gebhart/patrepeval huggingface dataset:
Rho-associated kinase inhibitor Y-27632 promotes survival of cynomolgus monkey embryonic stem cells (2008)

Non-human primates are suitable models for preclinical research aimed at cell-replacement therapies. Recently, it has been reported that Rho-associated kinase inhibitor Y-27632 markedly reduced dissociation-induced apoptosis of human embryonic stem (hES) cells, and is expected as a novel supplement for hES cell maintenance or differentiation inductions; however, the effects of the chemical are still to be determined in model animals. Here, we demonstrated the effect of Y-27632 on cynomolgus monkey ES (cyES) cells. Also, in cyES cells, Y-27632 treatment dramatically improved the efficiency of colony formation from single cells without affecting the pluripotent state and karyotype. Y-27632 supplementation was also effective for feeder-free culture and differentiation induction. Neural stem cells directly induced from cyES cells could give rise to neurons, astrocytes and dopamine producing cells. The present result not only suggests that the chemical was effective for improving the culture system of primate ES cells, but also the similarity between cyES and hES cells regarding the reactions to the chemical, which might be further evidence that cyES cells are superior models for hES cells.
Abstract 17070: Efficacy and Safety of Alirocumab: Pooled Analyses of 1048 Individuals With Diabetes Mellitus From Five Placebo-controlled Phase 3 Studies of at Least 52 Weeks Duration (2015)

Background: Individuals with diabetes (DM) are at high risk for CVD and may not achieve adequate control of LDL-C levels with current lipid-lowering therapies. Aim: To assess alirocumab (ALI) efficacy and safety in individuals with and without baseline DM. Methods: Five placebo (PBO)-controlled Phase 3 studies of 52-78 weeks were analyzed, comprising 1048 individuals with DM at study entry and 2444 with no DM (safety population). All individuals had hypercholesterolemia, and were on maximally tolerated background statin therapy. Efficacy data were pooled by initial ALI dose; 3 studies (n=1043, ITT analysis) used PBO or ALI 75 mg every 2 weeks (Q2W), increasing to 150 mg Q2W at W12 if LDL-C at W8 ≥ 70 mg/dL; 2 studies (n=2416, ITT analysis) initiated treatment with PBO or ALI 150 mg Q2W. All doses were 1 mL SC injection. Safety data were pooled for all 5 studies. Efficacy data are reported to W24, safety for ≥52 weeks. Results: Individuals with DM had lower mean baseline LDL-C levels. At W12, ALI 75 mg Q2W significantly reduced LDL-C levels from baseline vs PBO with treatment effect consistent regardless of DM status (Table). A higher proportion of participants with no DM received a dose increase at W12, leading to a greater magnitude of reduction at W24 in that group. For those initiating at ALI 150 mg Q2W, LDL-C reductions of 58.3% (DM) and 62.3% (no DM) vs PBO were achieved at W24 (Table). Improvements were seen in other parameters, including TGs, HDL-C, and Lp(a), largely irrespective of baseline DM status. Adverse event (AE) rates were generally comparable in both groups. AEs occurring in ≥5% of individuals in all subgroups were nasopharyngitis and URI. Injection site reactions (ISRs) were less frequent in those with DM: ALI 3.6% and PBO 2.8%, vs no DM: ALI 8.4% and PBO 6.1%. Conclusions: ALI demonstrated robust LDL-C reductions in individuals with and without DM. Safety observations were generally similar regardless of DM status, although those with DM reported fewer ISRs than those without.
A Dominant Mutation That Predisposes to Multiple Intestinal Neoplasia in the Mouse (1990)

In a pedigree derived from a mouse treated with the mutagen ethylnitrosourea, a mutation has been identified that predisposes to spontaneous intestinal cancer. The mutant gene was found to be dominantly expressed and fully penetrant. Affected mice developed multiple adenomas throughout the entire intestinal tract at an early age.
Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death (2006)

Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside beta-galactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose- and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.
Localization of ISG15 and Conjugated Proteins in Bovine Endometrium Using Immunohistochemistry and Electron Microscopy (2003)

