BAP1 loss augments sensitivity to BET inhibitors in cancer cells.

The tumor suppressor gene BAP1 encodes a widely expressed deubiquitinase for histone H2A. Both hereditary and acquired mutations are associated with multiple cancer types, including cutaneous melanoma (CM), uveal melanoma (UM), and clear cell renal cell carcinoma (ccRCC). However, there is no personalized therapy for BAP1-mutant cancers. Here, we describe an epigenetic drug library screening to identify small molecules that exert selective cytotoxicity against BAP1 knockout CM cells over their isogenic parental cells. Hit characterization reveals that BAP1 loss renders cells more vulnerable to bromodomain and extraterminal (BET) inhibitor-induced transcriptional alterations, G1/G0 cell cycle arrest and apoptosis. The association of BAP1 loss with sensitivity to BET inhibitors is observed in multiple BAP1-deficient cancer cell lines generated by gene editing or derived from patient tumors as well as immunodeficient xenograft and immunocompetent allograft murine models. We demonstrate that BAP1 deubiquitinase activity reduces sensitivity to BET inhibitors. Concordantly, ectopic expression of RING1A or RING1B (H2AK119 E3 ubiquitin ligases) enhances sensitivity to BET inhibitors. The mechanistic study shows that the BET inhibitor OTX015 exerts a more potent suppressive effect on the transcription of various proliferation-related genes, especially MYC, in BAP1 knockout cells than in their isogenic parental cells, primarily by targeting BRD4. Furthermore, ectopic expression of Myc rescues the BET inhibitor-sensitizing effect induced by BAP1 loss. Our study reveals new approaches to specifically suppress BAP1-deficient cancers, including CM, UM, and ccRCC.

[The establishment of the arsenic poisoning rats model caused by corn flour baked by high-arsenic coal].

OBJECTIVE: To establish coal arsenic poisoning rat model by feeding the rats with the corn powder baked by high arsenic coal as the main raw material. METHODS: Fifty Wistar rats, healthy, were randomly divided into 5 groups according to the figures of their weights, including control group, drinking arsenic poisoning water group, low, medium and high arsenic contaminated grain group, 10 rats for each.Rats in control group and drinking arsenic poisoning water group were fed with standard feed without any arsenic containing. Rats in water group would drink 100 mg/L As2O3 solution and the rats in arsenic grain groups would be fed with the arsenic contaminated grain at the dose of 25, 50 and 100 mg/kg, respectively. The duration would last for 3 months.General situation and weight were observed. At the same time, the arsenic contents of urine, hair, liver and kidney of the rats in each group were detected, as well as the histopathology changes of liver and kidney, and the ultra structure of liver was observed. RESULTS: The arsenic contents of urine (median(min-max)) of the rats in the arsenic water group, low, medium and high arsenic grain groups were separately 3055.59 (722.43-6389.05), 635.96(367.85-1551.31), 1453.84 (593.27-5302.94) and 3101.11 (666.64-6858.61) µg/g Cr; while the arsenic contents of hair of the rats in the above groups were separately (23.07 ± 10.38), (8.87 ± 3.31), (12.43 ± 6.65) and (25.68 ± 7.16) µg/g; the arsenic contents of liver of the rats in the above groups were separately (5.68 ± 3.13), (2.64 ± 1.52), (3.89 ± 1.76) and (5.34 ± 2.78) µg/g; and the arsenic contents of kidney were separately (6.90 ± 1.94), (3.48 ± 1.96), (5.03 ± 2.08) and (7.02 ± 1.62) µg/g; which were all significantly higher than those in the control group (86.70 (49.71-106.104) µg/g Cr,(1.28 ± 0.37) µg/g, (1.01 ± 0.34) µg/g and (1.82 ± 1.09) µg/g, respectively). The difference showed significance (P < 0.05). Under electron microscope detection, we observed the reduction of mitochondrial, the blurred mitochondrial cristae, some disappeared ridges, the reduced rough endoplasmic reticulum, and irregular uneven nuclear in the liver cells of rats in arsenic contaminated grain group. The contents of aspartate transaminase (AST) and total bile acid (TBA) in medium and high arsenic contaminated grain group were respectively (196.17 ± 46.18), (212.40 ± 35.14) U/L and (11.74 ± 4.07), (19.19 ± 4.68)µmol/L, which were higher than it in the control group (separately (143.10 ± 29.13) U/L and (6.23 ± 2.95)µmol/L). The contents of glutathione-S-transferases(GST), γ-glutamyltranspeptidase (GGT)and blood urea nitrogen (BUN)in high arsenic contaminated grain group were separately (196.21 ± 47.38)U/L, (1.71 ± 0.66)U/L, (9.54 ± 1.95)mmol/L, which were higher than that in the control group ((134.93 ± 24.80 )U/L, (0.75 ± 0.36)U/L, (7.67 ± 1.02)mmol/L, respectively). The contents of cholinesterase (CHE) in low, medium and high arsenic contaminated grain group were separately (259.90 ± 52.71)U/L, (263.44 ± 66.06)U/L and (244.90 ± 36.14)U/L, the contents of total protein(TP) in rats of high arsenic contaminated grain group were (62.64 ± 5.50)g/L, which was all lower than that in the control group ((448.33 ± 59.67)U/L, (69.38 ± 4.24)g/L, respectively). The contents of TBA in high arsenic contaminated grain group ( (19.19 ± 4.68) µmol/L) was higher than that in drinking water arsenic poisoning group ((15.15 ± 2.64)µmol/L). The differences of the above indexes were all significant (P < 0.05). CONCLUSION: The results showed the arsenic poisoning rat model produced by coal-burning were successfully established.

