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Fulltext Extrinsic factors involved in the differentiation of stem cells into insulin-producing cells: an overview

Wong RS

Exp Diabetes Res, 2011;2011:406182.
PMID: 21747828 DOI: 10.1155/2011/406182

Diabetes mellitus is a chronic disease with many debilitating complications. Treatment of diabetes mellitus mainly revolves around conventional oral hypoglycaemic agents and insulin replacement therapy. Recently, scientists have turned their attention to the generation of insulin-producing cells (IPCs) from stem cells of various sources. To date, many types of stem cells of human and animal origins have been successfully turned into IPCs in vitro and have been shown to exert glucose-lowering effect in vivo. However, scientists are still faced with the challenge of producing a sufficient number of IPCs that can in turn produce sufficient insulin for clinical use. A careful choice of stem cells, methods, and extrinsic factors for induction may all be contributing factors to successful production of functional beta-islet like IPCs. It is also important that the mechanism of differentiation and mechanism by which IPCs correct hyperglycaemia are carefully studied before they are used in human subjects.
Fulltext Apoptosis in cancer: from pathogenesis to treatment

Wong RS

J Exp Clin Cancer Res, 2011;30:87.
PMID: 21943236 DOI: 10.1186/1756-9966-30-87

Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. It is also one of the most studied topics among cell biologists. An understanding of the underlying mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some, the problem is due to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the culprit. Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die. The mechanism of apoptosis is complex and involves many pathways. Defects can occur at any point along these pathways, leading to malignant transformation of the affected cells, tumour metastasis and resistance to anticancer drugs. Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting apoptosis in cancer is feasible. However, many troubling questions arise with the use of new drugs or treatment strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely in human subjects.
Edible bird's nest: food or medicine?

Wong RS

Chin J Integr Med, 2013 Sep;19(9):643-9.
PMID: 23975128 DOI: 10.1007/s11655-013-1563-y

Edible bird's nest (EBN) is derived from the saliva of certain types of swiftlets. It is consumed in many parts of the world for its nutritional and medicinal values. Although many claims have been made on the therapeutic and health-promoting effects of EBN, scientific documentations regarding these effects are very limited in published literature. It is not until recently that the biological effects of EBN are being investigated and evidence-based studies are being conducted. Several studies have found that EBN may enhance cell proliferation and differentiation and various beneficial effects have been reported in vitro as well as in vivo. While these studies point towards the potential use of EBN in the treatment or even prevention of several diseases, the mechanisms of action of EBN remain largely unknown and more explorations are needed. This review is one of the very few scientific reviews on EBN which focuses on recent evidence-based discoveries.
Fulltext Mesenchymal stem cells: angels or demons?

Wong RS

J Biomed Biotechnol, 2011;2011:459510.
PMID: 21822372 DOI: 10.1155/2011/459510

Mesenchymal stem cells (MSCs) have been used in cell-based therapy in various disease conditions such as graft-versus-host and heart diseases, osteogenesis imperfecta, and spinal cord injuries, and the results have been encouraging. However, as MSC therapy gains popularity among practitioners and researchers, there have been reports on the adverse effects of MSCs especially in the context of tumour modulation and malignant transformation. These cells have been found to enhance tumour growth and metastasis in some studies and have been related to anticancer-drug resistance in other instances. In addition, various studies have also reported spontaneous malignant transformation of MSCs. The mechanism of the modulatory behaviour and the tumorigenic potential of MSCs, warrant urgent exploration, and the use of MSCs in patients with cancer awaits further evaluation. However, if MSCs truly play a role in tumour modulation, they can also be potential targets of cancer treatment.
Fulltext Leukaemic stem cells: drug resistance, metastasis and therapeutic implications

