gebhart/patrepeval huggingface dataset:
The Use of Recombinant Factor VIIa in Controlling Surgical Bleeding in Non-Haemophiliac Patients (2002)

Recombinant factor VIIa (rFVIIa, NovoSeven) is effective and appears safe in the management of bleeding episodes and provision of surgical cover in haemophilia patients with inhibitors. Additionally, rFVIIa has been considered as a universal haemostatic agent, prompting its use in the management of severe uncontrolled surgical bleeding in patients without pre-existing coagulopathies. Recombinant FVIIa has been used in 5 patients (aged 2.5 to 73.0 years; median 48 years) with uncontrolled bleeding during or after open-heart surgery. Satisfactory haemostasis was achieved with a single dose or rFVIIa 30 microg/kg, that resulted in reduction of blood loss from a mean of 4,170 ml (650-8,000 ml) to 262.5 ml (220-334 ml). No significant adverse events were reported. Recombinant FVIIa was also successfully used in controlling post-surgical bleeding in two patients with Crohn's disease, one patient with bleeding duodenal ulcer and another with false thoracic aneurysm. It was also effective in controlling bleeding post-splenectomy in a patient with chronic myeloid leukaemia, and following anterior exenteration in a patient with cervical carcinoma. A randomised study comparing the efficacy of a single perioperative dose of rFVIIa with placebo in patients undergoing transabdominal prostatectomy was conducted by Levi and colleagues [6]. An interim analysis showed a significant reduction in mean blood loss from 2,450 +/- 350 ml to 1,400 +/- 190 ml between placebo and rFVIIa groups respectively (p = 0.007). Among trauma patients, Kenet et al. reported success in treating uncontrolled bleeding from a gun-shot wound to the inferior vena cava, using two doses of rFVIIa 60 microg/kg [7]. This treatment has subsequently been used in 6 surgical patients with uncontrolled bleeding and in 7 cases of traumatic bleeding, with remarkable results. In conclusion, rFVIIa appears to be effective and safe in the management of uncontrolled surgical and traumatic haemorrhage in patients not known to have inherited coagulopathy.
Protein Kinase Cθ in T Cell Activation (2002)

The novel protein kinase C (PKC) isoform, PKC theta, is selectively expressed in T lymphocytes and is a sine qua non for T cell antigen receptor (TCR)-triggered activation of mature T cells. Productive engagement of T cells by antigen-presenting cells (APCs) results in recruitment of PKC theta to the T cell-APC contact area--the immunological synapse--where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation and IL-2 production. The transcription factors NF-kappa B and AP-1 are the primary physiological targets of PKC theta, and efficient activation of these transcription factors by PKC theta requires integration of TCR and CD28 costimulatory signals. PKC theta cooperates with the protein Ser/Thr phosphatase, calcineurin, in transducing signals leading to activation of JNK, NFAT, and the IL-2 gene. PKC theta also promotes T cell cycle progression and regulates programmed T cell death. The exact mode of regulation and immediate downstream substrates of PKC theta are still largely unknown. Identification of these molecules and determination of their mode of operation with respect to the function of PKC theta will provide essential information on the mechanism of T cell activation. The selective expression of PKC theta in T cells and its essential role in mature T cell activation establish it as an attractive drug target for immunosuppression in transplantation and autoimmune diseases.
1α, 25‐Dihydroxyvitamin D3 specific regulation of growth, morphology, and fibronectin in a human osteosarcoma cell line (1985)

The ability of the hormonally active vitamin D metabolite, 1 alpha, 25-dihydroxyvitamin D3, to affect cell growth, morphology and fibronectin production has been examined using the MG-63 human osteosarcoma cell line. Hormone treatment reduced cell growth rate, saturation density and [3H]thymidine incorporation. Inhibition was specific for 1 alpha, 25-dihydroxyvitamin D3 relative to other vitamin D metabolites (1 alpha, 25-dihydroxyvitamin D3 greater than 25-dihydroxyvitamin D3 greater than 24R,25-dihydroxyvitamin D3 greater than D3), antagonized by high concentrations of serum and readily reversed by removal of 1 alpha, 25-dihydroxyvitamin D3 from the culture medium. Hormone treatment also increased cell associated alkaline phosphatase activity up to twofold and altered morphology such that treated cells were more spread out on the culture dish and contained more cytoplasmic processes. Significantly, 1 alpha, 25-dihydroxyvitamin D3 increased cellular and medium concentrations of fibronectin, a glycoprotein known to be involved in cellular adhesiveness. MG-63 cells contain a specific 1 alpha, 25-dihydroxyvitamin D3 receptor which may mediate these responses.
Virus Inactivation of Fresh Frozen Plasma by a Solvent Detergent Procedure: Biological Results (1992)

