gebhart/patrepeval huggingface dataset:
CoMFA and CoMSIA 3D QSAR and Docking Studies on Conformationally-Restrained Cinnamoyl HIV-1 Integrase Inhibitors:  Exploration of a Binding Mode at the Active Site (2002)

Anti-HIV (human immunodeficiency virus) drug discovery has been increasingly focusing on HIV integrase (IN) as a potential therapeutic target. This enzyme is required for the integration of reverse transcribed proviral DNA into the host cell's genome and is essential for the propagation of the HIV life cycle. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D QSAR) studies and docking simulations were conducted on a series of potent conformationally restrained cinnamoyl inhibitors of HIV-1 IN (Artico; et al. J. Med. Chem. 1998, 41, 3948-3960). Predictive 3D QSAR models were established using SYBYL multifit molecular alignment rule, which had conventional r(2) and cross-validated coeffiecient (q(2)) values up to 0.981 and 0.721 for CoMFA and 0.975 and 0.804 for CoMSIA, respectively. These models were validated by an external test set (Burke; et al. J. Med. Chem. 1995, 38, 4171-4178). CoMFA and CoMSIA 3D QSAR models were also derived using a molecular alignment obtained by docking the compounds into the active site of HIV IN. These latter models were comparable to multifit-derived models in terms of relative descriptor field contributions and the partial least squares (PLS) contour maps. The CoMSIA 3D QSAR models performed better than the CoMFA models. The superior performance of CoMSIA was attributed to the large contribution of hydrogen-bonding interactions to the inhibitory activity differences among the compounds. This was supported by FlexX binding energy scores that correlated well with the inhibitory activity differences between hydroxylated compounds and their corresponding methoxy or deoxy counterparts. The CoMFA and CoMSIA PLS contour maps and MOLCAD-generated active site electrostatic, lipophilicity, and hydrogen-bonding potential surface maps, as well as the docking results, were integrated to propose a binding mode for the cinnamoyl inhibitors at the active site of HIV-1 IN.
Lenalidomide in the Treatment of Young Patients with Multiple Myeloma: From Induction to Consolidation/Maintenance Therapy (2012)

Multiple myeloma is the second most common hematologic malignancy. It accounts for 20,580 new cancer cases in the USA in 2009, including 11,680 cases in men, 8,900 cases in women, and 10,580 deaths overall. Although the disease remains still incurable, outcomes have improved substantially over recent years thanks to the use of high-dose therapy and the availability of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib. Various trials have shown the advantages linked to the use of novel agents in the transplant and not-transplant settings. In particular, this paper will present an overview of the results achieved with lenalidomide-containing combinations in patients eligible for high-dose therapies, namely, young patients. The advantages obtained should always be outweighed with the toxicity profile associated with the regimen used. Therefore, here, we will also provide a description of the main adverse events associated with lenalidomide and its combination.
Structure-Activity Relationships of 2′,5′-Oligoadenylate Analogue Modifications of Prostate-Specific Membrane Antigen (PSMA) Antagonists (2012)

Prostate-specific membrane antigen (PSMA) is an ideal biomarker for prostate cancer. A previously reported 2-5A conjugate RBI1033 (3) showed binding affinity more than 10 times higher than the parent urea-based compound (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid (1). The purpose of this work is to further optimize the structure of 3 to identify highly selective ligands of PSMA. It was found that conjugates having 2-5A in their structure showed extraordinary improved binding affinity to PSMA compared with compound 1. Removal of 2-5A significantly reduced its biological activity. The results will provide a path to agents for targeted imaging and treatment of prostate cancer.
In Vivo Transfer of GPI-Linked Complement Restriction Factors from Erythrocytes to the Endothelium (1995)

Many proteins are associated with the outer layer of the cell membrane through a posttranslationally added glycosyl phosphatidylinositol (GPI) anchor. The functional significance of this type of protein linkage is unclear, although it results in increased lateral mobility, sorting to the apical surface of the cell, reinsertion into cell membranes, and possibly cell signaling. Here evidence is presented that GPI-linked proteins can undergo intermembrane transfer in vivo. GPI-linked proteins expressed on the surface of transgenic mouse red blood cells were transferred in a functional form to endothelial cells in vivo. This feature of GPI linkage may be potentially useful for the delivery of therapeutic proteins to vascular endothelium.
Autoradiographic localization of cocaine binding sites by [3H]CFT ([3H]WIN 35,428) in the monkey brain (1990)

