tbuckley/cabot-search huggingface dataset:
Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition
Authors: Yuji Piao, Ji Liang, Lindsay Holmes, Verlene Henry, Erik Sulman, John F. de Groot
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy. Experimental Design: Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance. Results: Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared with untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene-set enrichment analysis showed that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11- and U87-resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells which had higher invasion rates in vitro compared with their respective parental cell lines. Conclusions: Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy. Clin Cancer Res; 19(16); 4392–403. ©2013 AACR.
Cytonuclear Interactions and Relaxed Selection Accelerate Sequence Evolution in Organelle Ribosomes
Authors: Daniel B. Sloan, Deborah A. Triant, Martin Wu, Douglas R. Taylor
Journal: Molecular Biology and Evolution (2013)

Many mitochondrial and plastid protein complexes contain subunits that are encoded in different genomes. In animals, nuclear-encoded mitochondrial proteins often exhibit rapid sequence evolution, which has been hypothesized to result from selection for mutations that compensate for changes in interacting subunits encoded in mutation-prone animal mitochondrial DNA. To test this hypothesis, we analyzed nuclear genes encoding cytosolic and organelle ribosomal proteins in flowering plants. The model angiosperm genus Arabidopsis exhibits low organelle mutation rates, typical of most plants. Nevertheless, we found that (nuclear-encoded) subunits of organelle ribosomes in Arabidopsis have higher amino acid sequence polymorphism and divergence than their counterparts in cytosolic ribosomes, suggesting that organelle ribosomes experience relaxed functional constraint. However, the observed difference between organelle and cytosolic ribosomes was smaller than in animals and could be partially attributed to rapid evolution in N-terminal organelle-targeting peptides that are not involved in ribosome function. To test the role of organelle mutation more directly, we used transcriptomic data from an angiosperm genus (Silene) with highly variable rates of organelle genome evolution. We found that Silene species with unusually fast-evolving mitochondrial and plastid DNA exhibited increased amino acid sequence divergence in ribosomal proteins targeted to the organelles but not in those that function in cytosolic ribosomes. Overall, these findings support the hypothesis that rapid organelle genome evolution has selected for compensatory mutations in nuclear-encoded proteins. We conclude that coevolution between interacting subunits encoded in different genomic compartments within the eukaryotic cell is an important determinant of variation in rates of protein sequence evolution.
Superoxide Dismutase Improves Gas Exchange and Pulmonary Hemodynamics in Premature Lambs
Authors: John P. Kinsella, Thomas A. Parker, Jonathan M. Davis, Steven H. Abman
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Oxidant stress may increase the severity of respiratory distress syndrome (RDS) after premature birth by altering vasoreactivity and increasing lung edema, but the acute effects of superoxide dismutase (SOD) treatment on gas exchange, lung compliance (CL), and pulmonary vascular resistance in premature animals with RDS are unknown.We studied the effects of intratracheal recombinant human SOD treatment (rhSOD) on gas exchange, CL, and pulmonary hemodynamics in 46 premature lambs with RDS.After C-section delivery, lambs were randomly assigned to treatment with SOD (2.5-10 mg/kg) with or without inhaled nitric oxide (iNO, 5 ppm), and mechanically ventilated for 4 hours. At the end of the study, pressure-volume curves and wet-dry lung weights were measured to assess CL and edema, respectively.Despite an initial rise in Pa(O(2)), Pa(O(2)) in control animals progressively declined over the 4-hour treatment period (Pa(O(2)) = 25.0 +/- 7.5 mm Hg at 4 hours). In comparison with control animals, early treatment with SOD at 5 and 10 mg/kg improved Pa(O(2)) at 4 hours (167 +/- 44 and 269 +/- 33 mm Hg, respectively; p < 0.05 vs. control), but did not decrease lung edema or improve CL. In contrast, late treatment with SOD did not improve Pa(O(2)). Treatment with iNO increased Pa(O(2)) (196 +/- 22 vs. 25 +/- 8 mm Hg, control animals; p < 0.01), but the response to iNO was not augmented by combined therapy (SOD + iNO). After 4 hours of ventilation with FI(O(2)) = 1.00, rhSOD treatment lowered pulmonary vascular resistance compared with control animals.Early intratracheal rhSOD treatment improves oxygenation in premature lambs with RDS and prevents the development of pulmonary hypertension.
The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome
Authors: Gerald W. Dorn, Richard N. Kitsis
Journal: Circulation Research (2014)

