tbuckley/cabot-search huggingface dataset:
Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights from in Vivo Manipulation of Sphingolipid Metabolism
Authors: William L. Holland, Scott A. Summers
Journal: Endocrine Reviews (2008)

Obesity and dyslipidemia are risk factors for metabolic disorders including diabetes and cardiovascular disease. Sphingolipids such as ceramide and glucosylceramides, while being a relatively minor component of the lipid milieu in most tissues, may be among the most pathogenic lipids in the onset of the sequelae associated with excess adiposity. Circulating factors associated with obesity (e.g., saturated fatty acids, inflammatory cytokines) selectively induce enzymes that promote sphingolipid synthesis, and lipidomic profiling reveals relationships between tissue sphingolipid levels and certain metabolic diseases. Moreover, studies in cultured cells and isolated tissues implicate sphingolipids in certain cellular events associated with diabetes and cardiovascular disease, including insulin resistance, pancreatic β-cell failure, cardiomyopathy, and vascular dysfunction. However, definitive evidence that sphingolipids contribute to insulin resistance, diabetes, and atherosclerosis has come only recently, as researchers have found that pharmacological inhibition or genetic ablation of enzymes controlling sphingolipid synthesis in rodents ameliorates each of these conditions. Herein we will review the role of ceramide and other sphingolipid metabolites in insulin resistance, β-cell failure, cardiomyopathy, and vascular dysfunction, focusing on these in vivo studies that identify enzymes controlling sphingolipid metabolism as therapeutic targets for combating metabolic disease.
fMet-Leu-Phe receptor expression by an interstitial cell in rabbit right atrium following left ventricular myocardial infarction.
Authors: C G Dunkel, J E Saffitz, A S Evers
Journal: Circulation Research (1989)

Previous studies have shown that rabbit hearts subjected to in vivo left ventricular myocardial infarction and subsequent ex vivo perfusion respond to N-formylmethionyl-leucyl-phenylalanine (fMLP) with enhanced eicosanoid synthesis. This synthetic response occurs primarily in the right cardiac atrium, a site distant from the injury, and is not the result of increased enzymatic capacity for arachidonate metabolism. To further investigate the mechanism of this enhanced synthetic response, [3H]fMLP binding was characterized and binding sites were localized autoradiographically in intact tissue sections prepared from control hearts and hearts subjected to left ventricular myocardial infarction (1, 2, and 4 days postinfarction). Analysis of binding isotherms revealed a saturable high affinity (KD approximately 1 nM) fMLP binding site in the right cardiac atrium. After myocardial infarction specific binding in right atria (2 day) increased 12-fold (Bmax = 14.8 +/- 2.4 fmol/cm2) compared with normal controls (Bmax = 1.2 +/- 0.1 fmol/cm2). Specific binding of fMLP also increased in the infarcted zone of left ventricle, but Bmax was only 30-50% that of right atria. Light microscopic autoradiography studies revealed that atrial fMLP binding sites were highly concentrated in small morphologically undifferentiated cells located in interstitial and perivascular spaces. These results demonstrate the existence of a formylated peptide receptor on a nonleukocytic cell and illustrate its regulation following left ventricular injury.
Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria
Authors: Antonio M. Risitano, Daniel Ricklin, Yijun Huang, Edimara S. Reis, Hui Chen, Patrizia Ricci, Zhuoer Lin, Caterina Pascariello, Maddalena Raia, Michela Sica, Luigi Del Vecchio, Fabrizio Pane, Florea Lupu, Rosario Notaro, Ranillo R. G. Resuello, Robert A. DeAngelis, John D. Lambris
Journal: Blood (2014)
Somatic p.T771R KDR (VEGFR2) Mutation Arising in a Sporadic Angioma During Ramucirumab Therapy
Authors: Young H. Lim, Ian D. Odell, Christine J. Ko, Keith A. Choate
Journal: JAMA Dermatology (2015)

