gebhart/patrepeval huggingface dataset:
Replication-defective chimeric helper proviruses and factors affecting generation of competent virus: expression of Moloney murine leukemia virus structural genes via the metallothionein promoter. (1987)

Two chimeric helper proviruses were derived from the provirus of the ecotropic Moloney murine leukemia virus by replacing the 5'long terminal repeat and adjacent proviral sequences with the mouse metallothionein I promoter. One of these chimeric proviruses was designed to express the gag-pol genes of the virus, whereas the other was designed to express only the env gene. When transfected into NIH 3T3 cells, these helper proviruses failed to generate competent virus but did express Zn2+-inducible trans-acting viral functions needed to assemble infectious vectors. One helper cell line (clone 32) supported vector assembly at levels comparable to those supported by the Psi-2 and PA317 cell lines transfected with the same vector. Defective proviruses which carry the neomycin phosphotransferase gene and which lack overlapping sequence homology with the 5' end of the chimeric helper proviruses could be transfected into the helper cell line without generation of replication-competent virus. Mass cultures of transfected helper cells produced titers of about 10(4) G418r CFU/ml, whereas individual clones produced titers between 0 and 2.6 X 10(4) CFU/ml. In contrast, defective proviruses which share homologous overlapping viral sequences with the 5' end of the chimeric helper proviruses readily generated infectious virus when transfected into the helper cell line. The deletion of multiple cis-acting functions from the helper provirus and elimination of sequence homology overlapping at the 5' ends of helper and vector proviruses both contribute to the increased genetic stability of this system.
New Drugs for the Treament of Chronic Lymphocytic Leukemia (2000)

Novel strategies are needed to improve the prognosis of patients with chronic lymphocytic leukemia CLL). One approach is to identify new drugs with unique mechanisms of action. Compound GW506U78, the prodrug for arabinosylguanine, is an interesting new purine analog, which induces responses in about one‐third of patients with relapsed or refractory CLL. A multicenter study is currently evaluating patients with CLL who have failed treatment with both fludarabine and an alkylating agent. Other agents in clinical development include retinoids and arsenicals which induce apoptosis, farnesyl transferase inhibitors, proteasome inhibitors and the signal transduction modulators, bryostatin and UCN‐01. UCN‐01 not only inhibits protein kinase C, but also modulates the G 2 checkpoint. In vitro synergy has been demonstrated with fludarabine and a phase I trial of this combination is ongoing at the National Cancer Institute, USA. Flavopiridol is a semisynthetic flavone derivative which is active against cycling as well as noncycling cells. It inhibits a variety of cyclins and induces apoptosis. The histone deacetylase inhibitor depsipeptide has selective activity against CLL cells in vitro. An increasing body of evidence has implicated angiogenesis in hematologic malignancies, such as multiple myeloma, lymphoma and CLL. Several angiogenesis inhibitors are currently in clinical trials, including thalidomide, SU5416 and SU6668. Future strategies must be directed at appropriate therapeutic targets using rational combinations of these drugs and other new compounds with the goal of curing patients with CLL.
The dynamics of viral marketing (2006)

We present an analysis of a person-to-person recommendation network, consisting of 4 million people who made 16 million recommendations on half a million products. We observe the propagation of recommendations and the cascade sizes, which we explain by a simple stochastic model. We then establish how the recommendation network grows over time and how effective it is from the viewpoint of the sender and receiver of the recommendations. While on average recommendations are not very effective at inducing purchases and do not spread very far, we present a model that successfully identifies product and pricing categories for which viral marketing seems to be very effective.
Operation and Utilization of Hydraulic-Actuated Service Tools for Reeled Tubing (1990)

