MyMedR

Displaying publications 1 - 20 of 21 in total

Abstract:

Sort:

A survey of the adoption and perception of mobile health applications among community pharmacists in Malaysia

Ng HL, Sellappans R, Loo JSE

Int J Pharm Pract, 2023 Sep 30;31(5):489-495.
PMID: 37526297 DOI: 10.1093/ijpp/riad042

OBJECTIVES: To determine the adoption and perception of mobile health (mHealth) applications among community pharmacists in Malaysia.
METHODS: A cross-sectional survey using a self-administered questionnaire was conducted with 300 community pharmacists in the Klang Valley, Malaysia using a stratified sampling approach. The questionnaire consisted of 36 questions with three sections: demographic data, adoption of mHealth applications and perception towards mHealth applications. Descriptive and inferential tests as well as exploratory factor analysis were used to analyse the data.
KEY FINDINGS: Adoption of mHealth applications by community pharmacists for both professional and personal use was relatively high at 79.7%. Utilised mHealth applications were primarily from the medical references category, while applications for patient monitoring, personal care and fitness were used to a lesser degree. Among mHealth application users, only 65.7% recommended them to their patients. Overall perception towards mHealth applications was positive, but perception towards the benefits and favour of mHealth applications for their patients was lower. This was corroborated by the factor analysis, which identified four main factors explaining 59.9% of variance in the dataset. These factors were perception towards use in their own professional practice, perception on benefits and use in their patients, perception on specific features of mHealth applications, and reliability of mHealth applications.
CONCLUSIONS: Adoption of mHealth applications among community pharmacists in Malaysia is high. Community pharmacists are more likely to use mHealth applications professionally and personally but less likely to recommend them to patients due to less favourable perceptions on how patients will benefit from mHealth applications.
Benchmarking the performance of MM/PBSA in virtual screening enrichment using the GPCR-Bench dataset

Yau MQ, Emtage AL, Loo JSE

J Comput Aided Mol Des, 2020 Nov;34(11):1133-1145.
PMID: 32851579 DOI: 10.1007/s10822-020-00339-5

Recent breakthroughs in G protein-coupled receptor (GPCR) crystallography and the subsequent increase in number of solved GPCR structures has allowed for the unprecedented opportunity to utilize their experimental structures for structure-based drug discovery applications. As virtual screening represents one of the primary computational methods used for the discovery of novel leads, the GPCR-Bench dataset was created to facilitate comparison among various virtual screening protocols. In this study, we have benchmarked the performance of Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) in improving virtual screening enrichment in comparison to docking with Glide, using the entire GPCR-Bench dataset of 24 GPCR targets and 254,646 actives and decoys. Reranking the top 10% of the docked dataset using MM/PBSA resulted in improvements for six targets at EF1% and nine targets at EF5%, with the gains in enrichment being more pronounced at the EF1% level. We additionally assessed the utility of rescoring the top ten poses from docking and the ability of short MD simulations to refine the binding poses prior to MM/PBSA calculations. There was no clear trend of the benefit observed in both cases, suggesting that utilizing a single energy minimized structure for MM/PBSA calculations may be the most computationally efficient approach in virtual screening. Overall, the performance of MM/PBSA rescoring in improving virtual screening enrichment obtained from docking of the GPCR-Bench dataset was found to be relatively modest and target-specific, highlighting the need for validation of MM/PBSA-based protocols prior to prospective use.
The effect of multiple simulation parameters on MM/PBSA performance for binding affinity prediction of CB1 cannabinoid receptor agonists and antagonists

Loo JSE, Yong AYY, Yong YN

Chem Biol Drug Des, 2020 11;96(5):1244-1254.
PMID: 32462752 DOI: 10.1111/cbdd.13733

Both the inactive- and active-state CB1 receptor crystal structures have now been solved, allowing their application in various structure-based drug design methods. One potential method utilizing these crystal structures is the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method of predicting relative binding free.
Awareness of osteoporosis risk assessment tools and screening recommendations among community pharmacists in Malaysia

Francis J, Toh LS, Sellappans R, Loo JSE

Int J Clin Pharm, 2021 Jun;43(3):604-612.
PMID: 33507463 DOI: 10.1007/s11096-020-01169-z

