tbuckley/cabot-search huggingface dataset:
T Cell Receptor Complementarity Determining Region 3 Length Analysis Reveals the Absence of a Characteristic Public T Cell Repertoire in Neonatal Tolerance
Authors: Emanual Maverakis, Jonathan T. Beech, Stephen S. Wilson, Anthony Quinn, Brian Pedersen, Eli E. Sercarz
Journal: The Journal of Experimental Medicine (2000)

All adult BALB/c mice immunized with hen egg white lysozyme (HEL) or its dominant determinant, peptide (p)106-116, mount a T cell response using a "public" Vbeta8.2Jbeta1.5 T cell clone. Neonatal exposure to tolerance-inducing doses of antigen can drastically diminish responsiveness in the draining lymph nodes but not in the spleens of animals challenged as adults with the cognate antigen. To determine the role of T cell deletion or anergy within the mechanisms of observed neonatal "tolerance," we treated neonatal BALB/c mice with HEL and directly followed the characteristic public clone using complementarity determining region 3 length T cell repertoire analysis. Our results confirm that despite intraperitoneal injection of neonates with a high dose of HEL emulsified in incomplete Freund's adjuvant, a strong splenic proliferative response to HEL was observed upon recall. However, the adult splenic T cell response of these neonatally treated mice lacked the usual Vbeta8.2Jbeta1.5 public clone characteristic of HEL-primed BALB/c mice. After challenge with HEL-complete Freund's adjuvant as adults, immunoglobulin (Ig)G2a isotype antibody was drastically reduced, and IgG1 was found to be the predominant anti-HEL IgG isotype expressed, indicating a deviation of cytokine response toward T helper type 2. 5-wk-old mice, nasally instilled with tolerogenic doses of HEL p106-116, also showed significant inhibition of this public T cell expansion. These results demonstrate that during neonatal and adult nasal tolerance induction, deletion/anergy removes the public clone, exposing a response of similar specificity but that is characterized by the T helper type 2 phenotype and a splenic residence.
Effective Targeting of Triple-Negative Breast Cancer Cells by PF-4942847, a Novel Oral Inhibitor of Hsp 90
Authors: Pramod P. Mehta, Pamela Whalen, Sangita M. Baxi, Pei-Pei Kung, Shinji Yamazaki, Min-Jean Yin
Journal: Clinical Cancer Research (2011)

Triple-negative breast cancer (TNBC) patients have poor prognoses and survival outcomes such that the development of new targeted therapies is in strong demand. Mechanisms associated with high proliferation and aggressive tumor progression, such as PI3K/PTEN aberration, epidermal growth factor receptor (EGFR) overexpression, and cell-cycle upregulation, play important roles in TNBC. The molecular chaperone Hsp90 is required for the conformational maturation and stability of a variety of proteins in multiple pathways, such as EGFR, AKT, Raf, cdk4, etc. Therefore, an Hsp90 inhibitor may show therapeutic benefit in TNBC by targeting multiple pathways.The novel oral Hsp90 inhibitor PF-4942847 was characterized in multiple in vitro and in vivo assays to determine its antitumor activity in TNBC cell lines. In addition, the correlation of AKT degradation and Hsp70 induction in host peripheral blood lymphocytes (PBL) and xenograft tumors was determined.PF-4942847 induces degradation of multiple client proteins, cell-cycle block, apoptosis, and inhibits cell proliferation in TNBC lines, subsequently leading to tumor growth inhibition in mouse xenograft models. The correlation of AKT degradation and Hsp70 induction between PBLs and xenograft tumors reveals a differential modulation of Hsp90 activity between host and tumor tissues, and suggests that AKT degradation in PBLs may serve as a pharmacodynamic biomarker in future clinical development.The novel oral Hsp90 inhibitor, PF-4942847, is a candidate for clinical development in TNBC by collaboratively targeting multiple signaling pathways. In addition, AKT degradation in PBLs may serve as a biomarker in clinical development.
Multidonor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for HIV-1 Neutralization by VRC01-Class Antibodies
Authors: Tongqing Zhou, Jiang Zhu, Xueling Wu, Stephanie Moquin, Baoshan Zhang, Priyamvada Acharya, Ivelin S. Georgiev, Han R. Altae-Tran, Gwo-Yu Chuang, M. Gordon Joyce, Young Do Kwon, Nancy S. Longo, Mark K. Louder, Timothy Luongo, Krisha McKee, Chaim A. Schramm, Jeff Skinner, Yongping Yang, Zhongjia Yang, Zhenhai Zhang, Anqi Zheng, Mattia Bonsignori, Barton F. Haynes, Johannes F. Scheid, Michel C. Nussenzweig, Melissa Simek, Dennis R. Burton, Wayne C. Koff, James C. Mullikin, Mark Connors, Lawrence Shapiro, Gary J. Nabel, John R. Mascola, Peter D. Kwong
Journal: Immunity (2013)
Myocardial electrical impedance mapping of ischemic sheep hearts and healing aneurysms.
Authors: M A Fallert, M S Mirotznik, S W Downing, E B Savage, K R Foster, M E Josephson, D K Bogen
Journal: Circulation (1993)

