gebhart/patrepeval huggingface dataset:
CrkRS (2001)

We have isolated and characterised a novel human protein kinase, Cdc2-related kinase with an arginine/serine-rich (RS) domain (CrkRS), that is most closely related to the cyclin-dependent kinase (CDK) family. CrkRS is a 1490 amino acid protein, the largest CDK-related kinase so far isolated. The protein kinase domain of CrkRS is 89% identical to the 46 kDa CHED protein kinase, but outside the kinase domains the two proteins are completely unrelated. CrkRS has extensive proline-rich regions that match the consensus for SH3 and WW domain binding sites, and an RS domain that is predominantly found in splicing factors. CrkRS is ubiquitously expressed in tissues, and maps to a single genetic locus. There are closely related protein kinases in both the Drosophila and Caenorhabditis elegans genomes. Consistent with the presence of an RS domain, anti-CrkRS antibodies stain nuclei in a speckled pattern, overlapping with spliceosome components and the hyperphosphorylated form of RNA polymerase II. Like RNA polymerase II, CrkRS is a constitutive MPM-2 antigen throughout the cell cycle. Anti-CrkRS immunoprecipitates phosphorylate the C-terminal domain of RNA polymerase II in vitro. Thus CrkRS may be a novel, conserved link between the transcription and splicing machinery.
Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin's lymphoma: combined data from 4 clinical trials. (2003)

Relapsed or refractory NHL in patients with adequate bone marrow reserve and <25% bone marrow involvement by NHL can be treated safely with (90)Y-ibritumomab tiuxetan RIT on the basis of a fixed, weight-adjusted dosing schedule. Dosimetry and pharmacokinetic results do not correlate with toxicity.
Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review). (2000)

Amyotrophic lateral sclerosis (ALS), also referred to as motor neurone disease, is a fatal neurological disease that is characterized clinically by progressive muscle weakness, muscle atrophy, and eventual paralysis. The neuropathology of ALS is primary degeneration of upper (motor cortical) and lower (brainstem and spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of affected muscle groups, and the lateral sclerosis refers to the hardening of the lateral white matter funiculus in spinal cord (corresponding to degeneration of the corticospinal tract) found at autopsy. Because the mechanisms for the motor neuron degeneration in ALS are not understood, this disease has no precisely known causes and no effective treatments. Very recent studies have identified that the degeneration of motor neurons in ALS is a form of apoptotic cell death that may occur by an abnormal programmed cell death (PCD) mechanism. In order to treat ALS effectively, we need to understand the mechanisms for motor neuron apoptosis more completely. Future studies need to further identify the signals for PCD activation in neurons as they relate to the pathogenesis of ALS and to clarify the molecular pathways leading to motor neuron apoptosis in animal and cell culture model systems. These studies should lead to a better understanding of motor neuron death and to the design of new therapeutic experiments critical for the future treatment of ALS.
Concurrent suppression of hyperlipidemia and intestinal polyp formation by NO-1886, increasing lipoprotein lipase activity in Min mice (2005)

We have previously reported a hyperlipidemic state in two strains of Apc-deficient mice, Min and Apc(1309), associated with low expression levels of lipoprotein lipase (LPL) in the liver and small intestine, and enforced induction of LPL mRNA by peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma agonists clearly suppressed hyperlipidemia and intestinal polyp formation in these mice. Meanwhile, a compound, NO-1886, has been shown to increase LPL mRNA and protein levels but not to possess PPARalpha and PPARgamma agonistic activity. In this study, therefore, the effects of NO-1886 on hyperlipidemia and intestinal polyp formation were investigated in Min mice. Administration of 400 and 800 ppm NO-1886 in the diet for 13 weeks from 7 weeks of age caused a reduction of serum triglycerides to 39% and 31% of the untreated value, respectively, and the values for very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were improved almost to the wild-type level with a corresponding elevation of the LPL mRNA. Moreover, total numbers of intestinal polyps in the groups receiving NO-1886 at 400 and 800 ppm were decreased to 48% and 42% of the control value, respectively. We also found that NO-1886 suppressed cyclooxygenase-2 transcriptional promoter activity in a reporter gene assay and reduced cyclooxygenase-2 mRNA levels in the small intestine of Min mice. These results indicate that suppression of serum lipid levels by increasing LPL activity may contribute to a reduction of intestinal polyp formation with Apc-deficiency, and NO-1886 and its derivatives could be useful as chemopreventive agents for colon cancer.
Serum Platelet Factor 4 Is an Independent Predictor of Survival and Venous Thromboembolism in Patients with Pancreatic Adenocarcinoma (2010)

