tbuckley/cabot-search huggingface dataset:
Regulated Overexpression of Heat Shock Protein 72 Protects Madin-Darby Canine Kidney Cells from the Detrimental Effects of High Urea Concentrations
Authors: Wolfgang Neuhofer, Karin Lugmayr, Maria-Luisa Fraek, Franz-X Beck
Journal: Journal of the American Society of Nephrology (2001)

Exposure of renal medullary cells to elevated extracellular NaCl concentrations is associated with increased heat shock protein 72 (HSP72) expression and improved resistance to subsequent exposure to a high urea concentration (600 mM). To establish a causal relationship between HSP72 expression and protection against high urea concentrations, HSP72 was inducibly overexpressed in Madin-Darby canine kidney (MDCK) cells, in the absence of hypertonic stress before urea exposure. For this purpose, the human stress-inducible HSP72 gene was cloned downstream from a dexamethasone (DEX)-inducible promoter in the eukaryotic expression vector pLKneo. This construct allowed robust induction of HSP72 by exposure of stably transfected MDCK cells (MDCK-LK72) to 0.1 microM DEX. Increased HSP72 abundance significantly improved survival rates after 24-h exposure of the cells to medium containing 600 mM urea (14 versus 43%). In mock-transfected or wild-type cells, DEX had no significant effect on HSP72 abundance or urea resistance. In accordance with those findings, lactate dehydrogenase activity in the supernatant was significantly reduced, compared with appropriate control samples, only in MDCK-LK72 cells overexpressing HSP72. Labeling with annexin V-FITC and propidium iodide, followed by flow cytometry, revealed that overexpression of HSP72 was associated with a reduction in the number of apoptotic-lysed cells, a concomitant retardation of apoptosis, and an increase in the number of viable cells. These data support the view that HSP72, which is very abundant in the renal inner medulla, is an important component of the defense mechanism of medullary cells against extreme concentrations of urea.
The Genomic Complexity Underlying Pulmonary Arterial Hypertension: From Mendel to Networks
Authors: Revathi Rajkumar, Ferhaan Ahmad
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

clinical trials will enroll patients with similar degrees of disease involvement.New delivery devices for inhaled medications may deliver therapies to the location of disease with less toxicity.In conclusion, the publication of this most recent inhaled antibiotic trial adds to our understanding of therapy (and trial design) for NCFB.Coupled with other inhaled antibiotic, oral macrolide, and inhaled mucolytic trials, this trial has helped us begin to understand the complexities of treating this disease.We need to remember that this is a very heterogeneous patient population, and ultimately, clinicians will need to target therapies and provide personalized care to patients with this disease.Combining different types of therapies and including airway clearance will also be important.Finally, we have barely scratched the surface on issues including early disease identification, the role of the microbiome (10), the impact and treatment of nontuberculous mycobacterial infection (11), and the interplay with chronic obstructive pulmonary disease (12).
Loperamide: studies on its mechanism of action.
Authors: B K Sandhu, J H Tripp, D C Candy, J T Harries
Journal: Gut (1981)

