gebhart/patrepeval huggingface dataset:
Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer (2017)

Liposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. We evaluated the antitumor activity of nal-IRI compared with irinotecan and topotecan in preclinical models of small-cell lung cancer (SCLC) including in a model pretreated with carboplatin and etoposide, a first-line regimen used in SCLC. Nal-IRI demonstrated antitumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in three patient-derived xenograft models. The antitumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in four out of five models. Further, nal-IRI demonstrated antitumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater antitumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment. These results support the clinical development of nal-IRI in patients with SCLC.
Plasmin-mediated Proteolysis Is Required for Hepatocyte Growth Factor Activation during Liver Repair (2009)

The physiological relevance of the activation of hepatocyte growth factor (Hgf) by the plasminogen (Plg) system of proteases and its contribution to tissue repair are largely undefined. Here, we investigated whether the defective liver repair in mice lacking Plg is due to impaired activation of Hgf. Loss of Plg in vivo suppressed Hgf activation and signaling through its Met tyrosine kinase receptor. Without Plg, hepatocytes were unresponsive to Hgf-induced proliferation and migration, with a more pronounced impairment in hepatocyte movement within the hepatic environment. Most notably, circumventing the defect in proteolytic activation of Hgf by the downstream expression of an activated Met receptor corrected the functional deficits and improved liver repair in Plg-deficient mice. These findings support a fibrinolysis-unrelated role for Plg in modulating cell proliferation and migration by activation of Hgf.
Single-chain Fv designs for protein, cell and gene therapeutics (1999)

AbstractOne decade after the invention of single-chain Fv (sFv) proteins and methods for their facile engineering in microbial systems, there have been several recent engineering advances which combine the avidity, effector and pharmacological properties of intact monoclonal antibodies (mAbs) with the simplicity of the sFv formats. These developments may serve as the prelude for a new wave of immunomolecule therapeutics which can surpass mAbs in efficacy, biodistribution and abundance of applications. Additionally, sFv formats are now used extensively in the fields of gene and cell therapy as intracellular target-binding drugs; targeting agents for vectors with redesigned tropism; and engineered chimeric receptors for targeted immune cells.Keywordsantibodybioconjugatedrug deliverygene therapyimmunotoxinmultivalentphage displayprotein engineeringribosome displaysingle-chain Fv
Panorama (2007)

Malicious programs spy on users' behavior and compromise their privacy. Even software from reputable vendors, such as Google Desktop and Sony DRM media player, may perform undesirable actions. Unfortunately, existing techniques for detecting malware and analyzing unknown code samples are insufficient and have significant shortcomings. We observe that malicious information access and processing behavior is the fundamental trait of numerous malware categories breaching users' privacy (including keyloggers, password thieves, network sniffers, stealth backdoors, spyware and rootkits), which separates these malicious applications from benign software. We propose a system, Panorama, to detect and analyze malware by capturing this fundamental trait. In our extensive experiments, Panorama successfully detected all the malware samples and had very few false positives. Furthermore, by using Google Desktop as a case study, we show that our system can accurately capture its information access and processing behavior, and we can confirm that it does send back sensitive information to remote servers in certain settings. We believe that a system such as Panorama will offer indispensable assistance to code analysts and malware researchers by enabling them to quickly comprehend the behavior and innerworkings of an unknown sample.
Ionicity and the theory of Schottky barriers (1977)

We have investigated the role of ionicity in metal-semiconductor Schottky barriers by examining interfaces of increasing semiconductor ionicity. The electronic structure of four separate interfaces consisting of jellium (of A1 density) in contact with the (111) surface of Si and the (110) surfaces of GaAs, ZnSe, and ZnS is investigated through the use of a self-consistent pseudopotential method. The barrier height and the surface density of states in the semiconductor band gap are determined. The phenomenological index of interface behavior $S$ (studied by Kurtin, McGill, and Mead for semiconductors of different ionicity) is discussed in terms of a simple model involving metal-induced states in the semiconductor gap.
Conformationally Constrained [p-(ω-Aminoalkyl)phenacetyl]-l-seryl-l-lysyl Dipeptide Amides as Potent Peptidomimetic Inhibitors of Candida albicans and Human Myristoyl-CoA:Protein N-Myristoyl Transferase (1997)

