tbuckley/cabot-search huggingface dataset:
Common gamma chain (γc) cytokines differentially potentiate TNFR family signaling in antigen-activated CD8+ T cells
Authors: Michael J McNamara, Melissa J Kasiewicz, Stefanie N Linch, Christopher Dubay, William L Redmond
Journal: Journal for ImmunoTherapy of Cancer (2014)

Several members of the common gamma chain (gc) cytokine family are already approved (IL-2) or actively being developed as vaccine adjuvants and cancer immunotherapies. Studies have indicated that co-administration of gc cytokines may enhance the efficacy of immunotherapies that function via direct activation of co-stimulatory T cell receptors. To define the specific influence of gc cytokines on the co-stimulatory capacity of CD8(+) T cells and identify combinations with synergistic potential, we investigated the direct impact of gc cytokines on the differentiation and transcriptional profile of recently antigen-primed CD8(+) T cells.Naïve CD8(+) T cells were activated with peptide-pulsed APCs. After 48 hours, CD8(+) T cells were harvested and re-cultured in media supplemented with IL-2, IL-4, IL-7, IL-15 or IL-21. After 24 hours, cells were analyzed by cytokine bead array, flow cytometry, and mRNA micro-array. Gene networks responsible for specific CD8(+) T cell functions were constructed through literature-meta review and publicly available annotation databases. Gene expression data from the experimental groups was imported into this network to visualize the impact of each gc cytokine on the functional polarization of recently-activated CD8(+) T cells.Among the gc cytokines, IL-2 induced the greatest increase in the expression of co-stimulatory receptors in recently-activated CD8(+) T cells. IL-2 increased significantly expression of 4-1BB, GITR, ICOS and OX40, at both the transcriptional and protein level. IL-2 also drove the greatest increase in cellular proliferation and the most robust shift towards a pro-survival phenotype, compared with the other gc cytokines. Both IL-4 and IL-21 enhanced expression of cytotoxic effector proteins, but drove distinct phenotypic polarizations, Th2/Tc2 and NK-like, respectively.Overall, these observations suggest that among gc cytokines, IL-2 may be uniquely capable of synergizing with therapeutic strategies that combine immunization with agonists of co-stimulatory T cell receptors. Previous studies have shown that the timing of IL-2 treatment relative to immunization plays a key role in defining the CD8(+) T cell response, and the findings from this study indicate that administration of exogenous IL-2 shortly after the initial antigen-priming event has concluded may augment the receptivity of these cells to subsequent TNFR co-stimulation.
Effect of obesity and erect/supine posture on lateral cephalometry: relationship to sleep-disordered breathing
Authors: PE Brander, IL Mortimore, NJ Douglas
Journal: European Respiratory Journal (1999)

Craniofacial and upper airway anatomy, obesity and posture may all play a role in compromising upper airway patency in patients with the sleep apnoea/hypopnoea syndrome. The aim of this study was to investigate the relationship between obesity, facial structure and severity of sleep-disordered breathing using lateral cephalometric measurements and to assess the effect of body posture on cephalometric measurements of upper airway calibre variables in obese and non-obese subjects. Lateral cephalometry was carried out in erect and supine postures in 73 awake male subjects randomly selected from patients referred for polysomnography who had a wide range of apnoea/hypopnoea frequencies (1-131 events x h sleep(-1)). Subjects were divided into non-obese (body mass index (BMI) &lt; 30 kg x m(-2); n=42) and obese (BMI &gt; or = 30 kg x m(-2); n=31) groups. Significant but weak correlations were found between apnoea/hypopnoea index (AHI) and measurements reflecting upper airway dimensions: uvular protrusion-posterior pharyngeal wall (r=-0.26, p&lt;0.05) and hyoid-posterior pharyngeal wall (r=0.26, p&lt;0.05). Multiple regression using both upper airway dimensions improved the correlation to AHI (r=0.34, p=0.01). Obese subjects had greater hyoid-posterior pharyngeal wall distances than non-obese subjects, both erect (42+/-5 versus 39+/-4 mm, respectively (mean+/-SD) p&lt;0.01) and supine (43+/-5 versus 40+/-4 mm, p&lt;0.05). Skeletal craniofacial structure was similar in obese and non-obese subjects. In conclusion, measurements reflecting upper airway size were correlated with the severity of sleep-disordered breathing. Differences in upper airway size measurements between obese and non-obese subjects were independent of bony craniofacial structure.
Gene Expression in Kidney Cancer Is Associated with Cytogenetic Abnormalities, Metastasis Formation, and Patient Survival
Authors: Holger Sültmann, Anja von Heydebreck, Wolfgang Huber, Ruprecht Kuner, Andreas Buneβ, Markus Vogt, Bastian Gunawan, Martin Vingron, Laszlo Füzesí, Annemarie Poustka
Journal: Clinical Cancer Research (2005)

