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Although endocrine therapies targeting estrogen receptor α (ERα) are effective in managing ER positive (+) breast cancer, many patients have primary resistance or develop resistance to endocrine therapies. In addition, ER+ breast cancer with PIK3CA activating mutations and 11q13-14 amplification have poor survival with unclear mechanism. We uncovered that higher expression of deubiquitinase USP35, located in 11q14.1, was associated with ER+ breast cancer and poor survival. Estrogen enhanced USP35 protein levels by downregulating USP35-targeting miRNA-140-3p and miRNA-26a-5p. USP35 promoted the growth of ER+ breast cancer in vitro and in vivo, and reduced the sensitivity of ER+ breast cancer cells to endocrine therapies such as tamoxifen and fulvestrant. Mechanistically, USP35 enhanced ERα stability by interacting and deubiquitinating ERα, and transcriptional activity of ERα by interacting with ERα in DNA regions containing estrogen response element. In addition, AKT, a key effector of PI3K, phosphorylated USP35 at Serine613, which promoted USP35 nuclear translocation, ERα transcriptional activity, and the growth of ER+ breast cancer cells. Our data indicate that USP35 and ERα form a positive feedback loop in promoting the growth of ER+ breast cancer. USP35 may be a treatment target for ER+ breast cancer with endocrine resistance or with PIK3CA mutations or hyperactivation of the PI3K pathway.

Elucidating the molecular mechanism of the migration and invasion is critical for identifying novel therapeutic targets and may significantly improve the prognosis of colorectal cancer. Emerging evidence suggests an involvement of dysregulated microRNAs in the process of tumorigenesis. Here, we show that miR-1225-5p prevents migration and invasion of colorectal cancer cells. Overexpression of miR-1225-5p significantly decreases the expression of Matrix Metalloproteases (MMPs)-1, 3, and 9. Knockdown of miR-1225-5p elevates ROS level via regulating Keap1/Nrf2 pathway. Furthermore, miR-1225-5p attenuates IL-17A-induced p38/AP-1-signaling pathway by suppressing IL-17RA expression. We also examined the biological effects of Rosmarinic acid (RA) on metastatic colorectal cancer cells. RA inhibited EMT via the p38/AP-1 signaling, and miR-1225-5p is essential for RA-mediated anti-metastatic effects.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that causes a range of social communication and behavioral impairments. ASD typically manifests in young children, often with developmental delay or intellectual disabilities (DD/ID) as comorbidities. Accruing evidence indicates that ASD is highly heritable and genomewide studies on ASD cohorts have defined numerous genetic contributors. Notably, most of these studies have been performed with individuals of European and Hispanic ancestry and thus there is a paucity of genetic analyses of ASD in the East Asian population. Here, we performed whole-exome sequencing on 772 ASD trios from China, combining with a previous study of 369 Chinese ASD trios, to identify de novo variants in a total of 1141 ASD trios. We found that ASD probands without DD/ID carried less disruptive de novo variants, including protein-truncating and missense variants, than ASD with DD/ID. Surprisingly, we showed that expression of genes with de novo variants found in ASD probands without DD/ID were enriched in a specific group of neural progenitor cells, suggesting a potential mechanism underlying high-functioning autism. Importantly, some ASD risk genes from this study are not present in the current ASD gene database, suggesting that there are novel genetic contributors to ASD in East Asian populations. We validated one such novel ASD risk gene – SLC35G1 by showing that mice harboring heterozygous deletion of Slc35g1 exhibited defects in social interaction behaviors. Together, this work nominates novel ASD risk genes and indicates that ASD genetic studies in different geographic populations are essential to reveal the comprehensive genetic architecture of ASD.

