tbuckley/cabot-search huggingface dataset:
The cleavage preference of the proteasome governs the yield of antigenic peptides.
Authors: M Eggers, B Boes-Fabian, T Ruppert, P M Kloetzel, U H Koszinowski
Journal: The Journal of Experimental Medicine (1995)

Proteasomes degrade endogenous proteins in the cytosol. The potential contribution of the proteasome to the effect of flanking sequences on the presentation of an antigenic epitope presented by the major histocompatibility complex class I allele Ld was studied. Peptides generated in cells from minigenes coding for peptides of 17- and 19-amino acid length were compared with the in vitro 20S proteasome degradation products of the respective synthetic peptides. The quality of generated peptides was independent of ubiquitination. In vivo and in vitro processing products were indistinguishable with respect to peptide size and abundance. Altering the neighboring sequence substantially improved the yield of the final antigenic nonapeptide by 20S proteasome cleavage. These results suggest that, in addition to the presence of major histocompatibility complex class I allelic motifs, the cleavage preference of the proteasome can define the antigenic potential of a protein.
Melanoma Therapy via Peptide-Targeted α-Radiation
Authors: Yubin Miao, Mark Hylarides, Darrell R. Fisher, Tiffani Shelton, Herbert Moore, Dennis W. Wester, Alan R. Fritzberg, Christopher T. Winkelmann, Timothy Hoffman, Thomas P. Quinn
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The therapeutic efficacy of a unique melanoma-targeting peptide conjugated with an in vivo generated α-particle-emitting radionuclide was evaluated in the B16/F1 mouse melanoma animal model. α-Radiation is densely ionizing, resulting in high concentrations of destructive radicals and irreparable DNA double-strand breaks. This high linear energy transfer overcomes radiation-resistant tumor cells and oxygen effects resulting in potentially high therapeutic indices in tumors such as melanoma. Experimental Design: The melanoma targeting peptide, 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-Re(Arg11)CCMSH, was radiolabeled with 212Pb, the parent of 212Bi, which decays via α and β decay. Biodistribution and therapy studies were done in the B16/F1 melanoma-bearing C57 mouse flank tumor model. Results: 212Pb[DOTA]-Re(Arg11)CCMSH exhibited rapid tumor uptake and extended retention coupled with rapid whole body disappearance. Radiation dose delivered to the tumor was estimated to be 61 cGy/μCi 212Pb administered. Treatment of melanoma-bearing mice with 50, 100, and 200 μCi of 212Pb[DOTA]-Re(Arg11)CCMSH extended their mean survival to 22, 28, and 49.8 days, respectively, compared with the 14.6-day mean survival of the placebo control group. Forty-five percent of the mice receiving 200 μCi doses survived the study disease-free. Conclusions: Treatment of B16/F1 murine melanoma–bearing mice with 212Pb[DOTA]-Re(Arg11)CCMSH significantly decreased tumor growth rates resulting in extended mean survival times, and in many cases, complete remission of disease. 212Pb-DOTA-Re(Arg11)CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.
Trainee satisfaction before and after the Calman reforms of specialist training: questionnaire survey
Authors: E. Paice
Journal: BMJ (2000)

To evaluate the impact of the Calman reforms of higher specialist training on trainee satisfaction.Questionnaire surveys using portable electronic survey units, two years apart.Postgraduate, teaching, district general, and community NHS trusts in North Thames. North Thames deanery includes London north of the Thames, Essex, and Hertfordshire.Trainees in all grades and all specialties: 3078 took part in the first survey and 3517 in the second survey.Trainees' satisfaction with training in their current post, including educational objectives, training agreements, induction, consultant feedback, hands on experience acquired, use of log books, consultant supervision, and overall satisfaction with the post.In the second survey respondents were more likely to have discussed educational objectives with their consultant, used a log book, and had useful feedback from their consultant. They were more likely to give high ratings to induction, consultant supervision, and hands on experience acquired in the post. Each of these elements was associated with increased satisfaction with the post overall. Improvements were most noticeable at the level of specialist registrar, but changes in the same direction were also seen in more junior grades.After the reforms of specialist training, trainees in all grades reported greater satisfaction with their current posts. The changes required extra training time and effort from consultants.
Biodistribution of trans-1,2-diammocyclohexane-trimellitato-platinum(II) attached to macromolecular carriers I. Poly(hydroxyethyl-d,l-asparagine) carrier
Authors: Marie Filipová-Vopršalová, Jaroslav Drobník, Blahoslav Šrámek, Jaroslav Květina
Journal: Journal of Controlled Release (1991)
Circulating Fibroblast Growth Factor-21 Is Elevated in Impaired Glucose Tolerance and Type 2 Diabetes and Correlates With Muscle and Hepatic Insulin Resistance
Authors: Alberto O. Chavez, Marjorie Molina-Carrion, Muhammad A. Abdul-Ghani, Franco Folli, Ralph A. DeFronzo, Devjit Tripathy
Journal: Diabetes Care (2009)

