gebhart/patrepeval huggingface dataset:
Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. (2000)

Interleukin 8 (IL-8) is mitogenic and chemotactic for endothelial cells. Within a neoplasm, IL-8 is secreted by inflammatory and neoplastic cells. The highly metastatic PC-3M-LN4 cell line overexpresses IL-8 relative to the poorly metastatic PC-3P cell line. We evaluated whether IL-8 expression by human prostate cancer growing within the prostate of athymic nude mice regulates tumor angiogenesis, growth, and metastasis. PC-3P cells were transfected with the full-length sense IL-8 cDNA, whereas PC-3M-LN4 cells were transfected with the full-sequence antisense IL-8 cDNA. Control cells were transfected with the neomycin resistance gene (Neo). In vitro, sense-transfected PC-3P cells overexpressed IL-8-specific mRNA and protein, which resulted in up-regulation of matrix metalloproteinase 9 (MMP-9) mRNA, and collagenase activity, resulting in increased invasion through Matrigel. After antisense transfection of the PC-3M-LN4 cells, IL-8 and MMP-9 expression, collagenase activity, and invasion were markedly reduced relative to controls. After orthotopic implantation, the sense-transfected PC-3P cells were highly tumorigenic and metastatic, with significantly increased neovascularity and IL-8 expression compared with either PC-3P cells or controls. Antisense transfection significantly reduced the expression of IL-8 and MMP-9 and tumor-induced neovascularity, resulting in inhibition of tumorigenicity and metastasis. These results demonstrate that IL-8 expression regulates angiogenesis in prostate cancer, in part by induction of MMP-9 expression, and subsequently regulates the growth and metastasis of human prostate cancer.
Threonine Deaminase from Escherichia coli (1973)

Abstract A procedure has been devised for the purification of the biosynthetic l-threonine deaminase (l-threonine hydrolase, deaminating: EC 4.2.1.16) from a genetically derepressed mutant, strain TIR8, of Escherichia coli K-12. The procedure produces a purification of 400-fold relative to derepressed enzyme levels and 4000-fold relative to repressed levels. The purity of the final enzyme preparation has been determined by sodium dodecyl sulfate gel electrophoresis and by sedimentation equilibrium experiments. The native enzyme, molecular weight 204,000, is a tetramer composed of four apparently identical subunits, molecular weight 51,000. When the native enzyme is resolved of its cofactor, pyridoxal 5'-monophosphate, catalytically inactive apodimers, molecular weight 102,000, are formed. Addition of pyridoxal 5'-monophosphate to the apodimers promotes reassociation to catalytically active tetramers. The kinetic data of the l-threonine deaminase reaction are similar with the pure enzyme and with partially purified preparations. l-Isoleucine is a competitive allosteric inhibitor. The enzyme exhibits cooperative homotropic interactions with respect to the substrate only in the presence of l-isoleucine. These interactions are reversed by l-valine. The enzyme exists in a pH-dependent equilibrium between two distinct and catalytically active species; a tetramer sensitive to l-isoleucine inhibition and a dimer insensitive to l-isoleucine inhibition. The tetramer is favored at pH values from 6.0 to 7.5 while at pH values from 8.5 to 10.0 the enzyme is present almost exclusively as the dimer. At pH 8.0 a mixture of the two is present.
SHARE: a methodology and environment for collaborative production development (2002)

The SHARE project seeks to apply information technologies in helping design teams gather, organize, reaccess, and communicate both informal and formal design information to establish a 'shared understanding' of the design and design process. The paper presents the visions of SHARE, along with the research and strategies undertaken to build an infrastructure toward its realization. A preliminary prototype environment is being used by designers working on a variety of industry sponsored design projects. This testbed continues to inform and guide the development of NoteMail, MovieMail, and Xshare, as well other components of the next generation SHARE environment that will help distributed design teams work together more effectively.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Comparison of Two Rapid Whole-Blood Tests for Helicobacter pylori Infection in Chinese Patients (1998)