In order to increase the safety of blood products, we have developed a procedure for the virus inactivation of fresh frozen plasma. Several batches have been prepared and with the first 10 batches, each of them composed of 60 litres of plasma, we have determined a set of biological parameters. Virus inactivation was realised using TnBP (1%) and Octoxynol 9 (1%). After their elimination with castor oil using chromatography on insolubilized C18 resin, glycine was added and the pH of the plasma was adjusted to 7.4. Plastic bags were aseptically filled with a mean volume of 200 ml of plasma. The mean levels of coagulation factors were all over 0.7 U/ml and their recovery from initial plasma was nearly the same as total protein except for factor VIII:C. The net loss in factor VIII:C was 16%, when including the dilution of plasma. In vivo and in vitro tests demonstrated that in the final product there were no activated factors. As in fresh frozen plasma, the protein concentration was over 50 g/l and the potassium level lower than 5 mmol/l. According to these results, virus- inactivated plasma has the same qualities of fresh frozen plasma and could now replace it.
Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies (2015)

Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA.
PB1 as a potential target for increasing the breadth of T-cell mediated immunity to Influenza A (2016)

Recently, we showed that combined intranasal and subcutaneous immunization with a non-replicating adenoviral vector expressing NP of influenza A, strain PR8, induced long-standing protection against a range of influenza A viruses. However, H-2<sup>b</sup> mice challenged with an influenza A strain mutated in the dominant NP<sub>366</sub> epitope were not efficiently protected. To address this problem, we envision the use of a cocktail of adenovectors targeting different internal proteins of influenza A virus. Consequently, we investigated the possibility of using PB1 as a target for an adenovector-based vaccine against influenza A. Our results showed that PB1 is not as immunogenic as the NP protein. However, by tethering PB1 to the murine invariant chain we were able to circumvent this problem and raise quite high numbers of PB1-specific CD8<sup>+</sup> T cells in the circulation. Nevertheless, mice immunized against PB1 were not as efficiently protected against influenza A challenge as similarly NP-vaccinated animals. The reason for this is not a difference in the quality of the primed cells, nor in functional avidity. However, under similar conditions of immunization fewer PB1-specific cells were recruited to the airways, and surface expression of the dominant PB1 peptide, PB1<sub>703</sub>, was less stable than in the case of NP<sub>366</sub>.
Cross-talk unfolded: MARCKS proteins (2002)

The proteins of the MARCKS (myristoylated alanine-rich C kinase substrate) family were first identified as prominent substrates of protein kinase C (PKC). Since then, these proteins have been implicated in the regulation of brain development and postnatal survival, cellular migration and adhesion, as well as endo-, exo- and phago-cytosis, and neurosecretion. The effector domain of MARCKS proteins is phosphorylated by PKC, binds to calmodulin and contributes to membrane binding. This multitude of mutually exclusive interactions allows cross-talk between the signal transduction pathways involving PKC and calmodulin. This review focuses on recent, mostly biophysical and biochemical results renewing interest in this protein family. MARCKS membrane binding is now understood at the molecular level. From a structural point of view, there is a consensus emerging that MARCKS proteins are ‘natively unfolded'. Interestingly, domains similar to the effector domain have been discovered in other proteins. Furthermore, since the effector domain enhances the polymerization of actin in vitro, MARCKS proteins have been proposed to mediate regulation of the actin cytoskeleton. However, the recent observations that MARCKS might serve to sequester phosphatidylinositol 4,5-bisphosphate in the plasma membrane of unstimulated cells suggest an alternative model for the control of the actin cytoskeleton. While myristoylation is classically considered to be a co-translational, irreversible event, new reports on MARCKS proteins suggest a more dynamic picture of this protein modification. Finally, studies with mice lacking MARCKS proteins have investigated the functions of these proteins during embryonic development in the intact organism.
A phase I/IIA pharmacokinetic (PK) and serial skin and tumor pharmacodynamic (PD) study of the EGFR irreversible tyrosine kinase inhibitor EKB-569 in combination with 5-fluorouracil (5FU), leucovorin (LV) and irinotecan (CPT-11) (FOLFIRI regimen) in patients (pts) with advanced colorectal cancer (ACC) (2004)