Inhibition of angiogenesis is an effective anticancer strategy because neoplasms require a rich blood supply. Ramucirumab, approved by the US Food and Drug Administration in 2014 to treat gastric adenocarcinomas and non-small cell lung carcinomas, targets vascular endothelial growth factor 2 (VEGFR2). We identified a patient prescribed a regimen of irinotecan hydrochloride, cetuximab, and ramucirumab for metastatic rectal cancer (diagnosed in November 2013 and treated through early January 2015) who developed a new-onset, expanding vascular lesion on his right leg. Via exome sequencing, we found that the lesion contained a single somatic mutation in KDR (encodes VEGFR2), possibly in response to ramucirumab. Vascular tumors are not a known complication of antiangiogenic therapeutics.Exome sequencing of the well-demarcated, blanching vascular lesion on the lateral right shin revealed a somatic p.T771R mutation in KDR, without evidence of other somatic mutations or loss of heterozygosity. Histological features included lobules of small vessels within the dermis, resembling a tufted angioma.A potential adverse effect of ramucirumab in combination therapy is the development of sporadic angiomas. The p.T771R mutation was previously implicated in autophosphorylation of VEGFR2 and reported in angiosarcomas alongside other driver mutations. Our observations suggest that this mutation confers a proliferative advantage in the setting of ramucirumab therapy. Patients receiving ramucirumab should be monitored for the development of new vascular lesions.
Can Fragmented QRS On 12 Derivation ECG Predict Thrombolytic Therapy Success In Acute ST Elevated Myocardial Infarction?
Authors: Zülkif Tanrıverdi, Mustafa Aytek Şimşek, Barış Ünal, Hüseyin Dursun, Ömer Kozan, Dayimi Kaya
Journal: Journal of the American College of Cardiology (2013)
ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity
Authors: Jiaping Gu, Chi Wai Lee, Yanjie Fan, Daniel Komlos, Xin Tang, Chicheng Sun, Kuai Yu, H Criss Hartzell, Gong Chen, James R Bamburg, James Q Zheng
Journal: Nature Neuroscience (2010)
MDA-9/Syntenin and IGFBP-2 Promote Angiogenesis in Human Melanoma
Authors: Swadesh K. Das, Sujit K. Bhutia, Belal Azab, Timothy P. Kegelman, Leyla Peachy, Prasanna K. Santhekadur, Santanu Dasgupta, Rupesh Dash, Paul Dent, Steven Grant, Luni Emdad, Maurizio Pellecchia, Devanand Sarkar, Paul B. Fisher
Journal: Cancer Research (2012)

Melanoma differentiation-associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma, and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, chorioallantoic membrane (CAM) assays and xenograft tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several proangiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/syntenin in which MDA-9/syntenin interacts with the extracellular matrix (ECM), activating Src and FAK resulting in activation by phosphorylation of Akt, which induces hypoxia inducible factor 1-α (HIF-1α). The HIF-1α activates transcription of insulin growth factor-binding protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell nonautonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (nonautonomous).
The effect of salicylates on the hemostatic properties of platelets in man
Authors: Harvey J. Weiss, Louis M. Aledort, Shaul Kochwa
Journal: Journal of Clinical Investigation (1968)

Ingestion of 1.5 g of aspirin, but not of sodium salicylate, produced a significant prolongation of the bleeding time in six normal male subjects when compared with the effects of a placebo. Similar differences in the effect of the two drugs on platelets was also observed. Aspirin ingestion resulted in impaired platelet aggregation by connective tissue and was associated with a decreased release of platelet adenosine diphosphate (ADP); sodium salicylate had no effect on these values. In vitro, incubation of platelet-rich plasma with an optimum aspirin concentration of 0.50 mmole/liter (0.045 mg/ml) inhibited both the adhesion of platelets to connective tissue and the release of ADP as well as the secondary wave of platelet aggregation produced with ADP or epinephrine; sodium salicylate had no effect on these reactions, which were also normal in patients with von Willebrand's disease. The inhibitory effect produced by ingesting a single 1.8 g dose of aspirin was detectable for 4-7 days at which time salicylate was no longer detectable in the blood, which suggested an irreversible effect on the platelet. Aspirin also inhibited the release of platelet adenosine triphosphate (ATP), but had no effect on the platelet surface charge, available platelet ATP or ADP, or the destruction of ADP by plasma ADPase. These studies lend further support to the hypothesis that ingestion of aspirin, in contrast to sodium salicylate, prolongs the bleeding time by inhibiting the release of platelet ADP, perhaps reflecting the findings in other cell systems which suggest that aspirin alters membrane permeability.
Increased neutral protease and collagenase activity in recessive dystrophic epidermolysis bullosa
Authors: K. TAKAMORI, K. NAITO, A. TANEDA, H. OGAWA
Journal: British Journal of Dermatology (1983)

