PURPOSE

Wilms tumor (WT) management has evolved into a multimodality paradigm that includes radiotherapy (RT), usually as an adjuvant or consolidative modality. Protocols are refined to maximize cure and compliance while minimizing acute toxicity and long-term effects. RT technique and timing are two factors that could improve these outcomes. We reviewed the evidence on survival and toxicity outcomes among WT patients with conventional versus advanced RT techniques and early versus delayed RT to inform a Department of Health (DOH) commissioned guideline.

We systematically searched PubMed, EuropePMC, EBSCOHost, HERDIN, systematic review and clinical trial registries and official websites of scientific societies for relevant publications and grey literature. Eligibility screening, risk-of-bias assessment and data extraction were performed using a single-reviewer approach. Given the study and data heterogeneity, only a qualitative synthesis was performed. Certainty of evidence assessment was done using the GRADE approach.

We screened 314 studies and included seven in the review, including a phase 1/2 trial and six retrospective studies, all from first-world countries (US, France, Netherlands), except one from a newly industrialized country (Brazil). The certainty of evidence on the survival and toxicity outcomes with advanced RT techniques was very low. Moderate-certainty evidence supports that giving RT >14 days after surgery leads to increased mortality.

Current evidence does not support the routine use of advanced RT techniques; proper contextualization is necessary. Tertiary centers managing WT should strive to administer RT within 14 days after surgery whenever possible.

Objectives: To study the association between metals mixture exposure and DNA oxidative damage using mixture analysis methods, and to explore the most significant exposure factors that cause DNA oxidative damage. Methods: Workers from steel enterprises were recruited in Shandong Province. Urinary metals were measured by using the inductively coupled plasma mass spectrometry method. The level of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was determined by using the ultra-high performance liquid chromatography-mass spectrometry method. Bayesian kernel machine regression (BKMR), elastic net regression and quantile g-computation regression were used to analyze the association between urinary metals and urinary 8-OHdG. Results: A total of 768 subjects aged (36.15±7.40) years old were included in the study. BKMR, elastic net regression and quantile g-computation all revealed an overall positive association between the mixture concentration and increased urinary 8-OHdG. The quantile g-computation results showed that with a 25% increase in metal mixtures, the urinary 8-OHdG level increased by 77.60%. The elastic net regression showed that with a 25% increase in exposure risk score, the urinary 8-OHdG level increased by 26%. The BKMR summarized the contribution of individual exposures to the response, and selenium, zinc, and nickel were significant contributors to the urinary 8-OHdG elevation. Conclusion: Exposure to mixed metals causes elevated levels of DNA oxidative damage, and selenium, zinc, and nickel are significant exposure factors.
Humans ; Adult ; Nickel/toxicity* ; Selenium ; Bayes Theorem ; Metals/toxicity* ; 8-Hydroxy-2'-Deoxyguanosine ; Oxidative Stress/physiology* ; Zinc ; DNA Damage

The purpose of this study was to explore the effect and mechanism of Xihuang Pills on rats with precancerous lesions of the breast. Of 48 healthy female rats, 8 were randomly selected as blank group, and the other 40 were treated with 7,12-dimethylbenzanthracene(DMBA) combined with estrogen and progestin to establish a model of precancerous lesions of the breast. The successfully modeled rats were randomly divided into a model group, a tamoxifen group(1.8 mg·kg~(-1)·d~(-1)), a Xihuang Pills low-dose group(0.3 g·kg~(-1)·d~(-1)), a medium-dose group(0.6 g·kg~(-1)·d~(-1)) and a high-dose group(1.2 g·kg~(-1)·d~(-1)). After 30 days of admi-nistration, the histopathological changes of viscera and breast were observed by haematoxylin and eosin(HE) staining, and the visceral index was calculated. Enzyme linked immunosorbent assay(ELISA) was used to detect the contents of estradiol(E_2) and progesterone(P) in serum. The protein expressions of vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) were detected by immunohistochemistry. The protein expressions of VEGF, vascular endothelial growth factor receptor 2(VEGFR2), phosphorylated-vascular endothelial growth factor receptor 2(p-VEGFR2), B-cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) were detected by Western blot and the mRNA expressions of VEGF, FGF2, CXC-chemokine receptor 4(CXCR4), cysteine aspartic acid-specific protease(caspase-3), and stromal cell-derived factor 1(SDF-1) were detected by real-time polymerase chain reaction(RT-PCR). HE staining revealed that the model group had some liver and kidney damages and severe hyperplastic mammary tissue, while the Xihuang Pills high-dose group had mild hyperplasia. Compared with the model group, the Xihuang Pills groups had lo-wer ovarian coefficient(P<0.05 or P<0.01) and Xihuang Pills high-dose group had lower uterine coefficient(P<0.01). ELISA results showed that compared with the model group, expressions of E_2 and P in Xihuang Pills high-dose group were significantly decreased(P<0.05 or P<0.01). Immunohistochemistry, Western blot and RT-PCR indicated that compared with the conditions in the model group, the protein and mRNA expressions of VEGF and FGF2 in the Xihuang Pills groups were down-regulated(P<0.05 or P<0.01), and the protein expression of Bcl-2 was lowered(P<0.01); there was a decrease in the protein expressions of VEGFR2 and p-VEGFR2(P<0.01), a down-regulation in the mRNA expressions of CXCR4 and SDF-1(P<0.01), while an increase in the mRNA expression of caspase-3(P<0.01) in both Xihuang Pills medium-dose and high-dose groups; the protein expression of Bax in Xihuang Pills high-dose group was increased(P<0.01). The above results indicated that Xihuang Pills can effectively intervene in precance-rous lesions of the breast, and the mechanism may be related to the regulation of E_2 and P secretion as well as the inhibition of angiogenesis and chemokine receptor expression, thus controlling the occurrence of precancerous lesions of the breast in rats.
Rats ; Female ; Animals ; Rats, Sprague-Dawley ; bcl-2-Associated X Protein ; Vascular Endothelial Growth Factor A/metabolism* ; Caspase 3 ; Vascular Endothelial Growth Factor Receptor-2 ; Fibroblast Growth Factor 2 ; Proto-Oncogene Proteins c-bcl-2 ; 9,10-Dimethyl-1,2-benzanthracene/toxicity* ; Precancerous Conditions ; Hyperplasia ; Receptors, Chemokine ; RNA, Messenger

