Establishment of a Knock-In Mouse Model with the SLC26A4 c.919-2A>G Mutation and Characterization of Its Pathology

Recessive mutations in the SLC26A4 gene are a common cause of hereditary hearing impairment worldwide. Previous studies have demonstrated that different SLC26A4 mutations may have different pathogenetic mechanisms. In the present study, we established a knock-in mouse model (i.e., Slc26a4tm1Dontuh/tm1Dontuh mice) homozygous for the c.919-2A>G mutation, which is a common mutation in East Asians. Mice were then subjected to audiologic assessment, a battery of vestibular evaluations, and inner ear morphological studies. All Slc26a4tm1Dontuh/tm1Dontuh mice revealed profound hearing loss, whereas 46% mice demonstrated pronounced head tilting and circling behaviors. There was a significant difference in the vestibular performance between wild-type and Slc26a4tm1Dontuh/tm1Dontuh mice, especially those exhibiting circling behavior. Inner ear morphological examination of Slc26a4tm1Dontuh/tm1Dontuh mice revealed an enlarged endolymphatic duct, vestibular aqueduct and sac, atrophy of stria vascularis, deformity of otoconia in the vestibular organs, consistent degeneration of cochlear hair cells, and variable degeneration of vestibular hair cells. Audiologic and inner ear morphological features of Slc26a4tm1Dontuh/tm1Dontuh mice were reminiscent of those observed in humans. These features were also similar to those previously reported in both knock-out Slc26a4−/− mice and Slc26a4loop/loop mice with the Slc26a4 p.S408F mutation, albeit the severity of vestibular hair cell degeneration appeared different among the three mouse strains

Expression and Characterizatoion of Human Factor IX and Factor IX-Factor X Chimeras in Mouse C127 Cells

This project aims to extract and analyze website source code at different time. Goal is to detect web tracking code and check if a website is GDPR compliant. It leads to the creation of a visualization tool to discover patterns in retrieved data

Function and Therapeutic Implication of C-Cam Cell-Adhesion Molecule in Prostate Cancer (Review)

Human neoplasms are often caused by cumulative alterations in oncogenes and tumor-suppressor genes. By identifying the early genetic changes involved in tumorigenesis, one can develop strategies to prevent and detect cancers at early stages, when treatment is most effective. C-CAM1, a cell- adhesion molecule (CAM) isoform (I), was recently shown to play a critical role in prostate cancer initiation and progression. Loss of C-CAM 1 expression occurs early in the development of prostate cancer, suggesting that C-CAM1 may help maintain the differentiated state of the prostate epithelium. Reintroduction of C-CAM1 into cancer cells can reverse their cancerous growth. Thus, the C-CAM1 molecule itself or drugs that increase C-CAM1 expression are promising agents for prostate cancer treatment. The mechanisms by which C-CAM1 suppresses tumorigenesis are different from those of p53 and Rb. Therefore, C-CAM1 therapy is a new form of prostate cancer treatment. To exploit C-CAM1's therapeutic potential, a human C-CAM1 adenovirus expression vector (Ad-hu-C-CAM1) has been used to treat prostate tumor xenografts in nude mice. The preliminary results have shown great promise. In addition, while C-CAM gene therapy may have immediate application in prostate cancer treatment, the knowledge to be learned from mechanistic studies of C-CAM1-mediated tumor suppression may also help us design better strategies for prevention and treatment for prostate cancer

Schedule-Dependence of C-Cam1 Adenovirus Gene Therapy in a Prostate Cancer Model

BACKGROUND: C-CAM1 functions as a tumor suppressor in prostate cancer. Thus C-CAM1 recombinant adenovirus therapy may be a promising treatment for prostate cancer. Understanding the time course of C-CAM1's antitumor activity is essential for designing an optimal schedule for C-CAM1 gene therapy. MATERIALS AND METHODS: PC3 cells were exposed to Ad-C-CAM1 and the time course of C-CAM1 expression was monitored by flow cytometry. Tumors generated in nude mice by subcutaneous injection of PC-3 cells were used for in vivo testing of C-CAM1's antitumor activity. Intratumoral injections of viruses (either Ad-C-CAM1 or Ad-beta-gal) or buffer only ( control) were performed according to two different schedules. Mice in Schedule A received a single injection, while mice in Schedule B received the same total amount of viruses in 3 equal doses at 2-week intervals. RESULTS: After single exposure to Ad-C-CAM1, PC-3 cells expressed abundant C-CAM1 protein which reached the highest level on day 3 and persisted for up to 5 days. PC-3 tumors in nude mice exhibited 2 to 3-week lag in tumor growth curves after a single Ad-C-CAM1 injection. In contrast, 14 of the 18 tumors receiving 3 fractionated Ad-C-CAM1 injections regressed completely, while the other 4 tumors shrank to significantly smaller sizes . CONCLUSIONS: Sustained expression of C-CAM1 is required for optimal tumor suppression. The schedule-dependence of C-CAM1's antitumor activity should be taken into account in optimizing gene therapy in clinical settings