gebhart/patrepeval huggingface dataset:
Rationale and Clinical Results of Multi-target Treatments in Oncology (2007)

During the last 10 years, the concept of targeted biological therapy for the treatment of cancer has emerged. Targeted agents entered clinical practice only recently, and the first drugs with demonstrated clinical efficacy were mainly inhibitors of the ErbB family of receptors (i.e., EGFR and HER-2), either monoclonal antibodies (MAbs) or tyrosine kinase inhibitors (TKIs). After the proof of concept for the clinical efficacy and tolerability of these selective agents, it was conceived that most tumors will depend on more than one signaling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signaling pathways or multiple steps in the same pathway, either by the development of multi-targeted agents or the combination of single targeted drugs. The recent FDA and EMEA approval of sorafenib and sunitinib, both multi-targeted TKIs, marked the coming of age of this new generation of drugs. Now a whole new wave of multi-targeted compounds is moving into clinical trials, raising in the minds of investigators important questions about the best strategies to pursue in their use and many doubts about their differences and the seeming redundancies in the pipelines of pharmaceutical companies. This review will deal with the rationale underlying the multi-targeted approach and with the available clinical experience with multi-targeted agents, especially focusing on molecules with anti-EGFR mechanisms of action.
Therapeutic potential of RNA interference against cancer (2006)

One of the most dramatic events of the past 5 years in the field of molecular biology has been the discovery of RNA interference (RNAi). Although RNAi is an evolutionarily conserved phenomenon for sequence-specific gene silencing in mammalian cells, exogenous small interfering RNA (siRNA) and vector-based short hairpin RNA (shRNA) can also invoke RNAi responses. Both are now not only experimental tools for analyzing gene function but are expected to be excellent avenues for drug target discovery and the emerging class of gene medicine for targeting incurable diseases such as cancer. The success of cancer therapeutic use of RNAi relies on the development of safe and efficacious delivery systems that introduce siRNA and shRNA expression vectors into target tumor cells. For their delivery, a variety of strategies have been used, most of them based on traditional gene therapy delivery systems. In this review, we present siRNA delivery method strategies and discuss the potential of RNAi-based gene therapy in cancer treatment.
Activity of ß-lactamases against ß-lactams (1988)

Resistance mediated by beta-lactamases is an important mechanism which has evolved in both Gram-positive and Gram-negative bacteria. There are a large number of different beta-lactamases produced by micro-organisms. Synthesis can be mediated by chromosomes, plasmids, or transposons. Enzyme kinetics for these different beta-lactamases are expressed as affinity of the enzyme for the substrate (1/Km) and rate of hydrolysis of the substrate by the enzyme (Vmax). Such kinetics at physiological concentrations of the enzyme and substrate are important factors in determining the activity of beta-lactam agents. Other factors include the cellular location and amount of enzyme. The clinical importance of subtle differences in beta-lactamase-mediated resistance for both Gram-positive and Gram-negative bacteria is becoming apparent. Antagonism of beta-lactams by beta-lactamases becomes increasingly more important as a resistance mechanism as our knowledge and understanding of this phenomenon grows.
13C‐NMR study of autotrophic CO2 fixation pathways in the sulfur‐reducing Archaebacterium Thermoproteus neutrophilus and in the phototrophic Eubacterium Chloroflexus aurantiacus (1992)

