tbuckley/cabot-search huggingface dataset:
A Universal Influenza A Vaccine Based on Adenovirus Expressing Matrix-2 Ectodomain and Nucleoprotein Protects Mice From Lethal Challenge
Authors: Dongming Zhou, Te-Lang Wu, Marcio O Lasaro, Brian P Latimer, Elizabeth M Parzych, Ang Bian, Yan Li, Hua Li, Jan Erikson, Zhiquan Xiang, Hildegund CJ Ertl
Journal: Molecular Therapy (2010)

A universal influenza vaccine, designed to induce broadly cross-reactive immunity against current and future influenza A virus strains, is in critical demand to reduce the need for annual vaccinations with vaccines chosen upon predicting the predominant circulating viral strains, and to ameliorate the threat of cyclically occurring pandemics that have, in the past, killed tens of millions. Here, we describe a vaccine regimen based on sequential immunization with two serologically distinct chimpanzee-derived replication-defective adenovirus (Ad) vectors expressing the matrix-2 protein ectodomain (M2e) from three divergent strains of influenza A virus fused to the influenza virus nucleoprotein (NP) for induction of antibodies to M2e and virus-specific CD8+ T cells to NP. In preclinical mouse models, the Ad vaccines expressing M2e and NP elicit robust NP-specific CD8+ T-cell responses and moderate antibody responses to all three M2e sequences. Most importantly, vaccinated mice are protected against morbidity and mortality following challenge with high doses of different influenza virus strains. Protection requires both antibodies to M2e and cellular immune responses to NP. A universal influenza vaccine, designed to induce broadly cross-reactive immunity against current and future influenza A virus strains, is in critical demand to reduce the need for annual vaccinations with vaccines chosen upon predicting the predominant circulating viral strains, and to ameliorate the threat of cyclically occurring pandemics that have, in the past, killed tens of millions. Here, we describe a vaccine regimen based on sequential immunization with two serologically distinct chimpanzee-derived replication-defective adenovirus (Ad) vectors expressing the matrix-2 protein ectodomain (M2e) from three divergent strains of influenza A virus fused to the influenza virus nucleoprotein (NP) for induction of antibodies to M2e and virus-specific CD8+ T cells to NP. In preclinical mouse models, the Ad vaccines expressing M2e and NP elicit robust NP-specific CD8+ T-cell responses and moderate antibody responses to all three M2e sequences. Most importantly, vaccinated mice are protected against morbidity and mortality following challenge with high doses of different influenza virus strains. Protection requires both antibodies to M2e and cellular immune responses to NP.
Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease
Authors: Danilo Fliser, Florian Kronenberg, Jan T. Kielstein, Christian Morath, Stefanie M. Bode-Bo[Combining Diaeresis]ger, Hermann Haller, Eberhard Ritz
Journal: Journal of the American Society of Nephrology (2005)

Reduced bioavailability of nitric oxide (NO) is thought to play an important role in progression of renal damage. The hypothesis that the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is involved in progression of kidney disease was tested. Plasma ADMA concentrations and other putative progression factors were assessed in 227 relatively young patients (45.7 ± 12.6 yr) with nondiabetic kidney diseases and mild to moderate renal failure. Progression assessed as doubling of serum creatinine and/or renal replacement therapy was evaluated prospectively. Baseline plasma ADMA concentrations in renal patients correlated significantly with serum creatinine (r = 0.595), GFR (r = −0.591), age (r = 0.281), and proteinuria (r = 0.184; all P < 0.01). Patients who reached an end point during follow-up were significantly older (P < 0.05) and had significantly higher creatinine, ADMA, and parathyroid hormone blood concentrations and protein excretion rates at baseline, whereas GFR and hemoglobin were significantly lower (all P < 0.01). Cox regression analysis revealed baseline serum creatinine (odds ratio 2.00; 95% confidence interval [CI] 1.61 to 2.49; P < 0.001) and ADMA (odds ratio 1.47; 95% CI 1.12 to 1.93 for an increment of 0.1 μmol/L; P < 0.006) as independent predictors of disease progression. In patients with ADMA levels above median, progression was significantly faster (P < 0.0001), and their mean follow-up time to a progression end point was 52.8 mo (95% CI 46.9 to 58.8) as compared with 71.6 mo (95% CI 66.2 to 76.9) in patients with ADMA levels below the median. The endogenous NO synthase inhibitor ADMA is significantly associated with progression of nondiabetic kidney diseases. Lowering plasma ADMA concentrations may be a novel therapeutic target to prevent progressive renal impairment.
Transmission of Multidrug-Resistant and Drug-Susceptible Tuberculosis within Households: A Prospective Cohort Study
Authors: Louis Grandjean, Robert H. Gilman, Laura Martin, Esther Soto, Beatriz Castro, Sonia Lopez, Jorge Coronel, Edith Castillo, Valentina Alarcon, Virginia Lopez, Angela San Miguel, Neyda Quispe, Luis Asencios, Christopher Dye, David A. J. Moore
Journal: PLoS Medicine (2015)