Villoboletus persicinus, gen. et sp. nov. (Boletaceae), a bolete with flocculent-covered stipe from northern China.

Some collections from northern China are proposed as the new genus and species Villoboletus persicinus based on morphological assessments and molecular phylogenetic evidence. It is circumscribed by the pink pileus, white context turning pale blue to bule when exposed, yellow hymenophore surface turning blue when bruised, stipe covered with plenty of flocculent hairs, ellipsoid-fusiform to subfusiform smooth basidiospores, and the presence of hymenial cystidia. Phylogenetic analyses inferred from four gene fragments (28S, tef1, rpb1, and rpb2) revealed a distinct position of this new genus in Boletaceae, but no place to accommodate it at subfamily rank.

New Species and New Records of Otidea from China Based on Molecular and Morphological Data.

Species of genus Otidea previously reported in China are mainly distributed in the northeast, northwest and southwest regions of China, but the species diversity of Otidea in north China is not very clear. In this study, newly collected Otidea specimens from northern China and some herbarium specimens deposited in three important Chinese fungus herbaria (HMAS, HKAS, HMJAU) were studied using morphological and phylogenetic methods. The internal transcribed spacers of the nrDNA (ITS), the nrRNA 28S subunit (nrLSU), the translation elongation factor 1-alpha (tef1-α), and the second largest subunit of RNA polymerase II (rpb2), were employed to elucidate the phylogenetic relationships between Otidea species. Results identified 16 species of Otidea, of which seven new species are described, namely O.aspera, O.cupulata, O. filiformis, O.khakicolorata, O. parvula, O.plicara and O.purpureobrunnea. Otidea bicolor and O. pruinosa are synonymized as O. subpurpurea. Two species, O. mirabilis and O. nannfeldtii, are being reported for the first time in China. The occurrence of O. bufonia, O. leporina and O. onotica are confirmed by molecular data in China.

Gomphocantharellus, a new genus of Gomphales.

The genus Gomphocantharellus and species Gomphocantharellus cylindrosporus are proposed as new based on morphological assessments and molecular phylogenetic evidence inferred from nucleotide sequences of mitochondrial (mt) adenosine triphosphate (ATPase) subunit 6 (atp6) and mt small subunit rDNA (mtSSU). Basidiomes of G. cylindrosporus are characterized by the peach to pinkish orange color, cantharelloid habit with a gill-like hymenophore with obtuse edges, smooth and cylindrical to allantoid basidiospores, and cylindrical to narrowly clavate flexuous pleurocystidia. The species resembles a species of Cantharellus but differs from the latter by the cylindrical basidiospores. Phylogenetic analyses confirm the placement of Gomphocantharellus as an independent lineage within the order Gomphales.

Phylogenetic Analysis Reveals Four New Species of Otidea from China.

The emergence of molecular systematics has greatly helped researchers to identify fungal species. China has abundant Otidea species resources, and a number of new species of Otidea have been recently proposed. However, many old specimens in herbaria are mainly identified by morphology rather than molecular methods. In this study, 11 specimens deposited in Chinese herbaria and one newly collected Otidea species from northern China were identified based on morphological and phylogenetic analyses. Four gene fragments (ITS, LSU, rpb2, and tef1-α) were used to elucidate the phylogenetic relationships of species within Otidea. A total of nine phylogenetic species are recognized, of which four are described as new species, namely O. bomiensis, O. gongnaisiensis, O. hanzhongensis, and O. shennongjiana. Among the known species were O. aspera and O. sinensis.

Two new Clitocella species from North China revealed by phylogenetic analyses and morphological characters.

