tbuckley/cabot-search huggingface dataset:
Increased Complement Activation in Human Type 1 Diabetes Pancreata
Authors: Patrick Rowe, Clive Wasserfall, Byron Croker, Martha Campbell-Thompson, Alberto Pugliese, Mark Atkinson, Desmond Schatz
Journal: Diabetes Care (2013)

OBJECTIVE Evidence supporting an association between complement (C) and type 1 diabetes (T1D) includes the identification of C-fixing islet cell autoantibodies in T1D sera and genetic associations with the major histocompatibility complex III C4 region on chromosome 6. Therefore, we investigated whether C activation was present in pancreata from those with or at increased risk (positive for T1D associated autoantibodies) for T1D. RESEARCH DESIGN AND METHODS Immunohistochemical techniques were used to measure the C degradation product C4d in organ donor pancreata from patients with T1D and type 2 diabetes and autoantibody-positive and autoantibody-negative subjects. RESULTS Median C4d antigen density differed across the groups (P &amp;lt; 0.0001) and was highest in patients with T1D. C4d immunostaining localized to the blood vessel endothelium and extracellular matrix surrounding blood vessels and exocrine ducts. Receiver operating characteristic analysis resulted in 81.8% sensitivity and 94.4% specificity for C4d staining. CONCLUSIONS These data suggest that C activation is occurring within pancreata from patients with T1D and C4d may be a biomarker for T1D.
Explicit equilibrium modeling of transcription-factor binding and gene regulation.
Authors: Joshua A Granek, Neil D Clarke
Journal: Genome biology (2005)

Abstract We have developed a computational model that predicts the probability of transcription factor binding to any site in the genome. GOMER (generalizable occupancy model of expression regulation) calculates binding probabilities on the basis of position weight matrices, and incorporates the effects of cooperativity and competition by explicit calculation of coupled binding equilibria. GOMER can be used to test hypotheses regarding gene regulation that build upon this physically principled prediction of protein-DNA binding.
Activation of macrophages for enhanced release of superoxide anion and greater killing of Candida albicans by injection of muramyl dipeptide.
Authors: N P Cummings, M J Pabst, R B Johnston
Journal: The Journal of Experimental Medicine (1980)

The adjuvant muramyl dipeptide (MDP) has been shown to affect a number of macrophage functions in vitro. We studied the effect of subcutaneous injection of MDP into mice. Cultured peritoneal macrophages from treated mice displayed increased spreading, total cell protein, and specific activity of beta-glucosaminidase a constituent of macrophage lysosomes, and of lactate dehydrogenase. Generation of superoxide anion (O2-) by MDP-treated macrophages stimulated by contact with phorbol myristate acetate was enhanced by over fivefold to levels achieved by macrophages from bacillus Calmette-Guérin-infected mice. The enhancement in stimulated O2- release was noted by 1 h after injection of MDP, peaked by 3 h, and remained high for at least 48 h. Priming for enhancement of O2- release by MDP was similar in athymic nude mice and in normal littermates, suggesting that mature T lymphocytes are not involved in this MDP effect. Priming for enhanced stimulated O2- release, and morphologic and enzymic changes, were not achieved by injection of the D-D stereoisomer of MDP. Phagocytosis of Candida albicans was only slightly greater by macrophages from mice give MDP, but MDP-stimulated cells killed two times more C. albicans in vitro than did cells from untreated animals. When MDP was given 18 h before, simultaneously with, or 24 h after lethal infectious challenge with C. albicans, treated mice were protected compared with controls. These results suggest that injection of MDP effectively and rapidly activates macrophages in the recipient animal. This agent should serve as an important probe of macrophage physiology and, perhaps ultimately, as a means of enhancing host defense in humans.
Cell Competition and Its Possible Relation to Cancer
Authors: Nicholas E. Baker, Wei Li
Journal: Cancer Research (2008)