The cocaine analog [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane ([3H]CFT or [3H]WIN 35,428 binds with high affinity and selectivity to cocaine receptors in the monkey caudate-putamen. [3H]CFT was used to map the regional distribution of cocaine binding sites in slide-mounted sections of monkey brains using autoradiographic techniques. Hemicoronal brain sections were incubated with [3H]CFT (3 nM) alone or in the presence of excess (-)-cocaine (30 microM) to mask the binding sites. High densities of [3H]CFT binding sites were detected in the caudate nucleus, putamen, and nucleus accumbens. In all three regions, binding was markedly reduced by coincubation with unlabeled (-)-cocaine, indicating low levels of nonspecific binding. Little or no binding was observed in the cortex, thalamus, globus pallidus, or white matter tracts at the levels studied. In order to characterize binding sites for [3H]CFT in tissue sections, competition experiments were conducted using a fixed concentration of [3H]CFT (3 nM) and a range of concentrations of (-)-cocaine, (+)-cocaine, CFT, Lu 19-005, GBR 12909, bupropion, and citalopram. The IC50 values for the drugs in tissue sections corresponded closely with their reported IC50 values in monkey caudate-putamen membranes (r = 0.99, p less than 0.001), suggesting that [3H]CFT binding is similar in the two preparations. These findings support the view that cocaine receptors labeled by [3H]CFT are localized predominantly in dopamine-rich brain regions implicated in the behavioral effects and abuse of cocaine.
Vascular Endothelial Growth Factor Inhibits the Development of Dendritic Cells and Dramatically Affects the Differentiation of Multiple Hematopoietic Lineages In Vivo (1998)

Defective function of dendritic cells (DC) in cancer has been recently described and may represent one of the mechanisms of tumor evasion from immune system control. We have previously shown in vitro that vascular endothelial growth factor (VEGF), produced by almost all tumors, is one of the tumor-derived factors responsible for the defective function of these cells. In this study, we investigated whether in vivo infusion of recombinant VEGF could reproduce the observed DC dysfunction. Continuous VEGF infusion, at rates as low as 50 ng/h (resulting in serum VEGF concentrations of 120 to 160 pg/mL), resulted in a dramatic inhibition of dendritic cell development, associated with an increase in the production of B cells and immature Gr-1(+) myeloid cells. Infusion of VEGF was associated with inhibition of the activity of the transcription factor NF-kappaB in bone marrow progenitor cells. Experiments in vitro showed that VEGF itself, and not factors released by VEGF-activated endothelial cells, affected polypotent stem cells resulting in the observed abnormal hematopoiesis. These data suggest that VEGF, at pathologically relevant concentrations in vivo, may exert effects on pluripotent stem cells that result in blocked DC development as well as affect many other hematopoietic lineages.
Superior Performance With Minimal Environmental Impact: A Novel Nonaqueous Drilling Fluid (1993)

ABSTRACT The first well utilizing a novel drilling fluid based on polyalphaolefin (PAO) chemistry has been drilled in the North Sea. In addition to excellent drilling performance, PAO drilling fluids exhibit low toxicity, low bioaccumulation, and are biodegradable. Success of the PAO mud has established the system as a viable synthetic-based alternative to oil-based muds. The non-aqueous PAO system was used to drill the 12.25-in. section of a well in the Central Basin of the North Sea. The interval from 6,300 to 15,067 ft (1,920 m to 4,592 m) was drilled at an angle of 55 deg. The formation consisted primarily of tertiary shales mixed with limestone stringers. Mud weight range was 15.0-15.5 ppg (1.8-1.86 s.g.). Comparisons with oil-based muds used in this area of the North Sea indicated the PAO fluid helped increase penetration rates and reduce torque and drag. Other performance benefits included superior hole cleaning and no evidence of weight material sag. Additionally, cuttings discharged into the sea retained an average of less than 10% PAO (&amp;lt;100 g/kg dry retort solids). Comparisons with other non-aqueous alternatives such as ester and ether-based fluids show PAO systems provide better elastomer compatibility, lime and cement tolerance, surface handling, synthetic/water ratio flexibility, and temperature stability. This paper covers drilling and fluid performance results of the first field trial of a PAO-based mud. Environmental data including toxicity, bioaccumulation, and cuttings beds studies also are discussed. Chemical and practical differences between PAO and other synthetic-based muds are presented.
Identification of vaccine candidate antigens of Staphylococcus aureus by serological proteome analysis (2002)