BACKGROUND This study was designed to examine the bulk electrical properties of myocardium and their variation with the evolution of infarction after coronary occlusion. These properties may be useful in distinguishing between normal, ischemic, and infarcted tissue on the basis of electrophysiological parameters. METHODS AND RESULTS The electrical impedance of myocardial tissue was studied in a sheep model of infarction. The animal model involved a one-stage ligation of the left anterior descending and second diagonal arteries at a point 40% of the distance from the apex to the base. By use of a four-electrode probe, an epicardial mapping system was developed that allowed for cardiac cycle gated and signal-averaged measurements. Subthreshold current (15 microA) was injected through two of the electrodes at frequencies of 1, 5, and 15 kHz and the induced potential measured with the other two electrodes. Epicardial maps of the left ventricle were obtained during acute infarction and at 1-, 2-, and 6-week intervals after occlusion. Results showed the average specific impedance of the myocardium before infarction to be 158 +/- 26 omega-cm independent of location on the epicardium. By 60 minutes after coronary occlusion, the specific impedance had increased by 199% (p &lt; 0.005, n = 9); it remained elevated for up to 4 hours. One week after infarction, the specific impedance decreased to 59% of the control value (p &lt; 0.025, n = 8). Six weeks after occlusion, the specific impedance remained low at 57% of that of the noninfarcted tissue (p &lt; 0.005, n = 9). The phase angle of the complex impedance was also measured and revealed similar changes. The hydroxyproline content of the tissue was assayed to assess infarct healing. CONCLUSIONS In this animal model, impedance is a bulk electrical property of tissue that varies with the evolution of myocardial infarction. Impedance mapping revealed significantly different values for normal, ischemic, and infarcted tissue and may prove useful in better defining the electrophysiological characteristics of such tissue.
BRCA1 Sequence Analysis in Women at High Risk for Susceptibility Mutations
Authors: Donna Shattuck-Eidens
Journal: JAMA (1997)

A mutation in the BRCA1 gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete.To identify BRCA1 mutations and to determine factors that best predict presence of a deleterious BRCA1 mutation in patients with breast and/or ovarian cancer.A complete sequence analysis of the BRCA1 coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland.Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of BRCA1 mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the BRCA1 locus.Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations.In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (unilateral or bilateral breast cancer, with or without ovarian cancer), early age at diagnosis, Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious BRCA1 mutation.Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious BRCA1 mutation for a wide range of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice.
Hereditary Lung Cancer Syndrome Targets Never Smokers with Germline EGFR Gene T790M Mutations
Authors: Adi Gazdar, Linda Robinson, Dwight Oliver, Chao Xing, William D. Travis, Junichi Soh, Shinichi Toyooka, Lori Watumull, Yang Xie, Kemp Kernstine, Joan H. Schiller
Journal: Journal of Thoracic Oncology (2014)
Immunologic Escape After Prolonged Progression-Free Survival With Epidermal Growth Factor Receptor Variant III Peptide Vaccination in Patients With Newly Diagnosed Glioblastoma
Authors: John H. Sampson, Amy B. Heimberger, Gary E. Archer, Kenneth D. Aldape, Allan H. Friedman, Henry S. Friedman, Mark R. Gilbert, James E. Herndon, Roger E. McLendon, Duane A. Mitchell, David A. Reardon, Raymond Sawaya, Robert J. Schmittling, Weiming Shi, James J. Vredenburgh, Darell D. Bigner
Journal: Journal of Clinical Oncology (2010)

