tbuckley/cabot-search huggingface dataset:
Efficiency of airway macrophage recovery by bronchoalveolar lavage in hamsters: a stereological approach
Authors: M Geiser, AL Serra, LM Cruz-Orive, M Baumann, V Im Hof, P Gehr
Journal: European Respiratory Journal (1995)

Macrophages play a central role in the defence of the respiratory tract against deposited particles. In addition to the well-studied alveolar macrophages, airway macrophages have been recognized as an important clearance factor. Bronchoalveolar lavage (BAL) has been used for functional and morphological investigations of macrophages in vitro, assuming that all macrophages are removed with equal probability from the lung surface. Airway macrophages have been found in close contact with the epithelial cells. These macrophages may not be easily removed by lavage, and they might constitute a functionally different macrophage population. We have tested the hypothesis that there exists a population of macrophages in the conducting airways that resists removal by lavage. We lavaged the lungs of four hamsters and fixed the lungs, thereafter, by intravascular perfusion. The number of macrophages in the intrapulmonary conducting airways was estimated with an unbiased stereological technique, the fractionator, and compared to the number of macrophages in the airways of four hamsters whose lungs had not been lavaged prior to fixation. This in situ study revealed that, in hamster lungs, 42% of the airway macrophages were not removed by BAL and that about 5% of all macrophages in the BAL fluid were airway macrophages. Additionally, ultrastructural alterations of the airway epithelium were found. It is concluded that there exists a population of airway macrophages that resists lavage. This is an aspect which has to be considered in studies performed with macrophages obtained by BAL, since they could represent a functionally different macrophage population.
Quantitative Proteomic Analysis of Proteins Released by Neoplastic Prostate Epithelium
Authors: Daniel B. Martin, David R. Gifford, Michael E. Wright, Andrew Keller, Eugene Yi, David R. Goodlett, Reudi Aebersold, Peter S. Nelson
Journal: Cancer Research (2004)

Abstract Prostate cancer is unusual among neoplasms in that it may be diagnosed at a curable stage through detection of a protein in serum, the serine protease prostate-specific antigen (PSA). PSA is secreted by both normal and neoplastic prostate epithelial cells in response to androgenic hormones and has found widespread use in cancer screening. Because PSA screening is controversial due to sensitivity and specificity issues, efforts continue to focus on the identification and characterization of additional markers that may be used for diagnostic and therapeutic purposes. In this study, we report the application of quantitative proteomic techniques that incorporate isotope coded affinity tag reagents and tandem mass spectrometry to comprehensively identify secreted and cell surface proteins from neoplastic prostate epithelium. LNCaP cells, a prostate tumor-derived cell line that secretes PSA in response to androgen exposure, were grown in a low protein-defined media under androgen-stimulated (A+) and -starved (A-) conditions. Proteomic analysis of the media identified in excess of 600 proteins, 524 of which could be quantified. Nine percent of the proteins had A+/A- ratios &amp;gt; 2.0, including PSA, and 2.5% had ratios &amp;lt; 0.5. A subset of these androgen-regulated proteins appeared to be expressed in abundance. Of these, selected mass spectrometry observations were confirmed by Western analysis. The findings suggest that androgen-mediated release of proteins may occur through the activation of proteolytic enzymes rather than exclusively through transcriptional or translational control mechanisms. On the basis of their known functional roles, several of the abundant androgen-regulated proteins may participate in the progression of neoplastic epithelial cell growth and should be considered as potential serum markers of neoplastic prostate diseases.
Widespread Ultraconservation Divergence in Primates
Authors: I. Ovcharenko
Journal: Molecular Biology and Evolution (2008)

