Medical and Health Sciences

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New prognostic index to detect the severity of asthma automatically using signal processing techniques of capnogram
(Universiti Teknologi Malaysia, 2013) Kazemi, Mohsen
Asthma is a chronic inflammatory disease of the bronchial tubes that happens approximately in 3% to 5% of all people in their life. Currently, capnography is a new method to monitor the asthmatic conditions, and unlike traditional methods, it is taken while the patient is breathing as comfortably as able. Previous studies concluded a significant correlation between the capnogram and the asthmatic patient. However, most of them are just manual studies conducted through the conventional time domain method based on the assumption that the capnogram is a stationary signal. However, manual analysis of capnogram is time-consuming and leads to erroneous results due to human factor such as tiredness. Therefore, a new prognostic index to automatic detection the severity of airway obstruction by processing the capnogram signal is presented in this research. First, in order to investigate the property of capnogram signal, the first and the second statistical orders of 73 asthmatic and 23 non-asthmatic patients’ capnogram were calculated. Based on the findings in this research, capnogram signals can be categorised as wide-sense nonstationary random signals. So, non-stationary techniques including linear predictive analysis and Burg algorithm analysis are used to process the capnogram signals. It should be noted that these techniques by windowing signal are based on this assumption that signal is locally stationary. Then, by means of Receiver Operating Characteristic (ROC) curve, the effectiveness of the extracted features to differentiate between asthmatic and non-asthmatic conditions is justified. Finally, selected features are used in a Gaussian radial basis function (GRBF) neural network. The output of this network is an integer prognostic index from 1 to 10 (depending on the severity of asthma) with an average good detection rate of 90.15% and an error rate of 9.85%. This developed algorithm is aspired to provide a fast and low-cost diagnostic system to help healthcare professional involved in respiratory care as it would be possible to monitor the severity of asthma automatically and instantaneously
Regeneration of dalapon tolerant nicotiana tabacum by expressing dehalogenase E gene through agrobacterium tumefaciens mediated transformation
(Universiti Teknologi Malaysia, 2013) Kaya, Yilmaz
A dehE gene from Rhizobium sp. encodes a dehalogenase capable of degrading 2,2-dichloropropionic acid, the active ingredient of the herbicide Dalapon. The gene encoding gus in the plant transformation vector, pCAMBIA1301, was replaced with dehE under the control of the 35S promoter from cauliflower mosaic virus. Transgenic Nicotiana tabacum plants were then produced that carried the modified pCAMBIA1301, and these transgenic plants were tolerant to Dalapon. Leaf discs of 7-week-old tobacco plants grown under in vitro conditions were inoculated with Agrobacterium tumefaciens strain LBA4404 that carries dehE. After transformation, the plants were subcultured in Murashige and Skoog medium supplemented with 50 µg/ml kanamycin, 25 µg/ml hygromycin, and 500 µg/ml cefotaxime for at least 6 weeks. The presence of dehE in N. tabacum was confirmed by PCR, and dehE expression was ascertained by real-time PCR. The confirmed real-time PCR results the transgenic tobacco plantlets were transferred to soil for further growth. The tolerance of genetically transformed N. tabacum plants to Dalapon was assessed under in vitro and plant growth chamber conditions. After 7 days of growth, the transgenic plants were treated with different concentrations of Dalapon ranging from 20 to 200 mg/l using a leaf-painting bioassay method. The transformed N. tabacum showed tolerance to Dalapon up 200 mg/l, whereas the N. tabacum TAPM 26 (control) could tolerate Dalapon only up to 60 mg/l. This experiment suggests that dehE can be expressed in N. tabacum and that transgenic plants are tolerant to Dalapon
Microfluidic fabric-based electrochemical device for detection of clinical analytes in physiological fluids
(Universiti Teknologi Malaysia, 2014) Malon Marugan, Radha Swathe Priya
In recent years, inexpensive alternative materials (paper, yarn/thread and fabric) have been proposed for the construction of new generation of point-of-care (POC) microfluidic diagnostic devices. The purpose of this study is to investigate the integration of electrochemical detection in fabric-based microfluidic device for quantitative measurement of biomarkers in physiological fluids. The device was fabricated using two methods, template for patterning the electrodes and wax-patterning for creating the hydrophilic/hydrophobic contrast. The electrodes incorporated within the fabricated device were evaluated using cyclic voltammetry. The feasability of the device to determine clinical analytes such as glucose, lactate and ascorbic acid (AA) in control serum, saliva and artificial urine samples, respectively was demonstrated using chronoamperometry at the optimal detection potential (-0.2 V vs. Ag/AgCl for glucose and lactate; 0.28 V vs. Ag/AgCl for AA). The levels of the analytes measured were within the margin of error of the actual concentrations. The sensitivity of the device for the determination of glucose, lactate and AA were 0.294 ± 0.082, 0.3169 ± 0.099 and 0.4202 ± 0.229 |iA/mM, respectively, which are within the physiological range (2 to 25, 0.1 to 5 and 0.5 to 10 mM, respectively) of these analytes. The influence of mechanical stress towards the morphology and electrochemical behaviour were examined for both microfluidic fabric-based electrochemical device (^FED) and microfluidic paper-based electrochemical device (^PED). The results implied that the proposed |iFED was more durable under mechanical stress (sensitivity drop of ~ 21.6%) in comparison to the |iPED (sensitivity drop of ~ 48.6%). A three dimensional (3D) |iFED prototype for sample collection and continuous assessment (t = 170 min) of dynamic electrochemical measurement was also developed and evaluated. The |iFED provided an efficient sample delivery towards the reaction chamber, allowing dynamic electrochemical measurement in real-time without interruption unlike the |iPED. This study shows the potential of the proposed |iFED as a novel microfluidic sensing platform for a variety of assays that require simplicity, low-cost, portability, flexibility and continuous real-time monitoring
