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Fulltext Utilization of implantable cardioverter-defibrillators for the prevention of sudden cardiac death in emerging countries: Improve SCA clinical trial

Zhang S, Ching CK, Huang D, Liu YB, Rodriguez-Guerrero DA, Hussin A, et al.

Heart Rhythm, 2020 03;17(3):468-475.
PMID: 31561030 DOI: 10.1016/j.hrthm.2019.09.023

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are underutilized in Asia, Latin America, Eastern Europe, the Middle East, and Africa. The Improve SCA Study is the largest prospective study to evaluate the benefit of ICD therapy in underrepresented geographies. This analysis reports the primary objective of the study.
OBJECTIVES: The objectives of this study was to determine whether patients with primary prevention (PP) indications with specific risk factors (1.5PP: syncope, nonsustained ventricular tachycardia, premature ventricular contractions >10/h, and low ventricular ejection fraction <25%) are at a similar risk of life-threatening arrhythmias as patients with secondary prevention (SP) indications and to evaluate all-cause mortality rates in 1.5PP patients with and without devices.
METHODS: A total of 3889 patients were included in the analysis to evaluate ventricular tachycardia or fibrillation therapy and mortality rates. Patients were stratified as SP (n = 1193) and patients with PP indications. The PP cohort was divided into 1.5PP patients (n = 1913) and those without any 1.5PP criteria (n = 783). The decision to undergo ICD implantation was left to the patient and/or physician. The Cox proportional hazards model was used to compute hazard ratios.
RESULTS: Patients had predominantly nonischemic cardiomyopathy. The rate of ventricular tachycardia or fibrillation in 1.5PP patients was not equivalent (within 30%) to that in patients with SP indications (hazard ratio 0.47; 95% confidence interval 0.38-0.57) but was higher than that in PP patients without any 1.5PP criteria (hazard ratio 0.67; 95% confidence interval 0.46-0.97) (P = .03). There was a 49% relative risk reduction in all-cause mortality in ICD implanted 1.5PP patients. In addition, the number needed to treat to save 1 life over 3 years was 10.0 in the 1.5PP cohort vs 40.0 in PP patients without any 1.5PP criteria.
CONCLUSION: These data corroborate the mortality benefit of ICD therapy and support extension to a selected PP population from underrepresented geographies.
Fulltext Three-dimensional culture environment increases the efficacy of platelet rich plasma releasate in prompting skin fibroblast differentiation and extracellular matrix formation

Rothan HA, Djordjevic I, Bahrani H, Paydar M, Ibrahim F, Abd Rahmanh N, et al.

Int J Med Sci, 2014;11(10):1029-38.
PMID: 25136258 DOI: 10.7150/ijms.8895

Platelet rich plasma clot- releasate (PRCR) shows significant influence on tissue regeneration in clinical trials. Although, the mechanism of PRCR effect on fibroblast differentiation has been studied on 2D culture system, a detailed investigation is needed to establish the role of PRCR in cell seeded in 3D scaffolds. Therefore, a study was conducted to evaluate the influence of PRCR in fibroblasts (DFB) differentiation and extracellular matrix formation on both 3D and 2D culture systems. Cell viability was measured using MTT assay and DFB differentiation was evaluated by determining the expression levels of nucleostamin and alpha smooth muscle actin (α-SMA), using indirect immunostaining and Western blotting. The expression levels of extracellular matrix genes (collagen-I, collagen-III, fibronectin and laminin) and focal adhesion formation gene (integrin beta-1) were measured using Real-time PCR. The PRCR at 10% showed significant effect on cells viability compared with 5% and 20% in both culture environments. The decrease in the expression levels of nucleostamin and the increase in α-SMA signify the DFB differentiation to myofibroblast-like cells that was prominently greater in 3D compared to 2D culture. In 3D culture systems, the total collage production, expression levels of the extracellular matrix gene and the focal adhesion gene were increased significantly compared to 2D culture. In conclusion, 3D culture environments enhances the proliferative and differentiation effects of PRCR on DFB, thereby potentially increases the efficacy of DFB for future tissue engineering clinical application.
The mortality analysis of primary prevention patients receiving a cardiac resynchronization defibrillator (CRT-D) or implantable cardioverter-defibrillator (ICD) according to guideline indications in the improve SCA study

Ching CK, Hsieh YC, Liu YB, Rodriguez DA, Kim YH, Joung B, et al.

