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Fulltext Strontium Sulfite: A New pH-Responsive Inorganic Nanocarrier to Deliver Therapeutic siRNAs to Cancer Cells

Karim ME, Shetty J, Islam RA, Kaiser A, Bakhtiar A, Chowdhury EH

Pharmaceutics, 2019 Feb 20;11(2).
PMID: 30791612 DOI: 10.3390/pharmaceutics11020089

Inorganic nanoparticles hold great potential in the area of precision medicine, particularly for treating cancer owing to their unique physicochemical properties, biocompatibility and improved pharmacokinetics properties compared to their organic counterparts. Here we introduce strontium sulfite nanoparticles as new pH-responsive inorganic nanocarriers for efficient transport of siRNAs into breast cancer cells. We employed the simplest nanoprecipitation method to generate the strontium sulfite nanoparticles (SSNs) and demonstrated the dramatic roles of NaCl and d-glucose in particle growth stabilization in order to produce even smaller nanosize particles (Na-Glc-SSN) with high affinity towards negatively charged siRNA, enabling it to efficiently enter the cancer cells. Moreover, the nanoparticles were found to be degraded with a small drop in pH, suggesting their potential capability to undergo rapid dissolution at endosomal pH so as to release the payload. While these particles were found to be nontoxic to the cells, they showed higher potency in facilitating cancer cell death through intracellular delivery and release of oncogene-specific siRNAs targeting ros1 and egfr1 mRNA transcripts, than the strontium sulfite particles prepared in absence of NaCl and d-glucose, as confirmed by growth inhibition assay. The mouse plasma binding analysis by Q-TOF LC-MS/MS demonstrated less protein binding to smaller particles of Na-Glc-SSNs. The biodistribution studies of the particles after 4 h of treatment showed Na-Glc-SSNs had less off-target distribution than SSNs, and after 24 h, all siRNAs were cleared from all major organs except the tumors. ROS1 siRNA with its potential therapeutic role in treating 4T1-induced breast tumor was selected for subsequent in vivo tumor regression study, revealing that ROS1 siRNA-loaded SSNs exerted more significant anti-tumor effects than Na-Glc-SSNs carrying the same siRNA following intravenous administration, without any systemic toxicity. Thus, strontium sulfite emerged as a powerful siRNA delivery tool with potential applications in cancer gene therapy.

Matched MeSH terms: Precision Medicine
Fulltext Advanced drug delivery systems can assist in targeting coronavirus disease (COVID-19): A hypothesis

Mehta M, Prasher P, Sharma M, Shastri MD, Khurana N, Vyas M, et al.

Med Hypotheses, 2020 Nov;144:110254.
PMID: 33254559 DOI: 10.1016/j.mehy.2020.110254

The highly contagious coronavirus, which had already affected more than 2 million people in 210 countries, triggered a colossal economic crisis consequently resulting from measures adopted by various goverments to limit transmission. This has placed the lives of many people infected worldwide at great risk. Currently there are no established or validated treatments for COVID-19, that is approved worldwide. Nanocarriers may offer a wide range of applications that could be developed into risk-free approaches for successful therapeutic strategies that may lead to immunisation against the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) which is the primary causative organism that had led to the current COVID-19 pandemic. We address existing as well as emerging therapeutic and prophylactic approaches that may enable us to effectively combat this pandemic, and also may help to identify the key areas where nano-scientists can step in.

Matched MeSH terms: Precision Medicine
Fulltext Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak

Low ZY, Farouk IA, Lal SK

Viruses, 2020 09 22;12(9).
PMID: 32972027 DOI: 10.3390/v12091058

Traditionally, drug discovery utilises a de novo design approach, which requires high cost and many years of drug development before it reaches the market. Novel drug development does not always account for orphan diseases, which have low demand and hence low-profit margins for drug developers. Recently, drug repositioning has gained recognition as an alternative approach that explores new avenues for pre-existing commercially approved or rejected drugs to treat diseases aside from the intended ones. Drug repositioning results in lower overall developmental expenses and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities. The greatest advantage of drug repositioning is that it breathes new life into the novel, rare, orphan, and resistant diseases, such as Cushing's syndrome, HIV infection, and pandemic outbreaks such as COVID-19. Repositioning existing drugs such as Hydroxychloroquine, Remdesivir, Ivermectin and Baricitinib shows good potential for COVID-19 treatment. This can crucially aid in resolving outbreaks in urgent times of need. This review discusses the past success in drug repositioning, the current technological advancement in the field, drug repositioning for personalised medicine and the ongoing research on newly emerging drugs under consideration for the COVID-19 treatment.

