Transcriptomic data of BT549 triple negative breast cancer cells treated with 20 µM NU7441, a DNA-dependent kinase inhibitor.

DNA-dependent protein kinase catalytic subunit (DNA-PK) is a multifunctional serine­threonine protein kinase that plays roles in non-homologous end joining of DNA repair in cells. NU7441 is a specific DNA-PKcs inhibitor. We investigated the effects of NU7441 on the transcriptome of BT549 triple negative breast cancer cells. Total RNA extracted from NU7441-treated or control BT549 cells was processed for preparation of sequencing libraries. Assessment of read quality was performed using fastqc tool. Trimming and filtering low-quality reads were performed using fastp. Reads were aligned by hisat2. SAM files were converted to BAM files using Samtools. The gene differential expression analysis, Gene Ontology (GO) analysis and KEGG pathway analysis were performed. After NU7441 treatment, total number of 2045 differential genes were selected according to |log2(FoldChange)| >= 1 & padj<= 0.05, among which 1365 genes were down-regulated and 680 genes were up-regulated. The differential expression genes in pattern recognition receptors (PRRs) immune responses signals, including NOD-like receptor signaling, Toll-like receptor signaling, RIG-I-like receptor signaling and cytosolic DNA-sensing pathways were noted in this paper.

Identification of the KIF18A alpha-4 helix as a therapeutic target for chromosomally unstable tumor cells.

Background: The mitotic kinesin, KIF18A, is required for proliferation of cancer cells that exhibit chromosome instability (CIN), implicating it as a promising target for treatment of a subset of aggressive tumor types. Determining regions of the KIF18A protein to target for inhibition will be important for the design and optimization of effective small molecule inhibitors. Methods: In this study, we used cultured cell models to investigate the effects of mutating S284 within the alpha-4 helix of KIF18A, which was previously identified as a phosphorylated residue. Results: Mutations in S284 cause relocalization of KIF18A from the plus-ends of spindle microtubules to the spindle poles. Furthermore, KIF18A S284 mutants display loss of KIF18A function and fail to support proliferation in CIN tumor cells. Interestingly, similar effects on KIF18A localization and function were seen after treatment of CIN cells with KIF18A inhibitory compounds that are predicted to interact with residues within the alpha-4 helix. Conclusion: These data implicate the KIF18A alpha-4 helix as an effective target for inhibition and demonstrate that small molecules targeting KIF18A selectively limit CIN tumor cell proliferation and result in phenotypically similar effects on mitosis at the single cell level compared to genetic perturbations.

New insight into PAH4 induced hepatotoxicity and the dose-response assessment in rats model.

PAH4 (sum of benzo[a]pyrene, chrysene, benz[a]anthracene and benzo[b]fluoranthene) has been proposed as better marker than benzo[a]pyrene to assess total PAHs exposure in foodstuffs. However, the toxicological behaviors of PAH4 combined exposure remain unclear. This study aimed to investigate PAH4 toxicity effects with non-targeted metabolomics approach and evaluate the external and internal dose-response relationships based on benchmark dose (BMD) analysis. Male Sprague-Dawley rats were treated by gavage with vehicle (corn oil) or four doses of PAH4 (10, 50, 250, 1000 µg/kg·bw) for consecutive 30 days. After the final dose, the liver, blood and urine samples of rats were subsequently collected for testing. The concentrations of urinary mono-hydroxylated PAHs metabolites (OH-PAHs) including 3-hydroxybenzo[a]pyrene (3-OHB[a]P), 3-hydroxychrysene (3-OHCHR) and 3-hydroxybenz[a]anthracene (3-OHB[a]A) were determined to reflect internal PAH4 exposure. Our results showed PAH4 exposure increased relative liver weight and serum aspartate aminotransferase (AST) activity and caused hepatocyte swelling and degeneration, implying hepatotoxicity induced by PAH4. Serum metabolomics suggested PAH4 exposure perturbed lipid metabolism through upregulating the expression of glycerolipids metabolites, which was evidenced by markedly increased serum triglyceride (TG) level and hepatic TG content. Additionally, urinary OH-PAHs concentrations presented strong positive correlations with the external dose, indicating they were able to reflect PAH4 exposure. Furthermore, PAH4 exposure led to a dose-response increase of hepatic TG content, based on which the 95% lower confidence value of BMDs for external and internal doses were estimated as 5.45 µg/kg·bw and 0.11 µmol/mol·Cr, respectively. In conclusion, this study suggested PAH4 exposure could induce hepatotoxicity and lipid metabolism disorder, evaluating the involved dose-response relationships and providing a basis for the risk assessment of PAHs.

