tbuckley/cabot-search huggingface dataset:
T Cells Compete for Access to Antigen-Bearing Antigen-Presenting Cells
Authors: Ross M. Kedl, William A. Rees, David A. Hildeman, Brian Schaefer, Tom Mitchell, John Kappler, Philippa Marrack
Journal: The Journal of Experimental Medicine (2000)

These studies tested whether antigenic competition between T cells occurs. We generated CD8+ T cell responses in H-2b mice against the dominant ovalbumin epitope SIINFEKL (ova8) and subdominant epitope KRVVFDKL, using either vaccinia virus expressing ovalbumin (VV-ova) or peptide-pulsed dendritic cells. CD8+ T cell responses were visualized by major histocompatibility complex class I–peptide tetrameric molecules. Transfer of transgenic T cells with high affinity for ova8 (OT1 T cells) completely inhibited the response of host antigen-specific T cells to either antigen, demonstrating that T cells can directly compete with each other for response to antigen. OT1 cells also inhibited CD8+ T cell responses to an unrelated peptide, SIYRYGGL, providing it was presented on the same dendritic cells as ova8. These inhibitions were not due to a more rapid clearance of virus or antigen-presenting cells (APCs) by the OT1 cells. Rather, the inhibition was caused by competition for antigen and antigen-bearing cells, since it could be overcome by the injection of large numbers of antigen-pulsed dendritic cells. These results imply that common properties of T cell responses, such as epitope dominance and secondary response affinity maturation, are the result of competitive interactions between antigen-bearing APC and T cell subsets.
In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation.
Authors: M Abbate, C Zoja, D Corna, M Capitanio, T Bertani, G Remuzzi
Journal: Journal of the American Society of Nephrology (1998)

Progression to end-stage renal failure is the final common pathway of many forms of glomerular disease, independent of the type of initial insult. Progressive glomerulopathies have in common persistently high levels of urinary protein excretion and tubulointerstitial lesions at biopsy. Among the cellular mechanisms that may determine progression regardless of etiology, the traffic of excess proteins filtered from glomerulus in renal tubule may have functional importance by initiating interstitial inflammation in the early phase of parenchymal injury. This study analyzes the time course and sites of protein accumulation and interstitial cellular infiltration in two different models of proteinuric nephropathies. In remnant kidneys after 5/6 renal mass ablation, albumin and IgG accumulation by proximal tubular cells was visualized in the early stage, preceding interstitial infiltration of MHC-II-positive cells and macrophages. By double-staining, infiltrates developed at or near tubules containing intracellular IgG or luminal casts. This relationship persisted thereafter despite more irregular distribution of infiltrate. Similar patterns were found in an immune model (passive Heymann nephritis), indicating that the interstitial inflammatory reaction develops at the sites of protein overload, regardless of the type of glomerular injury. Osteopontin was detectable in cells of proximal tubules congested with protein in both models at sites of interstitial infiltration, and by virtue of its chemoattractive action this is likely mediator of a proximal tubule-dependent inflammatory pathway in response to protein load. Protein overload of tubules is a key candidate process translating glomerular protein leakage into cellular signals of interstitial inflammation. Mechanisms underlying the proinflammatory response of tubular cells to protein challenge in diseased kidney should be explored, as well as ways of limiting protein reabsorption/deposition to prevent consequent inflammation and progressive disease.
Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells
Authors: Christine Varela, Jérôme Alexandre Denis, Jérôme Polentes, Maxime Feyeux, Sophie Aubert, Benoite Champon, Geneviève Piétu, Marc Peschanski, Nathalie Lefort
Journal: Journal of Clinical Investigation (2012)

Human pluripotent stem cells offer a limitless source of cells for regenerative medicine. Neural derivatives of human embryonic stem cells (hESCs) are currently being used for cell therapy in 3 clinical trials. However, hESCs are prone to genomic instability, which could limit their clinical utility. Here, we report that neural differentiation of hESCs systematically produced a neural stem cell population that could be propagated for more than 50 passages without entering senescence; this was true for all 6 hESC lines tested. The apparent spontaneous loss of evolution toward normal senescence of somatic cells was associated with a jumping translocation of chromosome 1q. This chromosomal defect has previously been associated with hematologic malignancies and pediatric brain tumors with poor clinical outcome. Neural stem cells carrying the 1q defect implanted into the brains of rats failed to integrate and expand, whereas normal cells engrafted. Our results call for additional quality controls to be implemented to ensure genomic integrity not only of undifferentiated pluripotent stem cells, but also of hESC derivatives that form cell therapy end products, particularly neural lines.
Alterations of myocardial amino acid metabolism in chronic ischemic heart disease.
Authors: G H Mudge, R M Mills, H Taegtmeyer, R Gorlin, M Lesch
Journal: Journal of Clinical Investigation (1976)

