gebhart/patrepeval huggingface dataset:
Cellular growth response to epidermal growth factor in colon carcinoma cells with an amplified epidermal growth factor receptor derived from a familial adenomatous polyposis patient. (1991)

The receptor binding and cellular growth responses to exogenous epidermal growth factor (EGF) were studied using the DiFi cell line established from a familial adenomatous polyposis patient. The number of cell membrane EGF receptors on DiFi cells, as measured by competitive radioligand binding assays and Scatchard analysis of 125I-EGF binding isotherms, was calculated to be 4.8 x 10(6) receptors/cell. An acid prewash step performed prior to ligand binding assays did not reveal additional receptor numbers. A single, low-affinity receptor population was identified by Scatchard analysis, with an apparent Kd of 4.6 nM. This result was confirmed by radioligand binding studies performed in the presence and absence of the receptor-antagonist monoclonal antibody 528 IgG that binds predominantly to the low-affinity form of the EGF receptor. DiFi cells at 50-60% confluence, when exposed to 50 nM exogenous EGF, exhibited a rapid but partial (30%) reduction in their cell membrane-associated receptor, characteristic of sequestration. Exposure of DiFi cells to 50 nM EGF for longer periods of time (4 h) did not result in any further reduction in EGF-receptor number. The cellular growth response of DiFi cells to exogenous EGF was studied in monolayer cultures as well as in a soft agarose assay. Inhibition of soft agar colony formation was observed at exogenous EGF concentrations greater than 1.7 nM, and inhibition of monolayer growth occurred at EGF concentrations greater than 1 nM. In immune complex kinase assays, the DiFi receptor showed similar specific activity to that from the well-characterized A431 cell line. Additionally, phosphorylation of the receptor on tyrosine was qualitatively similar to that of A431 cells, further suggesting that the DiFi receptors identified by EGF-binding studies were biologically functional.
TH1/TH2 CYTOKINES IN THE CENTRAL NERVOUS SYSTEM (2002)

For the past 20 years it has become increasingly evident that cytokines play an important role in both the normal development of the brain, acting as neurotrophic factors, and in brain injuries. Although cytokines and their receptors are synthesized and expressed in the brain (normally at low levels), increased cytokine production levels are now associated with various neurological disorders. T lymphocytes are the cells responsible for coordinating the immune response and a major source of cytokines. Different cytokines induce different subsets of T cells or have different effects on proliferation within a particular subset. Recent studies suggest that the immune response is in fact regulated by the balance between Th1 and Th2 cytokines. These two pathways are often mutually exclusive, the one resulting in protection and the other in progression of disease. Various studies describe the function and production of proinflammatory cytokines in the central nervous system (CNS) and their role in health and disease. Inflammation is upregulated following activation of Th1 cells, whereas Th2 cells may play a significant role in downregulating Th1 proinflammatory responses in those instances in which there is overproduction of Th2 cytokines. Although both Th1 and Th2 cytokines may influence CNS functioning, most studies have so far dealt with proinflammatory cytokines, probably because they directly affect CNS cells and are thought to be implicated in CNS pathology. It is of interest that endogenous glucocorticoids also control Th1-Th2 balance, favoring Th2 cell development. This review presents the evidence that cytokines have important functions in the CNS, both during development and as a part of brain pathology. In particular, the author highlighted recent work that supports a major role for the so-called inflammatory cytokines, Th1, and the anti-inflammatory Th2 cytokines.
Model and parameter identification of friction during robotic insertion of cochlear-implant electrode arrays (2009)

Robot-assisted cochlear implant surgery was proposed and proved to be efficient in reducing insertion forces on acrylic scala tympani models. During experiments, the authors discovered that the insertion force not only depends on the shape discrepancy between the scala tympani and the inserted electrode array, but also on the insertion speed. This paper presents a friction model that describes the whole insertion process and investigates the relationship between the insertion speed and the insertion force. Experimental and statistical results show the effectiveness of the model. Applying the friction model generates safety insertion force boundaries for future insertions and gives the optimal insertion speed. It also provides predictive force information for insertion speed feedback control law design which may be applied to robot-assisted cochlear implant surgeries.
U.K. Prospective Diabetes Study 16: Overview of 6 Years' Therapy of Type II Diabetes: A Progressive Disease (1995)

