Search results for: somatic marker

Authors: Fiston Masudi Tambwe, Lwanga Charles, Arfang Badji, Unzimai Innocent

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The development of maize varieties combining Provitamin A (PVA), high yield, and Striga resistance is an effective and affordable strategy to contribute to food security in sub-Saharan Africa, where maize is a staple food crop. There has been limited research on introgressing PVA genes into Striga-resistant maize genotypes. The objectives of this study were to: i) determine the mode of gene action controlling PVA carotenoid accumulation in Striga-resistant maize, ii) identify Striga-resistant maize hybrids with high PVA content and stable yield, and iii) validate the presence of PVA functional markers in offspring. Six elite, Striga-resistant inbred females were crossed with six high-PVA inbred males in a North Carolina Design II and their offspring were evaluated in four environments, following a 5x8 alpha lattice design with four hybrid checks. Results revealed that both additive and non-additive gene action control carotenoid accumulation in the present study, with a predominance of non-additive gene effects for PVA. Hybrids STR1004xCLHP0352 and STR1004xCLHP0046 - identified as Striga-resistant because they supported fewer Striga plants – were the highest-yielding genotypes with a moderate PVA concentration of 5.48 and 5.77 µg/g, respectively. However, those two hybrids were not stable in terms of yield across all environments. Hybrid STR1007xCLHP0046, however, supported fewer Striga plants, had a yield of 4.52 T/ha, a PVA concentration of 4.52 µg/g, and was also stable. Gel-based marker systems of CrtRB1 and LCYE were used to screen the hybrids and favorable alleles of CrtRB1 primers were detected in 20 hybrids, confirming good levels of PVA carotenoids. Hybrids with favorable alleles of LCYE had the highest concentration of non-PVA carotenoids. These findings will contribute to the development of high-yielding PVA-rich maize varieties in Uganda.

Keywords: gene action, stability, striga resistance, provitamin A markers, beta-carotene hydroxylase 1, CrtRB1, beta-carotene, beta-cryptoxanthin, lycopene epsilon cyclase, LCYE

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Authors: F. Polito, M. Cucinotta, A. Conti, C. Lo Giudice, C. Tomasello, F. Angileri, D. La Torre, M. Aguennouz

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Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors, with an extremely poor prognosis. Telomeres lenght is associated with tumor progression in several type of human cancers and telomere elongation is a common molecular feature of advanced malignancies. Among the telomeric shelterin proteins PTOP is required for telomeric protein complex assembly, telomerase recruitment and activity, and telomere length regulation through a PTOP-telomerase interaction. Previous studies suggest that PTOP upregulation is involved in radioresistance and telomere lengthening in colorectal cancer cells. Moreover, in human osteosarcoma cells PTOP deletion led to telomere shortening, increased apoptosis and radiation sensitivity enhancement. However, to date, little is known about the role of PTOP in progression of glioma cancers. In light of this background aim of the study is to investigate the expression of PTOP in different grades of human glioma and its correlation with the pathological grade of gliomas, grades of malignancy, proliferative activity and apoptosis. Fifteen Low Grade Astrocytomas (LGA), 18 Anaplastic Astrocytomas (AA) and 26 Glioblastoma Multiforme (GBM) samples were analyzed. Three samples of normal brain tissue (NBT) were used as controls. The expression levels of PTOP, h-TERT, BIRC1 and cyclin D1 were determined by real time PCR and/or western blot. Results obtained shows that PTOP expression in glioma tissues is tightly correlated with clinical grade ( p < 0.01 ). No correlation was found between PTOP expression and other clinicopathologic parameters. The expression of PTOP was positively correlated with the expression of hTERT and TERF1. Furthermore PTOP positively correlates with cyclin D1 and negatively correlates with the expression of BIRC1. Our findings indicate that PTOP might play key role in the progression of glioma regulating telomerase activity and likely through regulation of cell cycle and apoptosis. In conclusion results obtained prompted us to speculate that PTOP might represents a potential molecular bio marker and a therapeutic target for the treatment of glioblastoma tumors.

Keywords: glioblastoma, PTOP, telomere, brain tumors

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Authors: Soodabeh Shahid Sales, Azam Rastgar Moghadam, Mehrane Mehramiz, Malihe Entezari, Kazem Anvari, Mohammad Sadegh Khorrami, Saeideh Ahmadi Simab, Ali Moradi, Seyed Mahdi Hassanian, Majid Ghayour-Mobarhan, Gordon A. Ferns, Amir Avan

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Background Esophageal cancer has been reported as the eighth most common cancer universal and the seventh cause of cancer-related death in men .recent studies have revealed that cytochrome P450, family 1, subfamily B, polypeptide 1, which plays a role in metabolizing xenobiotics, is associated with different cancers. Therefore in the present study, we investigated the impact of CYP1B1-rs1056836 on esophagus squamous cell carcinoma (ESCC) patients. Method: 317 subjects, with and without ESCC were recruited. DNA was extracted and genotyped via Real-time PCR-Based Taq Man. Kaplan Meier curves were utilized to assess overall and progression-free survival. To evaluate the relationship between patients clinicopathological data, genotypic frequencies, disease prognosis, and patients survival, Pearson chi-square and t-test were used. Logistic regression was utilized to assess the association between the risk of ESCC and genotypes. Results: the genotypic frequency for GG, GC, and CC are respectively 58.6% , 29.8%, 11.5% in the healthy group and 51.8%, 36.14% and 12% in ESCC group. With respect to the recessive genetic inheritance model, an association between the GG genotype and stage of ESCC were found. Also, statistically significant results were not found for this variation and risk of ESCC. Patients with GG genotype had a decreased risk of nodal metastasis in comparison with patients with CC/CG genotype, although this link was not statistically significant. Conclusion: Our findings illustrated the correlation of CYP1B1-rs1056836 as a potential biomarker for ESCC patients, supporting further studies in larger populations in different ethnic groups. Moreover, further investigations are warranted to evaluate the association of emerging marker with dietary intake and lifestyle.

Keywords: Cytochrome P450, esophagus squamous cell carcinoma, dietary intake, lifestyle

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Authors: B. González-Yebra, B. Flores-Nieto, P. Aguilar-Salinas, M. Preciado Puga, A. L. González Yebra

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The monitoring of populations occupationally exposed to organic solvents has been an important issue for several shoe factories for years since the International Agency for Research on Cancer (IARC) has advised on the potential carcinogenic risk of chemicals related to occupations. In order to detect if exposition to organic solvents used in some Mexican shoe factories contributes to oral carcinogenesis, we performed monitoring in three factories. Occupational exposure was determined by using monitors 3M. Organic solvents were assessed by gas chromatography. Then, we recruited 30 shoe workers (30.2 ± 8.4 years) and 10 unexposed subjects (43.3 ± 11.2 years) for the micronuclei (MN) test and immunodetection of some cancer biomarkers (ki-67, p16, caspase-3) in scraped oral epithelial cells. Monitored solvents detected were acetone, benzene, hexane, methyl ethyl ketone, and toluene in acceptable levels according to Official Mexican Norm. We found by MN test higher incidence of nuclear abnormalities (karyorrhexis, pycnosis, karyolysis, condensed chromatin, and macronuclei) in the exposed group than the non-exposed group. On the other hand, we found, a negative expression for Ki-67 and p16 in exfoliated epithelial cells from exposed and non-exposed to organic solvents subjects. Only caspase-3 shown positive patter of expression in 9/30 (30%) exposed subjects, and we detected high karyolysis incidence in caspase-3 subjects (p = 0.021). The absence of expression of proliferation markers p16 and ki-67 and presence of apoptosis marker caspase-3 are indicating the absence of malignancy in oral epithelial cells and low risk for oral cancer. It is a fact that the MN test is a very effective method to detect nuclear abnormalities in exfoliated buccal cells from subjects that have been exposed to organic solvents in the shoe industry. However, in order to improve this tool and predict cancer risk is it is mandatory to implement complementary tests as other biomarkers that can help to detect malignancy in individuals occupationally exposed.

