tbuckley/cabot-search huggingface dataset:
Reduced Self-Reactivity of an Autoreactive T Cell After Activation with Cross-reactive Non–Self-Ligand
Authors: Markus Munder, Estelle Bettelli, Laurent Monney, Jacqueline M. Slavik, Lindsay B. Nicholson, Vijay K. Kuchroo
Journal: The Journal of Experimental Medicine (2002)

Autoreactive CD4+ T lymphocytes are critical to the induction of autoimmune disease, but because of the degenerate nature of T cell receptor (TCR) activation such receptors also respond to other ligands. Interaction of autoreactive T cells with other non–self-ligands has been shown to activate and expand self-reactive cells and induce autoimmunity. To understand the effect on the autoreactivity of naive cross-reactive T cells of activation with a potent nonself ligand, we have generated a TCR transgenic mouse which expresses a TCR with a broad cross-reactivity to a number of ligands including self-antigen. The activation of naive transgenic recombination activating gene (Rag)2−/− T cells with a potent non–self-ligand did not result in a enhancement of reactivity to self, but made these T cells nonresponsive to the self-ligand and anti-CD3, although they retained a degree of responsiveness to the non–self-ligand. These desensitized cells had many characteristics of anergic T cells. Interleukin (IL)-2 production was selectively reduced compared with interferon (IFN)-γ. p21ras activity was reduced and p38 mitogen-activated protein kinase (MAPK) was relatively spared, consistent with known biochemical characteristics of anergy. Surprisingly, calcium fluxes were also affected and the anergic phenotype could not be reversed by exogenous IL-2. Therefore, activation with a hyperstimulating non–self-ligand changes functional specificity of an autoreactive T cell without altering the TCR. This mechanism may preserve the useful reactivity of peripheral T cells to foreign antigen while eliminating responses to self.
Women's Recruitment Concludes
Authors: Rebecca Voelker
Journal: JAMA (1998)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Associations between Single-Nucleotide Polymorphisms in the PI3K–PTEN–AKT–mTOR Pathway and Increased Risk of Brain Metastasis in Patients with Non–Small Cell Lung Cancer
Authors: Qianxia Li, Ju Yang, Qianqian Yu, Huanlei Wu, Bo Liu, Huihua Xiong, Guangyuan Hu, Jing Zhao, Xianglin Yuan, Zhongxing Liao
Journal: Clinical Cancer Research (2013)

Non-small cell lung cancer (NSCLC) metastasizes fairly often to the brain, but identifying which patients will develop brain metastases is problematic. The phosphoinositide 3-kinase (PI3K)-AKT-mTOR signaling pathway is important in the control of cell growth, tumorigenesis, and cell invasion. We hypothesized that genotype variants in this pathway could predict brain metastasis in patients with NSCLC.We genotyped 16 single-nucleotide polymorphisms (SNP) in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) by using DNA from blood samples of 317 patients with NSCLC, and evaluated potential associations with the subsequent development of brain metastasis, the cumulative incidence of which was estimated with Kaplan-Meier analysis. Multivariate Cox regression analysis was used to analyze correlations between genotype variants and the occurrence of brain metastasis.In analysis of individual SNPs, the GT/GG genotype of AKT1: rs2498804, CT/TT genotype of AKT1: rs2494732, and AG/AA genotype of PIK3CA: rs2699887 were associated with higher risk of brain metastasis at 24-month follow-up [respective HRs, 1.860, 95% confidence interval (CI) 1.199-2.885, P = 0.006; HR 1.902, 95% CI 1.259-2.875, P = 0.002; and HR 1.933, 95% CI 1.168-3.200, P = 0.010]. We further found that these SNPs had a cumulative effect on brain metastasis risk, with that risk being highest for patients carrying both of these unfavorable genotypes (P = 0.003).Confirmation of our findings, the first to indicate that genetic variations in PI3K-AKT-mTOR can predict brain metastasis, in prospective studies would facilitate stratification of patients for brain metastasis prevention trials.
Evaluation of Tc-99m–Labeled Glycoprotein IIb/IIIa Receptor Antagonist DMP444 SPECT in Patients with Infective Endocarditis
Authors: FREDERIEKE M. BROUWERS, WIM J.G. OYEN, OTTO C. BOERMAN, JOHN A. BARRETT, FREEK W.A. VERHEUGT, FRANS H.M. CORSTENS, JOS W.M. VAN DER MEER
Journal: Clinical Nuclear Medicine (2003)

