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Masquerading as Sigmoid Adenocarcinoma: A Unique Presentation of High-Grade Serous Carcinoma Arising from Endometriosis.
Johnson WR, Kensinger CD, Desai MA, Hawkins AT
(2017) Am Surg 83: e316-317
MeSH Terms: Adenocarcinoma, Aged, Biopsy, Needle, Cystadenocarcinoma, Serous, Diagnosis, Differential, Endometrial Neoplasms, Endometriosis, Female, Humans, Immunohistochemistry, Risk Assessment, Sigmoid Neoplasms, Tomography, X-Ray Computed, Treatment Outcome
Added December 14, 2017
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1 Members
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14 MeSH Terms
Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease.
Williams AD, Korolkova OY, Sakwe AM, Geiger TM, James SD, Muldoon RL, Herline AJ, Goodwin JS, Izban MG, Washington MK, Smoot DT, Ballard BR, Gazouli M, M'Koma AE
(2017) PLoS One 12: e0179710
MeSH Terms: Biomarkers, Biopsy, Colitis, Ulcerative, Crohn Disease, Diagnosis, Differential, Gene Expression Profiling, Humans, Immunohistochemistry, Inflammatory Bowel Diseases, Intestinal Mucosa, Muramidase, Proctocolectomy, Restorative, Retrospective Studies, alpha-Defensins
Show Abstract · Added March 14, 2018
Inability to distinguish Crohn's colitis from ulcerative colitis leads to the diagnosis of indeterminate colitis. This greatly effects medical and surgical care of the patient because treatments for the two diseases vary. Approximately 30 percent of inflammatory bowel disease patients cannot be accurately diagnosed, increasing their risk of inappropriate treatment. We sought to determine whether transcriptomic patterns could be used to develop diagnostic biomarker(s) to delineate inflammatory bowel disease more accurately. Four patients groups were assessed via whole-transcriptome microarray, qPCR, Western blot, and immunohistochemistry for differential expression of Human α-Defensin-5. In addition, immunohistochemistry for Paneth cells and Lysozyme, a Paneth cell marker, was also performed. Aberrant expression of Human α-Defensin-5 levels using transcript, Western blot, and immunohistochemistry staining levels was significantly upregulated in Crohn's colitis, p< 0.0001. Among patients with indeterminate colitis, Human α-Defensin-5 is a reliable differentiator with a positive predictive value of 96 percent. We also observed abundant ectopic crypt Paneth cells in all colectomy tissue samples of Crohn's colitis patients. In a retrospective study, we show that Human α-Defensin-5 could be used in indeterminate colitis patients to determine if they have either ulcerative colitis (low levels of Human α-Defensin-5) or Crohn's colitis (high levels of Human α-Defensin-5). Twenty of 67 patients (30 percent) who underwent restorative proctocolectomy for definitive ulcerative colitis were clinically changed to de novo Crohn's disease. These patients were profiled by Human α-Defensin-5 immunohistochemistry. All patients tested strongly positive. In addition, we observed by both hematoxylin and eosin and Lysozyme staining, a large number of ectopic Paneth cells in the colonic crypt of Crohn's colitis patient samples. Our experiments are the first to show that Human α-Defensin-5 is a potential candidate biomarker to molecularly differentiate Crohn's colitis from ulcerative colitis, to our knowledge. These data give us both a potential diagnostic marker in Human α-Defensin-5 and insight to develop future mechanistic studies to better understand crypt biology in Crohn's colitis.
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14 MeSH Terms
Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus.
Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, Furey CG, Zhou X, Mansuri MS, Montejo J, Vera A, DiLuna ML, Delpire E, Alper SL, Gunel M, Gerzanich V, Medzhitov R, Simard JM, Kahle KT
(2017) Nat Med 23: 997-1003
MeSH Terms: Acetazolamide, Animals, Antioxidants, Blotting, Western, Bumetanide, Cerebral Hemorrhage, Cerebral Ventricles, Cerebrospinal Fluid, Choroid Plexus, Diuretics, Gene Knockdown Techniques, Gene Knockout Techniques, Hydrocephalus, Immunoblotting, Immunohistochemistry, Immunoprecipitation, Inflammation, NF-kappa B, Proline, Protein-Serine-Threonine Kinases, Rats, Rats, Wistar, Salicylanilides, Solute Carrier Family 12, Member 2, Sulfonamides, Thiocarbamates, Toll-Like Receptor 4
Show Abstract · Added April 3, 2018
The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.