Wong RS, Cheong SK

Malays J Pathol, 2012 Dec;34(2):77-88.
PMID: 23424769 MyJurnal

Although there have been many new developments in the treatment of leukaemia with the use of new anti-leukaemic agents and stem cell transplantation, drug resistance and treatment failure remain a great challenge for the attending physician. Several studies have suggested that leukaemic stem cells (LSCs) play a pivotal role in chemoresistance and metastasis and the mechanisms by which these cells do so have also been elucidated. There is increasing evidence to show that there exists a large pool of therapeutic targets in LSCs and that the eradication of these cells is feasible with some promising results. This article gives an overview of different types of cancer stem cells (CSCs) derived from various types of leukaemia, the mechanisms by which LSCs contribute to drug resistance and metastasis and some recent advances in targeted therapy against LSCs.
Fulltext An Application of Bayesian Approach in Modeling Risk of Death in an Intensive Care Unit

Wong RS, Ismail NA

PLoS One, 2016;11(3):e0151949.
PMID: 27007413 DOI: 10.1371/journal.pone.0151949

There are not many studies that attempt to model intensive care unit (ICU) risk of death in developing countries, especially in South East Asia. The aim of this study was to propose and describe application of a Bayesian approach in modeling in-ICU deaths in a Malaysian ICU.
Tocotrienol research: past into present

Wong RS, Radhakrishnan AK

Nutr Rev, 2012 Sep;70(9):483-90.
PMID: 22946849 DOI: 10.1111/j.1753-4887.2012.00512.x

The vitamin E family consists of eight isomers known as alpha-, beta-, gamma-, and delta-tocopherols and alpha-, beta-, gamma-, and delta-tocotrienols. Numerous studies focused on the health benefits of these isomers have been performed since the discovery of vitamin E in 1922. Recent discoveries on the potential therapeutic applications of tocotrienols have revolutionized vitamin E research. Nevertheless, despite the abundance of literature, only 1% of vitamin E research has been conducted on tocotrienols. Many new advances suggest that the use of tocotrienols for health improvement or therapeutic purposes is promising. Although the mechanisms of action of tocotrienols in certain disease conditions have been explored, more detailed investigations into the fundamentals of the health-promoting effects of these molecules must be elucidated before they can be recommended for health improvement or for the treatment or prevention of disease. Furthermore, many of the studies on the effects of tocotrienols have been carried out using cell lines and animal models. The effects in humans must be well established before tocotrienols are used as therapeutic agents in various disease conditions, hence the need for more evidence-based human clinical trials.
Role of mesenchymal stem cells in leukaemia: Dr. Jekyll or Mr. Hyde?

Wong RS, Cheong SK

Clin Exp Med, 2014 Aug;14(3):235-48.
PMID: 23794030 DOI: 10.1007/s10238-013-0247-4

Mesenchymal stem cells (MSCs) have captured the attention of researchers today due to their multipotent differentiation capacity. Also, they have been successfully applied clinically, in the treatment of various diseases of the heart and musculoskeletal systems, with encouraging results. Their supportive role in haematopoiesis and their anti-inflammatory and immunomodulatory properties have enhanced their contribution towards the improvement of engraftment and the treatment of graft-versus-host disease in patients receiving haematopoietic stem cell transplantation. However, there is a growing body of research that supports the involvement of MSCs in leukaemogenesis with several genetic and functional abnormalities having been detected in the MSCs of leukaemia patients. MSCs also exert leukaemia-enhancing effects and induce chemotherapy resistance in leukaemia cells. This paper addresses the key issues in the therapeutic value as well as the harmful effects of the MSCs in leukaemia with a sharp focus on the recent updates in the published literature.
Mood and performance in young malaysian karateka

