gebhart/patrepeval huggingface dataset:
Inhibition of the Heat Shock Protein 90 (Hsp90) chaperone with the novel agent IPI-504 to overcome resistance to tyrosine kinase inhibitors (TKIs) in metastatic GIST: Updated results of a phase I trial (2007)

10024 Background: Prior work from our team demonstrates that inhibition of the Hsp90 chaperone protein results in preferential destruction of the mutated KIT kinase in human GIST cell lines regardless of TKI-resistance mutations. To translate this into clinical application, we are conducting a phase I trial of IPI-504, a novel Hsp90 inhibitor, for patients (pts) with metastatic TKI-resistant GIST. Methods: Pts with metastatic TKI-resistant GIST were eligible to enter and receive IPI-504, IV in 250 cc of normal saline over 30 mins, on days 1, 4, 8 and 11 of a 21 day cycle. Serial monitoring with 18 FDG-PET/CT imaging at baseline, day 11, and day 21, as well as PK profiling of IPI- 504 and its major active metabolites (17-AAG and 17-AG), were performed on all pts. Results: 21 pts with progressive GIST after both prior imatinib and sunitinib have been entered at 5 dose levels (90 mg/m 2 IPI-504 [n=6], 150 [3], 225 [3], 300 [3], 400 [6]); 18 are now evaluable. The maximal tolerated dose has not been reached, and enrollment is ongoing. AEs possibly related to IPI-504 include Grade 1–2 elevation of alkaline phosphatase, fatigue, and headache; one DLT was observed in the 1 st and 5 th dose levels. PET demonstrated decreases in tumor FDG avidity in 1/6 pts, 1/3, 3/3, 1/3, and 2/3 at the respective dose levels in this schedule (3 patients were inevaluable by PET). Reactivation of tumor FDG uptake by PET was seen during the planned 10-day breaks in IPI-504 administration with reinduction of decreased tumor FDG avidity upon re-treatment with IPI-504. Although no RECIST-defined “anatomic responses” were noted, stable disease has allowed 7 pts to continue on study treatment for ≥ 4 cycles. Conclusions: Targeting Hsp90 is a novel therapeutic strategy in TKI-resistant GIST. IPI-504 has been well-tolerated overall, and the activity seen with decreased FDG avidity of GIST lesions, as well as the induction of SD in pts with documented prior progression, is promising with this non-TKI agent. Reactivation of PET signal in lesions during breaks in IPI-504 dosing is similar to flares with TKI discontinuation. To address this, a new schedule of continuous BIW dosing of IPI-504 has been added to optimize drug exposure. No significant financial relationships to disclose.
Development of the visual system of the chick--a review. (1992)

This article reviews recent and earlier findings that yield the present knowledge about the embryonic development of retina, tectum, and the retinotectal projection in the chick. Data and concepts dealing with cell proliferation, migration, and differentiation, the processes underlying the generation of cytoarchitecture in the nervous system are discussed for the avian visual system. Emphasis is also laid on the presentation of hypotheses and experiments about directed axonal growth along the visual pathway and concerning the mechanisms responsible for the establishment of specific connections between retinal ganglion cells and their central targets. Among the results, the following topics deserve special attention: 1) Investigations of morphogenetic factors in vitro, and the application of recombinant retroviruses in vivo to study cell lineages rendered new insights into the processes of cell determination and differentiation. The evolving picture in this progressing field is discussed. At present, however, the research of retinal and tectal histogenesis is still largely in the state of morphological description. 2) Both systems, retina and optic tectum, develop independently from each other but in corresponding spatio-temporal patterns, which provide that ingrowing retinal axons encounter receptive target tissue at appropriate locations at the time when connections are due to be formed. 3) Possible mechanisms of directed fibre growth are being elucidated by increasing efforts in research devoted to cell surface molecules, neurotrophic, and inhibitory substances, and their receptors. The axons of the primary visual pathway seem to be guided by local cues on glial endfeet and perhaps in the extracellular matrix, but so far, instructive molecules to which functional significance can be assigned have eluded discovery. 4) The question, how the retinotopic projection upon the tectum is created during development, remains still unsolved, although most results point to modified forms of the chemoaffinity hypothesis for its explanation. Sequential maturation and growth, selective fasciculation of orderly entering axons, recognition of positional tectal markers, and functionally controlled refinement may together contribute to the correct retinotectal projection.
Acute Doxorubicin Cardiotoxicity (1986)

