gebhart/patrepeval huggingface dataset:
Structure-Based Design, Synthesis, and Pharmacological Evaluation of 3-(Aminoalkyl)-5-fluoroindoles as Myeloperoxidase Inhibitors (2010)

Oxidized low-density lipoproteins (LDLs) accumulate in the vascular wall and promote local inflammation, which contributes to the progression of the atheromatous plaque. The key role of myeloperoxidase (MPO) in this process is related to its ability to modify APO B-100 in the intima and at the surface of endothelial cells. A series of 3-(aminoalkyl)-5-fluoroindole analogues was designed and synthesized by exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor. In vitro assays were used to study the effects of these compounds on the inhibition of MPO-mediated taurine chlorination and oxidation of LDLs. The kinetics of the interaction between the MPO redox intermediates, Compounds I and II, and these inhibitors was also investigated. The most potent molecules possessed a 4- or 5-carbon aminoalkyl side chain and no substituent on the amino group. The mode of binding of these analogues and the mechanism of inhibition is discussed with respect to the structure of MPO and its halogenation and peroxidase cycles.
Suppression of tumor promoter-induced inflammation of mouse ear by ursolic acid and 4,4-dimethylcholestane derivatives. (1990)

Inflammation is one of physiological responses of organisms when they suffer physically or chemically induced stress, and comprises complex processes influenced by chemical mediators such as prostaglandins, leukotriens and serotonin.l) Inflammation of the skin can be macroscopically detected by reddening and edema, which is suppressed by several types of anti-inflammatory agents such as cyclo-oxygenase inhibitors and phospholipase A2 inhibitors.
Synthesis and characterisation of some new N-nitrosodipeptides (1990)

The synthesis of 11 new N-nitrosodipeptides by aprotic nitrosation with N2O4 is described for N-(N′-acetyl-L-prolyl)glycine, -L-alanine, -L-phenylalanine; and N-phthalimidoacetylglycine peptides and their (benzyl or ethyl) esters. The UV–vis, IR, 1H NMR and MS properties of the new N-nitrosodipeptides are reported and their structural significance is analysed.
The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B (2004)

This international clinical trial evaluated the safety and efficacy of recombinant factor IX (rFIX) in previously untreated patients (PUPs) with severe or moderately severe hemophilia B (FIX activity, < or = 3 IU/dL). Sixty-three PUPs aged younger than 1 month to 14 years received rFIX (median treatment duration, 37 months; range, 4-64 months). Mean rFIX recovery (0.68 +/- 0.27 IU/dL per IU/kg) remained constant over 5 years and was similar in infants (1 month to < 2 years) and children (2 to < 12 years). Fifty-four PUPs used rFIX (median dose, 62.7 IU/kg per infusion; range, 8.2-292 IU/kg) to treat 997 hemorrhages. Bleeding was well controlled, with 75% of hemorrhages requiring only one rFIX infusion. Response to rFIX was "excellent" or "good" in 94% of cases. Effective hemostasis was achieved in 32 PUPs receiving rFIX for routine prophylaxis, with 91% of prophylaxis responses rated "excellent." rFIX administered for 30 surgical procedures in 23 PUPs achieved hemostasis for all rated procedures. Five patients experienced allergic-type manifestations, including 2 (3%) patients who developed FIX inhibitors (both > 5 BU/dL). rFIX was well tolerated, with no associated thrombotic events or evidence of viral transmission. These data indicate that rFIX is a safe and effective treatment for PUPs with hemophilia B.
Design of Sequence‐specific DNA Cleaving Molecules (1986)

The design of sequence-specific cleaving molecules for double-helical DNA requires the attachment of DNA cleaving moieties to sequence-specific DNA binding molecules. The site of attachment and choice of cleaving strategy will be dependent on the availability of molecular models for the sequence-specific binding of small molecules (i.e., 1000 MW) to right-handed double-helical DNA. Productive model building is possible because of recent progress in the development of analytical methods, such as footprinting and affinity cleaving, to determine the preferred binding locations, binding site sizes, and orientations of natural or synthetic sequence-specific DNA binding molecules on large DNA such as DNA restriction fragments (100-500 bp). &#13;\n&#13;\nThe natural product distamycin is a crescent-shaped tripeptide containing three N-methylpyrrolecarboxamides which binds in the minor groove of right-handed double-helical DNA with a strong perference for A•T rich sequences (FIG. I). The preferred sequences, binding site size, and orientation preference for tris-N-methylpyrrolecarboxamide are known from footprinting and affinity cleaving data. Moreover, from recent X-ray analysis of the complex of the dipeptide, netropsin, with the B-DNA dodecamer, S-CGCGAATTCGCG-3', Dickerson and co-workers have provided a molecular basis for the recognition of DNA by netropsin, and by extension, distamycin. They find that netropsin sits symmetrically in the center of the minor groove of A•T rich right-handed DNA and displaces the water molecules of the spine of hydration. Each of its three amide NH groups forms a bridge between adjacent adenine N3 or thymine O2 atoms on opposite helix strands." Dickerson and coworkers suggest that the base specificity of netropsin for contiguous sequences of A •T base pairs in B-DNA is provided not by hydrogen bonding but by close van der Waals contacts between adenine C2 hydrogens and CH groups on the pyrrole rings of the&#13;\noligopeptide molecules.
Maximal Rates of Excretion and Synthesis of Urea in Normal and Cirrhotic Subjects (1973)

