tbuckley/cabot-search huggingface dataset:
Glucocorticoids in T Cell Development and Function
Authors: Jonathan D. Ashwell, Frank W. M. Lu, Melanie S. Vacchio
Journal: Annual Review of Immunology (2000)

Glucocorticoids are small lipophilic compounds that mediate their many biological effects by binding an intracellular receptor (GR) that, in turn, translocates to the nucleus and directly or indirectly regulates gene transcription. Perhaps the most recognized biologic effect of glucocorticoids on peripheral T cells is immunosuppression, which is due to inhibition of expression of a wide variety of activationinduced gene products. Glucocorticoids have also been implicated in Th lineage development (favoring the generation of Th2 cells) and, by virtue of their downregulation of fasL expression, the inhibition of activation-induced T cell apoptosis. Glucocorticoids are also potent inducers of apoptosis, and even glucocorticoid concentrations achieved during a stress response can cause the death of CD4 + CD8 + thymocytes. Perhaps surprisingly, thymic epithelial cells produce glucocorticoids, and based upon in vitro and in vivo studies of T cell development it has been proposed that these locally produced glucocorticoids participate in antigen-specific thymocyte development by inhibiting activation-induced gene transcription and thus increasing the TCR signaling thresholds required to promote positive and negative selection. It is anticipated that studies in animals with tissue-specific GR-deficiency will further elucide how glucocorticoids affect T cell development and function.
Time course from first symptom to treatment in patients with non-small cell lung cancer referred for radiotherapy: a report by the CHART Steering Committee.
Authors: S. Dische, D. Gibson, M. Parmar, M. I. Saunders
Journal: Thorax (1996)

Only a small proportion of patients with non-small cell lung cancer (NSCLC) attending radiotherapy centres were suitable for inclusion in a randomised trial which compared continuous hyperfractionated accelerated radiotherapy (CHART) with conventional radical radiotherapy. As this was thought to be partly due to delays in the referral of patients to clinical oncologists, a prospective study was performed to determine the interval between first report of symptoms and first radiotherapy treatment in patients with NSCLC.The time course from first symptom to treatment was determined in all patients with NSCLC attending 10 cancer centres for radiotherapy to a primary tumour in a three month period.Only 5% of 484 patients were suitable for the trial of radical radiotherapy. The principal causes for exclusion were poor general condition (37%), too large a tumour (27%), and extrathoracic metastases (19%). The median time from first symptom to diagnosis was 13 weeks, from first symptom to first treatment 19 weeks, and from diagnosis to first treatment five weeks. In a quarter of the patients these intervals were greater than 25,33 weeks, and nine weeks, respectively.The reason for these long intervals needs investigation since earlier diagnosis and more immediate referral for consideration of treatment might increase the number of patients with NSCLC suitable for radical radiotherapy.
Prenatal Diagnosis of Homozygous α-Thalassemia
Authors: Andrée M. Dozy
Journal: JAMA (1979)

A Vietnamese couple were both carriers of alpha-thalessemia-1. The woman had a first pregnancy terminated in the delivery of a hydropic fetus due to homozygous alpha-thalassemia. The couple requested prenatal diagnosis for the second pregnancy. The DNA obtained from cultured amniotic fluid cells was studied pregnancy. The DNA obtained from cultured amniotic fluid cells was studied by hybridization with globin cDNA in solution and on filters (Southern technique). Both analyses demonstrated no alpha-globin structural genes were present. Following termination of the pregnancy, the diagnosis was established by the presence of only hemoglobins Barts (gamma 4) and Portland (zeta 2 gamma 2) in the fetal blood.
Diffusion Magnetic Resonance Imaging: an Early Surrogate Marker of Therapeutic Efficacy in Brain Tumors
Authors: Thomas L. Chenevert, Lauren D. Stegman, Jeremy M.G. Taylor, Patricia L. Robertson, Harry S. Greenberg, Alnawaz Rehemtulla, Brian D. Ross
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: A surrogate marker for treatment response that can be observed earlier than comparison of sequential magnetic resonance imaging (MRI) scans, which depends on relatively slow changes in tumor volume, may improve survival of brain tumor patients by providing more time for secondary therapeutic interventions. Previous studies in animals with the use of diffusion MRI revealed rapid changes in tumor water diffusion values after successful therapeutic intervention. Methods: The present study examined the sensitivity of diffusion MRI measurements in orthotopic rat brain tumors derived from implanted rat 9L glioma cells. The effectiveness of therapy for individual brain cancer patients was evaluated by measuring changes in tumor volume on neuroimaging studies conducted 6–8 weeks after the conclusion of a treatment cycle. Results: Diffusion MRI could detect water diffusion changes in orthotopic 9L gliomas after doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) that resulted in as little as 0.2 log cell kill, a measure of tumor cell death. Mean apparent diffusion coefficients in tumors were found to be correlated with and highly sensitive to changes in tumor cellularity (r = .78; two-sided P = .041). The feasibility of serial diffusion MRI in the clinical management of primary brain tumor patients was also demonstrated. Increased diffusion values could be detected in human brain tumors shortly after treatment initiation. The magnitude of the diffusion changes corresponded with clinical outcome. Conclusions: These results suggest that diffusion MRI will provide an early surrogate marker for quantification of treatment response in patients with brain tumors.
Immunofluorescence studies of the distribution of gastrin cells in different clinical states
Authors: A. G. E. Pearse, G. Bussolati
Journal: Gut (1970)