The effects of loperamide on net solute and water absorption, and prostaglandin E2 (PGE2) and cholera toxin-induced secretion were studied in the rat jejunum using an in vivo steady-state perfusion technique. Loperamide stimulated absorption of fluid, electrolytes, and glucose and reversed PGE2 and cholera toxin-induced secretion to absorption; this opiate analogue had no effect on cholera toxin stimulation of adenylate cyclase activity or the rise of tissue cyclic AMP (cAMP) concentrations. The opiate antagonist, naloxone, reduced the antisecretory effects of loperamide without affecting tissue levels of cAMP. These results indicate that loperamide inhibits PGE2 and cholera toxin-induced secretion, and that this phenomenon is independent of any direct effect that cholera toxin has on the adenylate cyclase system. The action of naloxone suggests, but does not prove, that loperamide exerts its effect via opiate receptors.
Is inflammation a potential therapeutic target in chronic thromboembolic pulmonary hypertension?
Authors: Rozenn Quarck, Marion Delcroix
Journal: European Respiratory Journal (2014)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but notoriously underdiagnosed complication of pulmonary embolism, which carries a poor prognosis if left untreated. CTEPH results from the obstruction of the pulmonary vascular bed by fibro-thrombotic material, which may completely occlude the lumen. Although massive or recurrent pulmonary embolism is thought to be the initiating event, a significant proportion of patients have no history of symptomatic pulmonary embolism and only a few patients with acute pulmonary embolism develop CTEPH [1]. As a consequence, the true prevalence and incidence of CTEPH remain unknown [2]. Current data, retrieved from registries, suggest that the incidence of CTEPH averages between three and 30 per million in the general population [3], and that the proportion of patients developing CTEPH after acute pulmonary embolism may vary between 0.1% and 9.1% [4]. The standard and potentially curative treatment for CTEPH is a surgical procedure, known as pulmonary endarterectomy (PEA) [5], which involves removing organised thrombi, neointima and media inner layers obstructing the pulmonary arteries (fig. 1b) [6]. PEA, when performed in experienced centres and on selected patients, shows low perioperative mortality, and provides major improvements in haemodynamics, symptoms and survival [7]. Moreover, CTEPH is a “dual” pulmonary vascular disorder combining major vessel obstruction and small vessel arteriopathy, which is histologically indistinguishable from idiopathic pulmonary arterial hypertension (PAH) in the non-occluded lung areas [8]. As a consequence, PAH-targeted therapy, including prostacyclin analogues, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors, has been largely used in CTEPH [9] and should be considered for inoperable patients or patients with persistent pulmonary hypertension after PEA [10]. More recently, riociguat, a stimulator of soluble guanylate cyclase, has been approved for the treatment of …
Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited.
Authors: D L Clemens, M A Horwitz
Journal: The Journal of Experimental Medicine (1995)

We have used the cryosection immunogold technique to study the composition of the Mycobacterium tuberculosis phagosome. We have used quantitative immunogold staining to determine the distribution of several known markers of the endosomal-lysosomal pathway in human monocytes after ingestion of either M. tuberculosis, Legionella pneumophila, or polystyrene beads. Compared with the other phagocytic particles studied, the M. tuberculosis phagosome exhibits delayed clearance of major histocompatibility complex (MHC) class I molecules, relatively intense staining for MHC class II molecules and the endosomal marker transferrin receptor, and relatively weak staining for the lysosomal membrane glycoproteins, CD63, LAMP-1, and LAMP-2 and the lysosomal acid protease, cathepsin D. In contrast to M. tuberculosis, the L. pneumophila phagosome rapidly clears MHC class I molecules and excludes all endosomal-lysosomal markers studied. In contrast to both live M. tuberculosis and L. pneumophila phagosomes, phagosomes containing either polystyrene beads or heat-killed M. tuberculosis stain intensely for lysosomal membrane glycoproteins and cathepsin D. These findings suggest that (a) M. tuberculosis retards the maturation of its phagosome along the endosomal-lysosomal pathway and resides in a compartment with endosomal, as opposed to lysosomal, characteristics; and (b) the intraphagosomal pathway, i.e., the pathway followed by several intracellular parasites that inhibit phagosome-lysosome fusion, is heterogeneous.
Efficient Presentation of Naturally Processed HLA Class I Peptides by Artificial Antigen-Presenting Cells for the Generation of Effective Antitumor Responses
Authors: Naoto Hirano, Marcus O. Butler, Zhinan Xia, Alla Berezovskaya, Andrew P. Murray, Sascha Ansén, Lee M. Nadler
Journal: Clinical Cancer Research (2006)

