Although most of the included studies were located through database searches, our subsequent hand search turned up several more relevant articles, most of which had not been indexed under terms relating. As a result, despite our extensive hand search, we may have missed some relevant articles if they were not indexed in MEDLINE or EMBASE under a term relating to administrative data or validation. Our findings are also subject to publication bias, wherein reports of HF codes having poor validity may have been differentially withheld from publication. The endoplasmic reticulum is the intracellular organelle where proteins with a signal sequence are originally directed to be folded and glycosylated before they are processed through the secretory pathway destined for cell membranes, organelles or the extracellular space. Proteins enter the secretory pathway through translocons in the ER membrane in association with ER lumenal chaperones, such as calnexin, BiP and protein disulfide isomerase. Only properly folded proteins leave the ER within vesicles to the Golgi and misfolded proteins are transported back into the cytosol for degradation by proteosomes. The ER lumen has a remarkable ability to maintain homeostasis and any physiological or pathological stimuli that leads to an increase in misfolded proteins, such as alterations in re-dox balance and calcium concentrations, glucose deprivation, presence of mutant proteins or even increased production of normal secretory proteins can trigger the ER stress response. Activation of the ER stress response is critical in the etiology of a number of diseases, including diabetes and neurodegeneration, as well as cancer. Cells react to ER stress by activating a series of sensors termed the Desmethyl Erlotinib unfolded protein response, which leads to a temporary inhibition of protein synthesis and an increase in synthesis of ER chaperone proteins which promote protein VU 0364439 folding, secretion and degradation to reduce the unfolded protein load in the ER. Trafficking through the secretory pathway has traditionally been measured in the medium by using radioactively labeled endogenous glycoproteins, or by DNA transfection of cells with viral glycoproteins or secreted alkaline phosphatase.