Evidence on Human Exposure to Pesticides and the Occurrence of Health Hazards in the Brazilian Population: A Systematic Review

Brazil is among the biggest pesticide consumers in the world, with its population severely exposed to tons of such substances, both because of environmental contamination and occupational use. The health consequences of pesticide exposure are well-documented, but still sparse regarding Brazilian population. This study systematically reviewed the Brazilian studies published that address the relationship between exposure to pesticides and health problems in the Brazilian population. Also, information about pesticide use in Brazil is provided. The included studies showed that exposure to pesticides has a relevant impact on the health of the Brazilian population, regardless of age and gender, and on workers in rural areas or not. Most poisoning events seem to result from the continuous use of pesticides, whether occupationally or environmentally, characterizing a public health problem. The major consequences reported in literature were damage to the central nervous system, cancer, deleterious effects on rural workers' health, intoxications, malformations, and endocrine changes. These findings point out the need to understand the impact of chronic exposure to pesticides on severely exposed people and highlight the importance of creating public policies to protect them and avoid disease occurrence.

High-dose drug heat map analysis for drug safety and efficacy in multi-spheroid brain normal cells and GBM patient-derived cells

To test the safety and efficacy of drugs via a high does drug heat map, a multi-spheroids array chip was developed by adopting a micropillar and microwell structure. In the chip, patient-derived cells were encapsulated in alginate and grown to maturity for more than 7 days to form cancer multi-spheroids. Multi-spheroids grown in conventional well plates require many cells and are easily damaged as a result of multiple pipetting during maintenance culture or experimental procedures. To address these issues, we applied a micropillar and microwell structure to the multi-spheroids array. Patient-derived cells from patients with Glioblastoma (GBM), the most common and lethal form of central nervous system cancer, were used to validate the array chip performance. After forming multi-spheroids with a diameter greater than 100μm in a 12×36 pillar array chip (25mm × 75mm), we tested 70 drug compounds (6 replicates) using a high-dose to determine safety and efficacy for drug candidates. Comparing the drug response of multi-spheroids derived from normal cells and cancer cells, we found that four compounds (Dacomitinib, Cediranib, LY2835219, BGJ398) did not show toxicity to astrocyte cell and were efficacious to patient-derived GBM cells.

Disability-Adjusted Life Years and Mortality Rate Attributed to Brain and Central Nervous System Cancer in the Middle East and North Africa Countries

<b><i>Background:</i></b> Primary brain tumors are among the main causes of death. This study aimed to determine the epidemiological features of the brain and central nervous system cancer in the Middle East and North Africa (MENA) region. <b><i>Methods:</i></b> In this study, data of the Global Burden of Disease (GBD) study were used to estimate the incidence, prevalence, deaths, disability-adjusted life years (DALYs), and mortality in 21 countries in the MENA region from 1990 to 2019 based on age and sex. The percentage of the changes of epidemiologic indicators was calculated between 1990 and 2019. <b><i>Results:</i></b> Palestine and Turkey had the highest rate of brain and central nervous system cancer in 2019. Saudi Arabia, Oman, Iraq, and Lebanon had the highest percentage of incidence rate changes from 1990 to 2019. The prevalence of brain and central nervous system cancer in the MENA region was increased from 7.51 (95% CI: 4.95–11.01) in 1990 to 16.45 (95% CI: 10.83–19.54) in 2019 (percentage of changes = 54.35%). The standardized age mortality rate in the MENA region was increased by 2.7% in 2019 compared to that in 1990. The rate of standardized age of DALY per 100,000 individuals in the MENA region decreased from 135.09 (95% CI: 92.57–199.92) in 1990 to 128.34 (95% CI: 87.81–151.3) in 2019. <b><i>Conclusion:</i></b> The incidence rate, prevalence, and standardized age mortality (per 100,000) had increased significantly in the MENA region in 2019 compared to those in 1990. Focusing on the diversity of the estimates of such indices in different countries of MENA can lead to the identification of important risk factors for brain cancer in future studies.

SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression

Atypical Teratoid Rhabdoid Tumor (AT/RT) is a rare pediatric central nervous system cancer often characterized by deletion or mutation of SMARCB1, a tumor suppressor gene. In this study, we found that SMARCB1 regulates Human Endogenous Retrovirus K (HERV-K, subtype HML-2) expression. HML-2 is a repetitive element scattered throughout the human genome, encoding several intact viral proteins that have been associated with stem cell maintenance and tumorigenesis. We found HML-2 env expression in both the intracellular and extracellular compartments in all AT/RT cell lines (n = 4) and in 95% of AT/RT patient tissues (n = 37) evaluated. SMARCB1 knock-down in neural stem cells (NSCs) led to an upregulation of HML-2 transcription. We found that SMARCB1 binds adjacent to the HML-2 promoter, repressing its transcription via chromatin immunoprecipitation; restoration of SMARCB1 expression in AT/RT cell lines significantly downregulated HML-2 expression. Further, targeted downregulation of HML-2 transcription via CRISPR-dCas9 coupled with suppressor proteins led to cellular dispersion, decreased proliferation, and cell death in vitro. HML-2 knock-down with shRNA, siRNA, and CRISPR-dCas9 significantly decreased Ras expression as measured by qRT-PCR, suggesting that HML-2 modulates MAPK/ERK signaling in AT/RT cells. Overexpression of NRAS was sufficient to restore cellular proliferation, and MYC, a transcription factor downstream of NRAS, was bound to the HERV-K LTR significantly more in the absence of SMARCB1 expression in AT/RT cells. We show a mechanism by which these undifferentiated tumors remain pluripotent, and we demonstrate that their formation is aided by aberrant HML-2 activation, which is dependent on SMARCB1 and its interaction with MYC.

High-dose drug heat map based on organoid array chip for drug selection with high safety and efficacy

An organoid array chip was developed by adopting a micropillar and microwell structure to test safety and efficacy of drugs using high dose drug heat map. In the chip, we encapsulated patient-derived cells in alginate and grow them to maturity for more than 7 days to form cancer organoids. When screening drug compounds in a high-density organoid array due to lack of number of patient-derived cells, changing media without damage of organoids is a very tedious and difficult process. Organoids grown in conventional well plates needed too many cells and were also easily damaged due to multiple pipetting during maintenance culture or during experimental procedures. To solve those problem, we applied a micropillar and microwell structure to the organoid array. We used patient-derived cells from patients with Glioblastoma multiforme (GBM), the most common and lethal form of central nervous system cancer, to validate the array chip performance. After forming more than 100µm-diameter organoids in 12 [[EQUATION]] 36 pillar array chip (25mm [[EQUATION]] 75mm), we tested 70 drug compounds (6 replicates) with high high-dose to find out high safety and efficacy drug candidates. Comparing the drug response of organoids derived from normal cells and cancer cells, we identified four compounds (Dacomitinib, Cediranib, Ly2835219, BGJ398) as drug candidates without toxicity to GBM cells.