Purpose Infective endocarditis (IE) is characterized by aggregation of activated platelets, fibrin, and bacteria. DMP444, a high-affinity glycoprotein IIb/IIIa receptor antagonist, binds to the fibrinogen-binding domain of activated platelets, depicting a key feature of IE. Tc-99m DMP444 scintigraphy was studied in a group of patients with possible IE. Methods Tc-99m DMP444 (600 MBq; 16 mCi) planar and SPECT images of the heart were recorded in patients with possible IE for as long as 6 hours after injection. Results were compared to echocardiography and the Duke classification. Results Sixteen patients (age range, 37 to 78 years) participated. DMP444 imaging was positive on SPECT in five patients, and all had definite endocarditis (affecting both prosthetic and native valves). Eleven patients were DMP444 negative, seven with no proof of IE. The remaining four patients were classified as having IE, but three had been receiving adequate intravenous antibiotic regimens for ≥2 weeks at the time of scintigraphy and one had Q-fever endocarditis. Conclusions DMP444 SPECT allows in vivo visualization of IE if it is performed within 1 to 2 weeks after the start of antibiotic treatment. Given the high affinity of DMP444 for activated platelets, the results indicate the involvement of activated platelets in early IE.
THE COFFEY-HUMBER CANCER TREATMENT
Authors: C. F. Charlton
Journal: JAMA (1930)

<h3>To the Editor:</h3> —In regard to the communication of Drs. Coffey and Humber (The Journal, February 1, p. 359) announcing the effect of an extract of the suprarenal cortex on malignant tissue, I have observed the same effects, namely, liquefaction, necrosis and sloughing, together with new capillary growth, on administration of an extract from the omentum of the pig. I announced this remedy to the Pasadena Branch of the Los Angeles County Medical Society, April 17, 1928. It has subsequently been in use in the wards of the Los Angeles General Hospital for more than a year. Furthermore, I have identified my extract as containing the active principle of the reticulo-endothelial system through its action on bile formation. Ranvier first described the omental portion of the reticulo-endothelial system more than fifty years ago. This substance has, accordingly, been given the name of "reticulin." It is an enzyme which digests the
Discovery of Mesothelin and Exploiting It as a Target for Immunotherapy
Authors: Ira Pastan, Raffit Hassan
Journal: Cancer Research (2014)

