gebhart/patrepeval huggingface dataset:
Stereochemical characteristics of the folate-antifolate transport mechanism in L1210 Leukemia cells. (1974)

Summary The rate of influx, extent of concentrative uptake, and the rate of efflux (loss) by active transport in L1210 leukemia cells has been compared for the pteridine antifolates, aminopterin and methotrexate, eight related quinazoline analogs, and two pyrimidine derivatives. The data reveal a difference in the stereochemical specificity for influx and efflux. Influx is preferential in the order pteridine, quinazoline, and pyrimidine. Influx of aminopterin is more rapid than that of methotrexate. l-Glutamylquinazolines were taken up faster than l-aspartylquinazolines, but influx of a d-glutamylquinazoline was slower than the corresponding d-glutamylquinazoline was slower than the corresponding d-aspartyl derivative. Influx of the quinazolines was faster when there was a methyl- or chloro- substitution at position 5. Influx of the pyrimidines was also faster when a methyl group was at position 6. Michaelis constants (Km) for influx of the various analogs varied from 1.42 × 10-6m to over 10-4m. Individual Vmax values were essentially the same (1.87 to 2.22 nmoles/min/g dry weight). The relationship between the values for initial velocity of influx (v), the Km and Vmax obtained with each analog are in agreement with that predicted by the Michaelis-Menten equation and is consistent with the notion that differences in rates of influx are attributable to differences in the affinity of the carrier for the system. Efflux is preferential in the order pteridine, pyrimidine, and quinazoline. Efflux of aminopterin and methotrexate occurs at the same rate. Both aspartyl- and glutamylquinazolines efflux at about the same rate, but the d-aspartyl and d-glutamyl forms efflux more rapidly than the corresponding l forms. A methyl, and particularly a chloro, substitution at position 5 of the quinazoline reduces the rate of efflux. The extent of concentrative uptake observed for each analog directly reflects the relative magnitude at which the influx and efflux processes operate and may be the physiological parameter most relevant to therapeutic efficacy.
Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64 Cu-SarAr immunoconjugates (2007)

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement (18)F-FDG. Copper-64 ((64)Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1-N-(4-aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6] eicosane-1,8-diamine) for use in developing a new class of tumor-specific (64)Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiolabeling with (64)Cu resulted in >95% of the (64)Cu being chelated by the immunoconjugate. Specific activities of at least 10 microCi/microg (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after (64)Cu labeling. Solid-phase radioimmunoassays and intact cell-binding assays confirmed retention of bioactivity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15-20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5-10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xenograft was significantly lower (<5% injected dose per gram). MicroPET imaging confirmed significant uptake of the tracer in GD-2-positive tumors, with minimal uptake in GD-2-negative tumors and nontarget tissues such as liver. The (64)Cu-SarAr-mAb system described here is potentially applicable to (64)Cu-PET imaging with a broad range of antibody or peptide-based imaging agents.
Molecular Characterization of PDGFR‐α/PDGF‐A and c‐KIT/SCF in Gliosarcomas (2005)

Gliosarcomas are rare and poorly characterized malignant brain tumors that exhibit a biphasic tissue pattern with areas of gliomatous and sarcomatous differentiation. These tumors are histological variants of glioblastoma, displaying a similar genetic profile and dismal prognosis. Up-regulation of PDGFR subfamily of tyrosine kinase members, PDGFR-alpha and c-Kit, and their intracellular effectors RAS/RAF/MAPK has a crucial role in the cancer development. In addition, signal transduction mediated by activating mutations of c-Kit and PDGFR can be effectively blocked by specific tyrosine kinase inhibitors, such as Imatinib mesylate. The aim of this study was to characterize the molecular alterations of PDGFR signaling in gliosarcomas. Six cases were analyzed by immunohistochemistry for the expression of PDGFR-alpha, c-Kit and their ligands PDGF-A and SCF, respectively. The cases were further evaluated for the presence of activating mutations of PDGFR-alpha (exons 12 and 18) and c-kit (exons 9, 11, 13, and 17), as well as B-RAF (exons 11 and 15). Expression of PDGF-A was found in all cases and co-expression of PDGFR-alpha was observed in three cases. Four cases showed expression of SCF, and c-Kit was observed only in one case that also expressed SCF. Generally, immunoreaction predominates in the glial component. The mutational analysis of PDGFR-alpha showed the presence of an IVS17-50insT intronic insertion in two cases, one of them also with a 2472C > T silent mutation; this silent mutation was also found in another case. Glioma cell line analysis of IVS17-50insT insertion showed no influence on PDGFR-alpha gene splicing. No mutations were detected in c-kit and B-RAF oncogenes. Our results indicate that activating mutations of PDGFR-alpha, c-kit and B-RAF are absent in gliosarcomas. Nevertheless, the presence of a PDGFR-a/PDGFA and c-Kit/SCF autocrine/paracrine stimulation loop in a proportion of cases, supports the potential role of specific tyrosine kinase inhibitors in the treatment of gliosarcomas.
Cooperative transit tracking using smart-phones (2010)

