gebhart/patrepeval huggingface dataset:
Abstract 1923: The mTOR kinase inhibitor, CC214, preferentially blocks the growth of EGFRvIII-activated glioblastomas (2012)

Abstract mTOR pathway hyper activation is a common feature in many cancers, including in nearly 90% of Glioblastomas. mTOR exists in two multiprotein complexes, which differ in regulation, function, and response to the allosteric mTOR inhibitor rapamycin. The failure of glioblastomas to clinically respond to rapamycin appears to be mediated both by inability of rapamycin to inhibit mTORC2 signaling, and by failure to fully suppress p4E-BP1, a critical effector of mTORC1. The new generation of mTOR kinase inhibitors (mTORki) has emerged as a new class of targeted cancer therapies capable of blocking mTOR more potently than rapalogs (such as Rapamycin). Here we demonstrate that CC214-1 and CC214-2, mTOR kinase inhibitors, have potent effects on the growth of glioblastoma in vitro and in vivo. Across a panel of GBM cell lines, CC214-1 was significantly more effective at suppressing 4E-BP1 phosphorylation and protein translation, and mTORC2 signaling than rapamycin, resulting in significantly more growth inhibition at equal levels of suppression of S6 phosphorylation. EGFRvIII, the constitutively active EGFR mutant frequently detected in GBMs strongly activates mTORC1 and mTORC2 signaling, potently sensitizing tumors to CC214-1. In contrast, PTEN expression suppressed mTOR signaling and reduced the response to CC214-1. In vivo CC214-2 significantly inhibited mTORC1 and mTORC2 signaling, significantly suppressing tumor growth by 50%. CC214-1 also potently activated autophagy. Addition of chloroquine suppressed autophagy resulting in significant CC214-1-dependent apoptotic cell death. These results demonstrate the potential activity of mTOR kinase inhibitors in GBM, and identify EGFRvIII expression and PTEN loss as molecular determinants of response. These data also suggest that mTOR kinase inhibitors, alone or in combination with autophagy inhibiting agents, are likely to have significant anti-tumor efficacy in GBM patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1923. doi:1538-7445.AM2012-1923
THE CONSERVATION OF CHARLES DICKENS'S MANUSCRIPTS (1994)

Summary The manuscripts of Charles Dickens's novels in the Victoria and Albert Museum had been rebound in a way harmful to the objects. A project was set up to research the history of the manuscripts, and to assesstheircondition. Particularattention was given to the treatment of corrosive iron-gall inks, and blue writing paper. Possible rebinding methods were also considered. This paper discusses the results of the research, the choice of treatment and rebinding.
Cobalt(II)-organische Phosphaniminato-Komplexe mit Heterocuban-Struktur. Kristallstrukturen von [CoBr(NPR3)]4 mit R = Me, Et, [Co(C≡C-CMe3)(NPMe3)]4 und [Co(C≡C-SiMe3)(NPEt3)]4 (1998)

Die durch Reaktion von CoBr2 mit den silylierten Phosphaniminen Me3SiNPR3 (R = Me, Et) in der Schmelze bei 180 °C in Gegenwart von KF zugänglichen Phosphaniminato-Komplexe [CoBr(NPR3)]4 lassen sich mit den lithiumorganischen Reagentien LiC≡C–CMe3 und LiC≡C–SiMe3 in THF bei 0 °C unter Erhalt der Heterocubanstrukturen in die Alkinyl-Komplexe [Co(C≡C–CMe3) · (NPMe3)]4 und [Co(C≡C–SiMe3)(NPEt3)]4 umwandeln. Nach den Kristallstrukturanalysen bilden alle vier Verbindungen Heterocuban-Strukuren mit nur wenig verzerrten Co4N4-Würfelgerüsten. Organo-Cobalt(II) Phosphorane Iminato Complexes with Heterocubane Structures. Crystal Structures of [CoBr(NPR3)]4 with R = Me, Et, [Co(C≡C–CMe3)(NPMe3)]4, and [Co(C≡C–SiMe3)(NPEt3)]4 The phosphorane iminato complexes [CoBr(NPR3)]4, which are accessible by reaction of CoBr2 with the silylated phosphorane imines Me3SiNPR3 (R = Me, Et) in the melt at 180 °C and in the presence of KF, can be transformed into the alkynyl complexes [Co(C≡C–CMe3) · (NPMe3)]4 and [Co(C≡C–SiMe3)(NPEt3)]4 on obtaining the heterocubane structures, when caused to react with the lithium organic reagents LiC≡C–CMe3 and LiC≡C–SiMe3 in THF at 0 °C. According to the crystal structure analyses all four of the compounds form heterocubane structures with only slightly distorted Co4N4 cubic structures.
Solution Synthesis and Characterization of Quantum Confined Ge Nanoparticles (1999)

