gebhart/patrepeval huggingface dataset:
Intestinal Inflammation and the Gut Microflora (1999)

The idea that the enteric microflora play a role in the pathogenesis or pathophysiology of inflammatory bowel disease (IBD) is not new. Indeed, identification of an infective cause for chronic IBD, and particularly for Crohn's disease, has been the focus of extensive research efforts. During the 1990s, there has been a noticeable re-emergence of interest in the link between bacteria and functional bowel disorders, and the value of antibiotic therapy to treat gut inflammatory disorders. A variety of experimental evidence from both laboratory model systems and clinical investigations is reviewed with respect to a pivotal role for enteric bacteria in gut inflammation. The voluminous scientific literature on this subject precludes any comprehensive synopsis of the area; instead, pertinent studies are cited to illustrate the ability of bacteria and their products to evoke or exacerbate gut inflammation.
Methods to Provide System-Wide ADS-B Back-Up, Validation and Security (2006)

A major part of the business case for automatic dependent surveillance-broadcast (ADS-B) is attributed to the savings generated by decommissioning or reducing reliance on conventional radar systems. In order to maintain some form of redundancy, a networked, system-wide back-up and validation approach is required. During the transition to end-state surveillance architectures, there are likely be a mixture of various types of surveillance sources including primary surveillance radar, secondary surveillance radar, multilateration, and ADS-B. This paper describes an integrated approach to the surveillance architecture and one means for facilitating the application of multiple surveillance sources. Surveillance sensor performance is based on the categories defined in ADS-B standards. The relevant parameters are navigation accuracy category (NAC), navigation integrity category (NIC), and surveillance integrity level (SIL). These standards have been adapted to create a generic surveillance performance categorization method. This method would enable air traffic service providers to develop criteria for combining information from multiple surveillance sensors. The categorization also enables a method for defining the associated aircraft separation requirements
(R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function (2014)

The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.
Pharyngitis—Principles of Judicious Use of Antimicrobial Agents (1998)

Accurate diagnosis of group A streptococcal pharyngitis and appropriate antimicrobial therapy are important, particularly to prevent nonsuppurative sequelae such as rheumatic fever. Most episodes of sore throat, however, are caused by viral agents. Clinical findings cannot reliably differentiate streptococcal from viral pharyngitis and most physicians tend to overestimate the probability of a streptococcal infection based on history and physical examination alone. Therefore, diagnosis should be based on results of a throat culture or an antigen-detection test with throat culture backup. Presumptively starting therapy pending results of a culture is discouraged because treatment often continues despite a negative test result. Other bacterial causes of pharyngitis are uncommon and often can be diagnosed based on nonpharyngeal findings. Penicillin remains the drug of choice for streptococcal pharyngitis because of its effectiveness, relatively narrow spectrum, and low cost. No group A streptococci are resistant to β-lactam antibiotics. High rates of resistance to macrolides has been documented in several areas; in Finland, decreased national rates of macrolide use led to a decline in the proportion of macrolide-resistant group A streptococci.
The Genus "Phaeoacremonium" from a Molecular Point of View (2000)

A molecular approach combined with phenotypic and morphological observations was used to delimit
Phaeoacremonium species involved in esca disease and grapevine declines. P. aleophilum and P. angustius were
synonymised, a new species P. viticola was reported and preliminary results concerning the delimitation of P. inflatipes
and P. parasiticum were presented. The incubation of isolates at 35°C appeared to be a discriminant character to
identify these two species, P. inflatipes having very low growth in comparison with P. parasiticum. Specific restriction
profiles were determined using the type strain of each species, and the method was applied to screen unidentified
isolates.
Characterization of Agglutinin-like Sequence Genes From Non-albicansCandida and Phylogenetic Analysis of the ALS Family (2001)