Mitochondrial research is experiencing a renaissance, in part, because of the recognition that these endosymbiotic descendants of primordial protobacteria seem to be pursuing their own biological agendas. Not only is mitochondrial metabolism required to produce most of the biochemical energy that supports their eukaryotic hosts (us) but mitochondria can actively (through apoptosis and programmed necrosis) or passively (through reactive oxygen species toxicity) drive cellular dysfunction or demise. The cellular mitochondrial collective autoregulates its population through biogenic renewal and mitophagic culling; mitochondrial fission and fusion, 2 components of mitochondrial dynamism, are increasingly recognized as playing central roles as orchestrators of these processes. Mitochondrial dynamism is rare in striated muscle cells, so cardiac-specific genetic manipulation of mitochondrial fission and fusion factors has proven useful for revealing noncanonical functions of mitochondrial dynamics proteins. Here, we review newly described functions of mitochondrial fusion/fission proteins in cardiac mitochondrial quality control, cell death, calcium signaling, and cardiac development. A mechanistic conceptual paradigm is proposed in which cell death and selective organelle culling are not distinct processes, but are components of a unified and integrated quality control mechanism that exerts different effects when invoked to different degrees, depending on pathophysiological context. This offers a plausible explanation for seemingly paradoxical expression of mitochondrial dynamics and death factors in cardiomyocytes wherein mitochondrial morphometric remodeling does not normally occur and the ability to recover from cell suicide is severely limited.
RANK ligand and osteoprotegerin: emerging roles in mucosal inflammation
Authors: A J Ashcroft
Journal: Gut (2005)

We read with interest the study by Byrne and colleagues ( Gut 2005; 54 :78–86) outlining the significant therapeutic opportunities provided by manipulation of the RANK/RANK ligand (RANKL)/osteoprotegerin (OPG) system using recombinant Fc-OPG. There are, however, a number of physiological effects of OPG that were not discussed and which demonstrate the depth of influence of the RANK/RANKL/OPG system on both inflammatory disease and possibly immune surveillance …
Endogenous Two-Photon Fluorescence Imaging Elucidates Metabolic Changes Related to Enhanced Glycolysis and Glutamine Consumption in Precancerous Epithelial Tissues
Authors: Antonio Varone, Joanna Xylas, Kyle P. Quinn, Dimitra Pouli, Gautham Sridharan, Margaret E. McLaughlin-Drubin, Carlo Alonzo, Kyongbum Lee, Karl Münger, Irene Georgakoudi
Journal: Cancer Research (2014)

Alterations in the balance between different metabolic pathways used to meet cellular bioenergetic and biosynthetic demands are considered hallmarks of cancer. Optical imaging relying on endogenous fluorescence has been used as a noninvasive approach to assess tissue metabolic changes during cancer development. However, quantitative correlations of optical assessments with variations in the concentration of relevant metabolites or in the specific metabolic pathways that are involved have been lacking. In this study, we use high-resolution, depth-resolved imaging, relying entirely on endogenous two-photon excited fluorescence in combination with invasive biochemical assays and mass spectrometry to demonstrate the sensitivity and quantitative nature of optical redox ratio tissue assessments. We identify significant differences in the optical redox ratio of live, engineered normal and precancerous squamous epithelial tissues. We establish that while decreases in the optical redox ratio are associated with enhanced levels of glycolysis relative to oxidative phosphorylation, increases in glutamine consumption to support energy production are associated with increased optical redox ratio values. Such mechanistic insights in the origins of optical metabolic assessments are critical for exploiting fully the potential of such noninvasive approaches to monitor and understand important metabolic changes that occur in live tissues at the onset of cancer or in response to treatment.
Effects of Short Daily versus Conventional Hemodialysis on Left Ventricular Hypertrophy and Inflammatory Markers
Authors: Juan Carlos Ayus, M. Reza Mizani, Steven G. Achinger, Ravi Thadhani, Alan S. Go, Shuko Lee
Journal: Journal of the American Society of Nephrology (2005)

