gebhart/patrepeval huggingface dataset:
Dual Inhibition of Bcl-2 and Bcl-xL Strikingly Enhances PI3K Inhibition-Induced Apoptosis in Human Myeloid Leukemia Cells through a GSK3- and Bim-Dependent Mechanism (2012)

Effects of concomitant inhibition of the PI3K/AKT/mTOR pathway and Bcl-2/Bcl-xL (BCL2L1) were examined in human myeloid leukemia cells. Tetracycline-inducible Bcl-2 and Bcl-xL dual knockdown sharply increased PI3K/AKT/mTOR inhibitor lethality. Conversely, inducible knockdown or dominant-negative AKT increased, whereas constitutively active AKT reduced lethality of the Bcl-2/Bcl-xL inhibitor ABT-737. Furthermore, PI3K/mTOR inhibitors (e.g., BEZ235 and PI-103) synergistically increased ABT-737-mediated cell death in multiple leukemia cell lines and reduced colony formation in leukemic, but not normal, CD34+ cells. Notably, increased lethality was observed in four of six primary acute myelogenous leukemia (AML) specimens. Responding, but not nonresponding, samples exhibited basal AKT phosphorylation. PI3K/mTOR inhibitors markedly downregulated Mcl-1 but increased Bim binding to Bcl-2/Bcl-xL; the latter effect was abrogated by ABT-737. Combined treatment also markedly diminished Bax/Bak binding to Mcl-1, Bcl-2, or Bcl-xL. Bax, Bak, or Bim (BCL2L11) knockdown or Mcl-1 overexpression significantly diminished regimen-induced apoptosis. Interestingly, pharmacologic inhibition or short hairpin RNA knockdown of GSK3α/β significantly attenuated Mcl-1 downregulation and decreased apoptosis. In a systemic AML xenograft model, dual tetracycline-inducible knockdown of Bcl-2/Bcl-xL sharply increased BEZ235 antileukemic effects. In a subcutaneous xenograft model, BEZ235 and ABT-737 coadministration significantly diminished tumor growth, downregulated Mcl-1, activated caspases, and prolonged survival. Together, these findings suggest that antileukemic synergism between PI3K/AKT/mTOR inhibitors and BH3 mimetics involves multiple mechanisms, including Mcl-1 downregulation, release of Bim from Bcl-2/Bcl-xL as well as Bak and Bax from Mcl-1/Bcl-2/Bcl-xL, and GSK3α/β, culminating in Bax/Bak activation and apoptosis. They also argue that combining PI3K/AKT/mTOR inhibitors with BH3 mimetics warrants attention in AML, particularly in the setting of basal AKT activation and/or addiction.
[Polymeric materials for biomedical purposes obtained by radiation methods. V. hybrid artificial pancreas]. (1994)

The authors present a review of works done on the elaboration of a hybrid-type artificial pancreas. The article discusses construction designs, applied polymeric materials as well as biocompatibility problems of polymeric membranes that encapsulate the Langerhans islets. On example of hydrogel membranes prepared by radiation crosslinking of poly(vinyl alcohol) (PVA) the dependence of the diffusion coefficients of glucose, insulin and immunoglobulin G on the crosslinking degree of hydrogels has been shown.
Gallium nitrate: the second metal with clinical activity. (1986)

Gallium nitrate is the anhydrate salt of the naturally occurring heavy metal. It has demonstrated antitumor activity in a variety of murine tumor models, including Walker carcinosarcoma 256, fibrosarcoma M-89, leukemia K-1964, adenocarcinoma 755, mammary carcinoma YMC, reticulum cell sarcoma A-RCS, lymphoma P1798, and osteosarcoma 124F. Preclinical studies performed in rats, rabbits, dogs, and monkeys showed the dose-limiting toxicity to be renal. The hepatic, pulmonary, gastrointestinal, hematologic, and integumentary systems were also involved. The major route of elimination is the kidneys, with 35%-71% of the infused dose excreted within 24 hours. Three phase I studies suggested the following phase II doses: 700-750 mg/m2 by short infusion, once every 2-3 weeks; 300 mg/m2/day by short infusion for 3 consecutive days, to be repeated every 2 weeks; and 300 mg/m2/day by continuous infusion for 7 consecutive days, to be repeated every 3-5 weeks. The major organ toxicity reported was renal; however, this can be adequately controlled either by hydration and osmotic diuresis or by use of continuous schedule. (Either maneuver appears to allow delivery of the recommended phase II dose with a less than 30% risk of change in serum creatinine.) In limited phase II evaluation, the drug has shown antitumor activity in patients with either refractory lymphomas or small cell lung carcinoma, with total objective response rates of 28% and 11%, respectively. In addition, it has been effective in the treatment of patients with cancer-related hypercalcemia by having an inhibitory effect on calcium reabsorption from bone. Single-agent phase II studies are planned in all major tumor types. Some are already ongoing in patients with genitourinary malignancies (renal, bladder, prostate, testicular), small cell lung carcinoma, and multiple myeloma. Metabolic studies are in progress at Memorial Sloan-Kettering Cancer Center to further elucidate the mechanism or mechanisms of the hypocalcemic effects.
Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain (2005)