Background The incidence of osteoporosis in Malaysia is increasing due to a fast-ageing population. Because of its silent nature, various osteoporosis risk assessment tools exist to detect high-risk patients and facilitate referrals for bone mineral density measurements. As an accessible point of contact, community pharmacists would benefit from the utilization of these tools and familiarity with guideline recommendations for osteoporosis screening. Aim This study aimed to investigate the awareness of osteoporosis risk assessment tools, practice behaviour towards osteoporosis, and knowledge of guideline recommendations among community pharmacists in the Klang Valley, Malaysia. Setting Community pharmacies. Methods This study was a cross-sectional study which sampled 284 community pharmacists practicing in the Klang Valley, using a stratified sampling approach. The study was conducted using a self-administered questionnaire which was divided into three sections: demographic data, knowledge of osteoporosis risk assessment tools and guideline recommendations, and practice behaviour towards osteoporosis. Practice behaviour was assessed with 15 items using a 5-point Likert scale. Main outcome measure. Proportion of respondents aware of osteoporosis risk assessment tools and respondent knowledge on guideline recommendations for osteoporosis screening. Results A total of 284 community pharmacists participated in the study. 84.1% of the respondents were aware of at least one risk assessment tool. However, only a small proportion of pharmacists (14.9%) regularly used these tools in their practice. Respondents perceived these tools to be relevant and beneficial, but perception towards their accessibility, ease-of-use, and administration time was mixed, suggesting unfamiliarity. Respondents preferred to conduct clinical assessments based on risk factors, with respondents identifying a mean of 10.1 ± 3.4 out of 15 risk factors. However, several clinically relevant risk factors were frequently unidentified. Knowledge of guideline recommendations among respondents was low. Conclusion There is some awareness of osteoporosis risk assessment tools but use in practice remains low among community pharmacists in Malaysia. There is potential to increase the use of these tools and knowledge of recommendations for osteoporosis screening and referral among community pharmacists.
Pharmacy students in private institutions of higher education: motivating factors when studying pharmacy and influences on university choice

Loo JSE, Lim SW, Ng YK, Tiong JJL

Int J Pharm Pract, 2017 Dec;25(6):429-437.
PMID: 28211115 DOI: 10.1111/ijpp.12352

OBJECTIVES: To identify factors influencing the decisions of Malaysian first-year pharmacy undergraduate students in private higher education when choosing to pursue a degree in pharmacy as well as their choice of private university.
METHODS: This cross-sectional study employed a validated, self-administered questionnaire which was administered to 543 first-year pharmacy students from nine different private universities. Factor analysis was utilised to extract key factors from the responses. Descriptive and inferential statistics were used to analyse the data.
KEY FINDINGS: Eight factors motivating students' decision to study pharmacy emerged from the responses, accounting for 63.8% of the variance observed. Students were primarily motivated by intrinsic interests, with work conditions and profession attributes also exerting significant influence. In terms of choice of private university, nine factors were identified, accounting for 73.8% of the variance observed. The image of the school and university were most influential factors in this context, followed by university safety, programme attributes and financial factors.
CONCLUSIONS: First-year pharmacy students in the private higher education sector are motivated by intrinsic interest when choosing to study pharmacy over other courses, while their choice of private university is influenced primarily by the image of the school and university.
Awareness of Beers Criteria and knowledge of potentially inappropriate medications among community pharmacists in the Klang Valley, Malaysia

