tbuckley/cabot-search huggingface dataset:
A Tissue Biomarker–Based Model That Identifies Patients with a High Risk of Distant Metastasis and Differential Survival by Length of Androgen Deprivation Therapy in RTOG Protocol 92-02
Authors: Alan Pollack, James J. Dignam, Dayssy A. Diaz, Qian Wu, Radka Stoyanova, Kyounghwa Bae, Adam P. Dicker, Howard Sandler, Gerald E. Hanks, Felix Y. Feng
Journal: Clinical Cancer Research (2014)

To examine the relationship between the expression of 7 promising apoptotic/cell proliferation proteins (Ki-67, p53, MDM2, bcl-2, bax, p16, and Cox-2) and risk of distant metastasis.RTOG 92-02 compared external beam radiotherapy (EBRT) to approximately 70 Gy + short-term androgen deprivation therapy (STADT) with EBRT + long-term ADT (LTADT). Immunohistochemical analysis was available for ≥4 biomarkers in 616 of 1,521 assessable cases. Biomarkers were evaluated individually and jointly via multivariable modeling of distant metastasis using competing risks hazards regression, adjusting for age, prostate-specific antigen, Gleason score, T stage, and treatment.Modeling identified four biomarkers (Ki-67, MDM2, p16 and Cox-2) that were jointly associated with distant metastasis. The c-index was 0.77 for the full model and 0.70 for the model without the biomarkers; a relative improvement of about 10% (likelihood ratio P < 0.001). Subdivision of the patients into quartiles based on predicted distant metastasis risk identified a high-risk group with 10-year distant metastasis risk of 52.5% after EBRT + STADT and 31% with EBRT + LTADT; associated 10-year prostate cancer-specific mortality (PCSM) risks were 45.9% and 14.5% with STADT and LTADT.Four biomarkers were found to contribute significantly to a model that predicted distant metastasis and identified a subgroup of patients at a particularly high risk of both distant metastasis and PCSM when EBRT + STADT was used. LTADT resulted in significant reductions in distant metastasis and improvements in PCSM, and there was a suggestion of greater importance in the very high risk subgroup.
Insertion of Phosphoglycerine Kinase (Pgk)-Neo 5′ of Jλ1 Dramatically Enhances Vjλ1 Rearrangement
Authors: Tianhe Sun, Ursula Storb
Journal: The Journal of Experimental Medicine (2001)

Gene-targeted mice were generated with a loxP-neomycin resistance gene (neor) cassette inserted upstream of the Jλ1 region and replacement of the glycine 154 codon in the Cλ1 gene with a serine codon. This insertion dramatically increases Vλ1-Jλ1 recombination. Jλ1 germline transcription levels in pre-B cells and thymus cells are also greatly increased, apparently due to the strong housekeeping phosphoglycerine kinase (PGK) promoter driving the neo gene. In contrast, deletion of the neo gene causes a significant decrease in VJλ1 recombination to levels below those in normal mice. This reduction is due to the loxP site left on the chromosome which reduces the Jλ1 germline transcription in cis. Thus, the correlation between germline transcription and variable (V), diversity (D), and joining (J) recombination is not just an all or none phenomenon. Rather, the transcription efficiency is directly associated with the recombination efficiency. Furthermore, Jλ1 and Vλ1 germline transcription itself is not sufficient to lead to VJ recombination in T cells or early pre-B cells. The findings may suggest that in vivo: (a) locus and cell type–specific transactivators direct the immunoglobulin or T cell receptor loci, respectively, to a “recombination factory” in the nucleus, and (b) transcription complexes deliver V(D)J recombinase to the recombination signal sequences.
Breast cancer
Authors: R. M. McLelland
Journal: CA A Cancer Journal for Clinicians (1995)

the algorithm on page 116 neglects the important role of fine-needle aspiration and/or core biopsy whether done by a radiologist or other physician before, if not sparing, the referral of the patient to a surgeon.In fact, a significant percentage of clinical and/or mammographically bothersome findings can be adequately evaluated by these means and many unnecessary surgical biopsies avoided.I would refer your readers to the excellent article "Stereotactic Breast Biopsy" by Robert A.
Glutathiolation Regulates Tumor Necrosis Factor-α–Induced Caspase-3 Cleavage and Apoptosis
Authors: Shi Pan, Bradford C. Berk
Journal: Circulation Research (2006)

