tbuckley/cabot-search huggingface dataset:
Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse.
Authors: D J Lenschow, S C Ho, H Sattar, L Rhee, G Gray, N Nabavi, K C Herold, J A Bluestone
Journal: The Journal of Experimental Medicine (1995)

Insulin-dependent diabetes mellitus (IDDM) is thought to be an immunologically mediated disease resulting in the complete destruction of the insulin-producing islets of Langerhans. It has become increasingly clear that autoreactive T cells play a major role in the development and progression of this disease. In this study, we examined the role of the CD28/B7 costimulation pathway in the development and progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse model. Female NOD mice treated at the onset of insulitis (2-4 wk of age) with CTLA4Ig immunoglobulin (Ig) (a soluble CD28 antagonist) or a monoclonal antibody (mAb) specific for B7-2 (a CD28 ligand) did not develop diabetes. However, neither of these treatments altered the disease process when administered late, at > 10 wk of age. Histological examination of islets from the various treatment groups showed that while CTLA4Ig and anti-B7-2 mAb treatment blocked the development of diabetes, these reagents had little effect on the development or severity of insulitis. Together these results suggest that blockade of costimulatory signals by CTLA4Ig or anti-B7-2 acts early in disease development, after insulitis but before the onset of frank diabetes. NOD mice were also treated with mAbs to another CD28 ligand, B7-1. In contrast to the previous results, the anti-B7-1 treatment significantly accelerated the development of disease in female mice and, most interestingly, induced diabetes in normally resistant male mice. A combination of anti-B7-1 and anti-B7-2 mAbs also resulted in an accelerated onset of diabetes, similar to that observed with anti-B7-1 mAb treatment alone, suggesting that anti-B7-1 mAb's effect was dominant. Furthermore, treatment with anti-B7-1 mAbs resulted in a more rapid and severe infiltrate. Finally, T cells isolated from the pancreas of these anti-B7-1-treated animals exhibited a more activated phenotype than T cells isolated from any of the other treatment groups. These studies demonstrate that costimulatory signals play an important role in the autoimmune process, and that different members of the B7 family have distinct regulatory functions during the development of autoimmune diabetes.
Molecular Characterization of the Tumor-Suppressive Function of Nischarin in Breast Cancer
Authors: Somesh Baranwal, Yanfang Wang, Rajamani Rathinam, Jason Lee, Lianjin Jin, Robin McGoey, Yuliya Pylayeva, Filippo G Giancotti, Gerard C. Blobe, Suresh K. Alahari
Journal: JNCI Journal of the National Cancer Institute (2011)

Nischarin (encoded by NISCH), an α5 integrin–binding protein, has been identified as a regulator of breast cancer cell invasion. We hypothesized that it might be a tumor suppressor and were interested in its regulation. We examined nischarin expression in approximately 300 human breast cancer and normal tissues using quantitative polymerase chain reaction and immunohistochemistry. Loss of heterozygosity analysis was performed by examining three microsatellite markers located near the NISCH locus in normal and tumor tissues. We generated derivatives of MDA-MB-231 human metastatic breast cancer cells that overexpressed nischarin and measured tumor growth from these cells as xenografts in mice; metastasis by these cells after tail vein injection; and α5 integrin expression, Rac, and focal adhesion kinase (FAK) signaling using western blotting. We also generated clones of MCF-7 human breast cancer cells in which nischarin expression was silenced and measured tumor growth in mouse xenograft models (n = 5 for all mouse experiments). P values were from two-sided Student t tests in pairwise comparisons. Normal human breast tissue samples had statistically significantly higher expression of nischarin mRNA compared with tumor tissue samples (mean level in normal breast = 50.7 [arbitrary units], in breast tumor = 16.49 [arbitrary units], difference = 34.21, 95% confidence interval [CI] = 11.63 to 56.79, P = .003), and loss of heterozygosity was associated with loss of nischarin expression. MDA-MB-231 cells in which nischarin was overexpressed had statistically significantly reduced tumor growth and metastasis compared with parental MDA-MB-231 cells (mean volume at day 40, control vs nischarin-expressing tumors, 1977 vs 42.27 mm3, difference = 1935 mm3, 95% CI = 395 to 3475 mm3, P = .025). Moreover, MCF-7 tumor xenografts in which nischarin expression was silenced grew statistically significantly faster than parental cells (mean volume at day 63, tumors with scrambled short hairpin RNA [shRNA] vs with nischarin shRNA, 224 vs 1262 mm3, difference = 1038 mm3, 95% CI = 899.6 to 1176 mm3, P < .001). Overexpression of nischarin was associated with decreased α5 integrin expression, FAK phosphorylation, and Rac activation. Nischarin may be a novel tumor suppressor that limits breast cancer progression by regulating α5 integrin expression and subsequently α5 integrin–, FAK-, and Rac-mediated signaling.
Use of Recombinant Human Stromal Cell–Derived Factor 1α–Loaded Fibrin/Hyaluronic Acid Hydrogel Networks to Achieve Functional Repair of Full‐Thickness Bovine Articular Cartilage Via Homing of Chondrogenic Progenitor Cells
Authors: Yin Yu, Marc J. Brouillette, Dongrim Seol, Hongjun Zheng, Joseph A. Buckwalter, James A. Martin
Journal: Arthritis & Rheumatology (2015)

