tbuckley/cabot-search huggingface dataset:
Isolation and Properties of Phagocytic Vesicles from Polymorphonuclear Leukocytes
Authors: Thomas P. Stossel, Thomas D. Pollard, Robert J. Mason, Martha Vaughan
Journal: Journal of Clinical Investigation (1971)

A method for the isolation of intact phagocytic vesicles from guinea pig peritoneal-exudate granulocytes and human peripheral-blood leukocytes is presented. After leukocytes ingested the particles of a stable emulsion of paraffin oil, the uningested emulsion was washed away and the cells were homogenized. The homogenate was placed in the middle of a three-step discontinuous sucrose gradient and centrifuged for 1 hr at 100,000 g. The phagocytic vesicles, containing the low density paraffin-oil particles, were simultaneously washed and collected by floatation, while the other organelles, chiefly granules, sedimented through the lower wash layer, and the particle-free supernatant remained in the middle of the gradient. Emulsion particles stained with Oil Red O were employed to assay the rate of phagocytosis and to mark the location of the particles in subcellular fractions. The dye was extracted from washed cells or cell fractions with dioxane and colorimetrically quantified. The purity of phagocytic vesicles obtained by this method was assessed by electron microscopy, chemical analysis, and assay of enzyme composition. Granule-associated enzymes, acid phosphatase, alkaline phosphatase, beta-glucuronidase, and peroxidase were present in the phagocytic vesicles and originated from the granules. Cyanide-resistant NADH (reduced form of diphosphopyridine nucleotide) oxidase was also found. Enzymes associated with the vesicles exhibited latency to Triton X-100. Uptake of particles and the transfer of total protein and phospholipid into phagocytic vesicles occurred simultaneously Accumulation of acid and alkaline phosphatase in the vesicles continued until phagocytosis ceased. Peroxidase, NADH oxidase, and beta-glucuronidase activities in the phagocytic vesicles, on the other hand, were maximal by 30 min and increased little thereafter even when phagocytosis was still going on.
Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma
Authors: Jesús F. San Miguel, Rudolf Schlag, Nuriet K. Khuageva, Meletios A. Dimopoulos, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria T. Petrucci, Antonio Palumbo, Olga S. Samoilova, Anna Dmoszynska, Kudrat M. Abdulkadyrov, Rik Schots, Bin Jiang, Maria-Victoria Mateos, Kenneth C. Anderson, Dixie L. Esseltine, Kevin Liu, Andrew Cakana, Helgi van de Velde, Paul G. Richardson
Journal: New England Journal of Medicine (2008)

The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy.We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression.The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%).Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)
Cancer in adolescents and young adults in north Netherlands (1989–2003): increased incidence, stable survival and high incidence of second primary tumours
Authors: J.C. van Gaal, E. Bastiaannet, M. Schaapveld, R. Otter, J.C. Kluin-Nelemans, E.S.J.M. de Bont, W.T.A. van der Graaf
Journal: Annals of Oncology (2008)
The Diagnostic Importance of MicroRNAs in Congestive Heart Failure
Authors: Huseyin Altug Cakmak, Hasan Ali Barman, Ender Coskunpinar, Yasemin Musteri Oltulu, Baris Ikitimur, Gunay Can, Sevgi Ozcan, Vural Ali Vural
Journal: Journal of the American College of Cardiology (2013)
Influence of the Microenvironment on Melanoma Cell Fate Determination and Phenotype
Authors: Lynne-Marie Postovit, Elisabeth A. Seftor, Richard E.B. Seftor, Mary J.C. Hendrix
Journal: Cancer Research (2006)

