gebhart/patrepeval huggingface dataset:
Bruton’s Tyrosine Kinase Inhibitors: Approaches to Potent and Selective Inhibition, Preclinical and Clinical Evaluation for Inflammatory Diseases and B Cell Malignancies (2012)

ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTBruton's Tyrosine Kinase Inhibitors: Approaches to Potent and Selective Inhibition, Preclinical and Clinical Evaluation for Inflammatory Diseases and B Cell MalignanciesYan Lou*, Timothy D. Owens*, Andreas Kuglstatter, Rama K. Kondru, and David M. GoldsteinView Author Information Discovery Chemistry, Small Molecule Research, pRED, Pharma Research and Early Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New Jersey 07110, United States*For Y.L.: phone, 973-235-7648; fax, 973-235-6263; e-mail, [email protected], [email protected]. For T.D.O.: phone, 650-416-7725; e-mail, [email protected]Cite this: J. Med. Chem. 2012, 55, 10, 4539–4550Publication Date (Web):March 6, 2012Publication History Received10 January 2012Published online21 March 2012Published inissue 24 May 2012https://pubs.acs.org/doi/10.1021/jm300035phttps://doi.org/10.1021/jm300035preview-articleACS PublicationsCopyright © 2012 American Chemical SocietyRequest reuse permissionsArticle Views4958Altmetric-Citations69LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Inhibition,Inhibitors,Monomers,Peptides and proteins,Selectivity Get e-Alerts
Treatment of Resistant Venous Stasis Ulcers and Dermatitis with the End-Diastolic Pneumatic Compression Boot (1986)

The end-diastolic pneumatic compression boot was used to treat 17 patients with difficult or refractory stasis dermatitis and ulcers. Decreases in induration, pigmentation, and palpable thrombi were observed and all patients were improved or healed. The boot treatment allowed effective local administration of antibiotics on gauze wrappings. Removal of the latter after treatments provided a means of nonsurgical debridement. Healing was maintained by periodic outpatient boot treatments in patients with close followup. Ulcers recurred in patients lost to followup but responded again to boot treatment. One diabetic man with knee contractures and both severe venous and arterial disease relapsed repetitively and lost both legs in spite of bilateral femoral-popliteal bypasses and his boot treatments.
The RD114/simian type D retrovirus receptor is a neutral amino acid transporter (1999)

The RD114/simian type D retroviruses, which include the feline endogenous retrovirus RD114, all strains of simian immunosuppressive type D retroviruses, the avian reticuloendotheliosis group including spleen necrosis virus, and baboon endogenous virus, use a common cell-surface receptor for cell entry. We have used a retroviral cDNA library approach, involving transfer and expression of cDNAs from highly infectable HeLa cells to nonpermissive NIH 3T3 mouse cells, to clone and identify this receptor. The cloned cDNA, denoted RDR, is an allele of the previously cloned neutral amino acid transporter ATB0 (SLC1A5). Both RDR and ATB0 serve as retrovirus receptors and both show specific transport of neutral amino acids. We have localized the receptor by radiation hybrid mapping to a region of about 500-kb pairs on the long arm of human chromosome 19 at q13.3. Infection of cells with RD114/type D retroviruses results in impaired amino acid transport, suggesting a mechanism for virus toxicity and immunosuppression. The identification and functional characterization of this retrovirus receptor provide insight into the retrovirus life cycle and pathogenesis and will be an important tool for optimization of gene therapy using vectors derived from RD114/type D retroviruses.
Seismic Velocity Model Calibration Using Dual Monitoring Well Data (2009)

Abstract A hydraulic fracture stimulation was monitored with borehole geophone arrays deployed in two observation wells. The resulting microseismic images showed that the first horizontal well stimulation was characterized by a diffuse cloud of microseismic events, and the production log indicated roughly uniform production along the length of the well. The second horizontal well stimulation was characterized by clustered microseisms, and the production log indicated significant production from the intersection of pre-existing fractures with the well. The resulting case study allowed a comparison of accuracies between a single observation well and two observation wells. A comparison was also made of the microseismic event location accuracy resulting from of the different configurations of observation wells. The dual well observations provide an opportunity for enhanced velocity model validation in addition to enhanced source imaging techniques to provide additional information about the fracture geometry.
Protein, peptide and non-peptide drug PEGylation for therapeutic application (2004)

