tbuckley/cabot-search huggingface dataset:
Notch Pathway Activity Identifies Cells with Cancer Stem Cell–like Properties and Correlates with Worse Survival in Lung Adenocarcinoma
Authors: Khaled A. Hassan, Luo Wang, Hasan Korkaya, Guoan Chen, Ivan Maillard, David G. Beer, Gregory P. Kalemkerian, Max S. Wicha
Journal: Clinical Cancer Research (2013)

The cancer stem cell theory postulates that tumors contain a subset of cells with stem cell properties of self-renewal, differentiation, and tumor initiation. The purpose of this study is to determine the role of Notch activity in identifying lung cancer stem cells.We investigated the role of Notch activity in lung adenocarcinoma using a Notch GFP reporter construct and a γ-secretase inhibitor (GSI), which inhibits Notch pathway activity.Transduction of lung cancer cells with Notch GFP reporter construct identified a subset of cells with high Notch activity (GFP-bright). GFP-bright cells had the ability to form more tumor spheres in serum-free media and were able to generate both GFP-bright and GFP-dim (lower Notch activity) cell populations. GFP-bright cells were resistant to chemotherapy and were tumorigenic in serial xenotransplantation assays. Tumor xenografts of mice treated with GSI had decreased expression of downstream effectors of Notch pathway and failed to regenerate tumors upon reimplantation in NOD/SCID mice. Using multivariate analysis, we detected a statistically significant correlation between poor clinical outcome and Notch activity (reflected in increased Notch ligand expression or decreased expression of the negative modulators), in a group of 443 patients with lung adenocarcinoma. This correlation was further confirmed in an independent group of 89 patients with adenocarcinoma in which Hes-1 overexpression correlated with poor overall survival.Notch activity can identify lung cancer stem cell-like population and its inhibition may be an appropriate target for treating lung adenocarcinoma.
Anti-monocyte chemoattractant protein 1 gene therapy attenuates experimental chronic pancreatitis induced by dibutyltin dichloride in rats
Authors: H F Zhao, T Ito, J Gibo, K Kawabe, T Oono, T Kaku, Y Arita, Q W Zhao, M Usui, K Egashira, H Nawata
Journal: Gut (2005)

Monocyte chemoattractant protein 1 (MCP-1) is a member of the C-C chemokine family and exerts strong chemoattractant activity in monocytes, macrophages, and lymphocytes. Rat pancreatic fibrosis induced by dibutyltin dichloride (DBTC) is considered to be an appropriate chronic pancreatitis model histologically and enzymatically, as has demonstrated in a previous study.We examined the effect of human dominant negative inhibitor of MCP-1 (mutant MCP-1) on progression of chronic pancreatitis induced by DBTC in a rat model.We used the experimental model of chronic pancreatitis induced by DBTC in rats. Mutant MCP-1 or empty plasmid at a dose of 50 microg/body weight was administrated into rat thigh muscles on days 4, 11, and 18 after administration of DBTC. On days 14 and 28, we evaluated the effect of mutant MCP-1 morphologically and biochemically.The mutant MCP-1 treated group inhibited early pancreatic inflammation and later pancreatic fibrosis histologically, and showed a decrease in serum MCP-1 concentration, intrapancreatic hydroxyproline, alpha-smooth muscle actin, and an increase in intrapancreatic amylase and protein content compared with the empty plasmid treated group. The mutant MCP-1 group also inhibited intrapancreatic mRNA expression of cytokines and chemokines.: Our findings suggest that monocyte/macrophage recruitment and the systemic MCP-1 signal pathway contribute to progression of chronic pancreatitis, and that blockade of MCP-1 may suppress the development of pancreatic fibrosis.
The effect of adjuvant prednisone combined with CMF on patterns of relapse and occurrence of second malignancies in patients with breast cancer
Authors: G. Marini, S. Murray, A. Goldhirsch, R.D. Gelber, M. Castiglione-Gertsch, K.N. Price, M.H.N. Tattersall, C.-M. Rudenstam, J. Collins, J. Lindtner, F. Cavalli, H. Cortés-Funes, A. Gudgeon, J.F. Forbes, E. Galligioni, A.S. Coates, H.-J. Senn
Journal: Annals of Oncology (1996)
A Gene Expression Signature Predicts Survival of Patients with Stage I Non-Small Cell Lung Cancer
Authors: Yan Lu, William Lemon, Peng-Yuan Liu, Yijun Yi, Carl Morrison, Ping Yang, Zhifu Sun, Janos Szoke, William L Gerald, Mark Watson, Ramaswamy Govindan, Ming You
Journal: PLoS Medicine (2006)