ABSTRACT The advent of highly deviated and horizontal well completions has created the need for a new line of service tools that do not rely upon gravity for the setting and retrieving of downhole tools. When using reeled tubing in downhole applications, in particular highly deviated or horizontal wells, frictional drag can limit the available forces required to set and pull flow controls, shift sleeves, shear pins, etc1 As such, tools are needed that take advantage of the pressure and flow capabilities of the reeled tubing to create an efficient system for servicing highly deviated and horizontal wells in addition to conventional vertical wellbores.
Droplet microfluidics for high-throughput biological assays (2012)

Droplet microfluidics offers significant advantages for performing high-throughput screens and sensitive assays. Droplets allow sample volumes to be significantly reduced, leading to concomitant reductions in cost. Manipulation and measurement at kilohertz speeds enable up to 10(8) samples to be screened in one day. Compartmentalization in droplets increases assay sensitivity by increasing the effective concentration of rare species and decreasing the time required to reach detection thresholds. Droplet microfluidics combines these powerful features to enable currently inaccessible high-throughput screening applications, including single-cell and single-molecule assays.
High-Throughput Chemical Screens Identify Disulfiram as an Inhibitor of Human Glioblastoma Stem Cells (2012)

Glioblastoma Multiforme (GBM) continues to have a poor patient prognosis despite optimal standard of care. Glioma stem cells (GSCs) have been implicated as the presumed cause of tumor recurrence and resistance to therapy. With this in mind, we screened a diverse chemical library of 2,000 compounds to identify therapeutic agents that inhibit GSC proliferation and therefore have the potential to extend patient survival. High-throughput screens (HTS) identified 78 compounds that repeatedly inhibited cellular proliferation, of which 47 are clinically approved for other indications and 31 are experimental drugs. Several compounds (such as digitoxin, deguelin, patulin and phenethyl caffeate) exhibited high cytotoxicity, with half maximal inhibitory concentrations (IC50) in the low nanomolar range. In particular, the FDA approved drug for the treatment of alcoholism, disulfiram (DSF), was significantly potent across multiple patient samples (IC50 of 31.1 nM). The activity of DSF was potentiated by copper (Cu), which markedly increased GSC death. DSF-Cu inhibited the chymotrypsin-like proteasomal activity in cultured GSCs, consistent with inactivation of the ubiquitin-proteasome pathway and the subsequent induction of tumor cell death. Given that DSF is a relatively non-toxic drug that can penetrate the blood-brain barrier, we suggest that DSF should be tested (as either a monotherapy or as an adjuvant) in pre-clinical models of human GBM. Data also support targeting of the ubiquitin-proteasome pathway as a therapeutic approach in the treatment of GBM.
Cadre regional strategique de gestion environnementale et sociale (2006)

This environmental assessment (EA) and the Pest and Pesticides Management Plan document support the implementation of the water resources management program, and the development of a multi-usage system in the Senegal River basin (PGIRE). It is expected that some activities will increase the use of pesticides and the development of control methods to fight agricultural ravaging threats and water-borne diseases, which would be threatening from environmental and social perspectives. The operation of Manantali and Diama dams considerably increased the size of irrigated and flooded cultures in the program area. Ecosystem changes and the intensification of cultures engendered a permanent threat to crops due to infestations and enemies to cultures. On the other hand, the increase of hydro-agricultural projects and the development of irrigation led to an increase in water-borne diseases such as malaria and schistosomiasis (river blindness) in the River's valley. Currently, these two problems can only be reached through the reasonable use of pesticides. However the use of pesticides itself poses some risks, including the absence of license agreements, and farmers' lack of knowledge about pesticide use. The report advocates promoting the integrated management of pesticides (use, storage, transport and disposal of containers); promoting regional expertise and coordination by reinforcing communication, investigation measures, and setting up a rapid information flow system. Other recommendations include building and equipping an environmental monitoring laboratory and storehouses, supporting the enforcement of phytosanitary legislation and regulations, designing a study for the research and development of alternative fighting methods, training producers and technicians, controlling cross border destructive vectors mainly grain-eating birds, supporting farmers' organizations, forming pesticide brigades, and improving research and development, among other measures.
Extending SQL-92 for OODB access (1995)

