gebhart/patrepeval huggingface dataset:
Phase I open-label, ascending dose trial of AGEN1884, an anti-CTLA-4 monoclonal antibody, in advanced solid malignancies: Dose selection for combination with PD-1 blockade. (2018)

3075 Background: AGEN1884 is a novel fully human IgG1 monoclonal antibody targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Objective: Assess the safety, maximum tolerated dose, and pharmacokinetic (PK) and pharmacodynamic characteristics of AGEN1884 in patients with advanced and refractory malignancies. Methods: Patients (≥18 years old) with relapsed/refractory lymphoma or solid cancers without curative treatment options received AGEN1884 at 0.1, 0.3, 1, 3 or 6 mg/kg in a “3+3” trial design. An additional 10 patients were enrolled in both 1 and 3 mg/kg dose expansion cohorts. AGEN1884 was administered intravenously (IV) every 3 weeks for 4 doses and then every 3, 6, or 12 weeks at the Investigator’s discretion. Results: As of 03Jan2018 data cutoff, 33 patients were enrolled in the following cohorts: 0.1 mg/kg (n = 5, 2 not evaluable [NE] for dose-limiting toxicity [DLT]), 0.3 mg/kg (n = 3), 1 mg/kg (n = 10), 3 mg/kg (n = 12, 2 NE for DLT) and 6 mg/kg (n = 3). Median age was 61 years (range 26–88), baseline ECOG scores were 0 (N = 4), 1 (N = 25), unknown (4), with a median of 10 (range 3–26) prior therapies. As of Jan 31, 2018, no DLT’s have been reported. Immune-related adverse events were reported in 10 (30.3%) of patients as follows: 0.1 mg/kg (1 [20.0%]), 0.3 mg/kg (1 [33.3%]), 1 mg/kg (1 [10%]), and 3 mg/kg (6 [50%]) and included hypophysitis, colitis, diarrhea, rash and pruritus. Most were mild-moderate consistent with published reports of other CTLA-4 inhibitors. 6 patients (18.2%) came off study due to disease progression or AE’s but none related to treatment. Of 11 subjects evaluable for response, 1 with angiosarcoma treated at 0.1 mg/kg attained a CR at 7 months after achieving a PR. Three subjects with SD: 1 at 0.3 mg/kg with adenoid cystic carcinoma at Week 21 who had SD for 53 weeks; 2 subjects at 3 mg/kg: 1 with breast cancer with SD at Week 6 and 1 with invasive metaplastic breast cancer at Week 12 on study. Conclusions: AGEN1884 was well tolerated at 0.1, 0.3, 1 and 3 mg/kg dose levels. Enrollment continues at 6 mg/kg. Updated safety and PK data will be presented. A starting dose level of 1 mg/kg has been selected for combination with PD-1 blockade. Clinical trial information: NCT02694822.
Fatty Liver (1991)

In vitro animal and human models were used to evaluate the potential of chemical shift magnetic resonance imaging (MRI) for assessing fatty liver. Phantoms of varying fat content were created from mayonnaise-agar preparations. Fatty liver was induced in eight rats by feeding them ethanol for three to six weeks (36% of total calories), whereas eight control rats were fed a normal diet. T1-weighted in-phase and opposed-phase MR images were obtained of the phantoms animals, and 28 human subjects. Additional images obtained in animals included long TR images with in-phase and opposed-phase technique, and hybrid chemical shift water and fat suppression. The rats were killed and histologic status was graded blindly by a hepatopathologist as normal, mild, moderate, or severe fatty change, for correlation with MR grading. Quantitative analysis of MR images included fat signal fraction for animals, and relative signal decrease between in-phase and opposed-phase images for phantom and human data. Phantom in-phase signal increased linearly with respect to fat content, whereas opposed-phase signal decreased linearly. MRI and histologic grading of rat livers were highly correlated, especially when based on water suppression images (r = 0.91, P = .0001). Opposed-phase images were also highly correlated, while fat suppression images were less effective. There was no overlap between MR-derived fat fractions for control (2.6%-5.7%) versus ethanol-fed rats (7.7%-17.9%, P = .0002). Human liver considered to be fatty by visual inspection (n = 8) had higher relative signal decrease than nonfatty liver (n = 22) (P less than .001). Phantom, animal, and human data demonstrate that comparison of T1-weighted in-phase and opposed-phase images is both practical and sensitive in the detection and grading of fatty liver.
Carbonic anhydrase inhibition as a cancer therapy: a review of patent literature, 2007 – 2009 (2010)

