tbuckley/cabot-search huggingface dataset:
Role of Stable Isotopes in Life—Testing Isotopic Resonance Hypothesis
Authors: Roman A. Zubarev
Journal: Genomics Proteomics & Bioinformatics (2011)

Stable isotopes of most important biological elements, such as C, H, N and O, affect living organisms. In rapidly growing species, deuterium and to a lesser extent other heavy isotopes reduce the growth rate. At least for deuterium it is known that its depletion also negatively impacts the speed of biological processes. As a rule, living organisms "resist" changes in their isotopic environment, preferring natural isotopic abundances. This preference could be due to evolutionary optimization; an additional effect could be due to the presence of the "isotopic resonance". The isotopic resonance phenomenon has been linked to the choice of earliest amino acids, and thus affected the evolution of genetic code. To test the isotopic resonance hypothesis, literature data were analyzed against quantitative and qualitative predictions of the hypothesis. Four studies provided five independent datasets, each in very good quantitative agreement with the predictions. Thus, the isotopic resonance hypothesis is no longer simply plausible; it can now be deemed likely. Additional testing is needed, however, before full acceptance of this hypothesis.
Effect of vasoactive intestinal polypeptide (VIP) antagonism on rat jejunal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins
Authors: F H Mourad, C F Nassar
Journal: Gut (2000)

The enteric nervous system is important in the pathophysiology of intestinal fluid secretion induced by cholera toxin (CT), Escherichia coli heat labile (LT), and heat stable (STa) toxins. The neurotransmitters involved are not fully elucidated. Vasoactive intestinal polypeptide (VIP), a potent intestinal secretagogue present in the enteric nervous system, is increased after exposure of the cat intestine to CT. Whether VIP is involved in the pathogenesis of cholera and other toxins in not known.To study in vivo the effect of VIP antagonism on jejunal fluid secretion induced by CT, LT, and STa.CT, LT (25 microg), or 0.9% NaCl was instilled in an isolated 25 cm segment of rat jejunum, and the VIP antagonist (VIPa) [4Cl-D-Phe(6), Leu(17)]-VIP (0.2 or 2 microg/kg/min) or 0.9% NaCl was given intravenously. Two hours later, single pass in vivo jejunal perfusion was performed to assess fluid movement. In STa experiments, intravenous VIPa or 0.9% NaCl was given and 30 minutes later the jejunal segment was perfused with a solution containing STa 200 microg/l.VIPa had no effect on basal intestinal fluid absorption. CT induced net fluid secretion (median -68 microl/min/g dry intestinal weight (interquartile range -80 to -56)) which was dose dependently reversed by VIPa (6.2 (-16 to 34) and 29 (17 to 42); p<0.01). Similarly, LT induced secretion (-63 (-73 to -30)) was attenuated by VIPa (0.2 microg/kg/min) (-15 (-24 to -1); p<0.01) and totally reversed to normal levels by VIPa (2 microg/kg/min) (37 (28-56); p<0. 01 compared with LT and not significant compared with normal controls). STa induced secretion (-17 (-19 to -2)) was also reversed by VIPa (12 (9-23) and 14 (0-26); p<0.01).VIP plays an important role in CT, LT, and STa induced intestinal secretion and may be the final putative neurotransmitter in the pathophysiology of these toxins.
T cells expressing specific V beta elements regulate immunoglobulin E production and airways responsiveness in vivo.
Authors: H Renz, K Bradley, J Saloga, J Loader, G L Larsen, E W Gelfand
Journal: The Journal of Experimental Medicine (1993)

The role of T cells expressing specific V beta elements was examined in the regulation of allergen-specific immunoglobulin (Ig)E production and airways responsiveness (AR). In BALB/c mice, inhalation of the allergen ovalbumin (OVA) induced an IgE anti-OVA response, immediate cutaneous reactivity, and increased AR. These results were associated with an expansion of V beta 8.1/8.2 T cells in local draining lymph nodes of the airways and the lung. Transfer of V beta 8.1/8.2 T cells from sensitized mice stimulated an IgE anti-OVA response, immediate cutaneous hypersensitivity, and increased AR in naive syngeneic recipients. In contrast, OVA-reactive V beta 2 T cells inhibited these effects. These data demonstrate for the first time that T cells with different V beta specificities play a critical role in the in vivo regulation of allergen-specific IgE production and AR.
Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells
Authors: Stephanie K. Dougan, Azucena Salas, Paul Rava, Amma Agyemang, Arthur Kaser, Jamin Morrison, Archana Khurana, Mitchell Kronenberg, Caroline Johnson, Mark Exley, M. Mahmood Hussain, Richard S. Blumberg
Journal: The Journal of Experimental Medicine (2005)