Articular cartilage damage after joint trauma seldom heals and often leads to osteoarthritis. We previously identified a migratory chondrogenic progenitor cell (CPC) population that responds chemotactically to cell death and rapidly repopulates the injured cartilage matrix, which suggests a potential approach for articular cartilage repair. This study was undertaken to determine whether recombinant human stromal cell-derived factor 1α (rhSDF-1α), a potent CPC chemoattractant, would improve the quality of cartilage regeneration, hypothesizing that increased recruitment of CPCs by rhSDF-1α would promote the formation of cartilage matrix upon chondrogenic induction.Full-thickness bovine chondral defects were filled with hydrogel, composed of fibrin and hyaluronic acid and containing rhSDF-1α. Cell migration was monitored, followed by chondrogenic induction. Regenerated tissue was evaluated by histology, immunohistochemistry, and scanning electron microscopy. Push-out tests and unconfined compression tests were performed to assess the strength of tissue integration and the mechanical properties of the regenerated cartilage.Use of rhSDF-1α dramatically improved CPC recruitment to the chondral defects at 12 days. After 6 weeks under chondrogenic conditions, cell morphology, proteoglycan density, and the ultrastructure of the repair tissue were all similar to that found in native cartilage. Compared with empty controls, neocartilage generated in rhSDF-1α-containing defects showed significantly greater interfacial strength, and acquired mechanical properties comparable to those of native cartilage.This study showed that stimulating local CPC recruitment prior to treatment with chondrogenic factors significantly improves the biochemical and mechanical properties of the cartilage tissue formed in chondral defects. This simple approach may be implemented in vivo as a one-step procedure by staging the release of chemokine and chondrogenic factors from within the hydrogel, which can be achieved using smart drug-delivery systems.
Is TNF-α really involved in giant cell arteritis pathogenesis?
Authors: Maxime Samson, Sylvain Audia, Nona Janikashvili, Bernard Bonnotte
Journal: Annals of the Rheumatic Diseases (2013)

Giant cell arteritis (GCA) is the most frequent vasculitis in people >50 years, and glucocorticoids (GC) remain the cornerstone of the treatment. However, this long-term treatment is responsible for numerous GC-related complications.1 Thus, reliable GC-sparing drugs need to be explored. Seror et al 2 have recently reported the inefficacy of adalimumab, a humanised anti-TNF-α therapy, as a GC-sparing drug in the treatment of GCA. These clinical results contrast with previous studies reporting a production of TNF-α by giant cells and macrophages in GCA lesions.3 However, recent advance in the knowledge of GCA pathogenesis have shown that macrophages and giant cells are not involved in the first steps of GCA pathogenesis as they are recruited following CD4 T cells infiltration.4 ,5 We recently demonstrated that CD4CD161+ T lymphocytes largely infiltrate GCA lesions generating Th1 and Th17 cells, and play a major role in GCA pathogenesis.4–,6 Thus, we investigated the …
Heterozygous ATR Mutations in Mismatch Repair–Deficient Cancer Cells Have Functional Significance
Authors: Kriste A. Lewis, Sally Mullany, Bijoy Thomas, Jeremy Chien, Ralitsa Loewen, Viji Shridhar, William A. Cliby
Journal: Cancer Research (2005)

Abstract ATR (ataxia telangiectasia and Rad3-related) function is necessary for the proper response to commonly used chemotherapeutic agents. Heterozygous truncating mutations in exon 10 of the ATR gene have been described in numerous cancers exhibiting microsatellite instability. We show that truncating mutations of ATR are capable of acting in a dominant-negative manner to abrogate ATR-dependent Chk1 phosphorylation and cell-cycle arrests after DNA damage. In addition, endometrial cell lines harboring ATR mutations are defective for ATR-dependent responses. These findings imply that ATR mutations play an important role in the development and clinical behavior of a subset of microsatellite instability–positive endometrial, colon, and stomach cancers.
Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines
Authors: W S Lim
Journal: Thorax (2001)

