gebhart/patrepeval huggingface dataset:
CAD, a c-Myc target gene, is not deregulated in Burkitt's lymphoma cell lines (2000)

Although the Myc family of transcription factors is upregulated in many human tumors, it is unclear which genes are targets for the deregulated Myc. Previous studies suggest that hamster and rat carbamoyl phosphate synthase, aspartate transcarbamylase, dihydroorotase Cad genes are regulated by c-Myc. In fact, of all putative target genes thought to be activated by c-Myc, only the Cad gene showed loss of growth regulation in rat cells nullizygous for c-Myc. However, it was unknown whether upregulation of CAD, which performs the first three rate-limiting steps of pyrimidine biosynthesis, contributes to c-Myc's role in human neoplasia. To explore this possibility, we cloned the human cad promoter. We found that c-Myc could bind to an E box in the human cad promoter in gel shift assays and that growth regulated transcription from the human cad promoter was dependent on this c-Myc binding site. However, the increased amount of c-Myc found in Burkitt's lymphoma cell lines did not lead to increased cad mRNA levels. Thus, we suggest that although c-Myc is clearly important for the normal transcriptional control of the cad promoter, it is unlikely that increased levels of CAD are important mediators of c-Myc-induced neoplasia. Therefore, an understanding of the mechanism by which overexpressed c-Myc contributes to the development of Burkitt's lymphoma requires the identification of additional c-Myc target genes.
Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. (1995)

Fibroblast growth factor 4 (FGF-4) has been shown to be a signaling molecule whose expression is essential for postimplantation mouse development and, at later embryonic stages, for limb patterning and growth. The FGF-4 gene is expressed in the blastocyst inner cell mass and later in distinct embryonic tissues but is transcriptionally silent in the adult. In tissue culture FGF-4 expression is restricted to undifferentiated embryonic stem (ES) cells and embryonal carcinoma (EC) cell lines. Previously, we determined that EC cell-specific transcriptional activation of the FGF-4 gene depends on a synergistic interaction between octamer-binding proteins and an EC-specific factor, Fx, that bind adjacent sites on the FGF-4 enhancer. Through the cloning and characterization of an F9 cell cDNA we now show that the latter activity is Sox2, a member of the Sry-related Sox factors family. Sox2 can form a ternary complex with either the ubiquitous Oct-1 or the embryonic-specific Oct-3 protein on FGF-4 enhancer DNA sequences. However, only the Sox2/Oct-3 complex is able to promote transcriptional activation. These findings identify FGF-4 as the first known embryonic target gene for Oct-3 and for any of the Sox factors, and offer insights into the mechanisms of selective gene activation by Sox and octamer-binding proteins during embryogenesis.
CEMENTED CARBIDES WITH HIGH-MELTING-POINT PRECIOUS-METAL BINDER PHASES (1974)

A study has been made of alloy systems consisting of TiC and WC in combination with ruthenium and ruthenium-palladium alloys. Particular attention was paid to alloys with high carbide contents, which have a potential application as cutting-tool materials. The alloys were successfully prepared using conventional powder-metallurgical techniques. Alloys based on the TiC-Ru system were particularly promising in preliminary machining tests. In this system, it was found that small amounts of the metals nickel, cobalt, or iron, which are normally picked up during milling, are necessary for the full densification of the alloys at convenient sintering temperatures (i.e. ∼ 1500°C). A more detailed study of TiC-(Ru,Ni) alloys showed that the small amount of nickel required for effective sintering does not seriously affect the properties of the alloy and that, with this quantity of nickel, the melting point of the binder phase is still significantly higher than that of conventional cemented carbides.
Acute congestive heart failure (1997)