Serum PF4 levels may be useful for patient stratification and for directing treatment options in patients with pancreatic cancer including anticoagulation prophylaxis. The relationship between high PF4 levels and poorer outcomes requires further study.
Splyregulation of sphingolipid signaling molecules is essential for Drosophila development (2003)

Sphingosine-1-phosphate is a sphingolipid metabolite that regulates cell proliferation, migration and apoptosis through specific signaling pathways. Sphingosine-1-phosphate lyase catalyzes the conversion of sphingosine-1-phosphate to ethanolamine phosphate and a fatty aldehyde. We report the cloning of the Drosophila sphingosine-1-phosphate lyase gene (Sply) and demonstrate its importance for adult muscle development and integrity, reproduction and larval viability. Sply expression is temporally regulated, with onset of expression during mid-embryogenesis. Sply null mutants accumulate both phosphorylated and unphosphorylated sphingoid bases and exhibit semi-lethality, increased apoptosis in developing embryos, diminished egg-laying, and gross pattern abnormalities in dorsal longitudinal flight muscles. These defects are corrected by restoring Sply expression or by introduction of a suppressor mutation that diminishes sphingolipid synthesis and accumulation of sphingolipid intermediates. This is the first demonstration of novel and complex developmental pathologies directly linked to a disruption of sphingolipid catabolism in metazoans.
COMBINATION OF METHOTREXATE AND SULPHASALAZINE VS METHOTREXATE ALONE: A RANDOMIZED OPEN CLINICAL TRIAL IN RHEUMATOID ARTHRITIS PATIENTS RESISTANT TO SULPHASALAZINE THERAPY (1994)

To compare efficacy, toxicity, and the pharmacokinetics of the combination of sulphasalazine (SASP) and methotrexate (MTX) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial. Forty RA patients with active arthritis despite adequate SASP therapy, were allocated randomly to regimes of either SASP+MTX or MTX alone. The patients were evaluated openly by a single observer for 24 weeks. In the first 15 patients using the combination, pharmacokinetics of MTX without and with SASP were studied. Thirty-eight patients completed the trial. The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group (-2.6 vs -1.3 respectively). The same pattern was seen concerning the other efficacy variables. There was no difference in the occurrence of toxicity. SASP had no influence on the pharmacokinetics of MTX. In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone, the toxicity of both therapies was similar. This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration.
Rediscovering natural products as a source of new drugs. (2005)

Extract: Since the very beginnings of human medicine, physicians have relied on chemical compounds produced by animals, plants and microorganisms, so-called natural products, to treat diseases. Natural products are directly or indirectly responsible for roughly one-half of all drugs currently in use. Of the 877 small-molecule new drug molecules introduced between 1981 and 2002, 49% were natural products or natural product analogs. Despite the great success of the 70s and 80s, the pharmaceutical industry de-emphasized natural products research during the following decade. In this article, we examine the underlying reasons for the decline, and assess future prospects for natural products research in drug discovery. In the 1990s, major pharmaceutical companies moved to a lead-finding strategy based on High Throughput Screening (HTS) of very large collections (libraries) of synthetic compounds. The move arose from the belief that techniques such as combinatorial chemistry could produce larger, more cost-effective libraries with improved hit rates and quality. Additionally, advances in molecular biology, cellular biology and genomics dramatically increased the number of molecular targets, prompting shorter drug discovery timelines. In today's drug discovery environment, rapid screening and identification of potential drug molecules is essential for success. This puts traditional natural products-based programs, with their reliance on the lengthy processes of the screening of extracts library, bioassay-guided isolation of the active components, structure elucidation and subsequent production scale-up, at a competitive disadvantage.
Episialin (MUC1) inhibits cytotoxic lymphocyte-target cell interaction. (1993)