J Cardiovasc Electrophysiol, 2021 08;32(8):2285-2294.
PMID: 34216069 DOI: 10.1111/jce.15149

BACKGROUND: In primary prevention (PP) patients the utilization of implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy-defibrillators (CRT-D) remains low in many geographies, despite the proven mortality benefit.
PURPOSE: The objective of this analysis was to examine the mortality benefit in PP patients by guideline-indicated device type: ICD and CRT-D.
METHODS: Improve sudden cardiac arrest was a prospective, nonrandomized, nonblinded multicenter trial that enrolled patients from regions where ICD utilization is low. PP patient's CRT-D or ICD eligibility was based upon the 2008 ACC/AHA/HRS and 2006 ESC guidelines. Mortality was assessed according to guideline-indicated device type comparing implanted and nonimplanted patients. Cox proportional hazards methods were used, adjusting for known factors affecting mortality risk.
RESULTS: Among 2618 PP patients followed for a mean of 20.8 ± 10.8 months, 1073 were indicated for a CRT-D, and 1545 were indicated for an ICD. PP CRT-D-indicated patients who received CRT-D therapy had a 58% risk reduction in mortality compared with those without implant (adjusted hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.28-0.61, p
Fulltext The extraction of crude enzyme of lipase from Penicillium candidum PCA 1/TT031 by way of solid state fermentation

Alhelli, A. M., Abd Manap, M. Y., Mohammed, A. S., Mirhosseini, S. H., Sukor, R., Khalil, E. S., et al.

International Food Research Journal, 2018;25(101):1-11.
MyJurnal

Solid-state fermentation (SSF), which is an excellent alternative for industrial enzyme production, entails the exploitation of cheap agro-industrial residues (low priced culture media). This paper delves into the cultivation of mould (GRAS Penicillium candium PCA 1/TT031) using wheat bran (WB) as the culture media. The parameters for crude enzymatic extraction of lipase production were optimized to achieve the highest possible lipase activity. An incubation period of 7 days (3.06 U/g WB), 2% of tributyrin (5.43 U/g WB), meat peptone equal to 2% (5.2 U/g WB), moisture content of 50% (v:w) (6.6 U/g WB), initial pH of 9.0( 8.6 U/g WB), inoculum size of 5×106 spore/g of WB (11.3 U/g WB), an incubation temperature of 20°C (13.6 U/g WB), and an extractant consisting of phosphate buffer pH 7.0 (14.7 U/g WB) were the conditions applied for this study.
The clinical benefit of cardiac resynchronization therapy for narrow QRS compared to broad QRS complex patients

Yap LB, Qadir F, Nguyen ST, Ma SK, Koh KW, Muhammad Z, et al.

Int J Cardiol, 2015 Mar 15;183:178-9.
PMID: 25666128 DOI: 10.1016/j.ijcard.2015.01.042
The association of mammalian DREAM complex and HPV16 E7 proteins

Rashid NN, Rothan HA, Yusoff MS

Am J Cancer Res, 2015;5(12):3525-33.
PMID: 26885443

The mammalian DREAM (Drosophila, RB, E2F, and Myb) complex was discovered in 2004 by several research groups. It was initially identified in Drosophila followed by Caenorhaditis elegans and later in mammalian cells. The composition of DREAM is temporally regulated during cell cycle; being associated with E2F-4 and either p107 or p130 in G0/G1 (repressive DREAM complexes) and with B-myb transcription factor in S/G2 (activator DREAM complex). High risk human papillomavirus (HPV) E6 and E7 oncoproteins expression are important for malignant transformation of cervical cancer cells. In particular, the E7 of high risk HPV binds to pRB family members (pRB, p107 and p130) for degradation. It has recently been discovered that the p107 and p130 'pocket proteins' are members of mammalian DREAM complexes. With this understanding, we would like to hypothesise the mammalian DREAM complex could plays a critical role for malignant transformation in cervical cancer cells.
Systematic Optimisation of Microtiter Plate Lectin Assay to Improve Sialic Acid Linkage Detection

