tbuckley/cabot-search huggingface dataset:
Attenuation of murine lupus nephritis by mycophenolate mofetil.
Authors: M C Van Bruggen, B Walgreen, T P Rijke, J H Berden
Journal: Journal of the American Society of Nephrology (1998)

Mycophenolate mofetil (MMF) is the morpholinoethyl ester of mycophenolic acid, which is its active metabolite. MMF is effective in prolonging survival of allografts and xenografts. However, little is known about the effects and the main mechanism of action of MMF in autoimmune diseases. In this study, the effect of MMF on the spontaneous disease progression in the MRL/lpr mouse model of lupus was examined. Eight-week-old MRL/lpr mice (n=18) were orally treated with MMF dissolved in a vehicle (90 mg/kg) once a day. Control animals received vehicle alone (n=17). The incidence of albuminuria (>300 microg/18 h) was significantly reduced by MMF treatment compared with vehicle-treated controls (cumulative incidence of albuminuria at 23 wk in MMF-treated mice; 22% versus 88% in controls; P=0.0001). The glomerulonephritis was histologically less severe in MMF-treated mice than in control mice (P=0.005). Furthermore, in immunofluorescence studies the amount of immunoglobulin and C3 deposits in the glomerular capillary wall was significantly less in MMF-treated mice (P < or = 0.002). Surprisingly, in vivo no clear-cut immune-modulating effects were observed because there were no differences between MMF-treated and control animals with regard to autoantibody formation. Also, spleen enlargement and numbers of CD3+, CD4+, and CD8+ T cells in spleen, lymph nodes, and peripheral blood were not different between both groups. Furthermore, no immunosuppressive properties of 90 mg/kg MMF were found in BALB/c mice on delayed-type hypersensitivity and primary antibody response to methylated bovine serum albumin. Interestingly, renal perfusion experiments revealed that binding of nucleosome/antinucleosome complexes to the glomerular basement membrane is decreased in MMF-treated mice compared with control mice. It is concluded that MMF suppresses the development of lupus glomerulonephritis and albuminuria in MRL/ lpr mice. The observed reduction of glomerular immunoglobulin deposits in MMF-treated mice and the renal perfusion studies indicate that MMF treatment leads to a decreased binding of immune complexes in the glomerular capillary wall in lupus nephritis.
Purification and Properties of Angiotensin-Converting Enzyme from Hog Lung
Authors: Frederic E. Dorer, Joseph R. Kahn, Kenneth E. Lentz, Melvin Levine, Leonard T. Skeggs
Journal: Circulation Research (1972)

Angiotensin-converting enzyme was purified 1500-fold from a homogenate of hog lungs. The purification procedure included fractionation with ammonium sulfate, inactivation of contaminating enzymes at pH 4.7, batch treatment with CM-cellulose, and chromatography on columns of DEAE-cellulose, hydroxyapatite, and Sephadex G-200. The enzyme was assayed with hippurylglycylglycine and, after pH 4.7 was established, with both hippurylglycylglycine and angiotensin I as substrates. The ratio of activity toward the two substrates remained constant throughout the later stages of purification. The final enzyme preparation, on analytical disc gel electrophoresis, showed one major protein band with the expected ratio of activities toward both substrates. The molecular weight was estimated to be approximately 300,000 by gel filtration. The pH optimums with hippurylglycylglycine and angiotensin I as substrates were 8.4 and 7.5, respectively, and chloride ion was required for optimal activity of the enzyme with both substrates. Hydrolysis of both substrates was inhibited by ethylenediaminetetraacetic acid (EDTA) or the pentapeptide pyroglutamyllysyltryptophanylalanylproline. It would, therefore, appear that a single enzyme, purified in the described manner, hydrolyzes both angiotensin I and hippurylglycylglycine.
CS-19 * PDGF SIGNALING DEPENDENCE IN PRONEURAL GLIOBLASTOMA, THE BEGINNING BUT NOT THE END
Authors: N. Lindberg, Y. Kim, J. Halliday, K. Pitter, E. C. Holland
Journal: Neuro-Oncology (2014)

