gebhart/patrepeval huggingface dataset:
Identification of a new cell adhesion motif in two homologous peptides from the COOH-terminal cell binding domain of human thrombospondin. (1993)

Thrombospondin-1 (TS1) contains at least four domains that support cell attachment. The COOH-terminal cell binding domain (CBD) was first identified with a monoclonal antibody against TS1 that blocked secretion-dependent platelet aggregation. Subsequently, this domain of TS1 has been found to bind a number of normal and transformed cells. We have localized attachment sites for human melanoma cells (G361) within the CBD to two noncontiguous 30-residue peptides designated C4 and C7 (Kosfeld, M. D., and Frazier, W. A. (1991) J. Biol. Chem. 267, 16230-16236). Here we report studies to define the active sequences within C4 and C7. An octapeptide, RFYVVMWK (4N1-1), from C4 and a pentapeptide, IRVVM (7N3-1), from C7 were found to support attachment of G361 melanomas, K562 erythroleukemia cells, HT1080 fibrosarcomas, C32 amelanotic melanomas, and endothelial cells. These peptides also inhibit the adhesion of cells to the recombinant CBD of TS1. The hexapeptide RFYVVM (4N1-2) also inhibits cell attachment. The inhibitory effect of combinations of C4- and C7-derived peptides is synergistic. The sequences 4N1-1 and 7N3-1 of TS1 share homology with two cell adhesive peptides from laminin (LM), LMF9 and LMPA22-2, respectively. These TS1 and LM peptides are interchangeable in inhibiting the adhesion of G361 cells to LM or TS1, suggesting a possible sharing of receptors by LM and TS1. K562 cells, however, bound only to TS1, and this binding was inhibited preferentially by the TS1 CBD peptides, indicating a receptor specific for TS1 which does not recognize LM. The active TS1 peptides are highly conserved among five species and four isoforms of TS1. Homologs of the TS1 peptides are found in tenascin, a matrix protein that shares several properties with TS1 and in factor VIII, alpha 2-macroglobulin, and von Willebrand factor.
General Catalytic Deficiency of Hepatitis C Virus RNA Polymerase with an S282T Mutation and Mutually Exclusive Resistance towards 2′-Modified Nucleotide Analogues (2006)

The hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B is an important target for antiviral therapies. NS5B is able to initiate viral RNA synthesis de novo and then switch to a fast and processive RNA elongation synthesis mode. The nucleotide analogue 2'-C-methyl CTP (2'-C-Me-CTP) is the active metabolite of NM283, a drug currently in clinical phase II trials. The resistance mutation S282T can be selected in HCV replicon studies. Likewise, 2'-O-Me nucleotides are active both against the purified polymerase and in replicon studies. We have determined the molecular mechanism by which the S282T mutation confers resistance to 2'-modified nucleotide analogues. 2'-C-Me-CTP is no longer incorporated during the initiation step of RNA synthesis and is discriminated 21-fold during RNA elongation by the NS5B S282T mutant. Strikingly, 2'-O-methyl CTP sensitivity does not change during initiation, but the analogue is no longer incorporated during elongation. This mutually exclusive resistance mechanism suggests not only that "2'-conformer" analogues target distinct steps in RNA synthesis but also that these analogues have interesting potential in combination therapies. In addition, the presence of the S282T mutation induces a general cost in terms of polymerase efficiency that may translate to decreased viral fitness: natural nucleotides become 5- to 20-fold less efficiently incorporated into RNA by the NS5B S282T mutant. As in the case for human immunodeficiency virus, our results might provide a mechanistic basis for the rational combination of drugs for low-fitness viruses.
Pyrazole and Isoxazole Derivatives as New, Potent, and Selective 20-Hydroxy-5,8,11,14-eicosatetraenoic Acid Synthase Inhibitors (2003)