Two new species of Clitocella are proposed based on morphological and phylogenetic investigations. Clitocellaborealichinensis sp. nov. is closely related to C.orientalis but distinguished from the latter by its slightly smaller basidiospores and hyphae of pileipellis with pale brown to brown intracellular or parietal pigment. Clitocellacolorata sp. nov. is closely related to C.popinalis and C.mundula in macromorphology but is differentiated from C.popinalis by its slightly smaller basidiospores and the difference in genetic profile, and from C.mundula by its relatively colorful pileus (white to yellowish white, grayish white to grayish brown, pink white). Phylogenetic analyses based on sequence data from five different loci (ITS, nrLSU, tef1, rpb2 and atp6) support the taxonomic position of the two new species in the genus Clitocella. The illustrations and descriptions for the new taxa are provided.

New Species of Mallocybe and Pseudosperma from North China.

Within the family Inocybaceae, many species of Mallocybe and Pseudosperma have been reported, but there are only a few reports on these two genera from north China. In this study, six collections of Mallocybe and 11 collections of Pseudosperma were studied by morphological and phylogenetic methods. Phylogenetic analyses based on sequence data from three or two different loci (ITS, LSU, and rpb2 for Mallocybe; ITS and LSU for Pseudosperma) are performed to infer species relationships within genera Mallocybe and Pseudosperma, respectively. Results indicate that eight species of Mallocybe and Pseudosperma are found in Shanxi province, north China; two new species of Mallocybe, M. depressa and M. picea, are described. Overall, six species belong to Pseudosperma, of which three are new: P. gilvum, P. laricis and P. pseudoniveivelatum.

Expression levels of chemokine (C-X-C motif) ligands CXCL1 and CXCL3 as prognostic biomarkers in rectal adenocarcinoma: evidence from Gene Expression Omnibus (GEO) analyses.

Rectal cancer is a life­threatening disease worldwide. Chemotherapy resistance is common in rectal adenocarcinoma patients and has unfavorable survival outcomes; however, its related molecular mechanisms remain unknown. To identify genes related to the initiation and progression of rectal adenocarcinoma, three datasets were obtained from the Gene Expression Omnibus database. In total, differentially expressed genes were analyzed from 294 tumor and 277 para-carcinoma samples from patients with rectal cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functions were investigated. Cytoscape software and MicroRNA Enrichment Turned Network were applied to construct a protein-protein interaction network of the dependent hub genes and related microRNAs. The Oncomine database was used to identify hub genes. Additionally, Gene Expression Profiling Interactive Analysis was applied to determine the RNA expression level. Tumor immune infiltration was assessed using the Tumor Immune Estimation Resource database. The expression profiles of hub genes between stages, and their prognostic value, were also evaluated. During this study, data from The Cancer Genome Atlas were utilized. In rectal adenocarcinoma, four hub genes including CXCL1, CXCL2, CXCL3, and GNG4 were highly expressed at the gene and RNA levels. The expression of CXCL1, CXCL2, and CXCL3 was regulated by has-miR-1-3p and had a strong positive correlation with macrophage and neutrophil. CXCL2 and CXCL3 were differentially expressed at different tumor stages. High expression levels of CXCL1 and CXCL3 predicted poor survival. In conclusion, the CXCL1 and CXCL3 genes may have potential for prognosis and molecular targeted therapy of rectal adenocarcinoma.

A taxonomic reassessment of the genus Balsamia from China.

Molecular analysis of the genus Balsamia was conducted with ITS and 28S sequences available, including newly gained sequences from Chinese specimens. Combined with the morphological examinations, a new hypogeous species, Balsamia lishanensis was described and illustrated from North China, which is morphologically characterized by reddish brown ascomata covered with fine warts, the whitish gleba with numerous small chambers, 3-5 layers peridium with reddish brown polygonal cells and the smooth and regular ellipsoid ascospores with one large oil drop. Two species previously described as Barssia were transferred to Balsamia. Balsamia platyspora was confirmed to be in existence in China based on newly collected specimen. A key to the Chinese Balsamia species was provided.

Influence of polysorbates (Tweens) on structural and antimicrobial properties for microemulsions.

Polysorbates (Tweens) are one of the most used excipients for essential oils encapsulation. In this work, the polysorbate based microemulsions (PMEs) for R-(+)-limonene (LMN) encapsulation were investigated for the structural and antimicrobial properties. PMEs were constructed using the pseudoternary phase diagrams, and then characterized for electrical conductivity, rheology, size distribution and particle geometry. Conductivity and rheological measurement results showed that Tween 80 and Tween 60 based microemulsions have identical phase transitions. Dynamic light scattering demonstrated that hydrodynamic diameters of oil-in-water microemulsions decreased from 30 nm to 25 nm during the dilution, while small-angle X-ray scattering indicated that their spherical geometries were maintained. PMEs exhibited enhanced antimicrobial efficiencies in vitro against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Interestingly, when Tween 80 was replaced by Tween 60, PME was observed more effective against S. aureus. The two PMEs structural analogues exhibited different antimicrobial efficiencies corresponding to the bioactivity of polysorbates. In conclusion, PMEs can be considered as a desirable system for LMN encapsulation to enhance its solubility and antimicrobial efficiency. Furthermore, the difference in the antimicrobial efficiency suggested that the choice of emulsifiers should be concerned to improve further applications.