Identification of the KIF18A alpha-4 helix as a therapeutic target for chromosomally unstable tumor cells.

The mitotic kinesin, KIF18A, is required for proliferation of cancer cells that exhibit chromosome instability (CIN), implicating it as a promising target for treatment of a subset of aggressive tumor types. Determining regions of the KIF18A protein to target for inhibition will be important for the design and optimization of effective small molecule inhibitors. In this study, we investigated the effects of mutating S284 within the alpha-4 helix of KIF18A, which was previously identified as a phosphorylated residue. Mutations in S284 cause relocalization of KIF18A from the plus-ends of spindle microtubules to the spindle poles. Furthermore, KIF18A S284 mutants display loss of KIF18A function and fail to support proliferation in CIN tumor cells. Interestingly, similar effects on KIF18A localization and function were seen after treatment of CIN cells with KIF18A inhibitory compounds that are predicted to interact with residues within the alpha-4 helix. These data implicate the KIF18A alpha-4 helix as an effective target for inhibition and demonstrate that small molecules targeting KIF18A selectively limit CIN tumor cell proliferation and result in phenotypically similar effects on mitosis at the single cell level compared to genetic perturbations.

Ultra-Processed Food Consumption and Risk of Overweight or Obesity in Chinese Adults: Chinese Food Consumption Survey 2017-2020.

Overweight and obesity have increased rapidly in the past few decades in China, and less research has focused on the association between the consumption of ultra-processed foods (UPFs) and overweight or obesity in Chinese adults. The objective of this study was to determine the relationship of UPF consumption with the risk of overweight or obesity in Chinese adults. Residents aged 18 years and above who participated in the nationally representative survey Chinese Food Consumption Survey in 2017-2020 were included in this study. Dietary intake data were collected via non-consecutive three-day 24 h dietary recalls and weighing household foods and condiments. According to the NOVA food classification system, UPFs were classified depending on the purpose and extent of food processing. Multiple logistic regression and multivariate-adjusted restricted cubic spline (RCS) regressions were performed to estimate the association between UPF consumption (categorized into quartiles: quartile 1 (Q1), quartile 2 (Q2), quartile 3 (Q3), and quartile 4 (Q4)) and risk of overweight or obesity. A total of 38,658 adults aged 18 years and above participated in the present study. The prevalence of overweight and obesity in adults was 33.0% (95% CI: 32.91-33.10) and 9.6% (95% CI 9.55-9.67), respectively. After a multivariable adjustment, the risk of overweight or obesity was increased by 10% in Q3 (OR: 1.10, 95% CI: 1.04-1.17) compared to Q1 as a reference. Women (OR: 1.10, 95% CI: 1.01-1.20) and adults living in small and medium-sized cities (OR: 1.13, 95% CI: 1.01-1.26) with higher UPF consumption had higher odds of overweight or obesity. Nevertheless, the effect of higher UPF consumption on the risk of overweight or obesity was relatively weak for overall adults in China. The top three categories of subgroups consumption of UPFs were 1: sugar-sweetened beverages; 2: sauces, cheeses, spreads, and gravies; and 3: ultra-processed breads and breakfast cereals. These findings provide evidence that higher UPF consumption was positively associated with overweight or obesity, which was defined based on Chinese criteria among women and adults living in small and medium-sized cities in China. Further studies, such as intervention trials, are needed to identify the mechanism of correlation between the consumption of UPFs and health-related outcomes in Chinese adults. From a public health perspective, with the prevalence of overweight and obesity growing and the increase in UPF consumption in Chinese adults, it is necessary to promote healthy food intake and a balanced diet through active nutritional education actions for overweight and obesity prevention and control.

[Comparative study on the essential composition content of commercial follow-up formula for young children with the requirements in the new national food safety standard in China from 2017 to 2022].