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MeSH Terms
Accelerated differentiation of human induced pluripotent stem cells to blood-brain barrier endothelial cells.
Hollmann EK, Bailey AK, Potharazu AV, Neely MD, Bowman AB, Lippmann ES
(2017) Fluids Barriers CNS 14: 9
MeSH Terms: Astrocytes, Blood-Brain Barrier, Cell Differentiation, Cell Line, Culture Media, Culture Techniques, Endothelial Cells, Humans, Immunohistochemistry, Induced Pluripotent Stem Cells, Male, Pericytes, Time Factors
Show Abstract · Added April 26, 2017
BACKGROUND - Due to their ability to limitlessly proliferate and specialize into almost any cell type, human induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to generate human brain microvascular endothelial cells (BMECs), which compose the blood-brain barrier (BBB), for research purposes. Unfortunately, the time, expense, and expertise required to differentiate iPSCs to purified BMECs precludes their widespread use. Here, we report the use of a defined medium that accelerates the differentiation of iPSCs to BMECs while achieving comparable performance to BMECs produced by established methods.
METHODS - Induced pluripotent stem cells were seeded at defined densities and differentiated to BMECs using defined medium termed E6. Resultant purified BMEC phenotypes were assessed through trans-endothelial electrical resistance (TEER), fluorescein permeability, and P-glycoprotein and MRP family efflux transporter activity. Expression of endothelial markers and their signature tight junction proteins were confirmed using immunocytochemistry. The influence of co-culture with astrocytes and pericytes on purified BMECs was assessed via TEER measurements. The robustness of the differentiation method was confirmed across independent iPSC lines.
RESULTS - The use of E6 medium, coupled with updated culture methods, reduced the differentiation time of iPSCs to BMECs from thirteen to 8 days. E6-derived BMECs expressed GLUT-1, claudin-5, occludin, PECAM-1, and VE-cadherin and consistently achieved TEER values exceeding 2500 Ω × cm across multiple iPSC lines, with a maximum TEER value of 4678 ± 49 Ω × cm and fluorescein permeability below 1.95 × 10 cm/s. E6-derived BMECs maintained TEER above 1000 Ω × cm for a minimum of 8 days and showed no statistical difference in efflux transporter activity compared to BMECs differentiated by conventional means. The method was also found to support long-term stability of BMECs harboring biallelic PARK2 mutations associated with Parkinson's Disease. Finally, BMECs differentiated using E6 medium responded to inductive cues from astrocytes and pericytes and achieved a maximum TEER value of 6635 ± 315 Ω × cm, which to our knowledge is the highest reported in vitro TEER value to date.
CONCLUSIONS - Given the accelerated differentiation, equivalent performance, and reduced cost to produce BMECs, our updated methods should make iPSC-derived in vitro BBB models more accessible for a wide variety of applications.
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13 MeSH Terms
A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach.
Petersen CP, Meyer AR, De Salvo C, Choi E, Schlegel C, Petersen A, Engevik AC, Prasad N, Levy SE, Peebles RS, Pizarro TT, Goldenring JR
(2018) Gut 67: 805-817
MeSH Terms: Animals, Flow Cytometry, Gastric Mucosa, Immunohistochemistry, Interleukin-13, Interleukin-33, Macrophages, Metaplasia, Mice, Mice, Inbred C57BL, Mice, Knockout, Parietal Cells, Gastric, Peptides, Real-Time Polymerase Chain Reaction, Receptors, Interleukin, Signal Transduction, Stomach
Show Abstract · Added April 18, 2017
OBJECTIVE - Alternatively activated macrophages (M2) are associated with the progression of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. However, the precise mechanism(s) and critical mediators that induce SPEM are unknown.
DESIGN - To determine candidate genes important in these processes, macrophages from the stomach corpus of mice with SPEM (DMP-777-treated) or advanced SPEM (L635-treated) were isolated and RNA sequenced. Effects on metaplasia development after acute parietal cell loss induced by L635 were evaluated in interleukin (IL)-33, IL-33 receptor (ST2) and IL-13 knockout (KO) mice.
