tbuckley/cabot-search huggingface dataset:
Autoimmunity to Gephyrin in Stiff-Man Syndrome
Authors: Margaret Husta Butler, Akito Hayashi, Norio Ohkoshi, Carmen Villmann, Cord-Michael Becker, Guoping Feng, Pietro De Camilli, Michele Solimena
Journal: Neuron (2000)

Stiff-Man syndrome (SMS) is a rare disease of the central nervous system (CNS) characterized by chronic rigidity, spasms, and autoimmunity directed against synaptic antigens, most often the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). In a subset of cases, SMS has an autoimmune paraneoplastic origin. We report here the identification of high-titer autoantibodies directed against gephyrin in a patient with clinical features of SMS and mediastinal cancer. Gephyrin is a cytosolic protein selectively concentrated at the postsynaptic membrane of inhibitory synapses, where it is associated with GABAA and glycine receptors. Our findings provide new evidence for a close link between autoimmunity directed against components of inhibitory synapses and neurological conditions characterized by chronic rigidity and spasms.
Toward the identification of a tolerogenic signature in IDO-competent dendritic cells
Authors: Ciriana Orabona, Paolo Puccetti, Carmine Vacca, Silvio Bicciato, Alessandra Luchini, Francesca Fallarino, Roberta Bianchi, Enrico Velardi, Katia Perruccio, Andrea Velardi, Vincenzo Bronte, Maria Cristina Fioretti, Ursula Grohmann
Journal: Blood (2005)
Interaction of human chagasic IgG with human colon muscarinic acetylcholine receptor: molecular and functional evidence
Authors: L Sterin-Borda
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> Gastrointestinal disorders is one of the clinical manifestations of chronic Chagas9 disease. The pathogenesis seems to be associated with autonomic dysfunction. Here, we consider the muscarinic cholinoceptor mediated alteration in distal colon function in chagasic megacolon. <h3>PATIENTS</h3> Patients were divided into four groups: group I, chronic chagasic patients with megacolon; group II, chronic chagasic patients without megacolon; group III, non-chagasic patients with megacolon; and group IV, normal healthy volunteers (control). <h3>METHODS</h3> Binding assay and immunoblot of cholinoceptors from human and rat colon and enzyme immunoassay (ELISA) using a synthetic 24mer peptide corresponding to the second extracellular loop of human M<sub>2</sub> muscarinic acetylcholine receptors (mAChR) were used to detect the presence of serum antibodies. The effect of antibodies on basal tone and 3′,5′-cyclic monophosphate (cAMP) production of human and rat distal colon strips were also tested. <h3>RESULTS</h3> Group I but not the other groups had circulating antibodies capable of interacting with human colon activating M<sub>2</sub> mAChR, as they competed with binding of specific radioligand to mAChR and interacted with the second extracellular loop of human M<sub>2</sub> mAChR. Moreover, affinity purified anti-M<sub>2</sub> peptide IgG from group I, in common with monoclonal antihuman M<sub>2</sub> mAChR, recognised bands with a molecular weight corresponding to colon mAChR. This antibody also displayed an agonist-like activity, increasing basal tone and decreasing cAMP accumulation. Both effects were blunted by AF-DX 116 and neutralised by the synthetic peptide. <h3>CONCLUSIONS</h3> In chagasic patients with megacolon there are antibodies that can recognise and activate M<sub>2</sub> mAChR. The implications of these autoantibodies in the pathogenesis of chagasic megacolon is discussed.
Oxidative Stress, Toxicology, and Pharmacology of CYP2E1
Authors: Andres A. Caro, Arthur I. Cederbaum
Journal: The Annual Review of Pharmacology and Toxicology (2004)