Immediate management of congestive heart failure (CHF) is directed at reduction of preload and afterload and augmentation of forward blood flow and cardiac output. A variety of pharmacologic agents (e.g., diuretics, positive inotropic agents, vasodilators, vasopressors) are available for use in the intensive care unit. For patients in cardiogenic shock after acute myocardial infarction, pharmacologic measures coupled with direct reperfusion therapy using percutaneous revascularization can be lifesaving. Unfortunately, many survivors of acute CHF require longterm therapy. Current drug therapy cannot cure CHF, but a search for useful and safe oral positive inotropic agents continues, with the hope of improving both the quantity and quality of patients' lives. Heart transplantation is an alternative for some patients with severe ventricular dysfunction.
Product Bound Structures of the Soluble Methane Monooxygenase Hydroxylase from Methylococcus capsulatus (Bath):  Protein Motion in the α-Subunit (2005)

The soluble methane monooxygenase hydroxylase (MMOH) alpha-subunit contains a series of cavities that delineate the route of substrate entrance to and product egress from the buried carboxylate-bridged diiron center. The presence of discrete cavities is a major structural difference between MMOH, which can hydroxylate methane, and toluene/o-xylene monooxygenase hydroxylase (ToMOH), which cannot. To understand better the functions of the cavities and to investigate how an enzyme designed for methane hydroxylation can also accommodate larger substrates such as octane, methylcubane, and trans-1-methyl-2-phenylcyclopropane, MMOH crystals were soaked with an assortment of different alcohols and their X-ray structures were solved to 1.8-2.4 A resolution. The product analogues localize to cavities 1-3 and delineate a path of product exit and/or substrate entrance from the active site to the surface of the protein. The binding of the alcohols to a position bridging the two iron atoms in cavity 1 extends and validates previous crystallographic, spectroscopic, and computational work indicating this site to be where substrates are hydroxylated and products form. The presence of these alcohols induces perturbations in the amino acid side-chain gates linking pairs of cavities, allowing for the formation of a channel similar to one observed in ToMOH. Upon binding of 6-bromohexan-1-ol, the pi helix formed by residues 202-211 in helix E of the alpha-subunit is extended through residue 216, changing the orientations of several amino acid residues in the active site cavity. This remarkable secondary structure rearrangement in the four-helix bundle has several mechanistic implications for substrate accommodation and the function of the effector protein, MMOB.
A phase I study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus platinum-based doublet chemotherapy (PT-doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts). (2013)

8072 Background: A phase I study ofnivolumab (a PD-1 receptor blocking Ab) demonstrated durable responses and a tolerable safety profile in NSCLC pts who failed ≥1 chemotherapy regimen. We report an interim analysis of a phase I study with nivolumab + PT-doublets in chemotherapy-naive advanced NSCLC pts. Methods: Stage IIIB/IV NSCLC pts were randomized by histology ≥9 wk prior to data lock (Dec 2012) to: A) nivolumab/gemcitabine/cisplatin; B) nivolumab/pemetrexed/cisplatin; or C) nivolumab/carboplatin/paclitaxel according to a phase I dose de-escalation design to assess the toxicities and incidence of DLTs in the first 6 wk of dosing. Nivolumab doses were started at 10 mg/kg IV Q3W and given until progression. PT-doublet was given for 4 cycles at standard dosing. At a tolerable dose, cohorts were expanded up to 20 pts. Results: 43 pts were treated with nivolumab + PT-doublet: Arm A, n=12 squamous (sq); Arm B, n=15 (non-sq); and Arm C, n=16 (3 sq + 13 non-sq). No DLTs were seen across arms. Gr 3-4 regimen-related AEs were 49% across arms, and 25%, 47%, and 69% for Arms A, B, and C, respectively. Select Gr 3-4 toxicities reported included: pneumonitis, rash, nephritis, and colitis (Table). 3 pts had Gr 3 pneumonitis and were addressed with management algorithms (dose discontinuation and immune-modulating therapies). 2 pts fully resolved, however 1 resolved pt subsequently died from Aspergillus pneumonia. 1 pt died of disease progression with unresolved pneumonitis (autopsy confirmed). Total/Confirmed ORRs (RECIST 1.1) were 43/33%, 40/33%, and 31/31% in Arms A, B, and C, respectively. Conclusions: No DLTs were seen with 10 mg/kg nivolumab combined with PT-doublets; maintenance treatment is ongoing. Similar to monotherapy, select nivolumab related toxicities can be addressed with management algorithms. Safety, durability, and confirmation of responses will be updated based on a 2013 data analysis, including a 5 mg/kg nivolumab dose cohort. Clinical trial information: NCT01454102. [Table: see text]
Combining text and heuristics for cost-sensitive spam filtering (2000)