Left ventricular hypertrophy (LVH) and inflammation independently increase risk for death in people who receive hemodialysis. A nonrandomized, controlled trial was conducted of the effect of short daily (6 sessions/wk of 3 h each) or conventional (three sessions/wk of 4 h each) hemodialysis on LVH and inflammatory factors. A total of 26 short daily hemodialysis and 51 matched conventional hemodialysis patients were enrolled, and baseline and 12-mo measures of echocardiographic left ventricular mass index (LVMI), serum C-reactive protein (CRP), serum calcium and phosphorus, and erythropoietin resistance index were collected. Baseline characteristics were similar between groups except that hemoglobin and serum calcium were lower and serum phosphorus was higher in the short daily hemodialysis group. At 12-mo follow-up, short daily hemodialysis patients experienced a 30% decrease in LVMI (154 +/- 33 to 108 +/- 25; P < 0.0001). After adjustment for potential confounders, short daily hemodialysis (beta = -41.63, P = 0.03) and percentage decrease in serum phosphorus (beta = -0.12, P = 0.04) predicted a 12-mo decrease in LVMI. Among short daily hemodialysis patients, there were significant reductions in median CRP levels [1.22 interquartile range (IQR) (0.37 to 3.70) to 0.05 IQR (0.05 to 1.17); P < 0.01] and erythropoietin resistance index [19.5 IQR (8.6 to 37.6) to 10.5 IQR (5.5 to 14.6); P < 0.001]. There were no significant changes in LVMI, CRP, or erythropoietin resistance index in the conventional hemodialysis group. Short daily hemodialysis is associated with improved fluid and phosphorus management and a reduction in LVH and inflammatory factors compared with conventional hemodialysis. Future trials are needed to determine whether short daily hemodialysis can reduce morbidity and mortality in this high-risk population.
Maximal exercise studies in Scottish athletes.
Authors: A. G. Leitch, L. Clancy
Journal: British Journal of Sports Medicine (1976)

We have studied maximal oxygen uptake, maximal heart rate, maximal exercise ventilation and the ventilatory response to exercise in 24 male and 14 female Scottish athletes. The values for maximal oxygen uptake are similar to those reported in other international studies. In eight athletes repeat measurements of maximal oxygen uptake 7-11 months after the initial study showed no change from the initial values. The values for the ventilatory response to exercise in our athletes were normal. The relationship is discussed between maximal oxygen uptake and ventilatory responses to exercise, hypoxia and hypercapnia and it is suggested that these may be related to athletic event.
PREPARATION AND FURTHER CHARACTERIZATION OF THE MN GLYCOPROTEIN OF HUMAN ERYTHROCYTE MEMBRANES
Authors: Hartwig Cleve, Hideo Hamaguchi, Thomas Hütteroth
Journal: The Journal of Experimental Medicine (1972)

Human erythrocyte membrane glycoproteins were solubilized and recovered in the aqueous phase after extraction of red cell ghosts with a mixture of chloroform and methanol. The major glycoprotein, the so-called MN glycoprotein, was prepared from this phase by gel filtration on Sepharose 4B columns in 6 M guanidine hydrochloride. By SDS-acrylamide gel electrophoresis the MN glycoproteins from the three major genetic types, MM, MN, and NN, were found to be relatively free from minor glycoprotein contaminants. The carbohydrate and amino acid composition did not reveal significant differences between the three MN genotypes. The specific activities of the purified glycoproteins were determined for inhibition of agglutinating anti-M and anti-N rabbit antisera and for inhibition of myxovirus hemagglutination. It was, furthermore, established that the purified MN glycoproteins contain a receptor for Phaseolus vulgaris phytohemagglutination. The red cell MN glycoprotein inhibits partially lymphocyte stimulation induced by unfractionated Phaseolus vulgaris phytohemagglutinin; the red cell MN glycoprotein does not influence the lymphocyte stimulation induced by purified Phaseolus vulgaris mitogen.
Patient self-management of continuous subcutaneous insulin infusion
Authors: P. Hamet, G. Abarca, D. Lopez, M. Hamet, M. Bourque, J. M. Peyronnard, L. Charron, P. Larochelle
Journal: Diabetes Care (1982)