The acute effects of doxorubicin on coronary perfusion and left ventricular pressures and intracellular phosphate metabolite levels, the latter obtained by 31P nuclear magnetic resonance, were measured simultaneously in isolated, isovolumic rat hearts (Langendorf preparation) perfused at constant flow. Nineteen experimental hearts were perfused for 70 min with oxygenated HEPES-buffered solution containing 6 mg/L doxorubicin. These were compared with 18 control hearts (C), perfused under identical conditions but without doxorubicin, by repeated measures analysis of variance. In the experimental group, coronary perfusion pressure steadily increased to 226.3 +/- 13.8% (mean +/- SEM) of initial levels (p less than 0.0001 vs. C). Because flow was constant, the increase in coronary perfusion pressure in experimental hearts indicates a greater than twofold increase in coronary resistance. Intracellular phosphocreatine and ATP decreased to 80.3 +/- 3.9% (p less than 0.005 vs. C) and 82.1 +/- 6.4% (p less than 0.05 vs. C), whereas inorganic phosphate increased to 149.7 +/- 19.1% (p less than 0.05 vs. C) of initial levels, respectively. Accompanying these changes, diastolic pressure steadily increased to 521.7 +/- 91.4% of initial levels (p less than 0.0001 vs. C). Developed pressure initially increased to 107.1 +/- 4.5% at 30 min, and thereafter decreased to 76.2 +/- 6.3% at 70 min (p less than 0.05 vs. C). Typical structural alterations in myocyte nuclei were noted. Cellular calcium was not increased in doxorubicin-exposed hearts. Thus, acute doxorubicin cardiotoxicity is characterized by an increase in coronary resistance and is closely correlated with alterations in ventricular function and a decrease in intracellular high-energy phosphate content.(ABSTRACT TRUNCATED AT 250 WORDS)
The Design and Implementation of a Data Level Database Inference Detection System (1999)

Inference is a way to subvert access control mechanisms of database systems. Most existing work on inference detection relies on analyzing functional dependencies in the database schema. This paper is an extension to our earlier effort in developing a data level inference detection system In this paper, we introduce the split query inference rule, make an extension to the overlapping inference rule, and provide an in depth discussion on the applications of the inference rules on union queries. Data level inference detection is inevitably expensive. We have developed a prototype of the inference detection system to evaluate its performance. The result shows that the system performs better with larger number of attributes and records in the database, and smaller number of projected attributes and return tuples of the queries. Therefore, the inference detection system could be practical when users retrieve a small amount of data compare to the size of the database.
Photodynamic therapy with hypericin induces vascular damage and apoptosis in the RIF‐1 mouse tumor model (2001)

Hypericin, a polycyclic quinone obtained from plants of the genus Hypericum, has been proven to be a potent photosensitizer. The mechanism of tumor eradication and mode of cell death induced by in vivo photodynamic therapy (PDT) with hypericin were investigated in the present study using 2 therapeutic protocols. RIF-1 tumors were exposed to laser light at either 0.5 hr or 6 hr after hypericin administration (5 mg/kg, i.v.). A significant reduction in tumor perfusion, as determined by the retention of fluorescein in the tumor tissue, was detected immediately after both PDT treatments. Further decrease in tumor perfusion was observed in the hours after treatment. The re-establishment of tumor perfusion, however, occurred 24 hr after 6 hr-interval PDT, but not after 0.5 hr-interval PDT. The kinetics of tumor cell survival estimated by the in vivo/in vitro clonogenic assay revealed no or limited cell death when tumors were explanted immediately after irradiation, whereas a delayed but progressive cell death was detected when tumors remained in situ after both PDT treatments. The detection of nucleosomal DNA fragmentation by agarose gel electrophoresis or TUNEL assay and the assessment of cell morphology by light microscopy indicated that apoptosis was the most prominent tumor response to hypericin-mediated PDT. Furthermore, immunohistochemical analysis of the tumor tissue showed an increased expression of both Fas and Fas ligand after irradiation, suggesting that this cell death pathway might contribute to the overall PDT-induced apoptotic response. In conclusion, our results demonstrate that apoptosis, likely occurring as a result of vascular damage, is responsible for the tumor eradication by PDT with hypericin in this tumor model.
Crystallographic studies of the anthrax lethal toxin (1999)