Examination of human gastric biopsies by an indirect immunofluorescence technique using antihuman gastrin confirms the variability in distribution and number of gastrin-secreting (G) cells (Solcia, Vassallo, and Capella, 1969) observed by morphological, cytochemical, and electron microscopical studies. In cases with presumed secondary hypersecretion a profound degree of G-cell hyperplasia is observed. Immunofluorescence with. antigastrin can provide valuable information on the state of the G cells in different physiological states, particularly if used in conjunction with other cytochemical techniques.
Enhancing Immunity Through Autophagy
Authors: Christian Münz
Journal: Annual Review of Immunology (2008)

Next to the proteasome, autophagy is the main catabolic pathway for the degradation of cytoplasmic constituents. The immune system uses it both as an effector mechanism to clear intracellular pathogens and as a mechanism to monitor its products for evidence of pathogen invasion and cellular transformation. Because autophagy delivers intracellular material for lysosomal degradation, its products are primarily loaded onto MHC class II molecules and are able to stimulate CD4 + T cells. This process might shape the self-tolerance of the CD4 + T cell repertoire and stimulate CD4 + T cell responses against pathogens and tumors. Beyond antigen processing, autophagy's role in cell survival is to assist the clonal expansion of B and T cells for efficient adaptive immune responses. These immune-enhancing functions make autophagy an attractive target for therapeutic manipulation in human disease.
Dystrophin Expression in Myofibers of Duchenne Muscular Dystrophy Patients Following Intramuscular Injections of Normal Myogenic Cells
Authors: Daniel Skuk, Brigitte Roy, Marlyne Goulet, Pierre Chapdelaine, Jean-Pierre Bouchard, Raynald Roy, Francine J Dugré, Jean-Guy Lachance, Louise Deschênes, Hélène Senay, Michel Sylvain, Jacques P Tremblay
Journal: Molecular Therapy (2004)

Three Duchenne muscular dystrophy (DMD) patients received injections of myogenic cells obtained from skeletal muscle biopsies of normal donors. The cells (30 x 10 (6)) were injected in 1 cm3 of the tibialis anterior by 25 parallel injections. We performed similar patterns of saline injections in the contralateral muscles as controls. The patients received tacrolimus for immunosuppression. Muscle biopsies were performed at the injected sites 4 weeks later. We observed dystrophin-positive myofibers in the cell-grafted sites amounting to 9 (patient 1), 6.8 (patient 2), and 11% (patient 3). Since patients 1 and 2 had identified dystrophin-gene deletions these results were obtained using monoclonal antibodies specific to epitopes coded by the deleted exons. Donor dystrophin was absent in the control sites. Patient 3 had exon duplication and thus specific donor-dystrophin detection was not possible. However, there were fourfold more dystrophin-positive myofibers in the cell-grafted than in the control site. Donor-dystrophin transcripts were detected by RT-PCR (using primers reacting with a sequence int eh deleted exons) only in the cell-grafted sites in patients 1 and 2. Dystrophin transcripts were more abundant in the cell-grafted than in the control site in patient 3. Therefore, significant dystrophin expression can be obtained in teh skeletal muscles of DMD patients following specific conditions of cell delivery and immunosuppression.
Pyridine Nucleotide Regulation of Cardiac Intermediary Metabolism
Authors: John R. Ussher, Jagdip S. Jaswal, Gary D. Lopaschuk
Journal: Circulation Research (2012)