Continuous subcutaneous insulin infusion (CSII) is one of the ways to control blood glucose for prolonged periods. This study was undertaken to establish the long-term feasibility and efficacy of CSII with patient self-management. Patients were instructed to maintain their calorie and carbohydrate intake. Basal infusion of insulin, representing 50% of the total pre-CSII dose, was supplemented by boluses of insulin based on carbohydrate intake for each meal. With this type of regimen, blood glucose and M-values were easily normalized during the physician-directed periods. This study demonstrated that near-normalization of blood glucose, M-values, and glycosylated hemoglobin was maintained after a 1 1/2-yr period of patient self-management. We attributed this successful management in part to the protocol used, in which boluses were related solely to carbohydrate intake while basal insulin was adjusted according to fasting blood glucose. The chronic normalization of blood glucose resulted in improvement of platelet function as witnessed by responsiveness to antiaggregating (PGE1) and aggregating (epinephrine) agents. An improvement was noticed in doppler measurement of ankle-arm blood pressure and a near-normalization of nerve latency and conductivity was observed.
Caveat Medicus: Consequences of Federal Investigations of Marketing Activities of Pharmaceutical Suppliers of Prostate Cancer Drugs
Authors: June M. McKoy, E. Allison Lyons, Eniola Obadina, Kenneth Carson, A. Simon Pickard, Paul Schellhammer, David McLeod, Cynthia E. Boyd, Norene McWilliams, Oliver Sartor, Glen T. Schumock, Kathryn McCaffery, Charles L. Bennett
Journal: Journal of Clinical Oncology (2005)

In the course of recent health care fraud investigations against TAP Pharmaceuticals (Lake Forest, IL) and AstraZeneca International (London, United Kingdom), each pled guilty to one violation of the Prescription Drug Marketing Act, settled claims related to alleged violations of the False Claims Act without admitting guilt, and paid fines, settlements for liabilities, and reimbursements of dollar 850 million and dollar 355 million, respectively. In a unique aspect of these cases, federal investigators brought criminal charges against 14 TAP employees and investigated the billing practices of several urologists. These investigations resulted in guilty pleas from both urologists and industry employees relative to the Prescription Drug Marketing Act or the False Claims Act and probationary sentences with payments of fines and restitution to the government for urologists who cooperated with federal investigations. One uncooperative urologist was found guilty of violating the Federal False Claims Act and sentenced to 6 months of home arrest, excluded from Medicare for 5 years, required to provide 600 hours of free medical care to indigent patients and patients covered by Medicare or Medicaid, and paid fines and restitution to the government. The cases against TAP and AstraZeneca have been followed by federal and state investigations of allegedly illegal marketing practices of other pharmaceutical firms and have resulted in negotiated settlements of dollar 3.8 billion and dollar 71.5 million, respectively. Believing that an Average Wholesale Price-based reimbursement system was an important driving factor for these marketing activities, Medicare has shifted to an Average Sales Price-based reimbursement system. This is expected to greatly impact the practice of outpatient oncology nationwide.
In vivo sites and cellular mechanisms of T reg cell–mediated suppression
Authors: Alexander Y. Rudensky, Daniel J. Campbell
Journal: The Journal of Experimental Medicine (2006)

Regulatory CD4 T (T reg) cells control immune responses to self-antigens and pathogens. However, where T reg cells act to curtail effector T cells in vivo and what stage of effector T cell activation or differentiation is targeted by T reg cells remain unknown. Furthermore, a requirement for direct effector T cell–T reg cell contact in vivo has not been ascertained. Varying answers to these important questions have been provided by several new studies.
Epicutaneous challenge of orally immunized mice redirects antigen-specific gut-homing T cells to the skin
Authors: Michiko K. Oyoshi, Abdallah Elkhal, Jordan E. Scott, Marc-Andre Wurbel, Jason L. Hornick, James J. Campbell, Raif S. Geha
Journal: Journal of Clinical Investigation (2011)

