Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma.

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development. However, it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors (TFs) except for the nuclear receptor family of TFs. Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma (GEA) or the therapeutic effects of targeting TF and transcription cofactor complexes. In this study, we found that ETS homologous factor (EHF) expression is promoted by a core transcriptional regulatory circuitry (CRC), specifically ELF3-KLF5-GATA6, and interference with its expression suppressed the malignant biological behavior of GEA cells. Importantly, we identified Ajuba LIM protein (AJUBA) as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA. Furthermore, we identified KRAS signaling as a common pathway downstream of EHF and AJUBA. Applicably, dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo. In conclusion, EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway. Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

NLRP3 Inflammasome: A key contributor to the inflammation formation.

Inflammation is an important part of the development of various organ diseases. The inflammasome, as an innate immune receptor, plays an important role in the formation of inflammation. Among various inflammasomes, the NLRP3 inflammasome is the most well studied. The NLRP3 inflammasome is composed of skeletal protein NLRP3, apoptosis-associated speck-like protein (ASC) and pro-caspase-1. There are three types of activation pathways: (1) "classical" activation pathway; (2) "non-canonical" activation pathway; (3) "alternative" activation pathway. The activation of NLRP3 inflammasome is involved in many inflammatory diseases. A variety of factors (such as genetic factors, environmental factors, chemical factors, viral infection, etc.) have been proved to activate NLRP3 inflammasome and promote the inflammatory response of the lung, heart, liver, kidney and other organs in the body. Especially, the mechanism of NLRP3 inflammation and its related molecules in its associated diseases remains not to be summarized, namely they may promote or delay inflammatory diseases in different cells and tissues. This article reviews the structure and function of the NLRP3 inflammasome and its role in various inflammations, including inflammations caused by chemically toxic substances.

Degree of stemness predicts micro-environmental response and clinical outcomes of diffuse large B-cell lymphoma and identifies a potential targeted therapy.

Some cells within a diffuse large B-cell lymphoma (DLBCL) have the genotype of a stem cell, the proportion of which is termed degree of stemness. We interrogated correlations between the degree of stemness with immune and stromal cell scores and clinical outcomes in persons with DLBCL. We evaluated gene expression data on 1,398 subjects from Gene Expression Omnibus to calculate the degree of stemness. Subjects were classified into low- and high-stemness cohorts based on restricted cubic spline plots. Weighted gene co-expression network analysis (WGCNA) was used to screen for stemness-related genes. Immune and stromal scores correlated with the degree of stemness (both P < 0.001). A high degree of stemness correlated with a shorter progression-free survival (PFS; Hazard Ratio [HR; 95% Confidence Interval [CI] =1.90 (1.37, 2.64; P < 0.001) and a shorter survival (HR = 2.29 (1.53, 3.44; P < 0.001). CDC7 expression correlated with the degree of stemness, and CDC7-inhibitors significantly increased apoptosis (P < 0.01), the proportion of cells in G1 phase (P < 0.01), and inhibited lymphoma growth in a mice xenograft model (P = 0.04). Our data indicate correlations between the degree of stemness, immune and stromal scores, PFS, and survival. These data will improve the prediction of therapy outcomes in DLBCL and suggest potential new therapies.

Population genetic data of 4 multicopy Y-STR markers in Chinese.

Novel Y chromosomal STR (Y-STR) markers have been continuously discovered during the past decades, promoting the widely application of Y-STRs in the area of forensic science. Here, four multicopy Y-STR markers were focused, including DYF383S1, DYF409S1, DYF411S1 and DYF371, which are rarely reported in China and differ in the number of copies on Y chromosome. Characterization of the markers was performed in population of Hunan province, China, based on sequence analysis. Allele nomenclature and allelic ladder were then developed to avoid the disunity of typing standard. To evaluate their forensic performance, gene diversity of the four loci was investigated in 548 unrelated male individuals from Hunan population. The number of haplotype was analyzed by both conservative (C-type) and expanded approach (E-type) for markers containing more than 2 copies. As detected, there were 7, 9, 13 alleles and 15, 22, 23 haplotypes for DYF383S1, DYF409S1 and DYF411S1, respectively. Thirty-two C-types and 56 E-types were found in DYF371, indicating the highest haplotype diversity (HD) among all tested loci (0.871 and 0.888 for C-type and E-type, respectively). Two other Y-STRs (DYF409S1, DYF411S1) also showed high haplotype diversity (>0.8) in the population. Combining the four loci, discrimination capacity reached 0.505 (C-type) or 0.533 (E-type), and the total HD values exceeded 0.991. The results inferred great potential of the multicopy markers to improve the resolution of paternal identification in China population.

Genetic analysis of 50 Y-STR loci in Dong, Miao, Tujia, and Yao populations from Hunan.

To investigate the genetic polymorphism of Y chromosome short tandem repeat (Y-STR) loci in Dong, Miao, Tujia, and Yao minority populations from Hunan Province, China. Fifty Y-STRs (DYS392, DYS389I/II, DYS447, DYS438, DYS527, DYS645, DYS596, DYS391, DYS456, DYS19, DYS593, DYS448, DYS627, DYS557, DYS437, DYS481, DYS533, DYS390, DYS385, DYF387S1, DYS460, DYS393, Y_GATA_H4, DYS439, DYS635, DYS444, DYS643, DYS549, DYS576, DYS570, DYS458, DYS449, DYS518, DYS531, DYS630, DYS622, DYS552, DYS510, DYS459a/b, DYS446, DYS443, DYS587, Y_GATA_A10, DYS520, DYS522) were analyzed for 2553 unrelated healthy male individuals from Hunan (643 Dong males, 666 Miao males, 633 Tujia males, 611 Yao males) using AGCU Y37 and AGCU Y SUPP STR amplification system. There were 624 different haplotypes in 643 unrelated Dong males, 662 in 666 unrelated Miao males, 627 in 633 unrelated Tujia males, and 587 in 611 unrelated Yao males. The haplotype diversities of Dong, Miao, Tujia, and Yao were determined as 0.999879, 0.999982, 0.999970, and 0.999860, respectively. Analysis of molecular variance (AMOVA) tests demonstrated that genetic distance between Miao and Tujia was the smallest (0.0003), while the genetic distance between Dong and Yao was the largest (0.0252). The 50 Y-STR loci in the four minority populations from Hunan Province revealed a highly polymorphic genetic distribution, which showed a high potential for population genetics and forensic practice.