gebhart/patrepeval huggingface dataset:
Molecular mechanism for inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase by rosuvastatin (2003)

The statins are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (HMG-CoAR), and are utilized to decrease levels of atherogenic lipoproteins in patients with, or who are at high risk of, cardiovascular disease. This study describes the inhibition of a recombinant, catalytic fragment of human HMG-CoAR by a new statin, rosuvastatin (CRESTOR(R)). Binding is reversible and involves an initial complex [inhibition constant involving the enzyme-inhibitor complex (E.I), K (i), approximately 1 nM], which undergoes a slow transition ( t ((1/2)) to reach steady state is 33-360 s) to give tighter association [steady-state inhibition constant involving E.I and the second E.I complex in a two-step mechanism (E.I*), K (i)*, approximately 0.1 nM]. At steady state, rosuvastatin is at least as potent as atorvastatin, cerivastatin and simvastatin. It is more potent than fluvastatin and pravastatin. For rosuvastatin, inhibition kinetics are competitive with respect to HMG-CoA and non-competitive when NADPH is varied. At 37 degrees C, binding is linked to a large favourable enthalpy change [Delta H degrees =-69.0 kJ/mol (-16.5 kcal/mol)] and a small entropic penalty [ T Delta S degrees =-9.6 kJ/mol (-2.3 kcal/mol)]. These characteristics, and the high affinity relative to that of 3 S -HMG-CoA ( K (d) approximately 6.6 microM), are discussed in relation to the crystal structures of complexes with HMG-CoAR.
E-Cadherin Suppresses Cellular Transformation by Inhibiting β-Catenin Signaling in an Adhesion-Independent Manner (2001)

E-cadherin is a tumor suppressor protein with a well-established role in cell-cell adhesion. Adhesion could contribute to tumor suppression either by physically joining cells or by facilitating other juxtacrine signaling events. Alternatively, E-cadherin tumor suppressor activity could result from binding and antagonizing the nuclear signaling function of beta-catenin, a known proto-oncogene. To distinguish between an adhesion- versus a beta-catenin signaling-dependent mechanism, chimeric cadherin constructs were expressed in the SW480 colorectal tumor cell line. Expression of wild-type E-cadherin significantly inhibits the growth of this cell line. Growth inhibitory activity is retained by all constructs that have the beta-catenin binding region of the cytoplasmic domain but not by E-cadherin constructs that exhibit adhesive activity, but lack the beta-catenin binding region. This growth suppression correlates with a reduction in beta-catenin/T cell factor (TCF) reporter gene activity. Importantly, direct inhibition of beta-catenin/TCF signaling inhibits the growth of SW480 cells, and the growth inhibitory activity of E-cadherin is rescued by constitutively activated forms of TCF. Thus, the growth suppressor activity of E-cadherin is adhesion independent and results from an inhibition of the beta-catenin/TCF signaling pathway, suggesting that loss of E-cadherin expression can contribute to upregulation of this pathway in human cancers. E-cadherin-mediated growth suppression was not accompanied by overall depletion of beta-catenin from the cytosol and nucleus. This appears to be due to the existence of a large pool of cytosolic beta-catenin in SW480 cells that is refractory to both cadherin binding and TCF binding. Thus, a small pool of beta-catenin that can bind TCF (i.e., the transcriptionally active pool) can be selectively depleted by E-cadherin expression. The existence of functionally distinct pools of cytosolic beta-catenin suggests that there are mechanisms to regulate beta-catenin signaling in addition to controlling its level of accumulation.
ChemInform Abstract: Non‐Steroidal Antiinflammatory Agents. Part 5. Basic Esters of Indometacin. (1991)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Complexity of COX-2 gene regulation (2008)

