tbuckley/cabot-search huggingface dataset:
Retinoblastoma Protein and CCAAT/Enhancer-Binding Protein β Are Required for 1,25-Dihydroxyvitamin D3-Induced Monocytic Differentiation of HL60 Cells
Authors: Yan Ji, George P. Studzinski
Journal: Cancer Research (2004)

Abstract Derivatives of vitamin D (deltanoids) are well known to have the ability to induce differentiation of a variety of malignant cells, including human leukemia cells, but the signaling pathways that lead to such an outcome are unclear. In this study we investigated the role of the retinoblastoma protein (pRb) and the CCAAT/enhancer-binding protein (C/EBP) β in 1,25-dihydroxyvitamin D3 (1,25D3)-induced monocytic differentiation of human leukemia HL60 cells. It was found that in this system, pRb is up-regulated within 12 h of exposure to the inducer, and the kinetics of its increase parallel the appearance of the early markers of differentiation, CD14 and monocyte-specific esterase. The increase in pRb expression was accompanied by a similar increase in C/EBPβ protein, and these two proteins coimmunoprecipitated, suggesting formation of a complex. Oligonucleotides antisense to pRb or C/EBPβ (but not to C/EBPα) or containing the C/EBP-binding sequence (“decoys”), all inhibited 1,25D3-induced differentiation. Inhibition of signaling by vitamin D receptor or by mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase pathways using pharmacological inhibitors ZK159222, PD98059, or SP600125, respectively, inhibited pRb and C/EBPβ expression and differentiation in a coordinate manner. In contrast, inhibition of the p38MAPK pathway by SB202190 potentiated differentiation and the up-regulation of pRb and C/EBPβ. We suggest that 1,25D3 may signal monocytic differentiation of HL60 cells in a vitamin D receptor-dependent manner that includes activation of extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase MAPK pathways, which then up-regulate pRb and C/EBPβ expression and in turn initiate the differentiation process.
The Association between α4-Integrin, P-Selectin, and E-Selectin in an Allergic Model of Inflammation
Authors: Samina Kanwar, Daniel C. Bullard, Michael J. Hickey, C. Wayne Smith, Arthur L. Beaudet, Barry A. Wolitzky, Paul Kubes
Journal: The Journal of Experimental Medicine (1997)

In this study, we examined the relationship between the endothelial selectins (P-selectin and E-selectin) and whether they are critical for α4-integrin–dependent leukocyte recruitment in inflamed (late phase response), cremasteric postcapillary venules. Animals were systemically sensitized and 2 wk later challenged intrascrotally with chicken ovalbumin. Leukocyte rolling flux, adhesion, and emigration were assessed at baseline and 4 and 8 h postantigen challenge. There was a significant increase in leukocyte rolling flux, adhesion, and emigration in sensitized and challenged mice at both 4 and 8 h. At 8 h, the increase in leukocyte rolling flux was ∼50% inhibitable by an anti–α4-integrin antibody, 98% inhibitable by fucoidin (a selectin-binding carbohydrate), and 100% inhibitable by an anti–P-selectin antibody. P-selectin–deficient animals displayed no leukocyte rolling or adhesion at 8 h after challenge. However, at 8 h there were many emigrated leukocytes in the perivascular space suggesting P-selectin–independent rolling at an earlier time point. Indeed, at 4 h postantigen challenge in P-selectin–deficient mice, there was increased leukocyte rolling, adhesion, and emigration. The rolling in the P-selectin– deficient mice at 4 h was largely α4-integrin dependent. However, there was an essential E-selectin– dependent component inasmuch as an anti–E-selectin antibody completely reversed the rolling, and in E-selectin and P-selectin double deficient mice rolling, adhesion and emigration were completely absent. These results illustrate that P-selectin underlies all of the antigen-induced rolling with a brief transient contribution from E-selectin in the P-selectin–deficient animals. Finally, the antigen-induced α4-integrin–mediated leukocyte recruitment is entirely dependent upon endothelial selectins.
Testing for faecal calprotectin (PhiCal) in the Norwegian Colorectal Cancer Prevention trial on flexible sigmoidoscopy screening: comparison with an immunochemical test for occult blood (FlexSure OBT)
Authors: Geir Hoff, Tom Grotmol, Espen Thiis-Evensen, Michael Bretthauer, Ghous G. Gondal, Morten H. Vatn
Journal: Gut (2004)