Matched MeSH terms: Precision Medicine
Fulltext Guidance on home blood pressure monitoring: A statement of the HOPE Asia Network

Kario K, Park S, Buranakitjaroen P, Chia YC, Chen CH, Divinagracia R, et al.

J Clin Hypertens (Greenwich), 2018 03;20(3):456-461.
PMID: 29450979 DOI: 10.1111/jch.13216

Hypertension is an important modifiable cardiovascular risk factor and a leading cause of death throughout Asia. Effective prevention and control of hypertension in the region remain a significant challenge despite the availability of several regional and international guidelines. Out-of-office measurement of blood pressure (BP), including home BP monitoring (HBPM), is an important hypertension management tool. Home BP is better than office BP for predicting cardiovascular risk and HBPM should be considered for all patients with office BP ≥ 130/85 mm Hg. It is important that HBPM is undertaken using a validated device and patients are educated about how to perform HBPM correctly. During antihypertensive therapy, monitoring of home BP control and variability is essential, especially in the morning. This is because HBPM can facilitate the choice of individualized optimal therapy. The evidence and practice points in this document are based on the Hypertension Cardiovascular Outcome Prevention and Evidence (HOPE) Asia Network expert panel consensus recommendations for HBPM in Asia.

Matched MeSH terms: Precision Medicine
Diabetes telemonitoring reduces the risk of hypoglycaemia during Ramadan: a pilot randomized controlled study

Lee JY, Lee SW, Nasir NH, How S, Tan CS, Wong CP

Diabet Med, 2015 Dec;32(12):1658-61.
PMID: 26103794 DOI: 10.1111/dme.12836

AIM: This pilot study evaluated the short-term benefits of a telemonitoring-supplemented focused diabetic education compared with education alone in participants with Type 2 diabetes who were fasting during Ramadan.
METHODS: In this pilot mixed-method study, we identified 37 participants and randomly allocated them to either a telemonitoring group (n = 18) or a group receiving Ramadan-focused pre-education only (usual care; n = 19). The telemonitoring group received goal-setting and personalized feedback.
RESULTS: The telemonitoring group was less likely to experience hypoglycaemia than the usual care group (odds ratio: 0.1273; 95% confidence interval: 0.0267-0.6059). No significant differences were noted in glycaemic control at the end of study. Participants viewed telemedicine as a more convenient alternative although technological barriers remain a concern.
CONCLUSIONS: The results of this study reinforce the need for monitoring as well as educational initiatives for Muslims with diabetes who fast during Ramadan. Telemonitoring offers an attractive option requiring further research. (Clinical Trial Registry No. NCT02189135).

Matched MeSH terms: Precision Medicine*
Fulltext Individually-tailored multifactorial intervention to reduce falls in the Malaysian Falls Assessment and Intervention Trial (MyFAIT): A randomized controlled trial

Tan PJ, Khoo EM, Chinna K, Saedon NI, Zakaria MI, Ahmad Zahedi AZ, et al.

PLoS One, 2018;13(8):e0199219.
PMID: 30074996 DOI: 10.1371/journal.pone.0199219

OBJECTIVE: To determine the effectiveness of an individually-tailored multifactorial intervention in reducing falls among at risk older adult fallers in a multi-ethnic, middle-income nation in South-East Asia.

DESIGN: Pragmatic, randomized-controlled trial.

SETTING: Emergency room, medical outpatient and primary care clinic in a teaching hospital in Kuala Lumpur, Malaysia.

PARTICIPANTS: Individuals aged 65 years and above with two or more falls or one injurious fall in the past 12 months.