The objective of the U.K. Prospective Diabetes Study is to determine whether improved blood glucose control in type II diabetes will prevent the complications of diabetes and whether any specific therapy is advantageous or disadvantageous. The study will report in 1998, when the median duration from randomization will be 11 years. This report is on the efficacy of therapy over 6 years of follow-up and the overall incidence of diabetic complications. Subjects comprised 4,209 newly diagnosed type II diabetic patients who after 3 months' diet were asymptomatic and had fasting plasma glucose (FPG) 6.0–15.0 mmol/l. The study consists of a randomized controlled trial with two main comparisons: 1) 3,867 patients with 1,138 allocated to conventional therapy, primarily with diet, and 2,729 allocated to intensive therapy with additional sulfonylurea or insulin, which increase insulin supply, aiming for FPG &amp;lt;6 mmol/l; and 2) 753 obese patients with 411 allocated to conventional therapy and 342 allocated to intensive therapy with metformin, which enhances insulin sensitivity. In the first comparison, in 2,287 subjects studied for 6 years, intensive therapy with sulfonylurea and insulin similarly improved glucose control compared with conventional therapy, with median FPG at 1 year of 6.8 and 8.2 mmol/l, respectively (P &amp;lt; 0.0001). and median HbA1c of 6.1 and 6.8%, respectively (P &amp;lt; 0.0001). During the next 5 years, the FPG increased progressively on all therapies (P &amp;lt; 0.0001) with medians at 6 years in the conventional and intensive groups, FPG 9.5 and 7.8 mmol/l, and HbA1c 8.0 and 7.1%, respectively. The glycemic deterioration was associated with progressive loss of β-cell function. In the second comparison, in 548 obese subjects studied for 6 years, metformin improved glucose control similarly to intensive therapy with sulfonylurea or insulin. Metformin did not increase body weight or increase the incidence of hypoglycemia to the same extent as therapy with sulfonylurea or insulin. A high incidence of clinical complications occurred by 6-year follow-up. Of all subjects, 18.0% had suffered one or more diabetes-related clinical endpoints, with 12.1% having a macrovascular and 5.7% a microvascular endpoint. Sulfonylurea, metformin, and insulin therapies were similarly effective in improving glucose control compared with a policy of diet therapy. The study is examining whether the continued improved glucose control, obtained by intensive therapy compared with conventional therapy (median over 6 years HbA1c 6.6% compared with 7.4%), will be clinically advantageous in maintaining health.
Nucleotide sequence of the Escherichia coli polA gene and primary structure of DNA polymerase I. (1982)

We report the nucleotide sequence of 3.2 kilobase pair region of the Escherichia coli polA gene, comprising the coding region for DNA polymerase I with about 400 base pairs of flanking sequence. The amino acid sequence for DNA polymerase I derived from our DNA sequence is largely consistent with previous protein chemical data. In the following paper, Brown et al. (Brown, W. E., Stump, K. H., and Kelley, W. S. (1982) J. Biol. Chem. 257, 1965-1972) present additional protein chemistry experiments that further confirm our sequence. Mild proteolysis of DNA polymerase I is known to produce two enzymatically active fragments (Brutlag, D., Atkinson, M. R., Setlow, P., and Kornberg, A. (1969) Biochem. Biophys. Res. Commun. 37, 982-989; Klenow, H., and Henningsen, I. (1970) Proc. Natl. Acad. Sci. U. S. A. 74, 5632-5636). We have located the site of this cleavage between residues 323 and 324 of the 928 amino acid polymerase molecule. By sequence comparison of the polA1 and wild type alleles, we have identified the polA1 mutation as a change from Trp (TGG) to amber (TAG) at residue 342.
Identification of the major tamoxifen-deoxyguanosine adduct formed in the liver DNA of rats treated with tamoxifen. (1996)

The antiestrogenic drug tamoxifen induces liver tumors in rats by a genotoxic mechanism. The key step has been proposed to be the formation of a reactive carbocation from the metabolite alpha-hydroxytamoxifen. This compound reacts with DNA in vitro to a small extent (1 in 10(5) DNA bases), giving products identical to those found in rat liver cells treated with tamoxifen. Now we have prepared the more reactive alpha-acetoxytamoxifen, which reacts with DNA in vitro to a much greater extent (1 in 50 bases). The products of this reaction were subjected to 32P postlabeling and shown by both TLC and reverse-phase liquid chromatography to be identical to those isolated from DNA treated with alpha-hydroxytamoxifen and to those found in the liver DNA of rat hepatocytes treated with tamoxifen or of the livers of rats treated with tamoxifen. The major product was also isolated as the nucleoside and characterized by UV, mass, and proton magnetic resonance spectroscopy. It is an adduct of tamoxifen and deoxyguanosine in which the alpha position of tamoxifen is linked covalently to the exocyclic amino group of deoxyguanosine.
Comparisons of Outcome and Prognostic Features Among Histologic Subtypes of Renal Cell Carcinoma (2003)

