Objective. Type I interferons (IFNs) play an important role in the pathogenesis of systemic lupus erythematosus (SLE). This phase Ia trial was undertaken to evaluate the safety, pharmacokinetics, and immunogenicity of anti-IFN␣ monoclonal antibody (mAb) therapy in SLE. During the trial, we also examined whether overexpression of an IFN␣/␤-inducible gene signature in whole blood could serve as a pharmacodynamic biomarker to evaluate IFN␣ neutralization and investigated downstream effects of neutralizing IFN␣ on BAFF and other key signaling pathways, i.e., granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), tumor necrosis factor ␣ (TNF␣), and IL-1␤, in SLE.Methods. Affymetrix Human Genome U133 Plus 2.0 microarrays were used to profile whole blood and lesional skin of patients receiving standard therapy for mild to moderate SLE. Selected IFN␣/␤-inducible proteins were analyzed by immunohistochemistry.Results. With the study treatment, we observed anti-IFN␣ mAb-specific and dose-dependent inhibition of overexpression of IFN␣/␤-inducible genes in whole blood and skin lesions from SLE patients, at both the transcript and the protein levels. In SLE patients with overexpression of messenger RNA for BAFF, TNF␣, IL-10, IL-1␤, GM-CSF, and their respective inducible gene signatures in whole blood and/or skin lesions, we observed a general trend toward suppression of the expression of these genes and/or gene signatures upon treatment with anti-IFN␣ mAb.Conclusion. IFN␣/␤-inducible gene signatures in whole blood are effective pharmacodynamic biomarkers to evaluate anti-IFN␣ mAb therapy in SLE. Anti-IFN␣ mAb can neutralize overexpression of IFN␣/␤-inducible genes in whole blood and lesional skin from SLE patients and has profound effects on signaling pathways that may be downstream of IFN␣ in SLE.

Nicotinic acetylcholine receptors (nAChRs) containing ␣7 subunits are thought to assemble as homomers. ␣7-nAChR function has been implicated in learning and memory, and alterations of ␣7-nAChR have been found in patients with Alzheimer's disease (AD). Here we report findings consistent with a novel, naturally occurring nAChR subtype in rodent, basal forebrain cholinergic neurons. In these cells, ␣7 subunits are coexpressed, colocalize, and coassemble with ␤2 subunit(s). Compared with homomeric ␣7-nAChRs from ventral tegmental area neurons, functional, presumably heteromeric ␣7␤2-nAChRs on cholinergic neurons freshly dissociated from medial septum/diagonal band (MS/DB) exhibit relatively slow kinetics of whole-cell current responses to nicotinic agonists and are more sensitive to the ␤2 subunit-containing nAChR-selective antagonist, dihydro-␤-erythroidine (DH␤E). Interestingly, presumed, heteromeric ␣7␤2-nAChRs are highly sensitive to functional inhibition by pathologically relevant concentrations of oligomeric, but not monomeric or fibrillar, forms of amyloid ␤ 1-42 (A␤ 1-42 ). Slow whole-cell current kinetics, sensitivity to DH␤E, and specific antagonism by oligomeric A␤ 1-42 also are characteristics of heteromeric ␣7␤2-nAChRs, but not of homomeric ␣7-nAChRs, heterologously expressed in Xenopus oocytes. Moreover, choline-induced currents have faster kinetics and less sensitivity to A␤ when elicited from MS/DB neurons derived from nAChR ␤2 subunit knock-out mice rather than from wild-type mice. The presence of novel, functional, heteromeric ␣7␤2-nAChRs on basal forebrain cholinergic neurons and their high sensitivity to blockade by low concentrations of oligomeric A␤ 1-42 suggests possible mechanisms for deficits in cholinergic signaling that could occur early in the etiopathogenesis of AD and might be targeted by disease therapies.

To identify potential pharmacodynamic biomarkers to guide dose selection in clinical trials using anti-interferon-alpha (IFN-α) monoclonal antibody (mAb) therapy for systemic lupus erythematosus (SLE), we used an Affymetrix human genome array platform and identified 110 IFN-α/β-inducible transcripts significantly upregulated in whole blood (WB) of 41 SLE patients. The overexpression of these genes was confirmed prospectively in 54 additional SLE patients and allowed for the categorization of the SLE patients into groups of high, moderate, and weak overexpressers of IFN-α/β-inducible genes. This approach could potentially allow for an accurate assessment of drug target neutralization in early trials of anti-IFN-α mAb therapy for SLE. Furthermore, ex vivo stimulation of healthy donor peripheral blood mononuclear cells with SLE patient serum and subsequent neutralization with anti-IFN-α mAb or anti-IFN-α receptor mAb showed that anti-IFN-α mAb has comparable effects of neutralizing the overexpression of type I IFN-inducible genes as that of anti-IFNAR mAb. These results suggest that IFN-α, and not other members of type I IFN family in SLE patients, is mainly responsible for the induction of type I IFN-inducible genes in WB of SLE patients. Taken together, these data strengthen the view of IFN-α as a therapeutic target for SLE.

Pancreatic neuroendocrine tumors (PanNETs) are complicated and often deadly neoplasms. A recent increased understanding of their molecular biology has contributed to expanded treatment options. DNA sequencing of samples derived from patients with PanNETs and rare genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Von Hippel-Lindau (VHL) syndrome reveals the involvement of MEN1, DAXX/ATRX, and the mammalian target of rapamycin (mTOR) pathways in PanNET tumorigenesis. Gene knock-out/knock-in studies indicate that inactivation of factors including MEN1 and abnormal PI3K/mTOR signaling uncouples endocrine cell cycle progression from the control of environmental cues such as glucose, leading to islet cell overgrowth. In addition, accumulating evidence suggests that further impairment of endothelial-endocrine cell interactions contributes to tumor invasion and metastasis. Recent phase III clinical trials have shown that therapeutic interventions, such as sunitinib and everolimus, targeting those signal transduction pathways improve disease-free survival rates. Yet, cure in the setting of advanced disease remains elusive. Further advances in our understanding of the molecular mechanisms of PanNETs and improved preclinical models will assist in developing personalized therapy utilizing novel drugs to provide prolonged control or even cure the disease.