Khairol Mokhtar NHI, Hussin A, Hamid AA, Zainal Ariffin SH, Shahidan MA

Comb Chem High Throughput Screen, 2021 Aug 02.
PMID: 34342257 DOI: 10.2174/1386207324666210802122538

AIMS: We aimed to develop a high-throughput lectin assay with minimized background signals to investigate the interactions of lectins and sialic acid glycans, focusing on prostate-specific antigen (PSA).
BACKGROUND: High background signals resulting from nonspecific binding are a significant concern for microtiter plate-based enzyme-linked lectin sorbent assays (ELLSAs), as they can mask specific binding signals and cause false-positive results.
METHODS: In this study, we constructed an ELLSA based on different washing step parameters, including the number of washing cycles, NaCl and Tween-20 concentrations, and the type of blocking agent and evaluated the effects on both specific and nonspecific binding signals. Furthermore, we performed a PSA binding assay using the optimized ELLSA.
RESULTS: The optimal washing parameters based on the highest specific binding signal proposed four cycles of washing steps using a washing buffer containing a high salt concentration (0.5 M NaCl) and mild detergent (0.05% Tween-20). The utilization of the optimized washing parameters in this assay was shown to be sufficient to obtain the optimal binding signals without the use of any blocking agent. Binding assays performed using the optimized ELLSA revealed that the glycan of the PSA sample used in this study mainly consists of terminal α2,6-linked sialic acid, as strongly recognized by Sambucus nigra agglutinin (SNA) with a KD value of 12.38 nM.
CONCLUSION: The ELLSA reported in this study provides a simple yet sensitive assay for sialic acid linkage recognition.
Fulltext Surface coverage and some soil chemicals properties at Punta Fort William, Greenwich Island, Antarctica

Hii, Y.S., Alias, S.A., Hussin, A., Zakaria, M.P., Moreano, H., Riofrio, M., et al.

ASM Science Journal, 2009;3(2):143-151.
MyJurnal

Surface coverage and some properties soil chemicals were assessed at the Punta Fort William, Greenwich Island during the summer from 1–11 February 2008. Twenty sampling points were established along two strip transects covering a total area of 160 m2. Punta Fort William was basically barren. Rocks, stones and pebbles covered 89.4% of the Punta Fort William. The diversity of vegetation in Punta Fort William was relatively low as compared to other South Shetland Islands. Mosses predominated the area and covered 9.1% of the total surface. Colobantus quitensis was the only vascular plant found at the Punta Fort William. It covered 0.5% of the total surface area. Lichens contributed 0.2% of the surface coverage. Although lichen coverage was low, its frequency of occurrence was among the highest. Total organic carbon (TOC) and total nitrogen (TN) in the study area ranged from 1 g to 39 g C kg–1 and 12 μg to 3892 μg N kg–1, respectively. The level of TOC and TN were comparable to those reported in other maritime locations in Antarctic. Higher levels of TOC and TN were detected in the areas with intensive biological activities. Hydrocarbon concentration was very low in this area and the sources of hydrocarbons were both natural and anthropogenic. The natural hydrocarbons source was mostly biogenic while the petrogenic hydrocarbons input was anthropogenic.
Successful placement of left ventricular pacing lead despite coronary sinus perforation into the pericardial space with an obstructive flap

Tamin SS, Hussin A, Za I, Halmey N, Azman W

Pacing Clin Electrophysiol, 2007 Feb;30(2):276-9.
PMID: 17338728

Coronary sinus perforation is a relatively uncommon but much feared complication that may occur during the placement of left ventricular pacing lead. Coronary sinus perforation, especially in the presence of an obstructive flap, usually indicates the need to abandon the implantation attempt, as there are difficulties in crossing the obstructive flap as well as uncertainty of whether the lead is in the true lumen or into the pericardial space. We describe our experience in successfully placing the left ventricular lead safely despite the problems arising from these circumstances.
Fulltext Small molecule grp94 inhibitors block dengue and Zika virus replication

Rothan HA, Zhong Y, Sanborn MA, Teoh TC, Ruan J, Yusof R, et al.