Caspase-3 cleavage and activation are known to play central roles in apoptosis. However, the mechanisms that regulate caspase-3 cleavage remain elusive. Glutaredoxin (Grx) is a ubiquitous redox molecule that is unique in its ability to regulate S-glutathiolation (glutathiolation) of proteins. Here we show the essential role of Grx in caspase-3 cleavage via regulation of caspase-3 glutathiolation. Grx activity was significantly upregulated by tumor necrosis factor-alpha in endothelial cells. Small interference RNA knock down of Grx significantly inhibited tumor necrosis factor-alpha-induced endothelial cell death because of attenuated caspase-3 cleavage concomitant with increased caspase-3 glutathiolation. Enhanced caspase-3 cleavage by wild-type Grx overexpression was reversed by catalytically inactive Grx (C22S), demonstrating a requirement for thioltransferase activity. Cysteine-to-serine mutations (C163S, C184S, and C220S) of caspase-3 that were predicted to prevent glutathiolation showed increased cleavage compared with wild-type caspase-3. This inverse correlation between caspase-3 glutathiolation and cleavage was further confirmed by the observation that in vitro glutathiolation of caspase-3 inhibited its cleavage with recombinant caspase-8. Furthermore, Grx association with caspase-3 was decreased by tumor necrosis factor-alpha. These findings demonstrate a novel mechanism of caspase-3 regulation by Grx in tumor necrosis factor-alpha-induced apoptosis.
Are deficiencies of prostaglandin‐E‐mediated immunoregulation involved in increased IgE synthesis of atopic mononuclear cells <i>in vitro</i>?
Authors: B. Melnik, G. Plewig, T. Tschung
Journal: Allergy (1991)

We demonstrate that spontaneous in vitro immunoglobulin E synthesis of atopic peripheral blood mononuclear cells could be suppressed by the addition of 10 −6 M to 10 −5 M prostaglandin E 1 (PGE 1 ) or PGE 2 . Impaired suppressor T lymphocyte maturation and function in atopic individuals are explained by an insufficient transmission of prostaglandin E (PGE) signals during thymic lymphocyte differentiation as well as an impaired ability of the atopic immune system to activate suppressor T cells by PGE‐mediated feed back mechanisms. Decreased levels of 6‐desaturated PGE‐precursor fatty acids in plasma, T lymphocytes, monocytes, adipose tissue and breast milk have been observed in atopic individuals. These insights might offer a novel approach to the prevention of atopic disease by substitution of the atopic pregnant and nursing woman and her newborn infant with long‐chain ω‐6‐fatty acids.
Vascular Endothelial Growth Factor Enhances Cardiac Allograft Arteriosclerosis
Authors: Karl B. Lemström, Rainer Krebs, Antti I. Nykänen, Jussi M. Tikkanen, Roope K. Sihvola, Eva M. Aaltola, Pekka J. Häyry, Jeanette Wood, Kari Alitalo, Seppo Ylä-Herttuala, Petri K. Koskinen
Journal: Circulation (2002)

Background — Cardiac allograft arteriosclerosis is a complex process of alloimmune response, chronic inflammation, and smooth muscle cell proliferation that includes cross talk between cytokines and growth factors. Methods and Results — Our results in rat cardiac allografts established alloimmune response as an alternative stimulus capable of inducing vascular endothelial growth factor (VEGF) mRNA and protein expression in cardiomyocytes and graft-infiltrating mononuclear inflammatory cells, which suggests that these cells may function as a source of VEGF to the cells of coronary arteries. Linear regression analysis of these allografts with different stages of arteriosclerotic lesions revealed a strong correlation between intragraft VEGF protein expression and the development of intimal thickening, whereas blockade of signaling downstream of VEGF receptor significantly reduced arteriosclerotic lesions. In addition, in cholesterol-fed rabbits, intracoronary perfusion of cardiac allografts with a clinical-grade adenoviral vector that encoded mouse VEGF 164 enhanced the formation of arteriosclerotic lesions, possibly secondary to increased intragraft influx of macrophages and neovascularization in the intimal lesions. Conclusions — Our findings suggest a positive regulatory role between VEGF and coronary arteriosclerotic lesion formation in the allograft cytokine microenvironment.
Visual White Matter Integrity in Schizophrenia
Authors: Pamela D. Butler, Matthew J. Hoptman, Jay Nierenberg, John J. Foxe, Daniel C. Javitt, Kelvin O. Lim
Journal: American Journal of Psychiatry (2006)

