tbuckley/cabot-search huggingface dataset:
GPR40 Modulators: New Kid on the Block
Authors: Ananda Basu, Yogish C. Kudva, Rita Basu
Journal: Diabetes Care (2013)

Impairments in insulin secretion and action are the pathophysiological hallmarks of type 2 diabetes (1,2). Pharmacological approaches to restore β-cell function have led to the use of insulin secretagogues that include sulphonylureas, glinides, and glucagon-like peptide-1–based therapies. Of these, the latter hold particular clinical advantage because glucagon-like peptide-1–modulated insulin secretion is glucose dependent (3,4), thereby minimizing the risk for hypoglycemia—the bane of clinicians managing diabetes across the world.

Fatty acids have long been known (5) to modulate human β-cell function. While acutely fatty acids amplify glucose-stimulated insulin secretion, chronic elevation of free fatty acid (FFA) levels has been thought to inhibit insulin secretion through the phenomenon of “lipotoxicity” (6,7). The cellular/molecular intermediates that are involved in this complex modulation, elegantly summarized in ref. 5, include malonyl CoA/long-chain acyl-CoA, triglyceride/FFA cycling through diacylglycerol, G-protein–coupled receptor 40 (GPR40) and phospholipase A2.

G-protein–coupled receptors have recently emerged as novel therapeutic targets because they appear to be closely involved in the pathology of various metabolic disorders including obesity, dyslipidemia, and type 2 diabetes (8). Since the seminal article (9) in 2003 about the role of GPR40 (also known as FFA1R: free fatty acid 1 receptor) in long-chain fatty acid–mediated glucose-stimulated insulin secretion from rodent and human β-cells, there have been over 60 publications investigating the properties and modulators of this receptor as yet another potential therapeutic approach for the management of type 2 diabetes. GPR40 is expressed most abundantly in humans in pancreatic β-cells …
The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model
Authors: C Hourioux, R Patient, A Morin, E Blanchard, A Moreau, S Trassard, B Giraudeau, P Roingeard
Journal: Gut (2007)

<b>Background and aims:</b> The prevalence and severity of liver steatosis are higher in patients infected with genotype 3 hepatitis C virus (HCV) than in patients infected with other genotypes. HCV core protein is known to affect lipid metabolism, inducing lipid droplet accumulation both in vitro and in vivo. An in vitro cellular model was used to investigate whether an HCV core protein with residues specific to genotype 3 increased this phenomenon. <b>Methods:</b> Sequence comparisons for HCV core protein domain II, which is known to interact with lipid droplets, identified the phenylalanine (F) residue at position 164 as the only residue specific to genotype 3. The area covered by lipid droplets in sections of cells producing a wild-type genotype 1a HCV core protein was compared with that in cells producing a Y164F mutant protein. <b>Results:</b> Cumulative lipid droplet area was significantly greater in sections of cells producing the Y164F mutant HCV core protein than in cells producing the wild-type protein (p&lt;0.001). The frequency of cell sections containing more than 3 μm<sup>2</sup> of lipid droplets, in particular, was higher for the mutant than for the wild-type protein. <b>Conclusion:</b> The data provide a molecular explanation for HCV genotype 3-specific lipid accumulation. This difference between genotypes may be due to phenylalanine having a higher affinity for lipids than tyrosine (Y). These observations provide useful information for further studies of the mechanisms involved in HCV-induced steatosis.
Experimental approaches to the study of primordial germ cell lineage and proliferation
Authors: M. De Felici
Journal: Human Reproduction Update (2004)

New information regarding primordial germ cell (PGC's) segregation and proliferation over the last decade is reviewed. Advances have been obtained in the mouse but current knowledge of human PGC's remains scant. Questions still fully or partially unresolved about the emergence of the germline in mammals are addressed. (i) When and where is the germ line set aside in the embryo? (ii) How is the germ line segregated from the somatic lineages? (iii) Which factors guide PGC's to the gonadal ridges? (iv) Which factors regulate PGC's proliferation? The main purpose of this review is to outline the information obtained using mainly in vitro culture systems about two aspects of these processes namely the segregation of PGC's and their proliferation.
Histologic Observations in Human Hepatitis Non-A, Non-B
Authors: Hans P. Dienes, Hans Popper, Wolfgang Arnold, Hartmut Lobeck
Journal: Hepatology (1982)