Antiviral Res, 2019 11;171:104590.
PMID: 31421166 DOI: 10.1016/j.antiviral.2019.104590

Two major flaviviruses, dengue virus (DENV) and Zika virus (ZIKV), cause severe health and economic burdens worldwide. Recently, genome-wide screenings have uncovered the importance of regulators of the Hrd1 ubiquitin ligase-mediated endoplasmic reticulum (ER)-associated degradation (ERAD) pathway for flavivirus replication in host cells. Here we report the identification of the compound Bardoxolone methyl (CDDO-me) as a potent inhibitor of the Hrd1 ubiquitin ligase-mediated ERAD, which possesses a broad-spectrum activity against both DENV and ZIKV. Cellular thermal shift assay (CETSA) suggested that CDDO-me binds to grp94, a key component of the Hrd1 pathway, at a low nanomolar concentration, whereas interaction was not detected with its paralog Hsp90. CDDO-me and the grp94 inhibitor PU-WS13 substantially suppressed DENV2 replication and the cytopathic effects caused by DENV and ZIKV infection. The antiviral activities of both compounds were demonstrated for all four DENV serotypes and four ZIKV strains in multiple human cell lines. This study defines grp94 as a crucial host factor for flavivirus replication and identified CDDO-me as a potent small molecule inhibitor of flavivirus infection. Inhibition of grp94 may contribute to the antiviral activity of CDDO-me. Further investigation of grp94 inhibitors may lead to a new class of broad-spectrum anti-flaviviral medications.
Fulltext Scalable Production of Recombinant Membrane Active Peptides and Its Potential as a Complementary Adjunct to Conventional Chemotherapeutics

Rothan HA, Ambikabothy J, Abdulrahman AY, Bahrani H, Golpich M, Amini E, et al.

PLoS One, 2015;10(9):e0139248.
PMID: 26418816 DOI: 10.1371/journal.pone.0139248

The production of short anticancer peptides in recombinant form is an alternative method for costly chemical manufacturing. However, the limitations of host toxicity, bioactivity and column purification have impaired production in mass quantities. In this study, short cationic peptides were produced in aggregated inclusion bodies by double fusion with a central protein that has anti-cancer activity. The anticancer peptides Tachiplicin I (TACH) and Latarcin 1 (LATA) were fused with the N- and C-terminus of the MAP30 protein, respectively. We successfully produced the recombinant TACH-MAP30-LATA protein and MAP30 alone in E. coli that represented 59% and 68% of the inclusion bodies. The purified form of the inclusion bodies was prepared by eliminating host cell proteins through multiple washing steps and semi-solubilization in alkaline buffer. The purified active protein was recovered by inclusive solubilization at pH 12.5 in the presence of 2 M urea and refolded in alkaline buffer containing oxides and reduced glutathione. The peptide-fusion protein showed lower CC50 values against cancer cells (HepG2, 0.35±0.1 μM and MCF-7, 0.58±0.1 μM) compared with normal cells (WRL68, 1.83±0.2 μM and ARPE19, 2.5±0.1 μM) with outstanding activity compared with its individual components. The presence of the short peptides facilitated the entry of the peptide fusion protein into cancer cells (1.8 to 2.2-fold) compared with MAP30 alone through direct interaction with the cell membrane. The cancer chemotherapy agent doxorubicin showed higher efficiency and selectivity against cancer cells in combination with the peptide- fusion protein. This study provides new data on the mass production of short anticancer peptides as inclusion bodies in E. coli by fusion with a central protein that has similar activity. The product was biologically active against cancer cells compared with normal cells and enhanced the activity and selective delivery of an anticancer chemotherapy agent.
Reversible thermo-pneumatic valves on centrifugal microfluidic platforms

Aeinehvand MM, Ibrahim F, Harun SW, Kazemzadeh A, Rothan HA, Yusof R, et al.