The ALS (agglutinin-like sequence) gene family of Candida albicans encodes cell-surface glycoproteins implicated in adhesion of the organism to host surfaces. Southern blot analysis with ALS-specific probes suggested the presence of ALS gene families in C. dubliniensis and C. tropicalis; three partial ALS genes were isolated from each organism. Northern blot analysis demonstrated that mechanisms governing expression of ALS genes in C. albicans and C. dubliniensis are different. Western blots with an anti-Als serum showed that cross-reactive proteins are linked by beta 1,6-glucan in the cell wall of each non-albicans Candida, suggesting similar cell wall architecture and conserved processing of Als proteins in these organisms. Although an ALS family is present in each organism, phylogenetic analysis of the C. albicans, C. dubliniensis, and C. tropicalis ALS genes indicated that, within each species, sequence diversification is extensive and unique ALS sequences have arisen. Phylogenetic analysis of the ALS and SAP (secreted aspartyl proteinase) families show that the ALS family is younger than the SAP family. ALS genes in C. albicans, C. dubliniensis, and C. tropicalis tend to be located on chromosomes that also encode genes from the SAP family, yet the two families have unexpectedly different evolutionary histories. Homologous recombination between the tandem repeat sequences present in ALS genes could explain the different histories for co-localized genes in a predominantly clonal organism like C. albicans.
Receptor mediated and fluid phase pathways for internalization of the ER Hsp90 chaperone GRP94 in murine macrophages (1999)

Immunization of mice with GRP94, the endoplasmic reticulum (ER) Hsp90, elicits cytotoxic T lymphocyte (CTL) responses to chaperone-bound, source cell-derived peptides. Elicitation of a CTL response requires that GRP94-associated peptides be transferred onto major histocompatability complex (MHC) class I molecules, a process that is postulated to accompany GRP94 internalization by antigen presenting cells, such as macrophages (Mphi) and dendritic cells (DC). In studies of GRP94 uptake in elicited Mphi, we report that Mphi display specific cell surface binding of GRP94, and that surface-bound GRP94 can be internalized via receptor mediated endocytosis. GRP94 internalized by this pathway co-localized predominately with transferrin-positive early endosomes. At time periods of up to 20 minutes, little trafficking of GRP94 to the lysosomal compartment was observed. When GRP94 was present in the medium, and thus accessible to both receptor-mediated and fluid phase internalization pathways, internalization was modestly inhibited in the presence of yeast mannan, a competitive inhibitor of mannose/fucose receptor activity, and substantially inhibited by dimethylamiloride, an inhibitor of macropinocytosis. GRP94 internalized via macropinocytosis did not display prominent co-staining with the lysosomal marker LAMP-2. These data identify multiple pathways of GRP94 internalization and indicate that receptor-dependent uptake of GRP94 is not dependent upon its high mannose oligosaccharide moiety. Most significantly, these data demonstrate the existence of cell surface receptor(s), apparently unique to antigen presenting cells, that function in the binding and internalization of the ER chaperone GRP94.
Tumor Cells Transduced with the MHC Class II Transactivator and CD80 Activate Tumor-Specific CD4+ T Cells Whether or Not They Are Silenced for Invariant Chain (2006)

The specificity and potency of the immune system make immunotherapy a potential strategy for the treatment of cancer. To exploit this potential, we have developed cell-based cancer vaccines consisting of tumor cells expressing syngeneic MHC class II and costimulatory molecules. The vaccines mediate tumor regression in mice and activate human CD4+ T cells in vitro. Previous vaccines were generated by transducing MHC II negative tumor cells with a single HLA-DR allele. Because expression of multiple MHC II alleles would facilitate presentation of a broader repertoire of tumor antigens, we have now transduced tumor cells with the MHC class II transactivator (CIITA), a regulatory gene that coordinately increases expression of all MHC II alleles. Previous studies in mice indicated that coexpression of the MHC II accessory molecule invariant chain (Ii) inhibited presentation of endogenously synthesized tumor antigens and reduced vaccine efficacy. To determine if Ii expression affects presentation of MHC class II-restricted endogenously synthesized tumor antigens in human tumor cells, HLA-DR-MCF10 breast cancer cells were transduced with the CIITA, CD80 costimulatory molecule gene, and with or without small interfering RNAs (siRNA) specific for Ii. Ii expression is silenced >95% in CIITA/CD80/siRNA transductants; down-regulation of Ii does not affect HLA-DR expression or stability; and Ii(+) and Ii(-) transductants activate human CD4+ T cells to DRB1*0701-restricted HER-2/neu epitopes. Therefore, tumor cells transduced with the CIITA, CD80, and with or without Ii siRNA present endogenously synthesized tumor antigens and are potential vaccines for activating tumor-specific CD4+ T cells.
Fine-scale deletion mapping of the distal long arm of chromosome 6 in 70 human ovarian cancers. (1992)