This paper describes the design and implementation of a query engine that provides extended SQL-based access to the data managed by an object-oriented database system. This query engine allows extended SQL queries to be embedded in C++ programs or issued interactively as from a command line interface. The language supported by the engine is the complete SQL-92 select statement plus object extensions for navigating along paths and embedded structures, querying nested sets, and invoking member functions. In addition, an object-oriented SQL view facility is provided. Using this view facility, one can define object-oriented views; one can also define views that flatten complex OODB schemas, allowing direct access by existing tools designed to provide remote access to relational databases. The view facility also supports the definition of views that include reference and set-valued columns based on other views, thus allowing entire "view schemas" to be created. This paper describes the SQL-92 query and view extensions and discusses a number of issues that arose on the way to the implementation that is currently running on top of the ObjectStore OODB system.
Identification of highly selective MMP‐14 inhibitory Fabs by deep sequencing (2017)

Matrix metalloproteinase (MMP)-14 is an important target for cancer treatment due to its critical roles in tumor invasion and metastasis. Previous failures of all compound-based broad-spectrum MMP inhibitors in clinical trials suggest that selectivity is the key for a successful therapy. With inherent high specificity, monoclonal antibodies (mAbs) therefore arise as attractive inhibitors able to target the particular MMP of interest. As a routine screening method, enzyme-linked immunosorbent assays (ELISA) have been applied to panned phage libraries for the isolation of mAbs inhibiting MMP-14. However, because of suboptimal growth conditions and insufficient antibody expression associated with monoclonal ELISA, a considerable number of potentially inhibitory clones might not be identified. Taking advantage of next-generation sequencing (NGS), we monitored enrichment profiles of millions of antibody clones along three rounds of phage panning, and identified 20 Fab inhibitors of MMP-14 with inhibition IC<sub>50</sub> values of 10-4,000 nM. Among these inhibitory Fabs, 15 were not found by monoclonal phage ELISA. Particularly, Fab R2C7 exhibited an inhibition potency of 100 nM with an excellent selectivity to MMP-14 over MMP-9. Inhibition kinetics and epitope mapping suggested that as a competitive inhibitor, R2C7 directly bound to the vicinity of the MMP-14 catalytic site. This study demonstrates that deep sequencing is a powerful tool to facilitate the systematic discovery of mAbs with protease inhibition functions. Biotechnol. Bioeng. 2017;114: 1140-1150. © 2017 Wiley Periodicals, Inc.
Local antibiotic therapy for severe open fractures. A review of 1085 consecutive cases (1995)

We reviewed 1085 consecutive compound limb fractures treated in 914 patients at the University of Louisville over a nine-year period. Of these fractures, 240 (group 1) received only systemic antibiotic prophylaxis and 845 (group 2) were managed by the supplementary local use of aminoglycoside-polymethylmethacrylate (PMMA) beads. There were no significant differences in age, gender, fracture type, fracture location or follow-up between the two groups. All had copious wound irrigation, meticulous debridement and skeletal stabilisation, but wound management and the use of local antibiotic depended on the surgeon's individual preference and there was no randomisation. In group 1 there was an overall infection rate of 12% as against 3.7% in group 2 (p < 0.001). Both acute infection and local osteomyelitis showed a decreased incidence in group 2, but this was statistically significant only in Gustilo type-IIIB and type-IIIC fractures for acute infection, and only in type-II and type-IIIB fractures for chronic osteomyelitis. Our review suggests that the adjuvant use of local antibiotic-laden PMMA beads may reduce the incidence of infection in severe compound fractures.
The current density distribution of resistive disk surface electrodes (1988)