Current diagnosis of renal cancer consists of histopathologic examination of tissue sections and classification into tumor stages and grades of malignancy. Until recently, molecular differences between tumor types were largely unknown. To examine such differences, we did gene expression measurements of 112 renal cell carcinoma and normal kidney samples on renal cell carcinoma-specific cDNA microarrays containing 4,207 genes and expressed sequence tags. The gene expression patterns showed deregulation of complete biological pathways in the tumors. Many of the molecular changes corresponded well to the histopathologic tumor types, and a set of 80 genes was sufficient to classify tumors with a very low error rate. Distinct gene expression signatures were associated with chromosomal abnormalities of tumor cells, metastasis formation, and patient survival. The data highlight the benefit of microarrays to detect novel tumor classes and to identify genes that are associated with patient variables and tumor properties.
Biosynthesis of Wyosine Derivatives in tRNA: An Ancient and Highly Diverse Pathway in Archaea
Authors: Valérie de Crécy-Lagard, Céline Brochier-Armanet, Jaunius Urbonavičius, Bernard Fernandez, Gabriela Phillips, Benjamin Lyons, Akiko Noma, Sophie Alvarez, Louis Droogmans, Jean Armengaud, Henri Grosjean
Journal: Molecular Biology and Evolution (2010)

Wyosine (imG) and its derivatives such as wybutosine (yW) are found at position 37 of phenylalanine-specific transfer RNA (tRNA Phe ), 3# adjacent to the anticodon in Eucarya and Archaea.In Saccharomyces cerevisiae, formation of yW requires five enzymes acting in a strictly sequential order: Trm5, Tyw1, Tyw2, Tyw3, and Tyw4.Archaea contain wyosine derivatives, but their diversity is greater than in eukaryotes and the corresponding biosynthesis pathways still unknown.To identify these pathways, we analyzed the phylogenetic distribution of homologues of the yeast wybutosine biosynthesis proteins in 62 archaeal genomes and proposed a scenario for the origin and evolution of wyosine derivatives biosynthesis in Archaea that was partly experimentally validated.The key observations were 1) that four of the five wybutosine biosynthetic enzymes are ancient and may have been present in the last common ancestor of Archaea and Eucarya, 2) that the variations in the distribution pattern of biosynthesis enzymes reflect the diversity of the wyosine derivatives found in different Archaea.We also identified 7-aminocarboxypropyl-demethylwyosine (yW-86) and its N4-methyl derivative (yW-72) as final products in tRNAs of several Archaea when these were previously thought to be only intermediates of the eukaryotic pathway.We confirmed that isowyosine (imG2) and 7-methylwyosine (mimG) are two archaeal-specific guanosine-37 derivatives found in tRNA of both Euryarchaeota and Crenarchaeota.Finally, we proposed that the duplication of the trm5 gene in some Archaea led to a change in function from N1 methylation of guanosine to C7 methylation of 4-demethylwyosine (imG-14).
Activity monitor outcomes in COPD – Assessment of variability of 6 monitors as part of the IMI PROactive project
Authors: Zafeiris Louvaris, Daniel Langer, Santiago Giavedoni, Yogini Raste, Hans Van Remoortel, Eloisa Maria Gatti Regueiro, Frederick Wilson, Ioannis Vogiatzis, Nicholas Hopkinson, Roberto Rabinovich, Barry Peterson, Thierry Troosters
Journal: European Respiratory Journal (2011)