Lab Chip, 2015 Aug 21;15(16):3358-69.
PMID: 26158597 DOI: 10.1039/c5lc00634a

Centrifugal microfluidic systems utilize a conventional spindle motor to automate parallel biochemical assays on a single microfluidic disk. The integration of complex, sequential microfluidic procedures on these platforms relies on robust valving techniques that allow for the precise control and manipulation of fluid flow. The ability of valves to consistently return to their former conditions after each actuation plays a significant role in the real-time manipulation of fluidic operations. In this paper, we introduce an active valving technique that operates based on the deflection of a latex film with the potential for real-time flow manipulation in a wide range of operational spinning speeds. The reversible thermo-pneumatic valve (RTPV) seals or reopens an inlet when a trapped air volume is heated or cooled, respectively. The RTPV is a gas-impermeable valve composed of an air chamber enclosed by a latex membrane and a specially designed liquid transition chamber that enables the efficient usage of the applied thermal energy. Inputting thermo-pneumatic (TP) energy into the air chamber deflects the membrane into the liquid transition chamber against an inlet, sealing it and thus preventing fluid flow. From this point, a centrifugal pressure higher than the induced TP pressure in the air chamber reopens the fluid pathway. The behaviour of this newly introduced reversible valving system on a microfluidic disk is studied experimentally and theoretically over a range of rotational frequencies from 700 RPM to 2500 RPM. Furthermore, adding a physical component (e.g., a hemispherical rubber element) to induce initial flow resistance shifts the operational range of rotational frequencies of the RTPV to more than 6000 RPM. An analytical solution for the cooling of a heated RTPV on a spinning disk is also presented, which highlights the need for the future development of time-programmable RTPVs. Moreover, the reversibility and gas impermeability of the RTPV in the microfluidic networks are validated on a microfluidic disk designed for performing liquid circulation. Finally, an array of RTPVs is integrated into a microfluidic cartridge to enable sequential aliquoting for the conversion of dengue virus RNA to cDNA and the preparation of PCR reaction mixtures.
Regional disparities and risk factors of mortality among patients at high risk of sudden cardiac death in emerging countries: a nonrandomized controlled trial

Zhao S, Ching CK, Huang D, Liu YB, Rodriguez-Guerrero DA, Hussin A, et al.

BMC Med, 2024 Mar 22;22(1):130.
PMID: 38519982 DOI: 10.1186/s12916-024-03310-5

BACKGROUND: Comprehensive data on patients at high risk of sudden cardiac death (SCD) in emerging countries are lacking. The aim was to deepen our understanding of the SCD phenotype and identify risk factors for death among patients at high risk of SCD in emerging countries.
METHODS: Patients who met the class I indication for implantable cardioverter-defibrillator (ICD) implantation according to guideline recommendations in 17 countries and regions underrepresented in previous trials were enrolled. Countries were stratified by the WHO regional classification. Patients were or were not implanted with an ICD at their discretion. The outcomes were all-cause mortality and SCD.
RESULTS: We enrolled 4222 patients, and 3889 patients were included in the analysis. The mean follow-up period was 21.6 ± 10.2 months. There were 433 (11.1%) instances of all-cause mortality and 117 (3.0%) cases of SCD. All-cause mortality was highest in primary prevention (PP) patients from Southeast Asia and secondary prevention (SP) patients from the Middle East and Africa. The SCD rates among PP and SP patients were both highest in South Asia. Multivariate Cox regression modelling demonstrated that in addition to the independent predictors identified in previous studies, both geographic region and ICD use were associated with all-cause mortality in patients with high SCD risk. Primary prophylactic ICD implantation was associated with a 36% (HR = 0.64, 95% CI 0.531-0.802, p
Fulltext Recombinant human adiponectin as a potential protein for treating diabetic tendinopathy promotes tenocyte progenitor cells proliferation and tenogenic differentiation in vitro