OBJECTIVE: To understand the distribution of the essential composition content of commercial follow-up formula for young children in China, to analyze the differences with the new requirements of national food safety standard, and to promote the implementation of the new national standard(GB 10767-2021). METHODS: The label information on the total of 483 follow-up formula for young children permitted from January 2017 to June 2022 were collected and recorded, the distribution of essential compositions were analyzed and compared with the new national food safety standard. RESULTS: Compared with GB 10767-2010, 23 essential compositions were revised in the new national standard, 2 new essential compositions, α-linolenic acid and carbohydrates, were required, and 8 minimum requirements and 4 maximum requirements were revised, 16 new maximum requirements were developed. The whole change of the new standard was major. Comparing with GB 10767-2021, there were 8 essential compositions in commercial products with 100% compliance rate and 9 with more than 95% compliance rate, the discordance rate of pantothenic acid, folic acid, vitamin C and Vitamin D was more than 20%, Vitamin D has the highest discordance rate 97.10%. CONCLUSION: Although the revision of the essential composition requirements in the new national standard is major, the compliance rate of almost essential compositions is high. A few of individual essential compositions in some commercial products cannot meet the new standards requirements, the main reason is those can not reach the increased new minimum requirements, especially on vitamin D.

Metabolism and elimination kinetics of mono-hydroxylated PAHs metabolites following single exposure to different combinations of PAH4 in rats.

The metabolism of polycyclic aromatic hydrocarbons (PAHs) and the elimination kinetics of their mono-hydroxylated metabolites (OH-PAHs) following single exposure to different combinations of four PAHs (PAH4) were studied. Male Sprague-Dawley rats were orally exposed to a single dose of benzo[a]pyrene (B[a]P) or PAH2 (B[a]P + chrysene), PAH3 (B[a]P + chrysene + benz[a]anthracene), and PAH4 (B[a]P + chrysene + B[a]A + benzo[b]fluoranthene) with each combination adjusted to the same dose of individual compound. OH-PAHs including 3-hydroxybenzo[a]pyrene, 3-hydroxychrysene, 3-hydroxybenz[a]anthracene, and 1-hydroxypyrene (1-OHP) were detected in serum and urine samples collected at six intervals over a 72-h period post-dosing. The hepatic mRNA levels of cytochrome P450 (CYPs) were determined to ascertain the expression induction of PAHs metabolic enzymes. Results showed OH-PAHs (except 1-OHP) peaked within 8 h in serum and were excreted from urine within 24-48 h. The serum and urinary concentration of 3-hydroxybenzo[a]pyrene was significantly increased after PAH4 exposure compared with other PAHs combinations. Inversely, urinary concentration of 3-hydroxychrysene was decreased after PAH4 exposure, and the kinetics of 3-hydroxybenz[a]anthracene or 1-OHP were not different depending on the PAHs combinations. Also, CYPs were markedly induced by PAHs. Notably, the induction levels of CYP1A1 and CYP1B1 were significantly higher after PAH4 exposure compared with B[a]P exposure. The results indicated the metabolism of B[a]P was accelerated after PAH4 exposure which might be partly due to the induction of CYPs. These results confirmed PAHs are rapidly metabolized and suggested potential interactions of PAHs may happen among PAH4 mixture.

Dietary Exposure Assessment of Rare Earth Elements in the Chinese Population.

Rare earth elements (REEs) are widely found in foods. A high intake of REEs may have associations with adverse effects on human health. This study aimed to investigate the concentrations of REEs in foods in China and to assess the risk of dietary REEs exposure in the Chinese population. The mean concentrations of the total REEs in 27,457 food samples from 11 food categories ranged from 0.04 to 1.41 mg/kg. The daily mean dietary exposure of the total REEs was 1.62 µg/kg BW in the general Chinese population and ranged from 1.61 to 2.80 µg/kg BW in different sex-age groups. The high consumer exposure (95th percentile, P95) was 4.83 µg/kg BW, 9.38% of the temporary ADI (tADI) of REEs (51.5 µg/kg BW). None of the P95 exposure exceeded the tADI in all of the sub-groups. Lanthanum, cerium, and yttrium accounted for approximately 63% of the total exposure of the 16 REEs. The hazard index of 16 REEs was far below 1. Therefore, the health risk of dietary REEs exposure in the general Chinese population was low. No cumulative risk was found for the 16 REEs in China. The results indicate there was no need to stipulate the limits of REEs in foods.

Catalytically inactive DNA ligase IV promotes DNA repair in living cells.

