gebhart/patrepeval huggingface dataset:
ET-35 * PACRITINIB: A NOVEL JAK/STAT INHIBITOR WITH TRANSLATIONAL RELEVANCE FOR GBM (2014)

Glioblastoma multiforme (GBM) is characterized by an aggressive clinical course, therapeutic resistance, and striking molecular heterogeneity. GBM-derived brain tumor initiating cells (BTICs) closely model this molecular heterogeneity and may have a key role in tumor recurrence and therapeutic resistance. Recent evidence, from our lab and others, indicates that the Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling pathway is an important mediator of tumor cell survival, growth, and invasion in a large group of GBMs. Thus, inhibition of the JAK/STAT3 pathway may hold great promise as a therapeutic strategy for GBM. However, to date, drugs targeting activated STAT3 in clinically relevant models have not been successfully transitioned into clinical studies. Here we investigated the efficacy of a novel JAK/STAT inhibitor, Pacritinib, in BTIC lines cultured from GBM patients. Pacritinib is currently in a multicenter, randomized, Phase 3 trial comparing its efficacy and safety with that of best available therapy in patients with primary myelofibrosis. In GBM BTICs, Pacritinib administration resulted in on-target JAK2/STAT3 inhibition at 1-2 µΜ that dramatically reduced cell survival in a large number of lines, regardless of endogenous MGMT promoter methylation or EGFR, PTEN, and TP53 mutational status. Pacritinib was also found to cross the blood-brain barrier in NOD-SCID mice, by liquid chromatography-mass spectrophometry, with no toxicity observed on repeated administration of up to 200mg/kg per day by oral gavage. Previous studies on different JAK/STAT3 inhibitors, by others and us, demonstrated toxicity at doses required to shut-off STAT3 signaling and achieve tumour cell death in vivo. We are currently investigating the actions of Pacritinib in orthotopic BTIC xenograft animal survival studies. Given its previously established human safety profile and demonstrated activity in the clinically relevant BTIC model, Pacritinib may hold considerable promise for clinical translation in GBM.
Fusion Proteins Consisting of Human Immunodeficiency Virus Type 1 Integrase and the Designed Polydactyl Zinc Finger Protein E2C Direct Integration of Viral DNA into Specific Sites (2004)

In order to establish a productive infection, a retrovirus must integrate the cDNA of its RNA genome into the host cell chromosome. While this critical process makes retroviruses an attractive vector for gene delivery, the nonspecific nature of integration presents inherent hazards and variations in gene expression. One approach to alleviating the problem involves fusing retroviral integrase to a sequence-specific DNA-binding protein that targets a defined chromosomal site. We prepared proteins consisting of wild-type or truncated human immunodeficiency virus type 1 (HIV-1) integrase fused to the synthetic polydactyl zinc finger protein E2C. The purified fusion proteins bound specifically to the 18-bp E2C recognition sequence as analyzed by DNase I footprinting. The fusion proteins were catalytically active and biased integration of retroviral DNA near the E2C-binding site in vitro. The distribution was asymmetric, and the major integration hot spots were localized within a 20-bp region upstream of the C-rich strand of the E2C recognition sequence. Integration bias was not observed with target plasmids bearing a mutated E2C-binding site or when HIV-1 integrase and E2C were added to the reaction as separate proteins. The results demonstrate that the integrase-E2C fusion proteins offer an efficient approach and a versatile framework for directing the integration of retroviral DNA into a predetermined DNA site.
p53 mutation in plasma DNA and its prognostic value in breast cancer patients. (2001)

Detection of p53 mutations in plasma DNA may be used as a prognostic factor and an early marker to indicate recurrence or distant metastasis.
Development of the stimulated Raman spectrum in single-mode silica fibers (1984)

The spectral development of stimulated Raman scattering in single-mode silica fibers was studied both experimentally and by computer modeling. The most striking feature that emerges is the rapid growth of a weak feature at 490 cm−1 at the expense of a broad band at 440 cm−1 as pump power increases. These experimental results are in good agreement with our numerical simulations, although neither experiments nor calculations show the spectral broadening of higher Stokes orders commonly observed with high pump powers and at infrared wavelengths. It is shown that, in general, spectral broadening from four-wave mixing should be important in the development of the stimulated Raman spectrum. However, the present experiments fall into a regime of relatively low pump powers at visible wavelengths in which four-wave mixing is negligible and the stimulated spectrum depends only on the shape of the Raman gain curve.
Targeting of the c-Abl Tyrosine Kinase to Mitochondria in the Necrotic Cell Death Response to Oxidative Stress (2001)