Rabies continues to poses serious threats to the public health in many countries. The development of novel inexpensive, safe and effective vaccines has become a high priority for rabies control worldwide. We previously generated a novel recombinant rabies vaccine by cloning rabies virus glycoprotein into a chimpanzee adenoviral vector, termed ChAd68-Gp. The present study evaluated the immune responses and protection afforded by this vaccine in beagle dogs. The results demonstrated that intramuscular immunization with both low-dose and high-dose of ChAd68-Gp induced strong immune responses and provided complete protection in beagles even at low-dose. However, when administered orally, high-dose vaccination was protective while low-dose vaccination was ineffective. Further investigation indicated that the low-pH value of gastric juice in the stomach of beagles might decompose the adenovirus. Therefore, suitable formulation for adenovirus-based oral vaccine should be considered and developed. The chimpanzee adenovirus-vectored rabies vaccine ChAd68-Gp warrants extensive test for clinical application.

We describe CT features of our three cases with localized Castleman disease in the retroperitoneum and review literature. Besides those CT features, which have been reported before, we mainly present some newly discovered CT findings of the disease. These new CT findings include the sign of peripheral 'rim-like' enhancement at the early phase of an enhanced CT scan, a higher ratio of the left sided retroperitoneal location to the right side and the presence of local peritoneal thickening around the lesion. In addition, the feeding artery of the lesion is more visually pronounced than ever before by a 16-detector CT scanner.After reviewing the literature and comparing with their histological findings, we suggest these newly discovered findings are relatively characteristic CT features of the disease. Moreover, multi-detector helical CT can now show more details of the disease than ever before.

Gastric cancer is a malignant disease of the digestive system with high rates of incidence and mortality. S‑phase kinase‑associated protein 2 (Skp2) is a novel oncogene, which has been identified to be important in tumor progression and metastasis. In order to clarify the role of Skp2 in human gastric cancer, the present study detected the expression of Skp2 in human gastric cancer tissues, and investigated the molecular mechanism of Skp2 in the progression of gastric carcinoma. The results of the initial bioinformatics analysis showed that Skp2 was significantly upregulated in 31 specimens of primary gastric cancer from a UK patient cohort, and in 10 gastric cancer lines of a side population, compared with normal gastric tissues (P

Background Mitochondrial defects have been associated with various human conditions including cancers. Methods We analyzed the mutations at the mitochondrial DNA (mtDNA) in patients with different thyroid lesions. In particular, in order to investigate if the accumulation of mtDNA mutations play a role in tumor progression, we studied the highly variable main control region of mtDNA, the displacement-loop (D-loop) in patients with non-tumor nodular goiters, with benign thyroid adenomas, and with malignant thyroid carcinomas. Total thyroid tumor or goiter samples were obtained from 101 patients, matched with nearby normal tissue and blood from the same subject. Results Noticeably, mitochondrial microsatellite instability (mtMSI) was detected in 2 of 19 nodular goiters (10.53%), and 8 of 77 (10.39%) malignant thyroid carcinomas. In addition, 6 patients, including 5 (6.49%) with malignant thyroid carcinomas and 1 (5.26%) with nodular goiter, were found to harbor point mutations. The majority of the mutations detected were heteroplasmic. General significance Our results indicate that mtDNA alterations in the D-loop region could happen before tumorigenesis in thyroid, and they might also accumulate during tumorigenesis.

We report CT features of four cases of Eosinophilic enteritis. The disease involves the jejunum in one case, the ileum in two cases, and the colon in the remaining case. Two cases demonstrate a predominantly mucosal type of eosinophilic enteritis, while the other two cases demonstrate a predominantly subserosal type. CT findings include bowel wall thickening in four cases, bowel fold thickening in two cases, layering of the bowel wall in two cases, luminal narrowing without obstruction in three cases, an intra-luminal granuloma mimicking a huge polyp in one case, an extra-luminal irregular granuloma markedly enhancing and slightly necrosing in one case, mesenteric lymphadenopathy with peripheral rim-like enhancement and marked necrosis in one case and ascites in one case. CT findings are more characteristic of an inflammatory disease rather than of a tumor, and these findings are helpful for assessing the extent and location of the disease. Moreover, combined with its typical clinical manifestations, CT findings may lead to the correct diagnosis.