Consecutive Chinese patients undergoing endoscopy for dyspepsia were tested for Helicobacter pylori infection by two rapid whole-blood tests: FlexPack HP (Abbott Laboratories) and Helisal One-Step (Cortecs Diagnostics). Biopsy-based tests (rapid urease test and histology) and the [13C]urea breath test were used as the "gold standard." One hundred sixty-one consecutive patients were studied, and 88 (54.7%) were confirmed to have H. pylori infection. The sensitivities, specificities, and positive and negative predictive values were 81.8%, 83.6% (P = 0.008), 85.7% (P = 0.04), and 79.2% for FlexPack HP and 84.1%, 63.0% (P = 0.008), 73.3% (P = 0.047), and 76.7% for Helisal One-Step, respectively.
Inhibition of Tissue Factor-Factor VIIa-catalyzed Factor X Activation by Factor Xa-Tissue Factor Pathway Inhibitor (1999)

The physiological inhibitor of tissue factor (TF).factor VIIa (FVIIa), full-length tissue factor pathway inhibitor (TFPI(FL)) in complex with factor Xa (FXa), has a high affinity for anionic phospholipid membranes. The role of anionic phospholipids in the inhibition of TF.FVIIa-catalyzed FX activation was investigated. FXa generation at a rotating disc coated with TF embedded in a membrane composed of pure phosphatidylcholine (TF.PC) or 25% phosphatidylserine and 75% phosphatidylcholine (TF.PSPC) was measured in the presence of preformed complexes of FXa.TFPI(FL) or FXa.TFPI(1-161) (TFPI lacking the third Kunitz domain and C terminus). At TF.PC, FXa.TFPI(FL) and FXa.TFPI(1-161) showed similar rate constants of inhibition (0.07 x 10(8) M(-1) s(-1) and 0.1 x 10(8) M(-1) s(-1), respectively). With phosphatidylserine present, the rate constant of inhibition for FXa.TFPI(FL) increased 3-fold compared with a 9-fold increase in the rate constant for FXa. TFPI(1-161). Incubation of TF.PSPC with FXa.TFPI(FL) in the absence of FVIIa followed by depletion of solution FXa.TFPI(FL) showed that FXa.TFPI(FL) remained bound at the membrane and pursued its inhibitory activity. This was not observed with FXa.TFPI(1-161) or at TF.PC membranes. These data suggest that the membrane-bound pool of FXa.TFPI(FL) may be of physiological importance in an on-site regulation of TF.FVIIa activity.
The Radiobiology of Conventional Radiotherapy and Its Application to Radionuclide Therapy (2005)

The linear-quadratic (LQ) model of radiobiological effect is well established in conventional, i.e., external beam, radiotherapy. Because the model is derived from sound biophysical principles, it is also emerging as the standard formalism for assessing biological responses for the whole range of radiotherapy treatments. A central feature of LQ methodology is the quantity known as the biologically effective dose (BED), which may be used to quantify the radiobiological impact of a treatment on both tumors and normal tissues. The BEDs commonly associated with conventional therapy may thus be compared to those expected from novel radiotherapy treatments, such as targeted radionuclide therapy. This approach also provides a mechanism for designing targeted treatments which are therapeutically equivalent to external beam treatments. In this paper the LQ methodology is outlined and worked examples are provided which demonstrate the tentative link between targeted radiotherapy doses and those used in conventional radiotherapy. The incorporation of an allowance for relative biological effectiveness (RBE) effects is also discussed. The complexity of the subject and the potentially large number of variables does place a restriction on overall predictive accuracy and the necessary caveats are outlined.
DNA/NYVAC Vaccine Regimen Induces HIV-Specific CD4 and CD8 T-Cell Responses in Intestinal Mucosa (2011)