3543 Background: In preclinical models, EKB-569 has shown growth inhibition of EGFR-expressing colorectal tumor cell lines with at least additive inhibition when combined with chemotherapy. Methods: We have conducted a phase I/IIA study with EKB-569 used in combination with the FOLFIRI regimen as first-line treatment in pts with ACC. The objectives were to determine its safety, MTD, PK profile, antitumor activity and correlation with EGFR-signalling pathways in skin and tumors before and after treatment. Oral EKB-569 was given daily starting on day 3 of cycle 1 (28 days per cycle) with IV infusion of FOLFIRI on days 1–2 and 15–16 (CPT-11 180 mg/m2 90 min, simultaneously with LV 400 mg/m2 120 min, followed by 5FU 400 mg/m2 bolus and 2400 mg/m2 46-h continuous infusion). Pts were enrolled to receive 10, 25, 50 or 75 mg EKB-569 (3–6 pts per cohort). Dose escalation was based on safety evaluation of pt cohorts within the first 28 days. After the initial escalation, 2 cohorts were added: 35 mg EKB-569, FOLFIRI and 50 mg EKB-569, modified FOLFIRI (5FU 300 mg/m2 bolus and 2000 mg/m2 46-h continuous infusion). Results: 47 pts were included, median age 62 yrs (range 19–77) and ECOG PS 0 in 64% and 1 in 33%. DLTs were grade 3 diarrhea (2 pts in the 75-mg cohort and 2 in the 50-mg/modified FOLFIRI cohort) and grade 3 fatigue (1 in the 50-mg cohort and 1 in the 50-mg/modified FOLFIRI cohort). Limiting grade 2 diarrhea was observed in the 50-mg cohort. Thus, the MTD was selected as 25-mg EKB-569. Of 39 pts evaluable so far, the response rate is 38% and the clinical benefit rate is 85%. EKB-569 treatment resulted in complete inhibition of pEGFR and significant inhibition of pMAPK in both skin samples (11 pts) and tumor samples (3 pts) with no change in pAKT activity. Conclusions: EKB-569 combined with FOLFIRI was generally well-tolerated and showed encouraging evidence of antitumor activity and inhibition of the EGFR pathway. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth; Wyeth Research Wyeth Research
Inferring Genetic Networks and Identifying Compound Mode of Action via Expression Profiling (2003)

The complexity of cellular gene, protein, and metabolite networks can hinder attempts to elucidate their structure and function. To address this problem, we used systematic transcriptional perturbations to construct a first-order model of regulatory interactions in a nine-gene subnetwork of the SOS pathway in Escherichia coli. The model correctly identified the major regulatory genes and the transcriptional targets of mitomycin C activity in the subnetwork. This approach, which is experimentally and computationally scalable, provides a framework for elucidating the functional properties of genetic networks and identifying molecular targets of pharmacological compounds.
Retrograde transport of mutant ricin to the endoplasmic reticulum with subsequent translocation to cytosol (1997)

Translocation of ricin A chain to the cytosol has been proposed to take place from the endoplasmic reticulum (ER), but attempts to visualize ricin in this organelle have failed. Here we modified ricin A chain to contain a tyrosine sulfation site alone or in combination with N-glycosylation sites. When reconstituted with ricin B chain and incubated with cells in the presence of Na(2)(35)SO(4), the modified A chains were labeled. The labeling was prevented by brefeldin A and ilimaquinone, and it appears to take place in the Golgi apparatus. This method allows selective labeling of ricin molecules that have already been transported retrograde to this organelle. A chain containing C-terminal N-glycosylation sites became core glycosylated, indicating retrograde transport to the ER. In part of the toxin molecules, the A chain was released from the B chain and translocated to the cytosol. The finding that glycosylated A chain was present in the cytosol indicates that translocation takes place after transport of the toxin to the ER.
Induction of Apoptosis by the Low-Affinity NGF Receptor (1993)