OBJECTIVE: To observe the acute toxic reaction of the Li-Dan-He-Ji granules, and to evaluate its safety. METHODS: Sixty C57BL6/J mice were randomly divided into normal control group, vehicle group and drug treatment group, with 10 females and 10 males in each group. According to the Technical guidelines for the study of toxicity of single drug administration, the maximum administration dosage (MAD) was used to intragastric administration of Li-Dan-He-Ji granules 0.04 mL/g (42.8 g/kg), three times within 24 hours, with an interval of 6 hours. The vehicle group was fed with the same pure water. The normal control group received no treatment. The mice were observed continuously for 14 days, and the appearance characteristics, behavioral activities, body weight changes and the number of deaths in each group were recorded. At the 14 days, blood samples were collected from the eyeballs, and routine blood tests such as white blood cell count (WBC), lymphocyte count (LYM), neutrophil count (NEU), lymphocyte percentage (LYM%), neutrophil percentage (NEU%), red blood cell count (RBC), hemoglobin (Hb), and platelet count (PLT) were performed. And alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr) and other biochemical indicators. The mice were then sacrificed, and the histopathological changes of liver and kidney were observed by hematoxylin-eosin (HE) staining. The organ indexes of heart, liver, spleen, lung, kidney and thymus were calculated. RESULTS: The median lethal dose (LD₅₀) of Li-Dan-He-Ji granules were not obtained. During the MAD experiment, the animals in each group did not die, their behavioral activities were normal, and there was no significant change in liver and kidney histopathological examination. There were no significant differences in body weight, blood routine, biochemical indexes and organ index among all groups (all P > 0.05). The body weight (g) of normal control female and male group, vehicle female and male group and drug female and male group before administration were 18.96±1.14, 19.65±1.45, 19.33±1.30, 19.53±1.22, 19.28±1.69 and 19.48±1.28; 14 days after administration were 27.69±0.81, 28.19±2.22, 27.77±1.00, 27.88±1.85, 27.92±1.33 and 28.07±1.93, respectively. CONCLUSIONS The Li-Dan-He-Ji granules have low oral toxicity, combined with clinical observation, can be safely used in infants.
Animals ; Female ; Humans ; Male ; Mice ; Body Weight ; Kidney ; Leukocyte Count ; Liver ; Toxicity Tests, Acute

The wide use of ZnO and CuO nanoparticles in research, medicine, industry, and other fields has raised concerns about their biosafety. It is therefore unavoidable to be discharged into the sewage treatment system. Due to the unique physical and chemical properties of ZnO NPs and CuO NPs, it may be toxic to the members of the microbial community and their growth and metabolism, which in turn affects the stable operation of sewage nitrogen removal. This study summarizes the toxicity mechanism of two typical metal oxide nanoparticles (ZnO NPs and CuO NPs) to nitrogen removal microorganisms in sewage treatment systems. Furthermore, the factors affecting the cytotoxicity of metal oxide nanoparticles (MONPs) are summarized. This review aims to provide a theoretical basis and support for the future mitigating and emergent treatment of the adverse effects of nanoparticles on sewage treatment systems.
Wastewater/toxicity* ; Sewage/chemistry* ; Zinc Oxide/chemistry* ; Waste Disposal, Fluid ; Nanoparticles/chemistry* ; Metal Nanoparticles/chemistry* ; Nitrogen/metabolism* ; Water Purification

