tbuckley/cabot-search huggingface dataset:
Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth
Authors: R. Bruce Montgomery, Elahe A. Mostaghel, Robert Vessella, David L. Hess, Thomas F. Kalhorn, Celestia S. Higano, Lawrence D. True, Peter S. Nelson
Journal: Cancer Research (2008)

Abstract Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription–PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59–0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03–0.44; P &amp;lt; 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P &amp;lt; 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment. [Cancer Res 2008;68(11):4447–54]
Arachidonic Acid Activates Phosphatidylinositol 3-Kinase Signaling and Induces Gene Expression in Prostate Cancer
Authors: Millie Hughes-Fulford, Chai-Fei Li, Jim Boonyaratanakornkit, Sina Sayyah
Journal: Cancer Research (2006)

Abstract Essential fatty acids are not only energy-rich molecules; they are also an important component of the membrane bilayer and recently have been implicated in induction of fatty acid synthase and other genes. Using gene chip analysis, we have found that arachidonic acid, an ω-6 fatty acid, induced 11 genes that are regulated by nuclear factor-κB (NF-κB). We verified gene induction by ω-6 fatty acid, including COX-2, IκBα, NF-κB, GM-CSF, IL-1β, CXCL-1, TNF-α, IL-6, LTA, IL-8, PPARγ, and ICAM-1, using quantitative reverse transcription-PCR. Prostaglandin E2 (PGE2) synthesis was increased within 5 minutes of addition of arachidonic acid. Analysis of upstream signal transduction showed that within 5 minutes of fatty acid addition, phosphatidylinositol 3-kinase (PI3K) was significantly activated followed by activation of Akt at 30 minutes. Extracellular signal-regulated kinase 1 and 2, p38 and stress-activated protein kinase/c-Jun-NH2-kinase were not phosphorylated after ω-6 fatty acid addition. Thirty minutes after fatty acid addition, we found a significant 3-fold increase in translocation of NF-κB transcription factor to the nucleus. Addition of a nonsteroidal anti-inflammatory drug (NSAID) caused a decrease in COX-2 protein synthesis, PGE2 synthesis, as well as inhibition of PI3K activation. We have previously shown that NSAIDs cause an inhibition of arachidonic acid–induced proliferation; here, we have shown that arachidonic acid–induced proliferation is also blocked (P &amp;lt; 0.001) by PI3K inhibitor LY294002. LY294002 also significantly inhibited the arachidonic acid–induced gene expression of COX-2, IL-1β, GM-CSF, and ICAM1. Taken together, the data suggest that arachidonic acid via conversion to PGE2 plays an important role in stimulation of growth-related genes and proliferation via PI3K signaling and NF-κB translocation to the nucleus. (Cancer Res 2006; 66(3): 1427-33)
Blood platelets contain tumor-derived RNA biomarkers
Authors: R. Jonas A. Nilsson, Leonora Balaj, Esther Hulleman, Sjoerd van Rijn, D. Michiel Pegtel, Maudy Walraven, Anders Widmark, Winald R. Gerritsen, Henk M. Verheul, W. Peter Vandertop, David P. Noske, Johan Skog, Thomas Würdinger
Journal: Blood (2011)
Developmental Stage and Level of Codon Usage Bias in Drosophila
Authors: Saverio Vicario, Christopher E. Mason, Kevin P. White, Jeffrey R. Powell
Journal: Molecular Biology and Evolution (2008)

Codon usage bias (CUB) is a ubiquitous observation in molecular evolution. As a model, Drosophila has been particularly well-studied and indications show that selection at least partially controls codon usage, probably through selection for translational efficiency. Although many aspects of Drosophila CUB have been studied, this is the first study relating codon usage to development in this holometabolous insect with very different life stages. Here we ask the question: What developmental stage of Drosophila melanogaster has the greatest CUB? Genes with maximum expression in the larval stage have the greatest overall CUB when compared with embryos, pupae, and adults. (The same pattern was observed in Drosophila pseudoobscura, see Supplementary Material online.) We hypothesize this is related to the very rapid growth of larvae, placing increased selective pressure to produce large amounts of protein: a 300-fold increase requiring an approximate doubling of protein content every 10 h. Genes with highest expression in adult males and early embryos, stages with the least de novo protein synthesis, display the least CUB. These results are consistent with the hypothesis that CUB is caused (at least in part) by selection for efficient protein production. This seems to hold on the individual gene level (highly expressed genes are more biased than lowly expressed genes) as well as on a more global scale where genes with maximum expression during times of very rapid growth and protein synthesis are more biased than genes with maximum expression during times of low growth.
THE INFLUENCE OF DIET UPON THE REGENERATION OF SERUM PROTEIN
Authors: Daniel Melnick, George R. Cowgill, Ethel Burack
Journal: The Journal of Experimental Medicine (1936)