Microsomal triglyceride transfer protein (MTP), an endoplasmic reticulum (ER) chaperone that loads lipids onto apolipoprotein B, also regulates CD1d presentation of glycolipid antigens in the liver and intestine. We show MTP RNA and protein in antigen-presenting cells (APCs) by reverse transcription–polymerase chain reaction and by immunoblotting of mouse liver mononuclear cells and mouse and human B cell lines. Functional MTP, demonstrated by specific triglyceride transfer activity, is present in both mouse splenocytes and a CD1d-positive mouse NKT hybridoma. In a novel in vitro transfer assay, purified MTP directly transfers phospholipids, but not triglycerides, to recombinant CD1d. Chemical inhibition of MTP lipid transfer does not affect major histocompatibility complex class II presentation of ovalbumin, but considerably reduces CD1d-mediated presentation of α-galactosylceramide (α-galcer) and endogenous antigens in mouse splenic and bone marrow–derived dendritic cells (DCs), as well as in human APC lines and monocyte-derived DCs. Silencing MTP expression in the human monocyte line U937 affects CD1d function, as shown by diminished presentation of α-galcer. We propose that MTP acts upstream of the saposins and functions as an ER chaperone by loading endogenous lipids onto nascent CD1d. Furthermore, our studies suggest that a small molecule inhibitor could be used to modulate the activity of NKT cells.
Angiogenesis-Dependent and Independent Phases of Intimal Hyperplasia
Authors: Rohit Khurana, Zhenwu Zhuang, Shalini Bhardwaj, Masahiro Murakami, Ebo De Muinck, Seppo Yla-Herttuala, Napoleone Ferrara, John F. Martin, Ian Zachary, Michael Simons
Journal: Circulation (2004)

Background— Neointimal vascular smooth muscle cell (VSMC) proliferation is a primary cause of occlusive vascular disease, including atherosclerosis, restenosis after percutaneous interventions, and bypass graft stenosis. Angiogenesis is implicated in the progression of early atheromatous lesions in animal models, but its role in neointimal VSMC proliferation is undefined. Because percutaneous coronary interventions result in induction of periadventitial angiogenesis, we analyzed the role of this process in neointima formation. Methods and Results— Local injury to the arterial wall in 2 different animal models induced periadventitial angiogenesis and neointima formation. Application of angiogenesis stimulators vascular endothelial growth factor (VEGF-A 165 ) or a proline/arginine-rich peptide (PR39) to the adventitia of the injured artery induced a marked increase in neointimal thickening beyond that seen with injury alone in both in vivo models. Inhibition of either VEGF (with soluble VEGF receptor 1 [sFlt1]) or fibroblast growth factor (FGF) (with a dominant=negative form of FGF receptor 1 [FGF-R1DN]), respectively, signaling reduced adventitial thickening induced by VEGF and PR39 to the level seen with mechanical arterial injury alone. However, neither inhibitor was effective in preventing neointimal thickening after mechanical injury when administered in the absence of angiogenic growth factor. Conclusions— Our findings indicate that adventitial angiogenesis stimulates intimal thickening but does not initiate it.
A Regulatory Role for Src Homology 2 Domain–Containing Inositol 5′-Phosphatase (Ship) in Phagocytosis Mediated by Fcγ Receptors and Complement Receptor 3 (α<b>M</b>β<b>2</b>; Cd11b/Cd18)
Authors: Dianne Cox, Benjamin M. Dale, Masaki Kashiwada, Cheryl D. Helgason, Steven Greenberg
Journal: The Journal of Experimental Medicine (2000)