Much of what has been reported in the patent literature during the period 2007 - 2009 is based on alleged therapeutic benefits of CA inhibitors in cancer. Recently appropriate CA-relevant cell and animal models of tumor hypoxia for the evaluation of compounds have become available and the verification of the ability of small molecules to modulate CA activity as a cancer therapy or as a diagnostic and/or prognostic tool is now possible and probable. The CA field will thus provide for a scientifically exciting and possibly rewarding next few years, accelerated by the growing interest in the potential clinical applications of this enzyme class in oncology.
Anion-exchange membranes in electrochemical energy systems (2014)

A detailed perspective on the use of anion-exchange membranes in fuel cells, electrolysers, flow batteries, reverse electrodialysis, and bioelectrochemical systems.
A phage P1 function that stimulates homologous recombination of the Escherichia coli chromosome. (1986)

Recombination between two different defective lacZ genes in the Escherichia coli chromosome (lac- X lac- recombination) was stimulated 2- to 8-fold by prophage P1, depending on the nature of the phage c1 repressor. The P1 BamHI restriction fragment B8 in a lambda-P1:B8 hybrid phage, stimulated lac- X lac- recombination 90-fold in the absence of P1 repressor. A gene necessary for recombination enhancement, designated ref, was localized to one end of B8. Ref expression from lambda-P1:B8 was repressed in trans by a P1 c+ prophage. Two P1 regulatory mutations, bof and lxc, derepressed prophage expression of ref and depressed a prophage function that complemented an E. coli mutant (ssb) deficient in the single-stranded DNA binding protein. Ref stimulation was dependent on preexisting E. coli recombination functions (RecA-RecBC and RecA-RecF). However, other (phage and plasmid) recombination processes involving these functions were not stimulated. ref::Tn5 phages plated and formed lysogens normally. Thus ref appears to be an integral, but not essential, phage gene that stimulates recombination of the host chromosome specifically.
High‐Sensitivity sequencing of large proteins: Partial structure of the rapamycin‐fkbp12 target (1994)

We report on studies leading to refinements of various steps of the protein internal sequencing process. Specifically, the developments comprise (1) higher-sensitivity chemical sequencing through background reduction; (2) improved peptide recovery from rapid in situ digests of nanogram amount, nitrocellulose-bound proteins; and (3) accurate UV spectroscopic identification of Trp- and Cys-containing peptides. In addition, we describe strategies for 2-dimensional liquid chromatographic peptide isolation from complex mixtures and a multi-analytical approach to peptide sequence analysis (Edman sequencing, matrix-assisted laser desorption mass spectrometry, and UV spectroscopy). Both strategies were applied in tandem to the primary structural analysis of a gel-purified, 250-kDa protein (mammalian target of rapamycin-FKBP12 complex), available in low picomolar quantities only. More than 300-amino acids worth of sequence was obtained in mostly uninterrupted stretches, several containing Trp, Cys, His, and Ser. That information has allowed the matching of a biological function of a mammalian protein to a yeast gene product with a well-characterized mutant phenotype. The results also demonstrate that extended chemical sequencing analysis (e.g., 26 successive amino acids) is now feasible, starting with initial yields well below 1 pmol.
Unit Segmentation of Argumentative Texts (2017)

The segmentation of an argumentative text into argument units and their nonargumentative counterparts is the first step in identifying the argumentative structure of the text. Despite its importance for argument mining, unit segmentation has been approached only sporadically so far. This paper studies the major parameters of unit segmentation systematically. We explore the effectiveness of various features, when capturing words separately, along with their neighbors, or even along with the entire text. Each such context is reflected by one machine learning model that we evaluate within and across three domains of texts. Among the models, our new deep learning approach capturing the entire text turns out best within all domains, with an F-score of up to 88.54. While structural features generalize best across domains, the domain transfer remains hard, which points to major challenges of unit segmentation.
Preliminary trial of 3,4‐diaminopyridine in patients with multiple sclerosis (1990)

