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  1. De Silva L, Chuah LH, Meganathan P, Fu JY
    Biofactors, 2016 Mar-Apr;42(2):149-62.
    PMID: 26948691 DOI: 10.1002/biof.1259
    Tumor metastasis involves some of the most complex and dynamic processes in cancer, often leading to poor quality of life and inevitable death. The search for therapeutic compounds and treatment strategies to prevent and/or manage metastasis is the ultimate challenge to fight cancer. In the past two decades, research focus on vitamin E has had a shift from saturated tocopherols to unsaturated tocotrienols (T3). Despite sharing structural similarities with tocopherols, T3 strive to gain scientific prominence due to their anti-cancer effects. Recent studies have shed some light on the anti-metastatic properties of T3. In this review, the roles of T3 in each step of the metastatic process are discussed. During the invasion process, signaling pathways that regulate the extracellular matrix and tumor cell motility have been reported to be modulated by T3. Although studies on T3 and tumor cell migration are fairly limited, they were shown to play a vital role in the suppression of angiogenesis. Furthermore, the anti-inflammatory effect of T3 could be highly promising in the regulation of tumor microenvironment, which is crucial in supporting tumor growth in distant organs. © 2016 BioFactors, 42(2):149-162, 2016.
  2. Ferreira de Sá AS, Leonardo-Silva L, Xavier-Santos S
    Biodivers Data J, 2022;10:e80226.
    PMID: 36761671 DOI: 10.3897/BDJ.10.e80226
    BACKGROUND: Saccharomycetales are ascomycetic yeasts and, amongst them, the genus Blastobotrys has approximately 30 known species. Blastobotrysmalaysiensis is a yeast species, described from cave samples, known until then only from Malaysia. In this study, we characterise a new strain and report the second occurrence record of this species. Here, Blastobotrysmalaysiensis URM 8507/SXS 675, was collected from sediments samples from a cave in the Parque Estadual de Terra Ronca (PETER) in Goiás, Brazil. Phylogenetic analyses revealed strong support with the sequence of the species type, as well as with other species of the clade. This new record contributes by providing new molecular data for the species and expanding the knowledge of its distribution beyond the Asian continent.

    NEW INFORMATION: First record of a yeast for the American continent and its second mention for the world.

  3. Fu JY, Htar TT, De Silva L, Tan DM, Chuah LH
    Molecules, 2017 Feb 04;22(2).
    PMID: 28165404 DOI: 10.3390/molecules22020233
    Vitamin E is recognized as an essential vitamin since its discovery in 1922. Most vegetable oils contain a mixture of tocopherols and tocotrienols in the vitamin E composition. Structurally, tocopherols and tocotrienols share a similar chromanol ring and a side chain at the C-2 position. Owing to the three chiral centers in tocopherols, they can appear as eight different stereoisomers. Plant sources of tocopherol are naturally occurring in the form of RRR while synthetic tocopherols are usually in the form of all-racemic mixture. Similarly, with only one chiral center, natural tocotrienols occur as the R-isoform. In this review, we aim to discuss a few chromatographic methods that had been used to separate the stereoisomers of tocopherols and tocotrienols. These methods include high performance liquid chromatography, gas chromatography and combination of both. The review will focus on method development including selection of chiral columns, detection method and choice of elution solvent in the context of separation efficiency, resolution and chiral purity. The applications for separation of enantiomers in vitamin E will also be discussed especially in terms of the distinctive biological potency among the stereoisoforms.
  4. Silva L, Qureshi N, Abdul-Hamid H, Weng S, Kai J, Leonardi-Bee J
    J Pers Med, 2021 Apr 15;11(4).
    PMID: 33920869 DOI: 10.3390/jpm11040302
    Familial hypercholesterolaemia (FH) is a common inherited cause of premature cardiovascular disease, but the majority of patients remain undiagnosed. The aim of this systematic review was to assess the effectiveness of interventions to systematically identify FH in primary care. No randomised, controlled studies were identified; however, three non-randomised intervention studies were eligible for inclusion. All three studies systematically identified FH using reminders (on-screen prompts) in electronic health records. There was insufficient evidence that providing comments on laboratory test results increased the identification of FH using the Dutch Lipid Clinic Network (DLCN) criteria. Similarly, using prompts combined with postal invitation demonstrated no significant increase in definite FH identification using Simon-Broome (SB) criteria; however, the identification of possible FH increased by 25.4% (CI 17.75 to 33.97%). Using on-screen prompts alone demonstrated a small increase of 0.05% (95% CI 0.03 to 0.07%) in identifying definite FH using SB criteria; however, when the intervention was combined with an outreach FH nurse assessment, the result was no significant increase in FH identification using a combination of SB and DLCN criteria. None of the included studies reported adverse effects associated with the interventions. Currently, there is insufficient evidence to determine which is the most effective method of systematically identifying FH in non-specialist settings.
  5. De Silva L, Fu JY, Htar TT, Muniyandy S, Kasbollah A, Wan Kamal WHB, et al.
    Int J Nanomedicine, 2019;14:1101-1117.
    PMID: 30863048 DOI: 10.2147/IJN.S184912
    Background and purpose: Niosomes are nonionic surfactant-based vesicles that exhibit certain unique features which make them favorable nanocarriers for sustained drug delivery in cancer therapy. Biodistribution studies are critical in assessing if a nanocarrier system has preferential accumulation in a tumor by enhanced permeability and retention effect. Radiolabeling of nanocarriers with radioisotopes such as Technetium-99m (99mTc) will allow for the tracking of the nanocarrier noninvasively via nuclear imaging. The purpose of this study was to formulate, characterize, and optimize 99mTc-labeled niosomes.