Nerve growth factor (NGF) binding to cellular receptors is required for the survival of some neural cells. In contrast to TrkA, the high-affinity NGF receptor that transduces NGF signals for survival and differentiation, the function of the low-affinity NGF receptor, p75NGFR, remains uncertain. Expression of p75NGFR induced neural cell death constitutively when p75NGFR was unbound; binding by NGF or monoclonal antibody, however, inhibited cell death induced by p75NGFR. Thus, expression of p75NGFR may explain the dependence of some neural cells on NGF for survival. These findings also suggest that p75NGFR has some functional similarities to other members of a superfamily of receptors that include tumor necrosis factor receptors, Fas (Apo-1), and CD40.
Modular robots (2002)

Modular reconfigurable robots-experimental systems made by interconnecting multiple, simple, similar units-can perform shape shifting. A robot made up of a chain of simple hinge joints could shape itself into a loop and move by rolling like a self-propelled tank tread; then break open the loop to form a serpentine configuration and slither under or over obstacles; and then rearrange its modules to "morph" into a multilegged spider, able to stride over rocks and bumpy terrain. This robot, dubbed PolyBot, is being built and experimented with at Xerox Palo Alto Research Center (PARC), in California. This paper describes the main features of PolyBot and how it works. Programming of PolyBot is also discussed.
Pulse generation in a cw dye laser by mode−locked synchronous pumping (1975)

A continuous train of &amp;lt;500 ps (detector limited) pulses has been produced with a cw dye laser pumped by a mode−locked argon ion laser. The cavity lengths of the dye laser and argon laser were made equal in order to synchronously amplify a single pulse oscillating in the dye laser. An intracavity acousto−optic modulator was used to dump dye laser pulses at rates as high as 10 MHz.
High Plasma Levels of Endothelin-1 and Atrial Natriuretic Peptide in Patients With Acute Ischemic Stroke (1994)

The plasma levels of endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) have been measured in 37 patients with acute ischemic stroke, on admission and 3 and 7 days thereafter. The plasma ET-1 levels at the onset of symptoms were about two-fold those observed in age-matched normal volunteers (3.5 +/- 2.26 v 1.54 +/- 0.9 pg/mL, respectively; P < .001). These levels remained significantly elevated during the 7-day study period. The neurologic deficit was assessed daily by Mathew's modified scale (MS). A significant correlation was found between neurologic status on admission and ET-1 plasma values; patients with worse neurologic status (MS < 45 points) had higher ET-1 plasma values than those with better neurologic status (MS > 45 points) (5.4 +/- 2.34 v 3.05 +/- 2.04 pg/mL, respectively, P < .05). The plasma ET-1 values did not correlate either with the site of the infarction or with its primary cause (cardioembolic, lacunar, or atherothrombotic). No significant differences were seen in plasma ET-1 concentrations between patients who eventually died and those who survived the acute event. The plasma ANP were about 18-fold higher in ischemic stroke patients on admission than in controls at admission (110.9 +/- 29.5 v 5.84 +/- 3.96 pg/mL, respectively, P < .01). These values remained significantly elevated on days 3 and 7. There was no correlation between the ANP plasma values and the neurologic status, the site or mechanism of the stroke, or the plasma ET-1 levels. In conclusion, ischemic stroke is associated with marked acute and long-duration increases of ET-1 and ANP.(ABSTRACT TRUNCATED AT 250 WORDS)
Suppressors of trp1 Fluorescence Identify a New Arabidopsis Gene, TRP4, Encoding the Anthranilate Synthase b Subunit (1993)

Krishna K. Niyogi, Robert L. Last, Gerald R. Fink, Brian Keith, Suppressors of trp1 Fluorescence Identify a New Arabidopsis Gene, TRP4, Encoding the Anthranilate Synthase β Subunit, The Plant Cell, Vol. 5, No. 9 (Sep., 1993), pp. 1011-1027
Exogenous and endogenous IL-10 regulate IFN-alpha production by peripheral blood mononuclear cells in response to viral stimulation. (1998)

