gebhart/patrepeval huggingface dataset:
A mechanism of quinolinic acid formation by brain in inflammatory neurological disease: Attenuation of synthesis from L-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate (1993)

Quinolinic acid (QUIN), kynurenic acid (KYNA) and L-kynurenine (L-KYN) are neuroactive kynurenine pathway metabolites that accumulate in inflammatory neurological diseases. These increases were attributed to the induction of indoleamine-2,3-dioxygenase (IDO), the enzyme that converts L-tryptophan into L-KYN. Direct conversion of L-tryptophan into QUIN by brain tissue occurs in conditions of CNS inflammation, but not by normal brain tissue. To investigate whether increased activity of enzymes distal to IDO may determine L-KYN conversion to QUIN, rhesus macaques were inoculated with poliovirus directly into the spinal cord, as a model of focal inflammatory neurological disease (FASEB J. 6, 2977-2989, 1992). Induction of spinal cord IDO (35.9-fold) accompanied smaller, but proportional increases in kynurenine-3-hydroxylase (2.4-fold) and kynureninase (2.3-fold) activities, which were correlated to CSF and tissue QUIN levels, as well as to measures of inflammatory lesions. 3-Hydroxyanthranilate-3,4-dioxygenase activity was unchanged. Cerebrospinal fluid KYNA levels increased in proportion to both IDO activity and L-KYN accumulation, though kynurenine aminotransferase activity was unaffected. Cerebrospinal fluid neopterin, a marker of macrophage and immune activation, accumulated in proportion to the responsive enzymes and metabolites. The cell types involved in producing QUIN were investigated in vitro. Human foetal brain cultures consisting of astrocytes and neurons converted large quantities of [13C6]L-tryptophan into L-KYN when stimulated by gamma-interferon, but very little [13C6]QUIN was formed unless macrophages (THP-1 cells) were first added to the cultures (to model a key component of brain inflammation). [13C6]L-Tryptophan was converted into [13C6]QUIN by either gamma-interferon stimulated macrophages, or following intracisternal administration into poliovirus-infected macaques. Inhibitors of the kynurenine pathway, 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilic acid, attenuated [13C6]QUIN formation by macrophages, and when co-infused with [13C6]L-tryptophan into poliovirus-infected macaques. These results suggest roles for increased activities of IDO, kynurenine-3-hydroxylase and kynureninase in accelerating the synthesis of QUIN, L-KYN and KYNA in conditions of brain inflammation. Macrophage infiltrates, and perhaps microglia, are important sources of QUIN, whereas constitutive brain cells and macrophages are sources of L-KYN. Drugs that inhibit kynurenine pathway enzymes attenuate QUIN formation in the CNS, and provide tools to examine the consequences of reduced QUIN accumulation.
Detection of Tumor PIK3CA Status in Metastatic Breast Cancer Using Peripheral Blood (2012)

Analysis of plasma-derived ctDNA for the detection of PIK3CA mutations in patients with metastatic breast cancer is feasible. Our results suggest that PIK3CA mutational status can change upon disease recurrence, emphasizing the importance of reassessing PIK3CA status on contemporary (not archival) biospecimens. These results have implications for the development of predictive biomarkers of response to targeted therapies.
Idarubicinol myelotoxicity: a comparison of in vitro data with clinical outcome in patients treated with high-dose idarubicin (2000)

We evaluated in vitro the toxicity of idarubicin and its active metabolite idarubicinol on haematopoietic progenitors, using human umbilical cord blood and peripheral blood progenitors to obtain dose-response curves. We treated 16 patients with poor prognosis lymphoma in a phase I-II trial of high-dose idarubicin and melphalan and investigated if idarubicinol persisting in patients' plasma at the time of transplantation (day 0), on day +1 and +2 could result in an inhibition of infused progenitors. Colony inhibition was correlated with pharmacokinetic data and with the time of patients' engraftment. Plasma samples obtained before idarubicin treatment demonstrated a colony-stimulating effect, increasing the cloning efficiency by 72%. The inhibitory activity on colony forming unit granulocyte-macrophage (CFU-GM) of patients' plasma collected on the day of transplantation was lower than expected from dose-response curves (21% measured vs 70% expected). The time to patients' WBC and PLT recovery correlated with the amount of CD34+ cells reinfused and, to a lesser extent, with the colony-inhibiting effect of patients' plasma. The correlation between idarubicinol concentration and CFU-GM inhibition was not significant. These data suggest that plasma drug concentration on the day of stem cell reinfusion may overestimate the toxicity of residual anthracyclines to the transplanted cells.
A new member of the troponin C superfamily: Comparison of the primary structures of rat oncomodulin and rat parvalbumin (1983)