Foong RTK, Sellappans R, Loo JSE

J Eval Clin Pract, 2020 Feb;26(1):165-171.
PMID: 31168913 DOI: 10.1111/jep.13180

BACKGROUND: Potentially inappropriate medications (PIMs) in older adults are detrimental to both clinical outcomes and health care costs, with their prominence set to increase in tandem with a fast-growing ageing population. Beers Criteria is one of the most commonly used guidelines that lists specific PIMs. Community pharmacists would therefore benefit from knowledge of Beers Criteria in detecting PIMs in primary care. This study therefore investigates the awareness of Beers Criteria and knowledge of PIMs among community pharmacists in the Klang Valley, Malaysia.
METHODS: The study was conducted using a self-administered questionnaire. Knowledge of PIMs was assessed using 10 clinical vignettes based on the 2015 Beers Criteria. Practice behaviour towards older customers was assessed using 10 items with a 5-point Likert scale. Descriptive and inferential statistics were used to analyse the data.
RESULTS: A total of 277 community pharmacists participated in the study. Only 27.1% of the pharmacists were aware of Beers Criteria, and of these, only 37.3% were aware of the latest 2015 update. The respondents demonstrated moderate knowledge of PIMs with a mean total score of 5.46 ± 1.89 out of a maximum of 10. Pharmacists who were aware of Beers Criteria had significantly higher scores (6.31 vs 5.14, P
An exploratory analysis of general practitioner prescribing patterns in Malaysia using a health insurance claims database

Su WS, Thum CM, Loo JSE

Int J Pharm Pract, 2022 Jan 07;30(1):59-66.
PMID: 34962576 DOI: 10.1093/ijpp/riab075

OBJECTIVES: To determine the prescribing patterns and identify potentially inappropriate prescribing practices among general practitioners in the private primary care sector by analysing a large electronic health insurance claims database.
METHODS: Medical claims records from February 2019 to February 2020 were extracted from a health insurance claims database. Data cleaning and data analysis were performed using Python 3.7 with the Pandas, NumPy and Matplotlib libraries. The top five most common diagnoses were identified, and for each diagnosis, the most common medication classes and medications prescribed were quantified. Potentially inappropriate prescribing practices were identified by comparing the medications prescribed with relevant clinical guidelines.
KEY FINDINGS: The five most common diagnoses were upper respiratory tract infection (41.5%), diarrhoea (7.7%), musculoskeletal pain (7.6%), headache (6.7%) and gastritis (4.0%). Medications prescribed by general practitioners were largely as expected for symptomatic management of the respective conditions. One area of potentially inappropriate prescribing identified was inappropriate antibiotic choice. Same-class polypharmacy that may lead to an increased risk of adverse events were also identified, primarily involving multiple paracetamol-containing products, non-steroidal anti-inflammatory drugs (NSAIDs), and antihistamines. Other areas of non-adherence to guidelines identified included the potential overuse of oral corticosteroids and oral salbutamol, and inappropriate gastroprotection for patients receiving NSAIDs.
CONCLUSIONS: While prescribing practices are generally appropriate within the private primary care sector, there remain several areas where some potentially inappropriate prescribing occurs. The areas identified should be the focus in continuing efforts to improve prescribing practices to obtain the optimal clinical outcomes while reducing unnecessary risks and healthcare costs.
A head-to-head comparison of MM/PBSA and MM/GBSA in predicting binding affinities for the CB1 cannabinoid ligands

Yau MQ, Liew CWY, Toh JH, Loo JSE

J Mol Model, 2024 Oct 31;30(11):390.
PMID: 39480515 DOI: 10.1007/s00894-024-06189-4

CONTEXT: The substantial increase in the number of active and inactive-state CB1 receptor experimental structures has provided opportunities for CB1 drug discovery using various structure-based drug design methods, including the popular end-point methods for predicting binding free energies-Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA). In this study, we have therefore evaluated the performance of MM/PBSA and MM/GBSA in calculating binding free energies for CB1 receptor. Additionally, with both MM/PBSA and MM/GBSA being known for their highly individualized performance, we have evaluated the effects of various simulation parameters including the use of energy minimized structures, choice of solute dielectric constant, inclusion of entropy, and the effects of the five GB models. Generally, MM/GBSA provided higher correlations than MM/PBSA (rMM/GBSA = 0.433 - 0.652 vs. rMM/PBSA = 0.100 - 0.486) regardless of the simulation parameters, while also offering faster calculations. Improved correlations were observed with the use of molecular dynamics ensembles compared with energy minimized structures and larger solute dielectric constants. Incorporation of entropic terms led to unfavorable results for both MM/PBSA and MM/GBSA for a majority of the dataset, while the evaluation of the various GB models exerted a varying effect on both the datasets. The findings obtained in this study demonstrate the utility of MM/PBSA and MM/GBSA in predicting binding free energies for the CB1 receptor, hence providing a useful benchmark for their applicability in the endocannabinoid system as well as other G protein-coupled receptors.
METHODS: The study utilized the docked dataset (Induced Fit Docking with Glide XP scoring function) from Loo et al., consisting of 46 ligands-23 agonists and 23 antagonists. The equilibrated structures from Loo et al. were subjected to 30 ns production simulations using GROMACS 2018 at 300 K and 1 atm with the velocity rescaling thermostat and the Parinello-Rahman barostat. AMBER ff99SB*-ILDN was used for the proteins, General Amber Force Field (GAFF) was used for the ligands, and Slipids parameters were used for lipids. MM/PBSA and MM/GBSA binding free energies were then calculated using gmx_MMPBSA. The solute dielectric constant was varied between 1, 2, and 4 to study the effect of different solute dielectric constants on the performance of MM/PB(GB)SA. The effect of entropy on MM/PB(GB)SA binding free energies was evaluated using the interaction entropy module implemented in gmx_MMPBSA. Five GB models, GBHCT, GBOBC1, GBOBC2, GBNeck, and GBNeck2, were evaluated to study the effect of the choice of GB models in the performance of MM/GBSA. Pearson correlation coefficients were used to measure the correlation between experimental and predicted binding free energies.
Evaluating the performance of MM/PBSA for binding affinity prediction using class A GPCR crystal structures