This review describes some of the biochemical and toxicological properties of CYP2E1, especially as it relates to alcohol metabolism and toxicity and the establishment of human hepatoma HepG2 cell lines that overexpress human CYP2E1. Ethanol, polyunsaturated fatty acids, and iron were found to be cytotoxic in HepG2 cells that overexpress CYP2E1. GSH appears to be essential in protecting HepG2 cells against the CYP2E1-dependent cytotoxicity, and GSH levels were elevated owing to a twofold increase in activity and expression of glutamate cysteine ligase. We suggest that this up-regulation of GSH synthesis was an adaptive response to attenuate CYP2E1-dependent oxidative stress and toxicity. Induction of a state of oxidative stress appears to play a central role in the CYP2E1-dependent cytotoxicity. Mitochondrial membrane potential decreased in the CYP2E1-expressing HepG2 cells, and this decrease shared similar characteristics with the developing toxicity. Alcohol-dependent liver injury is likely to be a multifactorial process involving several mechanisms. We believe that the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis contribute to the toxic actions of ethanol on the liver.
Monosomal Karyotype in Acute Myeloid Leukemia: A Better Indicator of Poor Prognosis Than a Complex Karyotype
Authors: Dimitri A. Breems, Wim L.J. Van Putten, Georgine E. De Greef, Shama L. Van Zelderen-Bhola, Klasien B.J. Gerssen-Schoorl, Clemens H.M. Mellink, Aggie Nieuwint, Martine Jotterand, Anne Hagemeijer, H. Berna Beverloo, Bob Löwenberg
Journal: Journal of Clinical Oncology (2008)

To investigate the prognostic value of various cytogenetic components of a complex karyotype in acute myeloid leukemia (AML).Cytogenetics and overall survival (OS) were analyzed in 1,975 AML patients age 15 to 60 years.Besides AML with normal cytogenetics (CN) and core binding factor (CBF) abnormalities, we distinguished 733 patients with cytogenetic abnormalities. Among the latter subgroup, loss of a single chromosome (n = 109) conferred negative prognostic impact (4-year OS, 12%; poor outcome). Loss of chromosome 7 was most common, but outcome of AML patients with single monosomy -7 (n = 63; 4-year OS, 13%) and other single autosomal monosomies (n = 46; 4-year OS, 12%) did not differ. Structural chromosomal abnormalities influenced prognosis only in association with a single autosomal monosomy (4-year OS, 4% for very poor v 24% for poor). We derived a monosomal karyotype (MK) as a predictor for very poor prognosis of AML that refers to two or more distinct autosomal chromosome monosomies (n = 116; 4-year OS, 3%) or one single autosomal monosomy in the presence of structural abnormalities (n = 68; 4-year OS, 4%). In direct comparisons, MK provides significantly better prognostic prediction than the traditionally defined complex karyotype, which considers any three or more or five or more clonal cytogenetic abnormalities, and also than various individual specific cytogenetic abnormalities (eg, del[5q], inv[3]/t[3;3]) associated with very poor outcome.MK enables (in addition to CN and CBF) the prognostic classification of two new aggregates of cytogenetically abnormal AML, the unfavorable risk MK-negative category (4-year OS, 26% +/- 2%) and the highly unfavorable risk MK-positive category (4-year OS, 4% +/- 1%).
Transplacental Effects of 1-Ethyl-1-Nitrosourea in Inbred Strains of Mice. III. Association Between Infectious or Subinfectious Endogenous Type-C RNA Tumor Virus Expression and Chemically Induced Tumorigenesis2
Authors: B. A. Diwan, H. Meier, R. J. Huebner
Journal: JNCI Journal of the National Cancer Institute (1973)