When the amino-acid sequence of the 108-residue, rat tumour calcium-binding protein, oncomodulin, was aligned with that of rat muscle parvalbumin, 55 homologous positions were found, with an additional 33 single base-pair substitutions. This extensive homology, with virtual identity of the calcium-binding domains, signalled oncomodulin to be a member of the troponin C superfamily. The presence of Cys-18 and Phe-66 in oncomodulin, plus its isoelectric point of 3.9, suggest that this tumour protein is a beta-parvalbumin, rather than a muscle alpha-parvalbumin.
Prediction of Gestational Diabetes Mellitus by Soluble (Pro)Renin Receptor During the First Trimester (2013)

Increased s(P)RR concentrations during the first trimester may predict the development of GDM later in pregnancy.
Overexpression of SERCA1a in the mdx Diaphragm Reduces Susceptibility to Contraction-Induced Damage (2010)

Although the precise pathophysiological mechanism of muscle damage in dystrophin-deficient muscle remains disputed, calcium appears to be a critical mediator of the dystrophic process. Duchenne muscular dystrophy patients and mouse models of dystrophin deficiency exhibit extensive abnormalities of calcium homeostasis, which we hypothesized would be mitigated by increased expression of the sarcoplasmic reticulum calcium pump. Neonatal adeno-associated virus gene transfer of sarcoplasmic reticulum ATPase 1a to the mdx diaphragm decreased centrally located nuclei and resulted in reduced susceptibility to eccentric contraction-induced damage at 6 months of age. As the diaphragm is the mouse muscle most representative of human disease, these results provide impetus for further investigation of therapeutic strategies aimed at enhanced cytosolic calcium removal.
A generalized RAKE receiver for interference suppression (2000)

Currently, a global third-generation cellular system based on code-division multiple-access (CDMA) is being developed with a wider bandwidth than existing second-generation systems. The wider bandwidth provides increased multipath resolution in a time-dispersive channel, leading to higher frequency-selectivity. A generalized RAKE receiver for interference suppression and multipath mitigation is proposed. The receiver exploits the fact that time dispersion significantly distorts the interference spectrum from each base station in the downlink of a wideband CDMA system. Compared to the conventional RAKE receiver, this generalized RAKE receiver may have more fingers and different combining weights. The weights are derived from a maximum likelihood formulation, modeling the intracell interference as colored Gaussian noise. This low-complexity detector is especially useful for systems with orthogonal downlink spreading codes, as orthogonality between own cell signals cannot be maintained in a frequency-selective channel. The performance of the proposed receiver is quantified via analysis and simulation for different dispersive channels, including Rayleigh fading channels. Gains on the order of 1-3.5 dB are achieved, depending on the dispersiveness of the channel, with only a modest increase in the number of fingers. For a wideband CDMA (WCDMA) system and a realistic mobile radio channel, this translates to capacity gains of the order of 100%.
Effects of serotonergic agents on neuronal nicotinic acetylcholine receptors. (1995)

In Xenopus oocytes expressing neuronal nicotinic acetylcholine receptors (nAcChoRs), made up of alpha 2 and beta 4 subunits, acetylcholine (AcCho) elicited ionic membrane currents (AcCho currents) that were modulated by serotonergic agents. Both agonists and antagonists specific for various serotonin (5-hydroxytryptamine, 5HT) receptor subtypes interacted directly with alpha 2 beta 4 nAcChoRs: 5HT, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin, methysergide, spiperone, and ketanserin reversibly reduced the amplitude of AcCho currents and accelerated their decay. The AcCho-current time course decayed with two exponential functions. In the presence of 5HT, the fast time constant of current decay (tau f) was not greatly modified, but the slow time constant (tau s) was reduced. With AcCho and 5HT both at 100 microM, tau s was reduced from 140 s to 85 s. The order of potency for inhibition of AcCho current amplitudes was (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin > methysergide > spiperone > ketanserin > 5HT. The inhibition was voltage-dependent but the magnitude of the voltage dependence for the different blockers did not correspond to their blocking potency: e.g., the block with spiperone was stronger than with 5HT, but it was less voltage-dependent. Our results suggest that serotonergic agents block neuronal nAcChoRs in a noncompetitive manner, similar to the block of muscle nAcChoR by curare and other substances. These results show that neuronal nAcChoR channels that have been activated by their specific neurotransmitter may be modulated by nonspecific neurotransmitters and their antagonists. These effects may help to better understand brain functions as well as the mode of action of the many serotonergic agents that are used in medical practice.
A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile (2013)

