tbuckley/cabot-search huggingface dataset:
Influence of apolipoprotein E polymorphism on apolipoprotein B-100 metabolism in normolipemic subjects.
Authors: T Demant, D Bedford, C J Packard, J Shepherd
Journal: Journal of Clinical Investigation (1991)

This study examined apolipoprotein (apo) B metabolism in normolipemic subjects homozygous for the apo E2 (n = 4), apo E3 (n = 5), or apo E4 (n = 5) phenotype. Radioiodinated very low density lipoprotein (VLDL1) (ultracentrifuge flotation rate [Sf] 60-400) and VLDL2 (Sf 20-60) were injected into volunteers and the conversion of apo B was followed through intermediate density lipoprotein (IDL) to low density lipoprotein (LDL). Subjects homozygous for E3 converted approximately 50% of LVDL2 to LDL, the remainder being lost by direct catabolism. Those with the E2 phenotype produced less VLDL1, but converted more of it to VLDL2 (compared to E3 subjects). They displayed a characteristic dyslipidemia with the presence of slowly catabolized VLDL1 and VLDL2 remnants. LDL levels were low owing to increased direct catabolism of VLDL2 and IDL and a reduced efficiency of delipidation; only 25% of VLDL2 apo B was directed to LDL production. In contrast, E4 subjects converted more VLDL2 apo B to LDL than E3 subjects. About 70% of VLDL2 apo B was found in LDL; direct catabolism of VLDL and IDL was reduced as was the fractional catabolic rate of LDL (0.2 vs. 0.26 in E3 subjects). These changes in the VLDL----IDL----LDL metabolic cascade can in part be explained by alterations in hepatic LDL receptors with E2 subjects having higher and E4 subjects lower activities than those in E3 homozygotes.
Effect of urogastrone on gastric secretion and serum gastrin concentration in patients with duodenal ulceration.
Authors: C G Koffman, J B Elder, P C Ganguli, H Gregory, C G Geary
Journal: Gut (1982)

A one-hour infusion of 0.25 micrograms/kg urogastrone administered to seven patients with duodenal ulceration resulted in significant reduction of basal acid secretion (p less than 0.05) but was without significant effect on basal pepsin and intrinsic factor secretion or on serum gastrin concentration. In another group of five patients with duodenal ulceration a one-hour infusion of urogastrone was given on five successive days. On day 1 and 5 urogastrone was administered after establishing a plateau response to intravenous pentagastrin 1.2 micrograms/kg/h. A mean reduction of 65% in acid output during the urogastrtone infusion was seen on day 1 and this was maintained during the next hour. On day 5 the pentagastrin-stimulated acid output was less than on day 1 and a further significant decrease was noted after urogastrone. Pepsin and intrinsic factor output were also significantly inhibited. There was no change in fasting serum gastrin or urogastrone concentration.
Tumor Rejection Induced by CD70-mediated Quantitative and Qualitative Effects on Effector CD8+ T Cell Formation
Authors: Ramon Arens, Koen Schepers, Martijn A. Nolte, Michiel F. van Oosterwijk, René A.W. van Lier, Ton N.M. Schumacher, Marinus H.J. van Oers
Journal: The Journal of Experimental Medicine (2004)