Synthesis and in vitro biological evaluation of hydroxyapatite-zeolite containing silver, zinc, fluoride for medical applications
(Universiti Teknologi Malaysia, 2014) Igbal, Nida
Hydroxyapatite (HA) (Ca10(P04)6(OH)2) is a basic mineral component of natural hard tissues (bone, enamel etc.) and has been used in a wide range of applications such as bone filler, coating on metal prostheses and drug delivery. However, pure HA implants have several limitations such as slow osseointegration rate and requiring long-term implant stability in bone tissues. Moreover, it still exhibits poor antibacterial activities. Therefore, the implant associated with bacterial infections poses a threat to host life in spite of sterilized operating conditions. In view of the aforementioned condition, considerable effort is currently conducted to develop a new biomedical material with enhanced bioactivity properties and should be effected in resisting the bacterial biofilm formation. In this present work, the synthesis of hydroxyapatite containing ions (Ag+, Zn2+ and F¯) and its bioactive composites with zeolites (Y and ZSM-5) were done using a microwave process. Then, hydroxyapatite-zeolite (ZSM-5) containing ions composites were prepared by mechanical mixing and sintering process. The phase composition, functional groups, surface morphology, and elemental composition of the synthesized bioceramics were examined by X-ray diffraction (XRD), fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM) and energy dispersive X-ray spectroscopy (EDS), respectively. The XRD, FTIR and EDS results confirmed the incorporation of ions and zeolite into the HA structure. The FESEM and TEM results revealed that the particles were in nanosize with a spherical morphology. The antibacterial activity using the disk diffusion method showed that the samples were active against gram-positive and gram-negative bacteria. The antibacterial effect was found to increase with the ions contents. The in vitro bioactivity results after soaking in simulated body fluid (SBF) solution proved that hydroxyapatite containing ions showed the apatite layer formation within 28 days, whereas the hydroxyapatite-zeolite and its ions containing composites showed apatite formation within 14 days, indicating the improvement in bioactivity which was due to the presence of zeolites. Furthermore, the MTT assay and cell adhesion results confirmed good proliferation and attachment of normal human osteoblast (NHOst) cells on the surface of composites. In conclusion, these results indicated that the low concentrations of hydroxyapatite-zeolite containing ions (Ag+, Zn2+ and F¯) exhibited good bioactivity and biocompatibility with sufficient antibacterial activity. Therefore, these composites can be used as bone substitute in bone implant applications
Viral infections, immunological reactions and genetic factors - Induced type 1 diabetes mellitus in erbil city
(Universiti Teknologi Malaysia, 2014) Ahmed, Najat Jabbar
Type 1 diabetes mellitus (T1DM) is on the increase in the Kurdistan Region of Iraq. It has been demonstrated that viral infection induces T1DM by destruction of beta cells through direct invasion or autoimmune reactions. Genetic factors also lead to immune disorders which induce T1DM. Despite the reports on effects of viral infection and autoimmune disturbance in the presence of HLA genes, there is no known report that shows the relationship between them in the Kurdish race. This study focused on how the relationship between viral infections, immunological reactions and genetic factors induces T1DM. Therefore, three viruses (cytomegalovirus, rubella and Coxsackie-B virus), two genes (Human Leukocyte Antigen-DR3, DR4), and six immunological parameters, including (T-helper ‘CD4’, T-cytotoxic ‘CD8’, Interleukin ‘IL-4 and 10, anti-glutamic acid decarboxylase ‘GAD’ Ab. and anti-insulin receptor ‘IR’ antibody, were studied to evaluate their relationship with T1DM. The study adopted a quantitative approach by interviewing 230 subjects (122 females and 108 males) of T1DM patients and another 130 nondiabetic individuals as a control group for collecting blood samples along with personal and family information related to this study. This study reveals that T1DM is more common among children especially those who consume cow’s milk during infancy and who have a family history of diabetes. The finding also revealed an interaction between the following three factors: immune system, viral infections and genetic factors, and concludes that they can induce T1DM. It was also show that viral infections recorded positive results among patients; for CMV it was 84%, rubella 44% and CSV 25%. However, for the genetic study positive results for HLA-DR3, HLA-DR4 and both together were recorded as 61 %, 73% and 56%, respectively. For immunological parameters, the mean of anti-GAD Ab, anti-IR Ab, IL-4, IL-10 and the ratio of CD4:CD8 showed significant differences between patients and the control group at p < 0.05. It is recommended that estimates of islet cell, insulin and tyrosine phosphatase-like protein autoantibodies, IL-6 and IL-17, detection of HCV, HBV, mumps and HLA-DQ, viruses among T1DM patients and paediatric cases be categorized and separated from adult cases.