Journal Article Increased neutral protease and collagenase activity in recessive dystrophic epidermolysis bullosa Get access K. TAKAMORI, K. TAKAMORI Department of Dermatology, School of Medicine, Juntendo University, Tokyo 113, Japan Kenji Takamori, M.D., Ph.D., Department of Dermatology, School of Medicine, Juntendo University, 2‐1‐1 Hongo, Bunkyo‐ku, Tokyo 113, Japan. Search for other works by this author on: Oxford Academic Google Scholar K. NAITO, K. NAITO Department of Dermatology, School of Medicine, Juntendo University, Tokyo 113, Japan Search for other works by this author on: Oxford Academic Google Scholar A. TANEDA, A. TANEDA Department of Dermatology, School of Medicine, Juntendo University, Tokyo 113, Japan Search for other works by this author on: Oxford Academic Google Scholar H. OGAWA H. OGAWA Department of Dermatology, School of Medicine, Juntendo University, Tokyo 113, Japan Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 108, Issue 6, 1 June 1983, Pages 687–694, https://doi.org/10.1111/j.1365-2133.1983.tb01081.x Published: 01 June 1983 Article history Accepted: 05 October 1982 Published: 01 June 1983
A Functional Variant in the Transcriptional Regulatory Region of Gene <i>LOC344967</i> Cosegregates with Disease Phenotype in Familial Nasopharyngeal Carcinoma
Authors: Ri-Cheng Jiang, Hai-De Qin, Mu-Sheng Zeng, Wei Huang, Bing-Jian Feng, Feng Zhang, Han-Kui Chen, Wei-Hua Jia, Li-Zhen Chen, Qi-Sheng Feng, Ru-Hua Zhang, Xing-Juan Yu, Mei-Zhen Zheng, Yi-Xin Zeng
Journal: Cancer Research (2006)

Abstract Nasopharyngeal carcinoma is a common malignancy in Southeast Asian countries, and genetic background is a well-known component of the complexity underlying its tumorigenic process. We have mapped a nasopharyngeal carcinoma susceptibility locus to chromosome 4p15.1-q12 in a previous linkage study on nasopharyngeal carcinoma pedigrees. In this study provided in this communication, we screened all the genes in this region, with a focus on exons, promoters, and the exon-intron boundary to identify nasopharyngeal carcinoma–associated mutations or functional variants. Importantly, we found a novel gene (LOC344967) with a single nucleotide polymorphism −32G/A in the promoter region. This gene is a member of the acyl CoA thioesterase family that plays an important role in fatty acid metabolism and is involved in the progression of various types of tumors. The −32A variant was found cosegregated with the disease phenotype in the nasopharyngeal carcinoma pedigrees that we previously used for the linkage study. Moreover, this −32A variant creates an activator protein (AP-1)–binding site in the transcriptional regulatory region of LOC344967, which significantly enhanced the binding of AP-1 to the promoter region and the transcription activity of the promoter in vivo. Furthermore, the expression of LOC344967 was significantly up-regulated at both mRNA and protein levels in nasopharyngeal carcinoma cells sharing the −32G/A genotype compared with nasopharyngeal carcinoma cells with the −32G/G genotype. Collectively, these results provide evidence that the −32A variant is a functional sequence change and may be related to nasopharyngeal carcinoma susceptibility in the families studied. (Cancer Res 2006; 66(2): 693-700)
31P-magnetic resonance spectroscopy assessment of subnormal oxidative metabolism in skeletal muscle of renal failure patients.
Authors: G E Moore, L A Bertocci, P L Painter
Journal: Journal of Clinical Investigation (1993)

In hemodialysis patients, erythropoietin increases hemoglobin, but often the corresponding increase in peak oxygen uptake is low. The disproportionality may be caused by impaired energy metabolism. 31P-magnetic resonance spectroscopy was used to study muscle energy metabolism in 11 hemodialysis patients, 11 renal transplant recipients, and 9 controls. Measurements were obtained during rest, static hand-grip, and rhythmic hand-grip; recoveries were followed to baseline. During static hand-grip, there were no between-group differences in phosphocreatine (PCr), inorganic phosphate (Pi), or PCr/(PCr + Pi), although intracellular pH was higher in hemodialysis patients than transplant recipients. During rhythmic hand-grip, hemodialysis patients exhibited greater fatigue than transplant recipients or controls, and more reduction in PCr/(PCr + Pi) than transplant recipients. Intracellular pH was higher in controls than either hemodialysis patients or transplant recipients. Recoveries from both exercises were similar in all groups, indicating that subnormal oxidative metabolism was not caused by inability to make ATP. The rhythmic data suggest transplantation normalizes PCr/(PCr + Pi), but not pH. In hemodialysis patients, subnormal oxidative metabolism is apparently caused by limited exchange of metabolites between blood and muscle, rather than intrinsic oxidative defects in skeletal muscle.
Prevalence of Nonpolypoid (Flat and Depressed) Colorectal Neoplasms in Asymptomatic and Symptomatic Adults
Authors: Roy M. Soetikno
Journal: JAMA (2008)

