gebhart/patrepeval huggingface dataset:
Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention (2006)

Several of the hormone-mediated cancers (breast, endometrial, ovarian, and prostate) represent major cancers in both incidence and mortality rates. The etiology of these cancers is in large part modulated by the hormones estrogen and testosterone. As advanced disease develops, the common treatment for these cancers is chemotherapy. Thus, genes that can alter tissue response to hormones and alter clinical response to chemotherapy are of major interest. The cytochrome P450 1B1 (CYP1B1) may be involved in disease progression and modulate the treatment in the above hormone-mediated cancers. This review will focus on the pharmacogenetics of CYP1B1 in relation to hormone-mediated cancers and provide an assessment of cancer risk based on CYP1B1 polymorphisms and expression. In addition, it will provide a summary of CYP1B1 gene regulation and expression in normal and neoplastic tissue.
Pressurized Aerosol versus Jet Aerosol Delivery to Mechanically Ventilated Patients Comparison of Dose to the Lungs (1990)

The purpose of this study was to compare deposition of aerosol to the lung from a metered-dose inhaler (MDI) and aerosol holding chamber and from a jet nebulizer in ventilator-dependent patients. Twenty-one patients were entered into the study, all receiving assisted ventilation and inhaled bronchodilators because of airflow limitation. The average age was 68 yr; there were 10 men and 11 women. The patients were randomized to receive either 4 puffs (800 micrograms) of radiolabeled fenoterol by MDI of 1.75 ml (1,750 micrograms) of radiolabeled fenoterol solution by nebulizer. Imaging of lung fields was made by a portable scintillation camera at 5-min intervals during the study. Results showed that 20 patients completed the study, 9 receiving fenoterol by MDI, and 11 by jet nebulizer. Four were excluded from analysis because of previous pneumonectomy, two from each group. Lung deposition measured as a percent of given dose from either system was 5.65 +/- 1.09 (mean +/- SEM) for MDI plus extension chamber and 1.22 +/- 0.35 for jet nebulizer (p less than 0.001). Therefore, this trial shows significantly greater efficiency of aerosol deposition to the lung in ventilator-dependent patients when using an MDI plus aerosol holding chamber than when using a jet nebulizer.
Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation (2003)

The production of red blood cells is tightly regulated by erythropoietin (Epo). The phosphoinositide 3-kinase (PI 3-kinase) pathway was previously shown to be activated in response to Epo. We studied the role of this pathway in the control of Epo-induced survival and proliferation of primary human erythroid progenitors. We show that phosphoinositide 3 (PI 3)-kinase associates with 4 tyrosine-phosphorylated proteins in primary human erythroid progenitors, namely insulin receptor substrate-2 (IRS2), Src homology 2 domain-containing inositol 5'-phosphatase (SHIP), Grb2-associated binder-1 (Gab1), and the Epo receptor (EpoR). Using different in vitro systems, we demonstrate that 3 alternative pathways independently lead to Epo-induced activation of PI 3-kinase and phosphorylation of its downstream effectors, Akt, FKHRL1, and P70S6 kinase: through direct association of PI 3-kinase with the last tyrosine residue (Tyr479) of the Epo receptor (EpoR), through recruitment and phosphorylation of Gab proteins via either Tyr343 or Tyr401 of the EpoR, or through phosphorylation of IRS2 adaptor protein. The mitogen-activated protein (MAP) kinase pathway was also activated by Epo in erythroid progenitors, but we found that this process is independent of PI 3-kinase activation. In erythroid progenitors, the functional role of PI 3-kinase was both to prevent apoptosis and to stimulate cell proliferation in response to Epo stimulation. Finally, our results show that PI 3-kinase-mediated proliferation of erythroid progenitors in response to Epo occurs mainly through modulation of the E3 ligase SCF(SKP2), which, in turn, down-regulates p27(Kip1) cyclin-dependent kinase (CDK) inhibitor via proteasome degradation.
CREB3L1 Is a Metastasis Suppressor That Represses Expression of Genes Regulating Metastasis, Invasion, and Angiogenesis (2013)

The unfolded protein response (UPR) is activated in response to hypoxia-induced stress such as in the tumor microenvironment. This study examined the role of CREB3L1 (cyclic AMP [cAMP]-responsive element-binding protein 3-like protein 1), a member of the UPR, in breast cancer development and metastasis. Initial experiments identified the loss of CREB3L1 expression in metastatic breast cancer cell lines compared to low-metastasis or nonmetastatic cell lines. When metastatic cells were transfected with CREB3L1, they demonstrated reduced invasion and migration in vitro, as well as a significantly decreased ability to survive under nonadherent or hypoxic conditions. Interestingly, in an in vivo rat mammary tumor model, not only did CREB3L1-expressing cells fail to form metastases compared to CREB3L1 null cells but regression of the primary tumors was seen in 70% of the animals as a result of impaired angiogenesis. Microarray and chromatin immunoprecipitation with microarray technology (ChIP on Chip) analyses identified changes in the expression of many genes involved in cancer development and metastasis, including a decrease in those involved in angiogenesis. These data suggest that CREB3L1 plays an important role in suppressing tumorigenesis and that loss of expression is required for the development of a metastatic phenotype.
Flash EEPROM Threshold Instabilities due to Charge Trapping During Program/Erase Cycling (2004)