Wong RS, Thung JS, Pieter W

J Sports Sci Med, 2006;5(CSSI):54-9.
PMID: 24357977

In an attempt to test the conceptual model by Lane and Terry, the purposes of this study were 1) to assess mood states in non-depressed and depressed young karate athletes; 2) to assess mood states in relation to performance in young karate athletes. The participants were recruited from the 2004 Malaysian Games (72 males, 19.20 ± 1.16 years; 37 females, 18.78 ± 0.88 years). The athletes were divided into winners (medalists) and losers. The Brunel Mood Scale (BRUMS) was administered prior to the start of competition. MANOVA was employed to treat the data, while Pearson correlations were calculated for mood states in each depressed mood group and by gender. In terms of non-depressed and depressed mood, tension in the females was higher in the depressed group (5.61 ± 3.02 vs. 3.11 ± 1.90, p = 0.026, eta(2) = 0.133), as was fatigue (3.64 ± 2.61 vs. 0.89 ± 1.69, p = 0.006, eta(2) = 0.199). Tension in the males was higher in the depressed group (4.41 ± 2.52 vs. 1.50 ± 1.55, p < 0.001, eta(2) = 0.215), as was anger (1.43 ± 1.88 vs. 0.25 ± 1.00, p = 0.019, eta(2) = 0.076). The highest associations among mood subscales were between anger and depression (r = 0.57), and between depression and fatigue ( r = 0.55) in depressed males. The female winning karateka scored higher on anger (3.08 ± 2.96 vs. 1.29 ± 2.24, p = 0.046, eta(2) = 0.109). The highest correlations between mood dimensions in depressed females were between depression and anger (r = 0.85) and between depression and confusion (r = 0.85). Contrary to previous research on the influence of depression on anger, only the female winners scored higher on anger. Several negative mood dimensions were higher in both male and female depressed groups, lending some support to the conceptual model advanced by Lane and Terry. Key PointsTo date, there is no information about the relationship between mood and martial arts performance in Malaysian athletes.There might be cultural differences in the way Malaysian athletes respond to psychological questionnaires.The mood-performance and depressed mood-non-depressed mood relationships might be mediated by age.
An unusual case of bilateral vestibulopathy, chronic subjective dizziness and spondyloarthropathy

Wong RS, Abdul Kadir SY

Gen Hosp Psychiatry, 2015 Jul-Aug;37(4):372.e3-4.
PMID: 25840702 DOI: 10.1016/j.genhosppsych.2015.03.011

Vertigo and dizziness are two common symptoms seen in everyday practice. However, in some cases, making a diagnosis can be challenging. This case report shows the relevance of a careful psychiatric history, which led to the diagnosis of chronic subjective dizziness associated with bilateral peripheral vestibulopathy.
Fulltext Medical education in Malaysia: quality versus quantity

Wong RS, Abdul Kadir SY

Perspect Med Educ, 2017 Feb;6(1):10-11.
PMID: 28050881 DOI: 10.1007/s40037-016-0319-8
Fulltext Characterisation of the binding properties of Bacillus thuringiensis 18 toxin on leukaemic cells

Wong RS, Mohamed SM, Nadarajah VD, Tengku IA

J Exp Clin Cancer Res, 2010;29:86.
PMID: 20591169 DOI: 10.1186/1756-9966-29-86

Various strains of Bacillus thuringiensis (Bt) have been found to produce parasporal proteins that are cytotoxic to human cancer cells. This study aims to establish the binding affinity of purified Bt 18 toxin for CEM-SS (T lymphoblastic leukaemia cell line), to determine if competition exists between the toxin and commercial anticancer drugs for the binding site on CEM-SS and to localise the binding site of the toxin on CEM-SS.
An External Independent Validation of APACHE IV in a Malaysian Intensive Care Unit