The interferon-stimulated gene ISG15, a ubiquitin homolog, becomes conjugated to and regulates uterine proteins in response to conceptus-derived interferon-tau on d 18 of pregnancy. It was hypothesized here that cellular localization of ISG15 within endometrial cells might provide insight regarding function. Uteri were collected from cows (approximately 21-d estrous cycle) on d 17-21/0 of the estrous cycle and pregnancy and d 23, 45, and 50 of pregnancy. Intracellular ISG15 and its conjugates were present on d 17 of pregnancy, peaked to highest levels from d 18 to 23 and then declined to low but detectable levels by d 45 (P < 0.05) based on Western blotting. ISG15 and its conjugates were not detected on d 50 of pregnancy or during the estrous cycle. Immunohistochemistry revealed that ISG15 was localized throughout the endometrium on d 18-23, with heaviest staining in the sublumenal stratum compactum and the glandular epithelium throughout the stratum spongiosum. By d 45 and 50, ISG15 was lightly stained only in the stratum compactum immediately beneath the lumenal epithelium. Using transmission electron microscopy and immunogold labeling, ISG15 was specifically localized to organelles and compartments of endometrial epithelial cells and stromal cells: nucleus, perinuclear space, cytosol, mitochondria, rough endoplasmic reticulum, and cell membrane. This specific localization in epithelial and stromal cells led to the conclusion that ISG15 has diverse intracellular functions. The sustained presence of conjugated ISG15 through d 50 of pregnancy might reflect stabilization of conjugated proteins in response to implantation and the development of the placenta.
Glucocorticoid receptor structure and function in glucocorticoid-resistant small cell lung carcinoma cells. (1996)

Human small cell lung carcinomas (SCLCs) frequently express the adrenocorticotrophin precursor gene proopiomelanocortin. Glucocorticoids usually fail to inhibit this ectopic adrenocorticotrophin production, in contrast to their effects in the pituitary. We have shown three human SCLC cell lines to be globally resistant to glucocorticoid action; in two of these lines this occurs despite the presence of glucocorticoid receptors (GR+). Accordingly, we have cloned and sequenced the GR coding region from one of these two GR+, SCLC cell lines, COR L24, and identified compound heterozygous mutations. One allele had a single nucleotide substitution of A to G in the NH2-terminal domain, which altered Asp to Ser at amino acid 363. The other allele contained a trinucleotide insertion at the 5' boundary of exon 4, which introduced an additional amino acid, Arg453, between the two zinc fingers of the DNA binding domain. In cotransfection studies using the glucocorticoid responsive mouse mammary tumor virus-luciferase Ser363 did not alter receptor function. In contrast, Arg453 encoded a GR with 48% Vmax activity compared to wild-type receptor (P < 0.001), with an unchanged EC50. Thus, GR mutations may contribute to the glucocorticoid-resistant phenotype of GR+ COR L24 cells, which could confer survival advantage to this highly malignant neuroendocrine tumor.
A Novel Bispecific, Trivalent Antibody Construct for Targeting Pancreatic Carcinoma (2008)

Preclinical and clinical studies have demonstrated the application of radiolabeled mAb-PAM4 for nuclear imaging and radioimmunotherapy of pancreatic carcinoma. We have now examined the ability of a novel PAM4-based, bispecific monoclonal antibody (mAb) construct, TF10, to pretarget a radiolabeled peptide for improved imaging and therapy. TF10 is a humanized, bispecific mAb, divalent for mAb-PAM4 and monovalent for mAb-679, reactive against the histamine-succinyl-glycine hapten. Biodistribution studies and nuclear imaging of the radiolabeled TF10 and/or TF10-pretargeted hapten-peptide (IMP-288) were conducted in nude mice bearing CaPan1 human pancreatic cancer xenografts. (125)I-TF10 cleared rapidly from the blood, with levels decreasing to <1% injected dose per gram (ID/g) by 16 hours. Tumor uptake was 3.47 +/- 0.66% ID/g at this time point with no accumulation in any normal tissue. To show the utility of the pretargeting approach, (111)In-IMP-288 was administered 16 hours after TF10. At 3 hours postadministration of radiolabeled peptide, imaging showed intense uptake within the tumors and no evidence of accretion in any normal tissue. No targeting was observed in animals given only the (111)In-peptide. Tumor uptake of the TF10-pretargeted (111)In-IMP-288 was 24.3 +/- 1.7% ID/g, whereas for (111)In-IMP-288 alone it was only 0.12 +/- 0.002% ID/g at 16 hours. Tumor/blood ratios were significantly greater for the pretargeting group ( approximately 1,000:1 at 3 hours) compared with (111)In-PAM4-IgG ( approximately 5:1 at 24 hours; P < 0.0003). Radiation dose estimates suggested that TF10/(90)Y-peptide pretargeting would provide a greater antitumor effect than (90)Y-PAM4-IgG. Thus, the results suggest that TF10 pretargeting may provide improved imaging for early detection, diagnosis, and treatment of pancreatic cancer as compared with directly radiolabeled PAM4-IgG.
Dual-band miniaturized microstrip fractal antenna for a small GSM 1800 + UMTS mobile handset (2004)