The "fitness" of an infectious pathogen is defined as the ability of the pathogen to survive, reproduce, be transmitted, and cause disease. The fitness of multidrug-resistant tuberculosis (MDRTB) relative to drug-susceptible tuberculosis is cited as one of the most important determinants of MDRTB spread and epidemic size. To estimate the relative fitness of drug-resistant tuberculosis cases, we compared the incidence of tuberculosis disease among the household contacts of MDRTB index patients to that among the contacts of drug-susceptible index patients.This 3-y (2010-2013) prospective cohort household follow-up study in South Lima and Callao, Peru, measured the incidence of tuberculosis disease among 1,055 household contacts of 213 MDRTB index cases and 2,362 household contacts of 487 drug-susceptible index cases. A total of 35/1,055 (3.3%) household contacts of 213 MDRTB index cases developed tuberculosis disease, while 114/2,362 (4.8%) household contacts of 487 drug-susceptible index patients developed tuberculosis disease. The total follow-up time for drug-susceptible tuberculosis contacts was 2,620 person-years, while the total follow-up time for MDRTB contacts was 1,425 person-years. Using multivariate Cox regression to adjust for confounding variables including contact HIV status, contact age, socio-economic status, and index case sputum smear grade, the hazard ratio for tuberculosis disease among MDRTB household contacts was found to be half that for drug-susceptible contacts (hazard ratio 0.56, 95% CI 0.34-0.90, p = 0.017). The inference of transmission in this study was limited by the lack of genotyping data for household contacts. Capturing incident disease only among household contacts may also limit the extrapolation of these findings to the community setting.The low relative fitness of MDRTB estimated by this study improves the chances of controlling drug-resistant tuberculosis. However, fitter multidrug-resistant strains that emerge over time may make this increasingly difficult.
Impairment of Apoptotic Cell Engulfment by Pyocyanin, a Toxic Metabolite of<i>Pseudomonas aeruginosa</i>
Authors: Stephen M. Bianchi, Lynne R. Prince, Kathleen McPhillips, Lucy Allen, Helen M. Marriott, Graham W. Taylor, Paul G. Hellewell, Ian Sabroe, David H. Dockrell, Peter W. Henson, Moira K. B. Whyte
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Cystic fibrosis lung disease is characterized by accumulation of apoptotic neutrophils, indicating impaired clearance of dying cells. Pseudomonas aeruginosa, the principal microbial pathogen in cystic fibrosis, manipulates apoptosis induction via production of toxic metabolites. Whether these metabolites, particularly pyocyanin, can also modulate apoptotic cell engulfment is unknown.To assess the effects of pyocyanin on apoptotic cell engulfment by macrophages in vitro and in vivo and to investigate potential mechanisms of the observed effects.Human monocyte-derived macrophages were treated with pyocyanin before challenge with apoptotic neutrophils, apoptotic Jurkat cells, or latex beads, and phagocytosis was assessed by light microscopy and flow cytometry. Effects of pyocyanin production on apoptotic cell clearance in vivo were assessed in a murine model, comparing infection by wild-type or pyocyanin-deficient P. aeruginosa. Oxidant production was investigated using fluorescent probes and pharmacologic inhibition and Rho GTPase signaling by immunoblotting and inhibitor studies.Pyocyanin treatment impaired macrophage engulfment of apoptotic cells in vitro, without inducing significant macrophage apoptosis, whereas latex bead uptake was preserved. Macrophage ingestion of apoptotic cells was reduced and late apoptotic/necrotic cells were increased in mice infected with pyocyanin-producing P. aeruginosa compared with the pyocyanin-deficient strain. Inhibition of apoptotic cell uptake involved intracellular generation of reactive oxygen species (ROS) and effects on Rho GTPase signaling. Antioxidants or blockade of Rho signaling substantially restored apoptotic cell engulfment.These studies demonstrate that P. aeruginosa can manipulate the inflammatory microenvironment through inhibition of apoptotic cell engulfment, and suggest potential strategies to limit pulmonary inflammation in cystic fibrosis.
Neuronal Nitric Oxide Synthase Is Expressed in Rat Vascular Smooth Muscle Cells
Authors: Chantal M. Boulanger, Christophe Heymes, Joëlle Benessiano, Robert S. Geske, Bernard I. Lévy, Paul M. Vanhoutte
Journal: Circulation Research (1998)

