Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 89

Search results for: therapeutics

89 Assessment of Barriers to the Clinical Adoption of Cell-Based Therapeutics

Authors: David Pettitt, Benjamin Davies, Georg Holländer, David Brindley

Abstract:

Cellular based therapies, whose origins can be traced from the intertwined concepts of tissue engineering and regenerative medicine, have the potential to transform the current medical landscape and offer an approach to managing what were once considered untreatable diseases. However, despite a large increase in basic science activity in the cell therapy arena alongside a growing portfolio of cell therapy trials, the number of industry products available for widespread clinical use correlates poorly with such a magnitude of activity, with the number of cell-based therapeutics in mainstream use remaining comparatively low. This research serves to quantitatively assess the barriers to the clinical adoption of cell-based therapeutics through identification of unique barriers, specific challenges and opportunities facing the development and adoption of such therapies.

Keywords: cell therapy, clinical adoption, commercialization, translation

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88 The Effect of Heat Stress on the Gastro-Intestinal Microbiota of Pigs

Authors: Yadnyavalkya Patil, Ravi Gooneratne, Xiang-Hong Ju

Abstract:

Heat stress (HS) negatively affects the physiology of pigs. In this study, 6 pigs will be subjected to temperatures of 35 ± 2℃ for 12 hrs/day for a duration of 21 days. The changes in the gastrointestinal tract (GIT) microbiota will be observed by analyzing the freshly collected faeces on days 1, 3, 7, 14 and 21. The changes will be compared to faeces from a set of 6 control pigs kept simultaneously at temperatures of 26 ± 2℃ for the same duration of 21 days. Different types of stresses such a weaning have a detrimental effect on GIT microflora. Similarly, HS is expected to have a harmful effect on the microbial diversity of the GIT. How these changes affect the immune system of the pigs will be studied and therapeutics to reduce the negative effects of HS will be developed.

Keywords: GIT microbiota, heat stress, immune system, therapeutics

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87 Tunable Control of Therapeutics Release from the Nanochannel Delivery System (nDS)

Authors: Thomas Geninatti, Bruno Giacomo, Alessandro Grattoni

Abstract:

Nanofluidic devices have been investigated for over a decade as promising platforms for the controlled release of therapeutics. The nanochannel drug delivery system (nDS), a membrane fabricated with high precision silicon techniques, capable of zero-order release of drugs by exploiting diffusion transport at the nanoscale originated from the interactions between molecules with nanochannel surfaces, showed the flexibility of the sustained release in vitro and in vivo, over periods of time ranging from weeks to months. To improve the implantable bio nanotechnology, in order to create a system that possesses the key features for achieve the suitable release of therapeutics, the next generation of nDS has been created. Platinum electrodes are integrated by e-beam deposition onto both surfaces of the membrane allowing low voltage (<2 V) and active temporal control of drug release through modulation of electrostatic potentials at the inlet and outlet of the membrane’s fluidic channels. Hence, a tunable administration of drugs is ensured from the nanochannel drug delivery system. The membrane will be incorporated into a peek implantable capsule, which will include drug reservoir, control hardware and RF system to allow suitable therapeutic regimens in real-time. Therefore, this new nanotechnology offers tremendous potential solutions to manage chronic disease such as cancer, heart disease, circadian dysfunction, pain and stress.

Keywords: nanochannel membrane, drug delivery, tunable release, personalized administration, nanoscale transport, biomems

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86 Anti-Fibrillation Propensity of a Flavonoid Baicalein against the Fibrils of Hen Egg White Lysozyme: Potential Therapeutics for Lysozyme Amyloidosis

Authors: Naveed Ahmad Fazili

Abstract:

More than 20 human diseases involve the fibrillation of a specific protein/peptide which forms pathological deposits at various sites. Hereditary lysozyme amyloidosis is a systemic disorder which mostly affects liver, spleen and kidney. This conformational disorder is featured by lysozyme fibril formation. In vivo lysozyme fibrillation was simulated under in vitro conditions using a strong denaturant GdHCl at 3M concentration. Sharp decline in the ANS fluorescence intensity compared to the partially unfolded states, almost 20 fold increase in ThT fluorescence intensity, increase in absorbance at 450 nm suggesting turbidity, negative ellipticity peak in the far-UVCD at 217 nm, red shift of 50 nm compared to the native state in congo red assay and appearance of a network of long rope like fibrils in TEM analysis suggested HEWL fibrillation. Anti-fibrillation potency of baicalein against the preformed fibrils of HEWL was investigated following ThT assay in which there was a dose dependent decrease in ThT fluorescence intensity compared to the fibrillar state of HEWL with the maximum effect observed at 150 μM baicalein concentration, loss of negative ellipticity peak in the far-UVCD region, dip in the Rayleigh scattering intensity and absorbance at 350 nm and 450 nm respectively together with a reduction in the density of fibrillar structure in TEM imaging. Thus, it could be suggested that baicalein could prove to be a positive therapeutics for hereditary human lysozyme amyloidosis.

Keywords: amyloid fibrils, baicalein, congo red, negative ellipticity, therapeutics

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85 Cloning and Expression of Azurin: A Protein Having Antitumor and Cell Penetrating Ability

Authors: Mohsina Akhter

Abstract:

Cancer has become a wide spread disease around the globe and takes many lives every year. Different treatments are being practiced but all have potential side effects with somewhat less specificity towards target sites. Pseudomonas aeruginosa is known to secrete a protein azurin with special anti-cancer function. It has unique cell penetrating peptide comprising of 18 amino acids that have ability to enter cancer cells specifically. Reported function of Azurin is to stabilize p53 inside the tumor cells and induces apoptosis through Bax mediated cytochrome c release from mitochondria. At laboratory scale, we have made recombinant azurin through cloning rpTZ57R/T-azu vector into E.coli strain DH-5α and subcloning rpET28-azu vector into E.coli BL21-CodonPlus (DE3). High expression was ensured with IPTG induction at different concentrations then optimized high expression level at 1mM concentration of IPTG for 5 hours. Purification has been done by using Ni+2 affinity chromatography. We have concluded that azurin can be a remarkable improvement in cancer therapeutics if it produces on a large scale. Azurin does not enter into the normal cells so it will prove a safe and secure treatment for patients and prevent them from hazardous anomalies.

