tbuckley/cabot-search huggingface dataset:
Anergy and Cytokine-Mediated Suppression as Distinct Superantigen-Induced Tolerance Mechanisms in Vivo
Authors: Carla Miller, Jack A. Ragheb, Ronald H. Schwartz
Journal: The Journal of Experimental Medicine (1999)

Recombinant-activating gene 2 (RAG-2−/−) T cell receptor–transgenic mice repeatedly injected with the superantigen staphylococcal enterotoxin A entered a tolerant state in which splenic CD4+ T cells produced little interleukin (IL)-2, interferon γ, or IL-4. This state resulted from a combination of both clonal anergy and cytokine-mediated immunosuppression. The anergy persisted for at least 3 wk and could be distinguished from the suppression by a decrease in IL-2 production per cell, a block in the activation of early response kinases, and a failure to be reversed with anti–transforming growth factor (TGF)-β. Full suppression lasted for only 1 wk and involved both IL-10 and TGF-β, but required additional unknown molecules for optimal effect. These experiments show that complex in vivo interactions of multiple peripheral tolerance mechanisms can now be dissected at both the cellular and molecular levels.
Abuse of Amphetamine Prescribers
Authors: L. McKenzie Gross
Journal: JAMA (1973)

<h3>To the Editor.—</h3> Believing that overweight and its camp followers, diabetes, hypertension, strokes, and heart disease constitute the greatest enemies of the American people, I cannot help but rise in protest to the obvious attempts by the Food and Drug Administration (FDA) dictators, by their "staged reports," to remove from the medical armamentarium anorexiants, used so successfully by thousands of American physicians as an aid to patients wishing to lose weight. That the amphetamines can and are being abused is not denied. Any drug can be abused and will be by some. However, it has been my experience in more than 20 years of practice, that the amphetamines, when used correctly, enjoy a position unexceeded by any other drug in helping the patient to lose weight, where otherwise he simply would not. Amphetamines have the ability to dull the appetite and help in the war against obesity. For the American
Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1)
Authors: Gaël Ménasché, Chen Hsuan Ho, Ozden Sanal, Jérôme Feldmann, Ilhan Tezcan, Fügen Ersoy, Anne Houdusse, Alain Fischer, Geneviève de Saint Basile
Journal: Journal of Clinical Investigation (2003)

Griscelli syndrome (GS) is a rare autosomal recessive disorder that associates hypopigmentation, characterized by a silver-gray sheen of the hair and the presence of large clusters of pigment in the hair shaft, and the occurrence of either a primary neurological impairment or a severe immune disorder. Two different genetic forms, GS1 and GS2, respectively, account for the mutually exclusive neurological and immunological phenotypes. Mutations in the gene encoding the molecular motor protein Myosin Va (MyoVa) cause GS1 and the dilute mutant in mice, whereas mutations in the gene encoding the small GTPase Rab27a are responsible for GS2 and the ashen mouse model. We herein present genetic and functional evidence that a third form of GS (GS3), whose expression is restricted to the characteristic hypopigmentation of GS, results from mutation in the gene that encodes melanophilin (Mlph), the ortholog of the gene mutated in leaden mice. We also show that an identical phenotype can result from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern. This spectrum of GS conditions pinpoints the distinct molecular pathways used by melanocytes, neurons, and immune cells in secretory granule exocytosis, which in part remain to be unraveled.
EUR<i>Observational</i> Research Programme: The Heart Failure Pilot Survey (ESC‐HF Pilot)
Authors: Aldo P. Maggioni, Ulf Dahlström, Gerasimos Filippatos, Ovidiu Chioncel, Marisa Crespo Leiro, Jaroslaw Drozdz, Friedrich Fruhwald, Lars Gullestad, Damien Logeart, Marco Metra, John Parissis, Hans Persson, Piotr Ponikowski, Mathias Rauchhaus, Adriaan Voors, Olav Wendelboe Nielsen, Faiez Zannad, Luigi Tavazzi
Journal: European Journal of Heart Failure (2010)
An isologous antigen-antibody reaction with human neutrophiles, related to neonatal neutropenia.
Authors: P Lalezari, G E Bernard
Journal: Journal of Clinical Investigation (1966)