Rothan HA, Suhaeb AM, Kamarul T

Int J Med Sci, 2013;10(13):1899-906.
PMID: 24324367 DOI: 10.7150/ijms.6774

Adiponectin is an adipocyte-secreting hormone that increases cell sensitivity to insulin. It has been previously demonstrated that this hormone protects against Type II Diabetes and, is found to concurrently promote cell proliferation and differentiation. It is postulated that diabetic patients who suffer from tendinopathy may benefit from using adiponectin, which not only improves the metabolism of diabetic ridden tenocytes but also promotes progenitor cell proliferation and differentiation in tendons. These changes may result in tendon regeneration, which, in diabetic tendinopathy, is difficult to treat. Considering that such findings have yet to be demonstrated, a study was thus conducted using diabetic ridden human tenocyte progenitor cells (TPC) exposed to recombinant adiponectin in vitro. TPC were isolated from tendons of diabetic patients and exposed to 10 μg/ml adiponectin. Cell proliferation rate was investigated at various time points whilst qPCR were used to determine the tenogenic differentiation potential. The results showed that adiponectin significantly reduced blood glucose in animal models. The proliferation rate of adiponectin-treated TPCs was significantly higher at 6, 8 and 10 days as compared to untreated cells (p<0.05). The levels of tenogenic genes expression (collagen I, III, tenomodulin and scleraxis) were also significantly upregulated; whilst the osteogenic (Runx2), chondrogenic (Sox9) and adipogenic (PPARУγ) gene expressions remained unaltered. The results of this study suggest that adiponectin is a potential promoter that not only improves diabetic conditions, but also increases tendon progenitor cell proliferation and differentiation. These features supports the notion that adiponectin may be potentially beneficial in treating diabetic tendinopathy.
Fulltext Protegrin-1 inhibits dengue NS2B-NS3 serine protease and viral replication in MK2 cells

Rothan HA, Abdulrahman AY, Sasikumer PG, Othman S, Rahman NA, Yusof R

J Biomed Biotechnol, 2012;2012:251482.
PMID: 23093838 DOI: 10.1155/2012/251482

Dengue diseases have an economic as well as social burden worldwide. In this study, the antiviral activity of protegrin-1 (PG-1, RGGRLCYCRRRFCVCVGR) peptide towards dengue NS2B-NS3pro and viral replication in Rhesus monkey kidney (MK2) cells was investigated. The peptide PG-1 was synthesized by solid-phase peptide synthesis, and disulphide bonds formation followed by peptide purification was confirmed by LC-MS and RPHPLC. Dengue NS2B-NS3pro was produced as a single-chain recombinant protein in E. coli. The NS2B-NS3pro assay was carried out by measuring the florescence emission of catalyzed substrate. Real-time PCR was used to evaluate the inhibition potential of PG-1 towards dengue serotype-2 (DENV-2) replication in MK2 cells. The results showed that PG-1 inhibited dengue NS2B-NS3pro at IC(50) of 11.7 μM. The graded concentrations of PG-1 at nontoxic range were able to reduce viral replication significantly (P < 0.001) at 24, 48, and 72 hrs after viral infection. However, the percentage of inhibition was significantly (P < 0.01) higher at 24 hrs compared to 48 and 72 hrs. These data show promising therapeutic potential of PG-1 against dengue infection, hence it warrants further analysis and improvement of the peptide features as a prospective starting point for consideration in designing attractive dengue virus inhibitors.
Potential DNA Vaccine for Haemorrhagic Septiceamia Disease

Chelliah S, Velappan RD, Lim KT, Swee CWK, Nor Rashid N, Rothan HA, et al.