Wong RS, Ismail NA, Tan CC

Ann Acad Med Singap, 2015 Apr;44(4):127-32.
PMID: 26041636

INTRODUCTION: Intensive care unit (ICU) prognostic models are predominantly used in more developed nations such as the United States, Europe and Australia. These are not that popular in Southeast Asian countries due to costs and technology considerations. The purpose of this study is to evaluate the suitability of the acute physiology and chronic health evaluation (APACHE) IV model in a single centre Malaysian ICU.
MATERIALS AND METHODS: A prospective study was conducted at the single centre ICU in Hospital Sultanah Aminah (HSA) Malaysia. External validation of APACHE IV involved a cohort of 916 patients who were admitted in 2009. Model performance was assessed through its calibration and discrimination abilities. A first-level customisation using logistic regression approach was also applied to improve model calibration.
RESULTS: APACHE IV exhibited good discrimination, with an area under receiver operating characteristic (ROC) curve of 0.78. However, the model's overall fit was observed to be poor, as indicated by the Hosmer-Lemeshow goodness-of-fit test (Ĉ = 113, P <0.001). Predicted in-ICU mortality rate (28.1%) was significantly higher than the actual in-ICU mortality rate (18.8%). Model calibration was improved after applying first-level customisation (Ĉ = 6.39, P = 0.78) although discrimination was not affected.
CONCLUSION: APACHE IV is not suitable for application in HSA ICU, without further customisation. The model's lack of fit in the Malaysian study is attributed to differences in the baseline characteristics between HSA ICU and APACHE IV datasets. Other possible factors could be due to differences in clinical practice, quality and services of health care systems between Malaysia and the United States.
δ- and γ-tocotrienols induce classical ultrastructural apoptotic changes in human T lymphoblastic leukemic cells

Wong RS, Radhakrishnan AK, Ibrahim TA, Cheong SK

Microsc Microanal, 2012 Jun;18(3):462-9.
PMID: 22640960 DOI: 10.1017/S1431927612000177

Tocotrienols are isomers of the vitamin E family, which have been reported to exert cytotoxic effects in various cancer cells. Although there have been some reports on the effects of tocotrienols in leukemic cells, ultrastructural evidence of tocotrienol-induced apoptotic cell death in leukemic cells is lacking. The present study investigated the effects of three isomers of tocotrienols (alpha, delta, and gamma) on a human T lymphoblastic leukemic cell line (CEM-SS). Cell viability assays showed that all three isomers had cytotoxic effects (p < 0.05) on CEM-SS cells with delta-tocotrienol being the most potent. Transmission electron microscopy showed that the cytotoxic effects by delta- and gamma-tocotrienols were through the induction of an apoptotic pathway as demonstrated by the classical ultrastructural apoptotic changes characterized by peripheral nuclear chromatin condensation and nuclear fragmentation. These findings were confirmed biochemically by the demonstration of phosphatidylserine externalization via flow cytometry analysis. This is the first study showing classical ultrastructural apoptotic changes induced by delta- and gamma-tocotrienols in human T lymphoblastic leukemic cells.
Fulltext The Intersection of ChatGPT, Clinical Medicine, and Medical Education

Wong RS, Ming LC, Raja Ali RA

JMIR Med Educ, 2023 Nov 21;9:e47274.
PMID: 37988149 DOI: 10.2196/47274

As we progress deeper into the digital age, the robust development and application of advanced artificial intelligence (AI) technology, specifically generative language models like ChatGPT (OpenAI), have potential implications in all sectors including medicine. This viewpoint article aims to present the authors' perspective on the integration of AI models such as ChatGPT in clinical medicine and medical education. The unprecedented capacity of ChatGPT to generate human-like responses, refined through Reinforcement Learning with Human Feedback, could significantly reshape the pedagogical methodologies within medical education. Through a comprehensive review and the authors' personal experiences, this viewpoint article elucidates the pros, cons, and ethical considerations of using ChatGPT within clinical medicine and notably, its implications for medical education. This exploration is crucial in a transformative era where AI could potentially augment human capability in the process of knowledge creation and dissemination, potentially revolutionizing medical education and clinical practice. The importance of maintaining academic integrity and professional standards is highlighted. The relevance of establishing clear guidelines for the responsible and ethical use of AI technologies in clinical medicine and medical education is also emphasized.
Bacillus thuringiensis parasporal proteins induce cell-cycle arrest and caspase-dependant apoptotic cell death in leukemic cells