OBJECTIVE Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance. RESEARCH DESIGN AND METHODS Forty-one subjects (8 lean with normal glucose tolerance [NGT], 9 obese with NGT, 12 with impaired fasting glucose [IFG]/impaired glucose tolerance [IGT], and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m2 per min) combined with 3-[3H] glucose infusion. RESULTS Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 ± 0.3 ng/ml in lean subjects with NGT to 4.9 ± 0.2 in obese subjects with NGT to 5.2 ± 0.2 in subjects with IGT and to 5.3 ± 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = −0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose [r = 0.312, P = 0.05], 2-h plasma glucose [r = 0.414, P = 0.01], and A1C [r = 0.325, P = 0.04]). CONCLUSIONS Plasma FGF-21 levels are increased in insulin-resistant states and correlate with hepatic and whole-body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes.
Methodologies for comparing complex computational models of eye-movement control in reading: Just fitting the data is not enough
Authors: Ronan Reilly, Ralph Radach
Journal: Behavioral and Brain Sciences (2003)

As the number of computational models of eye-movement control in reading increases, so too will their coverage and complexity. This will make their comparison and testing increasingly challenging. We argue here that there is a need to develop a methodology for constructing and evaluating such models, and outline aspects of a possible methodology.
Neuronal Coding of Prediction Errors
Authors: Wolfram Schultz, Anthony Dickinson
Journal: Annual Review of Neuroscience (2000)

Associative learning enables animals to anticipate the occurrence of important outcomes. Learning occurs when the actual outcome differs from the predicted outcome, resulting in a prediction error. Neurons in several brain structures appear to code prediction errors in relation to rewards, punishments, external stimuli, and behavioral reactions. In one form, dopamine neurons, norepinephrine neurons, and nucleus basalis neurons broadcast prediction errors as global reinforcement or teaching signals to large postsynaptic structures. In other cases, error signals are coded by selected neurons in the cerebellum, superior colliculus, frontal eye fields, parietal cortex, striatum, and visual system, where they influence specific subgroups of neurons. Prediction errors can be used in postsynaptic structures for the immediate selection of behavior or for synaptic changes underlying behavioral learning. The coding of prediction errors may represent a basic mode of brain function that may also contribute to the processing of sensory information and the short-term control of behavior.
Congenital Absence of Ovaries with Rudimentary Uterus
Authors: J. Ramage
Journal: BMJ (1896)

MEMORANDA.[APRILJ 2$, r8g& two club-shaped pieces about 3 inches long covered with phosphlates, accompanlied with a good deal of pain before and durinig the passage.The bladder was washed out and the catheter removed.On1 July 26th the wound was dressed.The patient had had no occasion to have the catheter passed.On July 3ISt tlhe stitches were removed and the dressings left off.There was no suppuration in either wound, and the catheter was never passed from July 25tlh, teen days after the operation, to the present date (October i8th, 1895).Onle of tihe testicles was sent to the Clinical Researclh Asso- ciation.The following is their report: " On tearing out the seminal tubules a fewv spermatozoa are seen.Owing to im- mersion in spirit tlley are much shrunken.There is no naked-eye evidence of disease in tlhe portion of testis sent."A section showed characters of the senile testicle.After the operation for about ten days the old gentleman's mind was somewhat peculiar.He did not believe himself at home, and did not kiiow his relatives who were nursing hiim, trying at times to be violent, and I almost thought I was going to see one of those cases we hear so muclh about, namely, insanity following this operation.He fancied strange people were in. the room, and heard strange voices talking to him.Happily this speedily passed away and lhas given him no furtlher trouble.His present state is as follows: Sinice ten days afer cz.e operation no catheter has been used at all.He can now g,o four or five lhours at a stretchl witlhout passing water which comes in a good stream and " beautifully clear " as hie calls it.He has, lie says, put on a stone in weiaht; is aslhamed of the amount he eats, aind his bowels are regular; and lie says " his life is a pleasure to him " and is able to drive about and attend to various little duties.The onily pain he feels is
Resuscitation of children who nearly drown.
Authors: R G Wilson
Journal: BMJ (1991)