IL-10 is an important regulator of the production of proinflammatory cytokines. Its effect on IFN-alpha production, however, has not been reported. In this study, PBMC from healthy donors were stimulated with virus in the presence of IL-10. Human IL-10 (hIL-10) caused reductions in both the frequency of IFN-alpha-producing cells (IPC) and bulk IFN in response to herpes simplex virus type-1 (HSV-1), Sendai virus, Newcastle disease virus, and vesicular stomatitis virus. The inhibitory effect occurred when IL-10 was added 2 or 4 h before, or 2 h poststimulation with HSV or Sendai virus, but not when added 4 h postinduction. Unlike IL-10, IL-4 did not affect the IFN-alpha response to HSV. However, when PBMC were induced with Sendai virus, IFN-alpha production was also reduced by IL-4. IL-10 treatment of PBMC resulted in strong reductions in the steady state levels of both HSV- and Sendai virus-induced IFN-alpha1, -alpha2, and -beta mRNA as determined by RT-PCR. IFN-alpha production to Sendai virus occurs predominantly by monocytes, whereas most enveloped viruses stimulate low frequency "natural IFN-producing cells (NIPC)," which are thought to be dendritic cells. Peripheral blood dendritic cells were found to express the IL-10 receptor, suggesting that IL-10 may directly act on the dendritic IPC. Addition of monoclonal anti-IL-10 to PBMC resulted in a significant increase in both the frequency of IPC and the amount of secreted IFN-alpha in response to HSV but not Sendai virus. We conclude that human IL-10 can serve as both an endogenous and exogenous regulator of IFN-alpha production.
Structural analysis of the core COMPASS family of histone H3K4 methylases from yeast to human (2011)

Histone H3 lysine 4 (H3K4) methylation is catalyzed by the highly evolutionarily conserved multiprotein complex known as Set1/COMPASS or MLL/COMPASS-like complexes from yeast to human, respectively. Here we have reconstituted fully functional yeast Set1/COMPASS and human MLL/COMPASS-like complex in vitro and have identified the minimum subunit composition required for histone H3K4 methylation. These subunits include the methyltransferase C-terminal SET domain of Set1/MLL, Cps60/Ash2L, Cps50/RbBP5, Cps30/WDR5, and Cps25/Dpy30, which are all common components of the COMPASS family from yeast to human. Three-dimensional (3D) cryo-EM reconstructions of the core yeast complex, combined with immunolabeling and two-dimensional (2D) EM analysis of the individual subcomplexes reveal a Y-shaped architecture with Cps50 and Cps30 localizing on the top two adjacent lobes and Cps60-Cps25 forming the base at the bottom. EM analysis of the human complex reveals a striking similarity to its yeast counterpart, suggesting a common subunit organization. The SET domain of Set1 is located at the juncture of Cps50, Cps30, and the Cps60-Cps25 module, lining the walls of a central channel that may act as the platform for catalysis and regulative processing of various degrees of H3K4 methylation. This structural arrangement suggested that COMPASS family members function as exo-methylases, which we have confirmed by in vitro and in vivo studies.
Automated Fabrication of 2‐nm Solid‐State Nanopores for Nucleic Acid Analysis (2014)

We demonstrate the automated and reproducible fabrication of sub-2-nm nanopores in 10-nm thick silicon nitride membranes, through controlled dielectric breakdown in solution. Our results reveal that under the appropriate conditions, nanopores can be fabricated with a size no larger than 2.0 ± 0.5-nm in diameter for a sample of N = 23 nanopores, with an average and standard deviation of 1.3 ± 0.6-nm. The dimensions of these nanopores are confirmed by using individual translocating DNA molecules as molecular rulers. We show that a 2.0-nm and a 2.1-nm diameter nanopore are capable of distinguishing single-stranded DNA versus double-stranded DNA, and that a 2.4-nm diameter nanopore can be used to investigate the overstretching transition in short dsDNA fragments. These results highlight the reliability and precision of the automated fabrication of nanopores via controlled dielectric breakdown, showing great promise for the manufacturing of future nanopore-based technologies.
Neutralizing antibody to TGFβ modulates stromalfibrosis but not regression of photoablative effect following PRK (1998)

This study confirms our earlier observations that increased corneal light reflectivity following PRK is predominantly due to: (1) distortion of the photoablated stromal surface leading to prominent reflections; and (2) increased reflections from activated and transformed keratocytes. Anti-TGFbeta reduced keratocyte activation and transformation and inhibited stromal fibrosis, leading to a reduction in early light reflectivity as well as to a more rapid decline. Of greatest interest is the unexpected finding that anti-TGFbeta treatment inhibited stromal fibrosis without reducing or delaying post-PRK stromal re-thickening. Based on these findings we propose that corneal thickness may be tightly and dynamically regulated by an unknown, non-TGFbeta mediated pathway. We propose that anti-TGFbeta treatment may be useful in reducing post-PRK corneal haze development in patients by: (1) inhibiting the recruitment of highly reflective, activated keratocytes, (2) inhibiting myofibroblast transformation, and 3) reducing stromal fibrosis.