To define a small region on chromosome 6q containing a putative tumor suppressor gene for ovarian cancer, we examined loss of heterozygosity in 70 ovarian tumors of three histological types with nine restriction fragment length polymorphism markers located at 6q24-27. Among 33 cancers of serous type that were informative at one or more loci, 17 showed allelic loss at a few or all loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12 clear-cell tumors revealed loss of heterozygosity. This result supported our earlier suggestion that alteration of a gene on chromosome 6q may play an important role during development of serous ovarian tumors (Sato et al., Cancer Res., 51: 5118-5122, 1991). Frequent losses were observed between loci defined by CI6-119 (D6S195) at 6q26 and CI6-49 (D6S161) at 6q27. A detailed deletion map indicated a commonly deleted region between loci defined by CI6-111 (D6S193) and CI6-24 (D6S149); these two markers are estimated to be 1.9 cM apart on the basis of linkage analysis. Our results further define a region containing a tumor suppressor gene involved in ovarian carcinoma within an approximately 2-megabase-long segment of chromosome 6q.
Pharmacokinetics and metabolism of torasemide in man. (1988)

Torasemide (1-isopropyl-3-([4-(3-methyl-phenylamino)pyridine]-3- sulfonyl)urea) is a potent new loop diuretic. The pharmacokinetics, absolute bioavailability and metabolic disposition of torasemide have been studied after administration of a standard-release tablet to healthy volunteers. According to a latin square design 9 subjects received in random order single doses of either 20 mg i.v. over 1 h or 20 or 40 mg p.o. On each of the three occasions, torasemide and its metabolites were analysed in plasma and urine up to 24 h. From the results of urinary excretion and plasma AUC, the availability of torasemide from the tablet was 80% to 90%, i.e. nearly complete. The kinetics were linear with dose. The time of peak was reached at 1 h, the elimination half-life varied from 3 h to 4 h. None of the metabolites M1, M3 or M5 found in plasma exhibited a longer half-life. Only a quarter of the low systemic clearance of torasemide (41 ml/min) was accounted for by renal clearance. The distribution volume of 15.5 l was in the order of the extracellular fluid volume. The total amount of torasemide and metabolites recovered in urine was 83%, i.e. 25% torasemide, 11% M1, 3% M3 (both active), and 44% M5 (inactive). Therefore, M1 and M3 probably contribute to the diuretic action of torasemide. Since the renal clearances of the metabolites exceeded that of the parent drug, renal impairment may change their elimination kinetics.
Selective Interaction Between Proteins and the Outermost Surface of Polyelectrolyte Multilayers: Influence of the Polyanion Type, pH and Salt (2001)

Protein adsorption was studied by in-situ ATR-FT-IR spectroscopy of consecutively deposited polyelectrolyte multilayer systems terminated either with poly(ethyleneimine) (PEI) or polyanions, such as poly-(acrylic acid) (PAC), poly(maleic acid-co-propylene) (PMA-P) or poly(vinyl sulfate) (PVS). The influence of the polyanion type, pH and ionic strength was investigated. Negatively charged human serum albumin (HSA) was strongly repelled by multilayers terminated with weak polyanions (PAC, PMA-P), whereas moderate attraction was observed for those terminated with the strong polyanion PVS. Changing the pH from 7.4 to 5 resulted in enhanced HSA adsorption onto PAC-terminated multilayers. An increase in ionic strength diminished the attractive HSA adsorption onto PEI-terminated multilayers. For the PEI/PAC system, the biomedically relevant adsorption of human fibrinogen (FGN) is determined via its isoelectric point in accordance with three other proteins.
Transforming Growth Factor β Can Stimulate Smad1 Phosphorylation Independently of Bone Morphogenic Protein Receptors (2009)