Enhancing human breast cancer cells destruction using combination of adenovirus expressing P53 and hyperthermia treatment
(Universiti Teknologi Malaysia, 2015) Elengoe, Asita
In Malaysia, breast cancer is the most common cancer where 1 in 19 Malaysian women will be diagnosed with breast cancer by the age of 85. Moreover, lack of specific symptoms in the early stage of disease leading to delay in diagnosis. Unfortunately, current treatments by chemotherapeutic agents, surgery and radiation are not fully effective for the treatment of breast cancer. Thus, there is an urgency in developing new approaches for the treatment of breast cancer patients. In this study, a novel therapeutic regimen, combining the effects of recombinant adenovirus and hyperthermia was investigated. Firstly, Adenovirus serotype 5 was constructed by cloning of p53 gene into a defective recombinant adenovirus vector, Ad5-p53-DsRed Monomer N1. The Ad5-p53-DsRed Monomer N1 (MOI of 100) was then used to infect breast cancer cells (MDA-MB 231 and MCF-7) with or without combination of hyperthermia treatment (42ºC for 2 hours). The cell killing and viral concentration were then determined by MTT assay and viral plaque formation assay respectively. After that, the heat shock protein (Hsp70) and p53 protein expression in transfected cells were quantitated using ELISA assay. Activated-Caspase 3/7, 8 and 9 were also evaluated to study the apoptotic pathway of cancer cells. Furthermore, the novel protein interaction between nucleotide binding domain (NBD) Hsp70 and human Ad5 E1A 32 kDa motif (PNLVP); and NBD and p53 motif (SCMGGMNR) were investigated through bioinformatics tools such as Gromacs and Autodock softwares. It was found that MDA-MB 231 and MCF-7 cells infected with virus Ad5-p53- DsRed Monomer N1 alone resulted in 46.77±2.74% and 42.26±1.78% cell killing respectively while hyperthermia in combination with virus were 84.82±1.64% and 80.13±3.30% respectively. The Hsp70 expression of both cancer cells was also increased to 170.57% (MDA-MB 231) and 169.83% (MCF-7). Moreover, p53 expression in MDA-MB 231 and MCF-7 cells by virus combined with heat treatment (85.72 ng/L and 79.05 ng/L respectively) could lead to enhanced oncolytic property compared to virus treatment alone (47.82 ng/L and 40.54 ng/L respectively). In addition, caspase activity was first time reported that apoptosis process started at very early stage of infection in breast cancer cells with hyperthermia compared to virus alone. This was due to the evident that the highest kinetic energy was found in caspase 3 whereas virus alone the highest in caspase 8. In conclusion, Hsp70 induction by hyperthermia treatment enhanced Ad5-p53-DsRed Monomer N1 replication and oncolysis in MDA-MB 231 and MCF-7 cells through apoptotic pathway. Besides that, NBD of Hsp70 had the best interaction with PNLVP motif at 42°C. Thus, combining Ad5-p53 with hyperthermia treatment could be a potential approach for breast cancer treatment
Development of niosome-loaded bromelain as anti-inflammatory agent
(Universiti Teknologi Malaysia, 2015) Chermahini, Siavash Hosseinpour
Inflammation can be considered as common human being anxiousness. Nonsteroidal anti-inflammatory drugs (NSAIDS) are usually prescribed to reduce inflammation but they may lead to serious side-effects. Recently anti-inflammatory property of bromelain have been documented, but oral administration of bromelain requires higher concentration as compared to topical delivery. Hence, topical delivery of bromelain as a more favorable anti-inflammatory solution for skin inflammation, but it has to overcome stratum corneum (SC) skin barrier. The aims of this study were to design a bromelain delivery system based on niosome and to evaluate the efficacy of the bromelain-niosome system. Moreover, anti-inflammatory effect of niosome encapsulated bromelain was studied by Interleukin-6 (IL-6) and Tumor Necrotic Factor–alpha (TNF-a) response. This potential anti-inflammatory property of niosome encapsulated bromelain was investigated in-vitro and in-vivo, using human skin fibroblast cell line (HSF 1184) and mice, respectively. Lipopolysaccharide (LPS) was used in volume of 1.5 µg/mL in-vitro and 7.5 µg/mL in-vivo to induce inflammation. The current results showed that 20 µg/mL niosome encapsulated with 10% bromelain after four hours of post treatment significantly eliminated inflammation in HSF 1184 cell line as compared to non-encapsulated bromelain, vehicle (niosome), and controls. Similar result was achieved in mice where 20 mg niosome encapsulated with 10% bromelain was found able to eliminate inflammation after 30 minutes of post treatment. In conclusion, this research provides scientific evidence to show effective transdermal delivery of niosome encapsulated bromelain to reach targeted dermal cells and show its pharmaceutical potential to eliminate skin inflammation.