MyristoylCoA:protein N-myristoyltransferase (NMT) covalently attaches the 14-carbon saturated fatty acid myristate, via an amide bond, to the N-terminal glycine residues of a variety of cellular proteins. Genetic studies have shown that NMT is essential for the viability of the principal fungal pathogens which cause systemic infection in immunosuppressed humans and hence is a target for development of fungicidal drugs. We have generated a class of potent peptidomimetic inhibitors of the NMT from one such fungal pathogen, Candida albicans. The N-terminal tetrapeptide from a substrate analog inhibitor, ALYASKL-NH2, was replaced with an omega-aminoalkanoyl moiety having an optimal 11-carbon chain for inhibition (11-aminoundecanoyl-SKL-NH2, 3a, IC50 = 1.2 +/- 0.14 microM). A series of replacements for the C-terminal Leu established that residues containing a lipophilic side chain were most effective, with cyclohexylalanine having the greatest potency (3g, IC50 = 0.36 +/- 0.06 microM). Removal of the carboxamide moiety led to a metabolically stable dipeptide inhibitor containing an N-(cyclohexylethyl)lysinamide (17e, IC50 = 0.11 +/- 0.03 microM). Partial rigidification of the flexible aminoundecanoyl chain produced the dipeptide p-(omega-aminohexyl)phenacetyl-L-seryl-L-lysyl-N-(cyclohexyleth yl)amide (26b, IC50 = 0.11 +/- 0.04 microM). Subsequent incorporation of an alpha-methyl substituent into 26b provided the dipeptide analog [2-[p-(omega-aminohexyl)phenyl]propionyl]-L-seryl-L-lysyl-N-(cyclohex ylethyl)amide, a very potent inhibitor (48, IC50 = 0.043 +/- 0.006 microM), which retained the three essential elements required for recognition by the acyl transferase's peptide binding site.
Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet-type von Willebrand disease. (1991)

Platelet-type von Willebrand disease (PT-vWD) is an autosomal dominant bleeding disorder characterized by abnormally enhanced binding of von Willebrand factor (vWF) by patient platelets. Although the platelet glycoprotein (GP) Ib/IX complex is known to constitute the platelet's ristocetin-dependent receptor for vWF, a unique structural abnormality within this complex has not previously been identified in PT-vWD. Using the polymerase chain reaction to amplify genomic DNA coding for the alpha chain of GP Ib (GP Ib alpha) and then sequencing the amplified DNA following cloning into M13mp18 and M13mp19 phage vectors, we have found a single point mutation in the GP Ib alpha coding region of PT-vWD DNA resulting in the substitution of valine for glycine at residue 233. This substitution within the vWF-binding region of GP Ib alpha is likely to exert a significant influence on the conformation of the resulting protein. Competitive oligonucleotide primer assay for this mutation showed a homozygous wild-type pattern in genomic DNA from the 161 normal volunteers studied and from 6 phenotypically normal members of a PT-vWD family. All 7 affected members of this family studied were heterozygous for the mutant allele. Platelet GP Ib alpha mRNA reverse-transcribed and studied by competitive oligonucleotide primer assay showed similar expression of the mutant and wild-type alleles in the affected PT-vWD patients. Absence in the normal population, tight linkage with phenotypic expression of disease, and absence of any additional abnormality of GP Ib alpha in these patients identify the glycine-to-valine substitution as a point mutation underlying functional abnormality of the vWF receptor in PT-vWD.
Conductive polymers derived from iron, ruthenium, and osmium metalloporphyrins: The shish-kebab approach (1986)

The synthesis and characterization of pyrazine-bridged polymers of iron(II/III), ruthenium(II/III), and osmium(II/III) octaethylporphyrin (dubbed "shish-kebab" polymers) are presented. Optical and dc conductivity measurements reveal that the ruthenium and osmium polymers, when partially oxidized, are highly conductive. Electrochemical and ESR results are presented that indicate the existence of an interesting metal-centered conduction pathway. Unlike most of the previously reported porphyrinic molecular metals in which the conduction electrons are macrocyclic-based, electron transport in these materials proceeds exclusively along the metal-pyrazine backbone.
Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial. (2004)

GHRH was well tolerated and effectively increased levels of IGF-1 in HIV-infected men with lipodystrophy. Total and regional body composition improved in response to GHRH, with increased lean mass and reduced truncal and visceral fat. Use of GHRH may potentially be a beneficial treatment strategy for this population.
Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease (2016)

Parkinson's disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. We found that IRX4204 promotes the survival and maintenance of nigral dopaminergic (DA) neurons in a dose-dependent manner in primary mesencephalic cultures. Brain bioavailability studies demonstrate that IRX4204 can cross the blood brain barrier and reach the brain at nM concentration. Oral administration of IRX4204 can activate nuclear receptor Nurr1 downstream signaling in the substantia nigra (SN) andattenuate neurochemical and motor deficits in a rat model of PD. Our study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signaling and promote SN DA neuron survival in PD prevention and/or treatment.
NF-κB: a new player in angiostatic therapy (2008)