Keywords: azurin, pseudomonas aeruginosa, cancer, therapeutics

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84 Predicting Potential Protein Therapeutic Candidates from the Gut Microbiome

Authors: Prasanna Ramachandran, Kareem Graham, Helena Kiefel, Sunit Jain, Todd DeSantis

Abstract:

Microbes that reside inside the mammalian GI tract, commonly referred to as the gut microbiome, have been shown to have therapeutic effects in animal models of disease. We hypothesize that specific proteins produced by these microbes are responsible for this activity and may be used directly as therapeutics. To speed up the discovery of these key proteins from the big-data metagenomics, we have applied machine learning techniques. Using amino acid sequences of known epitopes and their corresponding binding partners, protein interaction descriptors (PID) were calculated, making a positive interaction set. A negative interaction dataset was calculated using sequences of proteins known not to interact with these same binding partners. Using Random Forest and positive and negative PID, a machine learning model was trained and used to predict interacting versus non-interacting proteins. Furthermore, the continuous variable, cosine similarity in the interaction descriptors was used to rank bacterial therapeutic candidates. Laboratory binding assays were conducted to test the candidates for their potential as therapeutics. Results from binding assays reveal the accuracy of the machine learning prediction and are subsequently used to further improve the model.

Keywords: protein-interactions, machine-learning, metagenomics, microbiome

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83 Characterization of the Catalytic and Structural Roles of the Human Hexokinase 2 in Cancer Progression

Authors: Mir Hussain Nawaz, Lyudmila Nedyalkova, Haizhong Zhu, Wael M. Rabeh

Abstract:

In this study, we aim to biochemically and structurally characterize the interactions of human HK2 with the mitochondria in addition to the role of its N-terminal domain in catalysis and stability of the full-length enzyme. Here, we solved the crystal structure of human HK2 in complex with glucose and glucose-6-phosphate (PDB code: 2NZT), where it is a homodimer with catalytically active N- and C-terminal domains linked by a seven-turn α-helix. Different from the inactive N-terminal domains of isozymes 1 and 3, the N- domain of HK2 not only capable to catalyze a reaction but it is responsible for the thermodynamic stabilizes of the full-length enzyme. Deletion of first α-helix of the N-domain that binds to the mitochondria altered the stability and catalytic activity of the full-length HK2. In addition, we found the linker helix between the N- and C-terminal domains to play an important role in controlling the catalytic activity of the N-terminal domain. HK2 is a major step in the regulation of glucose metabolism in cancer making it an ideal target for the development of new anticancer therapeutics. Characterizing the structural and molecular mechanisms of human HK2 and its role in cancer metabolism will accelerate the design and development of new cancer therapeutics that are safe and cancer specific.

Keywords: cancer metabolism, enzymology, drug discovery, protein stability

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82 A Next Generation Multi-Scale Modeling Theatre for in silico Oncology

Authors: Safee Chaudhary, Mahnoor Naseer Gondal, Hira Anees Awan, Abdul Rehman, Ammar Arif, Risham Hussain, Huma Khawar, Zainab Arshad, Muhammad Faizyab Ali Chaudhary, Waleed Ahmed, Muhammad Umer Sultan, Bibi Amina, Salaar Khan, Muhammad Moaz Ahmad, Osama Shiraz Shah, Hadia Hameed, Muhammad Farooq Ahmad Butt, Muhammad Ahmad, Sameer Ahmed, Fayyaz Ahmed, Omer Ishaq, Waqar Nabi, Wim Vanderbauwhede, Bilal Wajid, Huma Shehwana, Muhammad Tariq, Amir Faisal

Abstract:

Cancer is a manifestation of multifactorial deregulations in biomolecular pathways. These deregulations arise from the complex multi-scale interplay between cellular and extracellular factors. Such multifactorial aberrations at gene, protein, and extracellular scales need to be investigated systematically towards decoding the underlying mechanisms and orchestrating therapeutic interventions for patient treatment. In this work, we propose ‘TISON’, a next-generation web-based multiscale modeling platform for clinical systems oncology. TISON’s unique modeling abstraction allows a seamless coupling of information from biomolecular networks, cell decision circuits, extra-cellular environments, and tissue geometries. The platform can undertake multiscale sensitivity analysis towards in silico biomarker identification and drug evaluation on cellular phenotypes in user-defined tissue geometries. Furthermore, integration of cancer expression databases such as The Cancer Genome Atlas (TCGA) and Human Proteome Atlas (HPA) facilitates in the development of personalized therapeutics. TISON is the next-evolution of multiscale cancer modeling and simulation platforms and provides a ‘zero-code’ model development, simulation, and analysis environment for application in clinical settings.