Abstract Appropriate presentation of tumor-associated antigens (TAA) by antigen-presenting cells (APC) is required for the development of clinically relevant antitumor T-cell responses. One common approach, which uses APC pulsed with synthetic peptides, can sometimes generate ineffective immune responses. This failure may, in part, be attributed to the formation of HLA/synthetic pulsed peptide complexes that possess different conformations compared with those of endogenously presented peptides. In addition, endogenous peptides may undergo post-translational modifications, which do not occur with synthetic peptides. Because our goal is to induce immunity that can recognize TAA that are endogenously presented by tumors, we designed an APC that would not only express the required immunoaccessory molecules but also naturally process and present target antigenic peptides. In this study, we generated an artificial APC (aAPC) that can endogenously present any chosen HLA-A*0201 (A2)–restricted peptide by processing a fusion protein that contains a unique “LTK” sequence linked to the antigenic peptide. Proteasome-dependent processing is so effective that the presented peptide can be directly eluted from the cell surface and identified by biochemical methods. Furthermore, we found that aAPC, engineered to endogenously present peptide derived from the melanoma antigen MART1, can be used to prime and expand antitumor CTL that target MART1-expressing tumor cells in a HLA-A2-restricted manner. Our engineered aAPC could serve as an “off-the-shelf” APC designed to constitutively express class I–restricted TAA peptides and could be used to generate effective T-cell responses to treat human disease.
Randomized Study to Assess the Effectiveness of Slow- and Moderate-Release Polymer-Based Paclitaxel-Eluting Stents for Coronary Artery Lesions
Authors: Antonio Colombo, Janusz Drzewiecki, Adrian Banning, Eberhard Grube, Karl Hauptmann, Sigmund Silber, Dariusz Dudek, Stephen Fort, Francois Schiele, Krysztof Zmudka, Giulio Guagliumi, Mary E. Russell
Journal: Circulation (2003)

Early clinical studies demonstrated the feasibility of local paclitaxel delivery in reducing restenosis after treatment of de novo coronary lesions in small patient populations.We conducted a randomized, double-blind trial of 536 patients at 38 medical centers evaluating slow-release (SR) and moderate-release (MR) formulations of a polymer-based paclitaxel-eluting stent (TAXUS) for revascularization of single, primary lesions in native coronary arteries. Cohort I compared TAXUS-SR with control stents, and Cohort II compared TAXUS-MR with a second control group. The primary end point was 6-month percent in-stent net volume obstruction measured by intravascular ultrasound. Secondary end points were 6-month angiographic restenosis and 6- and 12-month incidence of major adverse cardiac events, a composite of cardiac death, myocardial infarction, and repeat revascularization. At 6 months, percent net volume obstruction within the stent was significantly lower for TAXUS stents (7.9% SR and 7.8% MR) than for respective controls (23.2% and 20.5%; P<0.0001 for both). This corresponded with a reduction in angiographic restenosis from 17.9% to 2.3% in the SR cohort (P<0.0001) and from 20.2% to 4.7% in the MR cohort (P=0.0002). The incidence of major adverse cardiac events at 12 months was significantly lower (P=0.0192) in the TAXUS-SR (10.9%) and TAXUS-MR (9.9%) groups than in controls (22.0% and 21.4%, respectively), predominantly because of a significant reduction in repeat revascularization of the target lesion in TAXUS-treated patients.Compared with a bare metal stent, paclitaxel-eluting stents reduced in-stent neointimal formation and restenosis and improved 12-month clinical outcome of patients with single de novo coronary lesions.
Survival of Patients With Type 1 Diabetes Receiving Renal Replacement Therapy in 1980–2007
Authors: Mikko Haapio, Jaakko Helve, Per-Henrik Groop, Carola Grönhagen-Riska, Patrik Finne
Journal: Diabetes Care (2010)