The distribution and evolution of ultraconserved elements (UCEs, DNA stretches that are perfectly identical in primates and rodents) were examined in genomes of 3 primate species (human, chimpanzee, and rhesus macaque). It was found that the number of UCEs has decreased throughout primate evolution. At least 26% of ancestral UCEs have diverged in hominoids, whereas an additional 17% have accumulated one or more single nucleotide polymorphisms in the human genome. Sequence polymorphism analyses indicate that mutation fixation within an UCE can trigger a relaxation in the selective constraint on that element. Homogeneous mutation accumulations in UCEs served as a template by which purifying selection acted more effectively on protein-coding UCEs. Gene ontology annotation suggests that UCE sequence variation, primarily occurring in noncoding regions, might be linked to the reprogramming of the expression pattern of transcription factors and developmentally important genes. Many of these genes are expressed in the central nervous system. Finally, UCE sequence variability within human populations has been identified, including population-specific nonsynonymous changes in protein-coding regions.
Three-Dimensional Color Doppler Echocardiography for Direct Measurement of Vena Contracta Area in Mitral Regurgitation
Authors: Stephen H. Little, Bahar Pirat, Rahul Kumar, Stephen R. Igo, Marti McCulloch, Craig J. Hartley, Jiaqiong Xu, William A. Zoghbi
Journal: JACC. Cardiovascular imaging (2008)
Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator–activated receptor γ
Authors: Ki Hoon Han, Mi Kyung Chang, Agnes Boullier, Simone R. Green, Andrew Li, Christopher K. Glass, Oswald Quehenberger
Journal: Journal of Clinical Investigation (2000)

The CCR2-mediated recruitment of monocytes into the vessel wall plays an important role in all stages of atherosclerosis. In recent studies, we have shown that lipoproteins can modulate CCR2 expression and have identified native LDL as a positive regulator. In contrast, oxidized LDL (OxLDL), which is mainly formed in the aortic intima, reduces CCR2 expression, promotes monocyte retention, and may cause pathological accumulation of monocytes in the vessel wall. We now provide evidence that OxLDL reduces monocyte CCR2 expression by activating intracellular signaling pathways that may involve peroxisome proliferator-activated receptor gamma (PPARgamma). Receptor-mediated uptake of the lipoprotein particle was required and allows for delivery of the exogenous ligand to the nuclear receptor. The suppression of CCR2 expression by OxLDL was mediated by lipid components of OxLDL, such as the oxidized linoleic acid metabolites 9-HODE and 13-HODE, known activators of PPARgamma. Modified apoB had no such effect. Consistent with a participation of the PPARgamma signaling pathway, BRL49653 reduced CCR2 expression in freshly isolated human monocytes ex vivo and in circulating mouse monocytes in vivo. These results implicate PPARgamma in the inhibition of CCR2 gene expression by oxidized lipids, which may help retain monocytes at sites of inflammation, such as the atherosclerotic lesion.
Lifecourse predictors of adult respiratory function: results from the Newcastle Thousand Families Study
Authors: P W G Tennant, G J. Gibson, M S Pearce
Journal: Thorax (2008)

<h3>Background:</h3> Impaired development in utero is suggested to increase the risk of poor respiratory health in adulthood, although a consensus has not been reached. A possible explanation for discrepancies between previous studies is inconsistent controlling for potential confounding factors, particularly childhood infections. Also, little is known regarding the relative importance of factors operating at different stages of the lifecourse. We have used detailed longitudinal data from the Newcastle Thousand Families cohort to assess the impact of birth weight, and various other factors acting throughout the lifecourse, on predicting forced expiratory volume in 1 s (FEV<sub>1</sub>). <h3>Methods:</h3> Detailed information was collected prospectively during childhood, including birth weight, childhood infections and socioeconomic circumstances. At age 49–51 years, 412 study members attended for clinical examination and measurement of FEV<sub>1</sub>. These data were analysed in relation to a range of factors from across the lifecourse using linear regression models. <h3>Results:</h3> After adjustment for all other significant variables, increasing birth weight, standardised for sex and gestational age (p = 0.011), being breast fed for more than 4 weeks (p = 0.017), less frequent childhood lower respiratory tract infections (LRTI) (p = 0.015), non- smoking (p&lt;0.001), lower body fat percentage (p = 0.010), male sex (p&lt;0.001), no history of asthma (p = 0.013) and greater adult height (p&lt;0.001) were all independently associated with higher adult FEV<sub>1</sub>. <h3>Conclusion:</h3> Adult lung function is influenced by numerous factors during an individual's lifetime, acting both directly and indirectly throughout the lifecourse. As expected, sex, height and smoking were the most important predictors of FEV<sub>1</sub>, but birth weight, breast feeding and childhood LRTIs also contributed significantly.
Correlated expression of atrial myosin heavy chain and regulatory light chain isoforms with pressure overload hypertrophy in the non-human primate
Authors: R. D Henkel, C. M Kammerer, L. V Escobedo, J. L VandeBerg, R. A Walsh
Journal: Cardiovascular Research (1993)