Anthrax lethal toxin comprises two proteins: protective antigen (PA; MW 83 kDa) and lethal factor (LF; MW 87 kDa). We have recently determined the crystal structure of the 735-residue PA in its monomeric and heptameric forms (Petosa et al. 1997). It bears no resemblance to other bacterial toxins of known three-dimensional structure, and defines a new structural class which includes homologous toxins from other Gram-positive bacteria. We have proposed a model of membrane insertion in which the water-soluble heptamer undergoes a substantial pH-induced conformational change involving the creation of a 14-stranded beta-barrel. Recent work by Collier's group (Benson et al. 1998) lends strong support to our model of membrane insertion. 'Lethal factor' is the catalytic component of anthrax lethal toxin. It binds to the surface of the cell-bound PA heptamer and, following endocytosis and acidification of the endosome, translocates to the cytosol. We have made substantial progress towards an atomic resolution crystal structure of LF. Progress towards a structure of the 7:7 translocation complex between the PA heptamer and LF will also be discussed.
Lab-on-a-chip devices: How to close and plug the lab? (2014)

Lab-on-a-chip (LOC) devices are broadly used for research in the life sciences and diagnostics and represent a very fast moving field. LOC devices are designed, prototyped and assembled using numerous strategies and materials but some fundamental trends are that these devices typically need to be (1) sealed, (2) supplied with liquids, reagents and samples, and (3) often interconnected with electrical or microelectronic components. In general, closing and connecting to the outside world these miniature labs remain a challenge irrespectively of the type of application pursued. Here, we review methods for sealing and connecting LOC devices using standard approaches as well as recent state-of-the-art methods. This review provides easy-to-understand examples and targets the microtechnology/engineering community as well as researchers in the life sciences.
Components of a Ubiquitin Ligase Complex Specify Polyubiquitination and Intracellular Trafficking of the General Amino Acid Permease (2001)

Gap1p, the general amino acid permease of Saccharomyces cerevisiae, is regulated by intracellular sorting decisions that occur in either Golgi or endosomal compartments. Depending on nitrogen source, Gap1p is transported to the plasma membrane, where it functions for amino acid uptake, or to the vacuole, where it is degraded. We found that overexpression of Bul1p or Bul2p, two nonessential components of the Rsp5p E3-ubiquitin ligase complex, causes Gap1p to be sorted to the vacuole regardless of nitrogen source. The double mutant bul1Delta bul2Delta has the inverse phenotype, causing Gap1p to be delivered to the plasma membrane more efficiently than in wild-type cells. In addition, bul1Delta bul2Delta can reverse the effect of lst4Delta, a mutation that normally prevents Gap1p from reaching the plasma membrane. Evaluation of Gap1p ubiquitination revealed a prominent polyubiquitinated species that was greatly diminished in a bul1Delta bul2Delta mutant. Both a rsp5-1 mutant and a COOH-terminal truncation of Gap1p behave as bul1Delta bul2Delta, causing constitutive delivery of Gap1p to the plasma membrane and decreasing Gap1p polyubiquitination. These results indicate that Bul1p and Bul2p, together with Rsp5p, generate a polyubiquitin signal on Gap1p that specifies its intracellular targeting to the vacuole.
Invited tutorial: Phase Change Memory: Replacement or transformational (2012)