Overexpression of the enzyme COX-2 (cyclo-oxygenase-2) is associated with various pathophysiological conditions, including inflammatory diseases and different cancers. Increased synthesis of COX-2 in fetal membranes and the myometrium is also linked with the onset of term and preterm labour. COX-2 gene regulation is controlled at various levels including gene transcription and post-transcriptional events. The present article focuses on the complexity of COX-2 gene regulation and reviews current concepts that highlight: (i) transcription of COX-2 is induced rapidly and transiently in response to a plethora of stimuli; (ii) COX-2 mRNA stability and translational efficiency is governed by multiple regulatory elements within the 3'-untranslated region; (iii) specific microRNAs and RNA-binding proteins influence COX-2 mRNA stability; and (iv) regulation of COX-2 involves alternative polyadenylation.
A DSA-Based Method Using Contrast-Motion Estimation for the Assessment of the Intra-Aneurysmal Flow Changes Induced by Flow-Diverter Stents (2012)

The MAFA ratio based on DSA flow quantification appears to be a reliable predictor for the assessment of stent treatment outcomes in this small study. These results open the door for perioperative flow quantification and provide indices that may help clinicians make appropriate intraprocedural decisions.
Current and emerging drugs for the treatment of inflammatory bowel disease (2011)

During the last decade a large number of biological agents against tumor necrosis factor-α (TNF-α), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-α inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn's disease and ulcerative colitis.
Antigen Processing Defects in Cervical Carcinomas Limit the Presentation of a CTL Epitope from Human Papillomavirus 16 E6 (2001)

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with the development of cervical cancer. The E6 and E7 proteins of HPV are constitutively expressed in cervical carcinoma cells making them attractive targets for CTL-based immunotherapy. However, few studies have addressed whether cervical carcinomas can process and present HPV E6/E7-derived Ags for recognition by CTL. We generated HLA-A*0201-restricted CTL clones against HPV16 E6(29-38) that recognized HPV16 E6 Ags transfected into B lymphoblastoid cells. These CTL were unable to recognize HLA-A*0201(+) HPV16 E6(+) cervical carcinoma cell lines even when the level of endogenous HPV16 E6 in these cells was increased by transfection. This defect in presentation of HPV16 E6(29-38) correlated with low level expression of HLA class I, proteasome subunits low molecular mass protein 2 and 7, and the transporter proteins TAP1 and TAP2 in the cervical carcinoma cell lines. The expression of all of these proteins could be up-regulated by IFN-gamma, but this was insufficient for CTL recognition unless the level of HPV16 E6 Ag was also increased by transfection. CTL recognition of the HPV16 E6(29-38) epitope in 721.174 B cells was dependent on TAP expression but independent of immunoproteasome expression. Collectively, these findings suggest that presentation of the HPV16 E6(29-38) epitope in cervical carcinoma cell lines is limited both by the level of TAP expression and by the low level or availability of the source HPV E6 oncoprotein. These observations place constraints on the use of this, and potentially other, HPV-derived CTL epitopes for the immunotherapy of cervical cancer.
Pulmonary Penetration of Alpha 1 -Proteinase Inhibitor Administered Parenterally to Dogs (1987)

To study the penetration of alpha 1-proteinase inhibitor (A1Pl) into the lungs of healthy dogs, 83 mg/kg of active A1Pl was administered intravenously over 30 min followed by a bolus of 131I-A1Pl. Animals were lavaged 2 to 72 h after infusion, sequential gamma camera scans were acquired, and urine was analyzed for the excretion of desmosine. After a distribution phase, infused A1Pl left the bloodstream with a half-life of 103 +/- 24 h. Analysis of plasma antiprotease activity demonstrated preservation of function of the infused A1Pl. Lavage fluid A1Pl concentration and activity were significantly increased 24 h after infusion. Gamma camera scans demonstrated that lung, liver, and spleen acquired 131I-A1Pl similarly; radioactivities per gram of tissue of these organs were similar at autopsy. Excretion of desmosine did not decrease from a baseline of 157 +/- 59 nmol/24 h after A1Pl infusion, indicating no effect of A1Pl infusion on background elastolysis. These data suggest that intravenous administration of A1Pl can raise lung antiproteinase levels within 24 h despite the absence of preferential uptake by the lung of the infused protein.
OBSERVATIONS ON HALLUX VALGUS (1951)