The unresolved autotrophic CO2 fixation pathways in the sulfur-reducing Archaebacterium Thermoproteus neutrophilus and in the phototrophic Eubacterium Chloroflexus aurantiacus have been investigated. Autotrophically growing cultures were labelled with [1,4-13C1]succinate, and the 13C pattern in cell constituents was determined by 1H- and 13C-NMR spectroscopy of purified amino acids and other cell constituents. In both organisms succinate contributed to less than 10% of cell carbon, the major part of carbon originated from CO2. All cell constituents became 13C-labelled, but different patterns were observed in the two organisms. This proves that two different cyclic CO2 fixation pathways are operating in autotrophic carbon assimilation in both of which succinate is an intermediate. The 13C-labelling pattern in T. neutrophilus is consistent with the operation of a reductive citric acid cycle and rules out any other known autotrophic CO2 fixation pathway. Surprisingly, the proffered [1,4-13C1]succinate was partially converted to double-labelled [3,4-13C2]glutamate, but not to double-labelled aspartate. These findings suggest that the conversion of citrate to 2-oxoglutarate is readily reversible under the growth conditions used, and a reversible citrate cleavage reaction is proposed. The 13C-labelling pattern in C. aurantiacus disagrees with any of the established CO2 fixation pathways; it therefore demands a novel autotrophic CO2 fixation cycle in which 3-hydroxypropionate and succinate are likely intermediates. The bacterium excreted substantial amounts of 3-hydroxypropionate (5 mM) and succinate (0.5 mM) at the end of autotrophic growth. Autotrophically grown Chloroflexus cells contained acetyl-CoA carboxylase and propionyl-CoA carboxylase activity. These enzymes are proposed to be the main CO2-fixing enzymes resulting in malonyl-CoA and methylmalonyl-CoA formation; from these carboxylation products 3-hydroxypropionate and succinate, respectively, can be formed.
Induction of Th17 Cellular Immunity With a Novel Nanoemulsion Adjuvant (2010)

T17 (T-helper-17) cytokine responses have been recently recognized as an important component for the protective immunity produced by vaccination. However, the mechanism by which immune adjuvants induce T17 immunity has not been defined. We have developed a novel mucosal nanoemulsion (NE) adjuvant that produces a robust humoral and T1 cellular immunity. Herein, we demonstrate that immunization with NE adjuvant induces a T17 response to diverse antigens in both outbred and inbred mice. CD86 deficiency had a limited effect on the induction of IL-17, however, double CD80/CD86, CD40, and IL-6 (interleukin 6) mutant mice failed to produce T17 immunity in response to NE adjuvant. Mice deficient in TLR2 and TLR4 (Toll-like receptors 2 and 4) had a diminished IL-17 response. Our data indicate that nasal mucosal immunization with NE adjuvant produces T1 and T17 immunity; that this process requires IL-6, CD40, and at least one of the CD80/CD86 molecules; and that the induction of TH17 is enhanced by the presence of TLR2 and TLR4 receptors. This unique approach to vaccination may have a significant role in protection against mucosal and intracellular pathogens.
ADAM10 as a Therapeutic Target for Cancer and Inflammation (2009)

Both cancer and chronic inflammatory diseases are often marked by homeostatic signal transduction pathways run amok. Cleavage of membrane-bound substrates by extracellular metalloproteinases is frequently the rate limiting step in activating many of these pathways, resulting either in liberation of active ligands (shedding) or initiating further processing into bioactive cytoplasmic domains (regulated intramembrane proteolysis or RIP). ADAM10 is a member of the ADAM (A Disintegrin And Metalloproteinase) family of transmembrane metalloproteinases implicated in the RIPing and shedding of dozens of substrates that drive cancer progression and inflammatory disease, including Notch, E-cadherin, EGF, ErbB2 and inflammatory cytokines. ADAM10's emerging role as a significant contributor to these pathologies has led to intense interest in it as a potential drug target for disease treatment. Here we discuss some of the established functions of ADAM10 and the implications of its inhibition in disease progression.
Elevated Levels of the IGF-Binding Protein Protease MMP-1 in Asthmatic Airway Smooth Muscle (1999)