Keywords: biomarkers, oral cancer, organic solvents, shoe industries

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Authors: Katie Emerson, Sara Perez-Ojalvo, Jim Komorowski, Danielle Greenberg

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The purpose of this study was to evaluate arginase activity levels in response to combinations of an inositol-stabilized arginine silicate (ASI; Nitrosigine®), L-arginine, and Inositol. Arginine acts as a vasodilator that promotes increased blood flow resulting in enhanced delivery of oxygen and nutrients to the brain and other tissues. ASI alone has been shown to improve performance on cognitive tasks. Arginase, found in human serum, catalyzes the conversion of arginine to ornithine and urea, completing the last step in the urea cycle. Decreasing arginase levels maintains arginine and results in increased nitric oxide production. This study aimed to determine the most effective combination of ASI, L-arginine and inositol for minimizing arginase levels and therefore maximize ASI’s effect on cognition. Serum was taken from untreated healthy donors by separation from clotted factors. Arginase activity of serum in the presence or absence of test products was determined (QuantiChrom™, DARG-100, Bioassay Systems, Hayward CA). The remaining ultra-filtrated serum units were harvested and used as the source for the arginase enzyme. ASI alone or combined with varied levels of Inositol were tested as follows: ASI + inositol at 0.25 g, 0.5 g, 0.75 g, or 1.00 g. L-arginine was also tested as a positive control. All tests elicited changes in arginase activity demonstrating the efficacy of the method used. Adding L-arginine to serum from untreated subjects, with or without inositol only had a mild effect. Adding inositol at all levels reduced arginase activity. Adding 0.5 g to the standardized amount of ASI led to the lowest amount of arginase activity as compared to the 0.25g 0.75g or 1.00g doses of inositol or to L-arginine alone. The outcome of this study demonstrates an interaction of the pairing of inositol with ASI on the activity of the enzyme arginase. We found that neither the maximum nor minimum amount of inositol tested in this study led to maximal arginase inhibition. Since the inhibition of arginase activity is desirable for product formulations looking to maintain arginine levels, the most effective amount of inositol was deemed preferred. Subsequent studies suggest this moderate level of inositol in combination with ASI leads to cognitive improvements including reaction time, executive function, and concentration.

Keywords: arginine, inositol, arginase, cognitive benefits

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Authors: Misty Attwood, Helgi Schioth

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Transmembrane proteins are important components in many essential cell processes such as signal transduction, cell-cell signalling, transport of solutes, structural adhesion activities, and protein trafficking. Due to their involvement in diverse critical activities, transmembrane proteins are implicated in different disease pathways and hence are the focus of intense interest in understanding functional activities, their pathogenesis in disease, and their potential as pharmaceutical targets. Further, as the structure and function of proteins are correlated, investigating a group of proteins with the same tertiary structure, i.e., the same number of transmembrane regions, may give understanding about their functional roles and potential as therapeutic targets. In this in silico bioinformatics analysis, we identify and comprehensively characterize the previously unstudied group of proteins with five transmembrane-spanning regions (5TM). We classify nearly 60 5TM proteins in which 31 are members of ten families that contain two or more family members and all members are predicted to contain the 5TM architecture. Furthermore, nine singlet proteins that contain the 5TM architecture without paralogues detected in humans were also identifying, indicating the evolution of single unique proteins with the 5TM structure. Interestingly, more than half of these proteins function in localization activities through movement or tethering of cell components and more than one-third are involved in transport activities, particularly in the mitochondria. Surprisingly, no receptor activity was identified within this family in sharp contrast with other TM families. Three major 5TM families were identified and include the Tweety family, which are pore-forming subunits of the swelling-dependent volume regulated anion channel in astrocytes; the sidoreflexin family that acts as mitochondrial amino acid transporters; and the Yip1 domain family engaged in vesicle budding and intra-Golgi transport. About 30% of the proteins have enhanced expression in the brain, liver, or testis. Importantly, 60% of these proteins are identified as cancer prognostic markers, where they are associated with clinical outcomes of various tumour types, indicating further investigation into the function and expression of these proteins is important. This study provides the first comprehensive analysis of proteins with 5TM regions and provides details of the unique characteristics and application in pharmaceutical development.

Keywords: 5TM, cancer prognostic marker, drug targets, transmembrane protein

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Authors: Peter W. Woodruff, Georgios Ponirakis, Reem Ibrahim, Amani Ahmed, Hoda Gad, Ioannis N. Petropoulos, Adnan Khan, Ahmed Elsotouhy, Surjith Vattoth, Mahmoud K. M. Alshawwaf, Mohamed Adil Shah Khoodoruth, Marwan Ramadan, Anjushri Bhagat, James Currie, Ziyad Mahfoud, Hanadi Al Hamad, Ahmed Own, Peter Haddad, Majid Alabdulla, Rayaz A. Malik

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Introduction:- We aimed to test the hypothesis that, using corneal confocal microscopy (a non-invasive method for assessing corneal nerve fibre integrity), patients with schizophrenia would show neuronal abnormalities compared with healthy participants. Schizophrenia is a neurodevelopmental and progressive neurodegenerative disease, for which there are no validated biomarkers. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic imaging biomarker that can be used to detect neuronal abnormalities in neuropsychiatric syndromes. Methods:- Patients with schizophrenia (DSM-V criteria) without other causes of peripheral neuropathy and healthy controls underwent CCM, vibration perception threshold (VPT) and sudomotor function testing. The diagnostic accuracy of CCM in distinguishing patients from controls was assessed using the area under the curve (AUC) of the Receiver Operating Characterstics (ROC) curve. Findings:- Participants with schizophrenia (n=17) and controls (n=38) with comparable age (35.7±8.5 vs 35.6±12.2, P=0.96) were recruited. Patients with schizophrenia had significantly higher body weight (93.9±25.5 vs 77.1±10.1, P=0.02), lower Low Density Lipoproteins (2.6±1.0 vs 3.4±0.7, P=0.02), but comparable systolic and diastolic blood pressure, HbA1c, total cholesterol, triglycerides and High Density Lipoproteins were comparable with control participants. Patients with schizophrenia had significantly lower corneal nerve fiber density (CNFD, fibers/mm2) (23.5±7.8 vs 35.6±6.5, p<0.0001), branch density (CNBD, branches/mm2) (34.4±26.9 vs 98.1±30.6, p<0.0001), and fiber length (CNFL, mm/mm2) (14.3±4.7 vs 24.2±3.9, p<0.0001) but no difference in VPT (6.1±3.1 vs 4.5±2.8, p=0.12) and electrochemical skin conductance (61.0±24.0 vs 68.9±12.3, p=0.23) compared with controls. The diagnostic accuracy of CNFD, CNBD and CNFL to distinguish patients with schizophrenia from healthy controls were, according to the AUC, (95% CI): 87.0% (76.8-98.2), 93.2% (84.2-102.3), 93.2% (84.4-102.1), respectively. Conclusion:- In conclusion, CCM can be used to help identify neuronal changes and has a high diagnostic accuracy to distinguish subjects with schizophrenia from healthy controls.

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Authors: Vandana Mohan, Ashwani Koul

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Aim: To evaluate the potential of Aqueous Tinospora cordifolia stem extract (Aq.Tc) and Arabinogalactan (AG) on pulmonary carcinogenesis and associated tumor markers. Background: Lung cancer is one of the most frequent malignancy with high mortality rate due to limitation of early detection resulting in low cure rates. Current research effort focuses on identifying some blood-based biomarkers like CEA, ctDNA and LDH which may have potential to detect cancer at an early stage, evaluation of therapeutic response and its recurrence. Medicinal plants and their active components have been widely investigated for their anticancer potentials. Aqueous preparation of T. Cordifolia extract is enriched in the polysaccharide fraction i.e., AG when compared with other types of extract. Moreover, reports are available of polysaccharide fraction of T. Cordifolia in in vitro lung cancer models which showed profound anti-metastatic activity against these cell lines. However, not much has been explored about its effect in in vivo lung cancer models and the underlying mechanism involved. Experimental Design: Mice were randomly segregated into six groups. Group I animals served as control. Group II animals were administered with Aq. Tc extract (200 mg/kg b.w.) p.o.on the alternate days. Group III animals were fed with AG (7.5 mg/kg b.w.) p.o. on the alternate days (thrice a week). Group IV animals were installed with Benzo(a)pyrene (50 mg/kg b.w.), i.p. twice within an interval of two weeks. Group V animals received Aq. Tc extract as in group II along with it B(a)P was installed after two weeks of Aq. Tc administration following the same protocol as for group IV. Group VI animals received AG as in group III along with it B(a)P was installed after two weeks of AG administration. Results: Administration of B(a)P to mice resulted in increased tumor incidence, multiplicity and pulmonary somatic index with concomitant increase in serum/plasma markers like CEA, ctDNA, LDH and TNF-α.Aq.Tc and AG supplementation significantly attenuated these alterations at different stages of tumorigenesis thereby showing potent anti-cancer effect in lung cancer. A pronounced decrease in serum/plasma markers were observed in animals treated with Aq.Tc as compared to those fed with AG. Also, extensive hyperproliferation of alveolar epithelium was prominent in B(a)P induced lung tumors. However, treatment of Aq.Tc and AG to lung tumor bearing mice exhibited reduced alveolar damage evident from decreased number of hyperchromatic irregular nuclei. A direct correlation between the concentration of tumor markers and the intensity of lung cancer was observed in animals bearing cancer co-treated with Aq.Tc and AG. Conclusion: These findings substantiate the chemopreventive potential of Aq.Tc and AG against lung tumorigenesis. Interestingly, Aq.Tc was found to be more effective in modulating the cancer as reflected by various observations which may be attributed to the synergism offered by various components of Aq.Tc. Further studies are in progress to understand the underlined mechanism in inhibiting lung tumorigenesis by Aq.Tc and AG.

