tbuckley/cabot-search huggingface dataset:
Letter by Krishnan et al Regarding Article, “Platelet Expression Profiling and Clinical Validation of Myeloid-Related Protein-14 as a Novel Determinant of Cardiovascular Events”
Authors: Unni Krishnan, Alison H. Goodall, Peter Bugert
Journal: Circulation (2007)

The article by Healy et al 1 raises interesting possibilities in coronary artery disease by suggesting a new candidate biomarker for stable coronary artery disease and postulating a novel source for myeloid-related protein-14 (MRP-14).In our opinion, however, there are some factors that may need to be considered before platelets can be determined to be a source of MRP-14.Patients with ST-elevation myocardial infarction in the study 1 had significantly raised leukocyte counts, a factor that was not included in the multivariate model.Because leukocytes are a well-known source of MRP-14, this could explain the raised plasma levels of this protein in the patient group.Epidemiological studies suggest that leukocyte count is an independent predictor of coronary events in asymptomatic individuals.It would, therefore, be expected that leukocyte counts would be raised in the patient cohort in the validation study, significantly affecting the level of MRP-14 in plasma.Although leukocyte contamination of the platelet preparations was monitored by analysis of CD45ϩ events by flow cytometry, this method may not provide the sensitivity to accurately detect contamination by leukocytes.In addition, this method may fail to detect leukocyte microparticles that may lack the CD45 antigen but that would be isolated with the platelets and could contribute to the mRNA pool.Given the 12 500-fold relative abundance of mRNA in leukocytes compared with platelets 2 only, tiny levels of leukocyte contamination could account for the presence of MRP-14 in the platelet transcriptome.The authors suggest that previous work in platelet transcriptome profiling has demonstrated the presence of MRP-14 in platelets. 3However, the reference cited states that the signal for the specific mRNA on microarray analysis was in the negative range.Further microarray hybridization analysis of Ͼ34 000 genes in platelets using different glass slide microarray systems suggests that platelets do not express the MRP-14 gene. 4Detailed analyses of platelet proteome have not indicated the presence of There is no doubt that the identification of raised plasma levels of MRP-14 in stable coronary artery disease would open new avenues in early risk stratification. Hver, whether this gene is expressed in platelets should be considered with caution.
Focal and multi-focal plaque macrophage distributions in patients with acute and stable presentations of coronary artery disease
Authors: Briain D. MacNeill, Ik-Kyung Jang, Brett E. Bouma, Nicusor Iftimia, Masamichi Takano, Hiroshi Yabushita, Milen Shishkov, Christopher R. Kauffman, Stuart L. Houser, H. Thomas Aretz, Denise DeJoseph, Elkan F. Halpern, Guillermo J. Tearney
Journal: Journal of the American College of Cardiology (2004)
REACTION TO EXTREME STRESS: IMPENDING DEATH BY EXECUTION
Authors: HARVEY BLUESTONE, CARL L. MCGAHEE
Journal: American Journal of Psychiatry (1962)

Traditional ego defense mechanisms alleviate distress. They also mitigate anxiety and depression which would otherwise overwhelm the prisoner in a death cell. Some psychiatrists allege that the death fear (whether on the battlefield or in the death house) serves as an irrational surrogate for some other fear–such as castration. This over-simplified explanation does scant justice to the inescapable certainty shared by all, but anticipated only by man.
Actin from Heart Muscle: Isolation, Purification, and Physicochemical Properties
Authors: ARNOLD M. KATZ, ELIZABETH J. HALL
Journal: Circulation Research (1963)

A systematic study of the preparation of actin from cardiac muscle has led to the use of a modification of Straub's original technique which gave good yields of an F-actin with very high polymerizing activity. The G-actin obtained by this method was found to be homogneous in starch gel electrophoresis; the sedimentation behavior suggested that small amounts of oligomers of G-actin may have been present in addition to monomeric G-actin, but there was no evidence of impurity. The partial specific volume of dog cardiac actin was approximately 0.715 ml/g, the sedimentation coefficient extrapolated to infinite dilution of the protein was 3.44 S, and the intrinsic viscosity was 0.16 dl/g. Precise measurement of the diffusion coefficient was not feasible due to the instability of the G-actin monomers in solutions of high ionic strength. The sedimentation behavior of rabbit cardiac actin was similar to that of dog cardiac actin. The molecular weight of dog cardiac actin, estimated from sedimentation and viscosity data, was 62, 300. Since this estimate of molecular weight is similar to published values for rabbit skeletal actin, the different properties of cardiac and skeletal muscle cannot be attributed to a major physicochemical difference between the actins of these two tissues.
Transgenic Model of Aldosterone-Driven Cardiac Hypertrophy and Heart Failure
Authors: Wenning Qin, Amy E. Rudolph, Brian R. Bond, Ricardo Rocha, Eric A.G. Blomme, Joseph J. Goellner, John W. Funder, Ellen G. McMahon
Journal: Circulation Research (2003)

Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11β-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse α-myosin heavy chain promoter. This enzyme converts glucocorticoids to receptor-inactive metabolites, allowing aldosterone occupancy of cardiomyocyte mineralocorticoid receptors. Transgenic mice were normotensive but spontaneously developed cardiac hypertrophy, fibrosis, and heart failure and died prematurely on a normal salt diet. Eplerenone, a selective aldosterone blocker, ameliorated this phenotype. These studies confirm the deleterious consequences of inappropriate activation of cardiomyocyte mineralocorticoid receptors by aldosterone and reveal a tonic inhibitory role of glucocorticoids in preventing such outcomes under physiological conditions. In addition, these data support the hypothesis that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure.
Reply to P. Baldo et al
Authors: Francesco Perrone, Massimo Di Maio, Ciro Gallo
Journal: Journal of Clinical Oncology (2015)

We thank Baldo et al for their interest in our article on under-reporting of toxicity by physicians participating in three prospective clinical trials managed at the National Cancer Institute (NCI) of Naples. They assign to us more merits than we actually have because the three trials were all sponsored by the NCI of Naples, which holds the physical and intellectual property of all the data. There were supporters (Merck for gemcitabine-coxib in NSCLC [GECO], Roche for tarceva or chemotherapy [TORCH], Sanofi for elderly breast cancer docetaxel adjuvant [ELDA], and Associazione Italiana per la Ricerca sul Cancro—the largest Italian charity—for almost all our work), but they played no role in writing protocols, conducting the studies, doing statistical analysis, and writing the manuscripts. This may happen in Italy under the auspices of an Italian law promulgated in 2004 that defines the opportunity and some rules for independent academic (so-called nonprofit) clinical trials. We agree that the use of uniform terminology is crucial for effective data sharing. However, we do not believe that the Medical Dictionary for Regulatory Activities (MedDRA) resolves the issue, or at least not directly. In fact, MedDRA includes a huge number of terms (more than 66,000) and is not dedicated to oncology. In addition, it does not include rating scales, which are crucial to define the importance of adverse events occurring to patients with cancer. On the contrary, Common Terminology Criteria for Adverse Events (CTCAE) is dedicated to oncology and therefore includes a reasonably lower number of terms (790 in the 4.0 version) and a scoring system developed from the historical WHO scale. It is easily and frequently used by oncologists, even in clinical practice. Finally, CTCAE is not subject to any copyright restrictions, whereas MedDRA is a licensed dictionary. However, it should be noted that the choice between the two systems is simplified by the fact that starting with CTCAE version 4.0, the terminology is periodically harmonized with MedDRA terms. We also agree that procedures of pharmacovigilance are of paramount importance to fully describe the toxicity profile of a drug or a class of drugs. This is particularly crucial when the information about toxicity coming from pivotal trials is based on a limited number of patients, as has become increasingly common in oncology in recent years. However, if under-reporting in pharmacovigilance, as previously discussed by Baldo and De Paoli, is a real problem, especially in oncology, where toxicity of anticancer drugs is often considered normal, under-reporting represents an even more serious problem in clinical trials, in which reporting of adverse events is not left to spontaneous initiative of physicians but is explicitly mandated by study protocol. In this context, we strongly support the adoption in clinical trials of tools like the PRO-CTCAE, which might overcome most of the reasons of under-reporting by physicians.
Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses
Authors: Silvia B. Boscardin, Julius C.R. Hafalla, Revati F. Masilamani, Alice O. Kamphorst, Henry A. Zebroski, Urvashi Rai, Alexandre Morrot, Fidel Zavala, Ralph M. Steinman, Ruth S. Nussenzweig, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2006)