The Src homology 2 domain–containing inositol 5′-phosphatase (SHIP) is recruited to immunoreceptor tyrosine-based inhibition motif (ITIM)–containing proteins, thereby suppressing phosphatidylinositol 3-kinase (PI 3-kinase)–dependent pathways. The role of SHIP in phagocytosis, a PI 3-kinase–dependent pathway, is unknown. Overexpression of SHIP in macrophages led to an inhibition of phagocytosis mediated by receptors for the Fc portion of IgG (FcγRs). In contrast, macrophages expressing catalytically inactive SHIP or lacking SHIP expression demonstrated enhanced phagocytosis. To determine whether SHIP regulates phagocytosis mediated by receptors that are not known to recruit ITIMs, we determined the effect of SHIP expression on complement receptor 3 (CR3; CD11b/CD18; αMβ2)–dependent phagocytosis. Macrophages overexpressing SHIP demonstrated impaired CR3-mediated phagocytosis, whereas macrophages expressing catalytically inactive SHIP demonstrated enhanced phagocytosis. CR3-mediated phagocytosis in macrophages derived from SHIP−/− mice was up to 2.5 times as efficient as that observed in macrophages derived from littermate controls. SHIP was localized to FcγR- and CR3-containing phagocytic cups and was recruited to the cytoskeleton upon clustering of CR3. In a transfected COS cell model of activation-independent CR3-mediated phagocytosis, catalytically active but not inactive SHIP also inhibited phagocytosis. We conclude that PI 3-kinase(s) and SHIP regulate multiple forms of phagocytosis and that endogenous SHIP plays a role in modulating β2 integrin outside-in signaling.
N-Cadherin Is Regulated by Activin A and Associated with Tumor Aggressiveness in Esophageal Carcinoma
Authors: Keiji Yoshinaga, Hiroshi Inoue, Tohru Utsunomiya, Hideto Sonoda, Takaaki Masuda, Koshi Mimori, Yoichi Tanaka, Masaki Mori
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Activin A is a member of the transforming growth factor β superfamily and plays an important role in the differentiation of embryonic stem cells. We have reported previously that the expression of activin A is associated with lymph node metastasis in esophageal cancer, and our purpose in the current work is to clarify the molecular mechanism of the aggressive behavior of tumors that have high activin A expression. Experimental Design: We have compared the gene expression profiles of human esophageal carcinoma cell lines that were stably transfected with activin βA, which is a subunit of activin A, with those of control human esophageal carcinoma cell lines, using a cDNA microarray. Results: We found that the expression level of neuronal cadherin (N-cadherin) was higher in the transfectants than in the control cells. N-cadherin was located on the cell surface of the transfectants, irrespective of the expression of epithelial cadherin (E-cadherin), and the expression of N-cadherin mRNA was significantly associated with that of activin βA mRNA in clinical samples of esophageal carcinoma (n = 51; r = 0.855). A clinicopathologic analysis suggested that expression of N-cadherin mRNA was associated with the depth of tumor wall invasion, and a group of patients with high expression of N-cadherin mRNA showed a significantly poorer prognosis than a group of patients with low N-cadherin expression (P = 0.046). Conclusions: These results indicate that activin A might mediate the expression of N-cadherin and that this may be associated with depth of invasion and poor prognosis.
Glycation Gap Is Associated With Macroproteinuria but Not With Other Complications in Patients With Type 2 Diabetes
Authors: Emmanuel Cosson, Isabela Banu, Camille Cussac-Pillegand, Qinda Chen, Sabrina Chiheb, Yahya Jaber, Minh Tuan Nguyen, Nathalie Charnaux, Paul Valensi
Journal: Diabetes Care (2013)

OBJECTIVE We investigated whether glycation gap (G-Gap), an index of intracellular glycation of proteins, was associated with diabetes complications. RESEARCH DESIGN AND METHODS We measured concomitantly HbA1c and fructosamine in 925 patients with type 2 diabetes to calculate the G-Gap, defined as the difference between measured HbA1c, and fructosamine-based predicted HbA1c. Patients were explored for retinopathy, nephropathy, peripheral neuropathy, cardiac autonomic neuropathy (n = 512), and silent myocardial ischemia (n = 506). RESULTS Macroproteinuria was the only complication that was associated with G-Gap (prevalence in the first, second, and third tertile of G-Gap: 2.9, 6.2, and 11.0%, respectively; P &amp;lt; 0.001). The G-Gap was higher in patients with macroproteinuria than in those without (1.06 ± 1.62 vs. 0.03 ± 1.30%; P &amp;lt; 0.0001). Because HbA1c was associated with both G-Gap (HbA1c 7.0 ± 1.4, 7.9 ± 1.4, and 10.1 ± 1.8% in the first, second, and third G-Gap tertile, respectively; P &amp;lt; 0.0001) and macroproteinuria (HbA1c 8.8 ± 2.2% if macroproteinuria, 8.3 ± 2.0% if none; P &amp;lt; 0.05), and because it could have been a confounder, we matched 54 patients with macroproteinuria and 200 patients without for HbA1c. Because macroproteinuria was associated with lower serum albumin and fructosamine levels, which might account for higher G-Gap, we calculated in this subpopulation albumin-indexed fructosamine and G-Gap; macroproteinuria was independently associated with male sex (odds ratio [OR] 3.2 [95% CI 1.5–6.7]; P &amp;lt; 0.01), hypertension (2.9 [1.1–7.5]; P &amp;lt; 0.05), and the third tertile of albumin-indexed G-Gap (2.3 [1.1–4.4]; P &amp;lt; 0.05) in multivariate analysis. CONCLUSIONS In type 2 diabetic patients, G-Gap was associated with macroproteinuria, independently of HbA1c, albumin levels, and confounding factors, suggesting a specific role of intracellular glycation susceptibility on kidney glomerular changes.
Stemming the Tide of Cancer for <i>BRCA1/2</i> Mutation Carriers
Authors: Henry T. Lynch, Joseph N. Marcus, Wendy S. Rubinstein
Journal: Journal of Clinical Oncology (2008)