Proneural glioblastoma (GBM) is characterized by PDGF signaling through receptor and/or ligand overexpression or amplification. Despite this, clinical trials using the tyrosine kinase receptor inhibitor Gleveec for GBM have failed. The inability to respond to PDGFR inhibition could either be at the ligand/receptor level where the amount of ligand or receptor is sufficient to promote downstream signaling despite levels of PDGFR inhibition achieved clinically, or due to constitutive activation of downstream pathways making receptor activation less important. In addition to activation of PDGFR signaling, proneural GBMs frequently harbor alterations of tumor suppressor genes CDKN2A, PTEN and TP53. To understand if loss of these tumor suppressor genes drives tumor progression and evolution of independence from PDGF signaling, and thus therapeutic resistance, we used a combination of human and mouse proneural GBMs. Patient-derived primary cell cultures did not respond to PDGFR inhibition with reduction in proliferation when treated with Vatalanib, indicating that tumor cells were PDGF-independent and consistent with failed clinical trials. Despite reduction in receptor phosphorylation with drug treatment, no effects on downstream signaling in the PI3K and MAPK pathways were seen. Using the in vivo mouse RCAS/TVA model of proneural GBM we found that genetic knock down of PDGFRA expression inhibited tumor formation and that simultaneously knocking down expression of CDKN2A, PTEN or TP53 could not eliminate the need for PDGF signaling for tumor initiation. However, loss of CDKN2A and PTEN in PDGF-driven tumors with high PDGFRA expression accelerated tumorigenesis and lead to failure to respond to PDGFR inhibition by Vatalanib in vivo. We propose that PDGF signaling is crucial during tumor initiation but once loss of CDKN2A, PTEN and/or TP53 occurs during tumor evolution, constitutive activation of the PI3K and MAPK pathways occurs making tumor cells independent of upstream activation through PDGFRA.
LAB-MOLECULAR EPIDEMIOLOGY
Authors: L. Bie, G. Zhao, M. McClland, Y. Ju, P. Y. Li, D. J. Zhou, Z. Jin, L. Bie, R. B. Jenkins, Y. Xiao, H. Sicotte, P. A. Decker, T. M. Kollmeyer, H. M. Hansen, M. L. Kosel, S. Zheng, K. M. Walsh, T. Rice, P. Bracci, I. Smirnov, J. F. Patoka, G. Hsuang, J. L. Wiemels, T. Tehan, A. R. Pico, M. D. Prados, M. S. Berger, A. A. Caron, S. R. Fink, C. Halder, A. L. Rynearson, B. L. Fridley, B. P. O'Neill, C. Giannini, D. H. Lachance, J. K. Wienke, J. E. Eckel-Passow, M. R. Wrensch, D. Aref, A. Perry, M. Taylor, C. Eberhardt, J. Olson, C. Moffatt, S. Croul, C. Maurice, K. Belanger, F. Berthelet, X. Weng, E. S. Amirian, Y. Liu, H. Okada, S. N. Sarkar, M. L. Bondy, M. E. Scheurer, R. Verhaak, Y. Liu, E. S. Amirian, H. Okada, S. Sarkar, M. Scheurer, M. Bondy, Y. Liu, B. Melin, Z. Wang, P. Rajaraman, S. Chanock, M. Bondy, G. Consortium, A. Smith, W. P. Accomando, E.-A. Houseman, C. J. Marsit, J. K. Weincke, K. T. Kelsey
Journal: Neuro-Oncology (2012)
Can We Systematically Review Studies That Evaluate Complex Interventions?
Authors: Sasha Shepperd, Simon Lewin, Sharon Straus, Mike Clarke, Martin P. Eccles, Ray Fitzpatrick, Geoff Wong, Aziz Sheikh
Journal: PLoS Medicine (2009)

The UK Medical Research Council defines complex interventions as those comprising "a number of separate elements which seem essential to the proper functioning of the interventions although the 'active ingredient' of the intervention that is effective is difficult to specify." A typical example is specialist care on a stroke unit, which involves a wide range of health professionals delivering a variety of treatments. Michelle Campbell and colleagues have argued that there are "specific difficulties in defining, developing, documenting, and reproducing complex interventions that are subject to more variation than a drug". These difficulties are one of the reasons why it is challenging for researchers to systematically review complex interventions and synthesize data from separate studies. This PLoS Medicine Debate considers the challenges facing systematic reviewers and suggests several ways of addressing them.
AIDS: Cures? Crisis!
Authors: D. Starin
Journal: Journal of the Royal Society of Medicine (2007)

There is an eerie cloud hanging over The Gambia, as if the skies are holding back tears, waiting, waiting for a torrential storm of violent desperation. The people are also waiting. Waiting for tomorrow. Always tomorrow. Always hoping things will improve. Hoping the rains will be sufficient. Hoping the crops will be ample. Hoping the rats and insects will not eat the maize and groundnuts and sorghum before they are taken to market. Hoping their children will not get sick. Hoping they will not get sick.
Determining When Quality Improvement Initiatives Should Be Considered Research
Authors: David Casarett, Jason H. T. Karlawish, Jeremy Sugarman
Journal: JAMA (2000)