When normal individuals eat 0.33 g protein N/kg body weight (BW)((3/4)) per day, they excrete 10-15 mg urea N/h per kg BW((3/4)). If they now ingest (at 0 h) 0.27 (dose A), 0.40 (dose B), 0.53 (dose C), 0.94 (dose D), or 1.33 (dose E) g protein N/kg BW((3/4)) (in the form of casein, ovalbumin, or lactalbumin), the rate of urea N excretion accelerates within 4 h. At dose C a maximal rate of urinary urea N excretion (MRUE) is reached, which averages 55 mg urea N/h per kg BW((3/4)) and which persists for 16 h. Higher doses of protein do not further accelerate urea excretion, but prolong the duration of MRUE to 28 h (after dose E). Blood urea N (BUN) rises by 7-20 mg/100 ml during the first 8 h after dose C to E, and remains stable within +/-5 mg/100 ml during the ensuing 8-28 h of MRUE. Each increment of protein above dose C causes a further increment in plasma alpha-amino N. During infusion of free amino acids at a rate of 110 or 165 mg amino acid N/h per kg BW((3/4)) for 12 h, rate of urea excretion increases to the MRUE value produced by dose C-E of oral protein.These findings indicate that MRUE corresponds to a period of maximal rate of urea synthesis (MRUS). MRUS is greater than MRUE because one fraction of newly formed urea is hydrolyzed in the gastrointestinal tract, and another fraction may accumulate temporarily in body water during the MRUE period. Oral neomycin reduces the proportion of urea hydrolyzed in the gut to less than 20%; its extent is measured by recovery in the urine of a tracer dose of [(14)C]urea injected intramuscularly during determination of MRUE. Accumulation of urea in body water is estimated from increment in BUN during the period of MRUE measurement (8-24 h after dose E of casein) and from body water measured with (3)H(2)O. Then MRUS is calculated as: ([mg urea N excreted between 8 and 24 h after dose E] + [BUN at 24 h - BUN at 8 h] x [body water]) x (100/% recovery [(14)C]urea) x (1/kg BW((3/4))) x (1/16 h).MRUS in 10 normal subjects averaged 65 mg urea N/h per kg BW((3/4)) (range 55-76), and in 34 cirrhotics 27 mg urea N/h per kg BW((3/4)) (range 6-64). Among 19 cirrhotic patients fed 40, 60, 80, or 100 g protein daily for successive 10 day periods, the occurrences of hyperammonemia, hyperaminoacidemia, and encephalopathy at each level of protein intake were inversely related to MRUS value.
Comparison of MIMO antenna configurations in picocell and microcell environments (2003)

This paper presents the results achieved with a dual-polarized multiple-input multiple-output (MIMO) measurement system in the 2 GHz range. Results from continuous measurement routes were used in evaluating and comparing different MIMO antenna configurations. Different pattern and polarization diversity possibilities were studied using two methods: elements were selected from the antenna arrays used in measurements, and as another option, in the mobile station the incident waves were estimated and used in different dipole antenna arrays. The capacity limit seems to be higher in an indoor picocell than in an outdoor microcell environment. At the mobile station, directive elements result in 35% higher average capacities than those of the omnidirectional elements; however, the capacity of the directive elements also depends on the azimuth direction of arrival of the incident field. Dual-polarized antenna configurations have approximately 14% higher capacities than copolarized configurations. Increasing the number of mobile antenna elements increases the capacity in those environments where the angular spread of the incident field is large. Increasing the distance between elements at the fixed station increases the capacity - especially in microcells where signals arrive from specific directions.
Is it currently possible to evaluate the risk posed by PERVs for clinical xenotransplantation? (2018)

H-J S is director at SchuBiomed Consultancy and provides consultancy in the biomedical sector worldwide. JD and LS have no conflicts of interest.
Biomarkers for the early detection of acute kidney injury (2007)