Spam filtering is a text categorization task that shows especial features that make it interesting and difficult. First, the task has been performed traditionally using heuristics from the domain. Second, a cost model is required to avoid misclassification of legitimate messages. We present a comparative evaluation of several machine learning algorithms applied to spam filtering, considering the text of the messages and a set of heuristics for the task. Cost-oriented biasing and evaluation is performed.
Expression of a globulin-like protein gene, Gea8, in somatic and zygotic embryos (1999)

A carrot gene, Gea8 (Globular embryo abundant), has been identified that encodes a novel seed protein that is abundantly expressed in embryos from the globular to the cotyledon stages and in endosperm of maturation-stage seeds. Analysis of the Gea8 gene revealed that it encodes a protein with approximately 47% sequence similarity (25% sequence identity) to both dicot and monocot globulins, a class of seed storage proteins. However, the Gea8 promoter region lacks some of the key regulatory elements characteristic of other known globulins, especially the ‘G box’ sequence. Analysis of Gea8 mRNA accumulation during both somatic and zygotic embryogenesis showed that mRNA for this gene accumulates by the globular stage of embryogenesis and reaches a high abundance by the heart stage that is sustained throughout embryo development. Expression is also high in the developing endosperm of seeds of both carrot and Arabidopsis. In addition, analysis of the developmental and spatial expression of the Gea8 gene, using several Gea8 promoter/GUS fusion constructs, suggests that the promoter contains at least two separable regions directing the spatial accumulation of Gea8 mRNA in the heart and torpedo stages of embryogenesis. These studies suggest that Gea8 is a new form of seed protein that is expressed early in embryo development, initially in an embryo-specific pattern, and subsequently in both the embryo and the endosperm through regulation by a complex promoter.
Pyridostigmine partially reverses dexamethasone-induced inhibition of the growth hormone response to growth hormone-releasing hormone (1992)

The GH response to insulin-induced hypoglycaemia and growth hormone-releasing hormone (GHRH) has been shown to be impaired in subjects with Cushing's syndrome and in healthy volunteers given oral glucocorticoids. Pyridostigmine is an anticholinesterase that stimulates GH secretion, probably by inhibition of hypothalamic somatostatin secretion. This work was designed to study the site of action of glucocorticoids in inhibiting the secretion of GH. Eight healthy male volunteers were studied on three occasions in random order. They took 2 mg oral dexamethasone or placebo at precisely 6-hourly intervals for 48 h before receiving 120 mg oral pyridostigmine or placebo, followed 60 min later by GHRH (100 micrograms) i.v. Samples for measuring GH were obtained at 15 min intervals for 2 h. The 'area under the curve' (AUC) for each of the treatments was significantly different: dexamethasone-pyridostigmine-GHRH (mean +/- S.E.M., 1938 +/- 631 mU/min per l), dexamethasone-placebo-GHRH (634 +/- 211) and placebo-placebo-GHRH (4267 +/- 1183) (P < 0.02, Wilcoxon test). In conclusion, dexamethasone given for 48 h significantly inhibited the AUC for GH following treatment with GHRH. However, pretreatment with pyridostigmine significantly reversed the inhibition although this was still partial. Our data suggested that this short-term suppressive effect of dexamethasone was independent of GHRH, and most probably relates to stimulation of the release of somatostatin.
Focused ion beam microsurgery for electronics (1986)

Methods of making and breaking connections on an Al conductor test pattern using a focused ion beam (FIB) are demonstrated. Submicrometer dimension connections between crossing conductors separated by oxide were fabricated in 7 s. Resistances of the connections were measured to be 3 Ω and were tested up to 50 mA. Milled cuts in 0.65- µm-thick 10-µm-wide conductors produced open-circuit resistances > 20 MΩ in 300 s. The combined imaging, restructuring, and verification capability of FIB microsurgery is shown.
Spastizität messen (2009)

