tbuckley/cabot-search huggingface dataset:
Antibody mediated hepatocyte injury in methyl dopa induced hepatotoxicity.
Authors: J Neuberger, J G Kenna, K Nouri Aria, R Williams
Journal: Gut (1985)

To investigate the mechanisms underlying the hepatotoxicity induced by methyl dopa, we have examined sera from nine patients with liver damage following the use of the drug for evidence of sensitisation to drug altered liver cell membrane antigens using both immunofluorescence and antibody dependent cell mediated cytotoxicity. Five sera induced significant cytotoxicity to hepatocytes isolated from rabbits pretreated with methyl dopa after exposure to the mixed function oxidase inducer, Arachlor 1254. Sera from 10 patients on methyl dopa but with normal liver function and 32 patients with other drug and viral induced liver damage, gave normal cytotoxicity values. Two of the antibody positive sera gave a specific immunofluorescence pattern at the periphery of human hepatocytes when tested on liver biopsy specimens taken from patients taking methyl dopa. These findings are consistent with the view that immune mechanisms directed against drug associated antigens are involved in severe liver damage from methyl dopa administration and that metabolic activation of the drug is implicated in the generation of drug associated antigen. The need for a combination of immune and metabolic factors may explain the rarity of this condition.
Enhanced Antitumor Activity of T Cells Engineered to Express T-Cell Receptors with a Second Disulfide Bond
Authors: Cyrille J. Cohen, Yong F. Li, Mona El-Gamil, Paul F. Robbins, Steven A. Rosenberg, Richard A. Morgan
Journal: Cancer Research (2007)

Adoptive transfer of genetically T-cell receptor (TCR)-modified lymphocytes has been recently reported to cause objective cancer regression. However, a major limitation to this approach is the mispairing of the introduced chains with the endogenous TCR subunits, which leads to reduced TCR surface expression and, subsequently, to their lower biological activity. We here show that it is possible to improve TCR gene transfer by adding a single cysteine on each receptor chain to promote the formation of an additional interchain disulfide bond. We show that cysteine-modified receptors were more highly expressed on the surface of human lymphocytes compared with their wild-type counterparts and able to mediate higher levels of cytokine secretion and specific lysis when cocultured with specific tumor cell lines. Furthermore, cysteine-modified receptors retained their enhanced function in CD4(+) lymphocytes. We also show that this approach can be employed to enhance the function of humanized and native murine receptors in human cells. Preferential pairing of cysteine-modified receptor chains accounts for these observations, which could have significant implications for the improvement of TCR gene therapy.
Peroxisome proliferator–activated receptor δ limits the expansion of pathogenic Th cells during central nervous system autoimmunity
Authors: Shannon E. Dunn, Roopa Bhat, Daniel S. Straus, Raymond A. Sobel, Robert Axtell, Amanda Johnson, Kim Nguyen, Lata Mukundan, Marina Moshkova, Jason C. Dugas, Ajay Chawla, Lawrence Steinman
Journal: The Journal of Experimental Medicine (2010)

Peroxisome proliferator–activated receptors (PPARs; PPAR-α, PPAR-δ, and PPAR-γ) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-δ, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-δ (PPAR-δ−/−) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-γ+IL-17A− and IFN-γ+IL-17A+ CD4+ cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-δ−/− mice occurred as a result of a constellation of immune system aberrations that included higher CD4+ cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-δ in inhibiting the production of IFN-γ and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-δ serves as an important molecular brake for the control of autoimmune inflammation.
Glomerular ultrafiltration coefficient after ischemic renal injury in dogs.
Authors: V J Savin, R V Patak, G Marr, A S Hermreck, S M Ridge, K Lake
Journal: Circulation Research (1983)