<h3>BACKGROUND</h3> Since the last British study of the microbial aetiology of community acquired pneumonia (CAP) about 20 years ago, new organisms have been identified (for example, <i>Chlamydia pneumoniae</i>), new antibiotics introduced, and fresh advances made in microbiological techniques. Pathogens implicated in CAP in adults admitted to hospital in the UK using modern and traditional microbiological investigations are described. <h3>METHODS</h3> Adults aged 16 years and over admitted to a teaching hospital with CAP over a 12 month period from 4 October 1998 were prospectively studied. Samples of blood, sputum, and urine were collected for microbiological testing by standard culture techniques and new serological and urine antigen detection methods. <h3>RESULTS</h3> Of 309 patients admitted with CAP, 267 fulfilled the study criteria; 135 (50.6%) were men and the mean (SD) age was 65.4 (19.6) years. Aetiological agents were identified from 199 (75%) patients (one pathogen in 124 (46%), two in 53 (20%), and three or more in 22 (8%)): <i>Streptococcus pneumoniae</i> 129 (48%), influenza A virus 50 (19%), <i>Chlamydia pneumoniae</i> 35 (13%), <i>Haemophilus influenzae</i> 20 (7%), <i>Mycoplasma pneumoniae</i> 9 (3%), <i>Legionella pneumophilia</i> 9 (3%), other <i>Chlamydia</i>spp 7 (2%), <i>Moraxella catarrhalis</i> 5 (2%), <i>Coxiella burnetii </i>2 (0.7%), others 8 (3%). Atypical pathogens were less common in patients aged 75 years and over than in younger patients (16% <i>v</i>27%; OR 0.5, 95% CI 0.3 to 0.9). The 30 day mortality was 14.9%. Mortality risk could be stratified by the presence of four "core" adverse features. Three of 60 patients (5%) infected with an atypical pathogen died. <h3>CONCLUSION</h3> <i>S pneumoniae</i> remains the most important pathogen to cover by initial antibiotic therapy in adults of all ages admitted to hospital with CAP. Atypical pathogens are more common in younger patients. They should also be covered in all patients with severe pneumonia and younger patients with non-severe infection.
Coordinated Adenine Nucleotide Phosphohydrolysis and Nucleoside Signaling in Posthypoxic Endothelium
Authors: Holger K. Eltzschig, Juan C. Ibla, Glenn T. Furuta, Martin O. Leonard, Kenneth A. Jacobson, Keiichi Enjyoji, Simon C. Robson, Sean P. Colgan
Journal: The Journal of Experimental Medicine (2003)

Limited oxygen delivery to tissues (hypoxia) is common in a variety of disease states. A number of parallels exist between hypoxia and acute inflammation, including the observation that both influence vascular permeability. As such, we compared the functional influence of activated polymorphonuclear leukocytes (PMN) on normoxic and posthypoxic endothelial cells. Initial studies indicated that activated PMN preferentially promote endothelial barrier function in posthypoxic endothelial cells (&amp;gt;60% increase over normoxia). Extension of these findings identified at least one soluble mediator as extracellular adenosine triphosphate (ATP). Subsequent studies revealed that ATP is coordinately hydrolyzed to adenosine at the endothelial cell surface by hypoxia-induced CD39 and CD73 (&amp;gt;20-and &amp;gt;12-fold increase in mRNA, respectively). Studies in vitro and in cd39-null mice identified these surface ecto-enzymes as critical control points for posthypoxia-associated protection of vascular permeability. Furthermore, insight gained through microarray analysis revealed that the adenosine A2B receptor (AdoRA2B) is selectively up-regulated by hypoxia (&amp;gt;5-fold increase in mRNA), and that AdoRA2B antagonists effectively neutralize ATP-mediated changes in posthypoxic endothelial permeability. Taken together, these results demonstrate transcription coordination of adenine nucleotide and nucleoside signaling at the vascular interface during hypoxia.
Surrogate Light Chain Expressing Human Peripheral B Cells Produce Self-reactive Antibodies
Authors: Eric Meffre, Anne Schaefer, Hedda Wardemann, Patrick Wilson, Eric Davis, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2003)

