gebhart/patrepeval huggingface dataset:
Suicide gene therapy : methods and reviews (2004)

Suicide gene therapy has become a major element in anticancer gene therapy and holds great promise for the future. In Suicide Gene Therapy: Methods and Reviews, prominent researchers and clinicians comprehensively detail the theory and practice of this exciting and elegant therapeutic approach. In their multidisciplinary treatment, the authors cover all the major aspects of suicide gene therapy, including the design and use of vectors in gene transduction, various enzyme and prodrug systems, the mechanistic analysis of the bystander effect, the design and synthesis of prodrugs, the immunological implications, and its clinical impact. They also describe and expound upon all the cutting-edge methods needed to explore, study, and advance understanding of the basic biology underlying gene therapy. Each fully tested method includes step-by-step instructions, a discussion of the principle behind the technique, equipment and reagent lists, tips on troubleshooting and avoiding pitfalls, and notes on the interpretation and use of results. Authoritative and up-to-date, Suicide Gene Therapy: Methods and Reviews not only summarizes our knowledge of suicide gene therapy today, but also provides the experimental means to advance its future development and therapeutic applications
Antibiotic efficacy is linked to bacterial cellular respiration (2015)

Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes--the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy.
High throughput analysis of differential gene expression (1998)

Elucidation of the changes in gene expression associated with biological processes is a central problem in biology. Advances in molecular and computational biology have led to the development of powerful, high-thoughput methods for the analysis of differential gene expression. These tools have opened up new opportunities in disciplines ranging from cell and developmental biology to drug development and pharmacogenomics. In this review, the attributes of five commonly used differential gene expression methods are discussed: expressed sequence tag (EST) sequencing, cDNA microarray hybridization, subtractive cloning, differential display, and serial analysis of gene expression (SAGE). The application of EST sequencing and microarray hybridization is illustrated by the discovery of novel genes associated with osteoblast differentiation. The application of subtractive cloning is presented as a tool to identify genes regulated in vivo by the transcription factor pax-6. These and other examples illustrate the power of genomics for discovering novel genes that are important in biology and which also represent new targets for drug development. The central theme of the review is that each of the approaches to identifying differentially expressed genes is useful, and that the experimental context and subsequent evaluation of differentially expressed genes are the critical features that determine success. J. Cell. Biochem. Suppls. 30/31:286–296, 1998. © 1998 Wiley-Liss, Inc.
Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade (2016)

Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that the presence of somatic mutations is associated with benefit from checkpoint inhibition. A hypothesis was posited that neoantigen homology to pathogens may in part explain the link between somatic mutations and response. To further examine this hypothesis, we reanalyzed cancer exome data obtained from our previously published study of 64 melanoma patients treated with CTLA-4 blockade and a new dataset of RNA-Seq data from 24 of these patients. We found that the ability to accurately predict patient benefit did not increase as the analysis narrowed from somatic mutation burden, to inclusion of only those mutations predicted to be MHC class I neoantigens, to only including those neoantigens that were expressed or that had homology to pathogens. The only association between somatic mutation burden and response was found when examining samples obtained prior to treatment. Neoantigen and expressed neoantigen burden were also associated with response, but neither was more predictive than somatic mutation burden. Neither the previously described tetrapeptide signature nor an updated method to evaluate neoepitope homology to pathogens was more predictive than mutation burden. Cancer Immunol Res; 5(1); 84-91. ©2016 AACR.
Regulation of Carbon Catabolism inBacillusSpecies (2000)

The gram-positive bacterium Bacillus subtilisis capable of using numerous carbohydrates as single sources of carbon and energy. In this review, we discuss the mechanisms of carbon catabolism and its regulation. Like many other bacteria, B. subtilis uses glucose as the most preferred source of carbon and energy. Expression of genes involved in catabolism of many other substrates depends on their presence (induction) and the absence of carbon sources that can be well metabolized (catabolite repression). Induction is achieved by different mechanisms, with antitermination apparently more common in B. subtilis than in other bacteria. Catabolite repression is regulated in a completely different way than in enteric bacteria. The components mediating carbon catabolite repression in B. subtilis are also found in many other gram-positive bacteria of low GC content.
Free hydroxyl radicals are formed on reaction between the neutrophil‐derived species Superoxide anion and hypochlorous acid (1993)

