tbuckley/cabot-search huggingface dataset:
DNA Hypomethylation at <i>ALOX12</i> Is Associated with Persistent Wheezing in Childhood
Authors: Eva Morales, Mariona Bustamante, Nadia Vilahur, Georgia Escaramis, Magda Montfort, Rafael de Cid, Raquel Garcia-Esteban, Maties Torrent, Xavier Estivill, Joan O. Grimalt, Jordi Sunyer
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Epigenetic changes may play a role in the occurrence of asthma-related phenotypes.Objectives: To identify epigenetic marks in terms of DNA methylation of asthma-related phenotypes in childhood, and to assess the effect of prenatal exposures and genetic variation on these epigenetic marks.Methods: Data came from two cohorts embedded in the Infancia y Medio Ambiente (INMA) Project: Menorca (n = 122) and Sabadell (n = 236). Wheezing phenotypes were defined at age 4–6 years. Cytosine-guanine (CpG) dinucleotide site DNA methylation differences associated with wheezing phenotypes were screened in children of the Menorca study using the Illumina GoldenGate Panel I. Findings were validated and replicated using pyrosequencing. Information on maternal smoking and folate supplement use was obtained through questionnaires. Dichlorodiphenyldichloroethylene was measured in cord blood or maternal serum. Genotypes were extracted from genome-wide data.Measurement and Main Results: Screening identified lower DNA methylation at a CpG site in the arachidonate 12-lipoxygenase (ALOX12) gene in children having persistent wheezing compared with those never wheezed (P = 0.003). DNA hypomethylation at ALOX12 loci was associated with higher risk of persistent wheezing in the Menorca study (odds ratio per 1% methylation decrease, 1.13; 95% confidence interval, 0.99–1.29; P = 0.077) and in the Sabadell study (odds ratio, 1.16; 95% confidence interval, 1.03–1.37; P = 0.017). Higher levels of prenatal dichlorodiphenyldichloroethylene were associated with DNA hypomethylation of ALOX12 in the Menorca study (P = 0.033), but not in the Sabadell study (P = 0.377). ALOX12 DNA methylation was strongly determined by underlying genetic polymorphisms.Conclusions: DNA methylation of ALOX12 may be an epigenetic biomarker for the risk of asthma-related phenotypes.
Hellebrin and its aglycone form hellebrigenin display similar in vitro growth inhibitory effects in cancer cells and binding profiles to the alpha subunits of the Na+/K+-ATPase
Authors: Laetitia Moreno Y Banuls, Adriana Katz, Walter Miklos, Alessio Cimmino, Daniel M. Tal, Elena Ainbinder, Martin Zehl, Ernst Urban, Antonio Evidente, Brigitte Kopp, Walter Berger, Olivier Feron, Steven Karlish, Robert Kiss
Journal: Molecular Cancer (2013)

Abstract Background Surface-expressed Na + /K + -ATPase (NaK) has been suggested to function as a non-canonical cardiotonic steroid-binding receptor that activates multiple signaling cascades, especially in cancer cells. By contrast, the current study establishes a clear correlation between the IC 50 in vitro growth inhibitory concentration in human cancer cells and the Ki for the inhibition of activity of purified human α1β1 NaK. Methods The in vitro growth inhibitory effects of seven cardiac glycosides including five cardenolides (ouabain, digoxin, digitoxin, gitoxin, uzarigenin-rhamnoside, and their respective aglycone forms) and two bufadienolides (gamabufotalin-rhamnoside and hellebrin, and their respective aglycone forms) were determined by means of the MTT colorimetric assay and hellebrigenin-induced cytotoxic effects were visualized by means of quantitative videomicroscopy. The binding affinity of ten of the 14 compounds under study was determined with respect to human α1β1, α2β1 and α3β1 NaK complexes. Lactate releases and oxygen consumption rates were also determined in cancer cells treated with these various cardiac glycosides. Results Although cardiotonic steroid aglycones usually display weaker binding affinity and in vitro anticancer activity than the corresponding glycoside, the current study demonstrates that the hellebrin / hellebrigenin pair is at odds with respect to this rule. In addition, while some cardiac steroid glycosides (e.g., digoxin), but not the aglycones, display a higher binding affinity for the α2β1 and α3β1 than for the α1β1 complex, both hellebrin and its aglycone hellebrigenin display ~2-fold higher binding affinity for α1β1 than for the α2β1 and α3β1 complexes. Finally, the current study highlights a common feature for all cardiotonic steroids analyzed here, namely a dramatic reduction in the oxygen consumption rate in cardenolide- and bufadienolide-treated cells, reflecting a direct impact on mitochondrial oxidative phosphorylation. Conclusions Altogether, these data show that the binding affinity of the bufadienolides and cardenolides under study is usually higher for the α2β1 and α3β1 than for the α1β1 NaK complex, excepted for hellebrin and its aglycone form, hellebrigenin, with hellebrigenin being as potent as hellebrin in inhibiting in vitro cancer cell growth.
Successful Treatment of Class V+IV Lupus Nephritis with Multitarget Therapy
Authors: Hao Bao, Zhi-Hong Liu, Hong-Lang Xie, Wei-Xin Hu, Hai-Tao Zhang, Lei-Shi Li
Journal: Journal of the American Society of Nephrology (2008)

