gebhart/patrepeval huggingface dataset:
STAT-3 Inhibitors: State of the Art and New Horizons for Cancer Treatment (2011)

The signal transducers and activators of transcription (STATs) include a class of cytoplasmic signaling proteins whose role in the regulation of cell growth and survival is mediated by phosphorylation of a critical tyrosine residue within the STAT protein. This occurs in response to cytokines and growth factors modulating the expression of specific target genes. In particular, phosphorylation induces STAT:STAT dimer formation between two monomers, via reciprocal phosphoTyr (pTyr)-SH2 domain interactions. To date, seven members of the STAT family, all with different roles, have been identified in mammals. After dimerization, phosphorylated STATs enter the nucleus and, working co-ordinately with other transcriptional co-activators and transcription factors, induce increased transcriptional initiation. In healthy human and animal cells, ligand-dependent activation of STATs is a transient process, lasting for several minutes to several hours. In contrast, in many cancerous cell lines and tumors, where growth factor dysregulation is frequently at the heart of cellular transformation, the STAT proteins (in particular STAT1, 3 and 5) are persistently tyrosine-phosphorylated or activated; abnormal levels of STAT3 activation have been observed in breast, ovarian, prostate, hematological and head and neck cancer cell lines. Thus, in this review, we examine the most important classes of agents designed to disrupt STAT3 signaling, with particular regard to STAT3 dimerization inhibitors, which could play a significant role in the future of cancer and adjuvant cancer therapies.
Activation Mechanism for CRAC Current and Store-operated Ca2+ Entry (2006)

Here we tested the role of calcium influx factor (CIF) and calcium-independent phospholipase A2 (iPLA2) in activation of Ca2+ release-activated Ca2+ (CRAC) channels and store-operated Ca2+ entry in rat basophilic leukemia (RBL-2H3) cells. We demonstrate that 1) endogenous CIF production may be triggered by Ca2+ release (net loss) as well as by simple buffering of free Ca2+ within the stores, 2) a specific 82-kDa variant of iPLA2beta and its corresponding activity are present in membrane fraction of RBL cells, 3) exogenous CIF (extracted from other species) mimics the effects of endogenous CIF and activates iPLA2beta when applied to cell homogenates but not intact cells, 4) activation of ICRAC can be triggered in resting RBL cells by dialysis with exogenous CIF, 5) molecular or functional inhibition of iPLA2beta prevents activation of ICRAC, which could be rescued by cell dialysis with a human recombinant iPLA2beta, 6) dependence of ICRAC on intracellular pH strictly follows pH dependence of iPLA2beta activity, and 7) (S)-BEL, a chiral enantiomer of suicidal substrate specific for iPLA2beta, could be effectively used for pharmacological inhibition of ICRAC and store-operated Ca2+ entry. These findings validate and significantly advance our understanding of the CIF-iPLA2-dependent mechanism of activation of ICRAC and store-operated Ca2+ entry.
High Sensitivity Detection of Plasma Proteins by Multiple Reaction Monitoring of N-Glycosites (2007)

The detection and quantification of plasma (serum) proteins at or below the ng/ml concentration range are of critical importance for the discovery and evaluation of new protein biomarkers. This has been achieved either by the development of high sensitivity ELISA or other immunoassays for specific proteins or by the extensive fractionation of the plasma proteome followed by the mass spectrometric analysis of the resulting fractions. The first approach is limited by the high cost and time investment for assay development and the requirement of a validated target. The second, although reasonably comprehensive and unbiased, is limited by sample throughput. Here we describe a method for the detection of plasma proteins at concentrations in the ng/ml or sub-ng/ml range and their accurate quantification over 5 orders of magnitude. The method is based on the selective isolation of N-glycosites from the plasma proteome and the detection and quantification of targeted peptides in a quadrupole linear ion trap instrument operated in the multiple reaction monitoring (MRM) mode. The unprecedented sensitivity of the mass spectrometric analysis of minimally fractionated plasma samples is the result of the significantly reduced sample complexity of the isolated N-glycosites compared with whole plasma proteome digests and the selectivity of the MRM process. Precise quantification was achieved via stable isotope dilution by adding (13)C- and/or (15)N-labeled reference analytes. We also demonstrate the possibility of significantly expanding the number of MRM measurements during one single LC-MS run without compromising sensitivity by including elution time constraints for the targeted transitions, thus allowing quantification of large sets of peptides in a single analysis.
Formal requirements for virtualizable third generation architectures (1974)