Penggunaan sisa udang untuk penghasilan kitinase oleh 'trichoderma virens' menggunakan fermentasi keadaan pepejal
(Universiti Teknologi Malaysia, 2015) Rachmawaty
The chitinase production by Trichoderma virens using shrimp waste as a substrate was studied in solid state fermentation with 70% of moisture content. Six different pretreatment methods namely oven pretreatment, microwave pretreatment, boiling and crushing pretreatment, sun-dried pretreatment and chemical pretreatment were conducted on shrimp waste with non-treated shrimp waste as a control. The highest chitinase activity was obtained from microwave pretreatment on the third day of fermentation with chitinase activity of 0.194 U/g IDS, 3.2 fold higher than the untreated shrimp waste (0.06 U/g IDS). Study on the effect of nitrogen source on chitinase production using general factorial design showed that ammonium sulphate with 30.29 mM nitrogen gave significant effect compared toyeast extract with 7.43 mM nitrogen. Two level factorial design, incubation time, temperature, and substrate moisture also have a significant impact on the production of chitinase. Central composite design (CCD) was used in optimizing the conditions for chitinase production of shrimp waste by solid-state fermentation. Chitinase production was found to have increased 2.46 times (0.487 U/g IDS) at optimum condition: temperature of 27.9 ° C, 54.5% of substrate moisture and six days of incubation time. The optimal degradation showed an improvement of chitinase production of 2.46 fold as compared to before optimization using CCD. For partial characterization of chitinase, the optimum temperature and pH are at 60 °C and pH 3.0, respectively. Chitinase retained 72% of its activity at 70 °C. However, the loss of the chitinase activity occurred after 60 minutes of incubation at 70 °C and 80 °C with residual activity are 48% and 28%, respectively. Chitinase was more stable in acidic than in alkaline pH. The molecular weight of chitinase was 50 and 42 kDa for endochitinase, 33 and 25 kDa for eksokitinase and 18 kDa for protease. Extraction of crude chitinase from Trichoderma virens can inhibit the growth of Ganoderma boninense
Biomechanical evaluation and new improvement on ankle external fixator
(Universiti Teknologi Malaysia, 2015) Ramlee, Muhammad Hanif
An ankle external fixator is a medical device that can be used for temporary fixation in order to limit movement during treatment. This device has been effectively proven in clinical studies to promote the healing process. The stability of the construct could also be attributed to clinical outcomes. However, this knowledge is limited in the literature. Therefore, the main purpose of this study was to biomechanically evaluate and optimise the external fixator with the aim of producing a better construct for the improvement of stress distribution. In this project, the biomechanical study using a finite element method involved several analyses of the effects of external fixator designs as well as its material properties. In order to do that, first and foremost, a three-dimensional ankle model was reconstructed using CT data images which consisted of tibia, fibula, talus, calcaneus, navicular, three cuneiform, cuboid and five metatarsal bones. The cartilages were developed with an estimated uniform thickness of 1 mm. A total of 34 ligaments and 3 plantar fascias were also modelled. Two pathological conditions of ankle problems were simulated with the external fixator by applying axial compression loads based on the swing and stance phase. The results of the finite element study showed that the Delta frame configuration had better stability in terms of relative micromovement, displacement and von Mises stress as compared to the Mitkovic and Unilateral external fixators. In addition, the use of 6 mm pin and 11 mm connecting bar were more favourable options to provide a stable construction. However, the use of extra pins at cuboid and medial cuneiform bone did not contribute to enhance stability. For better improvement of the external fixator, additional hollow cylinder fitted at the pin was considered to decrease stress.
Enhancing wireless power transfer efficiency for potential use in cardiovascular applications
(Universiti Teknologi Malaysia, 2016) Lum, Kin Yun
Left Ventricular Assist Devices (LVAD) are being used to assist blood circulation in heart failure patients. The requirement to have a continuous energy supply is deteriorating the patients' life quality since they need either to carry along two heavy battery packs or to attach a power cable. For this reason, a wireless power transmission (WPT) system is developed to power the LVAD. Within its effective charging region, the WPT system will offer an autonomous charging process which may lead to a smaller battery pack and cableless experience to the user. Previous WPT systems for cardiovascular applications are either compromised by poor transfer efficiency, short transmission distance or safety issues. To address these problems, an impedance matching WPT system is being designed. For increasing the overall transfer efficiency, both sides impedance matching technique and low loss matching networks are being worked on. In addition, efficiency specific design approach is being developed to reduce design complexity. As a result, the transfer efficiency and transmission distance of the impedance matched WPT have been increased by a factor of 7 and 6 times respectively. The conceptual idea for implementing such a system is also discussed in this thesis. Furthermore, safety measurements have been performed to ensure the system is safe to be used
Biomedical diagnostic tools for in vivo local and systemic assessments
(Universiti Teknologi Malaysia, 2016) Ulum, Mokhamad Fakhrul
Novel bioactive-degradable metals for a temporary medical implant may have improved tissue-implant reaction properties. Although several diagnostic tools are available, in details, most of them have difficulties in tracing the properties. Therefore, a deep fundamental understanding on the local and systemic responses is needed for the development of new diagnostic tools. This research project consists of two parts. The first part explored the ability of conventionally available diagnostic tools to locally monitor tissue-implant reaction due to insertion of novel iron-bioceramic composites in sheeps. The clinical radiology, visual inspection, and histological imaging indicated biodegradation and tissueimplant interaction, locally. The second part assessed the systemic body responses to implants. The results also indicated increasing biomarkers level (inflammatory cells, plasma ion, and sex-steroid hormones) in blood circulation. This project then focused on the fabrication of simple, quick, and low-cost cotton-based microfluidic analytical device for systemic assessment, as well as for other applications through the development of one-step whole blood processing and assay using EDTA-treated cotton-thread microfluidic analytical device (µTAD). A further advance improvement of the EDTA-treated µTAD to be pipette-less integrated system using mosquito proboscis-inspired needle with µTAD (p(-)µCAD) for sampling-to-answer diagnostic was also performed in this project. The p(-)µCAD was able to collect whole blood, plasma separation, and albumin detection with its calibration. As a conclusion, this research has contributed in the development of a new bio-inspired diagnostic tool using a versatile, abundant, and affordable material for systemic body fluid assessment