Resistance to several prevalent infectious diseases requires both cellular and humoral immune responses. T cell immunity is initiated by mature dendritic cells (DCs) in lymphoid organs, whereas humoral responses to most antigens require further collaboration between primed, antigen-specific helper T cells and naive or memory B cells. To determine whether antigens delivered to DCs in lymphoid organs induce T cell help for antibody responses, we targeted a carrier protein, ovalbumin (OVA), to DCs in the presence of a maturation stimulus and assayed for antibodies to a hapten, (4-hydroxy-3-nitrophenyl) acetyl (NP), after boosting with OVA-NP. A single DC-targeted immunization elicited long-lived T cell helper responses to the carrier protein, leading to large numbers of antibody-secreting cells and high titers of high-affinity antihapten immunoglobulin Gs. Small doses of DC-targeted OVA induced higher titers and a broader spectrum of anti-NP antibody isotypes than large doses of OVA in alum adjuvant. Similar results were obtained when the circumsporozoite protein of Plasmodium yoelii was delivered to DCs. We conclude that antigen targeting to DCs combined with a maturation stimulus produces broad-based and long-lived T cell help for humoral immune responses.
Sialyl Lewisx-containing oligosaccharide attenuates myocardial reperfusion injury in cats.
Authors: M Buerke, A S Weyrich, Z Zheng, F C Gaeta, M J Forrest, A M Lefer
Journal: Journal of Clinical Investigation (1994)

Neutrophil (PMN) adhesion to the vascular endothelium is an important mechanism of myocardial reperfusion injury. The adhesion process is initially mediated by selectins (e.g., P- and L-selectin), and monoclonal antibodies directed against these adhesion molecules exert cardioprotective activity in ischemia/reperfusion models. The counterreceptors for these selectins are thought to be carbohydrate-containing moieties. In this connection, we studied the effect of a soluble sialyl Lewisx-containing oligosaccharide (SLex-OS) on PMN-endothelial interactions in a feline model of myocardial ischemia/reperfusion (MI/R). SLex-OS (10 mg/kg), administered 10 min before R, significantly reduced myocardial necrosis compared with its vehicle 270 min after reperfusion (6 +/- 1% vs. 35 +/- 4% of area at risk, P < 0.01). The cardioprotection was confirmed by significantly lower plasma creatine kinase activities in SLex-OS vs. vehicle-treated cats (P < 0.01). Cardiac contractility (dP/dt max) of cats receiving SLex-OS was significantly preserved after 270 min of R (97 +/- 2% vs. 78 +/- 5% of initial, P < 0.01). Furthermore, endothelium-dependent relaxation to acetylcholine in coronary artery rings isolated from MI/R cats treated with SLex-OS was significantly preserved (73 +/- 7% vs. 22 +/- 6% vasorelaxation, P < 0.01). In vitro PMN adherence to coronary vascular endothelium after 270 min of R was significantly attenuated in the SLex-OS-treated group compared with the vehicle group (14 +/- 5 vs. 91 +/- 12 PMN/mm2, P < 0.01). Our results indicate that a SLex-OS is cardioprotective and preserves coronary endothelial function after MI/R, indicating an important role of sialyl Lewisx in PMN accumulation, endothelial dysfunction, and myocardial injury in myocardial ischemia/reperfusion.
Effects of Pioglitazone Versus Glipizide on Body Fat Distribution, Body Water Content, and Hemodynamics in Type 2 Diabetes
Authors: Ananda Basu, Michael D. Jensen, Frances McCann, Debabrata Mukhopadhyay, Michael J. Joyner, Robert A. Rizza
Journal: Diabetes Care (2006)