Development of methods for detection of leu- kocyte antigens has made possible the classification of human leukocytes into different antigenic types, distinct from those of erythrocytes.To date several such antigen systems have been de- scribed (1-4).Studies on the distribution of some of these antigens in various blood cells have indicated that they are present in both granulo- cytic and nongranulocytic cells, as well as in platelets (5, 6).It has been shown that these antigens are also present in certain nonhemato- poietic tissues, such as placenta, kidney, and lung (5, 7).This study concerns a new leukocyte antigen, the first that appears to be specific for neutro- philes.In 2 unrelated families, this antigen was responsible for maternal immunization during pregnancy, and the subsequent transplacental transfer of the antibody appeared to be responsible for neonatal neutropenia. MethodsAntibody sources.Test plasmas used in this study were obtained from 3 multiparous female donors.Maternal plasma DeR was obtained 7 years after the last pregnancy.The first, the third, and the fourth children of this donor had documented neonatal neutropenia and were subjects of a previous publication (8).St plasma was obtained from the mother of a pair of dizygotic twins.The twins were the third and the fourth children of the family, and both had neonatal neutropenia (9).The third plasma, containing a monospecific antibody *
<i>In vitro</i> and <i>In vivo</i> Targeting Properties of Iodine-123- or Iodine-131–Labeled Monoclonal Antibody 14C5 in a Non–Small Cell Lung Cancer and Colon Carcinoma Model
Authors: Ingrid Burvenich, Steve Schoonooghe, Bart Cornelissen, Peter Blanckaert, Elisabeth Coene, Claude Cuvelier, Nico Mertens, Guido Slegers
Journal: Clinical Cancer Research (2005)

The monoclonal antibody (mAb) 14C5 is a murine IgG1 directed against a yet undefined molecule involved in cell substrate adhesion found on the surface of malignant breast cancer tissue. mAb 14C5 is able to inhibit cell substrate adhesion and invasion of breast cancer cells in vitro. In normal tissues as well as in the stroma surrounding in situ carcinomas of the breast, no expression of the antigen 14C5 occurs. The aim of this study was to investigate the in vitro and in vivo targeting properties of 123I- and 131I-labeled mAb 14C5 as a novel agent for radioimmunodetection and radioimmunotherapy.Internalization of mAb 14C5 was investigated with 125I-labeled mAb 14C5 and by confocal laser scanning microscopy. Biodistribution studies of 131I-labeled mAb 14C5 and planar gamma imaging were done in nude mice bearing an A549 (non-small cell lung carcinoma) or a LoVo (colon carcinoma) tumor.Internalization studies with both A549 and LoVo cells showed that 125I-labeled mAb 14C5 is slowly internalized with approximately 30% of the initially bound mAb 14C5 internalized after 2 hours at 37 degrees C. Internalization of mAb 14C5 could be visualized with confocal laser scanning microscopy. In vivo, radioisotope uptake peaked at 24 hours for both tumor models (n = 5) with no significant difference in percentage of injected dose/g tissue (A549 10.4 +/- 0.8 and LoVo 9.3 +/- 0.8). Via planar gamma camera imaging, A549 lung tumors as well as LoVo colon tumors could be clearly visualized.The in vitro and in vivo targeting properties of 123I- and 131I-labeled mAb 14C5 are promising and could provide a new antibody-based agent for radioimmunodetection and radioimmunotherapy of patients bearing antigen 14C5-expressing tumors.
Aggressiveness of Cancer Care Near the End of Life: Is It a Quality-of-Care Issue?
Authors: Craig C. Earle, Mary Beth Landrum, Jeffrey M. Souza, Bridget A. Neville, Jane C. Weeks, John Z. Ayanian
Journal: Journal of Clinical Oncology (2008)

The purpose of this article is to review the literature and update analyses pertaining to the aggressiveness of cancer care near the end of life. Specifically, we will discuss trends and factors responsible for chemotherapy overuse very near death and underutilization of hospice services. Whether the concept of overly aggressive treatment represents a quality-of-care issue that is acceptable to all involved stakeholders is an open question.
Decreased glomerulosclerosis in aging by angiotensin-converting enzyme inhibitors.
Authors: L Ferder, F Inserra, L Romano, L Ercole, V Pszenny
Journal: Journal of the American Society of Nephrology (1994)