Two of the four human FGF8 splice isoforms, FGF8a and FGF8b, are expressed in the mid-hindbrain region during development. Although the only difference between these isoforms is the presence of an additional 11 amino acids at the N terminus of FGF8b, these isoforms possess remarkably different abilities to pattern the midbrain and anterior hindbrain. To reveal the structural basis by which alternative splicing modulates the organizing activity of FGF8, we solved the crystal structure of FGF8b in complex with the "c" splice isoform of FGF receptor 2 (FGFR2c). Using surface plasmon resonance (SPR), we also characterized the receptor-binding specificity of FGF8a and FGF8b, the "b" isoform of FGF17 (FGF17b), and FGF18. The FGF8b-FGFR2c structure shows that alternative splicing permits a single additional contact between phenylalanine 32 (F32) of FGF8b and a hydrophobic groove within Ig domain 3 of the receptor that is also present in FGFR1c, FGFR3c, and FGFR4. Consistent with the structure, mutation of F32 to alanine reduces the affinity of FGF8b toward all these receptors to levels characteristic of FGF8a. More importantly, analysis of the mid-hindbrain patterning ability of the FGF8b(F32A) mutant in chick embryos and murine midbrain explants shows that this mutation functionally converts FGF8b to FGF8a. Moreover, our data suggest that the intermediate receptor-binding affinities of FGF17b and FGF18, relative to FGF8a and FGF8b, also account for the distinct patterning abilities of these two ligands. We also show that the mode of FGF8 receptor-binding specificity is distinct from that of other FGFs and provide the first biochemical evidence for a physiological FGF8b-FGFR1c interaction during mid-hindbrain development. Consistent with the indispensable role of FGF8 in embryonic development, we show that the FGF8 mode of receptor binding appeared as early as in nematodes and has been preserved throughout evolution.
Drug and enzyme targeting. Methods in enzymology. Volume 112 (1985)

In evaluating methods of drug and enzyme targeting, studies are included which discuss microencapsulation techniques and the preparation and purification of various drug conjugates and radiopharmaceuticals, which can be used as a carrier that either releases the drug more slowly or targets the drug more selectively on the desired tissue. Separate abstracts have been prepared for five chapters of this volume for inclusion in the Energy Data Base.
Performance of database workloads on shared-memory systems with out-of-order processors (1998)

Database applications such as online transaction processing (OLTP) and decision support systems (DSS) constitute the largest and fastest-growing segment of the market for multiprocessor servers. However, most current system designs have been optimized to perform well on scientific and engineering workloads. Given the radically different behavior of database workloads (especially OLTP), it is important to re-evaluate key system design decisions in the context of this important class of applications.This paper examines the behavior of database workloads on shared-memory multiprocessors with aggressive out-of-order processors, and considers simple optimizations that can provide further performance improvements. Our study is based on detailed simulations of the Oracle commercial database engine. The results show that the combination of out-of-order execution and multiple instruction issue is indeed effective in improving performance of database workloads, providing gains of 1.5 and 2.6 times over an in-order single-issue processor for OLTP and DSS, respectively. In addition, speculative techniques enable optimized implementations of memory consistency models that significantly improve the performance of stricter consistency models, bringing the performance to within 10--15% of the performance of more relaxed models.The second part of our study focuses on the more challenging OLTP workload. We show that an instruction stream buffer is effective in reducing the remaining instruction stalls in OLTP, providing a 17% reduction in execution time (approaching a perfect instruction cache to within 15%). Furthermore, our characterization shows that a large fraction of the data communication misses in OLTP exhibit migratory behavior; our preliminary results show that software prefetch and writeback/flush hints can be used for this data to further reduce execution time by 12%.
Monoclonal Antibodies to Human Fibrin: Interaction with other Animal Fibrins (1996)