Abstract Cell competition can occur when cells of different genotypes share the same developing compartment, with one genotype displacing the other as a result of a proliferative advantage. Studies of cell competition in Drosophila have identified an active process of cell assassination and corpse engulfment, and also roles for Myc and the Warts/Hippo tumor suppressor pathway. Here, we discuss the possible relevance of cell competition to cancer. [Cancer Res 2008;68(14):5505–7]
Different Strokes for Different Folks: New Paradigms for Staging Oropharynx Cancer
Authors: David M. Brizel
Journal: Journal of Clinical Oncology (2015)

The majority of patients with head and neck squamous carcinomas(HNCs)presentwithlocallyand/orregionallyadvanced(stageIII orIV)butnonmetastaticdisease.Historically,curewasonlyattainable in 30% to 40% of these patients after treatment with surgery and/or radiotherapy (RT). Both disease and treatment-induced morbidities were high. Cytotoxic chemotherapy was initially investigated in the late 1970s and early 1980s. Subsequent randomized trials of concurrentchemoradiotherapy(CRT)inthe1990sand2000sdemonstrated significant improvements in survival compared with RT alone. 1-3 A meta-analysis of 16,485 patients demonstrated a 6.5%
Study of lymphoid cells from inflamed synovial membranes.
Authors: G Loewi, E.M Lance, J Reynolds
Journal: Annals of the Rheumatic Diseases (1975)

Synovectomy specimens from patients with rheumatoid arthritis were cultured and after 24 hours the nonadherent cells were removed. These were found to include cells with the morphological characteristics of lymphocytes. Using the sheep-cell rosetting test, up to 94% of these cells were found to be T cells, and while T cells could be found in all the supernatant cell populations studied, not all made a mitogen response. None or only a very small number of B cells were found by staining for surface immunoglobulin. The possible roles which T lymphocytes might play in chronic inflammation in the rheumatoid synovium are discussed in relation to experimental work, and factors which attract T cells into areas of nonspecific inflammation are similarly considered in the light of animal experiments.
Notch2 Is Preferentially Expressed in Mature B Cells and Indispensable for Marginal Zone B Lineage Development
Authors: Toshiki Saito, Shigeru Chiba, Motoshi Ichikawa, Atsushi Kunisato, Takashi Asai, Kiyoshi Shimizu, Tomoyuki Yamaguchi, Go Yamamoto, Sachiko Seo, Keiki Kumano, Etsuko Nakagami-Yamaguchi, Yoshio Hamada, Shinichi Aizawa, Hisamaru Hirai
Journal: Immunity (2003)
Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction
Authors: Markus Müschen, Daniel Re, Berit Jungnickel, Volker Diehl, Klaus Rajewsky, Ralf Küppers
Journal: The Journal of Experimental Medicine (2000)

Somatic hypermutation specifically modifies rearranged immunoglobulin (Ig) genes in germinal center (GC) B cells. However, the bcl-6 gene can also acquire somatic mutations during the GC reaction, indicating that certain non-Ig genes can be targeted by the somatic hypermutation machinery. The CD95 gene, implicated in negative selection of B lymphocytes in GCs, is specifically expressed by GC B cells and was recently identified as a tumor suppressor gene being frequently mutated in (post) GC B cell lymphomas. In this study, the 5′ region (5′R) and/or the last exon coding for the death domain (DD) of the CD95 gene were investigated in naive, GC, and memory B cells from seven healthy donors. About 15% of GC and memory, but not naive, B cells carried mutations within the 5′R (mutation frequency 2.5 × 10−4 per basepair). Mutations within the DD were very rare but could be efficiently selected by inducing CD95-mediated apoptosis: in 22 apoptosis-resistant cells, 12 DD mutations were found. These results indicate that human B cells can acquire somatic mutations of the CD95 gene during the GC reaction, which potentially confers apoptosis resistance and may counteract negative selection through the CD95 pathway.
Norfuraneol dephosphorylates eNOS at threonine 495 and enhances eNOS activity in human endothelial cells
Authors: Christoph A. Schmitt, Elke H. Heiss, Yasmin Aristei, Theodor Severin, Verena M. Dirsch
Journal: Cardiovascular Research (2008)

