Displaying publications 61 - 77 of 77 in total

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  1. Ihara H, Kasamatsu S, Kitamura A, Nishimura A, Tsutsuki H, Ida T, et al.
    Chem Res Toxicol, 2017 09 18;30(9):1673-1684.
    PMID: 28837763 DOI: 10.1021/acs.chemrestox.7b00120
    Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles.
  2. Kumar J, Naina Mohamed I, Mohamed R, Ugusman A, Muzaimi M, Mohamed W, et al.
    Front Pharmacol, 2024;15:1428492.
    PMID: 39086393 DOI: 10.3389/fphar.2024.1428492
    Despite extensive preclinical research over the years, a significant gap remains in our understanding of the specific effects of methamphetamine (METH) and amphetamine (AMPH) withdrawal. Understanding these differences could be pivotal to unveiling the unique pathophysiology underlying each stimulant. This may facilitate the development of targeted and effective treatment strategies tailored to the specific characteristics of each substance. Following PRISMA guidelines, this systematic review was conducted to examine alterations in spontaneous locomotor activity, specifically horizontal activity, in animals experiencing withdrawal from extended and repeated administration of AMPH or METH. Original articles were retrieved from four electronic databases, supplemented by a review of the references cited in the published papers. A total of thirty-one full-length articles (n = 31) were incorporated in the analysis. The results indicated that six studies documented a significant increase in horizontal activity among animals, seven studies reported decreased locomotion, and eighteen studies (8 AMPH; 10 METH) reported no significant alterations in the animals' locomotor activity. Studies reporting heightened locomotion mainly employed mice undergoing withdrawal from METH, studies reporting diminished locomotion predominantly involved rats undergoing withdrawal from AMPH, and studies reporting no significant changes in horizontal activity employed both rats and mice (12 rats; 6 mice). Drug characteristics, routes of administration, animal models, dosage regimens, duration, and assessment timing seem to influence the observed outcomes. Despite more than 50% of papers enlisted in this review indicate no significant changes in the locomotion during the stimulant withdrawal, the unique reactions of animals to withdrawal from METH and AMPH reported by some underscore the need for a more nuanced understanding of stimulant withdrawal.
  3. Mohd-Ali B, Chen LY, Shahimin MM, Arif N, Abdul Hamid H, Wan Abdul Halim WH, et al.
    PMID: 37641786 DOI: 10.51329/mehdiophthal1447
    BACKGROUND: Magnetic resonance imaging (MRI) has been used to investigate eye shapes; however, reports involving children are scarce. This study aimed to determine ocular dimensions, and their correlations with refractive error, using three-dimensional MRI in emmetropic versus myopic children.

    METHODS: Healthy school children aged < 10 years were invited to take part in this cross-sectional study. Refraction and best-corrected distance visual acuity (BCDVA) were determined using cycloplegic refraction and a logarithm of the minimum angle of resolution (logMAR) chart, respectively. All children underwent MRI using a 3-Tesla whole-body scanner. Quantitative eyeball measurements included the longitudinal axial length (LAL), horizontal width (HW), and vertical height (VH) along the cardinal axes. Correlation analysis was used to determine the association between the level of refractive error and the eyeball dimensions.

    RESULTS: A total of 70 eyes from 70 children (35 male, 35 female) with a mean (standard deviation [SD]) age of 8.38 (0.49) years were included and analyzed. Mean (SD) refraction (spherical equivalent, SEQ) and BCDVA were -2.55 (1.45) D and -0.01 (0.06) logMAR, respectively. Ocular dimensions were greater in myopes than in emmetropes (all P < 0.05), with no significant differences according to sex. Mean (SD) ocular dimensions were LAL 24.07 (0.91) mm, HW 23.41 (0.82) mm, and VH 23.70 (0.88) mm for myopes, and LAL 22.69 (0.55) mm, HW 22.65 (0.63) mm, and VH 22.94 (0.69) mm for emmetropes. Significant correlations were noted between SEQ and ocular dimensions, with a greater change in LAL (0.46 mm/D, P < 0.001) than in VH (0.27 mm/D, P < 0.001) and HW (0.22 mm/D, P = 0.001).