Micropuncture studies of acute renal failure after ischemic renal injury suggest that glomerular ultrafiltration coefficient may remain normal in the period immediately after ischemia and decline significantly during the following 18-24 hours. The present series of in vitro experiments was designed to evaluate glomerular ultrafiltration coefficient and glomerular oncometric and rheological properties in ischemic acute renal failure in dogs. To obtain glomeruli prior to ischemia, a right nephrectomy was performed and glomeruli were isolated for studies of filtration and cell and extracellular spaces. The left renal pedicle then was occluded for 90 minutes; glomeruli isolated from biopsies of this kidney were studied at intervals up to 48 hours after ischemia. Glomeruli were isolated by sieving renal cortical fragments, and filtration was induced by an oncotic gradient. The glomerular ultrafiltration coefficient remained near control levels for the first hour after ischemia, but declined significantly at 24 and 48 hours. Specifically, glomerular ultrafiltration coefficient of glomeruli isolated from normal kidneys was 16.5 +/- 0.9 nl/min per mm Hg (n = 15). Immediately following ischemia, glomerular ultrafiltration coefficient remained essentially unchanged (15.9 +/- 1.1 nl/min per mm Hg, n = 4). At 1 hour, there was a small decrease in glomerular ultrafiltration coefficient (14.4 +/- 1.3 nl/min per mm Hg, n = 4). At 24 hours, glomerular ultrafiltration coefficient was significantly decreased (9.8 +/- 0.5 nl/min per mm Hg, n = 9, P less than 0.01) and remained at that level at 48 hours (9.5 +/- 0.5 nl/min per mm Hg, n = 8, P less than 0.001). In experimental glomeruli, the oncometric response was diminished and erythrocyte movement along glomerular capillaries was impaired. Total water and inulin spaces were measured in glomeruli from control and 48-hour postischemic periods, and glomerular morphology was studied by transmission and scanning electron microscopy at the same time.(ABSTRACT TRUNCATED AT 250 WORDS)
Prediction of <i>MYCN</i> Amplification in Neuroblastoma Using Serum DNA and Real-Time Quantitative Polymerase Chain Reaction
Authors: Takahiro Gotoh, Hajime Hosoi, Tomoko Iehara, Yasumichi Kuwahara, Shinya Osone, Kunihiko Tsuchiya, Miki Ohira, Akira Nakagawara, Hiroshi Kuroda, Tohru Sugimoto
Journal: Journal of Clinical Oncology (2005)

Purpose MYCN amplification (MNA) indicates a poor prognosis in neuroblastoma (NB) and is routinely assayed for therapy stratification. We aimed to develop a diagnostic tool to predict MYCN status using serum DNA, which, in cancer patients, predominantly originates from tumor-released DNA. Patients and Methods Using DNA-based real-time quantitative polymerase chain reaction, we simultaneously quantified MYCN (2p24) and a reference gene, NAGK (2p12), and evaluated MYCN copy number as an MYCN/NAGK (M/N) ratio in 87 NB patients whose MYCN status had been determined by Southern blotting. Of these patients, 17 had MYCN-amplified NB, and 70 had nonamplified NB. Results The serum M/N ratio in the MNA group (median, 199.32; range, 17.1 to 901.6; 99% CI, 107.0 to 528.7) was significantly (P &lt; .001) higher than the ratio in the non-MNA group (median, 0.87; range, 0.25 to 4.6; 99% CI, 0.82 to 1.26; Mann-Whitney U test). The sensitivity and specificity of the serum M/N ratio as a diagnostic test were both 100% when the serum M/N ratio cutoff was set at 10.0. Among six MNA patients whose clinical courses were followed, the serum ratios decreased to the normal range in the patients in remission (n = 3), whereas the ratios increased to high levels in the patients who relapsed (n = 2) or failed to achieve remission (n = 1). Conclusion Measurement of the serum M/N ratio seems to be a promising method for accurately assessing MYCN status in NB, although a larger set of patients needs to be examined to confirm this result.
Repeated Immunization: Possible Adverse Effects
Authors: CHARLES S. WHITE
Journal: Annals of Internal Medicine (1974)