The Clostridium difficile toxins A and B are primarily responsible for symptoms of C. difficile associated disease and are prime targets for vaccine development. We describe a plasmid-based system for the production of genetically modified toxins in a non-sporulating strain of C. difficile that lacks the toxin genes tcdA and tcdB. TcdA and TcdB mutations targeting established glucosyltransferase cytotoxicity determinants were introduced into recombinant plasmids and episomally expressed toxin mutants purified from C. difficile transformants. TcdA and TcdB mutants lacking glucosyltransferase and autoproteolytic processing activities were ~10 000-fold less toxic to cultured human IMR-90 cells than corresponding recombinant or native toxins. However, both mutants retained residual cytotoxicity that could be prevented by preincubating the antigens with specific antibodies or by formalin treatment. Such non-toxic formalin-treated mutant antigens were immunogenic and protective in a hamster model of infection. The remaining toxicity of untreated TcdA and TcdB mutant antigens was associated with cellular swelling, a phenotype consistent with pore-induced membrane leakage. TcdB substitution mutations previously shown to block vesicular pore formation and toxin translocation substantially reduced residual toxicity. We discuss the implications of these results for the development of a C. difficile toxoid vaccine.
Assessment of Heavy Metal Contamination of Seawater and Marine Limpet,Patella vulgataL., from Northwest Spain (2003)

In the present work, both seawater and limpets (Patella vulgata L.) were collected from different sampling points in the Vigo estuary area (Galicia, NW Spain) and their heavy metal concentrations (Zn, Cd, Pb, Cu) were determined by means of a voltammetric technique. The results showed a direct relationship between the heavy metal levels in seawater and the content in biological samples, especially those obtained from limpet soft tissues, directly related to the increasing importance of anthropogenic environmental contamination. Heavy metal concentrations were usually higher in soft tissues than in shell, with a maximum difference corresponding to Cd and Zn (average of 93.6 and 86 folds, respectively). As expected, heavy metal content was higher in animal samples situated in inner part of the estuary zone, except for cadmium content in soft tissues, where a maximum of 5.62 ppm was quantified in limpet soft tissues collected next to the open sea area. Statistical analysis allowed the establishment of a clear relationship between Zn and Cd content in both shells and soft tissues from limpet, and especially between Zn and Cu in soft tissues (p < 0.001).
Assessment of tissue prolapse after balloon-expandable stenting: Influence of stent cell geometry (2008)

Restenosis is a re-narrowing or blockage of an artery at the same site where treatment, such as a balloon angioplasty or stent procedure, has already taken place. Several clinical trials have shown a significant reduction in the restenosis rates with endovascular stenting. The purpose of stenting is to maintain the arterial lumen open by a scaffolding action that provides radial support. However, stenting can cause a vascular injury during the deployment. Indeed, in-stent restenosis remains a major problem in percutaneous coronary intervention, requiring patients to undergo repeated procedures and surgery. The loading imposed by the deployment of the stent on the artery is involved in the restenosis process. Furthermore, it is well known that the stent design plays a role in the outcome of the stenting interventional procedure. This study compares the mechanical effects of the expansion of five different designs of balloon-expandable stents in a coronary artery by means of numerical models based on the finite element method. An index for the evaluation of the tissue prolapse based on the expanded configuration reached by the stent cells is proposed. The effects of the balloon inflation and deflation are included in the present study. Wall stresses and tissue prolapse of the vessel wall within the stent cells are evaluated and compared among the different stent designs. Results show that the printed area does not predict prolapse, and that the proposed index (PI) does correlate with tissue prolapse.
Stromelysin-3 Protein Expression in Invasive Breast Cancer: Relation to Proliferation, Cell Survival and Patients’ Outcome (2002)

