gebhart/patrepeval huggingface dataset:
Systemic Administration of a Matrix-Targeted Retroviral Vector Is Efficacious for Cancer Gene Therapy in Mice (2001)

Targeting cytocidal vectors to tumors and associated vasculature in vivo is a long-standing goal of human gene therapy. In the present study, we demonstrated that intravenous infusion of a matrix (i.e., collagen)-targeted retroviral vector provided efficacious gene delivery of a cytocidal mutant cyclin G1 construct (designated Mx-dnG1) in human cancer xenografts in nude mice. A nontargeted CAE-dnG1 vector (p = 0.014), a control matrix-targeted vector bearing a marker gene (Mx-nBg; p = 0.004), and PBS served as controls (p = 0.001). Enhanced vector penetration and transduction of tumor nodules (35.7 +/- 1.4%, mean +/- SD) correlated with therapeutic efficacy without associated toxicity. Kaplan-Meier survival studies were conducted in mice treated with PBS placebo, the nontargeted CAE-dnG1 vector, and the matrix-targeted Mx-dnG1 vector. Using the Tarone log-rank test, the overall p value for comparing all three groups simultaneously was 0.003, with a trend that was significant to a level of 0.004, indicating that the probability of long-term control of tumor growth was significantly greater with the matrix-targeted Mx-dnG1 vector than with the nontargeted CAE-dnG1 vector or PBS placebo. The present study demonstrates that a matrix-targeted retroviral vector deployed by peripheral vein injection (1) accumulated in angiogenic tumor vasculature within 1 hr, (2) transduced tumor cells with high-level efficiency, and (3) enhanced therapeutic gene delivery and long-term efficacy without eliciting appreciable toxicity.
LEDGF/p75 Determines Cellular Trafficking of Diverse Lentiviral but Not Murine Oncoretroviral Integrase Proteins and Is a Component of Functional Lentiviral Preintegration Complexes (2004)

Human immunodeficiency virus type 1 (HIV-1), feline immunodeficiency virus (FIV), and Moloney murine leukemia virus (MoMLV) integrases were stably expressed to determine their intracellular trafficking. Each lentiviral integrase localized to cell nuclei in close association with chromatin while the murine oncoretroviral integrase was cytoplasmic. Fusions of pyruvate kinase to the lentiviral integrases did not reveal transferable nuclear localization signals. The intracellular trafficking of each was determined instead by the transcriptional coactivator LEDGF/p75, which was required for nuclear localization. Stable small interfering RNA expression eliminated detectable LEDGF/p75 expression and caused dramatic, stable redistribution of each lentiviral integrase from nucleus to cytoplasm while the distribution of MoMLV integrase was unaffected. In addition, endogenous LEDGF/p75 coimmunoprecipitated specifically with each lentiviral integrase. In vitro integration assays with preintegration complexes (PICs) showed that endogenous LEDGF/p75 is a component of functional HIV-1 and FIV PICs. However, HIV-1 and FIV infection and replication in LEDGF/p75-deficient cells was equivalent to that in control cells, whether cells were dividing or growth arrested. Two-long terminal repeat circle accumulation in nondividing cell nuclei was also equivalent to that of LEDGF/p75 wild-type cells. Virions produced in LEDGF/p75-deficient cells had normal infectivity. We conclude that LEDGF/p75 fully accounts for cellular trafficking of diverse lentiviral, but not oncoretroviral, integrases and is the main lentiviral integrase-to-chromatin tethering factor. While lentiviral PIC nuclear import is unaffected by LEDGF/p75 knockdown, this protein is a component of functional lentiviral PICs. A role in HIV-1 integration site distribution merits investigation.
Virtual memory support for multiple page sizes (2002)

The advent of computers with 64-bit virtual address spaces and giga-bytes of physical memory will provide applications with many more orders of magnitude of memory than is possible today. However, to tap the potential of this new hardware, we need to re-examine how virtual memory is traditionally managed. We concentrate in this note on two aspects of virtual memory: software support for multiple page sizes, and memory management policies tuned to large amounts of physical memory. We argue for the need to examine these areas, and we identify several questions that need to be answered. In particular, we show that providing support for multiple page sizes is not as straightforward as may initially appear.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications (2011)