Adaptive nonlinear multivariate brain connectivity analysis of motor imagery movements using graph theory
(Universiti Teknologi Malaysia, 2016) Hamedi, Mahyar
Recent studies on motor imagery (MI)-based brain computer interaction (BCI) reported that the interaction of spatially separated brain areas in forms of functional or effective connectivity leads to a better insight of brain neural patterns during MI movements and can provide useful features for BCIs. However, existing studies suffer from unrealistic assumptions or technical weaknesses for processing brain signals, such as stationarity, linearity and bivariate analysis framework. Besides, volume conduction effect as a critical challenge in this area and the role of subcortical regions in connectivity analysis have not been considered and studied well. In this thesis, the neurophysiological connectivity patterns of healthy human brain during different MI movements are deeply investigated. At first, an adaptive nonlinear multivariate statespace model known as dual extended Kalman filter is proposed for connectivity pattern estimation. Several frequency domain functional and effective connectivity estimators are developed for nonlinear non-stationary signals. Evaluation results show superior parameter tracking performance and hence more accurate connectivity analysis by the proposed model. Secondly, source-space time-varying nonlinear multivariate brain connectivity during feet, left hand, right hand and tongue MI movements is investigated in a broad frequency range by using the developed connectivity estimators. Results reveal the similarities and the differences between MI tasks in terms of involved regions, density of interactions, distribution of interactions, functional connections and information flows. Finally, organizational principles of brain networks of MI movements measured by all considered connectivity estimators are extensively explored by graph theoretical approach where the local and global graph structures are quantified by computing different graph indexes. Results report statistical significant differences between and within the MI tasks by using the graph indexes extracted from the networks formed particularly by normalized partial directed coherence. This delivers promising distinctive features of the MI tasks for non-invasive BCI applications
Synthesis and characterization of spions-bromelan-folic acid on folic acid receptor positive cancer model
(Universiti Teknologi Malaysia, 2016) Nasiri, Rozita
Engineering of a physiologically compatible, stable and targetable delivery vehicle superparamagnetic iron oxide nanoparticles-Bromelain-folic acid (SPIONs-Br- FA) was reported. Initially, the synthesized bare SPIONs were coated with citric acid (CA) in order to increase biocompatibility, stability and solubility of the SPIONs. Moreover, through CA coating, carboxyl functional groups for further reactions were produced. Br (as an anti-cancer agent) and FA (as a targeting agent to the folic acid receptor positive (FAR+) cancer cells) were conjugated to the synthesized nanocarrier through 1-ethyl-3-(3-dimethylaminpropyl)carbodiimide hydrochloride/ Nhydroxysuccinimide (EDC/NHS) click chemistry. Subsequently, characterization and physico-chemical analyses were carried out through methods such as Fourier transform infrared spectroscopy, atomic absorption spectroscopy (AAS), dynamic light scattering, vibrating sample magnetometer, x-ray diffraction, transmission electron microscopy (TEM) and field emission scanning electron microscopy. The in vitro tetrazolium dye (MTT) assay and blood compatibility tests were performed to confirm the biocompatibility of the engineered nano delivery system. High level of SPIONs-FA binding to FAR+ cell lines (HeLa, MDA-MB-231 and 4 T1) compared to folic acid receptor negative (FAR-) cell lines (HSF 1184 and MDA-MB-468) was assured via qualitative and quantitative in vitro binding studies (Prussian blue assay and AAS analysis). The reason may be higher transport of SPIONs-FA through the mechanism of receptor endocytosis pathway into FAR+ cells in comparison with the mechanism of passive diffusion of SPIONs into the FAR- cells. Cytotoxicity studies carried out in human cell lines (HSF 1184, MDA-MB-468, MDA-MB-231 and HeLa) and mouse breast cancer cells (4 T1) showed significant dose advantage with SPIONs-Br-FA in reducing the half maximal inhibitory concentration (IC50) values compared with neat Br. Through morphological observation studies by inverted microscope and acridine orange/ethidium bromide fluorescent staining method, it was disclosed that the cells had undergone apoptosis since the shrinkage as well as the apoptotic bodies were obviously seen. The results showed that SPIONs-Br-FA was a rewarding candidate to suppress the migration of the FAR+ cancer cells as well as to inhibit colony formation of the FAR+ cancer cells compared to neat Br. The percentage of apoptotic cells (apoptotic index) with more condensed and fragmented chromatin increased sharply in SPIONs-Br-FA treated cells compared to the neat Br. Overall, the SPIONs-Br-FA induced higher percentage of apoptotic cells than the neat Br. Moreover, after treatment protocol performance on 4 T1 tumor bearing mice, the qualitative and quantitative biodistribution study were carried out in vital organs and tumor using colorimetric method (AAS) and TEM method which indicate significant tumor targetability of SPIONs-FA. Finally, the tumor volume and inhibition growth rate were measured in 4 T1 tumor bearing mice treated with different SPIONs formulations to investigate the effectiveness of SPIONs- Br-FA. Administration of SPIONs-Br-FA through tail vein (three times a week) during the four-week treatment period reduced the tumor burden of tumor bearing mice and also increased their life-span when compared with SPIONs-Br and neat Br at same concentration of bromelain. In conclusion, the current results indicated the dualfunctional synthesized SPIONs-Br-FA is a promising tool in the field of biomedicine, chiefly cancer therapy.
