1stOncology™: Cancer Intelligence Service – Page 17247 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

MiR-130b ameliorates murine lupus nephritis through targeting type I interferon pathway on resident renal cells.

Type I Interferon (IFN) is a critical pathogenic factor during the progression of Lupus Nephritis (LN). Although microRNAs (miRNAs) have been shown to control IFN response in immune cells of LN, the role of miRNAs in resident renal cells remain unclear. Here, we investigated the role of miR-130b in IFN pathway in renal cells, and its therapeutic effect in LN.
Kidney tissues from patients and mouse model of LN were collected for detecting miR-130b levels. Primary renal mesangial cells (RMCs) were used to determine the role of miR-130b in IFN pathway. We overexpressed miR-130b by administrating miR-130b agomir in an IFNα-accelerated LN mouse model to test its therapeutic efficacy.
Downregulated miR-130b expression was observed in kidney tissues from patients and mouse model of LN. Further analysis showed that underexpression of miR-130b negatively correlated with abnormal activation of IFN response in LN patients. In vitro, overexpressing miR-130b suppressed the downstream of type I IFN pathway in RMCs by targeting interferon regulatory factor 1 (IRF1). The opposite effect was observed when inhibited internal miR-130b expression. The inverse correlation between IRF1 and miR-130b levels was detected in renal biopsies from LN patients. More importantly, in vivo administration of miR-130b agomir reduced IFNα-accelerated LN progression, including decreased proteinuria, lower levels of complexes deposition and lack of glomeruli lesion.
miR-130b is a novel negative regulator of type I IFN pathway in renal cells. Overexpression of miR-130b in vivo ameliorates IFNα-accelerated LN, providing potential novel strategies for LN therapeutic intervention. This article is protected by copyright. All rights reserved.
© 2016, American College of Rheumatology.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

Metabolism of AM404 From Acetaminophen at Human Therapeutic Dosages in the Rat Brain.

Acetaminophen, an analgesic and antipyretic drug, has been used clinically for more than a century. Previous studies showed that acetaminophen undergoes metabolic transformations to form an analgesic compound, N-(4-hydroxyphenyl) arachidonamide (AM404), in the rodent brain. However, these studies were performed with higher concentrations of acetaminophen than are used in humans.
The aim of the present study was to examine the metabolism of AM404 from acetaminophen in the rat brain at a concentration of 20 mg/kg, which is used in therapeutic practice in humans, and to compare the pharmacokinetics between them.
We used rat brains to investigate the metabolism of AM404 from acetaminophen at concentrations (20 mg/kg) used in humans. In addition, we determined the mean pharmacokinetic parameters for acetaminophen and its metabolites, including AM404.
The maximum plasma concentrations of acetaminophen and AM404 in the rat brain were 15.8 µg/g and 150 pg/g, respectively, with corresponding AUC0-2h values of 8.96 μg hour/g and 117 pg hour/g. The tmax for both acetaminophen and AM404 was 0.25 hour.
These data suggest that AM404’s concentration-time profile in the brain is similar to those of acetaminophen and its other metabolites. Measurement of blood acetaminophen concentration seems to reflect the concentration of the prospective bioactive substance, AM404.

Profile of ramucirumab in the treatment of metastatic non-small-cell lung cancer.

The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC.

MUC1 (CD227): a multi-tasked molecule.

Mucin 1 (MUC1 [CD227]) is a high-molecular weight (&gt;400 kDa), type I membrane-tethered glycoprotein that is expressed on epithelial cells and extends far above the glycocalyx. MUC1 is overexpressed and aberrantly glycosylated in adenocarcinomas and in hematological malignancies. As a result, MUC1 has been a target for tumor immunotherapeutic studies in mice and in humans. MUC1 has been shown to have anti-adhesive and immunosuppressive properties, protects against infections, and is involved in the oncogenic process as well as in cell signaling. In addition, MUC1 plays a key role in the reproductive tract, in the immune system (affecting dendritic cells, monocytes, T cells, and B cells), and in chronic inflammatory diseases. Evidence for all of these roles for MUC1 is discussed herein and demonstrates that MUC1 is truly a multitasked molecule.

Applications of polymer micelles for imaging and drug delivery.

Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers, are widely considered as convenient nano-carriers for a variety of applications, such as diagnostic imaging, and drug and gene delivery. They have demonstrated a variety of favorable properties including biocompatibility, longevity, high stability in vitro and in vivo, capacity to effectively solubilize a variety of poorly soluble drugs, changing the release profile of the incorporated pharmaceutical agents, and the ability to accumulate in the target zone based on the enhanced permeability and retention effect. Moreover, additional functions can be imparted to the micelle-based delivery systems by engineering their surface for specific applications. Various targeting ligands can be attached for cell or intracellular accumulation at a site of interest. Also, the chelation or incorporation of imaging moieties into the micelle structure enables in vivo biodistribution studies. Moreover, pH-, thermo-, ultrasound-, enzyme- and light-sensitive block-copolymers allow for controlled micelle dissociation and triggered drug release in response to the pathological environment-specific stimuli and/or externally applied signals. The combination of these approaches can further improve specificity and efficacy of micelle-based drug delivery to promote the development of smart multifunctional micelles.
© 2015 Wiley Periodicals, Inc.