In the present study, we have investigated the anatomic distribution in blood and gut mucosal tissues of memory poxvirus-specific CD4 and CD8 T cells in subjects vaccinated with smallpox and compared it with vector (NYVAC)-specific and HIV insert-specific T-cell responses induced by an experimental DNA-C/ NYVAC-C vaccine regimen. Smallpox-specific CD4 T-cell responses were present in the blood of 52% of the subjects studied, while smallpox-specific CD8 T cells were rarely detected (12%). With one exception, smallpox-specific T cells were not measurable in gut tissues. Interestingly, NYVAC vector-specific and HIV-specific CD4 and CD8 T-cell responses were detected in almost 100% of the subjects immunized with DNA-C/NYVAC-C in blood and gut tissues. The large majority (83%) of NYVAC-specific CD4 T cells expressed α4β7 integrins and the HIV coreceptor CCR5. These results demonstrate that the experimental DNA-C/NYVAC-C HIV vaccine regimen induces the homing of potentially protective HIV-specific CD4 and CD8 T cells in the gut, the port of entry of HIV and one of the major sites for HIV spreading and the depletion of CD4 T cells.
Persistent Na+Current Modifies Burst Discharge By Regulating Conditional Backpropagation of Dendritic Spikes (2003)

The estimation and detection of stimuli by sensory neurons is affected by factors that govern a transition from tonic to burst mode and the frequency characteristics of burst output. Pyramidal cells in the electrosensory lobe of weakly electric fish generate spike bursts for the purpose of stimulus detection. Spike bursts are generated during repetitive discharge when a frequency-dependent broadening of dendritic spikes increases current flow from dendrite to soma to potentiate a somatic depolarizing afterpotential (DAP). The DAP eventually triggers a somatic spike doublet with an interspike interval that falls inside the dendritic refractory period, blocking spike backpropagiation and the DAP. Repetition of this process gives rise to a rhythmic dendritic spike failure, termed conditional backpropagation, that converts cell output from tonic to burst discharge. Through in vitro recordings and compartmental modeling we show that burst frequency is regulated by the rate of DAP potentiation during a burst, which determines the time required to discharge the spike doublet that blocks backpropagation. DAP potentiation is magnified through a positive feedback process when an increase in dendritic spike duration activates persistent sodium current (I(NaP)). I(NaP) further promotes a slow depolarization that induces a shift from tonic to burst discharge over time. The results are consistent with a dynamical systems analysis that shows that the threshold separating tonic and burst discharge can be represented as a saddle-node bifurcation. The interaction between dendritic K(+) current and I(NaP) provides a physiological explanation for a variable time scale of bursting dynamics characteristic of such a bifurcation.
Miniaturized PCR chips for nucleic acid amplification and analysis: latest advances and future trends (2007)

The possibility of performing fast and small-volume nucleic acid amplification and analysis on a single chip has attracted great interest. Devices based on this idea, referred to as micro total analysis, microfluidic analysis, or simply 'Lab on a chip' systems, have witnessed steady advances over the last several years. Here, we summarize recent research on chip substrates, surface treatments, PCR reaction volume and speed, architecture, approaches to eliminating cross-contamination and control and measurement of temperature and liquid flow. We also discuss product-detection methods, integration of functional components, biological samples used in PCR chips, potential applications and other practical issues related to implementation of lab-on-a-chip technologies.
Quantification of Cerebral A1 Adenosine Receptors in Humans using [18F]CPFPX and PET (2004)

Adenosine is an important neuromodulator. Basic cerebral effects of adenosine are exerted by the A1 adenosine receptor (A1AR), which is accessible in vivo by the novel ligand [F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([F]CPFPX) and positron emission tomography (PET). The present study investigates the applicability of kinetic models to describe the cerebral kinetics of [F]CPFPX in order to quantify A1AR density in vivo. Six healthy volunteers underwent dynamic PET scanning and arterial blood sampling after bolus injection of [F]CPFPX. For quantitative analysis, a standard two-tissue compartment model (2TCM) was compared with a one-tissue compartment model (1TCM) and Logan's graphical analysis (GA). The 2TCM described the cerebral kinetics of [F]CPFPX significantly better than the 1TCM (in all regions and subjects examined). The estimated values of the regional total distribution volumes (DVt) correlated strongly between the 2TCM and GA (linear regression r = 0.99, slope: 1.007). The DVt correlation between the 2TCM and the 1TCM was comparably high, but there was a significant bias towards lower DVt estimates given by the 1TCM (r: 0.99, slope: 0.929). It is concluded that a 2TCM satisfactorily accounts for the cerebral kinetics of [F]CPFPX. GA represents an attractive alternative method of analysis.
Optimization of Benzodiazepinones as Selective Inhibitors of the X-Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain (2013)

The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.
Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes (2011)

