Citations

Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein–Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the γ-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.

Objective: There are no Food and Drug Administration (FDA)-approved medications indicated for the treatment of frontotemporal dementia (FTD). We sought to determine the most commonly used drugs used to treat behavioral variant FTD (bvFTD) in specialized dementia clinics. Methods: Medication and demographic data from the Alzheimer’s Disease Research Centers of California (ARCC) and a multicenter FTD natural history study (NHS) data set were compared in bvFTD and Alzheimer’s disease (AD), and effects of demographic variables were assessed using logistic regression. Results: Overall, the percentage of patients taking one or more FDA-approved AD or psychiatric medications was similar in bvFTD and AD; however, after controlling for demographic variables, acetylcholinesterase inhibitor (AChI) use was less common in bvFTD, whereas memantine use remained similar in the 2 groups. Conclusions: Despite lack of evidence for efficacy, the use of AChIs and memantine is common in bvFTD. Clinical trials should be pursued to determine the optimal therapeutic interventions for bvFTD.

Background Treatment of the multiligament-injured knee remains controversial. Purpose To compare clinical and functional outcomes of a consecutive series of multiligament-injured knees that underwent repair of the fibular collateral ligament (FCL) and posterolateral corner (PLC), followed by delayed cruciate ligament reconstructions, with those that had single-stage multiligament reconstruction. Study Design Cohort study; Level of evidence, 3. Methods Patients with multiligament knee injury treated by a single surgeon were identified in our prospective database. Between February 2004 and May 2005, patients underwent repair of medial- and lateral-sided injuries, followed by delayed cruciate ligament reconstructions. Between May 2005 and February 2007, patients underwent single-stage multiligament knee reconstruction. All patients followed a standard rehabilitation protocol. Inclusion criteria were minimum 2-year follow-up and multiligament knee injury including the FCL/PLC. International Knee Documentation Committee subjective and Lysholm scores and objective clinical data were documented. Results We identified 45 knees (42 patients); 17 knees (14 patients) were excluded, leaving 28 knees (28 patients) in the study. The repair/staged group (10 knees in 10 patients) had a mean follow-up of 34 months (range, 24-49 months). The reconstruction group (18 knees in 18 patients) had a mean follow-up of 28 months (range, 24-41 months). Four of the 10 FCL/PLC repairs (40%) and 1 of the 18 FCL/PLC reconstructions (6%) failed (P = .04). After revision reconstructions, there were no statistically significant differences between mean International Knee Documentation Committee subjective scores (79 vs. 77, P = .92) and mean Lysholm scores (85 vs 88, P = .92). Regression analysis showed no effect on failure based on age, sex, injury mechanism, time to surgery, interval between stages, total number of ligaments injured, or location of tear. Conclusion Our series demonstrated a statistically significant higher rate of failure for repair compared with reconstruction of the FCL/PLC. Reconstruction of the FCL/PLC structures is a more reliable option than repair alone in the setting of a multiligament knee injury.