In this study we applied serological proteome analysis (Klade, C. S. et al. Proteomics 2001, 1, 890-898) for identification of bacterial vaccine candidate antigens. First, approximately one hundred sera from healthy individuals and patients suffering from Staphylococcus aureus infections were screened for antibodies against staphylococcal lysates and recombinant proteins representing surface antigens. Two pools (healthy donors, patients) each consisting of five sera with the highest antiproteinaceous IgG reactivity were selected. Second, S. aureus COL was grown under different conditions and the number of antigens expressed was monitored by Western blot analysis. Third, surface proteins were enriched by digesting the bacterial cell wall under isotonic conditions and subsequent removal of protoplasts. These protein preparations were resolved by two-dimensional electrophoresis (2-DE) (pI 4-7). 2-DE immunoblotting using the preselected serum pools at 1:10 000-1:100 000 dilutions revealed a number of highly immunogenic staphylococcal proteins. Twenty-one spots were isolated by preparative 2-DE, and analysed by matrix-assisted laser desorption/ionization mass spectrometry and tandem mass spectrometry sequencing of tryptic peptides. This led to the identification of 15 proteins including known and novel vaccine candidates. Seroreactivity of several antigens including serine-aspartate repeat containing protein D, immuno-dominant staphylococcal antigen and a novel 309 amino acid lipoprotein was independently confirmed by enzyme-linked immunosorbent assay and Western blot analysis of purified recombinant proteins. In conclusion, serological proteome analysis proved to be a powerful tool for the identification of novel staphylococcal antigens, which provide a basis for rational vaccine design.
Double-Reciprocal Crossover Mediated by FLP-Recombinase:  A Concept and an Assay, (1997)

FLP recombinase induces a double-reciprocal crossover event between sets of different FLP recognition target (FRT) sites. Therefore, if these sites flank an expression cassette at a given genomic locus, it can be exchanged for another cassette that has been constructed in the analogous was [Schlake & Bode (1994) Biochemistry 33, 12746-12751]. Here we demonstrate that an integrated expression cassette, flanked by a wild type and a mutated site, remains completely stable in the presence of constitutive FLP activity, obviating the need for a timing of this parameter. Therefore the only variable left for optimization is the initial concentration of the exchange plasmid. Since the exchange plasmid lacks a promoter, random integration is not expected to confer resistance to the selection marker, the expression of which requires the acquisition of the SV40 promoter provided at the predetermined integration site. Due to the presence of a luciferase reporter in a specific bicistronic expression cassette, recombination generates bioluminescence upon recombination, indicating the extent of the exchange reaction. This principle is utilized to compare the potential of various cell lines to support the exchange reaction and to adjust the optimum parameters.
In-vehicle man-machine interaction-the SOCRATES approach (2002)