Real-time transit tracking is gaining popularity as a means for transit agencies to improve the rider experience. However, many transit agencies lack either the funding or initiative to provide such tracking services. In this paper, we describe a crowd-sourced alternative to official transit tracking, which we call cooperative transit tracking.
Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: Results of a Randomized Phase III Trial (2013)

OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.
Role of adiponectin receptors in endothelin-induced cellular hypertrophy in cultured cardiomyocytes and their expression in infarcted heart (2006)

Adiponectin, an adipocyte-derived protein, has cardioprotective actions. We elucidated the role of the adiponectin receptors AdipoR1 and AdipoR2 in the effects of adiponectin on endothelin-1 (ET-1)-induced hypertrophy in cultured cardiomyocytes, and we examined the expression of adiponectin receptors in normal and infarcted mouse hearts. Recombinant full-length adiponectin suppressed the ET-1-induced increase in cell surface area and [ 3 H]leucine incorporation into cultured cardiomyocytes compared with cells treated with ET-1 alone. Transfection of small interfering RNA (siRNA) specific for AdipoR1 or AdipoR2 reversed the suppressive effects of adiponectin on ET-1-induced cellular hypertrophy in cultured cardiomyocytes. Adiponectin induced phosphorylation of AMP-activated protein kinase (AMPK) and inhibited ET-1-induced ERK1/2 phosphorylation, which were also reversible by transfection of siRNA for AdipoR1 or AdipoR2 in cultured cardiomyocytes. Transfection of siRNA for α 2 -catalytic subunits of AMPK reduced the inhibitory effects of adiponectin on ET-1-induced cellular hypertrophy and ERK1/2 phosphorylation. Effects of globular adiponectin were similar to those of full-length adiponectin, and siRNA for AdipoR1 reversed the actions of globular adiponectin. Compared with normal left ventricle, expression levels of AdipoR1 mRNA and protein were decreased in the remote, as well as the infarcted, area after myocardial infarction in mouse hearts. In conclusion, AdipoR1 and AdipoR2 mediate the suppressive effects of full-length and globular adiponectin on ET-1-induced hypertrophy in cultured cardiomyocytes, and AMPK is involved in signal transduction through these receptors. AdipoR1 and AdipoR2 might play a role in the pathogenesis of ET-1-related cardiomyocyte hypertrophy after myocardial infarction.
TOMBO: thin observation module by bound optics (2003)

A typical imaging lens requires the same order of working distance as the diameter. As far as the conventional imaging system is employed, thickness of the system is determined by the diameter which is related to the field area of the imaging devices. One motivation of our research is to break through the thickness restriction by replacing an imaging lens with an array of microlenses. The system is called TOMBO (thin observation module by bound optics) after the Japanese name for the dragonfly. Effective cooperation of the compact compound-imaging system and image reconstruction processing enables us to capture high-resolution images with very thin hardware configuration.
Phosphine oxides and lithium aluminum hydride-sodium borohydride-cerium(III) chloride: synthesis and reactions of phosphine-boranes (1985)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPhosphine oxides and lithium aluminum hydride-sodium borohydride-cerium(III) chloride: synthesis and reactions of phosphine-boranesTsuneo Imamoto, Tetsuo Kusumoto, Nobuyo Suzuki, and Kazuhiko SatoCite this: J. Am. Chem. Soc. 1985, 107, 18, 5301–5303Publication Date (Print):September 1, 1985Publication History Published online1 May 2002Published inissue 1 September 1985https://pubs.acs.org/doi/10.1021/ja00304a061https://doi.org/10.1021/ja00304a061research-articleACS PublicationsRequest reuse permissionsArticle Views2622Altmetric-Citations193LEARN 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-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Long-Term Adjuvant Interferon Treatment of Human Osteosarcoma: A pilot study (1995)

During the period from 1971 to 1990 all osteosarcoma patients referred to the Karolinska Hospital without signs of metastases received human leukocyte interferon (IFN) as adjuvant treatment. Patients referred between 1985 and 1990 were given more intensive human leukocyte IFN treatment, i.e. a standard dose of 3 MU s.c. daily for 3-5 years. These 19 patients, all followed for 5 years, were included in a pilot study which entailed patients with central localization where radical surgery was not feasible. Metastases developed in 9 patients, of whom 3 had local recurrences. Sixty-three percent are free of disease at 5 years. Side-effects were negligible and long-term toxicity practically non-existent. It is suggested that a randomized multicenter IFN trial should be instituted on patients with poor prognosis receiving chemotherapy and/or that IFN treatment should be combined with other therapeutic modalities--irradiation, chemotherapy or anti-angiogenic substances--in osteosarcoma.
Synthesis and Biological Evaluation of Phosphono Analogues of Capsular Polysaccharide Fragments from Neisseria meningitidis A (2007)