Mol Biotechnol, 2020 May;62(5):289-296.
PMID: 32185600 DOI: 10.1007/s12033-020-00244-0

Pasteurella multocida is the main cause of haemorrhagic septicaemia (HS) outbreak in livestock, such as cattle and buffaloes. Conventional vaccines such as alum-precipitated or oil-adjuvant broth bacterins were injected subcutaneously to provide protection against HS. However, the immunity developed is only for short term and needed to be administered frequently. In our previous study, a short gene fragment from Pasteurella multocida serotype B was obtained via shotgun cloning technique and later was cloned into bacterial expression system. pQE32-ABA392 was found to possess immunogenic activity towards HS when tested in vivo in rat model. In this study, the targeted gene fragment of ABA392 was sub-cloned into a DNA expression vector pVAX1 and named as pVAX1-ABA392. The new recombinant vaccine was stable and expressed on mammalian cell lines. Serum sample collected from a group of vaccinated rats for ELISA test shows that the antibody in immunized rats was present at high titer and can be tested as a vaccine candidate with challenge in further studies. This successful recombinant vaccine is immunogenic and potentially could be used as vaccine in future against HS.
Polymethacrylate coated electrospun PHB fibers: An exquisite outlook for fabrication of paper-based biosensors

Hosseini S, Azari P, Farahmand E, Gan SN, Rothan HA, Yusof R, et al.

Biosens Bioelectron, 2015 Jul 15;69:257-64.
PMID: 25765434 DOI: 10.1016/j.bios.2015.02.034

Electrospun polyhydroxybutyrate (PHB) fibers were dip-coated by polymethyl methacrylate-co-methacrylic acid, poly(MMA-co-MAA), which was synthesized in different molar ratios of the monomers via free-radical polymerization. Fabricated platfrom was employed for immobilization of the dengue antibody and subsequent detection of dengue enveloped virus in enzyme-linked immunosorbent assay (ELISA). There is a major advantage for combination of electrospun fibers and copolymers. Fiber structre of electrospun PHB provides large specific surface area available for biomolecular interaction. In addition, polymer coated parts of the platform inherited the premanent presence of surface carboxyl (-COOH) groups from MAA segments of the copolymer which can be effectively used for covalent and physical protein immobilization. By tuning the concentration of MAA monomers in polymerization reaction the concentration of surface -COOH groups can be carefully controlled. Therefore two different techniques have been used for immobilization of the dengue antibody aimed for dengue detection: physical attachment of dengue antibodies to the surface and covalent immobilization of antibodies through carbodiimide chemistry. In that perspective, several different characterization techniques were employed to investigate the new polymeric fiber platform such as scanning electron microscopy (SEM), atomic force microscopy (AFM), water contact angle (WCA) measurement and UV-vis titration. Regardless of the immobilization techniques, substantially higher signal intensity was recorded from developed platform in comparison to the conventional ELISA assay.
Fulltext Polycaprolactone Triol-Citrate Scaffolds Enriched with Human Platelet Releasates Promote Chondrogenic Phenotype and Cartilage Extracellular Matrix Formation

Rothan HA, Mahmod SA, Djordjevic I, Golpich M, Yusof R, Snigh S

Tissue Eng Regen Med, 2017 Apr;14(2):93-101.
PMID: 30603466 DOI: 10.1007/s13770-017-0023-8

In this paper we report the differentiating properties of platelet-rich plasma releasates (PRPr) on human chondrocytes within elastomeric polycaprolactone triol-citrate (PCLT-CA) porous scaffold. Human-derived chondrocyte cellular content of glycosaminoglycans (GAGs) and total collagen were determined after seeding into PCLT-CA scaffold enriched with PRPr cells. Immunostaining and real time PCR was applied to evaluate the expression levels of chondrogenic and extracellular gene markers. Seeding of chondrocytes into PCLT-CA scaffold enriched with PRPr showed significant increase in total collagen and GAGs production compared with chondrocytes grown within control scaffold without PRPr cells. The mRNA levels of collagen II and SOX9 increased significantly while the upregulation in Cartilage Oligomeric Matrix Protein (COMP) expression was statistically insignificant. We also report the reduction of the expression levels of collagen I and III in chondrocytes as a consequence of proximity to PRPr cells within the scaffold. Interestingly, the pre-loading of PRPr caused an increase of expression levels of following extracellular matrix (ECM) proteins: fibronectin, laminin and integrin β over the period of 3 days. Overall, our results introduce the PCLT-CA elastomeric scaffold as a new system for cartilage tissue engineering. The method of PRPr cells loading prior to chondrocyte culture could be considered as a potential environment for cartilage tissue engineering as the differentiation and ECM formation is enhanced significantly.
Fulltext Phytoestrogen (Daidzein) Promotes Chondrogenic Phenotype of Human Chondrocytes in 2D and 3D Culture Systems