Immunologic targeting of tumor-specific gene mutations may allow precise eradication of neoplastic cells without toxicity. Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively activated and immunogenic mutation not expressed in normal tissues but widely expressed in glioblastoma multiforme (GBM) and other neoplasms.A phase II, multicenter trial was undertaken to assess the immunogenicity of an EGFRvIII-targeted peptide vaccine and to estimate the progression-free survival (PFS) and overall survival (OS) of vaccinated patients with newly diagnosed EGFRvIII-expressing GBM with minimal residual disease. Intradermal vaccinations were given until toxicity or tumor progression was observed. Sample size was calculated to differentiate between PFS rates of 20% and 40% 6 months after vaccination.There were no symptomatic autoimmune reactions. The 6-month PFS rate after vaccination was 67% (95% CI, 40% to 83%) and after diagnosis was 94% (95% CI, 67% to 99%; n = 18). The median OS was 26.0 months (95% CI, 21.0 to 47.7 months). After adjustment for age and Karnofsky performance status, the OS of vaccinated patients was greater than that observed in a control group matched for eligibility criteria, prognostic factors, and temozolomide treatment (hazard ratio, 5.3; P = .0013; n = 17). The development of specific antibody (P = .025) or delayed-type hypersensitivity (P = .03) responses to EGFRvIII had a significant effect on OS. At recurrence, 82% (95% CI, 48% to 97%) of patients had lost EGFRvIII expression (P < .001).EGFRvIII-targeted vaccination in patients with GBM warrants investigation in a phase III, randomized trial.
Electrophysiological and antiarrhythmic effects of propranolol in canine acute myocardial ischemia.
Authors: J Kupersmith, H Shiang, R S Litwak, M V Herman
Journal: Circulation Research (1976)

To correlate the antiarrhythmic and electrophysiological effects of propranolol in acute myocardial ischemia, we examined the effects of temporary (15-minute) ligations of the left anterior descending coronary artery in studies on 15 dogs. We recorded bipolar electrograms and monophasic action potentials from the ischemic and normal zones and measured the intervals from the onset of QRS in a standard electrocardiogram lead to the major deflection of electrograms recorded from the ischemic and normal zones. We also determined monophasic action potential duration (APD) and effective refractory period (ERP). Data for control ligations were compared to those during which propranolol, 40 mug/kg, was administered intravenously immediately after ligation. Propranolol reduced the mean number of ventricular beats per minute (from 15 to 6) (P less than 0.01). Propranolol slowed conduction in the ischemic zone (by 10 msec at peak effect, P less than 0.01) and had no or only a very slight effect (by 1-msec at 15 minutes, P less than 0.05) on conduction in the normal zone. Propranolol also prolonged APD in the ischemic (32-msec) and normal (14-msec) zones (P less than 0.01), prolonged ERP in the ischemic (41-msec) and normal (20-msec) zones (P less than 0.01), and reduced the APD/ERP ratio in the ischemic (1.62 to 1.47) (P less than 0.01) and normal (1.62 to 1.55) (P less than 0.05) zones. During the control ligation, APD in the ischemic zone was 25 msec shorter than in the normal zone (P less than 0.01), but with propranolol the difference was not significant. The effects of propranolol in slowing conduction in the ischemic zone, in prolonging refractoriness, in reducing APD/ERP, and in reducing the disparity in APD between ischemic and normal zones may explain its demonstrated antiarrhythmic effects in acute myocardial ischemia.
The involvement of suppressor T cells in Ir gene regulation of secondary antibody responses of primed (responder X nonresponder)F1 mice to macrophage-bound L-glutamic acid60-L-alanine30-L-tyrosine.
Authors: R N Germain, B Benacerraf
Journal: The Journal of Experimental Medicine (1978)