Virtual machine systems have been implemented on a limited number of third generation computer systems, e.g. CP-67 on the IBM 360/67. From previous empirical studies, it is known that certain third generation computer systems, e.g. the DEC PDP-10, cannot support a virtual machine system. In this paper, model of a third-generation-like computer system is developed. Formal techniques are used to derive precise sufficient conditions to test whether such an architecture can support virtual machines.
Minimum Volume Embedding (2007)

Minimum Volume Embedding (MVE) is an algorithm for non-linear dimensionality reduction that uses semidefinite programming (SDP) and matrix factorization to find a low-dimensional embedding that preserves local distances between points while representing the dataset in many fewer dimensions. MVE follows an approach similar to algorithms such as Semidefinite Embedding (SDE), in that it learns a kernel matrix using an SDP before applying Kernel Principal Component Analysis (KPCA). However, the objective function for MVE directly optimizes the eigenspectrum of the data to preserve as much of its energy as possible within the few dimensions available to the embedding. Simultaneously, remaining eigenspectrum energy is minimized in directions orthogonal to the embedding thereby keeping data in a so-called minimum volume manifold. We show how MVE improves upon SDE in terms of the volume of the preserved embedding and the resulting eigenspectrum, producing better visualizations for a variety of synthetic and real-world datasets, including simple toy examples, face images, handwritten digits, phylogenetic trees, and social networks. 1
Optimizing clinical use of mesalazine (5-aminosalicylic acid) in inflammatory bowel disease (2011)

Mesalazine [5-aminosalicylic acid (5-ASA)] has been used for over 30 years in the treatment of inflammatory bowel disease (IBD). It is a highly effective, safe, and well-tolerated drug for treatment of mild to moderate ulcerative colitis, which represents most patients with this disease. Recent studies of patient adherence to 5-ASA therapies in ulcerative colitis have highlighted the need for regimens that enable long-term compliance to significantly reduce the risk of troublesome and debilitating flares in the short term, and possibly colon cancer in the long term. Indeed, much of the recent innovation in clinical use of 5-ASA in colitis has come from studies of novel delivery mechanisms and simplified oral dosing schedules. These studies have provided much needed clarity on essential matters such as starting dose, dose escalation, and efficacy in terms of the ideal clinical endpoint - mucosal healing. Various manufacturers are re-evaluating their products to determine the safety and efficacy of such dosing regimens. Although once widely employed in the treatment of Crohn's disease (CD), the accumulated body of evidence now suggests that there is a much more limited role for 5-ASA in this particular form of inflammatory bowel disease. Recent 5-ASA randomized-controlled trials, comparative studies, and outcomes research have led to refined treatment strategies and awareness for practitioners to better inform, engage and facilitate patients in optimal use of 5-ASA in inflammatory bowel disease.
Trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: a highly potent selective dopamine D1 full agonist (1990)

trans-10,11-Dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenan thridine (4a, dihydrexidine) has been found to be a highly potent and selective agonist of the dopamine D1 receptor in rat brain. Dihydrexidine had an EC50 of approximately 70 nM in activating dopamine-sensitive rat striatal adenylate cyclase and a maximal stimulation equal to or slightly greater than that produced by dopamine. Dihydrexidine had an IC50 of 12 nM in competing for [3H]SCH23390 (1a) binding sites in rat striatal homogenate, and of 120 nM versus [3H]spiperone. These data demonstrate that dihydroxidine has about ten-fold selectivity for D1/D2 receptors. More importantly, however, is the fact that dihydrexidine is a full agonist. Previously available agents, such as SKF38393 (1b), while being somewhat more selective for the D1 receptor, are only partial agonists. The isomeric cis-dihydroxybenzo[a]-phenanthridine neither stimulated cAMP synthesis nor inhibited the cAMP synthesis induced by dopamine. The cis isomer also lacked appreciable affinity for [3H]-1a binding sites. N-Methylation of the title compound decreased affinity for D1 sites about 7-8-fold and markedly decreased ability to stimulate adenylate cyclase. Addition of an N-n-propyl group reduced affinity for D1 sites by about 50-fold and essentially abolished the ability to stimulate adenylate cyclase. However, this latter derivative had twice the affinity of the D2-selective agonist quinpirole for the D2 receptor. The results are discussed in the context of a conceptual model for the agonist state of the D1 receptor.
Use of the Gottingen Minipig as a Model of Diabetes, with Special Focus on Type 1 Diabetes Research (2004)