Keywords: systems oncology, cancer systems biology, cancer therapeutics, personalized therapeutics, cancer modelling

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81 Nitric Oxide: Role in Immunity and Therapeutics

Authors: Anusha Bhardwaj, Shekhar Shinde

Abstract:

Nitric oxide (NO•) has been documented in research papers as one of the most versatile player in the therapeutics. It is identified as a biological multifunctional messenger molecule which is synthesized by the action of nitric oxide synthase (NOS) enzyme from L-arginine. The protective and the toxic effect in conjunction form the complete picture of the biological function of nitric oxide in humans. The dual nature is because of various factors such as concentration of NO, the isoform of NOS involved, type of cells in which it is synthesized, reaction partners like proteins, reactive oxygen intermediates, prosthetic groups, thiols etc., availability of the substrate L-arginine, intracellular environment in which NO is produced and generation of guanosine 3, 5’- cyclic monophosphate (cGMP). Activation of NOS through infection or trauma leads to one or more systemic effects including enhanced immune activity against invading pathogens, vaso/bronchodilatation in the cardiovascular and respiratory systems and altered neurotransmission which can be protective or toxic. Hence, NO affects the balance between healthy signaling and neurodegeneration in the brain. In lungs, it has beneficial effects on the function of airways as a bronchodilator and acts as the neurotransmitter of bronchodilator nerves. Whereas, on the other hand, NO may have deleterious effects by amplifying the asthmatic inflammatory response and also act as a vasodilator in the airways by increasing plasma exudation. But NOS Inhibitors and NO donors hamper the signalling pathway and hence a therapeutic application of NO is compromised.

Keywords: nitric oxide, multifunctional, dual nature, therapeutic applications

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80 Exploration of Probiotics and Anti-Microbial Agents in Fermented Milk from Pakistani Camel spp. Breeds

Authors: Deeba N. Baig, Ateeqa Ijaz, Saloome Rafiq

Abstract:

Camel is a religious and culturally significant animal in Asian and African regions. In Pakistan Dromedary and Bactrian are common camel breeds. Other than the transportation use, it is a pivotal source of milk and meat. The quality of its milk and meat is predominantly dependent on the geographical location and variety of vegetation available for the diet. Camel milk (CM) is highly nutritious because of its reduced cholesterol and sugar contents along with enhanced minerals and vitamins level. The absence of beta-lactoglobulin (like human milk), makes CM a safer alternative for infants and children having Cow Milk Allergy (CMA). In addition to this, it has a unique probiotic profile both in raw and fermented form. Number of Lactic acid bacteria (LAB) including lactococcus, lactobacillus, enterococcus, streptococcus, weissella, pediococcus and many other bacteria have been detected. From these LAB Lactobacilli, Bifidobacterium and Enterococcus are widely used commercially for fermentation purpose. CM has high therapeutic value as its effectiveness is known against various ailments like fever, arthritis, asthma, gastritis, hepatitis, Jaundice, constipation, postpartum care of women, anti-venom, dropsy etc. It also has anti-diabetic, anti-microbial, antitumor potential along with its robust efficacy in the treatment of auto-immune disorders. Recently, the role of CM has been explored in brain-gut axis for the therapeutics of neurodevelopmental disorders. In this connection, a lot of grey area was available to explore the probiotics and therapeutics latent in the CM available in Pakistan. Thus, current study was designed to explore the predominant probiotic flora and antimicrobial potential of CM from different local breeds of Pakistan. The probiotics have been identified through biochemical, physiological and ribo-typing methods. In addition to this, bacteriocins (antimicrobial-agents) were screened through PCR-based approach. Results of this study revealed that CM from different breeds of camel depicted a number of similar probiotic candidates along with the range of limited variability. However, the nucleotide sequence analysis of selected anti-listerial bacteriocins exposed least variability. As a conclusion, the CM has sufficient probiotic availability and significant anti-microbial potential.

Keywords: bacteriocins, camel milk, probiotics potential, therapeutics

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79 Aza-Flavanones as Small Molecule Inhibitors of MicroRNA-10b in MDA-MB-231 Breast Cancer Cells

Authors: Debasmita Mukhopadhyay, Manika Pal Bhadra

Abstract:

MiRNAs contribute to oncogenesis either as tumor suppressors or oncogenes. Hence, discovery of miRNA-based therapeutics are imperative to ameliorate cancer. Modulation of miRNA maturation is accomplished via several therapeutic agents, including small molecules and oligonucleotides. Due to the attractive pharmacokinetic properties of small molecules over oligonucleotides, we set to identify small molecule inhibitors of a metastasis-inducing microRNA. Cytotoxicity profile of aza-flavanone C1 was analyzed in a panel of breast cancer cells employing the NCI-60 screen protocols. Flow cytometry, immunofluorescence and western blotting of apoptotic or EMT markers were performed to analyze the effect of C1. A dual luciferase assay unequivocally suggested that C1 repressed endogenous miR-10b in MDA-MB-231 cells. A derivative of aza-flavanone C1 is shown as a strong inhibitor miR-10b. Blockade of miR-10b by C1 resulted in decreased expression of miR-10b targets in an aggressive breast cancer cell line model, MDA-MB-231. Abrogation of TWIST1, an EMT-inducing transcription factor also contributed to C1 mediated apoptosis. Moreover C1 exhibited a specific and selective down-regulation of miR-10b and did not function as a general inhibitor of miRNA biogenesis or other oncomiRs of breast carcinoma. Aza-flavanone congener C1 functions as a potent inhibitor of the metastasis-inducing microRNA, miR-10b. Our present study provides evidence for targeting metastasis-inducing microRNA, miR-10b with a derivative of Aza-flavanone. Better pharmacokinetic properties of small molecules place them as attractive agents compared to nucleic acids based therapies to target miRNA. Further work, in generating analogues based on aza-flavanone moieties will significantly improve the affinity of the small molecules to bind miR-10b. Finally, it is imperative to develop small molecules as novel miRNA-therapeutics in the fight against cancer.

