Carcinogen Exposure Research Articles

PLGA-Loaded Nedaplatin (PLGA-NDP) Inhibits 7,12-Dimethylbenz[a]anthracene (DMBA) Induced Oral Carcinogenesis via Modulating Notch Signaling Pathway and Induces Apoptosis in Experimental Hamster Model.

The present study is designed to evaluate the nanotherapeutic efficacy of prepared PLGA-loaded Nedaplatin (PLGA-NDP) against 7,12-dimethyl benz(a)anthracene (DMBA)-induced experimental oral carcinogenesis in hamster buccal pouch (HBP) model. The buccal pouch of golden Syrian hamsters was painted with 0.5% DMBA in liquid paraffin three times a week for 14 weeks, ultimately leading to the development of oral squamous cell carcinoma (OSCC). Oral administration of PLGA-NDP (preinitiation) and Cisplatin delivery (5 mg/kg b.wt) started 1 week before the carcinogen exposure and continued on alternative days. Post-administration of PLGA-NDP (5 mg/kg b.wt) started 2 days after carcinogen (DMBA) induction until the end of the experiment. After the 14th week, we observed that DMBA-painted hamsters exhibited tumor formation, morphological alterations, and well-differentiated OSSC in addition to the responsive molecular proteins during oral carcinogenesis. Furthermore, immunoblotting analysis demonstrated that PLGA-NDP inhibits Notch signaling, as evidenced by downregulation of Bcl-Xl, Bcl-2, p21, PGE2, HGF, and CXCL12 proteins, and upregulation of p53 and Bax. This apoptotic response is crucial for PLGA-NDP to induce apoptosis. In addition, RT-PCR results showed that PLGA-NDP nanoparticles play a downregulatory role in the therapeutic action of the notch signaling gene (Notch1, Notch 2, Hes1, Hey1, and Jagged1) at the mRNA transcription level in HBP carcinoma. Taken together, these data indicate that PLGA-NDP is a potent inhibitor of oral carcinogenesis and the expansion of cells that specifically target the Notch signaling pathway indicates that obstructing Notch signaling could potentially serve as a new and innovative therapeutic approach for oral squamous cell carcinoma (OSCC).

Impact of Global Warming on Cancer Development: A Review of Environmental Carcinogens and Human Immunogenetics

This paper examines the impact of global warming on cancer development, specifically focusing on the intensified effects of environmental carcinogens such as ultraviolet (UV) radiation and air pollutants. Our review elucidates the intricate interplay between global warming, ecological carcinogens, human immunogenetics, and cancer susceptibility. The analysis highlights the exacerbating effects of rising temperatures and changes in atmospheric conditions on exposure to UV radiation and air pollutants, including particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), nitrogen dioxide (NO2), nitrogen oxides (NOx), and ground-level ozone (O3). Furthermore, the study explores the pivotal role of human immunogenetics in modulating individual responses to carcinogen exposure and shaping cancer susceptibility and progression. Genetic variations in key immune-related genes and their influence on the interplay between environmental carcinogens and cancer development are discussed. The paper underscores the importance of longitudinal cohort studies, integrative approaches, and interdisciplinary collaborations to advance our understanding of the complex interactions between global warming, environmental carcinogens, human immunogenetics, and cancer biology. Additionally, evidence-based public health interventions targeting environmental carcinogens and personalized prevention strategies based on genetic susceptibility profiles and environmental exposure assessments are proposed to address the growing challenges of environmentally induced cancers.

Enhanced health risk of soil heavy metal exposure following an extreme rainstorm under climate change