<h3>Context</h3>Colorectal cancer is the second leading cause of cancer death in the United States. Prevention has focused on the detection and removal of polypoid neoplasms. Data are limited on the significance of nonpolypoid colorectal neoplasms (NP-CRNs).<h3>Objectives</h3>To determine the prevalence of NP-CRNs in a veterans hospital population and to characterize their association with colorectal cancer.<h3>Design, Setting, and Patients</h3>Cross-sectional study at a veterans hospital in California with 1819 patients undergoing elective colonoscopy from July 2003 to June 2004.<h3>Main Outcome Measures</h3>Endoscopic appearance, location, size, histology, and depth of invasion of neoplasms.<h3>Results</h3>The overall prevalence of NP-CRNs was 9.35% (95% confidence interval [95% CI], 8.05%-10.78%; n = 170). The prevalence of NP-CRNs in the subpopulations for screening, surveillance, and symptoms was 5.84% (95% CI, 4.13%-8.00%; n = 36), 15.44% (95% CI, 12.76%-18.44%; n = 101), and 6.01% (95% CI, 4.17%-8.34%; n = 33), respectively. The overall prevalence of NP-CRNs with in situ or submucosal invasive carcinoma was 0.82% (95% CI, 0.46%-1.36%; n = 15); in the screening population, the prevalence was 0.32% (95% CI, 0.04%-1.17%; n = 2). Overall, NP-CRNs were more likely to contain carcinoma (odds ratio, 9.78; 95% CI, 3.93-24.4) than polypoid lesions, irrespective of the size. The positive size-adjusted association of NP-CRNs with in situ or submucosal invasive carcinoma was also observed in subpopulations for screening (odds ratio, 2.01; 95% CI, 0.27-15.3) and surveillance (odds ratio, 63.7; 95% CI, 9.41-431). The depressed type had the highest risk (33%). Nonpolypoid colorectal neoplasms containing carcinoma were smaller in diameter as compared with the polypoid ones (mean [SD] diameter, 15.9 [10.2] mm vs 19.2 [9.6] mm, respectively). The procedure times did not change appreciably as compared with historical controls.<h3>Conclusion</h3>In this group of veteran patients, NP-CRNs were relatively common lesions diagnosed during routine colonoscopy and had a greater association with carcinoma compared with polypoid neoplasms, irrespective of size.
In Vivo Liver Regeneration Potential of Human Induced Pluripotent Stem Cells from Diverse Origins
Authors: Hua Liu, Yonghak Kim, Saul Sharkis, Luigi Marchionni, Yoon-Young Jang
Journal: Science Translational Medicine (2011)

Hepatic cells derived from human induced pluripotent stem cells of various origins contribute to liver regeneration in vivo.
Terminal Differentiation, Advanced Organotypic Maturation, and Modeling of Hypertrophic Growth in Engineered Heart Tissue
Authors: Malte Tiburcy, Michael Didié, Oliver Boy, Peter Christalla, Stephan Döker, Hiroshi Naito, Bijoy Chandapillai Karikkineth, Ali El-Armouche, Michael Grimm, Monika Nose, Thomas Eschenhagen, Anke Zieseniss, Doerthe M. Katschinski, Nazha Hamdani, Wolfgang A. Linke, Xiaoke Yin, Manuel Mayr, Wolfram-Hubertus Zimmermann
Journal: Circulation Research (2011)

