletal muscle, statistically significant differences were noted between NW and OW as well as OW and FLO (p < 0.05). However, such differences were not observed for body and bone mineral percentages. Correlation existed between visceral adiposity and BMI was stronger than that detected between visceral adiposity and obesity degree. Correlation between visceral adiposity and BMR was significant at the 0.05 level. Visceral adiposity was not correlated with body mineral mass but correlated with bone mineral mass whereas significant negative correlations were observed with percentages of these parameters (p < 0.001). BMR was not correlated with body mineral percentage whereas a negative correlation was found between BMR and bone mineral percentage (p < 0.01). It is interesting to note that mineral percentages of both body as well as bone are highly affected by the visceral adiposity. Bone mineral percentage was also associated with BMR. From these findings, it is plausible to state that minerals are highly associated with the critical stages of obesity as prominent parameters.Keywords: bone, men, minerals, obesity
Procedia PDF Downloads 1174221 Real-time PCR to Determine Resistance Genes in ESBLEscherichia Coli Strains Stored in the Epidemic Diseases Laboratory of the National Institute of Hygiene (INH)
Authors: A. Qasmaoui, F. Ohmani, Z. Zaine, I. El Akrad, J. Hamamouchi, K. Halout, B. Belkadi, R. Charof
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The evolution of antibiotic resistance is a crucial aspect of the problem related to the intensive use of these substances in medicine for humans and animals. The production of ESBL extended spectrum β-lactamase enzymes is the main mechanism of resistance to β-lactam antibiotics in Escherichia coli. The objective of our work is to determine the resistance genes in E. coli strains.ESBL coli stored at the epidemic diseases laboratory of the National Institute of Hygiene. The strains were identified according to the classic bacteriological criteria. An antibiogram was performed on the strains isolated by the Mueller Hinton agar disc diffusion method. The production of ESBL in the strains was detected by the synergy assay technique and confirmed for the presence of the blaCTX-M1, blaCTX-M2, blaTEM, blaSHV, blaOXA-48 genes by gene amplification . Of the 27 observed strains of E.coli, 17 isolated strains present the phenotype of extended-spectrum Beta-lactamase with a percentage of 63%.. All 18 cefotaxime-resistant strains were analyzed for an ESBL phenotype. All strains were positive in the double-disc synergy assay. The fight against the emergence and spread of these multi-resistant antibiotic-resistant strains requires the reasonable use of antibiotics.Keywords: E coli, BLSE, CTX, TEM, SHV, OXA, résistance aux antibiotique
Procedia PDF Downloads 184220 Wearable Monitoring and Treatment System for Parkinson’s Disease
Authors: Bulcha Belay Etana, Benny Malengier, Janarthanan Krishnamoorthy, Timothy Kwa, Lieva Vanlangenhove
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Electromyography measures the electrical activity of muscles using surface electrodes or needle electrodes to monitor various disease conditions. Recent developments in the signal acquisition of electromyograms using textile electrodes facilitate wearable devices, enabling patients to monitor and control their health status outside of healthcare facilities. Here, we have developed and tested wearable textile electrodes to acquire electromyography signals from patients suffering from Parkinson’s disease and incorporated a feedback-control system to relieve muscle cramping through thermal stimulus. In brief, the textile electrodes made of stainless steel was knitted into a textile fabric as a sleeve, and their electrical characteristic, such as signal-to-noise ratio, was compared with traditional electrodes. To relieve muscle cramping, a heating element made of stainless-steel conductive yarn sewn onto a cotton fabric, coupled with a vibration system, was developed. The system integrated a microcontroller and a Myoware muscle sensor to activate the heating element as well as the vibration motor when cramping occurred. At the same time, the element gets deactivated when the muscle cramping subsides. An optimum therapeutic temperature of 35.5°C is regulated and maintained continuously by a heating device. The textile electrode exhibited a signal-to-noise ratio of 6.38dB, comparable to that of the traditional electrode’s value of 7.05 dB. For a given 9 V power supply, the rise time for the developed heating element was about 6 minutes to reach an optimum temperature.Keywords: smart textile system, wearable electronic textile, electromyography, heating textile, vibration therapy, Parkinson’s disease
Procedia PDF Downloads 774219 The Role of Immunologic Diamonds in Dealing with Mycobacterium Tuberculosis; Responses of Immune Cells in Affliction to the Respiratory Tuberculosis
Authors: Seyyed Mohammad Amin Mousavi Sagharchi, Elham Javanroudi
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Introduction: Tuberculosis (TB) is a known disease with hidden features caused by Mycobacterium tuberculosis (MTB). This disease, which is one of the 10 deadliest in the world, has caused millions of deaths in recent decades. Furthermore, TB is responsible for infecting about 30% population of world. Like any infection, TB can activate the immune system by locating and colonization in the human body, especially in the alveoli. TB is granulomatosis, so MTB can absorb the host’s immune cells and other cells to form granuloma. Method: Different databases (e.g., PubMed) were recruited to prepare this paper and fulfill our goals to search and find effective papers and investigations. Results: Immune response to MTB is related to T cell killers and contains CD1, CD4, and CD8 T lymphocytes. CD1 lymphocytes can recognize glycolipids, which highly exist in the Mycobacterial fatty cell wall. CD4 lymphocytes and macrophages form granuloma, and it is the main line of immune response to Mycobacteria. On the other hand, CD8 cells have cytolytic function for directly killing MTB by secretion of granulysin. Other functions and secretion to the deal are interleukin-12 (IL-12) by induction of expression interferon-γ (INF-γ) for macrophages activation and creating a granuloma, and tumor necrosis factor (TNF) by promoting macrophage phagolysosomal fusion. Conclusion: Immune cells in battle with MTB are macrophages, dendritic cells (DCs), neutrophils, and natural killer (NK) cells. These immune cells can recognize the Mycobacterium by various receptors, including Toll-like receptors (TLRs), Nod-like receptors (NLRs), and C-type lectin receptors (CLRs) located in the cell surface. In human alveoli exist about 50 dendritic macrophages, which have close communication with other immune cells in the circulating system and epithelial cells to deal with Mycobacteria. Against immune cells, MTB handles some factors (e.g., cordfactor, O-Ag, lipoarabinomannan, sulfatides, and adenylate cyclase) and practical functions (e.g., inhibition of macrophages).Keywords: mycobacterium tuberculosis, immune responses, immunological mechanisms, respiratory tuberculosis