We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene D4 (LTD4) is co-mitogenic with insulin-like growth factors (IGFs) in airway smooth-muscle (ASM) cells in vitro. This synergistic effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-produced IGF binding proteins (IGFBPs), which are cell growth-inhibitory proteins. We also identified this IGFBP protease to be the matrix metalloproteinase-1 (MMP-1), and showed that this enzyme had a significant role in modulating IGF action in ASM cells. In the present study, we tested the hypothesis that ASM hyperplasia in vivo involves induction of MMP-1 leading to IGFBP proteolysis. We detected the presence of MMP-1 and measured its levels in human airway tissue sections prepared from nonasthmatic and asthmatic subjects. Six nonasthmatic and six asthmatic airway tissue samples were analyzed for immunoreactive MMP-1 through an immunohistochemical detection method. Both the bronchial and tracheal smooth-muscle cells from different regions of the same sample were examined and documented. The immunostaining for MMP-1 was significantly elevated in both the bronchial and tracheal smooth-muscle cells of the airway sections from asthmatic samples relative to that of the nonasthmatic samples. The differences in levels of MMP-1, IGFBP-2, IGFBP-3, and IGFBP proteolytic activity were quantified using densitometric analyses of the ASM tissue extracts that were separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The MMP-1 levels in the asthmatic airway tissue extracts were 12-fold higher than those found in control samples. In addition, IGFBP-2 and IGFBP-3, which we have previously demonstrated to be proteolytic substrates of MMP-1, were found to be cleaved in asthmatic airway tissue extracts. Furthermore, the asthmatic airway extracts contained IGFBP proteolytic activity that was shown by immunodepletion studies to be due to MMP-1. These observations demonstrate that MMP-1 may play a significant role in inducing ASM hyperplasia and airway obstruction in asthma by modulating the IGF axis.
Cytokine induction by the immunomodulators imiquimod and S-27609 (1995)

Imiquimod (R-837, S-26308) and the analogue S-27609 were evaluated for cytokine induction in human blood cells. Both compounds induced interferon-alpha (IFN), tumor necrosis factor-alpha (TNF), interleukin (IL)-1 beta, and IL-6 with S-27609 being 5 to 10 times more potent. Imiquimod and S-27609 also induced IL-1 alpha, IL-1 receptor antagonist, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), and macrophage inflammatory protein-1 alpha. The profile of cytokines induced by imiquimod and S-27609 was different from those seen with lipopolysaccharide and polyinosinic-polycytidylic acid. Kinetic studies with both imiquimod and S-27609 revealed induction of cytokines as early as 1-4 h after stimulation. Although most of the cytokines produced by S-27609 were secreted, significant concentrations of IL-1 alpha and IL-1 beta remained intracellular. Monocytes were largely responsible for the cytokines produced. Finally, S-27609-induced mRNA expression for TNF, IFN, and IL-8, and this induction did not require protein synthesis. Taken together, these studies extend previous findings by showing induction of additional cytokines and providing insight into the mechanism of cytokine induction by these molecules.
Brain as a paradigm of organ growth: Hedgehog–Gli signaling in neural stem cells and brain tumors (2005)

The Hedgehog-Gli (Hh-Gli) signaling pathway is essential for numerous events during the development of many animal cell types and organs. In particular, it controls neural cell precursor proliferation in dorsal brain structures and regulates the number of neural stem cells in distinct embryonic, perinatal, and adult niches, such as the developing neocortex, the subventricular zone of the lateral ventricle of the forebrain, and the hippocampus. We have proposed that Hh-Gli signaling regulates dorsal brain growth during ontogeny and that its differential regulation underlays evolutionary change in the morphology (size and shape) of dorsal brain structures. It is also critically involved in sporadic brain tumorigenesis--as well as several other human cancer--suggesting that tumors derive from stem cells or progenitors maintaining an inappropriate active Hh-Gli pathway. Importantly, we and others have demonstrated that human sporadic tumors from the brain and other organs require sustained HH-GLI signaling for sustained growth and survival. Modulating HH-GLI signaling thus represents a novel rational avenue to treat, on one hand, brain degeneration and injury by inducing controlled HH-GLI-mediated regeneration and growth, and on the other hand, to combat cancer by blocking its abnormal activity in tumor cells.
Tumor Necrosis Factor, Other Cytokines and Disease (1993)