    CONCLUSIONS: Myopic eyeballs are larger than those with emmetropia. The eyeball elongates as myopia increases, with the greatest change in LAL, the least in HW, and an intermediate change in VH. These changes manifest in both sexes at a young age and low level of myopia. These data may serve as a reference for monitoring the development of refractive error in young Malaysian children of Chinese origin.

  4. Chalitsios CV, Akyea RK, Abdul-Hamid H, Leonardi-Bee J, Kanchau JD, Kamal A, et al.
    Int J Gen Med, 2023;16:5885-5888.
    PMID: 38111851 DOI: 10.2147/IJGM.S423091
  5. Lee KW, Yap SF, Murdan S, Zainudin Z, Abdul Hamid H, Emamjomeh M, et al.
    Acta Paediatr, 2024 May;113(5):892-911.
    PMID: 38351491 DOI: 10.1111/apa.17152
    AIM: To determine the prevalence of group B Streptococcus (GBS) carriage among parturient women and neonates, and the relative risk of vertical transmission, the relative risk of early and late-onset GBS and the pooled incidence of early-late-onset GBS infection.

    METHODS: A systematic search of relevant cohort studies from three electronic databases to identify all relevant studies published up to 7 November 2022. The review was conducted in accordance with PRISMA guidelines. Estimates were pooled using random-effects meta-analyses.

    RESULTS: A total of 54 articles with 355 787 matched pairs of parturient women and neonates from 30 countries were included in the analysis. The pooled prevalence of GBS colonisation was 17.1% among the pregnant women and 1.0% among neonates. The pooled prevalence of vertical transmission of GBS was 4.5% and the pooled relative risk of GBS colonisation of neonates born to mothers with GBS was 9.9.

    CONCLUSION: We support the implementation of targeted intrapartum antibiotic prophylaxis for all women who are positive for GBS as well as women with risks factors for early onset GBS in their infants regardless of their GBS colonisation status.

  6. Saminathan TA, Rodzlan Hasani WS, Robert Lourdes TG, Mohd Yusoff MF, Ismail H, Akmal Abd Hamid H, et al.
    Asia Pac J Public Health, 2019 10;31(7_suppl):53S-60S.
    PMID: 31189348 DOI: 10.1177/1010539519854873
    We assessed the prevalence of cessation of e-cigarette and its associated factors among adolescents in Malaysia. This study analyzed data from the Tobacco and E-Cigarette Survey among Malaysian Adolescent (TECMA) in 2016, a cross-sectional study with 2-stage stratification cluster sampling. A total of 14 832 school-going adolescents aged 10 to 19 years participated in this survey. A complex sampling design and multiple logistic regression analysis were applied. Nearly half of the adolescents (49.9%; 95% confidence interval [CI] = 44.9-55.0) who had ever used e-cigarette ceased the usage. Based on multivariate analysis, adolescents were more likely to quit e-cigarette because they could not afford the e-cigarette (adjusted odds ratio [aOR] = 2.39, 95% CI = 1.78-3.20), if they are aged 13 year and older (aOR = 1.80, 95% CI = 1.25-2.61), and those who claimed their e-cigarette does not contain nicotine (aOR = 1.35, 95% CI = 1.03-1.78). E-cigarette prevention efforts among adolescents could consider the cessation factors described in this study.
  7. Ramli AS, Daher AM, Nor-Ashikin MN, Mat-Nasir N, Ng KK, Miskan M, et al.
    Biomed Res Int, 2013;2013:760963.
    PMID: 24175300 DOI: 10.1155/2013/760963
    Metabolic syndrome (MetS) is a steering force for the cardiovascular diseases epidemic in Asia. This study aimed to compare the prevalence of MetS in Malaysian adults using NCEP-ATP III, IDF, and JIS definitions, identify the demographic factors associated with MetS, and determine the level of agreement between these definitions. The analytic sample consisted of 8,836 adults aged ≥30 years recruited at baseline in 2007-2011 from the Cardiovascular Risk Prevention Study (CRisPS), an ongoing, prospective cohort study involving 18 urban and 22 rural communities in Malaysia. JIS definition gave the highest overall prevalence (43.4%) compared to NCEP-ATP III (26.5%) and IDF (37.4%), P < 0.001. Indians had significantly higher age-adjusted prevalence compared to other ethnic groups across all MetS definitions (30.1% by NCEP-ATP III, 50.8% by IDF, and 56.5% by JIS). The likelihood of having MetS amongst the rural and urban populations was similar across all definitions. A high level of agreement between the IDF and JIS was observed (Kappa index = 0.867), while there was a lower level of agreement between the IDF and NCEP-ATP III (Kappa index = 0.580). JIS definition identified more Malaysian adults with MetS and therefore should be recommended as the preferred diagnostic criterion.
  8. Abdul-Razak S, Daher AM, Ramli AS, Ariffin F, Mazapuspavina MY, Ambigga KS, et al.
    BMC Public Health, 2016;16(1):351.
    PMID: 27097542 DOI: 10.1186/s12889-016-3008-y
    Hypertension is the leading cardiovascular risk factor globally as well as in Malaysia. This study aimed to estimate the prevalence, awareness, treatment, control and the socio demographic determinants of hypertension among Malaysian adults.
  9. Abu Bakar ZH, Damanhuri HA, Makpol S, Wan Kamaruddin WMA, Abdul Sani NF, Amir Hamzah AIZ, et al.
    J Alzheimers Dis, 2019;70(s1):S43-S62.
    PMID: 30594926 DOI: 10.3233/JAD-180511
    BACKGROUND: Many studies on biochemical and psychological variables have aimed to elucidate the association between aging and cognitive function. Demographic differences and protein expression have been reported to play a role in determining the cognitive capability of a population.

