tbuckley/cabot-search huggingface dataset:
HUMAN IMMUNITY TO THE MENINGOCOCCUS
Authors: Irving Goldschneider, Emil C. Gotschlich, Malcolm S. Artenstein
Journal: The Journal of Experimental Medicine (1969)

Susceptibility to systemic meningococcal disease is related to a selective deficiency of humoral antibodies to pathogenic strains of meningococci. In a study of the age-specific incidence of meningococcal meningitis in the United States, it was found that the proportion of individuals with serum bactericidal activity to meningococci of serogroups A, B, and C was reciprocally related to the incidence of disease. The prevalence of bactericidal activity was highest at birth and among adults, and lowest in infants between 6 and 24 months of age. Sera from 51 of 54 prospective cases of meningococcal disease among military recruits were deficient in antibodies to homologous and heterologous strains of pathogenic meningococci as determined by serum bactericidal activity and indirect immunofluorescence. Such sera, however, could support the bactericidal activity of purified human gamma globulin (Cohn fraction II), and such individuals could respond immunologically to infection with meningococci. The implication is that susceptible persons are deficient in antimeningococcal antibodies because they have not received significant exposure to meningococcal antigens in the past. The fate of individuals who lack bactericidal antibodies to pathogenic meningococci was determined during an outbreak of group C meningitis among military recruits. The incidence of disease was found to be primarily associated with the incidence of exposure of susceptibles to the pathogenic strains. Whereas 81.5% of the presumed susceptibles acquired a meningococcal strain, only 24.1% acquired an organism similar to the prevalent disease-producing strains. Of the exposed susceptibles, 38.5% developed systemic meningococcal disease.
Vascular bed–specific regulation of the von Willebrand factor promoter in the heart and skeletal muscle
Authors: Ju Liu, Lei Yuan, Grietje Molema, Erzsébet Regan, Lauren Janes, David Beeler, Katherine C. Spokes, Yoshiaki Okada, Takashi Minami, Peter Oettgen, William C. Aird
Journal: Blood (2010)
JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis
Authors: Claire Harrison, Jean-Jacques Kiladjian, Haifa Kathrin Al-Ali, Heinz Gisslinger, Roger Waltzman, Viktoriya Stalbovskaya, Mari McQuitty, Deborah S. Hunter, Richard Levy, Laurent Knoops, Francisco Cervantes, Alessandro M. Vannucchi, Tiziano Barbui, Giovanni Barosi
Journal: New England Journal of Medicine (2012)

Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis.We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography.A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy.Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).
Transcardiac alteration of neutrophil function relates to myocardial ischaemia/reperfusion injury
Authors: S. Hoshida, T. Kuzuya, H. Fuji, H. Oe, M. Hori, T. Kamada, M. Tada
Journal: Cardiovascular Research (1993)

Objective: The aim was to define the relation between transcardiac changes in neutrophil function in myocardial ischaemia and the progression of myocardial necrosis. Methods: Samples of blood from carotid artery, jugular vein, and cardiac vein streaming from the ischaemic area were taken simultaneously in a canine coronary occlusion-reperfusion model of myocardial infarction. Neutrophil function was evaluated by neutrophil count, whole blood chemiluminescence and leucocyte infiltration into the ischaemic myocardium. Myocardial necrosis was assessed by plasma creatine kinase and dual staining technique using Evans blue dye and triphenyltetrazolium chloride. Effects of a free radical scavenger, N-2-mercaptopropionyl glycine (MPG), initiated 15 min before reperfusion and continued during the reperfusion phase, were also examined. Results: Whole blood chemiluminescence of the cardiac vein was reduced at 90 min after coronary artery occlusion as compared to carotid artery [5.8(SEM 0.5) v 7.5(0.7) count·103 cell neutrophil−1·10 min−1, p<0.05], and then increased abruptly after reperfusion to peak after 10 min of reperfusion [7.1(0.7) count·103 cell neutrophil−1·10 min−1]. The neutrophil count in cardiac venous blood was significantly reduced within 5 min of reperfusion. MPG significantly attenuated the reperfusion associated increase in cardiac vein whole blood chemiluminescence and the decrease in the cardiac venous blood neutrophil count. The increase in myocardial free radical generation 1-3 h after reperfusion, as assessed by the electron paramagnetic resonance spin trapping technique, was reduced markedly, as was the extent of leucocyte infiltration into the ischaemic myocardium. Under these conditions, administration of MPG significantly reduced myocardial infarct size [40.3(4.5)% v 21.4(4.2)%, p<0.05]. A marked increase in transcardiac creatine kinase release after reperfusion observed in control dogs was also reduced significantly. Conclusions: A transient alteration of neutrophil function occurs in the coronary circulation immediately after reperfusion, which may augment neutrophil infiltration and free radical generation in the ischaemic myocardium, leading to the propagation of myocardial ischaemia/reperfusion injury. Cardiovascular Research 1993;27:377-383
A cloned cell line mediating natural killer cell function inhibits immunoglobulin secretion.
Authors: G Nabel, W J Allard, H Cantor
Journal: The Journal of Experimental Medicine (1982)