The ubiquitously expressed c-Abl tyrosine kinase is activated in the response of cells to genotoxic and oxidative stress. The present study demonstrates that reactive oxygen species (ROS) induce targeting of c-Abl to mitochondria. We show that ROS-induced localization of c-Abl to mitochondria is dependent on activation of protein kinase C (PKC)delta and the c-Abl kinase function. Targeting of c-Abl to mitochondria is associated with ROS-induced loss of mitochondrial transmembrane potential. The results also demonstrate that c-Abl is necessary for ROS-induced depletion of ATP and the activation of a necrosis-like cell death. These findings indicate that the c-Abl kinase targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death.
Mutational activation of the beta-catenin proto-oncogene is a common event in the development of Wilms' tumors. (1999)

Activation of beta-catenin-mediated transcription is the nuclear end point of organ-specific Wnt signaling. In the developing kidney, Wnt-4, a secreted glycoprotein, acts as an autoinducer of the mesenchymal to epithelial transition that underlies normal nephron development. Dysregulation of this epithelial transformation process may lead to Wilms' tumors (WTs). In this study, we investigated the potential role of the beta-catenin proto-oncogene, a candidate downstream target molecule of Wnt-4 signaling, in the development of WTs. In 6 of 40 tumors (15%), mutation analysis revealed heterozygous missense mutations or small deletions that result in the loss of important regulatory phosphorylation sites within the beta-catenin protein. These findings indicate that activating beta-catenin mutations may play a significant role in the development of WTs and establish a direct link between Wilms' tumorigenesis and the Wnt signal transduction pathway governing normal kidney development.
SUCCESSFUL ISLET AUTO- AND ALLOTRANSPLANTATION IN DIABETIC PIGS1 (1998)

We conclude that autotransplantation with a sufficient islet mass can induce normoglycemia with a normal insulin secretion response to glucose stimulation in pancreatectomized diabetic pigs and that allotransplantation can be successfully achieved when 15-deoxyspergualin and antithymocyte globulin are combined with the triple-drug immunosuppression described above. However, this immunosuppressive protocol results in a high rate of infectious complications.
The human lipid phosphate phosphatase-3 decreases the growth, survival, and tumorigenesis of ovarian cancer cells: validation of the lysophosphatidic acid signaling cascade as a target for therapy in ovarian cancer. (2003)

Lysophosphatidic acid (LPA) is present at elevated concentrations in the ascites and plasma of ovarian cancer patients. Ovarian cancer cells produce and release LPA both constitutively and after stimulation. LPA can induce proliferation, survival, invasiveness, and resistance to chemotherapy of ovarian cancer cells. This suggests that LPA may be critically important for the development or progression of ovarian cancer and is thus a potential target for therapy. In this study, we demonstrate that introduction of the integral membrane protein, human lipid phosphate phosphohydrolase-3 (hLPP-3) enzyme, which hydrolyzes phosphatidic acid, LPA, sphingosine, and ceramide phosphate in vitro with selectivity for LPA, into SKOV3 and OVCAR-3 ovarian cancer cells decreases colony-forming activity, increases apoptosis, and decreases tumor growth in vitro and in vivo. Strikingly, coculture of hLPP-3-expressing cells with nontransfected parental cells decreased the colony-forming activity of the parental cells, compatible with hLPP-3 decreasing levels of an extracellular mediator, likely LPA. Compatible with this contention, the expression of hLPP-3 was associated with increased rates of extracellular LPA hydrolysis. The effects of hLPP-3 on colony-forming activity were substantially reversed by the LPP-resistant LPA analogue, O-methylphosphothionate. The ability of O-methylphosphothionate to ameliorate the effects of hLPP-3, combined with the inability of an enzymatically inactive hLPP-3 to alter cellular function, suggests that the major effect of hLPP-3 was to increase the hydrolysis of extracellular LPA. Thus genetic or pharmacological manipulation of LPA metabolism, receptor activation, or downstream signaling is an attractive approach for therapy of ovarian cancer.
Small Airways Dimensions in Asthma and in Chronic Obstructive Pulmonary Disease (1993)