A novel microstrip GSM1800 + UMTS dual-band antenna based on a Koch fractal shaped patch element is presented. The antenna has been developed to be used in small handsets of future multi-standard mobile communication systems. The fractal miniaturization technique has been combined with a patch inverted F antenna (PIFA) structure. The effect of a small ground plane has been taken into account. The antenna prototype has been fabricated and tested. Good agreement has been obtained between numerical simulations and experimental results providing validation of the design procedure.
Activation of AXIN2 Expression by β-Catenin-T Cell Factor (2002)

The Wnt pathway regulates cell fate, proliferation, and apoptosis, and defects in the pathway play a key role in many cancers. Although Wnts act to stabilize beta-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3beta, and Axin1 or its homolog Axin2/Axil/conductin promotes beta-catenin phosphorylation and subsequent proteasomal degradation. We found that the rat Axil gene was strongly induced upon neoplastic transformation of RK3E cells by mutant beta-catenin or gamma-catenin or after ligand-induced activation of a beta-catenin-estrogen receptor fusion protein. Expression of Wnt1 in murine breast epithelial cells activated the conductin gene, and human cancers with defective beta-catenin regulation had elevated AXIN2 gene and protein expression. Expression of AXIN2/Axil was strongly repressed in cancer cells by restoration of wild type adenomatous polyposis coli function or expression of a dominant negative form of T cell factor (TCF)-4. TCF binding sites in the AXIN2 promoter played a key role in the ability of beta-catenin to activate AXIN2 transcription. In contrast to AXIN2/Axil, expression of human or rat Axin1 homologs was nominally affected by beta-catenin-TCF. Because Axin2 can inhibit beta-catenin abundance and function, the data implicate AXIN2 in a negative feedback pathway regulating Wnt signaling. Additionally, although Axin1 and Axin2 have been thought to have comparable functions, the observation that Wnt pathway activation elevates AXIN2 but not AXIN1 expression suggests that there may be potentially significant functional differences between the two proteins.
Delayed-type hypersensitivity response is a predictor of peripheral blood T-cell immunity after HER-2/neu peptide immunization. (2000)

Many groups that immunize cancer patients with cancer vaccines use the generation of a delayed-type hypersensitivity (DTH) response as the primary measure of the ability to immunize a patient to a tumor cell or specific tumor antigen. This study examines whether the development of a tumor antigen-specific DTH response, measured after vaccination with peptide-based vaccines, correlates to in vitro assessment of peripheral blood antigen-specific T-cell responses. The HER-2/neu protein was used as a model tumor antigen. Thirty-two patients who completed a course of immunization with HER-2/neu peptide-based vaccines were analyzed. HER-2/neu peptide-specific DTH responses (n = 93) and peripheral blood T-cell responses (n = 93) were measured 30 days after the final immunization. Size of DTH induration was correlated with HER-2/neu-specific T-cell proliferative responses assessed from peripheral blood lymphocytes isolated concurrently with peptide skin test placement. HER-2/neu peptide-specific DTH responses > or =10 mm2 correlated significantly to a measurable peptide-specific peripheral blood T-cell response defined as stimulation index >2.0 (P = 0.0006). However, antigen-specific DTH responses with magnitudes between 5 and 9 mm2 were not significantly associated with the development of systemic immunity. DTH responses between 5 and 9 mm2 carried an odds ratio of 1.3 (P = 0.61) in predicting a measurable systemic tumor antigen response. The findings presented here demonstrate that tumor antigen-specific DTH responses > or =10 mm2 correlate with measurable in vitro antigen-specific lymphocytic proliferation and are, in this model system, a reflection of systemic immunization.
Cross-neutralization of human immunodeficiency virus type 1 and 2 and simian immunodeficiency virus isolates (1992)