Ten patients with multiple sclerosis (MS) were enrolled in a preliminary trial of the potassium channel blocker, 3,4-diaminopyridine, to evaluate drug toxicity and pharmacokinetics. The patients were treated with oral 3,4-diaminopyridine, first with increasing single doses up to 100 mg and then with divided dosage for up to 3 weeks. Paresthesias were reported by all patients and abdominal pain was dose limiting in 6 patients. 3,4-Diaminopyridine levels and half-life varied widely from patient to patient. Cerebrospinal fluid levels of 3,4-diaminopyridine were about 10% of those in serum. Neither seizures nor epileptiform changes on electroencephalographic examination occurred. Small reversible improvements in specific neurological deficits were seen on examination in all patients and reversible improvement in visual evoked response latencies were found in 2 patients. These results suggest that further study of 3,4-diaminopyridine in patients with MS is warranted.
Clusterin (SGP‐2, ApoJ) expression is downregulated in low‐ and high‐grade human prostate cancer (2003)

Clusterin is overexpressed during tissue and cell involution and downregulated in proliferating cells. Its role in cell survival, cell death and neoplastic transformation remains debated. We studied the expression and distribution of clusterin mRNA and protein in human prostate carcinoma (CaP) specimens of different degrees of malignancy. Fresh CaP specimens were obtained from 25 patients subjected to long-term androgen ablation before surgery. Clusterin expression was studied by Northern and Western analysis, in situ hybridization and immunohistochemistry, in comparison with Gas1 and histone H3 mRNA (markers of cell quiescence and S phase of the cell cycle, respectively). Clusterin is downregulated in CaP in comparison with matched benign controls. In low-grade CaP, clusterin colocalized with Gas1 to the stromal compartment, and in some glands, the basal lamina was heavily stained. In high-grade CaP clusterin stained the remnants of stromal matrix while histone H3 localized to cancer cells, which were very rarely clusterin positive. High clusterin expression was found in the branches of a nerve infiltrated by tumor. The periglandular clusterin expression found in low-grade CaP could result from induction of quiescence and/or apoptosis of prostatic fibroblasts lining those glands in which tumor invasion is at an initial stage, involving basal lamina. In advanced CaP, the staining of the remnants of the extracellular matrix suggests a role for clusterin in the process of dismantling the stromal organization caused by cancer progression.
Distinguishing between Folate Receptor-α-mediated Transport and Reduced Folate Carrier-mediated Transport in L1210 Leukemia Cells (1995)

L1210 leukemia cells transport reduced folates and methotrexate via a well defined reduced folate carrier system and, in the absence of low folate selective pressure, do not express an alternate endocytotic route mediated by cell surface folate receptors. This laboratory previously described an L1210 leukemia cell line, MTXrA, with acquired resistance to methotrexate (MTX) due to the loss of mobility of the reduced folate carrier. We now report on the transfection of MTXrA with a cDNA encoding the murine homolog of the human folate receptor isoform of KB cells to produce MTXrA-TF1, which constitutively expresses high levels of FR-alpha. MTXrA-TF1 and L1210 cells were utilized to compare transport of methotrexate mediated by FR-alpha and the reduced folate carrier, respectively. Methotrexate influx in the two lines was similar when the extracellular level was 0.1 microM, but as the methotrexate concentration increased, influx via the reduced folate carrier increased in comparison to influx mediated by FR-alpha. Transport kinetics indicated both a approximately 20-fold lower influx Kb and Vmax for MTXrA-TF1 as compared to L1210 cells. The two cell lines exhibited distinct influx properties. Methotrexate influx in MTXrA-TF1 was markedly inhibited by 50 nM folic acid and metabolic poisons. In L1210 cells, 1.0 microM folic acid did not affect MTX influx, and metabolic poisons either had no effect on or increased methotrexate influx. Removal of extracellular chloride markedly inhibited transport in MTXrA-TF1 but stimulated influx in L1210 cells. When the pH was decreased to 6.2, methotrexate influx was not altered in MTXrA-TF1 but was reduced in L1210 cells. Probenecid and sulfobromophthalein inhibit methotrexate influx in both L1210 and MTXrA-TF1 cell lines; however, inhibition in MTXrA-TF1 could be accounted for on the basis of inhibition of methotrexate binding to FR-alpha. The data indicate that the reduced folate carrier and FR-alpha function independently and exhibit distinct properties. FR-alpha expressed at sufficient levels can mediate influx of MTX and folates into cells at rates comparable to the reduced folate carrier and hence has pharmacologic and physiologic importance.
Mechanistic Insights into SARS Coronavirus Main Protease by Computational Chemistry Methods (2013)