1. By the technique of quantitative plasmapheresis the effects of single proteins in artificial synthetic diets were studied with respect to their value in promoting the regeneration of serum protein. 2. The ratio of (a) the amount of serum protein per week removed by bleeding above that regenerated by the dog when eating the protein-free diet, to (b) the dietary protein increment (i.e., above that required for nitrogen equilibrium) was termed the potency ratio. The results indicated that serum protein was slightly superior to casein and lactalbumin in promoting the regeneration of serum protein. However, the respective potency ratios, varying from approximately 0.51 to 0.36, were comparable and not widely divergent as those reported by others. It was concluded that, whereas in some individuals dietary proteins may be able to produce a significant increase in the serum protein concentration, the potency ratios are not sufficiently different to warrant the administration of any one protein in preference to another. 3. The inhibitory effect of the basal protein-free diet with respect to serum protein regeneration in the dog was also demonstrated by the inability of the protein concentration to attain the normal level in spite of discontinued plasmapheresis. However, a subsequent fasting period resulted in a progressive rise in the serum protein concentration until the normal value was approximated. These observations are interpreted as indicating that the products of tissue protein catabolism can be utilized in the formation of new serum protein. 4. The experimental production of what seems to be an inhibition of the serum protein regenerating mechanism was described. This observation together with the hypothetical evidence presented by Bloomfield (17) and Weech and his associates (9) suggests that the most profitable line of approach to solution of the problem of hypoproteinemia lies not so much in the evaluation of dietary factors but in finding a way for stimulating internally the serum protein regenerating mechanism, which seems to involve in some manner the capacity of the tissue to furnish protein for the needs of the plasma. 5. A hypothesis explaining the mechanisms responsible for serum protein formation was presented and the experimental support for it discussed. The rôle of tissue protein catabolism in this function was emphasized.
Effect of CPAP on intrinsic PEEP, inspiratory effort, and lung volume in severe stable COPD
Authors: F J O'Donoghue
Journal: Thorax (2002)

<b>Background:</b> Intrinsic positive end expiratory pressure (PEEPi) constitutes an inspiratory threshold load on the respiratory muscles, increasing work of breathing. The role of continuous positive airway pressure (CPAP) in alleviating PEEPi in patients with severe stable chronic obstructive pulmonary disease is uncertain. This study examined the effect of CPAP on the inspiratory threshold load, muscle effort, and lung volume in this patient group. <b>Methods:</b> Nine patients were studied at baseline and with CPAP increasing in increments of 1 cm H<sub>2</sub>O to a maximum of 10 cm H<sub>2</sub>O. Breathing pattern and minute ventilation (V̇i), dynamic PEEPi, expiratory muscle activity, diaphragmatic (PTPdi/min) and oesophageal (PTPoes/min) pressure-time product per minute, integrated diaphragmatic (EMGdi) and intercostal EMG (EMGic) and end expiratory lung volume (EELV) were measured. <b>Results:</b> Expiratory muscle activity was present at baseline in one subject. In the remaining eight, PEEPi was reduced from a mean (SE) of 2.9 (0.6) cm H<sub>2</sub>O to 0.9 (0.1) cm H<sub>2</sub>O (p&lt;0.05). In two subjects expiratory muscle activity contributed to PEEPi at higher pressures. There were no changes in respiratory pattern but V̇i increased from 9.2 (0.6) l/min to 10.7 (1.1) l/min (p&lt;0.05). EMGdi remained stable while EMGic increased significantly. PTPoes/min decreased, although this did not reach statistical significance. PTPdi/min decreased significantly from 242.1 (32.1) cm H<sub>2</sub>O.s/min to 112.9 (21.7) cm H<sub>2</sub>O.s/min). EELV increased by 1.1 (0.3) l (p&lt;0.01). <b>Conclusion:</b> High levels of CPAP reduce PEEPi and indices of muscle effort in patients with severe stable COPD, but only at the expense of substantial increases in lung volume.
Stop smoking prevention in the BOLD study
Authors: Louisa Gnatiuc, Bernet Kato, Peter Burney
Journal: European Respiratory Journal (2012)

Background: Tobacco smoking is a risk factor for COPD. Stop smoking strategies are associated with slower lung function decline. We used the BOLD data to describe the use of stop smoking prevention across 20 sites.