Objective: Patients with schizophrenia have visual-processing deficits. This study examines visual white matter integrity as a potential mechanism for these deficits. Method: Diffusion tensor imaging was used to examine white matter integrity at four levels of the visual system in 17 patients with schizophrenia and 21 comparison subjects. The levels examined were the optic radiations, the striate cortex, the inferior parietal lobule, and the fusiform gyrus. Results: Schizophrenia patients showed a significant decrease in fractional anisotropy in the optic radiations but not in any other region. Conclusions: This finding indicates that white matter integrity is more impaired at initial input, rather than at higher levels of the visual system, and supports the hypothesis that visual-processing deficits occur at the early stages of processing.
Mitochondrial Disorders in the Nervous System
Authors: Salvatore DiMauro, Eric A. Schon
Journal: Annual Review of Neuroscience (2008)

Mitochondrial diseases (encephalomyopathies) have traditionally been ascribed to defects of the respiratory chain, which has helped researchers explain their genetic and clinical complexity. However, other mitochondrial functions are greatly important for the nervous system, including protein importation, organellar dynamics, and programmed cell death. Defects in genes controlling these functions are attracting increasing attention as causes not only of neurological (and psychiatric) diseases but also of age-related neurodegenerative disorders. After discussing some pathogenic conundrums regarding the neurological manifestations of the respiratory chain defects, we review altered mitochondrial dynamics in the etiology of specific neurological diseases and in the physiopathology of more common neurodegenerative disorders.
AGREEMENT OF CAPILLARY-OBTAINED ACYLATED GHRELIN, ACTIVE GLP-1, GLUCAGON, INSULIN AND LEPTIN WITH THEIR VENOUS EQUIVALENTS
Authors: BP Green, JT Gonzalez, K Thomas, CJ Dodd-Reynolds, J Bryans, E Stevenson, PLS Rumbold
Journal: British Journal of Sports Medicine (2013)

The purpose of the present study was to examine whether the expression of capillary-derived appetite peptides accurately reflects concentrations of their venous equivalents. Fingertip capillary (2×0.3 mL) and venous blood samples (2×4 mL) were collected simultaneously from 19 healthy adult volunteers [mean age 24.1 ( SD 5.7) years, body mass 73.7 ( SD 10.9) kg;], for determination of acylated ghrelin, GLP-1 7–36 , glucagon, insulin and leptin. Samples were obtained at baseline (t=0 min) and at 30, 60, 90 and 120 min following consumption of a standardised breakfast. Bland-Altman plots were constructed with their 95% limits of agreement and confidence intervals. All analysis was computed using time-averaged area under the curve data (AUC). Where data were heteroscedastic, data were log transformed and reported as ratio limits of agreement (LOA). With the exception of acylated ghrelin ( r 2 =0.51), venous and capillary blood samples displayed strong correlations between all hormonal peptides ( r 2 ≥0.84). GLP-1 7–36 and glucagon illustrated no systematic difference between capillary and venous blood samples (0.44±0.63 and −0.19±7.63 pg·mL −1 , respectively). Capillary leptin, acylated ghrelin and insulin, on average, underestimated their venous equivalents. Mean log transformed ratio LOA for leptin, insulin and acylated ghrelin were 0.89 (1.19), 0.82 (1.79) and 0.44 (3.12), respectively. Fingertip capillary blood sampling appears appropriate in appetite-related research. Further research is warranted to clarify the acceptability of capillary sampling in lieu of venous blood sampling for the determination appetite peptides.
Regulation of CDKN2B expression by interaction of Arnt with Miz-1 - a basis for functional integration between the HIF and Myc gene regulatory pathways
Authors: Reidun Aesoy, Katarina Gradin, Kathrine S Aasrud, Erling A Hoivik, Jorge L Ruas, Lorenz Poellinger, Marit Bakke
Journal: Molecular Cancer (2014)