Arteriovenous differences (A-V) of all naturally occurring amino acids, lactate, and oxygen were measured simultaneously with coronary sinus blood flow (CSBF) in 8 normal subjects and 11 patients with coronary artery disease at rest and during pacing stress. Mean values for CSBF and myocardial oxygen consumptions (MVO2) for the two groups were similar at rest and during pacing, although mean CSBF and MVO2 increased significantly in both groups in the paced as compared to the rest state. Alanine (ala) was the only amino acid released by the myocardium, while only glutamic acid(glu) demonstrated uptake. Mean A-V ala was negative at rest in the control and coronary disease groups (-4.8+/-3.8 vs. -22.0+/-3.0 nmol/ml, respectively), but was significantly more negative in the coronary group (P less than 0.001) and not statistically different than zero in the normals. A-V ala became significantly negative with pacing in the normals (-10.0+/-4.3 nmol/ml), remained unchanged in the coronary group (-23.0+/-2.9 nmol/ml), and was significantly more negative in the coronary group (P less than 0.05). Calculation of data on the basis of net ala flux ([A-V] X [CSBF X hematocrit]) yielded similar results as that obtained with A-V differences. A-V glu was significantly positive in normals (27.7 +/- 8.9 nmol/ml, P less than 0.01) and coronary patients (59.9 +/- 8.9 nmol/ml, P less than 0.01) at rest but significantly greater in the latter group (P less than 0.001). With pacing, A-V glu remained significantly greater than zero in coronary patients (35.3 +/- 6.3 nmol/ml) and decreased to zero in the normals (4.3 +/- 11.8 nmol/ml). Calculation of net glu flux (nmol/min) at rest yielded data similar to that based on A-V difference. With pacing, net glu flux in the coronary patients did not decrease due to the augmentation of CSBF. No relation between A-V glu or ala and CSBF, MVO2 or A-V lactate was noted. The data demonstrate that specific alterations of myocardial amino acid metabolism characterize patients with chronic ischemic heart disease.
Using cerebrospinal fluid for the diagnosis of tuberculous meningitis with GeneXpert
Authors: Robert F. Luo, Rajiv L. Gaur, Niaz Banaei
Journal: European Respiratory Journal (2014)

Using cerebrospinal fluid for the diagnosis of tuberculous meningitis with GeneXpertTo the Editor:We read with interest the systematic review by C. Denkinger and co-workers on the use of the Xpert MTB/ RIF assay for diagnosing extrapulmonary tuberculosis (TB) [1], particularly in light of World Health Organization (WHO) endorsement of Xpert MTB/RIF and its recent policy statement on extrapulmonary TB [1][2][3].Given the severe clinical course and high mortality associated with TB meningitis, combined with the lack of TB culture capacity in much of the developing world, WHO has endorsed testing cerebrospinal fluid (CSF) with the automated Xpert MTB/RIF assay as a first-line test over conventional microscopy in patients with suspected TB meningitis [2].This policy recommendation came as a ''strong recommendation given the urgency of rapid diagnosis'' despite the ''very low quality of evidence'' [2].Cerebrospinal fluid testing with Xpert MTB/RIF may not require complex sample processing protocols http://ow.ly/xkGjg
Differential Expression of Tumor Target Binding and Cytolytic Activities in Bone Marrow Culture-Derived Macrophages&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: K C Lee, V J La Posta
Journal: JNCI Journal of the National Cancer Institute (1986)