We previously described a cloned cell line that combines information for a unique display of cell surface antigens and specialized function similar to activated natural killer (NK) cells. In addition to conventional cellular targets such as the YAC-1 and MBL-2 lymphomas, this cloned line also lysed lipopolysaccharide-activated B lymphocytes. To determine whether some NK cells can inhibit B cell function, we tested the ability of NK-like clones to suppress Ig secretion in vitro and in vivo. These cloned cells suppressed Ig secretion when they constituted as few as 0.2% of the total cell population and inhibition did not require identity at the H-2 locus. We suggest that some NK cells might recognize non-major histocompatibility complex gene products on activated B lymphocytes and lyse these cells, and this might represent a fundamental cell-cell interaction that regulates antibody secretion by activated B cells.
Application of topical mitomycin C to the base of shave-removed keloid scars to prevent their recurrence
Authors: J.N.R. Bailey, A.E. Waite, W.J. Clayton, M.H.A. Rustin
Journal: British Journal of Dermatology (2007)

Keloid scars are formed by over-activity of fibroblasts producing collagen and they cause significant morbidity both from their appearance and from their symptoms. Existing treatments are often unsatisfactory. Topical mitomycin C is known to inhibit fibroblast proliferation.To determine whether application of mitomycin C to the base of shave-removed keloids would prevent their recurrence.Ten patients had all or part of their keloid shave-removed. After haemostasis topical mitomycin C 1 mg mL(-1) was applied for 3 min. This application was repeated after 3 weeks. The keloids were photographed before treatment and the patients were reviewed every 2 months for a total of 6 months when a final photograph of the keloid site was taken. The patients and the Clinical Trials Unit staff scored the outcome on a linear analogue scale of 0-10, where 0 = disappointed and 10 = delighted. The pretreatment and 6-month post-treatment photographs were also assessed by two dermatologists who were not involved in the clinical trial.Four of the 10 patients were delighted with the outcome of treatment and only one was disappointed. On average there was an 80% satisfied outcome.This new treatment of keloids has been shown to be effective in the majority of patients but further studies are required to confirm this benefit.
Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells
Authors: Catherine Riou, Bader Yassine-Diab, Julien Van grevenynghe, Roland Somogyi, Larry D. Greller, Dominic Gagnon, Sylvain Gimmig, Peter Wilkinson, Yu Shi, Mark J. Cameron, Roberto Campos-Gonzalez, Robert S. Balderas, David Kelvin, Rafick-Pierre Sekaly, Elias K. Haddad
Journal: The Journal of Experimental Medicine (2006)