(Responder [R] X nonresponder [NR])F1 mice give indistinguishable primary in vitro plaque-forming cell (PFC) responses to either R or NR parental macrophages (Mphi) pulsed with the Ir-gene controlled antigen L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT). However, such (R X NR)F1 mice, if primed to GAT, retained in vitro responsiveness to GAT-R-Mphi, but no longer responded to GAT-NR-Mphi. This suggested (a) a possible Mphi-related locus for Ir gene activity in this model, and (b) the occurrence of active suppression after priming with GAT leading to a selective loss of the usual primary responsiveness of (R X NR)F1 mice to GAT-NR-Mphi. This latter interpretation was tested in the current study. [Responder C57BL/6 (H-2b) X nonresponder DBA/1 (H-2q)]F1 mice were primed with 100 microgram GAT in pertussis adjuvant. 4-8 wk later, spleen cells from such mice were tested alone or mixed with normal unprimed F1 spleen cells for PFC responses to GAT-R-Mphi and GAT-NR-Mphi. The primed cells failed to respond to GAT-NR-Mphi, and moreover, actively suppressed the normal response of unprimed F1 cells to GAT-NR-Mphi. If the primed spleen cell donor had been treated with 5 mg/kg cyclophosphamide 3 days before priming or with 5-10 microliter/day of an antiserum to the I-Jb subregion [B10.A(5R) anti B10.A(3R)] during the first 4 days postpriming (both procedures known to inhibit suppressor T-cell activity), cells from such mice responded in secondary culture to both GAT-R-Mphi and also GAT-NR-MPhi. In addition, such spleen cells no longer were capable of suppressing normal F1 cells in response to GAT-NR-Mphi. Similar data were obtained using [CBA (H-2k) X DBA/1 (H-2q)]F1. Further, it was shown that (a) primary responsiveness to GAT-NR-Mphi was not an artifact of in vitro Mphi pulsing, because in vivo GAT-pulsed Mphi showed the same activity and (b) the secondary restriction for Mphi-antigen presentation was controlled by H-2 linked genes. These data suggest an important role for suppressor T cells in H-2 restricted secondary PFC responses, and also provide additional support for the hypothesis that Ir-gene controlled differences in Mphi antigen presentation are related to both suppressor cell generation and overall responsiveness in the GAT model.
Constellation Pharmacology: A New Paradigm for Drug Discovery
Authors: Russell W. Teichert, Eric W. Schmidt, Baldomero M. Olivera
Journal: The Annual Review of Pharmacology and Toxicology (2015)

Constellation pharmacology is a cell-based high-content phenotypic-screening platform that utilizes subtype-selective pharmacological agents to elucidate the cell-specific combinations (constellations) of key signaling proteins that define specific cell types. Heterogeneous populations of native cells, in which the different individual cell types have been identified and characterized, are the foundation for this screening platform. Constellation pharmacology is useful for screening small molecules or for deconvoluting complex mixtures of biologically active natural products. This platform has been used to purify natural products and discover their molecular mechanisms. In the ongoing development of constellation pharmacology, there is a positive feedback loop between the pharmacological characterization of cell types and screening for new drug candidates. As constellation pharmacology is used to discover compounds with novel targeting-selectivity profiles, those new compounds then further help to elucidate the constellations of specific cell types, thereby increasing the content of this high-content platform.
Low-dose, beta-particle emission from 'stent' wire results in complete, localized inhibition of smooth muscle cell proliferation.
Authors: T A Fischell, B K Kharma, D R Fischell, P G Loges, C W Coffey, D M Duggan, A J Naftilan
Journal: Circulation (1994)

