Eradication of leukemia stem cells (LSCs) is the ultimate goal of treating acute myeloid leukemia (AML). We recently showed that the combined loss of Runx1/Cbfb inhibited the development of ...MLL-AF9-induced AML. However, c-Kit
/Gr-1
cells remained viable in Runx1/Cbfb-deleted cells, indicating that suppressing RUNX activity may not eradicate the most immature LSCs. In this study, we found upregulation of several hemostasis-related genes, including the thrombin-activatable receptor PAR-1 (protease-activated receptor-1), in Runx1/Cbfb-deleted MLL-AF9 cells. Similar to the effect of Runx1/Cbfb deletion, PAR-1 overexpression induced CDKN1A/p21 expression and attenuated proliferation in MLL-AF9 cells. To our surprise, PAR-1 deficiency also prevented leukemia development induced by a small number of MLL-AF9 leukemia stem cells (LSCs) in vivo. PAR-1 deficiency also reduced leukemogenicity of AML1-ETO-induced leukemia. Re-expression of PAR-1 in PAR-1-deficient cells combined with a limiting-dilution transplantation assay demonstrated the cell-dose-dependent role of PAR-1 in MLL-AF9 leukemia: PAR-1 inhibited rapid leukemic proliferation when there were a large number of LSCs, while a small number of LSCs required PAR-1 for their efficient growth. Mechanistically, PAR-1 increased the adherence properties of MLL-AF9 cells and promoted their engraftment to bone marrow. Taken together, these data revealed a multifaceted role for PAR-1 in leukemogenesis, and highlight this receptor as a potential target to eradicate primitive LSCs in AML.
We collected surface sediment samples from 174 locations in India, Indonesia, Malaysia, Thailand, Vietnam, Cambodia, Laos, and the Philippines and analyzed them for polycyclic aromatic hydrocarbons ...(PAHs) and hopanes. PAHs were widely distributed in the sediments, with comparatively higher concentrations in urban areas (∑PAHs: ∼1000 to ∼100
000
ng/g-dry) than in rural areas (∼10 to ∼100
g-dry), indicating large sources of PAHs in urban areas. To distinguish petrogenic and pyrogenic sources of PAHs, we calculated the ratios of alkyl PAHs to parent PAHs: methylphenanthrenes to phenanthrene (MP/P), methylpyrenes
+
methylfluoranthenes to pyrene
+
fluoranthene (MPy/Py), and methylchrysenes
+
methylbenz
aanthracenes to chrysene
+
benz
aanthracene (MC/C). Analysis of source materials (crude oil, automobile exhaust, and coal and wood combustion products) gave thresholds of MP/P
=
0.4, MPy/Py
=
0.5, and MC/C
=
1.0 for exclusive combustion origin. All the combustion product samples had the ratios of alkyl PAHs to parent PAHs below these threshold values. Contributions of petrogenic and pyrogenic sources to the sedimentary PAHs were uneven among the homologs: the phenanthrene series had a greater petrogenic contribution, whereas the chrysene series had a greater pyrogenic contribution. All the Indian sediments showed a strong pyrogenic signature with MP/P
≈
0.5, MPy/Py
≈
0.1, and MC/C
≈
0.2, together with depletion of hopanes indicating intensive inputs of combustion products of coal and/or wood, probably due to the heavy dependence on these fuels as sources of energy. In contrast, sedimentary PAHs from all other tropical Asian cities were abundant in alkylated PAHs with MP/P
≈
1–4, MPy/Py
≈
0.3–1, and MC/C
≈
0.2–1.0, suggesting a ubiquitous input of petrogenic PAHs. Petrogenic contributions to PAH homologs varied among the countries: largest in Malaysia whereas inferior in Laos. The higher abundance of alkylated PAHs together with constant hopane profiles suggests widespread inputs of automobile-derived petrogenic PAHs to Asian waters.
Hemophagocytic lymphohistiocytosis (HLH) is characterized by dysregulated immune activation. Primary HLH involves hereditary deficits in cytotoxic lymphocytes while secondary HLH is triggered by ...extrinsic factors. The HLH‐2004 criteria are widely used for clinical diagnosis, yet their specificity for HLH or their ability to differentiate primary from secondary disease is unclear, potentially leading to inappropriate treatment. We describe several cases where fulfillment of HLH‐2004 criteria obscured the diagnoses of underlying malignancies and delayed curative management. These issues are remedied without waiting for genetic testing results through an alternative diagnostic approach using flow cytometry–based immunologic assays and a thorough investigation for malignancy.