RESULTS - Profiling of metaplasia-associated macrophages in the stomach identified an M2a-polarised macrophage population. Expression of IL-33 was significantly upregulated in macrophages associated with advanced SPEM. L635 induced metaplasia in the stomachs of wild-type mice, but not in the stomachs of IL-33 and ST2 KO mice. While IL-5 and IL-9 were not required for metaplasia induction, IL-13 KO mice did not develop metaplasia in response to L635. Administration of IL-13 to ST2 KO mice re-established the induction of metaplasia following acute parietal cell loss.
CONCLUSIONS - Metaplasia induction and macrophage polarisation after parietal cell loss is coordinated through a cytokine signalling network of IL-33 and IL-13, linking a combined response to injury by both intrinsic mucosal mechanisms and infiltrating M2 macrophages.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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17 MeSH Terms
Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors.
Polosukhina D, Love HD, Correa H, Su Z, Dahlman KB, Pao W, Moses HL, Arteaga CL, Lovvorn HN, Zent R, Clark PE
(2017) Mol Oncol 11: 405-421
MeSH Terms: Animals, Base Sequence, Cell Movement, Cell Proliferation, Cell Transformation, Neoplastic, Disease Progression, Enzyme Activation, Humans, Immunohistochemistry, Kidney Neoplasms, Mice, Inbred C57BL, Mutation, Neoplasm Metastasis, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins p21(ras), Wilms Tumor, beta Catenin
Show Abstract · Added May 5, 2017
Wilms tumor (WT) is the most common renal neoplasm of childhood and affects 1 in 10 000 children aged less than 15 years. These embryonal tumors are thought to arise from primitive nephrogenic rests that derive from the metanephric mesenchyme during kidney development and are characterized partly by increased Wnt/β-catenin signaling. We previously showed that coordinate activation of Ras and β-catenin accelerates the growth and metastatic progression of a murine WT model. Here, we show that activating KRAS mutations can be found in human WT. In addition, high levels of phosphorylated AKT are present in the majority of WT. We further show in a mouse model and in renal epithelial cells that Ras cooperates with β-catenin to drive metastatic disease progression and promotes in vitro tumor cell growth, migration, and colony formation in soft agar. Cellular transformation and metastatic disease progression of WT cells are in part dependent on PI3K/AKT activation and are inhibited via pharmacological inhibition of this pathway. Our studies suggest both KRAS mutations and AKT activation are present in WT and may represent novel therapeutic targets for this disease.
© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
1 Communities
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18 MeSH Terms
New and Emerging Diagnostic and Prognostic Immunohistochemical Biomarkers in Prostate Pathology.
Giannico GA, Arnold SA, Gellert LL, Hameed O
(2017) Adv Anat Pathol 24: 35-44
MeSH Terms: Biomarkers, Tumor, Humans, Immunohistochemistry, Male, Prognosis, Prostatic Neoplasms
Show Abstract · Added April 18, 2017
The diagnosis of minimal prostatic adenocarcinoma can be challenging on prostate needle biopsy, and immunohistochemistry may be used to support the diagnosis of cancer. The International Society of Urologic Pathology currently recommends the use of the basal cell markers high-molecular-weight cytokeraratin and p63, and α-methylacyl-coenzyme-A racemase. However, there are caveats associated with the interpretation of these markers, particularly with benign mimickers. Another issue is that of early detection of presence and progression of disease and prediction of recurrence after clinical intervention. There remains a lack of reliable biomarkers to accurately predict low-risk cancer and avoid over treatment. As such, aggressive forms of prostate cancer may be missed and indolent disease may be subjected to unnecessary radical therapy. New biomarker discovery promises to improve early detection and prognosis and to provide targets for therapeutic interventions. In this review, we present the emerging immunohistochemical biomarkers of prostate cancer PTEN, ERG, FASN, MAGI-2, and SPINK1, and address their diagnostic and prognostic advantages and limitations.
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6 MeSH Terms
Embryonic Mutant Huntingtin Aggregate Formation in Mouse Models of Huntington's Disease.
Osmand AP, Bichell TJ, Bowman AB, Bates GP
(2016) J Huntingtons Dis 5: 343-346
MeSH Terms: Animals, Axons, Brain, Disease Models, Animal, Huntingtin Protein, Huntington Disease, Immunohistochemistry, Mice, Transgenic, Protein Aggregation, Pathological
Show Abstract · Added April 26, 2017
The role of aggregate formation in the pathophysiology of Huntington's disease (HD) remains uncertain. However, the temporal appearance of aggregates tends to correlate with the onset of symptoms and the numbers of neuropil aggregates correlate with the progression of clinical disease. Using highly sensitive immunohistochemical methods we have detected the appearance of diffuse aggregates during embryonic development in the R6/2 and YAC128 mouse models of HD. These are initially seen in developing axonal tracts and appear to spread throughout the cerebrum in the early neonate.
