gebhart/patrepeval huggingface dataset:
Enzymatic treatment of long-term human marrow cultures reveals the preferential location of primitive hemopoietic progenitors in the adherent layer (1983)

Recent studies with long-term mouse marrow cultures have indicated the importance of the adherent layer as a primary reservoir of the most primitive stem cells, from which derivative stem cells and more differentiated progenitors are continuously generated. We have now examined the role of the adherent cell layer in long-term human marrow cultures from this point of view. Prerequisite to such an undertaking was the development of a nontoxic and reproducible method for detaching the adherent layer and making it into a single-cell suspension suitable for characterization by colony assays. Both trypsin and collagenase could be used to obtain suspensions that met these criteria. Lack of toxicity was demonstrated by the preservation of CFU-E, BFU-E, and CFU- C plating efficiency in fresh human marrow cell suspensions exposed to the same enzymatic treatments. Collagenase treatment of long-term marrow culture adherent layers was considered superior because it freed all hemopoietic colony-forming cells but left some of the other cells still adherent. Using this method, we found that CFU-C, BFU-E, and CFU- G/E were consistently detectable in the adherent layer for at least 8 wk, with the majority of the BFU-E and CFU-G/E being located in the adherent layer (70%-75% after 2–3 wk and more than 90% by 7–8 wk). Although corresponding numerical differences in adherent and nonadherent CFU-C populations were not observed, the colonies derived from them showed marked differences in the size they achieved; the adherent layer being the exclusive site of CFU-C, with a very high proliferative capacity. These findings emphasize the importance of assessing the progenitor content of the adherent layer of long-term human marrow cultures and provide an appropriate methodology.
Support Vector Machine-based Method for Subcellular Localization of Human Proteins Using Amino Acid Compositions, Their Order, and Similarity Search (2005)

Here we report a systematic approach for predicting subcellular localization (cytoplasm, mitochondrial, nuclear, and plasma membrane) of human proteins. First, support vector machine (SVM)-based modules for predicting subcellular localization using traditional amino acid and dipeptide (i + 1) composition achieved overall accuracy of 76.6 and 77.8%, respectively. PSI-BLAST, when carried out using a similarity-based search against a nonredundant data base of experimentally annotated proteins, yielded 73.3% accuracy. To gain further insight, a hybrid module (hybrid1) was developed based on amino acid composition, dipeptide composition, and similarity information and attained better accuracy of 84.9%. In addition, SVM modules based on a different higher order dipeptide i.e. i + 2, i + 3, and i + 4 were also constructed for the prediction of subcellular localization of human proteins, and overall accuracy of 79.7, 77.5, and 77.1% was accomplished, respectively. Furthermore, another SVM module hybrid2 was developed using traditional dipeptide (i + 1) and higher order dipeptide (i + 2, i + 3, and i + 4) compositions, which gave an overall accuracy of 81.3%. We also developed SVM module hybrid3 based on amino acid composition, traditional and higher order dipeptide compositions, and PSI-BLAST output and achieved an overall accuracy of 84.4%. A Web server HSLPred (www.imtech.res.in/raghava/hslpred/ or bioinformatics.uams.edu/raghava/hslpred/) has been designed to predict subcellular localization of human proteins using the above approaches.
Principles for Better Information Security through More Accurate, Transparent Risk Scoring (2010)

This paper explores approaches for scoring information security risk that could lead to investment drivers and drive appropriate levels of security. Our approach is grounded on two important factors that determine cyber risk: (1) the information security resources (e.g., technologies, skills, and policies) that reduce the likelihood and consequences of successful information exploits; and (2) the security processes and capabilities that drive a continuous improvement of the security resources in use. The quality of a cyber defense system is the result of the integration of these two factors. This manuscript proposes such a two-factor hierarchical system of scoring, details candidate measures, and explores economic conditions for selecting appropriate measures. We review several scoring systems available that contain elements from this proposed system and discuss conditions for market adoption of information security scoring.
Effect of Lipophilic Ion-Exchanger Leaching on the Detection Limit of Carrier-Based Ion-Selective Electrodes (2001)