Objective: The aim was to determine the extent to which myosin heavy chain and light chain isoform transitions in atrial myocardium are coordinately regulated under pathological conditions in tissue from normal baboons, hypertensive baboons with myocardial hypertrophy, and baboons in which hypertrophy had regressed. Methods: Quantitative distributions of myosin heavy chain (MHC) and regulatory myosin light chain (MLC2) isoforms in atrial myocardium from 35 adult baboons were determined by electrophoresis under denaturing conditions and laser densitometry. Results: A significant association was observed between the ratios of MHC and MLC2 isoforms in atrial myocardium (r=0.73, p<0.001, n=69). Expressions of α MHC and atrial MLC2 (ALC2) isoforms were correlated in atrial myocardium, as were those of β MHC and ventricular MLC2 (VLC2) isoforms. In a subset of baboons with experimentally induced renal hypertension (n=12) both β MHC and VLC2 isoforms were found at higher levels in left atria than were present in normotensive baboons (p=0.006, n=15). Left atria from hypertensive baboons with regressed LVH contained intermediate levels of both β MHC and VLC2 isoforms. Conclusions: There is tight coupling between the expression of myosin subunit isoforms under pathological conditions from a primate species closely related to humans. The data suggest that the synthesis of these subunits of myosin may be coordinated at the molecular level. Cardiovascular Research 1993;27:416-422
Vascular anatomy defines sites of indomethacin induced jejunal ulceration along the mesenteric margin
Authors: A Anthony, R E Pounder, A P Dhillon, A J Wakefield
Journal: Gut (1997)

Indomethacin induces ulceration in the rat jejunum with sparing of the ileum. The ulcers localise between vasa recta along the mesenteric margin of the bowel, observations that have not been fully explained.To examine the relationship between the localisation of experimental ulcers and the vascular anatomy of the rat small intestine.The normal vascular anatomy of the rat jejunum and ileum was studied and compared using arterial carbon ink perfusion. The anatomical localisation of early and advanced lesions induced by indomethacin was examined with particular reference to the vasculature. Mucosal injury induced by feeding vessel ligation for 24 hours or brief ischaemia-reperfusion injury was examined. The existence of anatomically sensitive sites to indomethacin was tested in a two dose study.In the rat jejunum, poorly vascularised sites along the mesenteric margin were highly susceptible to indomethacin induced injury, such sites being absent from the ileum. Villous contraction was a feature of both early indomethacin injury and ischaemia-reperfusion injury in the rat jejunum. Twenty four hour ligation of jejunal vasa brevia selectively induced ischaemic injury along the mesenteric margin. Two doses of indomethacin to rats did not induce greater injury than a single dose.Results support the hypothesis that the rat jejunum possesses vascularly compromised sites along the mesenteric margin that are susceptible to indomethacin induced injury. Indomethacin may cause ischaemia-reperfusion injury selectively at these sites.
Epidermal Growth Factor Receptor Copy Number Alterations Correlate With Poor Clinical Outcome in Patients With Head and Neck Squamous Cancer
Authors: Stephane Temam, Hidetoshi Kawaguchi, Adel K. El-Naggar, Jaroslav Jelinek, Hongli Tang, Diane D. Liu, Wenhua Lang, Jean-Pierre Issa, J. Jack Lee, Li Mao
Journal: Journal of Clinical Oncology (2007)