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1 7 CYTOKINES AND EFFECTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1 8 Cell Sources and Stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1 8 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 REGULA TORS AND EFFECTORS OF CYTOKINE EFFECTS . . . . . . . . . . . . 322 Factors that Enhance Effects of TNF . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Factors that Suppress Effects of TNF . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Secondary Mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Locations of Production in Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 Development of Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 CYTOKINES AND DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Shock and Tissue Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Cachexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 Insulin Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 HlV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333 Adult Respiratory Distress Syndrome and Reperfusion Injury . . . . . . . . . . . . . 333 Diseases of Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334 FUTURE OF CYTOKINES IN THE BIOLOGY OF DISEASE . . . . . . . . . . . . . 335
A high-throughput screen to identify enhancers of ADAR-mediated RNA-editing (2013)

Adenosine to inosine deamination of RNA is widespread in metazoa. Inosines are recognized as guanosines and, therefore, this RNA-editing can influence the coding potential, localization and stability of RNAs. Therefore, RNA editing contributes to the diversification of the transcriptome in a flexible manner. The editing reaction is performed by adenosine deaminases that act on RNA (ADARs), which are essential for normal life and development in many organisms. Changes in editing levels are observed during development but also in neurological pathologies like schizophrenia, depression or tumors. Frequently, changes in editing levels are not reflected by changes in ADAR levels suggesting a regulation of enzyme activity. Until now, only a few factors are known that influence the activity of ADARs. Here we present a two-stage in vivo editing screen aimed to isolate enhancers of editing. A primary, high-throughput yeast-screen is combined with a more accurate secondary screen in mammalian cells that uses a fluorescent read-out to detect minor differences in RNA-editing. The screen was successfully employed to identify DSS1/SHFM1, the RNA binding protein hnRNP A2/B1 and a 3' UTR as enhancers of editing. By varying intracellular DSS1/SHFM1 levels, we can modulate A to I editing by up to 30%. Proteomic analysis indicates an interaction of DSS1/SHFM1 and hnRNP A2/B1 suggesting that both factors may act by altering the cellular RNP landscape. An extension of this screen to cDNAs from different tissues or developmental stages may prove useful for the identification of additional enhancers of RNA-editing.
Monophosphoryl lipid A as a prophylactic for sepsis and septic shock. (1995)

The ability of monophosphoryl lipid A (MLA) to provide prophylactic protection against septic shock was evaluated in a mouse model of induced endotoxin hypersensitivity. Treatments of hypersensitized animals with low doses of MLA attenuated endotoxin lethality and endotoxin-mediated liver damage. These effects were related to the ability of MLA to suppress accumulation of TNF-alpha and IFN-gamma in the bloodstream of animals. MLA treatments had only a modest effect in suppressing the accumulation of nitrate in the bloodstream. This implied that MLA did not suppress induction of macrophage and hepatocyte nitric oxide synthetases that contribute to antimicrobial defense and protect against endotoxin-mediated liver damage. The MLA treatments did not appear to compromise inflammatory defenses against local infection since locally recruited leukocytes remained responsive to endotoxin after hypersensitivity had been attenuated. In agreement with these findings, other studies have shown that the induction of endotoxin tolerance by MLA parallels the induction of resistance of animals to lethal challenges with either Gram negative or Gram positive bacteria. As predicted from preclinical studies, human trials of the clinical form of MLA (MPL-immunostimulant) have confirmed that MLA could attenuate systemic responses to endotoxin in normal volunteers, including the attenuation of blood cytokine accumulation and attenuation of symptomatic responses.
Double-stranded RNA induces mRNA degradation inTrypanosomabrucei (1998)

Double-stranded RNA (dsRNA) recently has been shown to give rise to genetic interference in Caenorhabditis elegans and also is likely to be the basis for phenotypic cosuppression in plants in certain instances. While constructing a plasmid vector for transfection of trypanosome cells, we serendipitously discovered that in vivo expression of dsRNA of the alpha-tubulin mRNA 5' untranslated region (5' UTR) led to multinucleated cells with striking morphological alterations and a specific block of cytokinesis. Transfection of synthetic alpha-tubulin 5' UTR dsRNA, but not of either strand individually, caused the same phenotype. On dsRNA transfection, tubulin mRNA, but not the corresponding pre-mRNA, was rapidly and specifically degraded, leading to a deficit of alpha-tubulin synthesis. The transfected cells were no longer capable of carrying out cytokinesis and eventually died. Analysis of cytoskeletal structures from these trypanosomes revealed defects in the microtubules of the flagellar axoneme and of the flagellar attachment zone, a complex cortical structure that we propose is essential for establishing the path of the cleavage furrow at cytokinesis. Last, dsRNA-mediated mRNA degradation is not restricted to alpha-tubulin mRNA but can be applied to other cellular mRNAs, thus establishing a powerful tool to genetically manipulate these important protozoan parasites.
Evidence-Based Practice and Qualitative Research: A Primer for Library and Information Professionals (2007)