A group of intensively immunized men, who had been subjected to detailed medical evaluations in 1956 and in 1962, was reexamined in 1971 and compared with a carefully matched control group. Clinical and laboratory studies were done to detect adverse effects induced by repeated parenteral inoculation with a variety of vaccines and toxoids. No clinical sequels attributable to long-term immunization were identified. Only one laboratory abnormality described in previous studies, elevated serum hexosamine, was observed. Few other abnormalities were detected in the immunized group; mean values were depressed for serum
Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis
Authors: Estrella Garcia Gonzalez, Enrico Selvi, Epifania Balistreri, Alfiya Akhmetshina, Katrin Palumbo, Sauro Lorenzini, Pietro Enea Lazzerini, Cinzia Montilli, Pier Leopoldo Capecchi, Monica Lucattelli, Caterina Baldi, Elena Gianchecchi, Mauro Galeazzi, Franco Laghi Pasini, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis. <h3>Objective</h3> To determine whether AjA can modulate fibrogenesis in murine models of scleroderma. <h3>Material and methods</h3> Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre-established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR-γ, and its endogenous ligand 15d-PGJ2, and TGFβ were assessed before and after AjA treatment. <h3>Results</h3> AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist. <h3>Conclusions</h3> AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma.
Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial
Authors: F. Boccardo, A. Rubagotti, P. Guglielmini, A. Fini, G. Paladini, M. Mesiti, M. Rinaldini, S. Scali, M. Porpiglia, C. Benedetto, N. Restuccia, F. Buzzi, R. Franchi, B. Massidda, V. Distante, D. Amadori, P. Sismondi
Journal: Annals of Oncology (2006)
A1.36 Active immunisation against peptides of vegf improves joint inflammation and destruction in collagen-induced arthritis
Authors: Luca Semerano, Emilie Duvallet, Nadia Belmellat, Nicolas Schall, Maëlle Monteil, Anna Starzec, Marc Lecouvey, Sylviane Muller, Marie-Christophe Boisser, Eric Assier
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Angiogenesis is a key pathophysiological process in rheumatoid arthritis (RA). VEGF-A is considered the major player in both physiological and pathological angiogenesis. VEGF–VEGFR system blockade delays synovitis onset and ameliorates collagen-induced arthritis (CIA). We previously demonstrated the effectiveness of active anti-cytokine immunisation in RA models, with a class of therapeutics called kinoids. The kinoids (heterocomplexes consisting of a cytokine conjugated to a carrier protein, the keyhole limpet hemocyanin, KLH) induce the endogenous production of polyclonal anti-cytokine Abs. Here we tested the effectiveness in CIA of two distinct peptidic vaccines obtained by conjugation of one of two different VEGF-derived peptides to KLH. <h3>Objectives</h3> To demonstrate the inhibitory effect on CIA of sustained VEGF blockade by vaccines based on VEGF-derived peptides linked to KLH (Vpep-K). <h3>Materials and Methods</h3> Two peptides were chosen in the sequence of the VEGF murine isoformVEGF-A<sub>164</sub> (90% identity and 93% homology with the human VEGF-A<sub>165</sub>): Vpep1 (16 aminoacids (aa), position 98-113) localised in the region cleaved by the plasmin between the exons 4 and 5, and Vpep2 (77 carboxy-terminal aa) which comprises the Arginine 164, essential for binding of VEGF to Neuropilin-1 (NRP1). Each peptide was linked to keyhole limpet hemocyanin (KLH) to form Vpep1-kinoid (Vpep1-K) and Vpep2-kinoid (Vpep2-K), respectively. CIA was induced in 48 DBA/1 male mice with two injections of 100µg of bovine collagen type II (day 0 and 21). Mice were divided in 4 groups to receive one of the following: Vpep1-K, Vpep2-K, KLH or PBS emulsified in Incomplete Freund Adjuvant (IFA, 5 intra muscular injections at days -36, -22, -8, 7 and 37). Sera were sampled from each mouse three times during the experiment (days -44, -2, 48). <h3>Results</h3> Vpep1-K group showed lower arthritic scores compared to KLH and PBS groups (p&lt;0.05). At histological analysis, inflammation and destruction scores of the paws were lower in Vpep1-K group versus KLH and PBS group (p&lt;0.005). Vpep1-K and Vpep2-K groups showed anti-VEGF Ab production as assessed by ELISA at day -2 and sacrifice. <h3>Conclusions</h3> Active immunotherapy with the kinoid of a single VEGF-derived peptide (Vpep1-K) induces anti-VEGF antibodies and ameliorates collagen-induced arthritis. Active anti-angiogenic immunotherapy based on peptidic vaccines might be a potential strategy to control chronic inflammation.
Neuromuscular effects of G93A-SOD1 expression in zebrafish
Authors: Stacey A Sakowski, J Simon Lunn, Angela S Busta, Sang Su Oh, Grettel Zamora-Berridi, Madeline Palmer, Andrew A Rosenberg, Stephen G Philip, James J Dowling, Eva L Feldman
Journal: Molecular Neurodegeneration (2012)