Animal models of type 1 diabetes remain essential tools for investigation of the etiology and pathogenesis of the disease and, importantly, for the development of effective new treatments. Although a range of well-characterized and widely used models of type 1 diabetes in rodents are currently available, large animal models are a valuable complement to rodent models for both physiological and practical reasons. The pig is very useful in many aspects as a model for human physiology and pathophysiology because many organ systems of this species, as well as physiological and pathophysiological responses, resemble those of the human. The Göttingen minipig is particularly suitable for long-term studies because of its inherent small size and ease of handling, even at full maturity. Of particular relevance to the field of type 1 diabetes are the many similarities evident between humans and pigs with regard to pharmacokinetics of compounds after subcutaneous administration, structure and function of the gastrointestinal tract, morphology of the pancreas, and the overall metabolic status of the two species. Because spontaneous type 1-like diabetes is very rare in pigs, a model of the condition must be induced experimentally, either surgically or chemically. This process is discussed, and the use of the pig as a model in islet transplantation and diabetic complications is briefly summarized.
Improving response time of programmable logic controllers by use of a Boolean coprocessor (2003)

Programmable-logic controllers (PLCs) are widely used to control technical processes in the industrial environment. In the requirements for next-generation PLCs, their fast response to events from the controlled processes plays a central role. The author shows that the response time of a low-cost PLC can be shortened by at least a factor of ten by using a special Boolean coprocessor in conjunction with the PLC (micro-) processor. The speedup is achieved by two means: (1) an architecture of the Boolean coprocessor designed for very fast execution of instructions on bit data, and (2) parallel execution of bit- and word-instruction streams with an efficient synchronization mechanism between them. The Boolean coprocessor's design is completed at the register transfer level. Simulation at the register transfer level and a gate-level simulation of the critical data path indicate an instruction-cycle time of less than 0.3 mu s. The VLSI realization of the design requires a gate array of 4000 gates with a 2-kb fast on-chip RAM.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Frequent Epigenetic Silencing of the Folate-Metabolising Gene Cystathionine-Beta-Synthase in Gastrointestinal Cancer (2012)

A novel finding from this study is that the folate metabolism enzyme CBS mRNA levels are frequently downregulated through CpG methylation of the CBS gene in gastric cancer and CRC, suggesting that CBS functions as a tumor suppressor gene. These findings warrant further study of CBS as an epigenetic biomarker for molecular diagnosis of gastrointestinal cancers.
Renin Angiotensin System in Cognitive Function and Dementia (2013)

Angiotensin II represents a key molecule in hypertension and cerebrovascular pathology. By promoting inflammation and oxidative stress, enhanced Ang II levels accelerate the onset and progression of cell senescence. Sustained activation of RAS promotes end-stage organ injury associated with aging and results in cognitive impairment and dementia. The discovery of the angiotensin-converting enzyme ACE2-angiotensin (1–7)-Mas receptor axis that exerts vasodilator, antiproliferative, and antifibrotic actions opposed to those of the ACE-Ang II-AT 1 receptor axis has led to the hypothesis that a decrease in the expression or activity of angiotensin (1–7) renders the systems more susceptible to the pathological actions of Ang II. Given the successful demonstration of beneficial effects of increased expression of ACE2/formation of Ang1–7/Mas receptor binding and modulation of Mas expression in animal models in containing cerebrovascular pathology in hypertensive conditions and aging, one could reasonably hope for analogous effects regarding the prevention of cognitive decline by protecting against hypertension and cerebral microvascular damage. Upregulation of ACE2 and increased balance of Ang 1–7/Ang II, along with positive modulation of Ang II signaling through AT 2 receptors and Ang 1–7 signaling through Mas receptors, may be an appropriate strategy for improving cognitive function and treating dementia.
The prevalence and associations of fatigue in systemic lupus erythematosus (2000)

