Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy.

Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells.

Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors.

CSF1 receptor inhibition of tenosynovial giant cell tumor using novel disease-specific MRI measures of tumor burden.

Monitoring treatment of tenosynovial giant cell tumor (TGCT) is complicated by the irregular shape and asymmetrical growth of the tumor. We compared responses to pexidartinib by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with those by tumor volume score (TVS) and modified RECIST (m-RECIST).

Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT.

Purpose: To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity.

Patients And Methods: From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO).

Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial.

Background: Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection.

Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.

Background: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R).

Methods: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation.

Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis.

Background: Peginesatide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease. We evaluated the safety and efficacy of peginesatide, as compared with another ESA, darbepoetin, in 983 such patients who were not undergoing dialysis.

Methods: In two randomized, controlled, open-label studies (PEARL 1 and 2), patients received peginesatide once a month, at a starting dose of 0.

Interactions between Tat of HIV-2 and transcription factor Sp1.

Tat of HIV-2 (Tat-2) requires host cellular factors for optimal function. We show that transactivation by Tat-2 of the HIV promoter requires cis-acting binding sites for Sp1 or Sp1 brought to the promoter via a heterologous system. We demonstrate that an activation domain in Tat-2 consists of one of two potential alpha-helices in the amino-terminal region, the cysteine-rich region, and the core region and that this independent activation domain requires cis-acting Sp1-binding sites for function.

STAT1 pathway is involved in activation of caprine arthritis-encephalitis virus long terminal repeat in monocytes.

The caprine arthritis-encephalitis virus (CAEV) long terminal repeat (LTR) is activated by gamma interferon (IFN-gamma) in promonocytic cells. We have previously shown that a 70-bp element is necessary and sufficient for the response of the CAEV LTR to this cytokine. At the 5' end, this 70-bp IFN-gamma response element contains sequence similarity to the gamma activated site (GAS).

Activation of caprine arthritis-encephalitis virus long terminal repeat by gamma interferon.

Caprine arthritis-encephalitis virus (CAEV) is a lymphotropic lentivirus whose replication increases during monocyte maturation. We examined gene expression directed by the CAEV long terminal repeat (LTR) in a promonocytic cell line stimulated with several agents. Our results demonstrate that the CAEV LTR is activated by treatment of immature monocytes with gamma interferon (IFN-gamma) or a phorbol ester but not with tumor necrosis factor alpha or lipopolysaccharide.

Function of exon 2 in optimal trans-activation by Tat of HIV type 2.

HIV-1 and HIV-2 are human retroviruses whose life cycles require viral regulatory proteins, one of which is the trans-activator, Tat. Tat of HIV-1 (Tat-1) displays modular function with independent activation function localized to the amino-terminal, cysteine-rich, and core regions and independent RNA-binding function localized to a basic region. These functional domains are contained in the first of two exons encoding Tat-1; deletion of exon 2 does not contribute to functional domains of Tat-1.

Second exon of Tat of HIV-2 is required for optimal trans-activation of HIV-1 and HIV-2 LTRs.

To determine conditions for optimal trans-activation by Tat of HIV-2, genomic DNAs and cDNAs encoding Tat of HIV-2 were tested on their homologous (HIV-2) and heterologous (HIV-1) long terminal repeats (LTRs). It has been previously reported that Tat of HIV-2 could efficiently trans-activate only its own LTR but not that of HIV-1. The inefficient trans-activation of HIV-1 is due, in part, to an acidic residue in the basic, RNA-binding domain of Tat of HIV-2.

Activation of human monocyte--derived macrophages with lipopolysaccharide decreases human immunodeficiency virus replication in vitro at the level of gene expression.

Activation of T lymphocytes infected with the human immunodeficiency virus-1 (HIV-1) results in enhancement of viral replication mediated in part by activation of cellular NF kappa B capable of binding directly to sequences in the viral long terminal repeat, or LTR. Together with CD4+ T cells, macrophages constitute a major target for infection by HIV-1. Unlike lymphocytes, however, stimulation of mononuclear phagocytes is not associated with cell division and proliferation.

Differences in transcriptional enhancers of HIV-1 and HIV-2. Response to T cell activation signals.

T cell activation results in high levels of HIV replication and is thought to be one mechanism leading to the conversion from latent to active viral infection. In HIV-1, the sequences that respond to these signaling events are found in the long terminal repeat (LTR) and comprise the transcriptional enhancer, which contains two conserved binding sites for the nuclear factor kappa B (NF kappa B). The corresponding region in the second AIDS retrovirus, HIV-2, contains a conserved and a divergent NF kappa B binding site.

Human immunodeficiency virus long terminal repeat responds to T-cell activation signals.

Human immunodeficiency virus (HIV), the causative agent of AIDS, infects and kills lymphoid cells bearing the CD4 antigen. In an infected cell, a number of cellular as well as HIV-encoded gene products determine the levels of viral gene expression and HIV replication. Efficient HIV-replication occurs in activated T cells.