Widespread concerns raised in changes in the health risk of soil heavy metals exposure due to extreme rainstorm under climate change. However, the impacts of extreme rainstorm on human exposure risk and the underlying mechanisms are still unclear. In this study, soil properties, speciation distribution and bioaccessibility of Ni, Cu, Zn, Cd and Pb in soil samples, which were collected before and after extreme rainstorm, were measured, subsequently the soil oral exposure risk of heavy metals was assessed based on bioaccessibility. Results indicate that extreme rainstorm can significantly enhance the accumulated non-carcinogenic and carcinogenic exposure risk by 10.1–188.3 %, with lowland soil posing 1.3–1.7 times higher risk than highland soil. The increase in exposure risk varies among elements in highland and lowland soil. Specifically, the exposure risk for Cd and Pb increased by 2.5–9.7 times, whereas that for Cu decreased by 43.2 % - 60.6 %. The risk of Zn and Ni exposure exhibits complex trends, with an increase of 37.2 %–104.8 % in lowland soil but a decrease of 9.4 %–46.5 % in highland soil. Bioaccessibility variations are the primary risk factors for soil heavy metal exposure during extreme rainstorms, not total concentration. Mechanistically, the extreme rainstorm directly increases soil moisture content and reduce organic matter concentration, leading to an increment in the proportion of bio-utilization speciation and decrement in the speciation bounding to Fe/Mn oxides of soil heavy metals. Furthermore, the bioaccessibility of soil heavy metal positively correlates with their bio-utilization speciation and negatively correlates with their speciation bounding to Fe/Mn oxides, which ultimately increasing exposure risk. Our study suggests the necessity that attentions should be paid to the enhanced health risk associated with soil heavy metal exposure following extreme rainstorm, particularly for population residing in lowland areas.

Abstract IA-07: RAS mutation tropism: insight into tumor initation

Abstract How we get cancer, a process termed tumor initiation, remains an enigma, which has crucial clinical implications for early detection, prevention, and interception. Backtracking to catch the moment a specific mutagenic event in a single gene from an individual cell occurred decades before manifesting as cancer is challenging. However, the RAS family of small GTPases thate are commonly mutated in cancer provide some insight. Despite over 50 possible oncogenic RAS mutations, each cancer type exhibits a predilection or ‘tropism’ towards a distinct and often unique subset of these mutations. For example, most pancreatic ductal adenocarcinomas are driven by a G12D/V mutation in KRAS. As RAS mutations are often initiating, this tropism ostensibly reflects the fundamental biology underlying tumor initiation, which becomes embedded in the genome of the resulting tumors. Fortunately, the process of RAS mutation tropism can be studied in mice exposed to the environmental carcinogen urethane. Such carcinogenesis both captures the moment of tumor initiation (the point of carcinogen exposure) and displays RAS mutation tropism (lung lesions are induced by a specific RAS mutation). By using ultra-sensitive sequencing to detect mutations immediately after urethane exposure in different mouse genetic backgrounds, we find that the mutagenic bias of this carcinogen influences the type of RAS mutations generated. However, biological selection for an optimal or ‘sweet spot’ of oncogenic signaling ultimately appears to dictate which mutations go on to initiate tumorigenesis. Analysis of sequence datasets from human lung cancer suggests a similar dominant role for biological selection in the RAS mutation tropism of this cancer. In summary, RAS mutation tropism appears to be a combination of mutational bias, and even more so, biological selection, providing critical insights into the origins of cancers like pancreatic. Citation Format: Christopher M Counter. RAS mutation tropism: insight into tumor initation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-07.

Mother and child environmental carcinogens exposure history: a tool to bridge environmental health and clinical sciences

Mother and child environmental carcinogens exposure history: a tool to bridge environmental health and clinical sciences

Overrepresentation of New Workers in Jobs with Multiple Carcinogen Exposures in Canada.

Background. In Canada, understanding the demographic and job-related factors influencing the prevalence of new workers and their exposure to potential carcinogens is crucial for improving workplace safety and guiding policy interventions. Methods. Logistic regression was performed on the 2017 Labour Force Survey (LFS), to estimate the likelihood of being a new worker based on age, industry, occupation, season, and immigration status. Participants were categorized by sector and occupation using the North American Industry Classification System (NAICS) 2017 Version 1.0 and National Occupational Classification (NOC) system 2016 Version 1.0. Finally, an exposures-per-worker metric was used to highlight the hazardous exposures new workers encounter in their jobs and industries. Results. Individuals younger than 25 years had 3.24 times the odds of being new workers compared to those in the 25-39 age group (adjusted odds ratios (OR) = 3.24, 95% confidence interval (95% CI) = 3.18, 3.31). Recent immigrants (less than 10 years in the country) were more likely to be new workers than those with Canadian citizenship (OR 1.36, 95% CI: 1.32, 1.41). The total workforce exposures-per-worker metric using CAREX Canada data was 0.56. By occupation, new workers were the most overrepresented in jobs in natural resources and agriculture (20.5% new workers), where they also experienced a high exposures-per-worker metric (1.57). Conclusions. Younger workers (under 25 years) and recent immigrants who had arrived 10 or fewer years prior were more likely to be new workers, and were overrepresented in jobs with more frequent hazardous exposures (Construction, Agriculture, and Trades).