We studied the transplacental effects of 1-ethyl-1-nitrosourea (ENU) in strains AKR/J, DBA/2J, SWR/J, C57BL/6J, and C57L/J with respect to possible viralchemical cocarcinogenesis. a) The incidence of type-C RNA viral genome expression, particularly the species-specific, group-specific antigen (gs-AG) increased after transplacental administration of ENU. b) A significant association existed between gs-AG and, in some cases, complete virus expression and chemically induced tumors in mice. However, c) the rate of tumor induction and infectious or subinfectious (gs-AG) viral expression was influenced by the host genotype or strain of mouse. Specifically, d) the induction of tumors by ENU in AKR/J and DBA/2J mice with complete viral expression was accelerated, and e) with the specific oncogenic viral mechanism inherent, but largely unexpressed, in strains SWR/J, C57BL(6J, and C57L/J, ENU induced tumors as wei as gs-AG expression in most mice. Also, f) a previously unrevealed genetic propensity of AKR/J mice for pulmonary tumorigenesis was found with ENU treatment.
Immunosuppression of TH2 responses in Trichinella spiralis infection by Helicobacter pylori neutrophil-activating protein
Authors: Gianfranco Del Prete, Lorena Chiumiento, Amedeo Amedei, Maria Piazza, Mario M. D'Elios, Gaia Codolo, Marina de Bernard, Massimo Masetti, Fabrizio Bruschi
Journal: Journal of Allergy and Clinical Immunology (2008)
Increase in prevalence and severity of asthma in young adults in Copenhagen
Authors: E. F. Hansen
Journal: Thorax (2000)

<h3>BACKGROUND</h3> It is the general impression that the prevalence of asthma has increased during recent decades. A study was undertaken to investigate asthma prevalence, respiratory symptoms, and lung function in young adults in the City of Copenhagen 15 years apart. <h3>METHODS</h3> Men and women aged 20–35 years were sampled from the general population living in a defined area of central Copenhagen. The first examination took place in 1976–8 and comprised 1034 subjects (response rate 67.2%). A new sample comprising 1104 subjects (response rate 62.6%) from exactly the same area was examined 15 years later in 1991–4. All participants answered a questionnaire on respiratory symptoms and diseases and performed spirometric tests with measurement of forced expiratory volume in one second (FEV<sub>1</sub>) and forced vital capacity (FVC). <h3>RESULTS</h3> The prevalence of self-reported asthma increased from 1.5% in the first survey to 4.8% in the second survey (p&lt;0.001). Asthmatic subjects had, on average, poorer lung function than non-asthmatic subjects in terms of FEV<sub>1</sub> and this difference was more pronounced in the second survey than in the first (10.0% of predicted versus 2.4% of predicted). Smoking decreased significantly from 62% in 1976–8 to 45% in 1991–4 (p&lt;0.001). <h3>CONCLUSIONS</h3> The prevalence of self-reported asthma has increased significantly among young adults in Copenhagen over a 15 year period. The severity of asthma, as judged by the level of FEV<sub>1</sub>, has also increased. These findings cannot be explained by changes in smoking habits.
Th1/Th2 paradigm: not seeing the forest for the trees?
Authors: A. J. M. van Oosterhout, A. C. Motta
Journal: European Respiratory Journal (2005)

In this issue of the European Respiratory Journal , Irifune et al. 1 describe the effects of adoptive transfer of T-helper cell type 1 (Th1) cells in a mouse asthma model. Since the 1980s, the Th1/Th2 dichotomy has been considered the cornerstone of immune responses 2. Th1 cells (secreting interleukin (IL)-2 and interferon (IFN)-γ) lead to cell-mediated responses, whereas Th2 cells (secreting IL-4, IL-5 and IL-13) mediate for humoural immune responses 2. Accordingly, allergy results from an imbalance in favour of a Th2 response, and is negatively regulated by Th1 cells. However, while numerous studies support this theory, concurrently, data are accumulating that do not fit with the model in its original form.