Our knowledge of the molecular mechanisms leading to neuroaxonal damage and demise in MS is steadily increasing. Experimental therapies targeting neuroaxonal ionic imbalances and energy metabolism in part show promising results. A better understanding of the molecular mechanisms underlying chronic progression will substantially aid the development of new treatment strategies.
The effects of excess renal copper on kidney function in the diabetic rat. (1986)

Fifteen male Sprague-Dawley rats (250 g - 300 g) were randomly divided into 5 control and 10 diabetic. Diabetes was induced by streptozotocin injection. Five diabetic rats were treated with penicillamine to chelate copper. All rats were anesthetized for renal clearance studies three weeks following streptozotocin injection. Inulin, sodium p-aminohippurate (PAH) and dextrose were infused i.v. and serial blood and urine samples collected for inulin, PAH and glucose analysis. Renal copper was determined following euthanasia. The glomerular filtration rate (GFR) and tubular maximum (Tm) for PAH and glucose were calculated. These values and the renal copper levels were compared between the three groups using the student's t-test. GFR and the Tm for PAH and glucose were increased in both diabetic groups as compared to the control group (p less than .05), but no difference was noted between the two diabetic groups. Renal copper levels were increased in the non-treated diabetic rats but not in the penicillamine-treated rats (p less than .01) indicating that penicillamine effectively removed copper from the diabetic kidney. The conclusion is that excess renal copper in the diabetic rat does not affect renal function in the early stages of diabetes.
Phosphoinositide 3-Kinase Is Required for Insulin-Induced but Not for Growth Hormone- or Hyperosmolarity-Induced Glucose Uptake in 3T3-L1 Adipocytes (1997)

The regulatory mechanism of glucose uptake in 3T3-L1 adipocytes was investigated with the use of recombinant adenovirus vectors encoding various dominant negative proteins. Infection with a virus encoding a mutant regulatory subunit of phosphoinositide (PI) 3-kinase that does not bind the 110-kDa catalytic subunit (Δp85) inhibited the insulin-induced increase in PI 3-kinase activity coprecipitated by antibodies to phosphotyrosine and glucose uptake in a virus dose-dependent manner. Overexpression of a dominant negative RAS mutant in which Asp57 is replaced with tyrosine (RAS57Y) or of a dominant negative SOS mutant that lacks guanine nucleotide exchange activity (ΔSOS) abolished the insulin-induced increase in mitogen-activated protein kinase activity, but had no effect on PI 3-kinase activity or glucose uptake. Although GH and hyperosmolarity attributable to 300 mm sorbitol each promoted glucose uptake and translocation of glucose transporter (GLUT)4 to an extent comparable to that of insulin, these stimuli triggered little or no association of PI 3-kinase activity with tyrosine-phosphorylated proteins. Overexpression of Δp85 or treatment of cells with wortmannin, an inhibitor of PI 3-kinase activity, had no effect on glucose uptake or translocation of GLUT4 stimulated by GH or hyperosmolarity. Moreover, overexpression of ΔSOS or RAC17N also did not affect the increase in glucose uptake induced by these stimuli. A serine/threonine kinase Akt, a constitutively active mutant of which was previously shown to stimulate glucose uptake, is activated by insulin, GH, and hyperosmolarity to ∼4-fold, ∼2.1-fold, and∼ 2.3-fold over basal level, respectively. These results suggest that insulin-induced but neither GH- or hyperosmolarity-induced glucose uptake is PI 3-kinase-dependent, and neither RAS nor RAC is required for glucose uptake induced by these stimuli in 3T3-L1 adipocytes.
Learning and inferring transportation routines (2004)

This paper introduces a hierarchical Markov model that can learn and infer a user’s daily movements through the commu-nity. The model uses multiple levels of abstraction in order to bridge the gap between raw GPS sensor measurements and high level information such as a user’s mode of transporta-tion or her goal. We apply Rao-Blackwellised particle filters for efficient inference both at the low level and at the higher levels of the hierarchy. Significant locations such as goals or locations where the user frequently changes mode of trans-portation are learned from GPS data logs without requiring any manual labeling. We show how to detect abnormal be-haviors (e.g. taking a wrong bus) by concurrently tracking his activities with a trained and a prior model. Experiments show that our model is able to accurately predict the goals of a per-son and to recognize situations in which the user performs un-known activities.
The Papanicolaou Test for Cervical Cancer Detection (1989)