Overexpression of epidermal growth factor receptor (EGFR) is common in head and neck squamous cell carcinoma (HNSCC). Recent studies showed that EGFR inhibitors are effective for patients with HNSCC. This study analyzed the genetic nature of EGFR gene in HNSCC and its clinical correlations.The EGFR gene copy numbers in 134 HNSCC tumors were determined using quantitative real-time polymerase chain reaction. The status of EGFR gene copy numbers was analyzed with clinical parameters including clinical outcome. Mutation status of EGFR exons 18, 19, and 21 was determined in the HNSCC tumors.Aberrant EGFR copy numbers were found in 32 (24%) of 134 tumors, including 22 (17%) with increased copy number and 10 (7%) with decreased copy number. Patients whose tumors had EGFR copy number alterations (particularly patients with increased copy numbers) had significantly poorer overall, cancer-specific, and disease-free survivals compared with patients with normal copy numbers (P < .0001). At 5 years after initial diagnosis, 20 (91%) of the 22 patients with increased copy numbers died of disease compared with 30 (29%) of the 102 patients with normal copy number. No mutations on EGFR exons 18, 19, and 21 were detected in any of the tumors.A subset of HNSCC manifests EGFR copy number alterations, and this is associated with a poor clinical outcome, suggesting a biologic role of the alterations. The rare mutation or small deletion at EGFR exons 18 to 21 indicates a minimal role of these events in HNSCC.
Risk of Multiple Sclerosis Exacerbation During Pregnancy and Breast-feeding
Authors: Lorene M. Nelson
Journal: JAMA (1988)

Studies in the past have reported an increased risk of exacerbations in multiple sclerosis during the postpartum period; it is not known whether breast-feeding alters this risk. We interviewed 435 women regarding pregnancy and breast-feeding history, providing for analysis 191 pregnancies that had occurred during a nonprogressive phase of the disease. The exacerbation rates during the nine-month postpartum period (34%) were more than three times the exacerbation rate during the nine months of pregnancy (10%). The exacerbation risk was highest in the three-month period following childbirth and appeared to stabilize after the sixth postpartum month. The exacerbation rates in breast-feeding and non—breast-feeding pregnancies were 38% and 31%, respectively. The average time to exacerbation was similar in breast-feeding (3.0 months) and non—breast-feeding (3.1 months) pregnancies. Although differential exacerbation rates during pregnancy and the postpartum period may be related to hormonal effects on the immune system, the hormonal effects of breast-feeding do not appear to similarly affect the risk of exacerbation. (<i>JAMA</i>1988;259:3441-3443)
Effect of the staging schema on melanoma cancer reporting, 1999 to 2006
Authors: Sue-Min Lai, Jessica B. King, Sarma Garimella, John Keighley, Mary Lewis
Journal: Journal of the American Academy of Dermatology (2011)

Staging schemas have changed multiple times over the past 10 years.We sought to examine the impact of staging schemas on the distribution of stages at diagnosis over time.We examined the stage at diagnosis for melanoma cancer cases diagnosed between 1999 and 2006 using data provided by the Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries (NPCR) programs. The staging schemas were summary staging 1977 (SS1977), summary staging 2000 (SS2000), derived SS2000, and SEER historic staging systems.Melanoma was predominantly staged as a localized disease in all schemas. Using SEER data, the proportion of localized melanomas diagnosed in 2001 to 2003 using SS2000 was about 2.5% lower than the proportion diagnosed in 1999 to 2000 using SS1977, whereas the proportion of cases staged as regional was 2.7% higher using the SS2000 than SS1977. The distribution of stages for cases diagnosed in 2001 to 2003 using SS2000 was similar to that for cases diagnosed in 2004 to 2006 using a derived SS2000. Shift in stage distribution among SS1977, SS2000, and SEER historic staging was found to be about 6% (localized to regional) and about 17.5% (unknown to regional stage). The distribution of changes in stage observed for the SEER cases was not evident for cases from NPCR.SEER historic staging was not available for NPCR cases.Changes in staging rules resulted in cases being moved from the localized to the regional stage and from unknown to the regional stage. Without staging rules that have been consistently applied to melanomas over many years, surveillance of prevention, treatment, and control of this condition is difficult.
An integrative ‘Omics’ solution to the detection of recombinant human erythropoietin and blood doping
Authors: Yannis P Pitsiladis, Jérôme Durussel, Olivier Rabin
Journal: British Journal of Sports Medicine (2014)