Keywords: Arabinogalactan, Benzo(a)pyrene B(a)P, carcinoembryonic antigen (CEA), circulating tumor DNA (ctDNA), lactate dehydrogenase (LDH), Tinospora cordifolia

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Authors: T. Almutairi, K. Naudi, N. Nairn, X. Ju, B. Eng, J. Whitters, A. Ayoub

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Purpose: At present Cone Beam Computed Tomography (CBCT) imaging does not record dental morphology accurately due to the scattering produced by metallic restorations and the reported magnification. The aim of this pilot study is the development and validation of a new method for the replacement of the distorted dentition of CBCT scans with the dental image captured by the digital intraoral camera. Materials and Method: Six dried skulls with orthodontics brackets on the teeth were used in this study. Three intra-oral markers made of dental stone were constructed which were attached to orthodontics brackets. The skulls were CBCT scanned, and occlusal surface was captured using TRIOS® 3D intraoral scanner. Marker based and surface based registrations were performed to fuse the digital intra-oral scan(IOS) into the CBCT models. This produced a new composite digital model of the skull and dentition. The skulls were scanned again using the commercially accurate Laser Faro® arm to produce the 'gold standard' model for the assessment of the accuracy of the developed method. The accuracy of the method was assessed by measuring the distance between the occlusal surfaces of the new composite model and the 'gold standard' 3D model of the skull and teeth. The procedure was repeated a week apart to measure the reproducibility of the method. Results: The results showed no statistically significant difference between the measurements on the first and second occasions. The absolute mean distance between the new composite model and the laser model ranged between 0.11 mm to 0.20 mm. Conclusion: The dentition of the CBCT can be accurately replaced with the dental image captured by the intra-oral scanner to create a composite model. This method will improve the accuracy of orthognathic surgical prediction planning, with the final goal of the fabrication of a physical occlusal wafer without to guide orthognathic surgery and eliminate the need for dental impression.

Keywords: orthognathic surgery, superimposition, models, cone beam computed tomography

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Authors: Aline Woine, Moïra Mikolajczak, Virginie Dardier, Isabelle Roskam

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Background information: Becoming a parent is said to be the happiest event one can ever experience in one’s life. This popular (and almost absolute) truth–which no reasonable and decent human being would ever dare question on pain of being singled out as a bad parent–contrasts with the nuances that reality offers. Indeed, while many parents do thrive in their parenting role, some others falter and become progressively overwhelmed by their parenting role, ineluctably caught in a spiral of exhaustion. Parental burnout (henceforth PB) sets in when parental demands (stressors) exceed parental resources. While it is now generally acknowledged that PB affects the parent’s behavior in terms of neglect and violence toward their offspring, little is known about the impact that the syndrome might have on the children’s internalized (anxious and depressive symptoms, somatic complaints, etc.) and/or externalized (irritability, violence, aggressiveness, conduct disorder, oppositional disorder, etc.) behaviors. Furthermore, at the time of writing, to our best knowledge, no research has yet tested the reverse effect, namely, that of the child's internalized and/or externalized behaviors on the onset and/or maintenance of parental burnout symptoms. Goals and hypotheses: The present pioneering research proposes to fill an important gap in the existing literature related to PB by investigating the bidirectional effect between PB and the child’s internalized and/or externalized behaviors. Relying on a cross-lagged longitudinal study with three waves of data collection (4 months apart), our study tests a transactional model with bidirectional and recursive relations between observed variables and at the three waves, as well as autoregressive paths and cross-sectional correlations. Methods: As we write this, wave-two data are being collected via Qualtrics, and we expect a final sample of about 600 participants composed of French-speaking (snowball sample) and English-speaking (Prolific sample) parents. Structural equation modeling is employed using Stata version 17. In order to retain as much statistical power as possible, we use all available data and therefore apply the maximum likelihood with a missing value (mlmv) as the method of estimation to compute the parameter estimates. To limit (in so far is possible) the shared method variance bias in the evaluation of the child’s behavior, the study relies on a multi-informant evaluation approach. Expected results: We expect our three-wave longitudinal study to show that PB symptoms (measured at T1) raise the occurrence/intensity of the child’s externalized and/or internalized behaviors (measured at T2 and T3). We further expect the child’s occurrence/intensity of externalized and/or internalized behaviors (measured at T1) to augment the risk for PB (measured at T2 and T3). Conclusion: Should our hypotheses be confirmed, our results will make an important contribution to the understanding of both PB and children’s behavioral issues, thereby opening interesting theoretical and clinical avenues.

Keywords: exhaustion, structural equation modeling, cross-lagged longitudinal study, violence and neglect, child-parent relationship

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Authors: Komal Vig, Syamala Soumyakrishnan, Yadav Baral

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Bypass surgery, using the autologous vein has been one of the most effective treatments for cardiovascular diseases (CVD). More recently tissue engineering including engineered vascular grafts to synthesize blood vessels is gaining usage. Dacron and ePTFE has been employed for vascular grafts, however, these does not work well for small diameter grafts (<6 mm) due to intimal hyperplasia and thrombosis. In the present study PTFE was treated with LTP to improve the endothelialization of intimal surface of graft. Scaffolds were also modified with polyvinylpyrrolidone coated silver nanoparticles (Ag-PVP) and the antimicrobial peptides, p753 and p359. Human umbilical vein endothelial cells (HUVEC) were plated on the developed scaffolds and cell proliferation was determined by the MTT assay. Cells attachment on scaffolds was visualized by microscopy. mRNA expressions levels of different cell markers were investigated using quantitative real-time PCR (qPCR). X ray photoelectron spectroscopic confirmed the introduction of oxygenated functionalities from LTP air plasma. Microscopic and MTT assays indicated increase in cell viability in LTP treated scaffolds. Gene expression studies shows enhanced expression of cell adhesion marker Integrin- α 5 gene after LTP treatment. The KB test displayed a zone of inhibition for Ag-PVP, p753 and p359 of 19mm, 14mm, and 12mm respectively. To determine toxicity of antimicrobial agents to cells, MTT Assay was performed using HEK293 cells. MTT Assay exhibited that Ag-PVP and the peptides were non-toxic to cells at 100μg/mL and 50μg/mL, respectively. Live/dead analysis and plate count of treated bacteria exhibited bacterial inhibition on develop scaffold compared to non-treated scaffold. SEM was performed to analyze the structural changes of bacteria after treatment with antimicrobial agents. Gene expression studies were conducted on RNA from bacteria treated with Ag-PVP and peptides using qRT-PCR. Based on our initial results, more scaffolds alternatives will be developed and investigated for cell growth and vascularization studies.