Die Behandlung von Patienten mit einer Spastikgleicht häufig der alten Redensart „Zwei Schritte vor und einer zurück“. Diese Ver änderungen gilt es zu dokumentieren. Werden unterstützend zur Physiotherapie Medikamente eingesetzt, ist es umso wichtiger, zu messen, ob diese wirken unddem Patienten Erleichterung bringen. Die Tardieu-Skala ist eine anerkannte Methode, um die Entwicklung oder Veränderung der Spastik zu dokumentieren.
Hydrogen generation using water-insoluble polymer-bound ruthenium(ii) complexes (1997)

Water-insoluble free-standing films of partially quaternized poly(1-vinylimidazole)-bound ruthenium(II) complexes are prepared, and photoinduced hydrogen generation is observed with light irradiation (λ > 440 nm) of aqueous solutions containing the polymer-bound ruthenium(II) complex film, methyl viologen, triethanolamine and bis(2,2′-bipyridine)platinum(II).
Extracellular calcium sensed by a novel cation channel in hippocampal neurons (1997)

Extracellular concentrations of Ca2+ change rapidly and transiently in the brain during excitatory synaptic activity. To test whether such changes in Ca2+ can play a signaling role we examined the effects of rapidly lowering Ca2+ on the excitability of acutely isolated CA1 and cultured hippocampal neurons. Reducing Ca2+ excited and depolarized neurons by activating a previously undescribed nonselective cation channel. This channel had a single-channel conductance of 36 pS, and its frequency of opening was inversely proportional to the concentration of Ca2+. The inhibition of gating of this channel was sensitive to ionic strength but independent of membrane potential. The ability of this channel to sense Ca2+ provides a novel mechanism whereby neurons can respond to alterations in the extracellular concentration of this key signaling ion.
Denervated Schwann Cells Attract Macrophages by Secretion of Leukemia Inhibitory Factor (LIF) and Monocyte Chemoattractant Protein-1 in a Process Regulated by Interleukin-6 and LIF (2002)

Injury to peripheral nerves results in the infiltration of immune cells, which remove axonal- and myelin-derived material. Schwann cells could play a key role in this process by regulating macrophage infiltration. We show here that medium conditioned by primary denervated Schwann cells or the Schwannoma cell line RN22 produces chemotactic activity for macrophages. The presence of blocking antibodies to macrophage chemoattractant protein-1 (MCP-1) or leukemia inhibitory factor (LIF) reduced this activity to approximately 35 and 65% of control levels, respectively, and only 15% remained in the presence of both antibodies. The presence of chemotactic LIF in Schwann cell-conditioned medium was confirmed by using cells from lif-/- mice. Although interleukin-6 (IL-6) is not itself a chemotactic factor, we found that medium from il-6-/- nerves showed only 40% of the activity secreted by wild-type nerves. Furthermore, IL-6 rapidly induced LIF mRNA in primary Schwann cells, and LIF rapidly induced MCP-1 mRNA expression. Treatment of RN22 Schwannoma cells with IL-6 or LIF enhanced the secretion of the chemotactic activity of these cells. These observations show that Schwann cells attract macrophages by secreting MCP-1 and LIF. They also provide evidence for an autocrine-signaling cascade involving IL-6, LIF, and MCP-1, which amplifies the Schwann cell-derived chemotactic signals gradually, in agreement with the delayed entry of macrophages to injured nerves.
A new method for long-term monitoring of the ballistocardiogram, heart rate, and respiration (1981)