The nitric oxide synthase (NOS) inhibitor nitro-L-arginine augmented the contractions to angiotensin (Ang) II in carotid artery rings without endothelium from spontaneously hypertensive rats (SHR) but not normotensive Wistar-Kyoto rats, suggesting the possibility of nonendothelial NOS activity in SHR arteries. In SHR artery without endothelium, the potentiation of Ang II contraction by nitro-L-arginine was prevented by L-arginine, but not by D-arginine, and was observed also in the presence of oxyhemoglobin, monomethyl-L-arginine, and 7-nitroindazole, but not in the presence of aminoguanidine. In further support of NOS activation by Ang II in nonendothelial cells, Ang II but not acetylcholine stimulated cGMP levels by 2-fold in SHR arteries without endothelium; nitro-L-arginine decreased both basal and Ang II-stimulated cGMP levels. When NOS activity in SHR arteries was measured, no calcium-independent L-citrulline formation was detectable, while up to 47% of the total calcium-dependent NOS activity was present in nonendothelial cells. Expression of neuronal NOS was revealed in the media of SHR arteries by immunohistochemistry, Western blot, and reverse transcriptase-polymerase chain reaction. Expression of this NOS isoform was greater in SHR than in Wistar-Kyoto rat preparations. Finally, endothelial NOS was observed in the endothelium, but no detectable levels of inducible NOS were found in these tissues. These results demonstrate the expression of neuronal NOS in rat vascular smooth muscle cells and its activation on stimulation by Ang II in spontaneously hypertensive, but not normotensive, animals.
Pathophysiology of exertional death associated with sickle cell trait: can we make a parallel with vaso-occlusion mechanisms in sickle cell disease?
Authors: Philippe Connes, Kimberly G Harmon, Michael F Bergeron
Journal: British Journal of Sports Medicine (2012)

Whether sickle cell trait (SCT) carriers are at greater risk for exertional death has been a subject of intense debate.1 Large epidemiological studies in warfighters2 and athletes3 clearly show an increased risk for exercise-related sudden death in SCT carriers compared with non-SCT carriers.

The pathogenesis of exertional death in SCT carriers is unknown.4 However, the mechanisms initiating these adverse events could be parallel to the ones involved in the vaso-occlusion crises in sickle cell disease (SCD). Vaso-occlusion in patients with SCD involves haemorheological alterations, inflammation, vascular-adhesion processes and endothelial dysfunction.5 Comparisons of exercise responses between SCT carriers and non-SCT carriers demonstrated slightly decreased red blood cell deformability, increased …
Molecular Pathways: Adaptive Kinome Reprogramming in Response to Targeted Inhibition of the BRAF–MEK–ERK Pathway in Cancer
Authors: Gary L. Johnson, Timothy J. Stuhlmiller, Steven P. Angus, Jon S. Zawistowski, Lee M. Graves
Journal: Clinical Cancer Research (2014)