A solution synthesis of crystalline Ge nanoparticles (nc-Ge ) is reported. The metathesis reaction of NaGe with excess GeCl4 in glyme solvents produces nc-Ge. Metathesis reactions between KGe and excess GeCl4 or GeCl2:(dioxane) in glyme and Mg2Ge and excess GeCl4 in diglyme and triglyme were also investigated. The surface of these nanoparticles is terminated with alkyl groups by reaction with alkyl Li and Grignard reagents. The alkyl-terminated crystalline Ge nanoparticles (R̂-nc-Ge) were characterized by Fourier transform infrared spectroscopy, high-resolution transmission electron microscopy, powder X-ray diffraction, UV−vis absorption spectroscopy, photoluminescence, and photoluminescence excitation spectroscopy. The optical properties of R̂-nc-Ge made by this method agree with predictions from quantum confinement models.
Molecular cloning and analysis of the human Tec protein-tyrosine kinase. (1994)

Mouse Tec is a non-receptor type protein-tyrosine kinase and is highly expressed in many hematopoietic cell lines. To investigate the roles of the Tec kinase in the human hematopoietic system, we isolated cDNAs encoding the human Tec kinase. The human tec cDNAs can encode a peptide of 631 amino acid residues with a calculated molecular mass of 73,624. The predicted human Tec protein is highly homologous to those of the members of the Tec family including mouse Tec type IV (94% homology), mouse Tsk/Itk (60%), and human Btk (57%). The homology between human Tec and other members of the Tec family can be observed not only in the Src homology 3 (SH3), SH2, and kinase domains, but also in the N-terminal unique domain. Northern blot analysis demonstrated that the major transcripts of tec could be detected at 2.6 kb and 3.6 kb in a wide range of human hematopoietic cell lines including myeloid, B-, and T-cell lineages. Interestingly, high expression of the tec gene could be detected in all of the three patients examined with myelodysplastic syndrome. The human tec gene was mapped by fluorescence in situ hybridization (FISH) to chromosome 4p12.
Glutathione loading prevents free radical injury in red blood cells after storage (2000)

We have previously demonstrated that the loss of glutathione (GSH) and GSH-peroxidase (GSH-PX) in banked red blood cells (RBCs) is accompanied by oxidative modifications of lipids, proteins and loss of membrane integrity. The objective of this study was to determine whether artificial increases in antioxidant (GSH) or antioxidant enzyme (catalase) content could protect membrane damage in the banked RBCs following an oxidant challenge. RBCs stored at 1-6 degrees C for 0, 42 and 84 days in a conventional additive solution (Adsol) were subjected to oxidative stress using ferric/ascorbic acid (Fe/ASC) before and after enriching them with GSH or catalase using a hypotonic lysis-isoosmotic resealing procedure. This lysis-resealing procedure in the presence of GSH/catalase raised intracellular GSH and catalase concentrations 4-6 fold, yet produced only a small reduction in mean cell volume (MCV), mean cell hemoglobin (MCH) and mean cell hemoglobin concentrations (MCHC). Indicators of oxidative stress and membrane integrity were measured, including acetylcholinesterase (AChE) activity, GSH concentration, phosphatidylserine (PS) externalization (prothrombin-converting activity) and transmembrane lipid movements (14C-lyso phosphatidylcholine flip-flop and PS transport). GSH-enrichment protected AChE activity in fresh (0 day) and stored (42 and 84 days) RBCs from Fe/ASC oxidation by 10, 23 and 26%, respectively, compared with not-enriched controls. Following oxidative stress, the rate of transbilayer lipid flip-flop did not increase in fresh cells, but increased 9.3% in 42-day stored cells. Phosphatidylserine exposure, as measured by prothrombinase activity, increased 2.4-fold in fresh and 5.2-fold in 42-day stored cells exposed to Fe/ASC. Previous studies have shown that 42-day storage causes a moderate decrease in PS transport (approximately 50%), whereas transport rates declined by up to 75% in stored RBCs when challenged with Fe/ASC. GSH-enrichment prevented the increase in passive lipid flip-flop and the increase in prothrombinase activity, but offered no protection against oxidative damage of PS transport. In contrast to these effects, catalase-enrichment failed to protect GSH levels and AChE activity upon oxidative stress. Membrane protein thiol oxidation was assessed by labeling reactive protein thiols with 5-acetalamidofluorescein followed by immunoblotting with antifluorescein antibodies. Significant oxidation of membrane proteins was confirmed by a greater loss of thiols in stored RBCs than in fresh RBCs. These results demonstrate that it may be possible to prevent storage-mediated loss of AChE, increased lipid flip-flop, and increased PS exposure, by maintaining or increasing GSH levels of banked RBCs.
The Atherogenic Lipoprotein Profile Associated With Obesity and Insulin Resistance Is Largely Attributable to Intra-Abdominal Fat (2003)

