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Fulltext A black finger does not equal a dead finger

Shalimar, A., William, H., Levin, K.B., Parminder G.S., Nur Azuatul, A.K., Tan, J.A.

Medicine & Health, 2018;13(2):229-234.
MyJurnal

Revascularisation and replant surgery occasionally produces sub-optimal results. We present two cases of near total amputation of the digits. The first patient was an 11-year-old boy with a middle finger avulsion injury sustained after the finger was caught in a washing machine with the flexor digitorum profundus still attached. The second patient was a 42-year-old male who sustained a machete attack and had near total amputation of his small and ring fingers with a 2 cm skin bridge still attached. All patients underwent revascularization with repair of only one digital artery for each finger as the opposite artery was non-viable. No digital veins were repaired. Relief of venous congestion was done by pin-prick six times a day up till one week. At one week post-surgery, the fingers were discoloured black but had good pulp turgor and full contour with arterial bleed on pin-prick. Inexperienced surgeons may view this as gangrene and amputate the fingers. However, we continued observation and at one month post-surgery, the black skin had desloughed and the underlying skin was pink.
Fulltext Augmentation rhinoplasty in cleft lip nasal deformity: preliminary patients' perspective

Tiong WH, Zain MA, Basiron NH

Plast Surg Int, 2014;2014:202560.
PMID: 25254115 DOI: 10.1155/2014/202560

The correction of cleft lip nasal deformity is challenging and there have been numerous methods described in the literature with little demonstrated technical superiority of one over another. The common clinical issues associated with cleft lip nasal deformity are its lack of symmetry, alar collapse on the affected side, obtuse nasal labial angle, short nasal length, loss of tip definition, and altered columella show among others. We carried out augmentation of cleft lip rhinoplasties with rib graft in 16 patients over the one-year study period. Each of these patients was reviewed and given questionnaire before and after surgery to evaluate their response on the outcome to the approach. Preoperatively, nasal asymmetry is the main complaint (14/16, 87.5%) among our series of patients. Postoperatively, 12 (75%) patients out of the 16 reported significant improvement in their nasal symmetry with the other four marginal. All patients reported excellent nasal projection postoperatively with good nasal tip definition. Our series of patients reported overall good satisfaction outcome and will recommend this procedure to other patients with cleft lip nasal deformity. In conclusion, augmentation of cleft lip rhinoplasty can be employed to achieve perceivable and satisfactory outcome in patients with cleft lip nasal deformity.
Habitat heterogeneity and niche structure of trees in two tropical rain forests

Potts MD, Davies SJ, Bossert WH, Tan S, Nur Supardi MN

Oecologia, 2004 May;139(3):446-53.
PMID: 14997378

Dispersal-assembly theories of species coexistence posit that environmental factors play no role in explaining community diversity and structure. Dispersal-assembly theories shed light on some aspects of community structure such as species-area and species-abundance relationships. However, species' environmental associations also affect these measures of community structure. Measurements of species' niche breadth and overlap address this influence. Using a new continuous measure of niche and a dispersal-assembly null model that maintains species' niche breadth and aggregation, we tested two hypotheses assessing the effects of habitat heterogeneity on the ability of dispersal-assembly theories to explain community niche structure. We found that in both homogenous and heterogeneous environments dispersal-assembly theories cannot fully explain observed niche structure. The performance of the dispersal-assembly null models was particularly poor in heterogeneous environments. These results indicate that non-dispersal based mechanisms are in part responsible for observed community structure and measures of community structure which include species' environmental associations should be used to test theories of species diversity.
Exploring drivers of pre-exposure prophylaxis uptake among gay, bisexual, and other men who have sex with men in Malaysia

Eger WH, Adaralegbe A, Khati A, Azwa I, Wickersham JA, Osborne S, et al.

