tbuckley/cabot-search huggingface dataset:
Role of JNK in Mammary Gland Development and Breast Cancer
Authors: Cristina Cellurale, Nomeda Girnius, Feng Jiang, Julie Cavanagh-Kyros, Shaolei Lu, David S. Garlick, Arthur M. Mercurio, Roger J. Davis
Journal: Cancer Research (2011)

cJun NH(2)-terminal kinase (JNK) signaling has been implicated in the developmental morphogenesis of epithelial organs. In this study, we employed a compound deletion of the murine Jnk1 and Jnk2 genes in the mammary gland to evaluate the requirement for these ubiquitously expressed genes in breast development and tumorigenesis. JNK1/2 was not required for breast epithelial cell proliferation or motility. However, JNK1/2 deficiency caused increased branching morphogenesis and defects in the clearance of lumenal epithelial cells. In the setting of breast cancer development, JNK1/2 deficiency significantly increased tumor formation. Together, these findings established that JNK signaling is required for normal mammary gland development and that it has a suppressive role in mammary tumorigenesis.
Polar Activity Watch 200: a new device to accurately assess energy expenditure
Authors: J V Brugniaux, A Niva, I Pulkkinen, R M T Laukkanen, J-P Richalet, A P Pichon
Journal: British Journal of Sports Medicine (2008)

Objectives Energy expenditure (EE) based on movement detection is calculated by a new device, the Activity Watch 200 (AW200). The aim of this study was to validate EE measured by this device against indirect calorimetry (IC) and to assess the reproducibility of AW200 measurements. Design EE was assessed during a 9.7 km hike. 10 men and 10 women in the age range 35–45 years, and 5 men and 6 women in the age range 50–55 years were tested. One in five participants of each age- and sex-matched group was equipped with a portable metabograph (Oxycon Mobil) for IC measurements. Data were collected every 30 min during the hike, and IC was extrapolated for the remaining four other participants of the group. Results During the total hike, there was a high correlation between EE obtained from the AW200 and the IC calculation (r = 0.987, p&lt;0.001). Identical values of EE were calculated by both methods during the first 90 min of the hike. However, EE calculated by the AW200 at 120 min and at the end of the hike was lower (p&lt;0.05). Bland–Altman analysis showed limits of agreements between 105 and 279 kJ after 30 and 120 min, respectively. EE measured by the AW200 was well correlated with IC measurements, and limits of agreement between devices were below 10% of the measured values for hike durations longer than 60 min. Conclusion The AW200 appears to be a very useful and accurate device for measuring EE during exercise in recreational hikers and provides a useful tool for keeping track of personal EE.
MicroRNA-Cancer Connection: The Beginning of a New Tale
Authors: George Adrian Calin, Carlo Maria Croce
Journal: Cancer Research (2006)

Abstract Cancer initiation and progression can involve microRNAs (miRNA), which are small noncoding RNAs that can regulate gene expression. Their expression profiles can be used for the classification, diagnosis, and prognosis of human malignancies. Loss or amplification of miRNA genes has been reported in a variety of cancers, and altered patterns of miRNA expression may affect cell cycle and survival programs. Germ-line and somatic mutations in miRNAs or polymorphisms in the mRNAs targeted by miRNAs may also contribute to cancer predisposition and progression. We propose that alterations in miRNA genes play a critical role in the pathophysiology of many, perhaps all, human cancers. (Cancer Res 2006; 66(15): 7390-4)
Ultrastructural immunocytochemical localisation of lysozyme in human bronchial glands.
Authors: D Bowes, B Corrin
Journal: Thorax (1977)

An immunocytochemical unlabelled antibody method using rabbit antihuman lysozyme, antirabbit immunoglobulin, and soluble rabbit antihorseradish peroxidase/horseradish peroxidase complexes was used to study the fine structural distribution of lysozyme in human bronchial glands. None was identified in mucous cells but there was heavy staining of the serous cell granules. The serous cell granules were not stained uniformly, suggesting the presence of other secretory products but lysozyme secretion appears to be a major function of these cells. The pathological implications of this are discussed.
Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation
Authors: Guanhua Xie, Steve S Choi, Wing-Kin Syn, Gregory A Michelotti, Marzena Swiderska, Gamze Karaca, Isaac S Chan, Yuping Chen, Anna Mae Diehl
Journal: Gut (2012)