Superoxide anion reacts with hypochlorous acid to yield free hydroxyl radicals, as shown by the hydroxylation of benzoate. This reaction is analogous to the Haber-Weiss reaction but in the absence of metal ions is at least six orders of magnitude faster.
Outcomes of MDS Patients with Chromosome 7 Abnormalities Treated with 5-Azacytidine. (2007)

Abstract Chromosome 7 abnormalities occurring in isolation or as part of complex cytogenetics confer an adverse prognosis in patients with myelodysplastic syndromes (MDS). Preliminary clinical data from various groups has suggested that the use of 5-azacytidine, a DNA methyl transferase inhibitor, in this sub-group of poor risk patients may be associated with an improved clinical response. We report on a retrospective analysis on the outcomes of 31 MDS patients with chromosome 7 abnormalities treated with 5-azacytidine. 5-azacytidine was administered subcutaneously at 75mg/m2 daily for 7 days and each cycle was repeated every 28 days. The median age of the cohort was 61 years (range: 17–80). Based on the WHO classification, 4 patients (13%) were RCMD/RCMD-RS, 17 were RAEB I/II (55%), 8 patients had acute myeloid leukemia transformed from MDS (26%), an additional 2 patients had secondary MDS. The IPSS of the cohort was Int-1(n=1), Int-2(n=12), high-risk(n=18). 13(42%) patients had isolated chromosome 7 abnormalities, 8(58%) had chromosome 7 abnormalities as part of a more complex cytogenetic profile. 10 patients(33%) had previously been treated prior to therapy with 5 azacytidine. 5 patients were withdrawn from treatment after 1 cycle due to drug intolerance or disease progression and were excluded from further analysis. The remaining 26 patients received a median of 6 cycles of treatment (range: 2–28 cycles). Response criteria was based on the modified IWG response criteria for MDS (Cheson et al Blood 2007). 7 patients achieved a complete response (CR), 3 partial response (PR), with haematological improvement (HI) in a further patient. The median cycles of treatment before response was 2, with median response duration of 10.5 months (range: 4–20 months). Overall response rate (CR+PR+HI) was 6/12 (50%) for patients with isolated chromosome 7 abnormalities as compared with 5/14 (36%) for patients with complex cytogenetics (p=0.15). 7 patients had a complete cytogenetic response, with a further 2 patients achieving a partial cytogenetic response. These cytogenetic responses were observed in 4/12 patients with isolated chromosome 7, and 5/16 patients with complex cytogenetics. The median survival of the cohort was 19.8 months (95%CI: 16.3–23.3). Patients with isolated chromosome 7 abnormalities had median survival of 24.8 months (95%CI: 17.8–31.8) compared with those with complex cytogenetics (17.3 months, 95%CI: 8.3–26.3, p=0.10). In addition, patients achieving cytogenetic remission (complete or partial) had an improved overall survival when compared with non-responders (median OS: 24.8 vs 19.8 months, p=0.05). WHO classification, IPSS, patient age, and history of prior therapy were all not significant predictors of response or overall survival in this cohort. In summary, 5-azacytidine is able to induce high remission rates in a cohort of high risk MDS patients with chromosome 7 abnormalities.
EXTENDED PRESENCE OF ANTIDE (NAL-LYS GnRH ANTAGONIST) IN CIRCULATION: PROLONGED DURATION OF GONADOTROPIN INHIBITION MAY DERIVE FROM ANTIDE BINDING TO SERUM PROTEINS* (1990)