The complex detection system leading to the discovery and treatment of precancerous lesions and early cancer of the uterine cervix is described in detail and discussed. By far the most difficult and underestimated component of this system is the screening and interpretation of cervical (Papanicolaou) smears. Cytologic case finding may fail because of inadequate samples, insufficient time devoted to screening, or human fatigue. Other weak points of the system, such as an inadequate clinical component, inadequate patient compliance, poor reproducibility of diagnoses, and ineffective aftercare, are also described. For example, obtaining a second smear to confirm or refute a diagnosis of cellular atypia is often a misleading practice. Although this cancer detection system has been shown to be effective in reducing the rate of morbidity and mortality from invasive cervical cancer in appropriately screened populations, there is no evidence that the Papanicolaou test has succeeded anywhere in complete eradication of this theoretically preventable disease. It is important to inform the public about the potential failures of the system and the reasons for them.
Stimuli-responsive dendrimers in drug delivery (2016)

Dendrimers have shown great promise as carriers in drug delivery due to their unique structures and superior properties. However, the precise control of payload release from a dendrimer matrix still presents a great challenge. Stimuli-responsive dendrimers that release payloads in response to a specific trigger could offer distinct clinical advantages over those dendrimers that release payloads passively. These smart polymers are designed to specifically release their payloads at targeted regions or at constant release profiles for specific therapies. They represent an attractive alternative to targeted dendrimers and enable dendrimer-based therapeutics to be more effective, more convenient, and much safer. The wide range of stimuli, either endogenous (acid, enzyme, and redox potentials) or exogenous (light, ultrasound, and temperature change), allows great flexibility in the design of stimuli-responsive dendrimers. In this review article, we will highlight recent advances and opportunities in the development of stimuli-responsive dendrimers for the treatment of various diseases, with emphasis on cancer. Specifically, the applications of stimuli-responsive dendrimers in drug delivery as well as their mechanisms are intensively reviewed.
Effects of femoral tunnel placement on knee laxity and forces in an anterior cruciate ligament graft (2002)

The purpose of this study was to measure the effects of variation in placement of the femoral tunnel upon knee laxity, graft pretension required to restore normal anterior-posterior (AP) laxity and graft forces following anterior cruciate ligament (ACL) reconstruction. Two variants in tunnel position were studied: (1) AP position along the medial border of the lateral femoral condyle (at a standard 11 o'clock notch orientation) and (2) orientation along the arc of the femoral notch (o'clock position) at a fixed distance of 6-7 mm anterior to the posterior wall. AP laxity and forces in the native ACL were measured in fresh frozen cadaveric knee specimens during passive knee flexion-extension under the following modes of tibial loading: no external tibial force, anterior tibial force, varus-valgus moment, and internal-external tibial torque. One group (15 specimens) was used to determine effects of AP tunnel placement, while a second group (14 specimens) was used to study variations in o'clock position of the femoral tunnel within the femoral notch. A bone-patellar tendon-bone graft was placed into a femoral tunnel centered at a point 6-7 mm anterior to the posterior wall at the 11 o'clock position in the femoral notch. A graft pretension was determined such that AP laxity of the knee at 30 deg of flexion was restored to within 1 mm of normal; this was termed the laxity match pretension. All tests were repeated with a graft in the standard 11 o'clock tunnel, and then with a graft in tunnels placed at other selected positions. Varying placement of the femoral tunnel 1 h clockwise or counterclockwise from the 11 o'clock position did not significantly affect any biomechanical parameter measured in this study, nor did placing the graft 2.5 mm posteriorly within the standard 11 o'clock femoral tunnel. Placing the graft in a tunnel 5.0 mm anterior to the standard 11 o'clock tunnel increased the mean laxity match pretension by 16.8 N (62%) and produced a knee which was on average 1.7 mm more lax than normal at 10 deg of flexion and 4.2 mm less lax at 90 deg. During passive knee flexion-extension testing, mean graft forces with the 5.0 mm anterior tunnel were significantly higher than corresponding means with the standard 11 o'clock tunnel between 40 and 90 deg of flexion for all modes of constant tibial loading. These results indicate that AP positioning of the femoral tunnel at the 11 o'clock position is more critical than o'clock positioning in terms of restoring normal levels of graft force and knee laxity profiles at the time of ACL reconstruction.
Identification and Location of Brain Protein 4.1 (1984)