DNA double strand breaks (DSBs) are induced by external genotoxic agents (ionizing radiation or genotoxins) or by internal processes (recombination intermediates in lymphocytes or by replication errors). The DNA ends induced by these genotoxic processes are often not ligatable, requiring potentially mutagenic end-processing to render ends compatible for ligation by non-homologous end-joining (NHEJ). Using single molecule approaches, Loparo et al. propose that NHEJ fidelity can be maintained by restricting end-processing to a ligation competent short-range NHEJ complex that 'maximizes the fidelity of DNA repair'. These in vitro studies show that although this short-range NHEJ complex requires DNA ligase IV (Lig4), its catalytic activity is dispensable. Here using cellular models, we show that inactive Lig4 robustly promotes DNA repair in living cells. Compared to repair products from wild-type cells, those isolated from cells with inactive Lig4 show a somewhat increased fraction that utilize micro-homology (MH) at the joining site consistent with alternative end-joining (a-EJ). But unlike a-EJ in the absence of NHEJ, a large percentage of joints isolated from cells with inactive Lig4 occur with no MH - thus, clearly distinct from a-EJ. Finally, biochemical assays demonstrate that the inactive Lig4 complex promotes the activity of DNA ligase III (Lig3).

Phthalate acid esters and polycyclic aromatic hydrocarbons concentrations with their determining factors among Chinese pregnant women: A focus on dietary patterns.

BACKGROUND: Pregnant women are susceptible to adverse health effects associated with phthalate acid esters (PAEs) and polycyclic aromatic hydrocarbons (PAHs), and diet is a significant exposure source. Little is known about the contributions of dietary patterns during pregnancy to the exposure variability of these environmental contaminants. OBJECTIVES: To identify dietary patterns in relation to PAEs and PAHs exposure in the Chinese pregnant population. METHODS: Dietary data and urinary concentrations of environmental pollutants were obtained from 1190 pregnant women in the Tongji Birth Cohort (TJBC). PAEs and PAHs were measured in spot urine samples. Food intake was assessed using a food-frequency questionnaire. Dietary patterns were constructed by principal component analysis (PCA). Through PCA, we also extracted three chemical mixture scores that represent different co-exposure patterns of PAEs and PAHs. Multiple linear regression models were adopted to identify predictors of PAEs and PAHs exposure. RESULTS: Four dietary patterns were identified by PCA that explained 44.9 % of the total variance of food intake. We found egg-dairy products pattern, whole grain-tuber crop pattern, and meat-aquatic products pattern were positively associated with specific pollutants exposure. In contrast, fruit-nut-vegetable pattern was negatively correlated with PAEs and PAHs exposure. Every SD increase in this pattern score was associated with 14.36 % reduced mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) (95 % CI: -24.50 ~ -2.96, p-trend = 0.01), 10.86 % reduced 2-hydroxynaphthalene (2-OHNap) (95 % CI: -20.07 ~ -0.60, p-trend = 0.04), 19.35 % reduced 9-hydroxyphenanthrene (9-OHPhe) (95 % CI: -34.49 ~ -0.70, p-trend = 0.01), and 8.33 % reduced scores of PAHs group (95 % CI: -15.97 ~ -0.10, p-trend = 0.02). In addition, disposable tableware usage and passive smoking were suggested as potentially modifiable sources of PAEs and PAHs exposure, respectively. CONCLUSION: Adhering to egg-dairy products pattern, whole grain-tuber crop pattern, and meat-aquatic products pattern may be related to increased PAEs and PAHs exposure, while following fruit-nut-vegetable pattern seems to correlate with a lower burden of such exposure.

[Eating out of home of urban adults in eighteen provinces (autonomous regions, municipalities) of China in 2017].

OBJECTIVE: To analyze the eating out of home behavior of urban adults in China. METHODS: Samples were chosen from China Food Consumption Survey in 2017. A total of 17 234 participants aged 18 and above were included in the final analysis. The food frequency questionnaire were used to collect eating out of home status in the past week. χ~2 test was used to compare the difference in the rate of eating out of home and dining places among different groups. Non-parametric test was used to compare the differences in dining out times. RESULTS: The overall prevalence of eating out of home was 55.6% in urban adults aged in 2017. The average number of eating out of home was 2.8 times. The proportion of eating in hotels and restaurants was 36.0%. The proportion of eating in the canteen of school, workplace and other places was 19.8%. The rate of eating out of home and dining out times were higher among male, 18-44 years old, people with higher educational level and higher household income. The proportion of students eating in canteen was higher. The proportion of professional technicians and service staff eating in hotels and restaurants were higher. CONCLUSION: Eating out of home is more common among urban adults aged 18 and above in China. Young people aged 18-44 years old eat out more often in the past week. The proportion of people eating in hotels and restaurants is higher.

Perianal ulcerative tuberculosis: A case report.