We have recently reported that an immunotoxin targeting mesothelin produced durable major tumor regressions in patients with extensive treatment-refractory mesothelioma. These unprecedented tumor responses have prompted us to review how mesothelin was discovered and the advances that led to these tumor responses. This review is not comprehensive but focuses on major developments over the past 20 years since mesothelin was first identified in our laboratory. Mesothelin is a cell-surface glycoprotein whose expression in normal human tissues is restricted to mesothelial cells. Because it is highly expressed by many solid tumors, it is an attractive immunotherapy target. Antibody-based therapies currently in clinical trials include an immunotoxin, a chimeric monoclonal antibody, and an antibody drug conjugate. In addition, a mesothelin tumor vaccine and a mesothelin- chimeric antigen receptor are being evaluated in the clinic. SS1P, an anti-mesothelin immunotoxin, was the first mesothelin-directed therapy to enter the clinic, and its use showed that mesothelin-targeted therapy was safe in patients. More importantly, our recent work has shown that SS1P in combination with pentostatin and cyclophosphamide can result in durable tumor regression in patients with advanced mesothelioma and opens up the possibility that such an approach can benefit patients with many common cancers.
A8.9 Characterisation of Cell Metabolic Changes in Osteoarthritic Labrum Cells
Authors: Juchtmans Nele, AM Dhollander Aad, Lambrecht Stijn, Elewaut Dirk
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> Little is known about the cell metabolism of the acetabular labrum, a horseshoe-shaped structure sealing the hip joint. It performs similar functions as the menisci in the knee though the metabolic aspects of labrum cells show fibrochondrocyte characteristics, different from menisci and cartilage. The goal of this study was to investigate whether labrum cells derived from osteoarthritic tissue have different cell metabolic characteristics compared with labrum cells derived from healthy tissue. Furthermore this study aimed to investigate specific processes of functional importance in the pathology of osteoarthritis. <h3>Materials and Methods</h3> Labrum cells from 5 OA patients en 3 healthy control patients were isolated and cultured in the 3-Dimensional alginate culture system. A genome wide gene expression analysis was performed using the Affymetrix microarray technology. Differential gene expression levels were confirmed on additional patient samples by quantitative PCR (qPCR), western blot and immunohistochemistry. <h3>Results</h3> Gene expression analysis showed, as expected, downregulation of aggrecan and several matrix degrading enzymes such as (MMP’s) and (ADAMTS’s) were up regulated in OA. qPCR confirmation occurred for 20 of the most pronounced differences between normal and OA labrum. Of these 20 genes the Short leucine-rich repeat proteins (SLRP’s) asporin (ASPN) and osteomodulin (OMD) were of special interest, both showed a reduced expression level and protein presence in OA labrum cells. More over stimulation in vitro of labrum cell with IL1β down regulated the expression of both proteins. <h3>Conclusions</h3> Labrum cells derived from OA patients show a consistent altered metabolism compared to cells isolated from healthy controls. The reduced expression of ECM genes in OA labrum point towards a distorted ECM synthesis. Together with the observed increase in ECM degradation by MMP’s, our data indicate that both distorted anabolism and catabolism contribute to degeneration of labrum tissue in OA. The short leucine-rich proteins (SLPR’s) ASPN and OMD were of special interest as these exhibited the most pronounced expression differences. In conclusion this study clearly indicates that similar events occur during OA development in labrum and cartilage. Though labrum specific expression differences are observed that merit further investigation.
Global Drug-Resistance Patterns and the Management of Latent Tuberculosis Infection in Immigrants to the United States
Authors: Kamran Khan, Peter Muennig, Maryam Behta, Joshua Graff Zivin
Journal: New England Journal of Medicine (2002)

In the United States, an increasingly disproportionate burden of tuberculosis among the foreign-born population has led to calls for improvements in the detection and treatment of latent infection in new immigrants. Current treatment guidelines do not take into account global differences in drug-resistance patterns or their implications for the treatment of immigrants. The use of multinational surveillance systems to guide the management of latent infection according to region-specific drug-resistance profiles could improve the efficiency of efforts to reduce the burden of tuberculosis in immigrants to the United States.We constructed a decision-analysis model by using a hypothetical cohort of all documented immigrants entering the United States from developing nations. Region-specific drug-resistance profiles were derived from data on 30,388 cases of infection. The model examined the effectiveness and cost effectiveness of four strategies: no intervention or tuberculin skin testing followed by treatment with isoniazid, treatment with rifampin, or treatment with rifampin plus pyrazinamide for those with a positive test result.A strategy of detecting and treating latent tuberculosis infection was cost-saving among immigrants from Mexico, Haiti, sub-Saharan Africa, South Asia, and developing nations in East Asia and the Pacific. This strategy was highly cost effective among immigrants from other developing nations. Rifampin plus pyrazinamide was the preferred strategy for treating latent infection in immigrants from Vietnam, Haiti, and the Philippines.For new immigrants to the United States from developing nations, a strategy of detecting and treating latent tuberculosis infection would lead to substantial health and economic benefits. Because of the high prevalence of resistance to isoniazid, treatment with a rifampin-containing regimen should be strongly considered for immigrants from Vietnam, Haiti, and the Philippines.
Screening for central hypothyroidism is unjustified
Authors: A. Price
Journal: BMJ (2001)

EDITOR—If we do enough tests on enough people we will always pick up abnormalities; we must also take account of the false positive rate of any testing strategy. These points are missing from Waise and Belchetz's article on unsuspected central hypothyroidism.1

Most patients in general practice for whom measurement of thyroid stimulating hormone concentration is requested have vague symptoms. This has a firm foundation: the …
Angina Pectoris Associated with Ventricular Bigeminy, Controlled by Procaine Amide
Authors: David Davis
Journal: New England Journal of Medicine (1952)