Keywords: breast cancer, microRNA, metastasis, EMT

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78 Mannose-Functionalized Lipopolysaccharide Nanoparticles for Macrophage-Targeted Dual Delivery of Rifampicin and Isoniazid

Authors: Mumuni Sumaila, Viness Pillay, Yahya E. Choonara, Pradeep Kumar, Pierre P. Kondiah

Abstract:

Tuberculosis (TB) remains a serious challenge to public health globally, despite every effort put together to curb the disease. Current TB therapeutics available have proven to be inefficient due to a multitude of drawbacks that range from serious adverse effects/drug toxicity to inconsistent bioavailability, which ultimately contributes to the emergence of drug-resistant TB. An effective ‘cargo’ system designed to cleverly deliver therapeutic doses of anti-TB drugs to infection sites and in a sustained-release manner may provide a better therapeutic choice towards winning the war against TB. In the current study, we investigated mannose-functionalized lipopolysaccharide hybrid nanoparticles for safety and efficacy towards macrophage-targeted simultaneous delivery of the two first-line anti-TB drugs, rifampicin (RF) and isoniazid (IS). RF-IS-loaded lipopolysaccharide hybrid nanoparticles were fabricated using the solvent injection technique (SIT), incorporating soy lecithin (SL) and low molecular weight chitosan (CS) as the lipid and polysaccharide components, respectively. Surface-functionalized nanoparticles were obtained through the reaction of the aldehyde group of mannose with free amine functionality present at the surface of the nanoparticles. The functionalized nanocarriers were spherical with average particle size and surface charge of 107.83 nm and +21.77 mV, respectively, and entrapment efficiencies (EE) were 53.52% and 69.80% for RF and IS, respectively. FTIR spectrum revealed high-intensity bands between 1663 cm⁻¹ and 1408 cm⁻¹ wavenumbers (absent in non-functionalized nanoparticles), which could be attributed to the C=N stretching vibration produced by the formation of Schiff’s base (–N=CH–) during the mannosylation reaction. In vitro release studies showed a sustained-release profile for RF and IS, with less than half of the total payload released over a 48-hour period. The nanocarriers were biocompatible and safe, with more than 80% cell viability achieved when incubated with RAW 264.7 cells at concentrations 30 to 500 μg/mL over a 24-hour period. Cellular uptake studies (after a 24-hour incubation period with the murine macrophage cells, RAW 264.7) revealed a 13- and a 9-fold increase in intracellular accumulation of RF and IS, respectively, when compared with the unformulated RF+IS solution. A 6- and a 3-fold increase in intracellular accumulation of RF and IS, respectively, were observed when compared with the non-functionalized nanoparticles. Furthermore, fluorescent microscopy images showed nanoparticle internalization and accumulation within the RAW 264.7 cells, which was more significant in the mannose-functionalized system compared to the non-functionalized nanoparticles. The overall results suggested that the fabricated mannose-functionalized lipopolysaccharide nanoparticles are a safe and promising platform for macrophage-targeted delivery of anti-TB therapeutics. However, in vivo pharmacokinetic/pharmacodynamics studies are required to further substantiate the therapeutic efficacy of the nanosystem.

Keywords: anti-tuberculosis therapeutics, hybrid nanosystem, lipopolysaccharide nanoparticles, macrophage-targeted delivery

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77 Evaluation of the Inhibitory Activity of Natural Extracts From Spontaneous Plant on the Α-Amylase and Α–Glucosidase and Their Antioxidant Activities

Authors: Ihcen Khacheba, Amar Djeridane, Abdelkarim Kamli, Mohamed Yousfi

Abstract:

Plant materials constitute an important source of natural bioactive molecules. Thus plants have been used from antiquity as sources of medicament against various diseases. These properties are usually attributed to secondary metabolites that are the subject of a lot of research in this field. This is particularly the case of phenolic compounds plants that are widely renowned in therapeutics as anti-inflammatories, enzyme inhibitors, and antioxidants, particularly flavonoïds. With the aim of acquiring a better knowledge of the secondary metabolism of the vegetable kingdom in the region of Laghouat and of the discovering of new natural therapeutics, 10 extracts from 5 Saharan plant species were submitted to chemical screening.The analysis of the preceding biological targets led to the evaluation of the biological activity of the extracts of the species Genista Corsica. The first step, consists in extracting and quantifying phenolic compounds. The second step has been devoted to stugying the effects of phenolic compounds on the kinetics catalyzed by two enzymes belonging to the class of hydrolase (the α-amylase and α-glucosidase) responsible for the digestion of sugars and finally we evaluate the antiantioxidant potential. The analysis results of phenolic extracts show clearly a low content of phenolic compounds in investigated plants. Average total phenolics ranged from 0.0017 to 11.35 mg equivalent gallic acid/g of the crude extract. Whereas the total flavonoids content lie between 0.0015 and 10.,96 mg/g equivalent of rutin. The results of the kinetic study of enzymatic reactions show that the extracts have inhibitory effects on both enzymes, with IC50 values ranging from 95.03 µg/ml to 1033.53 µg/ml for the α-amylase and 279.99 µg/ml to 1215.43 µg/ml for α-glucosidase whose greatest inhibition was found for the acetone extract of June (IC50 = 95.03 µg/ml). The results the antioxidant activity determined by ABTS, DPPH, and phosphomolybdenum tests clearly showed a good antioxidant capacity comparatively to antioxidants taken as reference the biological potential of these plants and could find their use in medicine to replace synthetic products.