Background: Limited data exist on the validity of activity monitors to capture day-to-day variability in physical activity (PA). As part of the Proactive project we aimed at assessing the coefficient of variation (CV), the correlation between different activity monitors and their outcomes and their capability to detect less activity during Sundays, known to be less active days.  Methods: PA was measured in 64 COPD patients (Age 68±6 yr FEV1 57±19% pred. 6MWD 429±112 m) for 14 consecutive days. Three of the following monitors were worn simultaneously: SenseWear armband (SW n=57); RT3 (n=27); Actiwatch (AW n=30); Actigraph (AG n=30); Minimod (MM n=37) or Kenz (KZ n=27).  Results: Patients were generally inactive with 5495±3528 (MM); 4508±3528 (SW); 3847±2641 (AG) steps per day. CV was similar for step count assessed by MM (46%), SW (44%), AG (45%) and for walking time (MM 43%). CV was significantly less (20-30%) for energy expenditure, EE (SW), average METS (SW), sedentary time (SW) activity counts (AW), for average EE (MM; 17%) and activity level (KZ; 10%) compared to all other outcomes. All monitors identified Sundays as less active days. Differences were larger for motion related outcomes (SW 27%, MM 26%, AG 25%, AW 14%, RT3 13% lower), than for total EE (KZ 5%, average METS SW 8%, total EE MM 3%).  Conclusion: Walking related outcomes from activity monitors reflect daily variation in physical activity to the same extent. The outcomes from activity monitors assessing the same construct correlate moderately well whilst all monitors seem to be able to pick up less and more active days.  Funding IMI-JU PROactive GA#115011
Local Administration of PF-3512676 CpG-B Instigates Tumor-Specific CD8+ T-Cell Reactivity in Melanoma Patients
Authors: Barbara G. Molenkamp, Berbel J.R. Sluijter, Paul A.M. van Leeuwen, Saskia J.A.M. Santegoets, Sybren Meijer, Pepijn G.J.T.B. Wijnands, John B.A.G. Haanen, Alfons J.M. van den Eertwegh, Rik J. Scheper, Tanja D. de Gruijl
Journal: Clinical Cancer Research (2008)

Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. Local administration of PF-3512676 (formerly known as CpG 7909) has shown immunostimulatory effects of both dendritic cell and T-cell subsets in the melanoma SLN. Here, we set out to ascertain whether these PF-3512676-induced immunostimulatory effects translate into higher frequencies of melanoma-specific CD8(+) T cells.Twenty-four stage I to III melanoma patients were randomized to preoperative local administration of either PF-3512676 or saline. CD8(+) T cells from SLN and peripheral blood were tested for reactivity by IFN-gamma ELISPOT assay against several HLA-A1/A2/A3-restricted epitopes derived from various melanoma-associated antigens (MAA) in 21 of 24 enrolled patients. Frequencies of natural killer (NK) cells and frequencies and maturation state of dendritic cell subsets in the SLN were determined by flow cytometry.Melanoma-specific CD8(+) T-cell response rates against >1 MAA epitope in the SLN were 0 of 11 for the saline group versus 5 of 10 for the PF-3512676-administered group (P = 0.012). Of these 5 responding patients, 4 also had a measurable response to >1 MAA epitope in the blood. Increased frequencies in the SLN of both MAA-specific CD8(+) T cells and NK cells correlated to CpG-induced plasmacytoid dendritic cell maturation.These data show an increase in melanoma-specific CD8(+) T-cell frequencies as well as an increased effector NK cell rate after a single dose of PF-3512676 and thus support the utility of local PF-3512676 administration as adjuvant treatment in early-stage melanoma to try and halt metastatic spread.
Magnetic resonance imaging in patients with rheumatoid arthritis with complete remission treated with disease-modifying antirheumatic drugs or anti-tumour necrosis factor agents
Authors: M U Martinez-Martinez, E Cuevas-Orta, G Reyes-Vaca, L Baranda, R Gonzalez-Amaro, C Abud-Mendoza
Journal: Annals of the Rheumatic Diseases (2006)