The equilibrium partitioning of lipophilic ion-exchanger salts from ion-selective polymeric membrane electrodes (ISEs) and its possible effect on the lower detection limit of these sensors is described. Predictions are made on the basis of various parameters, including the knowledge of tetraphenylborate potassium salt partitioning constants, the selectivity of ionophore-free ion-exchanger membranes, and ionophore stability constants in the membrane. Ion-exchanger lipophilicities are significantly increased if the membrane contains an ionophore that strongly binds the primary ion. Predicted detection limits are on the order of 10(-5)-10(-8) M for ionophore-free membranes, and may reach levels as low as 10(-18) M with adequate ionophores in the membrane. Experiments are performed for well-described lead-selective membranes containing different tetraphenylborate derivatives, and detection limits appear to be independent of the ion-exchanger used. However, they are much higher if a more hydrophilic carborane cation-exchanger is incorporated in the membrane. The first finding confirms recent theory, which states that transmembrane ion fluxes, given by a small level of ion-exchange at the sample side by interfering ions, normally dictate the detection limit of these sensing systems. Predicted detection limits on the basis of ion-exchanger leaching alone are here listed for a number of analytically relevant cases. For potassium-selective electrodes containing BME-44 and tetraphenylborate as ion-exchanger, the experimental detection limits are in agreement with predicted values. These results suggest that the detection limit of many current ISEs for ultratrace level analysis are, in optimal cases, dictated by transmembrane ion fluxes; however, because improved chemical solutions are being developed to reduce such effects, simple ion-exchanger partitioning may indeed become an important mechanism that can give higher detection limits than practically desired, and should not be ruled out.
Results of a placebo-controlled phase III trial of immunotherapy with APC8015 for patients with hormone refractory prostate cancer (HRPC) (2005)

4500 Background APC8015 is an immunotherapy cellular product consisting of autologous peripheral blood mononuclear cells enriched for a dendritic cell fraction pulsed with PA2024, a Prostatic Acid Phosphatase (PAP)-GM-CSF construct. We previously reported results including time to objective progression (TTP) and time to onset of disease related pain (TDRP) from a randomized trial in metastatic HRPC. Reported here are final overall survival (OS) data from this trial, as well as results of immunologic testing. Methods Patients (pts) with asymptomatic, metastatic HRPC were randomized (2:1) to receive APC8015 (n=82) or placebo (n=45) every 2 weeks x 3. Eligible pts had > 25% of cancer cells positive for PAP by central pathology review. The primary endpoint was TTP. TDRP was a secondary endpoint and pts were monitored for OS at 36 months. Monitoring was by weekly pain logs and serial radiologic imaging. Progression and pain were centrally reviewed and pts were followed per protocol for survival for 3 years following randomization. T-cell proliferation to PA2024 was evaluated by 3H-thymidine uptake. The T-Cell Stimulation Index (TCSI) was defined as: counts per minute (cpm) with antigen/cpm without antigen. The TCSI-ratio was defined as the median TCSI at 8 weeks/median TCSI at pre-treatment. Results 127 pts were randomized between 1/00 and 10/01. In an intent-to-treat (ITT) analysis, median OS was 25.9 months for pts on APC8015 compared with 22.0 months for those on placebo (p=0.020, log-rank, hazard ratio 1.625). At 36 months, 33% of APC8015 pts were alive, compared with 11% of placebo pts. The TCSI-ratio was 16.9 for APC8015 and 1.99 for placebo (p=.003, Wilcoxon Rank Sum). Treatment was generally well tolerated. Grade 1 and 2 fevers and rigors were the most common treatment-related AEs. Conclusions In an ITT analysis, treatment with APC8015 resulted in a statistically significant OS advantage of 3.9 months in pts with asymptomatic HRPC, representing the first survival advantage attributed to an immunotherapy product in prostate cancer. APC8015 pts also had an 8-fold increase in the TCSI-ratio. These data support this approach in the treatment of pts with metastatic HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Dendreon Dendreon Dendreon Dendreon Dendreon Dendreon
Two-Photon Imaging of Cortical Surface Microvessels Reveals a Robust Redistribution in Blood Flow after Vascular Occlusion (2005)