<h3>Objective</h3> Vascular remodelling during liver damage involves loss of healthy liver sinusoidal endothelial cell (LSEC) phenotype via capillarisation. Hedgehog (Hh) signalling regulates vascular development and increases during liver injury. This study therefore examined its role in capillarisation. <h3>Design</h3> Primary LSEC were cultured for 5 days to induce capillarisation. Pharmacological, antibody-mediated and genetic approaches were used to manipulate Hh signalling. Effects on mRNA and protein expression of Hh-regulated genes and capillarisation markers were evaluated by quantitative reverse transcription PCR and immunoblot. Changes in LSEC function were assessed by migration and tube forming assay, and gain/loss of fenestrae was examined by electron microscopy. Mice with acute or chronic liver injury were treated with Hh inhibitors; effects on capillarisation were assessed by immunohistochemistry. <h3>Results</h3> Freshly isolated LSEC expressed Hh ligands, Hh receptors and Hh ligand antagonist Hhip. Capillarisation was accompanied by repression of Hhip and increased expression of Hh-regulated genes. Treatment with Hh agonist further induced expression of Hh ligands and Hh-regulated genes, and upregulated capillarisation-associated genes; whereas Hh signalling antagonist or Hh ligand neutralising antibody each repressed expression of Hh target genes and capillarisation markers. LSEC isolated from <i>Smo<sup>loxP/loxP</sup></i> transgenic mice that had been infected with adenovirus expressing Cre-recombinase to delete Smoothened showed over 75% knockdown of Smoothened. During culture, Smoothened-deficient LSEC had inhibited Hh signalling, less induction of capillarisation-associated genes and retention of fenestrae. In mice with injured livers, inhibiting Hh signalling prevented capillarisation. <h3>Conclusions</h3> LSEC produce and respond to Hh ligands, and use Hh signalling to regulate complex phenotypic changes that occur during capillarisation.
Familial dilated cardiomyopathy: clinical features in French families
Authors: Laurence Mangin, Philippe Charron, Frédérique Tesson, Alain Mallet, Olivier Dubourg, Michel Desnos, Azziz Benaïsche, Christian Gayet, Pierre Gibelin, Jean‐Marc Davy, Jacques Bonnet, Daniel Sidi, Ketty Schwartz, Michel Komajda
Journal: European Journal of Heart Failure (1999)
Signal Transduction Mediated by the T Cell Antigen Receptor: The Role of Adapter Proteins
Authors: Lawrence E. Samelson
Journal: Annual Review of Immunology (2002)

Engagement of the T cell antigen receptor (TCR) leads to a complex series of molecular changes at the plasma membrane, in the cytoplasm, and at the nucleus that lead ultimately to T cell effector function. Activation at the TCR of a set of protein tyrosine kinases (PTKs) is an early event in this process. This chapter reviews some of the critical substrates of these PTKs, the adapter proteins that, following phosphorylation on tyrosine residues, serve as binding sites for many of the critical effector enzymes and other adapter proteins required for T cell activation. The role of these adapters in binding various proteins, the interaction of adapters with plasma membrane microdomains, and the function of adapter proteins in control of the cytoskeleton are discussed.
Specialty Differences in Primary Care Physician Reports of Papanicolaou Test Screening Practices: A National Survey, 2006 to 2007
Authors: K. Robin Yabroff, Mona Saraiya, Helen I. Meissner, David A. Haggstrom, Louise Wideroff, Gigi Yuan, Zahava Berkowitz, William W. Davis, Vicki B. Benard, Steven S. Coughlin
Journal: Annals of Internal Medicine (2009)

