tbuckley/cabot-search huggingface dataset:
Comparison of the Effect of the Carcinogen &lt;italic&gt;N&lt;/italic&gt;-Hydroxy-&lt;italic&gt;N-2&lt;/italic&gt;-fluorenylacetamide in Infant and Weanling Rats
Authors: J. H. Weisburger, M. Klein, E. K. Weisburger, R. M. Glass, G. Woodard, M. T. I. Cronin
Journal: JNCI Journal of the National Cancer Institute (1970)

The effect of administering 12 intragastric doses of N-hydroxy-N-2-fluorenylacetamide over a 4-week period to infant male and female Fischer rats, followed by carcinogen in the diet for 7–9 months, was compared with the results seen when intra gastric carcinogen treatment was begun with weanling rats or when the carcinogen was included in the diet only from weaning onward. Other groups of infants or weanlings were given the carcinogen only by gastric intubation for 30 days or 12 doses. Autopsies were performed after 32 weeks on males and after 39 weeks on females to test whether treatment of very young animals would yield a cancerous response faster than in older animals. In the short experimental period, intubation of the carcinogen only during infancy resulted in no detectable cancer, whereas parallel administration to weanlings induced a few tumors in the liver and intestine. However, liver tumors were induced in animals given carcinogen in the diet, whether or not they had also received carcinogen as infants. Lesions at other sites in these animals included tumors of the urinary bladder, the ear duct (mostly in females), and occasional tumors in other organs. More intestinal carcinomas and polyps seemed to arise when exposure to N-hydroxy-N-2-fluorenylacetamide was begun with infants rather than with weanlings. It is concluded that in this system, with rats treated for a relatively short experimental period, continued administration of N-hydroxy-N-2-fluorenylacetamide in the diet yielded a variety of tumors, whereas treatment only during infancy resulted in no neoplastic lesions.
EPA programs of vinyl chloride monitoring in ambient air.
Authors: W F Dimmick
Journal: Environmental Health Perspectives (1981)

Before development of an emission standard for vinyl chloride, the Environmental Protection Agency (EPA) conducted three programs to measure vinyl chloride (VC) concentrations in air around plants which either manufacture VC or use it. A brief monitoring survey conducted by EPA Regional Offices found VC in ambient air around poly(vinyl chloride) (PVC) production plants. As a consequence of this survey, a second monitoring program was established to measure VC in the air around VC and PVC production plants. This program found some relatively high concentrations of VC in ambient air around the plants. This program found maximum 24-hr average rations concentrations ranging from 0.32 to 10.6 parts of VC per million parts of air. The program also found an apparent relationship between certain emission excursions and ambient VC concentrations. A third monitoring program was established to measure VC around PVC fabrication plants. This monitoring program found much less VC around PVC fabrication plants than around VC and PVC production plants. In conclusion, VC was found in ambient air around VC production plants and PVC fabrication plants. However, the data show that much less VC escapes into surrounding air from PVC fabricating plants than from VC and PVC production plants.
Flaws in evolutionary theory and interpretation
Authors: Robert O. Deaner, Carel P. van Schaik
Journal: Behavioral and Brain Sciences (2001)

We make three points. First, even if Finlay et al.'s proposed developmental mechanisms hold, there remains great scope for selection on specific brain structures. Second, the positive covariance among the size of brain structures provides far less support for the proposed developmental mechanisms than Finlay et al. acknowledge. Third, even if the proposed mechanisms are the primary size determinants for most brain structures, these structures should not be considered “spandrels.”
Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia
Authors: Robert Tamayev, Luciano D’Adamio
Journal: Molecular Neurodegeneration (2012)