The central role of the BRAF-MEK-ERK pathway in controlling cell fate has made this pathway a primary target for deregulated activation in cancer. BRaf is activated by Ras proteins allowing Ras oncogenes to constitutively activate the pathway. Activating BRaf mutations are also frequent in several cancers, being the most common oncogenic mutation in thyroid carcinoma and melanoma. There are currently two inhibitors, vemurafenib and dabrafenib, approved for treatment of malignant melanoma having activating BRaf mutations. Concurrent administration of BRAF and MAP-ERK kinase (MEK) inhibitor (trametinib) is significantly more active in patients with BRAF-mutant melanoma than either single agent alone, but progression to resistance ultimately occurs by different mechanisms that increase the activation of extracellular signal-regulated kinase (ERK). Such adaptive changes in tumor cell signaling networks allow bypass of targeted oncoprotein inhibition. This is true with targeted inhibitors for BRaf and MEK as well as specific inhibitors for AKT, mTOR, and many receptor tyrosine kinases such as EGF receptor (EGFR) and HER2. It is this adaptive response to targeted kinase inhibitors that contributes to the failure of single-agent kinase inhibitors to have durable responses. This failure is seen in virtually all cancers treated with single-agent kinase inhibitors, most of which are not as dependent on a single signaling pathway such as BRaf-MEK-ERK in melanoma. Thus, understanding the breadth of adaptive reprogramming responses to specific targeted kinase inhibition will be critical to develop appropriate combination therapies for durable clinical responses.
Activation of the Sphingosine Kinase–Signaling Pathway by High Glucose Mediates the Proinflammatory Phenotype of Endothelial Cells
Authors: Lijun Wang, Xiao-Ping Xing, Andrew Holmes, Carol Wadham, Jennifer R. Gamble, Mathew A. Vadas, Pu Xia
Journal: Circulation Research (2005)

Vascular endothelial cells are key targets for hyperglycemic damage that facilitates vascular inflammation and the vasculopathy associated with diabetes mellitus. However, the mechanisms underlying this damage remain undefined. We now demonstrate that hyperglycemia induces activation of sphingosine kinase (SphK), which represents a novel signaling pathway that mediates endothelial damage under ambient high glucose conditions. SphK activity was significantly increased in aorta and heart of streptozotocin-induced diabetic rats. Interestingly, this increase in SphK activity was prevented by insulin treatment, which achieved euglycemia in the diabetic animals. Hyperglycemia-induced increase in SphK activity was also evident in endothelial cells that received long-term exposure to high glucose (22 mmol/L). Studies using a small interfering RNA strategy demonstrated that endogenous SphK1, but not SphK2, is the major isoenzyme that was activated by high glucose. In addition, an increase in SphK1 phosphorylation was detected in a protein kinase C– and extracellular signal–regulated kinase 1/2–dependent manner, which accounts for the high glucose–induced increases in SphK activity. Importantly, inhibition of SphK1 by either a chemical inhibitor ( N ′, N ′-dimethylsphingosine) or expression of a dominant-negative mutant of SphK1 (SphK G82D ), or SphK1-specific small interfering RNA, strongly protected endothelial cells against high glucose–induced damage, as characterized by an attenuation in the expression of proinflammatory adhesion molecules, adhesion of leukocytes to endothelial cells, and nuclear factor κB activation. Thus, interventions that target the SphK-signaling pathway may have the potential to prevent vascular lesions under hyperglycemic conditions.
Prospective Study of Regular Aspirin Use and the Risk of Breast Cancer
Authors: K. M. Egan, M. J. Stampfer, E. Giovannucci, B. A. Rosner, G. A. Colditz
Journal: JNCI Journal of the National Cancer Institute (1996)

Evidence suggests that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit tumor development in the large bowel. An inverse association between the use of NSAIDs and the incidence of breast cancer has been observed, but this association has not been statistically significant in all studies. We analyzed data from the prospective Nurses' Health Study to evaluate the influence of aspirin use on breast cancer risk. We studied a population of 89 528 female registered nurses who reported no history of breast or other cancers (excluding nonmelanoma skin cancer) and who returned a mailed questionnaire in 1980 that elicited information concerning breast cancer risk factors and current and past aspirin use. Follow-up questionnaires were mailed to the participants every 2 years; the women were followed through 1992. Information concerning current aspirin use was obtained from each biennial questionnaire, except in 1986. Cases of breast cancer were identified through questionnaire responses, and permission was sought for a review of medical records to confirm the diagnoses. Our analysis was based on 2414 cases of invasive breast cancer, which included 2303 cases confirmed with medical records and 111 cases for which no records were obtained. Relative risks (RRs) with 95% confidence intervals (CIs), adjusted for age or age plus other known or potential breast cancer risk factors (i.e., multivariate), were calculated. Regular aspirin use (two or more tablets per week) in 1980 was unrelated to breast cancer incidence during the succeeding 12-year period (with no regular aspirin use as the referent, multivariate RR = 1.03; 95% CI = 0.95–1.12). The corresponding risk estimate for consistent regular aspirin use during the period from 1980 through 1988 was 1.01 (95% CI = 0.80–1.27). The risks were similar for heavy aspirin use (for more than two tablets per day [i.e., >14 per week] in 1980 and in 1980 through 1988, the multivariate RRs [95% CIs] were 1.05 [0.89–1.23] and 1.09 [0.75–1.60], respectively) and for extended durations of regular use (e.g., for 20 years or more of regular use, multivariate RR = 1.00; 95% CI = 0.71–1.41). Our results indicate that regular aspirin use does not reduce the risk of breast cancer. [J Natl Cancer Inst 1996;88:988–93]
Why measure C reactive protein?
Authors: M Z Mazlam, H J Hodgson
Journal: Gut (1994)