Procedia PDF Downloads 1094218 A Prospective Study on the Efficacy of Mesenchymal Stem Cells in Intervertebral Disc Regeneration
Authors: Prabhu Thangaraju, Manoj Deepak, A. Sivakumar
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Removal of inter vertebral disc along with spinal fusion has many disadvantages such as causing stress fractures. If it is possible regenerate the spine it would be possible avoid the complications of the surgery and achieve better results. Our study involves the use of mesenchymal stem cells in regenerating the discs. Our study involved 10 patients who presented with degenerative disc disease between 2008-2011 in our hospital. After adequate pre-operative check prepared mesenchymal stem cells were injected into the disc spaces. These patients were subjected to conservative therapy for a minimum of six weeks before they were accepted into the study. They were followed up regularly for a minimum of 2years with serial radiographs and MRI. 8 out of the 10 patients had completed reduction in the pain. The T2 weighted MRI images in 9 out of the 10 patients showed a bright signal compared the previous Images which indicated that there was improvement in the hydration levels. From the case study of 10 patients who were subjected to mesenchymal cell therapy in our hospital, we can conclude that the use of mesenchymal cells in treatment of intervertebral disc degeneration in a safe and effective option.Keywords: mesenchymal stem cells, intervertebral disc, the spine, disc degeneration
Procedia PDF Downloads 3714217 Effect of Diet Inulin Prebiotic on Growth, Reproductive Performance, Carcass Composition and Resistance to Environmental Stresses in Zebra Danio (Danio rerio)
Authors: Ehsan Ahmadifar
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In this research, the effects of different levels (control group (T0), (T1)1, (T2)2 and (T3)3 gr Inulin per Kg diet) of prebiotic Inulin as nutritional supplement on Danio rerio were investigated for 4 month. Since the beginning of feeding larvae until adult (average weight: 67.1 g, length: 4.5 cm) were fed with experimental diets. The survival rate of fish had no significant effect on rate survival (P > 0.05). The highest food conversion ratio (FCR) was in control group and the lowest was observed in T3. Treatment of T3 significantly caused the best feed conversion ratio in Zebra fish (P < 0.05). By increasing the inulin diet during the experiment, specific growth rate increased. The highest and the lowest body weight gain and condition factor were observed in T3 and control, respectively (P < 0.05). Adding 3 gr inulin in Zebra fish diet can improve the performance of the growth indices and final biomass, also this prebiotic can be considered as a suitable supplement for Cyprinidae diet. In the first sampling stage for feeding fish, fat and muscle protein was significantly higher than the second sampling stage (P < 0.05). Given that the second stage fish were full sexual maturity, the amount of fat in muscle decreased (P < 0.05). Moisture and ash levels were significantly (P < 0.05) higher in the second stage sampling than the first stage. Overall, different stage of living affected on muscle chemical composition muscle. Reproductive performance in treatment T2 and T3 were significantly higher than other treatments (P < 0.05). According to the results, the prebiotic inulin does not have a significant impact on the sex ratio in zebrafish (P > 0.05). Based on histology of the gonads, the use of dietary inulin accelerates the process of gonad development in zebrafish.Keywords: inulin, zebrafish, reproduction, histology
Procedia PDF Downloads 3054216 Biodegradation of Chlorpyrifos in Real Wastewater by Acromobacter xylosoxidans SRK5 Immobilized in Calcium Alginate
Authors: Saira Khalid, Imran Hashmi
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Agrochemical industries produce huge amount of wastewater containing pesticides and other harmful residues. Environmental regulations make it compulsory to bring pesticides to a minimum level before releasing wastewater from industrial units.The present study was designed with the objective to investigate biodegradation of CP in real wastewater using bacterial cells immobilized in calcium alginate. Bacterial strain identified as Acromobacter xylosoxidans SRK5 (KT013092) using 16S rRNA nucleotide sequence analysis was used. SRK5 was immobilized in calcium alginate to make calcium alginate microspheres (CAMs). Real wastewater from industry having 50 mg L⁻¹ of CP was inoculated with free cells or CAMs and incubated for 96 h at 37˚C. CP removal efficiency with CAMs was 98% after 72 h of incubation, and no lag phase was observed. With free cells, 12h of lag phase was observed. After 96 h of incubation 87% of CP removal was observed when inoculated with free cells. No adsorption was observed on vacant CAMs. Phytotoxicity assay demonstrated considerable loss in toxicity. Almost complete COD removal was achieved at 96 h with CAMs. Study suggests the use of immobilized cells of SRK5 for bioaugmentation of industrial wastewater for CP degradation instead of free cells.Keywords: biodegradation, chlorpyrifos, immobilization, wastewater
Procedia PDF Downloads 1784215 Regression for Doubly Inflated Multivariate Poisson Distributions
Authors: Ishapathik Das, Sumen Sen, N. Rao Chaganty, Pooja Sengupta