Abstract Background A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid-β precursor protein (APP) processing, which is genetically linked to Alzheimer’s disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by β-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDD KI ). β-cleavage of APP yields the β-carboxyl-terminal (β-CTF) and the amino-terminal-soluble APPβ (sAPPβ) fragments. γ-secretase processing of β-CTF generates Aβ, which is considered the main cause of AD. However, inhibiting Aβ production did not rescue the deficits of FDD KI mice, suggesting that sAPPβ/β-CTF, and not Aβ, are the toxic species causing memory loss. Results Here, we have further analyzed the effect of γ-secretase inhibition. We show that treatment with a γ-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDD KI mice. This deleterious effect on memory correlates with increased levels of the β/α-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDD KI mice, which is consistent with inhibition of γ-secretase activity. Conclusion This harmful effect of the GSI is in sharp contrast with a pathogenic role for Aβ, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic β/α-CTFs caused by GSI treatment. However, γ-secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other γ-secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting γ-secretase in the therapy of AD. Overall, the data also indicate that FDD KI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD.
Low-molecular-weight heat shock proteins in a desert fish (Poeciliopsis lucida): homologs of human Hsp27 and Xenopus Hsp30
Authors: C. E. Norris, M. A. Brown, E. Hickey, L. A. Weber, L. E. Hightower
Journal: Molecular Biology and Evolution (1997)

The heat shock response of a fish which inhabits a highly stressful environment (Poeciliopsis lucida, a minnow from river systems of the Sonoran desert in northwestern Mexico) was investigated. Cells derived from this fish exhibited a typical heat shock response when exposed to elevated temperature, synthesizing high levels of 90 kDa, 70 kDa, and 30 kDa heat shock proteins (Hsp90, Hsp70, and Hsp30), as well as lower amounts of other heat shock proteins. Additional small heat shock proteins (sHSPs), including Hsp27, were induced after a prolonged heat shock at a time when synthesis of Hsp70 and Hsp30 was decreasing. Characterization of cDNA clones for hsp27 and hsp30 revealed that both are members of the alpha-crystallin/sHSP superfamily but belong to separate lineages within this gene family. The multiple isoforms of P. lucida Hsp30 appear to be members of a multigene family and are most closely related to salmon and Xenopus Hsp30s. In contrast, Hsp27 is highly similar to mammalian and avian sHSPs; it was synthesized as three isoforms which represented differentially phosphorylated forms of a single polypeptide. In Poeciliopsis, the various sHSPs may each perform a subset of the roles attributed to mammalian sHSPs. The conservation of phosphorylation sites in Hsp27 may indicate an involvement in signal transduction to the actin cytoskeleton. The hsp30 genes appear to have diverged more rapidly than the corresponding hsp27 genes; the various members of the Hsp30 family may function as molecular chaperones and, in this role, may be less evolutionarily constrained. Finally, the presence of these two classes of sHSP in a single taxon indicates that these two lineages arose by gene duplication early in the evolution of vertebrates and raises questions about the fate of homologs of Hsp30 in mammals and of Hsp27 in Xenopus.
Molecular engineering of short half-life small peptides (VIP, αMSH and γ<sub>3</sub>MSH) fused to latency-associated peptide results in improved anti-inflammatory therapeutics
Authors: Sandrine Vessillier, Gill Adams, Trinidad Montero-Melendez, Rita Jones, Michael Seed, Mauro Perretti, Yuti Chernajovsky
Journal: Annals of the Rheumatic Diseases (2011)