Tumor cells communicate bidirectionally with the surrounding microenvironment, sending and receiving topographical and molecular cues that direct diverse cellular phenomena, including differentiation, growth, and invasion. The microenvironment has long been acknowledged as a facilitator of melanoma progression, and recent studies have illuminated tumor-associated factors, including hypoxia and the extracellular matrix, as important mediators of melanocyte transformation and transdifferentiation. Although these findings portray the microenvironment as a perilous obstacle to the successful treatment of advanced melanomas, it is important to note that certain molecular milieus may be capitalized on as potential treatment modalities. Indeed, our group and others have elucidated the unique ability of embryonic microenvironments to normalize aggressive melanoma cells toward a more benign melanocytic phenotype. The microenvironment therefore presents a novel target for the treatment and ultimately the prevention of melanoma progression and metastasis.
Maximum growth and survival of estrogen receptor-alpha positive breast cancer cells requires the Sin3A transcriptional repressor
Authors: Stephanie J Ellison-Zelski, Elaine T Alarid
Journal: Molecular Cancer (2010)

Sin3A is an evolutionarily conserved transcriptional repressor which regulates gene expression as part of the multi-protein Sin3 repressive complex. It functions as a scaffold upon which proteins with enzymatic activity dock, including chromatin modifying histone deacetylases. Although regulation of transcription by Sin3A has been studied in detail, little is understood about the function of Sin3A in cancer cells. We previously showed that Sin3A is expressed in breast cancer cells and is a repressor of estrogen receptor-alpha (ERα, ESR1) gene expression. Here, we expand our previous studies to elucidate the function of Sin3A in the control of gene expression and growth of breast cancer cells. Analysis of gene expression following knockdown of Sin3A revealed changes in both basal and regulated gene transcription. Genes of known importance in breast cancer and estrogen signaling, including ERBB2, PGR, MYC, CLU, and NCOA2, were among those identified as Sin3A-responsive. The mechanism of Sin3A action varied among genes and was found to be mediated through both HDAC1/2 -dependent and -independent activities. Loss of Sin3A inhibited breast cancer cell growth by increasing apoptosis without affecting cell cycle progression. Analysis of both ERα-positive and ERα-negative cell lines revealed that the effects of Sin3A on growth were cell-type specific, as Sin3A expression promoted maximum growth of only the ERα-positive cells, and, notably, Sin3A protein itself was increased by estrogen. Further gene expression experiments revealed that Sin3A repressed expression of key apoptotic genes, including TRAIL, TRAILR1, CASP10, and APAF1, in ERα-positive, but not ERα-negative, cell lines, which could provide a mechanistic explanation for cell-type differences in growth. This study identifies Sin3A as a regulator of gene expression, survival, and growth in ERα-positive breast cancer cells. Sin3A regulates the transcription of genes involved in breast cancer and apoptosis and acts through multiple mechanisms not limited to histone deacetylase function. These findings reveal previously undescribed functions of Sin3A in breast cancer and provide evidence for an important role of this transcriptional repressor in ERα-positive tumor cell growth.
Transplant Nephrectomy Improves Survival following a Failed Renal Allograft
Authors: Juan Carlos Ayus, Steven G. Achinger, Shuko Lee, Mohamed H. Sayegh, Alan S. Go
Journal: Journal of the American Society of Nephrology (2009)

There is a growing number of patients returning to dialysis after a failed kidney transplant, and there is increasing evidence of higher mortality among this population. Whether removal of the failed renal allograft affects survival while receiving long-term dialysis is not well understood. We identified all adults who received a kidney transplant and returned to long-term dialysis after renal allograft failure between January 1994 and December 2004 from the US Renal Data System. Among 10,951 transplant recipients who returned to long-term dialysis, 3451 (31.5%) received an allograft nephrectomy during follow-up. Overall, 34.6% of these patients died during follow-up. Receiving an allograft nephrectomy associated with a 32% lower adjusted relative risk for all-cause death (adjusted hazard ratio 0.68; 95% confidence interval 0.63 to 0.74) after adjustment for sociodemographic characteristics, comorbidity burden, donor characteristics, interim clinical conditions associated with receiving allograft nephrectomy, and propensity to receive an allograft nephrectomy. In conclusion, within a large, nationally representative sample of high-risk patients returning to long-term dialysis after failed kidney transplant, receipt of allograft nephrectomy independently associated with improved survival.
Multiple Plaque Rupture and C-Reactive Protein in Acute Myocardial Infarction
Authors: Atsushi Tanaka, Kenei Shimada, Toshihiko Sano, Masashi Namba, Tsunemori Sakamoto, Yukio Nishida, Takahiko Kawarabayashi, Daiju Fukuda, Junichi Yoshikawa
Journal: Journal of the American College of Cardiology (2005)
Transcriptional Biomarkers of Steroidogenesis and Trophoblast Differentiation in the Placenta in Relation to Prenatal Phthalate Exposure
Authors: Jennifer J. Adibi, Robin M. Whyatt, Russ Hauser, Hari K. Bhat, Barbara J. Davis, Antonia M. Calafat, Lori A. Hoepner, Frederica P. Perera, Deliang Tang, Paige L. Williams
Journal: Environmental Health Perspectives (2009)