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9 MeSH Terms
Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy.
Wang X, Yao B, Wang Y, Fan X, Wang S, Niu A, Yang H, Fogo A, Zhang MZ, Harris RC
(2017) Diabetes 66: 494-504
MeSH Terms: Albuminuria, Animals, Cells, Cultured, Cyclooxygenase 2, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Fibrosis, Immunoblotting, Immunohistochemistry, Kidney, Macrophages, Male, Mice, Mice, Knockout, NF-kappa B, Neutrophil Infiltration, Neutrophils, Nitric Oxide Synthase Type II, Real-Time Polymerase Chain Reaction, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, T-Lymphocytes
Show Abstract · Added April 26, 2017
Diabetic nephropathy (DN) is characterized by increased macrophage infiltration, and proinflammatory M1 macrophages contribute to development of DN. Previous studies by us and others have reported that macrophage cyclooxygenase-2 (COX-2) plays a role in polarization and maintenance of a macrophage tissue-reparative M2 phenotype. We examined the effects of macrophage COX-2 on development of DN in type 1 diabetes. Cultured macrophages with COX-2 deletion exhibited an M1 phenotype, as demonstrated by higher inducible nitric oxide synthase and nuclear factor-κB levels but lower interleukin-4 receptor-α levels. Compared with corresponding wild-type diabetic mice, mice with COX-2 deletion in hematopoietic cells (COX-2 knockout bone marrow transplantation) or macrophages (CD11b-Cre COX2) developed severe DN, as indicated by increased albuminuria, fibrosis, and renal infiltration of T cells, neutrophils, and macrophages. Although diabetic kidneys with macrophage COX-2 deletion had more macrophage infiltration, they had fewer renal M2 macrophages. Diabetic kidneys with macrophage COX-2 deletion also had increased endoplasmic reticulum stress and decreased number of podocytes. Similar results were found in diabetic mice with macrophage PGE receptor subtype 4 deletion. In summary, these studies have demonstrated an important but unexpected role for macrophage COX-2/prostaglandin E/PGE receptor subtype 4 signaling to lessen progression of diabetic kidney disease, unlike the pathogenic effects of increased COX-2 expression in intrinsic renal cells.
© 2017 by the American Diabetes Association.
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24 MeSH Terms
Loss of Axin2 Causes Ocular Defects During Mouse Eye Development.
Alldredge A, Fuhrmann S
(2016) Invest Ophthalmol Vis Sci 57: 5253-5262
MeSH Terms: Alleles, Animals, Axin Protein, Disease Models, Animal, Eye, Eye Diseases, Gene Expression Regulation, Developmental, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Knockout, Organogenesis, Polymerase Chain Reaction, Wnt Signaling Pathway
Show Abstract · Added April 18, 2017
Purpose - The scaffold protein Axin2 is an antagonist and universal target of the Wnt/β-catenin pathway. Disruption of Axin2 may lead to developmental eye defects; however, this has not been examined. The purpose of this study was to investigate the role of Axin2 during ocular and extraocular development in mouse.
Methods - Animals heterozygous and homozygous for a Axin2lacZ knock-in allele were analyzed at different developmental stages for reporter expression, morphology as well as for the presence of ocular and extraocular markers using histologic and immunohistochemical techniques.
Results - During early eye development, the Axin2lacZ reporter was expressed in the periocular mesenchyme, RPE, and optic stalk. In the developing retina, Axin2lacZ reporter expression was initiated in ganglion cells at late embryonic stages and robustly expressed in subpopulations of amacrine and horizontal cells postnatally. Activation of the Axin2lacZ reporter overlapped with labeling of POU4F1, PAX6, and Calbindin. Germline deletion of Axin2 led to variable ocular phenotypes ranging from normal to severely defective eyes exhibiting microphthalmia, coloboma, lens defects, and expanded ciliary margin. These defects were correlated with abnormal tissue patterning in individual affected tissues, such as the optic fissure margins in the ventral optic cup and in the expanded ciliary margin.
Conclusions - Our results reveal a critical role for Axin2 during ocular development, likely by restricting the activity of the Wnt/β-catenin pathway.
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14 MeSH Terms