Perianal tuberculosis (TB) is an extremely rare form of mycobacterial infection, in which the anal mucocutaneous junction becomes infected by autoinoculation from an active draining gastrointestinal tract infection. The case of a 73-year-old immunocompetent male patient, who came in with a refractory perianal ulcer is presented. The patient had no history of TB and his lab tests for TB were all negative. A chest X-ray showed streak and nodular opacities in both upper lungs. The ulcer was biopsied twice and a diagnosis of TB was finally rendered by histological examination with confirmatory Polymerase chain reaction (PCR). The lesion was finally cured by intensive anti-TB treatment. Perianal TB needs to be excluded in patients with a refractory perianal ulcer, including immunocompetent cases without TB history. Biopsies and microbiological tests should be performed for any suspicious lesion and repeated if there is high clinical concern. Consideration of differential diagnoses, especially inflammatory bowel disease, is essential. Early and sufficient antitubercular treatment should be initiated to minimize morbidity.

Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations.

ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.

Application of the maximum cumulative ratio (MCR) as a screening tool for the evaluation of multiple metal mixtures in shellfish in Chinese population.

The objective of this study was to investigate the potential effects from exposure to multiple metals, including cadmium (Cd), chromium (Cr), arsenic (As), mercury (Hg), nickel (Ni) and lead (Pb) that exist in shellfish in Chinese populations, and evaluate the impacts of cumulative exposures among individuals. A total 15,469 individual shellfish samples were analyzed following a protocol for elemental analysis. A total of 25,669 respondents were selected through stratified multi-stage cluster sampling from  31 survey sites in China. Individual shellfish consumption data and body weight were collected and analyzed with a 24-hour dietary recall method on three non-consecutive days. The consumers were divided into two groups: aged 2-12 years group and aged ≥13 years. Exposure levels were estimated based using a semi-probabilistic risk assessment method and cumulative exposures among individual persons using the maximum cumulative ratio (MCR) method. The mean, median and 95th percentile of all metals exposure for age 2-12 years group were higher than age ≥13 years group, but none exceeded the respective reference doses of the metals. The mean hazard indices (HI) of each metal in shellfish for both age groups were less than 1. The MCR values calculated among 1283 consumers ranged from 1.28 to 3.25 with the average MCR value was 2.22. There were 51 (3.98%) consumers in group I, 1186 (92.44%) consumers in group II, 26(2.03%) consumers in group III A, and 20 (1.56%) consumers in group III B. And cadmium (Cd) and lead (Pb) produced the HQMax that trigged cumulative exposures. It was concluded that heavy metals did not present a potential health risk to people solely through shellfish. The cumulative risks indicated that 7.56% of the surveyed consumers were of concern because of high HI of metals exposure, and Cd, Pb, and Ni made significant contributions to the potential risk.

Risk assessment of rare earth elements in fruits and vegetables from mining areas in China.

Assessment of contaminated food through the dietary intake is essential for human health. To investigate the health risk of rare earth element (REE) exposure to fruits and vegetables in mining areas in China, we collected 288 fruit samples and 942 vegetable samples from four representative mining points (Bayan Obo in Inner Mongolia, Weishan in Shandong, Maoming in Guangdong, Longnan in Jiangxi) and their control areas. The content of REEs was determined by inductively coupled plasma-mass spectrometry (ICP-MS). The total REEs in fruits from mining and control areas were 12.90 µg kg-1 and 11.89 µg kg-1, and in vegetables were 92.90 µg kg-1 and 62.38 µg kg-1, and the difference was statistically significant in vegetables (P = 0.048). The drupes had more REE concentration in fruits (68.41 µg kg-1, 16.90 µg kg-1 in mining and control areas, respectively) (P < 0.01), and the leafy vegetables had more REE concentration in vegetables (245.81 µg kg-1, 123.51 µg kg-1 in mining and control areas, respectively) (P < 0.01). With the enrichment of light rare earth elements (LREE), the REE distribution patterns coincided in mining and control areas and different types of fruits and vegetables. The health risk assessment indicated that the estimated daily intakes (0.02-0.06 µg kg-1 day-1, 0.53-1.22 µg kg-1 day-1 for fruits and vegetables, respectively) were lower than the allowable daily intake value (60.4 µg kg-1 day-1). In mining areas, REEs obtained from fruits and vegetables were insufficient to cause health damage to human beings. However, sustained exposure to low REEs, especially for children, still needs attention.

The contamination and estimation of dietary intake for perchlorate and chlorate in infant formulas in China.