Keywords: low temperature plasma, vascular graft, HUVEC cells, antimicrobial

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Authors: Eisha Vienna M. Fernandez, Cristan Q. Cabanilla, Hiyasmin Lim, John Donnie A. Ramos

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Allergy is a multifactorial disease affecting a significant proportion of the population. It is developed through the interaction of allergens and the presence of certain polymorphisms in various susceptibility genes. In this study, the correlation of the 105A/C single nucleotide polymorphism (SNP) of the IL-18 gene and house dust mite-specific IgE among Filipino allergic and non-allergic population was investigated. Atopic status was defined by serum total IgE concentration of ≥100 IU/mL, while house dust mite allergy was defined by specific IgE value ≥ +1SD of IgE of nonatopic participants. Two hundred twenty match-paired Filipino cases and controls aged 6-60 were the subjects of this investigation. The level of total IgE and Specific IgE were measured using Enzyme-Linked Immunosorbent Assay (ELISA) while Polymerase Chain Reaction – Restriction Fragment Length Polymorphism (PCR-RFLP) analysis was used in the SNP detection. Sensitization profiles of the allergic patients revealed that 97.3% were sensitized to Blomia tropicalis, 40.0% to Dermatophagoides farinae, and 29.1% to Dermatophagoides pteronyssinus. Multiple sensitization to HDMs was also observed among the 47.27% of the atopic participants. Any of the allergy classes of the atopic triad were exhibited by the cases (allergic asthma: 48.18%; allergic rhinitis: 62.73%; atopic dermatitis: 19.09%), and two or all of these atopic states are concurrently occurring in 26.36% of the cases. A greater proportion of the atopic participants with allergic asthma and allergic rhinitis were sensitized to D. farinae, and D. pteronyssinus, while more of those with atopic dermatitis were sensitized to D. pteronyssinus than D. farinae. Results show that there is overrepresentation of the allele “A” of the 105A/C IL-18 gene SNP in both cases and control groups of the population. The genotype that predominate the population is the heterozygous “AC”, followed by the homozygous wild “AA”, and the homozygous variant “CC” being the least. The study confirmed a positive association between serum specific IgE against B. tropicalis and D. pteronyssinus and the allele “C” (Bt P=0.021, Dp P=0.027) and “AC” (Bt P=0.003, Dp P=0.026) genotype. Findings also revealed that the genotypes “AA” (OR:1.217; 95% CI: 0.701-2.113) and “CC” (OR, 3.5; 95% CI: 0.727-16.849) increase the risk of developing allergy. This indicates that the 105A/C IL-18 gene SNP is a candidate genetic marker for HDM allergy among Filipino patients.

Keywords: house dust mite allergy, interleukin-18 (IL-18), single nucleotide polymorphism,

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Authors: Sungpil Ha, Ju Yong Kang, Sangbaek Park, Seung-Ju Lee, Soo-Won Chae

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The growing number of obese patients in aging societies has led to an increase in the number of patients with knee medial osteoarthritis (OA). Artificial joint insertion is the most common treatment for knee medial OA. Surgery is effective for patients with serious arthritic symptoms, but it is costly and dangerous. It is also inappropriate way to prevent a disease as an early stage. Therefore Non-operative treatments such as toe-in gait are proposed recently. Toe-in gait is one of non-surgical interventions, which restrain the progression of arthritis and relieves pain by reducing knee adduction moment (KAM) to facilitate lateral distribution of load on to knee medial cartilage. Numerous studies have measured KAM in various foot progression angle (FPA), and KAM data could be obtained by motion analysis. However, variations in stress at knee cartilage could not be directly observed or evaluated by these experiments of measuring KAM. Therefore, this study applied motion analysis to major gait points (1st peak, mid –stance, 2nd peak) with regard to FPA, and to evaluate the effects of FPA on the human lower extremity, the finite element (FE) method was employed. Three types of gait analysis (toe-in, toe-out, baseline gait) were performed with markers placed at the lower extremity. Ground reaction forces (GRF) were obtained by the force plates. The forces associated with the major muscles were computed using GRF and marker trajectory data. MRI data provided by the Visible Human Project were used to develop a human lower extremity FE model. FE analyses for three types of gait simulations were performed based on the calculated muscle force and GRF. We observed the maximum stress point during toe-in gait was lower than the other types, by comparing the results of FE analyses at the 1st peak across gait types. This is the same as the trend exhibited by KAM, measured through motion analysis in other papers. This indicates that the progression of knee medial OA could be suppressed by adopting toe-in gait. This study integrated motion analysis with FE analysis. One advantage of this method is that re-modeling is not required even with changes in posture. Therefore another type of gait simulation or various motions of lower extremity can be easily analyzed using this method.

Keywords: finite element analysis, gait analysis, human model, motion capture

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Authors: Noam Markovitz

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People with physical disabilities constitute a very large and simultaneously a diverse group of general population, as the term physical disabilities is extensive and covers a wide range of disabilities. Therefore, individuals with physical disabilities are often faced with a new, threatening and stressful reality leading possibly to a multi-crisis in their lives due to the great changes they experience in somatic, socio-economic, occupational and psychological level. The current study seeks to advance understanding of the complex adaptation to physical disabilities by expanding the dynamic-adaptational model of the pursuit of happiness in a hostile world with a new conception of physical self-integrity. Physical self-integrity incorporates an objective dimension, namely physical self-functioning (PSF), and a subjective dimension, namely physical self-concept (PSC). Both of these dimensions constitute an experience of wholeness in the individual’s identification with her or his physical body. The model guiding this work is dialectical in nature and depicts two systems in the individual’s sense of happiness: subjective well-being (SWB) and meaning in life (MIL). Both systems serve as self-adaptive agents that moderate the complementary system of the hostile-world scenario (HWS), which integrates one’s perceived threats to one’s integrity. Thus, in situations of increased HWS, the moderation may take a form of joint activity in which SWB and MIL are amplified or a form of compensation in which one system produces a stronger effect while the other system produces a weaker effect. The current study investigated PSC in relations to SWB and MIL through pleasantness and meanings that are physically or metaphorically grounded in one’s body. In parallel, PSC also relates to HWS by activating representations of inappropriateness, deformation and vulnerability. In view of possibly dialectical positions of opposing and complementary forces within the current model, the current field study that aims to explore PSC as appearing in an independent, cross-sectional, design addressing the model’s variables in a focal group of people with physical disabilities. This study delineated the participation of the PSC in the adaptational functions of SWB and MIL vis-à-vis HWS-related life adversities. The findings showed that PSC could fully complement the main variables of the pursuit of happiness in a hostile world model. The assumed dialectics in the form of a stronger relationship between SWB and MIL in the face of physical disabilities was not supported. However, it was found that when HWS increased, PSC and MIL were strongly linked, whereas PSC and SWB were weakly linked. This highlights the compensatory role of MIL. From a conceptual viewpoint, the current investigation may clarify the role of PSC as an adaptational agent of the individual’s positive health in complementary senses of bodily wholeness. Methodologically, the advantage of the current investigation is the application of an integrative, model-based approach within a specially focused design with a particular relevance to PSC. Moreover, from an applicative viewpoint, the current investigation may suggest how an innovative model may be translated to therapeutic interventions used by clinicians, counselors and practitioners in improving wellness and psychological well-being, particularly among people with physical disabilities.

Keywords: older adults, physical disabilities, physical self-concept, pursuit of happiness in a hostile-world

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Authors: Nezihe Şengün, Ragip Pala

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To prevent overweight and obesity, individuals need to consume food and beverages according to their nutritional needs, engage in regular exercises, and regularly monitor their body weight. This study aimed to examine the effects of exercise, diet, or combined intervention on changes in blood lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) and the level of malondialdehyde (MDA), a marker of oxidative stress, in parallel with the increase in body weight due to poor nutrition and sedentary lifestyle conditions. The study included a total of 48 female students aged 18-28 years with a BMI between 25.0 and 29.9 kg/m². They were divided into four groups: control (C), exercise (Ex), diet (D), and exercise+diet (Ex+D). Those in the exercise groups received aerobic exercises at 60-70% intensity (10 minutes warm-up, 30 minutes running, 10 minutes cool-down), while those in the diet groups were provided with a diet program based on the calculation of energy needs considering basal metabolic rate, physical activity level, age, and BMI. The students’ body weight, body fat mass, Body Mass Index (BMI), and waist-hip ratios were measured at the beginning (day 1) and end (day 60) of the 8-week intervention period. Their total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and MDA levels were evaluated and analyzed, considering a statistical significance level of p<0.05. As a result, female students in the Ex+D group had the largest difference in body weight, body fat mass, BMI, and waist-hip ratios, and this difference was statistically significant. Except for those in the C group, those in the other groups experienced a decrease in their total cholesterol, LDL cholesterol, and triglyceride levels and an increase in their HDL cholesterol levels. The decrease in total cholesterol, LDL cholesterol, and triglyceride levels was statistically significant for those in the D group, and the increase in HDL cholesterol level was statistically significant for those in the Ex+D group (p<0.05). A decrease in MDA level was found in all groups except those in the C group, and this decrease was significantly higher in the Ex group. In conclusion, our study revealed that the most effective way to achieve weight loss is through a combination of exercise and diet. The application of Ex+D is considered to balance blood lipid levels and suppress oxidative stress.