Int J STD AIDS, 2022 Aug;33(9):821-828.
PMID: 35772943 DOI: 10.1177/09564624221106535

BACKGROUND: Pre-exposure prophylaxis (PrEP) is a valuable HIV prevention strategy, particularly among men who have sex with men (MSM); however, PrEP uptake is below the threshold needed to curb the HIV epidemic among this group, especially in settings like Malaysia, where same-sex sexual behavior is illegal.
METHODS: A sample of 355 participants completed an online survey between June and July 2020, recruited through geosocial networking apps for MSM and social networking websites (e.g. Facebook). We used descriptive and multivariable analyses to examine correlates of PrEP use within this population.
RESULTS: The sample was predominantly Malay (53.5%), had monthly incomes greater than RM 3000 (USD 730) (52.7%), and a tertiary level of education (84.5%). About 80% of participants heard of PrEP prior to the survey, with significantly less (18.3%) having ever taken PrEP. In the adjusted multivariable logistic model, using drugs before or during sexual intercourse ("chemsex") (AOR: 3.37; 95% CI: 1.44-7.89), being diagnosed with a sexually transmitted infection in the last 12 months (AOR: 2.08; 95% CI: 1.13-3.85), HIV testing in the previous 6 months (AOR: 3.23; 95% CI: 1.74-5.99), and disclosure of sexual orientation (AOR: 1.85; 95% CI: 1.02-3.34) were associated with having taken PrEP in the past.
CONCLUSIONS: This study revealed that PrEP use among Malaysian MSM is relatively low, despite high awareness, and is associated with healthcare engagement and high-risk behaviors. These results highlight the need to tailor outreach activities for individuals at increased risk for HIV and those disengaged with the health system.
Fulltext Intra-articular hyaluronic acid (HA) and platelet rich plasma (PRP) injection versus hyaluronic acid (HA) injection alone in patients with grade III and IV knee osteoarthritis (OA): a retrospective study on functional outcome

Saturveithan C, Premganesh G, Fakhrizzaki S, Mahathir M, Karuna K, Rauf K, et al.

Malays Orthop J, 2016 Jul;10(2):35-40.
PMID: 28435559 MyJurnal DOI: 10.5704/MOJ.1607.007

Introduction: Intra-articular hyaluronic acid (HA) is widely utilized in the treatment of knee osteoarthritis whereas platelet rich plasma (PRP) enhances the regeneration of articular cartilage. This study analyses the efficacy of HA and PRP in grade III and IV knee osteoarthritis. Methodology: This is a cross sectional study with retrospective review of 64 patients (101 knees) which includes 56 knees injected with HA+ PRP, and 45 knees with HA only. Results: During the post six months International Knee Documentation Committee (IKDC) evaluation, HA+PRP group showed marked improvement of 24.33 compared to 12.15 in HA group. Decrement in visual analogue score (VAS) in HA+PRP was 1.9 compared to 0.8 in HA group. Conclusion: We propose intra-articular HA and PRP injections as an optional treatment modality in Grade III and IV knee osteoarthritis in terms of functional outcome and pain control for up to six months when arthroplasty is not an option.
Study site: Melaka General Hospital, Malaysia
Composition of deposited sediment and its temporal variation in a disturbed tropical catchment in the Kelantan river basin, Peninsular Malaysia

Sugumaran D, Blake WH, Millward GE, Yusop Z, Mohd Yusoff AR, Mohamad NA, et al.

Environ Sci Pollut Res Int, 2023 Jun;30(28):71881-71896.
PMID: 35411514 DOI: 10.1007/s11356-022-19904-6

Pristine tropical river systems are coming under increasing pressure from the development of economic resources such as forestry and mining for valuable elements. The Lebir catchment, north eastern Malaysia, is now under development as a result of unregulated tree felling and mining for essential and rare metals. Two sediment cores, one in the upstream reaches and the other from the downstream reaches, were taken from flood prone area of the Lebir River, Malaysia, and analysed for their elemental composition by XRF, specifically Al, Si, Fe, Ca, K, Mg, Mn, V, Cu, Ni, Pb, Cr, Zn, As, Th and U. Activities of fallout radionuclides, 137Cs and 210Pb were also determined to from a geochronological context. The elemental concentrations in the soils were assessed in terms of their enrichment factor and Si, Ca, K, Mg, Mn, V, Cu, Ni and Zn were found not to be enriched, whereas As, Th and U had elevated enrichment factors. The Th and U were particularly enriched in the downstream core indicating inputs from a tributary that drains a catchment with known deposits of Th and possibly U. The results suggest that the growth in economic development is fostering the transport of contaminants by the major rivers which, in turn, is contaminating the riverine floodplains. This points to the need for a more integrated and holistic approach to river basin management to maintain the environmental quality of these fragile aquatic systems.
Altered phenotype and function of NK cells infiltrating human papillomavirus (HPV)-associated genital warts during HIV infection

Bere A, Tayib S, Kriek JM, Masson L, Jaumdally SZ, Barnabas SL, et al.