A survey of this type cannot be used to point to any definite factor or factors predisposing to the development of hallux valgus. Nevertheless, a comparison of measurements in the morbid and control groups shows several outstanding differences: 1) There was a high degree of correlation between valgus and intermetatarsal angle in the two groups combined (coefficient, 0Â·7) but the correlation was higher in those cases with a degree of valgus greater than 25 degrees than in the remainder (coefficients, 0Â·36 and 0Â·53). 2) In the control group the first metatarsal was longer than tile second by a mean measure of 2 millimetres; in the morbid group by a mean measure of 4 millimetres. For a high degree of valgus and a low intermetatarsal angle the first metatarsal tends to be longer than the second by a significantly greater amount than when the high valgus is associated with iligh intermetatarsal angle. 3) In 90 per cent of the control cases there was a lateral displacement of the medial sesamoid of the first metatarsal of 3 degrees or less, whereas 88 per cent of the morbid group showed a displacement of 4 degrees or more. There was very little overlap in the distributions of this observation in the two groups. There was a high correlation between the degree of this displacement and the severity of hallux valgus. 4) Rotation of the hallux was not observed among the controls; in the morbid group those cases showing rotation had an average degree of valgus of 36 degrees while the rest had an average of 19 degrees. The mean degree of valgus in the morbid group was 32Â·0 degrees and that of the controls 15Â·5 degrees. The mean angle between the axes of the first and second metatarsals was 13Â·0 degrees in the morbid group and 8Â·5 degrees in the controls. Since tile morbid group consisted largely of women (98 per cent) it is important to know that in the control group the only measure showing a statistically significant sex difference is that of intermetatarsal angle, but that, even so, the mean difference is only 1Â·3 degrees. Thus tile sex difference between the two groups is probably only of minor importance. The role of age in influencing the observations cannot be clearly elucidated from the data at present available. It can only be stated that there is no positive indication that age is a controlling factor in the departure observed in the morbid group from the control observations.
Glutamine Synthetase in the Phloem Plays a Major Role in Controlling Proline Production (1999)

, , Anis M. Limami, Maud Lelandais, Yvette Roux, Rajbir S. Sangwan, Bertrand Hirel, Glutamine Synthetase in the Phloem Plays a Major Role in Controlling Proline Production, The Plant Cell, Vol. 11, No. 10 (Oct., 1999), pp. 1995-2011
Small-molecule pan-IAP antagonists: a patent review (2010)

The feasibility of disrupting IAP protein interactions with pro-apoptotic proteins using monovalent and bivalent Smac-derived peptidomimetic compounds has been broadly established. Four such compounds have entered or been approved to enter human clinical trials, which will hopefully allow the utility of this potential therapeutic approach to be evaluated in cancer patients.
Adaptive protocols for information dissemination in wireless sensor networks (1999)

In this paper, we present a family of adaptive protocols, called SPIN (Sensor Protocols for Information via Negotiation), that efficiently disseminates information among sensors in an energy-constrained wireless sensor network. Nodes running a SPIN communication protocol name their data using high-level data descriptors, called meta-data. They use meta-data negotiations to eliminate the transmission of redundant data throughout the network. In addition, SPIN nodes can base their communication decisions both upon application-specific knowledge of the data and upon knowledge of the resources that are available to them. This allows the sensors to efficiently distribute data given a limited energy supply. We simulate and analyze the performance of two specific SPIN protocols, comparing them to other possible approaches and a theoretically optimal protocol. We find that the SPIN protocols can deliver 60% more data for a given amount of energy than conventional approaches. We also find that, in terms of dissemination rate and energy usage, the SPlN protocols perform close to the theoretical optimum.
Mapping PAM4 (clivatuzumab), a monoclonal antibody in clinical trials for early detection and therapy of pancreatic ductal adenocarcinoma, to MUC5AC mucin (2013)

These data implicate MUC5AC as a specific mucin species to which PAM4 is reactive. Furthermore, this realization may allow for the improvement of the current PAM4 serum-based immunoassay for detection of early-stage PDAC by the application of anti-MUC5AC MAbs as probes in this sandwich EIA.
Cannabinoids Inhibit N- and P/Q-Type Calcium Channels in Cultured Rat Hippocampal Neurons (1997)