Mahmod SA, Snigh S, Djordjevic I, Mei Yee Y, Yusof R, Ramasamy TS, et al.

Tissue Eng Regen Med, 2017 Apr;14(2):103-112.
PMID: 30603467 DOI: 10.1007/s13770-016-0004-3

Clinical investigations have shown a significant relationship between osteoarthritis (OA) and estrogens levels in menopausal women. Therefore, treatment with exogenous estrogens has been shown to decrease the risk of OA. However, the effect estrogen has not been clearly demonstrated in the chondrocytes using phytoestrogens, which lack the specific side-effects of estrogens, may provide an alternative therapy. This study was designed to examine the possible effects of phytoestrogen (daidzein) on human chondrocyte phenotype and extracellular matrix formation. Phytoestrogens which lack the specific side-effects of estrogens may provide beneficial effect without causing hormone based side effect. Human chondrocytes cells were cultured in 2D (flask) and 3D (PCL-CA scaffold) systems. Daidzein cytotoxic effect was determined by MTT assay. Chondrocyte cellular content of glycosaminoglycans (GAGs), total collagen and chondrogenic gene expression were determined in both culture systems after treatment with daidzein. Daidzein showed time-dependent and dose-independent effects on chondrocyte bioactivity. The compound at low doses showed significant (p 0.05). The expression levels of Fibronectin, Laminin and Integrin β1 were significantly increased especially in 3D culture system. This study was illustrated the potential positive effects of daidzein on maintenance of human chondrocyte phenotype and extracellular matrix formation suggesting an attractive and viable alternative therapy for OA.
Phenotypic and genotypic characterization of induced acyclovir-resistant clinical isolates of herpes simplex virus type 1

Hussin A, Md Nor NS, Ibrahim N

Antiviral Res, 2013 Nov;100(2):306-13.
PMID: 24055837 DOI: 10.1016/j.antiviral.2013.09.008

Eleven strains of acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) were generated from HSV-1 clinical isolates by exposure to ACV. Genotype of the thymidine kinase (TK) and DNA polymerase (pol) genes from these mutants were further analyzed. Genotypic analysis revealed four non-synonymous mutations in TK gene associated with gene polymorphism and two to three non-synonymous mutations in DNA pol gene. Seven and six strains contained at least one resistance-associated mutation at TK and DNA pol gene, respectively. Resistance-associated mutations within the TK gene consisted of 64% of non-synonymous frameshift mutations within the homopolymer region of G's and C's, and 36% of non-synonymous nucleotide substitutions of the conserved gene region (C336Y, R51W and R222H), nucleotide that produced stop codon (L288Stop) and two amino acid substitutions outside the conserved region (E39G & L208F). There were 10 non-synonymous amino acid substitutions located outside the conserved region with the unclear significance to confer resistance observed. Resistance-associated mutations in DNA pol gene include insertion of G at the homopolymer region of G's (794-797) and amino acid substitutions inside (V621S) or outside (H1228D) the conserved region. In silico analysis of the mutated TK (C336Y, R51W and L208F), and DNA pol (V621S and H1228D) suggested structural changes that might alter the stability of these proteins. However, there were several mutations with unclear significance to confer ACV-resistance identified, especially mutations outside the conserved region.

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