The pyridine nucleotides NAD(+) and NADP(+) play a pivotal role in regulating intermediary metabolism in the heart. The intracellular NAD(+)/NADH ratio controls flux through various dehydrogenase enzymes involved in both anaerobic and aerobic metabolism and also regulates posttranslational protein modification. The intracellular NADP(+)/NADPH ratio controls flux through the pentose phosphate pathway (PPP) and the polyol pathway, while also regulating ion channel function and oxidative stress. Not only does the NAD(+)/NADH ratio regulate the rates of ATP production, it can also modify energy substrate preference. For instance, in many forms of heart disease a greater contribution from fatty acids for oxidative energy metabolism increases fatty acid β-oxidation-derived NADH, which can activate pyruvate dehydrogenase (PDH) kinase isoforms that inhibit PDH and subsequent glucose oxidation. As such, novel therapies that overcome fatty acid β-oxidation-induced inhibition of PDH improve cardiac efficiency and subsequent function during ischemia/reperfusion and in heart failure. Furthermore, recent studies have implicated a pivotal role for increased PPP-derived NADPH in mediating oxidative stress observed in heart failure. In this article, we review the multiple actions of NAD(+)/NADH and NADP(+)/NADPH in regulating intermediary metabolism in the heart. A better understanding of the roles of NAD(+)/NADH and NADP(+)/NADPH in cellular physiology and pathology could potentially be used to exploit pyridine nucleotide modification in the treatment of a number of different forms of heart disease.
The Use of Complementary and Alternative Medicine Therapies in Type 2 Diabetic Patients in Mexico
Authors: Nicolas Argáez-López, Niels H. Wacher, Jesus Kumate-Rodríguez, Miguel Cruz, Juan Talavera, Erika Rivera-Arce, Xavier Lozoya
Journal: Diabetes Care (2003)

The growing utilization of complementary and alternative medicine (CAM) therapies represents one of the characteristic phenomena facing scientific medicine. Studies of the patient’s opinions and attitudes toward CAM therapies are scarce. Among doctors, it is widely considered that the use of CAM therapies is only linked to a particular social or cultural background. We undertook a cross-sectional study designed to evaluate the spontaneous use of CAM therapies among 573 type 2 diabetic patients (aged 51.9 ± 10 years) in nine family medicine clinics in Mexico City, using a questionnaire form.

Almost 62% (353) of participants make use of CAM therapies, a higher percentage than that reported in the U.S. (8%) and Canada (37.3%). Our patients were younger, more likely …
Innate resistance of PD-1 blockade through loss of function mutations in JAK resulting in inability to express PD-L1 upon interferon exposure
Authors: Daniel Shin, Angel Garcia-Diaz, Jesse Zaretsky, Helena Escuin-Ordinas, Siwen Hu-Lieskovan, Nicolaos J Palaskas, Willy Hugo, Marie Sara Komenan, Bartosz Chmielowski, Grace Cherry, Beata Berent-Maoz, Thomas G Graeber, Roger Lo, Begonya Comin-Anduix, Antoni Ribas
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts PD-L1-negative tumors assessed by immunohistochemistry often still respond to PD-1 blockade. PD-L1 is inducible by interferon, therefore, absolute negative tumors are the ones unable to up-regulate PD-L1 in response to interferons. Genetic mutations in the interferon receptor
Antigenic Modulation and Turnover in Human Neutrophils
Authors: Sigmund A. Weitzman, Mary C. Desmond, Thomas P. Stossel
Journal: Journal of Clinical Investigation (1979)