Cannabinoids and their analogues have been found to inhibit N- and P/Q-type Ca2+ currents in cell lines and sympathetic neurons transfected with cannabinoid CB1 receptor. However, the effects of cannabinoids on Ca2+ currents in the CNS are largely unexplored. In this study we investigated whether these compounds inhibit Ca2+ channels in cultured rat hippocampal neurons. With the use of antibodies directed against the amino-terminus of the CB1 receptor, we found that in 5-day cultures pyramidally shaped neurons expressed somatic CB1 receptors, whereas in 4-wk cultures the receptor was predominately located on neurites. In early cultures, the cannabimimetic WIN 55,212-2 reversibly inhibited whole cell Ba2+ current in a concentration-dependent (K(1/2) = 21 nM) and pertussis-toxin-sensitive fashion. Inhibition was reduced by the CB1 antagonist SR141716. The current was unaffected by the nonpsychoactive enantiomer WIN 55,212-3. Maximal inhibition by the nonclassical cannabinoid agonist CP 55,940 and by an endogenous cannabinoid, anandamide, were similar to that seen with maximal concentrations of WIN 55,212-2. The Ba2+ current modulated by cannabinoids was carried by N-type (omega-conotoxin-GVIA-sensitive) and P/Q-type (omega-conotoxin-MVIIC-sensitive) channels. These results demonstrate cannabinoid-receptor-mediated inhibition of distinct Ca2+ channels in central neurons. Because the channels that underlie these currents are chiefly located presynaptically, and are required for evoked neurotransmitter release, our results suggest a major role for cannabinoids (endogenous and exogenous) in the modulation of synaptic transmission at CNS synapses.
Identification of Direct Genomic Targets Downstream of the Nuclear Factor-κB Transcription Factor Mediating Tumor Necrosis Factor Signaling (2005)

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that controls expression of inflammatory genetic networks. Although the nuclear factor-kappaB (NF-kappaB) pathway is crucial for mediating cellular TNF responses, the complete spectrum of NF-kappaB-dependent genes is unknown. In this study, we used a tetracycline-regulated cell line expressing an NF-kappaB inhibitor to systematically identify NF-kappaB-dependent genes. A microarray data set generated from a time course of TNF stimulation in the presence or absence of NF-kappaB signaling was analyzed. We identified 50 unique genes that were regulated by TNF (Pr(F)<0.001) and demonstrated a change in signal intensity of+/-3-fold relative to control. Of these, 28 were NF-kappaB-dependent, encoding proteins involved in diverse cellular activities. Quantitative real-time PCR assays of eight characterized NF-kappaB-dependent genes and five genes not previously known to be NF-kappaB-dependent (Gro-beta and-gamma, IkappaBepsilon, interleukin (IL)-7R, and Naf-1) were used to determine whether they were directly or indirectly NF-kappaB regulated. Expression of constitutively active enhanced green fluorescent.NF-kappaB/Rel A fusion protein transactivated all but IL-6 and IL-7R in the absence of TNF stimulation. Moreover, TNF strongly induced all 12 genes in the absence of new protein synthesis. High probability NF-kappaB sites in novel genes were predicted by binding site analysis and confirmed by electrophoretic mobility shift assay. Chromatin immunoprecipitation assays show the endogenous IkappaBalpha/epsilon, Gro-beta/gamma, and Naf-1 promoters directly bound NF-kappaB/Rel A in TNF-stimulated cells. Together, these studies systematically identify the direct NF-kappaB-dependent gene network downstream of TNF signaling, extending our knowledge of biological processes regulated by this pathway.
A rapid and accurate approach to identify single nucleotide polymorphisms of mitochondrial DNA using MALDI-TOF mass spectrometry (2008)

Possible fields which could benefit from this powerful and sensitive tool include forensic medicine, tracing of matrilineage, transplantation immunology, transfusion medicine, the diagnosis of mtDNA mutation related disorders, and the research regarding aging, apoptosis and carcinogenesis based on physiologic and pathogenic alterations of mtDNA for the analysis of large-scale samples, multiple SNPs or rare mtDNA.
Enzymatic phosphatidylcholine hydrolysis in organic solvents: An examination of selected commercially available lipases (1994)