Matrix metalloproteinases constitute one of the major extracellular matrix degrading enzymic families implicated in cancer development. Stromelysin-3 in particular, a member of the matrix metalloproteinases belonging to the stromelysins' subgroup, seems to be closely related to invasiveness and tumor progression. In this study, we proceeded to the evaluation of stromelysin-3 protein's expression in paraffin sections of 133 cases of invasive breast carcinomas and statistically estimated its relations with known clinicopathological prognostic parameters and patients' survival, proliferation markers Ki-67 and TopoIIalpha and the antiapoptotic protein bcl-2. Presence of stromelysin-3 was immunodetected, in the 73% of our cases, in stromal cells (65%) and in epithelial tumor cells (26.26%). Stromelysin-3 epithelial positivity presented statistically significant correlations with TopoIIalpha and Ki-67 proliferation indices (P =.042 and P =.031, respectively) and worse disease outcome through multivariate statistics (P =.014). Stromelysin-3 fibroblastic expression was significantly associated with nuclear grade (P =.024), ductal histological type (P =.037), TopoIIalpha (P =.001) and Ki-67 (P =.019), inversely with bcl-2 protein (P =.027) and with adverse overall survival through univariate analysis (P =.017). The subgroup of patients with stromelysin-3 co-expression in stromal and malignant epithelial cells showed statistically significant associations with Ki-67 and TopoIIalpha (P =.019, P <.0001, respectively), an inverse one with bcl-2 protein (P =.027) and furthermore with impaired survival (P =.002) through multivariate analysis. In conclusion, stromelysin-3 protein expression correlated with proliferation indices TopoIIalpha and Ki-67 and the anti-apoptotic protein bcl-2, data confirming stromelysin-3's contribution to breast cancer progression. Moreover its expression was shown to have a direct negative effect on patients' survival, especially in the subgroup of patients with simultaneous epithelial and stromal expression.
The Cellular and Molecular Basis of Odor Adaptation (2000)

An important recent advance in the understanding of odor adaptation has come from the discovery that complex mechanisms of odor adaptation already take place at the earliest stage of the olfactory system, in the olfactory cilia. At least two rapid forms and one persistent form of odor adaptation coexist in vertebrate olfactory receptor neurons. These three different adaptation phenomena can be dissected on the basis of their different onset and recovery time courses and their pharmacological properties, indicating that they are controlled, at least in part, by separate molecular mechanisms. Evidence is provided for the involvement of distinct molecular steps in these forms of odor adaptation, including Ca(2+) entry through cyclic nucleotide-gated (CNG) channels, Ca(2+)-dependent CNG channel modulation, Ca(2+)/calmodulin kinase II-dependent attenuation of adenylyl cyclase, and the activity of the carbon monoxide/cyclic GMP second messenger system. Identification of these molecular steps may help to elucidate how the olfactory system extracts temporal and intensity information and to which extent odor perception is influenced by the different mechanisms underlying adaptation.
Experimental Study on the Burning Behavior of Automotive Internal Decorating Materials (2014)

Experimental study on the burning behavior of four kinds of common automotive internal decorating materials including fur cushion, flannel cushion, dacron seat cover and felt carpet by means of cone calorimeter are introduced in this paper. Compared with the four kinds of materials from the perspective of ignition time, HRR, peak HRR and carbon monoxide release rate under different heating flux, burning behaviors of these materials are analyzed. According to analysis results, the risk of automotive fire disasters can be objectively evaluated. In a word,it’s helpful to study their burning behaviors and point out proper methods of application.
Argatroban Anticoagulation in Patients With Heparin-Induced Thrombocytopenia (2003)

Argatroban therapy, compared with historical control, improves outcomes, particularly new thrombosis and death due to thrombosis, in patients with heparin-induced thrombocytopenia.
Formulation of highly soluble poly(ethylene glycol)‐peptide DNA condensates (1999)