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Dependent multivariate count data occur in several research studies. These data can be modeled by a multivariate Poisson or Negative binomial distribution constructed using copulas. However, when some of the counts are inflated, that is, the number of observations in some cells are much larger than other cells, then the copula based multivariate Poisson (or Negative binomial) distribution may not fit well and it is not an appropriate statistical model for the data. There is a need to modify or adjust the multivariate distribution to account for the inflated frequencies. In this article, we consider the situation where the frequencies of two cells are higher compared to the other cells, and develop a doubly inflated multivariate Poisson distribution function using multivariate Gaussian copula. We also discuss procedures for regression on covariates for the doubly inflated multivariate count data. For illustrating the proposed methodologies, we present a real data containing bivariate count observations with inflations in two cells. Several models and linear predictors with log link functions are considered, and we discuss maximum likelihood estimation to estimate unknown parameters of the models.Keywords: copula, Gaussian copula, multivariate distributions, inflated distributios
Procedia PDF Downloads 1564214 Potential Impacts of Maternal Nutrition and Selection for Residual Feed Intake on Metabolism and Fertility Parameters in Angus Bulls
Authors: Aidin Foroutan, David S. Wishart, Leluo L. Guan, Carolyn Fitzsimmons
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Maximizing efficiency and growth potential of beef cattle requires not only genetic selection (i.e. residual feed intake (RFI)) but also adequate nutrition throughout all stages of growth and development. Nutrient restriction during gestation has been shown to negatively affect post-natal growth and development as well as fertility of the offspring. This, when combined with RFI may affect progeny traits. This study aims to investigate the impact of selection for divergent genetic potential for RFI and maternal nutrition during early- to mid-gestation, on bull calf traits such as fertility and muscle development using multiple ‘omics’ approaches. Comparisons were made between High-diet vs. Low-diet and between High-RFI vs. Low-RFI animals. An epigenetics experiment on semen samples identified 891 biomarkers associated with growth and development. A gene expression study on Longissimus thoracis muscle, semimembranosus muscle, liver, and testis identified 4 genes associated with muscle development and immunity of which Myocyte enhancer factor 2A [MEF2A; induces myogenesis and control muscle differentiation] was the only differentially expressed gene identified in all four tissues. An initial metabolomics experiment on serum samples using nuclear magnetic resonance (NMR) identified 4 metabolite biomarkers related to energy and protein metabolism. Once all the biomarkers are identified, bioinformatics approaches will be used to create a database covering all the ‘omics’ data collected from this project. This database will be broadened by adding other information obtained from relevant literature reviews. Association analyses with these data sets will be performed to reveal key biological pathways affected by RFI and maternal nutrition. Through these association studies between the genome and metabolome, it is expected that candidate biomarker genes and metabolites for feed efficiency, fertility, and/or muscle development are identified. If these gene/metabolite biomarkers are validated in a larger animal population, they could potentially be used in breeding programs to select superior animals. It is also expected that this work will lead to the development of an online tool that could be used to predict future traits of interest in an animal given its measurable ‘omics’ traits.Keywords: biomarker, maternal nutrition, omics, residual feed intake
Procedia PDF Downloads 1914213 Indoleamine 2,3 Dioxygenase and Regulatory T Cells in Acute Myeloid Leukemia
Authors: Iman M. Mansour, Rania A. Zayed, Fadwa S. Abdel-Azim, Lamyaa H. Abdel-Latif
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Background and Objectives: The microenvironment of acute myeloid leukemia (AML) is suppressive for immune cells. Regulatory T cells (Tregs) have been recognized to play a role in helping leukemic cells to evade immunesurveillance. The mesenchymal stem cells (MSCs) are essential contributors in immunomodulation of the microenvironment as they can promote differentiation of Tregs via the indoleamine 2,3-dioxygenase (IDO) pathway. The aim of the present work was to evaluate the expression of IDO in bone marrow derived MSCs and to study its correlation to percentage of Tregs. Methods: 37 adult bone marrow samples were cultured in appropriate culture medium to isolate MSCs. Successful harvest of MSCs was determined by plastic adherence, morphology and positive expression of CD271 and CD105; negative expression of CD34 and CD45 using flowcytometry. MSCs were examined for IDO expression by immunocytochemistry using anti-IDO monoclonal antibody. CD4+ CD25+ cells (Tregs) were measured in bone marrow samples by flowcytometry. Results: MSCs were successfully isolated from 20 of the 37 bone marrow samples cultured. MSCs showed higher expression of IDO and Tregs percentage was higher in AML patients compared to control subjects (p=0.002 and p<0.001 respectively). A positive correlation was found between IDO expression and Tregs percentage (p value=0.012, r=0.5). Conclusion: In this study, we revealed an association between high IDO expression in MSCs and elevated levels of Tregs which has an important role in the pathogenesis of AML, providing immunosuppressive microenvironment.Keywords: acute myeloid leukemia, indoleamine 2, 3-dioxygenase, mesenchymal stem cells, T regulatory cells
Procedia PDF Downloads 3594212 Bioarm, a Prothesis without Surgery
Authors: J. Sagouis, A. Chamel, E. Carre, C. Casasreales, G. Rudnik, M. Cerdan