Background: Cervical cancer screening guidelines were substantially revised in 2002 and 2003. Little information is available about primary care physicians' current Papanicolaou (Pap) test screening practices, including initiation, frequency, and stopping. Objective: To assess current Pap test screening practices in the United States. Design: Cross-sectional survey. Setting: Nationally representative sample of physicians during 2006 to 2007. Participants: 1212 primary care physicians. Measurements: The survey included questions about physician and practice characteristics and recommendations for Pap screening presented as clinical vignettes describing women by age and by sexual and screening histories. A composite measure—guideline-consistent recommendations—was created by using responses to vignettes in which major guidelines were uniform. Results: Most physicians reported providing Pap tests to their eligible patients (91.0% [95% CI, 89.0% to 92.6%]). Among Pap test providers (n = 1114), screening practices, including number of tests ordered or performed, use of patient reminder systems, and cytology method used, varied by physician specialty (P < 0.001). Although most Pap test providers reported that screening guidelines were very influential in their clinical practice, few had guideline-consistent recommendations for starting and stopping Pap screening across multiple vignettes (22.3% [CI, 19.9% to 25.0%]). Guideline-consistent recommendations varied by specialty (obstetrics/gynecology, 16.4%; internal medicine, 27.5%; and family or general practice, 21.1%). Compared with obstetricians/gynecologists, internal medicine specialists and family or general practice specialists were more likely to have guideline-consistent screening recommendations (odds ratio, 1.98 [CI, 1.22 to 3.23] and 1.45 [CI, 0.99 to 2.13], respectively) in multivariate analysis. Limitation: Physician self-report may reflect idealized rather than actual practice. Conclusion: Primary care physicians' recommendations for Pap test screening are not consistent with screening guidelines, reflecting overuse of screening. Implementation of effective interventions that focus on potentially modifiable physician and practice factors is needed to improve screening practice. Primary Funding Source: National Cancer Institute, Centers for Disease Control and Prevention, and Agency for Healthcare Research and Quality.
T-Cell Immune Function in Tumor, Skin, and Peripheral Blood of Advanced Stage Melanoma Patients: Implications for Immunotherapy
Authors: Esther P.M. Tjin, Debby Konijnenberg, Gabrielle Krebbers, Henk Mallo, Jan W. Drijfhout, Kees L.M.C. Franken, Chantal M.A.M. van der Horst, Jan D. Bos, Omgo E. Nieweg, Bin B.R. Kroon, John B.A.G. Haanen, Cornelis J.M. Melief, Florry A. Vyth-Dreese, Rosalie M. Luiten
Journal: Clinical Cancer Research (2011)

To predict the potential antitumor effect of antigen-specific T cells in melanoma patients, we investigated T-cell effector function in relation to tumor-escape mechanisms.CD8(+) T cells isolated from tumor, adjacent normal skin, and peripheral blood of 17 HLA-A2(+) patients with advanced-stage melanoma were analyzed for their antigen specificity and effector function against melanocyte differentiation antigens MART-1, gp100, and tyrosinase by using HLA-A2/peptide tetramers and functional assays. In addition, the presence of tumor-escape mechanisms PD-L1/PD-1 pathway, FoxP3 and loss of HLA or melanocyte differentiation antigens, both required for tumor cell recognition and killing, were studied.Higher percentages of melanocyte antigen-specific CD8(+) T cells were found in the melanoma tissues as compared with adjacent normal skin and peripheral blood. Functional analysis revealed 2 important findings: (i) in 5 of 17 patients, we found cytokine production after specific peptide stimulation by tumor-infiltrating lymphocytes (TIL), not by autologous peripheral blood lymphocytes (PBL); (ii) CD8(+) T cells from 7 of 17 patients did not produce cytokines after specific stimulation, which corresponded with significant loss of tumor HLA-A2 expression. The presence of other tumor-escape mechanisms did not correlate to T-cell function.Our data show that functional T-cell responses could be missed when only PBL and not TIL are evaluated, emphasizing the importance of TIL analysis for immunomonitoring. Furthermore, loss of tumor HLA-A2 may explain the lack of T-cell functionality. These findings have important implications for selecting melanoma patients who may benefit from immunotherapy.
Cisplatin, raltitrexed, levofolinic acid and 5-fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: A phase I–II trial of the Southern Italy Cooperative Oncology Group (SICOG)
Authors: F. Caponigro, P. Cornelia, F. Rivellini, A. Avallone, A. Budillon, E. Di Gennaro, N. Mozzillo, F. Ionna, V. De Rosa, L. Manzione, G. Cornelia
Journal: Annals of Oncology (2000)
Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction
Authors: Bertram Pitt, Willem Remme, Faiez Zannad, James Neaton, Felipe Martinez, Barbara Roniker, Richard Bittman, Steve Hurley, Jay Kleiman, Marjorie Gatlin
Journal: New England Journal of Medicine (2003)

Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
Tetrahydrobiopterin and the regulation of hypoxic pulmonary vasoconstriction
Authors: B.N. Francis, M.R. Wilkins, L. Zhao
Journal: European Respiratory Journal (2010)

Tetrahydrobiopterin (BH(4)) is an essential cofactor for nitric oxide synthases (NOS). This study investigated the effect of increasing BH(4) levels on hypoxia-induced pulmonary vasoconstriction (HPV). Sprague Dawley rats and hph-1 (BH(4) deficient) mice were given BH(4) before and during HPV in an isolated perfused lung preparation. BH(4) inhibited HPV in a concentration-dependent manner and increased NO metabolites in the perfusate. Bradykinin-induced reductions in HPV were blunted in hph-1 mice and pre-administration of BH(4) restored the response. The effect of BH(4) was attenuated by l-NAME (NOS inhibitor), PTIO (NO scavenger), and catalase (H(2)O(2) catalyser) administered prior to HPV but enhanced by MnTMPyP (superoxide dismutase mimetic). The effect of BH(4) on HPV was partially recapitulated by NH(4), a stereoisomer that shares antioxidant properties with BH(4) but is not a NOS cofactor. The bioavailability of BH(4) is an important determinant of the pulmonary vascular response to hypoxia. Its effects are mediated via nitric oxide, hydrogen peroxide and its antioxidant properties, and are attenuated by oxidant stress. Pharmacological administration of BH(4) may have therapeutic potential in pulmonary hypertension.
Rapid Sequence Evolution of Transcription Factors Controlling Neuron Differentiation in Caenorhabditis
Authors: Richard Jovelin
Journal: Molecular Biology and Evolution (2009)

Whether phenotypic evolution proceeds predominantly through changes in regulatory sequences is a controversial issue in evolutionary genetics. Ample evidence indicates that the evolution of gene regulatory networks via changes in cis-regulatory sequences is an important determinant of phenotypic diversity. However, recent experimental work suggests that the role of transcription factor (TF) divergence in developmental evolution may be underestimated. In order to help understand what levels of constraints are acting on the coding sequence of developmental regulatory genes, evolutionary rates were investigated among 48 TFs required for neuronal development in Caenorhabditis elegans. Allelic variation was then sampled for 28 of these genes within a population of the related species Caenorhabditis remanei. Neuronal TFs are more divergent, both within and between species, than structural genes. TFs affecting different neuronal classes are under different levels of selective constraints. The regulatory genes controlling the differentiation of chemosensory neurons evolve particularly fast and exhibit higher levels of within- and between-species nucleotide variation than TFs required for the development of several neuronal classes and TFs required for motorneuron differentiation. The TFs affecting chemosensory neuron development are also more divergent than chemosensory genes expressed in the neurons they differentiate. These results illustrate that TFs are not as highly constrained as commonly thought and suggest that the role of divergence in developmental regulatory genes during the evolution of gene regulatory networks requires further attention.
Glioblastoma Proto-oncogene <i>SEC61γ</i> Is Required for Tumor Cell Survival and Response to Endoplasmic Reticulum Stress
Authors: Zheming Lu, Lei Zhou, Patrick Killela, Ahmed B. Rasheed, Chunhui Di, William E. Poe, Roger E. McLendon, Darell D. Bigner, Christopher Nicchitta, Hai Yan
Journal: Cancer Research (2009)