    OBJECTIVE: This study aimed to determine the effect of age on the protein profile of Malay individuals and its association with cognitive competency.

    METHODS: A total of 160 individuals were recruited and grouped accordingly. Cognitive competency of each subject was assessed with several neuropsychological tests. Plasma samples were collected and analyzed with Q Exactive HF Orbitrap. Proteins were identified and quantitated with MaxQuant and further analyzed with Perseus to determine differentially expressed proteins. PANTHER, Reactome, and STRING were applied for bioinformatics output.

    RESULTS: Our data showed that the Malay individuals are vulnerable to the deterioration of cognitive function with aging, and most of the proteins were differentially expressed in concordance. Several physiological components and pathways were shown to be involved, giving a hint of a promising interpretation on the induction of aging toward the state of the Malays' cognitive function. Nevertheless, some proteins have shown a considerable interaction with the generated protein network, which provides a direction of focus for further investigation.

    CONCLUSION: This study demonstrated notable changes in the expression of several proteins as age increased. These changes provide a promising platform for understanding the biochemical factors affecting cognitive function in the Malay population. The exhibited network of protein-protein interaction suggests the possibility of implementing regulatory intervention in ameliorating Malay cognitive function.

  10. Muhammad Nawawi KN, Mokhtar NM, Wong Z, Mohd Azman ZA, Hsin Chew DC, Rehir R, et al.
    PeerJ, 2021;9:e12425.
    PMID: 34820182 DOI: 10.7717/peerj.12425
    Background: The incidence rate of colorectal cancer (CRC) in Asian countries is increasing. Furthermore, recent studies have shown a concerning rise in the incidence of CRC among younger patients aged less than 50 years. This study aimed to analyze the incidence trends and clinicopathological features in patients with early-onset CRC (EOCRC) and later-onset CRC (at age ≥ 50 years).

    Methods: A retrospective analysis was performed on 946 patients with CRC diagnosed from 1997 to 2017 at Universiti Kebangsaan Malaysia Medical Centre. The time trend was assessed by dividing the two decades into four 5-year periods. The mean age-standardized and age-specific incidence rates were calculated by using the 5-year cumulative population of Kuala Lumpur and World Health Organization standard population. The mean incidence was expressed per 100,000 person-years.

    Results: After a stable (all age groups) CRC incidence rate during the first decade (3.00 per 100,000 and 3.85 per 100,000), it sharply increased to 6.12 per 100,000 in the 2008-2012 period before decreasing to 4.54 per 100,000 in the 2013-2017 period. The CRC incidence trend in later-onset CRC showed a decrease in the 2013-2017 period. Contrariwise, for age groups of 40-44 and 45-49 years, the trends showed an increase in the latter 15 years of the study period (40-44 years: 1.44 to 1.92 to 2.3 per 100,000; 45-49 years: 2.87 to 2.94 to 4.01 per 100,000). Malays' EOCRC incidence rate increased from 2008-2012 to 2013-2017 for both the age groups 40-44 years (1.46 to 2.89 per 100,000) and 45-49 years (2.73 to 6.51 per 100,000). Nearly one-fifth of EOCRC cases were diagnosed at an advanced stage (Dukes D: 19.9%), and the majority of them had rectal cancer (72.8%).