Data in the literature show that both the prevalence of Th1-mediated autoimmune and Th2-mediated allergic diseases have increased simultaneously in recent decades 3–5. Furthermore, helminth infections, which induce strong Th2 responses, have paradoxically been shown to protect against allergy 6. These observations are in contradiction to the view of mutual cross-regulation between the two arms of the Th1/Th2 balance. Finally, studies regarding this balance in mouse asthma models have failed to provide clear evidence of counter-regulation between the two subtypes. For these latter studies, at least two …
Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality.
Authors: M I Hawa, D Fava, F Medici, Y J Deng, A L Notkins, G De Mattia, R D Leslie
Journal: Diabetes Care (2000)

OBJECTIVE: To determine the isotypes and clonality of antibodies to GAD (GADA) and IA-2 (IA-2A) in patients with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied the following consecutive series of patients who attended a diabetes center for antibodies to GADA and IA-2A: 52 newly diagnosed type 1 diabetic patients, 199 type 2 diabetic patients, 200 control patients, and a cohort of 34 nondiabetic identical twins of patients with type 1 diabetes (15 of whom developed diabetes) who were followed prospectively. RESULTS: GADA or IA-2A were detected in 37 (71%) type 1 diabetic patients compared with only 10 (5%) type 2 diabetic patients (P&amp;lt;0.0001). Both GAD and IA-2 antibodies, regardless of the type of diabetes, were usually subclass restricted to IgG1 and were polyclonal. IgM, IgG3, and IgE isotypes were also detected, but all isotypes of GADA and IA-2A were less prevalent than IgG1 (P&amp;lt;0.017 for either antibody). There was no evidence of spreading or switching of isotypes before the onset of type 1 diabetes. CONCLUSIONS: These observations suggest that the pathogenesis of antigen-specific antibodies in type 1 and type 2 diabetes is similar and probably involves a chronic nonrandom antigen-driven polyclonal B-cell activation that is consistent with a Th1-type immune response.
Sebum excretion in hypopituitarism
Authors: S.K. GOOLAMALI, J.L. BURTON, SAM SHUSTER
Journal: British Journal of Dermatology (1973)

The sebum excretion rate (SER) was measured in thirty-one patients with hypopituitarism of diverse aetiology, and the mean SER was found to be greatly decreased compared with control patients of the same age. The decrease was apparent even in patients who were receiving replacement therapy with hydrocortisone, thyroxine and testosterone. These findings confirm the importance of the pituitary gland in maintaining sebaceous activity in man, and the nature of the pituitary sebotrophic factor is discussed.
Nonsentinel Lymph Node Status in Patients With Cutaneous Melanoma: Results From a Multi-Institution Prognostic Study
Authors: Sandro Pasquali, Simone Mocellin, Nicola Mozzillo, Andrea Maurichi, Pietro Quaglino, Lorenzo Borgognoni, Nicola Solari, Dario Piazzalunga, Luigi Mascheroni, Giuseppe Giudice, Roberto Patuzzo, Corrado Caracò, Simone Ribero, Ugo Marone, Mario Santinami, Carlo Riccardo Rossi
Journal: Journal of Clinical Oncology (2014)

We investigated whether the nonsentinel lymph node (NSLN) status in patients with melanoma improves the prognostic accuracy of common staging features; then we formulated a proposal for including the NSLN status in the current melanoma staging system.We retrospectively collected the clinicopathologic data of 1,538 patients with positive SLN status who underwent completion lymph node dissection (CLND) at nine Italian centers. Multivariable Cox regression survival analysis was used to identify independent prognostic factors. Literature meta-analysis was used to summarize the available evidence on the prognostic value of the NSLN status in patients with positive SLN.NSLN metastasis was observed in 353 patients (23%). After a median follow-up of 45 months, NSLN status was an independent prognostic factor for melanoma-specific survival (hazard ratio [HR] = 1.34; 95% CI, 1.18 to 1.52; P < .001). NSLN status efficiently stratified the prognosis of patients with two to three positive lymph nodes (n = 387; HR = 1.39; 95% CI, 1.07 to 1.81; P = .013), independently of other staging features. Searching the literature, this patient subgroup was investigated in other two studies. Pooling the results (n = 620 patients; 284 NSLN negative and 336 NSLN positive), we found that NSLN status is a highly significant prognostic factor (summary HR = 1.59; 95% CI, 1.27 to 1.98; P < .001) in patients with two to three positive lymph nodes.These findings support the independent prognostic value of the NSLN status in patients with two to three positive lymph nodes, suggesting that this information should be considered for the routine staging in patients with melanoma.
Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: the role of skin testing
Authors: J. Torres, A. Romano, C. Mayorga, M. Carmen, A. E. Guzman, M. Reche, C. Juarez, M. Blanca
Journal: Allergy (2001)