Hypoxia- and Myc-dependent transcriptional regulatory pathways are frequently deregulated in cancer cells. These pathways converge in many cellular responses, but the underlying molecular mechanisms are unclear. The ability of Miz-1 and Arnt to interact was identified in a yeast two-hybrid screen. The mode of interaction and the functional consequences of complex formation were analyzed by diverse molecular biology methods, in vitro. Statistical analyses were performed by Student's t-test and ANOVA. In the present study we demonstrate that the aryl hydrocarbon receptor nuclear translocator (Arnt), which is central in hypoxia-induced signaling, forms a complex with Miz-1, an important transcriptional regulator in Myc-mediated transcriptional repression. Overexpression of Arnt induced reporter gene activity driven by the proximal promoter of the cyclin-dependent kinase inhibitor 2B gene (CDKN2B), which is an established target for the Myc/Miz-1 complex. In contrast, mutated forms of Arnt, that were unable to interact with Miz-1, had reduced capability to activate transcription. Moreover, repression of Arnt reduced endogenous CDKN2B expression, and chromatin immunoprecipitation demonstrated that Arnt interacts with the CDKN2B promoter. The transcriptional activity of Arnt was counteracted by Myc, but not by a mutated variant of Myc that is unable to interact with Miz-1, suggesting mutually exclusive interaction of Arnt and Myc with Miz-1. Our results also establish CDKN2B as a hypoxia regulated gene, as endogenous CDKN2B mRNA and protein levels were reduced by hypoxic treatment of U2OS cells. Our data reveal a novel mode of regulation by protein-protein interaction that directly ties together, at the transcriptional level, the Myc- and hypoxia-dependent signaling pathways and expands our understanding of the roles of hypoxia and cell cycle alterations during tumorigenesis.
<b> <i>herg1</i> </b> Gene and HERG1 Protein Are Overexpressed in Colorectal Cancers and Regulate Cell Invasion of Tumor Cells
Authors: Elena Lastraioli, Leonardo Guasti, Olivia Crociani, Simone Polvani, Giovanna Hofmann, Harry Witchel, Lapo Bencini, Massimo Calistri, Luca Messerini, Marco Scatizzi, Renato Moretti, Enzo Wanke, Massimo Olivotto, Gabriele Mugnai, Annarosa Arcangeli
Journal: Cancer Research (2004)

Abstract The acquisition of the capacity to invade surrounding tissues confers a more malignant phenotype to tumor cells and is necessary for the establishment of metastases. The understanding of the molecular mechanisms underlying cell invasion in human solid tumors such as colorectal cancers could provide not only more sensitive prognostic analyses but also novel molecular targets for cancer therapy. We report in this article that K+ ion channels belonging to the HERG family are important determinants for the acquisition of an invasive phenotype in colorectal cancers. The herg1 gene and HERG1 protein are expressed in many colon cancer cell lines, and the activity of HERG channels modulates colon cancer cell invasiveness. Moreover, the amount of HERG1 protein expressed on the plasma membrane is directly related to the invasive phenotype of colon cancer cells. Finally, both the herg1 gene and HERG1 protein were expressed in a high percentage of primary human colorectal cancers, with the highest incidence occurring in metastatic cancers, whereas no expression could be detected either in normal colonic mucosa or in adenomas.
Proton pump inhibitors and gastric neoplasia
Authors: E J Kuipers
Journal: Gut (2006)

Proton pump inhibitors (PPIs) are very effective in maintaining symptomatic and endoscopic remission of acid peptic disorders, such as gastro-oesophageal reflux disease. Side effects with respect to function and morphology of the gastric mucosa are common. Helicobacter pylori eradication can partially prevent and reverse these effects without impairing PPI therapy for gastro-oesophageal reflux disease. This makes long term PPI treatment a safe therapy for patients with acid peptic disorders. The potential side effects of such therapy are discussed here.
A comparative study of conventional premedication (pethidine, promethazine, and atropine) and neuroleptanalgesia (droperidol and phenoperidine) for peroral endoscopy
Authors: W. D. Reed, B. E. Hopkins, R. A. Joske, B. H. Laurence
Journal: Gut (1971)

A double blind comparison of conventional premedication (pethidine, promethazine, and atropine) and neuroleptanalgesia (droperidol and phenoperidine) failed to demonstrate any difference in either the comfort of the patient or ease of instrumentation in 70 upper gastrointestinal tract endoscopies. Further trials are needed before conventional premedication is abandoned.
Oxidative stress during reperfusion of human hearts: potential sources of oxygen free radicals
Authors: S. Curello, C. Ceconi, F. de Giuli, A. F. Panzali, B. Milanesi, M. Calarco, A. Pardini, P. Marzollo, O. Alfieri, F. Messineo, R. Ferrari
Journal: Cardiovascular Research (1995)