INTERVENTION: Individually-tailored interventions, included a modified Otago exercise programme, HOMEFAST home hazards modification, visual intervention, cardiovascular intervention, medication review and falls education, was compared against a control group involving conventional treatment.

PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was any fall recurrence at 12-month follow-up. Secondary outcomes were rate of fall and time to first fall.

RESULTS: Two hundred and sixty-eight participants (mean age 75.3 ±7.2 SD years, 67% women) were randomized to multifactorial intervention (n = 134) or convention treatment (n = 134). All participants in the intervention group received medication review and falls education, 92 (68%) were prescribed Otago exercises, 86 (64%) visual intervention, 64 (47%) home hazards modification and 51 (38%) cardiovascular intervention. Fall recurrence did not differ between intervention and control groups at 12-months [Risk Ratio, RR = 1.037 (95% CI 0.613-1.753)]. Rate of fall [RR = 1.155 (95% CI 0.846-1.576], time to first fall [Hazard Ratio, HR = 0.948 (95% CI 0.782-1.522)] and mortality rate [RR = 0.896 (95% CI 0.335-2.400)] did not differ between groups.

CONCLUSION: Individually-tailored multifactorial intervention was ineffective as a strategy to reduce falls. Future research efforts are now required to develop culturally-appropriate and affordable methods of addressing this increasingly prominent public health issue in middle-income nations.

TRIAL REGISTRATION: ISRCTN Registry no. ISRCTN11674947.

Study site: emergency department, medical outpatients and primary care clinic at a teaching hospital in Kuala Lumpur, Malaysia

Matched MeSH terms: Precision Medicine/methods*
The influence of genetic polymorphisms on the efficacy and side effects of anastrozole in postmenopausal breast cancer patients

Abubakar MB, Wei K, Gan SH

Pharmacogenet Genomics, 2014 Dec;24(12):575-81.
PMID: 25203739 DOI: 10.1097/FPC.0000000000000092

Breast cancer is a common cause of cancer mortality among women. Several genetic factors have been implicated in its development. Current treatment guidelines for estrogen receptor-positive breast cancer recommend that anastrozole [or any of the other two aromatase inhibitors (letrozole and exemestane)] is used as an alternative to tamoxifen or following several years of tamoxifen treatment. Nevertheless, this approach is still associated with many challenges, ranging from the recurrence of breast cancer to considerable interindividual variability in the tolerability of anastrozole, which may cause adverse effects, such as musculoskeletal symptoms, and lead to the withdrawal of many patients from treatment. Variabilities in the genes encoding the drug target (aromatase) or its metabolizing enzymes (CYP3A and UGT1A) contribute toward the interindividual variability in anastrozole's pharmacokinetics and/or pharmacodynamics. This paper reviews the role of genetic polymorphisms of CYP19A1, CYP3A4, and UGT1A4 in the responses of female hormone receptor-positive postmenopausal breast cancer patients to anastrozole. Many reviews in the literature have suggested that the study of functional polymorphisms and investigation of relevant genetic markers may provide valuable information in predicting responses to anastrozole in terms of its therapeutic and adverse effects. Nevertheless, more studies are required before the knowledge of its pharmacogenomics can be applied to the individualization of treatment to ensure that patients receive the maximum benefits. Therefore, future analyses, including but not limited to genome-wide association studies, are encouraged to address some of the gray areas in the pharmacogenomics of anastrozole therapy in postmenopausal breast cancer cases; this will help in providing guidance for future pharmacogenomics protocols when anastrozole is utilized in patients' management.

Matched MeSH terms: Precision Medicine
Fulltext Systematic pharmacogenomics analysis of a Malay whole genome: proof of concept for personalized medicine

Salleh MZ, Teh LK, Lee LS, Ismet RI, Patowary A, Joshi K, et al.