Human B cells that coexpress surrogate and conventional light chains (V-preB+L+) show an unusual heavy and light chain antibody repertoire that display evidence of receptor editing. However, it is unclear whether V-preB+L+ B cells have been silenced by receptor editing or still express autoreactive antibodies. Here we report that 68% of the antibodies expressed by V-preB+L+ B cells are autoreactive. A majority of these autoantibodies are true antinuclear antibodies (ANA), and 50% of the ANAs are also reactive with a diverse group of antigens that include dsDNA, ssDNA, immunoglobulin, insulin, and bacterial lipopolysaccharide. Such antibodies are rarely encountered among conventional B cells. We conclude that V-preB+L+ B cells are a unique subset of normal circulating human B cells that escape central tolerance mechanisms and express self-reactive antibodies including potentially harmful ANAs.
Disseminated Neuroblastoma in Children Older Than One Year at Diagnosis: Comparable Results With Three Consecutive High-Dose Protocols Adopted by the Italian Co-Operative Group for Neuroblastoma
Authors: Bruno De Bernardi, Brigitte Nicolas, Luca Boni, Paolo Indolfi, Modesto Carli, Luca Cordero di Montezemolo, Alberto Donfrancesco, Andrea Pession, Massimo Provenzi, Andrea di Cataldo, Antonino Rizzo, Gian Paolo Tonini, Sandro Dallorso, Massimo Conte, Claudio Gambini, Alberto Garaventa, Federico Bonetti, Andrea Zanazzo, Paolo D’Angelo, Paolo Bruzzi
Journal: Journal of Clinical Oncology (2003)

Purpose: To compare the outcomes associated with modifications in three consecutive protocols employed by the Italian Co-Operative Group for Neuroblastoma (ICGNB) in disseminated neuroblastoma. Patients and Methods: Between January 1985 and November 1997, a total of 359 children aged 1 to 15 years with newly diagnosed stage 4 neuroblastoma were enrolled in three consecutive protocols. Compared with ICGNB-85, the ICGNB-89 protocol contained two more chemotherapy cycles, and some drugs were given at greater doses, whereas in the ICGNB-92 protocol, the induction phase included a chelating agent, and individual cycles contained four drugs instead of two. Results: A total of 330 of 359 evaluable children were included in this analysis; 106 children were treated with ICGNB-85, 65 children were treated with ICGNB-89, and 159 children were treated with ICGNB-92 protocols. Radical resection of primary tumor was carried out in 59.4%, 50.8%, and 57.9% of the patients, respectively. Major tumor response after induction therapy was achieved in 66.7%, 69.2%, and 68.6% of the patients, respectively. A total of 218 of 232 patients received consolidation therapy consisting of conventional chemotherapy in 65 patients and of high-dose chemotherapy in 153 patients. Disease recurrence or progression occurred in 82.1%, 69.2%, and 74.8% of the patients, respectively. Therapy-related deaths occurred in 1.9%, 12.3%, and 6.9% of the patients, respectively. Five-year overall survival (OS) for the three studies was 26%, 23%, and 28%, and event-free survival (EFS) was 19%, 17%, and 17%, respectively. Conclusion: The therapeutic modifications adopted in the ICGNB-89 and ICGNB-92 protocols were not associated with a significant improvement in response rate or in the 5-year OS and EFS as compared with the ICGNB-85 protocol. Attempts at intensifying chemotherapy were associated with greater toxicity.
Potency and stability of C terminal truncated human epidermal growth factor
Authors: D P Calnan, A Fagbemi, J Berlanga-Acosta, T Marchbank, T Sizer, K Lakhoo, A D Edwards, R J Playford
Journal: Gut (2000)

<h3>INTRODUCTION</h3> Epidermal growth factor (EGF) is normally present as EGF<sub>1–53</sub>. A variety of C terminal truncated forms have been used in preliminary trials for treating gastrointestinal injury but their relative potency and stability when used in a clinical setting are unclear. Therefore, we compared the biological activity of recombinant EGF<sub>1–53</sub>, EGF<sub>1–52</sub>, EGF<sub>1–51</sub>, and the C terminal peptides EGF<sub>44–53</sub> and EGF<sub>49–53</sub>. <h3>METHODS</h3> Purity of forms was confirmed by mass spectrometry. Bioactivity of the different EGF forms was determined using [methyl-<sup>3</sup>H] thymidine incorporation into primary rat hepatocytes and their ability to reduce indomethacin (20 mg/kg subcutaneously)/restraint induced gastric injury in rats. Stability of EGF peptides was determined by serial sampling from a syringe driver system containing EGF/4% albumin in saline. <h3>RESULTS</h3> Biological activity assays of EGF<sub>1–53</sub>, EGF<sub>1–52</sub>, and EGF<sub>1–51</sub> gave almost identical thymidine uptake dose-response curves (maximal responses increasing baseline uptake from 4400 (600) cpm (mean (SEM)) to about 22 000 (2000) cpm when EGF was added at 1.6 nM). EGF<sub>44–53</sub> and EGF<sub>49–53</sub> did not stimulate <sup>3</sup>H thymidine uptake. Control rats had 47 (4) mm<sup>2</sup> damage/stomach, EGF<sub>1–51</sub>, EGF<sub>1–52</sub>, and EGF<sub>1–53</sub> at 0.16 and 0.80 nmol/kg/h each reduced gastric injury by about 50% and 80%, respectively (both doses p&lt;0.01 compared with control but no significant difference between the different forms). EGF was stable at room temperature for seven days but biological activity decreased by 35% and 40% at two and three weeks, respectively (both p&lt;0.01). Exposure to light did not affect bioactivity. <h3>CONCLUSION</h3> EGF<sub>1–51</sub>and EGF<sub>1–52</sub> are as biologically active as full length EGF<sub>1–53</sub> but the C terminal penta- and decapeptides are ineffective. Clinical trials of EGF can probably use infusion systems for at least 48 hours at room temperature and with exposure to light, without reducing biological efficacy.
APUD cells and neuroepithelial bodies in hamster lung: methods, quantitation, and response to injury.
Authors: J R Palisano, J Kleinerman
Journal: Thorax (1980)