Our objective was to compare cancer-specific survival and to examine associations with outcome among the histologic subtypes of renal cell carcinoma (RCC). We studied 2385 patients whose first surgery between 1970 and 2000 was a radical nephrectomy for sporadic, unilateral RCC. All RCC tumors were classified following the 1997 Union Internationale Contre le Cancer and American Joint Committee on Cancer guidelines. There were 1985 (83.2%) patients with clear cell, 270 (11.3%) with papillary, 102 (4.3%) with chromophobe, 6 (0.3%) with collecting duct, 5 (0.3%) with purely sarcomatoid RCC and no underlying histologic subtype, and 17 (0.7%) with RCC, not otherwise specified. Cancer-specific survival rates at 5 years for patients with clear cell, papillary, and chromophobe RCC were 68.9%, 87.4%, and 86.7%, respectively. Patients with clear cell RCC had a poorer prognosis compared with patients with papillary and chromophobe RCC (p <0.001). This difference in outcome was observed even after stratifying by 1997 tumor stage and nuclear grade. There was no significant difference in cancer-specific survival between patients with papillary and chromophobe RCC (p = 0.918). The 1997 TNM stage, tumor size, presence of a sarcomatoid component, and nuclear grade were significantly associated with death from clear cell, papillary, and chromophobe RCC. Histologic tumor necrosis was significantly associated with death from clear cell and chromophobe RCC, but not with death from papillary RCC. Our results demonstrate that there are significant differences in outcome and associations with outcome for the different histologic subtypes of RCC, highlighting the need for accurate subtyping.
Translocation of Diphtheria Toxin A-fragment to the Cytosol (1989)

Diphtheria toxin contains a trypsin-sensitive region with 3 closely spaced arginines in the sequence (Asn189, Arg190, Val191, Arg192, Arg193, Ser194). Cleavage of the toxin to yield A- and B-fragments ("nicking") appears to occur in a stochastic manner after either of these arginine residues. Isoelectric focusing of A-fragment prepared in vitro showed four bands of varying intensity with pI between 4.5 and 5.0, three of which could be accounted for by the three different cleavage sites. Exposure of cells with surface-bound toxin to pH less than 5.3 induces translocation of A-fragment to a position where it is shielded from external Pronase, presumably in the cytosol. A-fragment translocated in this manner had the same pI as the most acidic A-fragments, indicating that only A-fragments lacking both Arg192 and Arg193 are translocation-competent. This was confirmed by amino acid sequencing. Treatment of A-fragment with carboxypeptidase B eliminated the two bands with the highest pI while there was a concomitant increase in the bands corresponding to the two most acidic A-fragments. Such treatment of nicked diphtheria toxin increased the amount of translocated A-fragment and the ability of toxin to form cation-selective pores in the cell membrane. The site of trypsin cleavage therefore appears to be one of the factors limiting toxin entry to the cytosol.
Liver cell uptake and degradation of soluble immunoglobulin G immune complexes in vivo and in vitro in rats (1996)

Immune complexes were formed between dinitrophenylated human serum albumin (DNP-HSA) and polyclonal rabbit immunoglobulin G (IgG) anti-DNP antibodies at antibody excess. The antigen was labelled with isotope (125I-tyramine-cellobiose) or fluorochrome, (6-[fluorescein-5-(and-6)-carboxamido] hexanoic-acid, succinimidyl ester). The radiolabelled antigen, native or antibody complexed, was given intravenously to rats. Radioactivity was measured in various organs at 1 hour following injection. The liver was the main site for removal of the antigen as well as of the immune complexes. Within the liver, immune complexes were mainly associated with nonparenchymal liver cells, the total recovery from Kupffer cells being about 10 times greater than from the liver endothelial cells. The uncomplexed radiolabelled antigen was readily degraded by both cells types. After IgG complexing, the degradation decreased, both in Kupffer cells and in liver endothelial cells. In vitro experiments with isolated liver cells, showed that IgG complexing increased antigen uptake to about the same extent in Kupffer cells and in liver endothelial cells. The degradation of both antigen and immune complexes was less efficient in vitro than in vivo. Immune complex uptake in vitro was shown also by confocal fluorescence microscopy in Kupffer cells and in liver endothelial cells. Also in vitro, only minor uptake was found in the hepatocytes. We conclude that both liver endothelial cells and Kupffer cells are involved in the hepatic handling of soluble IgG immune complexes, but we found no evidence for substantial uptake by hepatocytes. (Hepatology 1996 Jul;24(1):169-75)
Systemic administration of ciliary neurotrophic factor induces cachexia in rodents. (1994)