Turnover of membrane constituents appears important in many biologic processes. We studied this process in neutrophils by immunologic methods. The capacity of neutrophils to recognize other neutrophils coated with antibodies against membrane antigens was used to determine the changes that occur after attachment of the antibody to the neutrophil membrane. Neutrophils were sensitized for 30 min at 22°C with antibodies from three patients with antineutrophil autoantibodies. The sensitized neutrophils were recognized by normal neutrophils, which responded with an increase in glucose oxidation. If, after sensitization, the sensitized neutrophils were not immediately exposed to normal neutrophils, but instead were incubated at 37°C for varying times, the capacity to elicit a recognition response decayed and was gone by 30 min. Additionally, the capacity of the cells to be resensitized by reexposure to antibody also decayed during this period. However, after further incubation at 37°C, the neutrophils recovered the capacity to become sensitized; and this recovery was not inhibited by the addition of cycloheximide. Control incubations with normal immunoglobulin (Ig)G did not elicit a recognition response. The decay in recognition response was temperature dependent. Direct immunofluorescent studies with fluorescein-conjugated antineutrophil IgG revealed that the antibodies were cleared by aggregation and endocytosis. We conclude that: (a) neutrophils clear antibody from the cell surface by a temperature-dependent mechanism; (b) antigenicity is cleared concomitantly; (c) the mechanism of clearance involves internalization; and (d) with time, antigenicity reappears on the cell surface.
Cost-Effectiveness of Populationwide Educational Approaches to Reduce Serum Cholesterol Levels
Authors: Anna N.A. Tosteson, Milton C. Weinstein, Maria G.M. Hunink, Murray A. Mittleman, Lawrence W. Williams, Paula A. Goldman, Lee Goldman
Journal: Circulation (1997)

Background The aim of the present study was to estimate the cost-effectiveness of populationwide approaches to reduce serum cholesterol levels in the US adult population. Methods and Results This cost-effectiveness analysis was made from data from the literature and the Coronary Heart Disease Policy Model and was based on the US population age 35 to 84 years. Study interventions were populationwide programs to reduce serum cholesterol levels with costs and cholesterol-lowering effects similar to those reported from the Stanford Three-Community Study, the Stanford Five-City Project, and in North Karelia, Finland. The main outcome measures were cost-effectiveness ratios, defined as the change in projected cost divided by the change in projected life-years when the population receives the intervention compared with the population without the intervention. A populationwide program with the costs ($4.95 per person per year) and cholesterol-lowering effects (an average 2% reduction in serum cholesterol levels) of the Stanford Five-City Project would prolong life at an estimated cost of only $3200 per year of life saved. Under a wide variety of assumptions, a populationwide program would achieve health benefits at a cost equivalent to that of many currently accepted medical interventions. Such programs would also lengthen life and save resources under many scenarios, especially if the program affected persons with preexisting heart disease or altered other coronary risk factors. Conclusions Populationwide programs should be part of any national health strategy to reduce coronary heart disease.
Sunitinib Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer: A Phase III Trial
Authors: Giorgio V. Scagliotti, Maciej Krzakowski, Aleksandra Szczesna, Janos Strausz, Anatoly Makhson, Martin Reck, Rafal F. Wierzbicki, Istvan Albert, Michael Thomas, Jose Elias Abrao Miziara, Zsolt S. Papai, Nina Karaseva, Sumitra Thongprasert, Elsa Dalmau Portulas, Joachim von Pawel, Ke Zhang, Paulina Selaru, Lesley Tye, Richard C. Chao, Ramaswamy Govindan
Journal: Journal of Clinical Oncology (2012)

Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non-small-cell lung cancer (NSCLC), based on the importance of the signaling pathways involved in tumor growth, angiogenesis, and metastasis. This phase III trial investigated overall survival (OS) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC.Patients previously treated with one to two chemotherapy regimens (including one platinum-based regimen) for recurrent NSCLC, and for whom erlotinib was indicated, were randomly assigned (1:1) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d, stratified by prior bevacizumab use, smoking history, and epidermal growth factor receptor expression. The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.In all, 960 patients were randomly assigned, and baseline characteristics were balanced. Median OS was 9.0 months for sunitinib plus erlotinib versus 8.5 months for erlotinib alone (hazard ratio [HR], 0.922; 95% CI, 0.797 to 1.067; one-sided stratified log-rank P = .1388). Median PFS was 3.6 months versus 2.0 months (HR, 0.807; 95% CI, 0.695 to 0.937; one-sided stratified log-rank P = .0023), and ORR was 10.6% versus 6.9% (two-sided stratified log-rank P = .0471), respectively. Treatment-related toxicities of grade 3 or higher, including rash/dermatitis, diarrhea, and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm.In patients with refractory NSCLC, sunitinib plus erlotinib did not improve OS compared with erlotinib alone, but the combination was associated with a statistically significantly longer PFS and greater ORR. The incidence of grade 3 or higher toxicities was greater with combination therapy.
Allergy Frontiers and Future
Authors: I. Terreehorst
Journal: European Respiratory Journal (2006)