Keywords: obesity, exercise, diet, body mass index, blood lipids

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Authors: Hager Elsheikh, Juliane Glaubitz, Frank Ulrich Weiss, Matthias Sendler

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Aim: Acute pancreatitis (AP) and chronic pancreatitis (CP) are both accompanied by a prominent immune response which influences the course of disease. Whereas during AP the pro-inflammatory immune response dominates, during CP a fibroinflammatory response regulates organ remodeling. The transcription factor signal transducer and activator of transcription 6 (STAT6) is a crucial part of the Type 2 immune response. Here we investigate the role of STAT6 in a mouse model of AP and CP. Material and Methods: AP was induced by hourly repetitive i.p. injections of caerulein (50µg/kg/bodyweight) in C57Bl/6 J and STAT6-/- mice. CP was induced by repetitive caerulein injections 6 times a day, 3 days a week over 4 weeks. Disease severity was evaluated by serum amylase/lipase measurement, H&E staining of pancreas. Pancreatic infiltrate was characterized by immunofluorescent labeling of CD68, CD206, CCR2, CD4 and CD8. Pancreas fibrosis was evaluated by Azan blue staining. qRT-PCR was performed of Arg1, Nos2, Il6, Il1b, Col3a, Socs3 and Ym1. Affymetrix chip array analyses were done to illustrate the IL4/IL13/STAT6 signaling in bone marrow derived macrophages. Results: AP severity is mitigated in STAT6-/- mice, as shown by decreased serum amylase and lipase, as well as histological damage. CP mice surprisingly showed only slightly reduced fibrosis of the pancreas. Also staining of CD206 a classical marker of alternatively activated macrophages showed no decrease of M2-like polarization in the absence of STAT6. In contrast, transcription profile analysis in BMDM showed complete blockade of the IL4/IL13 pathway in STAT6-/- animals. Conclusion: STAT6 signaling pathway is protective during AP and mitigates the pancreatic damage. During chronic pancreatitis the IL4/IL13 – STAT6 axisis involved in organ fibrogenesis. Notably, fibrosis is not dependent on a single signaling pathway, and alternative macrophage activation is also complex and involves different subclasses (M2a, M2b, M2c and M2d) which could be independent of the IL4/IL13 STAT6 axis.

Keywords: chronic pancreatitis, macrophages, IL4/IL13, Type immune response

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Authors: Dipanshu Sur, Ratnabali Chakravorty, Rimi Pal, Siddhartha Chatterjee, Joyshree Chaterjee, Amal Mallik

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Background: Women with polycystic ovary disease (PCOD) frequently suffer from metabolic disturbances. PCOD is a common ovulatory disorder in young women, which affects 5-10% of the population and results in infertility due to anovulation. Importantly, aromatase in ovarian granulosa and luteinized granulosa cells plays an important role for women of reproductive age. Generation and metabolism of androgen is directly related to aromatase activity. The E2/T ratio provides important information about aromatase activity because conversion of androgens to estrogens is mediated by CYP19, suggesting that the E2/T ratio may be a direct marker of aromatase activity. The nature of the interaction between ovarian aromatase activity and PCOD in women has been controversial, and the impact of weight gain on aromatase activity as well as E2 levels is unknown. Aim: The objective of this study was to investigate the association and relation between aromatase activity and levels of body mass index (BMI) from a reproductive hormone perspective in a group of women with or without PCOD. Methods: We designed a cohort study which included 200 individuals. It enrolled 100 cases of PCOD based on 2006 Rotterdam criteria and 100 ovulatory normal- non PCOD, healthy, age-matched controls. Plasma sex hormones viz. estradiol (E2), testosterone (T), follicle stimulating hormone (FSH), and luteinizing hormone (LH) were measured by ELISA on the second day of the menstrual cycle, together with BMI and E2/T were calculated. Aromatase activity in PCOD patients with different BMI, T and E2 levels were compared. Results: PCOD patients showed significantly increased levels of BMI, E2 (P=0.004), T and LH, while their E2/T (P= <0.001), FSH and FSH/LH values were decreased compared with the control group. Higher E2 levels correlated with a relatively enhanced E2/T as well as T and LH levels but reduced BMI, FSH and FSH/LH levels in women with PCOD. Hyperandrogenic PCOD patients had increased E2 levels but their aromatase activity was markedly inhibited independent of their BMI values. Conclusions: We found a significant decrease of ovarian aromatase activity in women with PCOD as compared to controls. Our study showed that ovarian aromatase activity in PCOD was decreased which was independent of BMI. Enhancing aromatase activity may become an optimized strategy for developing therapies for PCOD women, especially those with obesity.

Keywords: aromatase activity, polycystic ovary disease, obesity, body mass index

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Authors: Tasneem Chopra

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The 1968 Summer Olympics will forever be remembered for the silent protest against racism exhibited by American athletes Tommy Smith and John Carlos. Also standing on the medal podium was Australian Peter Norman, whose silent solidarity as a white sportsman completes the powerful, evocative image of that night in Mexico City. In the 50 years since Norman’s stance of solidarity with his American counterparts, Australian sports has traveled a wide arc of racism narratives, with athletes still experiencing episodes of bigotry, both on the pitch and elsewhere. Aboriginal athletes, like tennis champion Yvonne Goolagong, have endured the plaudits of appreciation for their achievements on both the national and international stage, while simultaneously being subject to both prejudice and even questions as to their right to represent their country as full, acceptable citizens. Racism in Australia is directed toward Australian athletes of colour as well as foreign sportspeople who visit the country. The complex, mutating nature of racism in Australia is also informed by the culture of silence, where fellow athletes stand mute in light of their colleagues’ experience with bigotry. This paper analyses the phenomenon of sports racism in Australia over the past fifty years, culminating in the most recent showdown between Heretier Lumumba, former Collingwood football player, and his public allegations of racism experienced by team mates over his 10 year career. It shall examine the treatment and mistreatment of athletes because of their race and will further assess how such public perceptions both shape Australian culture or are themselves a manifestation of preexisting pathologies of bigotry. Further, it will examine the efficacy of anti-racism initiatives in responding to this hate. This paper will analyse the growing influence of corporate and media entities in crafting the economics of Australian sports and assess the role of such factors in creating the narrative of racism in the nation, both as a sociological reality as well as a marker of national identity. Finally, this paper will examine the political, social and economic forces that contribute to the culture of silence in Australian society in defying racism.

Keywords: aboriginal, Australia, corporations, silence

Procedia PDF Downloads 157

Authors: Maha Z. Rizk, Sami A. Fattah, Heba M. Darwish, Sanaa A. Ali, Mai O. Kadry

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Although it is known that nano-TiO2 and other nanoparticles can induce liver toxicity, the mechanisms and the molecular pathogenesis are still unclear. The present study investigated some biochemical indices of nano-sized Titanium dioxide (TiO2 NPS) toxicity in mice liver and the ameliorative efficacy of individual and combined doses of idebenone, carnosine and vitamin E. Nano-anatase TiO2 (21 nm) was administered as a total oral dose of 2.2 gm/Kg daily for 2 weeks followed by the afore-mentioned antioxidants daily either individually or in combination for 1month. TiO2-NPS induced a significant elevation in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic oxidative stress biomarkers [lipid peroxides (LP), and nitric oxide levels (NOX), while it significantly reduced glutathione reductase (GR), reduced glutathione (GSH) and glutathione peroxidase(GPX) levels. Moreover the quantitative RT-PCR analysis showed that nano-anatase TiO2 can significantly alter the mRNA and protein expressions of the fibrotic factors TGF-B1, VEGFand Smad-2. Histopathological examination of hepatic tissue reinforced the previous biochemical results. Our results also implied that inflammatory responses and liver injury may be involved in nano-anatase TiO2-induced liver toxicity Tumor necrosis factor-α (TNF-α) and Interleukin -6 (IL-6) and increased the percent of DNA damage which was assessed by COMET assay in addition to the apoptotic marker Caspase-3. Moreover mRNA gene expression observed by RT-PCR showed a significant overexpression in nuclear factor relation -2 (Nrf2), nuclear factor kappa beta (NF-Kβ) and the apoptotic factor (bax), and a significant down regulation in the antiapoptotic factor (bcl2) level. In conclusion idebenone, carnosine and vitamin E ameliorated the deviated previously mentioned parameters with variable degrees with the most pronounced role in alleviating the hazardous effect of TiO2 NPS toxicity following the combination regimen.