Four monoclonal antibodies have previously been raised in our laboratory for possible use in thrombus imaging and the targeting of thrombolytic agents. These antibodies were raised to various human fibrin-related immunogens and each antibody had been selected for its specificity towards fibrin and not fibrinogen. To study further these antibodies in animal circulation models both in vivo and in vitro, their selectivity towards human fibrin as opposed to other animal fibrins was examined. In this study dissociation constants for each antibody with each of six species fibrins (human, baboon, pig, dog, sheep and rabbit) were estimated using both fibrin clots and monolayers. Some limited data were also obtained with Sepharose-fibrin. Of the antibodies two (denoted 12B3B10 and 12B3A11) are seen to bind almost exclusively to human fibrin with dissociation constants of about 8 x 10(-10) M using fibrin clots and monolayers. These same two mabs bound to baboon fibrin with a dissociation constant of 2 x 10(-9) M, while neither displayed significant levels of binding to the fibrins from dog, pig, sheep and rabbit. The other two antibodies investigated (1H10 and 5F3) were found to bind well to fibrins of human, baboon, pig and dog, with dissociation constants in the range of 1.4-4.2 x 10(-9) M. However neither 1H10 nor 5F3 displayed significant recognition of sheep and rabbit fibrins. Both 1H10 and 5F3 were also found by means of competitive ELISA's to retain their selectivity to baboon, dog and pig fibrins in the presence of their respective fibrinogens.
Effects of pulsed magnetic fields on neurite outgrowth from chick embryo dorsal root ganglia (1996)

We have previously shown that neurite outgrowth from 6-day chick embryo dorsal root ganglia (DRG) in vitro was stimulated when nerve growth factor (NGF) and pulsed magnetic fields (PMF) are used in combination. 392 DRGs were studied in a field excited by a commercial PMF generator. We have now analyzed an additional 416 DRGs exposed to very similar PMF's produced by an arbitrary wavefrom generator and power amplifier. We reproduced our previous findings that combination of NGF and bursts of asymmetric, 220 microsecond-wide, 4.0 mT-peak pulses induced significantly (p < 0.05) greater outgrowth than NGF alone, that fields without NGF do not significantly alter outgrowth, and that, unlike NGF alone, 4.0 mT fields and NGF can induce asymmetric outgrowth. The asymmetry does not seem to have a preferred orientation with respect to the induced electric field. Analysis of the data for the entire 808 DRGs confirms these findings. Importantly, we find similar results for pulse bursts repeated at 15 or 25 Hz.
Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Summary and Appraisal of Published Evidence (2001)

Although suggestions for appropriate management can be made on the basis of available evidence, the supporting literature is scarce and further high-quality research is necessary. Such research will require an improved, generally acceptable, and transportable definition of acute exacerbation of COPD, as well as improved methods for observing and measuring outcomes.
Hematopoietic effects of a granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein (1991)

The common functional characteristics of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) may be explained by the presence of a subpopulation of cell surface receptors capable of binding both growth hormones. A GM-CSF/IL-3 fusion protein (pIXY 321) was produced in a yeast expression host. Receptor binding studies with HL-60, JM-1, AML-193, and KG-1 cell lines suggested that the GM-CSF and IL-3 regions had adopted a native conformation within the fusion protein. The fusion protein also exhibited enhanced biologic activity compared with GM-CSF or IL-3 in assays of normal, primary human hematopoietic progenitor cells. pIXY 321 may offer significant clinical advantages over the individual cytokines.
Variable host–pathogen compatibility in Mycobacterium tuberculosis (2006)