Edited by J. Bienenstock, J. Ring and A.G. Togias    Published by Hogrefe and Huber, Germany    Pages: 353. Price: £44.95, €69.95. ISBN: 0-88937-279-9

Allergy Frontiers and Future    Allergy Frontiers and Future documents the proceedings of the 24th Symposium of the Collegium Internationale Allergologicum, which was held in Bermuda in November 2002. The book reflects, as stated by the President, Johannes Ring, discussions held at the Symposium and summarises the wide spectrum of experimental and clinical research in the field of allergy. It is published as a supplement …
Legal Problems in Psychiatric Drug Prescription
Authors: WILLIAM S. APPLETON
Journal: American Journal of Psychiatry (1968)

Psychopharmacology is a relatively new treatment modality, and little legal precedent directly applicable to drug use in the office practice of psychotherapy exists. Because of growing concern among psychiatrists about legal risks in prescribing drugs, the author submitted a number of relevant questions to the Food and Drug Administration and a legal expert; the questions were also discussed at a law-drug conference at the Massachusetts Mental Health Center. The conclusions reached are discussed in this paper.
Vasopressin Increases Plasma Membrane Accumulation of Urea Transporter UT-A1 in Rat Inner Medullary Collecting Ducts
Authors: Janet D. Klein, Otto Fröhlich, Mitsi A. Blount, Christopher F. Martin, Tekla D. Smith, Jeff M. Sands
Journal: Journal of the American Society of Nephrology (2006)

Urea transport, mediated by the urea transporter A1 (UT-A1) and/or UT-A3, is important for the production of concentrated urine. Vasopressin rapidly increases urea transport in rat terminal inner medullary collecting ducts (IMCD). A previous study showed that one mechanism for rapid regulation of urea transport is a vasopressin-induced increase in UT-A1 phosphorylation. This study tests whether vasopressin or directly activating adenylyl cyclase with forskolin also increases UT-A1 accumulation in the plasma membrane of rat IMCD. Inner medullas were harvested from rats 45 min after injection with vasopressin or vehicle. UT-A1 abundance in the plasma membrane was significantly increased in the membrane fraction after differential centrifugation and in the biotinylated protein population. Vasopressin and forskolin each increased the amount of biotinylated UT-A1 in rat IMCD suspensions that were treated <i>ex vivo</i>. The observed changes in the plasma membrane are specific, as the amount of biotinylated UT-A1 but not the calcium-sensing receptor was increased by forskolin. Next, whether forskolin or the V<sub>2</sub>-selective agonist dDAVP would increase apical membrane expression of UT-A1 in MDCK cells that were stably transfected with UT-A1 (UT-A1-MDCK cells) was tested. Forskolin and dDAVP significantly increased UT-A1 abundance in the apical membrane in UT-A1-MDCK cells. It is concluded that vasopressin and forskolin increase UT-A1 accumulation in the plasma membrane in rat IMCD and in the apical plasma membrane of UT-A1-MDCK cells. These findings suggest that vasopressin regulates urea transport by increasing UT-A1 accumulation in the plasma membrane and/or UT-A1 phosphorylation.
Mechanism of hypogonadism in cirrhotic males.
Authors: G R Green
Journal: Gut (1977)

Men with chronic liver disease frequently develop clinical signs of hypogonadism and overt feminisation. Associated with these features, they have been found to have a reduced production of testosterone with low plasma concentrations, but only a minority of cirrhotic men would seem to have a marginal increase in circulating biologically potent oestrogens. Furthermore, this latter finding does not correlate with the presence of clinical feminisation. The original hypothesis to explain these changes now seems less likely to be true and no other single hypothesis has, on its own, been found to provide an adequate explanation for all the clinical and biochemical features found in cirrhotic men. It may be that the pathogenesis of endocrine changes in cirrhotic men is multifactorial--for instance, a combination of decreased hepatic clearance of some oestrogenic compounds, an autoimmune mediated primary testicular defect, and a specific potentiation effect by alcohol. Alternatively, it may be that none of these suggested mechanisms is of importance and that the endocrine changes are mediated instead by other mechanisms which remain, as yet, undiscovered or unconsidered. The fascination which this problem has held for clinicians and biochemists for many years seems likely to persist for some time to come.