For humans, daily life is characterized by routine interaction with many different tools for which corresponding actions are specified and performed according to well-learned procedures. The current study used functional MRI (fMRI) repetition suppression (RS) to identify brain areas underlying the transformation of visually defined tool properties to corresponding motor programs for conventional use. Before grasping and demonstrating how to use a specific tool, participants passively viewed either the same (repeated) tool or a different (non-repeated) tool. Repetition of tools led to reduced fMRI signals (RS) within a selective network of parietal and premotor areas. Comparison with newly learned, arbitrarily defined control actions revealed specificity of RS for tool use, thought to reflect differences in the extent of previous sensorimotor experience. The findings indicate that familiar tools are visually represented within the same sensorimotor areas underlying their dexterous use according to learned properties defined by previous experience. This interpretation resonates with the broader concept of affordance specification considered fundamental to action planning and execution whereby action-relevant object properties (affordances) are visually represented in sensorimotor areas. The current findings extend this view to reveal that affordance specification in humans includes learned object properties defined by previous sensorimotor experience. From an evolutionary perspective, the neural mechanisms identified in the current study offer clear survival advantage, providing fast efficient transformation of visual information to appropriate motor responses based on previous experience.
Antidepressants in Amniotic Fluid: Another Route of Fetal Exposure
Authors: Ada M. Loughhead, Angela D. Fisher, D. Jeffrey Newport, James C. Ritchie, Michael J. Owens, C. Lindsay DeVane, Zachary N. Stowe
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: The authors’ goal was to determine the concentration of antidepressants in amniotic fluid during maternal treatment of depression. METHOD: Women treated with antidepressants undergoing amniocentesis for obstetrical reasons were enrolled. Antidepressant concentrations in amniotic fluid and maternal serum were determined with high-performance liquid chromatography. RESULTS: Amniotic fluid was obtained from 27 women, and the amniotic fluid’s antidepressant concentrations were highly variable. For the parent compounds, the amniotic fluid concentrations of selective serotonin uptake inhibitors averaged 11.6% (SD=9.9%) of maternal serum concentrations (N=22). Amniotic fluid to maternal serum ratios were higher for venlafaxine: 172% (SD=91%) (N=3). Of interest, the amniotic fluid to maternal serum ratios for the metabolites (N=19) did not demonstrate a consistent pattern compared to the parent compound ratios. In 10 subjects, the amniotic fluid to maternal serum ratio for the metabolites was higher than the parent compound and lower in the remaining nine subjects. CONCLUSIONS: The pattern of antidepressant concentrations in amniotic fluid is similar to recent data for placental passage. Although the significance of amniotic fluid exposure remains to be determined, these results demonstrate that maternally administered antidepressants are accessible to the fetus in a manner not previously appreciated.
Spontaneous Diabetic Myonecrosis
Authors: Javier Reyes-Balaguer, Elena Solaz-Moreno, Carmen Morata-Aldea, Patricia Elorza-Montesinos
Journal: Diabetes Care (2005)

Diabetic muscle infarction is an unusual complication of late-stage diabetes. The first case was reported in 1965 by Angervall and Stener (1). There have been <100 cases reported since then (4). Clinical presentation is an acute atraumatic painful swelling of the affected muscle and a palpable mass. Diabetic muscle infarction has predilection for the quadriceps and thigh muscles and is found in diabetic subjects with established nephropathy and retinopathy (2).

We report a case of spontaneous quadriceps necrosis in a type 2 diabetic patient on hemodialysis. A 59-year-old woman had a type 2 diabetes history of >20 years and unsatisfactory glycemic control despite insulin …