Previous data from this laboratory revealed a rapid (-12h) and unexpectedly long (-30 days) inhibition of pituitary gonadotropin secretion after a single injection of Antide (Nal-Lys GnRH antagonist) in ovariectomized (OVX) monkeys. Although the apparent mechanism of action of Antide is competitive occupancy of GnRH receptors, the etiology of the prolonged action is unknown. Here, we report development of a radioreceptor assay to measure circulating Antide levels to determine the mechanism(s) of its long duration of action. Five long-term OVX monkeys were injected with Antide (3.0 mg/kg). Blood samples were collected daily for 30 days, and thereafter on alternate days until day 60. Following sc or iv Antide injection, peripheral luteinizing hormone (LH) levels declined from 281 +/- 19 ng/ml to 29 +/- 3 ng/ml within one day (P less than 0.05). LH levels slowly recovered to pretreatment levels within 35 +/- 7 days. Peripheral Antide levels were 16,531 +/- 4,432 ng/ml within 15 minutes following iv injection, and 52 +/- 21 ng/ml at 1 day after sc Antide injection. Interestingly, thereafter clearance of Antide-from the peripheral circulation was very slow, with an apparent t1/2 (second phase) of 6.5 days following iv administration. Detectable Antide levels were present in the peripheral circulation for more than one month in all five monkeys. In a second experiment, incubation of 125I-Tyro Antide with OVX monkey serum resulted in binding of the labelled peptide to serum proteins and reduction of 125I-Tyro Antide binding to pituitary receptors. Following gel permeation chromatography, greater than 70% of the radioactivity was associated with a 66 kDa protein(s). In conclusion, the prolonged duration of gonadotropin inhibition by Antide seems to derive from the long circulatory half-life of this molecule. In turn, this extended action of Antide may be manifest, at least in part, by binding to serum protein(s) that serves as a built-in peripheral depot release mechanism.
Mechanism of the Ligand‐Free CuI‐Catalyzed Azide–Alkyne Cycloaddition Reaction (2005)

Ein kräftiger Motor: Die Cu-katalysierte Azid-Alkin-Cycloaddition (siehe Schema) beruht auf der schnellen Bildung von CuI-Acetylid-Komplexen aus terminalen Alkinen 2 und deren Fähigkeit zur Aktivierung organischer Azide 1. Eine kinetische Studie zu dieser Reaktion ergab eine bimolekulare Abhängigkeit vom Metall. Eine ungewöhnlich schnell verlaufende intramolekulare Variante lässt auf eine Kupfer-Triazol-Spezies 3 als reaktives Intermediat schließen. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2005/z461496_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Granulocyte colony-stimulating factor receptors in human acute myelocytic leukemia (1989)

The binding of granulocyte colony-stimulating factor (G-CSF) to normal and human acute myeloid leukemia (AML) cells was investigated with radiolabeled recombinant human G-CSF (rhG-CSF). In all 14 cases of primary AML specific receptors for G-CSF were demonstrated on purified blast cells. The average numbers of G-CSF receptors ranged from very low to 428 receptors per cell (mean). Normal granulocytes showed G-CSF binding sites on their surface at higher densities (703 to 1,296 sites per cell). G-CSF receptors appeared to be of a single affinity type with a dissociation constant (kd) ranging between 214 and 378 pmol/L for AML blasts and 405 to 648 pmol/L for granulocytes. In 12 of 14 cases, including those with relatively low specific binding, G-CSF was a potent inducer of DNA synthesis of blasts in vitro; therefore, apparently relatively few receptors are required to permit activation of AML cell growth. However, in two cases cell cycling was not activated in response to G-CSF despite G-CSF receptor availability. The results show that G-CSF receptors of high affinity are frequently expressed on the blasts of human AML, but their presence may not be a strict indicator of the proliferative responsiveness of the cells to G-CSF.
Turning Signals On and Off: GLUT4 Traffic in the Insulin-Signaling Highway (2005)

