gebhart/patrepeval huggingface dataset:
Phosphorylation of a cytosolic 65-kDa protein induced by interleukin 1 in glucocorticoid pretreated normal human peripheral blood mononuclear leukocytes. (1987)

The authors have previously observed that glucocorticoids dramatically increase the number of interleukin 1 (IL-1) receptors on normal human peripheral blood mononuclear cells (PBMC) (from approximately 100 to 2000 receptors/cell) without significant change in the binding affinity (Kd = approximately 2.6 x 10(-10) M). We, therefore, used such a receptor-enriched glucocorticoid-pretreated PBMC to investigate whether IL-1 induces/increases the phosphorylation of any cell-associated proteins, including possible autophosphorylation of IL-1 receptors. Extraction of 125I-labeled IL-1 alpha cross-linked to IL-1 receptor on steroid-treated PBMC yielded two bands estimated to be 60 and 70 kDa in molecular mass. No molecules were significantly cross-linked with 125I-labeled IL-1 alpha on untreated PBMC. Carrier-free recombinant human IL-1 alpha induced phosphorylation of an acidic 65-kDa protein (pp65) at serine residues within 5 min more effectively in glucocorticoid-treated PBMC than in untreated PBMC. Fractionation of extracts of IL-1-stimulated prednisolone-pretreated PBMC by ultracentrifugation showed that pp65 is located in the cytosol, suggesting that pp65 is not the IL-1 receptor itself. Protein kinase inhibitors, HA1004 and W-7, but not H-7, significantly inhibited the induction of the phosphorylation of 65-kDa protein by IL-1. These data indicate that the glucocorticoid-induced IL-1 receptor is functional and either contains or is closely associated with a serine kinase that is distinct from protein kinase C.
Epidemiology of necrotizing enterocolitis (1994)

Necrotizing enterocolitis (NEC) is a worldwide problem that has emerged in the past 25 years as the most common gastrointestinal emergency in neonatal intensive care units (NICU). In the United States the incidence ranges from 1 to 7.7% of NICU admissions. Ninety percent of the patients are premature infants. Mucosal injury, bacterial colonization and formula feeding are the three major pathogenetic factors that have been documented in most infants who have developed NEC. However, NEC may develop only if a threshold of injury, imposed by the coincidence of at least two of three events (intestinal ischemia, pathogenic bacteria, and excess of protein substrate) is exceeded. Immunological immaturity of the gut in premature babies may represent the crucial risk factor.
Mutants ofListeria monocytogenesDefective in In Vitro Invasion and Cell-to-Cell Spreading Still Invade and Proliferate in Hepatocytes of Neutropenic Mice (2000)

Listeria monocytogenes mutants defective in the actA gene, the plcB gene, and the inlA and inlB genes were less virulent when injected intravenously into BALB/c mice. The growth of these strains as well as of the virulent wild-type strains was increased by treating mice with a neutrophil-specific depleting monoclonal antibody, RB6-8C5. Histologic examination of the livers of the treated animals showed intrahepatocytic proliferation of the listeriae in all cases. Our data show that more than one pathway exists that allows L. monocytogenes to invade parenchymal cells. One pathway most likely involves the actA and plcB gene products, and a second one probably involves the internalins.
Multifactorial Analysis of Conditional Reprogramming of Human Keratinocytes (2015)

Co-culture of human primary epithelial cells with irradiated 3T3 fibroblast feeder cells (J2 cells) and the Rho kinase inhibitor Y-27632 (Y) allows for the unrestricted growth of cells of epithelial origin by the process termed conditional reprogramming. To better understand the nature of the signaling processes associated with conditionally reprogrammed cells, the effect of the two critical components of the co-culture conditions, J2 cells and Y, on the growth of human foreskin keratinocytes (HFKs) was evaluated by gene expression profiling, reverse-phase protein arrays and siRNA screening. J2 cells and Y acted cooperatively to down-regulate differentiation, and upregulate proliferation and cell adhesion, including increased pT308Akt and pERK, and reduced TGF-β pathway signaling. These findings establish a mechanistic basis for the unlimited growth potential of human epithelial cells that will be invaluable to assess the effect of genetic changes in pathologic tissues and their response to therapeutic agents.
Human Bone Marrow–Derived Mesenchymal Stem Cells for Intravascular Delivery of Oncolytic Adenovirus Δ24-RGD to Human Gliomas (2009)