The molecular events involved in the establishment and maintenance of CD4+ central memory and effector memory T cells (TCM and TEM, respectively) are poorly understood. In this study, we demonstrate that ex vivo isolated TCM are more resistant to both spontaneous and Fas-induced apoptosis than TEM and have an increased capacity to proliferate and persist in vitro. Using global gene expression profiling, single cell proteomics, and functional assays, we show that the survival of CD4+ TCM depends, at least in part, on the activation and phosphorylation of signal transducer and activator of transcription 5a (STAT5a) and forkhead box O3a (FOXO3a). TCM showed a significant increase in the levels of phosphorylation of STAT5a compared with TEM in response to both IL-2 (P<0.04) and IL-7 (P<0.002); the latter is well known for its capacity to enhance T cell survival. Moreover, ex vivo TCM express higher levels of the transcriptionally inactive phosphorylated forms of FOXO3a and concomitantly lower levels of the proapoptotic FOXO3a target, Bim. Experiments aimed at blocking FOXO3a phosphorylation confirmed the role of this phosphoprotein in protecting TCM from apoptosis. Our results provide, for the first time in humans, an insight into molecular mechanisms that could be responsible for the longevity and persistence of CD4+ TCM.
P17.86 * IDENTIFICATION OF REGULATED GENES IN GLIOMA-ASSOCIATED MICROGLIA/MACROPHAGES USING MICROARRAY
Authors: M. Synowitz, F. Szulkowski, I. R. Holtmann, H. W. Boddeke, H. Kettenmann, A. Pelz, S. A. Wolf
Journal: Neuro-Oncology (2014)

OBJECTIVE: Glioma, such as anaplastic astrocytoma and glioblastoma multiforme, belong to the most aggressive neoplasms in humans. Microglia and peripheral macrophages are attracted towards glioma and their abundance positively correlates with malignancy, invasiveness and tumor grade. Glioma exhibit an immunosuppressive milieu, and glioma—associated microglia/macrophages are polarized towards an M2—like anti— inflammatory phenotype and actively support tumor growth, e.g. via the release of immune—suppressive cytokines, and factors that stimulate angiogenesis and tumor invasion. Here we seek to identify new glioma—regulated genes to further elucidate the pathways of glioma—microglia interaction. METHODS: In order to achieve this, we compared the gene expression profiles of glioma— associated microglia/macrophages isolated from experimental allogeneic GL261 tumors and human gliomas with microglia and peritoneal macrophages isolated from control animals and humans. RESULTS: The microarray experiment we performed with RNA samples from CD11b+ MACS—sorted cells from GL261 tumors and naïve brains revealed highly altered gene expression patterns in tumor—associated microglia/macrophages. More than 600 genes were more than 5—fold up— or downregulated in tumor—associated cells when compared to control cells. The qPCR validation we performed with FACS—sorted samples confirmed the regulation of our target genes and revealed that genes are either strongly upregulated in tumour—associated microglia or macrophages, but not in both cell types at the same time. This demonstrates that intrinsic microglia and invading macrophages fulfill different tasks in the tumor. We are currently collecting samples from the RCAS tumor model to validate the expression of our target genes in an independent mouse tumor model. CONCLUSIONS: In future experiments we will confirm the expression of our target genes on protein level, using FACS, IHC and western blot. Furthermore we will test the expression of our target genes in RNA samples we are currently collecting from CD11b+ MACS—sorted cells from human glioblastoma and normal brain samples.
Estimation of the Glycation Gap in Diabetic Patients With Stable Glycemic Control
Authors: Santiago Rodríguez-Segade, Javier Rodríguez, José M. García Lopez, Felipe F. Casanueva, Félix Camiña
Journal: Diabetes Care (2012)