THE occurrence of premature ventricular beats during an attack of angina pectoris was first demonstrated by Mackenzie1 with pulse tracings and by Goldhammer and Scherf2 electrocardiographically. Proger, Minnich and Magendantz,3 in a study of the circulatory response of patients with angina pectoris to exercise, showed that one group developed premature beats during attacks and that attacks could be abolished and the exercise tolerance increased by quinidine. This action of quinidine was confirmed by Riseman and Brown,4 who further established the value of this drug in a large group of patients with angina pectoris. In 1948 Porter5 reported 4 cases of . . .
Control of distension of varicose veins achieved by leg bandages, as used after injection sclerotherapy.
Authors: P H Fentem, M Goddard, B A Gooden, C K Yeung
Journal: BMJ (1976)

A study was performed to determine whether the pressures routinely produced by bandaging for compression sclerotherapy of varicose veins are adequate to maintain the superfical veins almost empty of blood. The results suggest that well-applied bandages can provide sufficient support to combat the high distending pressures found in varicose veins. The large variation among different surgeons, however, indicates that any clinical assessment of compression sclerotherapy should include measurement of the pressure at which the bandages are applied.
Functional Evaluation of Prolactin Secretion in Patients with Hypothalamic-Pituitary Disorders
Authors: G. Tolis, M. Goldstein, H. G. Friesen
Journal: Journal of Clinical Investigation (1973)

Prolactin secretion was assessed in 23 patients with hypothalamic-pituitary disorders using L-Dopa suppression, chlorpromazine (CPZ), and thyrotropin-releasing hormone (TRH) stimulation tests. Based on the responses to these tests, three groups of patients were identified: those with panhypopituitarism (group I) and those with partial hypopituitarism either with (group II) or without (group III) evidence of hypothalamic involvement. Panhypopituitary patients (group I) consistently had low serum prolactin values and failed to respond to all tests. Patients with hypothalamic involvement (group II) exhibited (a) elevated basal prolactin values. (b) an increase in serum prolactin after TRH stimulation. (c) blunted response to L-Dopa, and (d) lack of response to chlorpromazine stimulation. Patients with partial hypopituitarism but without hypothalamic involvement (group III) had normal serum prolactin levels and suppressed normally after L-Dopa; although the magnitude of response to both stimulatory agents was significantly lower than normally found the ratio of prolactin levels post-CPZ and TRH (Delta prolactin CPZ/Delta prolactin TRH) was similar to the ratio of normal individuals suggesting that these patients (group III) had a normal hypothalamic-pituitary prolactin axis. In the 23 patients studied, the most consistent disorder of pituitary function proved to be an abnormal response to one or other of the three tests employed for the evaluation of prolactin secretion. Hence these tests have considerable potential as a sensitive screening procedure in the evaluation of patients suspected of having hypothalamic-pituitary disease.
Risks and benefits of antimalarial drugs.
Authors: D. R. Fish, M. L. Espir
Journal: BMJ (1989)

Simple, incentive based behaviour modification, with or without a modest programme of psychotherapy involving outpatient visits every four to six weeks, seems to be associated with a useful cure rate in children with lower bowel function disorders. Appreciable social disadvantage seems to be the most important factor mitigating against a successful outcome, associated with non-compliance with treatment. Failure to respond to treatment was associated with important psychological problems. These were more common in the socially disadvantaged groups. Children from satisfactory social backgrounds who have lower bowl disturbances can be effectively treated by fairly simple programmes. More elaborate and expensive strategies should be reserved for those whose psychosocial circumstances make it possible to predict a less satisfactory outcome.
AN ANTIGENIC BASIS FOR VIRULENCE IN STRAINS OF SALMONELLA TYPHIMURIUM
Authors: Charles R. Jenkin
Journal: The Journal of Experimental Medicine (1962)

A study has been made of the antigenic relationships between a virulent and an avirulent strain of Salmonella typhimurium. Evidence is presented which supports the hypothesis that the susceptibility of the mouse to infection by S. typhimurium is due to an antigenic relationship between host and parasite. The antigen shared between host and parasite, appears to be absent or is masked in the avirulent strain.
Role of MgADP in the development of diastolic dysfunction in the intact beating rat heart.
Authors: R Tian, M E Christe, M Spindler, J C Hopkins, J M Halow, S A Camacho, J S Ingwall
Journal: Journal of Clinical Investigation (1997)