Specimens from 57 patients with acute or chronic hepatitis non–A, non–B (HNANB), mostly mild to moderate, were studied by light and, in 22 instances, by electron microscopy. They were compared to specimens of hepatitis A and hepatitis B on file or obtained simultaneously with the HNANB cases. In the HNANB material, two types of light–microscopic lesions were noted in the lobular parenchyma singly or in combination. One was an eosinophilic alteration of the hepatocytic cytoplasm associated with many acidophilic bodies. Conspicuous alteration were often accompanied by microvesicular steatosis. This lesion was associated with nuclear particles detectable by electron microscopy. The second lesion consisted of sinusoidal cell activation which was prominent in some cases. From experiences with chimpanzees, these features were tentatively considered to be stages of the same process. Both lesions were associated with portal and usually mild periportal inflammation which was not related to the degree and type of parenchymal reaction. They were also observed in chronic stages, making the differentiation between acute and chronic HNANB difficult. Active hepatitis B seems to differ from HNANB primarily by the conspicuous presence of lymphocytes in the lobular parenchyma often in contact with hepatocytes, acidophilic bodies, and a more uniform portal inflammatory reaction. In hepatitis A, hepatocellular injury was conspicuously periportal. In HNANB, a cytopathic effect rather than lymphocytic immune attack appears to be of greater significance than in the other forms of viral hepatitis. The recurrence of lobular mainly eosinophilic changes may explain chronicity.
Clnk, a Novel Slp-76–Related Adaptor Molecule Expressed in Cytokine-Stimulated Hemopoietic Cells
Authors: Ming Yu Cao, Dominique Davidson, Jie Yu, Sylvain Latour, André Veillette
Journal: The Journal of Experimental Medicine (1999)

We have identified a novel Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76)–related molecule which we have termed Clnk (for cytokine-dependent hemopoietic cell linker). Unlike its relatives SLP-76 and B cell linker protein (Blnk), Clnk is not expressed uniformly within a given hemopoietic cell lineage. Even though it can be detected in several cell types, including T cells, natural killer cells, and mast cells, its expression seems to be strictly dependent on sustained exposure to cytokines such as interleukin (IL)-2 and IL-3. Strong support for the notion that Clnk is involved in immunoreceptor signaling was provided by the observation that it inducibly associated with at least one tyrosine-phosphorylated polypeptide (p92) in response to immunoreceptor stimulation. Moreover, transient expression of Clnk caused an increase in immunoreceptor-mediated signaling events in a T cell line. Taken together, these results show that Clnk is a novel member of the SLP-76 family selectively expressed in cytokine-stimulated hemopoietic cells. Furthermore, they suggest that Clnk may be involved in a cross-talk mechanism between cytokine receptor and immunoreceptor signaling.
Enhanced Functional Gap Junction Neoformation by Protein Kinase A–Dependent and Epac-Dependent Signals Downstream of cAMP in Cardiac Myocytes
Authors: Satoshi Somekawa, Shigetomo Fukuhara, Yoshikazu Nakaoka, Hisakazu Fujita, Yoshihiko Saito, Naoki Mochizuki
Journal: Circulation Research (2005)