For many years proteins have been investigated as therapeutic agents, but unfortunately their potential advantages could not be completely exploited. The main drawbacks are their intrinsic short life in the body, immunological adverse reaction and proteolytic digestion. Among all the approaches studied for overcoming these problems, PEGylation (the modification of molecules with polyethylene glycol [PEG]) achieved the most interesting results, leading to a novel series of products that have already reached the market, and hopefully other promising agents will soon be available. Since the first studies in this field, the conjugation of PEG to a protein has shown the possibility of improving the pharmacokinetic profile of a linked drug. In the last few years this technology, firstly developed for proteins, has been transferred to non-peptide drugs, opening a new area of investigation that is now receiving increasing interest. This leads to new opportunities for many therapeutic treatments as it is possible to use molecules that could not before be exploited due to limitations such as inadequate water solubility, high nonspecific toxicity and poor pharmacokinetic profiles. In this review the most recent achievements in PEGylation of protein, peptide and non-peptide drugs are described concerning the binding chemistry, and many examples from the literature are reported, in the fields of both protein therapeutics and non-peptide drugs.
Structure-function relationships in the interaction of alpha-thrombin with blood platelets. (1977)

Highly purified alpha-thrombin has been chemically modified in an attempt to determine which features of the molecule are important for normal platelet-thrombin interactions. Modifying agents included diisopropylphosphorofluoridate and 1-chloro-3-tosylamido-7-amino-L-2-heptanone, which modify serine and histidine, respectively, at the catalytic site, as well as N-bromosuccinimide and 2-hydroxy-5-nitrobenzyl bromide, which modify a single tryptophan at or near the fibrinogen-binding site. Active site-directed modification did not appreciably affect the binding characteristics, but prevented platelet activation. In contrast, modification of tryptophan at the macromolecular substrate-binding site resulted in the loss of high affinity binding of thrombin to platelets, while low affinity binding was apparently unaffected. This modification altered but did not abolish the ability of thrombin to effect platelet aggregation and release of [14C]serotonin. These results suggest that residues at the catalytic site are not involved in binding and that the macromolecular substrate-binding site of alpha-thrombin participates in high affinity binding to platelets. These data are also consistent with the existence of at least two types of binding sites for thrombin on the platelet surface as well as more than one platelet-binding region on the thrombin molecule.
Decoding the Pluripotency Network: The Emergence of New Transcription Factors (2013)

Since the successful isolation of mouse and human embryonic stem cells (ESCs) in the past decades, massive investigations have been conducted to dissect the pluripotency network that governs the ability of these cells to differentiate into all cell types. Beside the core Oct4-Sox2-Nanog circuitry, accumulating regulators, including transcription factors, epigenetic modifiers, microRNA and signaling molecules have also been found to play important roles in preserving pluripotency. Among the various regulations that orchestrate the cellular pluripotency program, transcriptional regulation is situated in the central position and appears to be dominant over other regulatory controls. In this review, we would like to summarize the recent advancements in the accumulating findings of new transcription factors that play a critical role in controlling both pluripotency network and ESC identity.
Activation of Reactive MALDI Adduct Ions Enables Differentiation of Dihydroxylated Vitamin D Isomers (2017)

Vitamin D compounds are secosteroids, which are best known for their role in bone health. More recent studies have shown that vitamin D metabolites and catabolites such as dihydroxylated species (e.g., 1,25- and 24,25-dihydroxyvitamin D<sub>3</sub>) play key roles in the pathologies of various diseases. Identification of these isomers by mass spectrometry is challenging and currently relies on liquid chromatography, as the isomers exhibit virtually identical product ion spectra under collision induced dissociation conditions. Here, we developed a simple MALDI-CID method that utilizes ion activation of reactive analyte/matrix adducts to distinguish isomeric dihydroxyvitamin D<sub>3</sub> species, without the need for chromatography separation or chemical derivatization techniques. Specifically, reactive 1,5-diaminonaphthalene adducts of dihydroxyvitamin D<sub>3</sub> compounds formed during MADI were activated and specific cleavages in the secosteroid's backbone structure were achieved that produced isomer-diagnostic fragment ions. Graphical Abstract ᅟ.
Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates. (1985)