Delta24-RGD is an infectivity-augmented, conditionally replicative oncolytic adenovirus with significant antiglioma effects. Although intratumoral delivery of Delta24-RGD may be effective, intravascular delivery would improve successful application in humans. Due to their tumor tropic properties, we hypothesized that human mesenchymal stem cells (hMSC) could be harnessed as intravascular delivery vehicles of Delta24-RGD to human gliomas. To assess cellular events, green fluorescent protein-labeled hMSCs carrying Delta24-RGD (hMSC-Delta24) were injected into the carotid artery of mice harboring orthotopic U87MG or U251-V121 xenografts and brain sections were analyzed by immunofluorescence for green fluorescent protein and viral proteins (E1A and hexon) at increasing times. hMSC-Delta24 selectively localized to glioma xenografts and released Delta24-RGD, which subsequently infected glioma cells. To determine efficacy, mice were implanted with luciferase- labeled glioma xenografts, treated with hMSC-Delta24 or controls, and imaged weekly by bioluminescence imaging. Analysis of tumor size by bioluminescence imaging showed inhibition of glioma growth and eradication of tumors in hMSC-Delta24-treated animals compared with controls (P < 0.0001). There was an increase in median survival from 42 days in controls to 75.5 days in hMSC-Delta24-treated animals (P < 0.0001) and an increase in survival beyond 80 days from 0% to 37.5%, respectively. We conclude that intra-arterially delivered hMSC-Delta24 selectively localize to human gliomas and are capable of delivering and releasing Delta24-RGD into the tumor, resulting in improved survival and tumor eradication in subsets of mice.
Frequency and spectrum of mutations at codons 12 and 13 of the c-K-ras gene in human tumors. (1991)

The frequency of point mutations at codons 12 and 13 of the c-K-ras gene has been determined in a panel of more than 400 human tumors. Mutant c-K-ras genes were detected in about 75% of adenocarcinomas of the pancreas (n = 84); 40% of adenomas (n = 72) and carcinomas (n = 244) of the colon end rectum; 30% of carcinomas of the bile duct (n = 19); 25% of carcinomas of the lung (n = 92), and in lower frequency in other carcinomas, including liver, stomach, and kidney. No mutations were found in carcinomas of the breast, prostate, esophagus, and gall bladder, among others. Comparative analysis of the spectrum of mutations show that while G to A transitions were the most frequent mutations in pancreatic and colo-rectal tumors, G to T transversions were more prevalent in lung carcinomas. The aspartic acid mutation at codon 13 (GGC----GAC) was relatively frequent in colo-rectal tumors but rare in pancreatic and lung carcinomas. The differences in the mutation spectrum of the c-K-ras gene in cancers of the gastrointestinal and respiratory tracts are suggestive of differential exposure to genotoxic agents.
Streptococcus mutans and Lactobacillus Detection in the Assessment of Dental Root Surface Caries Risk (1985)

Forty-five subjects contributing 150 root surfaces with gingival recession were sampled seven times over a 32-month period. We calculated isolation frequencies of lactobacilli on selective Rogosa SL agar and S. mutans in a sensitive enrichment broth and on mitis salivarius agar. Both S. mutans and lactobacilli were isolated more frequently from surfaces which became carious than from those remaining caries-free. Isolation frequencies were also higher for caries-free surfaces in caries-active subjects than for caries-free surfaces in caries-inactive subjects. The presence or absence of S. mutans and lactobacilli in samples taken at baseline could discriminate between subjects who were to be root-caries-active and those who were to remain root-caries-inactive during the subsequent observation period. Moreover, if both bacteria were detected or only S. mutans was detected on a root surface at its entry into the study, that surface had a greater risk for developing a root lesion. However, the tests could not predict which root surfaces within the mouths of caries-active subjects were to become carious. Analysis of the data suggests that simple microbiological detection tests may be useful in identifying patients at high risk of root caries.
The role of the asparagine-linked oligosaccharides of the alpha-subunit in human thyrotropin bioactivity (1996)

