tbuckley/cabot-search huggingface dataset:
De Novo Synthesis of Cyclooxygenase-1 Counteracts the Suppression of Platelet Thromboxane Biosynthesis by Aspirin
Authors: Virgilio Evangelista, Stefano Manarini, Angelo Di Santo, Marta L. Capone, Emanuela Ricciotti, Luigia Di Francesco, Stefania Tacconelli, Andrea Sacchetti, Sandra D’Angelo, Antonio Scilimati, Maria G. Sciulli, Paola Patrignani
Journal: Circulation Research (2006)

Aspirin affords cardioprotection through the acetylation of serine 529 in human cyclooxygenase-1 (COX-1) of anucleated platelets, inducing a permanent defect in thromboxane A 2 (TXA 2 )–dependent platelet function. However, heterogeneity of COX-1 suppression by aspirin has been detected in cardiovascular disease and may contribute to failure to prevent clinical events. The recent recognized capacity of platelets to make proteins de novo paves the way to identify new mechanisms involved in the variable response to aspirin. We found that in washed human platelets, the complete suppression of TXA 2 biosynthesis by aspirin, in vitro, recovered in response to thrombin and fibrinogen in a time-dependent fashion (at 0.5 and 24 hours, TXB 2 averaged 0.1±0.03 and 3±0.8 ng/mL; in the presence of arachidonic acid [10 μmol/L], it was 2±0.7 and 25±7 ng/mL, respectively), and it was blocked by translational inhibitors, by rapamycin, and by inhibitors of phosphatidylinositol 3-kinase. The results that COX-1 mRNA was readily detected in resting platelets and that [ 35 S]-methionine was incorporated into COX-1 protein after stimulation strongly support the occurrence of de novo COX-1 synthesis in platelets. This process may interfere with the complete and persistent suppression of TXA 2 biosynthesis by aspirin necessary for cardioprotection.
Tubular Expression of Angiotensin II Receptors and Their Regulation in IgA Nephropathy
Authors: Loretta Y.Y. Chan, Joseph C.K. Leung, Sydney C.W. Tang, Cindy B.Y. Choy, Kar Neng Lai
Journal: Journal of the American Society of Nephrology (2005)

Enhanced renal expression for the renin-angiotensin system (RAS) is detected in IgA nephropathy (IgAN). Previous data showed an altered glomerular expression of angiotensin II type 1 receptor (AT1R), suggesting a regulatory response to high intrarenal angiotensin II (Ang II) concentration in IgAN. In this study, the expression and regulation of Ang II receptors were examined in human proximal tubular epithelial cells (PTEC) in IgAN. Tubular expression of AT1R and Ang II type 2 receptor (AT2R) was increased in IgAN. In vitro culture experiment showed that the upregulation of Ang II receptors was not due to the direct effect of IgA but the indirect effect after IgA deposition on human mesangial cell. When PTEC were cultured with conditioned culture medium from human mesangial cells activated with IgA, Ang II production was upregulated, leading to inflammation and apoptosis via the AT1R and AT2R, respectively. Sequential expression of Ang II receptors determined the injury of PTEC induced by mediators in the conditioned medium. The initial interaction between Ang II and AT1R activated both protein kinase C and mitogen-activated protein kinase pathways, leading to inflammatory responses. This early AT1R-dependent event was followed by upregulation of AT2R expression and continued Ang II release. The interaction between Ang II and AT2R subsequently led to expression of cleaved poly[ADP-ribose] polymerase through downregulation of the mitogen-activated protein kinase pathway. The data suggest that appropriate control of Ang II receptor activities in PTEC may ameliorate tubulointerstitial injury in IgAN.
Nasal airway changes assessed by acoustic rhinometry and mediator release during immediate and late reactions to allergen challenge
Authors: Burton Zweiman, John Getsy, Mark Kalenian, Andrew Lane, Lawrence B. Schwartz, Richard Doty, Donald Lanza
Journal: Journal of Allergy and Clinical Immunology (1997)