The binding and killing of a number of murine (DBA/2J) leukemia cell lines by murine bone marrow-derived macrophages (M phi s) were studied under various conditions to provide clues to the nature and specificity of tumor recognition by M phi s. Under test was the hypothesis that tumor target binding by activated M phi s is effected by saturable, high-affinity, trypsin and low temperature-sensitive receptors, whereas target binding by normal M phi s is of low affinity, nonsaturable, insensitive to low temperature and trypsin, and is believed not to be mediated by conventional receptors. The results obtained showed that this scenario was realized only rarely and that each target cell line had its own distinctive binding characteristics. Thus target binding by both unactivated and activated M phi s can be sensitive or insensitive to trypsin and low temperature depending on the target in question. This finding suggests that the binding of different targets is mediated by distinct receptors or different combinations of receptors. Contrary to previous reports, the binding of all targets tested was found to decrease with M phi activation and induction of cytotoxicity, but whatever binding strength that remained was obviously adequate for the manifestation of cytotoxicity. Fractionation of M phi s according to size (and hence maturity) revealed that tumor binding capacity (per unit surface area) increased with M phi size. Although target binding decreased in all M phi fractions after activation, it still correlated with cytotoxic activity and cell size for a given activated M phi population. Thus target binding correlates well with antitumor potential in unactivated Møs and with cytotoxic activity in activated M phi s.
Front-line paclitaxel–vinorelbine versus paclitaxel–carboplatin in patients with advanced non-small-cell lung cancer: a randomized phase III trial
Authors: G.P. Stathopoulos, M. Veslemes, N. Georgatou, D. Antoniou, P. Giamboudakis, K. Katis, D. Tsavdaridis, S.K. Rigatos, I. Dimitroulis, S. Bastani, S. Loukides, K. Vergos, K. Marossis, T. Grigoratou, E. Kalatzi, M. Charalambatou, A. Paspalli, P. Michalopoulou, M. Stoka, A. Gerogianni
Journal: Annals of Oncology (2004)
Screening for Coronary Artery Disease in Patients With Diabetes
Authors: Jeroen J. Bax, Lawrence H. Young, Robert L. Frye, Robert O. Bonow, Helmut O. Steinberg, Eugene J. Barrett
Journal: Diabetes Care (2007)

Coronary artery disease (CAD) accounts for a large fraction of the morbidity, mortality, and cost of diabetes. Recognizing this, nearly 10 years ago the American Diabetes Association published a consensus recommendation that clinicians consider a risk factor–guided screening approach to early diagnosis of CAD in both symptomatic and asymptomatic patients. Subsequent clinical trial results have not supported those recommendations. Since the prior consensus statement, newer imaging methods, such as coronary artery calcium scoring and noninvasive angiography with computed tomography (CT) techniques, have come into use. These technologies, which allow quantitation of atherosclerotic burden and can predict risk of cardiac events, might provide an approach to more widespread coronary atherosclerosis screening. However, over this same time interval, there has been recognition of diabetes as a cardiovascular disease (CVD) equivalent, clear demonstration that medical interventions should provide primary and secondary CVD risk reduction in diabetic populations, and suggestive evidence that percutaneous coronary revascularization may not provide additive survival benefit to intensive medical management in patients with stable CAD. This additional evidence raises the question of whether documenting asymptomatic atherosclerosis or ischemia in people with diabetes is warranted. More data addressing this issue will be forthcoming from the BARI 2-D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. Until then, for patients with type 2 diabetes who are asymptomatic for CAD, we recommend that testing for atherosclerosis or ischemia, perhaps with cardiac CT as the initial test, be reserved for those in whom medical treatment goals cannot be met and for selected individuals in whom there is strong clinical suspicion of very-high-risk CAD. Better approaches to identify such individuals based on readily obtained clinical variables are sorely needed.
Cisplatin induces the pro-apoptotic conformation of bak in a delta-MEKK1-dependent manner
Authors: Aleksandra Mandic, Kristina Viktorsson, Johan Hansson, Stig Linder, Maria Shoshan
Journal: Nature Genetics (2001)

Cisplatin induces the pro-apoptotic conformation of the Bcl-2 family protein Bak in four out of four human melanoma cell lines, whereas an effect on the pro-apoptotic conformation of Bax was seen in only one (FM55 cells).Expression of a kinase-inactive fragment of MEKK1 (dnMEKK) efficiently blocked the modulation of Bak and cytochrome c release, whereas DEVDase activation and nuclear fragmentation were reduced by half.Expression of a kinase-active MEKK1 fragment (dpMEKK) was sufficient to modulate Bak in three out of four cell lines, whereas an effect on Bax was seen only in FM55 cells.In the DFW cell line, dpMEKK stimulated a similar degree of Bak modulation as cisplatin but did not induce nuclear fragmentation.Together with the knowledge that dnMEKK was insufficient to block apoptosis completely, this finding indicates that cisplatin may induce apoptosis by means of additional mechanisms.We conclude that a proapoptotic MEKK1 pathway is necessary for cisplatin-induced Bak modulation, and that this modulation represents one of several cisplatin-induced apoptotic mechanisms or processes.
Cyanide poisoning from apricot seeds
Authors: M. J. Rubino
Journal: JAMA (1979)