OBJECTIVE—Pioglitazone, a peroxisome proliferator–activated receptor agonist and glipizide, an insulin secretagogue, are commonly used to treat type 2 diabetes. Our study was designed to examine the effects of pioglitazone versus glipizide on body water, body composition, and hemodynamic parameters in the presence of comparable glycemic control between groups. RESEARCH DESIGN AND METHODS—We studied 19 diabetic subjects randomly assigned to either 45 mg pioglitazone (n = 8) or 10 mg (median dose) glipizide (n = 11) for 12 weeks. Body water content was measured with deuterated water, body composition by dual-energy X-ray absorptiometry and computed tomography, and cardiac output and systemic vascular resistance by acetylene rebreathing technique both before and after therapy. RESULTS—Pioglitazone increased (P &amp;lt; 0.001 from baseline) total body water (+2.4 ± 0.5 l) accounting for 75% of the total weight gain (+3.1 ± 2.0 kg) but did not alter vascular endothelial growth factor concentrations. Total abdominal (−32.2 ± 19 cm2) and visceral fat area (−16.1 ± 8 cm2) tended to decrease with pioglitazone but increased (P &amp;lt; 0.02 for differences between groups) with glipizide (+38.4 ± 17 cm2 abdominal; +19.1 ± 9 cm2 visceral). Pioglitazone tended to reduce (P = 0.05) diastolic (−8.4 ± 4 mmHg) and mean (−9.5 ± 5 mmHg; P = 0.08) blood pressure and reduced (P &amp;lt; 0.001) systemic vascular resistance (2,785 ± 336 vs. 2,227 ± 136 dynes/s per m2), while there were no differences in these parameters with glipizide. Neither therapy altered circulating catecholamine concentrations. CONCLUSIONS—When pioglitazone and glipizide are given in doses sufficient to achieve equivalent glycemic control in people with type 2 diabetes, pioglitazone increases total body water, thereby accounting for the majority of weight gain, tended to decrease visceral and abdominal fat content and blood pressure, and reduces systemic vascular resistance.
An unusual cause of haemoptysis in a smoker
Authors: M J McDonnell, J Garvey, D G Lohan, G J O'Sullivan, K Redmond, J E Jackson, R M Rutherford
Journal: Thorax (2013)

A 33-year-old Caucasian male smoker presented to our rapid access lung cancer clinic with a single episode of moderate haemoptysis and no other respiratory or systemic symptoms. There was no relevant past medical history. As an adopted child he was unaware of any significant family history. The only finding on clinical examination was decreased air entry on the right side. Laboratory tests were all normal. Chest x-ray demonstrated a small right hemithorax with marked mediastinal displacement to the right, increased soft tissue opacity adjacent to the right side of the mediastinum causing widening of the right paratracheal stripe and loss of silhouette of the right heart border, and increased interstitial opacity throughout the right lung (figure 1A). A CT scan of the thorax confirmed the presence of a large amount of abnormal low attenuation soft tissue around the right side of the mediastinum, which also involved the azygo-oesophageal space causing considerable thickening of the oesophageal wall (figure …
Induction of Endothelial Nitric Oxide Synthase Expression by Melanoma Sensitizes Endothelial Cells to Tumor Necrosis Factor-Driven Cytotoxicity
Authors: Simone Mocellin, Maurizio Provenzano, Carlo Riccardo Rossi, Pierluigi Pilati, Romano Scalerta, Mario Lise, Donato Nitti
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The cascade of molecular events leading to tumor necrosis factor (TNF)-mediated tumor regression is still incompletely elucidated. We investigated the role of endothelial nitric oxide synthase in determining the tumor-selective activity of TNF. Experimental Design: Using quantitative real-time PCR, endothelial nitric oxide synthase gene levels were measured in melanoma metastases of the skin and normal skin biopsies obtained from 12 patients before undergoing TNF-based therapy. In vitro, the ability of melanoma cells supernatant to affect endothelial nitric oxide synthase transcription by endothelial cells and the influence of nitric oxide synthase inhibition on TNF cytotoxicity toward endothelial cells was evaluated. Results: Endothelial nitric oxide synthase transcript abundance resulted significantly greater in tumor samples rather than in normal skin samples and in patients showing complete response to TNF-based treatment rather than in those showing partial/minimal response. In vitro, melanoma cells’ supernatant induced endothelial nitric oxide synthase gene expression by endothelial cells. Nitric oxide synthase inhibition slowed endothelial cells proliferation and, if induced before TNF administration, decreased the cytokine-mediated cytotoxicity on endothelial cells. Conclusions: Taken together, these findings support the hypothesis that high expression of endothelial nitric oxide synthase in the tumor microenvironment might increase or be a marker for endothelial cells sensitivity to TNF. These observations may have important prognostic and/or therapeutic implications in the clinical setting.
Androgens as adjuvant treatment in postmenopausal female patients with rheumatoid arthritis.
Authors: A Booji, C M Biewenga-Booji, O Huber-Bruning, C Cornelis, J W Jacobs, J W Bijlsma
Journal: Annals of the Rheumatic Diseases (1996)