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Robotics provides answers to amputees. The most expensive solutions surgically connect the prosthesis to nerve endings. There are also several types of non-invasive technologies that recover nerve messages passing through the muscles. After analyzing these messages, myoelectric prostheses perform the desired movement. The main goal is to avoid all surgeries, which can be heavy and offer cheaper alternatives. For an amputee, we use valid muscles to recover the electrical signal involved in a muscle movement. EMG sensors placed on the muscle allows us to measure a potential difference, which our program transforms into control for a robotic arm with two degrees of freedom. We have shown the feasibility of non-invasive prostheses with two degrees of freedom. Signal analysis and an increase in degrees of freedom is still being improved.Keywords: prosthesis, electromyography (EMG), robotic arm, nerve message
Procedia PDF Downloads 2494211 BSYJ Promoting Homing and Differentiation of Mesenchymal Stem Cells at the Retina of Age-Related Macular Degeneration Model Mice Induced by Sodium Iodate
Authors: Lina Liang, Kai Xu, Jing Zhang
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Purpose: Age-related macular degeneration (AMD) is a major leading cause of visual impairment and blindness with no cure currently established. Cell replacement is discussed as a potential therapy for AMD. Besides intravitreal injection and subretinal injection, intravenous administration has been explored as an alternative route. This study is to observe the effect of BSYJ, a traditional Chinese medicine on the homing and differentiation of mesenchymal stem cells transplanted via tail vein injection in an age-related macular degeneration mouse model. Methods: Four-week-old C57BL/6J mice were injected with 40 mg/kg NaIO₃ to induce age-related macular degeneration model. At the second day after NaIO₃ injection, 1×10⁷ GFP labeled bone marrow-derived mesenchymal stem cells (GFP-MSCs) were transplanted via tali vein injection into the experimental mice. Then the mice were randomly divided into two groups, gavaged with either BSYJ solution (BSYJ group, n=12) or distilled water (DW group, n=12). 12 age-matched healthy C57BL/6J mice were fed regularly as normal control. At day 7, day 14, and day 28 after treatment, retina flat mounting was used to detect the homing of mesenchymal stem cells at the retina. Double-labeling immunofluorescence was used to determine the differentiation of mesenchymal stem cells. Results: At 7, 14, 28 days after treatment, the numbers of GFP-MSCs detected by retina flatmount were 10.2 ± 2.5, 14.5 ± 3.4 and 18.7 ± 5.8, respectively in the distilled water group, while 15.7 ± 3.8, 32.3 ± 3.5 and 77.3 ± 6.4 in BSYJ group, the differences between the two groups were significant (p < 0.05). At 28 days after treatment, it was shown by double staining immunofluorescence that there were more GFP positive cells in the retina of BSYJ group than that of the DW group, but none of the cells expressed RPE specific genes such as RPE65 and CRALBP, or photoreceptor genes such as recoverin and rhodopsin either in BSYJ group or DW group. However, GFAP positive cells were found among the cells labeled with GFP, and the double labeling cells were much more in the BSYJ group than the distilled water group. Conclusion: BSYJ could promote homing of mesenchymal stem cells at the retina of age-related macular degeneration model mice induced by NaIO₃, and the differentiation towards to glial cells. Acknowledgement: National Natural Foundation of China (No: 81473736, 81674033,81973912).Keywords: BSYJ, differentiation, homing, mesenchymal stem cells
Procedia PDF Downloads 1444210 Synergistic Anti-Proliferation Effect of PLK-1 Inhibitor and Livistona Chinensis Fruit Extracts on Lung Adenocarcinoma A549 Cells
Authors: Min-Chien Su, Tzu-Hsuan Hsu, Guan-Xuan Wu, Shyh-Ming Kuo
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Lung cancer is one of the clinically challenging malignant diseases worldwide. For efficient therapeutics in cancer, combination therapy has developed to acquire a better outcome. PLK-1 was one of the major factors affecting cell mitosis in cancer cells, its inhibitor Bi6727 was proven effective in treating several different cancers namely oral cancer, colon cancer and lung cancer. Despite its low toxicity toward normal cells compared to traditional chemotherapy, it is still yet to be evaluated in detail. Livistona Chinensis (LC) is a Chinese herb that used as a traditional prescription to treat lung cancer. Due to the uncertainty of the efficacy of LC, we utilized a water extraction method to extract the Livistona Chinensis and then lyophilized into powder for further study. In this study we investigated the antiproliferation activities of Bi6727 and LC extracts (LCE) on A549 non-small lung cancer cells. The IC50 of Bi6727 and LCE on A549 are 60 nM and 0.8 mg/mL, respectively. The fluorescent staining images shown nucleolus damage in cells treated with Bi6727 and mitochondrial damage after treated with LCE. A549 cells treated with Bi6727 and LCE showed increased expression of Bax, Caspase-3 and Caspase-9 proteins from Western blot assay. LCE also inhibited A549 cells growth keeping cells at G2-M phase from cell cycle assay. Apoptosis assay results showed that LCE induced late apoptosis of A549 cells. JC-1 assay showed that the mitochondria damaged at the LCE concentration of 0.4 mg/mL. In our preliminary anti-proliferation test of combined LCE and Bi-6727 on A549 cells, we found a dramatically decrease in proliferation after treated with LCE first for 24-h and then Bi-6727 for extra 24-h. This was an important finding regarding synergistic anti-proliferation effect of these drugs, However, the usage, the application sequence of LCE and Bi-6727 on A549 cells and their related mechanisms still need to be evaluated. In summary, the drugs exerted anti-proliferation effect on A549 cells independently. We hopefully combine the usage of these two drugs will bring a different and potential outcome in treating lung cancer.Keywords: anti-proliferation, A549, Livistona Chinensis fruit extracts, PLK-1 inhibitor
Procedia PDF Downloads 1414209 Intensive Crosstalk between Autophagy and Intracellular Signaling Regulates Osteosarcoma Cell Survival Response under Cisplatin Stress
Authors: Jyothi Nagraj, Sudeshna Mukherjee, Rajdeep Chowdhury