Microdroplet‐assisted protein adduct formation and characterization by mass spectrometry

AbstractThere have been increasing interests in developing proteomics‐based protein adduct detection for monitoring carcinogen exposure risk. Generating adducted protein standards and characterizing the adduction sites by bottom‐up proteomics, however, require lengthy adduction and enzymatic digestion. Here we demonstrated that microdroplet can greatly accelerate the catechol estrogen adduction on hemoglobin (Hb) as well as one‐pot reaction of adduction and enzyme digestion in millisecond for bottom‐up characterization. The adducted Hb generated by microdroplet reaction was characterized to contain one to two catechol estrogens with the β chain of Hb (Hb‐β) by online in situ intact measurement of mass spectrometry. The adduction sites were further identified to be C112‐Hb‐β or C93‐Hb‐β by microdroplet one‐pot or two‐step adduction and digestion. These results were consistent with the intact measurement and also same as the bulk or endogenous reaction. This method is expected to be applicable to prepare protein standards adducted by other reactive oxidizing species to greatly save time and sample amount.

The Study of Exposure to Occupational Carcinogens in Iran: A Scoping Review

Background: Occupational exposure to carcinogens is a significant issue in occupational health and public welfare, with carcinogens encompassing a wide range of substances such as chemicals, metals, dust particles, and organic materials. This scoping review aims to identify, map, and summarize the existing literature on occupational carcinogen exposure in Iran across various industries and settings. It categorizes the types of carcinogens investigated, evaluates the methodologies employed for exposure assessment, and identifies research gaps and areas needing further exploration. Methods: A systematic search was conducted across multiple databases including PubMed, Scopus, Web of Science, Scientific Information Database (SID), and Magiran. A total of 715 articles were identified, with inclusion criteria focusing on studies conducted in Iran, directly related to occupational carcinogen exposure, and available in full text in English or Persian. Title and abstract screening, followed by full-text evaluation, was performed by two independent reviewers. Key data were extracted and thematically analyzed to synthesize findings. Results: The review highlights prevalent types of occupational carcinogens studied in Iran and the industries that have been the primary focus of research. It discusses the various methodological approaches used to assess and quantify exposure levels, identifies key findings related to exposure and associated health risks, and uncovers significant gaps in the literature. Conclusion: This scoping review provides a nuanced portrait of occupational carcinogen exposure in Iran, identifying critical research gaps and offering a foundation for future studies. By consolidating existing knowledge, it aims to contribute to the enhancement of occupational health and safety practices in Iran, guiding the development of targeted interventions and regulatory policies.

Oral squamous cell carcinoma: Effect of tobacco and alcohol on cancer location.

The underlying factors of oral squamous cell cancers (OSCC) have been elucidated, but studies have focused little on etiological differences in affected oral cavity sites. The aim of this retrospective study was to clarify the role of carcinogen exposure in OSCC of different oral cavity areas. A cross-sectional study of patients with primary OSCC was conducted retrospectively, based on patient records from Helsinki University Hospital, Finland, between January 2016 and December 2020. The patients' self-reported history of tobacco smoking and alcohol use was explained by tumor site, age, sex, tumor size, and lymph node status in a logistic regression model. The information on smoking and alcohol use was compiled from a patient background form. In 519 patients, tumors occurred most often in the tongue (51%), gingiva (21%), or floor of the mouth (FOM; 15%). FOM had 26-fold greater odds for a history of smoking and alcohol use than other tumor sites (OR=25.78; 95% CI: 8.02-82.95; p<0.001). Gingival and buccal sites were associated significantly less with smoking and alcohol use (OR=0.43, 95% CI: 0.28-0.67; p<0.001 and OR=0.47; 95% CI: 0.25-0.92; p<0.026, respectively). Patients of older age were less likely to have a history of smoking and alcohol use (AOR=0.95; 95% CI: 0.94-0.97; p<0.001) than younger patients. Tumor size (T3-4) and FOM increased the odds for history of smoking and alcohol use (AOR=1.73; 95% CI: 1.15-2.60; p=0.009 and AOR=26.15; 95% CI: 8.01-84.84; p<0.001, respectively). OSCC of oral cavity sites has notable differences in etiology. FOM seems to be related almost exclusively to conventional smoking and heavy alcohol use.