In a previous paper, we reported the N-hydroxyformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor. Despite its attraction as a potential therapeutic agent for cerebral diseases, the preparation of an injectable formulation of HET0016 was limited by its poor solubility under neutral conditions and instability under acidic conditions. The instability of HET0016 in acidic conditions is due to the N-hydroxyformamidine moiety, which is considered to be essential for the potent and selective activity seen in our previous study. The activity was maintained when the N-hydroxyformamidine moiety was replaced by an imidazole ring (3a; IC(50) = 5.7 +/- 1.0 nM), but this was associated with a loss of selectivity for cytochrome p450s (CYPs). However, other azole derivatives such as isoxazole derivative 23 (IC(50) value 38 +/- 10 nM) and pyrazole derivative 24 (IC(50) value 23 +/- 12 nM) showed potent and selective activities with improved stability.
Supernode partitioning (1988)

Supercompilers must reschedule computations defined by nested DO-loops in order to make an efficient use of supercomputer features (vector units, multiple elementary processors, cache memory, etc…). Many rescheduling techniques like loop interchange, loop strip-mining or rectangular partitioning have been described to speedup program execution. We present here a class of partitionings that encompasses previous techniques and provides enough flexibility to adapt code to multiprocessors with two levels of parallelism and two levels of memory.
Robust multiple-station magnetotelluric data processing (1997)

A R Y Although modern magnetotelluric ( MT) data are highly multivariate (multiple components, recorded at multiple stations), commonly used processing methods are based on univariate statistical procedures. Here we develop a practical robust processing scheme which is based on multivariate statistical methods. With this approach we use data from all channels to improve signal-to-noise ratios, and to diagnose possible biases due to coherent noise. To illustrate our approach we use data from two-and three-station wide-band MT arrays from an area south of San Francisco, California, where contamination of the MT signal by spatially coherent cultural electromagnetic noise is severe at some periods. To deal with such coherent noise we adopt a two-stage procedure. In the first stage we focus on reducing the effects of incoherent noise, and testing for the presence of coherent noise. To this end we have developed a robust multivariate errors-in-variables ( RMEV) estimator, which estimates background noise levels, cleans up outliers in all channels, and determines the 'coherence dimension' of the array data. In the absence of coherent noise, the coherence dimension of the data will be two (corresponding to two polarizations of the plane-wave MT source fields). In this case the RMEV estimator provides direct estimates of MT impedances and inter-station transfer functions. We show, with synthetic and real data examples, that in some cases these estimates can be significantly better than those obtained with more standard robust remote reference estimators. When MT data is severely contaminated by coherent noise (as for our example arrays for periods of 4-50s) the coherence dimension of the data will exceed two. The RMEV estimate thus provides a clear warning of coherent noise contamination. Although there appears to be no completely general automatic way to deal with this circumstance, useful results can be obtained from severely contaminated data in some cases. We show in particular how the RMEV estimator can be adapted to separate the MT signal from coherent noise for two special cases: when at least one site is unaffected by coherent noise, and when coherent noise sources are intermittent. We give examples of significant improvements in MT impedance estimates obtained with the RMEV estimate for each of these cases.
Clinical and experimental studies of anti-tumoural effects of electrochemical therapy (ECT) alone or in combination with chemotherapy. (1994)

The present experimental study shows that anticancer agents may accumulate around electrodes placed in saline and in lung when the electrodes are charged with direct electric current. We also observed that electrochemical therapy (ECT) in combination with chemotherapy was more effective for treatment of localized tumours (human lung cancer PC-13 transplated to nude mice) than was ECT or systemic chemotherapy alone. In a clinical study, 26 patients (27 lesions) received ECT with or without systemic chemotherapy. We observed a decrease in tumour size in more than 70% of the cases, and in two cases the use of ECT alone resulted in complete regression of the tumour. In one case there was an increase in tumour size. The main side-effects observed during treatment of lung cancer was pain during treatment, fever after treatment, and pneumothorax. We conclude that ECT may be effective in controlling localised tumours. The clinical use of ECT is, however, associated with several problems and the mechanism of this treatment has not yet been completely established.
Animal models for motor neuron disease. (1999)

