Prognostic value of circulating chromogranin A and soluble tumor necrosis factor receptors in advanced nonsmall cell lung cancer

Abstract

Improving the catalytic activity of cellulases requires screening variants against solid substrates. Expressing cellulases in microbial hosts is time‐consuming, can be cellulase specific, and often leads to inactive forms and/or low yields. These limitations have been obstacles for improving cellulases in a high‐throughput manner. We have developed a cell‐free expression system and used it to express 54 chimeric bacterial and archaeal endoglucanases (EGs), with and without cellulose binding modules (CBMs) at either the N‐ or C‐terminus, in active enzyme yields of 100–350 µg/mL. The platform was employed to systematically study the role of CBMs in cellulose hydrolysis toward a variety of natural and pretreated solid substrates, including ionic‐liquid pretreated Miscanthus and AFEX‐pretreated corn stover. Adding a CBM generally increased activity against crystalline Avicel, whereas for pretreated substrates the effect of CBM addition depended on the source of cellulase. The cell‐free expression platform can thus provide insights into cellulase structure‐function relationships for any substrate, and constitutes a powerful discovery tool for evaluating or engineering cellulolytic enzymes for biofuels production. Biotechnol. Bioeng. 2010;107:601–611. © 2010 Wiley Periodicals, Inc.

Chromogranin A Regulates Tumor Self-Seeding and Dissemination

“…CgA is present in the serum of normal subjects at about 1 nmol/L levels (25). Higher circulating levels (in the nanomolar range) have been detected in patients with neuroendocrine tumors and in subpopulations of patients with breast cancer, prostate cancer, small and nonsmall cell lung cancer (11,(26)(27)(28), or in patients with heart failure, renal failure, hypertension, rheumatoid arthritis, giant cell arthritis, sepsis, and atrophic gastritis, or treated with proton pump inhibitors (9,25,26,29,30). Thus, the doses used in this study are biologically relevant as they are in the range of those found in patients with nonneuroendocrine tumors.…”

Chromogranin A Restricts Drug Penetration and Limits the Ability of NGR-TNF to Enhance Chemotherapeutic Efficacy

“…1D). Notably, these levels of CgA are in the range of those observed in certain cancer patients with nonneuroendocrine tumors (31,37).…”

“…Administration of 1 mg of CgA, i.p., generated circulating levels of about 3 to 5 nmol/L at the time of NGR-TNF administration in our murine models. This dose was selected to achieve circulating levels similar to those observed in subpopulation of patients with nonneuroendocrine tumors (11,12,31,37). For example, although serum CgA in the blood of normal subjects is about 1 nmol/L (21), increased levels of CgA, up to 4 to 8 nmol/L have been detected in the sera of a subgroup of patients with NSCLC, despite the lack of neuroendocrine differentiation, with important prognostic implication (37).…”

“…This dose was selected to achieve circulating levels similar to those observed in subpopulation of patients with nonneuroendocrine tumors (11,12,31,37). For example, although serum CgA in the blood of normal subjects is about 1 nmol/L (21), increased levels of CgA, up to 4 to 8 nmol/L have been detected in the sera of a subgroup of patients with NSCLC, despite the lack of neuroendocrine differentiation, with important prognostic implication (37). Considering that the combination of NGR-TNF and chemotherapy is currently under investigation in patients with NSCLC, hepatocellular carcinoma, or other nonneuroendocrine tumors (9)(10)(11)(12)(13)(14), the results showing inhibitory activity of CgA in animal models of nonneuroendocrine tumors might be clinically relevant.…”

“…Interestingly, in 3 studies carried out on SCLC, NSCLC, and prostate cancer, the response rates to chemotherapy inversely correlated with baseline CgA (37,47,48). However, another study on prostate cancer, a tumor that may undergo neuroendocrine differentiation, showed higher response rates in patients with high baseline CgA (49).…”