Methods: Reported use of stop smoking advice and medicines was assessed among population based samples of smokers aged 40+ with and without Chronic Airways Obstruction (CAO) (FEV1/FVC<Lower Limits of Normal).

Results: Smoking prevalence ranged from 8.5% in Mumbai, India to 69.5% in Cape Town, S. Africa. The rate of stop smoking prevention use ranged from 0% in Mumbai and Pune, India to 24.7% in Lexington, USA. It was higher in current smokers than in ex-smokers (13.3% vs 6.3%, p<0.0001), in those with CAO than in those without CAO (15.3% vs 7.7%, p<0.0001) and in high income countries (HIC) than in low and middle income countries (LMIC) (11.6% vs 1.9%, p<0.0001).

The use of stop smoking prevention was more likely in women, younger, more educated people (OR=1.36; 95%CI 1.18-1.56), those with low lung function (OR=3.93; 95%CI 1.58–9.75), comorbidities (OR=1.41; 95%CI 1.04-1.91), symptoms (OR= 1.71; 95%CI 1.21-2.42) and increased with each 10pack-years smoked (OR=3.47; 95%CI2.61- 4.61). Overall positive effects did vary across sites except for the effect of gender and education but these differences do not explain the difference in use between LMIC and HICs.

Ecological analyses suggest little positive effect of high usage of stop smoking prevention.

Conclusion: Use of stop smoking prevention is associated with chronic respiratory disease and pack-years smoked, is higher in current smokers than in ex-smokers and in HICs than in LMICs. Understanding factors influencing use and optimising use in current-smokers and LMICs are important.
Vascular Endothelial Growth Factor Receptor-1 Regulates Postnatal Angiogenesis Through Inhibition of the Excessive Activation of Akt
Authors: Jun-ichiro Nishi, Tohru Minamino, Hideyuki Miyauchi, Aika Nojima, Kaoru Tateno, Sho Okada, Masayuki Orimo, Junji Moriya, Guo-Hua Fong, Kenji Sunagawa, Masabumi Shibuya, Issei Komuro
Journal: Circulation Research (2008)

Vascular endothelial growth factor (VEGF) binds both VEGF receptor-1 (VEGFR-1) and VEGF receptor-2 (VEGFR-2). Activation of VEGFR-2 is thought to play a major role in the regulation of endothelial function by VEGF. Recently, specific ligands for VEGFR-1 have been reported to have beneficial effects when used to treat ischemic diseases. However, the role of VEGFR-1 in angiogenesis is not fully understood. In this study, we showed that VEGFR-1 performs “fine tuning” of VEGF signaling to induce neovascularization. We examined the effects of retroviral vectors expressing a small interference RNA that targeted either the VEGFR-1 gene or the VEGFR-2 gene. Deletion of either VEGFR-1 or VEGFR-2 reduced the ability of endothelial cells to form capillaries. Deletion of VEGFR-1 markedly reduced endothelial cell proliferation and induced premature senescence of endothelial cells. In contrast, deletion of VEGFR-2 significantly impaired endothelial cell survival. When VEGFR-1 expression was blocked, VEGF constitutively activated Akt signals and thus induced endothelial cell senescence via a p53-dependent pathway. VEGFR-1 +/− mice exhibited an increase of endothelial Akt activity and showed an impaired neovascularization in response to ischemia, and this impairment was ameliorated in VEGFR-1 +/− Akt1 +/− mice. These results suggest that VEGFR-1 plays a critical role in the maintenance of endothelial integrity by modulating the VEGF/Akt signaling pathway.
Comparable Long-Term Survival After Unrelated and HLA-Matched Sibling Donor Hematopoietic Stem Cell Transplantations for Acute Leukemia in Children Younger Than 18 Months
Authors: Mary Eapen, Pablo Rubinstein, Mei-Jie Zhang, Bruce M. Camitta, Cladd Stevens, Mitchell S. Cairo, Stella M. Davies, John J. Doyle, Joanne Kurtzberg, Michael A. Pulsipher, Juan J. Ortega, Andromachi Scaradavou, Mary M. Horowitz, John E. Wagner
Journal: Journal of Clinical Oncology (2005)