Episialin (MUC1) is a mucin-like glycoprotein abundantly expressed on most carcinoma cells. As a result of its extended and rigid structure, it reduces intercellular adhesion. We investigated whether this antiadhesion function allows tumor cells expressing high levels of episialin to escape from immune recognition. To test this hypothesis, we transfected episialin-negative (episialin-) melanoma cells (A375) with the MUC1 cDNA-encoding episialin. The results demonstrated that episialin-positive (episialin+) melanoma cells were significantly less susceptible to lysis than episialin- melanoma cells by both alloantigen or rIL-2-stimulated cytotoxic effector cells. In addition, cold target inhibition experiments with episialin+ and episialin- cells clearly demonstrated preferential lysis of episialin- cells. Furthermore, antibody blocking studies showed that lysis of episialin+, but not of episialin-, melanoma cells was predominantly dependent on the leukocyte function-associated Ag-1/intracellular adhesion molecule adhesion route, suggesting that episialin+ target cells adhere less efficiently to effector cells than episialin- target cells. This notion was supported by the observation that conjugate formation of the effector cells with episialin+ target cells was significantly impaired. From these results we conclude that over-expression of episialin as found on many tumor cells may indeed affect efficient lysis by cytotoxic lymphocytes and thus may contribute to escape from immune surveillance.
Identification of a 1,2,4,5‐Tetraoxane Antimalarial Drug‐Development Candidate (RKA 182) with Superior Properties to the Semisynthetic Artemisinins (2010)

Fighting drug resistence: From a library of over 150 1,2,4,5-tetraoxanes, the candidate RKA 182 was selected for preclinical development as an antimalarial agent. RKA 182 has outstanding in vitro activity against resistant strains of P. falciparum and retains this level of activity against southeast asian isolates that failed artemisinin-based combination therapy.
Impacts of an automatic emergency call system on accident consequences (2005)

Työn päätavoitteena oli selvittää, kuinka paljon yleiseurooppalaisella hätäviestijärjestelmällä (eCall) voitaisiin vähentää liikenneonnettomuuksissa kuolleiden määrää Suomessa. \nTyön muina tavoitteina oli muun muassa saada tietoa viiveistä liikenneonnettomuustilanteissa ja arvioida saatujen tulosten perusteella, kuinka paljon ja kuinka suuressa osassa onnettomuuksia eCall-järjestelmä nopeuttaisi hälytyksen tekemistä ja avun paikalle saapumista. \n\n Nykytilan kuvauksessa käytiin läpi onnettomuustapahtuman tärkeimmät ajanjaksot ja nopean avun merkitys vammapotilaalle. \nLisäksi selvitettiin nykyinen viranomaistoiminta liikenneonnettomuustilanteissa ja arvioitiin, mitä vaikutuksia eCall-järjestelmällä olisi siihen. \nTyössä on myös kuvattu automaattisen hätäviestijärjestelmän yleistä toimintaa. \n\neCall-järjestelmän vaikutuksia liikenneonnettomuuksissa kuolleiden määrään selvitettiin liikenneonnettomuuksien tutkijalautakuntien vuosina 2001-2003 tutkimista onnettomuuksista saatujen tietojen avulla. \nLiikenneonnettomuuden tapahtumahetkestä avun hälyttämiseen kuluvaa aikaa arvioitiin tutkijalautakunta-aineistosta päättelemällä, tutkijalautakunnan määrittämää tapahtuma-aikaa ja hätäpuhelun hätäkeskukseen tuloaikaa vertaamalla sekä hätäkeskuspäivystäjille osoitetulla kyselyllä. \n\nNoin 82 %:ssa kaikista vähintään yhden moottoriajoneuvossa mukana olleen kuolemaan johtaneista onnettomuuksista avun hälytys tehtiin viiden minuutin sisällä onnettomuuden tapahtumisesta. \nOnnettomuuden ja avun hälytyksen välillä kului 5-30 minuuttia noin 14 %:ssa onnettomuuksista ja yli 30 minuuttia noin 4 %:ssa onnettomuuksista. \nKevyen liikenteen osallisen kuolemaan johtaneissa onnettomuuksissa viiveet olivat hieman lyhyempiä. \n\neCall-järjestelmä olisi voinut erittäin todennäköisesti estää 4,7 % moottoriajoneuvossa mukana olleiden osallisten kuolemista. \nKevyen liikenteen ja moottoriajoneuvon välisissä onnettomuuksissa järjestelmällä ei todennäköisesti olisi ollut vaikutusta kuolleiden määrään. \nKaikkiaan eCall-järjestelmällä arvioitiin voitavan välttää 4-8 % Suomen liikennekuolemista. eCall-järjestelmän hyöty-kustannussuhteeksi saatiin 0,5 - 2,3. \nHyöty-kustannussuhteen arvioitiin kuitenkin olevan suurempi, jos eCall järjestelmästä välillisesti saatavat hyödyt olisi pystytty arvioimaan ja arvottamaan rahaksi. \n\nTyön tulosten perusteella eCall-järjestelmä suositellaan otettavaksi käyttöön Suomessa mahdollisimman nopeasti ja laajasti. \nMyös vakavasti loukkaantuneita koskevaa tilastointia suositellaan kehitettävän.
Diffusion Soldering (1992)