<b>Background:</b> Screening for colorectal cancer (CRC) using guaiac based faecal occult blood tests (FOBT) has an estimated programme sensitivity of &gt;60% but &lt;30% for strictly asymptomatic CRC in a single screening round. In search for improved non-invasive tests for screening, we compared a test for faecal calprotectin (PhiCal) with a human haemoglobin immunochemical FOBT (FlexSure OBT). <b>Methods:</b> In the Norwegian Colorectal Cancer Prevention (NORCCAP) trial, screenees in one screening arm were offered screening with combined flexible sigmoidoscopy (FS) and FlexSure OBT. They were also requested to bring a fresh frozen sample of stool for the PhiCal test which was performed on samples from screenees with CRC (n = 16), high risk adenoma (n = 195), low risk adenoma (n = 592), and no adenoma (n = 1518) (2321 screenees in total). A positive PhiCal test was defined by a calprotectin level ⩾50 μg/g. <b>Results:</b> The PhiCal test was positive in 24–27% of screenees whether they had no adenoma, low risk adenoma, or high risk adenoma. Ten (63%) of 16 CRCs gave a positive PhiCal test. The total positivity rate in this population was 25% for the PhiCal test compared with 12% for FlexSure OBT, with a sensitivity for advanced neoplasia of 27% and 35%, respectively. Specificity for "any neoplasia" was 76% for the PhiCal test and 90% for FlexSure OBT. <b>Conclusions:</b> In colorectal screening, the performance of the PhiCal test on a single spot from one stool sample was poorer than a single screening round with FlexSure OBT and cannot be recommended for population screening purposes. The findings indicate a place for FlexSure OBT in FOBT screening.
Melatonin improves ultraviolet<scp>B</scp>‐induced oxidative damage and inflammatory conditions in cutaneous tissue of a diurnal<scp>I</scp>ndian palm squirrel<i><scp>F</scp>unambulus pennanti</i>
Authors: S. Goswami, C. Haldar
Journal: British Journal of Dermatology (2014)

Background Skin is exposed to various abiotic and biotic factors. Solar radiation, of which ultraviolet (UV) rays are a principle component, increases the free radical load, and the accumulation of reactive oxygen species (ROS) causes lipid peroxidation, DNA damage and apoptosis, and is also associated with inflammatory responses recruiting molecules [nuclear factor (NF)-κB, interleukin (IL)-6] that can potentially further aggravate the damaged milieu of the cells. One of the potent causes of skin cancers is exposure to UV rays. UV radiation generates a wide range of biological responses such as adaptive, inflammatory and immunological reactions in the skin. Objective To examine the effects of pretreatment with melatonin on UVB (290–320 nm) radiation-mediated damage to the skin of a diurnal rodent Funambulus pennanti. Results The UVB radiation (1·5 J cm−2 for 30 min daily on the shaved abdominal area) for 4 days caused a significant increase in the lipid peroxidation products (thiobarbituric acid reactive substances, TBARS) and decreased the activity of the antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) of the skin. Pretreatment with melatonin (100 μg 100 g−1 bodyweight subcutaneously) improved the damage induced by UVB radiation on the skin and might act via a receptor-independent mechanism. No significant effect of melatonin pretreatment was found on the expression pattern of MT1 (melatonin membrane receptor) and RORα (nuclear retinoic orphan receptor alpha), which suggests a receptor-independent action. However, NF-κB and inflammatory cytokine IL-6 levels were downregulated in the squirrels pretreated with melatonin before the UVB radiation. Conclusion UVB radiation induced oxidative stress in the skin culminating in an inflammatory response. The action of melatonin in protecting the skin from oxidative damage occurs in a receptor-independent manner by lowering the oxidative damage and inflammatory response. On the other hand, melatonin decreased the expression of NF-κB and the circulating proinflammatory cytokine IL-6, suggesting an anti-inflammatory action in protecting the skin from UVB radiation.
Antenatal retinoic acid does not alter alveolization or postnatal lung function in preterm sheep
Authors: K.E. Willet, A.H. Jobe, M Ikegami, J Newnham, P.d Sly
Journal: European Respiratory Journal (2000)