with ankylosing spondylitis ATI developed within 24 weeks in association with undetectable serum trough infliximab levels, inefficacy of infliximab and infusion reactions.The number of patients, however, is too small to draw definite conclusions, but interestingly, these data point in the same direction as described previously in rheumatoid arthritis. 3 Lower serum trough infliximab levels could be explained by enhanced clearance because of immune complex formation between anti-infliximab antibodies and infliximab.To prevent ATI formation that might inhibit the efficacy of infliximab, it might be helpful to increase the dosage of infliximab (as occurs in treatment of rheumatoid arthritis with infliximab), to shorten the interval between infliximab infusions (as is currently the strategy in Crohn's disease) or to provide coadministration of other immunosuppressives (such as methotrexate).These data should be confirmed in a larger group of patients with ankylosing spondylitis to develop a more patient-specific treatment, which might predict the inefficacy of infliximab at an early stage and might prevent adverse reactions.
Role for miR-204 in human pulmonary arterial hypertension
Authors: Audrey Courboulin, Roxane Paulin, Nellie J. Giguère, Nehmé Saksouk, Tanya Perreault, Jolyane Meloche, Eric R. Paquet, Sabrina Biardel, Steeve Provencher, Jacques Côté, Martin J. Simard, Sébastien Bonnet
Journal: The Journal of Experimental Medicine (2011)

Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease.
Mortality in Infants Discharged From Neonatal Intensive Care Units in Georgia
Authors: David M. Allen
Journal: JAMA (1989)

Although neonatal intensive care units (NICUs) have contributed to advances in neonatal survival, little is known about the epidemiology of deaths that occur after NICU discharge. To determine mortality rates following NICU discharge, we used linked birth, death, and NICU records for infants born to Georgia residents from 1980 through 1982 and who were admitted to NICUs participating in the state's perinatal care network. Infants who died after discharge (n = 120) had a median duration of NICU hospitalization of 20 days (range, 1 to 148 days) and a median birth weight of 1983 g (range, 793 to 5159 g). The postdischarge mortality rate was 22.7 per 1000 NICU discharges. This rate is more than five times the overall postneonatal mortality rate for Georgia from 1980 to 1982. The most common causes of death were congenital heart disease (23%), sudden infant death syndrome (21%), and infection (13%). Demographic characteristics commonly associated with infant mortality were not strongly associated with the mortality following NICU discharge. (<i>JAMA</i>. 1989;261:1763-1766)
Randomized Phase III Study of Docetaxel Compared With Paclitaxel in Metastatic Breast Cancer
Authors: S.E. Jones, J. Erban, B. Overmoyer, G.T. Budd, L. Hutchins, E. Lower, L. Laufman, S. Sundaram, W.J. Urba, K.I. Pritchard, R. Mennel, D. Richards, S. Olsen, M.L. Meyers, P.M. Ravdin
Journal: Journal of Clinical Oncology (2005)

This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen.Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent.In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time.Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.
Comparison of Intracardiac Cell Transplantation: Autologous Skeletal Myoblasts Versus Bone Marrow Cells
Authors: Richard B. Thompson, Sitaram M. Emani, Bryce H. Davis, Ewout J. van den Bos, Yoshihisa Morimoto, Damian Craig, Donald Glower, Doris A. Taylor
Journal: Circulation (2003)