Abstract Eight commercial lipase preparations were examined for the ability to hydrolyze phosphatidylcholine (PC) in hexane solutions. Only the enzymes from Humicola lanuginosa, Rhizopus delemar and Candida rugosa displayed appreciable activity. Solvent polarity was the largest single factor affecting activity. The H. lanuginosa sample was most active in polar solvents. The R. delemar preparation was most active in polar (2‐hexamone) and nonpolar (decane) solvents and least active in solvents of intermediate polarity (hexane). The solvent dependence of the activity of the C. rugosa enzyme varied with the ratio of substrate to enzyme. Different degrees of activity were retained by the three enzymes after passive immobilization on Celite, controlled‐pore glass, polypropylene and Amberlite XAD‐7 resins. No single resin yielded the best retained activity for all three preparations. When examined in 2‐octanone, hexane and isooctane, the Celite‐immobilized R. delemar and H. lanuginosa enzymes exhibited highest activity in 2‐octanone, while immobilized C. rugosa was most active in isooctane. The water content at which maximum activity was observed was relatively independent of solvent polarity and the amount of catalyst but was proportional to the amount of PC in the reaction. The retention of activity by immobilized Rhizomucor miehei lipase (Lipozyme) during multiple hydrolytic cycles required a reduction in the water content of the system below that yielding optimal activity in a single cycle.
N-Linked glycosylation of a baculovirus-expressed recombinant glycoprotein in insect larvae and tissue culture cells (1998)

The potential of insect cell cultures and larvae infected with recombinant baculoviruses to produce authentic recombinant glycoproteins cloned from mammalian sources was investigated. A comparison was made of the N-linked glycans attached to secreted alkaline phosphatase (SEAP) produced in four species of insect larvae and their derived cell lines plus one additional insect cell line and larvae of one additional species. These data survey N-linked oligosaccharides produced in four families and six genera of the order Lepidoptera. Recombinant SEAP expressed by recombinant isolates of Autographa californica and Bombyx mori nucleopolyhedroviruses was purified from cell culture medium, larval hemolymph or larval homogenates by phosphate affinity chromatography. The N-linked oligosaccharides were released with PNGase-F, labeled with 8-aminonaphthalene-1-3-6-trisulfonic acid, fractionated by polyacrylamide gel electrophoresis, and analyzed by fluorescence imaging. The oligosaccharide structures were confirmed with exoglycosidase digestions. Recombinant SEAP produced in cell lines of Lymantria dispar (IPLB-LdEIta), Heliothis virescens (IPLB-HvT1), and Bombyx mori (BmN) and larvae of Spodoptera frugiperda, Trichoplusia ni , H.virescens , B.mori , and Danaus plexippus contained oligosaccharides that were structurally identical to the 10 oligosaccharides attached to SEAP produced in T.ni cell lines. The oligosaccharide structures were all mannose-terminated. Structures containing two or three mannose residues, with and without core fucosylation, constituted more than 75% of the oligosaccharides from the cell culture and larval samples.
Hepatic Differentiation of Mouse Embryonic Stem Cells in Three-Dimensional Polymer Scaffolds (2009)

Embryonic stem cells (ESCs) can have unlimited proliferation potential and the capability to differentiate into almost all types of tissues. The use of ESCs as a novel source of hepatocytes has therefore recently received much attention. To date, however, the efficient and mass differentiation of ESCs into hepatocytes in vitro has been proven to be difficult. In this study, we investigated a three-dimensional (3D) mouse ESC hepatic differentiation system. Cells derived from 5-day-old embryoid bodies were mixed with Matrigel and immediately seeded in a biodegradable polymer scaffold composed of poly-l-lactic acid and polyglycolic acid. Exogenous growth factors and hormones were added sequentially for 20 days to promote hepatic histogenesis. The system enabled spontaneous spheroid formation and mass cultivation of embryoid body-derived cells. The 3D differentiated hepatocyte-like cells were able to express several liver-specific markers and proteins, secrete albumin, store glycogen, and allow the uptake of low-density lipoproteins. These findings suggest that this supportive 3D environment with appropriate inducing factors could provide mouse ESC-derived cells with an environment closely mimicking that of hepatogenesis in vivo.