Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer.

Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that expression of SAM and SH3 domain-containing protein 1 (SASH1) is negatively correlated with expression of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1, and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation, and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration, and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis, and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

Unequal crossing over between CYP11B2 and CYP11B1 causes 11 ß -hydroxylase deficiency in a consanguineous family.

Cytochrome P450 (CYP) family CYP11B2/CYP11B1 chimeric genes have been shown to arise from unequal crossing over of the genes encoding aldosterone synthase (CYP11B2) and 11ß-hydroxylase (CYP11B1) during meiosis. The activity deficiency or impaired activity of aldosterone synthase and 11ß-hydroxylase resulting from these chimeric genes are important reasons for 11ß-hydroxylase deficiency (11ß-OHD). Here，two patients with pseudoprecocious puberty and hypokalemia hypertension and three carriers in a consanguineous marriage family were studied. A single CYP11B2/CYP11B1 chimera consisting of the promoter and exons 1 through 5 of CYP11B2, exons 8 and 9 of CYP11B1, and a breakpoint consisting of part of exon 6 of CYP11B2 and part of exon 6, intron 6, and exon 7 of CYP11B1 were detected in the patients and carriers. At the breakpoint of the chimera, a c 0.1086 G > C ( p.Leu.362 =) synonymous mutation in exon 6 of CYP11B2, a c 0.1157 C＞G(p. A386V) missense mutation in exon 7 of CYP11B1, and an intronic mutation in intron 6 were detected. The allele model of the CYP11B2/CYP11B1 chimera demonstrated homozygosity and heterozygosity in the patients and the carriers, respectively. Molecular docking and enzymatic activity analyses indicated that the CYP11B2/CYP11B1 chimeric protein interacted with the catalytic substrate of aldosterone synthase and had similar enzymatic activity to aldosterone synthase. Our study indicated that deletion of CYP11B1 and CYP11B2 abolished the enzymatic activity of 11 ß-hydroxylase and aldosterone synthase; however, the compensation of the enzymatic activity of aldosterone synthase by the CYP11B2/CYP11B1 chimeric protein maintained normal aldosterone levels in vitro. All of the above findings explained the 11ß-OHD phenotypes of the proband and patients in the family.

Estimating the bioavailability of acetochlor to wheat using in situ pore water and passive sampling.

The intensive use of acetochlor in China leads to its extensive existence in soil which may result in contamination of crops and commodities. Therefore, it is vital to assess the bioavailability and phytotoxicity of acetochlor to crops. In this study, four measurements involved in in situ pore water extraction (CIPW), passive sampling extraction (Cfree), ex situ pore water extraction (CEPW), and organic solvent extraction (Csoil) were conducted to assess the bioavailability and phytotoxicity of acetochlor to wheat plant plants in five soils. The results showed that the acetochlor concentrations accumulated in wheat foliage and roots were in the range of 0.11-0.87 mg/kg and 0.09-2.02 mg/kg in the five tested soils, respectively, and had a significant correlation with the acetochlor values analyzed by CIPW (R2 = 0.83-0.90, p < 0.0001) or the Cfree method (R2 = 0.86-0.92, p < 0.0001). The acetochlor concentrations in the five soils measured by these two methods were also correlated with the IC50 values of acetochlor in wheat foliage and roots (R2 > 0.69, p ≤ 0.05). The results indicated that the CIPW and Cfree methods were effective in evaluating acetochlor toxicity to wheat and the acetochlor concentrations in wheat. The effects of soil physical and chemical properties including pH, organic matter content (OMC), clay content, and cation exchange capacity (CEC) on the acetochlor toxicity to wheat were analyzed, and soil OMC was found to be the dominant factor affecting the toxicity of acetochlor in the soil-wheat system.

Bioavailability and toxicity of imazethapyr in maize plant estimated by four chemical extraction techniques in different soils.

The bioavailability and toxicity of herbicides on the crop depend on its uptake efficiency from the soil, and thus the assessment of the bioavailable fraction of herbicides in soil is a crucial work. In this study, we investigated the uptake concentration and toxicity of imazethapyr in maize plant using four chemical measurements, including the extraction of in situ pore water (CIPW), ex situ pore water (CEPW), organic solvent (Csoil) and passive sampling (Cfree) in five soils. The results obtained that the CIPW in a specific soil had the most significant correlation with the uptake concentration of imazethapyr in maize plant (R2 = 0.8851-0.9708), followed by CEPW (R2 = 0.8911-0.9565) and Cfree (R2 = 0.7881-0.9673). However, Cfree showed a higher correlation when considering all five soils, and thus Cfree can describe the bioavailability beyond the types of soil. Additionally, the median inhibition concentrations (IC50) of imazethapyr to maize plant ranged from 5.0 to 6.9 mg/kg in five soils, and the CIPW, CEPW and Cfree had better relationships with the IC50 (R2 > 0.8681) than the Csoil (R2 = 0.6782). The effects of soil properties on the phytotoxicity of imazethapyr, including pH, organic matter content, cation exchange capacity and clay content, were studied, and the soil pH was shown to be a main factor. This study demonstrated that the freely dissolved fraction and soil pore water concentration of imazethapyr in soil can be used to evaluate its bioavailability and toxicity to maize.

A novel (4,6)-connected double-layered Ba(II) coordination polymer based on the flexible tricarboxylate ligand 2,2',2''-[1,3,5-triazine-2,4,6-triyltris(sulfanediyl)]triacetic acid.

In the title compound, poly[[triaqua{µ(4)-2-[4,6-bis(carboxymethylsulfanyl)-1,3,5-triazin-2-ylsulfanyl]acetato}{µ(2)-2-[4,6-bis(carboxymethylsulfanyl)-1,3,5-triazin-2-ylsulfanyl]acetato}barium(II)] monohydrate], {[Ba(C(9)H(8)N(3)O(6)S(3))(2)(H(2)O)(3)]·H(2)O}(n), each Ba(II) atom is nine-coordinated by six O atoms from carboxylate groups of four different 2-[4,6-bis(carboxymethylsulfanyl)-1,3,5-triazin-2-ylsulfanyl]acetate ligands and three O atoms from water molecules. The triazine ligand is partially deprotonated, as verified by intermolecular hydrogen-bonding parameters, and adopts µ(2)-η(1):η(1) and µ(4)-η(1):η(1):η(2) coordination modes to connect the Ba(II) centres, forming a novel double-layered structure. Topological analysis indicates that the whole structure is a novel (4,6)-connected net, considering the ligands and Ba(II) centres as four- and six-connected nodes, respectively.