gebhart/patrepeval huggingface dataset:
Transforming growth factor- beta and IL-1 beta act in synergy to enhance IL-6 secretion by the intestinal epithelial cell line, IEC-6. (1993)

Intestinal epithelial cells are a potentially important source for a number of cytokines that may modulate the immune response at the intestinal mucosa. We have recently begun to study the mechanisms that regulate IL-6 production by intestinal epithelial cells using the nontransformed crypt-like rat intestinal epithelial cell line IEC-6 as a model. Culture of the IEC-6 cells with human rIL-1 beta resulted in an enhanced secretion of IL-6 by the cells. RT-PCR analysis of IL-1 beta-treated cells showed an enhanced level of IL-6 mRNA at 4 h, suggesting that IL-1 beta enhanced IL-6 gene expression. In a previous study, transforming growth factor-beta (TGF-beta 1) was also found to enhance IL-6 secretion by the IEC-6 cells and because both IL-1 beta and TGF-beta may be present in inflamed mucosal tissue, the effect of adding both cytokines together was next investigated. Culture of the IEC-6 cells with both TGF-beta 1 and IL-1 beta resulted in a synergistic enhancement of IL-6 secretion that was seen even at high levels of both TGF-beta and IL-1 beta. IL-6 mRNA levels from cells treated with both TGF-beta 1 and IL-1 beta were also determined to be enhanced when compared to that of cells treated with IL-1 beta or TGF-beta 1 only, as determined by RT-PCR analysis. Pretreatment of the IEC-6 cells with TGF-beta 1 for 2 or 3 days before addition of the IL-1 beta induced the IEC-6 cells to differentiate and become more sensitive to stimulation by IL-1 beta. Subsequent experiments determined that TGF-beta enhanced the capacity of the IEC-6 cells to bind labeled IL-1 beta indicating that TGF-beta may have enhanced the expression of IL-1 receptors on the cells. These results suggest that the intestinal epithelial cell may represent an important source of IL-6 in inflammatory responses at the intestinal mucosa and that TGF-beta could potentiate this function.
Cytogenetic profiling using fluorescencein situ hybridization (FISH) and comparative genomic hybridization (CGH) (1993)

Fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) allow cytogenetic analyses of primary tumors without culture. CGH allows detection and mapping of allelic imbalance by simultaneous in situ hybridization of differentially labeled tumor (green fluorescing) and normal DNA (red fluorescing) to a normal human metaphase spread. Regions of increased or decreased copy number in the tumor are mapped onto the normal metaphase chromosomes as increases or decreases in the green to red fluorescence ratio. This technique gives a comprehensive assessment of gene dosage imbalance throughout the tumor. However, it is limited, at present, to fairly large tumors containing few normal cells. FISH, on the other hand, allows analysis of DNA sequence copy number at specific loci in single nuclei. A wide variety of DNA probes is available for FISH, including chromosome-specific probes which hybridize to alpha-satellite pericentromeric DNA regions (to detect changes in specific chromosome copy number and overall ploidy) and specific locus probes targeting 20-150 kilobase sequences (to detect specific amplifications, deletions, breakpoints, or rearrangements). FISH using these probes has been applied to interphase nuclei in touch preparations, smears from fine needle aspirates, and thin (< 6 microns) and thick (> 20 microns) sections cut from formalin-fixed, paraffin-embedded tissue. Analysis of thick sections allows accurate actual signal enumeration within the histological context. This approach may allow analysis of subtle premalignant, early malignant, and infiltrating tumors in which malignant cells must be differentiated from nonmalignant cells.(ABSTRACT TRUNCATED AT 250 WORDS)
A Systematic Method for Clinical Description and Classification of Personality Variants (1987)

A systematic method for clinical description and classification of both normal and abnormal personality variants is proposed based on a general biosocial theory of personality. Three dimensions of personality are defined in terms of the basic stimulus-response characteristics of novelty seeking, harm avoidance, and reward dependence. The possible underlying genetic and neuroanatomical bases of observed variation in these dimensions are reviewed and considered in relation to adaptive responses to environmental challenge. The functional interaction of these dimensions leads to integrated patterns of differential response to novelty, punishment, and reward. The possible tridimensional combinations of extreme (high or low) variants on these basic stimulus-response characteristics correspond closely to traditional descriptions of personality disorders. This reconciles dimensional and categorical approaches to personality description. It also implies that the underlying structure of normal adaptive traits is the same as that of maladaptive personality traits, except for schizotypal and paranoid disorders.
Identification of nearest-neighbor peptides in protease digests by mass spectrometry for construction of sequence-ordered tryptic maps (1991)