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Autophagy has recently been linked with cancer cell survival post drug insult contributing to acquisition of resistance. However, the molecular signaling governing autophagic survival response is poorly explored. In our study, in osteosarcoma (OS) cells cisplatin shock was found to activate both MAPK and autophagy signaling. An activation of JNK and autophagy acted as pro-survival strategy, while ERK1/2 triggered apoptotic signals upon cisplatin stress. An increased sensitivity of the cells to cisplatin was obtained with simultaneous inhibition of both autophagy and JNK pathway. Furthermore, we observed that the autophagic stimulation upon drug stress regulates other developmentally active signaling pathways like the Hippo pathway in OS cells. Cisplatin resistant cells were thereafter developed by repetitive drug exposure followed by clonal selection. Basal levels of autophagy were found to be high in resistant cells to. However, the signaling mechanism leading to autophagic up-regulation and its regulatory effect differed in OS cells upon attaining drug resistance. Our results provide valuable clues to regulatory dynamics of autophagy that can be considered for development of improved therapeutic strategy against resistant type cancers.Keywords: JNK, autophagy, drug resistance, cancer
Procedia PDF Downloads 2904208 Fluorescence Gold Nanoparticles: Sensing Properties and Cytotoxicity Studies in MCF-7 Human Breast Cancer Cells
Authors: Cristina Núñez, Rufina Bastida, Elena Labisbal, Alejandro Macías, María T. Pereira, José M. Vila
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A highly selective quinoline-based fluorescent sensor L was designed in order to functionalize gold nanoparticles (GNPs@L). The cytotoxicity of compound L and GNPs@L on the MCF-7 breast cancer cells was explored and it was observed that L and GNPs@L compounds induced apoptosis in MCF-7 cancer cells. The cellular uptake of the hybrid system GNPs@L was studied using confocal laser scanning microscopy (CLSM).Keywords: cytotoxicity, fluorescent probes, nanoparticles, quinoline
Procedia PDF Downloads 3824207 A Comparative Study for Various Techniques Using WEKA for Red Blood Cells Classification
Authors: Jameela Ali, Hamid A. Jalab, Loay E. George, Abdul Rahim Ahmad, Azizah Suliman, Karim Al-Jashamy
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Red blood cells (RBC) are the most common types of blood cells and are the most intensively studied in cell biology. The lack of RBCs is a condition in which the amount of hemoglobin level is lower than normal and is referred to as “anemia”. Abnormalities in RBCs will affect the exchange of oxygen. This paper presents a comparative study for various techniques for classifyig the red blood cells as normal, or abnormal (anemic) using WEKA. WEKA is an open source consists of different machine learning algorithms for data mining applications. The algorithm tested are Radial Basis Function neural network, Support vector machine, and K-Nearest Neighbors algorithm. Two sets of combined features were utilized for classification of blood cells images. The first set, exclusively consist of geometrical features, was used to identify whether the tested blood cell has a spherical shape or non-spherical cells. While the second set, consist mainly of textural features was used to recognize the types of the spherical cells. We have provided an evaluation based on applying these classification methods to our RBCs image dataset which were obtained from Serdang Hospital-Malaysia, and measuring the accuracy of test results. The best achieved classification rates are 97%, 98%, and 79% for Support vector machines, Radial Basis Function neural network, and K-Nearest Neighbors algorithm respectivelyKeywords: red blood cells, classification, radial basis function neural networks, suport vector machine, k-nearest neighbors algorithm
Procedia PDF Downloads 4804206 Wound Healing Potential and Comparison of Mummy Substance Effect on Adipose and Wharton’s Jelly-Derived Mesenchymal Stem Cells Co-Cultured with Human Fibroblast
Authors: Sepideh Hassanpour Khodaei
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Background/Objectives: The purpose of this study is to evaluate the effect of mummy substances on two issues of proliferation and production of matrix protein synthesis in wound healing. Methods: The methodology used for this aim involves isolating mesenchymal stem cells and human fibroblasts procured at Pastor Institute, Iran. The cells were treated with mummy substances separately and co-cultured between ASCs and WJSCs, and fibroblasts. Proliferation was assessed by Ki67 method in monolayer conditions. Synthesis of components of extracellular matrix (ECM) such as collagen type I, type III, and fibronectin 1 (FN1) was determined by qPCR. Results: The effects of adipocyte stem cells (ASCs), Wharton Jelly Stem Cells (WJSCs), and Mummy material on fibroblast proliferation and migration were evaluated. The present finding underlined the importance of Mummy material, ASCs, and WJSCs in the proliferation and migration of fibroblast cells. Furthermore, the expression of collagen I, III, and FN1 was increased in the presence of the above material and cells. Conclusion: This study presented an effective in vitro method for the healing process. Hence, the prospect of utilizing Mummy material and stem cell-based therapies in wound healing as a therapeutic approach is promising.Keywords: mummy material, wound healing, adipose tissue, Wharton’s jelly
Procedia PDF Downloads 1084205 ADCOR © Muscle Damage Rapid Detection Test Based on Skeletal Troponin I Immunochromatography Reaction
Authors: Muhammad Solikhudin Nafi, Wahyu Afif Mufida, Mita Erna Wati, Fitri Setyani Rokim, M. Al-Rizqi Dharma Fauzi