Transforming growth factor-beta (TGFbeta) superfamily ligands control a diverse set of cellular processes by activating type I and type II serine-threonine receptor kinases. Canonical TGFbeta signaling is mediated via the TbetaRI/ALK5 type I receptor that phosphorylates Smad2 and Smad3 in their SXS motif to facilitate their activation and subsequent role in transcriptional regulation. Canonical bone morphogenic protein (BMP) signaling is mediated via the ALK1/2/3/6 type I receptors that phosphorylate Smad1, Smad5, and Smad8 in their SXS motif. However, studies in endothelial cells have shown that TGFbeta can also lead to the phosphorylation of Smad1, dependent on ALK1 receptor activity. Here we present data showing that TGFbeta can significantly induce Smad1 phosphorylation in several non-endothelial cell lineages. Additionally, by using chemical inhibitors specific for the TGFbeta/activin/nodal (ALK4/5/7) and BMP (ALK1/2/3/6) type I receptors, we show that in some cell types TGFbeta induces Smad1 phosphorylation independently of the BMP type I receptors. Thus, TGFbeta-mediated Smad1 phosphorylation appears to occur via different receptor complexes in a cell type-specific manner.
A Phase I trial of bryostatin-1 in children with refractory solid tumors: a Pediatric Oncology Group study. (1999)

Bryostatin-1, a macrocyclic lactone, appears to elicit a wide range of biological responses including modulation of protein kinase C (PKC). PKC, one of the major elements in the signal transduction pathway, is involved in the regulation of cell growth, differentiation, gene expression, and tumor promotion. Because of the potential for a unique mechanism of interaction with tumorgenesis, a Phase I trial of bryostatin-1 was performed in children with solid tumors to: (a) establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); (b) establish the pharmacokinetic profile in children; and (c) document any evidence of antitumor activity. A 1-h infusion of bryostatin-1 in a PET formulation (60% polyethylene glycol 400, 30% ethanol, and 10% Tween 80) was administered weekly for 3 weeks to 22 children (age range, 2-21 years) with malignant solid tumors refractory to conventional therapy. Doses ranged from 20 to 57 microg/m2/ dose. Pharmacokinetics were performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. Twenty-two patients on five dose levels were evaluable for toxicities. At the 57 microg/m2/dose level dose-limiting myalgia (grade 3) was observed in three patients; two of those patients also experienced photophobia or eye pain, and one experienced headache. Symptoms occurred in all patients within 24-72 h after the second dose of bryostatin-1 with resolution within 1 week of onset. Other observed toxicities (grades 1 and 2) included elevation in liver transaminases, thrombocytopenia, fever, and flu-like symptoms. The bryostatin-1 infusion was typically well tolerated. Although stable disease was noted in several patients, no complete or partial responses were observed. The recommended Phase II dose of bryostatin-1 administered as a 1-h infusion weekly for 3 of every 4 weeks to children with solid tumors is 44 microg/m2/dose. Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.
Cell-based assays for high-throughput screening (2006)

The fifth international World Pharmaceutical Congress was organised by the Cambridge Healthtech Institute and contained six concurrent conferences in parallel. This report focuses on the third annual conference: 'Cell-based assays for HTS'. The major topics of this meeting were technologies for setting up screening assays, cells as biological reagents for screening campaigns, three-dimensional cell culture and the use of stem cells for drug screening. Technology-based presentations focused on the latest developments for cell-based screening, such as the open microscopy environment, a cell culture array as a kind of 'cell culture on a chip', a cellular microarray for analysing the binding behaviour of cells and aptamer technology. Further talks described success stories using the β-galactosidase enzyme fragment complementation assays from Applied Biosystems (InteraX) and from DiscoveRx for the drug discovery process. Other presentations focused on the Cell Sensor Technology from Invitrogen and a dual luciferase-based technology for G-protein-coupled receptors from Promega. One talk presented a comparison of fluorometric laser imaging plate reader system and ion works devices for ion channel-based assays, as well as the challenges facing high-throughput screening (HTS) of ligand gated ion channels. Two lectures highlighted the growing role of three-dimensional cell culture and the potential use for drug discovery. A key point of interest was also the role of cells as a reagent in an HTS environment and the attempts made by different companies to overcome issues for cell-based screening campaigns. In this context, several talks focused on the use of frozen and/or division-arrested cells for drug discovery processes. An interesting topic, the use of stem cells in the drug discovery process, was covered by two presentations.
Kinesin Walks Hand-Over-Hand (2003)