Lung cancer is the leading cause of cancer-related death in the United States. Nearly 50% of patients with stages I and II non-small cell lung cancer (NSCLC) will die from recurrent disease despite surgical resection. No reliable clinical or molecular predictors are currently available for identifying those at high risk for developing recurrent disease. As a consequence, it is not possible to select those high-risk patients for more aggressive therapies and assign less aggressive treatments to patients at low risk for recurrence.In this study, we applied a meta-analysis of datasets from seven different microarray studies on NSCLC for differentially expressed genes related to survival time (under 2 y and over 5 y). A consensus set of 4,905 genes from these studies was selected, and systematic bias adjustment in the datasets was performed by distance-weighted discrimination (DWD). We identified a gene expression signature consisting of 64 genes that is highly predictive of which stage I lung cancer patients may benefit from more aggressive therapy. Kaplan-Meier analysis of the overall survival of stage I NSCLC patients with the 64-gene expression signature demonstrated that the high- and low-risk groups are significantly different in their overall survival. Of the 64 genes, 11 are related to cancer metastasis (APC, CDH8, IL8RB, LY6D, PCDHGA12, DSP, NID, ENPP2, CCR2, CASP8, and CASP10) and eight are involved in apoptosis (CASP8, CASP10, PIK3R1, BCL2, SON, INHA, PSEN1, and BIK).Our results indicate that gene expression signatures from several datasets can be reconciled. The resulting signature is useful in predicting survival of stage I NSCLC and might be useful in informing treatment decisions.
HEMOGLOBIN LABELED BY RADIOACTIVE LYSINE
Authors: W. F. Bale, C. L. Yuile, L. DeLaVergne, L. L. Miller, G. H. Whipple
Journal: The Journal of Experimental Medicine (1949)

A dog, doubly depleted of blood cells and plasma proteins, was fed dl-lysine labeled with C(14) in the epsilon carbon position. In the first 8 hours 28 per cent of the administered C(14) was excreted in the urine; in the first 72 hours, 35 per cent. Twenty-four hours after feeding, 4.2 per cent of the fed C(14) was circulating in the plasma, decreasing to 1 per cent at the end of 17 days. The C(14) content of the blood cells increased from 1 per cent at 24 hours to 5.5 per cent in 5 days and 6.8 per cent in 22 days. Evidence based on the rate of decrease of the C(14) content of circulating blood cells is presented indicating an average life of 115 days for the erythrocyte protein as an entity not interchanging with extracellular constituents. This corresponds closely to the life span of the dog erythrocyte, 112 to 133 days according to the best evidence otherwise available and indicates that this experiment has actually measured the life span of the dog erythrocyte. Following breakdown of blood erythrocytes the protein comprising them is not used preferentially for the formation of new erythrocytes.
Prenatal acetaminophen exposure and risk of wheeze at age 5 years in an urban low-income cohort
Authors: M. S. Perzanowski, R. L. Miller, D. Tang, D. Ali, R. S. Garfinkel, G. L. Chew, I. F. Goldstein, F. P. Perera, R. G. Barr
Journal: Thorax (2009)