Quality improvement initiatives have become a major force in shaping health care. These initiatives are diverse but share a common goal of generating knowledge that will guide improvements in health care. Although quality improvement occupies an uncertain territory between clinical care and research, this difference is extremely important. If a quality improvement initiative is research, federal regulations require a variety of procedures that must be followed to protect the human subjects involved. Conversely, if the same initiative is not research, the regulations outlining these procedures are not applicable. This article proposes 2 criteria to determine whether a quality improvement initiative should be reviewed as research. Such an initiative should be reviewed and regulated as research if (1) the majority of patients involved are not expected to benefit directly from the knowledge to be gained or (2) if additional risks or burdens are imposed to make the results generalizable. Implementation of these criteria offers the possibility that the rights and interests of those who participate in quality improvement initiatives will be protected.
Dietary Mutagens and the Risk of Breast Cancer
Authors: K. M. Egan, E. Giovannucci
Journal: JNCI Journal of the National Cancer Institute (1998)

In this issue of the Journal, Zheng et al. (1) report a positive association between the preference for well-done red meat and risk of postmenopausal breast cancer. Using color photographs of hamburger, bacon, and beefsteak showing increasing levels of doneness (from extremely rare to very well done), women who selected a cooking preference for ‘‘very well done’’ for each of these foods had a risk nearly five times higher than that for women who consistently selected a preference for rare/medium cooking. Overall consumption of red meat itself had only a weak association with risk, and white meats, including chicken, turkey, and fish, were not statistically significant risk factors regardless of cooking method. The specificity of the findings to meat preparation tends to rule out saturated fat as the causative factor and is consistent with the possibility that mutagens, including heterocyclic amines, formed during high-temperature cooking of meats may be mammary carcinogens in humans. The browned and charred surface of meats contains a hash of laboratory carcinogens. Among these are the heterocyclic amines, formed through chemical reactions involving amino acids. The formation of heterocyclic amines requires high temperatures, such as are found in radiative or conductive cooking (e.g., grilling or frying) but not as a rule in indirect convection (e.g., roasting) or boiling (e.g., poaching or steaming) methods (2). These substances are capable of inducing tumors in a number of species (2) and are reportedly among some of the most powerful mutagenic agents, based on the Ames test (3). Heterocyclic amines involving creatinine as a precursor are numerically most important. Among these, 2-amino-1-methyl-6phenylimidazo[4,5-b]pyridine (PhIP) predominates, accounting for approximately one half of the total heterocyclic amine intake in the U.S. diet. Five compounds, i.e., PhIP, 2-amino3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx), 2-amino3,4,8-trimethylimidazo[4,5-f]quinoxaline ( DiMeIQx), 2-amino-3-methylimidazo[4,5-f ]quinoline (IQ), and 2-amino9H-pyrido[2,3-b]indole (AaC), make up approximately two thirds of the total intake (4). Based on animal bioassay data, the relative mutagenic potency of these compounds varies by a factor of more than 20, with IQ and DiMeIQx at the high end, PhIP and AaC at the low end, and MeIQx at an intermediate level of potency (4). Thus, the absolute concentration of specific heterocyclic amines in foods must be weighed against their individual potential for genetic damage when they are evaluated as potential human carcinogens. Major dietary sources of these compounds vary from population to population depending on a number of factors, including cultural mores and meat availability. In a study of female registered nurses (5), the major predictor of PhIP in the diet was grilled or broiled chicken, whereas the chief source of DiMeIQx was pan-fried steak.
Antibodies to the ADP/ATP carrier, an autoantigen in myocarditis and dilated cardiomyopathy, penetrate into myocardial cells and disturb energy metabolism in vivo.
Authors: K Schulze, B F Becker, H P Schultheiss
Journal: Circulation Research (1989)

