Pollution of water sources, largely from wide-scale agricultural fertilizer use has resulted in nitrate and nitrite contamination of drinking water. The effects on human health of raised nitrate and ...nitrite levels in drinking water are currently unclear.
We conducted a systematic review of peer-reviewed literature on the association of nitrate and nitrite in drinking water with human health with a specific focus on cancer.
We searched eight databases from 1 January 1990 until 28 February 2021. Meta-analyses were conducted when studies had the same exposure metric and outcome.
Of 9835 studies identified in the literature search, we found 111 studies reporting health outcomes, 60 of which reported cancer outcomes (38 case-control studies; 12 cohort studies; 10 other study designs). Most studies were set in the USA (24), Europe (20) and Taiwan (14), with only 3 studies from low and middle-income countries. Nitrate exposure in water (59 studies) was more commonly investigated than nitrite exposure (4 studies). Colorectal (15 studies) and gastric (13 studies) cancers were the most reported. In meta-analyses (4 studies) we identified a positive association of nitrate exposure with gastric cancer, OR = 1.91 (95%CI = 1.09–3.33) per 10 mg/L increment in nitrate ion. We found no association of nitrate exposure with colorectal cancer (10 studies; OR = 1.02 95%CI = 0.96–1.08) or cancers at any other site.
We identified an association of nitrate in drinking water with gastric cancer but with no other cancer site. There is currently a paucity of robust studies from settings with high levels nitrate pollution in drinking water. Research into this area will be valuable to ascertain the true health burden of nitrate contamination of water and the need for public policies to protect human health.
•We reviewed 60 studies on the risks of developing 17cancer types associated with nitrate and nitrite in drinking water.•We found an association between nitrate exposure and the risk of developing gastric cancer, but not with other cancer types.•There are very few studies from low- and middle-income countries.•The available evidence is not conclusive, and study designs are highly heterogeneous.
Oxidative stress occurs whenever the release of reactive oxygen species (ROS) exceeds endogenous antioxidant capacity. In this paper, we review the specific role of several cardiovascular risk ...factors in promoting oxidative stress: diabetes, obesity, smoking, and excessive pollution. Specifically, the risk of developing heart failure is higher in patients with diabetes or obesity, even with optimal medical treatment, and the increased release of ROS from cardiac mitochondria and other sources likely contributes to the development of cardiac dysfunction in this setting. Here, we explore the role of different ROS sources arising in obesity and diabetes, and the effect of excessive ROS production on the development of cardiac lipotoxicity. In parallel, contaminants in the air that we breathe pose a significant threat to human health. This paper provides an overview of cigarette smoke and urban air pollution, considering how their composition and biological effects have detrimental effects on cardiovascular health.
Temperate reefs are at the forefront of warming-induced community alterations resulting from poleward range shifts. This tropicalisation is exemplified and amplified by tropical species' invasions of ...temperate herbivory functions. However, whether other temperate ecosystem functions are similarly invaded by tropical species, and by what drivers, remains unclear. We examine tropicalisation footprints in nine reef fish functional groups using trait-based analyses and biomass of 550 fish species across tropical to temperate gradients in Japan and Australia. We discover that functional niches in transitional communities are asynchronously invaded by tropical species, but with congruent invasion schedules for functional groups across the two hemispheres. These differences in functional group tropicalisation point to habitat availability as a key determinant of multi-species range shifts, as in the majority of functional groups tropical and temperate species share functional niche space in suitable habitat. Competition among species from different thermal guilds played little part in limiting tropicalisation, rather available functional space occupied by temperate species indicates that tropical species can invade. Characterising these drivers of reef tropicalisation is pivotal to understanding, predicting, and managing marine community transformation.
Epidemiological evidence suggests that fine particulate matter (PM2.5) in air pollution promotes the formation of deep venous thrombosis. However, no evidence is available on the effects of PM2.5 ...lead to disseminated intravascular coagulation (DIC). For the first time, this study explored the effects of PM2.5 on DIC via coagulation disorders in vivo. SD rats received intratracheal instillation of PM2.5 once every three days for one month. Doppler ultrasound showed that the pulmonary valve (PV) and aortic valve (AV) peak flow were decreased after exposure to PM2.5. Fibrin deposition and bleeding were observed in lung tissue and vascular endothelial injury was found after exposure to PM2.5. Expression of thrombomodulin (TM) in vessel was downregulated after PM2.5-treated, whereas the levels of proinflammatory factors and adhesion molecules (IL-6, IL-1β, CRP, ICAM-1 and VCAM-1) were markedly elevated after exposure to PM2.5. Tissue factor (TF) and the coagulation factor of FXa were increased, while vWF was significantly lowered induced by PM2.5. Thrombin-antithrombin complex (TAT) and fibrinolytic factor (t-PA) were elevated, while there was no significantly change in the expression of anticoagulant factors (TFPI and AT-III). To clarify the relationship between PM2.5 and DIC, we examined the general diagnostic indices of DIC: PM2.5 prolonged PT and increased the expression of D-dimer but decreased platelet count and fibrinogen. In addition, the gene levels of JAK1 and STAT3 showed an upward trend, whereas there was little effect on JAK2 expression. And inflammatory factors (IL-6, IL-1β and TNF) in blood vessels of were up-reglated in PM2.5-treated rats. In summary, our results found that PM2.5 could induce inflammatory response, vascular endothelial injury and prothrombotic state, eventually resulted in DIC. It will provide new evidence for a link between PM2.5 and cardiovascular disease.