Charge trapping over the channel can occur from program/erase cycling of Flash memory cells, increasing the cell threshold voltage and causing threshold shifts in retention tests when charges detrap. The empirical characteristics of these effects are discussed. Trapping has a square-root dependence on program/erase cycle count. Detrapping scales with the logarithm of time and is thermally accelerated with an activation energy of 1.1 to 1.2 eV. Detrapping has only a weak dependence on electric field. These mechanisms are intrinsic, yet there is a wide variation in behavior from one cell to another related to Poisson statistical variations. Common reliability characterization methods need to be re-thought in light of the characteristics of this and other mechanisms. In particular, performing extensive program/erase cycling with no delays between cycles is unrealistic for this mechanism, and alternative distributed-cycling schemes are proposed.
ChemInform Abstract: Oligonucleotides Functionalized by Fluorescein and Rhodamine Dyes: Michael Addition of Methyl Acrylate to 2′‐Deoxypseudouridine. (2000)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Development of a Rhenium-186-Labeled MAG3-Conjugated Bisphosphonate for the Palliation of Metastatic Bone Pain Based on the Concept of Bifunctional Radiopharmaceuticals (2005)

Rhenium-186-1-hydroxyethylidene-1,1-diphosphonate (186Re-HEDP) has been used for the palliation of metastatic bone pain. Delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of (186)Re-HEDP in vivo. In this study, on the basis of the concept of bifunctional radiopharmaceuticals, we designed a stable 186Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate]oxorhenium(V) (186Re-MAG3-HBP). As a precursor, [1-hydroxy-1-phosphono-4-[2-[2-[2-(2-tritylmercaptoacetylamino)acetylamino]acetylamino]acetylamino]butyl]phosphonic acid (Tr-MAG3-HBP) was synthesized by the conjugation of N-[(tritylmercapto)acetyl]glycylglycylglycine (Tr-MAG3) with the bisphosphonate analogue. After deprotection of the trityl group of Tr-MAG3-HBP, 186Re-labeling was performed by reacting 186ReO4- with SnCl2 in citrate buffer. After purification by HPLC, 186Re-MAG3-HBP showed a radiochemical purity of over 95%. To compare the stability of 186Re-MAG3-HBP and 186Re-HEDP, these (186)Re complexes were incubated in phosphate buffer. No measurable decomposition of 186Re-MAG3-HBP occurred over a 24-h period, while only approximately 30% of 186Re-HEDP remained intact 24 h postincubation. In biodistribution experiments, the radioactivity level of 186Re-MAG3-HBP in bone was significantly higher than that of (186)Re-HEDP. Blood clearance of 186Re-MAG3-HBP was faster than that of 186Re-HEDP. In addition, the gastric accumulation of 186Re-MAG3-HBP radioactivity was lower than that of 186Re-HEDP. In conclusion, 186Re-MAG3-HBP is expected to be a useful radiopharmaceutical for the palliation of metastatic bone pain.
Natriuretic Peptides and Nitric Oxide Induce Endothelial Apoptosis via a cGMP–Dependent Mechanism (1999)

Apoptosis is a mode of cell death in which the cell participates in its own demise. We studied whether endothelium-derived relaxing factor, nitric oxide (NO), and natriuretic peptides affect apoptosis of rat vascular endothelial cells via a cGMP-dependent pathway and whether such effects are antagonized by an endothelium-derived vasoconstrictor, endothelin-1 (ET-1). Three natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide) induced endothelial apoptosis as demonstrated by nucleosomal laddering on agarose gel electrophoresis and by the terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling method. This dose-dependent relation was assessed by quantifying the fragmented and intact DNA contents by the diphenylamine method. The atrial natriuretic peptide-induced endothelial apoptosis was completely blocked by a guanylate cyclase-coupled receptor antagonist (HS-142-1) and an inhibitor of cGMP-dependent protein kinase (KT5823). An NO donor, NOR3 ((+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide; FK409) also induced endothelial apoptosis; the effect of this compound was abrogated by KT5823 and an inhibitor of soluble guanylate cyclase, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). A cGMP derivative, 8-bromo-cGMP, but not the cAMP derivative 8-bromo-cAMP, caused endothelial apoptosis; the effect of ODQ was also abrogated by KT5823. Endothelial apoptosis induced by ANP, NOR3, and 8-bromo-cGMP was similarly antagonized by ET-1. ANP, NOR3, and 8-bromo-cGMP caused marked accumulations of the tumor suppressor gene product p53 but not of bcl-2, as determined by Western blot analysis. These results demonstrate for the first time that endothelium-derived NO and natriuretic peptides are proapoptotic factors for endothelial cells, whereas the endothelium-derived vasoconstrictor ET-1 is an antiapoptotic factor, suggesting that the countervailing balance between these vasodilators and vasoconstrictors, in addition to regulation of vascular tonus, may contribute to endothelial cell integrity.
Therapeutic potential of antisense oligonucleotides as modulators of alternative splicing (2003)

