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Background and Aim-Eosinophilic esophagitis (EoE) is characterized by medically/surgicallyresistant gastroesophageal reflux symptoms and dense squamous eosinophilia. Studies suggest that histological assessment of esophageal eosinophilia alone cannot reliably separate patients with EoE from those with gastroesophageal reflux disease (GERD). Our goal was to develop an assay to identify EoE patients and perhaps differentiate EoE from other causes of esophageal eosinophilia.

Cell migration requires spatial and temporal processes that detect and transfer extracellular stimuli into intracellular signals. The platelet-derived growth factor (PDGF) receptor is a cell surface receptor on fibroblasts that regulates proliferation and chemotaxis in response to PDGF. How the PDGF signal is transmitted accurately through the receptor into cells is an unresolved question. Here, we report a new intracellular signaling pathway by which DOCK4, a Rac1 guanine exchange factor, and Dynamin regulate cell migration by PDGF receptor endocytosis. We showed by a series of biochemical and microscopy techniques that Grb2 serves as an adaptor protein in the formation of a ternary complex between the PDGF receptor, DOCK4, and Dynamin, which is formed at the leading edge of cells. We found that this ternary complex regulates PDGFdependent cell migration by promoting PDGF receptor endocytosis and Rac1 activation at the cell membrane. This study revealed a new mechanism by which cell migration is regulated by PDGF receptor endocytosis.Chemoattractants bind to cell surface receptors, resulting in the cytoskeletal reorganization that permits the migration of cells toward a stimulus. In fibroblasts, the platelet-derived growth factor receptor ␤ (PDGFR␤) is a cell surface receptor tyrosine kinase (RTK) that regulates cell proliferation and chemotaxis in response to PDGF. PDGF binding activates PDGF receptor autophosphorylation, which in turn mediates a series of intracellular signaling cascades initiated by the association of SH2 domain-containing adaptor proteins (25). The adaptor protein Grb2 at the plasma membrane binds to Ras exchange factor Sos1, activating mitogen-activated protein kinase (MAPK) and cell proliferation signals (19). Grb2 also plays a critical role in receptor internalization via its interaction with dynamin, an exchange factor that facilitates receptor entry into endocytic vesicles (32). Grb2 regulates ubiquitination and the degradation of the receptor via its interaction with Cbl, an E3 ubiquitin ligase (33). While the role of Grb2 in modulating receptor levels and facilitating growth factor-dependent mitogenic signals is defined, its role in coordinating receptor-dependent chemotaxis has not been elucidated.The small GTPase Rac1 plays a crucial role in PDGF-mediated chemotaxis by regulating cortical actin at the leading edge of cells. PDGF receptor activation promotes GTP loading and the translocation of Rac1 to the cell membrane via guanine exchange factors (GEFs). The DOCK family of Rac1 GEFs, also called CDM proteins (for Caenorhabditis elegans ced-5, vertebrate DOCK180, and Drosophila myoblast city), are regulators of cell migration and have been implicated in various biological processes, such as lymphocyte migration, phagocytosis, and cancer progression (6,10,30,35). In migrating fibroblasts, DOCK proteins localize to the cell's leading edge via their interaction with the phospholipid PIP3, but a direct molecular link to PDGF has not been established (5). Biochemical studies show that R...

Context:Correcting hypovolemia is extremely important. Central venous pressure measurement is often done to assess volume status. Measurement of inferior vena cava (IVC) is conventionally done in the subcostal view using ultrasonography. It may not be possible to obtain this view in all patients.Aims:We therefore evaluated the limits of agreement between the IVC diameter measurement and variation in subcostal and that by the lateral transhepatic view.Settings and Design:Prospective study in a tertiary care referral hospital intensive care unit.Subjects and Methods:After Institutional Ethics Committee approval and informed consent, we obtained 175 paired measurements of the IVC diameter and variation in both the views in adult mechanically ventilated patients. The measurements were carried out by experienced researchers. We then obtained the limits of agreement for minimum, maximum diameter, percentage variation of IVC in relation to respiration.Statistical Analysis Used:Bland–Altman's limits of agreement to get precision and bias.Results:The limits of agreement were wide for minimum and maximum IVC diameter with variation of as much as 4 mm in both directions. However, the limits of agreement were much narrower when the percentage variation in relation to respiration was plotted on the Bland–Altman plot.Conclusions:We conclude that when it is not possible to obtain the subcostal view, it is possible to use the lateral transhepatic view. However, using the percentage variation in IVC size is likely to be more reliable than the absolute diameter alone. It is possible to use both views interchangeably.

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Fig. 1), and multiple small, shallow ulcers in the rectum (• " Fig. 2). Pathologic examination of biopsies showed exudates with necrosis, and pieces of colonic mucosa with severe acute and chronic inflammation, and focal acute cryptitis, plus multiple vacuolated and amoeboid structures (• " Fig. 3). Subsequent stool study with a special trichrome stain confirmed the diagnosis of Blastocystis hominis. He was treated with metronidazole for 10 days with symptom resolution, and no recurrence of diarrhea.

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Combinatorial libraries of artificial zinc-finger transcription factors (ZF-TFs) provide a robust tool for inducing and understanding various functional components of the cancer phenotype. Herein, we utilized combinatorial ZF-TF library technology to better understand how breast cancer cells acquire resistance to fulvestrant, a clinically important anti-endocrine therapeutic agent. From a diverse collection of nearly 400,000 different ZF-TFs, we isolated six ZF-TF library members capable of inducing stable, long-term anti-endocrine drug-resistance in two independent estrogen receptor-positive breast cancer cell lines. Comparative gene expression profile analysis of the six different ZF-TF-transduced breast cancer cell lines revealed five distinct clusters of differentially expressed genes. One cluster was shared among all 6 ZF-TF-transduced cell lines and therefore constituted a common fulvestrant-resistant gene expression signature. Pathway enrichment-analysis of this common fulvestrant resistant signature also revealed significant overlap with gene sets associated with an estrogen receptor-negative-like state and with gene sets associated with drug resistance to different classes of breast cancer anti-endocrine therapeutic agents. Enrichment-analysis of the four remaining unique gene clusters revealed overlap with myb-regulated genes. Finally, we also demonstrated that the common fulvestrant-resistant signature is associated with poor prognosis by interrogating five independent, publicly available human breast cancer gene expression datasets. Our results demonstrate that artificial ZF-TF libraries can be used successfully to induce stable drug-resistance in human cancer cell lines and to identify a gene expression signature that is associated with a clinically relevant drug-resistance phenotype.