In contrast to infrequent and low-titer cross-neutralization of human immunodeficiency virus type 1 (HIV-1) isolates by HIV-2- and simian immunodeficiency virus (SIV)-positive sera, extensive cross-neutralization of HIV-2NIH-Z, SIVMAC251, and SIVAGM208K occurs with high titer, suggesting conservation of epitopes and mechanism(s) of neutralization. The V3 regions of HIV-2 and SIV isolates, minimally related to the HIV-1 homolog, share significant sequence homology and are immunogenic in monkeys as well as in humans. Whereas the crown of the V3 loop is cross-reactive among HIV-1 isolates and elicits neutralizing antibodies of broad specificity, the SIV and especially HIV-2 crown peptides were not well recognized by cross-neutralizing antisera. V3 loop peptides of HIV-2 isolates did not elicit neutralizing antibodies in mice, guinea pigs, or a goat and together with SIV V3 peptides did not inhibit serum neutralization of HIV-2 and SIV. Thus, the V3 loops of HIV-2 and SIV do not appear to constitute simple linear neutralizing epitopes. In view of the immunogenicity of V3 peptides, the failure of conserved crown peptides to react with natural sera implies a significant role of loop conformation in antibody recognition. Our studies suggest that in addition to their grouping by envelope genetic relatedness, HIV-2 and SIV are neutralized similarly to each other but differently from HIV-1. The use of linear peptides of HIV-2 and SIV as immunogens may require greater attention to microconformation, and alternate subunit approaches may be needed in exploiting these viruses as vaccine models. Such approaches may also be applicable to the HIV-1 system in which conformational epitopes, in addition to the V3 loop, participate in virus neutralization.
The efficacy of interferon-alpha treatment in human T-lymphotropic virus type-I-associated myelopathy. (1990)

We investigated the efficacy of interferon-alpha (IFN-alpha) treatment in 5 patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM). Treatment with IFN-alpha yielded clinical improvement of gait, and sensory and/or sphincter disturbance in 4 out of the 5 HAM patients. IFN-alpha treatment did not bring about uniform changes in lymphocyte subsets or anti-HTLV-I antibody titer of peripheral blood. Although the stimulation indexes to phytohemagglutinin, concanavalin A, and pokeweed mitogen were decreased in the culture of the peripheral blood lymphocytes (PBL) in the 5 HAM patients before the treatment, the stimulation indexes to these mitogens were significantly increased except in 1 case after the IFN-alpha treatment. These changes were based primarily on the depression of the spontaneous proliferation of PBL without mitogen. These results appear to point out a very important phenomenon for the investigation of the pathogenesis of HAM.
A New Route to 11-Ketosteroids by Fission of a ▵9(11)-Ethylene Oxide1,2 (1951)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA New Route to 11-Ketosteroids by Fission of a ▵9(11)-Ethylene Oxide1,2Hans Heymann and Louis F. FieserCite this: J. Am. Chem. Soc. 1951, 73, 11, 5252–5265Publication Date (Print):November 1, 1951Publication History Published online1 May 2002Published inissue 1 November 1951https://pubs.acs.org/doi/10.1021/ja01155a074https://doi.org/10.1021/ja01155a074research-articleACS PublicationsRequest reuse permissionsArticle Views182Altmetric-Citations48LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Occupational and environmental causes of parkinsonism. (1992)

Occupational causes of parkinsonism have usually been identified by direct temporal association of an exposure with disease symptoms, although recently a latent period between exposure and disease causation is being investigated. This review presents the definition of parkinsonism as contrasted with Parkinson's disease, notes the general concepts important to the consideration of toxic effects on the central nervous system, and addresses each group of agents known to cause parkinsonism, including common sources of exposure, clinical course, and proposed mechanisms of toxicity. Agents discussed include manganese, carbon disulfide, organic solvents, carbon monoxide, and MTPT and similar agents.
Capillary Rise of Nanostructured Microwicks (2018)

Capillarity refers to the driving force to propel liquid through small gaps in the absence of external forces, and hence enhanced capillary force has been pursued for various applications. In this study, flower like ZnO nanostructures are successfully deposited to enhance capillarity of microwick structures that are specially designed to augment boiling heat transfer performance. Microreactor-assisted nanomaterial deposition, MAND<sup>TM</sup>, is employed with a flow cell to deposit the ZnO nanostructures on a large sized microwick (4.3 cm × 10.7 cm) with dual-channel configuration. A capillary rise experiment based on the mass gain method is first performed using water and ethanol (EtOH) as the working liquids to demonstrate the enhanced capillary force induced by the ZnO nanostructure on the microwick structure. It is found that the coating of ZnO nanostructure effectively propels the working fluids through the nano- or micro pores created from the ZnO nanostructure and consequently improves the capillary force. In order to investigate the wicking mechanism of the ZnO coated microwick structure, the capillary rise result based on height measurement was compared with analytical models. It is found that the gravity effect and viscous force play an important role in wicking rise of the coated wick structure. This study aims at demonstrating the capability of the integrated MAND process with a flow cell for producing a large scaled nanostructured surface, which eventually has a great potential for enhanced boiling heat transfer.