We report the enhanced inhibitory potency of methotrexate (MTX) polyglutamates and dihydrofolate pentaglutamate on the catalytic activity of phosphoribosylaminoimidazolecarboxamide (AICAR) transformylase purified from MCF-7 human breast cancer cells. In the present work, MTX (4-amino-10-methylpteroylglutamic acid) and dihydrofolate, both monoglutamates, were found to be weak competitive inhibitors of AICAR transformylase with Kis of 143 and 63 microM, respectively, and their inhibitory capacity was largely unaffected by the glutamated state of the folate cosubstrate. In contrast, MTX polyglutamates were found to be potent competitive inhibitors, with an approximately 10-fold increase in inhibitory potency with the addition of each glutamate group up to four (i.e., the pentaglutamate derivative). MTX tetra-and pentaglutamates were the most potent, with equivalent Kis of 5.6 X 10(-8) M or 2500-fold more potent than MTX. Dihydrofolate pentaglutamate was as potent an inhibitor as MTX pentaglutamate, with a Ki of 4.3 X 10(-8) M. The potent inhibitory effects demonstrated by the polyglutamate compounds when tested against the folate monoglutamate substrate were sharply curtailed when folate pentaglutamate was used as the substrate. MTX and dihydrofolate pentaglutamates were only 7- and 25-fold more potent than their monoglutamate counterparts under these conditions. A model depicting these complex interactions is postulated. These findings have significant implications regarding the mechanism of action of MTX.
Association of antisense oligonucleotides with lipoproteins prolongs the plasma half-life and modifies the tissue distribution (1991)

In order to direct antisense oligonucleotides to specific tissues or cell types in vivo, we are exploring the possibility to utilize lipoproteins as transport vehicles. A 16-mer oligonucleotide (ODN) was derivatized at the 5' prime through a 32P phosphate spacer with cholesterol, yielding a 32P-labeled amphiphatic cholesteryl-oligonucleotide (cholODN). Incubation of cholODN with low-density lipoprotein (LDL) for 2 hr at 37 degrees C resulted in the formation of a cholODN-LDL complex that migrates as a single peak on agarose gel electrophoresis. The cholODN was found to bind quantitatively to both high-density lipoproteins (HDL) and LDL, but not to albumin. Stable oligonucleotide-LDL particles with up to 50 molecules of cholODN per LDL particle could be obtained. In contrast, the control ODN did not show affinity for plasma lipoproteins. Upon injection into rats, cholODN became rapidly associated with plasma lipoproteins while control ODNs were recovered in the lipoprotein deficient serum fraction. The plasma half-life of cholODN (9-11 min) is considerably prolonged as compared with the control ODN (t1/2 less than 1 min). The cholODN-LDL was at least 5 min stable against degradation by rat plasma nucleases. It is concluded that derivatization of antisense oligonucleotides with cholesterol profoundly modifies their in vivo fate and opens possibilities for efficient and specific receptor-dependent targeting, mediated by lipoproteins coupled with specific recognition markers to various hepatic cell types.
Pseudomonas exotoxin-based immunotoxins containing the antibody LL2 or LL2-Fab' induce regression of subcutaneous human B-cell lymphoma in mice. (1993)