To describe outcomes after unrelated donor stem cell transplantation (HCT) in children (< 18 months at diagnosis) with acute leukemia and compare these with outcomes after human leukocyte antigen (HLA)-matched sibling donor HCT.We compared the results of unrelated donor HCT with bone marrow (n = 85) or cord blood grafts (n = 81) and HLA-matched sibling donor HCT with bone marrow grafts (n = 101) for acute myeloid or acute lymphoblastic leukemia using Cox proportional hazards models. Unrelated donor HCT recipients were younger, more likely to have MLL gene rearrangement, to have advanced leukemia, and to receive irradiation before HCT.Treatment-related mortality rates were 6%, 15%, and 31% after matched sibling, unrelated donor bone marrow, and cord blood HCT, respectively. Risks of relapse, overall and leukemia-free survival were significantly associated with disease status at transplantation. Though leukemia recurrence was lowest after unrelated donor HCT in first clinical remission (CR), overall survival, and leukemia-free survival rates were similar after matched sibling and unrelated donor HCT, after adjustment for disease status. Relapse, overall and leukemia-free survival did not differ by graft type (bone marrow v cord blood) or type of leukemia. Three-year probabilities of leukemia-free survival were 49% and 54% after HLA-matched sibling and unrelated donor transplantation in first CR, respectively. Corresponding rates for those with advanced leukemia were 20% and 30%.Unrelated donor HCT should be considered for infants with acute leukemia in first CR using the same eligibility criteria as are currently used for those with HLA matched sibling donors.
Systematics and Mitochondrial Genome Evolution of Australian Rosellas (Aves: Platycercidae)
Authors: JR Ovenden, AG Mackinlay, RH Crozier
Journal: Molecular Biology and Evolution (1987)

.We used six restriction endonucleases (D&I, HinfI, HpaII, MM, TagI, and Zmo37), each with a unique four-base recognition site, to digest 26 mitochondrial genomes from six Platycercus species in an investigation of the systematics of this speciose and variable Australian genus. The resulting fragments were end labeled and separated by means of polyacrylamide-gel electrophoresis. The number of substitutions per nucleotide site between each of the genomes was estimated on the basis of the distribution of fragments between samples by means of the method of Nei and Li. These pairwise distances were used to construct evolutionary trees either by assuming an evolutionary clock or by allowing the branch lengths to vary independently. The presence or absence of each restriction fragment was also scored and used as characters in Wagner parsimony analysis. In general, the phylogenies produced from mitochondrial genome diversity mirror the current classification of the genus, except for P. icterotis, which is not clustered with either of the superspecies of Platycercus and, as such, should probably be placed in a third group. To confirm that the family of parrots to which Platycercus belongs has a conservative nuclear genome, Nei’s genetic distance between and within Platycercus and other related species was estimated by means of cellogel electrophoresis of liver isozymes. Of the 26 Platycercus mitochondrial genomes studied, 23 different haplotypes were identified according to the limits of resolution of the technique. The mean interspecific mitochondrial genome diversity was 0.0457, and the intraspecific genome diversity varied between 0.003 1 (for P. caledonicus) and 0.0 142 (for P. eximius). These diversity values indicate either that the rate of rosella genome evolution is 2-3 orders of magnitude below the rate reported for primates or that the effective sizes of the rosella populations are 2-3 orders of magnitude below the sizes estimated on the basis of ecological methods.
Functional consequences of anti-sense RNA-mediated inhibition of CD8 surface expression in a human T cell clone.
Authors: J E Hambor, M L Tykocinski, D R Kaplan
Journal: The Journal of Experimental Medicine (1988)