A highly interconnected network of arterioles overlies mammalian cortex to route blood to the cortical mantle. Here we test if this angioarchitecture can ensure that the supply of blood is redistributed after vascular occlusion. We use rodent parietal cortex as a model system and image the flow of red blood cells in individual microvessels. Changes in flow are quantified in response to photothrombotic occlusions to individual pial arterioles as well as to physical occlusions of the middle cerebral artery (MCA), the primary source of blood to this network. We observe that perfusion is rapidly reestablished at the first branch downstream from a photothrombotic occlusion through a reversal in flow in one vessel. More distal downstream arterioles also show reversals in flow. Further, occlusion of the MCA leads to reversals in flow through approximately half of the downstream but distant arterioles. Thus the cortical arteriolar network supports collateral flow that may mitigate the effects of vessel obstruction, as may occur secondary to neurovascular pathology.
Static detection of cross-site scripting vulnerabilities (2008)

Web applications support many of our daily activities, but they often have security problems, and their accessibility makes them easy to exploit. In cross-site scripting (XSS), an attacker exploits the trust a web client (browser) has for a trusted server and executes injected script on the browser with the server's privileges. In 2006, XSS constituted the largest class of newly reported vulnerabilities making it the most prevalent class of attacks today. Web applications have XSS vulnerabilities because the validation they perform on untrusted input does not suffice to prevent that input from invoking a browser's JavaScript interpreter, and this validation is particularly difficult to get right if it must admit some HTML mark-up. Most existing approaches to finding XSS vulnerabilities are taint-based and assume input validation functions to be adequate, so they either miss real vulnerabilities or report many false positives.
Microwave Assisted Dealkylation of Alkyl Aryl Ethers in Ionic Liquids (2004)

Alkyl aryl ethers undergo selective dealkylation in 1-butyl pyridinium bromide and 1-butyl-3-methyl imidazolium bromide ionic liquids under microwave irradiation to give the corresponding phenols in high yields. The ionic liquids serve the dual purpose of solvent as well as reagent and allow easy isolation of products.
AMPA receptor agonists: Resolution, configurational assignment, and pharmacology of (+)-(S)- and (-)-(R)-2-amino-3-[3-hydroxy-5-(2-pyridyl)-isoxazol-4-yl]-propionic acid (2-Py-AMPA) (1997)

We have previously shown that whereas (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA) shows the characteristics of a partial agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, (S)-APPA is a full AMPA receptor agonist and (R)-APPA a weak competitive AMPA receptor antagonist. This observation led us to introduce the new pharmacological concept, functional partial agonism. Recently we have shown that the 2-pyridyl analogue of APPA, (RS)-2-amino-3-[3-hydroxy-5-(2-pyridyl)isoxazol-4-yl]propionic acid (2-Py-AMPA), is a potent and apparently full AMPA receptor agonist, and this compound has now been resolved into (+)- and (-)-2-Py-AMPA (ee > or = 99.0%) by chiral HPLC using a Chirobiotic T column. The absolute stereochemistry of the enantiomers of APPA has previously been established by X-ray analysis, and on the basis of comparative studies of the circular dichroism spectra of the enantiomers of APPA and 2-Py-AMPA, (+)- and (-)-2-Py-AMPA were assigned the (S)- and (R)-configuration, respectively. In a series of receptor binding studies, neither enantiomer of 2-Py-AMPA showed detectable affinity for kainic acid receptor sites or different sites at the N-methyl-D-aspartic acid (NMDA) receptor complex. (+)-(S)-2-Py-AMPA was an effective inhibitor of [3H]AMPA binding (IC50 = 0.19 +/- 0.06 microM) and a potent AMPA receptor agonist in the rat cortical wedge preparation (EC50 = 4.5 +/- 0.3 microM) comparable with AMPA (IC50 = 0.040 +/- 0.01 microM; EC50 = 3.5 +/- 0.2 microM), but much more potent than (+)-(S)-APPA (IC50 = 5.5 +/- 2.2 microM; EC50 = 230 +/- 12 microM). Like (-)-(R)-APPA (IC50 > 100 microM), (-)-(R)-2-Py-AMPA (IC50 > 100 microM) did not significantly affect [3H]AMPA binding, and both compounds were weak AMPA receptor antagonists (Ki = 270 +/- 50 and 290 +/- 20 microM, respectively).
PCR in situ: a rapid alternative to in situ hybridization for mapping short, low copy number sequences without isotopes. (1993)