Clin Immunol, 2014 Feb;150(2):210-9.
PMID: 24440646 DOI: 10.1016/j.clim.2013.12.005

HIV-infected individuals experience more persistent HPV infections and are less likely to resolve genital warts. This study compared phenotype and functions of NK and T cells from genital warts and blood from 67 women. We compared in vitro functional responses of NK and T cells by multiparametric flow cytometry. HIV+ women had significantly lower frequencies of CD4 T cells in warts (p = 0.001) and blood (p = 0.001). While the distribution of NK cell subsets was similar, HIV+ women tended to have lower frequencies of CD56(Dim) NK cells in both blood (p = 0.0001) and warts (p = 0.006) than HIV- women. Wart NK cells from HIV+ women expressed significantly lower CD107a and produced IFN-γ. HAART status was not associated with differences in NK cell functionality. We conclude that wart NK cells from HIV+ women have defects in their ability to degranulate and/or secrete IFN-γ, which may provide insights into why HIV+ women fail to spontaneously resolve genital warts.
Fulltext Clinic-Integrated Mobile Health Intervention ("JomPrEP" App) to Improve Uptake of HIV Testing and Pre-exposure Prophylaxis Among Men Who Have Sex With Men in Malaysia: Protocol for an Intervention Development and Multiphase Trial

Shrestha R, Wickersham JA, Khati A, Azwa I, Ni Z, Kamarulzaman A, et al.

JMIR Res Protoc, 2022 Dec 21;11(12):e43318.
PMID: 36542425 DOI: 10.2196/43318

BACKGROUND: Men who have sex with men (MSM) are disproportionately affected by the HIV epidemic in Malaysia and globally. Cross-cutting prevention strategies such as mobile health (mHealth), particularly smartphone apps, hold great promise for HIV prevention efforts among Malaysian MSM, especially when linked to HIV testing and pre-exposure prophylaxis (PrEP).
OBJECTIVE: This study aims to adapt an existing app to create and test a clinic-integrated app (JomPrEP), a virtual platform to deliver HIV testing and PrEP services for MSM in Malaysia.
METHODS: The JomPrEP project involves developing and testing an app-based platform for HIV prevention among Malaysian MSM and will be conducted in 2 phases. In phase I (development phase), we will adapt an existing mHealth app (HealthMindr) to create a new clinic-integrated app called "JomPrEP" to deliver holistic HIV prevention services (eg, HIV testing, PrEP, support services for mental health and substance use) among MSM in Malaysia. During phase II (testing phase), we will use a type I hybrid implementation science trial design to test the efficacy of JomPrEP while gathering information on implementation factors to guide future scale-up in real-world settings.
RESULTS: As of September 2022, we have completed phase I of the proposed study. Based on a series of formative work completed during phase I, we developed a fully functional, clinic-integrated JomPrEP app, which provides a virtual platform for MSM in Malaysia to facilitate their engagement in HIV prevention in a fast and convenient manner. Based on participant feedback provided during phase I, we are currently optimizing JomPrEP and the research protocols for a large-scale efficacy trial (phase II), which will commence in January 2023.
CONCLUSIONS: Scant HIV prevention resources coupled with entrenched stigma, discrimination, and criminalization of same-sex sexual behavior and substance use hamper access to HIV prevention services in Malaysia. If found efficacious, JomPrEP can be easily adapted for a range of health outcomes and health care delivery services for MSM, including adaptation to other low- and middle-income countries.
TRIAL REGISTRATION: ClinicalTrials.gov NCT05325476; https://clinicaltrials.gov/ct2/show/NCT05325476.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/43318.
Fulltext The combinatorial diversity of KIR and HLA class I allotypes in Peninsular Malaysia

Tao S, Kichula KM, Harrison GF, Farias TDJ, Palmer WH, Leaton LA, et al.