We identified the ADP/ATP carrier, located within the inner mitochondrial membrane, to be an organ- and conformation-specific autoantigen in myocarditis and dilated cardiomyopathy. We also showed that autoantibodies to the ADP/ATP carrier inhibit the nucleotide transport in vitro. Specific binding of the autoantibodies to the carrier was demonstrated by radioimmunoassay and the immunoblot technique; the inhibition of the nucleotide transport was determined by the inhibitor stop method. To establish if these autoantibodies might also affect cardiac energy metabolism in vivo, we measured whether they are capable of penetrating into myocytes and whether subcellular ATP/ADP ratios and phosphorylation potentials of ATP change in hearts of guinea pigs that have been immunized with the isolated ADP/ATP carrier. An intracellular deposition of autoantibodies was observed by direct immunofluorescence and by immunoperoxidase staining on cryosections of the myocardial tissue of animals immunized with the ADP/ATP carrier. Furthermore, binding of autoantibodies to mitochondrial membrane structures was shown by immunoelectron-microscopic methods. The cytosolic and intramitochondrial distribution of adenine nucleotides in stimulated, isolated perfused hearts of guinea pigs immunized with the ADP/ATP carrier was measured by nonaqueous fractionation. Compared with controls performing equal external heart work, the cytosolic ATP decreased in the immunized animals, whereas the mitochondrial ATP increased strongly; ADP concentrations showed an opposite change. Thus, a resultant cytosolic decrease and a marked mitochondrial increase of the ATP/ADP ratio was established. As a consequence, the cytosolic-mitochondrial phosphorylation potential of ATP was diminished. These findings demonstrate that antibodies against intracellular antigens are able to penetrate into living cells, and that autoimmunity to the ADP/ATP carrier may contribute to the pathophysiology of myocarditis and dilated cardiomyopathy by causing an autoantibody-mediated imbalance between intracellular energy delivery and demand.
Improving Primary Care for Patients With Chronic Illness
Authors: Thomas Bodenheimer, Edward H. Wagner, Kevin Grumbach
Journal: JAMA (2002)

The chronic care model is a guide to higher-quality chronic illness management within primary care. The model predicts that improvement in its 6 interrelated components—self-management support, clinical information systems, delivery system redesign, decision support, health care organization, and community resources—can produce system reform in which informed, activated patients interact with prepared, proactive practice teams. Case studies are provided describing how components of the chronic care model have been implemented in the primary care practices of 4 health care organizations.
Smoke-free legislation and childhood hospitalisations for respiratory tract infections
Authors: Jasper V. Been, Christopher Millett, John Tayu Lee, Constant P. van Schayck, Aziz Sheikh
Journal: European Respiratory Journal (2015)

Second-hand smoke exposure is a major risk factor for respiratory tract infections (RTIs). Although evidence suggests important early-life health benefits of smoke-free public environments, the impact on childhood RTIs is unclear. We investigated the association between England's smoke-free legislation and childhood RTI hospitalisations.We used the Hospital Episode Statistics database to obtain nationwide data on hospital admissions for acute RTIs among children (<15 years of age) from 2001 to 2012. Hospitalisation counts were disaggregated by month, age group, sex and small-area level, and linked to urbanisation, region, deprivation index and corresponding population estimates. Negative binomial regression analyses were adjusted for confounders, seasonal variation, temporal autocorrelation, population-size changes and underlying incidence trends. Models allowed for sudden and gradual changes following the smoke-free legislation. We performed sensitivity and subgroup analyses, and estimated number of events prevented.We analysed 1 651 675 hospital admissions. Introduction of smoke-free legislation was followed by an immediate reduction in RTI admissions (-3.5%, 95% CI -4.7- -2.3%), this mainly being attributable to a decrease in lower RTI admissions (-13.8%, 95% CI -15.6- -12.0%). The reductions in admissions for upper RTI were more incremental.The introduction of national smoke-free legislation in England was associated with ∼11 000 fewer hospital admissions per year for RTIs in children.
V(D)J Recombination: Modulation of <i>RAG1</i> and <i>RAG2</i> Cleavage Activity on 12/23 Substrates by Whole Cell Extract and DNA-bending Proteins
Authors: Dennis J. Sawchuk, Frances Weis-Garcia, Sohail Malik, Eva Besmer, Michael Bustin, Michel C. Nussenzweig, Patricia Cortes
Journal: The Journal of Experimental Medicine (1997)

Antigen receptor gene rearrangement is directed by DNA motifs consisting of a conserved heptamer and nonamer separated by a nonconserved spacer of either 12 or 23 base pairs (12 or 23 recombination signal sequences [RSS]). V(D)J recombination requires that the rearranging DNA segments be flanked by RSSs of different spacer lengths, a phenomenon known as the 12/23 rule. Recent studies have shown that this restriction operates at the level of DNA cleavage, which is mediated by the products of the recombination activating genes RAG1 and RAG2. Here, we show that RAG1 and RAG2 are not sufficient for 12/23 dependent cleavage, whereas RAG1 and RAG2 complemented with whole cell extract faithfully recapitulates the 12/23 rule. In addition, HMG box containing proteins HMG1 and HMG2 enhance RAG1- and RAG2-mediated cleavage of substrates containing 23 RSS but not of substrates containing only 12 RSS. These results suggest the existence of a nucleoprotein complex at the cleavage site, consisting of architectural, catalytic, and regulatory components.
Culture as an aggregate of individual differences
Authors: Kyungil Kim, Joonghwan Jeon, Youngjun Park
Journal: Behavioral and Brain Sciences (2014)