A new technique for rapid localization of short, low copy number sequences is described, which uses a form of PCR on preparations of fixed metaphase chromosomes on microscope slides, with the temperature cycling controlled by a flatbed thermal cycler. In its present form, the method is capable of detecting very low copy number sequences, and further development is expected to achieve the target of localizing unique sequences. It has advantages over conventional fluorescent in situ hybridization, both in the speed (easily complete within a work-day) and in the potential sensitivity.
Use of polyiminophosphazene bases for ring‐opening polymerizations (1996)

Abstract The polyiminophosphazene bases Et‐P 2 and t ‐Bu‐P 4 were used as a promoter for ethylene oxide and siloxane polymerizations. Initiation by an alcohol in combination with t ‐Bu‐P 4 lead to an extremely rapid polymerization reaction of octamethylcyclotetrasiloxane. In the case of ethylene oxide, well‐defined polymers were obtained, however the rate of polymerization decreased during the polymerization reaction due to decomposition of the counterion. In combination with organolithium compounds, the phosphazene bases lead to well‐defined polymers in the case of cyclotrisiloxanes as well as in the case of ethylene oxide.
The amino-acid composition of potato protein and of cooked potato (1958)

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HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer (2019)

Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of <i>HER2</i> amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for <i>HER2</i> amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.
Palladium-Catalyzed Reaction of Aryl Iodides with Acetic Anhydride. A Carbon Monoxide-Free Synthesis of Acetophenones (2003)

[reaction: see text] The palladium-catalyzed reaction of aryl iodides with acetic anhydride provides a straightforward and experimentally simple carbon monoxide-free route to acetophenones. The reaction tolerates a wide range of functionalized aryl iodides. Acetophenones are isolated in excellent yield with a variety of neutral, slightly electron-rich, and slightly electron-poor aryl iodides, whereas moderate yields are obtained with aryl iodides containing strongly electron-withdrawing substituents.
A Phase I Study of Cantuzumab Mertansine Administered as a Single Intravenous Infusion Once Weekly in Patients with Advanced Solid Tumors (2004)

This study identified a safe and tolerable dose of the novel immunoconjugate prodrug cantuzumab mertansine. The evidence of antitumor activity suggests that additional clinical development is warranted, with a focus on tumors that express high levels of CanAg and which are known to be sensitive to antimicrotubule agents.
Body distribution of polysorbate‐80 and doxorubicin-loaded [14C]poly(butyl cyanoacrylate) nanoparticles after i.v. administration in rats (2005)

Previously it was shown that poly(butyl cyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80 are able to cross the blood-brain barrier (BBB) after i.v. administration. The objective of the present study was to investigate the influence of polysorbate 80 and doxorubicin-loading on the body distribution in rats. The biodistribution profile and brain concentration of (14)C-radiolabeled PBCA nanoparticles, polysorbate 80 coated (14)C-PBCA nanoparticles, and doxorubicin-loaded (14)C-PBCA nanoparticles were determined by radioactivity counting after i.v. administration in rats. The (14)C-PBCA nanoparticles showed a significant accumulation in the organs of the reticuloendothelial system (RES). Polysorbate 80 coating of the (14)C-PBCA nanoparticles decreased this accumulation to about 40% after 1 h post injection. The brain concentration was increased about 2-fold after polysorbate 80-coating at this time point. The presence of doxorubicin in this preparation, however, decreased the brain concentration to levels similar to uncoated particles, probably caused by the positive charge of this compound. After longer time periods after injection the differences between the three preparations decreased.
Evolving anticancer drug valproic acid: Insights into the mechanism and clinical studies (2005)