An estimated 60% of all human genes undergo alternative splicing, a highly regulated process that produces splice variants with different functions. Such variants have been linked to a variety of cancers, and genetic diseases such as thalassemia and cystic fibrosis. This Perspective describes a promising approach to RNA repair based on the use of antisense oligonucleotides to modulate alternative splicing and engender the production of therapeutic gene products.
Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration (2009)

MDMA (3,4-methylenedioxymethamphetamine or "ecstasy") is a recreationally used drug with remarkable and characteristic prosocial effects. In spite of abundant attention in the scientific literature, the mechanism of its prosocial effects has not been elucidated in humans. Recently, research in animals has suggested that the neuropeptide oxytocin may induce these effects. In a double blind, randomized, crossover, and placebo-controlled study in 15 healthy volunteers we assessed blood oxytocin and MDMA concentrations and subjective prosocial effects after oral administration of 100 mg MDMA or placebo. MDMA induced a robust increase of blood oxytocin concentrations and an increase of subjective prosocial feelings. Within subjects, the variations in these feelings were significantly and positively correlated with variation in oxytocin levels, and the correlations between these feelings and oxytocin were significantly stronger than those between these feelings and blood MDMA levels. MDMA induces oxytocin release in humans, which may be involved in the characteristic prosocial effects of ecstasy.
Agonism and Antagonism at the Insulin Receptor (2012)

Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR antagonist, exhibited partial agonistic effects in the 1-10 nM range, showing altogether a bell-shaped dose-response curve. Intriguingly, the agonistic effects of S961 were seen only on mitogenic endpoints ((3)H-thymidine incorporation), and not on metabolic endpoints ((14)C-glucose incorporation in adipocytes and muscle cells). The agonistic effects of S961 were observed in 3 independent cell lines, with complete concordance between mitogenicity ((3)H-thymidine incorporation) and phosphorylation of the IR and Akt. Together with the B29-B'29 crosslinked dimer, S961 is a rare example of a mixed agonist/antagonist for the human IR. A plausible mechanistic explanation based on the bivalent crosslinking model of IR activation is proposed.
Synthesis of a Stable and Specific Surface Plasmon Resonance Biosensor Surface Employing Covalently Immobilized Peptide Nucleic Acids (2000)

Biosensors allow the real-time and label-free observation of biochemical reactions between various ligands including antigen-antibody reactions and nucleic acids hybridizations. In our studies, we used a surface plasmon resonance biosensor to elucidate the hybridization characteristics of a peptide nucleic acid (PNA) ligand immobilized on sensor surfaces either through covalent or streptavidin-biotin coupling. A biotin-labeled PNA was employed in the latter approach whereas the covalent immobilization included the following steps: A maleimide group was attached to the N-terminal of the PNA using N-succinimidyl 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC). To generate free thiol groups for coupling, a carboxylated dextran matrix of the sensor surface was activated with N-hydroxysuccinimide (NHS) and N-ethyl-N'-(dimethylaminopropyl)-carbodiimide (EDC) and thiolated by addition of cystamine dihydrochloride followed by reduction with 1, 4-dithioerythrite (DTE). Finally, the modified PNA was coupled to the sulfhydryl groups of the activated dextran matrix. Repetitive hybridizations of a single-stranded synthetic DNA oligomer to the PNAs demonstrated the superior stability of covalent immobilization compared to noncovalent immobilization. Differentiation of point mutations in the analyte molecule was accomplished at 40 degrees C using guanidine thiocyanate concentrations of 1.5-1.7 M. In further experiments, we showed that a perfectly matched PNA allows the detection of a single-stranded DNA at a sensitivity of less than 1% in a background of single-stranded DNA having a single C to T point mutation in the region complementary to the PNA. Consequently, covalently bound PNAs provide a stable and reproducible environment for the development of mutation-specific DNA analysis assays.
Lifetimes of the negative molecular hydrogen ions:H2−,D2−, andHD− (2006)