Continuous-flow fast atom bombardment mass spectrometry was used for the identification of the intermediates and end products of the tryptic digest of polypeptides throughout the time-course of the reactions. Precursor/product relationships for these peptides were determined with the aid of a simple personal computer program. The C-terminal tryptic peptides were identified by performing a tryptic digest in 50% 18O-enriched buffer which resulted in labeling of all non-C-terminal peptides with 18O. This information, along with the precursor/product correlations, was used to create a sequence-ordered tryptic map of the original polypeptide. Ion intensities of intermediate hydrolysis products are compared for enzyme to substrate ratios of 1:100 and 1:1000 (w/w) over the course of the reaction. Intermediates were found to have significantly longer lifetimes when lower levels of trypsin were present.
Probabilistic Group Nearest Neighbor Queries in Uncertain Databases (2008)

The importance of query processing over uncertain data has recently arisen due to its wide usage in many real-world applications. In the context of uncertain databases, previous works have studied many query types such as nearest neighbor query, range query, <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">top</i> - <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">k</i> query, <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">skyline</i> <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">query</i> , and <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">similarity</i> <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">join</i> . In this paper, we focus on another important query, namely, probabilistic group nearest neighbor (PGNN) query, in the uncertain database, which also has many applications. Specifically, given a set, <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Q</i> , of query points, a PGNN query retrieves data objects that minimize the aggregate distance (e.g., <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">sum</i> , <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">min</i> , and <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">max</i> ) to query set <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Q</i> . Due to the inherent uncertainty of data objects, previous techniques to answer group nearest neighbor (GNN) query cannot be directly applied to our PGNN problem. Motivated by this, we propose effective pruning methods, namely, spatial pruning and probabilistic pruning, to reduce the PGNN search space, which can be seamlessly integrated into our PGNN query procedure. Extensive experiments have demonstrated the efficiency and effectiveness of our proposed approach, in terms of the wall clock time and the <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">speed</i> - <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">up</i> <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">ratio</i> against <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">linear</i> <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">scan</i> .
The Mutational Landscape of Head and Neck Squamous Cell Carcinoma (2011)

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.
Profound defects in pancreatic β-cell function in mice with combined heterozygous mutations in Pdx-1 , Hnf-1 α, and Hnf-3 β (2002)

Defects in pancreatic beta-cell function contribute to the development of type 2 diabetes, a polygenic disease that is characterized by insulin resistance and compromised insulin secretion. Hepatocyte nuclear factors (HNFs) -1alpha, -3beta, -4alpha, and Pdx-1 contribute in the complex transcriptional circuits within the pancreas that are involved in beta-cell development and function. In mice, a heterozygous mutation in Pdx-1 alone, but not Hnf-1alpha(+/-), Hnf-3beta(+/-), or Hnf-4alpha(+/-), causes impaired glucose-stimulated insulin secretion in mice. To investigate the possible functional relationships between these transcription factors on beta-cell activity in vivo, we generated mice with the following combined heterozygous mutations: Pdx-1(+/-)/Hnf-1alpha(+/-), Pdx-1(+/-)/Hnf-3beta(+/-), Pdx-1(+/-)/Hnf-4alpha(+/-), Hnf-1alpha(+/-)/Hnf-4alpha(+/-), and Hnf-3beta(+/-)/Hnf-4alpha(+/-). The greatest loss in function was in combined heterozygous null alleles of Pdx-1 and Hnf-1alpha (Pdx-1(+/-)/Hnf-1alpha(+/-)), or Pdx-1 and Hnf-3beta (Pdx-1(+/-)/Hnf-3beta(+/-)). Both double mutants develop progressively impaired glucose tolerance and acquire a compromised first- and second-phase insulin secretion profile in response to glucose compared with Pdx-1(+/-) mice alone. The loss in beta-cell function in Pdx-1(+/-)/Hnf-3beta(+/-) mice was associated with decreased expression of Nkx-6.1, glucokinase (Gck), aldolase B (aldo-B), and insulin, whereas Nkx2.2, Nkx-6.1, Glut-2, Gck, aldo-B, the liver isoform of pyruvate kinase, and insulin expression was reduced in Pdx-1(+/-)/Hnf-1alpha(+/-) mice. The islet cell architecture was also abnormal in Pdx-1(+/-)/Hnf-3beta(+/-) and Pdx-1(+/-)/Hnf-1alpha(+/-) mice, with glucagon-expressing cells scattered throughout the islet, a defect that may be connected to decreased E-cadherin expression. Our data suggest that functional interactions between key islet regulatory factors play an important role in maintaining islet architecture and beta-cell function. These studies also established polygenic mouse models for investigating the mechanisms contributing to beta-cell dysfunction in diabetes.
Progress toward inducing immunologic tolerance to factor VIII (2013)