Ciliary neurotrophic factor (CNTF) has previously been shown to promote the survival of several classes of neurons and glial. We report here that in addition to its effects on the nervous system, CNTF can induce potent effects in extra-neural tissues. Implantation of C6 glioma cells engineered to secrete CNTF either subcutaneously or into the peritoneal cavity of adult mice, or systemic injections of purified rat or human recombinant CNTF, resulted in a rapid syndrome of weight loss resulting in death over a period of 7-10 d. This weight loss could not be explained by a reduction in food intake and involved losses of both fat and skeletal muscle. CNTF also induced the synthesis of acute phase proteins such as haptoglobin. Implantation of C6 lines expressing a nonsecreted form of CNTF, or the parental C6 line itself, did not result in wasting effects. Analysis of this CNTF-induced wasting indicates similarities with the previously described cachectins, tumor necrosis factor, interleukin 6, and leukemia inhibitory factor, but does not involve the induction of these cytokines.
Development and Evaluation of Reverse Transcription-Loop-Mediated Isothermal Amplification (RT-LAMP) Assay Coupled with a Portable Device for Rapid Diagnosis of Ebola Virus Disease in Guinea (2016)

Given the current absence of specific drugs or vaccines for Ebola virus disease (EVD), rapid, sensitive, and reliable diagnostic methods are required to stem the transmission chain of the disease. We have developed a rapid detection assay for Zaire ebolavirus based on reverse transcription-loop-mediated isothermal amplification (RT-LAMP) and coupled with a novel portable isothermal amplification and detection platform. The RT-LAMP assay is based on primer sets that target the untranscribed trailer region or nucleoprotein coding region of the viral RNA. The test could specifically detect viral RNAs of Central and West African Ebola virus strains within 15 minutes with no cross-reactivity to other hemorrhagic fever viruses and arboviruses, which cause febrile disease. The assay was evaluated using a total of 100 clinical specimens (serum, n = 44; oral swab, n = 56) collected from suspected EVD cases in Guinea. The specificity of this diagnostic test was 100% for both primer sets, while the sensitivity was 100% and 97.9% for the trailer and nucleoprotein primer sets, respectively, compared with a reference standard RT-PCR test. These observations suggest that our diagnostic assay is useful for identifying EVD cases, especially in the field or in settings with insufficient infrastructure.
A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo (2002)

Constitutively activating internal tandem duplication (ITD) and point mutations of the receptor tyrosine kinase FLT3 are present in up to 41% of patients with acute myeloid leukemia (AML). These FLT3/ITD mutations are likely to be important because their presence is associated with a poor prognosis. Both types of mutations appear to activate the tyrosine kinase activity of FLT3. We describe here the identification and characterization of the indolocarbazole derivative CEP-701 as a FLT3 inhibitor. This drug potently and selectively inhibits autophosphorylation of wild-type and constitutively activated mutant FLT3 in vitro in FLT3/ITD-transfected cells and in human FLT3-expressing myeloid leukemia-derived cell lines. We demonstrate that CEP-701 induces a cytotoxic effect on cells in a dose-responsive fashion that parallels the inhibition of FLT3. STAT5 and ERK1/2, downstream targets of FLT3 in the signaling pathway, are inhibited in response to FLT3 inhibition. In primary leukemia blasts from AML patients harboring FLT3/ITD mutations, FLT3 is also inhibited, with an associated cytotoxic response. Finally, using a mouse model of FLT3/ITD leukemia, we demonstrate that the drug inhibits FLT3 phosphorylation in vivo and prolongs survival. These findings form the basis for a planned clinical trial of CEP-701 in patients with AML harboring FLT3- activating mutations.
Chemokine/Cytokine Cocktail in Idiopathic Pulmonary Fibrosis (2006)