Gap junctions (GJs) constituted by neighboring cardiac myocytes are essential for gating ions and small molecules to coordinate cardiac contractions. cAMP is suggested to be a potent stimulus for enhancement of GJ function. However, it remains elusive how cAMP potentiates the GJ of cardiomyocytes. Here we demonstrated that the gating function of GJ is enhanced by the protein kinase A (PKA)-dependent signal, and that the accumulation of connexin43 (Cx43), the most abundant Cx in myocytes, is enhanced by an exchange protein directly activated by cAMP (Epac) (Rap1 activator)-dependent signal. The gating function of GJs was analyzed by microinjected dye transfer method. The accumulation of Cx43 was analyzed by quantitative immunostaining. Using the PKA-specific activator N6-benzoyladenosine-3',5'-cyclic monophosphate (6Bnz) and Epac-specific activator 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8CPT), we could delineate the two important downstream signals of cAMP for enhanced GJ neoformation. Whereas 6Bnz potentiated gating function of GJs with slight accumulation of Cx43 at cell-cell contacts, 8CPT remarkably enhanced the accumulation of Cx43 with a slight effect on gating. We further noticed that adherens junctions (AJs) were maturated by 8CPT, as marked by increased neural-cadherin immunostaining. Because AJ formation precedes the GJ formation, AJ formation accelerated by Epac-Rap1 signal may result in enhanced GJ formation. The involvement of Epac-Rap1 signal in GJ neoformation was further confirmed by evidence that inactivation of Rap1 by overexpression of Rap1GAP1b perturbed the accumulation of Cx43 at cell-cell contacts. Collectively, PKA and Epac cooperatively enhance functional GJ neoformation in cardiomyocytes.
Angiogenic endothelium shows lactadherin-dependent phagocytosis of aged erythrocytes and apoptotic cells
Authors: Marcel H. A. M. Fens, Enrico Mastrobattista, Anko M. de Graaff, Frits M. Flesch, Anton Ultee, Jan T. Rasmussen, Grietje Molema, Gert Storm, Raymond M. Schiffelers
Journal: Blood (2008)
Activation of Natural Killer Cells and Dendritic Cells upon Recognition of a Novel CD99-like Ligand by Paired Immunoglobulin-like Type 2 Receptor
Authors: Ikuo Shiratori, Kouetsu Ogasawara, Takashi Saito, Lewis L. Lanier, Hisashi Arase
Journal: The Journal of Experimental Medicine (2004)

Paired receptors that consist of highly related activating and inhibitory receptors are widely involved in the regulation of the immune system. Here, we report a mouse orthologue of the human activating paired immunoglobulin-like type 2 receptor (PILR) β, which was cloned from a cDNA library of natural killer (NK) cells based on its ability to associate with the DAP12 signaling adaptor protein. The activating PILRβ was expressed not only on NK cells but also on dendritic cells and macrophages. Furthermore, we have identified a novel CD99-like molecule as a ligand for the activating PILRβ and inhibitory PILRα receptors. Transcripts of PILR ligand are present in many tissues, including some T cell lines. Cells expressing the PILR ligand specifically activated NK cells and dendritic cells that express the activating PILRβ. Our findings reveal a new regulatory mechanism of innate immunity by PILR and its CD99-like ligand.
A Genome-Wide Association Study of Overall Survival in Pancreatic Cancer Patients Treated with Gemcitabine in CALGB 80303
Authors: Federico Innocenti, Kouros Owzar, Nancy L. Cox, Patrick Evans, Michiaki Kubo, Hitoshi Zembutsu, Chen Jiang, Donna Hollis, Taisei Mushiroda, Liang Li, Paula Friedman, Liewei Wang, Dylan Glubb, Herbert Hurwitz, Kathleen M. Giacomini, Howard L. McLeod, Richard M. Goldberg, Richard L. Schilsky, Hedy L. Kindler, Yusuke Nakamura, Mark J. Ratain
Journal: Clinical Cancer Research (2011)

Cancer and Leukemia Group B 80303 was a randomized, phase III study in patients with advanced pancreatic cancer treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint.DNA from 351 patients was genotyped for more than 550,000 single-nucleotide polymorphisms (SNP). Associations between OS and SNPs were investigated using the log-linear 2-way multiplicative Cox proportional hazards model. The subset of 294 genetically European patients was used for the primary analysis.A nonsynonymous SNP in interleukin (IL)17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (P ≤ 10(-7)). Median OS was significantly shorter (P = 2.61 × 10(-8)) for the rs763780 heterozygotes [3.1 months; 95% confidence interval (CI), 2.3-4.3] than for the patients without this variant (6.8 months; 95% CI, 5.8-7.3). After adjustment by stratification factors, the P value for the association was 9.51 × 10(-7).The variant 161R form of IL-17F is a natural antagonist of the antiangiogenic effects of wild-type 161H IL-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenetic potential of pancreatic cancers in patients with variant IL-17F is higher than that of tumors in patients with wild-type IL-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer.
Effect of inhibition of nitric oxide synthesis on epicardial coronary artery caliber and coronary blood flow in humans.
Authors: D C Lefroy, T Crake, N G Uren, G J Davies, A Maseri
Journal: Circulation (1993)

