tbuckley/cabot-search huggingface dataset:
Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis
Authors: Olga A. Mareninova, Kip Hermann, Samuel W. French, Mark S. O’Konski, Stephen J. Pandol, Paul Webster, Ann H. Erickson, Nobuhiko Katunuma, Fred S. Gorelick, Ilya Gukovsky, Anna S. Gukovskaya
Journal: Journal of Clinical Investigation (2013)

The pathogenic mechanisms underlying acute pancreatitis are not clear. Two key pathologic acinar cell responses of this disease are vacuole accumulation and trypsinogen activation. We show here that both result from defective autophagy, by comparing the autophagic responses in rodent models of acute pancreatitis to physiologic autophagy triggered by fasting. Pancreatitis-induced vacuoles in acinar cells were greater in number and much larger than those induced with fasting. Degradation of long-lived proteins, a measure of autophagic efficiency, was markedly inhibited in in vitro pancreatitis, while it was stimulated by acinar cell starvation. Further, processing of the lysosomal proteases cathepsin L (CatL) and CatB into their fully active, mature forms was reduced in pancreatitis, as were their activities in the lysosome-enriched subcellular fraction. These findings indicate that autophagy is retarded in pancreatitis due to deficient lysosomal degradation caused by impaired cathepsin processing. Trypsinogen activation occurred in pancreatitis but not with fasting and was prevented by inhibiting autophagy. A marker of trypsinogen activation partially localized to autophagic vacuoles, and pharmacologic inhibition of CatL increased the amount of active trypsin in acinar cells. The results suggest that retarded autophagy is associated with an imbalance between CatL, which degrades trypsinogen and trypsin, and CatB, which converts trypsinogen into trypsin, resulting in intra-acinar accumulation of active trypsin in pancreatitis. Thus, deficient lysosomal degradation may be a dominant mechanism for increased intra-acinar trypsin in pancreatitis.
Mechanisms of photoreceptor death and survival in mammalian retina
Authors: Jonathan Stone, Juliani Maslim, Krisztina Valter-Kocsi, Kyle Mervin, Felicity Bowers, Yi Chu, Nigel Barnett, Jan Provis, Geoff Lewis, Steven K Fisher, Silvia Bisti, Claudia Gargini, Luigi Cervetto, Saul Merin, Jacob Pe'er
Journal: Progress in Retinal and Eye Research (1999)
PDK1 Attenuation Fails to Prevent Tumor Formation in PTEN-Deficient Transgenic Mouse Models
Authors: Katharine Ellwood-Yen, Heike Keilhack, Kaiko Kunii, Brian Dolinski, Yamicia Connor, Kun Hu, Kumiko Nagashima, Erin O'Hare, Yusuf Erkul, Alessandra Di Bacco, Diana Gargano, Nirah H. Shomer, Minilik Angagaw, Erica Leccese, Paula Andrade, Melissa Hurd, Myung K. Shin, Thomas F. Vogt, Alan Northrup, Ekaterina V. Bobkova, Shailaja Kasibhatla, Roderick T. Bronson, Martin L. Scott, Giulio Draetta, Victoria Richon, Nancy Kohl, Peter Blume-Jensen, Jannik N. Andersen, Manfred Kraus
Journal: Cancer Research (2011)

PDK1 activates AKT suggesting that PDK1 inhibition might suppress tumor development. However, while PDK1 has been investigated intensively as an oncology target, selective inhibitors suitable for in vivo studies have remained elusive. In this study we present the results of in vivo PDK1 inhibition through a universally applicable RNAi approach for functional drug target validation in oncogenic pathway contexts. This approach, which relies on doxycycline-inducible shRNA expression from the Rosa26 locus, is ideal for functional studies of genes like PDK1 where constitutive mouse models lead to strong developmental phenotypes or embryonic lethality. We achieved more than 90% PDK1 knockdown in vivo, a level sufficient to impact physiological functions resulting in hyperinsulinemia and hyperglycemia. This phenotype was reversible on PDK1 reexpression. Unexpectedly, long-term PDK1 knockdown revealed a lack of potent antitumor efficacy in 3 different mouse models of PTEN-deficient cancer. Thus, despite efficient PDK1 knockdown, inhibition of the PI3K pathway was marginal suggesting that PDK1 was not a rate limiting factor. Ex vivo analysis of pharmacological inhibitors revealed that AKT and mTOR inhibitors undergoing clinical development are more effective than PDK1 inhibitors at blocking activated PI3K pathway signaling. Taken together our findings weaken the widely held expectation that PDK1 represents an appealing oncology target.
Urinary Coproporphyrin isomers in Rotor's syndrome: A study in eight families
Authors: Yoshitaka Shimizu, Hiroshi Naruto, Setsuko Ida, Masateru Kohakura
Journal: Hepatology (1981)