Prospective “common arm” comparison of US SWOG S0424 and Japanese JME studies in early-stage non-small cell lung cancer (NSCLC): Survival differences in the context of race, gender and smoking.

8036 Background: In NSCLC, overall frequencies and subtype distribution of EGFR and KRAS mutations differ significantly between Japanese and US patients. In many NSCLC clinical trials, Japanese patient outcomes appear superior to those in western populations. Since 2009, SWOG and Japanese investigators have used the “Common Arm” analytic method to interpret globally-conducted lung cancer clinical trials, providing a mechanism for direct patient-level comparisons in matching trials performed in the US and Japan. S0424 and the Japanese Molecular Epidemiology Study (JME) are large prospective molecular epidemiology studies conducted by SWOG and Japanese investigators and prospectively planned for “Common Arm” analysis. We investigated the effects of mutation distribution on overall survival in early stage NSCLC using data from JME and S0424. Methods: Both studies were designed to accrue representative proportions of ever-smokers (ES) versus never-smokers (NS) in male and female cohorts. Accrual to S0424 was completed in 2011 with 981 pts enrolled (Cheng et al JNCI 2018); JME was completed in 2012 with 957 pts (Kawaguchi et al JCO 2016). A comprehensive questionnaire was used to capture lifestyle, carcinogenic exposures, demographic and clinical data. Five years of follow-up was completed for each study. The association between baseline characteristics and mutation types were analyzed using multivariate logistic regression. The product-limit method was used to estimate overall survival and Cox regression models were fit to estimate hazard ratios. p-values were two-sided and p-values &lt; 0.05 were considered significant. Results: Evaluable pts: 876 for JME; 957 for S0424. Demographic distribution: S0424: 87% Caucasian, 5% Asian, 4% Black; JME: 100% Japanese. As expected, multivariate logistic models adjusting for age, smoking status, gender and BMI showed JME were more likely to have EGFR mutations (p &lt; 0.0001) and less likely to have KRAS mutations (p = 0.02). EGFR mutations were associated with never-smoking (p &lt; 0.0001) and female sex (p &lt; 0.0001); KRAS was associated with smoking (p &lt; 0.0001). Adjusting for age, smoking status and gender, overall survival was greater in JME patients (p &lt; 0.0001,HR = 0.49 (95% CI: 0.40-0.60)). In the subset of pts without an EGFR mutation, survival still favored the JME cohort (p &lt; 0.001, HR = 0.68 (0.53-0.86). Conclusions: Patient level comparison of US (SWOG) and Japanese (JME) patients with early stage NSCLC demonstrated longer survival in Japanese patients even after adjusting for EGFR mutation frequency. Identification of factors that contribute to this finding are under investigation. Female sex remained a risk factor for EGFR mutation-driven disease in both populations. This analysis forms the basis for applying this population-related model in other clinical settings.

Clinical and genetic characteristics of carriers of the TP53 c.541C > T, p.Arg181Cys pathogenic variant causing hereditary cancer in patients of Arab-Muslim descent.

TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 (TP53): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1-69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2-54)-19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers.

An Overview of Lung Cancer

Lung cancer is characterised by unregulated cell growth. The most prevalent cancer killer worldwide is lung cancer. Lung cancer diagnoses and deaths are rising worldwide. Males and females over 70 have the highest lung cancer risk. Since 50% of lung cancer patients acquire a new cough, smokers or former smokers should be concerned. Lung cancer's complex pathogenesis is yet unknown. Smoking and carcinogen exposure can cause lung epithelial dysplasia. The most prevalent lung cancer diagnosis methods are flexible bronchoscopy and transthoracic sampling. Immunotherapy helps the immune system recognise and fight cancer cells as foreign intruders. Radiation and four to six chemotherapy cycles are usual for mediastinal or hilar lymph node LS-SCLC.