Background: Penicillin is no longer the most commonly prescribed β‐lactam, and the pattern of reactions has changed. We studied the diagnostic value of skin testing in penicillin‐allergic subjects from a population where benzylpenicillin is not now the most frequently used β‐lactam. Methods: Patients with a history of immediate allergic reactions to penicillins were studied with: skin tests with major and minor determinants of benzylpenicillin (BPO/MDM), amoxicillin, and ampicillin; in vitro determination of specific IgE; and controlled administration for those with a positive history but negative skin and in vitro tests. A reaction was considered immediate when symptoms appeared within a maximum of 1 h after drug intake. Results: After testing, 290 patients (71% having anaphylaxis and 29% having urticaria) proved to be allergic. Amoxicillin was involved in 64.8% and benzylpenicillin in 2.8% of the patients. Skin test positivity to at least one determinant appeared in 70% of cases, amoxicillin being the most frequent. The overall sensitivity decreased markedly when only BPO and MDM were considered. In 13.1% of patients, the diagnosis was established by in vitro test and in 16.9% by controlled administration. Of the 290 patients, 42.1% were positive to determinants generated from benzylpenicillin and 57.9% were selective responders. Conclusions: Sensitivity of skin tests to BPO was lower than reported, being partly replaced by minor determinants, mostly amoxicillin. The incorporation of additional reagents and the development of new tests are required, and these will probably change as the patterns of consumption vary.
Comparison of Latanoprost and Timolol in Pediatric Glaucoma: A Phase 3, 12-Week, Randomized, Double-Masked Multicenter Study
Authors: Tomoko Maeda-Chubachi, Katherine Chi-Burris, Brad D. Simons, Sharon F. Freedman, Peng T. Khaw, Barbara Wirostko, Eric Yan
Journal: Ophthalmology (2011)
Identification of an Aberrantly Spliced Form of HDMX in Human Tumors: A New Mechanism for HDM2 Stabilization
Authors: Simona Giglio, Francesca Mancini, Francesca Gentiletti, Giorgia Sparaco, Lara Felicioni, Fabio Barassi, Carla Martella, Andrea Prodosmo, Stefano Iacovelli, Fiamma Buttitta, Antonella Farsetti, Silvia Soddu, Antonio Marchetti, Ada Sacchi, Alfredo Pontecorvi, Fabiola Moretti
Journal: Cancer Research (2005)

Abstract The HDMX protein is closely related to HDM2 with which it shares different structural domains, particularly the p53 binding domain and the ring finger domain, where the two HDM proteins interact. Several oncogenic forms derived from splicing of HDM2 have been described in cancer. This work aimed at investigating whether analogous forms of HDMX exist in human tumors. Here, we report the characterization of an aberrantly spliced form of HDMX, HDMX211, isolated from the thyroid tumor cell line, ARO. HDMX211 binds and stabilizes the HDM2 protein. Although it lacks the p53 binding domain, HDMX211 also stabilizes p53 by counteracting its degradation by HDM2. However, the resulting p53 is transcriptionally inactive and increasingly associated to its inhibitor HDM2. Expression of HDMX211 strongly enhances the colony-forming ability of human cells in the presence or absence of wild-type p53. Conversely, depletion of HDMX211 by small interfering RNA significantly reduces the growth of ARO cells and increases their sensitivity to chemotherapy. Screening of lung cancer biopsies shows the presence of HDMX211 in samples that overexpress HDM2 protein, supporting a pathologic role for this new protein. This is the first evidence of a variant form of HDMX that has oncogenic potential independently of p53. HDMX211 reveals a new mechanism for overexpression of the oncoprotein HDM2. Most interestingly, it outlines a possible molecular explanation for a yet unclarified tumor phenotype, characterized by simultaneous overexpression of HDM2 and wild-type p53.
Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
Authors: Heesang Song, Yonghe Li, Jiyeon Lee, Alan L. Schwartz, Guojun Bu
Journal: Cancer Research (2009)