Obesity and insulin resistance are both associated with an atherogenic lipoprotein profile. We examined the effect of insulin sensitivity and central adiposity on lipoproteins in 196 individuals (75 men and 121 women) with an average age of 52.7 years. Subjects were subdivided into three groups based on BMI and their insulin sensitivity index (S(I)): lean insulin sensitive (n = 65), lean insulin resistant (n = 73), and obese insulin resistant (n = 58). This categorization revealed that both obesity and insulin resistance determined the lipoprotein profile. In addition, the insulin-resistant groups had increased central adiposity. Increasing intra-abdominal fat (IAF) area, quantified by computed tomography scan and decreasing S(I), were important determinants of an atherogenic profile, marked by increased triglycerides, LDL cholesterol, and apolipoprotein B and decreased HDL cholesterol and LDL buoyancy (Rf). Density gradient ultracentrifugation (DGUC) revealed that in subjects who had more IAF and were more insulin resistant, the cholesterol content was increased in VLDL, intermediate-density lipoprotein (IDL), and dense LDL fractions whereas it was reduced in HDL fractions. Multiple linear regression analysis of the relation between the cholesterol content of each DGUC fraction as the dependent variable and IAF and S(I) as independent variables revealed that the cholesterol concentration in the fractions corresponding to VLDL, IDL, dense LDL, and HDL was associated with IAF, and that S(I) additionally contributed independently to VLDL, but not to IDL, LDL, or HDL. Thus an atherogenic lipoprotein profile appears to be the result primarily of an increase in IAF, perhaps via insulin resistance.
Pharmacokinetic and pharmacodynamic analysis of 5-aza-2’-deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy (2013)

5-Aza-2'-deoxycytidine (5-AZA-CdR, decitabine), an epigenetic drug that inhibits DNA methylation, is currently used to treat myelodysplastic syndrome (MDS), and is under investigation for treating acute myeloid leukemia (AML) and other malignancies. 5-AZA-CdR can reactivate tumor suppressor genes silenced by aberrant DNA methylation, a frequent event in all types of cancer. Because this epigenetic change is reversible, it is a good target for 5-AZA-CdR therapy. We have reviewed the preclinical data of 5-AZA-CdR to analyze the concentrations and exposure times required to eradicate cancer stem cells. We analyzed the dose-schedules used in animal models that show potent antineoplastic activity of 5-AZA-CdR. We attempted to correlate the preclinical data with the responses obtained in clinical trials of 5-AZA-CdR in patients with cancer. The pharmacokinetics and drug distribution of 5-AZA-CdR are key parameters because adequate therapeutic drug levels are required to eliminate cancer stem cells in all anatomic compartments. The plasma half-life of 5-AZA-CdR in humans is approximately 20 minutes due to the high levels in the liver of cytidine deaminase, the enzyme that inactivates this analogue. This provides a rationale to use an inhibitor of cytidine deaminase in combination with 5-AZA-CdR. Low-dose 5-AZA-CdR is effective for MDS and AML and can induce complete remissions (CR). However, maintenance of CR with low-dose 5-AZA-CdR is difficult. Based on analyses of preclinical and clinical data, low dose 5-AZA-CdR has the potential to be an effective form of therapy in some patients with cancer. For patients who do not respond to low dose therapy we recommend dose-intensive treatment with 5-AZA-CdR. Patients who are candidates for intensive dose 5-AZA-CdR should have a good bone marrow status so as to permit adequate recovery from myelosuppression, the major toxicity of 5-AZA-CdR. Solid tumors are also interesting targets for therapy with 5-AZA-CdR. Both low dose and intensive therapy with 5-AZA-CdR can reduce the proliferative potential of tumor stem cells in animal models. We propose novel dose schedules of 5-AZA-CdR for investigation in patients with cancer. The full chemotherapeutic potential of 5-AZA-CdR to treat cancer merits further clinical investigation and can only be realized when its optimal dose-schedule is determined.
Effects of varying nitrogen supply at different stages of the reproductive phase on spikelet and grain production and on grain nitrogen in wheat (1973)