We have found that acoustic rhinometry is a reliable means of assessing nasal airway caliber changes during the immediate reaction to nasal allergen challenge of sensitive subjects. Comparison of such changes with symptoms and patterns of mediator release could help in the understanding of mechanisms of immediate and late-phase reactions after allergen challenge and their clinical relevance.Nasal minimal cross-sectional area (MCA) was assessed sequentially for 6 hours after two blinded challenges in random order with pollen antigens and buffer diluent in five sensitive human subjects. Comparisons were made with: (1) symptom scores; (2) olfaction changes; and (3) nasal secretion levels of histamine, tryptase, leukotriene C4, serum albumin (a marker of vascular permeability), lactoferrin (a marker of local glandular secretion), and inflammatory cells in nasal scrapings.In four of five subjects there was a significantly greater decrease in MCA after antigen challenge than after diluent challenge, correlating with the degree of subjective nasal congestion. In two of these four subjects there was a prominent second late-phase decrease in MCA at 3 to 5 hours, whereas the MCA was persistently decreased in an additional subject with accompanying subjective congestion. No significant decrease in olfactory acuity occurred. Levels were significantly higher in nasal secretions obtained after antigen challenge than in those obtained after buffer challenge with histamine (9 +/- 2.7 ng/ml vs 1.2 +/- 0.5 ng/ml; p = 0.04); tryptase (95 +/- 83 ng/ml vs 3 +/- 0.9 ng/ml; p = 0.02), leukotriene C4 (5293 +/- 1385 ng/ml vs 578 +/- 183 ng/ml; p = 0.02), and albumin (123 +/- 9 ng/ml vs 19 +/- 1.6 ng/ml; p = 0.005) but not with lactoferrin (4.6 +/- 1.2 ng/ml vs 4.1 +/- 28 ng/ml; p = not significant). Granulocyte exudation was seen after antigen challenge but not after buffer diluent challenge. However, there was not a precise correlation between decreases in MCA with changes in levels of these mediators in individual subjects.Acoustic rhinometry can quantitatively assess congestion during immediate and late-phase reactions after nasal challenge without significant correlation to the degree of individual inflammatory events assessed.
Methods for Improving Regression Analysis for Skewed Continuous or Counted Responses
Authors: Abdelmonem A. Afifi, Jenny B. Kotlerman, Susan L. Ettner, Marie Cowan
Journal: Annual Review of Public Health (2006)

Standard inference procedures for regression analysis make assumptions that are rarely satisfied in practice. Adjustments must be made to insure the validity of statistical inference. These adjustments, known for many years, are used routinely by some health researchers but not by others. We review some of these methods and give an example of their use in a health services study for a continuous and a count outcome. For the continuous outcome, we describe retransformation using the smear factor, accounting for missing cases via multiple imputation and attrition weights and improving results with bootstrap methods. For the count outcome, we describe zero inflated Poisson and negative binomial models and the two-part model to account for overabundance of zero values. Recent advances in computing and software development have produced user-friendly computer programs that enable the data analyst to improve prediction and inference based on regression analysis.
Response to 'Lapses at the NEJM'
Authors: J. M Drazen
Journal: Journal of the Royal Society of Medicine (2006)

JRSM 1 ) overlooks the most salient message of the recent Vioxx matter: authors must take responsibility for the integrity of their work.Integrity is not defined by what an author can get past an editor.It is the indisputable obligation of researchers to include all relevant data in manuscript submissions-especially in research involving drug safety.The VIGOR authors, two of whom were Merck employees, withheld critical data on the cardiovascular toxicity of Merck's drug Vioxx.As soon as we learned that the authors knew of these data well before the article was published, we began preparing our Expression of Concern.By bringing this matter to public attention, we underscored its importance.The tale Smith tells is riddled with distortions and unsubstantiated opinions.These inaccuracies seem designed to serve an agenda he already has put forth: that journals are information-laundering vehicles for industry, a cynical view that we do not share.We stepped forward when we did, exposing ourselves to criticism, for the sake of open and honest discourse between authors and editors.Smith contends that medical journals have been damaged and the NEJM has been embarrassed.To the contrary, we are proud of our actions.We wanted to serve our readers by correcting the record and to affirm with authors the importance of accuracy and completeness.On the second point, we already have seen authors taking greater care to ensure the completeness of their submissions.
Why has Swann failed?
Authors: A I Maitland
Journal: BMJ (1980)