In vivo priming of antigen-specific CD8+ T cells results in their expansion and differentiation into effector T cells followed by contraction into a memory T cell population that can be maintained for life. Recent evidence suggests that after initial antigenic stimulation, the magnitude and kinetics of the CD8+ T cell response are programmed. However, it is unclear to what extent CD8+ T cell instruction in vivo is modulated by costimulatory signals. Here, we demonstrate that constitutive ligation of the tumor necrosis factor receptor family member CD27 by its ligand CD70 quantitatively augments CD8+ T cell responses to influenza virus infection and EL-4 tumor challenge in vivo by incrementing initial expansion and maintaining higher numbers of antigen-specific T cells in the memory phase. Concomitantly, the quality of antigen-specific T cells improved as evidenced by increased interferon (IFN)-γ production and a greater cytotoxic potential on a per cell basis. As an apparent consequence, the superior effector T cell formation induced by CD70 protected against a lethal dose of poorly immunogenic EL4 tumor cells in a CD8+ T cell– and IFN-γ–dependent manner. Thus, CD70 costimulation enhances both the expansion and per cell activity of antigen-specific CD8+ T cells.
Phase I Clinical Study of AZD2171, an Oral Vascular Endothelial Growth Factor Signaling Inhibitor, in Patients With Advanced Solid Tumors
Authors: Joachim Drevs, Patrizia Siegert, Michael Medinger, Klaus Mross, Ralph Strecker, Ute Zirrgiebel, Jan Harder, Hubert Blum, Jane Robertson, Juliane M. Jürgensmeier, Thomas A. Puchalski, Helen Young, Owain Saunders, Clemens Unger
Journal: Journal of Clinical Oncology (2007)

AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy.In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed.Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2 lamda(z)) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related.Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.
Treatment of Chilblains
Authors: R. J. Gourlay
Journal: BMJ (1958)

The prevalence of chronic kidney disease (CKD) at stage 3–5 is estimated at 8.5% in the UK, but the recorded rate of CKD from Quality and Outcomes Framework (QOF) registers in 2007–2008 was 2.9%. This study aimed to identify practice or patient characteristics associated with recorded rates of CKD. Demographic and QOF data for 230 general practices were combined into a database for cross-sectional analysis. Regression analyses investigated factors associated with CKD recording; deprivation, location in Leicester city or Northamptonshire, and low recording of hypertension and stroke were associated with low CKD recording.
Connective Tissue Growth Factor Plays an Important Role in Advanced Glycation End Product–Induced Tubular Epithelial-to-Mesenchymal Transition
Authors: Wendy C. Burns, Stephen M. Twigg, Josephine M. Forbes, Josefa Pete, Christos Tikellis, Vicki Thallas-Bonke, Merlin C. Thomas, Mark E. Cooper, Phillip Kantharidis
Journal: Journal of the American Society of Nephrology (2006)

Epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both TGF-β1 and advanced glycation end products (AGE) are able to induce EMT in cell culture. This study examined the role of the prosclerotic growth factor connective tissue growth factor (CTGF) as a downstream mediator of these processes. EMT was assessed by the expression of α-smooth muscle actin, vimentin, E-cadherin, and matrix proteins and the induction of a myofibroblastic phenotype. CTGF, delivered in an adenovirus or as recombinant human CTGF (250 ng/ml), was shown to induce a partial EMT. This was not blocked by neutralizing anti–TGF-β1 antibodies, suggesting that this action was TGF-β1 independent. NRK-52E cells that were exposed to AGE-modified BSA (AGE-BSA; 40 μM) or TGF-β1 (10 ng/ml) also underwent EMT. This was associated with the induction of CTGF gene and protein expression. Transfection with siRNA to CTGF was able to attenuate EMT-associated phenotypic changes after treatment with AGE or TGF-β1. These <i>in vitro</i> effects correlate with the <i>in vivo</i> finding of increased CTGF expression in the diabetic kidney, which co-localizes on the tubular epithelium with sites of EMT. In addition, inhibition of AGE accumulation was able to reduce CTGF expression and attenuate renal fibrosis in experimental diabetes. These findings suggest that CTGF represents an important independent mediator of tubular EMT, downstream of the actions of AGE or TGF-β1. This interaction is likely to play an important role in progressive diabetic nephropathy and strengthens the rationale to consider CTGF as a potential target for the treatment of diabetic nephropathy.
Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil
Authors: P. Pfeiffer, D. Nielsen, J. Bjerregaard, C. Qvortrup, M. Yilmaz, B. Jensen
Journal: Annals of Oncology (2008)
Skin ulcers in estuarine fishes: a comparative pathological evaluation of wild and laboratory-exposed fish.
Authors: W K Vogelbein, J D Shields, L W Haas, K S Reece, D E Zwerner
Journal: Environmental Health Perspectives (2001)