This paper discusses the man-machine interaction (MMI) activities as part of the DRIVE II project, SOCRATES (System of Cellular RAdio for Traffic Efficiency and Safety). SOCRATES consists of three pilot projects based in London, Gothenburg and the Rhein/Hessen area of Germany, and a Kernel project which forms a focus for research and aims to feed back results to be implemented by the pilot projects. During the DRIVE I programme, the original SOCRATES project successfully proved the technology and demonstrated the feasibility of the SOCRATES approach. Hence, little effort was spent in developing the man-machine interface. The next phase of SOCRATES, in the DRIVE II programme, builds on the concept, and will implement dynamic route guidance (DRG) systems for a number of vehicles at each of the pilot sites. In addition, the initial route planning and DRG facilities are being extended to include applications such as driver information, local warnings, emergency call etc. It is therefore imperative that in the progression from field trials onwards commercial implementation, that man-machine interaction issues are addressed. As the facilities offered to the driver become more complex, so the need to simplify the interaction with the man-machine interface become greater. The interface for both DRG and for additional applications must be considered from a user point of view and the effects on driving performance considered. The MMI activities to date have included the identification of problem areas and the synthesis of data from behavioural science research which may offer solutions. The human factors issues fall into three categories: (i) Application issues. For example, what are the special requirements of an interface for a multi-function system, with particular reference to stationary or on-the-move interaction? (ii) Evaluation issues. How can the pilot studies gain both system effectiveness and behavioural data from the pilot trials? (iii) Research issues. These include consideration of the use of new technologies, such as head-up displays, in an automotive environment. This paper discusses the human factors and MMI issues being addressed within SOCRATES and relates them to research data and the pilot trials activities.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Fiducial registration error and target registration error are uncorrelated (2009)

Image-guidance systems based on fiducial registration typically display some measure of registration accuracy based on the goodness of fit of the fiducials. A common measure is fiducial registration error (FRE), which equals the root-meansquare error in fiducial alignment between image space and physical space. It is natural for the surgeon to regard the displayed estimate of error as an indication of the accuracy of the system's ability to provide guidance to surgical targets for a given case. Thus, when the estimate is smaller than usual, it may be assumed that the target registration error (TRE) is likely to be smaller than usual. We show that this assumption, while intuitively convincing, is in fact wrong. We show it in two ways. First, we prove to first order that for a given system with a given level of normally distributed fiducial localization error, all measures of goodness of fit are statistically independent of TRE, and therefore FRE and TRE are uncorrelated. Second, we demonstrate by means of computer simulations that they are uncorrelated for the exact problem as well. Since TRE is the true measure of registration accuracy of importance to the success of the surgery, our results show that no estimate of accuracy for a given patient that is based on goodness of fiducial fit for that patient gives any information whatever about true registration accuracy for that patient. Therefore surgeons should stop using such measures as indicators of registration quality for the patients on whom they are about to operate.
FCRL1 on chronic lymphocytic leukemia, hairy cell leukemia, and B-cell non-Hodgkin lymphoma as a target of immunotoxins (2007)

FCRL1 (Fc receptor-like 1) is a cell-surface membrane protein belonging to FCRL family and is preferentially expressed on B cells. To evaluate FcRL1 as an immunotherapy target for B-cell malignancies, we prepared anti-FCRL1 mAbs without cross-reactivity to other FCRL family proteins and analyzed FCRL1 protein expression on malignant cells from patients and on B-cell lines. Frequent FCRL1 expression was observed by flow cytometry on 12 B-cell non-Hodgkin lymphoma (B-NHL) cell lines and many patient samples: 12 of 14 chronic lymphocytic leukemia (CLL), 7 of 7 follicular lymphoma (FL), 13 of 17 hairy cell leukemia (HCL), and 2 of 3 mantle cell lymphoma (MCL). Two recombinant immunotoxins, E3(Fv)-PE38 and E9(Fv)-PE38, were constructed. Both immunotoxins bound to FCRL1-positive cells with similar affinities (3.4 and 3.2 nM) and were cytotoxic to cell lines, but E9(Fv)-PE38 was 4- to 20-fold more cytotoxic than E3(Fv)-PE38. The concentrations that inhibited response by 50% (IC(50)s) of E9(Fv)-PE38 on 11 different FCRL1-positive cell lines ranged from 1.0 ng/mL to 90 ng/mL and correlated with the FCRL1 expression levels. Our results suggest that anti-FCRL1 immunotoxin E9(Fv)-PE38 exhibits remarkably specific cytotoxicity and merits further evaluation for the treatment of FCRL1-positive malignancies, including CLL, HCL, FL, MCL, and other B-NHL.
A cytochrome P450 terpenoid hydroxylase linked to the suppression of insect juvenile hormone synthesis (1998)