Abstract We question Smaldino's argument that culture plays the active role of maintaining and transmitting social organizations of differentiated individuals. Culture is an aggregate of individual differences in psychological variables within and between groups; it was not designed by group-level selection to maintain the structured organization of individuals. We conclude that Smaldino fails to present the crucial mechanism by which group-level traits are maintained, transmitted, and evolve.
Rapid Increase in the Use of Oral Antidiabetic Drugs in the United States, 1990–2001
Authors: Diane K. Wysowski, George Armstrong, Laura Governale
Journal: Diabetes Care (2003)

OBJECTIVE—To describe the use of oral antidiabetic drugs for management of type 2 diabetes in the U.S. from 1990 through 2001. RESEARCH DESIGN AND METHODS—Data on oral antidiabetic drugs were derived from two pharmaceutical marketing databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index. RESULTS—In 1990, 23.4 million outpatient prescriptions of oral antidiabetic agents were dispensed. By 2001, this number had increased 3.9-fold, to 91.8 million prescriptions. Glipizide and glyburide, two sulfonylurea medications, accounted for ∼77% of prescriptions of oral antidiabetic drugs in 1990 and 35.5% of prescriptions in 2001. By 2001, the biguanide metformin (approved in 1995) had captured ∼33% of prescriptions, and the thiazolidinedione insulin sensitizers (rosiglitazone and pioglitazone marketed beginning in 1999) accounted for ∼17% of market share. Compared with patients treated in 1990, those in 2001 were proportionately younger and they more often used oral antidiabetic drugs and insulin in combination. Internists and general and family practitioners were the primary prescribers of this class of drugs. CONCLUSIONS—Consistent with the reported increase in the prevalence of type 2 diabetes, the number of dispensed outpatient prescriptions of oral antidiabetic drugs increased rapidly between 1990 and 2001. This period was marked by an increase in the treatment of younger people and the use of oral antidiabetic drugs in combination. With the approval in the last decade of several new types of oral antidiabetic medications with different mechanisms of action, options for management of type 2 diabetes have expanded.
Taking TRIPS to India — Novartis, Patent Law, and Access to Medicines
Authors: Janice M. Mueller
Journal: New England Journal of Medicine (2007)

Interview with Janice Mueller on a pharmaceutical-industry challenge to Indian patent laws. (06:46)Download In August and September 2006, patients with cancer, lawyers for patient advocacy groups, and representatives of nongovernmental organizations (NGOs) converged on the offices of Novartis in Mumbai, India, to protest the company's efforts to obtain an Indian patent on Gleevec, the company's brand-name version of imatinib mesylate. Gleevec (spelled Glivec outside the United States) is used to treat chronic myeloid leukemia, and Novartis has patented the drug in 35 countries. The protesters also decried the drug's high price: Novartis sells it in India (where only 5% of people have private health insurance) for $26,000 per year; generic-drug manufacturers offer the . . .
Biology, Models, and the Analysis of Tumor Xenograft Experiments
Authors: Daniel F. Heitjan
Journal: Clinical Cancer Research (2011)

Abstract Advances in statistical modeling and analysis technology have improved our ability to derive valid inferences from tumor xenograft experiments. Further challenges in this area include the modeling of intertumor heterogeneity and the development of robust statistical models that describe key parameters in the underlying tumor biology. Clin Cancer Res; 17(5); 949–52. ©2011 AACR.
Inadequate Dissemination of Phase I Trials: A Retrospective Cohort Study
Authors: Evelyne Decullier, An-Wen Chan, François Chapuis
Journal: PLoS Medicine (2009)

Drug development is ideally a logical sequence in which information from small early studies (Phase I) is subsequently used to inform and plan larger, more definitive studies (Phases II-IV). Phase I trials are unique because they generally provide the first evaluation of new drugs in humans. The conduct and dissemination of Phase I trials have not previously been empirically evaluated. Our objective was to describe the initiation, completion, and publication of Phase I trials in comparison with Phase II-IV trials.