Samples of polyethylene pellets were collected at 30 beaches from 17 countries and analyzed for organochlorine compounds. PCB concentrations in the pellets were highest on US coasts, followed by ...western Europe and Japan, and were lower in tropical Asia, southern Africa and Australia. This spatial pattern reflected regional differences in the usage of PCBs and was positively correlated with data from Mussel Watch, another monitoring approach. DDTs showed high concentrations on the US west coast and in Vietnam. In Vietnam, DDT was predominant over its metabolites (DDE and DDD), suggesting the principal source may be current usage of the pesticide for malaria control. High concentrations of pesticide HCHs were detected in the pellets from southern Africa, suggesting current usage of the pesticides in southern Africa. This study demonstrates the utility and feasibility of the International Pellet Watch approach to monitor POPs at a global scale.
Lead (Pb) and cadmium (Cd) are toxic metals that exist ubiquitously in the environment. Children in polluted areas are particularly vulnerable to metal exposure, where clinical signs and symptoms ...could be nonspecific. Absorbed metals are excreted primarily in urine and reflect exposure from all sources. We analyzed Pb and Cd concentrations in blood, feces and urine of children from polluted townships near a lead-zinc mine in Kabwe, Zambia, to determine concurrent childhood exposure to the metals. Moreover, the study determined the Pb and Cd relationships among urine, feces and blood as well as accessed the potential of urine and fecal analysis for biomonitoring of Pb and Cd exposure in children. Fecal Pb (up to 2252 mg/kg, dry weight) and urine Pb (up to 2914 μg/L) were extremely high. Concentrations of Cd in blood (Cd-B) of up to 7.7 μg/L, fecal (up to 4.49 mg/kg, dry weight) and urine (up to 18.1 μg/L) samples were elevated. metal levels were higher in younger children (0–3 years old) than older children (4–7). Positive correlations were recorded for Pb and Cd among blood, urine and fecal samples whereas negative correlations were recorded with age. These findings indicate children are exposed to both metals at their current home environment. Moreover, urine and feces could be useful for biomonitoring of metals due to their strong relationships with blood levels. There is need to conduct a clinical evaluation of the affected children to fully appreciate the health impact of these metal exposure.
•We measured lead and cadmium excretion levels in children near a Pb-Zn mine in Zambia.•Fecal and urine Pb levels up to 2252 mg/kg and 2914 μg/L, respectively, were very high.•Cd in fecal (up to 4.49 mg/kg) and urine (up to 18.1 μg/L) samples were elevated.•Positive correlations were observed between fecal and urinary levels of Pb and Cd.•Children living near the Pb-Zn mine are at serious risks of Pb and Cd poisoning.
Organochlorine pesticides such as dichlorodiphenyltrichloroethane (DDT) have been used in agriculture and for disease control purposes over many decades. Reports suggest that DDT exposure may result ...in a number of adverse effects in humans. In the KwaZulu-Natal Province of South Africa, DDT is sprayed annually in homes (indoor residual spraying) to control the mosquito vector of malaria. In the northern part of the Province, samples of free-range chicken meat (n = 48) and eggs (n = 13), and commercially produced chicken meat (n = 6) and eggs (n = 11), were collected and analysed. Of the free-range chicken meat samples, 94% (45/48) contained DDTs (ΣDDTs median 6.1 ng/g wet weight ww, maximum 79.1 ng/g ww). Chicken egg contents were also contaminated (ΣDDTs in free-range eggs median 9544 ng/g ww, maximum 96.666 ng/g ww; and in commercial eggs median 1.3 ng/g ww, maximum 4.6 ng/g ww). The predominant DDT congener detected was p,pʹ-DDE in both free-range meat (>63%) and eggs (>66%), followed by p,pʹ-DDT and then p,pʹ-DDD. Based on estimated daily intake values, calculated human risk ratio (carcinogenic) values were >1 for DDTs detected in both free-range chicken products. Consumption of free-range eggs poses a particularly high health risk.