To examine the possible beneficial effect of androgens in postmenopausal women with active rheumatoid arthritis.107 women participated in a double blind placebo controlled trial to evaluate the effect of 50 mg testosterone propionate intramuscularly every two weeks for one year.An improvement in ESR, Dutch health assessment questionnaire, and pain was noted. In addition, 21% of patients treated with testosterone fulfilled the ACR improvement criteria after one year, versus only 4% of the placebo group. The treatment was well tolerated.Testosterone may improve the general wellbeing of postmenopausal women with active rheumatoid arthritis.
Contribution of Cyclooxygenase-2 to Elevated Biosynthesis of Thromboxane A <sub>2</sub> and Prostacyclin in Cigarette Smokers
Authors: Brendan F. McAdam, Daniel Byrne, Jason D. Morrow, John A. Oates
Journal: Circulation (2005)

Background— Cigarette smoking is highly pathogenic to the vasculature. In smokers, the biosynthesis of both thromboxane (Tx) A 2 and prostacyclin is increased. We hypothesized that the excess in prostacyclin biosynthesis in smokers was derived from the inducible cyclooxygenase-2 (COX-2). We further hypothesized that if the overproduction of prostacyclin in smokers were restraining platelet activation, then inhibition of COX-2 would lead to an increase in the activation of platelets, with a corresponding increase in the biosynthesis of TxA 2 . Methods and Results— Smokers and nonsmokers received rofecoxib 25 mg twice daily or placebo for 1 week each in random sequence. The systemic biosynthesis of TxA 2 and prostacyclin was assessed by analysis of their respective urinary metabolites, 11-dehydrothromboxane B 2 (Tx-M) and 2′3-donor–6-keto-PGF 1α (PGI-M). Serum TxB 2 was measured as an indicator of platelet COX-1 activity. Results are expressed as mean±SE with median and range. The elevated PGI-M in smokers (189±25, median 174, range 85 to 390 pg/mg creatinine) was reduced by rofecoxib to 78±27, median 71.5, range 50 to 135 pg/mg creatinine ( P =0.002), and in nonsmokers, PGI-M at baseline (115±10, median 107, range 67 to 198 pg/mg creatinine) fell to 56±15, median 50, range 34 to 125 pg/mg creatinine ( P =0.001) with rofecoxib. The increased excretion of Tx-M in smokers (284±26, median 252, range 200 to 569 pg/mg creatinine) was reduced by 21% to 223±16, median 206, range 154 to 383 pg/mg creatinine by rofecoxib ( P =0.04) but was not changed in nonsmokers. Levels of serum TxB 2 were not different in smokers and nonsmokers and were unaffected by rofecoxib. Conclusions— The increased prostacyclin biosynthesis in smokers is derived largely from the inducible COX-2. COX-2 also contributes to the increased biosynthesis of TxA 2 in smokers, most likely from inflammatory cells.
Identification of Aberrantly Methylated Genes in Association with Adult T-Cell Leukemia
Authors: Jun-ichirou Yasunaga, Yuko Taniguchi, Kisato Nosaka, Mika Yoshida, Yorifumi Satou, Tatsunori Sakai, Hiroaki Mitsuya, Masao Matsuoka
Journal: Cancer Research (2004)

Abstract In this study, we identified 53 aberrantly hypermethylated DNA sequences in adult T-cell leukemia (ATL) cells using methylated CpG island amplification/representational difference analysis method. We also observed a proportionate increase in the methylation density of these regions with disease progression. Seven genes, which were expressed in normal T cells, but suppressed in ATL cells, were identified near the hypermethylated regions. Among these silenced genes, Kruppel-like factor 4 (KLF4) gene is a cell cycle regulator and early growth response 3 (EGR3) gene is a critical transcriptional factor for induction of Fas ligand (FasL) expression. Treatment with 5-aza-2′-deoxycytidine resulted in the recovery of their transcription, indicating that their silencing might be associated with DNA hypermethylation. To study their functions in ATL cells, we transfected recombinant adenovirus vectors expressing KLF4 and EGR3 genes. Expression of KLF4 induced apoptosis of ATL cells whereas enforced expression of EGR3 induced the expression of FasL gene, resulting in apoptosis. Thus, suppressed expression of EGR3 enabled ATL cells to escape from activation-induced cell death mediated by FasL. Our results showed that the methylated CpG island amplification/representational difference analysis method allowed the isolation of hypermethylated DNA regions specific to leukemic cells and thus shed light on the roles of DNA methylation in leukemogenesis.