Angiogenesis is considered a promising target in the treatment of cancer. Most of the angiogenesis inhibitors in late-stage clinical testing or approved for the treatment of cancer act indirectly on endothelial cells. They either neutralize angiogenic growth factors from the circulation or block the signaling pathways activated by these growth factors. Another group of angiogenesis inhibitors are the direct angiostatic compounds. These agents have a direct effect on the endothelium, affecting cellular regulatory pathways, independently of the tumor cells. The reason that this category of agents is lagging behind regarding their translation to the clinic may be the lack of sufficient knowledge on the mechanism of action of these compounds. The transcription factor NF-kappaB has been recently connected with multiple aspects of angiogenesis. In addition, several recent studies report that angiogenesis inhibition is associated to NF-kappaB activation. This is of special interest since in tumor cells NF-kappaB activation has been associated to inhibition of apoptosis and currently novel treatment strategies are being developed based on inhibition of NF-kappaB. The paradigm that systemic NF-kappaB inhibition can serve as an anti-cancer strategy, therefore, might need to be re-evaluated. Based on recent data, it might be speculated that NF-kappaB activation, when performed specifically in endothelial cells, could be an efficient strategy for the treatment of cancer.
Lamina Propria Mononuclear Cells Express and Respond to Interleukin-2 Differently in Crohn's Disease and Ulcerative Colitis. (1996)

Lymphokine-activated killer (LAK) cell activity and messenger RNA (mRNA) expression for interleukin-2 (IL-2) were analyzed using lamina propria mononuclear cells (LPMC) in inflammatory bowel disease patients. Compared with control LPMC, Crohn's disease (CD) LPMC exhibited significantly higher levels of LAK cell activity, whereas ulcerative colitis (UC) cells showed significantly lower levels of cytolytic activity with a difference in the frequency of CD3+, CD56+ and CD3+, CD56+ LAK precursor cells. After incubation with IL-2, the proportion of CD3+, CD56+ lymphocytes continued to be higher in CD cultures and substantially lower in UC cultures. Freshly isolated CD LPMC exhibited significantly higher levels of IL-2 mRNA than controls. However, no significant difference was observed between UC and control cells. The level of IL-2 expression or responsiveness to IL-2 may be responsible for different mucosal immune reactivity between CD and UC patients.
Hydrotropic Dendrimers of Generations 4 and 5:  Synthesis, Characterization, and Hydrotropic Solubilization of Paclitaxel (2004)

Polyglycerol dendrimers (PGDs) with 4-5 generations were synthesized and used to investigate the effect of dendritic architecture and its generation on aqueous solubilization of paclitaxel (PTX), a poorly water-soluble drug. Chemical and physical properties of the PGDs were characterized by NMR, MALDI-TOF mass, GPC, viscosity, and dynamic light scattering measurements. The PTX solubility in all the solutions of PGDs, even below 10 wt %, was much higher than that in PEG400 that is commonly used as a cosolvent or a hydrotropic agent. Increase in the PTX solubility by PGDs was dependent on the dendrimer generation. The dendritic structure was the reason for the enhanced solubility of PTX even at low concentrations. (1)H NMR spectra of PTX before and after mixing with PGDs in D(2)O suggested that the aromatic rings and some methyne groups of PTX were surrounded by PGDs. PGDs, which do not require hydrophobic segment as in polymeric micelles, provide an alternative method of hydrotropic solubilization of poorly soluble drugs.
High‐resolution structures of scytalone dehydratase‐inhibitor complexes crystallized at physiological pH (1999)

Scytalone dehydratase is a molecular target of inhibitor design efforts aimed at preventing the fungal disease caused by Magnaporthe grisea. A method for cocrystallization of enzyme with inhibitors at neutral pH has produced several crystal structures of enzyme–inhibitor complexes at resolutions ranging from 1.5 to 2.2 Å. Four high resolution structures of different enzyme–inhibitor complexes are described. In contrast to the original X-ray structure of the enzyme, the four new structures have well-defined electron density for the loop region comprising residues 115–119 and a different conformation between residues 154 and 160. The structure of the enzyme complex with an aminoquinazoline inhibitor showed that the inhibitor is in a position to form a hydrogen bond with the amide of the Asn131 side chain and with two water molecules in a fashion similar to the salicylamide inhibitor in the original structure, thus confirming design principles. The aminoquinazoline structure also allows for a more confident assignment of donors and acceptors in the hydrogen bonding network. The structures of the enzyme complexes with two dichlorocyclopropane carboxamide inhibitors showed the two chlorine atoms nearly in plane with the amide side chain of Asn131. The positions of Phe53 and Phe158 are significantly altered in the new structures in comparison to the two structures obtained from crystals grown at acidic pH. The multiple structures help define the mobility of active site amino acids critical for catalysis and inhibitor binding. Proteins 1999;35:425–439. © 1999 Wiley-Liss, Inc.
Fragment‐based Identification of Hsp90 Inhibitors (2009)

Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by fragment screening using a high-concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure-based drug design (SBDD) approach.
Measurement of thermal conductivity of individual multiwalled carbon nanotubes by the 3-ω method (2005)