Patients with atopic dermatitis (AD) often suffer from food allergy and develop flares upon skin contact with food allergens. However, it is unclear whether T cells sensitized to allergens in the gut promote this skin inflammation. To address this question, we orally immunized WT mice and mice lacking the skin-homing chemokine receptor Ccr4 (Ccr4-/- mice) with OVA and then challenged them epicutaneously with antigen. Allergic skin inflammation developed in the WT mice but not in the mutants and was characterized by epidermal thickening, dermal infiltration by eosinophils and CD4+ T cells, and upregulation of Th2 cytokines. T cells purified from mesenteric lymph nodes (MLNs) of orally immunized WT mice transferred allergic skin inflammation to naive recipients cutaneously challenged with antigen, but this effect was lost in T cells purified from Ccr4-/- mice. In addition, the ability of adoptively transferred OVA-activated T cells to home to the skin following cutaneous OVA challenge was ablated in mice that lacked lymph nodes. These results indicate that cutaneous exposure to food antigens can reprogram gut-homing effector T cells in LNs to express skin-homing receptors, eliciting skin lesions upon food allergen contact in orally sensitized AD patients.
Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study
Authors: Kaoru Kubota, Masaaki Kawahara, Mitsumasa Ogawara, Yutaka Nishiwaki, Kiyoshi Komuta, Koichi Minato, Yuka Fujita, Satoshi Teramukai, Masanori Fukushima, Kiyoyuki Furuse
Journal: The Lancet Oncology (2008)
Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA trials
Authors: Aimée R Kreimer, Frank Struyf, Maria Rowena Del Rosario-Raymundo, Allan Hildesheim, S Rachel Skinner, Sholom Wacholder, Suzanne M Garland, Rolando Herrero, Marie-Pierre David, Cosette M Wheeler
Journal: The Lancet Oncology (2015)
Specialist Nurse–Led Clinics to Improve Control of Hypertension and Hyperlipidemia in Diabetes
Authors: James M. Mason, Nick Freemantle, J. Martin Gibson, John P. New
Journal: Diabetes Care (2005)

OBJECTIVE—To determine the cost-effectiveness of specialist nurse–led clinics provided to improve lipid and blood pressure control in diabetic patients receiving hospital-based care. RESEARCH DESIGN AND METHODS—A policy of targeting improved care through specialist nurse–led clinics is evaluated using a novel method, linking the cost-effectiveness of antihypertensive and lipid-lowering treatments with the cost and level of behavioral change achieved by the specialist nurse–led clinics. Treatment cost-effectiveness is modeled from the U.K. Prospective Diabetes Study and Heart Protection Study treatment trials, whereas specialist nurse–led clinics are evaluated using the Specialist Nurse–Led Clinics to Improve Control of Hypertension and Hyperlipidemia in Diabetes (SPLINT) trial. RESULTS—Good lipid and blood pressure control are cost-effective treatment goals for patients with diabetes. Modeling findings from treatment trials, blood pressure lowering is estimated to be cost saving and life prolonging (−$1,400/quality-adjusted life-year [QALY]), whereas lipid-lowering is estimated to be highly cost-effective ($8,230/QALY). Investing in nurse-led clinics to help achieve these benefits imposes an addition on treatment cost-effectiveness leading to higher estimates: $4,020/QALY and $19,950/QALY, respectively. For both clinics combined, the estimated cost-effectiveness is $9,070/QALY. Using an acceptability threshold of $50,000/QALY, the likelihood that blood pressure–lowering clinics are cost-effective is 77%, lipid clinics 99%, and combined clinics 83%. CONCLUSIONS—A method is described for evaluating the cost-effectiveness of policies to change patient uptake of health care. Such policies are less attractive than treatment cost-effectiveness (which implies cost-less self-implementation). However, specialist nurse–led clinics, as an adjunct to hospital-based diabetic care, combining both lipid and blood pressure control, appear effective and likely to provide excellent value for money.