Treatment of class V+IV lupus nephritis remains unsatisfactory despite the progress made in the treatment of diffuse proliferative lupus nephritis. In this prospective study, 40 patients with class V+IV lupus nephritis were randomly assigned to induction therapy with mycophenolate mofetil, tacrolimus, and steroids (multitarget therapy) or intravenous cyclophosphamide (IVCY). Patients were treated for 6 mo unless complete remission was not achieved, in which case treatment was extended to 9 mo. An intention-to-treat analysis revealed a higher rate of complete remission with multitarget therapy at both 6 and 9 mo (50 and 65%, respectively) than with IVCY (5 and 15%, respectively). At 6 mo, eight (40%) patients in each group experienced partial remission, and at 9 mo, six (30%) patients receiving multitarget therapy and eight (40%) patients receiving IVCY experienced partial remission. There were no deaths during this study. Most adverse events were less frequent in the multitarget therapy group. Calcineurin inhibitor nephrotoxicity was not observed, but three patients developed new-onset hypertension with multitarget therapy. In conclusion, multitarget therapy is superior to IVCY for inducing complete remission of class V+IV lupus nephritis and is well tolerated.
Aerosol delivery of chemotherapy in an orthotopic model of lung cancer
Authors: F. Gagnadoux, A. L. Pape, E. Lemarié, S. Lerondel, I. Valo, V. Leblond, J-L. Racineux, T. Urban
Journal: European Respiratory Journal (2005)

The aim of this study was to evaluate the effect on tumour growth of gemcitabine delivered by aerosol in an orthotopic model of lung carcinoma. Large cell carcinoma (NCI-H460) cells were implanted intrabronchially in 24 male BALB/c nude mice on day (d) 0. Aerosols were delivered once a week from d1 to d29 using an endotracheal sprayer. Altogether, 16 animals received gemcitabine at 8 (n = 8) and 12 mg·kg −1 (n = 8), and eight received a vehicle aerosol. Animals were sacrificed on d36 for histological examination. All animals in the vehicle group developed a large infiltrating carcinoma. Comparatively, four of 13 (31%) animals treated with gemcitabine had no visible tumour and nine of 13 (69%) had a smaller carcinoma with a mean± sem largest tumour diameter of 2.05±0.7 versus 5±0.3 mm in the vehicle group. Gemcitabine was well tolerated at 8 mg·kg −1 . At 12 mg·kg −1 , three cases of fatal pulmonary oedema were observed, prompting a dose reduction to 8 mg·kg −1 in the remaining animals. A dose effect was observed, with more marked tumour growth inhibition in the animals treated at 12 mg·kg −1 on d1 and d8. In conclusion, in this study, an animal model of aerosolised chemotherapy in lung cancer was developed and demonstrated inhibition of orthotopic tumour growth by aerosol delivery of gemcitabine.
Using Nutrition for Intervention and Prevention against Environmental Chemical Toxicity and Associated Diseases
Authors: Bernhard Hennig, Adrienne S. Ettinger, Ronald J. Jandacek, Sung Koo, Craig McClain, Harold Seifried, Allen Silverstone, Bruce Watkins, William A. Suk
Journal: Environmental Health Perspectives (2007)