The SARS virus is the etiological agent of the severe acute respiratory syndrome, a deadly disease that caused more than 700 causalities in 2003. One of its viral proteins, the SARS coronavirus main protease, is considered as a potential drug target and represents an important model system for other coronaviruses. Despite extensive knowledge about this enzyme, it still lacks an effective anti-viral drug. Furthermore, it possesses some unusual features related to its active-site region. This work gives atomistic insights into the SARS coronavirus main protease and tries to reveal mechanistic aspects that control catalysis and inhibition. Thereby, it applies state-of-the-art computational methods to develop models for this enzyme that are capable to reproduce and interpreting the experimental observations. The theoretical investigations are elaborated over four main fields that assess the accuracy of the used methods, and employ them to understand the function of the active-site region, the inhibition mechanism, and the ligand binding. The testing of different quantum chemical methods reveals that their performance depends partly on the employed model. This can be a gas phase description, a continuum solvent model, or a hybrid QM/MM approach. The latter represents the preferred method for the atomistic modeling of biochemical reactions. A benchmarking uncovers some serious problems for semi-empirical methods when applied in proton transfer reactions. To understand substrate cleavage and inhibition of SARS coronavirus main protease, proton transfer reactions between the Cys/His catalytic dyad are calculated. Results show that the switching between neutral and zwitterionic state plays a central role for both mechanisms. It is demonstrated that this electrostatic trigger is remarkably influenced by substrate binding. Whereas the occupation of the active-site by the substrate leads to a fostered zwitterion formation, the inhibitor binding does not mimic this effect for the employed example. The underlying reason is related to the coverage of the active-site by the ligand, which gives new implications for rational improvements of inhibitors. More detailed insights into reversible and irreversible inhibition are derived from in silico screenings for the class of Michael acceptors that follow a conjugated addition reaction. From the comparison of several substitution patterns it becomes obvious that different inhibitor warheads follow different mechanisms. Nevertheless, the initial formation of a zwitterionic catalytic dyad is found as a common precondition for all inhibition reactions. Finally, non-covalent inhibitor binding is investigated for the case of SARS coranavirus main protease in complex with the inhibitor TS174. A novel workflow is developed that includes an interplay between theory and experiment in terms of molecular dynamic simulation, tabu search, and X-ray structure refinement. The results show that inhibitor binding is possible for multiple poses and stereoisomers of TS174.
Construction and selection of recombinant plasmids containing full-length complementary DNAs corresponding to rat insulins I and II. (1979)

We have used a synthetic deoxydecanucleotide to generate an insulin-specific cDNA probe suitable for selecting transformants that contain nearly full-length cDNAs corresponding to the mRNAs coding for rat insulins I and II. Double-stranded cDNA was synthesized from x-ray-induced rat insulinoma poly(A)-RNA, inserted in pBR322 plasmid DNA by the homopolymeric tailing technique, and cloned in Escherichia coli chi 1776. Colony hybridization with oligonucleotide-primed cDNA yielded 16 positive clones of which 7 corresponded to rat insulin I mRNA and 9 to rat insulin II mRNA. Restriction endonuclease maps of representative clones of each group indicated that these contained the complete coding sequences, as was confirmed by nucleotide sequence analysis of the 5' region of the cloned DNA for rat insulin II. Nucleotide sequence analysis also established the amino acid sequence of the prepeptide of rat preproinsulin II. Comparison of the amino acid sequence of the prepeptides of rat preproinsulin I and II shows that three conservative amino acid substitutions have occurred in this region of the molecule.
Distributed rational decision making (1999)

Introduction Automated negotiation systems with self-interested agents are becoming increasingly important. One reason for this is the technology push of a growing standardized communication infrastructure---Internet, WWW, NII, EDI, KQML, FIPA, Concordia, Voyager, Odyssey, Telescript, Java, etc---over which separately designed agents belonging to different organizations can interact in an open environment in realtime and safely carry out transactions. The second reason is strong application pull for computer support for negotiation at the operative decision making level. For example, we are witnessing the advent of small transaction electronic commerce on the Internet for purchasing goods, information, and communication bandwidth [29]. There is also an industrial trend toward virtual enterprises: dynamic alliances of small, agile enterprises which together can take advantage of economies of scale when available (e.g., respond to mor
Magnetoencephalography in Presurgical Evaluation of Children with the Landau‐Kleffner Syndrome (1999)

(a) The intrasylvian cortex is a likely pacemaker of epileptic discharges in LKS, and (b) MEG provides useful presurgical information of the cortical spike dynamics in LKS patients.
Cotinine levels and self-reported smoking status in patients attending a bronchoscopy clinic (2003)

