The endoplasmic reticulum (ER) resident PKR-like kinase (PERK) is necessary for Akt activation in response to ER stress. We demonstrate that PERK harbors intrinsic lipid kinase, favoring diacylglycerol (DAG) as a substrate and generating phosphatidic acid (PA). This activity of PERK correlates with activation of mTOR and phosphorylation of Akt on Ser473. PERK lipid kinase activity is regulated in a phosphatidylinositol 3-kinase (PI3K) p85␣-dependent manner. Moreover, PERK activity is essential during adipocyte differentiation. Because PA and Akt regulate many cellular functions, including cellular survival, proliferation, migratory responses, and metabolic adaptation, our findings suggest that PERK has a more extensive role in insulin signaling, insulin resistance, obesity, and tumorigenesis than previously thought. The cellular membrane phospholipid phosphatidylinositol (PtdIns) and its metabolites are critical signaling molecules. PtdIns is synthesized at the endoplasmic reticulum (ER) membrane (1) and can then be phosphorylated at the 3, 4, and 5 positions of the inositol ring, generating a variety of monophosphorylated metabolites. These metabolites serve as precursors for additional phosphorylation events that result in the generation of PtdInsP 2 and PtdInsP 3 (10,42,48). PtdIns(4,5)P 2 is in turn hydrolyzed by phospholipase C (PLC), generating diacylglycerol (DAG) and inositol-1,4,5-triphosphate, resulting in the formation of additional molecules capable of intracellular signaling (38). PtdIns(3,4,5)P 3 (PIP 3 ) is generated by the PtdIns3-kinase (PI3K) superfamily of lipid kinases (16). PI3K activity and PIP 3 production are regulated by growth factors and chemokines, leading to the activation of Akt, one of the key growth and survival pathways in the cell. Additionally, generation of phosphatidic acid via the mitogen-stimulated activation of phospholipase D (PLD) provides another signal promoting Akt activation due to the phosphatidic acid-dependent assembly of the mTORC2 complex (18, 49).PI3K class I A is composed of a 110-kDa catalytic subunit (p110) and an 85-kDa adaptor/regulatory subunit (p85). Mammalian cells have three p110 isoforms (p110␣, -, and -␦), encoded by three separate genes and at least seven adaptor proteins that are generated through alternative splicing of transcripts encoded by three distinct genes, p85␣, p85, and p55␥. The p85 subunit has two Src homology 2 (SH2) domains that dock with phosphorylated tyrosine residues generated by activated tyrosine kinases (3, 11). The p85 SH2 domain mediates recruitment of the cytosolic PI3Ks to cellular membranes where their lipid substrates reside. The p110 subunit-binding site within p85 is located between the two SH2 domains (inter-SH2 domain) (13, 21).The ER transmembrane serine/threonine kinase PERK, or EIF2AK3 (26, 45), is activated under conditions of physiological ER stress such as low carbon source (glucose deprivation), low oxygen (hypoxia), or increased synthetic demand in secretory tissues, as well as by chemical inducers of ER str...
Background:The recent expansion of three-dimensional (3D) printing technology into the field of neurosurgery has prompted a widespread investigation of its utility. In this article, we review the current body of literature describing rapid prototyping techniques with applications to the practice of neurosurgery.Methods:An extensive and systematic search of the Compendex, Scopus, and PubMed medical databases was conducted using keywords relating to 3D printing and neurosurgery. Results were manually screened for relevance to applications within the field.Results:Of the search results, 36 articles were identified and included in this review. The articles spanned the various subspecialties of the field including cerebrovascular, neuro-oncologic, spinal, functional, and endoscopic neurosurgery.Conclusions:We conclude that 3D printing techniques are practical and anatomically accurate methods of producing patient-specific models for surgical planning, simulation and training, tissue-engineered implants, and secondary devices. Expansion of this technology may, therefore, contribute to advancing the neurosurgical field from several standpoints.
Background Advances in white matter tractography enhance neurosurgical planning and glioma resection, but is limited by biological variables such as edema, mass effect, and tract infiltration, or selection biases related to regions of interest (ROIs) or fractional anisotropy (FA) values. Objective To provide an automated tract identification paradigm that corrects for artifacts created by tumor edema and infiltration, as well as providing a consistent, accurate method of fiber tractography. Methods An automated tract identification paradigm was developed and evaluated for glioma surgery. A fiber bundle atlas was generated from six healthy participants. Fibers of a test set (including three healthy participants and ten patients with brain tumors) were clustered adaptively using this atlas. Reliability of identified tracts in both groups was assessed by comparison with two experts, using Cohen's kappa to quantify concurrence. We evaluated six major fiber bundles: cingulum bundle (CB), fornix (FR), uncinate fasciculus (UF), arcuate fasciculus (AF), inferior fronto-occipital fasciculus (IFOF), and inferior longitudinal fasciculus (ILF) – the latter three tracts mediating language function. Results The automated paradigm demonstrated a reliable and practical method to identify white mater tracts, despite mass effect, edema, and tract infiltration. When the tumor demonstrated significant mass effect or shift, the automated approach was useful to provide an initialization to guide the expert with identification of the specific tract of interest. Conclusion We report a reliable paradigm for automated identification of white matter pathways in patients with gliomas. This approach should enhance the neurosurgical objective of maximal safe resections.
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