Motor neuron disease is a general term applied to a broad class of neurodegenerative diseases that are characterized by fatally progressive muscular weakness, atrophy, and paralysis attributable to loss of motor neurons. At present, there is no cure for most motor neuron diseases, including amyotrophic lateral sclerosis (ALS), the most common human motor neuron disease--the cause of which remains largely unknown. Animal models of motor neuron disease (MND) have significantly contributed to the remarkable recent progress in understanding the cause, genetic factors, and pathologic mechanisms proposed for this class of human neurodegenerative disorders. Largely driven by ALS research, animal models of MND have proven their usefulness in elucidating potential causes and specific pathogenic mechanisms, and have helped to advance promising new treatments from "benchside to bedside." This review summarizes important features of selected established animal models of MND: genetically engineered mice and inherited or spontaneously occurring MND in the murine, canine, and equine species.
Are NSAIDs useful to treat Alzheimer’s disease or mild cognitive impairment? (2010)

Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect subjects carrying one or more epsilon4 allele of the apolipoprotein E (APOE epsilon4) against the onset of Alzheimer's disease (AD). The biological mechanism of this protection is not completely understood and may involve the anti-inflammatory properties of NSAIDs or their ability of interfering with the beta-amyloid (Abeta) cascade. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and cyclooxygenase-2 (COX-2) selective inhibitors in mild-to-moderate AD patients produced negative results. A secondary prevention study with rofecoxib, a COX-2 selective inhibitor, in patients with mild cognitive impairment was also negative. A primary prevention study (ADAPT trial) of naproxen (a non-selective COX inhibitor) and celecoxib (a COX-2 selective inhibitor) in cognitively normal elderly subjects with a family history of AD was prematurely interrupted for safety reasons after a median period of treatment of 2 years. Although both drugs did not reduce the incidence of dementia after 2 years of treatment, a 4-year follow-up assessment surprisingly revealed that subjects previously exposed to naproxen were protected from the onset of AD by 67% compared to placebo. Thus, it could be hypothesized that the chronic use of NSAIDs may be beneficial only in the very early stages of the AD process in coincidence of initial Abeta deposition, microglia activation and consequent release of pro-inflammatory mediators. When the Abeta deposition process is already started, NSAIDs are no longer effective and may even be detrimental because of their inhibitory activity on chronically activated microglia that on long-term may mediate Abeta clearance. The research community should conduct long-term trials with NSAIDs in cognitively normal APOE epsilon4 carriers.
Applications of Raman spectroscopy in cancer diagnosis (2018)

Novel approaches toward understanding the evolution of disease can lead to the discovery of biomarkers that will enable better management of disease progression and improve prognostic evaluation. Raman spectroscopy is a promising investigative and diagnostic tool that can assist in uncovering the molecular basis of disease and provide objective, quantifiable molecular information for diagnosis and treatment evaluation. This technique probes molecular vibrations/rotations associated with chemical bonds in a sample to obtain information on molecular structure, composition, and intermolecular interactions. Raman scattering occurs when light interacts with a molecular vibration/rotation and a change in polarizability takes place during molecular motion. This results in light being scattered at an optical frequency shifted (up or down) from the incident light. By monitoring the intensity profile of the inelastically scattered light as a function of frequency, the unique spectroscopic fingerprint of a tissue sample is obtained. Since each sample has a unique composition, the spectroscopic profile arising from Raman-active functional groups of nucleic acids, proteins, lipids, and carbohydrates allows for the evaluation, characterization, and discrimination of tissue type. This review provides an overview of the theory of Raman spectroscopy, instrumentation used for measurement, and variation of Raman spectroscopic techniques for clinical applications in cancer, including detection of brain, ovarian, breast, prostate, and pancreatic cancers and circulating tumor cells.
Cobalt-mediated Dimerization of the Human Natural Killer Cell Inhibitory Receptor (2000)