An experimental approach for defining the function of CD8 has been developed by linking anti-sense RNA mutagenesis and T cell cloning technologies. We have transfected an anti-sense CD8 episomal expression vector into a CD8+ nontransformed human T cell clone that is specific for the human class I alloantigen HLA-B35. Expression of CD8 on this T cell clone, JH.ARL.1, was selectively and efficiently inhibited. Stimulation of this CD8- variant with specific alloantigen resulted in a marked loss of a number of functional responses, including cytotoxicity, proliferation, IL-2 secretion, and IL-2-R expression. However, these same functional responses could be elicited with stimuli that do not require antigen recognition to activate the T cell (anti-CD3 mAbs, PHA). The results of our study support the hypothesis that CD8 is required for recognition of class I MHC alloantigens that results in activation of T cell functional responses.
EPIDEMIC CERVICAL ADENITIS
Authors: J. G. Sharp
Journal: BMJ (1913)

DlCL " ~UN tlhymus sexual precocity occur;.It is difficult, however, to know wllicli is the cause and which the effect.Further clinical investigations slhould tbrow light on this jluestior.. Excess of Thy))ns Secretion.In the condition kniiown as status lymphaticus tllere is abnormal persistence of tlle thymus, and since the secondary or pubescenit development of the sextual organs is associated witlh retrogressionl of the thymus there is under-developnmelnt of the genital organs witli amenor- rhoea if the tliyinutis persist.Individuals withl a per- sistenit thynius ustually die early, and I do not think the conditioni hias as yet beenl colnsidered at all seriously fromll the genital point of viewv.Retrogression of the thymus miglht be assisted, if the viewv be true that development of the genitals cauises retrogression of the thymus-a question wlhiclh lhas already been discussed.-~~~~~REFEREN-CES.
Severe Bradycardia With Clonidine
Authors: Linda Van Etta
Journal: JAMA (1978)

To the Editor.—  While the Wenckebach phenomenon and moderate sinus bradycardia from clonidine had been reported in 1971 by Yeh et al,1only recently were two cases of atrioventricular block recorded by Kilber and Gazes (238:1930, 1977) and two cases of symptomatic sinus bradycardia recorded by Scherman et al.2Another case of severe symptomatic sinus bradycardia occurred in our hospital recently.  Report of a Case.—  A 57-year-old diabetic hypertensive man was admitted to Northwestern Hospital in Minneapolis for treatment of pneumonia. Because of severe hypokalemia when treated with thiazide diuretics, he had been taking only clonidine hydrochloride, 0.3 mg twice a day, for the previous six months. Blood pressure readings during the first few days of hospitalization ranged from 140/80 mm Hg to 187/110 mm Hg. His pulse rate ranged from 52 to 82 beats per minute. Clonidine dosage was increased to 0.4 mg twice a day. Over the
Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium.
Authors: G Hasenfuss, H Reinecke, R Studer, M Meyer, B Pieske, J Holtz, C Holubarsch, H Posival, H Just, H Drexler
Journal: Circulation Research (1994)

Expression of sarcoplasmic reticulum (SR) Ca(2+)-ATPase was shown to be reduced in failing human myocardium. The functional relevance of this finding, however, is not known. We investigated the relation between myocardial function and protein levels of SR Ca(2+)-ATPase in nonfailing human myocardium (8 muscle strips from 4 hearts) and in myocardium from end-stage failing hearts with dilated (10 muscle strips from 9 hearts) or ischemic (7 muscle strips from 5 hearts) cardiomyopathy. Myocardial function was evaluated by the force-frequency relation in isometrically contracting muscle strip preparations (37 degrees C, 30 to 180 min-1). In nonfailing myocardium, twitch tension rose with increasing rates of stimulation and was 76% higher at 120 min-1 compared with 30 min-1 (P &lt; .02). In failing myocardium, there was no significant increase in average tension at stimulation rates above 30 min-1. At 120 min-1, twitch tension was decreased by 59% (P &lt; .05) in dilated cardiomyopathy and 76% (P &lt; .05) in ischemic cardiomyopathy compared with nonfailing myocardium. Protein levels of SR Ca(2+)-ATPase, normalized per total protein or per myosin, were reduced by 36% (P &lt; .02) or 32% (P &lt; .05), respectively, in failing compared with nonfailing myocardium. SR Ca(2+)-ATPase protein levels were closely related to SR Ca2+ uptake, measured in homogenates from the same hearts (r = .70, n = 16, and P &lt; .005).(ABSTRACT TRUNCATED AT 250 WORDS)