The thermal conductivity of individual multiwalled carbon nanotubes (outer diameter of ∼45nm) was obtained by employing the 3-ω method. To this end, the third-harmonic amplitude as a response to the applied alternate current at fundamental frequency (ω) is expressed in terms of thermal conductivity. A microfabricated device composed of a pair of metal electrodes 1μm apart is used to place a single nanotube across the designated metal electrodes by utilizing the principle of dielectrophoresis. The multiwalled carbon nanotube was modeled as a one-dimensional diffusive energy transporter and its thermal conductivity was measured to be 650–830W∕mK at room temperature.
Halogen-based plasma etching of novel field-effect transistor gate materials (2009)

Vacuum Beam Studies of Ruthenium EtchingRu is known to have two volatile oxidation products, RuO&lt;sub&gt;3&lt;/sub&gt; and RuO&lt;sub&gt;4&lt;/sub&gt;, although the etch rate is negligible when Ru is exposed to an O&lt;sub&gt;2&lt;/sub&gt; plasma discharge. The introduction of a small amount of additive gas, such as Cl&lt;sub&gt;2&lt;/sub&gt;, has been shown to increase the Ru etch rate sixfold. The reason for this dramatic shift in etching is poorly understood, primarily because it is difficult if not impossible to study plasma-surface interactions in a plasma environment. The unique capabilities of the beam system have made it possible to explore the mechanism of Ru etching. It has been shown that under 500 eV Ar+ ion bombardment, the addition of O radicals lowered the etch rate by a factor of 2.5. This process was relatively insensitive to temperature over the range studied (room temperature to ~175Â°C). It was also shown that O radicals alone spontaneously etched Ru at a very slow rate over the entire temperature range.Statistical Analysis of Polysilicon Etching and Gate Profile Evolution in Dual-Doped Polysilicon GatesPolysilicon gate etching for the 90nm lithography node and below requires extremely precise control of the gate CD and profile. Generally speaking, the current requirement for Gate CD control is that the 3 sigma should less than ~5 nm for all gates, including across the chip, across the wafer, wafer-to-wafer, lot-to-lot, and tool-to-tool variations. Similarly, for gate sidewall angle control, the 3 sigma angle variation should be less than ~1 degree, inclusive of all sources of variation. This is particularly challenging for technologies which employ dual-doped gates, since the chemistry and physics of the etching process induces a different profile evolution between gates with different doping.The goal of this project was to identify a parameter space where the differences in gate profile evolution across different polysilicon dopant types were minimized. Blanket etch rates and patterned wafers were used to determine the effect of different gate etch process variables on the gate profile. The materials studied were undoped polysilicon and polysilicon that had been doped with P, As, Sb, and B. Prediction models were created for the blanket etch rate studies that were used to optimize the processing conditions and to propose some simple mechanisms that identify which species are adsorbed on the surface.
Growth Hormone (GH)-independent Dimerization of GH Receptor by a Leucine Zipper Results in Constitutive Activation (2000)

Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers of the growth hormone receptor (GHR) signaling domain. The entire extracellular domain of the GHR was replaced by the hemagglutinin-tagged zipper sequence of either the c-Fos or c-Jun transcription factor (termed Fos-GHR and Jun-GHR, respectively). Transient transfection of Fos-GHR or Jun-GHR resulted in activation of the serine protease inhibitor 2.1 promoter in Chinese hamster ovary-K1 cells to a level equal to that achieved by fully activated wild type GHR. Furthermore, stable expression of Jun-GHR alone or Fos-GHR and Jun-GHR together in the interleukin 3-dependent BaF-B03 cell line resulted in cell proliferation after interleukin 3 withdrawal at a rate equal to maximally stimulated wild type GHR-expressing cells. Activation of STAT 5b was also observed in Fos-Jun-GHR-expressing cells at a level equal to that in chronically GH-treated GHR-expressing cells. Thus, forced dimerization of the transmembrane and cytoplasmic domains of the GHR in the absence of the extracellular domain can lead to the constitutive activation of known GH signaling end points, supporting the view that proximity of Janus kinase 2 (JAK2) kinases is the essential element in signaling. Such constitutively active GH receptors may have particular utility for transgenic livestock applications.
Interleukin-8 as a Stratification Tool for Interventional Trials Involving Pediatric Septic Shock (2008)

A serum IL-8 level of 220 pg/ml or less, obtained within 24 hours of admission, predicts a high likelihood of survival in children with septic shock. We propose that IL-8 can be used to exclude such patients from interventional clinical trials and ultimately derive a study population with a more favorable risk to benefit ratio when subjected to a study agent.
Further Improvements of the Synthesis of Alkynes from Aldehydes. (2004)

Abstract For Abstract see ChemInform Abstract in Full Text.