The current-density distribution of resistive disk surface electrodes is analyzed using a model in which the body is locally represented by a planar two-layer resistive medium and the electrode by a resistive disk with a concentric perfectly conducting feed contact. The exact current-density distribution on and in the electrode is obtained by solving a three-dimensional Laplace's equation numerically by means of the moment method. The following physical factors that affect the current-density distribution are analyzed: electrode size, feed region size, electrode thickness, electrode resistivity, skin conductivity, and skin thickness. The results demonstrate both an edge peak, which occurs with a highly conducting electrode on a uniform medium, and a peak in the current density near the feed region, which occurs if the electrode properties are not well matched to the properties of the tissues.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
The pH dependence of insulin binding. A quantitative study. (1982)

A model is presented to study quantitative the effect of pH on a ligand-receptor interaction. Assuming that binding is only possible if all the "active groups" are in the correct ionic state, and that the ionic state of the other residues does not affect the association constant, it is possible to measure the number and pK values of the active groups. This model is applied to insulin and insulin analogs binding to its cellular receptor. Two active groups are responsible for the marked pH dependence of the reaction: a deprotonated residue of pK 7.6 at 25 degrees C (ionization heat: 1.5 kcal . mol-1) and a protonated residue of pK 8.0 at 25 degrees C (ionization heat: 12 kcal . mol-1). The first active group might be a carboxyl residue, in a hydrophobic environment, probably belonging to the receptor molecule. The second active group was further identified as the A1 alpha-amino residue of insulin by the study of insulin analogs.
Development and validation of a 32-gene prognostic index for prostate cancer progression (2013)

The accurate determination of the risk of cancer recurrence is an important unmet need in the management of prostate cancer. Patients and physicians must weigh the benefits of currently available therapies against the potential morbidity of these treatments. Herein we describe the development of a gene expression-based continuous risk index and a validation of this test in an independent, blinded cohort of post-radical prostatectomy (RP) patients. A gene expression signature, prognostic for prostate-specific antigen (PSA) recurrence, was identified through a bioinformatic analysis of the expression of 1,536 genes in malignant prostate tissue from a training cohort of consecutive patients treated with RP. The assay was transferred to a real-time RT-PCR platform, and a continuous risk index model was constructed based on the expression of 32 genes. This 32-gene risk index model was validated in an independent, blinded cohort of 270 RP patients. In multivariate analyses, the risk index was prognostic for risk of PSA recurrence and had added value over standard prognostic markers such as Gleason score, pathologic tumor stage, surgical margin status, and presurgery PSA (hazard ratio, 4.05; 95% confidence interval, 1.50-10.94; P = 0.0057). Furthermore, RP patients could be stratified based on the risk of PSA recurrence and the development of metastatic disease. The 32-gene signature identified here is a robust prognostic marker for disease recurrence. This assay may aid in postoperative treatment selection and has the potential to impact decision making at the biopsy stage.
Inhaled protein/peptide-based therapies for respiratory disease (2016)

Asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are all chronic pulmonary diseases, albeit with different etiologies, that are characterized by airflow limitation, chronic inflammation, and abnormal mucus production/rheology. Small synthetic molecule-based therapies are commonly prescribed for all three diseases. However, there has been increased interest in “biologicals” to treat these diseases. Biologicals typically constitute protein- or peptide-based therapies and are often more potent than small molecule-based drugs. In this review, we shall describe the pros and cons of several different biological-based therapies for respiratory disease, including dornase alfa, a recombinant DNAase that reduces mucus viscosity and short palate lung and nasal epithelial clone 1 (SPLUNC1)-derived peptides that treat Na+ hyperabsorption and rebalance CF airway surface liquid homeostasis.
Transformation of Sugarbeet (Beta vulgaris) byAgrobacterium tumefaciens (1990)