A major problem in treating hemophilia A patients with therapeutic factor VIII (FVIII) is that 20% to 30% of these patients produce neutralizing anti-FVIII antibodies. These antibodies block (inhibit) the procoagulant function of FVIII and thus are termed "inhibitors." The currently accepted clinical method to attempt to eliminate inhibitors is immune tolerance induction (ITI) via a protocol requiring intensive FVIII treatment until inhibitor titers drop. Although often successful, ITI is extremely costly and is less likely to succeed in patients with high-titer inhibitors. During the past decade, significant progress has been made in clarifying mechanisms of allo- and autoimmune responses to FVIII and in suppression of these responses. Animal model studies are suggesting novel, less costly methods to induce tolerance to FVIII. Complementary studies of anti-FVIII T-cell responses using blood samples from human donors are identifying immunodominant T-cell epitopes in FVIII and possible targets for tolerogenic efforts. Mechanistic experiments using human T-cell clones and lines are providing a clinically relevant counterpoint to the animal model studies. This review highlights recent progress toward the related goals of lowering the incidence of anti-FVIII immune responses and promoting durable, functional immune tolerance to FVIII in patients with an existing inhibitor.
Fish-Oil Fatty Acid Supplementation in Active Rheumatoid Arthritis (1987)

fish-oil ingestion results in subjective alleviation of active rheumatoid arthritis and reduction in neutrophil leukotriene B4 production. Further studies are needed to elucidate mechanisms of action and optimal dose and duration of fish-oil supplementation.
Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced cancer: Safety data from 1300 patients enrolled in the phase 1b JAVELIN Solid Tumor trial. (2016)

3055 Background: Avelumab* is a fully human anti-PD-L1 IgG1 antibody showing preliminary efficacy in multiple tumor types. We report updated safety data of single-agent avelumab in patients (pts) with locally advanced or metastatic (LA/M) solid tumors from a phase 1b trial (NCT01772004). Methods: Pts from 16 different expansion cohorts (including NSCLC, gastric, ovarian, urothelial, mesothelioma, and breast), all unselected for PD-L1 expression, received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Treatment-emergent adverse events (AEs) were graded by NCI-CTCAE v4.0. Results: As of Nov 5, 2015, 1,300 pts received avelumab and were followed for ≥ 4 wks. Median age was 63 y (range 20-91), ECOG PS was 0 (37.7%), 1 (62.1%), or 2-3 (0.2%), and median number of prior lines of anticancer therapy was 2 (range 1-13). Median duration of treatment with avelumab and number of administrations were 11.5 wks (range 2-104) and 5 infusions (range 1-50), respectively. Treatment-related (TR) AEs occurred in 813 pts (62.5%), and the most common ( ≥ 5%) were fatigue (n = 212, 16.3%), infusion-related reaction (IRR; n = 209, 16.1%), nausea (n = 108, 8.3%), chills (n = 102, 7.8%), diarrhea (n = 79, 6.1%), and pyrexia (n = 72, 5.5%). Grade ≥ 3 TRAEs occurred in 124 pts (9.5%). The most frequent ( ≥ 0.5%) grade ≥ 3 TRAEs were GGT elevation (n = 9, 0.7%), IRR (n = 9, 0.7%), fatigue (n = 8, 0.6%), lipase elevation (n = 8, 0.6%), anemia (n = 7, 0.5%), and dyspnea (n = 6, 0.5%). Potential immune-related (ir) TRAEs were reported for 93 pts (7.2%); the most frequent ( ≥ 1.0%) were hypothyroidism (n = 45; 3.5%) and pneumonitis (n = 13; 1.0%). TRAEs resulted in permanent discontinuation for 79 pts (6.1%): 25 (1.9%) due to an IRR and 14 (1.1%) due to a potential irTRAE. TRAEs were considered the primary cause of death by the investigator for 5 pts (0.4%): radiation pneumonitis (1), pneumonitis (1), autoimmune hepatitis/liver failure (2), and respiratory distress/sepsis (1). Conclusions: Single-agent avelumab showed an acceptable safety profile in a heavily pretreated population and large dataset of pts with LA/M malignancies. Additional analyses and phase 3 trials are ongoing. *Proposed INN. Clinical trial information: NCT01772004.
Identification and Plasma Concentrations of the N-Terminal Fragment of Proatrial Natriuretic Factor in Man* (1988)