    Conclusion: The incidence of EOCRC increased over the period 1997-2017; the patients were predominantly Malays, diagnosed at a later stage, and with cancer commonly localized in the rectal region. All the relevant stakeholders need to work on the management and prevention of CRC in Malaysia.

  11. Abu Hussain SM, Miptah HN, Shibraumalisi NA, Mohamed-Yassin MS, Baharudin N, Badlishah-Sham SF, et al.
    Digit Health, 2024;10:20552076241242795.
    PMID: 38571876 DOI: 10.1177/20552076241242795
    OBJECTIVE: This study aimed to determine the usability of the EMPOWER-SUSTAIN Self-Management Mobile App© and evaluate the factors associated with its usability among patients with cardiovascular risk factors in primary care.

    METHODOLOGY: This was a cross-sectional study, conducted among patients aged ≥ 18 years with cardiovascular risk factors attending a university primary care clinic. Patients were given the app to use for at least three months. Those who fulfilled the eligibility criteria were recruited. Data gathered were on sociodemographic, clinical characteristics, self-management support by doctors, utilisation of the app at home and social support in using the app. The previously translated and validated Malay version of the mHealth App Usability Questionnaire was used to measure usability. The mean usability score was calculated and linear regressions analysis was conducted to determine the factors associated with the usability of the app.

    RESULTS: A total of 247 patients with at least one cardiovascular risk factor(s) were recruited. The mean age was 60.2 (±8.2). The majority were Malays (86.2%) and half of them were males (52.2%). The total mean (±SD) usability score was 5.26 (±0.67) indicating a high usability of the app. Usability of the app declined with increasing age in the simple linear regressions analysis. The multiple linear regressions yielded that being Malay (b = 0.31, 95% CI 0.08,0.54), using the app at home to understand their medications (b = 0.33, 95% CI 0.12,0.53) and having social support from family members and friends (b = 0.28, 95% CI 0.07,0.49) were significantly associated with higher usability of the app.

    CONCLUSION: The usability of the EMPOWER-SUSTAIN Self-Management Mobile App© was high among patients with cardiovascular risk factors in our primary care clinic. This finding supports the widespread use of this app among our patients. Involvement of family members and friends should be encouraged to improve the usability of the app.