The toxic dinoflagellate Pfiesteria piscicida Steidinger &amp; Burkholder has recently been implicated as the etiologic agent of acute mass mortalities and skin ulcers in menhaden, Brevoortia tyrannus, and other fishes from mid-Atlantic U.S. estuaries. However, evidence for this association is largely circumstantial and controversial. We exposed tilapia (Oreochromis spp.) to Pfiesteria shumwayae Glasgow &amp; Burkholder (identification based on scanning electron microscopy and molecular analyses) and compared the resulting pathology to the so-called Pfiesteria-specific lesions occurring in wild menhaden. The tilapia challenged by high concentrations (2,000-12,000 cells/mL) of P. shumwayaeexhibited loss of mucus coat and scales plus mild petecchial hemorrhage, but no deeply penetrating chronic ulcers like those in wild menhaden. Histologically, fish exhibited epidermal erosion with bacterial colonization but minimal associated inflammation. In moribund fish, loss of epidermis was widespread over large portions of the body. Similar erosion occurred in the mucosa lining the oral and branchial cavities. Gills exhibited epithelial lifting, loss of secondary lamellar structure, and infiltration by lymphoid cells. Epithelial lining of the lateral line canal (LLC) and olfactory organs exhibited severe necrosis. Visceral organs, kidney, and neural tissues (brain, spinal cord, ganglia, peripheral nerves) were histologically normal. An unexpected finding was the numerous P. shumwayae cells adhering to damaged skin, skin folds, scale pockets, LLC, and olfactory tissues. In contrast, histologic evaluation of skin ulcers in over 200 wild menhaden from Virginia and Maryland portions of the Chesapeake Bay and the Pamlico Estuary, North Carolina, revealed that all ulcers harbored a deeply invasive, highly pathogenic fungus now known to be Aphanomyces invadans. In menhaden the infection always elicited severe myonecrosis and intense granulomatous myositis. The consistent occurrence of this fungus and the nature and severity of the resulting inflammatory response indicate that these ulcers are chronic (age &gt;1 week) and of an infectious etiology, not the direct result of an acute toxicosis initiated by Pfiesteria toxin(s) as recently hypothesized. The disease therefore is best called ulcerative mycosis (UM). This study indicates that the pathology of Pfiesteria laboratory exposure is fundamentally different from that of UM in menhaden; however, we cannot rule out Pfiesteria as one of many possible early initiators predisposing wild fishes to fungal infection in some circumstances.
To be in remission or not: is that the question?
Authors: P L C M van Riel
Journal: Annals of the Rheumatic Diseases (2005)

Monitoring disease activity regularly is preferable to classification as remission at one point in time

The goal of the management of rheumatoid arthritis (RA) is to suppress disease activity as much as possible, to prevent loss of function, and to prevent or control joint damage.1 As for most chronic diseases, cure—meaning complete disappearance of all signs and symptoms which persist after stopping treatment—occurs only seldomly. Therefore often the term “remission” is used to define a state which approaches cure as closely as possible. However, remission in RA is not clearly defined, and might, alternatively, be understood to be absence of disease activity, absence of measurable disease activity, or very low disease activity, probably without clinical consequences like progressive damage to the joints or functional loss.2 For the assessment of remission of disease activity in RA, disease activity is probably best regarded as a continuum, and remission can be seen as a state at the very end of it.