Keywords: Nano-anatase TiO2, TGF-B1, SMAD-2

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Authors: J. Oustric, L. Berti, J. Santini

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Nowadays, the objective of durable agriculture, and in particular organic agriculture, is to reduce the level of fertilizer inputs used in crops. Limiting the quantity of fertilizer inputs would optimize the economical result and minimizing the environmental impact. Nutrient deficiency, particularly of a major nutrient (N, P, and K), can seriously affect fruit production and quality. In citrus crops, rootstock/scion combinations. In citrus crop, scion/rootstock combinations are used frequently to improve tolerance to various abiotic stresses. New rootstocks are needed to respond to these constraints, and the use of new tetraploid rootstocks better adapted to lower nutrient intake could offer a promising way forward. The aim of this work was to determine whether a better tolerance to nutrient deficiency could be observed in a doubled diploid seedling and whether this tolerance could be observed in common clementine scion if used as rootstocks. We selected diploid (CM2x) and doubled diploid (CM4x) Citrumelo 4475 seedlings and common clementine (C) grafted onto Citrumelo 4475 diploid (C/CM2x) and doubled diploid (C/CM4x) rootstocks. Nutrient deficiency effects on the seedlings and scion/rootstock combinations were analyzed by studying anatomical, structural and ultrastructural determinants (chlorosis, stomata, ostiole and cells and their organelles), photosynthetic properties (leaf net photosynthetic rate (Pₙₑₜ), stomatal conductance (gₛ), chlorophyll a fluorescence (Fᵥ/Fₘ)) and oxidative marker (malondialdehyde). Nutrient deficiency affected differently foliar tissues, physiological parameters, and oxidative metabolism in leaves of seedlings depending on their ploidy level and of common clementine scion depending on their rootstocks ploidy level. Both CM4x and C/CM4x presented lower foliar damages (chlorosis, chloroplasts, mitochondria, and plastoglobuli), photosynthesis processes alteration (Pₙₑₜ, gₛ, and Fᵥ/Fₘ), and malondialdehyde accumulation than CM2x and C/CM2x after nutrient deficiency. Doubled diploid Citrumelo 4475 can improve nutrient deficiency tolerance, and its use as a rootstock allows to confer this tolerance to the common clementine scion.

Keywords: nutrient deficiency, oxidative stress, photosynthesis, polyploid rootstocks

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Authors: Covadonga Rodrigo, Felipe Alvarez Arrieta, Ana Garcia Serrano

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Mobile augmented reality technologies have become very popular in the last years in the educational field. Researchers have studied how these technologies improve the engagement of the student and better understanding of the process of learning. But few studies have been made regarding the accessibility of these new technologies applied to digital humanities. The goal of our research is to develop an accessible mobile application with embedded augmented reality main characters of the art work and gamification events accompanied by multi-sensorial activities. The mobile app conducts a learning itinerary around the artistic work, driving the user experience in and out the museum. The learning design follows the inquiry-based methodology and social learning conducted through interaction with social networks. As for the software application, it’s being user-centered designed, following the universal design for learning (UDL) principles to assure the best level of accessibility for all. The mobile augmented reality application starts recognizing a marker from a masterpiece of a museum using the camera of the mobile device. The augmented reality information (history, author, 3D images, audio, quizzes) is shown through virtual main characters that come out from the art work. To comply with the UDL principles, we use a version of the technology acceptance model (TAM) to study the easiness of use and perception of usefulness, extended by the authors with specific indicators for measuring accessibility issues. Following a rapid prototype method for development, the first app has been recently produced, fulfilling the EN 301549 standard and W3C accessibility guidelines for mobile development. A TAM-based web questionnaire with 214 participants with different kinds of disabilities was previously conducted to gather information and feedback on user preferences from the artistic work on the Museo del Prado, the level of acceptance of technology innovations and the easiness of use of mobile elements. Preliminary results show that people with disabilities felt very comfortable while using mobile apps and internet connection. The augmented reality elements seem to offer an added value highly engaging and motivating for the students.

Keywords: H.5.1 (multimedia information systems), artificial, augmented and virtual realities, evaluation/methodology

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Authors: Omar Khan, Shana Krstevska, Edwin George, Veronica Gorden, Fen Bao, Christina Caon, NP-C, Carla Santiago, Imad Zak, Navid Seraji-Bozorgzad

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Objective: To quantify cellular injury in the substantia nigra (SN) in patients with Parkinson's disease (PD) and to examine the effect of rasagiline of tissue injury in the SN in patients with PD. Background: N-acetylaspartate (NAA) quantified with MRS is a reliable marker of neuronal metabolic function. Fractional anisotropy (FA) and mean diffusivity (MD) obtained with DTI, characterize tissue alignment and integrity. Rasagline, has been shown to exert anti-apototic effect. We applied these advanced MRI techniques to examine: (i) the effect of rasagiline on cellular injury and metabolism in patients with early PD, and (ii) longitudinal changes seen over time in PD. Methods: We conducted a prospective longitudinal study in patients with mild PD, naive to dopaminergic treatment. The imaging protocol included multi-voxel proton-MRS and DTI of the SN, acquired on a 3T scanner. Scans were performed at baseline and month 3, during which the patient was on no treatment. At that point, rasagiline 1 mg orally daily was initiated and MRI scans are were obtained at 6 and 12 months after starting rasagiline. The primary objective was to compare changes during the 3-month period of “no treatment” to the changes observed “on treatment” with rasagiline at month 12. Age-matched healthy controls were also imaged. Image analysis was performed blinded to treatment allocation and period. Results: 25 patients were enrolled in this study. Compared to the period of “no treatment”, there was significant increase in the NAA “on treatment” period (-3.04 % vs +10.95 %, p= 0.0006). Compared to the period of “no treatment”, there was significant increase in following 12 month in the FA “on treatment” (-4.8% vs +15.3%, p<0.0001). The MD increased during “no treatment” and decreased in “on treatment” (+2.8% vs -7.5%, p=0.0056). Further analysis and clinical correlation are ongoing. Conclusions: Advanced MRI techniques quantifying cellular injury in the SN in PD is a feasible approach to investigate dopaminergic neuronal injury and could be developed as an outcome in exploratory studies. Rasagiline appears to have a stabilizing effect on dopaminergic cell loss and metabolism in the SN in PD, that warrants further investigation in long-term studies.

Keywords: substantia nigra, Parkinson's disease, MRI, neuronal loss, biomarker

Procedia PDF Downloads 298

Authors: Junichi Hosoi

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Epidermal Langerhans cells reside in upper layer of epidermis and play a role in immune surveillance. The finding of the close association of nerve endings to Langerhans cells triggered the research on systemic regulation of Langerhans cells. They disappear from epidermis after exposure to environmental and internal stimuli and reappear about a week later. Myeloid progenitor cells are assumed to be one of the sources of Langerhans cells. We examined the effects of cortisol on the reappearance of Langerhans cells in vitro. Cord-blood derived CD34-positive cells were cultured in the medium supplemented with stem cell factor/Flt3 ligand/granulocyte macrophage-colony stimulating factor/tumor necrosis factor alpha/bone morphologic protein 7/transforming growth factor beta in the presence or absence of cortisol. Cells were analyzed by flow cytometry for CD1a (cluster differentiation 1a), a marker of Langerhans cells and dermal dendritic cells, and CD39 (cluster differentiation factor 39), extracellular adenosine triphosphatase. Both CD1a-positive cells and CD39-positive cells were decreased by treatment with cortisol (suppression by 35% and 22% compared to no stress hormone, respectively). Differentiated Langerhans cells are attracted to epidermis by chemokines that are secreted from keratinocytes. Epidermal keratinocytes were cultured in the presence or absence of cortisol and analyzed for the expression of CCL2 (C-C motif chemokine ligand 2) and CCL20 (C-C motif chemokine ligand 20), which are typical attractants of Langerhans cells, by quantitative reverse transcriptase polymerase chain reaction. The expression of both chemokines, CCL2 and CCL20, were suppressed by treatment with cortisol (suppression by 38% and 48% compared to no stress hormone, respectively). We examined the possible regulation of the suppression by cortisol with plant extracts. The extracts of Ganoderma lucidum and Iris protected the suppression of the differentiation to CD39-positive cells and also the suppression of the gene expression of LC-chemoattractants. These results suggest that cortisol, which is either systemic or locally produced, blocks the supply of epidermal Langerhans cells at 2 steps, differentiation from the precursor and attraction to epidermis. The suppression is possibly blocked by some plant extracts.