hours in the age group 65-75 years,t not the three to four days quoted by Mr O'Reilly.Our second point concerns the action of opiates.Though epidural opiates may give rise to urinary retention, this may be a problem peculiar to this route of administration.Mr O'Reilly and Dr Wight and colleagues seem to confuse the effects of epidural opiates with those of opiates given by either intravenous or intramuscular routes-not noted for their ability to produce urinary retention.To extend this confusion further, as Dr Wight and colleagues have done, by'suggesting that naloxone should be used empirically to treat postoperative retention is to go far beyond any evidence.Further- more, they seem to ignore the fact that patients are given opiates postoperatively specifically to obtund the feeling of pain and reduce the concomitant adverse physiological sequelae.Giving naloxone as suggested would surely reverse the well established benefits of postoperative analgesia.Overall, though agreeing that unnecessary urethral catheterisation should be avoided if possible, we suggest that anaesthetic agents should riot be implicated in the aetiology of urinary retention in the absence ofany objective supporting evidence.
Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON
Authors: S Daenen, B van der Holt, A W Dekker, R Willemze, A W Rijneveld, B J Biemond, P Muus, A A van de Loosdrecht, H C Schouten, M van Marwijk Kooy, D A Breems, H Demuynck, J Maertens, P W Wijermans, S Wittebol, E W de Klerk, J J Cornelissen
Journal: Leukemia (2012)
Neuron-Derived Orphan Receptor-1 (NOR-1) Modulates Vascular Smooth Muscle Cell Proliferation
Authors: José Martínez-González, Jordi Rius, Ana Castelló, Claudia Cases-Langhoff, Lina Badimon
Journal: Circulation Research (2003)

Vascular smooth muscle cells (VSMCs) migration and proliferation play a key role in the pathophysiology of cardiovascular disease. However, the transcription factors that regulate VSMC activation are not completely characterized. By a mRNA-differential display approach, we have identified neuron-derived orphan receptor-1 (NOR-1), a transcription factor within the NGFI-B subfamily of nuclear receptors, as a immediate-early gene in VSMCs. Two NOR-1 isoforms (α and β) were identified and cloned from serum-induced porcine VSMC that shared high homology with the human isoforms. Northern blot analysis revealed a strong and transient (1 to 6 hours) upregulation of NOR-1 in both porcine and human coronary SMCs by growth factors (serum, platelet-derived growth factor-BB, and epidermal growth factor) and α-thrombin but not by cytokines. NOR-1 upregulation is processed through G protein–coupled receptors and tyrosine kinase receptors, and involves Ca 2+ mobilization, protein kinase C activation, and the mitogen-activated protein kinase pathway. This induction was closely dependent of the cAMP response elements present in NOR-1 promoter as transfection assays indicate. Human coronary atherosclerotic lesions overexpress NOR-1, and balloon angioplasty transiently induces NOR-1 in porcine coronary arteries with a pattern similar to that observed in VSMCs in culture. Antisense oligonucleotides against NOR-1 inhibited human coronary SMC proliferation (reduced de novo DNA synthesis, cell cycle progression, and VSMC wound repair) as efficiently as antisense against the protooncogene c- fos . These results show that NOR-1 modulates VSMC proliferation, and suggest that this transcription factor may play a role in both spontaneous and accelerated atherosclerosis.
Human Papillomavirus Type 16 E6 and E7 Cause Polyploidy in Human Keratinocytes and Up-Regulation of G2-M-Phase Proteins
Authors: Daksha Patel, Angela Incassati, Nancy Wang, Dennis J. McCance
Journal: Cancer Research (2004)