Restenosis after catheter-based revascularization has been demonstrated to be primarily caused by medial and/or intimal smooth muscle cell (SMC) proliferation. The objective of this study was investigate the ability of local emission of beta-particles from a 32P-impregnated titanium "stent" wire source to inhibit vascular SMC and endothelial cell proliferation in cell culture and to determine the dose-response characteristics of this inhibition.A series of experiments were performed using 0.20-mm-diameter titanium wires that were impregnated with varying low concentrations of 32P (activity range, 0.002 to 0.06 microCi/cm wire, n = 47) or 31P (nonradioactive control, n = 28) in cultures of rat and human aortic SMCs and in cultured bovine aortic endothelial cells. The zone of complete cell growth inhibition (in millimeters from stent wire) was measured using light microscopy in the cultures exposed to the radioactive (32P) or control (31P) wires at 6 and 12 days after plating. In both rat and human SMC cultures there was a distinct 5.5- to 10.6-mm zone of complete SMC inhibition at wire activity levels > or = 0.006 microCi/cm. In contrast, there was no zone of inhibition surrounding the control (31P impregnated) wires (P < .001 versus 32P wires at all wire activities > or = 0.006 microCi/cm for human and rat SMCs). Proliferating bovine endothelial cells were more radioresistant than SMCs, with no zone of inhibition observed at wire activity levels up to 0.019 microCi/cm (P < .001 versus SMCs at 0.006 microCi/cm and 0.019 microCi/cm).We conclude that very low doses of beta-particle emission from a 32P-impregnated stent wire (activity levels as low as 0.006 microCi/cm of wire) completely inhibit the growth and migration of both rat and human SMCs within a range of 5.5 to 10.6 mm from the wire. Endothelial cells appear to be much more radioresistant than SMCs. These data suggest that an intra-arterial stent impregnated with a low concentration of 32P may have a salutary effect on the restenosis process. Whether this approach can be used successfully and safely to inhibit restenosis in vivo and in the clinical setting is under investigation.
Genomic Investigation of Dedifferentiated Liposarcoma Suggests a Role for Therapeutic Targeting of the Tumor Epigenome
Authors: Paul S. Meltzer, Lee J. Helman
Journal: Cancer Discovery (2011)

Abstract A comprehensive genetic analysis of dedifferentiated liposarcomas suggests that epigenetic modifications are common and may alter the differentiation capacity in these tumors. Furthermore, these data suggest that treatment strategies aimed at altering histone acetylation and/or DNA methylation are worthy of further study. Cancer Discovery; 1(7); 555–6. ©2011 AACR. Commentary on Taylor et al., p. 587.
The glycocalyx of the sperm surface
Authors: S Schroter
Journal: Human Reproduction Update (1999)

The surface of mammalian spermatozoa is covered by a dense coating of carbohydrate-rich molecules forming a 20-60 nm thick glycocalyx. The majority of sugar residues are attached to proteins which are either integrated within the sperm membrane, or are more or less loosely associated with it. It is estimated that there may be several hundred different glycoproteins comprising the glycocalyx, some of which are synthesized within the testis. Others, however, are produced by the epithelia of the efferent ducts, epididymis and possibly other accessory glands, and become associated with the spermatozoa post-testicularly during transit through, and storage in, the male tract. The acquisition of the mature glycocalyx is associated with the attainment of full sperm fertilizing ability. Until its complete molecular structure is elucidated, the complex function of the glycocalyx remains obscure, though it may be related to membrane maturation and immunoprotection in the female tract, as well as to sperm-zona binding and fertilization.
S-ICAM-1 in patients with chronic (perennial) allergic rhinitis with or without bronchial hyperresponsiveness and with asthma
Authors: M. Gorska-Ciebiada, M. Ciebiada, A. Zakrzewska, P. Gorski, I. Grzelewska-Rzymowska
Journal: Journal of Allergy and Clinical Immunology (2005)
Risk factors for the development of respiratory distress syndrome and transient tachypnoea in newborn infants
Authors: C. Dani, M.F. Reali, G. Bertini, L. Wiechmann, A. Spagnolo, M. Tangucci, F.F. Rubaltelli, None and the Italian Group of Neonatal Pneumology
Journal: European Respiratory Journal (1999)

Respiratory distress syndrome (RDS) and transient tachypnoea (TT) are the most frequent acute respiratory diseases in the newborn. This study investigated the risk factors for RDS and TT in newborn infants. A population of 63,537 newborns was enrolled in a 12-month survey in Italy, 734 (1.15%) affected by RDS and 594 (0.93%) affected by TT. Multivariate regression analysis of maternal and perinatal data and the calculation of odds ratios (with 95% confidence intervals) were performed. It was demonstrated that gestational age, birthweight, maternal age, elective and emergency caesarean section (CS), and male sex were risk factors for RDS, while gestational age, maternal diseases, twinning, birthweight, operative vaginal delivery, elective and emergency CS, and male sex were risk factors for TT. The data confirm previous reports and demonstrate that advanced maternal age is a risk factor for RDS, while ruling out maternal diseases as independent risk factors for RDS.