Phthalates can alter steroidogenesis and peroxisome proliferator-activated receptor gamma (PPARgamma)mediated transcription in rodent tissues. The placenta offers a rich source of biomarkers to study these relationships in humans.We evaluated whether gestational phthalate exposures in humans were associated with altered human placental steroidogenesis and trophoblast differentiation as measured by markers of mRNA transcription.We measured seven target genes in placentas collected from 54 Dominican and African-American women at delivery in New York City using quantitative real-time polymerase chain reaction (qPCR), normalized to 18S rRNA. qPCR results for the target genes were log-transformed, converted to Z-scores, and grouped into two functional pathways: steroidogenesis (aromatase, cholesterol side chain cleavage enzyme, 17beta-hydroxysteroid dehydrogenase type 1, and cytochrome P450 1B1) and trophoblast differentiation (PPARgamma, aryl hydrocarbon receptor, and human chorionic gonadotropin). Repeated measures models were used to evaluate the association of phthalate metabolites measured in third-trimester urine samples with each group of target genes, accounting for correlation among the genes within a pathway.Higher urinary concentrations of five phthalate metabolites were associated with lower expression of the target genes reflecting trophoblast differentiation. Results were less consistent for genes in the steroidogenesis pathway and suggested a nonlinear dose-response pattern for some phthalate metabolites.We observed a significant association between prenatal exposure to phthalates and placental gene expression within two pathways. Further studies are warranted to understand the significance of this association with respect to fetal development and placental function.
Targeting Chemokine Receptors in HIV: A Status Report
Authors: Shawn E. Kuhmann, Oliver Hartley
Journal: The Annual Review of Pharmacology and Toxicology (2007)

Since the identification of CCR5 and CXCR4 as HIV coreceptors a little over a decade ago, there has been hope that coreceptor inhibitors will be able to make an impact on the HIV epidemic, both as novel therapeutic drugs and as agents used in prevention. Significant progress has been made in the understanding of how coreceptor choice might impact HIV pathology and how coreceptor blockade may affect health. In this review, we focus on some of the key issues that are emerging now that CCR5 has been validated as a promising target for HIV prevention strategies and at a time when a CCR5 inhibitor has been approved in the United States as the first in a new class of anti-HIV therapeutic drugs.
Hypotonicity-Induced Renin Exocytosis from Juxtaglomerular Cells Requires Aquaporin-1 and Cyclooxygenase-2
Authors: Ulla G. Friis, Kirsten Madsen, Per Svenningsen, Pernille B.L. Hansen, Ambika Gulaveerasingam, Finn Jørgensen, Christian Aalkjær, Ole Skøtt, Boye L. Jensen
Journal: Journal of the American Society of Nephrology (2009)