Acute kidney injury (AKI), previously referred to as acute renal failure (ARF), represents a persistent problem in clinical medicine. Despite significant improvements in therapeutics, the mortality and morbidity associated with AKI remain high. A major reason for this is the lack of early markers for AKI, akin to troponins in acute myocardial disease, and hence an unacceptable delay in initiating therapy. Fortunately, the application of innovative technologies such as functional genomics and proteomics to human and animal models of AKI has uncovered several novel genes and gene products that are emerging as biomarkers. The most promising of these are chronicled in this article. These include a plasma panel [neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C] and a urine panel [NGAL, interleukin 18 (IL-18), and kidney injury molecule 1 (KIM)-1]. As they represent sequentially expressed biomarkers, it is likely that the AKI panels will be useful for timing the initial insult and assessing the duration of AKI. Based on the differential expression of the biomarkers, it is also likely that the AKI panels will distinguish between the various types and etiologies of AKI. It will be important in future studies to validate the sensitivity and specificity of these biomarker panels in clinical samples from large cohorts and from multiple clinical situations.
A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer (2003)

free survival.
Overexpression of protein kinase C alpha-subtype in Swiss/3T3 fibroblasts causes loss of both high and low affinity receptor numbers for epidermal growth factor. (1990)

The full length cDNA coding for the alpha form of protein kinase C (PKC) was introduced into Swiss/3T3 cells using a retroviral expression system. This has enabled the generation of a series of cell lines stably expressing high levels of PKC alpha enzyme, as well as the appropriate control cell lines, carrying an integrated vector but lacking PKC alpha cDNA insert. PKC alpha-overexpressing cell lines did not display a transformed morphology nor were they capable of growth in soft agar. However, these cells exhibited enhanced growth rates especially under low serum conditions. Using Scatchard plot analysis of 125I-epidermal growth factor (EGF) binding to its receptor on the surface of PKC alpha-overproducing cells revealed reduction in EGF receptor numbers when compared to control cells, without change in affinities of remaining receptors. These data indicated that reduced receptor numbers for EGF were among the phenotypic changes occurring in these cells underlying their diminished dependence on external factors for growth. Furthermore, we provide evidence that reduced EGF receptor numbers found on the cell surface of PKC alpha-overproducing cells resulted from the decreased biosynthesis of EGF receptor molecules, which correlated also with lower levels of mRNA transcripts coding for the EGF receptor found in these cells. Hence, our studies imply that PKC alpha is involved in a cellular mechanism regulating the expression of EGF receptor molecules in Swiss/3T3 cells. Thus, deregulation of PKC alpha, i.e. by increasing its expression levels in specific cells may affect, in turn the expression of cell surface receptors including the EGF receptor. Similar molecular mechanisms may be involved in initial stages of neoplasia and tumor promotion.
Isoform-specific Expression of VEGF-B in Normal Tissues and Tumors (2001)

Vascular endothelial growth factor B (VEGF-B), a member of the VEGF/PDGF family, is highly expressed in many tissues with two differentially spliced transcripts generating two secreted isoforms, VEGF-B167 and VEGF-B186. In this work, we have investigated the expression of VEGF-B in tissues and cell lines using techniques that can distinguish the two isoforms. The results showed that the VEGF-B167 isoform was predominantly expressed in most tissues, accounting for more than 80% of the total VEGF-B transcripts. The VEGF-B186 isoform was expressed at lower levels and only in a limited number of tissues. Moreover, the VEGF-B186 isoform was up-regulated in mouse and human tumor cell lines and primary tumors compared with their corresponding normal tissues. Taken together, our data suggest a fine genetic control of the expression of the two isoforms of VEGF-B, implying tissue- and cell-specific roles of the two VEGF-B isoforms.
Exploring the potential of the monobody scaffold: effects of loop elongation on the stability of a fibronectin type III domain (2002)

The tenth fibronectin type III domain of human fibronectin (FNfn10) is a small, monomeric beta-sandwich protein, similar to the immunoglobulins. We have developed small antibody mimics, 'monobodies', using FNfn10 as a scaffold. We initially altered two loops of FNfn10 that are structurally equivalent to two of the hypervariable loops of the immunoglobulin domain. In order to assess the possibility of utilizing other loops in FNfn10 for target binding, we determined the effects of the elongation of each loop on the conformational stability of FNfn10. We found that all six loops of FNfn10 allowed the introduction of four glycine residues while retaining the global fold. Insertions in the AB and FG loops exhibited very small degrees of destabilization, comparable to or less than predicted entropic penalties due to the elongation, suggesting the absence of stabilizing interactions in these loops in wild-type FNfn10. Insertions in the BC, CD and DE loops, respectively, resulted in modest destabilization. In contrast, the EF loop elongation was highly destabilizing, consistent with previous studies showing the presence of stabilizing interactions in this loop. These results suggest that all loops, except for the EF loop, can be used for engineering a binding site, thus demonstrating excellent properties of the monobody scaffold.
Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy (2011)

Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.
alpha1-Adrenergic receptor stimulation of mitogenesis in human vascular smooth muscle cells: role of tyrosine protein kinases and calcium in activation of mitogen-activated protein kinase. (1999)

Signaling pathways of many G protein-coupled receptors overlap with those of receptor tyrosine kinases. We have found previously that alpha1-adrenergic receptors stimulate DNA synthesis and cell proliferation in human vascular smooth muscle cells; these effects were attenuated by the tyrosine protein kinase (TPK) inhibitor genistein and the mitogen-activated protein kinase (MAPK) antagonist 2-aminopurine. Experiments were designed to determine if activation of alpha1 receptors directly stimulated TPKs and MAPKs in human vascular smooth muscle cells. Norepinephrine stimulated time- and concentration-dependent tyrosine phosphorylation of multiple proteins, including p52-, 75-, 85-, 120-, and 145-kDa proteins. Increased TPK activity was demonstrated in proteins precipitated by an antiphosphotyrosine antibody, both in autophosphorylation assays and with a peptide substrate. These effects of norepinephrine were completely blocked by alpha1 receptor antagonists. A membrane-permeable Ca2+ chelator [1,2-bis(o-aminophenoxy)ethane-N,N, N',N'-tetraacetic acid tetra(acetoxymethyl)ester], completely blocked norepinephrine stimulation of phosphorylation of tyrosine proteins, suggesting that intracellular Ca2+ plays a critical role in alpha1 receptor stimulation phosphorylation of tyrosine proteins. Of the tyrosine-phosphorylated proteins, the results suggest that two of them are PLCgamma1 and adapter protein Shc. Also, alpha1 receptor stimulation caused a time-dependent increase in MAPK activity due to increased phosphorylation of p42/44(ERK1/2). The alpha1 receptor-mediated activation of MAPK was also attenuated by TPK inhibitors and intracellular Ca2+ chelator [1, 2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester]. These results suggest that phosphorylation of tyrosine proteins and intracellular Ca2+ plays a critical role in alpha1 receptor-stimulated MAPK signaling pathways, potentially contributing to increased DNA synthesis and cell proliferation.
The Prognostic Implication of the Basal-Like (Cyclin Ehigh/p27low/p53+/Glomeruloid-Microvascular-Proliferation+) Phenotype of BRCA1 -Related Breast Cancer (2004)

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27(Kip1), or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27(Kip1), p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27(Kip1) levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.
Systemic Steroids in Severe Sepsis and Septic Shock (2011)

Despite more than 5 decades of study and debate, the role of corticosteroid treatment in patients with severe sepsis and septic shock remains controversial. Data support a beneficial effect on systemic blood pressure in patients with septic shock. However, the ability of corticosteroid therapy to improve mortality in patients with severe sepsis and septic shock remains controversial, with contradictory results from recent large multicenter clinical trials. Although it appears clear that high-dose corticosteroid treatment provides no benefit and possibly harm in septic patients, the experimental design flaws and biases of recent low-dose (physiologic) steroid treatment trials limit their ability to provide adequate answers to the important questions of which septic patients should be treated, how much steroid to give, and the optimum duration of treatment. Unfortunately, the answer to these important questions is not readily evident based on the current evidence or the application of metaanalysis to the available clinical data. This concise evidence-based review highlights the strengths and weaknesses of the current data to inform the practicing clinician as to which patients are likely to derive significant benefit from corticosteroid treatment, while we await more definitive guidance from future multicenter, prospective, randomized, controlled trials designed to better answer these important therapeutic questions.
Prokinetics in the Management of Functional Gastrointestinal Disorders (2015)

A variety of common and some not common gastrointestinal syndromes are thought to be based on impaired gut motility. For some, the role of motility is well defined, for others and the functional gastrointestinal disorders, in particular, the role of hy-po- or dysmotility remains unclear. Over the years pharmacological and physiological laboratories have developed drugs which stimulate gut motility; many have been evaluated in motility and functional disorders with what can best be described as mixed results. Lack of receptor specificity and resultant expected and unexpected adverse events have led to the demise of some of these agents. Newer, more selective agents offer promise but the heterogeneity of the clinical disorders they target continues to pose a formidable challenge to drug development in this area.