The lifetimes of three isotopologs of the molecular hydrogen anion have been measured using an electrostatic ion-beam trap. Much longer lifetimes (up to $\ensuremath{\sim}2\phantom{\rule{0.3em}{0ex}}\mathrm{ms}$ for $\mathrm{D}_{2}{}^{\ensuremath{-}}$) than predicted by the most recent calculation are found, and it is proposed that more than one electronic state contributes to the overall lifetimes of these species.
A Distinctive Alveolar Macrophage Activation State Induced by Cigarette Smoking (2005)

Smoking induces a remarkably consistent and distinctive pattern of alveolar macrophage activation. These studies identify aspects of mouse models that are directly relevant to human smokers and also reveal novel potential mediators of smoking-related diseases.
Introducing service differentiation into IEEE 802.11 (2002)

The IETF is currently working on service differentiation for the Internet. However service differentiation at the IP layer is useless without support of lower layers. This support is even more critical in wireless environments because of the dynamism of the channel conditions and of the network topology. We present a service differentiation support for the IEEE 802.11. The idea is to scale the contention window according to the priority of each flow or user. Preliminary simulation results are shown when using this mechanism with TCP and UDP.
Design of all-accelerometer inertial measurement unit for tremor sensing in hand-held microsurgical instrument (2004)

We present the design of an all-accelerometer inertial measurement unit (IMU). The IMU forms part of an intelligent hand-held microsurgical instrument that senses its own motion, distinguishes between hand tremor and intended motion, and compensates in real-time the erroneous motion. The new IMU design consists of three miniature dual-axis accelerometers, two of which are housed in a sensor suite at the distal end of the instrument handle, and one located at the proximal end close to the instrument tip. By taking the difference between the accelerometer readings, we decouple the inertial and gravitational accelerations from the rotation-induced (centripetal and tangential) accelerations, hence simplifies the kinematic computation of angular motions. We have shown that the error variance of the Euler orientation parameters /spl theta//sub x/, /spl theta//sub y/ and /spl theta//sub z/ is inversely proportional to the square of the distance between the three sensor locations. Comparing with a conventional three gyros and three accelerometers IMU, the proposed design reduces the standard deviation of the estimates of translational displacements by 29.3% in each principal axis and those of the Euler orientation parameters /spl theta//sub x/, /spl theta//sub y/ and /spl theta//sub z/ by 99.1%, 99.1% and 92.8% respectively.
Abstract 3861: Hyaluronan-CD44v3 interaction with oct4/sox2/nanog promotes miR-302 expression leading to self-renewal, clonal formation and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma (2014)

Abstract Human Head and Neck Squamous Cell Carcinoma (HNSCC) is a highly malignant cancer associated with major morbidity and mortality. In this study we determined that human HNSCC-derived HSC-3 cells contain a subpopulation of cancer stem cells (CSCs) characterized by a high levels of CD44v3 and aldehyde dehydrogenase-1 (ALDH1) expression. These tumor cells also express several stem cell markers (the transcription factors-Oct4, Sox2 and Nanog) and display the hallmark CSC properties of self-renewal/clonal formation and the ability to generate heterogeneous cell populations. Importantly, hyaluronan (HA) stimulates the CD44v3 (an HA receptor) interaction with Oct4/Sox2/Nanog leading to both a complex formation and the nuclear translocation of three CSC transcription factors. Further analysis reveals that microRNA-302 (miR-302) is controlled by an upstream promoter containing Oct4/Sox2/Nanog binding sites, while chromatin immunoprecipitation (ChIP) assays demonstrate that stimulation of miR-302 expression by HA/CD44 is Oct4/Sox2/Nanog-dependent in HNSCC-specific CSCs. This process results in suppression of several epigenetic regulators (AOF1/AOF2 and DNMT1) and the upregulation of several survival proteins (cIAP-1, cIAP-2 and XIAP) leading to self-renewal, clonal formation and cisplatin resistance. These CSCs were transfected with a specific anti-miR-302 inhibitor in order to silence miR-302 expression and block its target functions. Our results demonstrate that the anti-miR-302 inhibitor not only enhances the expression of AOF1/AOF2 and DNMT1, but also abrogates the production of cIAP-1, cIAP-2 and XIAP and HA/CD44v3-mediated cancer stem cell functions. Taken together, these findings strongly support the contention that the HA-induced CD44v3 interaction with Oct4/Sox2/Nanog signaling plays a pivotal role in miR-302 production leading to AOF1/AOF2/DNMT1 downregulation and survival protein activation. All of these events are critically important for the acquisition of cancer stem cell properties including self-renewal, clonal formation and chemotherapy resistance in HA/CD44v3-activated head and neck cancer. Note: This abstract was not presented at the meeting. Citation Format: Lilly Y W Bourguignon, Gabriel Wong, Christine Earle. Hyaluronan-CD44v3 interaction with oct4/sox2/nanog promotes miR-302 expression leading to self-renewal, clonal formation and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3861. doi:10.1158/1538-7445.AM2014-3861