Human papillomavirus type 16 proteins E6 and E7 have been shown to cause centrosome amplification and lagging chromosomes during mitosis. These abnormalities during mitosis can result in missegregation of the chromosomes, leading to chromosomal instability. Genomic instability is thought to be an essential part of the conversion of a normal cell to a cancer cell. We now show that E6 and E7 together cause polyploidy in primary human keratinocytes soon after these genes are introduced into the cells. Polyploidy seems to result from a spindle checkpoint failure arising from abrogation of the normal functions of p53 and retinoblastoma family members by E6 and E7, respectively. In addition, E6 and E7 cause deregulation of cellular genes such as Plk1, Aurora-A, cdk1, and Nek2, which are known to control the G(2)-M-phase transition and the ordered progression through mitosis.
An exaggerated sensory component of the gastrocolonic response in patients with irritable bowel syndrome
Authors: M Simren
Journal: Gut (2001)

<h3>BACKGROUND/AIMS</h3> Visceral hypersensitivity is a feature of the irritable bowel syndrome (IBS). Postprandial symptoms are common in these patients. The effects of nutrients on colonic perception in IBS are incompletely understood. <h3>SUBJECTS</h3> We studied 13 healthy subjects and 16 patients with IBS—eight had diarrhoea predominant (IBS-D) and eight constipation predominant (IBS-C) IBS. <h3>METHODS</h3> Colonic perception thresholds to balloon distension and viscerosomatic referral pattern were assessed before and after duodenal infusion of lipid or saline, respectively. At the end of the infusions, plasma levels of gastrointestinal peptides were determined. <h3>RESULTS</h3> Lipids lowered the thresholds for first sensation, gas, discomfort, and pain in the IBS group but only for gas in the control group. The percent reduction in thresholds for gas and pain after lipids was greater in the IBS and IBS-D groups but not in the IBS-C group compared with controls. IBS patients had an increased area of referred discomfort and pain after lipids compared with before infusion whereas the referral area remained unchanged in controls. No group differences in colonic tone or compliance were observed. In both groups higher levels of cholecystokinin, pancreatic polypeptide, peptide YY, vasoactive intestinal polypeptide, and neuropeptide Y were seen after lipids. Motilin levels were higher in patients and differences in the subgroups were observed. Levels of corticotrophin releasing factor were lower in the constipated group than in the diarrhoea group. <h3>CONCLUSIONS</h3> Postprandial symptoms in IBS patients may be explained in part by a nutrient dependent exaggerated sensory component of the gastrocolonic response.
Fine Structure of the Endocardium in Adult Rats
Authors: H. Melax, T. S. Leeson
Journal: Cardiovascular Research (1967)

The endocardial endothelium is a complete layer with nuclei protruding into lumina, and greatly attenuated cytoplasm showing active micropinocytosis. Endothelial cell junctions characteristically are complex with interdigitation and overlapping of cytoplasmic processes. Subendothelial connective tissue is loose and collagenous, except in heart valves. Some elastin is present at the aortic ring but absent elsewhere.
Identification of Novel Protein Targets for Modification by 15-Deoxy-Δ12,14-Prostaglandin J2 in Mesangial Cells Reveals Multiple Interactions with the Cytoskeleton
Authors: Konstantinos Stamatakis, Francisco J. Sánchez-Gómez, Dolores Pérez-Sala
Journal: Journal of the American Society of Nephrology (2005)