The contents of perchlorate and chlorate were determined in a total of 278 samples of infant formulas marketed in China. The associated health risk via infant and young child formulas consumption for 0-36 month old children in China was also assessed. The contents of perchlorate and chlorate were measured by a validated method with LC-MS and the limit of detection (LOD) was 1.5 µg kg-1 and 3.0 µg kg-1 for perchlorate and chlorate, respectively. Perchlorate and chlorate were detected in about 85.8% (median 6.92 µg kg-1, maximum 74.20 µg kg-1) and 99.3% (median 52.80 µg kg-1, maximum 2780 µg/kg) of the samples. The exposures of infant and young children to perchlorate from formulas were lower than the provisional maximum tolerable daily intake (PMTDI, 0.7 µg/kg bw/day), which was established by U.S. Environmental Protection Agency (EPA). The European Food Safety Authority (EFSA) in 2015 also proposed a tolerable daily intake (TDI) of 3 µg/kg bw/day for chlorate based on the mean and average concentrations. Only for infants 0-6 month at the 95th percentile did exposures exceed the TDI of 3 µg/day for chlorate. Therefore, the safety of infant and young child formulas is excellent. To our knowledge, this is the first report to assess the exposure of infant and young child formulas in China to perchlorate and chlorate.

Toxic effects of atrazine on immune function in BALB/c mice.

This study was aimed to evaluate the toxic effects of different concentrations (23, 90, 360 mg/kg BW) of atrazine (ATZ) on immune function in BALB/c mice. Some parameters of general immunotoxicity, humoral immunity, cellular immunity, and non-specific immunity were tested. The studies showed that the high-dose ATZ induced a significant reduction in the final body weight of mice, the absolute and relative weights of spleen, the counts of white blood cell (WBC), lymphocyte (LYM), monocyte (MON), and the number of splenocyte. An increase in the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and cholesterol (CHO) in the high-dose ATZ group was observed. Pathological examination showed that the medium- and high-doses of ATZ caused atrophy and destruction of thymus, spleen, and hepatorenal toxicity. The serum interleukin-5(IL-5) level of mice and the number of plaque-forming cell (PFC) in spleen cells in the high-dose ATZ group decreased significantly while there was a significant increase of the serum immunoglobulin G (IgG) in the high-dose ATZ group when compared to the negative control group. In the high-dose ATZ group, the proliferation ability of T and B lymphocytes as well as the delayed-type hypersensitivity (DTH) response were significantly decreased. The low-dose ATZ (23 mg/kg BW) caused a significant decrease in the number of WBC and neutrophil (NEUT), as well as the proportion of polychromatic and normoblast. In summary, we thought the low-dose ATZ has a slight effect on the immune system; it can be preliminarily concluded that the lowest observed adverse effect level (LOAEL) of atrazine is 23 mg/kg BW in mice. Atrazine can cause immunotoxicity mainly through cellular and humoral immunity pathways.

Discovery and Evaluation of Pyrazolo[3,4-d]pyridazinone as a Potent and Orally Active Irreversible BTK Inhibitor.

The identification and lead optimization of a series of pyrazolo[3,4-d]pyridazinone derivatives are described as a novel class of potent irreversible BTK inhibitors, resulting in the discovery of compound 8. Compound 8 exhibited high potency against BTK kinase and acceptable PK profile. Furthermore, compound 8 demonstrated significant in vivo efficacy in a mouse-collagen-induced arthritis (CIA) model.

[Contamination of zearalenone and its dietary exposure assessment in coix seed in Shanghai].

OBJECTIVE: To analyze the zearalenone(ZEN) level in coix seed, and assess the risk of dietary exposure of ZEN in coix seed in Shanghai. METHODS: The ZEN contents of 147 coix seed samples collected in Shanghai were determined. The consumption data of 730 adults in Shanghai was collected by questionnaire survey with random sampling method. Dietary intake of ZEN from coix seed in Shanghai was simulated by Monte Carlo simulation. RESULTS: The total detection rate of ZEN in coix seed was 69. 39 %(102/147), with the content range of <1. 0-9361 µg/kg and the average value of 327. 7 µg/kg. The average exposure level of populations to ZEN in coix seed was 0. 0216 µg/(kg·d), which was much lower than the tolerable daily intake(TDI). The high exposure level(P95) of populations to ZEN in coix seed was 0. 0609 µg/(kg·d), which accounted for about 24% of TDI. There were about 1. 1% people with the dietary exposure to ZEN exceeding TDI on the basis of the ZEN contents in coix seed and consumption data of coix seed in Shanghai. CONCLUSION: The health risk of ZEN exposure of coix seed in Shanghai population is lower when taking coix seed regularly, and there are potential health risks when taking coix seed highly contaminated with ZEN at a higher dose for a long time.