The mechanism by which extracellular hypotonicity stimulates release of renin from juxtaglomerular (JG) cells is unknown. We hypothesized that osmotically induced renin release depends on water movement through aquaporin-1 (AQP1) water channels and subsequent prostanoid formation. We recorded membrane capacitance (<i>C</i><sub>m</sub>) by whole-cell patch clamp in single JG cells as an index of exocytosis. Hypotonicity increased <i>C</i><sub>m</sub> significantly and enhanced outward current. Indomethacin, PLA<sub>2</sub> inhibition, and an antagonist of prostaglandin transport impaired the <i>C</i><sub>m</sub> and current responses to hypotonicity. Hypotonicity also increased exocytosis as determined by a decrease in single JG cell quinacrine fluorescence in an indomethacin-sensitive manner. In single JG cells from COX-2<sup>−/ −</sup> and AQP1<sup>−/ −</sup> mice, hypotonicity increased neither <i>C</i><sub>m</sub> nor outward current, but 0.1-μM PGE<sub>2</sub> increased both in these cells. A reduction in osmolality enhanced cAMP accumulation in JG cells but not in renin-producing As4.1 cells; only the former had detectable AQP1 expression. Inhibition of protein kinase A blocked the hypotonicity-induced <i>C</i><sub>m</sub> and current response in JG cells. Taken together, our results show that a 5 to 7% decrease in extracellular tonicity leads to AQP1-mediated water influx in JG cells, PLA<sub>2</sub>/COX-2-mediated prostaglandin-dependent formation of cAMP, and activation of PKA, which promotes exocytosis of renin.
The requirement for DM in class II-restricted antigen presentation and SDS-stable dimer formation is allele and species dependent.
Authors: C C Stebbins, G E Loss, C G Elias, A Chervonsky, A J Sant
Journal: The Journal of Experimental Medicine (1995)

Recently several cell lines have been identified with mutations in a major histocompatibility complex (MHC)-linked protein that lead to defects in class II-restricted antigen presentation and a defect in the formation of class II SDS-stable dimers. The defect in these cells has recently been shown to result from the inability to express the MHC-encoded nonclassical class II molecule called DM. To further examine the role of DM in class II-restricted antigen presentation, we asked if this defect would equally affect different allelic and species variants of class II molecules. To investigate this, we transfected the parent cell lines T1 and 8.1.6 and their respective antigen presentation mutants T2 and 9.5.3 with the genes encoding I-Ad and examined the derived transfectants for their ability to present antigen, the conformation of I-Ad at the cell surface, association of I-Ad with invariant chain (Ii), and the ability to form I-Ad SDS-stable dimers. The lack of functional DM expression did not affect any of the anti-I-Ad monoclonal antibody (mAb) epitopes tested or the ability of I-Ad to associate and dissociate with Ii. Surprisingly, these studies also revealed that the antigen presentation defect observed for DR in the 9.5.3 cells did not compromise I-Ad-restricted antigen presentation. In addition, we found that the level of SDS-stable dimer formation did not correlate with antigen presentation capacity for I-Ad and that the amount of SDS-stable I-Ad dimer depends on the cellular context in which the class II molecule is expressed. Our results suggest that the ability to form SDS-stable dimer is not strictly correlated with class II-restricted antigen presentation. Finally, when two allelic forms of murine class II molecules were compared in the defective T2 cell line, it was found that I-Ak but not I-Ad forms SDS-stable dimers equivalent to that seen in the parental cell lines. Overall, our results suggest that DM may modulate rather than play a requisite role in I-Ad-restricted antigen presentation and SDS-stable dimer formation and that dependency on DM may be allele or species specific.
Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection
Authors: Paul J. Cote, Brent E. Korba, Roger H. Miller, James R. Jacob, Betty H. Baldwin, William E. Hornbuckle, Robert H. Purcell, Bud C. Tennant, John L. Gerin
Journal: Hepatology (2000)