The purpose of this study was to compare the dimensions of the peripheral airways in fatal asthma with those from patients with nonfatal asthma, mild COPD, and normal lung function. Lung specimens from eight individuals who had fatal asthmatic attacks were obtained at postmortem and compared with similar specimens from three asthmatic patients who died of an unrelated cause and four specimens obtained from known asthmatic patients who required lung resection for tumor. These 15 asthmatic lungs were also compared with lungs resected for peripheral neoplasms from 15 patients with normal airway function (FEV1, % of predicted > 85) and 15 patients with mild chronic airflow obstruction (FEV1, % of predicted < 85). All membranous airways with a long-short diameter ratio of 3:1 or less were examined. The smooth muscle and the tissue areas external and internal to the muscle layer were traced using a Bioquant BQ System 4. The same system was used to evaluate the fraction of the submucosa and adventitia taken up by blood vessels. The adventitial, submucosal, and muscle area of the asthmatic airways were greater than those of COPD and control (p < 0.01), and the muscle area was greater in COPD than in control lungs (p < 0.05). These parameters were also greater in the 8 patients with fatal asthma compared with the 7 patients with nonfatal asthma (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
The Analysis of German Separable Prefix Verbs in the Microsoft Natural Language Processing System (1997)

In this paper we present an analysis of separable prefixes in German within the Microsoft Natural Language Processing System. We illustrate a simple solution to the problem of separated prefixes in our augmented phrase structure grammar which uses binary syntactic rules. The solution is based on the treatment of separated prefixes as verbs. We discuss the semi-automatic generation of the necessary lexical entries and the syntactic analysis based on these entries. We show that under our approach only one new rule needs to be added to our grammar to accommodate the facts, and that only small modifications to existing rules are necessary 1 . 1. Separable Prefixes -- the Problem Separable prefixes in German pose an interesting linguistic and computational challenge 2 . In this section we briefly outline the relevant generalizations and facts. Separable prefixes can be separated from the verb stem in two ways: morphologically and syntactically. Morphologically, the prefix and the ste...
Screening of specific single-chain variable-fragment (scFv) antibody against human asialoglycoprotein receptor by capture phage enzyme-linked immunosorbent assay (2011)

This study screened specific single-chain variable fragment (scFv) antibody against asialoglycoprotein receptor (ASGPR) by capture phage enzyme-linked immunosorbent assay (ELISA). The CRDH1/pET3b plasmid containing ASGPR gene was employed to amplify the CRDH1 gene of subunit H1 of ASGPR through PCR, which was then directionally cloned into prokaryotic expression vector pET-32c. The expression of CRDH1 was induced by isopropyl β-D-1-thiogalactopyranoside (IPTG) and the expression products underwent affinity purification through a Ni2+-chelating column. The humanized phage antibody library was screened and identified by capture phage ELISA. Then, the selected CRDH1 single chain antibody was sequenced, expressed, purified and identified by Western blot and compared with the antibody from indirect phage ELISA.  The recombinant CRDH1 protein was a 35 kDa fusion protein which existed as an inclusion body. Affinity purification through a Ni2+-chelating column acquired the CRDH1 fusion protein. 44 colonies out of 60 colonies could specifically bind to CRDH1. Sequencing showed that 9 colonies had difference sequences and 9 colonies could express CRDH1 specific scFv. Furthermore, the purified scFv also specifically recognized rCRDH1. Capture phage ELISA effectively improved the GST fusion proteins, causing false positives and enhanced the positive rate. In addition, 9 rCRDH1 specific scFv antibodies were successfully obtained by capture phage ELISA.