BACKGROUND NG-Monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis, was used to determine the effects of inhibition of nitric oxide synthesis in the human coronary circulation. METHODS AND RESULTS Twelve patients (mean age, 52 +/- 2 years) with normal epicardial coronary arteries were studied. The surface ECG, systemic blood pressure, and coronary venous oxygen saturation (coronary SvO2), an index of coronary blood flow, were monitored continuously. Coronary artery diameter was measured by quantitative arteriography. L-NMMA was given as intracoronary infusions at 2 mL/min via the diagnostic arteriography catheter. In two patients, low doses (0.01 to 5 mumol/min) of L-NMMA were infused into the nondominant right coronary artery. There was no evidence of ischemia in these patients, who were not included in the final analysis. In 10 patients, higher doses of L-NMMA (4, 10, and 25 mumol/min, each for 5 minutes) were infused into the left coronary artery. In six patients, incremental doses of acetylcholine were infused (1, 10, and 100 nmol/min, each for 3 minutes) before and after the L-NMMA infusion. Finally, in all patients, sodium nitroprusside, a nitric oxide donor, was infused. No patient developed myocardial ischemia. The heart rate and systemic blood pressure remained unchanged throughout the infusions. L-NMMA (25 mumol/min), compared with the control saline infusion, caused a significant reduction in distal (-5.9 +/- 2.1%, P = 0.021) but not proximal left anterior descending coronary artery (LAD) diameter and a fall in coronary SvO2 from 37.5 +/- 2.8% to 34.3 +/- 2.8% (P = 0.019). Sodium nitroprusside dilated the proximal (17.8 +/- 6.9%, P = 0.033) and distal (24.5 +/- 6.5%, P = 0.006) LAD and increased the coronary SvO2 to 61.6 +/- 5.0% (P = 0.0002). Acetylcholine caused significant dilatation of the distal (13.8 +/- 5.4%, P = 0.049) but not proximal LAD and a significant increase in coronary SvO2 from 36.5 +/- 3.5% to 59.2 +/- 2.8% (P &lt; 0.0001). After L-NMMA, acetylcholine-induced dilatation of the distal LAD was abolished, but the rise in coronary SvO2 was unchanged. CONCLUSIONS Inhibition of nitric oxide synthesis in the human coronary circulation caused a decrease in basal distal LAD diameter and basal coronary blood flow assessed by coronary SvO2, indicating that there is a small basal release of nitric oxide in the distal epicardial coronary arteries and resistive vessels. Distal epicardial coronary artery dilatation in response to acetylcholine is nitric oxide dependent, but coronary resistive vessel dilatation is not.
Association of Systemic Lupus Erythematosus With Decreased Immunosuppressive Potential of the IgG Glycome
Authors: Frano Vučković, Jasminka Krištić, Ivan Gudelj, Maria Teruel, Toma Keser, Marija Pezer, Maja Pučić‐Baković, Jerko Štambuk, Irena Trbojević‐Akmačić, Clara Barrios, Tamara Pavić, Cristina Menni, Youxin Wang, Yong Zhou, Liufu Cui, Haicheng Song, Qiang Zeng, Xiuhua Guo, Bernardo A. Pons‐Estel, Paul McKeigue, Alan Leslie Patrick, Olga Gornik, Tim D. Spector, Miroslav Harjaček, Marta Alarcon‐Riquelme, Mariam Molokhia, Wei Wang, Gordan Lauc
Journal: Arthritis & Rheumatology (2015)

Objective Glycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1 , HLA–DQ2A/B , and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case–control study to determine whether SLE is associated with altered IgG glycosylation. Methods Using ultra‐performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China). Results Multiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N ‐acetylglucosamine (which affect antibody‐dependent cell‐mediated cytotoxicity). Conclusion The IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.
ProCAT: a data analysis approach for protein microarrays.
Authors: Xiaowei Zhu, Mark Gerstein, Michael Snyder
Journal: Genome biology (2006)