Immunology, 2021 Apr;162(4):389-404.
PMID: 33283280 DOI: 10.1111/imm.13289

Killer cell immunoglobulin-like receptors (KIRs) interact with polymorphic human leucocyte antigen (HLA) class I molecules, modulating natural killer (NK) cell functions and affecting both the susceptibility and outcome of immune-mediated diseases. The KIR locus is highly diverse in gene content, copy number and allelic polymorphism within individuals and across geographical populations. To analyse currently under-represented Asian and Pacific populations, we investigated the combinatorial diversity of KIR and HLA class I in 92 unrelated Malay and 75 Malaysian Chinese individuals from the Malay Peninsula. We identified substantial allelic and structural diversity of the KIR locus in both populations and characterized novel variations at each analysis level. The Malay population is more diverse than Malay Chinese, likely representing a unique history including admixture with immigrating populations spanning several thousand years. Characterizing the Malay population are KIR haplotypes with large structural variants present in 10% individuals, and KIR and HLA alleles previously identified in Austronesian populations. Despite the differences in ancestries, the proportion of HLA allotypes that serve as KIR ligands is similar in each population. The exception is a significantly reduced frequency of interactions of KIR2DL1 with C2+ HLA-C in the Malaysian Chinese group, caused by the low frequency of C2+ HLA. One likely implication is a greater protection from preeclampsia, a pregnancy disorder associated with KIR2DL1, which shows higher incidence in the Malay than in the Malaysian Chinese. This first complete, high-resolution, characterization of combinatorial diversity of KIR and HLA in Malaysians will form a valuable reference for future clinical and population studies.
Fulltext Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions

Kravchenko J, Corsini E, Williams MA, Decker W, Manjili MH, Otsuki T, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S111-27.
PMID: 26002081 DOI: 10.1093/carcin/bgv033

An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression.
Fulltext Environmental immune disruptors, inflammation and cancer risk

Thompson PA, Khatami M, Baglole CJ, Sun J, Harris SA, Moon EY, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S232-53.
PMID: 26106141 DOI: 10.1093/carcin/bgv038

An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.
Fulltext Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis

Hu Z, Brooks SA, Dormoy V, Hsu CW, Hsu HY, Lin LT, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S184-202.
PMID: 26106137 DOI: 10.1093/carcin/bgv036

One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.
Fulltext The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling

Engström W, Darbre P, Eriksson S, Gulliver L, Hultman T, Karamouzis MV, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S38-60.
PMID: 26106143 DOI: 10.1093/carcin/bgv030

The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.
Fulltext Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?

Robey RB, Weisz J, Kuemmerle NB, Salzberg AC, Berg A, Brown DG, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1(Suppl 1):S203-31.
PMID: 26106140 DOI: 10.1093/carcin/bgv037

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested.
Fulltext Disruptive chemicals, senescence and immortality

Carnero A, Blanco-Aparicio C, Kondoh H, Lleonart ME, Martinez-Leal JF, Mondello C, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1(Suppl 1):S19-37.
PMID: 26106138 DOI: 10.1093/carcin/bgv029

Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes.
Enhancing Human Health and Wellbeing through Sustainably and Equitably Unlocking a Healthy Ocean's Potential

Fleming LE, Landrigan PJ, Ashford OS, Whitman EM, Swift A, Gerwick WH, et al.

Ann Glob Health, 2024;90(1):41.
PMID: 39005643 DOI: 10.5334/aogh.4471

A healthy ocean is essential for human health, and yet the links between the ocean and human health are often overlooked. By providing new medicines, technologies, energy, foods, recreation, and inspiration, the ocean has the potential to enhance human health and wellbeing. However, climate change, pollution, biodiversity loss, and inequity threaten both ocean and human health. Sustainable realisation of the ocean's health benefits will require overcoming these challenges through equitable partnerships, enforcement of laws and treaties, robust monitoring, and use of metrics that assess both the ocean's natural capital and human wellbeing. Achieving this will require an explicit focus on human rights, equity, sustainability, and social justice. In addition to highlighting the potential unique role of the healthcare sector, we offer science-based recommendations to protect both ocean health and human health, and we highlight the unique potential of the healthcare sector tolead this effort.
Fulltext Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death

Narayanan KB, Ali M, Barclay BJ, Cheng QS, D'Abronzo L, Dornetshuber-Fleiss R, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S89-110.
PMID: 26106145 DOI: 10.1093/carcin/bgv032

Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis.
Fulltext Causes of genome instability: the effect of low dose chemical exposures in modern society

Langie SA, Koppen G, Desaulniers D, Al-Mulla F, Al-Temaimi R, Amedei A, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S61-88.
PMID: 26106144 DOI: 10.1093/carcin/bgv031

Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.
Fulltext The effect of environmental chemicals on the tumor microenvironment

Casey SC, Vaccari M, Al-Mulla F, Al-Temaimi R, Amedei A, Barcellos-Hoff MH, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S160-83.
PMID: 26106136 DOI: 10.1093/carcin/bgv035

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.
Fulltext Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression

Nahta R, Al-Mulla F, Al-Temaimi R, Amedei A, Andrade-Vieira R, Bay SN, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S2-18.
PMID: 26106139 DOI: 10.1093/carcin/bgv028

As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks.

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