Cancer control co-benefits of the climate-related provisions in the American Inflation Reduction Act.

The American Inflation Reduction Act (IRA) of 2022 contains climate-related provisions that may have noteworthy implications for cancer control and prevention. This commentary assesses the potential co-benefits of the IRA for cancer control efforts, specifically policies and programs to reduce carcinogen exposure via air quality monitoring and air pollution reduction. Allocations through the IRA for air quality improvement, paired with its environmental justice provisions, hold promise for advancing cancer prevention by targeting resources to communities most susceptible to environmental hazards. Moreover, climate resilience measures dictated by the IRA are crucial for oncology professionals grappling with the dual challenges of climate change and cancer care. Climate-driven extreme weather events can exacerbate carcinogen exposure and disrupt access to cancer care, underscoring the need for resilient health-care infrastructure. The IRA's provisions for clean energy incentives and infrastructure upgrades offer oncology care institutions opportunities to mitigate emissions and bolster resilience against climate-related disruptions, ultimately improving cancer outcomes. Climate-related initiatives funded by the IRA present a unique and timely avenue to advance equitable cancer control efforts. This commentary underscores the critical intersection between climate resilience policy and oncology care, highlighting the potential to promote a healthier and more resilient future for all.

A call for action: Formalin exposure and broader occupational hazards and assessing the risk of glioblastoma in clinician scientists

Physicians and surgeons have a threefold increased risk of glioblastoma compared with population controls. We discuss the potential role of dermatology neurotoxin and carcinogenic occupational exposure, particularly to formalin/formaldehyde; how to reduce those exposures; and the ethical imperative for dermatologists to protect themselves, their staff, and their patients.

Occupation and tongue cancer in Nordic countries.

Almost 200,000 tongue cancers were diagnosed worldwide in 2020. The aim of this study was to describe occupational risk variation in this malignancy. The data are based on the Nordic Occupational Cancer (NOCCA) study containing 14.9million people from the Nordic countries with 9020 tongue cancers diagnosed during 1961-2005. The standardized incidence ratio (SIR) of tongue cancer in each occupational category was calculated using national incidence rates as the reference. Among men, the incidence was statistically significantly elevated in waiters (SIR 4.36, 95% confidence interval (CI) 3.13--5.92), beverage workers (SIR 3.42, 95% CI 2.02-5.40), cooks and stewards (SIR 2.55, 95% CI 1.82-3.48), seamen (SIR 1.66, 95% CI 1.36-2.00), journalists (SIR 1.85, 95% CI 1.18-2.75), artistic workers (SIR 2.05, 95% CI 1.54-2.66), hairdressers (SIR 2.17, 95% CI 1.39-3.22), and economically inactive persons (SIR 1.57, 95% CI 1.42-1.73). Among women, the SIR was statistically significantly elevated only in waitresses (SIR 1.39, 95% CI 1.05-1.81). Statistically significant SIRs ≤ 0.63 were observed in male farmers, gardeners, forestry workers and teachers, and in female launderers. These findings may be related to consumption of alcohol and tobacco, but the effect of carcinogenic exposure from work cannot be excluded.