In this tutorial, a short account on the working principles of Phase Change Memory and its development will be introduced, followed by a comprehensive comparison with incumbent and other emerging memory technologies. Focus will be drawn to the technical requirements for the replacement of DRAM and NAND Flash with new memory technologies as these incumbent technologies are approaching their physical limits of conventional two-dimension scaling. Existing characteristics and the current state of the development of Phase Change Memory in the industry are examined to match the requirements of a replacement for DRAM and NAND Flash separately. The replacement scenario will be summarized with suggestions for further development. The transformational scenario begins with a study of the current landscape and future directions in enterprise computing and consumer electronics. We shall examine the opportunity of introducing a new memory system requiring holistic and collaborative efforts among the system and processor designers, as well as software engineers. Again, suggestions on further development directions for Phase Change Memory for the transformation scenario will be outlined.
The role of PD‐1 in regulation of macrophage apoptosis and its subversion by Leishmania donovani (2017)

Programmed death-1 receptor (PD-1) expressed in many immune cells is known to trigger T-cell exhaustion but the significance of macrophage-associated PD-1 in relevance to macrophage apoptosis is not known. This study is aimed to delineate whether PD-1 pathway has any role in eliciting macrophage apoptosis and, if so, then how the intra-macrophage parasite, <i>Leishmania donovani</i> modulates PD-1 pathway for protecting its niche. Resting macrophages when treated with H<sub>2</sub>O<sub>2</sub> showed increased PD-1 expression and apoptosis, which was further enhanced on PD-1 agonist treatment. The administration of either PD-1 receptor or PD-1 ligand-blocking antibodies reversed the process thus documenting the involvement of PD-1 in macrophage apoptosis. On the contrary, <i>L. donovani</i>-infected macrophages showed decreased PD-1 expression concurrent with inhibition of apoptosis. The activation of PD-1 pathway was found to negatively regulate the phosphorylation of pro-survival AKT, which was reversed during infection. Infection-induced PD-1 downregulation led to the activation of AKT resulting in phosphorylation and subsequent inhibition of proapoptotic protein BAD. Strong association of SHP2 (a SH2-containing ubiquitously expressed tyrosine-specific protein phosphatase) with PD-1 along with AKT deactivation observed in H<sub>2</sub>O<sub>2</sub>-treated macrophages was reversed by <i>L. donovani</i> infection. Kinetic analysis coupled with inhibitor-based approach and knockdown experiments demonstrated that <i>L</i>. <i>donovani</i> infection actively downregulated the PD-1 by deactivating NFATc1 as revealed by its reduced nuclear translocation. The study thus elucidates the detailed mechanism of the role of PD-1 in macrophage apoptosis and its negative modulation by <i>Leishmania</i> for their intracellular survival.
Expression of plasmolipin in oligodendrocytes (1991)

Plasmolipin is a plasma membrane proteolipid which has recently been described as a component of myelin (Cochary et al.: Journal of Neurochemistry 55:602-610, 1990). The present study reports the expression and localization of plasmolipin in primary glial cultures and secondary oligodendrocyte cultures. Double-label immunofluorescence showed that plasmolipin was expressed by galactocerebroside (GC)-positive oligodendrocytes, but was absent from astrocytes, characterized by their positive staining for glial fibrillary acidic protein (GFAP). At 1 week in culture plasmolipin staining was relatively weak in the cell body of some of the GC-positive cells. During the following 3 weeks in culture plasmolipin staining of oligodendrocytes gradually increased and was present in the cell body, its plasma membrane, and all the processes. However, the plasmolipin antibodies did not stain regions of the flat membrane sheets. Western blot analysis of homogenates from primary glial cultures showed that plasmolipin levels gradually increased during the first 5 weeks in culture. We conclude that the presence of plasmolipin in myelin is a result of its expression by oligodendrocytes.
Cystic fibrosis: A disorder with defective autophagy (2010)