Urinary coproporphyrin isomers were measured in 17 patients with Rotor's syndrome, 65 phenotypically normal relatives of 14 patients from eight families, and 21 normal subjects. Coproporphyrin I was elevated in Rotor's syndrome (p < 0.001) and, to a lesser degree, in phenotypically normal parents (p < 0.005), children, and siblings (p < 0.025) as compared to normal controls. Coproporphyrin III in patients, parents, and children did not differ from that in normal controls. Genetic analysis was consistent with transmission of Rotor's syndrome as an autosomal recessive trait with respect to urinary excretion of coproporphyrin I. After i.v. injection of σ-aminolevulinic acid, urinary coproporphyrin I increased to a similar extent in Rotor's syndrome and in normal subjects; urinary coproporphyrin III excretion was less in Rotor's syndrome than in normal subjects.
Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-α-2a and ribavirin in HIV/HCV co-infected patients
Authors: Marie-Louise C. Vachon, Stephanie H. Factor, Andrea D. Branch, Maria-Isabel Fiel, Maribel Rodriguez-Torres, Norbert Bräu, Richard K. Sterling, Jihad Slim, Andrew H. Talal, Douglas T. Dieterich, Mark S. Sulkowski
Journal: Journal of Hepatology (2010)
Magnitude of the genetic component in juvenile idiopathic arthritis
Authors: A SAVOLAINEN
Journal: Annals of the Rheumatic Diseases (2000)

CoVee consumption, RF, and the risk of RAStress is one of the factors that can trigger the onset of rheumatoid arthritis (RA).People working under deadline pressure, and people characterised as hard driving, "type A" personalities may be most likely to experience stress.These are the same people who may consume large quantities of coVee in order to stay at peak performance for longer periods of time.Possibly, therefore, the correlation reported by Heliövaara et al 1 between coVee consumption and RA may, in part, be due to the association between stress and RA.
Mesenchymal Stem Cell: Keystone of the Hematopoietic Stem Cell Niche and a Stepping-Stone for Regenerative Medicine
Authors: Paul S. Frenette, Sandra Pinho, Daniel Lucas, Christoph Scheiermann
Journal: Annual Review of Immunology (2013)

Mesenchymal stem cells (MSCs) are self-renewing precursor cells that can differentiate into bone, fat, cartilage, and stromal cells of the bone marrow. Recent studies suggest that MSCs themselves are critical for forming a niche that maintains hematopoietic stem cells (HSCs). The ease by which human MSC-like and stromal progenitor cells can be isolated from the bone marrow and other tissues has led to the rapid development of clinical investigations exploring their anti-inflammatory properties, tissue preservation capabilities, and regenerative potential. However, the identity of genuine MSCs and their specific contributions to these various beneficial effects have remained enigmatic. In this article, we examine the definition of MSCs and discuss the importance of rigorously characterizing their stem cell activity. We review their role and that of other putative niche constituents in the regulation of bone marrow HSCs. Additionally, how MSCs and their stromal progeny alter immune function is discussed, as well as potential therapeutic implications.
Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling
Authors: Nataša Obermajer, Jeffrey L. Wong, Robert P. Edwards, Kong Chen, Melanie Scott, Shabaana Khader, Jay K. Kolls, Kunle Odunsi, Timothy R. Billiar, Pawel Kalinski
Journal: The Journal of Experimental Medicine (2013)