To evaluate the effects of angiotensin-converting enzyme inhibition on renal aging, enalapril was administered in the drinking water to three groups of CF1 mice at doses of 20 mg/L (Group A), 10 mg/L (Group B), and 5 mg/L (Group C). These experimental groups were compared with 20 CF1 mice not receiving enalapril (Group D). At 2 yr, total body weight was 48.1 +/- 7.5 g in Group A, 47.7 +/- 7.1 g in Group B, 47.6 +/- 4.6 g in Group C, and 35.1 +/- 5.4 g in Group D. The ratio of kidney to total body weight, in percentages, was 1.8 +/- 0.3, 1.6 +/- 0.3, 1.9 +/- 0.2, and 1.5 +/- 0.1 in Groups A, B, C, and D, respectively. Morphometric studies of the kidneys revealed the glomerular diameter to be 86.7 +/- 18.0 microns, 96.9 +/- 6.3 microns, 91.1 +/- 11.4 microns, and 106.8 +/- 9.3 microns in Groups A, B, C, and D, respectively. The number of glomeruli per square millimeter of renal cortex was 9.6 +/- 3.7, 12.3 +/- 2.7, 12.4 +/- 8.6, and 3.2 +/- 1.5 in Groups A, B, C, and D, respectively. The mesangial area per glomerulus, in percentages, was 11.6 +/- 4.8, 13.9 +/- 2.9, 14.2 +/- 3.1, and 20.6 +/- 1.9 in Groups A, B, C, and D, respectively. The percentage of glomeruli with sclerosis was 0.1 +/- 0.1, 0.3 +/- 0.1, 0.6 +/- 0.2, and 11.6 +/- 1.9 in Groups A, B, C, and D, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Longitudinal Trajectories of HbA1c and Fasting Plasma Glucose Levels During the Development of Type 2 Diabetes
Authors: Yoriko Heianza, Yasuji Arase, Kazuya Fujihara, Shiun Dong Hsieh, Kazumi Saito, Hiroshi Tsuji, Satoru Kodama, Naoya Yahagi, Hitoshi Shimano, Nobuhiro Yamada, Shigeko Hara, Hirohito Sone
Journal: Diabetes Care (2012)

To describe the trajectory of HbA(1c) and glucose concentrations before the diagnosis of diabetes.The study comprised 1,722 nondiabetic Japanese individuals aged 26-80 years. Fasting plasma glucose (FPG) and HbA(1c) were measured annually for a mean of 9.5 (SD 1.8) years.Diabetes occurred in 193 individuals (FPG ≥ 7.0 mmol/L, self-reported clinician-diagnosed diabetes, or HbA(1c) ≥ 6.5%). Mean HbA(1c) values were >5.6% each year before diagnosis in diabetes cases. Mean HbA(1c) (5.69% [95% CI 5.50-5.88]) was higher in the 21 individuals who developed diabetes 10 years after the baseline examination than in nondiabetic individuals after 10 years (5.27% [5.25-5.28]). From 3 years to 1 year prediagnosis, HbA(1c) increased 0.09% (SE 0.01)/year, reaching 5.90% (5.84-5.96) 1 year prediagnosis. In the entire group, marked increases in HbA(1c) of 0.3% (SE 0.05%)/year and FPG of 0.63 (0.07) mmol/L/year predicted diabetes.HbA(1c) trajectory increased sharply after gradual long-term increases in diabetic individuals.
Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5).
Authors: S E Lloyd, S H Pearce, W Günther, H Kawaguchi, T Igarashi, T J Jentsch, R V Thakker
Journal: Journal of Clinical Investigation (1997)

The annual urinary screening of Japanese children above 3 yr of age has identified a progressive proximal renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. The disorder, which has a familial predisposition and occurs predominantly in males, has similarities to three X-linked proximal renal tubular disorders that are due to mutations in the renal chloride channel gene, CLCN5. We have investigated four unrelated Japanese kindreds with this tubulopathy and have identified four different CLCN5 mutations (two nonsense, one missense, and one frameshift). These are predicted to lead to a loss of chloride channel function, and heterologous expression of the missense CLCN5 mutation in Xenopus oocytes demonstrated a 70% reduction in channel activity when compared with the wild-type. In addition, single-stranded conformation polymorphism (SSCP) analysis was found to be a sensitive and specific mutational screening method that detected > 75% of CLCN5 mutations. Thus, the results of our study expand the spectrum of clinical phenotypes associated with CLCN5 mutations to include this proximal renal tubular disorder of Japanese children. In addition, the mutational screening of CLCN5 by SSCP will help to supplement the clinical evaluation of the annual urinary screening program for this disorder.
Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial.
Authors: Marcia S. Brose, Christopher Nutting, Barbara Jarzab, Rossella Elisei, Salvatore Siena, Lars Bastholt, Christelle de la Fouchardiere, Furio Pacini, Ralf Paschke, Young Kee Shong, Steven I. Sherman, Johannes WA Smit, John Woojune Chung, Harald Siedentop, Istvan Molnar, Martin Schlumberger
Journal: Journal of Clinical Oncology (2013)