    Methods: Niosomes were prepared from a mixture of sorbitan monostearate 60, cholesterol, and synthesized D-α-tocopherol polyethylene glycol 1000 succinate-diethylenetriaminepentaacetic acid (synthesis confirmed by 1H and 13C nuclear magnetic resonance spectroscopy). Niosomes were radiolabeled by surface chelation with reduced 99mTc. Parameters affecting the radiolabeling efficiency such as concentration of stannous chloride (SnCl2·H2O), pH, and incubation time were evaluated. In vitro stability of radiolabeled niosomes was studied in 0.9% saline and human serum at 37°C for up to 8 hours.

    Results: Niosomes had an average particle size of 110.2±0.7 nm, polydispersity index of 0.229±0.008, and zeta potential of -64.8±1.2 mV. Experimental data revealed that 30 µg/mL of SnCl2·H2O was the optimal concentration of reducing agent required for the radiolabeling process. The pH and incubation time required to obtain high radiolabeling efficiency was pH 5 and 15 minutes, respectively. 99mTc-labeled niosomes exhibited high radiolabeling efficiency (>90%) and showed good in vitro stability for up to 8 hours.

    Conclusion: To our knowledge, this is the first study published on the surface chelation of niosomes with 99mTc. The formulated 99mTc-labeled niosomes possessed high radiolabeling efficacy, good stability in vitro, and show good promise for potential use in nuclear imaging in the future.

  6. Akinyemi SA, Gitari WM, Thobakgale R, Petrik LF, Nyakuma BB, Hower JC, et al.
    Environ Geochem Health, 2020 Sep;42(9):2771-2788.
    PMID: 31900823 DOI: 10.1007/s10653-019-00511-3
    The chemical reactions of dry-disposed ash dump, ingressed oxygen, carbon dioxide, and infiltrating rainwater affect mineralogical transformation, redistribution, and migration of chemical species. Composite samples of weathered coal fly ash taken at various depths and fresh coal fly ash were examined using organic petrographic, X-ray diffraction, X-ray fluorescence techniques, and successive extraction procedures. Results obtained show relative enrichment of glass, Al-Fe-oxides, calcite, and tridymite in the weathered CFA, but the fresh CFA is enriched in mullite, inertinite, maghemite, and ettringite. The enrichment of the weathered CFA in amorphous glass suggests higher reactivity when compared to fresh CFA. The evident depletion of soluble oxides in the weathered CFA is attributed to flushing of the soluble salts by percolating rainwater. Comparative enrichment of examined elements in water-soluble, exchangeable, reducible, and residual fractions of the weathered CFA is partly due to the slow release of adsorbed chemical species from the alumina-silicate matrix and diffusion from the deeper sections of the particles of coal fly ash. Sodium and potassium show enrichment in the oxidisable fraction of fresh CFA. The estimated mobility factor indicates mobility for Ca, Mg, Na, Se, Mo, and Sb and K, Sr, V, Cu, Cr, Se, and B in fresh and weathered CFAs, respectively.
  7. De Silva L, Fu JY, Htar TT, Wan Kamal WHB, Kasbollah A, Muniyandy S, et al.
    Front Pharmacol, 2021;12:778396.
    PMID: 35069200 DOI: 10.3389/fphar.2021.778396
    The purpose of this work was to study the biodistribution of niosomes in tumor-implanted BALB/c mice using gamma scintigraphy. Niosomes were first formulated and characterized, then radiolabeled with Technetium-99 m (99mTc). The biodistribution of 99mTc-labeled niosomes was evaluated in tumor-bearing mice through intravenous injection and imaged with gamma scintigraphy. The labeled complexes possessed high radiolabeling efficiency (98.08%) and were stable in vitro (>80% after 8 h). Scintigraphic imaging showed negligible accumulation in the stomach and thyroid, indicating minimal leaching of the radiolabel in vivo. Radioactivity was found mainly in the liver, spleen and kidneys. Tumor-to-muscle ratio indicated a higher specificity of the formulation for the tumor area. Overall, the formulated niosomes are stable both in vitro and in vivo, and show preferential tumor accumulation.
  8. Ramli AS, Qureshi N, Abdul-Hamid H, Kamal A, Kanchau JD, Shahuri NS, et al.
    JMIR Res Protoc, 2023 Jun 02;12:e47911.
    PMID: 37137823 DOI: 10.2196/47911
    BACKGROUND: Familial hypercholesterolemia (FH) is predominantly caused by mutations in the 4 FH candidate genes (FHCGs), namely, low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB-100), proprotein convertase subtilisin/kexin type 9 (PCSK9), and the LDL receptor adaptor protein 1 (LDLRAP1). It is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels leading to premature coronary artery disease. FH can be clinically diagnosed using established clinical criteria, namely, Simon Broome (SB) and Dutch Lipid Clinic Criteria (DLCC), and can be identified using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT), a primary care screening tool.