Retinoic acid exposure has been shown to promote surfactant production in foetal rats and to promote alveolization in neonatal rats. It was hypothesized that antenatal retinoic acid treatment would promote alveolization and accelerate functional maturation in the lungs of late gestation preterm sheep. Foetuses received a single i.m. injection of all-trans retinoic acid (RA, 20 mg x kg(-1)) or vehicle control at 115 days gestation (term=150 days) and were delivered at 125 days gestation. To examine the longer term effects of RA on alveolization a second group of animals received RA or vehicle at 121 days gestation and were delivered at 146 days gestation. Liver retinol levels at time of delivery were 2-3-fold higher in both preterm and near-term RA treated animals, indicating a significant impact of RA treatment on retinol metabolism. Dynamic compliance, gas exchange, lung gas volume and saturated phosphatidylcholine pool size at 125 days were unaffected by antenatal RA treatment. Alveolar volume, wall thickness and number at 125 or 146 days were also unaffected by RA treatment. Retinoic acid, as administered in this study, does not appear to accelerate structural or functional maturation of the foetal sheep lung. Response to retinoic acid may be species dependent, highlighting a need for caution when interpreting results from animal based studies.
The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIα in Breast Cancer Cells
Authors: V. Ashutosh Rao, Sarah R. Klein, Keli K. Agama, Eriko Toyoda, Noritaka Adachi, Yves Pommier, Emily B. Shacter
Journal: Cancer Research (2009)

Abstract Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) is being developed as an iron chelator with selective anticancer activity. We investigated the mechanism whereby Dp44mT kills breast cancer cells, both as a single agent and in combination with doxorubicin. Dp44mT alone induced selective cell killing in the breast cancer cell line MDA-MB-231 when compared with healthy mammary epithelial cells (MCF-12A). It induces G1 cell cycle arrest and reduces cancer cell clonogenic growth at nanomolar concentrations. Dp44mT, but not the iron chelator desferal, induces DNA double-strand breaks quantified as S139 phosphorylated histone foci (γ-H2AX) and Comet tails induced in MDA-MB-231 cells. Doxorubicin-induced cytotoxicity and DNA damage were both enhanced significantly in the presence of low concentrations of Dp44mT. The chelator caused selective poisoning of DNA topoisomerase IIα (top2α) as measured by an in vitro DNA cleavage assay and cellular topoisomerase-DNA complex formation. Heterozygous Nalm-6 top2α knockout cells (top2α+/−) were partially resistant to Dp44mT-induced cytotoxicity compared with isogenic top2α+/+ or top2β−/− cells. Specificity for top2α was confirmed using top2α and top2β small interfering RNA knockdown in HeLa cells. The results show that Dp44mT is cytotoxic to breast cancer cells, at least in part, due to selective inhibition of top2α. Thus, Dp44mT may serve as a mechanistically unique treatment for cancer due to its dual ability to chelate iron and inhibit top2α activity. [Cancer Res 2009;69(3):948–57]
Influence of Mechanical, Cellular, and Molecular Factors on Collateral Artery Growth (Arteriogenesis)
Authors: Matthias Heil, Wolfgang Schaper
Journal: Circulation Research (2004)