A method has been developed for the regeneration of transformed plants of the commercially important crop sugarbeet (Beta vulgaris L.), using Agrobacterium tumefaciens. Binary vectors were used, carrying both screenable and selectable genes. Plant regeneration from shoot-base tissues was found to be relatively rapid and frequent compared with petioles or leaf tissue. Inoculation of cultured shoot-base tissues resulted in the production of transformed plants, as determined by (1) introduced resistance to kanamycin, (2) introduced CAT or GUS activity, and (3) Southern blot analysis to show the integration of foreign DNA. The transformation frequency was found to be dependent upon explant source, plant genotype and selection conditions used.
Variability in Cholesteryl Ester Transfer Protein in Healthy Japanese Hyper-HDL-cholesterolemic Subjects. (2002)

These results suggest that hyper-HDL-cholesterolemia may not be a single clinical entity, but a mixture of various pathophysiological conditions, and that the ratio of LDL-C to HDL-C and the size of LDL may be important factors in classifying these conditions.
Inhibiting EGF Receptor or SRC Family Kinase Signaling Overcomes BRAF Inhibitor Resistance in Melanoma (2012)

Therapies that target the driver oncogenes in cancer can achieve remarkable responses if patients are stratified for treatment. However, as with conventional therapies, patients often develop acquired resistance to targeted therapies, and a proportion of patients are intrinsically resistant and fail to respond despite the presence of an appropriate driver oncogene mutation. We found that the EGFR/SFK pathway mediated resistance to vemurafenib in BRAF -mutant melanoma and that BRAF and EGFR or SFK inhibition blocked proliferation and invasion of these resistant tumors, providing potentially effective therapeutic options for these patients.
Glycogen synthase kinase 3: more than a namesake (2009)

Glycogen synthase kinase 3 (GSK3), a constitutively acting multi-functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. These diverse multiple functions attributed to GSK3 can be explained by variety of substrates like glycogen synthase, tau protein and beta catenin that are phosphorylated leading to their inactivation. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti-diabetic but do not lead to up-regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti-diabetic therapeutic target.
Tissue inhibitor of metalloproteinases‐2 inhibits bFGF‐induced human microvascular endothelial cell proliferation (1993)

Tissue inhibitor of metalloproteinase-2 (TIMP-2), a protease inhibitor that binds to the latent and active forms of 72 kDa type IV collagenase (gelatinase A), was found to inhibit the in vitro proliferation of human microvascular endothelial (HME) cells stimulated with bFGF and 5% serum. The maximal inhibitory effect of TIMP-2 on incorporation of 3H-thymidine was evident 24 hours after bFGF stimulation of these cells and ranged between 45 and 60%. The half-maximal effective concentration of TIMP-2 was 107 +/- 12 nM (S.D.). In contrast, TIMP-1 was not found to slow the growth of HME cells. The inhibition of cell proliferation observed with TIMP-2 was not mimicked by addition to the culture medium of BB94, a general matrix metalloproteinase inhibitor, nor antibodies to the 72 kDa type IV collagenase. In addition to growth, two other cell functions associated with the angiogenic process were tested for sensitivity to TIMP-2. Cell adhesion to tissue culture plastic was slightly stimulated by TIMP-2, and cell migration was inhibited with short-term exposure to TIMP-2, but neither process was affected by longer-term exposure. The ability of TIMP-2 to inhibit cultured endothelial cell proliferation independent of protease inhibitory activity suggests that TIMP-2 may have additional actions which may limit neovascularization associated with solid tumor growth and metastasis in vivo.
A 5'-flanking region of the chicken acetylcholine receptor alpha-subunit gene confers tissue specificity and developmental control of expression in transfected cells. (1987)

The 5' end and promoter region of the alpha-subunit gene of chicken muscle acetylcholine receptor was mapped and sequenced. It includes a TATA and a CAAT box and a potential Sp1-binding site. When inserted in front of the chloramphenicol acetyltransferase gene, this promoter (including 850 base pairs of upstream sequence) directed high transient chloramphenicol acetyltransferase expression in transfected mouse C2.7 myotubes but not in C2.7 myoblasts or nonmyogenic 3T6 cells.