The short chain fatty acid valproic acid (VPA) and VPA-analogs modulate the biology of diverse tumor cell entities by inducing differentiation, inhibiting proliferation, increasing apoptosis, and immunogenicity and by decreasing metastatic and angiogenetic potential. This review updates an earlier one in 2002, reflecting the interest in VPA as a potent anticancer drug. A number of in vitro studies show that the types of known tumor cells susceptible to VPA is steadily increasing. Of special note is the strong antineoplastic activity of VPA in chemoresistant cancer cells. A novel and promising approach is combining VPA with other drugs to achieve a broad therapeutic index. Clinical studies are underway and the preliminary results indicate that VPA alone or in combination offers a promising avenue of treatment, both in solid and hematopoetic malignancies.
Multitarget FISH and LOH Analyses at Chromosome 3p in Non–Small Cell Lung Cancer and Adjacent Bronchial Epithelium (2005)

Multitarget fluorescence in situ hybridization (FISH; LAVysion, Vysis, Downers Grove, IL) targeting chromosomes 6p11-q11, 7p12, 8q24, and 5p15.2 was compared with results of microsatellite studies at chromosome 3p to identify molecular changes associated with tobacco use and tumor development in non-small cell lung cancer (NSCLC). Analyses were performed on 26 NSCLCs and matched benign bronchial epithelium; samples from 10 patients without NSCLC served as control samples. Significant molecular differences between tumor tissue and corresponding benign bronchi were found using FISH (P = .001) and loss of heterozygosity (LOH) analysis (P = .031). Bronchial epithelium from patients with NSCLC was genetically different from epithelium from patients without NSCLC in FISH analysis (P = .025). Receiver operating characteristic curve analysis revealed an optimal cutoff value of 5% atypical cells for bronchial epithelium. There was no statistical correlation with the patient's smoking history, and LOH analysis of bronchi did not differentiate between patients with and without NSCLC. Multicolor FISH analysis is able to detect a tumor-associated molecular field effect in bronchi adjacent to NSCLC.
Targeting potential drivers of COVID-19: Neutrophil extracellular traps (2020)

Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
Utilization of MHC Class I Transgenic Mice for Development of Minigene DNA Vaccines Encoding Multiple HLA-Restricted CTL Epitopes (1999)

We engineered a multiepitope DNA minigene encoding nine dominant HLA-A2.1- and A11-restricted epitopes from the polymerase, envelope, and core proteins of hepatitis B virus and HIV, together with the PADRE (pan-DR epitope) universal Th cell epitope and an endoplasmic reticulum-translocating signal sequence. Immunization of HLA transgenic mice with this construct resulted in: 1) simultaneous CTL induction against all nine CTL epitopes despite their varying MHC binding affinities; 2) CTL responses that were equivalent in magnitude to those induced against a lipopeptide known be immunogenic in humans; 3) induction of memory CTLs up to 4 mo after a single DNA injection; 4) higher epitope-specific CTL responses than immunization with DNA encoding whole protein; and 5) a correlation between the immunogenicity of DNA-encoded epitopes in vivo and the in vitro responses of specific CTL lines against minigene DNA-transfected target cells. Examination of potential variables in minigene construct design revealed that removal of the PADRE Th cell epitope or the signal sequence, and changing the position of selected epitopes, affected the magnitude and frequency of CTL responses. Our results demonstrate the simultaneous induction of broad CTL responses in vivo against multiple dominant HLA-restricted epitopes using a minigene DNA vaccine and underline the utility of HLA transgenic mice in development and optimization of vaccine constructs for human use.