Growth of collateral blood vessels (arteriogenesis) is potentially able to preserve structure and function of limbs and organs after occlusion of a major artery. The success of the remodeling process depends on the following conditions: (1) existence of an arteriolar network that connects the preocclusive with the postocclusive microcirculation; (2) activation of the arteriolar endothelium by elevated fluid shear stress; (3) invasion (but not incorporation) of bone marrow–derived cells; and (4) proliferation of endothelial and smooth muscle cells. Most organs of most mammals including man can rely on the existence of interconnecting arterioles in most organs and tissues with heart being the exception in rodents and pigs. Arterial occlusion lowers the pressure in the distal vasculature thereby creating a pressure gradient favoring increased flow through preexisting collaterals. This increases fluid shear stress leading to endothelial activation with cellular edema, upregulation of adhesion molecules, mitogenic-, thrombogenic-, and fibrinolytic factors, leading to monocyte invasion with matrix digestion. Smooth muscle cells migrate and proliferate and the vessel enlarges under the influence of increasing circumferential wall stress. Growth factors involved belong to the FGF family and signaling proceeds via the Ras/Raf- and the Rho cascades. Increases in vascular radius and wall thickness restore fluid shear stress and circumferential wall stress to normal levels and growth stops. Although increases in collateral vessel size are very substantial their maximal conductance amounts to only 40% of normal. Forced increases in FSS can reach almost 100%.
Immunohistochemical Staining for<i>Chlamydia pneumoniae</i>Is Increased in Lung Tissue from Subjects with Chronic Obstructive Pulmonary Disease
Authors: LIAN WU, STEPHEN J. M. SKINNER, NEIL LAMBIE, JANE C. VULETIC, FRANCESCO BLASI, PETER N. BLACK
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The seroprevalence of Chlamydia pneumoniae is increased in chronic obstructive pulmonary disease (COPD), and subjects with COPD are more likely to have a positive polymerase chain reaction for C. pneumoniae in their sputum. It has been suggested that C. pneumoniae may have a role in the pathogenesis of COPD. We undertook immunohistochemistical staining for C. pneumoniae in archival tissue from subjects who had undergone lobectomy for bronchial carcinoma. There were 16 subjects with COPD (FEV1 = 64 ± 8% [mean ± SD] predicted) and 21 subjects with normal lung function (FEV1 = 95 ± 11% predicted). There was no difference between the two groups in age or smoking history. Tissues from all of the subjects stained positively for C. pneumoniae, but in the subjects with COPD there were 14.5 positive cells per field (magnification × 400), as compared with 9.3 cells per field in the control subjects (p = 0.02). Fifty-four percent of the macrophages from the subjects with COPD stained positively for C. pneumoniae, as compared with 29% from the control subjects (p < 0.001). A second control group consisted of 18 younger individuals (mean age: 32 yr) who died accidentally. Only 44% of these subjects had positive staining for C. pneumoniae, and the mean number of cells per field was 0.4. These findings suggest that persistent infection with C. pneumoniae is common, and that there is increased immunostaining for C. pneumoniae in COPD. Further studies are necessary to determine whether chronic infection with C. pneumoniae is important in the pathogenesis of COPD.
In Vitro Evaluation of Cell-Mediated Immunity to Epstein-Barr Herpesvirus by Cell Migration Inhibition Tests2
Authors: Patrick K. Lai, Michael P. Alpers, Ewart M. Mackay-Scollay
Journal: JNCI Journal of the National Cancer Institute (1975)