OBJECTIVE Risks of end-stage renal disease and premature death in patients with type 1 diabetes have declined over the past decades. Data on the survival of patients receiving renal replacement therapy (RRT) are, however, limited. We investigated whether survival of patients with type 1 diabetes receiving RRT has improved over time and whether improvement can be attributable to progress in dialysis treatment or diabetes care. RESEARCH DESIGN AND METHODS An incident cohort of all patients with type 1 diabetes (n = 1,604) starting chronic RRT in Finland between 1980 and 2005 were followed until death or end of follow-up on 31 December 2007. The control group (n = 1,556) consisted of patients with glomerulonephritis who started RRT. All patients were identified from the Finnish Registry for Kidney Diseases. RESULTS Median survival time of patients with type 1 diabetes increased progressively from 3.60 years during 1980–1984 to &amp;gt;8 years in 2000–2005. In 2000–2005, the unadjusted relative risk of death was 0.55 compared with 1980–1984. After adjustment for the most important variables, the corresponding relative risk of death was only 0.23. For patients with glomerulonephritis, the adjusted relative risk decreased to a lesser extent to 0.30 (P = 0.007). CONCLUSIONS Survival of patients with type 1 diabetes and end-stage renal disease has improved since the 1980s despite a conspicuous increase in the age of patients who start RRT, suggesting not only true progress in dialysis therapy and overall treatment of patients with end-stage renal disease but possibly also improved management of diabetes.
Prognostic and Therapeutic Impact of Argininosuccinate Synthetase 1 Control in Bladder Cancer as Monitored Longitudinally by PET Imaging
Authors: Michael D. Allen, Phuong Luong, Chantelle Hudson, Julius Leyton, Barbara Delage, Essam Ghazaly, Rosalind Cutts, Ming Yuan, Nelofer Syed, Cristiana Lo Nigro, Laura Lattanzio, Malgorzata Chmielewska-Kassassir, Ian Tomlinson, Rebecca Roylance, Hayley C. Whitaker, Anne Y. Warren, David Neal, Christian Frezza, Luis Beltran, Louise J. Jones, Claude Chelala, Bor-Wen Wu, John S. Bomalaski, Robert C. Jackson, Yong-Jie Lu, Tim Crook, Nicholas R. Lemoine, Stephen Mather, Julie Foster, Jane Sosabowski, Norbert Avril, Chien-Feng Li, Peter W. Szlosarek
Journal: Cancer Research (2013)

Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [(18)F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response.
Hyperglycemia, Polyol Metabolism, and Complications of Diabetes Mellitus
Authors: K H Gabbay
Journal: Annual Review of Medicine (1975)

This brief review of the sorbitol pathway has attempted to present our current knowledge of this accessory pathway of glucose metabolism in the development of some diabetic complications. Clearly hyperglycemia in the diabetic patient is an important factor controlling the activity of the sorbitol pathway. Hyperglycemia in both diabetic patients and experimental animals results in significant accumulations of the products of this pathway in some tissues, and these diabetic manifestations. The development of inhibitors of the aldose reductase enzyme affords new means for preventing and treating some of these complications. Nevertheless, we are still hampered by the lack of knowledge of the normal role of this pathway in tissue metabolism. Many technical problems still exist concerning sensitive and specific assays for the products of the sorbitol pathway in tissue studies, as well as with valid techniques for the measuremtn of the activity of this pathway in clinical situations. It is hoped that clinical studies with aldose reductase inhibitors in the future will further clarify the importance of this accesory pathway of glucose metabolism in diabetes.
The relationship between ACL injuries and physical fitness in young competitive ski racers: a 10-year longitudinal study
Authors: Christian Raschner, Hans-Peter Platzer, Carson Patterson, Inge Werner, Reinhard Huber, Carolin Hildebrandt
Journal: British Journal of Sports Medicine (2012)

Epidemiological studies have shown a high incidence of anterior cruciate ligament (ACL) injuries among competitive alpine skiers. Little is known regarding modifiable risk factors in young skiers. There are still uncertainties in gender-related risk factors.The purpose of this study was to determine the relationship between ACL injuries and internal risk factors.Retrospective data analyses were performed based on a group of 175 female and 195 male alpine ski racers between the ages of 14 and 19 years. The athletes underwent physical testing annually from 1996 to 2006. Z score transformations normalised the age groups. Multivariate binary logistic regressions were calculated for men and women separately to detect significant predictors of ACL ruptures. t Tests were computed to reveal the differences in test scores between injured and non-injured athletes.A total of 57 (15%) ACL injuries occurred. The female-male risk ratio (RR) was higher in females (2.3, 95% CI 1.3 to 4.2). Z scores for relative leg force, ratio of absolute core flexion to extension force, relative core strength and reactive strength index were predictive variables for men. Z scores of all of these predictive variables except relative leg force were higher in the non-injured group. The ratios of absolute flexion to extension force and absolute core strength were predictive covariates for women. Z scores for absolute core strength were higher in the non-injured group.The risk of ACL injury was greater in female athletes. The findings suggest that core strength is a predominant critical factor for ACL injuries in young ski racers.
Adenylyl Cyclase 6 Deficiency Ameliorates Polycystic Kidney Disease
Authors: Sara Rees, Wararat Kittikulsuth, Karl Roos, Kevin A. Strait, Alfred Van Hoek, Donald E. Kohan
Journal: Journal of the American Society of Nephrology (2013)