Keywords: phenolic extracts, inhibition effect, α-amylase, α-glucosidase, antioxidant activity

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76 Interactive Virtual Patient Simulation Enhances Pharmacology Education and Clinical Practice

Authors: Lyndsee Baumann-Birkbeck, Sohil A. Khan, Shailendra Anoopkumar-Dukie, Gary D. Grant

Abstract:

Technology-enhanced education tools are being rapidly integrated into health programs globally. These tools provide an interactive platform for students and can be used to deliver topics in various modes including games and simulations. Simulations are of particular interest to healthcare education, where they are employed to enhance clinical knowledge and help to bridge the gap between theory and practice. Simulations will often assess competencies for practical tasks, yet limited research examines the effects of simulation on student perceptions of their learning. The aim of this study was to determine the effects of an interactive virtual patient simulation for pharmacology education and clinical practice on student knowledge, skills and confidence. Ethics approval for the study was obtained from Griffith University Research Ethics Committee (PHM/11/14/HREC). The simulation was intended to replicate the pharmacy environment and patient interaction. The content was designed to enhance knowledge of proton-pump inhibitor pharmacology, role in therapeutics and safe supply to patients. The tool was deployed into a third-year clinical pharmacology and therapeutics course. A number of core practice areas were examined including the competency domains of questioning, counselling, referral and product provision. Baseline measures of student self-reported knowledge, skills and confidence were taken prior to the simulation using a specifically designed questionnaire. A more extensive questionnaire was deployed following the virtual patient simulation, which also included measures of student engagement with the activity. A quiz assessing student factual and conceptual knowledge of proton-pump inhibitor pharmacology and related counselling information was also included in both questionnaires. Sixty-one students (response rate >95%) from two cohorts (2014 and 2015) participated in the study. Chi-square analyses were performed and data analysed using Fishers exact test. Results demonstrate that student knowledge, skills and confidence within the competency domains of questioning, counselling, referral and product provision, show improvement following the implementation of the virtual patient simulation. Statistically significant (p<0.05) improvement occurred in ten of the possible twelve self-reported measurement areas. Greatest magnitude of improvement occurred in the area of counselling (student confidence p<0.0001). Student confidence in all domains (questioning, counselling, referral and product provision) showed a marked increase. Student performance in the quiz also improved, demonstrating a 10% improvement overall for pharmacology knowledge and clinical practice following the simulation. Overall, 85% of students reported the simulation to be engaging and 93% of students felt the virtual patient simulation enhanced learning. The data suggests that the interactive virtual patient simulation developed for clinical pharmacology and therapeutics education enhanced students knowledge, skill and confidence, with respect to the competency domains of questioning, counselling, referral and product provision. These self-reported measures appear to translate to learning outcomes, as demonstrated by the improved student performance in the quiz assessment item. Future research of education using virtual simulation should seek to incorporate modern quantitative measures of student learning and engagement, such as eye tracking.

Keywords: clinical simulation, education, pharmacology, simulation, virtual learning

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75 Predicting Aggregation Propensity from Low-Temperature Conformational Fluctuations

Authors: Hamza Javar Magnier, Robin Curtis

Abstract:

There have been rapid advances in the upstream processing of protein therapeutics, which has shifted the bottleneck to downstream purification and formulation. Finding liquid formulations with shelf lives of up to two years is increasingly difficult for some of the newer therapeutics, which have been engineered for activity, but their formulations are often viscous, can phase separate, and have a high propensity for irreversible aggregation1. We explore means to develop improved predictive ability from a better understanding of how protein-protein interactions on formulation conditions (pH, ionic strength, buffer type, presence of excipients) and how these impact upon the initial steps in protein self-association and aggregation. In this work, we study the initial steps in the aggregation pathways using a minimal protein model based on square-well potentials and discontinuous molecular dynamics. The effect of model parameters, including range of interaction, stiffness, chain length, and chain sequence, implies that protein models fold according to various pathways. By reducing the range of interactions, the folding- and collapse- transition come together, and follow a single-step folding pathway from the denatured to the native state2. After parameterizing the model interaction-parameters, we developed an understanding of low-temperature conformational properties and fluctuations, and the correlation to the folding transition of proteins in isolation. The model fluctuations increase with temperature. We observe a low-temperature point, below which large fluctuations are frozen out. This implies that fluctuations at low-temperature can be correlated to the folding transition at the melting temperature. Because proteins “breath” at low temperatures, defining a native-state as a single structure with conserved contacts and a fixed three-dimensional structure is misleading. Rather, we introduce a new definition of a native-state ensemble based on our understanding of the core conservation, which takes into account the native fluctuations at low temperatures. This approach permits the study of a large range of length and time scales needed to link the molecular interactions to the macroscopically observed behaviour. In addition, these models studied are parameterized by fitting to experimentally observed protein-protein interactions characterized in terms of osmotic second virial coefficients.

Keywords: protein folding, native-ensemble, conformational fluctuation, aggregation

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74 Detecting Potential Biomarkers for Ulcerative Colitis Using Hybrid Feature Selection

Authors: Mustafa Alshawaqfeh, Bilal Wajidy, Echin Serpedin, Jan Suchodolski

Abstract:

Inflammatory Bowel disease (IBD) is a disease of the colon with characteristic inflammation. Clinically IBD is detected using laboratory tests (blood and stool), radiology tests (imaging using CT, MRI), capsule endoscopy and endoscopy. There are two variants of IBD referred to as Ulcerative Colitis (UC) and Crohn’s disease. This study employs a hybrid feature selection method that combines a correlation-based variable ranking approach with exhaustive search wrapper methods in order to find potential biomarkers for UC. The proposed biomarkers presented accurate discriminatory power thereby identifying themselves to be possible ingredients to UC therapeutics.

Keywords: ulcerative colitis, biomarker detection, feature selection, inflammatory bowel disease (IBD)

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73 Consumption Habits of Low-Fat Plant Sterol-Enriched Yoghurt Enriched with Phytosterols

Authors: M. J. Reis Lima, J. Oliveira, A. C. Sousa Pereira, M. C. Castilho, E. Teixeira-Lemos

Abstract:

The increasing interest in plant sterol enriched foods is due to the fact that they reduce blood cholesterol concentrations without adverse side effects. In this context, enriched foods with phytosterols may be helpful in protecting population against atherosclerosis and cardiovascular diseases. The aim of the present work was to evaluate in a population of Viseu, Portugal, the consumption habits low-fat, plant sterol-enriched yoghurt. For this study, 577 inquiries were made and the sample was randomly selected for people shopping in various supermarkets. The preliminary results showed that the biggest consumers of these products were women aged 45 to 65 years old. Most of the people who claimed to buy these products consumed them once a day. Also, most of the consumers under antidyslipidemic therapeutics noticed positive effects on hypercholesterolemia.