The accumulation of misfolded and/or ubiquitinated protein aggregates with a perturbation of autophagy has been described in several human pathologies. A sequestration of misfolded cystic: fibrosis transmembrane conductance regulator (CFTR) and cross-linked PPARγ has been observed in airway epithelia of cystic fibrosis (CF) patients. CF airways are also characterized by chronic inflammation, pro-oxidative environment and increased transglutaminase 2 (TG2) levels. We showed that defective CFTR drives autophagy inhibition through reactive oxygen species (ROS)-TG2- mediated aggresome sequestration of the Beclin 1 interactome. Rescuing Beclin 1 at the level of the endoplasmic reticulum and autophagy favors clearance of aggresomes, improves CFTR trafficking and ameliorates CF lung inflammation both in vitro and in vivo. Therefore, rescuing autophagy interrupts the vicious cycle linking defective CFTR and lung inflammation and may pave the way to the development of a novel class of drugs for the treatment of CF.
Extracellular Signal-regulated Kinase (ERK)-dependent Gene Expression Contributes to L1 Cell Adhesion Molecule-dependent Motility and Invasion (2004)

The cell adhesion molecule L1 has been implicated in a variety of motile processes, including neurite extension, cerebellar cell migration, extravasation, and metastasis. Homophilic or heterophilic L1 binding and concomitant signaling have been shown to promote cell motility in the short term. In this report, L1 is also shown to induce and maintain a motile and invasive phenotype by promoting gene transcription. In the presence of serum or platelet-derived growth factor, L1 promotes heightened and sustained activation of the extracellular signal-regulated kinase pathway. Activation of this pathway then induces the expression of motility- and invasion-associated gene products, including the beta(3)-integrin subunit, small GTPases, and the cysteine proteases cathepsin-L and -B. Induction of integrin alpha(v)beta(3) and rac-1 is shown to contribute directly to L1-dependent haptotaxis, whereas induction of cathepsins-L and -B promotes matrix invasion. This study provides a novel translational mechanism to account for the association between L1 expression and motile processes involved in metastasis and development.
The influence of laser parameters and scanning strategies on the mechanical properties of a stochastic porous material (2017)

Stochastic architectured porous materials were additively manufactured in Titanium and Stainless Steel The effect of laser parameters and scan strategies on strut thickness and strength of porous materials were investigated A linear relationship was found between the specific enthalpy, delivered by the laser to the meltpool, and strut thickness The optimum rate of energy for maximising strength of a porous material for a given stiffness was material dependent Maximizing the strength:stiffness and strength:weight ratio of a porous material is dependent on the scan strategy used
Studies in the Acetone Concentration in Blood, Urine, and Alveolar air: I. A Micromethod for the Estimation of Acetone in Blood, based on the Iodoform Method (1919)

Research Article| December 01 1919 Studies in the Acetone Concentration in Blood, Urine, and Alveolar air: I. A Micromethod for the Estimation of Acetone in Blood, based on the Iodoform Method Erik Matteo Prochet Widmark Erik Matteo Prochet Widmark 1The Physiological Institute, Lund, Sweden Search for other works by this author on: This Site PubMed Google Scholar Biochem J (1919) 13 (4): 430–445. https://doi.org/10.1042/bj0130430 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation Erik Matteo Prochet Widmark; Studies in the Acetone Concentration in Blood, Urine, and Alveolar air: I. A Micromethod for the Estimation of Acetone in Blood, based on the Iodoform Method. Biochem J 1 December 1919; 13 (4): 430–445. doi: https://doi.org/10.1042/bj0130430 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Journal Search Advanced Search This content is only available as a PDF. © 1919 CAMBRIDGE UNIVERSITY PRESS1919 Article PDF first page preview Close Modal You do not currently have access to this content.
Ground- and excited-state spectral and redox properties of cadmium(II) texaphyrin (1989)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTGround- and excited-state spectral and redox properties of cadmium(II) texaphyrinBhaskar G. Maiya, Anthony Harriman, Jonathan L. Sessler, Gregory Hemmi, Toshiaki Murai, and Thomas E. MalloukCite this: J. Phys. Chem. 1989, 93, 24, 8111–8115Publication Date (Print):November 1, 1989Publication History Published online1 May 2002Published inissue 1 November 1989https://pubs.acs.org/doi/10.1021/j100361a027https://doi.org/10.1021/j100361a027research-articleACS PublicationsRequest reuse permissionsArticle Views212Altmetric-Citations46LEARN 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 options Get e-Alerts