Background— Multiple cell types are being proposed for cardiac repair, but side-by-side comparisons are lacking. We tested the hypothesis that intracardiac transplantation of autologous bone marrow- or skeletal muscle-derived progenitor cells improve regional heart function to a similar degree. Methods and Results— Thirty-nine New Zealand White rabbits underwent cryoinjury of the left ventricle and simultaneous hind limb bone marrow aspiration or soleus muscle biopsy. Both muscle and bone marrow cells were expanded in vitro. After 2 weeks, 10 8 skeletal muscle (SM group) or bone marrow-derived progenitor cells (BM group) were injected into the cryoinjured region (SM: n=12; BM: n=8). Medium alone was injected into the remaining animals (Control: n=16). Regional systolic function was measured using micromanometry and sonomicrometry at baseline, before, and 4 weeks after cell injection. Cell treatment resulted in a similar degree of improvement in a derivative of stroke work in the SM and BM groups ( P =0.0026 and P =0.0085 versus Control, respectively). No significant difference was seen between BM and SM groups ( P =0.9). On histology, engrafted cells were found in all of the cell treated animals. Injected myoblasts formed myotubes or muscle cells throughout the scar that expressed slow and fast myosin heavy chain. A subset of bone marrow cells differentiated toward a myogenic phenotype, as indicated by expression of desmin and α-sarcomeric actin in the engrafted areas. Conclusion— Transplantation and myogenic differentiation of bone marrow-derived progenitor cells increased regional systolic heart function after myocardial injury to a similar degree as skeletal myoblasts.
Hepatitis B Virus Strains with Mutations in the Core Promoter in Patients with Fulminant Hepatitis
Authors: Shunichi Sato
Journal: Annals of Internal Medicine (1995)

Fulminant hepatitis B can be induced by hepatitis B virus (HBV) strains with mutations in the precore region that cannot encode hepatitis B e antigen (HBeAg). Such mutations are rarely seen in HBV DNA clones from patients with fulminant hepatitis B in the United States and France. Thus, the other mutations in HBV strains causing fulminant hepatitis B need to be identified.Retrospective clinical, serologic, and molecular biological studies of patients with fulminant hepatitis B.University and city hospitals in Japan.43 patients with fulminant hepatitis B.The precore region coding for a part of the HBeAg precursor and the core promoter regulating the transcription of precore messenger RNA were sequenced in HBV DNA clones.A point mutation from G to A at nucleotide 1896 in the precore region was detected in 519 (98%) of 529 HBV DNA clones from 38 patients. Two point mutations in the core promoter, from A to T at nucleotide 1762 and from G to A at nucleotide 1764, were detected in all 130 clones from the remaining 5 patients, who did not have mutations in the precore region, and in 20 (63%) of 32 clones from a patient with chronic hepatitis B who had transmitted HBV to 1 of these other 5 patients. Mutations in the core promoter were also detected in clones from 26 (68%) of the 38 patients with the precore mutation at nucleotide 1896. Neither HBeAg nor antibody to HBeAg was detected in 37 (90%) of the 41 patients tested.In Japan, fulminant hepatitis B is closely associated with HBV strains that do not produce HBeAg because of mutations in the precore region, which affect translation of HBeAg, or because of mutations in the core promoter, which affect transcription of the HBeAg coding region.
Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study
Authors: E. Díaz-Rubio, J. Sastre, A. Zaniboni, R. Labianca, H. Cortés-Funes, F. de Braud, C. Boni, M. Benavides, G. Dallavalle, M. Homerin
Journal: Annals of Oncology (1998)
Exercise testing in pulmonary sarcoidosis
Authors: C. Ingram, P. C Reid, R. Johnston
Journal: Thorax (1982)

The change in transfer coefficient (Kco) with increasing heart rate during exercise was studied in 25 normal subjects and in 21 patients with pulmonary sarcoidosis. The slope of the Kco response against heart rate was found to be 0·0053 mmol min<sup>−1</sup> kPa<sup>−1</sup> l<sup>−1</sup> per beat in the normal group but in many of the patients was two standard deviations or more below this normal slope, even when their routine function tests were normal. This response of Kco to exercise is a more sensitive index of changed function than more routine function tests in pulmonary sarcoidosis.