Acute hepadnavirus infections either resolve or progress to chronicity. Factors that influence chronicity as an outcome of hepatitis B virus (HBV) infection in humans can be studied experimentally in the woodchuck model. Accordingly, several woodchuck hepatitis virus (WHV) inocula were characterized. Representative inocula had high titers of infectious virus (approximately 10 7.7 -10 9.5 woodchuck 50% infectious doses per milliliter [WID 50% /mL] by subcutaneous inoculation), with 1 WID 50% ranging between 21 and 357 physical virion particles. WHV7P1 (standard high dose, 5 × 10 6 WID 50% ) produced a 72% chronicity rate ( i.e. , percent chronic of total infected) in neonatal woodchucks (1-3 days old). Comparable doses of WHV8P1 resulted in a lower chronicity rate in neonates (34% chronic) indicating that it represented a strain different from WHV7P1. Neonatal woodchucks were more susceptible to chronic infection by high doses of WHV7P1 (range, 65%-75% chronic) compared with 8-week-old weanlings (33% chronic) and adult woodchucks (0% chronic; i.e. , all resolved). High doses of cloned wild-type viruses also induced high rates of chronicity in neonates (70%-80% chronic). Chronicity rates in neonates were decreased for low doses of WHV7P1 (500 WID 50% , 9% chronic) and for high doses of a precore WHeAg-minus mutant WHV8 clone (17% chronic). Thus, both age and viral determinants can influence chronicity as an outcome of experimental WHV infection. Standardized inocula will enable the study of mechanisms that initiate and maintain chronic hepadnavirus infection and also provide a means for developing WHV carriers for therapeutic studies.
Comparison of breathing comfort during weaning with two ventilatory modes.
Authors: A R Knebel, S L Janson-Bjerklie, J D Malley, A G Wilson, J J Marini
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

In twenty-one patients ventilated for > or = 3 days, we compared similar levels of partial support provided by synchronized intermittent mandatory ventilation (SIMV) and pressure support ventilation (PSV) in terms of breathing comfort. On a single day, eligible subjects experienced, in random order, both SIMV and PSV weaning protocols (sequential 20% reductions in support at timed intervals) separated by a 1 to 3 h rest. Breathing comfort was defined by subjective ratings of dyspnea and anxiety. Subjects reported significant levels of preweaning dyspnea and anxiety despite resting for at least 6 h. Dyspnea and anxiety were not significantly different between the two methods at any level of support. Our findings suggest that dyspnea and anxiety are higher than expected on "full" ventilator support, and that comfort may not differ between PSV and SIMV during active withdrawal of machine support.
Late-breaking abstract: Persistently high exhaled nitric oxide and lung function decline in patients with controlled asthma at baseline
Authors: kazuto Matsunaga, Tomohiro Ichikawa, Keiichiro Akamatsu, Tsunahiko Hirano
Journal: European Respiratory Journal (2014)

Background:  To identify patients who are at risk of accelerated decline in lung function at an early stage of asthma is important. Recent evidence suggests that airway inflammation may be involved in the development of persistent airflow limitation.   Objective:  To investigate whether the persistently high level of exhaled nitric oxide fraction (FeNO) is associated with the decline in post-bronchodilator forced expiratory volume in 1 second (FEV1).   Methods:  A total of 140 patients with controlled asthma at baseline were enrolled, and were followed with spirometry and FeNO over a 3-year period. We investigated the data of a prospective analysis of the association between the FeNO level and change in FEV1.   Results : Analyses were performed on 122 patients who maintained high (≥40 ppb, n=27) or non-high (n=95) levels of FeNO over time. The baseline FeNO levels showed a weak but significant correlation with the annual rates of decline in FEV1 (r=0.23, p 40 mL/yr) compared with 18.9% in patients with non-high FeNO (p   Conclusion:  A persistently high level of FeNO among patients with controlled asthma was associated with an accelerated decline in lung function over time.
Generality, mathematical elegance, and evolution of numerical/object identity
Authors: Felice L. Bedford
Journal: Behavioral and Brain Sciences (2001)

Object identity, the apprehension that two glimpses refer to the same object, is offered as an example of combining generality, mathematics, and evolution. We argue that it applies to glimpses in time (apparent motion), modality (ventriloquism), and space (Gestalt grouping); that it has a mathematically elegant solution of nested geometries (Euclidean, Similarity, Affine, Projective, Topology); and that it is evolutionarily sound despite our Euclidean world. [Shepard]