ABSTRACT
OBJECTIVE@#To explore the genetic basis of a patient with clinically suspected Loeys-Dietz syndrome (LDS).@*METHODS@#A child who had presented at Beijing Anzhen Hospital in September 2018 was selected as the study subject. Clinical data and family history of the patient were collected, along with peripheral blood samples of the proband and his parents. Whole exome sequencing (WES) was carried out through next-generation sequencing.@*RESULTS@#Candidate variants were searched through bioinformatic analysis focusing on genes associated with hereditary aortic aneurysms. Candidate variant was verified by Sanger sequencing. The patient was found to have cardiovascular abnormalities including early-onset aortic dilatation and coarctation, and LDS syndrome was suspected. WES revealed that he has harbored a heterozygous c.1526G>T missense variant of the TGFBR2 gene. The same variant was not found in either parent and was predicted as likely pathogenic (PM1+PM2_Supporting+ PM6+PP3+PP4) based on the guidelines from the American College for Medical Genetics and Genomics (ACMG).@*CONCLUSION@#The TGFBR2 c.1526G>T variant probably underlay the LDS in this patient and was unreported previously in China. Above finding has enriched the mutational spectrum of the TGFBR2 gene associated with the LDS and provided a basis for the genetic counseling for the patient.
Subject(s)
Child , Humans , Male , China , Computational Biology , Family , Loeys-Dietz Syndrome/genetics , Mutation , Receptor, Transforming Growth Factor-beta Type II/geneticsABSTRACT
The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.
ABSTRACT
Objective To investigate the expression of vascular endothelial growth factor(VEGF) in human skin ulcer margin. Methods Ulcer biopsy samples were stained with anti VEGF and CD34 antibodies by immunohistochemistry .Results VEGF was not expressed in normal epidermis. The ulcer specimen was divided into normal,peripheral,marginal and central parts. Epidermis of normal part was not stained. VEGF was obviously expressed in peripheral upper epidermis of ulcer and lower epidermis of ulcer margin. Central part was not stained due to shedding of epidermis. And also CD34 staining demonstrated that dermal capillaries increased obviously and lumen dilated, which was marked in the periphery and the margin of ulcer. Conclusions VEGF is secreted in skin ulcerous epidermis and promotes angiogenesis and vascular dilataion which play a role in ulcer healing.