We have produced immunotoxins using LL2, a monoclonal antibody which binds to human B-cell lymphomas and which, in a radioiodinated form, induced responses in lymphoma patients (D.M. Goldberg et al., J. Clin. Oncol., 9: 548-564, 1991). We have coupled LL2 to Lys-PE38KDEL, a derivative of Pseudomonas exotoxin (PE) which does not bind to the PE receptor. LL2-PE38KDEL was cytotoxic toward several Burkitt's lymphoma lines, with 50% inhibitory concentration values ranging from 2 to 6 ng/ml (10-30 pM). Another immunotoxin, LL2-Fab'-PE38KDEL, was produced by chemically coupling the Fab' fragment of LL2 to Lys-PE38KDEL. LL2-Fab'-PE38KDEL also was cytotoxic toward the Burkitt's cells, with a 50% inhibitory concentration of 1-2 ng/ml (13-24 PM). The antibody LL2 alone had no cytotoxicity toward the malignant cells, and excess LL2 prevented the cytotoxicity of LL2-PE38KDEL and LL2-Fab'-PE38KDEL. Control immunotoxins UPC-10-PE38KDEL and Mu-9-Fab'-PE38KDEL were not cytotoxic. LL2-PE38KDEL and LL2-Fab'-PE38KDEL bound to cells with 50% and 17% of the affinity of LL2, respectively. Both immunotoxins, but not UPC-10-PE38KDEL, prevented the development of CA-46 tumors in nude mice. LL2-PE38KDEL and LL2-Fab'-PE38KDEL, but not the control immunotoxins, led to complete regressions of measurable s.c. CA-46 tumors in nude mice, when given at 50% and 35% of the 50% lethal dose, respectively. LL2 alone significantly retarded the growth of CA-46 tumors but did not cause complete tumor regressions. Immunotoxins containing derivatives of Pseudomonas exotoxin can be targeted to human B-cell lymphoma and merit further study as potential therapeutic agents.
Handling of Picoliter Liquid Samples in a Poly(dimethylsiloxane)-Based Microfluidic Device (1999)

Transportation, metering, and mixing of picoliter-sized liquid samples were realized in a microfluidic device with a main working area of one square millimeter. The device was constructed by sealing microfabricated grooves on a chip made of poly(dimethylsiloxane) (PDMS). Two different samples were segmented into 600-pL droplets in a microchannel with a cross section of W (100 μm) × H (25 μm), and the droplets were merged together. For acceleration of the mixing, the merged droplet was shuttled back and forth. Recirculation in a moving droplet was proven to be effective for high-speed mixing in this diffusion-dominated scale. All the handling operations were carried out using air pressure transferred through microfabricated vent valves which have been newly developed. The demonstrated strategy, including fabrication, leads to high-performance and low-cost micro total analysis systems (μTAS).
Contacts between simple metals and atomically clean silicon (1975)

Workfunction measurements of atomically clean silicon (111) surfaces produced by cleavage and of evaporated simple-metal films have been carried out in a UHV system at a base pressure of about 5*10-11 Torr. The barrier heights of the resulting intimate metal-silicon contacts have also been measured without breaking the vacuum. The barrier height values derived from I-V and photoelectric measurements are in excellent agreement. However, they are lower than the barrier height values obtained from differential capacitance measurements by about 0.1 eV depending on the metal. This discrepancy is in qualitative agreement with the Heine and Inkson theories for intimate metal-semiconductor contacts. The dependence of barrier height on metal workfunction cannot be described by a simple effect on the potential barrier of intimate metal-semiconductor contacts, over and above the effect of the metal workfunction.
Electrical Stimulation Accelerates Motor Functional Recovery in Autograft-Repaired 10 mm Femoral Nerve Gap in Rats (2009)

Electrical stimulation has been shown to enhance peripheral nerve regeneration after nerve injury. However, the impact of electrical stimulation on motor functional recovery after nerve injuries, especially over long nerve gap lesions, has not been investigated in a comprehensive manner. In the present study, we aimed to determine whether electrical stimulation (1 h, 20 Hz) is beneficial for motor functional recovery after a 10 mm femoral nerve gap lesion in rats. The proximal nerve stump was electrically stimulated for 1 h at 20 Hz frequency prior to nerve repair with an autologous graft. The rate of motor functional recovery was evaluated by single frame motion analysis and electrophysiological studies, and the nerve regeneration was investigated by double labeling and histological analysis. We found that brief electrical stimulation significantly accelerated motor functional recovery and nerve regeneration. Although the final outcome, both in functional terms and morphological terms, was not improved by electrical stimulation, the observed acceleration of functional recovery and axon regeneration may be of therapeutic importance in clinical setting.
Surgical methods for full-thickness skin grafts to induce alopecia areata in C3H/HeJ mice. (2013)