In silico identification of metabolites contributing to type 2 diabetes by integrating specific metabolic pathways
(Universiti Teknologi Malaysia, 2016) Shia, Yoke Lin
It is estimated in 2015 that one in eleven adults are suffering from diabetes, this is equivalent to a global population of 415 million. About 90% of the diabetes patients involve type 2 diabetes which is associated to the cellular impaired intermediates within the insulin signaling pathway. Three key intermediates, protein kinase B (PKB) /Akt, protein kinase C-zeta (PKC-ζ), and glucose transporter type 4 (GLUT4) are identified in most of the studies. The current study used a novel approach that integrates the cellular insulin signaling pathway with a systemic glucose regulation model via Michaelis–Menten equation that was able to estimate the insulin-dependent glucose consumption based on the concentration of plasma glucose and translocation percentage of glucose transporter GLUT4. Based on this model, the impact of a single intermediate such as PKB/Akt, PKC-ζ, and GLUT4 was investigated using the software COPASI parameter scan function by multiplying the phosphorylation or activation kinetic of each intermediate with a defective coefficient, dc. The coefficient dc was divided equally into five intervals ranging from 0-1. The same procedure was repeated to measure the effect of the combined impairment of two and subsequently three intermediates. The results showed that the combination of three impaired intermediates best represented the glucose consumption rate mimicking that in diabetic patients. Through the integration of cellular insulin signalling pathway with systemic glucose regulation, the first and second objectives of the study were fulfilled as the major metabolic and signalling pathways link to type 2 diabetes were modeled and a better understanding of the interaction between metabolic and signalling pathways was developed. The integration also fulfilled the third objective of the study as the single and combinational effect of insulin intermediates over the insulin-dependent glucose consumption in normal subject was analyzed. In short, the current study has provided insight into understanding of the underlying impaired glucose uptake in diabetic patients based on the combined impairment of three key intermediates in insulin signalling pathway
Kappa carrageenan-based hydrogel for floating drug delivery system in the stomach
(Universiti Teknologi Malaysia, 2016) Selvakumaran, Suguna
The main objective of drug delivery system is to attain an optimum concentration of the drug/bioactive agents in blood or tissue at a desired release rate. A problem frequently encountered with drug dosage is its inability to increase their residence time in the gastrointestinal tract, consequently leading to a poor drug release profile and low bioavailability. Therefore, development of an effective carrier is needed. This research aims to develop a potential dual effect drug carrier for floating drug delivery system in the stomach which targets the upper part of stomach and also benefits the lower part of stomach (stomach lining). Kappa carrageenan-based floating hydrogel was formulated using calcium carbonate as pore forming agents where it was further optimized using genipin (1.5 mM) and magnesium oxide nanoparticles (0.10 g) as compared to non-floating hydrogels. Characterization of hydrogel was carried out using Fourier transform infrared spectroscopy, x-ray diffraction, thermogravimetric analysis and field emission scanning electron microscope. The release behaviour of a model drug, ranitidine hydrochloride was firstly studied in simulated gastric fluid condition at 37 °C. The results showed that optimized floating hydrogels provided high performance (70%, 7 h) of controlled drug release profile with reduced initial burst release (18%, 30 min). The Korsmeyer-Peppas model further demonstrated that ranitidine hydrochloride release from hydrogels followed non- Fickian diffusion. The optimized floating hydrogel was then subjected to cytotoxicity analysis which proved its biocompatibility, non-toxicity and it is safe to use. Secondly, beneficial effect towards the lower part of stomach was determined from the presence of magnesium oxide nanoparticles in the hydrogel. The antibacterial activity was studied on the optimized floating hydrogel using E. coli and it showed 8.44% of bacterial inhibition. The characteristics of the hydrogel with floating behaviour more than 12 hours, reduced initial burst release with controlled drug release, along with effective bacterial inhibition and good biocompatibility suggested that the developed floating nanocomposite hydrogel is a promising drug carrier in the stomach
Corrosion behavior and mechanical properties of silicon and zinc-oxide coated magnesium-based bionanocomposite with hydroxyapatite and titania additives
(Universiti Teknologi Malaysia, 2016) Khalajabadi, Shahrouz Zamani
Magnesium (Mg)-based alloys were emerged as potential biodegradable material for temporary implants. However, their fast degradation in the high chloride environment of the physiological solution is detrimental unless inhibited. These Mg-based implants lose their mechanical integrity before the tissue is being sufficiently healed. Furthermore, the accumulation of hydrogen gas upon fast degradation in a physiological solution restricted their clinical applications. In this view, the present research is targeted to improve the biocorrosion behavior and mechanical properties of pure Mg by alloying it with nanostructured hydroxyapatite (HA), MgO, and TiO2 through milling-pressing-sintering powder metallurgy route. Four different Mg-based bionanocomposites including Mg/HA, Mg/HA/MgO, Mg/HA/TiO2 and Mg/HA/TiO2/MgO were synthesized to evaluate their bioimplantation efficacy. The Mg/HA/TiO2/MgO bionanocomposite was further coated with nano-Si, nano-ZnO single-layer, and nano-Si/ZnO double-layers using radio frequency magnetron sputtering technique to achieve such goal. The influence of varying amounts of the additives, the ball milling duration, the annealing temperature, and the coating agents on the biocorrosion and mechanical properties of these bionanocomposites were evaluated using electrochemical, immersion and compression tests. The phase evolution