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis. Results We demonstrate that transient genetic manipulation of zebrafish to express G93A- SOD1 , a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A- SOD1 to further characterize the consequences of G93A- SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease. Conclusions This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.
Insulin Increases <i>De Novo</i> Steroidogenesis in Prostate Cancer Cells
Authors: Amy A. Lubik, Jennifer H. Gunter, Stephen C. Hendy, Jennifer A. Locke, Hans H. Adomat, Vanessa Thompson, Adrian Herington, Martin E. Gleave, Michael Pollak, Colleen C. Nelson
Journal: Cancer Research (2011)

Abstract Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis. Cancer Res; 71(17); 5754–64. ©2011 AACR.
Familiality and Heritability of Subtypes of Attention Deficit Hyperactivity Disorder in a Population Sample of Adolescent Female Twins
Authors: Richard D. Todd, Erik R. Rasmussen, Rosalind J. Neuman, Wendy Reich, James J. Hudziak, Kathleen K. Bucholz, Pamela A.F. Madden, Andrew Heath
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly heritable but clinically heterogeneous syndrome. The study examined the familiality and heritability of ADHD subtypes as defined by DSM-IV and by latent-class analysis in a population sample of adolescent female twins. METHOD: To determine which elements of ADHD cluster together, latent-class analysis was applied to data obtained from parents on the 18 DSM-IV ADHD symptoms in 4,036 female twins age 13–23 years in a population sample identified from the registry of all births in Missouri for the years 1968–1996. Relative risk and odds ratios were used to assess within-subtype and between-subtype familiality and heritability of both DSM-IV and latent-class ADHD subtypes. RESULTS: Latent-class analysis was most compatible with the existence of three mild and three severe classes of ADHD symptoms in the general population. The three severe classes showed moderate overlap with DSM-IV ADHD subtypes. The primarily inattentive and combined subtypes of DSM-IV ADHD co-clustered within families. The primarily hyperactive/impulsive DSM-IV subtype and the individual latent-class analysis subtypes did not co-cluster. Subtypes defined by both approaches were highly heritable. CONCLUSIONS: Unlike DSM-IV subtypes of ADHD, latent-class ADHD subtypes appear to be independently transmitted in families. These classes may be more appropriate targets for molecular genetic studies of ADHD.
Inhibition of NOTCH Signaling by Gamma Secretase Inhibitor Engages the RB Pathway and Elicits Cell Cycle Exit in T-Cell Acute Lymphoblastic Leukemia Cells
Authors: Sudhir S. Rao, Jennifer O'Neil, Cole D. Liberator, James S. Hardwick, Xudong Dai, Theresa Zhang, Edyta Tyminski, Jing Yuan, Nancy E. Kohl, Victoria M. Richon, Lex H.T. Van der Ploeg, Pamela M. Carroll, Giulio F. Draetta, A. Thomas Look, Peter R. Strack, Christopher G. Winter
Journal: Cancer Research (2009)

Abstract NOTCH signaling is deregulated in the majority of T-cell acute lymphoblastic leukemias (T-ALL) as a result of activating mutations in NOTCH1. Gamma secretase inhibitors (GSI) block proteolytic activation of NOTCH receptors and may provide a targeted therapy for T-ALL. We have investigated the mechanisms of GSI sensitivity across a panel of T-ALL cell lines, yielding an approach for patient stratification based on pathway activity and also providing a rational combination strategy for enhanced response to GSI. Whereas the NOTCH1 mutation status does not serve as a predictor of GSI sensitivity, a gene expression signature of NOTCH pathway activity does correlate with response, and may be useful in the selection of patients more likely to respond to GSI. Furthermore, inhibition of the NOTCH pathway activity signature correlates with the induction of the cyclin-dependent kinase inhibitors CDKN2D (p19INK4d) and CDKN1B (p27Kip1), leading to derepression of RB and subsequent exit from the cell cycle. Consistent with this evidence of cell cycle exit, short-term exposure of GSI resulted in sustained molecular and phenotypic effects after withdrawal of the compound. Combination treatment with GSI and a small molecule inhibitor of CDK4 produced synergistic growth inhibition, providing evidence that GSI engagement of the CDK4/RB pathway is an important mechanism of GSI action and supports further investigation of this combination for improved efficacy in treating T-ALL. [Cancer Res 2009;69(7):3060–8]