Chan KK, Wong RS, Mohamed SM, Ibrahim TA, Abdullah M, Nadarajah VD

J Environ Pathol Toxicol Oncol, 2012;31(1):75-86.
PMID: 22591286

Bacillus thuringiensis (Bt) parasporal proteins with selective anticancer activity have recently garnered interest. This study determines the efficacy and mode of cell death of Bt 18 parasporal proteins against 3 leukemic cell lines (CEM-SS, CCRF-SB and CCRF-HSB-2).Cell-based biochemical analysis aimed to determine cell viability and the percentage of apoptotic cell death in treated cell lines; ultrastructural analysis to study apoptotic changes and Western blot to identify the parasporal proteins' binding site were performed. Bt 18 parasporal proteins moderately decreased viability of leukemic cells but not that of normal human T lymphocytes. Further purification of the proteins showed changes in inhibition selectivity. Phosphatidylserine externalization, active caspase-3, cell cycle, and ultrastructural analysis confirmed apoptotic activity and S-phase cell-cycle arrest. Western blot analysis demonstrated glyceraldehyde 3-phosphate dehydrogenase as a binding protein. We suggest that Bt 18 parasporal proteins inhibit leukemic cell viability by cell-cycle arrest and apoptosis and that glyceraldehyde 3-phosphate dehydrogenase binding initiates apoptosis.
Intensification of Inclusion Body Processing via Temperature-Based Refolding

Wong RS, Alias NNM, Ong EBB, Liew MWO

Methods Mol Biol, 2023;2617:189-200.
PMID: 36656525 DOI: 10.1007/978-1-0716-2930-7_13

Inclusion bodies (IB) are dense insoluble aggregates of mostly misfolded polypeptides that usually result from recombinant protein overexpression. IB formation has been observed in protein expression systems such as E. coli, yeast, and higher eukaryotes. To recover soluble recombinant proteins in their native state, IB are commonly first solubilized with a high concentration of denaturant. This is followed by concurrent denaturant removal or reduction and a transition into a refolding-favorable chemical environment to facilitate the refolding of solubilized protein to its native state. Due to the high concentration of denaturant used, conventional refolding approaches can result in dilute products and are buffer inefficient. To circumvent the limitations of conventional refolding approaches, a temperature-based refolding approach which combines a low concentration of denaturant (0.5 M guanidine hydrochloride, GdnHCl) with a high temperature (95 °C) during solubilization was proposed. In this chapter, we describe a temperature-based refolding approach for the recovery of core streptavidin (cSAV) from IB. Through the temperature-based approach, intensification was achieved through the elimination of a concentration step which would be required by a dilution approach and through a reduction in buffer volumes required for dilution or denaturant removal. High-temperature treatment during solubilization may have also resulted in the denaturation and aggregation of undesired host-cell proteins, which could then be removed through a centrifugation step resulting in refolded cSAV of high purity without the need for column purification. Refolded cSAV was characterized by biotin-binding assay and SDS-PAGE, while purity was determined by RP-HPLC.
Fulltext Fatal Pediatric Melioidosis and the Role of Hyperferritinemic Sepsis-Induced Multiple-Organ Dysfunction Syndrome

Mohan A, Paranchothy M, Segaran S, Wong RS, Chor YK, Podin Y, et al.

Am J Trop Med Hyg, 2022 Aug 17;107(2):393-396.
PMID: 35895426 DOI: 10.4269/ajtmh.22-0051

Melioidosis is reported to cause a high fatality rate in children, even in the absence of risk factors for disease. The aim of this study was to identify characteristics of fatal pediatric melioidosis infection. We performed a retrospective analysis of children aged < 15 years with culture-confirmed melioidosis admitted to Bintulu Hospital in Sarawak, Malaysian Borneo, from January 2011 to December 2020. Forty-one children had culture-confirmed melioidosis. Nine (22%) had a fatal outcome; 8 (89%) had no predisposing risk factors. Bacteremia, septic shock, and acute respiratory distress syndrome were present in all fatalities. Demographic characteristics, presenting manifestation, and disseminated infection were not significantly associated with mortality, whereas the presence of splenomegaly, cytopenia, disseminated intravascular coagulation, and hepatobiliary dysfunction, all of which are features of hyperferritinemic sepsis-induced multiple-organ dysfunction syndrome, were associated with mortality. Hyperferritinemic sepsis-induced multiple-organ dysfunction syndrome may be a key component in the pathogenesis of fatal pediatric melioidosis.
Fulltext Natural bioactive compounds targeting DNA methyltransferase enzymes in cancer: Mechanisms insights and efficiencies

Aanniz T, Bouyahya A, Balahbib A, El Kadri K, Khalid A, Makeen HA, et al.