Objective To facilitate the targeting to inflammation sites of small anti-inflammatory peptides, with short half-lives, by fusion with the latency-associated peptide (LAP) of transforming growth factor β1 through a cleavable matrix metalloproteinase (MMP) linker. This design improves efficacy, overcoming the limitations to their clinical use. Methods We generated latent forms of vasoactive intestinal peptide (VIP), α-melanocyte-stimulating hormone (MSH) and γ 3 MSH by fusion to LAP through an MMP cleavage site using recombinant DNA technology. The biological activities of these latent therapeutics were studied in vivo using monosodium urate (MSU)-induced peritonitis and collagen-induced arthritis (CIA) models. We assessed gene therapy and purified protein therapy. Results The recruitment of the polymorphonuclear cells induced by MSU injection into mouse peritoneal cavity was reduced by 35% with γ 3 MSH (1 nmol), whereas administration of a much lower dose of purified latent LAP–MMP–γ 3 MSH (0.03 nmol) attenuated leucocyte influx by 50%. Intramuscular gene delivery of plasmids coding LAP–MMP–VIP and LAP–MMP–αMSH at disease onset reduced the development of CIA compared with LAP–MMP, which does not contain any therapeutic moiety. Histological analysis confirmed a significantly lower degree of inflammation, bone and cartilage erosion in groups treated with LAP–MMP–VIP or LAP–MMP–αMSH. Antibody titres to collagen type II and inflammatory cytokine production were also reduced in these two groups. Conclusion Incorporation of small anti-inflammatory peptides within the LAP shell and delivered as recombinant protein or through gene therapy can control inflammatory and arthritic disease. This platform delivery can be developed to control human arthritides and other autoimmune diseases.
Regulation of endothelial barrier function during flow-induced conversion to an arterial phenotype
Authors: J SEEBACH, G DONNERT, R KRONSTEIN, S WERTH, B WOJCIAKSTOTHARD, D FALZARANO, C MROWIETZ, S HELL, H SCHNITTLER
Journal: Cardiovascular Research (2007)

Objective Flow-induced conversion of endothelial cells into an elongated arterial phenotype requires a coordinated regulation of cell junctions. Here we investigated the effect of acute and chronic flow on junction regulation.
Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF–induced expansion of myeloid progenitor cells
Authors: Mirjam H. A. Hermans, Gert-Jan van de Geijn, Claudia Antonissen, Judith Gits, Daphne van Leeuwen, Alister C. Ward, Ivo P. Touw
Journal: Blood (2003)
Intensive training in elite young female athletes
Authors: A D G Baxter-Jones, N Maffulli
Journal: British Journal of Sports Medicine (2002)

Assessment and Research Centre (FIFA, F-MARC), and the International Olympic Committee Medical Commission (IOC).The aim of the symposium was to provide recommendations for the improvement of safety and health of athletes who suffer concussive injuries in ice hockey, football (soccer), and other sports.To this end a range of experts were invited to address specific issues of epidemiology, basic and clinical science, grading systems, cognitive assessment, new research methods, protective equipment, management, prevention, and long term outcome, and to discuss a unitary model for understanding concussive injury.At the conclusion of the conference, a small group of experts were given a mandate by the conference delegates and organising bodies to draft a document describing the agreement position reached by those in attendance at that meeting.For the purpose of this paper, this group will be called the Concussion in Sport Group (CISG).
Rapid Decline of Kidney Function Increases Cardiovascular Risk in the Elderly
Authors: Michael G. Shlipak, Ronit Katz, Bryan Kestenbaum, David Siscovick, Linda Fried, Anne Newman, Dena Rifkin, Mark J. Sarnak
Journal: Journal of the American Society of Nephrology (2009)

Chronic kidney disease (CKD), defined at a specific time point, is an important risk factor for cardiovascular disease. Whether the rate of kidney function decline contributes additional cardiovascular risk is unknown. In the Cardiovascular Health Study, we compared the associations of changes in kidney function during the first 7 yr with the incidence of heart failure (HF), myocardial infarction (MI), stroke, and peripheral arterial disease (PAD) during the subsequent 8 yr. We defined a rapid decline in cystatin C–based estimated GFR as >3 ml/min per 1.73 m2/yr, on the basis of determination at baseline, year 3, and year 7. Among eligible participants, 1083 (24%) had rapid kidney decline. The incidence of each type of cardiovascular event was significantly higher among patients with rapid decline (all P < 0.001). After multivariate adjustment for demographics, cardiovascular disease risk factors, and baseline kidney function, rapid kidney function decline was significantly associated with HF (adjusted hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.13 to 1.53), MI (HR 1.48; 95% CI 1.21 to 1.83), and PAD (HR 1.67; 95% CI 1.02 to 2.75) but not with stroke (HR 1.19; 95% CI 0.97 to 1.45). The association of rapid decline with each outcome did not differ by the presence or absence of CKD. In conclusion, declining kidney function associates with higher risk for HF, MI, and PAD among patients with or without CKD.
THE SPECIFICITY OF ALLERGIC REACTIONS
Authors: S. B. Salvin, R. F. Smith
Journal: The Journal of Experimental Medicine (1961)