Nitric oxide (NO) is a ubiquitous mediator of inflammation and immunity, involved in the pathogenesis and control of infectious diseases, autoimmunity, and cancer. We observed that the expression of nitric oxide synthase-2 (NOS2/iNOS) positively correlates with Th17 responses in patients with ovarian cancer (OvCa). Although high concentrations of exogenous NO indiscriminately suppress the proliferation and differentiation of Th1, Th2, and Th17 cells, the physiological NO concentrations produced by patients’ myeloid-derived suppressor cells (MDSCs) support the development of RORγt(Rorc)+IL-23R+IL-17+ Th17 cells. Moreover, the development of Th17 cells from naive-, memory-, or tumor-infiltrating CD4+ T cells, driven by IL-1β/IL-6/IL-23/NO-producing MDSCs or by recombinant cytokines (IL-1β/IL-6/IL-23), is associated with the induction of endogenous NOS2 and NO production, and critically depends on NOS2 activity and the canonical cyclic guanosine monophosphate (cGMP)–cGMP-dependent protein kinase (cGK) pathway of NO signaling within CD4+ T cells. Inhibition of NOS2 or cGMP–cGK signaling abolishes the de novo induction of Th17 cells and selectively suppresses IL-17 production by established Th17 cells isolated from OvCa patients. Our data indicate that, apart from its previously recognized role as an effector mediator of Th17-associated inflammation, NO is also critically required for the induction and stability of human Th17 responses, providing new targets to manipulate Th17 responses in cancer, autoimmunity, and inflammatory diseases.
RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA
Authors: Cherilyn M. Sirois, Tengchuan Jin, Allison L. Miller, Damien Bertheloot, Hirotaka Nakamura, Gabor L. Horvath, Abubakar Mian, Jiansheng Jiang, Jacob Schrum, Lukas Bossaller, Karin Pelka, Natalio Garbi, Yambasu Brewah, Jane Tian, ChewShun Chang, Partha S. Chowdhury, Gary P. Sims, Roland Kolbeck, Anthony J. Coyle, Alison A. Humbles, T. Sam Xiao, Eicke Latz
Journal: The Journal of Experimental Medicine (2013)

Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE–DNA complexes indicated that DNA interacted with dimers of the outermost RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo.
Pulmonary medicine and (adult) critical care medicine in Europe
Authors: T. Evans, M.W Elliott, M. Ranieri, W. Seeger, T. Similowski, A. Torres, C. Roussos
Journal: European Respiratory Journal (2002)

There has been growing concern within the European Respiratory Society (ERS) that pulmonary physicians are becoming less involved in the practise of intensive care medicine (ICM). A Working Party (WP) was therefore established to identify issues that might explain this trend. No precise terms of reference were issued to guide this exercise. The WP ensured that its report focussed on improving patient care. With this proviso, the WP aimed to: 1) briefly identify the current working practices of pulmonary physicians practicing ICM in six European Union (EU) countries (France, Germany, Greece, Italy, Spain and UK); 2) discuss possible opportunities to expand the influence of pulmonary physicians in the provision of acute care; and 3) determine the implications of 1) for training programmes.

The following methods were employed. 1) Relevant literature was extracted and a draft report concerning the three points discussed previously was prepared and circulated to the members of the WP. 2) A 1-day meeting was held in Paris on March 26th, 2001, and the contents of the draft report discussed and refined. 3) A second draft was prepared and circulated. 4) A final report was forwarded to the executives of the ERS.

In Europe, ICM is one of the most recent clinical disciplines to evolve. The polio epidemic in Denmark in 1952 showed that careful airway management with the application of positive pressure ventilation could dramatically reduce mortality in patients who presented with paralysis of the respiratory muscles. This focus on airway care and ventilatory management encouraged anaesthesiologists to lead the way in the introduction of critical care facilities. Technological advances in the 1960s led to the development of sophisticated physiological monitoring equipment. The subsequent recognition that the diagnosis and management of critical illness required additional skills to those incorporated into training in anaesthesiology, attracted clinicians trained in …
Recovery from dynamic exercise dissociates ventilatory from pulmonary gas exchange responses in patients with chronic thromboembolic pulmonary hypertension
Authors: Roberta Ramos, Eloara Ferreira, Arakaki-Ota Jaquelina, Luiz Nery, J. Alberto Neder, Erika Treptow
Journal: European Respiratory Journal (2013)