BackgroundNutrition and lifestyle are well-defined modulators of chronic diseases. Poor dietary habits (such as high intake of processed foods rich in fat and low intake of fruits and vegetables), as well as a sedentary lifestyle clearly contribute to today’s compromised quality of life in the United States. It is becoming increasingly clear that nutrition can modulate the toxicity of environmental pollutants.ObjectivesOur goal in this commentary is to discuss the recommendation that nutrition should be considered a necessary variable in the study of human disease associated with exposure to environmental pollutants.DiscussionCertain diets can contribute to compromised health by being a source of exposure to environmental toxic pollutants. Many of these pollutants are fat soluble, and thus fatty foods often contain higher levels of persistent organics than does vegetable matter. Nutrition can dictate the lipid milieu, oxidative stress, and antioxidant status within cells. The modulation of these parameters by an individual’s nutritional status may have profound affects on biological processes, and in turn influence the effects of environmental pollutants to cause disease or dysfunction. For example, potential adverse health effects associated with exposure to polychlorinated biphenyls may increase as a result of ingestion of certain dietary fats, whereas ingestion of fruits and vegetables, rich in antioxidant and anti-inflammatory nutrients or bioactive compounds, may provide protection.ConclusionsWe recommend that future directions in environmental health research explore this nutritional paradigm that incorporates a consideration of the relationships between nutrition and lifestyle, exposure to environmental toxicants, and disease. Nutritional interventions may provide the most sensible means to develop primary prevention strategies of diseases associated with many environmental toxic insults.
Acute Kidney Injury and Cardiovascular Outcomes in Acute Severe Hypertension
Authors: Lynda A. Szczech, Christopher B. Granger, Joseph F. Dasta, Alpesh Amin, W. Frank Peacock, Peter A. McCullough, John W. Devlin, Matthew R. Weir, Jason N. Katz, Frederick A. Anderson, Allison Wyman, Joseph Varon
Journal: Circulation (2010)

Background— Little is known about the association of kidney dysfunction and outcome in acute severe hypertension. This study aimed to measure the association between baseline chronic kidney disease (estimated glomerular filtration rate), acute kidney injury (AKI, decrease in estimated glomerular filtration rate ≥25% from baseline) and outcome in patients hospitalized with acute severe hypertension. Methods and Results— The Studying the Treatment of Acute Hypertension (STAT) registry enrolled patients with acute severe hypertension, defined as ≥1 blood pressure measurement &gt;180 mm Hg systolic and/or &gt;110 mm Hg diastolic and treated with intravenous antihypertensive therapy. Data were compared across groups categorized by admission estimated glomerular filtration rate and AKI during admission. On admission, 79% of the cohort (n=1566) had at least mild chronic kidney disease (estimated glomerular filtration rate &lt;60 mL/min in 46%, &lt;30 mL/min in 22%). Chronic kidney disease patients were more likely to develop heart failure ( P &lt;0.0001), non–ST-elevation myocardial infarction ( P =0.003), and AKI ( P &lt;0.007). AKI patients were at greater risk of heart failure and cardiac arrest ( P ≤0.0001 for both). Subjects with AKI experienced higher mortality at 90 days ( P =0.003). Any acute loss of estimated glomerular filtration rate during hospitalization was independently associated with an increased risk of death (odds ratio, 1.05; P =0.03 per 10-mL/min decline). Other independent predictors of mortality included increasing age ( P &lt;0.0001), male gender ( P =0.016), white versus black race ( P =0.003), and worse baseline kidney function ( P =0.003). Conclusions— Chronic kidney disease is a common comorbidity among patients admitted with acute severe hypertension, and AKI is a frequent form of acute target organ dysfunction, particularly in those with baseline chronic kidney disease. Any degree of AKI is associated with a greater risk of morbidity and mortality.
IMMUNOLOGICAL STUDIES ON A C POLYSACCHARIDE COMPLEX OF GROUP A STREPTOCOCCI HAVING A DIRECT TOXIC EFFECT ON CONNECTIVE TISSUE
Authors: John H. Schwab, William J. Cromartie
Journal: The Journal of Experimental Medicine (1960)

A macromolecular complex of C polysaccharide and peptide derived from Group A streptococcal cells produces a multinodular, remittent, and intermittent lesion of dermal connective tissue following a single intradermal injection. This lesion is greatly modified, both in the gross and microscopically, in rabbits hyperimmunized with a Group A streptococcal vaccine. The immune serum, absorbed to yield only antibodies against C polysaccharide as indicated by agar diffusion techniques, will precipitate and neutralize the toxic material. This neutralization and in vitro precipitation can be inhibited with formamide-isolated C polysaccharide hapten and with N-acetylglucosamine, the primary directive group of this antigen. This clearly demonstrates that antibodies against the group-specific C polysaccharide are responsible for resistance to this toxic material. The immunological and other properties of the toxic C polysaccharide complex, the fact that it is a product of Group A streptococci, the gross and microscopic features of the experimental lesion produced with this substance, and the observations on the chronic course of the experimental lesion, indicate that this toxic material should be investigated as a possible factor in the pathogenesis of the non-suppurative sequelae associated with Group A streptococci.
Injury trend analysis from the US Open Tennis Championships between 1994 and 2009
Authors: Katie Sell, Brian Hainline, Michael Yorio, Mark Kovacs
Journal: British Journal of Sports Medicine (2012)