[Biological exposure limits caused by co exposure to fluoride and arsenic based on Wnt signaling pathway]. / 基于Wntä¿¡å·é€šè·¯æŽ¢è®¨æ°Ÿç ·æ··åˆæš´éœ²çš„ç”Ÿç‰©æš´éœ²é™å€¼.

Chronic fluoride-arsenic combined poisoning is a global public health problem. While the cause of the disease is clear, the pathogenesis is unknown. Given that there is no specific treatment, early prevention is particularly important. Biological exposure limits are designed to investigate the maximum allowable concentration of harmful effects from exogenous chemicals. To explore the biological exposure limits for mixed exposures of fluoride and arsenic, we compared the contents of fluorine and arsenic in the environmental media of the control and fluoride-arsenic combined exposure areas and analyzed the dose-effect and dose-response relationship between fluoride, arsenic and the key proteins of Wnt signaling pathways. The benchmark dose method was used to estimate the biological exposure limit for fluoride-arsenic combined exposure. The results showed that the content of fluoride in coal, clay, indoor air, outdoor air, chili and rice, as well as arsenic content in coal, clay, outdoor air, chili and rice was higher than that of the control. With the increase of fluoride and arsenic exposure levels, the glycogen synthase kinase 3β (GSK3β), β-catenincontents and the prevalence of Wnt/β-catenin signaling pathway antagonistic protein Dickkopf-1 (DKK1), GSK3β, Beta-catenin (β-catenin) gradually increased, but the content of DKK1 significantly decreased. Based on the Wnt signaling pathway, the biological exposure limit for fluoride-arsenic combined exposure was urinary fluoride of 0.52 mg·g-1 creatinine and urinary arsenic of 6.59 mg·g-1 creatinine. Our results had important guiding significance for early prevention of body damage caused by fluoride-arsenic combined poisoning.

A possible new mechanism and drug intervention for kidney damage due to arsenic poisoning in rats.

Arsenic poisoning is a worldwide endemic disease that affects thousands of people. Currently, the aetiology of the disease is known, but its pathogenesis is uncharacterized and there is no specific treatment. We established a rat model of coal-burning arsenic poisoning by feeding the animals corn powder baked with high arsenic coal. By observing subsequent changes in kidney and immune function, we found that arsenic induces both kidney and immune damage. Furthermore, there is a significant correlation between kidney and immune damage. Moreover, Ginkgo biloba, a known immune enhancer, was used as an intervention agent in arsenic poisoned rats to validate the relationship between kidney and immune damage. Meanwhile, we also explored the mechanism of Ginkgo biloba treatment of kidney damage in burning-coal arsenic poisoned rats. We found that Ginkgo biloba enhanced immune function in rats with arsenic poisoning and ameliorated arsenic-induced kidney damage. These results suggest that immune suppression may be one of the mechanisms underlying arsenic-induced kidney damage and that Ginkgo biloba might relieve kidney damage by enhancing immune function.

Correction: A possible new mechanism and drug intervention for kidney damage due to arsenic poisoning in rats.

[This corrects the article DOI: 10.1039/C5TX00165J.].

Arsenic may be involved in fluoride-induced bone toxicity through PTH/PKA/AP1 signaling pathway.

Chronic exposure to combined fluoride and arsenic continues to be a major public health problem worldwide, affecting thousands of people. In recent years, more and more researchers began to focus on the interaction between the fluorine and the arsenic. In this study, the selected investigation site was located in China. The study group was selected from people living in fluoride-arsenic polluted areas due to burning coal. The total number of participants was 196; including the fluoride-arsenic anomaly group (130) and the fluoride-arsenic normal group (63). By observing the changes in gene and protein expression of PTH/PKA/AP1 signaling pathway, the results show that fluoride can increase the expression levels of PTH, PKA, and AP1, but arsenic can only affect the expression of AP1; fluoride and arsenic have an interaction on the expression of AP1. Further study found that fluoride and arsenic can affect the mRNA expression level of c-fos gene (AP1 family members), and have an interaction on the expression of c-fos, but not c-jun. The results indicate that PTH/PKA/AP1 signaling pathway may play an important role in bone toxicity of fluoride. Arsenic can affect the expression of c-fos, thereby affecting the expression of transcription factor AP1, indirectly involved in fluoride-induced bone toxicity.