A specific RIA was developed to measure plasma atrial natriuretic factor (ANF) N-terminal immunoreactivity in man. Antibodies raised in rabbits against a rat ANF N-terminal fragment [ANF-(11-37)] had 100% cross-reactivity with human ANF-(1-30) and purified plasma N-terminal ANF immunoreactivity. The ED80 and ED50 of standard curves prepared using [125I]human ANF-(1-30) and human ANF-(1-30) were 31.5 +/- 5.4 (+/- SD) and 132.5 +/- 20.4 fmol/tube, respectively. The plasma ANF N-terminal peptide concentrations were assayed directly, without extraction, since dilution of plasma and addition of standard to plasma yielded parallel dose-responses in the RIA and virtually 100% recovery of ANF-(1-30) added to plasma. Purification of ANF N-terminal immunoreactivity from 1.5 L human plasma by affinity chromatography and amino acid sequencing suggested that it was closely related to ANF-(1-98), although some degraded peptides were also detected. The mean basal plasma ANF N-terminal peptide level measured in 34 normal subjects was 420 +/- 157 (+/- SD) pmol/L. The values were higher in plasma from patients with congestive heart failure (grades III and IV; 7,041 +/- 6,136 pmol/L; n = 13) or chronic renal failure (10,079 +/- 4,942 pmol/L; n = 20). In 9 patients with chronic renal failure, hemodialysis resulted in a 30% (P less than 0.05) decrease in plasma ANF-(99-126) levels, from 34.7 +/- 12.3 (+/- SD) to 23.2 + 6.1 pmol/L, but no changes in plasma ANF N-terminal peptide concentrations. These data indicate that the N-terminal portion of pro-ANF is cosecreted with ANF-(99-126). Its higher plasma levels in the basal state and during chronic renal failure suggest a different process of elimination than that of ANF-(99-126), which may be partly mediated by the kidney.
Mutations in lambda repressor's amino-terminal domain: implications for protein stability and DNA binding. (1983)

The DNA binding properties of 52 different single-amino acid substitutions in lambda repressor's amino-terminal domain have been characterized. Seven proteins bearing mutations that change solvent-exposed side chains have been purified. The amino-terminal domains of these mutant repressors are folded and are comparable to the wild-type amino-terminal domain in thermal stability. In contrast, a purified mutant repressor bearing a substitution in a buried side chain contains an amino-terminal domain with decreased thermal stability. We argue that mutations that alter solvent-exposed wild-type side chains define residues that form the operator DNA binding surface of lambda repressor whereas completely or partially buried mutations exert their effect by decreasing protein stability.
Adeno-Associated Virus Type 2 Rep78 Induces Apoptosis through Caspase Activation Independently of p53 (2000)