Advances in molecular genetics during the past decade have resulted in the identification of numerous germline mutations in an increasing number of hereditary cancer syndromes, producing a sea change in the clinical approach to these disorders. The best known of these cancer-causing mutations are BRCA1 and BRCA2, which predispose to the hereditary breast-ovarian cancer syndrome. These mutations account for upwards of 10% of the entire breast cancer (BC) burden and are causal for approximately half of hereditary BCs. The salient clinical and pathologic differences between BRCA1 and BRCA2 BC are discussed at length by Atchley et al in this issue of Journal of Clinical Oncology.1 In this commentary, we offer diverse thoughts on how recent advances in our understanding of the pathology and molecular functioning of BRCA1 and BRCA2 might point the way toward therapies for the corresponding BCs.
Use of ibutilide in cardioversion of patients with atrial fibrillation or atrial flutter treated with class IC agents
Authors: Richard H. Hongo, Sakis Themistoclakis, Antonio Raviele, Aldo Bonso, Antonio Rossillo, Kathryn A. Glatter, Yanfei Yang, Melvin M. Scheinman
Journal: Journal of the American College of Cardiology (2004)
Clinical and Biological Effects of an Agonist Anti-CD40 Antibody: A Cancer Research UK Phase I Study
Authors: Peter Johnson, Ruth Challis, Ferdousi Chowdhury, Yifang Gao, Melanie Harvey, Tom Geldart, Paul Kerr, Claude Chan, Anna Smith, Neil Steven, Ceri Edwards, Margaret Ashton-Key, Elisabeth Hodges, Alison Tutt, Christian Ottensmeier, Martin Glennie, Anthony Williams
Journal: Clinical Cancer Research (2015)

This phase I study aimed to establish the biologic effects and MTD of the agonistic IgG1 chimeric anti-CD40 antibody ChiLob7/4 in patients (pts) with a range of CD40-expressing solid tumors and diffuse large B-cell lymphoma, resistant to conventional therapy. Potential mechanisms of action for agonistic anti-CD40 include direct cytotoxic effects on tumor cells and conditioning of antigen-presenting cells.
MMR vaccine and Crohn's disease: ecological study of hospital admissions in England, 1991 to 2002
Authors: Valerie Seagroatt
Journal: BMJ (2005)

Valerie SeagroattIt has been hypothesised that the measles, mumps, and rubella vaccine (MMR vaccine) increases the risk of autism and Crohn's disease.Although a possible link with autism has been extensively studied and refuted, 1 a link with Crohn's disease has not.I tested this hypothesis by analysing trends in age specific admission rates for Crohn's disease in children and adolescents to determine if the introduction of MMR vaccine in 1988 increased rates in those populations that were offered the vaccine as infants.
Design of Nonpeptidic Topomimetics of Antiangiogenic Proteins With Antitumor Activities
Authors: Ruud P. M. Dings, Xuemei Chen, Debby M. E. I. Hellebrekers, Loes I. van Eijk, Ying Zhang, Thomas R. Hoye, Arjan W. Griffioen, Kevin H. Mayo
Journal: JNCI Journal of the National Cancer Institute (2006)