Background:  Exercise is characterized by an excessive ventilatory (V9E) response to metabolic demand (i.e., CO 2  output, V9CO 2 ) in chronic thromboembolic pulmonary hypertension (CTEPH). We investigated whether this would also be the case when the neural ventilatory drive (by feed-forward mechanisms) is likely to be reduced, e.g, immediately after exercise.  Methods : Forty-three patients with CTEPH (50 ± 13 yrs, cardiac index= 2.0 ± 0.5 L/kg/min -1 ; PVR= 1034 ± 402 dynes.s.cm -2 ) and 21 sedentary controls performed a ramp-incremental exercise test followed by unloaded recovery.  Results:  In patients, V9CO 2  (and O 2  uptake) kinetics were significantly delayed compared to V9E (1 st  min decrease in % peak values= 13 ± 7  vs  19 ± 1%; 2 nd  min= 26 ± 13  vs  33 ± 12%; 3 rd  min= 46 ± 12  vs  53 ± 10 %; 4 th  min= 54 ± 13  vs  59 ± 13%; 5  th   min= 61 ± 11  vs  65 ± 4%, p 2  throughout the recovery (p 2  ratio decreased (and end-tidal CO 2  (P ET CO 2 ) increased) as exercise ceased in 41/43 (95%) patients with opposite patterns (i.e, V9E/V9CO 2  increase and P ET CO 2  decrease) been found in all controls.  Conclusion:  Exercise recovery dissociates ventilatory to pulmonary gas exchange responses in patients with CTEPH. Although this might be related to lower post-exercise metabolic drive due to less lactacidosis in patients than controls, it might also indicate that enhanced neural drive - which was suddently reduced at exercise cessation- contributes to patients9 excessive exercise V9E.
Analysis of indicator distribution in the determination of cardiac output by thermal dilution
Authors: A. C. A. P. VLIERS, K. R. VISSER, W. G. ZIJLSTRA
Journal: Cardiovascular Research (1973)

The distribution of thermal indicator of room temperature from its introduction into the injection catheter until its detection by a thermistor in the pulmonary artery has been analysed. As a consequence the equations for calculating cardiac output have been derived and verified experimentally.
Chronic thromboembolic pulmonary hypertension: do we need a new definition?
Authors: Marc de Perrot, Eckhard Mayer
Journal: European Respiratory Journal (2014)

Chronic thromboembolic pulmonary hypertension (CTEPH) is the end result of persistent obstruction of the pulmonary arteries following episodes of acute and/or recurrent pulmonary emboli [1]. Pulmonary hypertension probably stems from a smaller pulmonary arterial cross sectional area due to thrombus organisation and a redistribution of blood flow through the patent pulmonary arterial bed producing an additional microvasculopathy [2]. Consequently many patients develop pulmonary hypertension despite adequate anticoagulation [3]. Once pulmonary hypertension occurs, the prognosis is poor due to right heart failure with a survival similar to other forms of pre-capillary pulmonary hypertension [4]. Patients suffering from CTEPH typically present with progressive dyspnoea that worsens over a period of months to years [5]. Dyspnoea is related to hypoxaemia, dead space ventilation and right heart dysfunction, severely affecting the quality of life [6, 7].

Pulmonary endarterectomy is the treatment of choice for CTEPH. The surgery leads to major clinical improvement due to improved haemodynamic parameters and oxygenation, and a reduction in dead space ventilation [7, 8]. The surgery is curative in a large proportion of patients with resolution of the pulmonary hypertension. Over the past 20 years, the technique of pulmonary endarterectomy under deep hypothermic circulatory arrest has been refined and can currently be performed …
Acupuncture for chronic headache in primary care: large, pragmatic, randomised trial
Authors: Andrew J Vickers, Rebecca W Rees, Catherine E Zollman, Rob McCarney, Claire M Smith, Nadia Ellis, Peter Fisher, Robbert Van Haselen
Journal: BMJ (2004)

Abstract Objective To determine the effects of a policy of “use acupuncture” on headache, health status, days off sick, and use of resources in patients with chronic headache compared with a policy of “avoid acupuncture.” Design Randomised, controlled trial. Setting General practices in England and Wales. Participants 401 patients with chronic headache, predominantly migraine. Interventions Patients were randomly allocated to receive up to 12 acupuncture treatments over three months or to a control intervention offering usual care. Main outcome measures Headache score, SF-36 health status, and use of medication were assessed at baseline, three, and 12 months. Use of resources was assessed every three months. Results Headache score at 12 months, the primary end point, was lower in the acupuncture group (16.2, SD 13.7, n = 161, 34% reduction from baseline) than in controls (22.3, SD 17.0, n = 140, 16% reduction from baseline). The adjusted difference between means is 4.6 (95% confidence interval 2.2 to 7.0; P = 0.0002). This result is robust to sensitivity analysis incorporating imputation for missing data. Patients in the acupuncture group experienced the equivalent of 22 fewer days of headache per year (8 to 38). SF-36 data favoured acupuncture, although differences reached significance only for physical role functioning, energy, and change in health. Compared with controls, patients randomised to acupuncture used 15% less medication (P = 0.02), made 25% fewer visits to general practitioners (P = 0.10), and took 15% fewer days off sick (P = 0.2). Conclusions Acupuncture leads to persisting, clinically relevant benefits for primary care patients with chronic headache, particularly migraine. Expansion of NHS acupuncture services should be considered.
Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease
Authors: David M. Holtzman, Kelly R. Bales, Shan Wu, Priyanka Bhat, Maia Parsadanian, Anne M. Fagan, Louis K. Chang, Yuling Sun, Steven M. Paul
Journal: Journal of Clinical Investigation (1999)

