The postnatal appearance and up-regulation of the NR2A subunit of the N-methyl-D-aspartate receptor contributes to the functional heterogeneity of the receptor during development. To elucidate the molecular mechanisms that regulate the neural and developmental specific expression of NR2A, an upstream ϳ9-kb region of the gene harboring the promoter was isolated and characterized in transgenic mice and transfected cortical neurons. Transgenic mouse lines generated with luciferase reporter constructs driven by either 9 or 1 kb of upstream sequence selectively transcribe the transgene in brain, as compared with other non-neural tissues. Reporter luciferase levels in dissociated cultures made from these mice are over 100-fold greater in neuronal/ glial co-cultures than in pure glial cultures. Analysis of NR2A 5-nested deletions in transfected cultures of cortical neurons and glia indicate that while sequences residing upstream of ؊1079 bp augment NR2A neuronal expression, sequences between ؊486 and ؊447 bp are sufficient to maintain neuronal preference. An RE1/ NRSE element is not necessary for NR2A neuron specificity. Furthermore, comparison of the 5-deletion constructs in cortical neurons grown for 5, 8, 11, or 14 days in vitro indicate that sequences between ؊1253 and ؊1180 bp are necessary for maturational up-regulation of NR2A. Thus, different cis-acting sequences control the regional and temporal expression of NR2A, implicating distinct regulatory pathways.The targeting of ion channels and neurotransmitter receptors to their correct cellular location is crucial for the proper development and connectivity of the nervous system. The first level of the intricate spatio-temporal organization required to form the central nervous system is ensuring that genes are transcribed in the appropriate cell types. Although studies on a small number of central nervous system-specific genes have significantly contributed to the identification of cis-and transacting elements necessary for neuron-specific transcription (1-4), the expression profiles of different neuronal genes are very diverse. This diversity provides a unique opportunity to identify novel mechanisms that confine gene expression to selective cell populations during development.
Introduction. Digoxin is used to control ventricular rate in atrial fibrillation (AF). There is conflicting evidence regarding safety of digoxin. We aimed to evaluate the risk of mortality with digoxin use in patients with AF using meta-analyses. Methods. PubMed was searched for studies comparing outcomes of patients with AF taking digoxin versus no digoxin, with or without heart failure (HF). Studies were excluded if they reported only a point estimate of mortality, duplicated patient populations, and/or did not report adjusted hazard ratios (HR). The primary endpoint was all-cause mortality. Adjusted HRs were combined using generic inverse variance and log hazard ratios. A multivariate metaregression model was used to explore heterogeneity in studies. Results. Twelve studies with 321,944 patients were included in the meta-analysis. In all AF patients, irrespective of heart failure status, digoxin is associated with increased all-cause mortality (HR [1.23], 95% confidence interval [CI] 1.16–1.31). However, digoxin is not associated with increased mortality in patients with AF and HF (HR [1.08], 95% CI 0.99–1.18). In AF patients without HF digoxin is associated with increased all-cause mortality (HR [1.38], 95% CI 1.12–1.71). Conclusion. In patients with AF and HF, digoxin use is not associated with an increased risk of all-cause mortality when used for rate control.
The reported criteria for retreatment of carotid stenosis were not rigorous and there is still significant ambiguity surrounding the indications for intervention.
Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations.
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