    OBJECTIVE: This study aims to (1) compare the detection rate of genetically confirmed FH and diagnostic accuracy between the FAMCAT, SB, and DLCC in the Malaysian primary care setting; (2) identify the genetic mutation profiles, including novel variants, in individuals with suspected FH in primary care; (3) explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing in primary care; and (4) evaluate the clinical utility of a web-based FH Identification Tool that includes the FAMCAT, SB, and DLCC in the Malaysian primary care setting.

    METHODS: This is a mixed methods evaluation study conducted in 11 Ministry of Health primary care clinics located at the central administrative region of Malaysia. In Work stream 1, the diagnostic accuracy study design is used to compare the detection rate and diagnostic accuracy of the FAMCAT, SB, and DLCC against molecular diagnosis as the gold standard. In Work stream 2, the targeted next-generation sequencing of the 4 FHCGs is used to identify the genetic mutation profiles among individuals with suspected FH. In Work stream 3a, a qualitative semistructured interview methodology is used to explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing. Lastly, in Work stream 3b, a qualitative real-time observation of primary care physicians using the "think-aloud" methodology is applied to evaluate the clinical utility of a web-based FH Identification Tool.

    RESULTS: The recruitment for Work stream 1, and blood sampling and genetic analysis for Work stream 2 were completed in February 2023. Data collection for Work stream 3 was completed in March 2023. Data analysis for Work streams 1, 2, 3a, and 3b is projected to be completed by June 2023, with the results of this study anticipated to be published by December 2023.

    CONCLUSIONS: This study will provide evidence on which clinical diagnostic criterion is the best to detect FH in the Malaysian primary care setting. The full spectrum of genetic mutations in the FHCGs including novel pathogenic variants will be identified. Patients' perspectives while undergoing genetic testing and the primary care physicians experience in utilizing the web-based tool will be established. These findings will have tremendous impact on the management of patients with FH in primary care and subsequently reduce their risk of premature coronary artery disease.

    INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47911.

  9. Saunus JM, Quinn MC, Patch AM, Pearson JV, Bailey PJ, Nones K, et al.
    J Pathol, 2015 Nov;237(3):363-78.
    PMID: 26172396 DOI: 10.1002/path.4583
    Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2)  = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.
  10. Thompson JJ, Morato RG, Niebuhr BB, Alegre VB, Oshima JEF, de Barros AE, et al.
    Curr Biol, 2021 Aug 09;31(15):3457-3466.e4.
    PMID: 34237270 DOI: 10.1016/j.cub.2021.06.029
    Large terrestrial carnivores have undergone some of the largest population declines and range reductions of any species, which is of concern as they can have large effects on ecosystem dynamics and function.1-4 The jaguar (Panthera onca) is the apex predator throughout the majority of the Neotropics; however, its distribution has been reduced by >50% and it survives in increasingly isolated populations.5 Consequently, the range-wide management of the jaguar depends upon maintaining core populations connected through multi-national, transboundary cooperation, which requires understanding the movement ecology and space use of jaguars throughout their range.6-8 Using GPS telemetry data for 111 jaguars from 13 ecoregions within the four biomes that constitute the majority of jaguar habitat, we examined the landscape-level environmental and anthropogenic factors related to jaguar home range size and movement parameters. Home range size decreased with increasing net productivity and forest cover and increased with increasing road density. Speed decreased with increasing forest cover with no sexual differences, while males had more directional movements, but tortuosity in movements was not related to any landscape factors. We demonstrated a synergistic relationship between landscape-scale environmental and anthropogenic factors and jaguars' spatial needs, which has applications to the conservation strategy for the species throughout the Neotropics. Using large-scale collaboration, we overcame limitations from small sample sizes typical in large carnivore research to provide a mechanism to evaluate habitat quality for jaguars and an inferential modeling framework adaptable to the conservation of other large terrestrial carnivores.
  11. Nogueira RG, Qureshi MM, Abdalkader M, Martins SO, Yamagami H, Qiu Z, et al.
    Neurology, 2021 Jun 08;96(23):e2824-e2838.
    PMID: 33766997 DOI: 10.1212/WNL.0000000000011885
    OBJECTIVE: To measure the global impact of COVID-19 pandemic on volumes of IV thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with 2 control 4-month periods.

    METHODS: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases.

    RESULTS: There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95% confidence interval [CI] -11.7 to -11.3, p < 0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95% CI -13.8 to -12.7, p < 0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95% CI -13.7 to -10.3, p = 0.001). Recovery of stroke hospitalization volume (9.5%, 95% CI 9.2-9.8, p < 0.0001) was noted over the 2 later (May, June) vs the 2 earlier (March, April) pandemic months. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was noted in 3.3% (1,722/52,026) of all stroke admissions.

    CONCLUSIONS: The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID-19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months.

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