Adeno-associated virus (AAV) type 2 Rep78 is a multifunctional protein required for AAV DNA replication, integration, and gene regulation. The biochemical activities of Rep78 have been described, but the effects of Rep proteins on the cell have not been characterized. We have analyzed Rep-mediated cytotoxicity. We demonstrated that Rep78 expression is sufficient to induce cell death and disruption of the cell cycle. Cell death was found to be mediated by apoptosis. Rep78 expression resulted in the activation of caspase-3, a terminal caspase directly involved in the execution of cell death. A peptidic inhibitor of caspase-3, Z-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK), abrogated Rep78-induced apoptosis, indicating that Rep78-mediated apoptosis is caspase-3 dependent. Rep78 induced apoptosis in wild-type p53-containing human embryonal carcinoma NT-2 cells and in p53-null promyelocytic human HL-60 cells, indicating that at least one pathway of Rep78-induced apoptosis is p53 independent. Apoptosis was shown to occur during the G(1) and early S phases of the cell cycle. By analyzing the effects of Rep78 mutations on cell viability, the cause of cell death was attributed in part to two biochemical activities of Rep78, DNA binding and ATPase/helicase activity. The endonuclease activity of Rep78 did not contribute to apoptosis induction.
Biological significance of circulating polyamines in oncology. (1991)

Malignant cell proliferation is associated with an increase intracellular polyamine metabolism which itself appears to be in equilibrium with the extracellular circulating polyamine compartments. Erythrocyte polyamine contents may be used clinically as an index of cell proliferation, but the exact biological roles of circulating polyamines, considered as physio(patho)logical parameters involved in the homeostatic(dys)regulation of cell proliferation, remain obscure. It is known that circulating polyamines help promote malignant cell proliferation and metastatic dissemination, but their ultimate targets are not yet completely understood. Either produced by actively proliferating normal or cancer cells, or absorbed from the gastro-intestinal tract (food and colonic microfloral population), circulating polyamines could favour in vivo malignant cell proliferation. 1) Since these organic polycations are more rapidly internalized by cancer cells than by normal ones, do they join and facilitate the malignant intracellular polyamine metabolism? 2) Does binding of polyamines to specific acceptor sites at the surface of cancer cells, thereby modulating endocytosis of biological factors present in the extracellular spaces, modify the homeostatic control of cell proliferation and differentiation? 3) Do modifications of blood polyamine compartmentalization, observed in cancerous organisms, responsible for new enzyme and/or immune capacities, contribute to tumor progression? Answering the above-mentioned questions would lead to new therapeutic approaches in human oncology.
Electrically small microstrip antennas (2002)

In this paper novel electrically small microstrip antennas are presented. First the basic mechanism for the size reduction is described with a planar structure as a simple example. Then the technique is extended to a cylindrical structure for "donut-shaped" radiation patterns for more practical applications.
Regulation of Plasma High-Density Lipoprotein Levels by the ABCA1 Transporter and the Emerging Role of High-Density Lipoprotein in the Treatment of Cardiovascular Disease (2004)

High-density lipoproteins (HDL) protect against cardiovascular disease. HDL removes and transports excess cholesterol from peripheral cells to the liver for removal from the body. HDL also protects low-density lipoproteins (LDL) from oxidation and inhibits expression of adhesion molecules in endothelial cells, preventing monocyte movement into the vessel wall. The ABCA1 transporter regulates intracellular cholesterol levels in the liver and in peripheral cells by effluxing excess cholesterol to lipid-poor apoA-I to form nascent HDL, which is converted to mature alpha-HDL by esterification of cholesterol to cholesteryl esters (CE) by lecithin cholesterol acyltransferase. The hepatic ABCA1 transporter and apoA-I are major determinants of levels of plasma alpha-HDL cholesterol as well as poorly lipidated apoA-I, which interact with ABCA1 transporters on peripheral cells in the process of reverse cholesterol transport. Cholesterol in HDL is transported directly back to the liver by HDL or after transfer of CE by the cholesteryl ester transfer protein (CETP) by the apoB lipoproteins. Current approaches to increasing HDL to determine the efficacy of HDL in reducing atherosclerosis involve acute HDL therapy with infusions of apoA-I or apoA-I mimetic peptides and chronic long-term therapy with selective agents to increase HDL, including CETP inhibitors.