SIR,-The limitations inherent in conducting controlled trials of methods of providing health services, which we refer to in our paper, mean that we have no information on the criteria which were used to transfer a selected group of patients from medical units during the acute phase of rehabilitation.But we have been able to examine the results of standard clinical tests which were designed to predict outcome following acute stroke, and which will form the subject of a future publication.No difference was found in the pattern of neurological impairment present in the transferred group compared with those
Abstract 3150: Exploring the role of Rap1Gap in the progression from DCIS to invasive breast carcinoma
Authors: Seema Shah, Kingsley Osuala, Shihong Mao, Quanwen Li, Bonnie Sloane, Stephen Krawetz, Raymond R. Mattingly
Journal: Cancer Research (2014)

Abstract Understanding the underlying mechanisms that drive malignant progression of breast cancer is important. The purpose of this study is to define the role of Rap1Gap in the progression of ductal carcinoma in-situ (DCIS) to invasive cancer. We employed an in-vitro three-dimensional (3D) overlay model that provides a physiologically relevant microenvironment to study mechanisms of mammary gland development and malignant progression. We previously employed next generation sequencing (NGS) and identified 63 consistently upregulated genes in three DCIS lines (SUM102, SUM225, MCF10.DCIS) compared to non-transformed mammary epithelial cells. To gain insight into common transcriptional elements of co-regulated genes that may be critical to the DCIS phenotype, we have mined our NGS data using Frameworker (Genomatix). The 63 upregulated genes are associated with 244 candidate promoters out of a total of 82,703 promoters in the entire human genome. Our analysis shows that the common framework RXRF-ZF02-ZF02-PLAG-HDBP is only present in the promoters of three genes: RAP1GAP, SPRY4 and PDGFB. All of these genes are upregulated in our DCIS signature, which means that this framework is hugely enriched (336-fold) over what would be expected by chance. Rap1Gap has tumor suppressor properties; its functions, via regulation of Rap1 activity, include regulation of cell adhesion, suppression of cell proliferation and metastasis. In other epithelial cancers, loss of Rap1Gap has been linked to epithelial to mesenchymal transition (EMT) and invasion. To begin study of Rap1Gap in breast cancer progression, we performed immunohistochemistry. We show strong Rap1Gap staining in DCIS with little to no expression in myoepithelial and stromal components. Immunoblotting results show that Rap1Gap levels in MCF10.CA1d cells (a model of invasive carcinoma) are reduced compared to those in MCF10.DCIS cells. Rap1Gap expression is low in additional basal breast cancer cell lines, but high in luminal ER+ /PR+ cell lines. We propose that over-expression of Rap1Gap may serve as a tumor suppressive mechanism in DCIS; subsequent reduction of Rap1Gap may be a switch for EMT and progression to an invasive phenotype. Citation Format: Seema Shah, Kingsley Osuala, Shihong Mao, Quanwen Li, Bonnie Sloane, Stephen Krawetz, Raymond R. Mattingly. Exploring the role of Rap1Gap in the progression from DCIS to invasive breast carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3150. doi:10.1158/1538-7445.AM2014-3150
Folates in plasma and bile of man after feeding folic acid—3H and 5-formyltetrahydrofolate (folinic acid)
Authors: Roy F. Pratt, Bernard A. Cooper
Journal: Journal of Clinical Investigation (1971)