The glycation gap (the difference between measured A1C and the value predicted by regression on fructosamine) is stable and is associated with microvascular complications of diabetes but has not hitherto been estimated within a clinically useful time frame. We investigated whether two determinations 30 days apart suffice for a reasonably reliable estimate if both A1C and fructosamine exhibit stability.We studied 311 patients with type 1 or type 2 diabetes for whom simultaneous measurements of A1C and serum fructosamine had been made on at least two occasions separated by 1 month (t(0) and t(1)). Glycemia was deemed stable if A1C(t(1)) - A1C(t(0)) and fructosamine(t(1)) - fructosamine(t(0)) were both less than their reference change values (RCVs). Instantaneous glycation gaps [gg(t(0)) and gg(t(1))] and their mean (GG), were calculated using the data from all stable patients for the required regression.Stable glycemia was shown by 144 patients. In 90% of unstable case subjects, a change in medication was identified as the cause of instability. Among 129 stable patients with an average of eight gg determinations prior to t(0), GG correlated closely with the mean of these prior determinations (r(2) = 0.902, slope 1.025, intercept -0.038).The glycation gap can be calculated reliably from pairs of A1C and fructosamine measurements taken 1 month apart if these measurements satisfy the RCV criteria for glycemic control.
Cancer-Associated Expression of <b> <i>Minichromosome Maintenance 3</i> </b> Gene in Several Human Cancers and Its Involvement in Tumorigenesis
Authors: Seon-Ah Ha, Seung Min Shin, Hong Namkoong, Heejeong Lee, Goang Won Cho, Soo Young Hur, Tae Eung Kim, Jin Woo Kim
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of our study was to identify an unique gene that shows cancer-associated expression, evaluates its potential usefulness in cancer diagnosis, and characterizes its function related to human carcinogenesis. Experimental Design: We used the differential display reverse transcription-PCR method with normal cervical, cervical cancer and metastatic tissues, and cervical cancer cell line to identify genes overexpressed in cancers. Results: We identified a minichromosome maintenance 3 (MCM3) gene that was overexpressed in various human cancers, including leukemia, lymphoma, and carcinomas of the uterine cervix, colon, lung, stomach, kidney and breast, and malignant melanoma. Western blot and immunohistochemical analyses also revealed that MCM3 protein was elevated in most of human cancer tissues tested. We compared the MCM3 protein expression levels in human cancers with conventional proliferation markers, Ki-67 and proliferating cell nuclear antigen. MCM3 antibody was the most specific for multiple human cancers, whereas proliferating cell nuclear antigen was relatively less effective in specificity, and Ki-67 failed to detect several human cancers. The down-regulation of MCM3 protein level was examined under serum starvation in both normal and cancer cells. Interestingly, MCM3 protein was stable in MCF-7 breast cancer cells even up to 96 hours after serum starvation, whereas it was gradually degraded in normal BJ fibroblast cells. Nude mice who received injections of HEK 293 cells stably transfected with MCM3 formed tumors in 6 weeks. Conclusions: Our study indicates that determination of MCM3 expression level will facilitate the assessment of many different human malignancies in tumor diagnosis, and MCM3 is involved in multiple types of human carcino-genesis.
Adenocarcinoma in the columnar epithelial lined lower (Barrett) oesophagus
Authors: A. Hawe, W. S. Payne, L. H. Weiland, R. S. Fontana
Journal: Thorax (1973)

<b>Hawe, A., Payne, W. S., Weiland, L. H., and Fontana, R. S. (1973).</b><i>Thorax</i>, <b>28</b>, 511-514. <b>Adenocarcinoma in the columnar epithelial lined lower (Barrett) oesophagus.</b> At the Mayo Clinic, five patients with Barrett oesophagus developed adenocarcinoma of the oesophagus at sites cephalad from the anatomic cardia but separated from it by a definite segment of columnar lined oesophagus. Twelve similar cases have been reported in the literature, including one from this institution. Of 85 Mayo Clinic patients in whom a clinical diagnosis of benign Barrett oesophagus was made in the 20-year period 1950-69, two subsequently developed oesophageal cancer. Since its description in 1950 by Barrett, the columnar epithelial lined lower oesophagus has been encountered with increasing frequency. The full clinical implications of this unusual condition are only partially appreciated at this time, and the present report, as well as previous ones, suggest that the condition may be premalignant.
High Urinary Calcium Excretion and Genetic Susceptibility to Hypertension and Kidney Stone Disease
Authors: Andrew Mente, R. John D’ A. Honey, John M. McLaughlin, Shelley B. Bull, Alexander G. Logan
Journal: Journal of the American Society of Nephrology (2006)