Pentoses are widely abundant in organic food. Thermal treatment of pentoses leads to the formation of norfuraneol (NF). The aim of this study was to show whether NF, which is taken up regularly, for example with cooked food, affects the human endothelial nitric oxide synthase (eNOS) system. The study was performed using cultured human umbilical vein endothelial cells (HUVEC), HUVEC-derived EA.hy926 cells, and bovine aortic endothelial cells. Nitric oxide (NO) release and eNOS activity were measured using diaminofluorescein-2 and [14C]l-arginine/[14C]l-citrulline conversion. Levels of (phospho-)eNOS were detected by western blotting. Reactive oxygen species (ROS) production was assessed using 2′,7′-dichlorodihydrofluorescein diacetate. Pharmacokinetic parameters of NF were calculated by VolSurf software. NF dose dependently increased eNOS activity and NO release (30–300 µM), but did not affect total eNOS protein or cellular ROS levels. The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation. Phosphorylation at eNOS-Ser1177 was not significantly altered by NF. Inhibition of protein kinase C with bisindolylmaleimide I (GFX) or calphostin C mimicked the effect of NF. In contrast to GFX, however, NF had no effect on phorbol-12-myristate-13-acetate-induced endothelial ROS formation. In silico, NF is stable towards CYP3A4 metabolism, shows low protein binding, and high tissue distribution. NF enhances endothelial NO release most likely by promoting specific dephosphorylation of eNOS-Thr495 via PP1 in vitro and may be a promising compound to enhance endothelial function in vivo.
Effects of histamine, ethanol, and a detergent on exudation and absorption across guinea pig airway mucosa in vivo.
Authors: L Greiff, I Erjefalt, P Wollmer, U Pipkorn, C G Persson
Journal: Thorax (1991)

This study examined effects of three substances that cause mucosal provocation (histamine, ethanol, and the detergent dioctylsodium sulphosuccinate (DOSS] on the flux of solutes across airway vascular mucosal barriers in anaesthetised guinea pigs. The inward flux was assessed as absorption of iodine-131 labelled albumin (MW 69,000) from the tracheobronchial surface into the circulation and the outward flux as the exudation of two intravenously administered plasma tracers--125I albumin (MW 69,000) and fluorescein isothiocyanate conjugated (FITC) dextran (MW 70,000)--into the airway. The absorption of technetium-99m labelled DTPA (MW 492) from the tracheobronchial airways was determined in separate experiments. Histamine (5.0 nmol) dissolved in 40 microliters saline and superfused on the tracheobronchial mucosal surface caused significant and similar entry of 125I albumin and FITC dextran into the airway lumen. This dose of histamine did not, however, alter the absorption of small (99mTc DTPA) or large (131I albumin) solutes across the airway mucosa. Ethanol (0.17 mumol), superfused in the same way, also caused significant exudation of the plasma tracers into the airway lumen. In addition, ethanol increased the absorption of 131I albumin without causing change in the disappearance rate of 99mTc DTPA. The detergent, DOSS (0.28 nmol), dissolved in ethanol (0.17 mumol), caused a pronounced increase in exudation and much increased absorption of small and large tracer solutes. Thus three patterns of change in airway mucosal barriers were found. The agents that are toxic to membranes, ethanol and DOSS, caused a bidirectional increase in permeability across the mucosa, whereas histamine caused only an outward exudative flux. The results obtained with histamine are similar to those seen previously with bradykinin, capsaicin, and allergen, suggesting that endogenous inflammatory mediators have a role in mucosal defence, producing entry of plasma exudates into the airway lumen without increasing the mucosal absorption of luminal material.
Translational Research in Acute Central Nervous System Injury
Authors: David S. Warner, Michael L. James, Daniel T. Laskowitz, Eelco F. Wijdicks
Journal: JAMA Neurology (2014)