The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor involved in the metabolism of various extracellular ligands, including proteinases, that play critical roles in tumor invasion. Although several studies have shown an increased expression of LRP1 in cancer cells, its function in tumor development and progression remains largely unclear. Here, we reveal a novel mechanism by which LRP1 induces the expression of matrix metalloproteinase 2 (MMP2) and MMP9 and thereby promotes the migration and invasion of human glioblastoma U87 cells. Knockdown of LRP1 expression greatly decreased U87 cell migration and invasion, which was rescued by the forced expression of a functional LRP1 minireceptor. Inhibition of ligand binding to LRP1 by a specific antagonist, receptor-associated protein, also led to reduced cancer cell migration and invasion. Because MMPs play critical roles in cancer cell migration and invasion, we examined the expression of several MMPs and found that the expression of functional MMP2 and MMP9 was selectively decreased in LRP1 knockdown cells. More importantly, decreased cell migration and invasion of LRP1 knockdown cells were completely rescued by exogenous expression of MMP2 or MMP9, suggesting that these MMPs are likely downstream targets of LRP1-mediated signaling. We further show that the level of phosphorylated extracellular signal-regulated kinase (ERK) was significantly decreased in LRP1-silenced cells, suggesting that ERK is a potential mediator of LRP1-regulated MMP2 and MMP9 expression in U87 cells. Together, our data strongly suggest that LRP1 promotes glioblastoma cell migration and invasion by regulating the expression and function of MMP2 and MMP9 perhaps via an ERK-dependent signaling pathway.
Almitrine bismesylate and oxygen therapy in hypoxic cor pulmonale.
Authors: T W Evans, J Tweney, J C Waterhouse, J Nichol, A J Suggett, P Howard
Journal: Thorax (1990)

The effect of oral treatment with the thiazine derivative almitrine bismesylate was studied in 28 patients with chronic obstructive pulmonary disease and arterial hypoxaemia receiving long term domiciliary oxygen therapy in a placebo controlled, double blind crossover trial. The initial treatment was given for three months and the second for two months. Because almitrine had an unexpectedly prolonged washout effect crossover analysis could not be performed; data from the placebo treatment administered in the second arm of the trial were used to calculate the half life of almitrine. Nine patients were withdrawn from the study (5 almitrine, 4 placebo). Patients9 tolerance of the drug was good. The estimated plasma half life of almitrine was 20.5 days, considerably longer than previously reported. Almitrine caused a significant improvement in arterial oxygen tension (PaO2) with a mean maximum increase of 0.7 kPa at a plasma concentration of 500 ng/ml. Higher plasma concentrations were not associated with any further increase in PaO2. There was no significant effect on arterial carbon dioxide tension (PaCO2). In a second, acute study at the end of each arm of the chronic trial nine patients were subjected to increasing oxygen delivery rates (2, 4, and 6 l/min) for 90 minutes or until blood gas concentrations plateaued. Almitrine increased PaO2 in a dose dependent fashion at all delivery rates, but the effect diminished as PaO2 approached normoxic levels. There was no significant effect on PaCO2. Almitrine treatment results in a significant improvement in PaO2 over that achieved by oxygen alone, an effect that diminishes at high flow rates. Whether this is of clinical benefit is not known. In view of the prolonged half life revised dosage schedules are required.