Yau MQ, Emtage AL, Chan NJY, Doughty SW, Loo JSE

J Comput Aided Mol Des, 2019 05;33(5):487-496.
PMID: 30989574 DOI: 10.1007/s10822-019-00201-3

The recent expansion of GPCR crystal structures provides the opportunity to assess the performance of structure-based drug design methods for the GPCR superfamily. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA)-based methods are commonly used for binding affinity prediction, as they provide an intermediate compromise of speed and accuracy between the empirical scoring functions used in docking and more robust free energy perturbation methods. In this study, we systematically assessed the performance of MM/PBSA in predicting experimental binding free energies using twenty Class A GPCR crystal structures and 934 known ligands. Correlations between predicted and experimental binding free energies varied significantly between individual targets, ranging from r = - 0.334 in the inactive-state CB1 cannabinoid receptor to r = 0.781 in the active-state CB1 cannabinoid receptor, while average correlation across all twenty targets was relatively poor (r = 0.183). MM/PBSA provided better predictions of binding free energies compared to docking scores in eight out of the twenty GPCR targets while performing worse for four targets. MM/PBSA binding affinity predictions calculated using a single, energy minimized structure provided comparable predictions to sampling from molecular dynamics simulations and may be more efficient when computational cost becomes restrictive. Additionally, we observed that restricting MM/PBSA calculations to ligands with a high degree of structural similarity to the crystal structure ligands improved performance in several cases. In conclusion, while MM/PBSA remains a valuable tool for GPCR structure-based drug design, its performance in predicting the binding free energies of GPCR ligands remains highly system-specific as demonstrated in a subset of twenty Class A GPCRs, and validation of MM/PBSA-based methods for each individual case is recommended before prospective use.
Assessing GPCR homology models constructed from templates of various transmembrane sequence identities: Binding mode prediction and docking enrichment

Loo JSE, Emtage AL, Ng KW, Yong ASJ, Doughty SW

J Mol Graph Model, 2017 Dec 29;80:38-47.
PMID: 29306746 DOI: 10.1016/j.jmgm.2017.12.017

GPCR crystal structures have become more readily accessible in recent years. However, homology models of GPCRs continue to play an important role as many GPCR structures remain unsolved. The new crystal structures now available provide not only additional templates for homology modelling but also the opportunity to assess the performance of homology models against their respective crystal structures and gain insight into the performance of such models. In this study we have constructed homology models from templates of various transmembrane sequence identities for eight GPCR targets to better understand the relationship between transmembrane sequence identity and model quality. Model quality was assessed relative to the crystal structure in terms of structural accuracy as well as performance in two typical structure-based drug design applications: ligand binding pose prediction and docking enrichment in virtual screening. Crystal structures significantly outperformed homology models in both assessments. Accurate ligand binding pose prediction was possible but difficult to achieve using homology models, even with the use of induced fit docking. In virtual screening using homology models still conferred significant enrichment compared to random selection, with a clear benefit also observed in using models optimized through induced fit docking. Our results indicate that while homology models that are reasonably accurate structurally can be constructed, without significant refinement homology models will be outperformed by crystal structures in ligand binding pose prediction and docking enrichment regardless of the template used, primarily due to the extremely high level of structural accuracy needed for such applications.
Leveraging binding pose metadynamics to optimise target fishing predictions for three diverse ligands and their true targets