Plants of wheat cv. Arawa confined to the main shoot were grown in solution culture in a glasshouse. Nitrogen supply was either high (150 p.p.111.) or low (15 p.p.m.) at three stages of development: between the double-ridge stage and floret initiation, between then and ear emergence, or after ear emergence, giving eight treatment combinations. Spikelet numbers were increased only by raising nitrogen supply at the doubleridge stage. Number of grains per spikelet also responded to treatment during the same period, but was greatest when high nitrogen was given until ear emergence. This response depended on the position of the spikelet within the ear, and the basal and terminal spikelets contributed least when nitrogen supply was low. Individual grain weight responded less to treatment than grain numbers. Nitrogen application had a large effect on leaf area duration, but the grain/leaf ratio (G) was depressed. Since their appeared to be no nitrogen effects on photosynthesis per unit flag leaf area, it is suggested that grain yield was controlled mainly by the capacity of the ear to accept carbohydrate, depending on the number of sites available for grain filling. Percentage grain nitrogen increased with lateness of nitrogen application. However, raising nitrogen supply before ear emergence and then decreasing it again also affected grain nitrogen in the ear, which suggests redistribution during grain filling
Antimalarials. 7-Chloro-4-(substituted amino)quinolines (1971)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAntimalarials. 7-Chloro-4-(substituted amino)quinolinesTara Singh, Robert George Stein, John F. Hoops, John H. Biel, Wallace K. Hoya, and Deanna R. CruzCite this: J. Med. Chem. 1971, 14, 4, 283–286Publication Date (Print):April 1, 1971Publication History Published online1 May 2002Published inissue 1 April 1971https://pubs.acs.org/doi/10.1021/jm00286a003https://doi.org/10.1021/jm00286a003research-articleACS PublicationsRequest reuse permissionsArticle Views365Altmetric-Citations15LEARN 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
Integration of environmental factors in process modelling for printed circuit board manufacturing. II. Fabrication (2002)

This paper presents a set of thermo-mechanical process models for unit processes in inner and outer layer circuitization. By assessing the thermal, mechanical and chemical behavior of these processes, energy utilization and raw waste mass streams can be estimated from process and board design parameters. The processes modeled through this methodology include laminate core fabrication, resist coating, exposure, development, copper etch, resist strip, oxide treatment, lamination, drilling, desmear/copper plating and solder masking. For each process, key solid, liquid and vapor waste streams are predicted through mass balance and thermal and fluid losses determined, The raw mass outputs can be weighted through a multi-criteria health hazard assessment to determine comparisons for waste stream "quality" within the control volume of the facility. In this manner, hazard assessment for products or facilities can be evaluated from the unit process level. A case study of a six-layer PCB design for a computer workstation is presented to illustrate design trade-off analyses and integration of the process models within a computer-aided design environmen.,.
Simulation of continuous solid phase synthesis: synthesis of methionine enkephalin and its analogs. (1992)

The method of continuous solid phase synthesis, i.e., synthesis performed on a continual carrier, transferable from one synthetic compartment to another by means of a mechanical device, allows one to perform multiple synthetic steps simultaneously on different regions of the carrier. This procedure was tested on the synthesis of methionine enkephalin and its analogs. Products, obtained in reasonable yields, were fully characterized. Possible arrangements and the use of continuous solid phase synthesizers are discussed.
C3 peptide enhances recovery from spinal cord injury by improved regenerative growth of descending fiber tracts (2010)