Two poly(ethylene glycol) (PEG)-peptides were synthesized and tested for their ability to bind to plasmid DNA and form soluble DNA condensates with reduced spontaneous gene expression. PEG-vinyl sulfone or PEG-orthopyridyl disulfide were reacted with the sulfhydryl of Cys-Trp-Lys(18) (CWK(18)) resulting in the formation of nonreducible (PEG-VS-CWK(18)) and reducible (PEG-SS-CWK(18)) PEG-peptides. Both PEG-peptides were prepared on a micromole scale, purified by RP-HPLC in >80% yield, and characterized by (1)H NMR and MALDI-TOF. PEG-peptides bound to plasmid DNA with an apparent affinity that was equivalent to alkylated (Alk)CWK(18), resulting in DNA condensates with a mean diameter of 80-90 nm and zeta (zeta) potential of +10 mV. The particle size of PEG-peptide DNA condensates was constant throughout the DNA concentration range of 0. 05-2 mg/mL, indicating these to be approximately 20-fold more soluble than AlkCWK(18) DNA condensates. The spontaneous gene transfer to HepG2 cells mediated by PEG-VS-CWK(18) DNA condensates was over two orders of magnitude lower than PEG-SS-CWK(18) DNA condensates and three orders of magnitude lower than AlkCWK(18) DNA condensates. PEG-VS-CWK(18) efficiently blocked in vitro gene transfer by reducing cell uptake. The results indicate that a high loading density of PEG on DNA is necessary to achieve highly soluble DNA condensates that reduce spontaneous in vitro gene transfer by blocking nonspecific uptake by HepG2 cells. These two properties are important for developing targeted gene delivery systems to be used in vivo.
Biological activities of lipopolysaccharides are determined by the shape of their lipid A portion (2000)

Lipopolysaccharide (LPS) represents a major virulence factor of Gram-negative bacteria ('endotoxin') that can cause septic shock in mammals including man. The lipid anchor of LPS to the outer membrane, lipid A, has a peculiar chemical structure, harbours the 'endotoxic principle' of LPS and is responsible for the expression of pathophysiological effects. Chemically modified lipid A can be endotoxically inactive, but may express strong antagonistic activity against LPS, a property that can be utilized in antisepsis treatment. We show here that these different biological activities are directly correlated with the molecular shape of lipid A. Only (hexaacyl) lipid A with a conical/concave shape, the cross-section of the hydrophobic region being larger than that of the hydrophilic region, exhibited strong interleukin-6 (IL-6)-inducing capacity. Most strikingly, a correlation between a cylindrical molecular shape of lipid A and antagonistic activity was established: IL-6 induction by enterobacterial LPS was inhibited by cylindrically shaped lipid A except for compounds with reduced headgroup charge. The antagonistic action is interpreted by assuming that lipid A molecules intercalate into the cytoplasmic membrane of mononuclear cells, and subsequently blocking of the putative signaling protein by the lipid A with cylindrical shape.
Hypomethylating Agents and Other Novel Strategies in Myelodysplastic Syndromes (2011)

Over the last decade, treatment approaches for patients with myelodysplastic syndromes (MDS) have improved significantly. Treatment of MDS is tailored to the specific risk characteristics of the patient. In general, patients are divided into lower- and higher-risk categories. Without therapy, prognosis of patients with higher-risk MDS is poor, and treatments should be directed to improve survival. Prognosis of patients with lower-risk MDS is more heterogeneous, and therapies are usually directed to minimize transfusion needs and potentially to alter the natural course of the disease. Treatment options for patients with higher-risk MDS include hypomethylating agents (azacitidine and decitabine), intensive chemotherapy (ICT), and allogeneic stem-cell transplantation (alloSCT). The use of the hypomethylating agents has transformed the approach to this patient population, in particular older individuals, for whom ICT and alloSCT are not an option. In lower-risk MDS, treatment strategies are used sequentially and usually include observation in patients with low risk and no transfusion dependency, growth factors, and lenalidomide for patients with alteration of chromosome 5 and anemia. The use of hypomethylating agents is less understood in this group of patients. AlloSCT is usually reserved for patients with lower-risk MDS closer to the time of transformation. In this short review, we discuss treatment alternatives for patients with MDS and delineate some of the ongoing challenges, including the development of better front-line strategies for patients with higher-risk disease, the concept of altering the natural course of the disease in lower-risk MDS, and the development of new treatment approaches for patients who do not benefit from hypomethylating agents.