To the Editor.—  Laetrile (amygdalin), found in the kernels of apricot seeds and other fruits, has recently been legalized in several states for the treatment of cancer. Amygdalin is a cyanogenic glycoside that on hydrolysis yields hydrogen cyanide. Although supporters of laetrile as a cancer remedy maintain it has no toxicity, several reports document its toxic effects (238:482, 1977; 238:1361, 1977; 239:1532,1978). We report yet another case of cyanide poisoning from the ingestion of apricot seeds.  Report of a Case.—  On June 8, 1978, a 49-year-old woman with nodular lymphoma diagnosed six years earlier ate 20 to 40 apricot pits, which she had purchased in a local health food store. The patient denied using the pits as a cancer treatment or preventive; rather, they were a substitute for her regular lunch. Within half an hour the patient noted headache, weakness, disorientation, and nausea. She vomited once or twice, regurgitating substantial
Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity in patients with genotype 1 chronic hepatitis C
Authors: Rami Moucari, Nicole Forestier, Dominique Larrey, Dominique Guyader, Patrice Couzigou, Yves Benhamou, Hélène Voitot, Michel Vidaud, Scott Seiwert, Bill Bradford, Stefan Zeuzem, Patrick Marcellin
Journal: Gut (2010)

<h3>Background/aim</h3> Insulin resistance (IR) is a major predictor of treatment failure in patients with hepatitis C virus (HCV) infection treated with peginterferon/ribavirin. The aim of this study was to evaluate the short-term effect of an HCV protease inhibitor monotherapy on IR in parallel with an antiviral effect. <h3>Patients/methods</h3> In a phase 1b placebo-controlled study, four cohorts of treatment-naïve patients with genotype 1 HCV received danoprevir (ITMN-191/RG7227), a protease inhibitor, or placebo (8/2 patients in each cohort respectively) in a gelatin capsule every 12 h (100, 200 mg) or 8 h (100, 200 mg) for 14 days. A fifth cohort including prior non-responders to peginterferon/ribavirin was similarly randomised to receive placebo or 300 mg danoprevir every 12 h. IR was assessed with the homeostasis model (HOMA-IR) at baseline and days 7, 14 and 15. <h3>Results</h3> Serum HCV-RNA and HOMA-IR correlated significantly (Spearman rho=0.379, p&lt;0.0001). At baseline, mean±SD serum HCV-RNA level and mean±SD HOMA-IR score were 6.2±0.5 log<sub>10</sub>IU/ml and 3.8±1.9, respectively. At the end of 14 days of monotherapy the mean±SD decrease in viral load was 2.2±1.3 log<sub>10</sub>IU/ml (p&lt;0.0001) in patients who received the active drug (n=40). In parallel, the mean±SD HOMA-IR score also decreased in these patients by 1.6±1.1 (p&lt;0.0001), with a close correlation between the extent of HOMA-IR improvement and the decrease in viral load. By contrast, serum HCV-RNA and HOMA-IR remained unchanged in patients who received placebo (n=10; 6.3±0.5 log<sub>10</sub>IU/ml and 3.8±2.5, respectively). <h3>Conclusion</h3> HCV protease inhibitor may restore insulin sensitivity in patients with genotype 1 HCV. The place of insulin sensitisers remains to be determined in the era of triple therapy.
T helper cells in murine germinal centers are antigen-specific emigrants that downregulate Thy-1.
Authors: B Zheng, S Han, G Kelsoe
Journal: The Journal of Experimental Medicine (1996)

After immunization, activated splenic T cells proliferate in periarteriolar lymphoid sheaths (PALS) and subsequently migrate to the lymphoid follicle where they enter nascent germinal centers. Analysis of TCR V(D)J gene rearrangements indicates extensive emigration, frequently involving more than a single white pulp region. These migrants constitute a unique set of T helper cells that express antigen-specific alpha beta TCR, CD3, and CD4, but little or no Thy-1, a differentiation antigen present on the great majority of peripheral murine T lymphocytes. The origin of CD4+ Thy-1 follicular T cells appears to be the Thy+ population in the PALS, as both sets commonly share identical V(D)J rearrangements.
Infections through blood from heart-lung machine
Authors: W. Ch. P. Geldof, A. G. Brom
Journal: Thorax (1972)