Sarcomere relaxation depends on dissociation of actin and myosin, which is regulated by a number of factors, including intracellular [MgATP] as well as MgATP hydrolysis products [MgADP] and inorganic phosphate [Pi], pHi, and cytosolic calcium concentration ([Ca2+]c). To distinguish the contribution of MgADP from the other regulators in the development of diastolic dysfunction, we used a strategy to increase free [MgADP] without changing [MgATP], [Pi], or pHi. This was achieved by applying a low dose of iodoacetamide to selectively inhibit the creatine kinase activity in isolated perfused rat hearts. [MgATP], [MgADP], [Pi], and [H+] were determined using 31P NMR spectroscopy. The [Ca2+]c and the glycolytic rate were also measured. We observed an approximately threefold increase in left ventricular end diastolic pressure (LVEDP) and 38% increase in the time constant of pressure decay (P < 0.05) in these hearts, indicating a significant impairment of diastolic function. The increase in LVEDP was closely related to the increase in free [MgADP]. Rate of glycolysis was not changed, and [Ca2+]c increased by 16%, which cannot explain the severity of diastolic dysfunction. Thus, our data indicate that MgADP contributes significantly to diastolic dysfunction, possibly by slowing the rate of cross-bridge cycling.
On hanging up my stethoscope
Authors: O. Samuel
Journal: BMJ (1996)

Today I retired from a career as a family doctor. In the past few weeks the patients have been notified of my impending departure and most of them have been lovely. I have enjoyed friendly farewells and received many letters and cards and I have been struck by how many people with whom I was involved many years ago have taken the trouble to write to say thank you. I used to believe that the only people to show gratitude were those who had been offered a fairly routine service, while those for whom a great deal of time and effort had been spent responded by changing doctors. I know now that this is far from the truth and I have a pile of post to prove it.

I was, however, startled out of my smug preretirement euphoria when I realised that almost every day one or two patients who came to see me, often with a minor matter but really to say goodbye, suddenly became distressed and …
Reversible Oxidative Modification
Authors: Gemma A. Figtree, Chia-Chi Liu, Stephanie Bibert, Elisha J. Hamilton, Alvaro Garcia, Caroline N. White, Karin K.M. Chia, Flemming Cornelius, Kaethi Geering, Helge H. Rasmussen
Journal: Circulation Research (2009)

Angiotensin II (Ang II) inhibits the cardiac sarcolemmal Na(+)-K(+) pump via protein kinase (PK)C-dependent activation of NADPH oxidase. We examined whether this is mediated by oxidative modification of the pump subunits. We detected glutathionylation of beta(1), but not alpha(1), subunits in rabbit ventricular myocytes at baseline. beta(1) Subunit glutathionylation was increased by peroxynitrite (ONOO(-)), paraquat, or activation of NADPH oxidase by Ang II. Increased glutathionylation was associated with decreased alpha(1)/beta(1) subunit coimmunoprecipitation. Glutathionylation was reversed after addition of superoxide dismutase. Glutaredoxin 1, which catalyzes deglutathionylation, coimmunoprecipitated with beta(1) subunit and, when included in patch pipette solutions, abolished paraquat-induced inhibition of myocyte Na(+)-K(+) pump current (I(p)). Cysteine (Cys46) of the beta(1) subunit was the likely candidate for glutathionylation. We expressed Na(+)-K(+) pump alpha(1) subunits with wild-type or Cys46-mutated beta(1) subunits in Xenopus oocytes. ONOO(-) induced glutathionylation of beta(1) subunit and a decrease in Na(+)-K(+) pump turnover number. This was eliminated by mutation of Cys46. ONOO(-) also induced glutathionylation of the Na(+)-K(+) ATPase beta(1) subunit from pig kidney. This was associated with a approximately 2-fold decrease in the rate-limiting E(2)-->E(1) conformational change of the pump, as determined by RH421 fluorescence. We propose that kinase-dependent regulation of the Na(+)-K(+) pump occurs via glutathionylation of its beta(1) subunit at Cys46. These findings have implications for pathophysiological conditions characterized by neurohormonal dysregulation, myocardial oxidative stress and raised myocyte Na(+) levels.