The principle of the static charge-sensitive-bed (SCSB) method is described. The method is simple and inexpensive. From the SCSB recording the ballistocardiogram (BCG) and respiratory movement can be simultaneously recorded by selective filtering of the original signal. The SCSB recording thus enables continuous long-term monitoring of the BCG, heart rate, respiratory rate, respiratory amplitude, and body movements. There are no electrodes or cables connected to the subject. The SCSB-BCG signal was studied by comparing the SCSB method with the conventional ultralow-frequency (ULF) acceleration BCG. The wave forms at rest and the amplitude responses to physical exercise were studied by both methods. Multiple recordings of the BCG, heart rate, respiratory movement, respiratory rate, and body movements after exercise and during sleep using the SCSB method are presented. The SCSB method opens new approaches to long-term studies of the regulation of myocardial performance, heart rate, and respiration. Applications of the SCSB method for clinical sleep studies, patient monitoring and cardiovascular screening examinations are discussed.
Randomized, double‐blind, placebo‐controlled trial of the once‐daily GLP ‐1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea ( GetGoal ‐L‐Asia) (2012)

In an Asian type 2 diabetes population insufficiently controlled by basal insulin ± sulfonylurea, once-daily lixisenatide significantly improved glycaemic control, with a pronounced postprandial effect, and was well tolerated.
Characterization of a gene cluster encoding the maleylacetate reductase from Ralstonia eutropha 335T, an enzyme recruited for growth with 4-fluorobenzoate (2004)

A gene cluster containing a gene for maleylacetate reductase (EC 1.3.1.32) was cloned from Ralstonia eutropha 335(T) (DSM 531(T)), which is able to utilize 4-fluorobenzoate as sole carbon source. Sequencing of this gene cluster showed that the R. eutropha 335(T) maleylacetate reductase gene, macA, is part of a novel gene cluster, which is not related to the known maleylacetate-reductase-encoding gene clusters. It otherwise comprises a gene for a hypothetical membrane transport protein, macB, possibly co-transcribed with macA, and a presumed regulatory gene, macR, which is divergently transcribed from macBA. MacA was found to be most closely related to TftE, the maleylacetate reductase from Burkholderia cepacia AC1100 (62 % identical positions) and to a presumed maleylacetate reductase from a dinitrotoluene catabolic gene cluster from B. cepacia R34 (61 % identical positions). By expressing macA in Escherichia coli, it was confirmed that macA encodes a functional maleylacetate reductase. Purification of maleylacetate reductase from 4-fluorobenzoate-grown R. eutropha 335(T) cells allowed determination of the N-terminal sequence of the purified protein, which was shown to be identical to that predicted from the cloned macA gene, thus proving that the gene is, in fact, recruited for growth of R. eutropha 335(T) with this substrate.
Lactoferrin and host defense (2002)

Lactoferrin is a multifunctional member of the transferrin family of nonheme iron-binding glycoproteins. Lactoferrin is found at the mucosal surface where it functions as a prominent component of the first line of host defense against infection and inflammation. The protein is also an abundant component of the specific granules of neutrophils and can be released into the serum upon neutrophil degranulation. While the iron-binding properties were originally believed to be solely responsible for the host defense properties ascribed to lactoferrin, it is now known that other mechanisms contribute to the broad spectrum anti-infective and anti-inflammatory roles of this protein. In this article, current information on the functions and mechanism of action of lactoferrin are reviewed, with particular emphasis on the activities that contribute to this protein's role in host defense. In addition, studies demonstrating that lactoferrin inhibits allergen-induced skin inflammation in both mice and humans, most likely secondary to TNF-alpha (tumor necrosis factor alpha) production, are summarized. Collectively, these results suggest that lactoferrin functions as a key component of mammalian host defense at the mucosal surface.
Site-specific antibody drug conjugates for cancer therapy (2013)

Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as guided missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs). The success of ADCs is dependent on four factors--target antigen, antibody, linker, and payload. The field has made great progress in these areas, marked by the recent approval by the US Food and Drug Administration of two ADCs, brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla). However, the therapeutic window for many ADCs that are currently in pre-clinical or clinical development remains narrow and further improvements may be required to enhance the therapeutic potential of these ADCs. Production of ADCs is an area where improvement is needed because current methods yield heterogeneous mixtures that may include 0-8 drug species per antibody molecule. Site-specific conjugation has been recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Here, we review and describe various site-specific conjugation strategies that are currently used for the production of ADCs, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases. In addition, we also summarize differences among these methods and highlight critical considerations when building next-generation ADC therapeutics.