Mycobacterium tuberculosis remains a major cause of morbidity and mortality worldwide. Studies have reported human pathogens to have geographically structured population genetics, some of which have been linked to ancient human migrations. However, no study has addressed the potential evolutionary consequences of such longstanding human-pathogen associations. Here, we demonstrate that the global population structure of M. tuberculosis is defined by six phylogeographical lineages, each associated with specific, sympatric human populations. In an urban cosmopolitan environment, mycobacterial lineages were much more likely to spread in sympatric than in allopatric patient populations. Tuberculosis cases that did occur in allopatric hosts disproportionately involved high-risk individuals with impaired host resistance. These observations suggest that mycobacterial lineages are adapted to particular human populations. If confirmed, our findings have important implications for tuberculosis control and vaccine development.
DGAT1, DGAT2 and PDAT Expression in Seeds and Other Tissues of Epoxy and Hydroxy Fatty Acid Accumulating Plants (2010)

Triacylglycerol (TAG) is the main storage lipid in plants. Acyl-CoA: diacylglycerol acyltransferase (DGAT1 and DGAT2) and phospholipid: diacylglycerol acyltransferase (PDAT) can catalyze TAG synthesis. It is unclear how these three independent genes are regulated in developing seeds, and particularly if they have specific functions in the high accumulation of unusual fatty acids in seed oil. The expression patterns of DGAT1, DGAT2 and a PDAT in relation to the accumulation of oil and epoxy and hydroxy fatty acids in developing seeds of the plant species Vernonia galamensis, Euphorbia lagascae, Stokesia laevis and castor that accumulate high levels of these fatty acids in comparison with soybean and Arabidopsis were investigated. The expression patterns of DGAT1, DGAT2 and the PDAT are consistent with all three enzymes playing a role in the high epoxy or hydroxy fatty acid accumulation in developing seeds of these plants. PDAT and DGAT2 transcript levels are present at much higher levels in developing seeds of epoxy and hydroxy fatty acid accumulating plants than in soybeans or Arabidopsis. Moreover, PDAT, DGAT1 and DGAT2 are found to be expressed in many different plant tissues, suggesting that these enzymes may have other roles in addition to seed oil accumulation. DGAT1 appears to be a major enzyme for seed oil accumulation at least in Arabidopsis and soybeans. For the epoxy and hydroxy fatty acid accumulating plants, DGAT2 and PDAT also show expression patterns consistent with a role in the selective accumulation of these unusual fatty acids in seed oil.
Fever: How May Circulating Pyrogens Signal the Brain? (1997)

Recent data suggest that fever may be initiated by products of liver macrophages that activate subdiaphragmatic vagal afferents. In the brain, these inputs may be transmitted to fever-producing sites via noradrenergic pathways;prostaglandin E2 may be the ultimate pyrogenic mediator.
Triggering through CD16 or phorbol esters enhances adhesion of NK cells to laminin via very late antigen 6. (1992)

Very late antigens VLA-1, VLA-2, VLA-3, and VLA-6, belonging to the beta 1 subfamily of integrins, have been identified as receptors for different binding domains of laminin (LM). We have detected VLA-6, but not VLA-1 and VLA-2 on a subset (50-70%) of fresh peripheral blood CD3-, CD16+, CD56+ human natural killer (NK) cells by immunofluorimetric and biochemical analysis. Binding assays performed on LM-coated plates showed that 10-15% of NK cells spontaneously adhere to LM, and this adhesion is mediated by VLA-6. Activation of NK cells through CD16 triggering or by phorbol ester results in a rapid increase of adhesion to LM, which is still mediated by VLA-6. The enhanced adhesiveness is not associated with changes in beta 1 LM receptor expression, while it correlates with changes in the phosphorylation status of alpha 6 subunit. The expression of VLA-6 on NK cells and the modulation of its avidity by activating stimuli may be relevant for NK cell migration and tissue location during inflammation or immune response.
Biosynthesis of 1‐alkenes in higher plants: stereochemical implications (1989)

Odd numbered 1-alkenes, such as 1-pentadecene or 1,8,11,14-heptadecatetraene are formed from palmitic or linolenic acid by fragmentative decarboxylation. Incubation studies with germinating safflower (Carthamus tinctorius) and (2R,3R)-12-phenyl[2,3-2H2]dodecanoic acid, (2S,3S)-12-phenyl[2,3-2H2]dodecanoic acid, (2R)-12-phenyl[2-2H]dodecanoic acid and (2S)-12-phenyl[2-2H]dodecanoic acid instead of the natural alpha-linolenic acid precursor revealed the fragmentation to be an overall anti elimination of the 3-pro(S) hydrogen and the carboxyl group (anti-periplanar transition state geometry). Externally offered 3-hydroxy acids are not fragmented to 1-alkenes. The most probable mechanistic alternatives are in agreement with abstraction of the 3-pro(S) hydrogen as a radical followed by electron transfer and fragmentation, or transient insertion of oxygen into the 3-pro(S) C-H bond and subsequent fragmentation into an 1-alkene and CO2 after appropriate activation. The mechanism seems to be of general importance for the biosynthesis of vinylic substructures of natural products from oxygenated precursors.
-Galactosidase A deficiency in Dutch patients on dialysis: a critical appraisal of screening for Fabry disease (2003)