Keywords: consumption habits, fermented milk, functional foods, low fat, phytosterols

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72 Application of Nanoparticles in Biomedical and MRI

Authors: Raziyeh Mohammadi

Abstract:

At present, nanoparticles are used for various biomedical applications where they facilitate laboratory diagnostics and therapeutics. The performance of nanoparticles for biomedical applications is often assessed by their narrow size distribution, suitable magnetic saturation, and low toxicity effects. Superparamagnetic iron oxide nanoparticles have received great attention due to their applications as contrast agents for magnetic resonance imaging (MRI. (Processes in the tissue where the blood brain barrier is intact in this way shielded from the contact to this conventional contrast agent and will only reveal changes in the tissue if it involves an alteration in the vasculature. This technique is very useful for detecting tumors and can even be used for detecting metabolic functional alterations in the brain, such as epileptic activity.SPIONs have found application in Magnetic Resonance Imaging (MRI) and magnetic hyperthermia. Unlike bulk iron, SPIONs do not have remnant magnetization in the absence of the external magnetic field; therefore, a precise remote control over their action is possible.

Keywords: nanoparticles, MRI, biomedical, iron oxide, spions

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71 Analysis of Expression Data Using Unsupervised Techniques

Authors: M. A. I Perera, C. R. Wijesinghe, A. R. Weerasinghe

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his study was conducted to review and identify the unsupervised techniques that can be employed to analyze gene expression data in order to identify better subtypes of tumors. Identifying subtypes of cancer help in improving the efficacy and reducing the toxicity of the treatments by identifying clues to find target therapeutics. Process of gene expression data analysis described under three steps as preprocessing, clustering, and cluster validation. Feature selection is important since the genomic data are high dimensional with a large number of features compared to samples. Hierarchical clustering and K Means are often used in the analysis of gene expression data. There are several cluster validation techniques used in validating the clusters. Heatmaps are an effective external validation method that allows comparing the identified classes with clinical variables and visual analysis of the classes.

Keywords: cancer subtypes, gene expression data analysis, clustering, cluster validation

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70 Targeted Photoactivatable Multiagent Nanoconjugates for Imaging and Photodynamic Therapy

Authors: Shazia Bano

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Nanoconjugates that integrate photo-based therapeutics and diagnostics within a single platform promise great advances in revolutionizing cancer treatments. However, to achieve high therapeutic efficacy, designing functionally efficacious nanocarriers to tightly retain the drug, promoting selective drug localization and release, and the validation of the efficacy of these nanoconjugates is a great challenge. Here we have designed smart multiagent, liposome based targeted photoactivatable multiagent nanoconjugates, doped with a photoactivatable chromophore benzoporphyrin derivative (BPD) labelled with an active targeting ligand cetuximab to target the EGFR receptor (over expressed in various cancer cells) to deliver a combination of therapeutic agents. This study establishes a tunable nanoplatform for the delivery of the photoactivatable multiagent nanoconjugates for tumor-specific accumulation and targeted destruction of cancer cells in complex cancer model to enhance the therapeutic index of the administrated drugs.

Keywords: targeting, photodynamic therapy, photoactivatable, nanoconjugates

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69 Targeted Delivery of Novel Copper-Based Nanoparticles for Advance Cancer Therapeutics

Authors: Arindam Pramanik, Parimal Karmakar

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We have explored the synergistic anti-cancer activity of copper ion and acetylacetone complex containing 1,3 diketone group (like curcumin) in metallorganic compound “Copper acetylacetonate” (CuAA). The cytotoxicity mechanism of CuAA complex was evaluated on various cancer cell lines in vitro. Among these, reactive oxygen species (ROS), glutathione level (GSH) in the cell was found to increase. Further mitochondrial membrane damage was observed. The fate of cell death was found to be induced by apoptosis. For application purpose, we have developed a novel biodegradable, non-toxic polymer-based nanoparticle which has hydrophobically modified core for loading of the CuAA. Folic acid is conjugated on the surface of the polymer (chitosan) nanoparticle for targeting to cancer cells for minimizing toxicity to normal cells in-vivo. Thus, this novel drug CuAA has an efficient anticancer activity which has been targeted specifically to cancer cells through polymer nanoparticle.

Keywords: anticancer, apoptosis, copper nanoparticle, targeted drug delivery

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68 Recent Advancement in Dendrimer Based Nanotechnology for the Treatment of Brain Tumor

Authors: Nitin Dwivedi, Jigna Shah

Abstract:

Brain tumor is metastatic neoplasm of central nervous system, in most of cases it is life threatening disease with low survival rate. Despite of enormous efforts in the development of therapeutics and diagnostic tools, the treatment of brain tumors and gliomas remain a considerable challenge in the area of neuro-oncology. The most reason behind of this the presence of physiological barriers including blood brain barrier and blood brain tumor barrier, lead to insufficient reach ability of therapeutic agents at the site of tumor, result of inadequate destruction of gliomas. So there is an indeed need empowerment of brain tumor imaging for better characterization and delineation of tumors, visualization of malignant tissue during surgery, and tracking of response to chemotherapy and radiotherapy. Multifunctional different generations of dendrimer offer an improved effort for potentiate drug delivery at the site of brain tumor and gliomas. So this article emphasizes the innovative dendrimer approaches in tumor targeting, tumor imaging and delivery of therapeutic agent.