Keywords: Langerhans cell, stress, CD39, chemokine

Procedia PDF Downloads 160

Authors: Alaa Abdellatif, Gabrièle Breda

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Background. Advanced therapy medicinal products (ATMPs) are innovative therapies that mainly target orphan diseases and high unmet medical needs. ATMP includes gene therapy medicinal products (GTMP), somatic cell therapy medicinal products (CTMP), and tissue-engineered therapies (TEP). Since legislation opened the way in 2007, 25 ATMPs have been approved in the EU, which is about the same amount as the U.S. Food and Drug Administration. However, not all of the ATMPs that have been approved have successfully reached the market and retained their approval. Objectives. We aim to understand all the factors limiting the market access to very promising therapies in a systemic approach, to be able to overcome these problems, in the future, with scientific, regulatory and commercial innovations. Further to recent reviews that focus either on specific countries, products, or dimensions, we will address all the challenges faced by ATMP development today. Methodology. We used mixed methods and a multi-level approach for data collection. First, we performed an updated academic literature review on ATMP development and their scientific and market access challenges (papers published between 2018 and April 2023). Second, we analyzed industry feedback from cell and gene therapy webinars and white papers published by providers and pharmaceutical industries. Finally, we established a comparative analysis of the regulatory guidelines published by EMA and the FDA for ATMP approval. Results: The main challenges in bringing these therapies to market are the high development costs. Developing ATMPs is expensive due to the need for specialized manufacturing processes. Furthermore, the regulatory pathways for ATMPs are often complex and can vary between countries, making it challenging to obtain approval and ensure compliance with different regulations. As a result of the high costs associated with ATMPs, challenges in obtaining reimbursement from healthcare payers lead to limited patient access to these treatments. ATMPs are often developed for orphan diseases, which means that the patient population is limited for clinical trials which can make it challenging to demonstrate their safety and efficacy. In addition, the complex manufacturing processes required for ATMPs can make it challenging to scale up production to meet demand, which can limit their availability and increase costs. Finally, ATMPs face safety and efficacy challenges: dangerous adverse events of these therapies like toxicity related to the use of viral vectors or cell therapy, starting material and donor-related aspects. Conclusion. As a result of our mixed method analysis, we found that ATMPs face a number of challenges in their development, regulatory approval, and commercialization and that addressing these challenges requires collaboration between industry, regulators, healthcare providers, and patient groups. This first analysis will help us to address, for each challenge, proper and innovative solution(s) in order to increase the number of ATMPs approved and reach the patients

Keywords: advanced therapy medicinal products (ATMPs), product development, market access, innovation

Procedia PDF Downloads 55

Authors: G. Cunningham, E. Cantor, X. Wu, F. Shen, G. Jiang, S. Philips, C. Bales, Y. Xiao, T. R. Cummins, J. C. Fehrenbacher, B. P. Schneider

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Background: Taxane-induced peripheral neuropathy (TIPN) is the most devastating survivorship issue for patients receiving therapy. Dose reductions due to TIPN in the curative setting lead to inferior outcomes for African American patients, as prior research has shown that this group is more susceptible to developing severe neuropathy. The mechanistic underpinnings of TIPN, however, have not been entirely elucidated. While it would be appealing to use primary tissue to study the development of TIPN, procuring nerves from patients is not realistically feasible, as nerve biopsies are painful and may result in permanent damage. Therefore, our laboratory has investigated paclitaxel-induced neuronal morphological and molecular changes using an ex vivo model of human-induced pluripotent stem cell (iPSC)-derived neurons. Methods: iPSCs are undifferentiated and endlessly dividing cells that can be generated from a patient’s somatic cells, such as peripheral blood mononuclear cells (PBMCs). We successfully reprogrammed PBMCs into iPSCs using the Erythroid Progenitor Reprograming Kit (STEMCell Technologiesᵀᴹ); pluripotency was verified by flow cytometry analysis. iPSCs were then induced into neurons using a differentiation protocol that bypasses the neural progenitor stage and uses selected small-molecule modulators of key signaling pathways (SMAD, Notch, FGFR1 inhibition, and Wnt activation). Results: Flow cytometry analysis revealed expression of core pluripotency transcription factors Nanog, Oct3/4 and Sox2 in iPSCs overlaps with commercially purchased pluripotent cell line UCSD064i-20-2. Trilineage differentiation of iPSCs was confirmed with immunofluorescent imaging with germ-layer-specific markers; Sox17 and ExoA2 for ectoderm, Nestin, and Pax6 for mesoderm, and Ncam and Brachyury for endoderm. Sensory neuron markers, β-III tubulin, and Peripherin were applied to stain the cells for the maturity of iPSC-derived neurons. Patch-clamp electrophysiology and calcitonin gene-related peptide (CGRP) release data supported the functionality of the induced neurons and provided insight into the timing for which downstream assays could be performed (week 4 post-induction). We have also performed a cell viability assay and fluorescence-activated cell sorting (FACS) using four cell-surface markers (CD184, CD44, CD15, and CD24) to select a neuronal population. At least 70% of the cells were viable in the isolated neuron population. Conclusion: We have found that these iPSC-derived neurons recapitulate mature neuronal phenotypes and demonstrate functionality. Thus, this represents a patient-derived ex vivo neuronal model to investigate the molecular mechanisms of clinical TIPN.

Keywords: chemotherapy, iPSC-derived neurons, peripheral neuropathy, taxane, paclitaxel

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Authors: Cheng-Chen Hsu

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Background: The ratio of the length of the second finger (index finger, 2D) to the fourth finger (ring finger, 4D) (2D:4D) is a putative marker of prenatal hormones. A low 2D:4D ratio is related to high prenatal testosterone (PT) levels. Physiological research has suggested that a low 2D:4D ratio is correlated with high sports ability. Aim: To examine the association between cardiorespiratory fitness and 2D:4D. Methods: Assessment of 2D:4D; Images of hands were collected from participants using a computer scanner. Hands were placed lightly on the surface of the plate. Image analysis was performed using Image-Pro Plus 5.0 software. Feature points were marked at the tip of the finger and at the center of the proximal crease on the second and fourth digits. Actual measurement was carried out automatically, 2D:4D was calculated by dividing 2nd by 4th digit length. YMCA 3-min Step Test; The test involves stepping up and down at a rate of 24 steps/min for 3 min; a tape recording of the correct cadence (96 beats/min) is played to assist the participant in keeping the correct pace. Following the step test, the participant immediately sits down and, within 5 s, the tester starts counting the pulse for 1 min. The score for the test, the total 1-min postexercise heart rate, reflects the heart’s ability to recover quickly. Statistical Analysis ; Pearson’s correlation (r) was used for assessing the relationship between age, physical measurements, one-minute heart rate after YMCA 3-minute step test (HR) and 2D:4D. An independent-sample t-test was used for determining possible differences in HR between subjects with low and high values of 2D:4D. All statistical analyses were carried out with SPSS 18 for Window. All P-values were two-tailed at P = 0.05, if not reported otherwise. Results: A median split by 2D:4D was applied, resulting in a high and a low group. One-minute heart rate after YMCA 3-minute step test was significantly difference between groups of male right-hand 2D:4D (p = 0.024). However, no difference in left-hand 2D:4D values between groups in male, and no digit ratio difference between groups in female. Conclusion: The results showed that cardiopulmonary fitness is related to right 2D:4D, only in men. We argue that prenatal testosterone may have an effect on cardiorespiratory fitness in male but not in female.

Keywords: college students, digit ratio, finger, step test, fitness

Procedia PDF Downloads 254

Authors: Alice Carter, Lucy Dumbell, Lorna Cameron, Victoria Lewis

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The Olympic discipline of eventing is the triathlon of equestrian sport, consisting of dressage, cross-country and show jumping. Falls on the cross-country are common and can be serious even causing death to rider. Research identifies an increased risk of a fall with an increasing number of obstacles and for jumping efforts later in the course suggesting fatigue maybe a contributing factor. Advice based on anecdotal evidence suggests riders undertake strength and conditioning programs to improve their ‘core’, thus improving their ability to maintain and control their riding position. There is little empirical evidence to support this advice. Therefore, the aim of this study is to investigate truck muscle fatigue and cognitive function during a simulated jumping test. Eight adult riders participated in a riding test on a Racewood Event simulator for 10 minutes, over a continuous jumping programme. The SEMG activity of six trunk muscles were bilaterally measured at every minute, and normalised root mean squares (RMS) and median frequencies (MDF) were computed from the EMG power spectra. Visual analogue scales (VAS) measuring Fatigue and Pain levels and Cognitive Function ‘tapping’ tests were performed before and after the riding test. Average MDF values for all muscles differed significantly between each sampled minute (p = 0.017), however a consistent decrease from Minute 1 and Minute 9 was not found, suggesting the trunk muscles fatigued and then recovered as other muscle groups important in maintaining the riding position during dynamic movement compensated. Differences between the MDF and RMS of different muscles were highly significant (H=213.01, DF=5, p < 0.001), supporting previous anecdotal evidence that different trunk muscles carry out different roles of posture maintenance during riding. RMS values were not significantly different between the sampled minutes or between riders, suggesting the riding test produced a consistent and repeatable effect on the trunk muscles. MDF values differed significantly between riders (H=50.8, DF = 5, p < 0.001), suggesting individuals may experience localised muscular fatigue of the same test differently, and that other parameters of physical fitness should be investigated to provide conclusions. Lumbar muscles were shown to be important in maintaining the position, therefore physical training program should focus on these areas. No significant differences were found between pre- and post-riding test VAS Pain and Fatigue scores or cognitive function test scores, suggesting the riding test was not significantly fatiguing for participants. However, a near significant correlation was found between time of riding test and VAS Pain score (p = 0.06), suggesting somatic pain may be a limiting factor to performance. No other correlations were found between the factors of participant riding test time, VAS Pain and Fatigue, however a larger sample needs to be tested to improve statistical analysis. The findings suggest the simulator riding test was not sufficient to provoke fatigue in the riders, however foundations for future studies have been laid to enable methodologies in realistic eventing settings.

