Attenuating homologous recombination stimulates an AID-induced antileukemic effect.

Activation-induced cytidine deaminase (AID) is critical in normal B cells to initiate somatic hypermutation and immunoglobulin class switch recombination. Accumulating evidence suggests that AID is also prooncogenic, inducing cancer-promoting mutations or chromosome rearrangements. In this context, we find that AID is expressed in >40% of primary human chronic lymphocytic leukemia (CLL) cases, consistent with other reports.

Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors.

Background: Single-dose infusion of the agonistic anti-CD40 monoclonal antibody (mAb) CP-870,893 accomplishes immune activation and clinical responses in patients with advanced cancers, but repeat dosing of this agent has not been reported.

Results: Twenty-seven patients were enrolled. The most common adverse event was transient, infusion-related cytokine release syndrome (CRS).

Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells.

Purpose: Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer.

Experimental Design: In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics.

Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous toll-like receptor 9 stimulation.

Background: CD40 activation of antigen presenting cells (APC) such as dendritic cells (DC) and B cells plays an important role in immunological licensing of T cell immunity. Agonist CD40 antibodies have been previously shown in murine models to activate APC and enhance tumor immunity; in humans, CD40-activated DC and B cells induce tumor-specific T cells in vitro. Although clinical translation of these findings for patients with cancer has been previously limited due to the lack of a suitable and available drug, promising clinical results are now emerging from phase I studies of the agonist CD40 monoclonal antibody CP-870,893.

Altering regulatory T cell function in cancer immunotherapy: a novel means to boost the efficacy of cancer vaccines.

Cancers express tumor associated antigens that should elicit immune attack, but spontaneous immune rejection of established cancer is rare. Recent data demonstrate that specific and active tumor-mediated mechanisms hinder host anti-tumor immunity. CD4+CD25+ T regulatory cells (Tregs) are important mediators of active immune evasion in cancer.

Evidence for an interaction between leptin, T cell costimulatory antigens CD28, CTLA-4 and CD26 (dipeptidyl peptidase IV) in BCG-induced immune responses of leptin- and leptin receptor-deficient mice.

We assessed changes of the enzyme dipeptidyl peptidase IV (DPP IV, CD26) in the context of leptin or leptin receptor deficiency. C57BL/6 mice, Leptin-deficient mice (ob/ob mice, B6.V-Lep) and Leptin-receptor-deficient mice (db/db mice, B6.

Two immunocytochemical protocols for immunofluorescent detection of c-Fos positive neurons in the rat brain.

The immediate-early-gene product c-Fos is a well known marker of neuronal activation in the central nervous system. Thus, immunocytochemical methods to detect c-Fos in the brain are important tools in experimental studies that aim to map activated brain areas on a cellular level. Accordingly, we describe here two alternative protocols for c-Fos detection which are based on an indirect immunofluorescence technique.

Intraperitoneal injection of ghrelin induces Fos expression in the paraventricular nucleus of the hypothalamus in rats.

Ghrelin is a 28-amino acid peptide hormone secreted from the stomach that acts as a gut-brain peptide with potent stimulatory effects on food intake. The aim of the present study was to investigate the effects of peripheral ghrelin (1 and 10 nmol/rat) injected intraperitoneally (i.p.

Stimulation of neurons in rat ARC inhibits gastric acid secretion via hypothalamic CRF1/2- and NPY-Y1 receptors.

Neuropeptide Y (NPY) neuronal projections from the arcuate nucleus (ARC) have been proposed to target corticotropin-releasing factor (CRF)-positive neurons in the paraventricular nucleus (PVN) as part of the ARC-PVN axis. The existence of a positive feedback loop involving CRF receptors in the PVN has been suggested. Exogenous NPY and CRF in the PVN have been shown to inhibit gastric acid secretion.

The expression of T-cell surface antigens CTLA-4, CD26, and CD28 is modulated by inhibition of dipeptidylpeptidase IV (DPP IV, CD26) activity in murine stress-induced abortions.

Inhibition of DPP IV has been shown to abrogate the stress-related increase in murine abortions and a concomitant increase in gamma-interferon. The aim of the present study was to investigate a potential impact of the DPP IV inhibitor Isoleucine Cyanopyrrolidide on the expression of surface antigens involved in T-cell responses. DBA/2-mated CBA mice were stressed on day 5.

Differential induction of c-fos expression in brain nuclei by noxious and non-noxious colonic distension: role of afferent C-fibers and 5-HT3 receptors.

Experimental animal models have been established to gain insight into the pathogenesis and the mechanisms of visceral hyperalgesia in the irritable bowel syndrome (IBS). However, data about the mechanisms and pathways involved in the induction of neuronal activity in forebrain and midbrain structures by a physiological GI stimulus, like colonic distension (CD), in the range from non-noxious to noxious intensities are scarce. Thus, the effect of proximal CD with non-noxious (10 mmHg) and noxious (40 and 70 mmHg) stimulus intensities on neuronal activity in brain nuclei, as assessed by c-fos expression, was established.