Journal Article In Vitro Evaluation of Cell-Mediated Immunity to Epstein-Barr Herpesvirus by Cell Migration Inhibition Tests Get access Patrick K. Lai, Patrick K. Lai Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael P. Alpers, Michael P. Alpers Search for other works by this author on: Oxford Academic PubMed Google Scholar Ewart M. Mackay-Scollay Ewart M. Mackay-Scollay Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 55, Issue 6, December 1975, Pages 1319–1322, https://doi.org/10.1093/jnci/55.6.1319 Published: 01 December 1975 Article history Received: 08 July 1975 Accepted: 07 August 1975 Published: 01 December 1975
Vertebrate Serpins: Construction of a Conflict-Free Phylogeny by Combining Exon-Intron and Diagnostic Site Analyses
Authors: Hermann Ragg, Tatjana Lokot, Paul-Bertram Kamp, William R. Atchley, Andreas Dress
Journal: Molecular Biology and Evolution (2001)

A combination of three independent biological features, genomic organization, diagnostic amino acid sites, and rare indels, was used to elucidate the phylogeny of the vertebrate serpin (serine protease inhibitor) superfamily. A strong correlation between serpin gene families displaying (1) a conserved exon-intron pattern and (2) family-specific combinations of amino acid residues at specific sites suggests that present-day vertebrates encompass six serpin gene families which evolved from primordial genes by massive intron insertion before or during early vertebrate radiation. Introns placed at homologous positions in the gene sequences in combination with diagnostic sequence characters may also constitute a reliable kinship indicator for other protein superfamilies.
Predicting Chronic Fine and Coarse Particulate Exposures Using Spatiotemporal Models for the Northeastern and Midwestern United States
Authors: Jeff D. Yanosky, Christopher J. Paciorek, Helen H. Suh
Journal: Environmental Health Perspectives (2008)

BackgroundChronic epidemiologic studies of particulate matter (PM) are limited by the lack of monitoring data, relying instead on citywide ambient concentrations to estimate exposures. This method ignores within-city spatial gradients and restricts studies to areas with nearby monitoring data. This lack of data is particularly restrictive for fine particles (PM with aerodynamic diameter &lt; 2.5 μm; PM2.5) and coarse particles (PM with aerodynamic diameter 2.5–10 μm; PM10–2.5), for which monitoring is limited before 1999. To address these limitations, we developed spatiotemporal models to predict monthly outdoor PM2.5 and PM10–2.5 concentrations for the northeastern and midwestern United States.MethodsFor PM2.5, we developed models for two periods: 1988–1998 and 1999–2002. Both models included smooth spatial and regression terms of geographic information system-based and meteorologic predictors. To compensate for sparse monitoring data, the pre-1999 model also included predicted PM10 (PM with aerodynamic diameter &lt; 10 μm) and extinction coefficients (km−1). PM10–2.5 levels were estimated as the difference in monthly predicted PM10 and PM2.5, with predicted PM10 from our previously developed PM10 model.ResultsPredictive performance for PM2.5 was strong (cross-validation R2 = 0.77 and 0.69 for post-1999 and pre-1999 PM2.5 models, respectively) with high precision (2.2 and 2.7 μg/m3, respectively). Models performed well irrespective of population density and season. Predictive performance for PM10–2.5 was weaker (cross-validation R2 = 0.39) with lower precision (5.5 μg/m3). PM10–2.5 levels exhibited greater local spatial variability than PM10 or PM2.5, suggesting that PM2.5 measurements at ambient monitoring sites are more representative for surrounding populations than for PM10 and especially PM10–2.5.ConclusionsWe provide semiempirical models to predict spatially and temporally resolved long-term average outdoor concentrations of PM2.5 and PM10–2.5 for estimating exposures of populations living in the northeastern and midwestern United States.
Gender and haplotype effects upon hematological manifestations of adult sickle cell anemia
Authors: M. H. Steinberg, H. Hsu, R. L. Nagel, P. F. Milner, J. G. Adams, L. Benjamin, S. Fryd, P. Gillette, J. Gilman, O. Josifovska, S. Hellman‐Erlingsson, S. Safaya, L. Huey, R. F. Rieder
Journal: American Journal of Hematology (1995)