<h3>Importance</h3> Research to improve outcomes from acute central nervous system (CNS) injury has progressed little, although limited examples (eg, induced hypothermia for out-of-hospital ventricular fibrillation cardiac arrest and birth asphyxia and tissue plasminogen activator for ischemic stroke) have proved that it is possible to favorably alter outcome. <h3>Objective</h3> To chronicle the evolution of preclinical research designed to provide therapeutic interventions for acute CNS injury. <h3>Evidence Review</h3> Preclinical literature cited by major clinical intervention trials was systematically assessed with respect to fulfillment of fundamental elements of experimental design in current guidelines. <h3>Findings</h3> Preclinical studies of acute CNS injury to date have a poor record of adhering to basic tenets of experimental design, including randomization, concealment of treatment allocation, definition of sustained robustness of therapeutic benefit, and emulation of clinical disease. Major clinical trials continue to be justified and conducted on the basis of weak preclinical evidence. Publication of preclinical research guidelines and endorsement by scientific journals have been insufficient to alter practice. Novel approaches to preclinical therapeutic development, including multicenter phase 3 trials and preclinical trial registries that document a priori experimental design and primary dependent variables, may overcome this intransigence and enhance possibility for therapeutic breakthroughs. <h3>Conclusions and Relevance</h3> Current knowledge of acute CNS injury dictates that therapeutic discovery and translation apply known tenets of sound experimental design and emulation of the clinical disorder targeted for therapeutic intervention. Peer-review systems must demand these qualities in proposed and published research to assess validity and potential for clinical translation.
Association of childhood allergic asthma with markers flanking the IL33 gene in Italian families
Authors: Francesca Belpinati, Giovanni Malerba, Elisabetta Trabetti, Roberta Galavotti, Luciano Xumerle, Lydia Pescollderungg, Attilio Loris Boner, Pier Franco Pignatti
Journal: Journal of Allergy and Clinical Immunology (2011)
Spontaneous pneumothorax in cystic fibrosis.
Authors: P F Mitchell-Heggs
Journal: Thorax (1970)

Much less is known of the lymphatics of the pleura and chest wall.There are two main directions of lymph flow-forwards to the internal mammary chain of nodes and vessels, and backwards to the posterior mediastinum.Some of the lymphatics of the lower intercostal spaces drain downwards, through the diaphragm, to reach the cisterna chyli.Some of the mediastinal lymphatics communicate directly with the thoracic duct while the majority run upwards to join the paratracheal and pulmonary lymphatics and then drain by one or more vessels into the veins at the base of the neck near the thoracic duct.The radiological appearances of the abnormal lymphatics in lymphangitis carcinomatosa, pulmonary oedema, etc., are discussed.Lymphography W. F. WHITE The lymphatics and lymph nodes draining many parts of the body may now be demonstrated by lymphography.
Serial Changes in Tissue Carbon Dioxide Content During Acute Respiratory Acidosis12
Authors: George Nichols
Journal: Journal of Clinical Investigation (1958)

The retention of CO2 in man and animals in chronic respiratory disease and during exposure to atmospheres with high partial pressures of CO2 was first shown a number of years ago (1-4).Its converse, the reduction of CO2 stores during hyperventilation, was demonstrated at the same time.However, considerable doubt has existed as to the site in the body occupied by this store of C02, how rapidly it equilibrates with blood and alveolar C02, and what effects its accumulation may have on acid-base equilibria in the extracellular and intracellular compartments.Brocklehurst and Henderson (1) found small changes in tissue CO2 stores in man in experiments lasting only two to three minutes, while Shaw (2), using cats and a longer equilibration time, postulated that as much as 80 per cent of the CO2 taken up was "buffered" by the tissues.Ferguson, Irving, and Plewes (3, 4) attempted to localize the area of storage, but were unable to account for all the CO2 taken up in cats although they found increases in blood, muscle, brain and kidney CO2 content.They pointed out that bone contained 40 to 50 per cent of the total body CO2 and were able to lower bone CO2 3 per cent by hyperventilation, but they failed to raise the bone CO2 content by increasing the CO2 tension in the inspired atmosphere for several hours.More re- cently, however, Freeman and Fenn found the bone CO2 of rats increased after exposure to 10 per cent CO2 in air for periods of 6 to 28 days (5).They also found considerable increases in muscle CO2.On the other hand, in brief (six hours) hyperventilation experiments with low
Suicide Attempt in Young People
Authors: Sidra J. Goldman-Mellor, Avshalom Caspi, HonaLee Harrington, Sean Hogan, Shyamala Nada-Raja, Richie Poulton, Terrie E. Moffitt
Journal: JAMA Psychiatry (2013)