During the 1st hr after feeding folic acid-(3)H ((3)H-PteGlu) to fasting human volunteers, plasma S. faecalis and (3)H activity were elevated to an equivalent degree, whereas after this, the (3)H activity exceeded S. faecalis activity, which suggests gradual conversion of folic acid-(3)H to methyltetrahydrofolate-(3)H (5-CH(3)H(4) PteGlu). The increase of L. casei activity exceeded the increase of S. faecalis and (3)H activity, which is consistent with flushing of endogenous methyltetrahydrofolate from the tissues by the administered folic acid-(3)H. Feeding of 5-formyltetrahydrofolate (+/-5CHOH(4)PteGlu) produced a large increase of plasma L. casei activity and only a slight increase of S. faecalis and P. cerevisiae activity, which is consistent with very rapid conversion of folinic acid to methyltetrahydrofolate. Bile folate concentration determined microbiologically was 2.3-9.8 times plasma folate. 40-80% of the bile folate was S. faecalis-active and 20-35% P. cerevisiae-active. Chromatography of bile folates on TEAE-cellulose showed several folates including four tentatively identified as 10-formyltetrahydrofolate (10-CHO-H(4)PteGlu), 10-formylfolate (10-CHO-PteGlu), and/or 10-formyldihydrofolate (10-CHOH(2)PteGlu), methyltetrahydrofolate, and possibly a triglutamate folate. After folate ingestion bile folate concentration increased rapidly. The distribution of bile folates measured by microbiological assay was similar after either folic or folinic acid feeding. Most of the (3)H label of folic acid-(3)H appeared in the biological folates of bile rather than in the folic acid fraction, which shows that the administered folic acid was rapidly transformed to other folates. Folate polyglutamate deconjugating enzyme activity was found to be much less than in serum. Polyglutamates of the type found in yeast were not found in bile. It is suggested that biliary folate may reflect the hepatic intracellular oligoglutamate folate pool rather than the folate as it appears in the hepatic portal blood.
Regulation of human eosinophil degranulation and activation by endogenous phospholipase A2.
Authors: S R White, M E Strek, G V Kulp, S M Spaethe, R A Burch, S P Neeley, A R Leff
Journal: Journal of Clinical Investigation (1993)

The unique granular proteins of eosinophils may have a pathogenetic role in asthma and in the defense against parasitic infestations. However, the mechanisms regulating eosinophil degranulation are largely unknown. We examined the hypothesis that release of these proteins is regulated by endogenous activation of phospholipase A2. Human eosinophils (HE) were isolated from the peripheral blood of 42 subjects either by Percoll density separation or by negative-selection immunomagnetic fractionation. Eosinophil activation was initiated in vitro with 10(-6) M FMLP and 5 micrograms/ml cytochalasin B and was assessed by measurement of eosinophil peroxidase (EPO), leukotriene C4 (LTC4) and superoxide radical (.O2-) secretion. Treatment of HE with 100 microM mepacrine before activation blocked EPO release (2.0 +/- 0.2 vs 10.2 +/- 2.1% cell content for activated HE, P < 0.004, n = 9), .O2- generation (2.6 +/- 0.9 vs 44.2 +/- 10.8 nmol/ml per 10(6) HE, P < 0.002, n = 5), and LTC4 secretion (68.2 +/- 32.2 vs 1,125.2 +/- 526.8 pg/ml per 10(6) HE, P < 0.04, n = 8). Pretreatment of HE with 100 microM 4-bromophenacyl bromide before activation similarly blocked EPO release, .O2- generation and LTC4 secretion. Addition of AA to HE after treatment with 100 microM mepacrine and before subsequent activation reversed the inhibition of both EPO (10.4 +/- 2.2% with 1 microM AA vs 2.0 +/- 0.2% for mepacrine, n = 5, P < 0.02) and LTC4 secretion (695.1 +/- 412.9 with 10 microM AA vs 68.2 +/- 32.2 pg/ml per 10(6) HE for mepacrine, n = 8, P < 0.04), but did not reverse inhibition of .O2- generation by mepacrine. We demonstrate that secretion of preformed cytotoxic proteins and .O2- by eosinophils is regulated endogenously by phospholipase A2.
Contrasting Cytotoxicity Kinetics of 5-Azacytidine and Dihydro-5-azacytidine Hydrochloride in L1210 Leukemia in Mice2, 3
Authors: Cary A. Presant, Dean Coulter, Frederick Valeriote, Vietti Teresa J.
Journal: JNCI Journal of the National Cancer Institute (1981)