<h3>Background</h3> Acetaminophen has been associated with asthma and is in part metabolised via the glutathione pathway. Inner-city minority children have high asthma morbidity and a relatively high frequency of a minor allele variant in the glutathione S transferase <i>Pi</i> gene (GSTP1). We hypothesised that prenatal acetaminophen exposure would predict wheeze at age 5 years in an inner-city minority cohort and examined whether this association was modified by common polymorphisms in genes related to the glutathione pathway. <h3>Methods</h3> An ongoing population-based birth cohort study of Dominican Republic and African-American children in New York prospectively assessed the use of analgesics during pregnancy and current wheeze at age 5 years in 301 children. Genotyping was conducted for GST polymorphisms. Binomial regression was used to adjust for potential confounders including postnatal acetaminophen use. <h3>Results</h3> 34% of mothers reported acetaminophen use during pregnancy and 27% of children had current wheeze at 5 years. Prenatal exposure to acetaminophen predicted current wheeze (multivariate relative risk 1.71; 95% CI 1.20 to 2.42; p=0.003), and the risk increased monotonically with increasing number of days of prenatal acetaminophen exposure (p trend &lt;0.001). 68% of children had at least one copy of the GSTP1 minor allele (Val). The risk of wheeze was modified by GSTP1 (additive interaction p=0.009) and was observed only among children with the GSTP1 minor allele. <h3>Conclusions</h3> Prenatal exposure to acetaminophen predicted wheeze at age 5 years in an inner-city minority cohort. The risk was modified by a functional polymorphism in GSTP1, suggesting a mechanism involving the glutathione pathway.
Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials
Authors: J. Pickup
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To compare glycaemic control and insulin dosage in people with type 1 diabetes treated by continuous subcutaneous insulin infusion (insulin infusion pump therapy) or optimised insulin injections. <b>Design:</b> Meta-analysis of 12 randomised controlled trials. <b>Participants:</b> 301 people with type 1 diabetes allocated to insulin infusion and 299 allocated to insulin injections for between 2.5 and 24 months. <b>Main outcome measures:</b> Glycaemic control measured by mean blood glucose concentration and percentage of glycated haemoglobin. Total daily insulin dose. <b>Results:</b> Mean blood glucose concentration was lower in people receiving continuous subcutaneous insulin infusion compared with those receiving insulin injections (standardised mean difference 0.56, 95% confidence interval 0.35 to 0.77), equivalent to a difference of 1.0 mmol/l. The percentage of glycated haemoglobin was also lower in people receiving insulin infusion (0.44, 0.20 to 0.69), equivalent to a difference of 0.51%. Blood glucose concentrations were less variable during insulin infusion. This improved control during insulin infusion was achieved with an average reduction of 14% in insulin dose (difference in total daily insulin dose 0.58, 0.34 to 0.83), equivalent to 7.58 units/day. <b>Conclusions:</b> Glycaemic control is better during continuous subcutaneous insulin infusion compared with optimised injection therapy, and less insulin is needed to achieve this level of strict control. The difference in control between the two methods is small but should reduce the risk of microvascular complications. <h3>What is already known on this topic</h3> Continuous subcutaneous insulin infusion (insulin pump therapy) produces good long term control of blood glucose concentrations in people with type 1 diabetes Control of blood glucose concentration is substantially better on pump therapy than conventional (non-optimised) injection therapy It is unclear how glycaemic control on pump therapy compares with modern optimised insulin injection regimens <h3>What this study adds</h3> Though glycaemic control was better during continuous subcutaneous insulin infusion than optimised insulin injection therapy, the difference was relatively small Continuous subcutaneous insulin infusion is an effective form of intensive insulin therapy that should lower the risk of microvascular complications Insulin pump therapy is unnecessary for most people with type 1 diabetes and should be reserved for those with special problems with optimised insulin injections
Cathepsin L is essential for onset of autoimmune diabetes in NOD mice
Authors: R. Maehr
Journal: Journal of Clinical Investigation (2005)

Lysosomal proteases generate peptides presented by class II MHC molecules to CD4+ T cells. To determine whether specific lysosomal proteases might influence the outcome of a CD4+ T cell-dependent autoimmune response, we generated mice that lack cathepsin L (Cat L) on the autoimmune diabetes-prone NOD inbred background. The absence of Cat L affords strong protection from disease at the stage of pancreatic infiltration. The numbers of I-A(g7)-restricted CD4+ T cells are diminished in Cat L-deficient mice, although a potentially diabetogenic T cell repertoire persists. Within the CD4+ T cell compartments of Cat L-deficient mice, there is an increased proportion of regulatory T cells compared with that in Cat L-sufficient littermates. We suggest that it is this displaced balance of regulatory versus aggressive CD4+ T cells that protects Cat L-deficient mice from autoimmune disease. Our results identify Cat L as an enzyme whose activity is essential for the development of type I diabetes in the NOD mouse.
Response to Comment on Balkau et al. Factors Associated With Weight Gain in People With Type 2 Diabetes Starting on Insulin. Diabetes Care 2014;37:2108–2113
Authors: Beverley Balkau, Philip D. Home, Maya Vincent, Michel Marre, Nick Freemantle
Journal: Diabetes Care (2014)

We very much concur with Nick Finer that weight is not everything (1). Finer argues that changes in body composition and not just change in weight are important, and he concludes that in any case, the benefits of insulin therapy on metabolic control must be balanced against penalties from weight gain.