Fatigue is a common complaint of patients with SLE and is associated with diminished ability to function. Apart from treating the primary disease, it may also be worthwhile to treat mood disorders and insomnia in order to reduce fatigue and improve quality of life.
Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair (2003)

During the menstrual cycle, the ovarian hormones oestradiol and progesterone control the ordered growth and differentiation of uterine cells. This remodelling process is critical for implantation of the developing embryo, the formation of the placenta, and maintenance of pregnancy. Failure of uterine tIssues to respond appropriately to ovarian hormone signalling results in defective placentation, associated with a spectrum of pregnancy disorders such as recurrent miscarriages and preeclampsia. These obstetrical disorders are a major cause of maternal and perinatal morbidity and mortality. Progesterone exerts its action on target cells, at least in part, through binding to the progesterone receptor (PR), a member of the steroid/thyroid hormone receptor superfamily of ligand-activated transcription factors. The mechanism by which progesterone controls the differentiation of human endometrial stromal cells, a process termed decidualization, in the secretory phase of the menstrual cycle is not well understood. Emerging evidence indicates that locally expressed factors and activation of the cAMP second messenger pathway integrate hormonal inputs and confer cellular specificity to progesterone action through the induction of diverse transcription factors capable of modulating PR function.
Impedance characteristics modeling of a two-terminal active capacitor (2017)

Conventional capacitors contribute to a considerable scale of system level size, cost and failure, and suffer from one or more issues on energy density, cost, and reliability. A two-terminal active capacitor, which has the same level of convenience as passive capacitors, is proposed recently to overcome the above issues. In this paper, the modeling of the active capacitor is investigated and a voltage feed-forward compensation scheme is proposed for overshoot reduction. Therefore, the impedance, equivalent capacitance, ESR, and ESL, of the active capacitor can be specified. A case study based on a single-phase full-bridge rectifier with an active capacitor demonstrates the theoretical analyses.
In vivo characterization of the liver fat 1H MR spectrum (2010)

A theoretical triglyceride model was developed for in vivo human liver fat (1) H MRS characterization, using the number of double bonds (-CH=CH-), number of methylene-interrupted double bonds (-CH=CH-CH(2)-CH=CH-) and average fatty acid chain length. Five 3 T, single-voxel, stimulated echo acquisition mode spectra (STEAM) were acquired consecutively at progressively longer TEs in a fat-water emulsion phantom and in 121 human subjects with known or suspected nonalcoholic fatty liver disease. T(2)-corrected peak areas were calculated. Phantom data were used to validate the model. Human data were used in the model to determine the complete liver fat spectrum. In the fat-water emulsion phantom, the spectrum predicted by the model (based on known fatty acid chain distribution) agreed closely with spectroscopic measurement. In human subjects, areas of CH(2) peaks at 2.1 and 1.3 ppm were linearly correlated (slope, 0.172; r = 0.991), as were the 0.9 ppm CH(3) and 1.3 ppm CH(2) peaks (slope, 0.125; r = 0.989). The 2.75 ppm CH(2) peak represented 0.6% of the total fat signal in high-liver-fat subjects. These values predict that 8.6% of the total fat signal overlies the water peak. The triglyceride model can characterize human liver fat spectra. This allows more accurate determination of liver fat fraction from MRI and MRS.
Lymph-node Changes Due to Polyvinyl Pyrrolidone (1957)

Polyvinyl pyrrolidone hasbeenwidely usedin recent yearsasa plasmaexpander, anda few side-effects havebeenreported, mostly reactions considered duetoallergic orsimilar mechanisms. A fewhistological changes havebeennotedin mansuchastheliver lesions reported byGall, Altemeier, Schiff, Hamilton, Braunstein, Giuseffi, andFreiman(1953) andtheworkofVickery (1956), butingeneral little isknownaboutthe tissue reactions itmaystimulate. Itmaythusbe ofinterest torecord briefly unusual lymph-node changes whichappear almost certainly tobedue topolyvinyl pyrrolidone. Herethematerial was notgiven asanintravenous infusion, butwasused asanabsorption-retarding agent inadrugwhich thepatient gaveherself bysubcutaneous orintramuscular injection inthethigh overaperiod of aboutayear. CaseReport
Phase 1b Dose Escalation Study of Erlotinib in Combination with Infusional 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Advanced Solid Tumors (2007)