Food consumption is an important route of human exposure to organochlorine pesticides (OCPs). In order to assess the potential human health risks associated with OCPs, edible cattle tissues (liver, ...kidney and tongue) were collected from three slaughter houses in Mansoura, Zagazig and Ismailia cities, Egypt. Levels of 22 OCPs such as hexachlorocyclohexanes (HCHs), dichlorodiphenyltrichloroethanes (DDTs), aldrin, dieldrin and endrin (Drins), chlordanes (CHLs), heptachlors (HPTs) and hexachlorobenzene (HCB) residues were investigated. Among the investigated OCPs, HCHs represented the most dominant group with high proportions of γ−HCH isomer (53–91% of total HCHs). Mansoura city had the highest OCPs contamination load ranged from 0.1 to 2827 ng g−1 lw (lipid weight). Surprisingly, tongue samples collected from Mansoura showed the highest concentration of HCHs (448 ng g−1 lw) in comparison to liver (152 ng g−1 lw) and kidney (266 ng g−1 lw). Generally, contamination pattern of OCPs was in the order of HCHs > Drins > CHLs > DDTs ≅ HCB and HPTs. Estimated daily intakes (EDIs) through dietary consumption of cattle tissues were lower than the recommended acceptable daily intakes (ADIs) established by FAO/WHO. However, the hazard ratios (HRs) based on cancer risk were greater than 1.0 for HCHs based on the average and 95th centile concentrations, indicating carcinogenic effects to consumers through cattle tissues consumption.
•We measured OCPs in edible cattle tissues from Egypt.•HCHs, DDTs, Drins, chlordanes, heptachlors, and HCB were investigated.•HCHs were the predominant contaminant.•EDIs of OCPs were significantly lower than ADIs.•Hazard ratios of HCHs showed a potential health concern.
The objective of this study was to identify potential mRNA expression changes in chicken livers associated with environmental exposure to dichloro-diphenyl-trichloroethane (DDT) and its metabolites ...(DDTs). In particular, we focused on genes relating to the immune system and metabolism. We analyzed liver samples from free-ranging chickens in KwaZulu-Natal, South Africa, for contamination by DDTs. This area predominantly uses DDT in its malaria control program, and homes are sprayed annually with the pesticide. Genes relating to the immune system and metabolism were selected as potential genetic biomarkers that could be linked to higher contamination with DDTs. RT-qPCR analysis on 39 samples showed strong correlations between DDTs contamination and mRNA expression for the following genes: AvBD1, AvBD2, AvBD6 and AvBD7 (down-regulated), and CYP17, ELOVL2 and SQLE (up-regulated). This study shows for the first time interesting and significant correlations between genetic material collected from environmentally-exposed chickens and mRNA expression of several genes involved in immunity and metabolism. These findings show the usefulness of analysis on field samples from a region with high levels of environmental contamination in detecting potential biomarkers of exposure. In particular, we observed clear effects from DDT contamination on mRNA expression of genes involved in immune suppression, endocrine-disrupting effects, and lipid dysregulation. These results are of interest in guiding future studies to further elucidate the pathways involved in and clinical importance of toxicity associated with DDT exposure from contaminated environments, to ascertain the health risk to livestock and any subsequent risks to food security for people.
Nairobi city in Kenya produces 2000 tons/day of garbage, and most of it is dumped onto the Dandora dumping site, home to a quarter-million residents. This study was conducted (1) to assess the ...contamination levels of nine metals and a metalloid (arsenic) in the blood of pigs, goats, sheep and cattle from Dandora, and (2) to identify a possible source of lead (Pb) pollution. Cadmium (Cd, 0.17–4.35 μg/kg, dry-wt) and Pb (90–2710 μg/kg) levels in blood were generally high, suggesting human exposure to Cd through livestock consumption and Pb poisoning among pigs (2600 μg/kg) and cattle (354 μg/kg). Results of Pb isotope ratios indicated that the major exposure route might differ among species. Our results also suggested a possibility that the residents in Dandora have been exposed to the metals through livestock consumption.
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•Metals extent in blood of livestock were examined.•Dandora dumping site, Kenya is study site.•Concentrations of Cd and Pb were high in the blood of livestock.•Pb isotope ratios indicated that major exposure route might differ among species.
Metal extent and stable Pb isotope ratio in livestock from Dandora, Kenya were examined.
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