of the synthesized bionanocomposites before and after immersing in the simulated body fluid (SBF) solution was characterized via X-ray diffraction, Fourier-transform infrared and X-ray photoelectron spectroscopy. The detailed microstructures were determined using field-emission scanning electron, transmission electron, and atomic force microscopies. The bionanocomposites wettability was measured via video contact angle method. Thermal gravimetric and differential thermal analysis were performed to evaluate the activation energy and the reaction kinetics of the prepared powder bionanocomposites. In vitro corrosion resistance was analysed using potentiodynamic polarization, immersion, pH variation, and hydrogen evolution tests. After 8 h of ball milling the corrosion resistance of Mg/xHA/10TiO2/10MgO (wt%) bionanocomposite for two different compositions of HA such as 12.5wt% and 27.5wt% was found to increase from 1.35 and 2.19 kΩ.cm2 to 2.25 and 4.78 kΩ.cm2, respectively. Meanwhile, by annealing at 630°C, these two bionanocomposites demonstrated reduced corrosion rates compared to those annealed at 500°C. Interestingly, the compression failure strain (ductility) of HA incorporated Mg was decreased by increasing milling time. The corrosion rate of Mg/12.5HA/10TiO2/10MgO coated with nano-Si/ZnO exhibited a significant reduction from 5.82 (uncoated) to 0.25 mm/year. The cell culture test authenticated that the Mg-based bionanocomposites appeared biocompatible in the presence of HA, MgO, TiO2 additives and nano-Si/ZnO coating. It is noticed that the synthesized Mg/12.5HA/10TiO2/10MgO coated with nano-Si/ZnO has a great potential to become a candidate for biodegradable implants
Enzymatic analysis of native and recombinant fibrinolytic enzyme from bacillus cereus 13BN isolated from belacan
(Universiti Teknologi Malaysia, 2016) Zakaria, Zarita
Fibrinolytic enzymes from natural sources have now attracted more attention than ever because they are less costly and have less undesirable side-effects as compared to modern chemical thrombolytic agents. A bacterial isolate designated as Bacillus cereus 13BN having excellent fibrinolytic enzyme was isolated from fermented shrimp paste, belacan. The enzyme has a dual mechanism of fibrin degradation; it directly degrades fibrin plus it can also act as a tissue type plasminogen activator (t-PA), which converts plasminogen to plasmin and consecutively degrades fibrin. T-PA also participates in a wide variety of connective tissue matrix alterations and upregulated by proinflammatory cytokines which can act as antidepressants. In silico analyses indicated that the enzyme belonged to the typical subtilisin-like serine protease group with a conserved region of a catalytic triad; Asp226, His298 and Ser658. Subtilisin-like 13BN gene was successfully cloned into pET22b (+) vector and then transformed into E. coli BL21 (DE3) to give recombinant BL-21(DE)-(pET22b(+)(SL-13BN). The vector carries an N-terminal pelB signal sequence for periplasmic translocation and a C-terminal His•Tag® for easy purification of the protein. Recombinant enzyme RSL-13 BN was over-expressed as extracellular enzyme (EX) at 41% of total fibrinolytic activity, besides been expressed as periplasmic enzyme (PE) at 56 % and solubilized inclusion bodies (SIB) at 3 %. Under optimized condition where cell mass was propagated by induction with 1 mM IPTG at 30 ºC for 16 hours, 14,616 UL-1 total activity by RSL-13BN could possibly be achieved. This is four fold higher than the extracellular native enzyme SL-13BN (3,468 UL-1). Purification of extracellular SL-13BN enzyme was preceded with ammonium sulphate precipitation, followed by anion exchange and gel filtration chromatography. Alternatively, following ammonium sulphate precipitation, single-step purification was performed for extracellular RSL-13BN enzyme using affinity chromatography utilizing His????-TrapTM Ni-NTA Sepharose column. Both native and recombinant enzymes have equivalent biochemical characteristics. These enzymes are serine proteases with plasminogen activator potential and have a molecular weight of 80kDa. Their strong fibrinolytic activity was verified through fibrin clot degradation pattern on SDS-PAGE gel. The proteolytic action of SL-13BN and RSL-13BN differ from the typical human plasmin in that they can completely hydrolyze whole fibrinogen and fibrin clots without the aid of other proteolytic enzymes.The optimum temperature for fibrinolysis for both was 50°C but their optimum pH differed slightly; pH 7.4 for SL-13BN and pH 7 for RSL-13BN. The activity of both enzymes was enhanced by Ca2+, Na+, K+, Mg2+ and Mn2+, but inhibited by Ag+, Co2+, Cu2+, Fe2+, Fe3+, Hg+, Zn2+, PMSF, EDTA and SDS. Purified SL-13BN had a Vmax of 2.665 U mg-1min-1and Km of 0.5722 mg mL-1 and purified RSL-13BN had a Vmax of 2.642 U mg-1min-1and Km of 0.5776 mg mL-1 towards fibrin. In conclusion, this study showed that RSL-13BN enzyme can be over-produced, acting as t-PA which can provide many medical benefits, easily purified as well as can hydrolyze fibrin and fibrinogen as a whole without the help of other proteolytic enzymes. This makes the enzyme a potential anticoagulant substitute for the treatment of thrombosis-linked diseases
Synthesis and characterization of nanozeolite NaY and its potential as alternative adjuvant theraphy for cancer
(Universiti Teknologi Malaysia, 2016) Ghazi, Noor Azhana