For a comparison of the kinetics of the cytotoxicity of dihydro-5-azacytidine hydrochloride (DHAzaCR) and 5-azacytidine (AzaCR) in L1210 leukemia, the spleen colony assay was used to determine the surviving fraction of normal hematopoietic colony-forming units (NCFU) and leukemia colony-forming units (LCFU). Increasing doses of DHAzaCR above 1 mg per mouse enhanced cytotoxicity to LCFU but not to NCFU. The NCFU dose-survival curve showed a plateau with DHAzaCR, such that increasing the dose from 1 to 80 mg per mouse produced no further decrease in NCFU survival. In contrast, AzaCR produced a biphasic dose-NCFU survival curve without a plateau. Although DHAzaCR produced less cytotoxicity on a milligram basis than did AzaCR, both DHAzaCR and AzaCR elicited a biphasic dosesurvival curve for LCFU. An infusion of DHAzaCR was less cytotoxic than was a similar dose of DHAzaCR administered as an iv bolus. Although high doses of AzaCR delayed LCFU repopulation, both low and high doses of DHAzaCR were associated with prompt LCFU repopulation. Confirming this prompt repopulation of LCFU, there was a good correlation between the increase in life-span of mice with leukemia predicted by LCFU data following DHAzaCR treatment. compared to the discrepancy between predicted survival and observed survival following AzaCR. Therefore, the kinetics of cytotoxicity of DHAzaCR differ from those of AzaCR.
The Role of Aberrant VHL/HIF Pathway Elements in Predicting Clinical Outcome to Pazopanib Therapy in Patients with Metastatic Clear-Cell Renal Cell Carcinoma
Authors: Toni K. Choueiri, André P. Fay, Robert Gagnon, Ying Lin, Brittany Bahamon, Victoria Brown, Jonathan E. Rosenberg, Thomas E. Hutson, Katherine L. Baker-Neblett, Christopher Carpenter, Yuan Liu, Lini Pandite, Sabina Signoretti
Journal: Clinical Cancer Research (2013)

Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking.We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent.The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib.In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC.
E. J. KUTH "How to Write and Publish Papers in the Medical Sciences"
Authors: H. E. Robson
Journal: British Journal of Sports Medicine (1983)

This appears to be the most easily understood book written so far by the 'father' of orthopaedic medicine, profusely illustrated by anatomical drawings made by his wife and numerous photographs in colour showing each stage of exam- ination, massage, manipulation or injection.The first part is devoted to the principles of diagnosis, not only history and static examination, but full and detailed assessment of function, and also of treatment by massage, manipulation or injection.The contraindications of each technique are mentioned, and the indications for leaving conditions alone as they will either resolve spontaneously in a short time or will defy treatment.A full differential diagnosis is given, and warnings propounded for the physician or therapist to be on the look out for malignant or neurological conditions that could present as soft tissue lesions.The next two parts describe soft tissue lesions in the appendicular skeleton and in the spine respectively, both traumatic and degenerative.The specific indications for each form of therapy are given for each condition, with precision.When to inject?-how much, -of what?-how often?-when should the condition be expected to resolve?These details should enable general practitioners as well as rheumatologists and casually surgeons to carry out many procedures with safety and to give a reasonably accurate prognosis.In the section on the spine, traction techniques are included, as well as epidural anaesthesia, but it is hoped that no one will attempt these unless properly instructed!Some physicians will dispute the advisability of Dr. Cyriax' injections into tendons, but he does warn most emphatically the necessity of several weeks local rest afterwards.In his hands, and with his caveats, the precedure seems successful.This is a most valuable and well produced book, not only for the orthopaedic physician, but also of use to all who treat soft tissue lesions, whether in accident and emergency departments, sports injuries clinics, general practice and also physiotherapy and podiatry practices.This book is not designed to replace Dr. Cyriax' 'Textbook of Orthopaedic Medicine', the standard reference book on the subject, but it has a place on the desk for easy and frequent access, as useful in its field for day-to-day consultation as MIMS is for the newly appointed general practitioner.