The ε4 allele of apolipoprotein E (apo E) is associated with an increased risk for developing Alzheimer's disease (AD). This may be due to interactions between apo E and the amyloid-β protein (Aβ). To assess the effects of human apo E isoforms on Aβ deposition in vivo, we bred apo E3 and apo E4 hemizygous (+/–) transgenic mice expressing apo E by astrocytes to mice homozygous (+/+) for a mutant amyloid precursor protein (APPV717F) transgene that develop age-dependent AD neuropathology. All mice were on a mouse apo E null (–/–) background. By nine months of age, APPV717F+/–, apo E–/– mice had developed Aβ deposition, and, as reported previously, the quantity of Aβ deposits was significantly less than that seen in APPV717F+/– mice expressing mouse apo E. In contrast to effects of mouse apo E, similar levels of human apo E3 and apo E4 markedly suppressed early Aβ deposition at nine months of age in APPV717F+/– transgenic mice, even when compared with mice lacking apo E. These findings suggest that human apo E isoforms decrease Aβ aggregation or increase Aβ clearance relative to an environment in which mouse apo E or no apo E is present. The results may have important implications for understanding mechanisms underlying the link between apo E and AD.
Phorbol diesters stimulate the development of an early murine progenitor cell. The burst-forming unit-megakaryocyte.
Authors: M W Long, L L Gragowski, C H Heffner, L A Boxer
Journal: Journal of Clinical Investigation (1985)

When murine (C57BL/6) bone marrow cells are cultivated with WEHI-3 conditioned media, a source of megakaryocyte-colony-stimulating activity (Mk-CSA), and phorbol myristate acetate (PMA), a previously undetected population of megakaryocyte (Mk) progenitor cells is observed. These new Mk colonies are reminiscent of erythroid bursts, in that they contain large numbers (40-500) of Mk and multiple foci (2-7) of development. These burst-forming units, Mk (BFU-Mk), are defined as having greater than or equal to 42 cells/colony and, at least, three foci of Mk development (colonies grown in soft agar cultures, all studies done at limiting dilutions; colonies detected by acetylcholinesterase [ACh-E] staining). CFU-Mk and BFU-Mk require two activities for optimal growth: Mk-CSA and PMA. However, the BFU-Mk require a tenfold greater concentration of PMA for optimal development (10(-6) vs. 10(-7) M). BFU-Mk detection is linear (over a range of 25-100 X 10(3) cells/ml), with the regression line passing through the origin. Bone marrow frequencies of these two progenitor cells are CFU-Mk, 36.7 +/- 2.5, and BFU-Mk, 7.3 +/- 0.7 per 10(5) total nucleated cells (mean +/- SEM; n = 28). The BFU-Mk have a restricted velocity sedimentation range (3.3-4.5 mmh-1 vs. 3.3-6.8 mmh-1 for CFU-Mk). Modal buoyant densities are 1.068 +/- 0.0002 and 1.070 +/- 0.002 for BFU-Mk and CFU-Mk, respectively. Thus, these cells are found among the smallest and less dense of the Mk progenitors, and are not clumps or clusters of CFU-Mk. Kinetic analysis indicates that CFU-Mk require 5-7 d for optimal growth, whereas BFU-Mk require 10-12 d. Examination of the proliferative potential (cells per colony) shows 19.3 +/- 1.5 cells per colony (n = 246 colonies) for day 10 CFU-Mk, vs. 118 +/- 6.0 for day 10 BFU-Mk (n = 163). Analysis of the cellularity/subcolony within each burst indicates 37.0 +/- 2.1 (n = 146) Mk/colony and 3.9 +/- 0.1 subcolonies/burst (n = 100). Finally, greater than 90% of the BFU-Mk contain only ACh-E positive cells, indicating that these are not mixed colonies. These results indicate that the BFU-Mk, compared with the CFU-Mk, require an increased amount of stimulation in order to differentiate, show delayed in vitro development, and have a higher proliferative potential. These data are consistent with the hypothesis that these cells are early progenitor cells in the Mk lineage that antedate the CFU-Mk.