Objective - This paper discusses the importance of qualitative research in evidence-based library and information practice (EBLIP), with a focus on practical tips for evaluating and implementing effective qualitative research projects. &#x0D; &#x0D; Methods - The paper provides a brief introduction to the nature of qualitative inquiry and its status within current models of evidence assessment. Three problems of excluding qualitative research from the evidence-base in library and information studies (LIS) are identified: 1) ignoring the social sciences and humanities traditions that inform research in the field; 2) privileging of quantitative and experimental methods over others in evidence assessment; and, 3) focusing attention away from the best evidence for LIS research problems. &#x0D; &#x0D; Results - Qualitative approaches commonly used in library and information contexts are discussed, along with strategies for assessing quality in this work and some of the common ethics-related issues that researchers and professionals must consider. &#x0D; &#x0D; Conclusions - LIS professionals are encouraged to: 1) select research methods – including qualitative approaches – that best suit LIS questions; 2) design collaborative projects that combine quantitative and qualitative approaches, that will address research questions in a more complete way; 3) consider qualitative measures of rigor in assessing quality – rather than imposing quantitative expectations; and 4) revise existing models of “evidence” to recognize the value and rigor of qualitative research projects.
Design and performance of a THz emission and detection setup based on a semi-insulating GaAs emitter (2002)

We have built a relatively simple, highly efficient, THz emission and detection system centered around a 15 fs Ti:sapphire laser. In the system, 200 mW of laser power is focused to a 120 μm diam spot between two silverpaint electrodes on the surface of a semi-insulating GaAs crystal, kept at a temperature near 300 K, biased with a 50 kHz, ±400 V square wave. Using rapid delay scanning and lock-in detection at 50 kHz, we obtain probe laser quantum-noise limited signals using a standard electro-optic detection scheme with a 1-mm-thick (110) oriented ZnTe crystal or a (110) oriented 0.1-mm-thick GaP crystal. The maximum THz-induced differential signal that we observe is ΔI/I=7×10−3, corresponding to a THz peak amplitude of 95 V/cm. The THz average power was measured to be about 40 μW, to our knowledge, the highest power reported so far generated with Ti:sapphire oscillators as a pump source. The system uses off-the-shelf electronics and requires no microfabrication techniques.
Synthesis of 5-methylaminomethyl-2-selenouridine in tRNAs: 31P NMR studies show the labile selenium donor synthesized by the selD gene product contains selenium bonded to phosphorus. (1992)

An enzyme preparation from Salmonella typhimurium catalyzes the conversion of 5-methylaminomethyl-2-thiouridine in tRNAs to 5-methylaminomethyl-2-selenouridine when supplemented with selenide and ATP. Similar preparations from a Salmonella mutant strain carrying a defective selD gene fail to catalyze this selenium substitution reaction. However, supplementation of the deficient enzyme preparation with the purified selD gene product (SELD protein) restored synthesis of seleno-tRNAs. In the absence of the complementary enzyme(s), the SELD protein catalyzes the synthesis of a labile selenium donor compound from selenide and ATP. 31P NMR studies show that among the products of this reaction are AMP and a compound containing selenium bonded to phosphorus. The reaction is completely dependent on the addition of both selenide and magnesium. The dependence of reaction velocity on ATP concentration shows sigmoidal kinetics, whereas dependence on selenide concentration obeys Michaelis-Menten kinetics indicating a Km value of 46 microM for selenide.