“Disease activity is a continuum with remission a state at the end of it” 

As no “gold standard” exists for the measurement of disease activity, the Disease Activity Score (DAS) and DAS28 (28 joint count) were developed and validated in the 1990s.3,4 These composite scores express disease activity, ranging from 0 to 9. To facilitate the interpretation of these …
Gallbladder Glycoprotein Secretion in Mice with Hemolytic Anemia and Pigment Gallstones
Authors: Thomas J. LaMont, Bradley S. Turner, Seldon E. Bernstein, Bruce W. Trotman
Journal: Hepatology (1983)

The nb/nb mouse with hereditary hemolytic anemia provides an animal model for the study of pigment gallstone disease. We measured glycoprotein synthesis and secretion in gallbladder neck and fundus of 6–month–old mice without stones, and in 12–month–old mice with and without stones in order to determine the effect of age and presence or absence of stones on mucin release. We observed that the gallbladder necks of 12–month–old nb/nb mice with pigment stones secreted more 3H–glucosamine–labeled glycoprotein (68.2 dpm per m¨g protein) than did the gallbladder necks of mice without pigment stones (31.1 dpm per m¨g protein). When expressed as a percentage of total glycoprotein synthesis in the gallbladder neck, secretion of glycoprotein was 23.4% in 6–month–old hemolytic mice and 28.7% in 12–month–old hemolytic mice without pigment stones. However, in the presence of pigment stones, the percentage of secreted glycoprotein rose to 40.8%, which differed significantly from both 6–month–old (p &amp;lt; 0.02) and 12–month–old mice without stones (p &amp;lt; 0.05). Our results suggest that the presence of gallstones in nb/ nb mice was associated with a localized increase in glycoprotein release from gallbladder neck. The mechanism for this increase may be precipitation of pigment–mucin concretions in the gallbladder neck glands which has been previously described in this animal model.
Improved clinical outcome of lupus nephritis during the past decade: importance of early diagnosis and treatment
Authors: C Fiehn, Y Hajjar, K Mueller, R Waldherr, A D Ho, K Andrassy
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> To evaluate the differences in the outcome of lupus nephritis diagnosed either in the 1980s or the 1990s in Heidelberg, Germany. <b>Methods:</b> Fifteen patients with biopsy confirmed lupus nephritis (LN) were followed up between 1980 and 1989 and 41 patients were followed up between 1990 and 2000. Their status at diagnosis and their treatment schedules and outcome were analysed. 68% had WHO IV nephritis. <b>Results:</b> In the decade from 1990 to 2000 there was significantly less proteinuria (46 <i>v</i> 17 g/l, p=0.008), significantly lower rates of renal failure (40% <i>v</i> 17%, p=0.02), and fewer histological signs of chronicity (33% <i>v</i> 10%, p=0.01) at the time of diagnosis of LN than in the decade from 1980 to 1989. The mean (SD) time from the first appearance of proteinuria until kidney biopsy was significantly shorter in the later decade (15.4 (15.6) <i>v</i> 3.9 (4.7) months). Although treatment schedules were not significantly different, the outcome of the disease was significantly better in the patients who were diagnosed with LN between 1990 and 2000 (p=0.045). Whereas 6/15 (40%) patients between 1980 and 1989 had terminal renal failure after a mean time of 94 months, in the group of 1990–2000 no patient developed terminal renal failure (median observation time 24 months). In both groups one patient died from infection. A high chronicity index in histology and the presence of arterial hypertension or renal failure, or both, at the time of diagnosis were significant risk factors for the development of terminal renal failure in the course of the disease. <b>Conclusions:</b> The outcome of patients with newly diagnosed LN was significantly better between 1990 and 2000 than between 1980 and 1989. Kidney damage and chronic histological changes at time of diagnosis were significantly less common between 1990 and 2000, which is attributable to earlier diagnosis and treatment in the later decade.
Constitutive Expression of the B7h Ligand for Inducible Costimulator on Naive B Cells Is Extinguished after Activation by Distinct B Cell Receptor and Interleukin 4 Receptor–mediated Pathways and Can Be Rescued by CD40 Signaling
Authors: Linda Liang, Evelyn M. Porter, William C. Sha
Journal: The Journal of Experimental Medicine (2002)