cAMP is an important mediator of cystogenesis in polycystic kidney disease (PKD). Several adenylyl cyclase (AC) isoforms could mediate cAMP accumulation in PKD, and identification of a specific pathogenic AC isoform is of therapeutic interest. We investigated the role of AC6 in a mouse model of PKD that is homozygous for the loxP-flanked PKD1 gene and heterozygous for an aquaporin-2-Cre recombinase transgene to achieve collecting duct-specific gene targeting. Collecting duct-specific knockout of polycystin-1 caused massive renal cyst formation, kidney enlargement, and severe kidney failure, with a mean survival time of 2 months. In contrast, coincident collecting duct-specific knockout of polycystin-1 and AC6 (also homozygous for the floxed ADCY6 gene) markedly decreased kidney size and cystogenesis, improved renal function, reduced activation of the B-Raf/ERK/MEK pathway, and greatly increased survival. Absence of collecting duct AC6 did not alter urinary cAMP excretion or kidney cAMP concentration. In conclusion, AC6 is a key mediator of cyst formation and renal injury in a model of PKD.
Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin.
Authors: M Bermann, C A Jaffe, W Tsai, R DeMott-Friberg, A L Barkan
Journal: Journal of Clinical Investigation (1994)

To investigate the mechanisms of the negative feedback inhibition of growth hormone (GH) secretion by IGF-I, we studied parameters of GH pulsatility in six normal, fed men before and during a 48-h infusion of recombinant human IGF-I (rhIGF-I) (10-15 micrograms/kg per h). Plasma levels of IGF-I increased from the baseline value of 163.5 +/- 9.3 micrograms/liter (mean +/- SE) to a new steady state of 452.0 +/- 20.9 micrograms/liter during the infusion. Plasma GH concentrations were measured every 10 min for 24 h during both saline and rhIGF-I infusions using a sensitive chemiluminescent assay. Overall, GH concentrations were suppressed during the rhIGF-I infusion by 85 +/- 3%, mainly by attenuating spontaneous GH pulse amplitude (77 +/- 4% suppression). The apparent GH pulse frequency was attenuated from 7.8 +/- 0.9 to 4.7 +/- 0.6 pulses/24 h (P = 0.006). Administration of rhIGF suppressed GH responses to exogenous GH-releasing hormone by 82 +/- 3%, and thyroid-stimulating hormone responses to thyrotropin-releasing hormone were also suppressed by 44 +/- 9%. This constellation of hormonal effects is most compatible with the rhIGF-I-induced stimulation of hypothalamic somatostatin secretion.
Parents' intellectual and emotional awareness of their child's impending death to cancer: a population-based long-term follow-up study
Authors: Unnur Valdimarsdóttir, Ulrika Kreicbergs, Arna Hauksdóttir, Hayley Hunt, Erik Onelöv, Jan-Inge Henter, Gunnar Steineck
Journal: The Lancet Oncology (2007)
Spatial patterning of BMP-2 and BMP-7 on biopolymeric films and the guidance of muscle cell fate
Authors: Jorge Almodóvar, Raphaël Guillot, Claire Monge, Julien Vollaire, Šeila Selimović, Jean-Luc Coll, Ali Khademhosseini, Catherine Picart
Journal: Biomaterials (2014)