	 

	Key words: Asialoglycoprotein receptor, enzyme linked immunosorbent assay, fusion protein, single-chain variable-fragment antibody.
The synthesis of blocked triplet-phosphoramidites and their use in mutagenesis (1995)

A general approach for the synthesis of oligonucleotide-triplet phosphoramidites and the synthesis of four such blocks are described. A strategy was devised to minimize the number of dimer precursors needed for synthesis of a complete set of triplet-amidite blocks encoding all 20 amino acids. Whereas synthesis of 20 triplet-amidite blocks consisting of codon sequences requires 16 dimer blocks, just seven dimer blocks are required to synthesize all required antisense sequences. The antisense sequences are then converted to codons in template mediated replication. Using a mixture of four triplet-amidites and conventional automated solid-phase DNA synthesis, short (6mer) and medium length (30mer) oligonucleotide mixtures were synthesized and analyzed. The latter was replicated in vitro and used as a mutagenic cassette to produce four mutants of Asp 221 in the enzyme thymidylate synthase. The method establishes the direction and utility for the production and use of triplet-amidite blocks in DNA synthesis.
Functional Particles by Dispersion Polymerization 4: Core - Shell Tunable Surface Microspheres for Selective Enzyme Adsorption (1996)

A core—shell microsphere sample prepared by dispersion polymerization using a polyacid as the steric stabilizer was studied for its endopectinlyase and endopolygalacturonase adsorption behavior. The endopectinlyase adsorption yield decreases with increasing the medium pH, whereas the opposite behavior is observed for the endopolygalacturonase adsorption yield. This opposite adsorption tendency is correlated to the microsphere surface nature which was proved to be hydrophilic according to the medium pH.
Truncated (N)-Methanocarba Nucleosides as A1 Adenosine Receptor Agonists and Partial Agonists: Overcoming Lack of a Recognition Element (2011)

A(1) adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A(1)AR were truncated to eliminate 5'-CH(2)OH. This modification previously converted A(3)AR agonists into antagonists, but the comparable effect at A(1)AR is unknown. In comparison to ribosides, affinity at the A(1)AR was less well preserved than at the A(3)AR, although a few derivatives were moderately A(1)AR selective, notably full agonist 21 (N(6)-dicyclopropylmethyl, K(i) 47.9 nM). Thus, at the A(1)AR recognition elements for nucleoside binding depend more on 5'region interactions, and in their absence A(3)AR selectivity predominates. Based on the recently reported agonist-bound AR structure, this difference between subtypes likely correlates with an essential His residue in transmembrane domain 6 of A(1) but not A(3)AR. The derivatives ranged from partial to full agonists in A(1)AR-mediated adenylate cyclase inhibition. Truncated derivatives have more drug-like physical properties than other A(1)AR agonists; this approach is appealing for preclinical development.
Vitamin D intake and incidence of multiple sclerosis (2004)

These results support a protective effect of vitamin D intake on risk of developing MS.
On-target Inhibition of Tumor Fermentative Glycolysis as Visualized by Hyperpolarized Pyruvate (2011)

Many cancer cells display the Warburg effect, that is, enhanced glycolysis followed by fermentation (conversion of pyruvate to lactate). Recently, the molecular basis for these effects has started to be elucidated, and the up-regulation of the lactate dehydrogenase A (LDH-A) isoform of lactate dehydrogenase is felt to be a major molecular mediator of this phenomenon. Moreover, LDH-A expression in tumor tissue and LDH-A levels in blood portend a bad prognosis, and LDH-A blockade can lead to tumor growth inhibition in tumor transplant models. We have extended existing data (some of which were published during the time when we were carrying out our studies) in two important ways: 1) inhibition of LDH-A in a glycolytic lung cancer cell line results in reactive oxygen species-mediated apoptosis and increased sensitivity to the chemotherapeutic drug paclitaxel and 2) inhibition of fermentative glycolysis can also be accomplished by activation of the pyruvate dehydrogenase complex by the drug dichloroacetate, now undergoing clinical trials, and that this phenomenon can be monitored in vivo in a noninvasive real-time manner through magnetic resonance spectroscopy using hyperpolarized pyruvate. Collectively, these data suggest that in vivo effects of drugs that redirect the fate of pyruvate, and hence are aimed at reversing the Warburg effect, could be monitored through the use of hyperpolarized magnetic resonance spectroscopy, a method that is scalable to human use.
Nascent polypeptide chains emerge from the exit domain of the large ribosomal subunit: immune mapping of the nascent chain. (1982)