Insulin stimulation of glucose uptake into skeletal muscle and adipose tissues is achieved by accelerating glucose transporter GLUT4 exocytosis from intracellular compartments to the plasma membrane and minimally reducing its endocytosis. The round trip of GLUT4 is intricately regulated by diverse signaling molecules impinging on specific compartments. Here we highlight the key molecular signals that are turned on and off by insulin to accomplish this task.
Synthesis and Photophysical Properties of Fluorescent Derivatives of Methylmercury (1996)

New fluorescent methylmercury acetylides carrying the anthracene, acridinone, and dansyl frameworks have been prepared and photophysically characterized. These compounds, which partially retain the fluorescence properties of the parent alkynes, suggest a promising use as luminescent labels for the analysis of methylmercury.
Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells (2010)

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an 'immature' neonatal to a 'mature' adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation.
LRU-WSR: integration of LRU and writes sequence reordering for flash memory (2008)

Most mobile devices are equipped with a NAND flash memory even if it has characteristics of not-in-place update and asymmetric I/O latencies among read, write, and erase operations: write/erase operations are much slower than a read operation in a flash memory. For the overall performance of a flash memory system, the buffer replacement policy should consider the above severely asymmetric I/O latencies. However, existing LRU buffer replacement algorithm cannot deal with the above problem. This paper proposes the LRU-WSR buffer replacement algorithm that enhances LRU by reordering writes of not-cold dirty pages from the buffer cache to flash storage. The enhanced LRU-WSR algorithm focuses on reducing the number of write/erase operations as well as preventing serious degradation of buffer hit ratio. The experimental results show that the LRU-WSR outperforms other algorithms including LRU, CF-LRU, and FAB <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1</sup> .
Vitamin D-mediated modifications in protein-DNA interactions at two promoter elements of the osteocalcin gene. (1990)

By the combined use of DNase I footprinting, electrophoretic mobility-shift assay, and methylation interference analysis, we have identified a series of sequence-specific protein-DNA interactions in the 5' flanking region of the rat osteocalcin gene. Stimulation of osteocalcin gene expression by 1,25-dihydroxyvitamin D3, a physiologic mediator of this bone-specific gene in vitro and in vivo, is associated with modifications in the binding of ROS 17/2.8 cell nuclear factors to two promoter segments that up-regulate transcription. One segment located between -462 and -437 exhibits a vitamin D-dependent increase in sequence-specific binding of nuclear factors. This element (CTGGGTGAATGAGGACATTACTGACC), identified at single nucleotide resolution, contains a region of hyphenated dyad symmetry and shares sequence homology with consensus steroid-responsive elements and with the sequence that has been identified as the vitamin D receptor binding site in the human osteocalcin gene. We have also observed that vitamin D stimulation of osteocalcin gene expression results in a 5-fold increase in protein binding to the region of the osteocalcin box, a 24-nucleotide segment in the proximal promoter with a CCAAT motif as the central core. Our results demonstrate protein-DNA interactions in a vitamin D-responsive element and in a second sequence, the osteocalcin box, both of which are involved in the physiologic regulation of the osteocalcin gene in response to 1,25-dihydroxyvitamin D3.
Prolactin and Autoimmunity (2018)

The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL) has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood.
Release of respiratory control in Escherichia coli after bacteriophage adsorption: process independent of DNA injection (1985)

Adsorption of phages T4, T5, and BF23 to previously starved Escherichia coli cells triggered the immediate release of respiratory control. A similar stimulation of respiration was induced after T4 ghost attachment, showing that this process was independent of the mechanism of DNA injection. Rather, this change in the respiratory rate was related to the transient depolarization of the cytoplasmic membrane also induced after phage and ghost adsorption. Both processes were suppressed by addition of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid in the case of T4 (phage and ghosts) but not of T5 and BF23. The increase in respiratory rate observed after phage adsorption was of a magnitude similar to that induced by protonophores. Since other treatments that depolarize the membrane without a massive proton influx did not increase the rate of respiration of starved bacteria with the same efficiency, these results suggest that phage adsorption induced an entry of protons into the cell cytoplasm.