TSH and the gonadotropins (FSH, LH, and hCG) are a family of heterodimeric proteins that share a common alpha-subunit and differ in their hormone-specific beta-subunit. The asparagine-linked (N-linked) oligosaccharides on these hormones are important in signal transduction. The N-linked oligosaccharides on the alpha-subunit have no effect on hCG and hFSH receptor binding, but are critical for their biological activity. Here, we analyzed the role of alpha-subunit N-linked oligosaccharides in human TSH (hTSH) bioactivity by site-directed mutagenesis and gene transfer. This was achieved by mutating the asparagine (Asn) residue in the N-linked glycosylation consensus sequence (Asn-X-Thr/Ser) to aspartic acid. The wild-type hTSH and its variants were expressed in Chinese hamster ovary cells. Wild-type alpha-subunit and its mutants (alpha 1, alpha 2, and alpha(1 + 2)) were efficiently combined with TSH beta-subunit and secreted as dimers. The bioactivity of TSH glycosylation variants was determined by measuring their abilities to stimulate cAMP formation and T3 secretion using a serum-free culture system of human thyroid follicles. Using this system, wild-type hTSH was significantly effective in the stimulation of cAMP formation and T3 secretion. Deletion of the oligosaccharide units from either site 1(alpha 1) or site 2(alpha 2) of the alpha-subunit increased the biological activity of the dimer by about 30%. However, deletion of carbohydrate units from both sites of hTSH alpha-subunit (alpha(1 + 2) resulted in a significant reduction in cAMP formation (by approximately 70%) and T3 secretion (by approximately 40%) compared to that with wild-type hTSH. These findings emphasize the importance of the alpha-subunit N-linked oligosaccharide chains on hTSH bioactivity.
Abstract B246: NVP-BGJ398: A potent and selective inhibitor of the fibroblast growth factor receptor family. (2011)

Abstract The mammalian fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) family comprises 22 FGF ligands, 18 of which exert their action through 4 highly conserved transmembrane tyrosine kinase receptors (FGFR1, FGFR2, FGFR3 and FGFR4). This highly complex signaling network regulates fundamental developmental pathways, physiological processes in the adult organism and a variety of cellular functions including proliferation, differentiation, and survival. Owing to such prominent roles, it is not surprising that different types of FGF/FGFR alterations, such as abnormal expression, mutations, and amplifications, have been found in diverse tumor types. A growing body of evidence linking deregulation of the FGF/FGFR system to the pathogenesis of cancer makes these receptors attractive targets for therapeutic intervention by a small molecular weight inhibitor approach. We have established a new and non-conventional strategy to mimic documented lead compounds which consists in the replacement of real rings by stable pseudo six-membered rings resulting from the formation of an intramolecular hydrogen bond in a planar conjugated system. More recently, we have reported an example of the application of such strategy to the design of a new class of protein kinase inhibitors featuring a N-pyrimidin-4-yl-urea motif as an alternative to the pyrido[2,3-d]pyrimidin-7-one core structure of a well-known class of protein kinase inhibitors. In this context, we have described a prototype compound displaying submicromolar activity against several tyrosine kinases including FGFR1. In this communication we illustrate the process, guided by the use of molecular modeling and biochemical and cellular assays, that led to the identification of NVP-BGJ398, a potent and selective FGFR antagonist currently in phase I clinical trial. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B246.
Inflammation, immunoregulation, and inducible nitric oxide synthase (1993)

Nitric oxide (NO), the molecule of the year 1992, is gaining recognition as an important biological mediator. Its multitude of physiologic and pathophysiologic functions result from both a wide distribution of synthesis and diverse mechanisms of action. Besides its functions as a potent vasodilator and neurotransmitter, NO is important in inflammation and immunity. Both beneficial and detrimental consequences of induced synthesis have been discovered. Information is now accumulating on the regulation and function of induced NO. The recent cloning of human inducible NO cDNA should assist in defining the role of inducible NO in human physiology and pathophysiology.
Increased expression of cell adhesion molecule P-selectin in active inflammatory bowel disease. (1995)

The pathogenic changes of inflammatory bowel disease (IBD) depend on migration of circulating leucocytes into intestinal tissues. Although leucocyte rolling and tenuous adhesion are probably regulated by inducible selectins on vascular endothelia, little is known about the expression of these molecules in Crohn's disease and ulcerative colitis. Using immunohistochemistry on surgically resected specimens, this study investigated endothelial P-selectin (CD62, granular membrane protein-140) in frozen sections of histologically uninvolved tissues adjacent to inflammation (Crohn's disease = 10; ulcerative colitis = 10), from highly inflamed areas (Crohn's disease = 20; ulcerative colitis = 13), and from normal bowel (n = 20). By light microscopy, two forms of P-selectin immunoreactivity were detected that apparently corresponded ultrastructurally to stored and released distributions. Compared with the normal gut, there was a 3.7-fold increase of P-selectin immunoreactivity on veins (p < 0.0001), venules (p < 0.0001), and capillaries (p < 0.05) in the highly inflamed gut, without differences between Crohn's disease and ulcerative colitis. In the uninvolved gut, P-selectin expression was similar to that seen in normal controls, except for a focal increase of P-selectin in the vicinity of small lymphocyte aggregates. The dramatic upregulation of P-selectin in the inflamed tissue and its potential role in leucocyte trafficking support the concept of P-selectin blocking therapy for the control of active IBD.
Mimicry of Antimicrobial Host-Defense Peptides by Random Copolymers (2007)

