Purpose: The insulin-like growth factor (IGF) signaling pathway is implicated in cellular mitogenesis, angiogenesis, tumor cell survival, and tumorigenesis. Inhibition of this pathway results in decreased cell growth, inhibition of tumor formation in animal models, and increased apoptosis in cells treated with cytotoxic chemotherapy. We generated and characterized a human monoclonal antibody that targeted the IGF receptor.Experimental Design: By use of XenoMouse technology, we generated CP-751,871, a fully human IgG2 antibody with high affinity (K d = 1.5 nmol/L) for human IGF-1R and evaluated its biological, pharmacologic, and antitumor properties.Results: This antibody blocks binding of IGF-1 to its receptor (IC 50 1.8 nmol/L), IGF-1-induced receptor autophosphorylation (IC 50 0.42 nmol/L) and induced the downregulation of IGF-1R in vitro and in tumor xenografts. The extent of IGF-1R down-regulation in vivo was proportional to CP-751,871 concentrations in the serum of tumor-bearing mice. Pharmacokinetic profiles in cynomolgus monkeys indicated a close to linear increase of exposure following i.v. dosing of antibody in the range of 3 to 100 mg/kg. CP-751,871 showed significant antitumor activity both as a single agent and in combination with Adriamycin, 5-fluorouracil, or tamoxifen in multiple tumor models. A biomarker assay was developed to establish the relationship between circulating antibody concentrations and down-regulation of IGF-1R in peripheral blood cells. The concentration of CP-751,871 required to down-regulate 50% of IGF-1R on peripheral blood cells was 0.3 nmol/L. Conclusion:These data suggest that inhibition of the IGF cascade by use of this monoclonal antibody may be of clinical benefit in the treatment of human cancers.

Faithfully recapitulating human physiology "in a dish" from a renewable source remains a holy grail for medicine and pharma. Many procedures have been described that, to a limited extent, exhibit human tissue-specific function in vitro. In particular, incomplete cellular differentiation and/or the loss of cell phenotype postdifferentiation play a major part in this void. We have developed an interdisciplinary approach to address this problem, using skill sets in cell biology, materials chemistry, and pharmacology. Pluripotent stem cells were differentiated to hepatocytes before being replated onto a synthetic surface. Our approach yielded metabolically active hepatocyte populations that displayed stable function for more than 2 weeks in vitro. Although metabolic activity was an important indication of cell utility, the accurate prediction of cellular toxicity in response to specific pharmacological compounds represented our goal. Therefore, detailed analysis of hepatocellular toxicity was performed in response to a custom-built and well-defined compound set and compared with primary human hepatocytes. Importantly, stem cell-derived hepatocytes displayed equivalence to primary human material. Moreover, we demonstrated that our approach was capable of modeling metabolic differences observed in the population. In conclusion, we report that pluripotent stem cell-derived hepatocytes will model toxicity predictably and in a manner comparable to current gold standard assays, representing a major advance in the field. STEM CELLS TRANSLATIONAL MEDICINE 2013;2:505-509

The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently described link between endoplasmic reticulum (ER) stress and dysregulation of lipid metabolism suggests a provocative integration of existing and emerging data. We provide new evidence from in vitro models indicating that proteasome inhibition and differential glucose transport blockade by protease inhibitors are proximal events eliciting an ER stress transcriptional response that can regulate lipogenic pathways in hepatocytes or adipocytes. Proteasome activity was inhibited in vitro by several protease inhibitors at clinically relevant (micromolar) levels. In the intact cells, protease inhibitors rapidly elicited a pattern of gene expression diagnostic of intracellular proteasome inhibition and activation of an ER stress response. This included induction of transcription factors GADD153, ATF4, and ATF3; amino acid metabolic enzymes; proteasome components; and certain ER chaperones. In hepatocyte lines, the ER stress response was closely linked to moderate increases in lipogenic and cholesterogenic gene expression. However, in adipocytes where GLUT4 was directly inhibited by some protease inhibitors, timedependent suppression of lipogenic genes and triglyceride synthesis was observed in coordination with the ER stress response. These results further link ER stress to dyslipidemia and contribute to a unifying mechanism for the pathophysiology of protease inhibitor-associated lipodystrophy, helping explain differences in clinical metabolic profiles among protease inhibitors.The development and clinical use of HIV protease inhibitors have contributed greatly to treatment of HIV-AIDS as a critical component of highly active antiretroviral therapy (HAART) regimens. With this efficacy has come recognition of an associated syndrome of metabolic side effects that is relevant in evaluating the long-term risk/benefit of treatment options (Calza et al., 2004). The constellation of metabolic problems with protease inhibitors includes hyperlipidemia, insulin resistance, peripheral lipoatrophy, central fat accumulation, and hepatic steatosis. Despite several hypotheses to explain clinical findings, the cellular and molecular mechanisms underlying this lipodystrophy-like syndrome are incompletely understood. Recent clinical studies in patients (Woerle et al., 2003;Calza et al., 2004) and in normal subjects (Purnell et al., 2000;Noor et al., 2002Noor et al., , 2004 have confirmed a direct connection between some protease inhibitors and metabolic effects, despite the complexity of multidrug therapy and virological and immunological responses during HAART. The recent emergence of a newer generation of protease inhibitor that exhibits antiviral efficacy without adverse affects on lipid or glucose parameters in the clinic (Haas et al

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Terahertz (THz) radiation (0.1~10 THz) shows great potential in agricultural products detection, biomedical, and security inspection in recent years. Machine learning methods are widely used to support the user demand of higher efficiency and high prediction accuracy. The technological and key challenges of machine learning methods are for THz spectroscopy and image data preprocessing, reconstruction algorithms, and qualitative and quantitative analysis. In this paper, an exhaustive review of recent related works of THz detection and imaging techniques and machine learning methods are presented. The application of machine learning methods combined with THz technology in quality inspection of agricultural products, biomedical, security inspection, and materials science are highlighted. Challenges of machine learning methods for these applications are addressed. The development trend and future perspectives of THz technology are also discussed.INDEX TERMS terahertz spectrum, terahertz imaging, machine learning, agricultural products, detection application.