Protein 4.1 is a membrane skeletal protein that converts the low-affinity interaction between spectrin and actin into a high-affinity ternary complex of spectrin, protein 4.1, and actin that is essential to the structural stability of the erythrocyte. Pig brain was shown to contain an 87-kilodalton immunoreactive analog of protein 4.1 that has partial sequence homology with pig erythrocyte protein 4.1 and the same location as spectrin in the cortical cytoplasm of neuronal and glial cell types of the cerebellum.
Walking Like Dinosaurs: Chickens with Artificial Tails Provide Clues about Non-Avian Theropod Locomotion (2014)

Birds still share many traits with their dinosaur ancestors, making them the best living group to reconstruct certain aspects of non-avian theropod biology. Bipedal, digitigrade locomotion and parasagittal hindlimb movement are some of those inherited traits. Living birds, however, maintain an unusually crouched hindlimb posture and locomotion powered by knee flexion, in contrast to the inferred primitive condition of non-avian theropods: more upright posture and limb movement powered by femur retraction. Such functional differences, which are associated with a gradual, anterior shift of the centre of mass in theropods along the bird line, make the use of extant birds to study non-avian theropod locomotion problematic. Here we show that, by experimentally manipulating the location of the centre of mass in living birds, it is possible to recreate limb posture and kinematics inferred for extinct bipedal dinosaurs. Chickens raised wearing artificial tails, and consequently with more posteriorly located centre of mass, showed a more vertical orientation of the femur during standing and increased femoral displacement during locomotion. Our results support the hypothesis that gradual changes in the location of the centre of mass resulted in more crouched hindlimb postures and a shift from hip-driven to knee-driven limb movements through theropod evolution. This study suggests that, through careful experimental manipulations during the growth phase of ontogeny, extant birds can potentially be used to gain important insights into previously unexplored aspects of bipedal non-avian theropod locomotion.
The Domain Structure of ICAM-1 and the Kinetics of Binding to Rhinovirus (1998)

Fragments of intercellular adhesion molecule 1 (ICAM- 1) containing only the two most N terminal of its five immunoglobulin SF domains bind to rhinovirus 3 with the same affinity and kinetics as a fragment with the entire extracellular domain. The fully active two-domain fragments contain 5 or 14 more residues than a previously described fragment that is only partially active. Comparison of X-ray crystal structures show differences at the bottom of domain 2. Four different glycoforms of ICAM- 1 bind with identical kinetics.
Vaccination with cell immunoglobulin mucin-1 antibodies and inactivated influenza enhances vaccine-specific lymphocyte proliferation, interferon-γ production and cross-strain reactivity (2006)

Summary Influenza virus causes a contagious and potentially serious infection of the upper respiratory tract. While neutralizing antibodies are protective against infection, the problem of antigenic drift remains, requiring the constant monitoring and development of new vaccines. The magnitude of this situation is underscored by the emergence of new potentially human pathogenic influenza strains, avian H5N1 being the most recent example. We present evidence that antibodies against T cell immunoglobulin mucin-1 (TIM-1), a recently identified immunomodulatory molecule, stimulate cellular immunity against influenza viruses and cross-strain immune reactivity. To determine potential immunostimulatory properties of anti-TIM-1, mice were vaccinated with inactivated influenza virus in the presence or absence of TIM-1-specific monoclonal antibodies. Development of cellular immunity against both the influenza strain used for immunization and serotypically distinct virus strains was monitored 3 weeks after vaccination by determining antigen-specific lymphocyte proliferation and cytokine production. Results show that TIM-1 antibodies enhance antigen-specific cellular proliferation (P &amp;lt; 0·05) and interferon (IFN)-γ production (P &amp;lt; 0·01). Using blocking anti-CD4 and CD8 antibodies, it was observed that antigen-specific cellular proliferation is CD4-dependent and that the majority of proliferating cells are CD4+. Finally, vaccination with inactivated influenza virus with TIM-1 antibody results in the significant (P &amp;lt; 0·001) induction of proliferation and IFN-γ production upon stimulation with one of three serologically distinct strains. TIM-1 antibodies demonstrate an adjuvant effect promoting antigen-specific cellular proliferation and IFN-γ production, which are important for the promotion of cell-mediated immunity. These results are the first to suggest that TIM-1 antibody may serve as a potent adjuvant in the development of new influenza virus vaccines.
Synthesis and Biological Evaluation of Diethylenetriamine Pentaacetic acid−Polyethylene Glycol−Folate:  A New Folate-Derived, 99mTc-Based Radiopharmaceutical (2005)