Efforts to generate antibacterial agents via mimicry of host-defense peptides have focused on discrete oligomers that can adopt a regular globally amphiphilic conformation in the presence of bacterial cell membranes and ultimately disrupt those membranes. Although considerable success has been achieved with this approach, application of the resulting molecules is hampered by the high cost associated with stepwise oligomer synthesis. We show that random poly-β-peptide copolymers, prepared by ring-opening polymerization of β-lactams, can be tuned to display good activity against a panel of four bacteria along with low lytic activity toward human red blood cells. These findings support a nonclassical design hypothesis for antibacterial agents.
Comparison of Reactivity of Monoclonal Antibody (3F2) to Trimeric Tumor Necrosis Factor (TNF-α) with That to Monomeric TNF-α1 (1995)

Biologically active TNF-alpha is a trimer. Our newly developed monoclonal antibody against recombinant human TNF-alpha (3F2) bound to TNF-alpha immobilized on a solid phase precoated with the same monoclonal antibody, 3F2. We therefore examined the possibility that 3F2 preferentially recognized trimeric TNF-alpha, and obtained the following results. (i) Treatment of TNF-alpha with 1% NP40 enhanced the dissociation from the trimer to the monomer. The treatment also reduced the reactivity of 3F2 to TNF-alpha immobilized on a solid phase precoated with either 3F2 or a rabbit anti-TNF-alpha antibody (PT50). (ii) When trimeric and monomeric TNF-alpha, obtained by gel filtration of NP40-treated TNF-alpha, were assayed with either PT50 (solid phase)/3F2 (fluid phase) or PT50/PT50, PT50/3F2 showed a higher response to trimeric TNF-alpha than to monomeric TNF-alpha, while PT50/PT50 showed the opposite result. (iii) The values for two fractions containing only trimeric TNF-alpha obtained on ELISA with PT50/3F2 fitted the standard curve for ELISA with PT50/3F2 which was made by using unseparated TNF-alpha. Taken together, these findings suggested that 3F2 preferentially recognizes trimeric TNF-alpha.
Wavelength dependence of the precision of noninvasive optical measurement of oxy‐, deoxy‐, and total‐hemoglobin concentration (2001)

The precision of noninvasive optical measurement of the concentration changes in oxy-, deoxy-, and total-hemoglobin depends on wavelength. For estimating the precision, we calculated the noise level of the concentration changes as the uncertainty in measurements using several wavelength pairs of light. Seven laser diodes (664-848 nm) were used simultaneously for spectroscopic measurement of brain activity during finger motor stimulation. We also used the analysis of error propagation from the uncertainty in direct measurements of absorbance changes to estimate indirectly the uncertainty of concentration changes. The measurement of the concentration changes made using an 830/664-nm pair are two times (oxy-Hb) and six times (deoxy-Hb) more precise than those made using an 830/782-nm pair.
Murine dendritic cells internalizeLeishmania major promastigotes, produce IL-12 p40 and stimulate primary T cell proliferationin vitro (1999)

Metacyclic Leishmania promastigotes (PM), transmitted by sand-fly bite, are likely to interact initially with cells of the dendritic cell (DC) lineage(s) in the epidermis or dermis. Epidermal Langerhans cells internalize L. major amastigotes (AM) and transport them to draining lymph nodes (Moll, H., Fuchs, H., Blank, C. and Röllinghoff, M., Eur. J. Immunol. 1993. 23: 1595) but little is known about the interaction of DC with PM. The present study demonstrates that DC are able to internalize PM and that the fate of the parasites within DC differs from that within macrophages (Mphi). DC took up small numbers of PM which did not differentiate into AM but appeared to be degraded; Mphi internalized large numbers of PM into parasitophorous vacuoles where they differentiated into AM. In response to direct stimulation with PM, DC from both C3H ("resistant" to L. major infection) and BALB/c ("susceptible") up-regulated production of IL-12 p40. In contrast, IL-12 production by Mphi was not detected. DC exposed to either metacyclic PM or PM culture supernatants were also able to stimulate proliferative responses in lymph node T cells from naive mice. These data indicate that DC have the capacity to promote protective Th1 immune responses in Leishmania infection and suggest that DC exposed to PM may be useful in immunotherapy and vaccination.
Effects of oxidative modification on thermal aggregation and gel properties of soy protein by peroxyl radicals (2011)