A comparative study of the Falck-Hillarp Technique, a modification of Eaton-Fedde procedure and silver staining of aldehyde-fixed tissue was carried out to determine the most efficient procedure to demonstrate neuroendocrine cells of the hamster and rat lung. The modified Eaton-Fedde procedure is the most efficient method of observing these cells, and is also the easiest to perform. With this method, the normal hamster lung contains a total of 2.00 x 10(-1) to 3.00 x 10(-1) neuroendocrine cells/mm in the small and large bronchioles. In the larger airways approximately 3.51 x 10(-1) neuroepithelial bodies (NEB)/mm are observed. Immediately after 24-hour exposure to NO2 the number of APUD cells dropped to approximately 25% of the control levels. These cells were decreased to 50% of the control levels throughout the 28 days of exposure. The number of NEB decreased transiently after 24 hours of NO2 but returned to normal numbers by day 14. We recommend the application of fluorescence techniques coupled with standardised sections and quantitative methods of study for analysis of APUD cells and NEB.
The significance of early recurrent wheeze for asthma outcomes in late childhood
Authors: Vegard Hovland, Amund Riiser, Petter Mowinckel, Kai-Håkon Carlsen, Karin C. Lødrup Carlsen
Journal: European Respiratory Journal (2012)

Recurrent early life wheeze is not always asthma, and up to 50% of children are reported to remit. With reports of adult asthma symptom relapse, we assessed the prognosis of recurrent bronchial obstruction (rBO) through adolescence in the Environment and Childhood Asthma (ECA) prospective birth cohort study. The present study is based on data from investigations at ages 2, 10 and 16 years of 550 young people (52% males) attending at 16 years of age. Based on the presence of rBO from 0–2 years, defined as recurrent (at least two episodes) doctor-diagnosed wheeze, and asthma from 2–10 years and 10–16 years, defined as at least two episodes of doctor-diagnosed asthma, symptoms and medication use, prognosis of rBO was assessed. Bronchial hyperresponsiveness (BHR) was diagnosed by a metacholine provocation dose ≤8 μmol that caused 20% reduction in the forced expiratory volume in 1 s. At 10–16 years, 34% of the 143 rBO children had asthma. All children with rBO had reduced lung function compared with the never asthmatics. Of the rBO children in remission, 48.4% had asthma symptoms, medication use and/or BHR compared with 26.7% with never asthma (p&lt;0.001). Only 34.3% of rBO children were without asthma symptoms, medication use or BHR by 16 years, possibly indicating future asthma risk.
THE IMMUNE SYSTEM AS A SUPERSYSTEM
Authors: Tomio Tada
Journal: Annual Review of Immunology (1997)

I coined a term “supersystem” to designate highly integrated life systems such as the immune system, nervous system, and embryogenesis. While the mechanistic system is defined as a set of diverse elements so connected and related as to form an organic whole for a particular purpose, the “supersystem” engenders its own elements from a single progenitor. The diverse elements thus generated form relationships by mutual adaptation and coadaptation, and thus they create a dynamic self-regulating system through self-organization. It is a closed self-satisfied system, yet open to the environment, receiving outside signals to transduce them into internal messages for self-regulation and expansion. Unlike a mechanistic system, the “supersystem” has no defined purpose and determines its own fate by referring to its self-established behavioral pattern. Both the immune and nervous systems develop and function as a typical “supersystem.” The prototype of the supersystem can be seen in embryogenesis and evolution. The concept of the supersystem can also be applied to the development of language, or a city, or other cultural phenomena that human beings have created as a result of their vital activities.