Soldering and diffusion bonding each have benefits and drawbacks. Solders are capable of bridging joints of irregular geometry but the joints tend to have significant void levels if they are of large area. Erosion of joint surfaces and embrittlement through interalloying with parent materials represent additional weaknesses. Diffusion bonding avoids these problems, but it is not as tolerant to rough mating surfaces and joint quality is highly sensitive to the cleanliness of the surfaces. This type of process usually requires the application of high loads. A hybrid of these two methods of joining known as diffusion soldering combines the merits of both. The metallurgical principles and some features of diffusion soldering are outlined, with reference to the silver/indium and silver/tin systems. The benefits of applying diffusion soldering processes to the fabrication of assemblies in the electronics industry are explained.
NOREPINEPHRINE AND INTESTINAL MUCOSAL PERFUSION IN VASODILATORY SHOCK AFTER CARDIAC SURGERY (2007)

Patients with norepinephrine-dependent vasodilatory shock after cardiac surgery (n = 10) were compared with uncomplicated postcardiac surgery patients (n = 10) with respect to jejunal mucosal perfusion, gastric-arterial PCO2 gradient, and splanchnic oxygen demand/supply relationship. Furthermore, the effects of norepinephrine-induced variations in MAP on these variables were evaluated in vasodilatory shock. Norepinephrine infusion rate was randomly and sequentially titrated to target MAPs of 60, 75, and 90 mmHg (0.25 +/- 0.24, 0.37 +/- 0.21, and 0.55 +/- 0.39 microg/kg per minute, respectively). Data on jejunal mucosal perfusion, jejunal mucosal hematocrit, and red blood cell (RBC) velocity (laser Doppler flowmetry) as well as gastric-arterial PCO2 gradient (gastric tonometry) and splanchnic oxygen and lactate extraction (hepatic vein catheter) were obtained. Splanchnic oxygen extraction was 71 +/- 16% in the vasodilatory shock group and 41 +/- 9% in the control group (P < 0.001), whereas splanchnic lactate extraction did not differ between the two groups. Jejunal mucosal perfusion (61%; P < 0.001), RBC velocity (35%; P < 0.01), and gastric-arterial mucosal PCO2 gradient (150%; P < 0.001) were higher in the vasodilatory shock group compared with those of the control group. Jejunal mucosal perfusion, jejunal mucosal hematocrit, RBC velocity, gastric-arterial mucosal PCO2 gradient, splanchnic oxygen extraction, and splanchnic lactate extraction were not affected by increasing infusion rates of norepinephrine. In patients with norepinephrine-dependent vasodilatory shock after cardiac surgery, intestinal mucosal perfusion was higher, whereas splanchnic and gastric oxygen demand/supply relationships were impaired compared with postoperative controls, suggesting that intestinal mucosal perfusion is prioritized in vasodilatory shock. Increasing MAP from 60 to 90 mmHg with norepinephrine in clinical vasodilatory shock does not affect intestinal mucosal perfusion and gastric or global splanchnic oxygen demand/supply relationships.
Role of sodium in mitochondrial membrane depolarization induced by P2X7 receptor activation in submandibular glands (2005)

The effect of ATP on mitochondrial membrane depolarization in rat submandibular glands was investigated. Exposure of the cell suspension to high concentrations of ATP induced a sustained depolarization of mitochondrial membrane. This effect was blocked in the presence of magnesium and reproduced by low concentrations of 2',3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP), suggesting the implication of the P2X(7) purinergic receptor. This point was confirmed by comparison of the response to ATP by wild-type and P2X(7) knock-out (P2X(7)R(-/-)) mice. Mitochondria took up calcium after ATP stimulation but the depolarization of the mitochondrial membrane by ATP was not affected by the removal of calcium from the extracellular medium. It was nearly fully suppressed in the absence of sodium and partially blocked by the mitochondrial Na/Ca exchanger inhibitor 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP-37157). Both ATP and monensin increased the uptake of extracellular sodium (as shown by the depolarization of the plasma membrane) but the sodium ionophore did not affect the mitochondrial membrane potential. It is concluded that the activation of P2X(7) receptors depolarizes the mitochondrial membrane. The uptake of extracellular sodium is necessary but not sufficient to induce this response.
Wnt signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. (2007)