Administration of recombinant human erythropoietin (rHumanEPO) improves sporting performance and hence is frequently subject to abuse by athletes, although rHumanEPO is prohibited by the WADA. Approaches to detect rHumanEPO doping have improved significantly in recent years but remain imperfect. A new transcriptomic-based longitudinal screening approach is being developed that has the potential to improve the analytical performance of current detection methods. In particular, studies are being funded by WADA to identify a 'molecular signature' of rHumanEPO doping and preliminary results are promising. In the first systematic study to be conducted, the expression of hundreds of genes were found to be altered by rHumanEPO with numerous gene transcripts being differentially expressed after the first injection and further transcripts profoundly upregulated during and subsequently downregulated up to 4 weeks postadministration of the drug; with the same transcriptomic pattern observed in all participants. The identification of a blood 'molecular signature' of rHumanEPO administration is the strongest evidence to date that gene biomarkers have the potential to substantially improve the analytical performance of current antidoping methods such as the Athlete Biological Passport for rHumanEPO detection. Given the early promise of transcriptomics, research using an 'omics'-based approach involving genomics, transcriptomics, proteomics and metabolomics should be intensified in order to achieve improved detection of rHumanEPO and other doping substances and methods difficult to detect such a recombinant human growth hormone and blood transfusions.
Strokes in Asians and Pacific-Islanders, Hispanics, and Native Americans.
Authors: F M Yatsu
Journal: Circulation (1991)

Stroke in Asian and Pacific-Islander populations remains the principal cause of death among adults, but its incidence in the United States approximates that of Caucasians. Although controversial, uncontrolled hypertension in certain population groups (e.g., northern Japanese) and high dietary saturated fat in others (e.g, Pacific-Islanders) are believed to be responsible for the high stroke incidence rates. The recent reduction in stroke frequency rates in these areas is thought to be the result of better hypertension control. In the Ni-Hon-San Study, the level of hypertension and its frequency were similar in Hawaii and Japan, but ischemic infarction and intracerebral hemorrhage were less frequent in Hawaii. Reduced meat and fat intake may contribute to small vessel disease in Japan. Stroke is the third major cause of death among Hispanic-Americans and Native Americans, yet there is a paucity of information, especially about stroke, in subgroups of these populations. There is also considerable ignorance and controversy about risk factors for stroke in these populations. The need for additional research is urgent.
Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway
Authors: Peixin Dong, Zhujie Xu, Nan Jia, Dajin Li, Youji Feng
Journal: Molecular Cancer (2009)

p53 is the most commonly mutated tumor suppressor gene in human cancers. In addition to the loss of tumor suppression function and exertion of dominant-negative effects over the remaining wild-type protein, several p53 mutants can gain novel oncogenic functions (gain-of-function, GOF) that actively regulate cancer development and progression. In human endometrial cancer, p53 mutation is more often associated with aggressive nonendometrioid cancer. However, it was unknown if p53 mutants contributed to endometrial cancer progression through the GOF properties. To clarify the relationship between expression of p53 GOF mutation (p53-R175H) and invasive potential of human endometrial cancer KLE cells, we tested the consequences of up-regulation and down-regulation of p53-R175H in KLE cells by inducing p53-R175H expression vector or suppressing the p53 gene with short hairpin RNA. We found that forced over-expression of p53-R175H significantly promoted cell migration and invasion, and induced activation of the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Conversely, suppression of p53-R175H with short hairpin RNA significantly inhibited cell migration and invasion, and resulted in attenuation of EGFR/PI3K/AKT pathway. These findings show for the first time that elevated expression of p53-R175H mutant may exert gain-of-function activity to activate the EGFR/PI3K/AKT pathway and thus may contribute to the invasive phenotype in endometrial cancer.