Injuries can be a debilitating aspect of professional tennis. Injury rates and trends at the US Open Tennis Championships over multiple years are unknown. The purpose of this study was to examine injury trends in professional tennis players competing in a major professional tennis tournament between 1994 and 2009.From 1994 to 2009, injury data from the US Open Tennis Championships were recorded. Injuries were classified by location and type using terminology derived from a consensus statement developed specifically for tennis. Injury rates were determined based on the exposure of an athlete to a match event, and were calculated as the ratio of injuries per 1000 match exposures (MEs).There was a statistically significant fluctuation in injuries across the timeframe analysed (p<0.05). There were 76.2±19.6 total injuries and 43.8±11.8 acute injuries per year seeking medical assistance. Muscle or tendon injuries were the most common type of acute injury. The rate of lower limb injuries was significantly higher than upper limb and trunk injuries (p<0.01). The ankle, followed by the wrist, knee, foot/toe and shoulder/clavicle were the most common injury sites.Acute injuries occurred more frequently than gradual-onset injuries, and most common injury types were similar to previously examined populations. However, there were differences in injury location trends compared to previous research, suggesting that further research in this elite-level population is warranted.
Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis
Authors: F. Wong, M. K. Nadim, J. A. Kellum, F. Salerno, R. Bellomo, A. Gerbes, P. Angeli, R. Moreau, A. Davenport, R. Jalan, C. Ronco, Y. Genyk, V. Arroyo
Journal: Gut (2011)

<h3>Objectives</h3> To propose an improvement on the current classification of renal dysfunction in cirrhosis. Clinicians caring for patients with cirrhosis recognize that the development of renal dysfunction is associated with significant morbidity and mortality. While most cases of renal dysfunction in cirrhosis are functional in nature, developed as a result of changes in haemodynamics, cardiac function, and renal auto-regulation, there is an increasing number of patients with cirrhosis and structural changes in their kidney as a cause of renal dysfunction. Therefore, there is a need for a newer classification to include both functional and structural renal diseases. <h3>Design</h3> A working party consisting of specialists from multiple disciplines conducted literature search and developed summary statements, incorporating the renal dysfunction classification used in nephrology. These were discussed and revised to produce this proposal. <h3>Setting</h3> Multi-disciplinary international meeting. <h3>Patients</h3> None. <h3>Interventions</h3> Literature search using keywords of cirrhosis, renal dysfunction, acute kidney injury (AKI), chronic kidney injury (CKD), and hepatorenal syndrome. <h3>Results</h3> Acute kidney injury will include all causes of acute deterioration of renal function as indicated by an increase in serum creatinine of &gt;50% from baseline, or a rise in serum creatinine of ≥26.4µmol/L (≥0.3mg/dL) in &lt;48hours. Chronic renal disease will be defined as an estimated glomerular filtration rate (GFR) of &lt;60ml/min calculated using the Modification of Diet in Renal Disease 6 (MDRD6) formula, recognising that the MDRD6 formula is not perfect for the cirrhotic patients and this may change as improved means of estimating GFR becomes available. Acute on chronic kidney disease will be defined as AKI superimposed on existing chronic renal disease using the above definitions for AKI and CKD. <h3>Conclusions</h3> Accepting this new classification will allow studies into the epidemiology, incidence, prevalence, natural history and the development of new treatments for these subtypes of renal dysfunction in cirrhosis.
GF-15, a Novel Inhibitor of Centrosomal Clustering, Suppresses Tumor Cell Growth <i>In Vitro</i> and <i>In Vivo</i>
Authors: Marc S. Raab, Iris Breitkreutz, Simon Anderhub, Mads H. Rønnest, Blanka Leber, Thomas O. Larsen, Ludmila Weiz, Gleb Konotop, Patrick J. Hayden, Klaus Podar, Johannes Fruehauf, Felix Nissen, Walter Mier, Uwe Haberkorn, Anthony D. Ho, Hartmut Goldschmidt, Kenneth C. Anderson, Mads H. Clausen, Alwin Krämer
Journal: Cancer Research (2012)