Yau MQ, Wan AJ, Tiong ASH, Yiap YS, Loo JSE

Chem Biol Drug Des, 2024 Jul;104(1):e14591.
PMID: 39010276 DOI: 10.1111/cbdd.14591

Computational target fishing plays an important role in target identification, particularly in drug discovery campaigns utilizing phenotypic screening. Numerous approaches exist to predict potential targets for a given ligand, but true targets may be inconsistently ranked. More advanced simulation methods may provide benefit in such cases by reranking these initial predictions. We evaluated the ability of binding pose metadynamics to improve the predicted rankings for three diverse ligands and their six true targets. Initial predictions using pharmacophore mapping showed no true targets ranked in the top 50 and two targets each ranked within the 50-100, 100-150, and 250-300 ranges respectively. Following binding pose metadynamics, ranking of true targets improved for four out of the six targets and included the highest ranked predictions overall, while rankings deteriorated for two targets. The revised rankings predicted two true targets ranked within the top 50, and one target each within the 50-100, 100-150, 150-200, and 200-250 ranges respectively. The findings of this study demonstrate that binding pose metadynamics may be of benefit in refining initial predictions from structure-based target fishing algorithms, thereby improving the efficiency of the target identification process in drug discovery efforts.
Scaffolding dermatological learning with near-peer teaching for preclinical-year medical students

Ting JSK, Tan YL, Veasuvalingam B, Yap AYM, Ghui SM, Yong JL, et al.

Clin Exp Dermatol, 2023 Aug 25;48(9):998-1006.
PMID: 37097177 DOI: 10.1093/ced/llad149

BACKGROUND: To date, to our knowledge, there has not been a study on dermatological teaching in the preclinical years (usually the first 2 years of medical school), where the majority of learning takes place in the form of lectures and seminars. Near-peer teaching (NPT) involves students who are at least one academic year more senior imparting knowledge to junior students. The principles behind scaffolding are having a more experienced teacher to guide learning, breaking down learning into smaller tasks and helping to build interest in learning.
OBJECTIVES: To investigate the feasibility and effectiveness of NPT in scaffolding dermatological learning among preclinical-year medical students.
METHODS: Near-peer teachers who are content experts in dermatology taught alongside conventional teaching with lecturers. We employed five quiz questions before and after the case launch lecture, where students were first exposed to dermatology. We also invited students to provide feedback using a questionnaire on NPT in dermatology at the end of the case 8 teaching week.
RESULTS: In total, 74 students participated in the pre- and post-lecture quiz questions, and 47 completed feedback. There was overwhelmingly positive feedback towards NPT, and various learning theories can help explain the success of this project.
CONCLUSIONS: Preclinical students enjoy dermatological teaching with the involvement of suitable near-peers. With the professional barrier removed, students can better relate to near-peers (and vice versa). Helping students understand the relevance of dermatology in the clinical setting at an early stage and adopting learning tools such as mnemonics, summary tables, comparison tables and mapping teaching with the learning curriculum clearly helped students learn about dermatology.
Melioidosis in Malaysia. IV. Intensive ecological study of Carey Island, Selangor, for Pseudomonas pseudomallei

Strauss JM, Ellison DW, Gan E, Jason S, Marcarelli JL, Rapmund G

Med J Malaya, 1969 Dec;24(2):94-100.
PMID: 4244150
Fulltext Cross-cultural color-odor associations

Levitan CA, Ren J, Woods AT, Boesveldt S, Chan JS, McKenzie KJ, et al.