In Africa, the beta-globin gene cluster haplotype may be associated with variation of Hb F levels in subjects with sickle cell anemia (SS). These observations have not yet been conclusively confirmed in SS out of Africa, perhaps because of small sample sizes, the predominance of haplotype heterozygotes, and diverse influences, including gender, upon Hb F levels. We studied 384 adult African-American SS patients (mean age, 31 years) and explored the relationship of gender, beta-globin gene cluster haplotype, and alpha thalassemia to hematological values and Hb F levels. Both haplotype and gender influenced Hb F concentration. In the total sample, Hb F was higher in females than in males (8.2 vs. 6.5%). In 35 males who were either homozygous for the Senegal chromosome or had the Senegal/Benin haplotype, the mean percent Hb F (8.0%) was equivalent to the Hb F level in females with Benin and Bantu haplotypes (approximately 7.5%). Both females and males homozygous for the Senegal haplotype chromosome or with the Senegal/Benin combination had a significant increase in Hb F compared to other groups. In 44 Senegal/Senegal or Senegal/Benin females the Hb F was 10.9%, or 1.0 g/dl, the highest value observed in all primary analysis groups. Preliminary analyses suggested that the presence of a Bantu chromosome blunted the gender-associated difference in Hb F, but Hb F differences between females with the Senegal/Benin haplotype (11.2%) and the Senegal/Bantu haplotype (8.8%) were not statistically significant. Hemoglobin concentrations were higher in males than in females except in subjects with at least one Senegal haplotype chromosome, where hemoglobin levels were equal. As expected, alpha thalassemia reduced the MCV, increased hemoglobin concentration, and lowered reticulocyte counts, regardless of haplotype. Hb F levels were not affected by the presence of alpha thalassemia in any group. We conclude that gender and beta-globin gene cluster haplotype interact significantly in the modulation of Hb F and anemia in adults with SS.
Addition of Nateglinide to Rosiglitazone Monotherapy Suppresses Mealtime Hyperglycemia and Improves Overall Glycemic Control
Authors: Vivian Fonseca, George Grunberger, Shamita Gupta, Sharon Shen, James E. Foley
Journal: Diabetes Care (2003)

OBJECTIVE—To determine the effects of nateglinide added to rosiglitazone monotherapy on glycemic control and on postprandial glucose and insulin levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—This 24-week, multicenter, double-blind, randomized study compared the efficacy of nateglinide (120 mg a.c.) and placebo added to rosiglitazone monotherapy (8 mg q.d.) in 402 patients with type 2 diabetes with HbA1c between 7 and 11% (inclusive). Efficacy parameters tested included HbA1c and plasma glucose and insulin levels in the fasting state and after a standardized meal challenge. Safety data were also collected. RESULTS—In placebo-treated patients, HbA1c did not change (Δ = 0.0 ± 0.1%). In patients randomized to nateglinide, HbA1c decreased from 8.3 to 7.5% (Δ = −0.8 ± 0.1%, P &amp;lt; 0.0001 vs. placebo). Target HbA1c (&amp;lt;7.0%) was achieved by 38% of patients treated with combination therapy and by 9% of patients remaining on rosiglitazone monotherapy. In nateglinide-treated patients, fasting plasma glucose levels decreased by 0.7 mmol/l, 2-h postprandial glucose levels decreased by 2.7 mmol/l, and 30-min insulin levels increased by 165 pmol/l compared with no changes from baseline of these parameters with placebo added to rosiglitazone (P &amp;lt; 0.001). CONCLUSIONS—By selectively augmenting early insulin release and decreasing prandial glucose excursions, nateglinide produced a clinically meaningful improvement in overall glycemic exposure in patients with type 2 diabetes inadequately controlled with rosiglitazone. Therefore, nateglinide substantially improves the likelihood of achieving a therapeutic target of HbA1c &amp;lt;7.0%.