In contrast to normal cells, malignant cells are frequently aneuploid and contain multiple centrosomes. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles in many cancer cells. Recently, we have shown that griseofulvin forces tumor cells with supernumerary centrosomes to undergo multipolar mitoses resulting in apoptotic cell death. Here, we describe the characterization of the novel small molecule GF-15, a derivative of griseofulvin, as a potent inhibitor of centrosomal clustering in malignant cells. At concentrations where GF-15 had no significant impact on tubulin polymerization, spindle tension was markedly reduced in mitotic cells upon exposure to GF-15. Moreover, isogenic cells with conditional centrosome amplification were more sensitive to GF-15 than parental controls. In a wide array of tumor cell lines, mean inhibitory concentrations (IC(50)) for proliferation and survival were in the range of 1 to 5 μmol/L and were associated with apoptotic cell death. Importantly, treatment of mouse xenograft models of human colon cancer and multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival. These results show the in vitro and in vivo antitumor efficacy of a prototype small molecule inhibitor of centrosomal clustering and strongly support the further evaluation of this new class of molecules.
Prostacyclin therapies for the treatment of pulmonary arterial hypertension
Authors: M. Gomberg-Maitland, H. Olschewski
Journal: European Respiratory Journal (2008)

Prostacyclin and its analogues (prostanoids) are potent vasodilators and possess antithrombotic, antiproliferative and anti-inflammatory properties. Pulmonary hypertension (PH) is associated with vasoconstriction, thrombosis and proliferation, and the lack of endogenous prostacyclin may considerably contribute to this condition. This supports a strong rationale for prostanoid use as therapy for this disease. The first experiences of prostanoid therapy in PH patients were published in 1980. Epoprostenol, a synthetic analogue of prostacyclin, and the chemically stable analogues iloprost, beraprost and treprostinil were tested in randomised controlled trials. The biological actions are mainly mediated by activation of specific receptors of the target cells; however, new data suggest effects on additional intracellular pathways. In the USA and some European countries, intravenous infusion of epoprostenol and treprostinil, as well as subcutaneous infusion of treprostinil and inhalation of iloprost, have been approved for therapy of pulmonary arterial hypertension. Iloprost infusion and beraprost tablets have been approved in few other countries. Ongoing clinical studies investigate oral treprostinil, inhaled treprostinil and the combination of inhaled iloprost and sildenafil in pulmonary arterial hypertension. Combination of other targeted therapies with prostanoids appears to be effective and safe. After 25 yrs of continued knowledge, prostanoids remain a mainstay in the treatment of pulmonary arterial hypertension.
Marine n-3 Polyunsaturated Fatty Acids in Adipose Tissue and the Risk of Acute Coronary Syndrome
Authors: Albert Marni Joensen, Kim Overvad, Claus Dethlefsen, Søren Paaske Johnsen, Anne Tjønneland, Lars Hvilsted Rasmussen, Erik Berg Schmidt
Journal: Circulation (2011)

Background— Marine n-3 polyunsaturated fatty acids may reduce coronary mortality. Previous data in relation to nonfatal coronary disease, however, have been inconsistent, which may be explained by the use of heterogeneous methods to assess the intake of marine n-3 polyunsaturated fatty acids. We investigated the hypothesis that the content of total and individual marine n-3 polyunsaturated fatty acids in adipose tissue is negatively associated with the incidence of acute coronary syndrome (ACS), including both fatal and nonfatal coronary disease. Methods and Results— In the Diet, Cancer and Health, a Danish cohort study, 57 053 subjects were enrolled and had an adipose tissue biopsy taken at inclusion. During a mean follow-up period of 7.6 years, we identified and verified all cases (n=1012) with an incident acute coronary syndrome diagnosis, and a random sample of the cohort (n=1630) had their fatty acid composition in adipose tissue determined by gas chromatography. We found negative dose-response associations between the content of total marine n-3 polyunsaturated fatty acids and individual n-3 polyunsaturated fatty acids in adipose tissue and the risk of acute coronary syndrome. Comparing men in the highest and lowest quintiles gave a hazard ratio of 0.65 (95% confidence interval, 0.45 to 0.95) for total n-3 polyunsaturated fatty acids and 0.51 (95% confidence interval, 0.36 to 0.73) for docosahexaenoic acid. Nonfatal cases constituted &gt;86% of cases, and the association was driven primarily by a reduction in the risk of nonfatal acute coronary syndrome. No consistent associations were found among women. Conclusion— Intake of marine n-3 polyunsaturated fatty acids may protect against acute coronary syndrome in men.