The improvement seen in HbA1c after treatment of people with type 2 diabetes by insulin is of fundamental importance. In the CREDIT study, …
Detection of tumor necrosis factor‐α in bone marrow plasma and peripheral blood plasma from patients with aplastic anemia
Authors: John C. Schultz, Nasrollah T. Shahidi
Journal: American Journal of Hematology (1994)

Abstract Plasma levels of interferon‐gamma (IFN‐γ) and tumor necrosis factor‐alpha (TNF‐α) were determined in healthy individuals and patients with aplastic anemia (ApAn). IFN‐γ was not detected in normal peripheral blood plasma (PBP) or bone marrow plasma (BMP) and was present in PBP from only 2 of 22 patients and in BMP from 1 of 14 patients and the levels were low (&lt; 1.5 U/ml). Elevated levels of TNF‐α were present in BMP and PBP from patients but not in control (healthy donor) PBP and BMP. Eleven of twenty‐four patients had elevated levels of TNF‐α in their PBP and 6 of 13 patients had detectable levels of TNF‐α in their BMP. Only one of the 14 healthy control donors had detectable TNF‐α and the level was very low (7 pg/ml), while 13 of the 27 ApAn patients had detectable TNF‐α ( P = .009, chi‐square test). Not surprisingly, the centers of the distributions of TNF‐α concentrations of the controls and ApAn patients differed significantly ( P &lt; .017 for control and patient PBP and P &lt; .056 for control and patient BMP, Wilcoxon rank‐sum test). Spontaneous production of IFN‐γ and TNF‐α by cultured bone marrow mononuclear cells was observed in four of seven patients but not in the six healthy controls ( P = 0.026). Spontaneous production of IFN‐γ and TNF‐α by cultured peripheral blood mononuclear cells from patients and controls was however similar. Phytohemagglutinin (PHA)‐induced production of IFN‐γ and TNF‐α by cultured mononuclear cells did not differ significantly between ApAn patients and normal controls. The significance of overproduction of TNF‐α in the pathophysiology of ApAn is discussed. © 1994 Wiley‐Liss, Inc.
Efficacy and safety of nebulized glycopyrrolate (EP-101) for administration using high efficiency nebulizer in patients with COPD
Authors: Dave Singh, Brian Leaker, Ahmet Tutuncu
Journal: European Respiratory Journal (2011)

Introduction:  EP-101 is a long-acting muscarinic antagonist formulation of glycopyrrolate optimized for nebulization in development for the treatment of COPD. This dose-ranging study assessed the efficacy and safety of single doses of nebulized EP-101 in patients with COPD.   Methods:  This was a randomized, double-blind, placebo-controlled, 6-period cross-over study in 42 patients with moderate-to-severe COPD. Patients were randomized to receive single doses of EP-101 (12.5, 50, 100, 200 and 400 μg) and placebo via a high efficiency nebulizer, with a 5-12 days of washout between treatments. Plasma PK was assessed in a subset of patients.   Results:  The study patients had a mean age of 62 years, COPD duration of 7.5 years, post-bronchodilator FEV 1  of 54% predicted normal, FEV 1 /FVC of 44.9%, FEV 1  reversibility of 27.3%. All treatments were well tolerated with similar AE rates between all treatments and no clinically relevant changes in vital signs (heart rate, systolic and diastolic blood pressure) and ECG parameters including QTc interval. Following treatment with EP-101 at all doses there was a rapid bronchodilatory response at 5 minutes. Statistically significant improvements in mean change in trough FEV 1  at 24 hours were reported at doses ≥50 μg compared with placebo (37mL, 72mL, 104mL, 118mL and 95mL at doses 12.5, 50, 100, 200 and 400 μg, respectively).   Conclusion:  Single doses of EP-101 ranging from 12.5 μg to 400 μg were well tolerated. EP-101 demonstrated rapid onset of bronchodilation with clinically meaningful improvements in lung function over 24 hours following nebulization in patients with COPD.  Funded by Elevation Pharmaceuticals Inc.
A Critical Role for Cd40–Cd40 Ligand Interactions in Amplification of the Mucosal Cd8 T Cell Response
Authors: Leo Lefrançois, Sara Olson, David Masopust
Journal: The Journal of Experimental Medicine (1999)