Summary Effects of protein oxidation on thermal aggregation and gel properties of soy protein by 2,2′‐azobis (2‐amidinopropane) dihydrochloride (AAPH)‐derived peroxyl radicals were investigated in this article. Incubation of soy protein to increase concentration of AAPH resulted in a decrease in particle size and content of thermal aggregates during thermal‐induced denaturation. Protein oxidation resulted in a decrease in water‐holding capacity (WHC), gel hardness and gel strength of soy protein gel. An increase in coarseness and interstice of the gel network was accompanied by uneven distribution of interstice as extent of oxidation of soy protein increased. A decrease in disulphide content and formation of oxidation aggregates in the process of oxidative modification were contributed to the decline of particle size and content of thermal aggregates during thermal‐induced denaturation, leading to a decrease in WHC, gel hardness and gel strength of soy protein gel.
A Novel Mutation in the Cystic Fibrosis Gene in Patients with Pulmonary Disease but Normal Sweat Chloride Concentrations (1994)

We have identified a point mutation in intron 19 of CFTR and abnormal epithelial function in patients who have cystic fibrosis-like lung disease but normal sweat chloride values. The identification of this mutation indicates that this syndrome is a form of cystic fibrosis. Screening for the mutation should prove diagnostically useful in this population of patients.
Developing Broadly Reactive HIV-1/AIDS Vaccines: A Review of Polyvalent and Centralized HIV-1 Vaccines (2007)

The development of an HIV/AIDS vaccine requires consideration of the large diversity of viral isolates. In 2005, there were 5 million new cases of HIV infection and over 4 million deaths due to AIDS. An HIV vaccine is needed to prevent the spread of this virus. One of the greatest challenges to developing a preventative HIV vaccine is the diversity of HIV-1 isolates. Env sequences can differ by as much as 35% between isolates from different clades and by as much as 10% within a clade. Two main strategies to address viral diversity for HIV vaccine development are the use of polymeric- or centralized-based immunogens. Polymeric-based vaccines, which have been used for polio and pneumococcus vaccines, use components from a range of viral isolates to increase the breadth of immune recognition. Centralized sequences decrease the sequence diversity by encoding the most common amino acid at each position from a diverse pool of viral isolates. These sequences are derived using the consensus, center-of-the-tree, or ancestral methods. The use of polyvalent- and centralized-based vaccines induce broadly reactive immune responses, however it is unclear whether the use of these sequences will increase protection against diverse HIV-1 infection. This review will summarize the current uses of polyvalent and centralized vaccines to increase immune breadth that may determine future directions for HIV-1 vaccine development.
The phylogenetic position of Serratia, Buttiauxella and some other genera of the family Enterobacteriaceae (1999)

The phylogenetic relationships of the type strains of 38 species from 15 genera of the family Enterobacteriaceae were investigated by comparative 16S rDNA analysis. Several sequences of strains from the genera Citrobacter, Erwinia, Pantoea, Proteus, Rahnella and Serratia, analysed in this study, have been analysed previously. However, as the sequences of this study differ slightly from the published ones, they were included in the analysis. Of the 23 enterobacterial genera included in an overview dendrogram of relatedness, members of the genera Xenorhabdus, Photorhabdus, Proteus and Plesiomonas were used as a root. The other genera formed two groups which could be separated, although not exclusively, by signature nucleotides at positions 590-649 and 600-638. Group A contains species of Brenneria, Buttiauxella, Citrobacter, Escherichia, Erwinia, Klebsiella, Pantoea, Pectobacterium and Salmonella. All seven type strains of Buttiauxella share 16S rDNA similarities greater than 99%. Group B embraces two phylogenetically separate Serratia clusters, a lineage containing Yersinia species, Rahnella aquatica, Ewingella americana, and also the highly related pair Hafnia alvei and Obesumbacterium proteus.