PLoS One, 2013;8(8):e71554.
PMID: 24009664 DOI: 10.1371/journal.pone.0071554

BACKGROUND: With a higher throughput and lower cost in sequencing, second generation sequencing technology has immense potential for translation into clinical practice and in the realization of pharmacogenomics based patient care. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the next step in future medicine in line with the vision of personalizing medicine.
METHODS: Genomic DNA obtained from a 55 years old, self-declared healthy, anonymous male of Malay descent was sequenced. The subject's mother died of lung cancer and the father had a history of schizophrenia and deceased at the age of 65 years old. A systematic, intuitive computational workflow/pipeline integrating custom algorithm in tandem with large datasets of variant annotations and gene functions for genetic variations with pharmacogenomics impact was developed. A comprehensive pathway map of drug transport, metabolism and action was used as a template to map non-synonymous variations with potential functional consequences.
PRINCIPAL FINDINGS: Over 3 million known variations and 100,898 novel variations in the Malay genome were identified. Further in-depth pharmacogenetics analysis revealed a total of 607 unique variants in 563 proteins, with the eventual identification of 4 drug transport genes, 2 drug metabolizing enzyme genes and 33 target genes harboring deleterious SNVs involved in pharmacological pathways, which could have a potential role in clinical settings.
CONCLUSIONS: The current study successfully unravels the potential of personal genome sequencing in understanding the functionally relevant variations with potential influence on drug transport, metabolism and differential therapeutic outcomes. These will be essential for realizing personalized medicine through the use of comprehensive computational pipeline for systematic data mining and analysis.

Matched MeSH terms: Precision Medicine
The creation and verification of cranial models using three-dimensional rapid prototyping technology in field of transnasal sphenoid endoscopy

Waran V, Menon R, Pancharatnam D, Rathinam AK, Balakrishnan YK, Tung TS, et al.

Am J Rhinol Allergy, 2012 Sep-Oct;26(5):e132-6.
PMID: 23168144 DOI: 10.2500/ajra.2012.26.3808

Surgical navigation systems have been used increasingly in guiding complex ear, nose, and throat surgery. Although these are helpful, they are only beneficial intraoperatively; thus, the novice surgeon will not have the preoperative training or exposure that can be vital in complex procedures. In addition, there is a lack of reliable models to give surgeons hands-on training in performing such procedures.

Matched MeSH terms: Precision Medicine
Fulltext Pharmacogenomics biomarkers for personalized methadone maintenance treatment: The mechanism and its potential use

Ramli FF

Bosn J Basic Med Sci, 2021 Apr 01;21(2):145-154.
PMID: 32841585 DOI: 10.17305/bjbms.2020.4897

Methadone has a wide pharmacokinetic interindividual variability, resulting in unpredicted treatment response. Pharmacogenomic biomarkers seem promising for personalized methadone maintenance treatment. The evidence supports the use of ABCB1 single-nucleotide polymorphism (SNP) 1236C>T with genotypes C/T or C/C (Jewish) and haplotypes AGCTT carrier, AGCGC heterozygote, or non-carrier (Caucasian), which have a predicted lower methadone dose requirement. In contrast, ABCB1 SNP 1236C>T with genotype T/T (Jewish); haplotypes AGCGC homozygote, AGCTT non-carrier (Caucasian), and ABCB1 3435C>T variant carrier; and haplotypes CGT, TTC, and TGT (Han Chinese) have a predicted higher methadone dose. For methadone plasma levels, ABCB1 diplotype non-CGC/TTT (Malay) predicted lower, and diplotype CGC/TTT (Malay), 3435C>T allelic carrier, haplotypes (CGT, TTC, TGT) (Han Chinese) predicted higher methadone levels. In terms of metabolism biomarkers, a lower methadone requirement was related to carriers of CYP2B6 genotypes *4(G/G) and *9(T/T) among Jewish patients, CYP2B6*9 genotype (T/T) and haplotypes (TA/TG); and CYP2C19 (*2/*2,*2/*3, and *3/*3; Han Chinese). Higher methadone dose was observed in CYP2C19*1 allelic carriers (Han Chinese) and CYP2D6 ultrarapid metabolizer (Caucasian). Lower methadone levels were reported in CYP2B6 SNPs, haplotypes TTT, and AGATAA (Han Chinese), CYP2C19 genotype *1/*1 (Han Chinese), allelic carrier *1xN (Caucasian), and CYP3A4 genotype *1/*1 (Caucasian). Carriers of CYP2B6 genotype *6/*6 (Caucasian), CYP2B6 haplotypes ATGCAG and ATGCTG (Han Chinese), and CYP3A4 genotype *1/*1B (Caucasian) had predicted higher methadone plasma levels. Specific pharmacokinetics biomarkers have potential uses for personalized methadone treatment in specific populations.