Neisseria meningitidis type A (MenA) is a Gram-negative encapsulated bacterium that may cause explosive epidemics of meningitis, especially in the sub-Saharan region of Africa. The development and manufacture of an efficient glycoconjugate vaccine against Neisseria meningitidis A is greatly hampered by the poor hydrolytic stability of its capsular polysaccharide, which is made up of (1-->6)-linked 2-acetamido-2-deoxy-alpha-D-mannopyranosyl phosphate repeating units. Since this chemical lability is a product of the inherent instability of the phosphodiester bridges, here we report the synthesis of phosphonoester-linked oligomers of N-acetyl mannosamine as candidates for stabilised analogues of the corresponding phosphate-bridged saccharides. The installation of each interglycosidic phosphonoester linkage was achieved by Mitsunobu coupling of a glycosyl C-phosphonate building block with the 6-OH moiety of a mannosaminyl residue. Each of the synthesised compounds contains an O-linked aminopropyl spacer at its reducing end (alpha- or beta-oriented) to allow for protein conjugation. The relative affinities of the synthetic molecules were investigated by a competitive ELISA assay and showed that a human polyclonal anti-MenA serum can recognise both the phosphonoester-bridged fragments 1-3 and their monomeric subunits, glycosides 20 and 21. Moreover, the biological results suggest that the abilities of these compounds to inhibit the binding of a specific antibody to MenA polysaccharide are dependent on the chain lengths of the molecules, but independent on the orientations of the anomeric linkers.
The Antifungal Protein from Aspergillus giganteus Causes Membrane Permeabilization (2003)

We investigated the inhibitory effects of the antifungal protein (AFP) from Aspergillus giganteus on the growth of several filamentous fungi. For this purpose, the MICs of AFP were determined and ranged from 0.1 micro g/ml for Fusarium oxysporum to 200 micro g/ml for Aspergillus nidulans. The antifungal activity of AFP was diminished in the presence of cations. We were able to show that incubation of AFP-sensitive fungi with the protein resulted in membrane permeabilization using an assay based on the uptake of the fluorescent dye SYTOX Green. No permeabilization by AFP could be detected at concentrations below the species-specific MIC. Furthermore, AFP-induced permeabilization could readily be detected after 5 min of incubation. Localization experiments with fluorescein isothiocyanate-labeled AFP and immunofluorescence staining with an AFP-specific antibody supported the observation that the protein interacts with membranes. After treatment of AFP-sensitive fungi with AFP, the protein was localized at the plasma membrane, whereas it was mainly detected inside the cells of AFP-resistant fungi. We conclude from these data that the growth-inhibitory effect of AFP is caused by permeabilization of the fungal membranes.
Phase II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. (2010)

7557 Background: The most common mechanism of acquired resistance to erlotinib (initial response followed by progressive disease) is development of a secondary mutation in the epidermal growth factor receptor (EGFR), suggesting that these tumors continue to depend upon EGFR signaling. We hypothesized that combined EGFR blockade would overcome acquired resistance to erlotinib in patients with lung adenocarcinoma. A prior phase I trial demonstrated the MTD of cetuximab given every 2 weeks in combination with erlotinib was 500 mg/m2. We conducted this phase II trial to determine the efficacy of cetuximab and erlotinib in patients with acquired resistance to erlotinib. Methods: Eligible patients had metastatic lung adenocarcinoma with either radiographic response (RECIST) to treatment with erlotinib or a documented EGFR mutation. All patients had previous treatment with erlotinib for more than 3 months, radiographic progression by RECIST during treatment with erlotinib, and continuous treatment with erlotinib for 1 month prior to initiating treatment. All patients met consensus definition of acquired resistance (Jackman JCO 28:357). Patients with grade 2 or greater skin toxicity on erlotinib monotherapy were not eligible. All patients received erlotinib 100 mg daily along with cetuximab 500 mg/m2 every two weeks. Results: Between December 2008 and July 2009, 13 patients were enrolled and treated. Median age was 60 (range 50-69), 9 women/4 men. The median time from beginning erlotinib was 19 months (range 5-72 months). Baseline EGFR mutations: exon 19 deletions (9), L858R (2), unknown (2). Acquired resistance T790M: present (7), absent (1), unknown (5). The median number of cycles received was 2 (range 1-7). Most common grade 3 and grade 4 toxicities were rash and hypomagnesemia. Response rate (CR+PR) was 0% (0/13, 95% CI 0-25%). Median progression-free and overall survival were 3 months and not reached (> 6 months). Conclusions: Combined EGFR inhibition with cetuximab 500 mg/m2 every 2 weeks and erlotinib 100 mg daily had no significant activity in patients with acquired resistance to erlotinib. Supported, in part, by Bristol-Myers Squibb and Imclone. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Genentech, ImClone Systems
Research communication copper-1,10-phenanthroline induces internucleosomal DNA fragmentation in HepG2 cells, resulting from direct oxidation by the hydroxyl radical (1996)