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•PM2.5 triggered vascular endothelial injury via inflammatory response.•PM2.5 activated TF-dependent coagulation and caused coagulation dysfunction.•PM2.5 induced fibrin deposition and bleeding in pulmonary and resulted in DIC.
This phase III, randomized, open-label, multicenter study compared the overall survival associated with irinotecan plus gemcitabine (IRINOGEM) versus gemcitabine monotherapy (GEM) in patients with ...chemotherapy-naive, locally advanced or metastatic pancreatic cancer.
IRINOGEM patients received starting doses of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given weekly for 2 weeks every 3-week cycle. GEM patients received gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks (induction) and then weekly for 3 of 4 weeks. The primary end point of the trial was survival. Secondary end points included tumor response, time to tumor progression (TTP), changes in CA 19-9, and safety.
In each arm, 180 randomly assigned patients comprised the intent-to-treat population evaluated for efficacy; 173 IRINOGEM and 169 GEM patients were treated. Median survival times were 6.3 months for IRINOGEM (95% CI, 4.7 to 7.5 months) and 6.6 months for GEM (95% CI, 5.2 to 7.8 months; log-rank P =.789). Tumor response rates were 16.1% (95% CI, 11.1% to 22.3%) for IRINOGEM and 4.4% (95% CI, 1.9% to 8.6%) for GEM (chi2 P <.001). Median TTP was 3.5 months for IRINOGEM versus 3.0 months for GEM (log-rank P =.352). However, subset analyses in patients with locally advanced disease suggested a TTP advantage with IRINOGEM versus GEM (median, 7.7 v 3.9 months). CA 19-9 progression was positively correlated with tumor progression. The incidence of grade 3 diarrhea was higher in the IRINOGEM group but grade 3 to 4 hematologic toxicities and quality-of-life outcomes were similar.
IRINOGEM safely improved the tumor response rate compared with GEM but did not alter overall survival.
Myelodysplastic syndromes (MDS) are stem cell disorders that can progress to acute myeloid leukemia. Although hematopoietic cell transplantation can be curative, additional therapies are needed for a ...disease that disproportionally afflicts the elderly. We tested the ability of a CD16xCD33 BiKE to induce natural killer (NK) cell function in 67 MDS patients. Compared with age-matched normal controls, CD7+ lymphocytes, NK cells, and CD16 expression were markedly decreased in MDS patients. Despite this, reverse antibody-dependent cell-mediated cytotoxicity assays showed potent degranulation and cytokine production when resting MDS-NK cells were triggered with an agonistic CD16 monoclonal antibody. Blood and marrow MDS-NK cells treated with bispecific killer cell engager (BiKE) significantly enhanced degranulation and tumor necrosis factor-α and interferon-γ production against HL-60 and endogenous CD33+ MDS targets. MDS patients had a significantly increased proportion of immunosuppressive CD33+ myeloid-derived suppressor cells (MDSCs) that negatively correlated with MDS lymphocyte populations and CD16 loss on NK cells. Treatment with the CD16xCD33 BiKE successfully reversed MDSC immunosuppression of NK cells and induced MDSC target cell lysis. Lastly, the BiKE induced optimal MDS-NK cell function irrespective of disease stage. Our data suggest that the CD16xCD33 BiKE functions against both CD33+ MDS and MDSC targets and may be therapeutically beneficial for MDS patients.
•NK cells and their expression of FcRγIII (CD16) are decreased in MDS and inversely correlate with a substantial increase in MDSCs.•CD16xCD33 BiKE potently activates blood and marrow MDS-NK cells at all diseases stages to lyse CD33+ MDS and CD33+ MDSC targets.
Although genetic polymorphisms in the
gene are associated with a variety of diseases, the physiological function of LRRK2 remains poorly understood. In this study, we report a crucial role for LRRK2 ...in the activation of the NLRC4 inflammasome during host defense against
serovar Typhimurium infection.
deficiency reduced caspase-1 activation and IL-1β secretion in response to NLRC4 inflammasome activators in macrophages.
mice exhibited impaired clearance of pathogens after acute
Typhimurium infection. Mechanistically, LRRK2 formed a complex with NLRC4 in the macrophages, and the formation of the LRRK2-NLRC4 complex led to the phosphorylation of NLRC4 at Ser533. Importantly, the kinase activity of LRRK2 is required for optimal NLRC4 inflammasome activation. Collectively, our study reveals an important role for LRRK2 in the host defense by promoting NLRC4 inflammasome activation.
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