357 Sclerosteosis and van Buchem disease are two rare, closely related skeletal disorders characterized by a substantial increase in bone mass. Sclerosteosis is due to premature termination mutations in the SOST gene on chromosome 17q12-q21, whereas in van Buchem disease a 52 kb homozygous deletion downstream of the SOST gene was identified. The SOST gene encodes a protein, named sclerostin, of which the expression in the adult is highly restricted to osteocytes. In particular, sclerostin is localized in mature osteocytes in mineralized cortical and cancellous bone. Sclerostin expression is absent in the bones of both patients with sclerosteosis and van Buchem disease. Increase in bone mass is due to increased osteoblast activity as demonstrated by the predominance of cuboibal, activeappearing osteoblasts, increased double tetracycline label spacing, and increased osteoid levels that mineralize normally, in bone biopsies of affected individuals. Osteoclast numbers seem not to be affected. In vitro studies confirmed that sclerostin is a negative regulator of bone formation. Moreover, transgenic mice with overexpression of sclerostin are osteopenic. Sclerostin is a member of the Dan family of glycoproteins of which many members have been reported to antagonize the activity of several growth factors, including BMPs and Wnts. Sclerostin has been shown to inhibit BMP-stimulated bone formation in vitro. DNA-electroporation of the calf muscle of mice using expression plasmids for BMP and sclerostin showed that sclerostin also inhibited BMP-induced ectopic bone formation in vivo. The mechanism by which sclerostin inhibits BMP-stimulated bone formation is, however, unclear. Sclerostin has been reported to attenuate BMP-stimulated Smad phosphorylation, but were unable to find any antagonistic effect of sclerostin on direct BMP-induced responses like Smad phosphorylation and Smad-driven transcriptional reporter activation in several osteogenic cell lines, this in contrast to noggin and/or soluble BMPR. Transcriptional profiling analysis of osteoblastic cultures indicated that sclerostin specifically affects BMP and Wnt signaling out of many other growth signaling pathways.
Analysis of Prostate-Specific Membrane Antigen Splice Variants in LNCap Cells (2006)

The prostate-specific membrane antigen (PSMA), a product of the folate hydrolase (FOLH1) gene, is highly expressed as a largely extracellular membrane-anchored protein in malignant prostate tissues and in nonprostatic tumor neovasculature. Treatment of prostate cancer LNCap cells with spliceswitching oligonucleotides (SSOs) modulated splicing of FOLH1 pre-mRNA from the full-length PSMA splice variant to three splice variants: the cytoplasmic PSM', alternatively spliced at exon 1, and the previously unexamined PSMADelta6 and PSMADelta18 variants, which lack exons 6 and 18, respectively. Application of SSOs decreased membrane PSMA levels and increased PSM', PSMADelta6, and PSMADelta18 transcripts. As a result, PSM' protein was translocated to the cytoplasm, and switching to PSMADelta6 and PSMADelta18 downregulated PSMA expression. NAALADase assays showed that PSM' retained enzymatic activity. PSMADelta6 and PSMADelta18 were not active, presumably due to a change in a reading frame that eliminated the NAALDase active site or the dimerization domain or both in these proteins.
Gene-trapping to identify and analyze genes expressed in the mouse hippocampus (1998)

Mice harboring random gene-trap insertions of a lacZ (beta-galactosidase)-neomycin resistance fusion cassette (beta-geo) were analyzed for expression in the hippocampus. In 4 of 15 lines reporter gene activity was observed in the hippocampal formation. In the obn line, enzyme activity was detected in the CA1-3 hippocampal subfields, in hpk expression was restricted to CA1, but in both lines reporter activity was also present in other brain regions. In the third line, kin, reporter activity was robustly expressed throughout the stratum pyrimidale of CA1-3, with only low-level expression elsewhere. The final line (glnC) displayed ubiquitous expression of the reporter and was not analyzed further. Fusion transcripts for the first three lines were characterized; all encode polypeptides with features of membrane-associated signalling proteins. The obn fusion identified a human cDNA (B2-1) encoding a pleckstrin homology (PH) domain, while hpk sequences matched the Epstein-Barr Virus (EBV) inducible G-protein coupled receptor, EBI-1. kin identified an alternative form of the abl-related nonreceptor tyrosine kinase c-arg. Electrophysiological studies on mice homozygous for the insertions revealed normal synaptic transmission, paired pulse facilitation and paired-pulse depression at Schaffer collateral-commissural CA1 synapses, and normal long-term potentiation (LTP) in obn and kin. hpk mice displayed an increase in hippocampal CA1 long-term potentiation (LTP), suggesting a role for this receptor in synaptic plasticity.