Abstract Protein microarrays provide a versatile method for the analysis of many protein biochemical activities. Existing DNA microarray analytical methods do not translate to protein microarrays due to differences between the technologies. Here we report a new approach, ProCAT, which corrects for background bias and spatial artifacts, identifies significant signals, filters nonspecific spots, and normalizes the resulting signal to protein abundance. ProCAT provides a powerful and flexible new approach for analyzing many types of protein microarrays.
Reduced Mortality Associated With the Use of ACE Inhibitors in Patients With Type 2 Diabetes
Authors: Dean T. Eurich, Sumit R. Majumdar, Ross T. Tsuyuki, Jeffrey A. Johnson
Journal: Diabetes Care (2004)

OBJECTIVE—ACE inhibitor therapy is widely used in lower-risk patients with type 2 diabetes to reduce mortality, despite limited evidence to support this clinical strategy. The aim of this study was to evaluate the association between ACE inhibitor use and mortality in patients with diabetes and no cardiovascular disease. RESEARCH DESIGN AND SETTINGS—Using the Saskatchewan health databases, 12,272 new users of oral hypoglycemic agents were identified between the years of 1991 and 1996. We excluded 3,202 subjects with previous cardiovascular disease. Of the remaining subjects, 1,187 “new users” of ACE inhibitors were identified (ACE inhibitor cohort). Subjects not receiving ACE inhibitor therapy throughout the follow-up period served as the control cohort (n = 4,989). Subjects were prospectively followed until death or the end of 1999. Multivariate Cox proportional hazards models were used to assess differences in all-cause and cardiovascular-related mortality between cohort groups. RESULTS—Subjects were 60.7 ± 13.7 years old, 43.6% female, and were followed for an average of 5.3 ± 2.1 years. Mean duration of ACE inhibitor therapy was 3.6 ± 1.8 years. We observed significantly fewer deaths in the ACE inhibitor group (102 [8.6%]) compared with the control cohort (853 [17.1%]), with an adjusted hazard ratio (HR) and 95% CI of 0.49 (0.40–0.61) (P &amp;lt; 0.001). Cardiovascular-related mortality was also reduced (40 [3.4%] vs. 261 [5.2%], adjusted HR, 0.63 [0.44–0.90]; P = 0.012). CONCLUSIONS—The use of ACE inhibitors was associated with a significant reduction in all-cause and cardiovascular-related mortality in a broad spectrum of patients with type 2 diabetes and no cardiovascular disease.
Oats to children with newly diagnosed coeliac disease: a randomised double blind study
Authors: L Hogberg
Journal: Gut (2004)

<b>Background:</b> Treatment of coeliac disease (CD) requires lifelong adherence to a strict gluten free diet (GFD) which hitherto has consisted of a diet free of wheat, rye, barley, and oats. Recent studies, mainly in adults, have shown that oats are non-toxic to CD patients. In children, only open studies comprising a small number of patients have been performed. <b>Aim:</b> To determine if children with CD tolerate oats in their GFD. <b>Patients and methods:</b> In this double blind multicentre study involving eight paediatric clinics, 116 children with newly diagnosed CD were randomised to one of two groups: one group was given a standard GFD (GFD-std) and one group was given a GFD with additional wheat free oat products (GFD-oats). The study period was one year. Small bowel biopsy was performed at the beginning and end of the study. Serum IgA antigliadin, antiendomysium, and antitissue transglutaminase antibodies were monitored at 0, 3, 6, and 12 months. <b>Results:</b> Ninety three patients completed the study. Median (range) daily oat intake in the GFD-oats group (n = 42) was 15 (5–40) g at the six month control and 15 (0–43) g at the end of the study. All patients were in clinical remission after the study period. The GFD-oats and GFD-std groups did not differ significantly at the end of the study regarding coeliac serology markers or small bowel mucosal architecture, including numbers of intraepithelial lymphocytes. Significantly more children in the youngest age group withdrew. <b>Conclusions:</b> This is the first randomised double blind study showing that the addition of moderate amounts of oats to a GFD does not prevent clinical or small bowel mucosal healing, or humoral immunological downregulation in coeliac children. This is in accordance with the findings of studies in adult coeliacs and indicates that oats, added to the otherwise GFD, can be accepted and tolerated by the majority of children with CD.