(99m)Technetium-labeled diethylenetriamine pentaacetic acid-polyethylene glycol-folate (DTPA-PEG-folate) was synthesized and tested as a radiopharmaceutical agent, which targeted the lymphatic system with metastatic tumor. Folic acid was reacted with H2N-PEG-NH2 to yield H2N-PEG-folate. After purification by anion-exchange chromatography, the product was reacted with cyclic DTPA. By removal of unreacted DTPA by size-exclusion chromatography, DTPA-PEG-Folate was obtained. Fluorescein-5-isothiocyanate (FITC)-labeled DTPA-PEG-folate and DTPA-PEG-OCH3 were prepared via a dicyclohexylcarbodiimide-mediated coupling. In vitro competitive binding test showed that the uptake of [125I] folic acid was inhibited by DTPA-PEG-folate and the 50% inhibitory concentration was 4.37 pmol/L (R2 = 0.9922). The relative affinity of DTPA-PEG-FITC was 0.18 for human folate receptor comparing with folic acid. In cultured tumor cells, uptake of fluorescence-labeled DTPA-PEG-folate was found to increase significantly in folate-deficient medium compared with that of untargeted DTPA-PEG-OCH3 and FITC-ethylenediamine. The competition with free folic acid blocked the cell uptake of DTPA-PEG-folate. These results confirmed the DTPA-PEG-folate entered into KB cells through the folate receptor endocytosis pathway in vitro. The radiolabeled yield of [(99m)Tc] DTPA-PEG-folate was in excess of 98%, and specific activities of 7.4 kBq (0.2 microCi/microg) were achieved. After subcutaneous injection, [(99m)Tc] DTPA-PEG-folate exhibited an initial increase and successive decline of accumulation in popliteal nodes in normal Wistar rats. Expect for the kidney, uptake by other tissues was rather low. In a normal rabbit imagine study, the lymphatic vessels were readily visualized by single-photon-emission computed tomography following subcutaneous injection of [(99m)Tc] DTPA-PEG-folate. In conclusion, the [(99m)Tc] DTPA-PEG-folate conjugate may have a potential as a lymphatic tumor-targeted radiopharmaceutical.
Molecular cloning and expression of human tumor necrosis factor and comparison with mouse tumor necrosis factor (1985)

U‐937 cells, a monocytic line derived from a human histiocytic lymphoma, were induced for human tumor necrosis factor (TNF) secretion into the medium and were used for the preparation of TNF mRNA. Biological activity of the latter was quantified in a Xenopus laevis oocyte injection system. TNF mRNA was enriched by gradient centrifugation and this size‐fractionated mRNA was used for synthesis of cDNA and inserted into the unique Pst I site of pAT153. A recombinant plasmid containing human TNF cDNA was selected by colony hybridization using an internal fragment of a mouse TNF cDNA clone [Fransen, L., Mueller, R., Marmenout, A., Tavernier, J., Van der Heyden, J., Kawashima, E., Chollet, A., Tizard, R., Van Heuverswyn, H., Van Vliet, A., Ruysschaert, M. R. &amp; Fiers, W. (1985) Nucleic Acids Res. 13 , 4417–4429] as a probe. The sequence of this human TNF cDNA is in agreement with the one published by Pennica et al. [Pennica, D., Nedwin, G. E., Hayflick, J. S., Seeburg, P. H., Derynck, R., Palladino, M. A., Kohr, W. J., Aggarwal, B. B. &amp; Goeddel, D. V. (1984) Nature (Lond.) 312 , 724–729]. The 157‐amino‐acid‐long mature sequence is about 80% homologous to mouse TNF and its hydrophilicity plot is also very similar, in spite of the apparent species specificity of TNF. In contrast to mouse TNF, it contains no potential N ‐glycosylation site. When compared to other cytokines, like IFN‐β, IFN‐γ, or IL‐2, there is a remarkably high preference for G · C pairs in the third‐letter positions. Expression of the TNF cDNA in monkey COS cells or in Escherichia coli gives rise to a protein having similar biological and serological properties as natural human TNF. A human genomic clone was also identified and sequenced; it was found to be in good agreement with the one recently published by Shirai et al. [Shirai, T., Yamaguchi, H., Ito, H., Todd, C. W. &amp; Wallace, R. B. (1985) Nature (Lond.) 313 , 803–806], except for some differences in the introns and 5′‐untranslated region.