The reliability of self-reported smoking behaviour can vary and may result in bias if errors in misclassification vary with outcome. We examined whether self-report was an accurate measure of current smoking status in patients with malignant or non-malignant respiratory disease. Smoking behaviour was assessed by self-report and by analysis of whole blood for cotinine, a biomarker of exposure to cigarette smoke, in 166 patients attending a bronchoscopy clinic. Cotinine levels ranged from 2.5 to >400 ng ml(-1) blood and were higher in self-reported current smokers (173+/-123 ng ml(-1)) than in never smokers (3.7+/-8.7 ng ml(-1)) or ex-smokers (20.5+/-49.0 ng ml(-1)). Cotinine levels in self-reported current smokers increased with the numbers of cigarettes smoked (p=0.06), and levels in smokers and ex-smokers decreased with the reported length of time since the last cigarette (p=0.001). Using a cotinine level of 20 ng ml(-1) and self-report as the gold standard, the sensitivity and specificity for defining current smoking status were 90.2% and 82.4%, respectively. Out of a total of 125 self-reported current non-smokers, 23 (18.4%) had cotinine levels greater than 20 ng ml(-1). Smoking prevalence was significantly underestimated by self-report (24.7%) when compared with that defined using blood cotinine levels (36.1%: p<0.001). Misclassification of current smoking status was particularly high in ex-smokers, in patients without malignant respiratory disease, in men, and in those below the median age. Such differential misclassification may result in bias in studies examining associations between current smoking habits and disease risk.
Biocompatible surfactants for water-in-fluorocarbon emulsions (2008)

Drops of water-in-fluorocarbon emulsions have great potential for compartmentalizing both in vitro and in vivo biological systems; however, surfactants to stabilize such emulsions are scarce. Here we present a novel class of fluorosurfactants that we synthesize by coupling oligomeric perfluorinated polyethers (PFPE) with polyethyleneglycol (PEG). We demonstrate that these block copolymer surfactants stabilize water-in-fluorocarbon oil emulsions during all necessary steps of a drop-based experiment including drop formation, incubation, and reinjection into a second microfluidic device. Furthermore, we show that aqueous drops stabilized with these surfactants can be used for in vitro translation (IVT), as well as encapsulation and incubation of single cells. The compatability of this emulsion system with both biological systems and polydimethylsiloxane (PDMS) microfluidic devices makes these surfactants ideal for a broad range of high-throughput, drop-based applications.
Synthesis and Antitumor Activities of Novel 6-5 Fused Ring Heterocycle Antifolates: N-[4-[.omega.-(2-Amino-4-substituted-6,7-dihydrocyclopenta[d]pyrimidin-5-yl)alkyl]benzoyl]-L-glutamic Acids (1994)

Novel antifolates with a 6-5 fused ring system, 6,7-dihydrocyclopenta [d]pyrimidine, (3a,b and 4a,b) were synthesized on the basis of combined modification of the heterocycle and bridge regions of the folate molecule. The synthetic method involves (1) synthesis of key intermediates of tert-butyl 4-[omega-(2-substituted-3-oxocyclopentanyl) alkyl]benzoates (8a,b and 9a,b) by a carbon-carbon radical coupling of tert-butyl 4-(omega-iodoalkyl)benzoates (7a,b) with 2-substituted-2-cyclopenten-1-ones (5 and 6) utilizing tributyltin hydride, (2) cyclization of either the methyl enol-ethers derived from the 2-cyanocyclopentanones (8a,b) or the 2-(methoxycarbonyl)cyclopentanones (9a,b) themselves by treatment with guanidine which leads to 6,7-dihydrocyclopenta [d]pyrimidines with a 4-(tert-butoxycarbonyl)phenylalkyl group (11a,b and 14a,b), (3) deprotection to the corresponding carboxylic acids (12a,b and 15a,b), and (4) amidation with diethyl glutamate and deesterification. Potent dihydrofolate reductase inhibition and highly potent cell growth inhibition were found with 2,4-diaminopyrimidine-fused cyclopentene compounds containing the trimethylene (3a) or ethylene bridge (3b) but not with the corresponding 2-amino-4-hydroxy analogs (4a,b). Compounds 3a and 3b were more growth inhibitory to several tumor cell lines (P388, colon 26, colon 38, and KB) than was methotrexate, with 3a being the most potent. Both 3a and 3b gave increases in the lifespan of P388 leukemic mice comparable to that observed with MTX. Both compounds were therapeutic against colon 26 colorectal carcinoma in mice. Compound 3a was highly effective against LC-6 non-small cell lung carcinoma in nude mice.