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing lung disease of unknown etiology and with an unfavorable outcome, leading ultimately to death due to respiratory failure. To date, no treatment strategies have been effective in modifying the natural course of IPF and its fatal outcome. The aberrant parenchymal remodeling is characterized by the expansion of fibroblasts/myofibroblasts, which form characteristic subepithelial foci, and by the abnormal deposition of extracellular matrix in the lung parenchyma. Although the pathophysiology underlying this disease has not yet been fully elucidated, animal models of pulmonary fibrosis have provided contributions in dissecting the molecular basis of this disease, focusing on the role of cytokines and chemokines as important pathogenetic mediators of lung fibrosis. Starting with the data obtained from animal models, this article provides a comment on a number of findings that suggest the possible role of the chemokine/cytokine system in the pathogenesis of IPF.
Neutralizing Activity in Human Milk Fractions against Respiratory Syncytial Virus (1986)

Neutralizing activity against respiratory syncytial virus (RSV) was measured in milk samples from 17 healthy women whose infants had an acute infection with respiratory syncytial virus (RSV) and from 27 women with healthy infants. All milk samples were obtained 2-8 months post partum. Neutralizing activity was detected in 36 samples. No major difference in neutralizing titers was observed between the two groups, and the titers were low. RSV-specific IgA was found in two samples, and RSV-specific IgG in one sample. RSV-specific IgM was not detected. In gel filtration studies, the neutralizing activity was eluted with an apparent molecular weight above 400,000. The neutralizing activity remained after removal of IgA by affinity chromatography. These findings suggest that both immunoglobulin and non-immunoglobulin components in human milk can neutralize RSV.
Structural Basis for the Glucocorticoid Response in a Mutant Human Androgen Receptor (ARccr) Derived from an Androgen-Independent Prostate Cancer (2002)

The crystal structure of a mutant androgen receptor (AR) ligand-binding domain (LBD) in complex with the agonist 9alpha-fluorocortisol has been determined at 1.95 A resolution. This mutant AR contains two mutations (L701H and T877A) and was previously reported as a high-affinity cortisol/cortisone responsive AR (AR(ccr)) isolated from the androgen-independent human prostate cancer cell lines MDA PCa 2a and 2b (Zhao et al. Nature Med. 2000, 6, 703-6). The three-dimensional structure of the AR(ccr) LBD complexed with 9alpha-fluorocortisol shows the typical conformation of an agonist-bound nuclear receptor in which helix 12 is precisely positioned as a "lid" for the ligand-binding pocket. Binding of 9alpha-fluorocortisol to the AR(ccr) involves favorable hydrogen bond patterns on the C17 and C21 substituents of the ligand due to the mutations at 701 and 877 in the AR(ccr). Our studies provide the first structural explanation for the glucocorticoid activation of AR(ccr), which is important for the development of new therapeutic treatments for androgen-independent prostate cancer.
Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein–Barr virus nuclear antigen 1 (1997)

The Epstein-Barr virus (EBV) encoded nuclear antigen (EBNA) 1 is expressed in latently infected B lymphocytes that persist for life in healthy virus carriers and is the only viral protein regularly detected in all EBV associated malignancies. The Gly-Ala repeat domain of EBNA1 was shown to inhibit in cis the presentation of major histocompatibility complex (MHC) class I restricted cytotoxic T cell epitopes from EBNA4. It appears that the majority of antigens presented via the MHC I pathway are subject to ATP-dependent ubiquitination and degradation by the proteasome. We have investigated the influence of the repeat on this process by comparing the degradation of EBNA1, EBNA4, and Gly-Ala containing EBNA4 chimeras in a cell-free system. EBNA4 was efficiently degraded in an ATP/ubiquitin/proteasome-dependent fashion whereas EBNA1 was resistant to degradation. Processing of EBNA1 was restored by deletion of the Gly-Ala domain whereas insertion of Gly-Ala repeats of various lengths and in different positions prevented the degradation of EBNA4 without appreciable effect on ubiquitination. Inhibition was also achieved by insertion of a Pro-Ala coding sequence. The results suggest that the repeat may affect MHC I restricted responses by inhibiting antigen processing via the ubiquitin/proteasome pathway. The presence of regularly interspersed Ala residues appears to be important for the effect.