Rationale: Cardiac tissue engineering should provide “realistic” in vitro heart muscle models and surrogate tissue for myocardial repair. For either application, engineered myocardium should display features of native myocardium, including terminal differentiation, organotypic maturation, and hypertrophic growth. Objective: To test the hypothesis that 3D-engineered heart tissue (EHT) culture supports (1) terminal differentiation as well as (2) organotypic assembly and maturation of immature cardiomyocytes, and (3) constitutes a methodological platform to investigate mechanisms underlying hypertrophic growth. Methods and Results: We generated EHTs from neonatal rat cardiomyocytes and compared morphological and molecular properties of EHT and native myocardium from fetal, neonatal, and adult rats. We made the following key observations: cardiomyocytes in EHT (1) gained a high level of binucleation in the absence of notable cytokinesis, (2) regained a rod-shape and anisotropic sarcomere organization, (3) demonstrated a fetal-to-adult gene expression pattern, and (4) responded to distinct hypertrophic stimuli with concentric or eccentric hypertrophy and reexpression of fetal genes. The process of terminal differentiation and maturation (culture days 7–12) was preceded by a tissue consolidation phase (culture days 0–7) with substantial cardiomyocyte apoptosis and dynamic extracellular matrix restructuring. Conclusions: This study documents the propensity of immature cardiomyocytes to terminally differentiate and mature in EHT in a remarkably organotypic manner. It moreover provides the rationale for the utility of the EHT technology as a methodological bridge between 2D cell culture and animal models.
Mutation of Tumor Suppressor Gene <i>Men1</i> Acutely Enhances Proliferation of Pancreatic Islet Cells
Authors: Robert W. Schnepp, Ya-Xiong Chen, Haoren Wang, Tim Cash, Albert Silva, J. Alan Diehl, Eric Brown, Xianxin Hua
Journal: Cancer Research (2006)

Abstract Multiple endocrine neoplasia type 1 (MEN1), an inherited tumor syndrome affecting endocrine organs including pancreatic islets, results from mutation of the tumor suppressor gene Men1 that encodes protein menin. Although menin is known to be involved in regulating cell proliferation in vitro, it is not clear how menin regulates cell cycle and whether mutation of Men1 acutely promotes pancreatic islet cell proliferation in vivo. Here we show that excision of the floxed Men1 in mouse embryonic fibroblasts (MEF) accelerates G0/G1 to S phase entry. This accelerated S-phase entry is accompanied by increased cyclin-dependent kinase 2 (CDK2) activity as well as decreased expression of CDK inhibitors p18Ink4c and p27Kip1. Moreover, Men1 excision results in decreased expression of p18Ink4c and p27Kip1 in the pancreas. Furthermore, complementation of menin-null cells with wild-type menin represses S-phase entry. To extend the role of menin in repressing cell cycle in cultured cells to in vivo pancreatic islets, we generated a system in which floxed Men1 alleles can be excised in a temporally controllable manner. As early as 7 days following Men1 excision, pancreatic islet cells display increased proliferation, leading to detectable enlargement of pancreatic islets 14 days after Men1 excision. These observations are consistent with the notion that an acute effect of Men1 mutation is accelerated S-phase entry and enhanced cell proliferation in pancreatic islets. Together, these results suggest a molecular mechanism whereby menin suppresses MEN1 tumorigenesis at least partly through repression of G0/G1 to S transition. (Cancer Res 2006; 66(10): 5707-15)
Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease
Authors: Edy Y Kim, John T Battaile, Anand C Patel, Yingjian You, Eugene Agapov, Mitchell H Grayson, Loralyn A Benoit, Derek E Byers, Yael Alevy, Jennifer Tucker, Suzanne Swanson, Rose Tidwell, Jeffrey W Tyner, Jeffrey D Morton, Mario Castro, Deepika Polineni, G Alexander Patterson, Reto A Schwendener, John D Allard, Gary Peltz, Michael J Holtzman
Journal: Nature Medicine (2008)
Fatal Leukemia in Interleukin 15 Transgenic Mice Follows Early Expansions in Natural Killer and Memory Phenotype Cd8+ T Cells
Authors: Todd A. Fehniger, Kazuhiro Suzuki, Anand Ponnappan, Jeffrey B. VanDeusen, Megan A. Cooper, Sorin M. Florea, Aharon G. Freud, Michael L. Robinson, Joan Durbin, Michael A. Caligiuri
Journal: The Journal of Experimental Medicine (2001)

Inflammation likely has a role in the early genesis of certain malignancies. Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis. Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms. Here, we engineered a transgenic mouse to overexpress IL-15 by eliminating these posttranscriptional checkpoints. IL-15 transgenic mice have early expansions in natural killer (NK) and CD8+ T lymphocytes. Later, these mice develop fatal lymphocytic leukemia with a T-NK phenotype. These data provide novel evidence that leukemia, like certain other cancers, can arise as the result of chronic stimulation by a proinflammatory cytokine.