Keywords: blood brain barrier, dendrimer, gliomas, nanotechnology

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67 Maackiain Attenuates Alpha-Synuclein Accumulation and Improves 6-OHDA-Induced Dopaminergic Neuron Degeneration in Parkinson's Disease Animal Model

Authors: Shao-Hsuan Chien, Ju-Hui Fu

Abstract:

Parkinson’s disease (PD) is a degenerative disorder of the central nervous system that is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and motor impairment. Aggregation of α-synuclein in neuronal cells plays a key role in this disease. At present, therapeutics for PD provides moderate symptomatic benefit but is not able to delay the development of this disease. Current efforts for the treatment of PD are to identify new drugs that show slow or arrest progressive course of PD by interfering with a disease-specific pathogenetic process in PD patients. Maackiain is a bioactive compound isolated from the roots of the Chinese herb Sophora flavescens. The purpose of the present study was to assess the potential for maackiain to ameliorate PD in Caenorhabditis elegans models. Our data reveal that maackiain prevents α-synuclein accumulation in the transgenic Caenorhabditis elegans model and also improves dopaminergic neuron degeneration, food-sensing behavior, and life-span in 6-hydroxydopamine-induced Caenorhabditis elegans model, thus indicating its potential as a candidate antiparkinsonian drug.

Keywords: maackiain, Parkinson’s disease, dopaminergic neurons, α-Synuclein

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66 Effect of Inulin-Substituted Ice Cream on Waist Circumference and Blood Pressure of Adolescents with Abdominal Obesity

Authors: Nur H. Ahmad, Silvia S. Inge, Vanessa A. Julliete, A. Veraditias, Laila F. Febinda

Abstract:

Abdominal obesity is a risk factor for metabolic syndrome and mostly found in adolescents. Waist circumference is related to abdominal obesity which has a significant effect on the increase of blood pressure. Inulin is one of prebiotic, that has health benefits by offering the potential for lipid management, that can be useful to decrease the risk factor of metabolic syndrome. The aim of the research is to evaluate the effect of 10 gram inulin-substituted ice cream in waist circumference and blood pressure of abdominal obesity adolescents. Inulin had the ability to produce Short Chain Fatty Acid which can improve blood pressure and waist circumference. Systolic blood pressure was significantly decreased in the treatment group (p=0.028) with the mean of reduction 7.35 ± 11.59 mmHg. However, diastolic blood pressure and waist circumference showed no significant effect. Waist circumference, systolic blood pressure and diastolic blood pressure was decreased in control group. These results suggest that inulin-substituted ice cream used as therapeutics and prevention for the early onset of metabolic syndrome.

Keywords: blood pressure, inulin, metabolic syndrome, waist circumference

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65 Dual-functional Peptide With Defective Interfering Genes Protecting Mice From Avian and Seasonal Influenza Virus Infection

Authors: Hanjun Zhao

Abstract:

Limited efficacy of current antivirals and antiviral-resistant mutations impair anti-influenza treatment. Here, we evaluated the in vitro and in vivo antiviral effect of three defective interfering genes (DIG-3) of influenza virus. Virus replication was significantly reduced in 293T and A549 cells transfected with DIG-3. Mice transfected with DIG-3 encoded by jetPEI-vector, as prophylaxis and therapeutics against A(H7N7) virus respectively, had significantly better survivals (80% and 50%) than control mice (0%). We further developed a dual-functional peptide TAT-P1, which delivers DIG-3 with high transfection efficiency and concomitantly exerts antiviral activity by preventing endosomal acidification. TAT-P1/DIG-3 was more effective than jetPEI/DIG-3 in treating A(H7N7) or A(H1N1)pdm09-infected mice and showed potent prophylactic protection on A(H7N7) or A(H1N1)pdm09-infected mice. The addition of P1 peptide, preventing endosomal acidification, could enhance the protection of TAT-P1/DIG-3 on A(H1N1)pdm09-infected mice. Dual-functional TAT-P1 with DIG-3 can effectively protect or treat mice infected by avian and seasonal influenza virus infection.

Keywords: antiviral peptide, dual-functional peptide, defective interfering genes, influenza virus

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64 CanVis: Towards a Web Platform for Cancer Progression Tree Analysis

Authors: Michael Aupetit, Mahmoud Al-ismail, Khaled Mohamed

Abstract:

Cancer is a major public health problem all over the world. Breast cancer has the highest incidence rate over all cancers for women in Qatar making its study a top priority of the country. Human cancer is a dynamic disease that develops over an extended period through the accumulation of a series of genetic alterations. A Darwinian process drives the tumor cells toward higher malignancy growing the branches of a progression tree in the space of genes expression. Although it is not possible to track these genetic alterations dynamically for one patient, it is possible to reconstruct the progression tree from the aggregation of thousands of tumor cells’ genetic profiles from thousands of different patients at different stages of the disease. Analyzing the progression tree is a way to detect pivotal molecular events that drive the malignant evolution and to provide a guide for the development of cancer diagnostics, prognostics and targeted therapeutics. In this work we present the development of a Visual Analytic web platform CanVis enabling users to upload gene-expression data and analyze their progression tree. The server computes the progression tree based on state-of-the-art techniques and allows an interactive visual exploration of this tree and the gene-expression data along its branching structure helping to discover potential driver genes.