4 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Vδ1 T Lymphocytes from B-CLL Patients Recognize ULBP3 Expressed on Leukemic B Cells and Up-Regulated by <b> <i>Trans</i> </b>-Retinoic Acid
Authors: Alessandro Poggi, Claudia Venturino, Silvia Catellani, Marino Clavio, Maurizio Miglino, Marco Gobbi, Alexander Steinle, Paolo Ghia, Stefania Stella, Federico Caligaris-Cappio, Maria Raffaella Zocchi
Journal: Cancer Research (2004)

Abstract We analyzed 38 untreated patients with chronic lymphocytic leukemia of B-cell type (B-CLL): 24 low-, 8 intermediate-, and 6 high-risk stage. In 15 patients (13 low risk and 2 intermediate risk), circulating Vδ1 T lymphocytes were significantly increased (100 to 300 cells/μL) compared with most intermediate, all high-risk stage, and 15 healthy donors (50 to 100 cells/μL). We studied these Vδ1 T lymphocytes and observed that they proliferated in vitro and produced tumor necrosis factor α or IFN-γ in response to autologous leukemic B cells but not to normal lymphocytes. However, they were unable to kill resting autologous B cells, which lack the MHC-related MIC-A antigen and express low levels of the UL16-binding protein (ULBP) 3 and undetectable levels of ULBP1, ULBP2, and ULBP4. All these molecules are reported ligands for the NKG2D receptor, which is expressed by γδ T cells and activates their cytolytic function. The Vδ1 T lymphocytes studied were able to lyse the ULBP3+ C1R B-cell line upon transfection with MIC-A. More importantly, they also lysed autologous B-CLL cells when transcription and expression of MIC-A or up-regulation of ULBP3 were achieved either by activation or by exposure to trans-retinoic acid. The NKG2D receptor expressed on Vδ1 T cells was involved in the recognition of B-CLL. Finally, in six patients with low numbers of circulating Vδ1 T cells and undetectable ULBP3, the disease progressed over 1 year, whereas no progression occurred in patients with high Vδ1 T lymphocytes and detectable/inducible ULBP3. These data suggest that Vδ1 T lymphocytes may play a role in limiting the progression of B-CLL.
Aerobic Fitness Is Associated With Cardiomyocyte Contractile Capacity and Endothelial Function in Exercise Training and Detraining
Authors: Ole Johan Kemi, Per Magnus Haram, Ulrik Wisløff, Øyvind Ellingsen
Journal: Circulation (2004)

Physical fitness and level of regular exercise are closely related to cardiovascular health. A regimen of regular intensity-controlled treadmill exercise was implemented and withdrawn to identify cellular mechanisms associated with exercise capacity and maximal oxygen uptake (VO2max).Time-dependent associations between cardiomyocyte dimensions, contractile capacity, and VO2max were assessed in adult rats after high-level intensity-controlled treadmill running for 2, 4, 8, and 13 weeks and detraining for 2 and 4 weeks. With training, cardiomyocyte length, relaxation, shortening, Ca2+ decay, and estimated cell volume correlated with increased VO2max (r=0.92, -0.92, 0.88, -0.84, 0.73; P<0.01). Multiple regression analysis identified cell length, relaxation, and Ca2+ decay as the main explanatory variables for VO2max (R2=0.87, P<0.02). When training stopped, exercise-gained VO2max decreased 50% within 2 weeks and stabilized at 5% above sedentary controls after 4 weeks. Cardiomyocyte size regressed in parallel with VO2max and remained (9%) above sedentary after 4 weeks, whereas cardiomyocyte shortening, contraction/relaxation- and Ca2+-transient time courses, and endothelium-dependent vasorelaxation regressed completely within 2 to 4 weeks of detraining. Cardiomyocyte length, estimated cell volume, width, shortening, and Ca2+ decay and endothelium-dependent arterial relaxation all correlated with VO2max (r=0.85, 0.84, 0.75, 0.63, -0.54, -0.37; P<0.01). Multiple regression identified cardiomyocyte length and vasorelaxation as the main determinants for regressed VO2max during detraining (R2=0.76, P=0.02).Cardiovascular adaptation to regular exercise is highly dynamic. On detraining, most of the exercise-gained aerobic fitness acquired over 2 to 3 months is lost within 2 to 4 weeks. The close association between cardiomyocyte dimensions, contractile capacity, arterial relaxation, and aerobic fitness suggests cellular mechanisms underlying these changes.
Oral mTOR Inhibitor Everolimus in Patients With Gemcitabine-Refractory Metastatic Pancreatic Cancer
Authors: Brian M. Wolpin, Aram F. Hezel, Thomas Abrams, Lawrence S. Blaszkowsky, Jeffrey A. Meyerhardt, Jennifer A. Chan, Peter C. Enzinger, Brittany Allen, Jeffrey W. Clark, David P. Ryan, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2008)