The MTD was defined as follows: 150 mg/d erlotinib, 85 mg/m(2) oxaliplatin; 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 600 mg/m(2) infusion 5-FU. At the MTD, the combination was well tolerated and showed antitumor activity, warranting further investigation in patients with advanced colorectal cancer and other solid tumors.
Behaviour of the Antitumor Agent Vanadocene Dichloride in Physiological and Therapeutic Media, Blood Plasma and Human Blood ‐ An EPR Study (1997)

By means of EPR spectroscopy the behaviour of the vanadocene dichloride (I), Cp(2)VCl(2) (Cp=eta(5)-C(5)H(5)), in various deoxygenated and non-deoxygenated physiological media and therapeutic solution as well as in blood plasma and stabilized human blood was studied. On the basis of measured values of isotropic spectroscopic splitting factor g(iso) and isotropic hyperfine coupling constant A(iso), the vanadocene species, [Cp(2)V(H(2)O)Cl](+) (II; g(iso)= 1.985, |A(iso)| = 7.68 mT), [Cp(2)V(H(2)O)(2)](2+) (III; g(iso)= 1.983, |A(iso)| = 7.92 mT), [Cp(2)V(OH(2) (IV; g(iso)= 1.991, |A(iso)| = 6.285 mT), [Cp(2)VCl(DMSO)](+) (V; g(iso)= 1.985, |A(iso)| = 7.69 mT), the vanadyl species [VO(DMSO)(5)](2+) (VI; g(iso)= 1.964, |A(iso)| = 10.78mT) and [VO(H(2)O)(5)](2+) (VII; g(iso)= 1.955, |A(iso)| = 11.56 mT) have been identified. From the measurements it follows that I does not react in its first coordination sphere with any component of a system used other than water and DMSO, resp. As to water-containing media, its behaviour is fully consistent with that of I in pure aqueous media. It was found the only vanadocene species present after application of the therapeutic solution of I into human blood to be IV not interacting in its first coordination sphere with any blood component.
A superactive insulin: [B10-aspartic acid]insulin(human). (1987)

The genetic basis for a case of familial hyperproinsulinemia has been elucidated recently. It involves a single point mutation in the proinsulin gene resulting in the substitution of aspartic acid for histidine-10 of the B chain of insulin. We have synthesized a human insulin analogue, [AspB10]insulin, corresponding to the mutant proinsulin and evaluated its biological activity. [AspB10]Insulin displayed a binding affinity to insulin receptors in rat liver plasma membranes that was 534 +/- 146% relative to the natural hormone. In lipogenesis assays, the synthetic analogue exhibited a potency that was 435 +/- 144% relative to insulin, which is statistically not different from its binding affinity. Reversed-phase HPLC indicated that the synthetic analogue is more apolar than natural insulin. We suggest that the observed properties reflect changes in the conformation of the analogue relative to natural insulin, which result in a stronger interaction with the insulin receptor. Thus, a single substitution of an amino acid residue of human insulin has resulted in a superactive hormone.
Effects of Mutations of a Phosphorylation Site in an Exposed Loop in Acidic Fibroblast Growth Factor (1999)

Acidic fibroblast growth factor (aFGF) contains a phosphorylation site recognized by protein kinase C. A non-mitogenic mutant growth factor is devoid of this phosphorylation site. We have changed amino acids in and close to the phosphorylation site and studied the consequences of this for binding of the growth factor to high affinity receptors as well as to heparin. We have also studied the ability of the mutants to stimulate DNA synthesis and cell proliferation as well as phosphorylation of mitogen-activated protein kinase and the ability of the growth factor mutants to be transported to the nucleus. The results indicate that while the mutations strongly affect the ability of the growth factor to bind to heparin, they do not affect much the binding to the specific FGF receptors, activation of mitogen-activated protein kinase or transport of the growth factor to the nucleus. The mutations affect to various extents the ability of the growth factor to stimulate DNA synthesis and to induce cell multiplication. We find that phosphorylation of aFGF is not required for mitogenic activity. The data suggest that altered interaction of the growth factor with a cellular component different from the receptor, possibly a component in the nucleus, is the reason for the different mitogenicity of the different growth factor mutants.