Intradermal injection of a simple hapten (e.g., 1-fluoro-2,4-dinitrobenzene) in water-in-oil emulsion results in contact hypersensitivity to surface application of the homologous hapten and, after appearance of circulating antibody, in Arthus type hypersensitivity to a conjugate of homologous hapten with guinea pig serum. Intradermal administration of this conjugate induces delayed and subsequently Arthus hypersensitivity to the conjugate, but no evidence of a contact reaction to the hapten alone. When a conjugate of hapten plus solubilized guinea pig skin is used as the sensitizing antigen, both contact hypersensitivity to the hapten and delayed and/or Arthus reactions to the conjugate develop. These observations are consistent with the hypothesis that the specificity of contact sensitivity is directed toward some particular protein of the skin which has been modified by combination with hapten.
Honokiol traverses the blood-brain barrier and induces apoptosis of neuroblastoma cells via an intrinsic bax-mitochondrion-cytochrome c-caspase protease pathway
Authors: J.-W. Lin, J.-T. Chen, C.-Y. Hong, Y.-L. Lin, K.-T. Wang, C.-J. Yao, G.-M. Lai, R.-M. Chen
Journal: Neuro-Oncology (2012)

Neuroblastomas, an embryonic cancer of the sympathetic nervous system, often occur in young children. Honokiol, a small-molecule polyphenol, has multiple therapeutic effects and pharmacological activities. This study was designed to evaluate whether honokiol could pass through the blood-brain barrier (BBB) and induce death of neuroblastoma cells and its possible mechanisms. Primary cerebral endothelial cells (CECs) prepared from mouse brain capillaries were cultured at a high density for 4 days, and these cells formed compact morphologies and expressed the ZO-1 tight-junction protein. A permeability assay showed that the CEC-constructed barrier obstructed the passing of FITC-dextran. Analyses by high-performance liquid chromatography and the UV spectrum revealed that honokiol could traverse the CEC-built junction barrier and the BBB of ICR mice. Exposure of neuroblastoma neuro-2a cells and NB41A3 cells to honokiolinduced cell shrinkage and decreased cell viability. In parallel, honokiol selectively induced DNA fragmentation and cell apoptosis rather than cell necrosis. Sequential treatment of neuro-2a cells with honokiol increased the expression of the proapoptotic Bax protein and its translocation from the cytoplasm to mitochondria. Honokiol successively decreased the mitochondrial membrane potential but increased the release of cytochrome c from mitochondria. Consequently, honokiol induced cascade activation of caspases-9, -3, and -6. In comparison, reducing caspase-6 activity by Z-VEID-FMK, an inhibitor of caspase-6, simultaneously attenuated honokiol-induced DNA fragmentation and cell apoptosis. Taken together, this study showed that honokiol can pass through the BBB and induce apoptotic insults to neuroblastoma cells through a Bax-mitochondrion-cytochrome c-caspase protease pathway. Therefore, honokiol may be a potential candidate drug for treating brain tumors.
Sarcopenia in COPD: prevalence, clinical correlates and response to pulmonary rehabilitation
Authors: S. E. Jones, M. Maddocks, S. S. C. Kon, J. L. Canavan, C. M. Nolan, A. L. Clark, M. I. Polkey, W. D.-C. Man
Journal: Thorax (2015)