The inhibition of angiogenesis is a promising avenue for cancer treatment. Although some angiostatic compounds are in the process of development and testing, these often prove ineffective in vivo or have unwanted side effects. We have designed, synthesized, and evaluated a small library of nonpeptidic, calixarene-based protein surface topomimetics that display chemical substituents to approximate the molecular dimensions and amphipathic features (hydrophobic and positively charged residues) of the antiangiogenic peptide anginex, which, like many antiangiogenic proteins, consists primarily of an antiparallel β-sheet structure as the functional unit. Two of the topomimetics (0118 and 1097) were potent angiogenesis inhibitors in vitro, as determined by endothelial cell proliferation, migration, and chick embryo chorioallantoic membrane assays. Moreover, both compounds were highly effective at inhibiting tumor angiogenesis and growth in two mouse models (MA148 human ovarian carcinoma and B16 murine melanoma). Our results demonstrate the feasibility of designing nonpeptidic protein surface topomimetics as novel pharmaceutical agents for clinical intervention against cancer through angiostatic or other mechanisms.
Age Responses to X Rays, &lt;italic&gt;Vinca&lt;/italic&gt; Alkaloids, and Hydroxyurea of Murine Lymphoma Cells Synchronized &lt;italic&gt;In Vivo&lt;/italic&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: H. Madoc-Jones, F. Mauro
Journal: JNCI Journal of the National Cancer Institute (1970)

A method is described for the induction of partial synchrony by means of hydroxyurea in a population of murine lymphoma cells in vivo. Three hours after lymphoma-bearing animals were each given a single intraperitoneal injection of hydroxyurea, the survival of femoral lymphoma colony-forming cells, as measured by the spleen-colony technique, was reduced to a plateau level of about 20%. The drug disappeared from both plasma and femoral marrow fluid between 3 and 4 hours after injection. The lymphoma cells surviving this treatment comprised a partially synchronized population. With this synchronization method, the survival of lymphoma cells treated, in different phases of the generation cycle in vivo, to X rays (374, 562, or 750 rads), vinblastine (1 mg/mouse, 3-hour exposure) vincristine (0.3,3 mg/mouse, 3-hour exposure) or hydroxyurea (a second challenge; 5 mg/mouse, 3-hour exposure) was determined. The lymphoma cells showed a peak in sensitivity to X rays at the G1/S transition and then grew more radioresistant as they passed through the S phase of the cell cycle. They had a maximal sensitivity to the two Vinca alkaloids as well as to hydroxyurea, when treated in the S phase. These age responses were similar to those of Chinese hamster or HeLa cells in vitro. The age response to X rays was analyzed in terms of variations in dose-survival curve parameters through the cycle; in addition, dose-fractionation studies indicated repair of sublethal damage at certain positions in the cell cycle.
Development and successful clinical application of preimplantation genetic haplotyping for Herlitz junctional epidermolysis bullosa
Authors: H. Fassihi, L. Liu, P.J. Renwick, P.R. Braude, J.A. McGrath
Journal: British Journal of Dermatology (2010)

Herlitz junctional epidermolysis bullosa (HJEB) is a severe, life-threatening, autosomal recessive blistering skin disease for which no cure is currently available. Prenatal diagnosis for couples at risk is feasible through fetal skin biopsy or analysis of DNA extracted from chorionic villi, but these methods can be applied only after pregnancy has been established. An alternative approach, which involves the analysis of single cells from embryos prior to establishment of pregnancy, is preimplantation genetic diagnosis (PGD). Until now, its clinical uptake has been hindered by lengthy delays in establishing mutation-specific protocols, and by the small amount of template DNA that can be obtained from a single cell. A new method that addresses these problems, preimplantation genetic haplotyping (PGH), relies on whole genome amplification followed by haplotyping of multiple polymorphic markers using standard DNA-based polymerase chain reaction (PCR) assays.To design and validate a generic PGH assay for HJEB and to transfer this into clinical practice.We established a multiplex PCR-based PGH assay involving 16 markers within and flanking the LAMB3 gene (the most frequently mutated gene in HJEB). The assay was then validated in 10 families with at least one previously affected offspring. After licensing by the Human Fertilisation and Embryology Authority (HFEA), the new test was used for PGD in a couple at risk of HJEB.The chromosome 1 LAMB3 markers within the assay were shown to be of sufficient heterogeneity to have widespread application for preimplantation testing of HJEB. In one couple that were heterozygous carriers of nonsense mutations in LAMB3, we used the new assay to identify unaffected embryos in a series of PGD cycles. Pregnancy was established in the third PGD cycle and a healthy, unaffected child was born. DNA analysis of cord blood confirmed the predicted single-cell mutation status of wild-type LAMB3 alleles.PGH represents a major step forward in widening the scope and availability of preimplantation testing for serious mapped single-gene disorders. We have established a generic test that is suitable for the majority of couples at risk of HJEB.
Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study)
Authors: C. Pinto, F. Di Fabio, E. Maiello, S. Pini, T. Latiano, C. Aschele, C. Garufi, A. Bochicchio, G. Rosati, G. Aprile, S. Giaquinta, V. Torri, A. Bardelli, M. Gion, A. Martoni
Journal: Annals of Oncology (2011)