In view of the current speculation regarding the possible role of reactive oxygen species (ROS) in apoptosis, both under physiological conditions and in response to chemicals that promote their intracellular formation, the present investigation was undertaken to examine whether DNA fragmentation during oxidative stress results from endonuclease activity (apoptosis) or from direct attack by ROS. We report that the incubation of HepG2 cells (a human-derived hepatoma cell line) with the copper(II) complex of 1,10-phenanthroline, CuII(OP)2, results in internucleosomal DNA fragmentation, which is widely recognized as being a hallmark of apoptosis. DNA fragmentation did not occur at low temperature, but activity was restored by the addition of ascorbic acid. It is proposed that DNA fragmentation results from the direct attack of hydroxyl radicals upon DNA. Hydroxyl radicals are produced from oxygen by the redox-cycling of CuII(OP)2, which is supported by metabolic processes at normal temperature. At low temperature ascorbic acid provides an artificial cellular reducing environment, thereby restoring hydroxyl radical formation. These findings were confirmed by the detection of internucleosomal DNA fragmentation following the exposure of isolated chromatin to a biomimetic CuII(OP)2 redox-cycling system. We conclude that DNA laddering, the widely employed hallmark of apoptosis, is not unique to endonuclease activity and may also result from direct attack upon DNA by the hydroxyl radical.
Expression of chimeric monomer and dimer proteins on the plasma membrane of mammalian cells (1999)

Targeting of proteins to the plasma membrane of cells may be useful for vaccine development, tissue engineering, genetic research, bioseparations, and disease treatment. The ability of different transmembrane domains (TM) to direct a reporter protein (human alpha-feto protein, AFP) to the surface of mammalian cells was examined. High surface expression was achieved with chimeric proteins composed of AFP and the TM and cytosolic tail of murine B7-1 (AFP-B7) as well as with AFP containing a GPI-anchor from decay-accelerating factor (AFP-DAF). Lower surface expression of AFP was observed when the TM of human platelet-derived growth factor receptor or the human asialoglycoprotein receptor H1 subunit were employed. Introduction of the hinge-CH2-CH3 region of human IgG (gamma1 domain) between AFP and TM allowed efficient formation of disulfide-linked dimers. Surface expression of AFP-gamma1-B7 dimers was impaired compared to AFP-B7 whereas AFP-gamma1-DAF dimers were efficiently targeted to the surface. Accumulation of chimeric proteins on the cell surface did not correlate with the level of protein expression. This study demonstrates that high levels of monomeric and dimeric proteins can be targeted to the cell membrane of mammalian cells by proper selection of TM.
Humoral and cell-mediated immunity to human papillomavirus type I (HPV-i) in human warts (1983)

The humoral and cell-mediated immune response to human papillomavirus type 1 (HPV-1) has been studied in 162 patients carrying papillomas of various clinical types: deep plantar wart or myrmecia, common wart, flat wart, and anogenital wart. Circulating antibodies were detected by immunodiffusion and microcomplement fixation, using purified HPV-1 particles as type-specific antigen. A significant association between myrmecia and anti-HPV-1 antibodies was found (39% of the cases). Cell-mediated immunity was evaluated by a study of delayed hypersensitivity (DH). The main capsid components of HPV-1 (HPV-1 CP), consisting mostly of a polypeptide of molecular weight 54,000, were injected intradermally. In addition to the type-specific antigens, HPV-1 CP contain other antigenic determinants shared by various types of human papilloma-viruses and masked in intact viral particles. The DH tests to HPV-1 CP showed no differences between the carriers of different papilloma types, confirming the presence of common antigenic determinants. Moreover, they gave rise to an increase or to new anti-HPV-1 antibody production mostly in myrmecia carriers (78% and 33% of the cases, respectively), and to new DH to HPV-1 CP in all groups of papilloma carriers (33% to 56%, depending on the clinical papilloma type).
Erythroblast Enucleation (2011)

Even though the production of orthochromatic erythroblasts can be scaled up to fulfill clinical requirements, enucleation remains one of the critical rate-limiting steps in the production of transfusable red blood cells. Mammalian erythrocytes extrude their nucleus prior to entering circulation, likely to impart flexibility and improve the ability to traverse through capillaries that are half the size of erythrocytes. Recently, there have been many advances in our understanding of the mechanisms underlying mammalian erythrocyte enucleation. This review summarizes these advances, discusses the possible future directions in the field, and evaluates the prospects for improved ex vivo production of red blood cells.