The role of CD40 ligand (CD40L) in CD8 T cell activation was assessed by tracking antigen-specific T cells in vivo using both adoptive transfer of T cell receptor transgenic T cells and major histocompatibility complex (MHC) class I tetramers. Soluble antigen immunization induced entry of CD8 cells into the intestinal mucosa and cytotoxic T lymphocyte (CTL) differentiation, whereas CD8 cells in secondary lymphoid tissue proliferated but were not cytolytic. Immunization concurrent with CD40L blockade or in the absence of CD40 demonstrated that accumulation of CD8 T cells in the mucosa was CD40L dependent. Furthermore, activation was mediated through CD40L expressed by the CD8 cells, since inhibition by anti-CD40L monoclonal antibodies occurred after adoptive transfer to CD40L-deficient mice. However, mucosal CD8 T cells in normal and CD40−/− mice were equivalent killers, indicating that CD40L was not required for CTL differentiation. Appearance of virus-specific mucosal, but not splenic, CD8 cells also relied heavily on CD40–CD40L interactions. The mucosal CTL response of transferred CD8 T cells was MHC class II and interleukin 12 independent. The results established a novel pathway of direct CD40L-mediated CD8 T cell activation.
Serum aminoterminal type III procollagen peptide reflects repair after acute myocardial infarction.
Authors: L T Jensen, K Hørslev-Petersen, P Toft, K D Bentsen, P Grande, E E Simonsen, I Lorenzen
Journal: Circulation (1990)

In 16 patients with acute myocardial infarction and in 15 controls, procollagen type III aminoterminal peptide in serum (PIIINP) was measured consecutively. Serum PIIINP was increased on the second to third postinfarction day (p less than 0.01) and remained elevated for more than 4 months. Peak values were observed on the third to seventh postinfarction day. The individual peak changes were correlated to infarction size calculated from serum CK-MB and serum lactate dehydrogenase (p = 0.60, p = 0.02). The changes in distribution of PIIINP-related antigens in serum after gel chromatography were similar to changes observed during wound healing in humans. PIIINP is cleaved off procollagen type III during the biosynthesis of type III collagen, which characterizes the early stages of repair and inflammation. Our findings suggest that serum PIIINP reflects the repair processes and scar formation following acute myocardial infarction. The serum PIIINP alterations in acute myocardial infarction differ essentially from the changes in myocardial enzymes reflecting myocardial injury. Serum PIIINP may therefore provide new and clinically relevant information on the healing of myocardial infarction.
CELL-BOUND RECEPTORS FOR ALLOANTIGENS ON NORMAL LYMPHOCYTES
Authors: Hans Binz, Jean Lindenmann, Hans Wigzell
Journal: The Journal of Experimental Medicine (1974)

Antialloantibodies were prepared in F1 hybrid rats by immunization with alloantibodies from one parent raised against antigens of the other parent. The Ig fraction of such antialloantibodies was iodinated and used to investigate the nature of idiotype-carrying normal lymphoid cells. Lymphoid cell populations of the proper genotype fixed radioactive antialloantibody in proportion to their B-cell content. Activated T-cell populations, when depleted of B cells, did not fix significant amounts of radioactivity. Idiotype-carrying cells were sensitive to rabbit antirat Ig serum lysis and to antialloantiserum lysis, but not to rabbit anti-T-serum lysis. Also, the normal idiotype-containing B cell could be shown to have the expected antigen-binding specificity of its receptor. This was shown by the use of fibroblast cell monolayers that adsorbed specifically those cells capable of fixing the proper antialloantibody.
E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment
Authors: Tomokatsu Ikawa, Hiroshi Kawamoto, Ananda W. Goldrath, Cornelis Murre
Journal: The Journal of Experimental Medicine (2006)

The helix-loop-helix protein, E47, is essential for both B- and T-lineage development. Here we demonstrate that in vitro E47 and Notch signaling act in concert to promote T cell development from fetal hematopoieitic progenitors and to restrain development into the natural killer and myeloid cell lineages. The expression of an ensemble of genes associated with Notch signaling is activated by E47, and additionally, Notch signaling and E47 act in parallel pathways to induce a T lineage–specific program of gene expression. Enforced expression of the intracellular domain of Notch rescues the developmental arrest at the T cell commitment stage in E2A-deficient fetal thymocytes. Finally, we demonstrate that regulation of Hes1 expression by Notch signaling and E47 is strikingly similar to that observed during Drosophila melanogaster sensory development. Based on these observations, we propose that in developing fetal thymocytes E47 acts to induce the expression of an ensemble of genes involved in Notch signaling, and that subsequently E47 acts in parallel with Notch signaling to promote T-lineage maturation.