No undiagnosed Fabry patients were found, indicating that in our studied cohort there is no large-scale underestimation of its prevalence. Even though screening of dialysis patients for Fabry disease might identify patients who remain otherwise unrecognized, screening of high-risk populations for alpha-Gal A deficiency should be carried out with caution since long-term efficacy of treatment is currently unknown.
Formation of Isoamylase by Pseudomonas (1968)

We have isolated a Pseudomonas sp. (strain SB15) which produces an isoamylase (EC 3.2.1.9). Highest yields of this enzyme were obtained when the bacterium was grown in shaken culture in a medium containing maltose, dextrin, starch, or isomaltose. Specific carbon and nitrogen sources were required for growth. The most satisfactory medium consisted of 2% maltose, 0.4% sodium glutamate, 0.3% diammonium hydrogen phosphate, and other inorganic salts. The optimal pH for enzyme production was 5 to 6. The enzyme is stable between pH 3 and 6 but is extremely labile above pH 7. It splits amylopectin completely by combined action with beta-amylase but does not attack pullulan.
Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis (2006)

Eosinophilic esophagitis (EE) is an emerging disorder with a poorly understood pathogenesis. In order to define disease mechanisms, we took an empirical approach analyzing esophageal tissue by a genome-wide microarray expression analysis. EE patients had a striking transcript signature involving 1% of the human genome that was remarkably conserved across sex, age, and allergic status and was distinct from that associated with non-EE chronic esophagitis. Notably, the gene encoding the eosinophil-specific chemoattractant eotaxin-3 (also known as CCL26) was the most highly induced gene in EE patients compared with its expression level in healthy individuals. Esophageal eotaxin-3 mRNA and protein levels strongly correlated with tissue eosinophilia and mastocytosis. Furthermore, a single-nucleotide polymorphism in the human eotaxin-3 gene was associated with disease susceptibility. Finally, mice deficient in the eotaxin receptor (also known as CCR3) were protected from experimental EE. These results implicate eotaxin-3 as a critical effector molecule for EE and provide insight into disease pathogenesis.
Autonomic epilepsy--the influence of epileptic discharges on heart rate and rhythm. (1999)

Epileptic discharges directly influence portions of the central autonomic network, within a brain area too small or too deep to be detected on EEG, most likely deep mesial structures such as the amygdala or portions of the hippocampus. The potential clinical applications of our results include (1) automatic seizure detection, (2) differentiation between seizures of temporal and frontal lobe origin, (3) detection of peri-ictal cardiac arrhythmias, and (4) clarification of SUDS (sudden unexplained death syndrome) in epilepsy.
Photon-Modulated Wettability Changes on Spiropyran-Coated Surfaces (2002)

A coating of photoresponsive spiropyran molecules covalently bound to a glass surface along with a mixture of organosilanes to control the surface environment was prepared. The relatively nonpolar spiropyran can be reversibly switched to a polar, zwitterionic merocyanine isomer that has a much larger dipole moment by UV light, and back again by visible light. The contact angle was 11°−14° lower for dry, spiropyran-coated surfaces after irradiation with UV than that for dry, spiropyran-coated surfaces after irradiation with visible light. The light-induced changes observed in the surface energy were correlated to the switching of the surface-bound spiropyran molecule between polar and nonpolar forms by means of fluorescence spectroscopy and epifluorescence microscopy. Water in capillary tubes coated with the photosensitive layer was observed to rise when the wavelength of incident light was switched from visible to UV. The UV-induced rise was of the order of 2.8 mm for a 500 μm diameter capillary. This microfluidic actuation of water in an enclosed capillary or microchannel using light is termed “photocapillarity”. Contact angle hysteresis prevented the water from flowing back down the capillary when the light was switched from UV back to visible.