Upon engagement of specific class I major histocompatibility complex (MHC) molecules on target cells, inhibitory receptors on natural killer (NK) cells deliver a negative signal that prevents the target cell lysis by NK cells. In humans, killer cell immunoglobulin-related receptors (KIR) with two immunoglobulin-like domains (KIR2D) modulate the lysis of target cells bearing specific HLA-C alleles (Moretta, A., Vitale, M., Bottino, C., Orengo, A. M., Morelli, L., Augugliaro, R., Barbaresi, M., Ciccone, E., and Moretta, L. (1993) J. Exp. Med. 178, 597-604). The transduction of inhibitory signals by KIR2D molecules is impaired by the zinc chelator, 1,10-phenanthroline, and mutation of a putative zinc-binding site (Rajagopalan, S., and Long, E. O. (1998) J. Immunol. 161, 1299-1305), but the mechanism by which zinc may affect the function of KIR remains unknown. In this study, the inhibitory NK receptor KIR2DL1 was discovered to dimerize in the presence of Co(2+) as observed on native gel electrophoresis and by gel filtration column chromatography. Furthermore, Co(2+)-mediated KIR2DL1 dimer binds to HLA-Cw4 with higher affinity than the wild type KIR2DL1 monomer. Replacement of the amino-terminal His residue by Ala abolishes the ability of KIR2DL1 to bind Co(2+), indicating that Co(2+)-mediated KIR2DL1 dimerization involves pairing of the D1 domain. Although not observed on native gels, the inhibitory receptor KIR2DL1 can be chemically cross-linked into dimers in the presence of Zn(2+) and its related divalent metal ions, suggesting that Co(2+)-mediated dimerization of KIR2DL1 may mimic a weaker interaction between KIR2DL1 and zinc in vivo.
Dynamic Impact of Methylation at the M.HhaI Target Site:  A Solid-State Deuterium NMR Study (2001)

Base methylation plays an important role in numerous biological functions of DNA, from inhibition of cleavage by endonucleases to inhibition of transcription factor binding. Studies of nucleic acid structure have shown little differences in unmethylated DNAs and the identical sequence containing methylated analogues. We have investigated changes in the local dynamics of DNA upon substitution of a methylated cytosine analogue for cytosine using solid-state deuterium NMR. In particular, we have observed changes in the local dynamics at the target site of the M. HhaI restriction system. These studies observe changes in the amplitudes of the local backbone dynamics at the actual target site of the HhaI methyltransferase. This conclusion is another indication that the significant result of base methylation is to perturb the local dynamics, and therefore the local conformational flexibility, of the DNA helix, inhibiting or restricting the protein's ability to manipulate the DNA helix in order to perform its chemical alterations.
Radioimmunotherapy of Solid Tumors: Searching for the Right Target (2010)

Radioimmunotherapy of solid tumors remains a challenge despite the tremendous success of ⁹⁰Y ibritumomab tiuxetan (Zevalin) and ¹³¹I Tositumomab (Bexxar) in treating non-Hodgkin's lymphoma. For a variety of reasons, clinical trials of radiolabeled antibodies against solid tumors have not led to responses equivalent to those seen against lymphoma. In contrast, promising responses have been observed with unlabeled antibodies that target solid tumor receptors associated with cellular signaling pathways. These observations suggest that anti-tumor efficacy of the carrier antibody might be critical to achieving clinical responses. Here, we review and compare tumor antigens targeted by radiolabeled antibodies and unlabeled antibodies used in immunotherapy. The review shows that the trend for radiolabeled antibodies under pre-clinical development is to also target antigens associated with signaling pathways that are essential for the growth and survival of the tumor.
Pathobiology of Pulmonary Hypertension (2007)