Alopecia areata is a cell-mediated autoimmune disease of humans and many domestic and laboratory animal species. C3H/HeJ inbred mice spontaneously develop alopecia areata at a low frequency (approximately 20% by 12 mo of age). Transferring full-thickness skin grafts from affected, older mice to young mice of the same strain reliably reproduces alopecia areata, thus enabling investigators to study disease pathogenesis or intervention with a variety of therapeutic approaches. We here describe in detail how to perform full-thickness skin grafts and the follow-up procedures necessary to consistently generate mice with alopecia areata. These engrafted mice can be used to study the pathogenesis of cell-mediated autoimmune disease and for drug-efficacy trials. This standard protocol can be used for many other purposes when studying abnormal skin phenotypes in laboratory mice.
Combination gene therapy for oral cancer in a murine model. (1996)

Combination therapy involving adenovirus-mediated transfer of the genes for herpes thymidine kinase (tk) and murine interleukin 2 (mIL-2) was used to treat head and neck cancer in C3H/HeJ mice. Tumors were generated by transcutaneous injection of 5 X 10(5) murine squamous carcinoma cells into the floor of the mouth of these syngeneic mice. After 1 week, recombinant adenoviral vectors containing both therapeutic and control genes in various combinations were injected directly into the established tumors, and subsequently all mice were administered ganciclovir twice daily (25 mg/kg) for 6 days. Animals receiving either tk alone or tk + mIL-2 demonstrated significant tumor regression compared to mIL-2 alone or control vector-treated mice (P < 0.008). Mice receiving both tk + mIL-2, however, also demonstrated a significantly greater regression of tumors compared to those treated with tk alone (P<0.008), indicating a synergistic effect of the combination gene therapy. This synergism was confirmed in survival studies because tk + mIL-2 treated mice showed increased survivals (P=0.0002). Clinical and microscopic exam of regional surrounding tissues and distant organs showed no evidence of cytotoxicity for representative animals in each experimental group. These results suggest that combination tk and mIL-2 gene therapy may provide a powerful new modality for the treatment of head and neck cancer.
Dre recombinase, like Cre, is a highly efficient site-specific recombinase in E. coli, mammalian cells and mice (2009)

Tyrosine site-specific recombinases (SSRs) including Cre and FLP are essential tools for DNA and genome engineering. Cre has long been recognized as the best SSR for genome engineering, particularly in mice. Obtaining another SSR that is as good as Cre will be a valuable addition to the genomic toolbox. To this end, we have developed and validated reagents for the Dre-rox system. These include an Escherichia coli-inducible expression vector based on the temperature-sensitive pSC101 plasmid, a mammalian expression vector based on the CAGGs promoter, a rox-lacZ reporter embryonic stem (ES) cell line based on targeting at the Rosa26 locus, the accompanying Rosa26-rox reporter mouse line, and a CAGGs-Dre deleter mouse line. We also show that a Dre-progesterone receptor shows good ligand-responsive induction properties. Furthermore, we show that there is no crossover recombination between Cre-rox or Dre-loxP. Hence, we add another set of efficient tools to the genomic toolbox, which will enable the development of more sophisticated mouse models for the analysis of gene function and disease.
The 1line keyboard (2011)

Current soft QWERTY keyboards often consume a large portion of the screen space on portable touchscreens. This space consumption can diminish the overall user experi-ence on these devices. In this paper, we present the 1Line keyboard, a soft QWERTY keyboard that is 140 pixels tall (in landscape mode) and 40% of the height of the native iPad QWERTY keyboard. Our keyboard condenses the three rows of keys in the normal QWERTY layout into a single line with eight keys. The sizing of the eight keys is based on users' mental layout of a QWERTY keyboard on an iPad. The system disambiguates the word the user types based on the sequence of keys pressed. The user can use flick gestures to perform backspace and enter, and tap on the bezel below the keyboard to input a space. Through an evaluation, we show that participants are able to quickly learn how to use the 1Line keyboard and type at a rate of over 30 WPM after just five 20-minute typing sessions. Using a keystroke level model, we predict the peak expert text entry rate with the 1Line keyboard to be 66--68 WPM.