Geo-spatial epidemiology of gallbladder cancer in Bihar, India

Recently, a substantial increase in gallbladder cancer (GBC) cases has been reported in Bihar, India. The region's groundwater can naturally contain harmful concentrations of arsenic, which appears to be epidemiologically linked to the unusually high incidence. However, the root causes remain largely unexplored. Recent findings of uranium in the state's groundwater may also have associations. This study investigates the geo-spatial epidemiology of GBC in Bihar, India—with a focus on the correlation between environmental carcinogens, particularly arsenic and uranium in groundwater, and the incidence of GBC. Utilizing data from 8460 GBC patients' registration records over an 11-year period at a single health center, the research employs Semi-parametric Geographically Weighted Poisson Regression (S-GWPR) to account for non-stationarity associations and explores significant factors contributing to GBC prevalence at a subdistrict level. The S-GWPR model outperformed the standard Poisson regression model. The estimates suggest that arsenic and uranium concentrations in groundwater did not present significant associations; however, this could be due to the lower resolution of this data at the district level, necessitating higher resolution data for accurate estimates. Other socio-environmental factors included demonstrated significant regional heterogeneity in their association with GBC prevalence. Notably, each 1 % increase in the coverage of well- and canal-irrigated areas is associated with a maximum of 3.0 % and 5.2 % rise in the GBC incidence rate, respectively, likely attributable to carcinogen exposure from irrigation water. Moreover, distance to the health center and domestic electricity connections appear to influence the number of reported GBC cases. The latter suggests that access to electricity might have facilitated the use of groundwater pumps—increasing exposure to carcinogens. The results underscore the necessity for targeted health policies and interventions based on fine-resolution spatial analysis, as well as ongoing environmental monitoring and research to better understand the multifaceted risk factors contributing to GBC.

“Characterization of residential proximity to sources of environmental carcinogens in clusters of Acute Lymphoblastic Leukemia in San Luis Potosi, Mexico”

BackgroundAcute Lymphoblastic Leukemia (ALL) is the most prevalent neoplasia in children and teenagers in Mexico. Although epidemiological data supports that children's residence close to emissions from vehicular traffic or industrial processes increases the risk of ALL; and the IARC states that benzene, PAHs, and PM 2.5 are well-known environmental carcinogens, there is a gap in linking these carcinogenic hazards with the sources and their distribution from scenario perspective. AimTo identify ALL clusters in the population under 19 years of age and characterize the environment at the neighborhood level by integrating information on sources of carcinogenic exposure using spatial analysis techniques in the Metropolitan Area of San Luis Potosi, Mexico. MethodsUsing the Kernel Density test, we designed an ecological study to identify ALL clusters from incident cases in the population under 19 years of age. A multicriteria analysis was conducted to characterize the risk at the community level from carcinogenic sources. A hierarchical cluster analysis was performed to characterize risk at the individual level based on carcinogenic source count within 1 km for each ALL case. ResultsEight clusters of carcinogenic sources were located within the five identified ALL clusters. The multicriteria analysis showed high-risk areas (by density of carcinogenic source) within ALL clusters. ConclusionsThis study has a limited source and amount of available data on ALL cases, so selection bias is present as well as the inability to rule out residual confounding factors, since covariates were not included. However, in this study, children living in environments with high vehicular density, gas stations, brick kilns, incinerators, commercial establishments burning biomass, or near industrial zones may be at higher risk for ALL.

Different Oncogenes and Reproductive Histories Shape the Progression of Distinct Premalignant Clones in Multistage Mouse Breast Cancer Models

A remote carcinogen exposure can predispose to breast cancer onset decades later, suggesting carcinogen-induced mutations generate long-lived premalignant clones. How subsequent events influence the progression of specific premalignant clones remains poorly understood. Here, we generated multistage mouse models of mammary carcinogenesis by combining chemical carcinogen exposure (using 7,12-dimethylbenzanthracene, DMBA) with transgenes that enable inducible expression of one of two clinically relevant mammary oncogenes: c-MYC (MYC) or PIK3CAH1047R (PIK). In prior work, DMBA exposure generated mammary clones bearing signature HrasQ61L mutations, which only progressed to mammary cancer after inducible Wnt1 oncogene expression. Here, after an identical DMBA exposure, MYC versus PIK drove cancer progression from mammary clones bearing mutations in distinct Ras family paralogs. For example, MYC drove cancer progression from either Kras- or Nras-mutant clones, whereas PIK transformed Kras-mutant clones only. These Ras mutation patterns were maintained whether oncogenic transgenes were induced within days of DMBA exposure or months later. Completing a full-term pregnancy (parity) failed to protect against either MYC- or PIK-driven tumor progression. Instead, a postpartum increase in mammary tumor predisposition was observed in the context of PIK-driven progression. However, parity decreased the overall prevalence of tumors bearing Krasmut, and the magnitude of this decrease depended on both the number and timing of pregnancies. These multistage models may be useful for elucidating biological features of premalignant mammary neoplasia.