Alcoholic liver disease(ALD), with its increasing morbidity and mortality, has seriously and extensively affected the health of people worldwide. Methyl ferulic acid(MFA) has been proven to significantly inhibit alcohol-induced lipid production in L02 cells through the AMP-activated protein kinase(AMPK) pathway, but its in-depth mechanism remains unclear. This study aimed to further clarify the mechanism of MFA in improving lipid accumulation in L02 cells through the microRNA-378b(miR-378b)-mediated calcium/calmodulin-dependent protein kinase kinase 2(CaMKK2)-AMPK signaling pathway based on existing researches. L02 cells were induced by 100 mmol·L~(-1) ethanol for 48 h to establish the model of ALD in vitro, and 100, 50, and 25 μmol·L~(-1) concentration of MFA was treated. MiR-378b plasmids(containing the overexpression plasmid-miR-378b mimics, silence plasmid-miR-378b inhibitor, and their respective negative control-miR-378b NCs) were transfected into L02 cells by electroporation to up-regulate or down-regulate the levels of miR-378b in L02 cells. The levels of total cholesterol(TC) and triglyceride(TG) in cells were detected by commercial diagnostic kits and automatic biochemical analyzers. The expression levels of miR-378b in L02 cells were detected by real-time quantitative polymerase chain reaction(qRT-PCR). CaMKK2 mRNA levels were detected by PCR, and protein expressions of related factors involved in lipid synthesis, decomposition, and transport in lipid metabolism were detected by Western blot. The results displayed that ethanol significantly increased TG and TC levels in L02 cells, while MFA decreased TG and TC levels. Ethanol up-regulated the miR-378b level, while MFA effectively inhibited the miR-378b level. The overexpression of miR-378b led to lipid accumulation in ethanol-induced L02 cells, while the silence of miR-378b improved the lipid deposition induced by ethanol. MFA activated the CaMKK2-AMPK signaling pathway by lowering miR-378b, thus improving lipid synthesis, decomposition, and transport, which improved lipid deposition in L02 cells. This study shows that MFA improves lipid deposition in L02 cells by regulating the CaMKK2-AMPK pathway through miR-378b.
Humans ; Ethanol/toxicity* ; AMP-Activated Protein Kinases/metabolism* ; Fatty Liver ; Triglycerides ; MicroRNAs/genetics* ; Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics*