  12. Kamal A, Kanchau JD, Shahuri NS, Mohamed-Yassin MS, Baharudin N, Abdul Razak S, et al.
    Am J Case Rep, 2023 Apr 27;24:e939489.
    PMID: 37185657 DOI: 10.12659/AJCR.939489
    BACKGROUND In Malaysia, the prevalence of genetically confirmed heterozygous familial hypercholesterolemia (FH) was reported as 1 in 427. Despite this, FH remains largely underdiagnosed and undertreated in primary care. CASE REPORT In this case series, we report 3 FH cases detected in primary care due to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein-B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. The mutations in case 1 (frameshift c.660del pathogenic variant in LDLR gene) and case 2 (missense c.10579C>T pathogenic variant in APOB gene) were confirmed as pathogenic, while the mutation in case 3 (missense c.277C>T mutation in PCSK9 gene) may have been benign. In case 1, the patient had the highest LDL-c level, 8.6 mmol/L, and prominent tendon xanthomas. In case 2, the patient had an LDL-c level of 5.7 mmol/L and premature corneal arcus. In case 3, the patient had an LDL-c level of 5.4 mmol/L but had neither of the classical physical findings. Genetic counseling and diagnosis were delivered by primary care physicians. These index cases were initially managed in primary care with statins and therapeutic lifestyle modifications. They were referred to the lipid specialists for up-titration of lipid lowering medications. First-degree relatives were identified and referred for cascade testing. CONCLUSIONS This case series highlights different phenotypical expressions in patients with 3 different FH genetic mutations. Primary care physicians should play a pivotal role in the detection of FH index cases, genetic testing, management, and cascade screening of family members, in partnership with lipid specialists.
  13. Nassir CMNCM, Ghazali MM, Hashim S, Idris NS, Yuen LS, Hui WJ, et al.
    Front Cardiovasc Med, 2021;8:632131.
    PMID: 33718454 DOI: 10.3389/fcvm.2021.632131
    Cerebral small vessel disease (CSVD) represents a spectrum of pathological processes of various etiologies affecting the brain microcirculation that can trigger neuroinflammation and the subsequent neurodegenerative cascade. Prevalent with aging, CSVD is a recognized risk factor for stroke, vascular dementia, Alzheimer disease, and Parkinson disease. Despite being the most common neurodegenerative condition with cerebrocardiovascular axis, understanding about it remains poor. Interestingly, modifiable risk factors such as unhealthy diet including high intake of processed food, high-fat foods, and animal by-products are known to influence the non-neural peripheral events, such as in the gastrointestinal tract and cardiovascular stress through cellular inflammation and oxidation. One key outcome from such events, among others, includes the cellular activations that lead to elevated levels of endogenous cellular-derived circulating microparticles (MPs). MPs can be produced from various cellular origins including leukocytes, platelets, endothelial cells, microbiota, and microglia. MPs could act as microthrombogenic procoagulant that served as a plausible culprit for the vulnerable end-artery microcirculation in the brain as the end-organ leading to CSVD manifestations. However, little attention has been paid on the potential role of MPs in the onset and progression of CSVD spectrum. Corroboratively, the formation of MPs is known to be influenced by diet-induced cellular stress. Thus, this review aims to appraise the body of evidence on the dietary-related impacts on circulating MPs from non-neural peripheral origins that could serve as a plausible microthrombosis in CSVD manifestation as a precursor of neurodegeneration. Here, we elaborate on the pathomechanical features of MPs in health and disease states; relevance of dietary patterns on MP release; preclinical studies pertaining to diet-based MPs contribution to disease; MP level as putative surrogates for early disease biomarkers; and lastly, the potential of MPs manipulation with diet-based approach as a novel preventive measure for CSVD in an aging society worldwide.
  14. Ramli AS, Lakshmanan S, Haniff J, Selvarajah S, Tong SF, Bujang MA, et al.
    BMC Fam Pract, 2014;15:151.
    PMID: 25218689 DOI: 10.1186/1471-2296-15-151
    Chronic disease management presents enormous challenges to the primary care workforce because of the rising epidemic of cardiovascular risk factors. The chronic care model was proven effective in improving chronic disease outcomes in developed countries, but there is little evidence of its effectiveness in developing countries. The aim of this study was to evaluate the effectiveness of the EMPOWER-PAR intervention (multifaceted chronic disease management strategies based on the chronic care model) in improving outcomes for type 2 diabetes mellitus and hypertension using readily available resources in the Malaysian public primary care setting. This paper presents the study protocol.
  15. Ramli AS, Selvarajah S, Daud MH, Haniff J, Abdul-Razak S, Tg-Abu-Bakar-Sidik TM, et al.
    BMC Fam Pract, 2016 11 14;17(1):157.
    PMID: 27842495
    BACKGROUND: The chronic care model was proven effective in improving clinical outcomes of diabetes in developed countries. However, evidence in developing countries is scarce. The objective of this study was to evaluate the effectiveness of EMPOWER-PAR intervention (based on the chronic care model) in improving clinical outcomes for type 2 diabetes mellitus using readily available resources in the Malaysian public primary care setting.

    METHODS: This was a pragmatic, cluster-randomised, parallel, matched pair, controlled trial using participatory action research approach, conducted in 10 public primary care clinics in Malaysia. Five clinics were randomly selected to provide the EMPOWER-PAR intervention for 1 year and another five clinics continued with usual care. Patients who fulfilled the criteria were recruited over a 2-week period by each clinic. The obligatory intervention components were designed based on four elements of the chronic care model i.e. healthcare organisation, delivery system design, self-management support and decision support. The primary outcome was the change in the proportion of patients achieving HbA1c 
  16. 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.

  17. Goodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, et al.
    Carcinogenesis, 2015 Jun;36 Suppl 1:S254-96.
    PMID: 26106142 DOI: 10.1093/carcin/bgv039
    Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
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