Matched MeSH terms: Precision Medicine
Diffuse large B-cell lymphoma in Southeast Asian cohort: expression patterns of B-cell receptor (BCR) repertoire and its linkage with molecular subtypes and response to R-CHOP therapy

Masir N, Akhter A, Roshan TM, Florence CS, Abdul-Rahman F, Tumian NR, et al.

J Clin Pathol, 2019 Sep;72(9):630-635.
PMID: 31189540 DOI: 10.1136/jclinpath-2019-205837

AIMS: Heightened B-cell receptor (BCR) activity in diffuse large B-cell lymphoma (DLBCL) is well established, and a subset of patients with relapsed DLBCL can benefit from BCR-targeted therapies. Universal outreach of such emerging therapies mandates forming a global landscape of BCR molecular signalling in DLBCL, including Southeast Asia.
METHODS: 79 patients with DLBCL (nodal, 59% and extranodal, 41%) treated with rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy were selected. Expression levels of BCR and linked signalling pathway molecules were inter-related with Lymph2Cx-based cell of origin (COO) types and overall survival (OS).
RESULTS: Activated B-cell (ABC) type DLBCL constituted 49% (39/79) compared with germinal centre B-cell (GCB) type DLBCL (29/79; 37%) and revealed poor prognosis (p=0.013). In ABC-DLBCL, high BTK expression exerted poor response to R-CHOP, while OS in ABC-DLBCL with low BTK expression was similar to GCB-DLBCL subtype (p=0.004). High LYN expression coupled with a poor OS for ABC-DLBCL as well as GCB-DLBCL subtypes (p=0.001). Furthermore, high coexpression of BTK/LYN (BTKhigh/LYNhigh) showed poor OS (p=0.019), which linked with upregulation of several genes associated with BCR repertoire and nuclear factor-kappa B pathway (p<0.01). In multivariate analysis, high BTK and LYN expression retained prognostic significance against established clinical predictive factors such as age, International Prognostic Index and COO (p<0.05).
CONCLUSIONS: Our data provide a clear association between high BCR activity in DLBCL and response to therapy in a distinct population. Molecular data provided here will pave the pathway for the provision of promising novel-targeted therapies to patients with DLBCL in Southeast Asia.

Matched MeSH terms: Precision Medicine/methods*
Genetic markers predicting sulphonylurea treatment outcomes in type 2 diabetes patients: current evidence and challenges for clinical implementation

Loganadan NK, Huri HZ, Vethakkan SR, Hussein Z

Pharmacogenomics J, 2016 06;16(3):209-19.
PMID: 26810132 DOI: 10.1038/tpj.2015.95

The clinical response to sulphonylurea, an oral antidiabetic agent often used in combination with metformin to control blood glucose in type 2 diabetes (T2DM) patients, has been widely associated with a number of gene polymorphisms, particularly those involved in insulin release. We have reviewed the genetic markers of CYP2C9, ABCC8, KCNJ11, TCF7L2 (transcription factor 7-like 2), IRS-1 (insulin receptor substrate-1), CDKAL1, CDKN2A/2B, KCNQ1 and NOS1AP (nitric oxide synthase 1 adaptor protein) genes that predict treatment outcomes of sulphonylurea therapy. A convincing pattern for poor sulphonylurea response was observed in Caucasian T2DM patients with rs7903146 and rs1801278 polymorphisms of the TCF7L2 and IRS-1 genes, respectively. However, limitations in evaluating the available studies including dissimilarities in study design, definitions of clinical end points, sample sizes and types and doses of sulphonylureas used as well as ethnic variability make the clinical applications challenging. Future studies need to address these limitations to develop personalized sulphonylurea medicine for T2DM management.

Matched MeSH terms: Precision Medicine
Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

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.

Matched MeSH terms: Precision Medicine

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