Human and Ecological Risk Assessment of Soil and Plants Metal Contamination in a Tropical Municipal Solid Waste Dumping Site

ABSTRACT The growing open waste dumpsite contributes to heavy metal leaching, harming public health and ecosystem services. Hence, the study’s novelty lies in its integrated assessment of heavy metal concentration (Cd, Cr, Cu, Fe, Ni, Pb, and Zn) in soil and plants, incorporating risk assessment using both single and combined indexes in the largest active waste dumpsite in Kelantan, Malaysia. Heavy metal in soil samples Cu (164.896 ± 205.096), Pb (122.177 ± 93.309), and Cr (32.74 ± 26.569) were recorded to exceed the standards, while in the studied plants (castor bean, papaya, pea eggplant, and water spinach), Pb concentrations in all plant parts have surpassed the Malaysia Food Regulation (1985) and FAO/WHO guidelines (2016). Translocation factor (TF) in Cu, Cr, and Pb in water spinach and Cr, Cu, and Cd in pea eggplant have TF > 1. Bioconcentration factor (BCF) was < 1 in pea eggplant and water spinach except for Pb in pea eggplant. Correlation analysis revealed a strong correlation between heavy metals in the soil while contrasts in the plants. The potential ecological risk index (PERI) reveals that the soil waste dumpsite is contaminated with heavy metals. The hazard index (HI) and lifetime cancer risk (LCR) values of heavy metals on the soil surface had negligible non-cancer risks posed to adults and indicate that soil ingestion and dermal absorption were the two primary carcinogenic risk exposure routes. These findings implied that Beris Lalang waste dumpsite is a potential source of toxic pollutants to the environment and the local population. It is recommended to conduct a comprehensive feasibility study and design an implementation plan for leachate treatment plant. Additionally, a comprehensive assessment of the specific contaminants present in the leachate and their potential impacts on the environment should be conducted to inform targeted and effective treatment strategies.

CGA mitigates HMGB1 mediated TLR4 activated hepatic cancer in urethane primed mice

BackgroundLiver cancer is fourth leading cause of cancer deaths worldwide. Urethane presents in herbicides, pesticides and food beverages as preservatives upregulate the expression of inflammatory cytokines in liver tissues for the genesis of cancer. It also naturally formed in fermented food products and distilled beverages. Study designBalb/c mice of approx same age and body weight were selected and divided into four groups G-I (PBS treated), G-II (urethane of 500 mg/kgb.w.), G-III (CGA of 50 mg/kg b.w.) and G-IV (urethane & CGA). Treatments were given on alternate day upto eight consecutive weeks and 3-12 month of latency period. Blood sample collected was used for counting of inflammatory immune cells by automated cell counter. Total RNA and protein samples isolated from dissected liver of sacrificed mice were used for molecular analysis at transcriptional and translational level. MethodsGene expression is assessed by RT-PCR at transcriptional level and by western blot at translational level. Immunological effects are evaluated by counting inflammatory immue cells and histopathology is done to examine hepatic tissues injury by carcinogen urethane. Hypothesis and purposeInflammatory cytokines create microenvironment for tumor initiation and development which is mediated through TLR-4 pathway activation via HMGB1 upon carcinogen exposure. Here aimed to find out the role of Chlorogenic acid (CGA) a phenolic compound naturally present in plants as anti-cancerous properties to prevent and cure cancer by acting upon HMGB1 & TLR4 pathway. ResultsAt transcriptional level up-regulated expression of HMGB1, TLR-4 pathway genes, pro-inflammatory cytokines IL-1β, IL-6, TNF-α and IL-18 in urethane treated mice is observed. Western blot results showed up-regulated expression of HMGB1 and NF-κB protein at translational level. CGA treated mice liver showed down-regulated expression of these inflammatory molecules. Increased number of inflammatory immune cells and presence of hepatic tissues injury in histopathological slides is observed in urethane treated mice that is mitigated by CGA. ConclusionCGA is an important anti-cancerous bioactive compound targets inflammatory cytokines and HMGB1 at molecular level to prevent, cure and mitigate liver cancer. Down regulated expression of HMGB1 and TLR-4 activation pathway in cancerous Balb/c mice liver proved its anti-cancerous properties to become a potential future drug.