The efficacy of zeolite as anticancer adjuvant is unclear, but natural zeolite clinoptilolite has been proven to have antiproliferation activity against cancer cells. This research investigated the potential of synthetic nanozeolite as anticancer adjuvant in vitro. Initial study proved the antiproliferation abilities of zeolite NaY (Zeo-NaY), commercial zeolite Y (CBV300) and beta (CP814E) against six types of cancer cells through 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The aim of this research was to synthesize nanozeolite NaY (Nano-NaY) with higher antiproliferation activity and tolerance to gastrointestinal condition using organotemplate-free method and rice husk ash (RHA) as the silica source. The newly-synthesized Nano-NaY was characterized by X-ray diffraction (XRD), Fourier transform infra-red (FTIR) spectroscopy, field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM) and surface area analysis. Structural stability of Nano-NaY was tested in simulated gastric fluid (SGF) and intestinal fluid (SIF) at different concentrations by monitoring its characteristic and elemental composition (Al3+, Si4+). Elemental composition (Ca2+, Mg2+) of nanozeolite-treated media were analyzed before and after preparation. Cytotoxicity of Nano-NaY was tested by MTT assay against colon cancer cells (HT-29) and normal liver cells (WRL-68). Pure Nano-NaY was successfully synthesized with the particles sized from 220 nm to 470 nm, and 788 m2/g surface area. Incubation of 30 mg/ml Nano-NaY in simulated gastrointestinal fluid (SGIF) resulted in slight dealumination of the Nano-NaY, but its structure remained stable. Reduction of Ca2+ and Mg2+ concentrations (35-85%) from nanozeolite-treated media suggested adsorption of the cations by Nano-NaY through ionic exchange mechanism. Antiproliferation activity and cytotoxicity of Nano-NaY were dependent on its micropore surface area (Smicropore), with initial half maximal inhibitory concentration (IC50) against HT-29 recorded at 1.26 mg/ml. The cytotoxicity against WRL-68 after incubation in SGIF was low (IC50 = 650 mg/ml). Thus, Nano-NaY might have the potential as an alternative adjuvant therapy for colorectal cancer
Three dimensional surface reconstruction of lower limb prosthetic model using infrared sensor array
(Universiti Teknologi Malaysia, 2016) Daud, Siti Asmah
This thesis addresses the development of a shape detector device using infrared sensor to reconstruct a three-dimensional image of an object. The threedimension image is produced based on the object surface using image processing technique. Conventionally, infrared sensors are used for detection of an obstacle and distance measurement to avoid collisions. However, it is not common to use infrared sensors to measure the size of an object. Hence, this research aims to investigate the feasibility of infrared sensors in measuring the object dimension for three-dimension image reconstruction. Experiments were executed to study the minimum distance range utilising GP2D120 infrared sensor. From the experiment, the distance between the sensor and object surface should be more than 5 cm. The scanning device consists of the infrared sensor array was placed in a black box with the object in the center. The scanning process required the object to turn 360 ° clockwise in an xy plane and the resolution for z-axis is 2 mm, in order to obtain data for the image reconstruction. Reference polygon shape models with various dimensions were used as scanning objects in the experiments. The device scans object diameter every 2 mm in thickness, 100 mm in height, and the total time required to collect data for each layer is 60 seconds. The reconstructed object accuracy is above 80 % based on the comparison between a solid and printed model dimension. Four different lower limb prosthetic models with different shapes were used as the object in the scanning experiments. The experimental findings show that the prosthetic shapes reconstructed with an average accuracy of 97 %. This system shows good reproducibility where the collected data using the infrared sensor device need further improvement so that it can be applied in medical field for orthotics and prosthetics purpose
Characterization of arsenate reduction by arsenic tolerant microbacterium foliorum strain SZ1 isolated from gold ores
(Universiti Teknologi Malaysia, 2016) Mohd. Bahari, Zaratulnur
Arsenic is a metalloid of global concern that primarily exists in two inorganic forms of severe toxicity, As (III) and As (V). The reduction of As (V) to As (III) increases toxicity, mobility and bioavailability of arsenic. Understanding how microorganisms reduce As (V) is important to elucidate As (V) reduction mechanism and inevitably, discover approaches to minimise its toxic impact on the environment. This study was aimed at investigating the capability of arsenic tolerant Microbacterium foliorum strain SZ1 isolated from gold ores to undergo As (V) reduction to As (III). This strain demonstrated complete reduction of 1 mM As (V) achieved within 120 hours under aerobic condition indicating a possible mechanism of detoxification through regulation of ars operon. Further optimization of factors enhancing As (V) reduction capacity of strain SZ1 resulted in complete reduction of 1 mM As (V) achieved within 36 hours in Tris minimal medium supplemented with 10 mM sucrose and 0.1 % (w/v) tryptone at pH 7. The effect of cell adaptation or acclimation towards As (V) reduction was investigated. Well-adapted strain SZ1 recorded complete reduction of 0.5 mM As (V) to 3 mM As (V) within 18 hours to 42 hours incubation. Exopolysaccharides (EPS) was observed to be secreted during reduction of As (V) and subjected to further characterization through chemical analysis of neutral carbohydrate and protein contents and Fourier transform infra-red (FT-IR) analysis. As As (V) concentration increased, so did the protein and carbohydrates concentration of EPS, indicating that EPS played an important role in enabling strain SZ1 to resist and reduce arsenic. Haldane inhibition model was used to fit the reduction rate at different initial As (V) concentrations and the parameters µmax, Ks and Ki were determined to be 0.14 h-1, 0.39 mM and 35.3 mM, respectively. In addition, presence of As (III) as the final product was further confirmed by detection through high performance liquid chromatography (HPLC) analysis. Field emission scanning electron microscopy analysis (FESEM) showed that cells grown in the presence of As (V) exhibited distinct changes in cell morphology and presence of EPS. Exploration of the draft genome of M. foliorum SZ1 identified the presence of ars operon (arsC-arsC-ACR3-arsT-arsC-arsR-arsC) and another two stand-alone genes, arsC and arsB which further confirmed SZ1’s tolerance towards high concentration of arsenic. From the screening of plant growth promoting (PGP) traits, strain SZ1 was able to produce siderophores and indole acetic acid which highlighted its potential use in microbe-assisted arsenic phytoremediation. This is the first study that elucidates the characterization of As (V) reduction by M. foliorum SZ1.

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