Keywords: breast cancer, progression tree, visual analytics, web platform

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63 Trastuzumab Decorated Bioadhesive Nanoparticles for Targeted Breast Cancer Therapy

Authors: Kasi Viswanadh Matte, Abhisheh Kumar Mehata, M.S. Muthu

Abstract:

Brest cancer, up-regulated with human epidermal growth factor receptor type-2 (HER-2) led to the concept of developing HER-2 targeted anticancer therapeutics. Docetaxel-loaded D-α-tocopherol polyethylene glycol succinate 1000 conjugated chitosan (TPGS-g-chitosan) nanoparticles were prepared with or without Trastuzumab decoration. The particle size and entrapment efficiency of conventional, non-targeted and targeted nanoparticles were found to be in the range of 126-186 nm and 74-78% respectively. In-vitro, MDA-MB-231 cells showed that docetaxel-loaded non-targeted and HER-2 receptor targeted TPGS-g-chitosan nanoparticles have enhanced the cellular uptake and cytotoxicity with a promising bioadhesion property, in comparison to conventional nanoparticles. The IC50 values of non-targeted and targeted nanoparticles from cytotoxic assay were found to be 43 and 223 folds higher than DocelTM. The in-vivo pharmacokinetic study showed 2.33, and 2.82-fold enhancement in relative bioavailability of docetaxel for non-targeted and HER-2 receptor targeted nanoparticles, respectively than DocelTM, and after i.v administration, non-targeted and targeted nanoparticle achieved 3.48 and 5.94 times prolonged half-life in comparison to DocelTM. The area under the curve (AUC), relative bioavailability (FR) and mean residence time (MRT) were found to be higher for non-targeted and targeted nanoparticles compared to DocelTM. Further, histopathology results of non-targeted and targeted nanoparticles showed less toxicity on vital organs such as lungs, liver, and kidney compared to DocelTM.

Keywords: breast cancer, HER-2 receptor, targeted nanomedicine, chitosan, TPGS

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62 Mining the Proteome of Fusobacterium nucleatum for Potential Therapeutics Discovery

Authors: Abdul Musaweer Habib, Habibul Hasan Mazumder, Saiful Islam, Sohel Sikder, Omar Faruk Sikder

Abstract:

The plethora of genome sequence information of bacteria in recent times has ushered in many novel strategies for antibacterial drug discovery and facilitated medical science to take up the challenge of the increasing resistance of pathogenic bacteria to current antibiotics. In this study, we adopted subtractive genomics approach to analyze the whole genome sequence of the Fusobacterium nucleatum, a human oral pathogen having association with colorectal cancer. Our study divulged 1499 proteins of Fusobacterium nucleatum, which has no homolog in human genome. These proteins were subjected to screening further by using the Database of Essential Genes (DEG) that resulted in the identification of 32 vitally important proteins for the bacterium. Subsequent analysis of the identified pivotal proteins, using the KEGG Automated Annotation Server (KAAS) resulted in sorting 3 key enzymes of F. nucleatum that may be good candidates as potential drug targets, since they are unique for the bacterium and absent in humans. In addition, we have demonstrated the 3-D structure of these three proteins. Finally, determination of ligand binding sites of the key proteins as well as screening for functional inhibitors that best fitted with the ligands sites were conducted to discover effective novel therapeutic compounds against Fusobacterium nucleatum.

Keywords: colorectal cancer, drug target, Fusobacterium nucleatum, homology modeling, ligands

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61 Isolation and Identification of Cytotoxic Compounds from Fruticose Lichen Roccella montagnei, and It’s in Silico Docking Study against CDK-10

Authors: Tripti Mishra, Shipra Shukla, Sanjeev Meena, , Ruchi Singh, Mahesh Pal, D. K. Upreti, Dipak Datta

Abstract:

Roccella montagnei belongs to lichen family Roccelleceae growing luxuriantly along the coastal regions of India. As Roccella has been shown to be bioactive, we prepared methanolic extract and assessed its anticancer potential. The methanolic extract showed significant in vitro cytotoxic activity against four human cancer cell lines such as Colon (DLD-1, SW-620), Breast (MCF-7), Head and Neck (FaDu). This prompted us to isolate bioactive compounds through column chromatography. Two compounds Roccellic acid and Everninic acid have been isolated, out of which Everninic acid is reported for the first time. Both the compounds have been tested for in vitro cytotoxic activity in which Roccellic acid showed strong anticancer activity as compared to the Everninic acid. CDK-10 (Cyclin-dependent kinase) contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases, therefore, constitute biomarkers of proliferation and attractive pharmacological targets for the development of anticancer therapeutics. Therefore both the isolated compounds were tested for in silico molecular docking study against CDK-10 isomer enzyme to support the cytotoxic activity.

Keywords: cytotoxic activity, everninic acid, roccellic acid, R. montagnei

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60 Determination of Biomolecular Interactions Using Microscale Thermophoresis

Authors: Lynn Lehmann, Dinorah Leyva, Ana Lazic, Stefan Duhr, Philipp Baaske

Abstract:

Characterization of biomolecular interactions, such as protein-protein, protein-nucleic acid or protein-small molecule, provides critical insights into cellular processes and is essential for the development of drug diagnostics and therapeutics. Here we present a novel, label-free, and tether-free technology to analyze picomolar to millimolar affinities of biomolecular interactions by Microscale Thermophoresis (MST). The entropy of the hydration shell surrounding molecules determines thermophoretic movement. MST exploits this principle by measuring interactions using optically generated temperature gradients. MST detects changes in the size, charge and hydration shell of molecules and measures biomolecule interactions under close-to-native conditions: immobilization-free and in bioliquids of choice, including cell lysates and blood serum. Thus, MST measures interactions under close-to-native conditions, and without laborious sample purification. We demonstrate how MST determines the picomolar affinities of antibody::antigen interactions, and protein::protein interactions measured from directly from cell lysates. MST assays are highly adaptable to fit to the diverse requirements of different and complex biomolecules. NanoTemper´s unique technology is ideal for studies requiring flexibility and sensitivity at the experimental scale, making MST suitable for basic research investigations and pharmaceutical applications.

Keywords: biochemistry, biophysics, molecular interactions, quantitative techniques

Procedia PDF Downloads 426