Objective: To investigate the effects of nicotine on the morphology, structure of offspring's dental germ, enamel organ and other dental tissues and the further potential epigenetic mechanisms by establishing prenatal nicotine exposure mouse model. Methods: Ten C57BL/6 pregnant mice were randomly divided into control group (physiological saline subcutaneous injection) and prenatal nicotine exposure (PNE) group (nicotine subcutaneous injection) by using a random number table. Postnatal day 0 (P0), postnatal day 14 (P14) and postnatal day 25 (P25) offspring mice were collected for subsequent experiments. The offspring mice were divided into offspring control group and offspring PNE group according to the maternal group respectively. Weights of P0 and P25 offspring mice were recorded. Micro-CT, scanning electron microscope (SEM) and Vickers hardness test were performed to analyze the related parameters of hard tissues including alveolar bones and mandibular incisors. Total RNAs were extracted from mandible tissues and the third generation of dental epithelial stem cells (DESC) in P25 mice. The relative expression levels of osteogenic and ameloblastic differentiation related genes were measured by real-time quantitative PCR (RT-qPCR). Immunohistochemical stainings of paraffin sections were then performed to observe the distribution and expression level of proliferating cell nuclear antigen (Pcna), amelogenin (Amelx), histone H3 trimethylated at lysine 27 (H3K27me3) and enhancer of zeste homolog 2 (Ezh2). Cell counting kit-8 (CCK-8) assays were used to detect the cell viabilities of DESCs after administrations of different concentrations of nicotine (0.01, 0.1, 1 mmol/L) and GSK126 (an inhibitor of histone methyltransferase Ezh2). Results: Compared with the control group, pregnant mice in PNE group were more likely to have adverse pregnancy outcomes, such as significantly lower offspring body weight [P0: offspring control (1.20±0.04) g, offspring PNE (0.99±0.02) g, P<0.001; P25: offspring control (15.26±1.70) g, offspring PNE (9.65±1.32) g, P<0.001] and increased stillbirths rate [offspring control (0), offspring PNE (46.40±9.30) %, P<0.001]. At P14 and P25, the distance parameters between the enamel mineralized deposits of mandibular incisors and the mesial surface of the first molar in offspring PNE group [P14: (-1 349±45) μm; P25: (-1 192±147) μm] was significantly decreased compared with the control group [P14: (-506±380) μm, P25: (504±198) μm] (P<0.05, P<0.001). The enamel column and enamel column stroma of incisors in offspring PNE group were blurred, arranged loosely and disorderly than those in the control group, while the microhardness of incisor enamel in offspring PNE group [(245.7±18.4) MPa] was significantly lower compared to the control group [(371.9±28.7) MPa] (P<0.001). HE staining showed disordered pre-ameloblast (Pre-Am) arrangement and delayed mineralization deposition point in offspring PNE group compared with the control group, while the length of transit-amplifying cell (TA) and Pre-Am region were prolonged as well. Immunohistochemical staining results displayed that the overall Pcna (P<0.05), H3K27me3 (P<0.01), Ezh2 (P<0.01) expression of labial cervical loop (LaCL) in PNE group were increased, while the positive signal of Amelx in ameloblast cytoplasm was impaired. In vitro, the addition of 1 mmol/L nicotine could significantly upregulate the expression level of Pcna (P<0.01) and downregulate the expression levels of B lymphoma Mo-MLV insertion region 1 (P<0.05), leucine rich repeats and immunoglobulin like domains 1 (P<0.05), Amelx (P<0.01). In addition, 1 mmol/L nicotine could also significantly enhance the proliferation activity of DESCs (P<0.001). Addition of 10 μmol/L GSK126, could rescue the proliferation activation effect of 1 mmol/L nicotine on DESCs. Conclusions: PNE may delay the process of enamel formation and lineage differentiation, leading to the abnormal proliferation of DESCs and changes of epigenetic modification state in H3K27me3, which affect the development of enamel in offspring mice,suggesting PNE might be one of risk environmental factor for tooth development.
Pregnancy ; Female ; Mice ; Animals ; Nicotine/toxicity* ; Proliferating Cell Nuclear Antigen ; Histones ; Mice, Inbred C57BL ; Dental Enamel

OBJECTIVE: To study the toxic effects of short-term exposure to gossypol on the testis and kidney in mice and whether these effects are reversible. METHODS: Twenty 7 to 8-week-old male mice were randomized into blank control group, solvent control group, gossypol treatment group and drug withdrawal group. In the former 3 groups, the mice were subjected to daily intragastric administration of 0.3 mL of purified water, 1% sodium carboxymethylcellulose solution, and 30 mg/mL gossypol solution for 14 days, respectively; In the drug withdrawal group, the mice were treated with gossypol solution in the same manner for 14 days followed by treatment with purified water for another 14 days. After the last administration, the mice were euthanized and tissue samples were collected. The testicular tissue was weighed and observed microscopically with HE and PAS staining; the kidney tissue was stained with HE and examined for mitochondrial ATPase activity. RESULTS: Compared with those in the control group, the mice with gossypol exposure showed reduced testicular seminiferous epithelial cells with rounded seminiferous tubules, enlarged space between the seminiferous tubules, interstitium atrophy of the testis, and incomplete differentiation of the spermatogonia. The gossypol-treated mice also presented with complete, non-elongated spermatids, a large number of cells in the state of round spermatids, and negativity for acrosome PAS reaction; diffuse renal mesangial cell hyperplasia, increased mesangial matrix, and adhesion of the mesangium to the wall of the renal capsule were observed, with significantly shrinkage or even absence of the lumens of the renal capsules and reduced kidney mitochondrial ATPase activity. Compared with the gossypol-treated mice, the mice in the drug withdrawal group showed obvious recovery of morphologies of the testis and the kidney, acrosome PAS reaction and mitochondrial ATPase activity. CONCLUSIONS Shortterm treatment with gossypol can cause reproductive toxicity and nephrotoxicity in mice, but these toxic effects can be reversed after drug withdrawal.
Mice ; Male ; Animals ; Gossypol/toxicity* ; Testis ; Seminiferous Tubules ; Spermatids ; Spermatogenesis ; Adenosine Triphosphatases/pharmacology*

Pregnancy ; Female ; Humans ; Pre-Eclampsia/epidemiology* ; Prenatal Exposure Delayed Effects ; Case-Control Studies ; China/epidemiology* ; Fluorocarbons/toxicity*

Cell Differentiation ; Myeloid Differentiation Factor 88/metabolism* ; NF-kappa B/metabolism* ; Particulate Matter/toxicity* ; Signal Transduction ; Toll-Like Receptor 4/metabolism* ; RAW 264.7 Cells