The aim was to examine the role of neutrophil activation in the genesis of oxidative stress during the early phases of reperfusion after ischaemia in patients subjected to aortocoronary bypass grafting.Ten selected patients were studied. All had normal ejection fraction and normal left ventricular end diastolic pressures before operation. Each patient required at least three grafts, so that the duration of aortic crossclamping exceeded 30 min, the minimum ischaemic period required to detect oxidative stress upon reperfusion. Oxidative stress was assessed by measuring the formation and release of oxidised glutathione (GSSG) in the coronary sinus 1 min before and 3 min after the start of the cardiopulmonary bypass, and then 1, 5, 10, and 20 min after removal of the aortic clamp, and again 5 and 10 min after the end of the cardiopulmonary bypass. The arterial-coronary sinus difference for neutrophils, elastase-alpha 1 protease complex (elastase), and creatine phosphokinase was also monitored at the same intervals.Before clamping GSSG was undetectable in arterial and coronary sinus blood. There was no significant arterial-coronary sinus difference for neutrophils or elastase [53(SEM 66) cell.ml-1 and 1.10(2.49) micrograms.litre-1, respectively[. Five minutes after re-establishment of coronary blood flow, there was both a release of GSSG into the coronary sinus [arterial-coronary sinus difference: 11(2.6) nmol.dl-1] and an accumulation of neutrophils in the heart [arterial-coronary sinus difference: 262(33), P < 0.01 cell.ml-1], whereas no elastase release from the heart was measured [arterial-coronary sinus difference 7.6(4.46) microgram.litre-1, NS]. The arterial levels of elastase increased progressively during the operation from 48(5) microgram.litre-1 (preclamping) to 405(62) microgram.litre-1, P < 0.01 (end of the cardiopulmonary bypass).These data indicate that, in man, neutrophils do accumulate in the myocardium during early reperfusion. However, they are not activated when oxidative stress occurs. It is unlikely that the neutrophil localisation in the heart has pathological significance in the production of oxygen free radicals during early reperfusion. Free radical accumulation in the coronary vessels may contribute to disorders of coronary flow associated with reperfusion.
Insights from Genome-Wide Association Studies of Drug Response
Authors: Kaixin Zhou, Ewan R. Pearson
Journal: The Annual Review of Pharmacology and Toxicology (2012)

Early genome-wide association studies (GWAS) using relatively small samples have identified both rare and common genetic variants with large impact on severe adverse drug reactions, dosing, and efficacy. Here we outline the challenges and recent successes of the GWAS approach in disease genetics and the ways in which these can be applied to pharmacogenomics for biological discovery, determination of heritability, and personalized treatment. We highlight that the genetic architecture of drug efficacy reflects a complex trait yet that of adverse drug reactions more closely mirrors the architecture of Mendelian diseases and how this difference affects future study design. Given that multiple layers of biological data are increasingly available on large samples from biorepositories linked to electronic medical records, GWAS will remain a key component of the systems biology approach to uncovering small to moderate genetic determinants of drug response; these discoveries should move us closer to a personalized approach to health care.
THE FILLING AND EMPTYING OF THE GALL BLADDER
Authors: Glover H. Copher, Shuichi Kodama, Evarts A. Graham
Journal: The Journal of Experimental Medicine (1926)

As a result of the control of the flow of bile into the duodenum largely by tonus and movements of the duodenum, bile intermittently enters the gall bladder where it is concentrated and undergoes other changes. The gall bladder empties itself of its content through the cystic duct (1) by the washing out of its contents by bile from the liver, (2) by the elasticity or contractile mechanism of its walls, and (3) by variations of intraabdominal pressure due to respiratory movements, contiguous organs, etc. A fourth manner of emptying of the gall bladder is by absorption of a portion of its content through its walls. The gall bladder is never entirely empty but tends to come to a state of partial collapse, when its contents are under minimum pressure. We have been unable to demonstrate rhythmic contractions of the gall bladder due to its musculature. If they are present they may aid but they are not essential for its emptying or filling. Experimentally, in the dog, a rubber bag which was substituted for the gall bladder functioned in a manner very similar to that of the normal gall bladder as shown by cholecystographic studies. The concentrating function, however, was absent.
Preeclampsia and Angiogenic Imbalance
Authors: Sharon Maynard, Franklin H. Epstein, S. Ananth Karumanchi
Journal: Annual Review of Medicine (2007)

Preeclampsia is a systemic syndrome of pregnancy that originates in the placenta and is characterized by widespread maternal endothelial dysfunction. Until recently, the molecular pathogenesis of preeclampsia was largely unknown, but recent work suggests a key role for altered expression of placental antiangiogenic factors. Soluble Flt1 and soluble endoglin, secreted by the placenta, are increased in the maternal circulation weeks before the onset of preeclampsia. These antiangiogenic factors produce systemic endothelial dysfunction, resulting in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, and the role of angiogenic proteins in early placental vascular development is just beginning to be explored. These discoveries have exciting clinical implications and are likely to transform the detection and treatment of preeclampsia in the future.