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High dose activity without any pre-exercise will impact Delayed Onset Muscle Soreness (DOMS). DOMS known as delayed pain post-exercise and induce skeletal injury which will decrease athletes’ performances. From now on, post-exercise muscle damage can be detected by measuring skeletal troponin I (sTnI) concentration in serum using ELISA but this method needs more time and cost. To prevent decreased athletes performances, screening need to be done rapidly. We want to introduce our new prototype to detect DOMS acutely. Rapid detection tests are based on immunological reaction between skeletal troponin I antibodies and sTnI in human serum or whole blood. Chemical methods that are used in the manufacture of diagnostic test is lateral flow immunoassay. The material used is rat monoclonal antibody sTnI, colloidal gold, anti-mouse IgG, nitrocellulose membrane, conjugate pad, sample pad, wick and backing card. The procedure are made conjugate (colloidal gold and mAb sTnI) and insert into the conjugate pad, gives spray sTnI mAb and anti-mouse IgG into nitrocellulose membrane, and assemble RDT. RDT had been evaluated by measuring the sensitivity of positive human serum (n = 30) and negative human serum (n = 30). Overall sensitivity value was 93% and specificity value was 90%. ADCOR as the first rapid detection test qualitatively showed antigen-antibody reaction and showed good overall performances for screening of muscle damage. Furthermore, these finding still need more improvements to get best results.Keywords: DOMS, sTnI, rapid detection test, ELISA
Procedia PDF Downloads 5134204 Assessment of the Impact of the Application of Kinesiology Taping on Joint Position Sense in Knee Joint
Authors: Anna Słupik, Patryk Wąsowski, Anna Mosiołek, Dariusz Białoszewski
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Introduction: Kinesiology Taping is one of the most popular techniques used for treatment and supporting physiological processes in sports medicine and physiotherapy. Often it is used to sensorimotor skills of lower limbs by athletes. The aim of the study was to determine the effect of the application of muscle Kinesiology Taping to feel the position setting in motion the joint active. Material and methods: The study involved 50 healthy people between 18 and 30 years of age, 30 men and 20 women (mean age 23.24 years). The participants were divided into two groups. The study group was qualified for Kinesiology Taping application (muscle application, type Y, for quadriceps femoris muscle), while the remaining people used the application made of plaster (placebo group). Testing was performed prior to applying taping, with the applied application (after 30 minutes), then 24 hours after wearing, and after removing the tape. Each evaluated joint position sense - Error of Active Reproduction of Joint Position. Results: The survey revealed no significant differences in measurement between the study group and the placebo group (p> 0.05). No significant differences in time taking into account all four measurements in the group with the applied CT application, which was supported by pairs (p> 0.05). Also in the placebo group showed no significant differences over time (p> 0.05). There was no significant difference between the errors committed in the direction of flexion and extension. Conclusions: 1. Application muscle Kinesiology Taping had no significant effect on the knee joint proprioception. Its use in order to improve sensorimotor seems therefore unjustified. 2. There are no differences between applications Kinesiology Taping and placebo indicates that the clinical effect of stretch tape is minimal or absent. 3. The results are the basis for the continuation of prospective, randomized trials of numerous and study group.Keywords: joint position sense, kinesiology taping, knee joint, proprioception
Procedia PDF Downloads 4034203 Epigenetic Mechanisms Involved in the Occurrence and Development of Infectious Diseases
Authors: Frank Boris Feutmba Keutchou, Saurelle Fabienne Bieghan Same, Verelle Elsa Fogang Pokam, Charles Ursula Metapi Meikeu, Angel Marilyne Messop Nzomo, Ousman Tamgue
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Infectious diseases are one of the most important causes of morbidity and mortality worldwide. These diseases are caused by micro-pathogenic organisms, such as bacteria, viruses, parasites, and fungi. Heritable changes in gene expression that do not involve changes to the underlying DNA sequence are referred to as epigenetics. Emerging evidence suggests that epigenetic mechanisms are important in the emergence and progression of infectious diseases. Pathogens can manipulate host epigenetic machinery to promote their own replication and evade immune responses. The Human Genome Project has provided new opportunities for developing better tools for the diagnosis and identification of target genes. Several epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA expression, have been shown to influence infectious disease outcomes. Understanding the epigenetic mechanisms underlying infectious diseases may result in the progression of new therapeutic approaches focusing on host-pathogen interactions. The goal of this study is to show how different infectious agents interact with host cells after infection.Keywords: epigenetic, infectious disease, micro-pathogenic organism, phenotype
Procedia PDF Downloads 804202 Effect of Wheat Germ Agglutinin- and Lactoferrin-Grafted Catanionic Solid Lipid Nanoparticles on Targeting Delivery of Etoposide to Glioblastoma Multiforme
Authors: Yung-Chih Kuo, I-Hsin Wang
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Catanionic solid lipid nanoparticles (CASLNs) with surface wheat germ agglutinin (WGA) and lactoferrin (Lf) were formulated for entrapping and releasing etoposide (ETP), crossing the blood–brain barrier (BBB), and inhibiting the growth of glioblastoma multiforme (GBM). Microemulsified ETP-CASLNs were modified with WGA and Lf for permeating a cultured monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes and for treating malignant U87MG cells. Experimental evidence revealed that an increase in the concentration of catanionic surfactant from 5 μM to 7.5 μM reduced the particle size. When the concentration of catanionic surfactant increased from 7.5 μM to 12.5 μM, the particle size increased, yielding a minimal diameter of WGA-Lf-ETP-CASLNs at 7.5 μM of catanionic surfactant. An increase in the weight percentage of BW from 25% to 75% enlarged WGA-Lf-ETP-CASLNs. In addition, an increase in the concentration of catanionic surfactant from 5 to 15 μM increased the absolute value of zeta potential of WGA-Lf-ETP-CASLNs. It was intriguing that the increment of the charge as a function of the concentration of catanionic surfactant was approximately linear. WGA-Lf-ETP-CASLNs revealed an integral structure