The PI3K/Akt/mTOR pathway is activated in the majority of pancreatic cancers, and inhibition of this pathway has antitumor effects in preclinical studies. We performed a multi-institutional, single-arm, phase II study of RAD001(everolimus), an oral inhibitor of mTOR, in patients who experienced treatment failure on first-line therapy with gemcitabine.Thirty-three patients with gemcitabine-refractory, metastatic pancreatic cancer were treated continuously with RAD001 at 10 mg daily. Prior treatment with fluorouracil in the perioperative setting was allowed. Patients were observed for toxicity, treatment response, and survival.Treatment with single-agent RAD001 was well-tolerated; the most common adverse events were mild hyperglycemia and thrombocytopenia. No patients were removed from the study because of drug-related adverse events. No complete or partial treatment responses were noted, and only seven patients (21%) had stable disease at the first restaging scans performed at 2 months. Median progression-free survival and overall survival were 1.8 months and 4.5 months, respectively. One patient (3%) had a biochemical response, defined as > or = 50% reduction in serum CA19-9.Although well-tolerated, RAD001 administered as a single-agent had minimal clinical activity in patients with gemcitabine-refractory, metastatic pancreatic cancer. Future studies in metastatic pancreatic cancer should assess the combination of mTOR inhibitors with other agents and/or examine inhibitors of other components of the PI3K/Akt/mTOR pathway.
Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature
Authors: B.T. Hennessy, A.M. Gauthier, L.B. Michaud, G. Hortobagyi, V. Valero
Journal: Annals of Oncology (2005)
Implications of the Precautionary Principle for Primary Prevention and Research
Authors: Philippe Grandjean
Journal: Annual Review of Public Health (2004)

The precautionary principle (PP) is an extension of the public health presage that prevention is better than cure. The PP has recently achieved new relevance in regard to serious but uncertain threats to human health and the environment and has now entered national and international legislation. However, frameworks for its unambiguous application in practice are yet to be designed. They will depend on legal and cultural circumstances and are likely to involve pluralities of perspectives and stakeholder participation. The rules for causal reasoning and dose dependence need to be addressed and may be conveniently expressed in accordance with probability theory. Although the PP will allow action before convincing evidence is secured, it is not science averse. However, it provides an occasion to review environmental health research strategies, methodologies, and research-reporting traditions. From this perspective, current research is afflicted by important biases and insufficient focus on major environmental health problems.
IL-25 drives remodelling in allergic airways disease induced by house dust mite
Authors: Lisa G Gregory, Carla P Jones, Simone A Walker, Devika Sawant, Kate H C Gowers, Gaynor A Campbell, Andrew N J McKenzie, Clare M Lloyd
Journal: Thorax (2012)

<h3>Background</h3> Overexpression of the transforming growth factor β family signalling molecule smad2 in the airway epithelium provokes enhanced allergen-induced airway remodelling in mice, concomitant with elevated levels of interleukin (IL)-25. <h3>Objective</h3> We investigated whether IL-25 plays an active role in driving this airway remodelling. <h3>Methods</h3> Anti-IL-25 antibody was given to mice exposed to either inhaled house dust mite (HDM) alone, or in conjunction with an adenoviral smad2 vector which promotes an enhanced remodelling phenotype. <h3>Results</h3> Blocking IL-25 in allergen-exposed mice resulted in a moderate reduction in pulmonary eosinophilia and levels of T helper type 2 associated cytokines, IL-5 and IL-13. In addition, IL-25 neutralisation abrogated peribronchial collagen deposition, airway smooth muscle hyperplasia and airway hyperreactivity in control mice exposed to HDM and smad2-overexpressing mice. IL-25 was shown to act directly on human fibroblasts to induce collagen secretion. Recruitment of endothelial progenitor cells to the lung and subsequent neovascularisation was also IL-25 dependent, demonstrating a direct role for IL-25 during angiogenesis in vivo. Moreover, the secretion of innate epithelial derived cytokines IL-33 and thymic stromal lymphopoietin (TSLP) was completely ablated. <h3>Conclusions</h3> In addition to modulating acute inflammation, we now demonstrate a role for IL-25 in orchestrating airway remodelling. IL-25 also drives IL-33 and TSLP production in the lung. These data delineate a wider role for IL-25 in mediating structural changes to the lung following allergen exposure and implicate IL-25 as a novel therapeutic target for the treatment of airway remodelling in asthma.