Increased urinary calcium excretion commonly is found in patients with hypertension and kidney stone disease (KSD). This study investigated the aggregation of hypertension and KSD in families of patients with KSD and hypercalciuria and explored whether obesity, excessive weight gain, and diabetes, commonly related conditions, also aggregate in these families. Consecutive patients with KSD, aged 18 to 50 yr, were recruited from a population-based Kidney Stone Center, and a 24-h urine sample was collected. The first-degree relatives of eligible patients (n = 333) and their spouse were interviewed by telephone to collect demographic and health information. Familial aggregation was assessed using generalized estimating equations. Multivariate-adjusted odds ratios (OR) revealed significant associations between hypercalciuria in patients and hypertension (OR 2.9; 95% confidence interval 1.4 to 6.2) and KSD (OR 1.9; 95% confidence interval 1.03 to 3.5) in first-degree relatives, specifically in siblings. No significant associations were found in parents or spouses or in patients with hyperuricosuria. Similarly, no aggregation with other conditions was observed. In an independent study of siblings of hypercalciuric patients with KSD, the adjusted mean fasting urinary calcium/creatinine ratio was significantly higher in the hypertensive siblings compared with normotensive siblings (0.60 ± 0.32 versus 0.46 ± 0.28 mmol/mmol; P < 0.05), and both sibling groups had significantly higher values than the unselected study participants (P < 0.001). Urinary sodium/creatinine and uric acid/creatinine ratios were not different among the groups. Although an environmental effect cannot be excluded fully, our findings suggest that the disturbance in calcium metabolism in hypertension and KSD has a genetic basis.
Multiple Origins and Rapid Evolution of Duplicated Mitochondrial Genes in Parthenogenetic Geckos (Heteronotia binoei; Squamata, Gekkonidae)
Authors: M. K. Fujita, J. L. Boore, C. Moritz
Journal: Molecular Biology and Evolution (2007)

Accumulating evidence for alternative gene orders demonstrates that vertebrate mitochondrial genomes are more evolutionarily dynamic than previously thought. Several lineages of parthenogenetic lizards contain large, tandem duplications that include rRNA, tRNA, and protein-coding genes, as well as the control region. Such duplications are hypothesized as intermediate stages in gene rearrangement, but the early stages of their evolution have not been previously studied. To better understand the evolutionary dynamics of duplicated segments of mitochondrial DNA, we sequenced 10 mitochondrial genomes from recently formed ( approximately 300,000 years ago) hybrid parthenogenetic geckos of the Heteronotia binoei complex and 1 from a sexual form. These genomes included some with an arrangement typical of vertebrates and others with tandem duplications varying in size from 5.7 to 9.4 kb, each with different gene contents and duplication endpoints. These results, together with phylogenetic analyses, indicate independent and frequent origins of the duplications. Small, direct repeats at the duplication endpoints imply slipped-strand error as a mechanism generating the duplications as opposed to a false initiation/termination of DNA replication mechanism that has been invoked to explain duplications in other lizard mitochondrial systems. Despite their recent origin, there is evidence for nonfunctionalization of genes due primarily to deletions, and the observed pattern of gene disruption supports the duplication-deletion model for rearrangement of mtDNA gene order. Conversely, the accumulation of mutations between these recent duplicates provides no evidence for gene conversion, as has been reported in some other systems. These results demonstrate that, despite their long-term stasis in gene content and arrangement in some lineages, vertebrate mitochondrial genomes can be evolutionary dynamic even at short timescales.
Use of the Electrocardiogram in Acute Myocardial Infarction
Authors: Peter J. Zimetbaum, Mark E. Josephson
Journal: New England Journal of Medicine (2003)

This review article describes the use of electrocardiograms in facilitating the clinical care of patients with acute myocardial infarction. Analysis of patterns of ST-segment elevation can help in making decisions about reperfusion therapy. Correct identification of arrhythmias and new conduction abnormalities is an important challenge.