with smooth particle contour, displayed a lighter exterior layer of catanionic surfactant, WGA, and Lf and showed a rigid interior region of solid lipids. A variation in the concentration of catanionic surfactant between 5 μM and 15 μM yielded a maximal encapsulation efficiency of ETP ata 7.5 μM of catanionic surfactant. An increase in the concentration of Lf/WGA decreased the grafting efficiency of Lf/WGA. Also, an increase in the weight percentage of ETP decreased its encapsulation efficiency. Moreover, the release rate of ETP from WGA-Lf-ETP-CASLNs reduced with increasing concentration of catanionic surfactant, and WGA-Lf-ETP-CASLNs at 12.5 μM of catanionic surfactant exhibited a feature of sustained release. The order in the viability of HBMECs was ETP-CASLNs ≅ Lf-ETP-CASLNs ≅ WGA-Lf-ETP-CASLNs > ETP. The variation in the transendothelial electrical resistance (TEER) and permeability of propidium iodide (PI) was negligible when the concentration of Lf increased. Furthermore, an increase in the concentration of WGA from 0.2 to 0.6 mg/mL insignificantly altered the TEER and permeability of PI. When the concentration of Lf increased from 2.5 to 7.5 μg/mL and the concentration of WGA increased from 2.5 to 5 μg/mL, the enhancement in the permeability of ETP was minor. However, 10 μg/mL of Lf promoted the permeability of ETP using Lf-ETP-CASLNs, and 5 and 10 μg/mL of WGA could considerably improve the permeability of ETP using WGA-Lf-ETP-CASLNs. The order in the efficacy of inhibiting U87MG cells was WGA-Lf-ETP-CASLNs > Lf-ETP-CASLNs > ETP-CASLNs > ETP. As a result, WGA-Lf-ETP-CASLNs reduced the TEER, enhanced the permeability of PI, induced a minor cytotoxicity to HBMECs, increased the permeability of ETP across the BBB, and improved the antiproliferative efficacy of U87MG cells. The grafting of WGA and Lf is crucial to control the medicinal property of ETP-CASLNs and WGA-Lf-ETP-CASLNs can be promising colloidal carriers in GBM management.Keywords: catanionic solid lipid nanoparticle, etoposide, glioblastoma multiforme, lactoferrin, wheat germ agglutinin
Procedia PDF Downloads 2374201 Normal Hematopoietic Stem Cell and the Toxic Effect of Parthenolide
Authors: Alsulami H., Alghamdi N., Alasker A., Almohen N., Shome D.
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Most conventional chemotherapeutic agents which are used for the treatment of cancers not only eradicate cancer cells but also affect normal hematopoietic Stem cells (HSCs) that leads to severe pancytopenia during treatment. Therefore, a need exists for novel approaches to treat cancer without or with minimum effect on normal HSCs. Parthenolide (PTL), a herbal product occurring naturally in the plant Feverfew, is a potential new chemotherapeutic agent for the treatment of many cancers such as acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). In this study we investigated the effect of different PTL concentrations on the viability of normal HSCs and also on the ability of these cells to form colonies after they have been treated with PTL in vitro. Methods: In this study, 24 samples of bone marrow and cord blood were collected with consent, and mononuclear cells were separated using density gradient separation. These cells were then exposed to various concentrations of PTL for 24 hours. Cell viability after culture was determined using 7ADD in a flow cytometry test. Additionally, the impact of PTL on hematopoietic stem cells (HSCs) was evaluated using a colony forming unit assay (CFU). Furthermore, the levels of NFҝB expression were assessed by using a PE-labelled anti-pNFκBP65 antibody. Results: this study showed that there was no statistically significant difference in the percentage of cell death between untreated and PTL treated cells with 5 μM PTL (p = 0.7), 10 μM PTL (p = 0.4) and 25 μM (p = 0.09) respectively. However, at higher doses, PTL caused significant increase in the percentage of cell death. These results were significant when compared to untreated control (p < 0.001). The response of cord blood cells (n=4) on the other hand was slightly different from that for bone marrow cells in that the percentage of cell death was significant at 100 μM PTL. Therefore, cord blood cells seemed more resistant than bone marrow cells. Discussion &Conclusion: At concentrations ≤25 μM PTL has a minimum or no effect on HSCs in vitro. Cord blood HSCs are more resistant to PTL compared to bone marrow HSCs. This could be due to the higher percentage of T-lymphocytes, which are resistant to PTL, in CB samples (85% in CB vs. 56% in BM. Additionally, CB samples contained a higher proportion of CD34+ cells, with 14.5% of brightly CD34+ cells compared to only 1% in normal BM. These bright CD34+ cells in CB were mostly negative for early-stage stem cell maturation antigens, making them young and resilient to oxidative stress and high concentrations of PTL.Keywords: stem cell, parthenolide, NFKB, CLL
Procedia PDF Downloads 484200 Conformal Coating Technology Applicable to Cell Therapeutics Using Click-Reactive Biocompatible Polymers
Authors: Venkat Garigapati
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Cell-based therapies are limited due to underlying host immune system activity. Microencapsulation of living cells to overcome this issue has some serious drawbacks, such as limitations of nutrient and oxygen diffusion, which pose a threat to the function and longevity of cells. The conformal coating could overcome the issues which are generally involved in traditional microencapsulation. Some of the theoretical advantages of conformal coating include superior nutrient and oxygen supply to cells, prolonged lifespan, improved drug-secreting cell functionality and an opportunity to load high cell doses in small volumes. Despite several advantages to the conformal coating, there are no suitable methods available to apply to living cells. The ultra-thin conformal coating was achieved utilizing click-reactive methacryloyloxyethyl phosphorylcholine (MPC) polymers, which are capable of specifically reacting one polymer to another at neutral pH in the aqueous isotonic system at the desired temperature suitable for living cells without the need of deleterious initiators. ARPE-19 (Adult Retinal Pigment Epithelial cell line-19) cell-spheroids and rat pancreatic islets were used in the formulation studies. The in vitro studies of coated ARPE-19 cell-spheroids and rat islets indicate that the coat was intact; cells were viable and functioning. The in vitro study results revealed that the conformal coating technology seems promising and in vivo studies are being planned.Keywords: cells, hydrogel, conformal coating, microencapsulation, insulin