Functional recovery and regeneration of corticospinal tract (CST) fibers following spinal cord injury by compression or dorsal hemisection in mice was monitored after application of the enzyme-deficient Clostridium botulinum C3-protein-derived 29-amino-acid fragment C3bot(154-182). This peptide significantly improved locomotor restoration in both injury models as assessed by the open-field Basso Mouse Scale for locomotion test and Rotarod treadmill experiments. These data were supported by tracing studies showing an enhanced regenerative growth of CST fibers in treated animals as visualized by anterograde tracing. Additionally, C3bot(154-182) stimulated regenerative growth of raphespinal fibers and improved serotonergic input to lumbar alpha-motoneurons. These in vivo data were confirmed by in vitro data, showing an enhanced axon outgrowth of alpha-motoneurons and hippocampal neurons cultivated on normal or growth-inhibitory substrates after application of C3bot(154-182). The observed effects were probably caused by a non-enzymatic downregulation of active RhoA by the C3 peptide as indicated by pull-down experiments. By contrast, C3bot(154-182) did not induce neurite outgrowth in primary cultures of dorsal root ganglion cells. In conclusion, C3bot(154-182) represents a novel, promising tool to foster axonal protection and/or repair, as well as functional recovery after traumatic CNS injury.
Direct Liquid Cooling of High Flux Micro and Nano Electronic Components (2006)

The inexorable rise in chip power dissipation and emergence of on-chip hot spots with heat fluxes approaching 1 =kW/cm/sup 2/ has turned renewed attention to direct cooling with dielectric liquids. Use of dielectric liquids in intimate contact with the heat dissipating surfaces eliminates the deleterious effects of solid-solid interface resistances and harnesses the highly efficient phase-change processes to the critical thermal management of advanced IC chips. In the interest of defining the state-of-the-art in direct liquid cooling, this paper begins with a discussion of the thermophysics of phase-change processes and a description of the available dielectric liquid cooling techniques and their history. It then describes the phenomenology of pool boiling, spray/jet impingement, gas-assisted evaporation, and synthetic jet impingement with dielectric liquids. Available correlations for predicting the heat transfer coefficients and limiting heat transfer rates, as well as documented empirical results for these promising techniques for on-chip hot spot cooling, are also provided and compared.
Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study (2018)

Background Erenumab was effective and well tolerated in a pivotal clinical trial of chronic migraine. Here, we evaluated efficacy and safety of monthly erenumab (70 mg or 140 mg) versus placebo in the subgroup of patients who had previously failed preventive treatment(s) (≥ 1, ≥ 2 prior failed medication categories) and in patients who had never failed. Methods Subgroup analyses evaluated change from baseline in monthly migraine days; achievement of ≥ 50% and ≥ 75% reduction in monthly migraine days; and change in monthly acute migraine-specific medication days. Adverse events were evaluated for each subgroup. Results Treatment with both doses of erenumab resulted in greater reductions in monthly migraine days (primary endpoint) at Month 3 (treatment difference [95% CI], never failed subgroup: -2.2 [-4.1, -0.3] for 70 mg and -0.5 [-2.4, 1.5] for 140 mg; ≥ 1 prior failed medication categories subgroup: -2.5 [-3.8, -1.2], for 70 mg and -3.3 [-4.6, -2.1] for 140 mg; ≥ 2 prior failed medication categories subgroup: -2.7 [-4.2, -1.2], for 70 mg and -4.3 [-5.8, -2.8] for 140 mg). Similar results were observed in the monthly acute migraine-specific medication days endpoint, and in the achievement of ≥ 50% and ≥ 75% reduction in monthly migraine days. There were no new or unexpected safety issues. Conclusion Erenumab showed consistent efficacy in chronic migraine patients who had failed prior preventive treatments and was well tolerated across subgroups.
Progress on new vaccine strategies for the immunotherapy and prevention of cancer (2004)

In recent years, great strides in understanding and regulating the immune system have led to new hope for harnessing its exquisite specificity to destroy cancer cells without affecting normal tissues. This review examines the fundamental immunologic advances and the novel vaccine strategies arising from these advances, as well as the early clinical trials studying new approaches to treat or prevent cancer.