ANZCTR:ACTRN12610000185066.
Phage Genetic Engineering Using CRISPR–Cas Systems (2018)

Since their discovery over a decade ago, the class of prokaryotic immune systems known as CRISPR⁻Cas have afforded a suite of genetic tools that have revolutionized research in model organisms spanning all domains of life. CRISPR-mediated tools have also emerged for the natural targets of CRISPR⁻Cas immunity, the viruses that specifically infect bacteria, or phages. Despite their status as the most abundant biological entities on the planet, the majority of phage genes have unassigned functions. This reality underscores the need for robust genetic tools to study them. Recent reports have demonstrated that CRISPR⁻Cas systems, specifically the three major types (I, II, and III), can be harnessed to genetically engineer phages that infect diverse hosts. Here, the mechanisms of each of these systems, specific strategies used, and phage editing efficacies will be reviewed. Due to the relatively wide distribution of CRISPR⁻Cas systems across bacteria and archaea, it is anticipated that these immune systems will provide generally applicable tools that will advance the mechanistic understanding of prokaryotic viruses and accelerate the development of novel technologies based on these ubiquitous organisms.
Delineation of distal ulnar nerve anatomy using ultrasound in volunteers to identify an optimum approach for neural blockade (2009)

Our study demonstrates that ultrasound can be utilized to identify the ulnar nerve and artery in the forearm. This implies that traditional landmarks will not be required prior to neural blockade. We have suggested a point for blockade of the nerve to reduce risk of vascular puncture.
STUDIES IN EXPERIMENTAL EXTRACORPOREAL THROMBOSIS (1927)

Thrombus formation has been studied in normal rabbits with an experimental method of establishing extracorporeal circulation. In the normal animal circulation in the extracorporeal loop usually ceases in from 6 to 10 minutes, or at most, in very large and vigorous animals, in 25 minutes.(1) Cessation of the circulation is due most frequently to obstruction of the venous cannula (sometimes of the arterial cannula) by a mass of white thrombi and secondary fibrin formation around it. The site of the clot is determined somewhat by the swiftness of the blood stream. In the collodion tube red mural thrombi are obtainable as a rule. They are flat and present a wide base resting on tiny white thrombi. After the complete obstruction of the circulation, the blood in the apparatus clots very rapidly. When the obstruction occurs very quickly either in the arterial or venous cannula, or when the blood stream is very slow, the clotting in the loop may occur before platelets are laid down in large numbers or before the formation of the white thrombi is evident. Mixed thrombi are found in the jugular vein, and have their inception in the white thrombi, in the cannula or from the injured intima. They extend in the direction of the blood flow.
HDL3-Mediated Inhibition of Thrombin-Induced Platelet Aggregation and Fibrinogen Binding Occurs via Decreased Production of Phosphoinositide-Derived Second Messengers 1,2-Diacylglycerol and Inositol 1,4,5-tris-Phosphate (1998)

We demonstrate that physiological concentrations of HDL3 inhibit the thrombin-induced platelet fibrinogen binding and aggregation in a time- and concentration-dependent fashion. The underlying mechanism includes HDL3-mediated inhibition of phosphatidylinositol 4,5-bis-phosphate turnover, 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate formation, and intracellular calcium mobilization. The inhibitory effects of HDL3 on inositol 1,4,5-tris-phosphate formation and intracellular calcium mobilization were abolished after covalent modification of HDL3 with dimethylsuberimidate. Furthermore, they could be blocked by calphostin C and bis-indolylmaleimide, 2 highly selective and structurally unrelated protein kinase C inhibitors. However, the inhibitory effects of HDL3 were not blocked by H89, a protein kinase A inhibitor. In addition, HDL3 failed to induce cAMP formation but stimulated the phosphorylation of the protein kinase C 40- to 47-kD major protein substrate. We observed a close temporal relationship between the HDL3-mediated inhibition of thrombin-induced inositol 1,4,5-tris-phosphate formation, intracellular calcium mobilization, and fibrinogen binding and the phosphorylation of the protein kinase C 40- to 47-kD major protein substrate. Taken together, these findings indicate that the HDL3-mediated inhibition of thrombin-induced fibrinogen binding and aggregation occurs via inhibition of phosphatidylinositol 4,5-bis-phosphate turnover and formation of 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. Protein kinase C may be involved in this process.
Results of a Phase II Trial Testing Interferon Alpha 2b and Cytarabine in Children with Chronic Myelogenous Leukemia. (2004)