The cyclopentenone prostaglandin 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2) has been shown to display protective effects against renal injury or inflammation. In cultured mesangial cells (MC), 15d-PGJ2 inhibits the expression of proinflammatory genes and modulates cell proliferation. Therefore, cyclopentenone prostaglandins (cyPG) have been envisaged as a promise in the treatment of renal disease. The effects of 15d-PGJ2 may be dependent on or independent from its role as a peroxisome proliferator-activated receptor agonist. It was shown recently that an important determinant for the peroxisome proliferator-activated receptor-independent effects of 15d-PGJ2 is the capacity to modify proteins covalently and alter their function. However, a limited number of protein targets have been identified to date. Herein is shown that a biotinylated derivative of 15d-PGJ2 recapitulates the effects of 15d-PGJ2 on the stress response and inhibition of inducible nitric oxide synthase levels and forms stable adducts with proteins in intact MC. Biotinylated 15d-PGJ2 was then used to identify proteins that potentially are involved in cyPG biologic effects. Extracts from biotinylated 15d-PGJ2-treated MC were separated by two-dimensional electrophoresis, and the spots of interest were analyzed by mass spectrometry. Identified targets include proteins that are regulated by oxidative stress, such as heat-shock protein 90 and nucleoside diphosphate kinase, as well as proteins that are involved in cytoskeletal organization, such as actin, tubulin, vimentin, and tropomyosin. Biotinylated 15d-PGJ2 binding to several targets was confirmed by avidin pull-down. Consistent with these findings, 15d-PGJ2 induced early reorganization of vimentin and tubulin in MC. The cyclopentenone moiety and the presence of cysteine were important for vimentin rearrangement. These studies may contribute to the understanding of the mechanism of action and therapeutic potential of cyPG.
A comparison of heart rate responses in racquet games.
Authors: D. Docherty
Journal: British Journal of Sports Medicine (1982)

The present study investigated the heart rate response to playing tennis with special reference to the skill levels and ages of the participants. Data obtained in a similar manner during earlier studies of badminton and squash players were compared with that obtained during tennis. The number of rallies, mean rally time and actual playing time in 30 minutes of play was also compared for the different skill levels and sports. Results showed that playing tennis raised the players' heart rates to 68-70% of their predicted maximum heart rate (PMHR). Playing squash and badminton could raise heart rates to 80-85% of the players' PMHR which was significantly higher than the values obtained for tennis. The actual skill level of the participants within their chosen sport did not have a significant effect in predicting the physical demands of squash or tennis but was important in predicting the heart rate response of badminton players. The more skillful the badminton player the greater the cardiac response as a result of game play. Analysis of time spent in actual play revealed that tennis players were involved in play for only five of the thirty minutes of game play, compared to 15 and 10 min respectively for squash and badminton. Skill level within each sport was only a significant factor in predicting length of play for squash players in which the medium and highly skilled groups played significantly longer than those of a lower level of skill.
Microarray-Based Determination of Estrogen Receptor, Progesterone Receptor, and HER2 Receptor Status in Breast Cancer
Authors: Paul Roepman, Hugo M. Horlings, Oscar Krijgsman, Marleen Kok, Jolien M. Bueno-de-Mesquita, Richard Bender, Sabine C. Linn, Annuska M. Glas, Marc J. van de Vijver
Journal: Clinical Cancer Research (2009)

The level of estrogen receptor (ER), progesterone receptor (PR), and HER2 aids in the determination of prognosis and treatment of breast cancer. Immunohistochemistry is currently the predominant method for assessment, but differences in methods and interpretation can substantially affect the accuracy, resulting in misclassification. Here, we investigated the association of microarray-based mRNA expression levels compared with immunohistochemistry.Microarray mRNA quantification of ER, PR, and HER2 was done by the developed TargetPrint test and compared with immunohistochemical assessment for breast tumors from 636 patients. Immunohistochemistry was done in a central laboratory and in an independent reference laboratory according to American Society of Clinical Oncology/College of American Pathologists guidelines for 100 cases. For HER2 immunohistochemistry 2+ cases, additional chromogenic in situ hybridization (CISH) was used to determine the final status.ER concordance between microarray and central immunohistochemistry was 93% [95% confidence interval (95% CI), 91-95%]. Only 4% of immunohistochemistry-positive samples were classified negative using microarray, whereas 18% of immunohistochemistry-negative samples showed a positive microarray ER status. Concordance for PR was 83% (95% CI, 80-86%) and 96% of all samples showed an identical classification of HER2 status by microarray and immunohistochemistry/CISH (95% CI, 94-98%). Nine percent of immunohistochemistry HER2-positive samples showed a negative microarray classification. Detailed review of 11 cases with discordant classifications by American Society of Clinical Oncology/College of American Pathologists and central immunohistochemistry indicated that microarray assessment was likely to add additional information in 5 cases.Microarray-based readout of ER, PR, and HER2 shows a high concordance with immunohistochemistry/CISH and provides an additional, objective, and quantitative assessment of tumor receptor status in breast cancer.