<h3>Background</h3> Age-related loss of muscle, sarcopenia, is recognised as a clinical syndrome with multiple contributing factors. International European Working Group on Sarcopenia in Older People (EWGSOP) criteria require generalised loss of muscle mass and reduced function to diagnose sarcopenia. Both are common in COPD but are usually studied in isolation and in the lower limbs. <h3>Objectives</h3> To determine the prevalence of sarcopenia in COPD, its impact on function and health status, its relationship with quadriceps strength and its response to pulmonary rehabilitation (PR). <h3>Methods</h3> EWGSOP criteria were applied to 622 outpatients with stable COPD. Body composition, exercise capacity, functional performance, physical activity and health status were assessed. Using a case–control design, response to PR was determined in 43 patients with sarcopenia and a propensity score-matched non-sarcopenic group. <h3>Results</h3> Prevalence of sarcopenia was 14.5% (95% CI 11.8% to&nbsp;17.4%), which increased with age and Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) stage, but did not differ by gender or the presence of quadriceps weakness (14.9 vs 13.8%, p=0.40). Patients with sarcopenia had reduced exercise capacity, functional performance, physical activity and health status compared with patients without sarcopenia (p&lt;0.001), but responded similarly following PR; 12/43 patients were no longer classified as sarcopenic following PR. <h3>Conclusions</h3> Sarcopenia affects 15% of patients with stable COPD and impairs function and health status. Sarcopenia does not impact on response to PR, which can lead to a reversal of the syndrome in select patients.
Risk assessment of clinical outcomes in Asian patients with chronic hepatitis B using enhanced liver fibrosis test
Authors: Beom Kyung Kim, Hyon‐Suk Kim, Eun Jin Yoo, Eun Ji Oh, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang‐Hyub Han, Seung Up Kim, Young Nyun Park
Journal: Hepatology (2014)

Serum fibrosis markers, such as the enhanced liver fibrosis (ELF) test, have been suggested as alternatives for liver biopsy (LB) in assessing liver fibrosis. We investigated the efficacy of the ELF test in predicting development of liver-related events (LREs) in patients with chronic hepatitis B (CHB). A total of 170 patients (103 men; 60.6%) with CHB who underwent LB and serological tests for determining ELFs were enrolled. All patients were followed up to monitor LRE development, defined as hepatic decompensation, hepatocellular carcinoma, and/or liver-related death. The mean age was 45.3 years. During the follow-up period (median, 41 months), 39 (22.9%) patients experienced LREs. In patients with LREs, age, proportion of male gender, ELF test results, age-spleen-platelet ratio (ASPRI), liver stiffness (LS) value, and proportion of histological cirrhosis were significantly higher than those in patients without LREs (all P < 0.05). Areas under the receiver operating characteristic curves to predict LRE development were 0.808 for the ELF test, 0.732 for LS value, 0.713 for histological fibrosis stages using Batts and Ludwig's scoring system, and 0.687 for ASPRI. On multivariate analysis, along with age, the ELF test was an independent predictor of LRE development (adjusted hazard ratio [HR], 1.438; P < 0.001). When we applied a three-tier stratification of our study population using cut-off ELF values of 8.10 and 10.40, patients with low (P = 0.002; adjusted HR: 0.045; 95% confidence interval [CI]: 0.006-0.330) and intermediate (P < 0.001; adjusted HR: 0.239; 95% CI: 0.122-0.469) ELF range were found less likely to develop LREs, compared to those with high ELF range.ELF is useful in a noninvasive prediction of LRE development. Transient elastography showed a statistically similar prognostic performance for LREs as the ELF, but other noninvasive tests were inferior.
Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
Authors: Carolyn Waugh Kinkade, Mireia Castillo-Martin, Anna Puzio-Kuter, Jun Yan, Thomas H. Foster, Hui Gao, Yvonne Sun, Xuesong Ouyang, William L. Gerald, Carlos Cordon-Cardo, Cory Abate-Shen
Journal: Journal of Clinical Investigation (2008)

The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2–interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.