<h3>Importance</h3> Suicidal behavior has increased since the onset of the global recession, a trend that may have long-term health and social implications. <h3>Objective</h3> To test whether suicide attempts among young people signal increased risk for later poor health and social functioning above and beyond a preexisting psychiatric disorder. <h3>Design</h3> We followed up a cohort of young people and assessed multiple aspects of their health and social functioning as they approached midlife. Outcomes among individuals who had self-reported a suicide attempt up through age 24 years (young suicide attempters) were compared with those who reported no attempt through age 24 years (nonattempters). Psychiatric history and social class were controlled for. <h3>Setting and Participants</h3> The population-representative Dunedin Multidisciplinary Health and Development Study, which involved 1037 birth cohort members comprising 91 young suicide attempters and 946 nonattempters, 95% of whom were followed up to age 38 years. <h3>Main Outcomes and Measures</h3> Outcomes were selected to represent significant individual and societal costs: mental health, physical health, harm toward others, and need for support. <h3>Results</h3> As adults approaching midlife, young suicide attempters were significantly more likely to have persistent mental health problems (eg, depression, substance dependence, and additional suicide attempts) compared with nonattempters. They were also more likely to have physical health problems (eg, metabolic syndrome and elevated inflammation). They engaged in more violence (eg, violent crime and intimate partner abuse) and needed more social support (eg, long-term welfare receipt and unemployment). Furthermore, they reported being lonelier and less satisfied with their lives. These associations remained after adjustment for youth psychiatric diagnoses and social class. <h3>Conclusions and Relevance</h3> Many young suicide attempters remain vulnerable to costly health and social problems into midlife. As rates of suicidal behavior rise with the continuing global recession, additional suicide prevention efforts and long-term monitoring and after-care services are needed.
Phase I Trial of Recombinant Immunotoxin Anti-Tac(Fv)-PE38 (LMB-2) in Patients With Hematologic Malignancies
Authors: Robert J. Kreitman, Wyndham H. Wilson, Jeffrey D. White, Maryalice Stetler-Stevenson, Elaine S. Jaffe, Steven Giardina, Thomas A. Waldmann, Ira Pastan
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To evaluate the toxicity, pharmacokinetics, immunogenicity, and antitumor activity of anti-Tac(Fv)-PE38 (LMB-2), an anti-CD25 recombinant immunotoxin that contains an antibody Fv fragment fused to truncated Pseudomonas exotoxin. PATIENTS AND METHODS: Patients with CD25 + hematologic malignancies for whom standard and salvage therapies failed were treated with LMB-2 at dose levels that ranged from 2 to 63 μg/kg administered intravenously over 30 minutes on alternate days for three doses (QOD × 3). RESULTS: LMB-2 was administered to 35 patients for a total of 59 cycles. Dose-limiting toxicity at the 63 μg/kg level was reversible and included transaminase elevations in one patient and diarrhea and cardiomyopathy in another. LMB-2 was well tolerated in nine patients at the maximum-tolerated dose (40 μg/kg QOD × 3); toxicity was transient and most commonly included transaminase elevations (eight patients) and fever (seven patients). Only six of 35 patients developed significant neutralizing antibodies after the first cycle. The median half-life was 4 hours. One hairy cell leukemia (HCL) patient achieved a complete remission, which is ongoing at 20 months. Seven partial responses were observed in cutaneous T-cell lymphoma (one patient), HCL (three patients), chronic lymphocytic leukemia (one patient), Hodgkin’s disease (one patient), and adult T-cell leukemia (one patient). Responding patients had 2 to 5 log reductions of circulating malignant cells, improvement in skin lesions, and regression of lymphomatous masses and splenomegaly. All four patients with HCL responded to treatment. CONCLUSION: LMB-2 has clinical activity in CD25 + hematologic malignancies and is relatively nonimmunogenic. It is the first recombinant immunotoxin to induce major responses in cancer. LMB-2 and similar agents that target other cancer antigens merit further clinical development.