PLoS One, 2014;9(7):e101651.
PMID: 25007343 DOI: 10.1371/journal.pone.0101651

Colors and odors are associated; for instance, people typically match the smell of strawberries to the color pink or red. These associations are forms of crossmodal correspondences. Recently, there has been discussion about the extent to which these correspondences arise for structural reasons (i.e., an inherent mapping between color and odor), statistical reasons (i.e., covariance in experience), and/or semantically-mediated reasons (i.e., stemming from language). The present study probed this question by testing color-odor correspondences in 6 different cultural groups (Dutch, Netherlands-residing-Chinese, German, Malay, Malaysian-Chinese, and US residents), using the same set of 14 odors and asking participants to make congruent and incongruent color choices for each odor. We found consistent patterns in color choices for each odor within each culture, showing that participants were making non-random color-odor matches. We used representational dissimilarity analysis to probe for variations in the patterns of color-odor associations across cultures; we found that US and German participants had the most similar patterns of associations, followed by German and Malay participants. The largest group differences were between Malay and Netherlands-resident Chinese participants and between Dutch and Malaysian-Chinese participants. We conclude that culture plays a role in color-odor crossmodal associations, which likely arise, at least in part, through experience.
Fulltext A leadless ventricular pacemaker providing atrioventricular synchronous pacing in the real-world setting: 12-Month results from the Micra AV post-approval registry

Garweg C, Chinitz JS, Marijon E, Haeberlin A, Winter S, Iacopino S, et al.

Heart Rhythm, 2024 Oct;21(10):1939-1947.
PMID: 38878939 DOI: 10.1016/j.hrthm.2024.06.008

BACKGROUND: Advances in leadless pacemaker technology have enabled accelerometer-based atrioventricular (AV) synchronous pacing by sensing atrial mechanical contraction.
OBJECTIVE: The purpose of this study was to report the performance of the Micra AV leadless pacemaker from the worldwide Micra AV post-approval registry (PAR) through 12 months.
METHODS: The Micra AV PAR is a prospective, single-arm, observational registry designed to assess the safety and effectiveness of Micra AV in a real-world setting. For the present interim analysis, major complications and system revisions through 12 months were summarized and compared to a historical cohort of 2667 patients implanted with a transvenous dual-chamber pacing system.
RESULTS: The device was successfully implanted in 796 of 801 patients (99.4%) at 97 centers in 19 countries. Micra AV patients were older (74.1 years vs 71.1 years; P < .0001) with a higher incidence of renal disease (22.3% vs 9.8%; P < .0001) compared with transvenous dual-chamber patients. Through 12 months, the major complication rate was 3.7% in Micra AV patients compared with 8.8% in transvenous dual-chamber patients (hazard ratio 0.42; 95% confidence interval 0.28-0.61; P < .001). The system revision rate was 1.5% in Micra AV patients compared with 5.5% for transvenous dual-chamber patients (hazard ratio 0.25; 95% confidence interval 0.13-0.47; P < .001); this reduction was largely driven by the absence of lead dislodgments requiring revision. The median AV synchrony index was 79.4% (interquartile range 65.2%-86.4%) in patients paced >90%.
CONCLUSION: The Micra AV leadless pacemaker was implanted with a high rate of success in patients with multiple comorbidities, with a significantly lower rate of complications and system revisions through 12 months compared to a historical cohort of patients with transvenous dual-chamber pacemakers.
Fulltext Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Ghoussaini M, French JD, Michailidou K, Nord S, Beesley J, Canisus S, et al.

Am J Hum Genet, 2016 Oct 06;99(4):903-911.
PMID: 27640304 DOI: 10.1016/j.ajhg.2016.07.017

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
Fulltext Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, et al.

Nat Genet, 2020 01;52(1):56-73.
PMID: 31911677 DOI: 10.1038/s41588-019-0537-1

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
Fulltext Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Dunning AM, Michailidou K, Kuchenbaecker KB, Thompson D, French JD, Beesley J, et al.

Nat Genet, 2016 Apr;48(4):374-86.
PMID: 26928228 DOI: 10.1038/ng.3521

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
Fulltext Association analysis identifies 65 new breast cancer risk loci

Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, et al.

Nature, 2017 Nov 02;551(7678):92-94.
PMID: 29059683 DOI: 10.1038/nature24284

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P
Fulltext Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al.

Autophagy, 2016;12(1):1-222.
PMID: 26799652 DOI: 10.1080/15548627.2015.1100356

Filters

Please provide feedback to Administrator (afdal@afpm.org.my)

External Links