Of 657 cultures of blood from the heart-lung machine during operations performed with extra-corporeal circulation, 16 (2·4%) proved to be positive. Of these 16 patients, 12 showed no clinical infective symptoms. The case histories of the remaining four patients are presented. In three of these cases a plausible explanation for the infected perfusion blood was found: an infected aortic aneurysm, an infected aortic valve prosthesis, and mediastinitis. In only one case was the cause of the infection sought in the heart-lung machine.
Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency
Authors: M. Neale Weitzmann, Cristiana Roggia, Gianluca Toraldo, Louise Weitzmann, Roberto Pacifici
Journal: Journal of Clinical Investigation (2002)

Postmenopausal bone loss stems from the inability of osteoblastic activity to match the increase in osteoclastic bone resorption induced by estrogen deficiency. However, the mechanism that uncouples osteoblast from osteoclast activities remains unexplained. We show that ovariectomy enhances the production of the osteoclastogenic cytokine IL-7, and that its neutralization in vivo prevents ovariectomy-induced bone loss. Surprisingly, serum osteocalcin levels, a biochemical marker of bone formation, suggested that the bone-sparing effects of IL-7 neutralization were due not only to inhibition of bone resorption, but also to stimulation of bone formation. Consistent with these data, addition of IL-7 to neonatal calvarial organ cultures blocked new bone formation, and injection of IL-7 into mice in vivo inhibited bone formation as measured by calcein incorporation into long bones. The antianabolic effects of IL-7 were consistent with an observed downregulation of the osteoblast-specific transcription factor core-binding factor α1/Runx2. Thus, because it targets both the osteoclast and the osteoblast pathways, IL-7 is central to the altered bone turnover characteristic of estrogen deficiency.
Effects of a Novel Platelet Nitric Oxide Donor (LA816), Aspirin, Clopidogrel, and Combined Therapy in Inhibiting Flow- and Lesion-Dependent Thrombosis in the Porcine Ex Vivo Model
Authors: Gemma Vilahur, E. Segalés, E. Salas, L. Badimon
Journal: Circulation (2004)

Background— Acetylsalicylic acid (ASA), or aspirin, plus clopidogrel is becoming the standard antithrombotic treatment in people with coronary disease. Novel approaches such as the use of platelet-selective nitric oxide (NO) donors may provide additional protection against thrombosis. We evaluated the antithrombotic properties of a novel platelet-selective NO donor (LA816) administered alone and in combination with ASA, clopidogrel, or ASA+clopidogrel. Methods and Results— Thrombogenicity was measured in the porcine experimental model and assessed as platelet-thrombus formation in the ex vivo Badimon perfusion chamber. Pigs were randomly divided into 4 groups: (1) placebo control, (2) clopidogrel, (3) ASA, and (4) ASA+clopidogrel (ASA and clopidogrel were given orally, 10 mg · kg −1 · d −1 for 3 d). The animals were anesthetized, heparinized, and catheterized, and the Badimon perfusion chamber was placed in an extracorporeal shunt. After baseline perfusions, all animal groups received the intravenous infusion of LA816 for 2 hours. Platelet aggregation, blood pressure, and heart rate also were evaluated during the experiments. LA816, clopidogrel, and ASA+clopidogrel produced a reduction of ≈45% on thrombus mass versus placebo control perfusions ( P &lt;0.05). Combined treatment of oral ASA+clopidogrel and intravenous LA816 produced a significant further reduction of 25% in platelet deposition (70% from placebo controls; P &lt;0.0001). LA816 intravenous treatment did not modify blood pressure or heart rate. Conclusions— Acute NO donation with LA816, without modifying hemodynamic parameters, provides the same inhibitory effect as that obtained with chronic treatment with clopidogrel+ASA. Moreover, LA816 provides platelet inhibitory effects in addition to those of the combined blockade of cyclooxygenase and P2y(12) receptor.
Sequential Platinum-Based Chemotherapy-Thoracic Radiotherapy in Early Stage Non–Small Cell Lung Cancer
Authors: Nick Thatcher, Corinne Faivre-Finn, Fiona Blackhall, Heather Anderson, Paul Lorigan
Journal: Clinical Cancer Research (2005)

Abstract Combined chemoradiotherapy (CTRT) is intended to reduce the risk of local regional recurrence and distant relapse in patients with early stage non–small cell lung cancer (NSCLC). Sequential CTRT allows full doses of each modality while avoiding the additive toxicity that occurs with concurrent therapy. This review will encompass studies in the three main settings where sequential CTRT has been applied in early stage NSCLC: as adjuvant therapy after resection, as neoadjuvant chemotherapy and surgery followed by radiotherapy, and in unresectable stage III disease.