Kinesin is a processive motor that takes 8.3-nm center-of-mass steps along microtubules for each adenosine triphosphate hydrolyzed. Whether kinesin moves by a “hand-over-hand” or an “inchworm” model has been controversial. We have labeled a single head of the kinesin dimer with a Cy3 fluorophore and localized the position of the dye to within 2 nm before and after a step. We observed that single kinesin heads take steps of 17.3 ± 3.3 nm. A kinetic analysis of the dwell times between steps shows that the 17-nm steps alternate with 0-nm steps. These results strongly support a hand-over-hand mechanism, and not an inchworm mechanism. In addition, our results suggest that kinesin is bound by both heads to the microtubule while it waits for adenosine triphosphate in between steps.
Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival (2012)

Hypoxia in the microenvironment of many solid tumours is an important determinant of malignant progression. The ISR (integrated stress response) protects cells from the ER (endoplasmic reticulum) stress caused by severe hypoxia. Likewise, autophagy is a mechanism by which cancer cells can evade hypoxic cell death. In the present paper we report that the autophagy-initiating kinase ULK1 (UNC51-like kinase 1) is a direct transcriptional target of ATF4 (activating transcription factor 4), which drives the expression of ULK1 mRNA and protein in severe hypoxia and ER stress. We demonstrate that ULK1 is required for autophagy in severe hypoxia and that ablation of ULK1 causes caspase-3/7-independent cell death. Furthermore, we report that ULK1 expression is associated with a poor prognosis in breast cancer. Collectively, the findings of the present study identify transcriptional up-regulation of ULK1 as a novel arm of the ISR, and suggest ULK1 as a potentially effective target for cancer therapy.
Circulating tumor cells: approaches to isolation and characterization (2011)

Circulating tumor cells (CTCs) shed from primary and metastatic cancers are admixed with blood components and are thus rare, making their isolation and characterization a major technological challenge. CTCs hold the key to understanding the biology of metastasis and provide a biomarker to noninvasively measure the evolution of tumor genotypes during treatment and disease progression. Improvements in technologies to yield purer CTC populations amenable to better cellular and molecular characterization will enable a broad range of clinical applications, including early detection of disease and the discovery of biomarkers to predict treatment responses and disease progression.
Gastrointestinal involvement in leukocytoclastic vasculitis and polyarteritis nodosa. (1981)

The records of 106 consecutive patients referred to the University of Colorado Medical Center (UCMC) vasculitis study group during a 5-yr period were evaluated for gastrointestinal (GI) manifestations attributable to vasculitis. There were 3 groups: 18 with leukocytoclastic vasculitis (LCV) on skin biopsy younger than 16 yr of age; 75 with LCV older than 16 yr of age; and 13 with polyarteritis nodosa (PAN). Significant GI manifestations at presentation or exacerbation of vasculitis occurred in 38 of 106 (36%) patients. These were more frequent in LCV patients younger than 16 yr (66%), than older LCV patients (26%) or PAN patients (46%). The commonest complaint was abdominal pain (79%), followed by nausea (63%), vomiting (37%) and diarrhea (23%). GI bleeding was present in 52% and acute abdomen in 21% of patients. No consistent radiologic findings were noted. Duodenal and peritoneal biopsies suggested vasculitis in 6 LCV patients. Seven exploratory laparotomies were performed in 4 LCV and 3 PAN patients. Intestinal infarction was found in 3 patients with PAN, but in one of the LCV patients. Two patients with LCV with an acute abdomen were not explored and responded promptly to iv corticosteroids. Thus, systemic vasculitis frequently involves the GI tract. In patients with LCV, recognition of this association and treatment with corticosteroids can avoid surgery. In our patients with PAN, however, acute abdominal signs indicated infarction requiring surgery and resection.