The recently described ligand–receptor pair, B7h–inducible costimulator (ICOS), is critical for germinal center formation and antibody responses. In contrast to the induced expression of the related costimulatory ligands B7.1 and B7.2, B7h is constitutively expressed on naive B cells and is surprisingly extinguished after antigen engagement and interleukin (IL)-4 cytokine signaling. Although signaling through both B cell receptor (BCR) and IL-4 receptor (R) converge on the extinction of B7h mRNA levels, BCR down-regulation occurs through Ca2+ mobilization, whereas IL-4R down-regulation occurs through a distinct Stat6-dependent pathway. During antigen-specific B cell activation, costimulation through CD40 signaling can reverse both BCR- and IL-4R–mediated B7h down-regulation. These data suggest that the CD40–CD40 ligand signaling pathway regulates B7h expression on activated B cells and may control whether antigen-activated B cells can express B7h and costimulate cognate antigen–activated T cells through ICOS.
Differential Treatment Benefit of Platelet Glycoprotein IIb/IIIa Inhibition With Percutaneous Coronary Intervention Versus Medical Therapy for Acute Coronary Syndromes
Authors: Karen S. Pieper, Anastasios A. Tsiatis, Marie Davidian, Vic Hasselblad, Neal S. Kleiman, Eric Boersma, Wei-Ching Chang, Jeffrey Griffin, Paul W. Armstrong, Robert M. Califf, Robert A. Harrington
Journal: Circulation (2004)

Although many believe that platelet glycoprotein IIb/IIIa inhibitors should be used only in acute coronary syndrome patients undergoing percutaneous coronary intervention, supporting data from randomized clinical trials are tenuous. The assumption that these agents are useful only in conjunction with percutaneous coronary intervention is based primarily on inappropriate subgroup analyses performed across the glycoprotein IIb/IIIa inhibitor trials.We describe the problems with these analytical techniques and demonstrate that different approaches to the question can result in opposing answers.Clinical-practice decisions and practice guidelines should be based on overall trial results and not analyses of post-randomization subgroups.
Relapse-Related Molecular Signature in Lung Adenocarcinomas Identifies Patients With Dismal Prognosis
Authors: Shuta Tomida, Toshiyuki Takeuchi, Yukako Shimada, Chinatsu Arima, Keitaro Matsuo, Tetsuya Mitsudomi, Yasushi Yatabe, Takashi Takahashi
Journal: Journal of Clinical Oncology (2009)

Purpose In order to aid the development of patient-tailored therapeutics, we attempted to identify a relapse-related signature that allows selection of a group of adenocarcinoma patients with a high probability of relapse. Patients and Methods Whole-genome expression profiles were analyzed in 117 lung adenocarcinoma samples using microarrays consisting of 41,000 probes. A weighted voting classifier for identifying patients with a relapse-related signature was constructed with an approach that allowed no information leakage during each training step, using 10-fold cross-validation and 100 random partitioning procedures. Results We identified a relapse-related molecular signature represented by 82 probes (RRS-82) through genome-wide expression profiling analysis of a training set of 60 patients. The robustness of RRS-82 in the selection of patients with a high probability of relapse was then validated with a completely blinded test set of 27 adenocarcinoma patients, showing a clear association of high risk RRS-82 with very poor patient prognosis regardless of disease stage. The discriminatory power of RRS-82 was further validated using an additional independent cohort of 30 stage I patients who underwent surgery at a distinct period of time as well as with the Duke data set on a different platform. Furthermore, completely separate training and validation procedures using another data set recently reported by the Director's Challenge Consortium also successfully confirmed the predictive power of the genes comprising RRS-82. Conclusion RRS-82 may be useful for identifying adenocarcinoma patients at very high risk for relapse, even those with cancer in the early stage.