A cDNA encoding a cytochrome P450 enzyme was isolated from a cDNA library of the corpora allata (CA) from reproductively active Diploptera punctata cockroaches. This P450 from the endocrine glands that produce the insect juvenile hormone (JH) is most closely related to P450 proteins of family 4 and was named CYP4C7. The CYP4C7 gene is expressed selectively in the CA; its message could not be detected in the fat body, corpora cardiaca, or brain, but trace levels of expression were found in the midgut and caeca. The levels of CYP4C7 mRNA in the CA, measured by ribonuclease protection assays, were linked to the activity cycle of the glands. In adult females, CYP4C7 expression increased immediately after the peak of JH synthesis, reaching a maximum on day 7, just before oviposition. mRNA levels then declined after oviposition and during pregnancy. The CYP4C7 protein was produced in Escherichia coli as a C-terminal His-tagged recombinant protein. In a reconstituted system with insect NADPH cytochrome P450 reductase, cytochrome b5, and NADPH, the purified CYP4C7 metabolized (2E,6E)-farnesol to a more polar product that was identified by GC-MS and by NMR as (10E)-12-hydroxyfarnesol. CYP4C7 converted JH III to 12-trans-hydroxy JH III and metabolized other JH-like sesquiterpenoids as well. This omega-hydroxylation of sesquiterpenoids appears to be a metabolic pathway in the corpora allata that may play a role in the suppression of JH biosynthesis at the end of the gonotrophic cycle.
Live data center migration across WANs (2007)

A significant concern for Internet-based service providers is the continued operation and availability of services in the face of outages, whether planned or unplanned. In this paper we advocate a cooperative, context-aware approach to data center migration across WANs to deal with outages in a non-disruptive manner. We specifically seek to achieve high availability of data center services in the face of both planned and unanticipated outages of data center facilities. We make use of server virtualization technologies to enable the replication and migration of server functions. We propose new network functions to enable server migration and replication across wide area networks (e.g., the Internet), and finally show the utility of intelligent and dynamic storage replication technology to ensure applications have access to data in the face of outages with very tight recovery point objectives.
Regulated expression at high copy number allows production of a growth-inhibitory oncogene product in Drosophila Schneider cells. (1989)

The Drosophila metallothionein promoter (Mtn) was used to obtain efficient, regulated expression of foreign gene products inserted in high copy numbers into Drosophila melanogaster Schneider 2 cells. An expression unit comprised of a reporter gene [Escherichia coli galactokinase (galK)] fused to the Mtn promoter was stably introduced into Schneider 2 cells in up to several hundred copies per cell in a single transfection-selection event. This system contrasts dramatically with other eukaryotic systems that permit only a few copies of a gene to be stably inserted in a single transfection-selection event. The transfected Drosophila S2 cell lines expressed high levels of both galK mRNA and protein in response to metal induction. Most important, and in contrast to mammalian cells, expression remained fully regulated even at high copy number, with low basal expression maintained in the absence of inducer. This regulated system was used to obtain efficient expression in Drosophila cells of an otherwise lethal or growth-inhibitory gene product, the human H-ras oncogene. The ability to obtain regulated high-level expression of potentially lethal foreign proteins is unique to the Drosophila cell system.
Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain (2005)

Questions have been raised about the potential neurotoxicity of the neuraxial use of ketamine although ketamine and its active enantiomer S(+)-ketamine have been used intrathecally and epidurally (caudally) for the management of perioperative pain and in a variety of chronic pain syndromes. Clinical experience following neuraxial administration of S(+)-ketamine has been documented without reference to local central nervous system toxicity following this approach. In addition, there are no preclinical safety data regarding stability, compatibility, and neurotoxicity on intrathecal use of single S(+)-ketamine or combinations of S(+)-ketamine, morphine, bupivacaine, and clonidine. In the present case, the continuous intrathecal administration of S(+)-ketamine, in combination with morphine, bupivacaine, and clonidine resulted in adequate pain relief in a patient suffering from intractable neuropathic cancer pain. However, postmortem observation of the spinal cord and nerve roots revealed severe histological abnormalities including central chromatolysis, nerve cell shrinkage, neuronophagia, microglial upregulation, and gliosis. Based on our results, neuraxial administration of S (+)-ketamine cannot be recommended for clinical practise before a systematic study of toxicology of neuraxial S(+)-ketamine in animals or humans has been performed.