Keywords: eventing, fatigue, horse-rider, surface EMG, trunk muscles

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Authors: Vichayada Laohapiboolkul

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Introduction: As the legal use of cannabis is being widely accepted throughout the world, medical cannabis has been explored in order to become an alternative cure for patients. Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are natural cannabinoids found in the Cannabis plant which is proved to have positive treatment for various diseases and symptoms such as chronic pain, neuropathic pain, spasticity resulting from multiple sclerosis, reduce cancer-associated pain, autism spectrum disorders (ASD), dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette's disorder. Regardless of all the medical benefits, THC, if not metabolized, can lead to mild up to severe adverse drug reactions (ADR). The enzyme CYP2C19 was found to be one of the metabolizers of THC. However, the suballele CYP2C19*2 manifests as a poor metabolizer which could lead to higher levels of THC than usual, possibly leading to various ADRs. Objective: The aim of this study was to investigate the distribution of CYP2C19, specifically CYP2C19*2, genes in Thai patients treated with medical cannabis along with adverse drug reactions. Materials and Methods: Clinical data and EDTA whole blood for DNA extraction and genotyping were collected from patients for this study. CYP2C19*2 (681G>A, rs4244285) genotyping was conducted using the Real-time PCR (ABI, Foster City, CA, USA). Results: There were 42 medical cannabis-induced ADRs cases and 18 medical cannabis tolerance controls who were included in this study. A total of 60 patients were observed where 38 (63.3%) patients were female and 22 (36.7%) were male, with a range of age approximately 19 - 87 years. The most apparent ADRs for medical cannabis treatment were dry mouth/dry throat (76.7%), followed by tachycardia (70%), nausea (30%) and a few arrhythmias (10%). In the total of 27 cases, we found a frequency of 18 CYP2C19*1/*1 alleles (normal metabolizers, 66.7%), 8 CYP2C19*1/*2 alleles (intermediate metabolizers, 29.6%) and 1 CYP2C19*2/*2 alleles (poor metabolizers, 3.7%). Meanwhile, 63.6% of CYP2C19*1/*1, 36.3% and 0% of CYP2C19*1/*2 and *2/*2 in the tolerance controls group, respectively. Conclusions: This is the first study to confirm the distribution of CYP2C19*2 allele and the prevalence of poor metabolizer genes in Thai patients who received medical cannabis for treatment. Thus, CYP2C19 allele might serve as a pharmacogenetics marker for screening before initiating treatment.

Keywords: medical cannabis, adverse drug reactions, CYP2C19, tetrahydrocannabinol, poor metabolizer

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Authors: Ayca Bilginoglu, Belma Turan

Abstract:

Metabolic syndrome, is associated impaired blood glucose level, insulin resistance, dyslipidemia caused by abdominal obesity. Also, it is related with cardiovascular risk accumulation and cardiomyopathy. The hypothesis of this study was to examine the effect of thiazolidinediones such as pioglitazone which is widely used insulin-sensitizing agents that improve glycemic control, on intracellular Na+ homeostasis in metabolic syndrome-induced cardiomyopathy in male rats. Male Wistar-Albino rats were randomly divided into three groups, namely control (Con, n=7), metabolic syndrome (MetS, n=7) and pioglitazone treated metabolic syndrome group (MetS+PGZ, n=7). Metabolic syndrome was induced by providing drinking water that was 32% sucrose, for 18 weeks. All of the animals were exposed to a 12 h light – 12 h dark cycle. Abdominal obesity and glucose intolerance had measured as a marker of metabolic syndrome. Intracellular Na+ ([Na+]i) is an important modulator of excitation–contraction coupling in heart. [Na+]i at rest and [Na+]i during pacing with electrical field stimulation in 0.2 Hz, 0.8 Hz, 2.0 Hz stimulation frequency were recorded in cardiomyocytes. Also, Na+ channel current (INa) density and I-V curve were measured to understand [Na+]i homeostasis. In results, high sucrose intake, as well as the normal daily diet, significantly increased body mass and blood glucose level of the rats in the metabolic syndrome group as compared with the non-treated control group. In MetS+PZG group, the blood glucose level and body inclined to decrease to the Con group. There was a decrease in INa density and there was a shift both activation and inactivation curve of INa. Pioglitazone reversed the shift to the control side. Basal [Na+]i either MetS and Con group were not significantly different, but there was a significantly increase in [Na+]i in stimulated cardiomyocytes in MetS group. Furthermore, pioglitazone had not effect on basal [Na+]i but it reversed the increase in [Na+]i in stimulated cardiomyocytes to the that of Con group. Results of the present study suggest that pioglitazone has a significant effect on the Na+ homeostasis in the metabolic syndrome induced cardiomyopathy in rats. All animal procedures and experiments were approved by the Animal Ethics Committee of Ankara University Faculty of Medicine (2015-2-37).

Keywords: insulin resistance, intracellular sodium, metabolic syndrome, sodium current

Procedia PDF Downloads 268

Authors: S. Koppikar, P. Kulkarni, D. Ingale , N. Wagh, S. Deshpande, A. Mahajan, A. Harsulkar

Abstract:

Crucial role of reactive oxygen species (ROS) in the progression Osteoarthritis (OA) pathogenesis has been endorsed several times though its exact mechanism remains unclear. Oxidative stress is known to instigate classical stress factors such as cytokines, chemokines and ROS, which hampers cartilage remodelling process and ultimately results in worsening the disease. Synovial fluid (SF) is a biological communicator between cartilage and synovium that accumulates redox and biochemical signalling mediators. The present work attempts to measure several oxidative stress markers in the synovial fluid obtained from knee OA patients with varying degree of disease severity. Thirty OA and five Meniscal-tear (MT) patients were graded using Kellgren-Lawrence scale and assessed for Nitric oxide (NO), Nitrate-Nitrite (NN), 2,2-diphenyl-1-picrylhydrazyl (DPPH), Ferric Reducing Antioxidant Potential (FRAP), Catalase (CAT), Superoxide dismutase (SOD) and Malondialdehyde (MDA) levels for comparison. Out of various oxidative markers studied, NO and SOD showed significant difference between moderate and severe OA (p= 0.007 and p= 0.08, respectively), whereas CAT demonstrated significant difference between MT and mild group (p= 0.07). Interestingly, NN revealed statistically positive correlation with OA severity (p= 0.001 and p= 0.003). MDA, a lipid peroxidation by-product was estimated maximum in early OA when compared to MT (p= 0.06). However, FRAP did not show any correlation with OA severity or MT control. NO is an essential bio-regulatory molecule essential for several physiological processes, and inflammatory conditions. However, due to its short life, exact estimation of NO becomes difficult. NO and its measurable stable products are still it is considered as one of the important biomarker of oxidative damage. Levels of NO and nitrite-nitrate in SF of patients with OA indicated its involvement in the disease progression. When SF groups were compared, a significant correlation among moderate, mild and MT groups was established. To summarize, present data illustrated higher levels of NO, SOD, CAT, DPPH and MDA in early OA in comparison with MT, as a control group. NN had emerged as a prognostic bio marker in knee OA patients, which may act as futuristic targets in OA treatment.

Keywords: antioxidant, knee osteoarthritis, oxidative stress, synovial fluid

Procedia PDF Downloads 455