The site of the nascent polypeptide chain as it leaves the ribosome has been localized on the "exit domain" of the Escherichia coli ribosome by using IgG antibodies directed against the enzyme beta-galactosidase (EC 3.2.1.23). Thus, a functional site has been mapped on intact 70S ribosomes. The exit site is on the large subunit, approximately 70 A from the interface between subunits and nearly 150 A from the central protuberance, the likely site of peptide transfer. It is adjacent to the region corresponding to the rough endoplasmic membrane binding region of the eukaryotic ribosome but distant from ribosomal components participating in mRNA recognition and polypeptide elongation (i.e., distant from the "translational domain"). These results, together with the protease protection experiments of others, provide evidence that the nascent protein chain probably passes through the ribosome in an unfolded, fully extended conformation.
Sensitization of Calcitonin Gene-Related Peptide Receptors by Receptor Activity-Modifying Protein-1 in the Trigeminal Ganglion (2007)

The neuropeptide calcitonin gene-related peptide (CGRP) from the trigeminal ganglion has been established as a key player in the pathogenesis of migraine. In this study, we provide evidence that the responsiveness of neuronal CGRP receptors is strongly enhanced in vitro and in vivo by expression of human receptor activity-modifying protein-1 (hRAMP1), an obligatory subunit of the CGRP receptor. We first demonstrated that activation of CGRP receptors on cultured trigeminal ganglion neurons increased endogenous CGRP mRNA levels and promoter activity. The promoter activation was cAMP dependent and blocked by the antagonist BIBN4096BS [1-piperidinecarboxamide, N-[2-[[5-amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)], a new antimigraine drug. Gene transfer using an adenoviral hRAMP1 expression vector increased the maximal production of cAMP by 1.8 +/- 0.2-fold and decreased the EC50 to 2.3 +/- 0.8 nM from 9.0 +/- 5.9 nM and 15.6 +/- 5.2 nM in uninfected and control-infected cultures, respectively. To establish whether RAMP1 is limiting in vivo as indicated from the culture studies, a transgenic mouse expressing hRAMP1 in the nervous system was generated. After CGRP injection into the whiskerpad, the hRAMP1 transgenic mice displayed 2.2 +/- 0.2-fold greater plasma extravasation, which is a measure of neurogenic inflammation. These results demonstrate that RAMP1 is functionally rate limiting for CGRP receptor activity in the trigeminal ganglion, which raises the possibility that elevated RAMP1 might sensitize some individuals to CGRP actions in migraine.
Laboratory diagnosis of Clostridium difficile-associated gastrointestinal disease: comparison of a monoclonal antibody enzyme immunoassay for toxins A and B with a monoclonal antibody enzyme immunoassay for toxin A only and two cytotoxicity assays (1992)

A total of 320 stool specimens obtained from 262 patients suspected of having Clostridium difficile-associated gastrointestinal disease were examined with two cytotoxicity assays (CTAs) and two commercially available enzyme immunoassays (EIAs). The CTAs were an in-house-developed procedure (University of Massachusetts Medical Center [UMMC], Worcester, Mass.) and a commercial test (Bartels CTA; Baxter Healthcare Corp., West Sacramento, Calif.). One EIA was a monoclonal antibody-based assay for C. difficile toxins A and B (Cambridge Biotech Corp. [CBC], Worcester, Mass.). The other EIA employed monoclonal antibodies directed against only toxin A (Meridian Diagnostics, Cincinnati, Ohio). True-positive and true-negative results were defined on the basis of the results of the four assays, clinical assessments of patients, and the results of other laboratory tests. The sensitivities of the four assays were as follows: Bartels CTA, 100%; UMMC CTA, 97.2%; CBC EIA, 84.5%; and Meridian EIA, 69.0%. The Bartels CTA demonstrated a specificity of 99.2%. The other three assays had a specificity of 100%.
Development of Human Anti-Murine T-Cell Receptor Antibodies in Both Responding and Nonresponding Patients Enrolled in TCR Gene Therapy Trials (2010)

A subset of patients treated with mTCR-engineered T cells developed antibodies directed to the mTCR variable regions and not to the constant region domains common to all mTCR. Overall, the development of a host immune response was not associated with the level of transduced cell persistence or response to therapy. In summary, patients treated with mTCR can develop an immune response to gene-modified cells in a minority of cases, but this may not affect clinical outcome.