Chem Biol Interact, 2024 Apr 01;392:110907.
PMID: 38395253 DOI: 10.1016/j.cbi.2024.110907

The regulation of gene expression is fundamental to health and life and is essentially carried out at the promoter region of the DNA of each gene. Depending on the molecular context, this region may be accessible or non-accessible (possibility of integration of RNA polymerase or not at this region). Among enzymes that control this process, DNA methyltransferase enzymes (DNMTs), are responsible for DNA demethylation at the CpG islands, particularly at the promoter regions, to regulate transcription. The aberrant activity of these enzymes, i.e. their abnormal expression or activity, can result in the repression or overactivation of gene expression. Consequently, this can generate cellular dysregulation leading to instability and tumor development. Several reports highlighted the involvement of DNMTs in human cancers. The inhibition or activation of DNMTs is a promising therapeutic approach in many human cancers. In the present work, we provide a comprehensive and critical summary of natural bioactive molecules as primary inhibitors of DNMTs in human cancers. The active compounds hold the potential to be developed as anti-cancer epidrugs targeting DNMTs.
Asian venous thromboembolism guidelines: updated recommendations for the prevention of venous thromboembolism

Liew NC, Alemany GV, Angchaisuksiri P, Bang SM, Choi G, DE Silva DA, et al.

Int Angiol, 2017 Feb;36(1):1-20.
PMID: 27606807 DOI: 10.23736/S0392-9590.16.03765-2

The Asian venous thromboembolism (VTE) prophylaxis guidelines were first published in 2012. Since its first edition, the Asian Venous Thrombosis Forum (AVTF) working group have updated the Asian VTE epidemiology and reviewed issues that were not addressed in the previous guidelines. The authors noted that the rising incidence of VTE across Asia may be attributable to aging population, dietary changes, and increasing incidence of obesity and diabetes. The new additions in the guideline include role of thrombophilia in VTE, bleeding risk in Asians, individual risk assessment, updates in the prevention of VTE in medically ill, bariatric surgery, cancer, orthopedic and trauma patients. The influence of primary thrombophilia in perioperative VTE is still unclear. The secondary risk factors, however, are similar between Asians and Caucasians. The group found no evidence of increased risk of bleeding while using pharmacological agents, including the use of novel anti-coagulants. At present, Caprini risk assessment model is widely used for individual risk assessment. Further validation of this model is needed in Asia. In medically ill patients, pharmacological agents are preferred if there is no bleeding risk. Intermittent pneumatic compression device (IPC) is recommended in patients with bleeding risk but we do not recommend using graduated compressive stockings. In bariatric patients, data on VTE is lacking in Asia. We recommend following current international guidelines. A high index of suspicion should be maintained during postbariatric surgery to detect and promptly treat portomesenteric venous thrombosis. Different cancer types have different thrombotic risks and the types of surgery influence to a large extent the overall VTE risk. Cancer patients should receive further risk assessment. In patients with higher thrombotic risk, either due to predisposing risk or concomitant surgery, low molecular weight heparin is indicated. Different countries appear to have different incidence of VTE following trauma and major orthopedic surgery. We recommend mechanical prophylaxis using IPC as the main method and additional pharmacological prophylaxis if the thrombotic risk is high. As for obstetric practice, we propose adherence to the UK Greentop guideline that is widely accepted and utilized across Asia. To improve VTE thromboprophylaxis implementation in the region, we propose that there should be better health education, establishment of hospital-based guidelines and multidisciplinary collaboration.

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