Procedia PDF Downloads 904199 Analysis of Selected Hematological Variables during Three Different Menstrual Phases between Sedentary and Sports Women
Authors: G. Vasanthi
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The purpose of the study was to analyse the red blood cells and white blood cells during three different menstrual phases between sedentary and sports women. To achieve this purpose, fifteen female sedentary post graduate students (M.A., M.Sc.) and fifteen students of Master of Physical Education and Sports (M.P.Ed.) women who regularly involved in vigouous sports training and participated in sports competition on different games were selected by adopting random sampling method. All the students were hostelers and their age group was between 20 to 22 years. The blood sample were collected during the mid-period of the three different phases to calculate the red blood cells and white blood cells. The data collected were treated statistically by using analysis of variance. The results reveal that the RBC and WBC is found to be significant between sedentary and sports women during the three different menstrual phases.Keywords: RBC, WBC, menstrual, proliferative, secretary, sedentary women, sports women
Procedia PDF Downloads 5034198 Reliability and Validity of Determining Ventilatory Threshold and Respiratory Compensation Point by Near-Infrared Spectroscopy
Authors: Tso-Yen Mao, De-Yen Liu, Chun-Feng Huang
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Purpose: This research intends to investigate the reliability and validity of ventilatory threshold (VT) and respiratory compensation point (RCP) determined by skeletal muscle hemodynamic status. Methods: One hundred healthy male (age: 22±3 yrs; height: 173.1±6.0 cm; weight: 67.1±10.5 kg) performed graded cycling exercise test which ventilatory and skeletal muscle hemodynamic data were collected simultaneously. VT and RCP were determined by combined V-slope (VE vs. VCO2) and ventilatory efficiency (VE/VO2 vs. VE/VCO2) methods. Pearson correlation, paired t-test, and Bland-Altman plots were used to analyze reliability, validity, and similarities. Statistical significance was set at α =. 05. Results: There are high test-retest correlations of VT and RCP in ventilatory or near-infrared spectroscopy (NIRS) methods (VT vs. VTNIRS: 0.95 vs. 0.94; RCP vs. RCPNIRS: 0.93 vs. 0.93, p<. 05). There are high coefficient of determination at the first timing point of O2Hb decreased (R2 = 0.88, p<. 05) with VT, and high coefficient of determination at the second timing point of O2Hb declined (R2 = 0.89, p< .05) with RCP. VO2 of VT and RCP are not significantly different between ventilatory and NIRS methods (p>. 05). Conclusion: Using NIRS method to determine VT and RCP is reliable and valid in male individuals during graded exercise. Non-invasive skeletal muscle hemodynamics monitor also can be used for controlling training intensity in the future.Keywords: anaerobic threshold, exercise intensity, hemodynamic, NIRS
Procedia PDF Downloads 3134197 Enhancing Sensitization of Cervical Cancer Cells to γ-Radiation Ellagic Acid
Authors: Vidhula Ahire, Amit Kumar, K. P. Mishra, Gauri Kulkarni
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Herbal polyphenols have gained significance because of their increasing promise in prevention and treatment of cancer. Therefore, development of a dietary compound as an effective radiosensitizer and a radioprotector is highly warranted for cervical cancer patients undergoing therapy. This study describes the cytotoxic effects of the flavonoid, ellagic acid (EA) when administered either alone or in combination with gamma radiation on cervical cancer HeLa cells in vitro. Apoptotic index and proliferation were measured by using trypan blue assay. Reproductive cell death was analyzed by clonogenic assay. Propidium iodide staining for flowcytometry was performed to analyze cell cycle modulation. Nuclear and mitochondrial changes were studied with specific dyes. DNA repair kinetics was analyzed by immunofluorescence assay. Evaluation and comparison of EA effects were performed with other clinically used breast cancer drugs. When tumor cells were exposed to 2 and 4 Gy of irradiation in presence of EA (10 μM), it yielded a synergistic cytotoxic effect on cervical cancer cells whereas in NIH3T3 cells it reversed the injury caused by irradiation and abetted in the regaining of normal healthy cells. At 24h ~25foci/cell was observed and 2.6 fold decrease in the mitochondrial membrane potential. Up to 40% cell were arrested in the G1 phase and 20-36% cells exhibited apoptosis. Our results demonstrate the role of increased apoptosis and cell cycle modulation in the mechanism of EA mediated radiosensitization of cervical cancer cells and thus advocating EA as an adjuvant for preclinical trials in cancer chemo- radiotherapy.Keywords: cervical cancer, ellagic acid, sensitization, radiation therapy
Procedia PDF Downloads 3224196 Targeting Mre11 Nuclease Overcomes Platinum Resistance and Induces Synthetic Lethality in Platinum Sensitive XRCC1 Deficient Epithelial Ovarian Cancers
Authors: Adel Alblihy, Reem Ali, Mashael Algethami, Ahmed Shoqafi, Michael S. Toss, Juliette Brownlie, Natalie J. Tatum, Ian Hickson, Paloma Ordonez Moran, Anna Grabowska, Jennie N. Jeyapalan, Nigel P. Mongan, Emad A. Rakha, Srinivasan Madhusudan
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Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n=331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p=0.002). In the ovarian cancer genome atlas (TCGA) cohort (n=498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p<0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n=1259), Mre11 overexpression was associated with poor PFS (p=0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer.Keywords: MRE11; XRCC1, ovarian cancer, platinum sensitization, synthetic lethality
Procedia PDF Downloads 129