Abstract Before the Imatinib era, a prospective phase II trial was conducted in 2000 to assess the efficacy and the tolerance a combination of interferon alpha 2b (IFN) and cytarabine in children and adolescents with chronic myelogenous leukemia in first chronic phase without a suitable HLA-identical donor. Children received daily IFN (5 million units/m2) and subcutaneous cytarabine (20 mg/m2) for monthly course of 10 days. Between September 2000 and March 2003, 14 children (10 males, 4 females) median age 12 years (range 2–16.5) were recruited from 12 french centres. Patients (pts) were evaluated for time to, rate of hematologic and cytogenetic responses, toxicity and progression free survival. The median duration of follow-up is 13 months (range 2–32 mo). Eight pts achieved a complete hematologic response after a median time of treatment of 3 months (range 0–4 mo) including a pt enrolled in complete hematologic response after 1 month of therapy with hydroxyurea. Three pts were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of complete hematologic response within 3 months of treatment, progression). The best cytogenetic response by 12 months was: major response in 7 pts including complete cytogenetic response in 2 pts, minor response in 3 pts and failure in 1 pt. The median time to major cytogenetic response was 7 months (range 3–12 mo). Thirteen pts discontinued treatment protocol with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (2 pts), loss of hematologic response (2 pts), absence of major cytogenetic response at 12 months (1 pt ), loss of major cytogenetic response (2pts), progression (3 pts), adverse event (1pt), other (2 pts). Probability of progression free survival at 18 months was 66% (95% CI, 34–98%). No treatment-related death occurred. The most frequently reported drug-related events were fever, mucositis, neutropenia and thrombocytopenia. Grade 3 and 4 non hematologic toxicity (fever and mucositis) was observed in 4 pts and grade 3 and 4 hematologic toxicity (anemia, neutropenia and thrombocytopenia) in 7 pts. The median total dose of IFN and cytarabine administered was 3.7 million units/m2 /day (range 2.3–5.1) and 20 mg/m2 /day (range 11–23). The median duration of IFN therapy was 11 months (range1–117 mo). The median number of courses of cytarabine was 7 (range 1–37). The combination of IFN and cytarabine is a well tolerated therapy providing hematologic and cytogenetic responses in children and adolescents with CML. Rates of hematologic and cytogenetic responses compare favourably with results observed in adults. Results should be compared to these of imatinib in children and adolescents.
Glucocorticoid-Induced TNF Receptor Family Related Gene Activation Overcomes Tolerance/Ignorance to Melanoma Differentiation Antigens and Enhances Antitumor Immunity (2006)

Glucocorticoid-induced TNF receptor family related protein (GITR) is present on many different cell types. Previous studies have shown that in vivo administration of an anti-GITR agonist mAb (DTA-1) inhibits regulatory T cells (Treg)-dependent suppression and enhances T cell responses. In this study, we show that administration of DTA-1 induces >85% tumor rejection in mice challenged with B16 melanoma. Rejection requires CD4+, CD8+, and NK1.1+ cells and is dependent on IFN-gamma and Fas ligand and independent of perforin. Depletion of Treg via anti-CD25 treatment does not induce B16 rejection, whereas 100% of the mice depleted of CD25+ cells and treated with DTA-1 reject tumors, indicating a predominant role of GITR on effector T cell costimulation rather than on Treg modulation. T cells isolated from DTA-1-treated mice challenged with B16 are specific against B16 and several melanoma differentiation Ags. These mice develop memory against B16, and a small proportion of them develop mild hypopigmentation. Consistent with previous studies showing that GITR stimulation increases Treg proliferation in vitro, we found in our model that GITR stimulation expanded the absolute number of FoxP3+ cells in vivo. Thus, we conclude that overall, GITR stimulation overcomes self-tolerance/ignorance and enhances T cell-mediated antitumor activity with minimal autoimmunity.