A variety of conditions can lead to the development of pulmonary arterial hypertension (PAH). Current treatments can improve symptoms and reduce the severity of the hemodynamic abnormality, but most patients remain quite limited, and deterioration in their condition necessitates a lung transplant. This review discusses current experimental and clinical studies that investigate the pathobiology of PAH. An emerging theme is the consideration of ways in which one might reverse the advanced occlusive structural changes in the pulmonary circulation causing PAH. The current debate concerning the role of regeneration through stem cells is presented. This review also highlights investigations in a number of laboratories relating the pathobiology of PAH to mutations causing loss of function of bone morphogenetic protein receptor II in patients with familial PAH, as well as sporadic cases.
Discriminative Learning Under Covariate Shift (2009)

We address classification problems for which the training instances are governed by an input distribution that is allowed to differ arbitrarily from the test distribution—problems also referred to as classification under covariate shift. We derive a solution that is purely discriminative: neither training nor test distribution are modeled explicitly. The problem of learning under covariate shift can be written as an integrated optimization problem. Instantiating the general optimization problem leads to a kernel logistic regression and an exponential model classifier for covariate shift. The optimization problem is convex under certain conditions; our findings also clarify the relationship to the known kernel mean matching procedure. We report on experiments on problems of spam filtering, text classification, and landmine detection.
On separating environmental and speaker adaptation (2003)

This paper presents a maximum likelihood (ML) approach, concerned to the background model estimation, in noisy acoustic non-stationary environments. The external noise source is characterised by a time constant convolutional and a time varying additive components. The HMM composition technique, provides a mechanism for integrating parametric models of acoustic background with the signal model, so that noise compensation is tightly coupled with the background model estimation. However, the existing continuous adaptation algorithms usually do not take advantage of this approach, being essentially based on the MLLR algorithm. Consequently, a model for environmental mismatch is not available and, even under constrained conditions a significant number of model parameters have to be updated. From a theoretical point of view only the noise model parameters need to be updated, being the clean speech ones unchanged by the environment. So, it can be advantageous to have a model for environmental mismatch. Additionally separating the additive and convolutional components means a separation between the environmental mismatch and speaker mismatch when the channel does not change for long periods. This approach was followed in the development of the algorithm proposed in this paper. One drawback sometimes attributed to the continuous adaptation approach is that recognition failures originate poor background estimates. This paper also proposes a MAP-like method to deal with this situation.
Cancer immunoediting: from immuno- surveillance to tumor escape (2002)

The concept that the immune system can recognize and destroy nascent transformed cells was originally embodied in the cancer immunosurveillance hypothesis of Burnet and Thomas. This hypothesis was abandoned shortly afterwards because of the absence of strong experimental evidence supporting the concept. New data, however, clearly show the existence of cancer immunosurveillance and also indicate that it may function as a component of a more general process of cancer immunoediting. This process is responsible for both eliminating tumors and sculpting the immunogenic phenotypes of tumors that eventually form in immunocompetent hosts. In this review, we will summarize the historical and experimental basis of cancer immunoediting and discuss its dual roles in promoting host protection against cancer and facilitating tumor escape from immune destruction.
Imidothiazoles (1968)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTImidothiazolesLeonard M. Rice, Kenneth R. Scott, and Charles H. GroganCite this: J. Med. Chem. 1968, 11, 1, 183–185Publication Date (Print):January 1, 1968Publication History Published online1 May 2002Published inissue 1 January 1968https://pubs.acs.org/doi/10.1021/jm00307a054https://doi.org/10.1021/jm00307a054research-articleACS PublicationsRequest reuse permissionsArticle Views210Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
WorldWideWeb : proposal for a HyperText Project (1990)

HyperText is a way to link and access information of various kinds as a web of nodes in which the user can browse at will.Potential/y, HyperText provides a single user-interface to many large classes of stored information such as reports, notes, data-bases, computer documentation and on-line systems help.We propose the implementation of a simple scheme to incorporate several different servers of machine-stored information already available at CERN, including an analysis of the requirements for information access needs by experiments.