Glioblastoma multiforme is the most prevalent type of adult brain tumor and one of the deadliest tumors known to mankind. The genetic understanding of glioblastoma multiforme is, however, limited, and the molecular mechanisms that facilitate glioblastoma multiforme cell survival and growth within the tumor microenvironment are largely unknown. We applied digital karyotyping and single nucleotide polymorphism arrays to screen for copy-number changes in glioblastoma multiforme samples and found that the most frequently amplified region is at chromosome 7p11.2. The high resolution of digital karyotyping and single nucleotide polymorphism arrays permits the precise delineation of amplicon boundaries and has enabled identification of the minimal region of amplification at chromosome 7p11.2, which contains two genes, EGFR and SEC61gamma. SEC61gamma encodes a subunit of a heterotrimeric protein channel located in the endoplasmic reticulum (ER). In addition to its high frequency of gene amplification in glioblastoma multiforme, SEC61gamma is also remarkably overexpressed in 77% of glioblastoma multiforme but not in lower-grade gliomas. The small interfering RNA-mediated knockdown of SEC61gamma expression in tumor cells led to growth suppression and apoptosis. Furthermore, we showed that pharmacologic ER stress agents induce SEC61gamma expression in glioblastoma multiforme cells. Together, these results indicate that aberrant expression of SEC61gamma serves significant roles in glioblastoma multiforme cell survival likely via a mechanism that is involved in the cytoprotective ER stress-adaptive response to the tumor microenvironment.
Intensive glucose control improves kidney outcomes in patients with type 2 diabetes
Authors: Vlado Perkovic, Hiddo Lambers Heerspink, John Chalmers, Mark Woodward, Min Jun, Qiang Li, Stephen MacMahon, Mark E. Cooper, Pavel Hamet, Michel Marre, Carl Erik Mogensen, Neil Poulter, Giuseppe Mancia, Alan Cass, Anushka Patel, Sophia Zoungas
Journal: Kidney International (2013)
DNA Repair Activity for Oxidative Damage and Risk of Lung Cancer
Authors: T. Paz-Elizur
Journal: JNCI Journal of the National Cancer Institute (2003)

Although smoking is a major cause of lung cancer, only a proportion of smokers develop lung cancer, suggesting a genetic predisposition in some individuals. Because tobacco smoking is associated with the increased formation of DNA lesions, including those induced from oxidative damage, we investigated whether the activity of the DNA repair enzyme 8-oxoguanine DNA N-glycosylase (OGG), which repairs the oxidative DNA lesion 8-oxoguanine, is associated with lung cancer.We conducted a molecular epidemiologic case-control study that included 68 case patients with non-small-cell lung cancer and 68 healthy control subjects, frequency matched for age and sex. Enzymatic OGG activity was determined in protein extracts prepared from peripheral blood mononuclear cells or lung tissue by assaying the cleavage product of a radiolabeled synthetic DNA oligonucleotide containing an 8-oxoguanine residue. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined by conditional logistic regression. All statistical tests were two-sided.OGG activity was lower in peripheral blood mononuclear cells from case patients than in those from control subjects. After adjustment for age and smoking status, individuals in the lowest tertile of OGG activity had an increased risk of non-small-cell lung cancer compared with individuals in the highest tertile (OR = 4.8, 95% CI = 1.5 to 15.9). The adjusted OR associated with a unit decrease in OGG activity was statistically significantly increased (OR = 1.9, 95% CI = 1.3 to 2.8). There was no interaction between OGG activity and smoking status. The estimated relative risk of lung cancer for smokers with low OGG activity was 34- or 124-fold higher for smokers with a low OGG activity of 6.0 or 4.0 U/ micro g protein, respectively, than for nonsmokers with a normal OGG activity of 7.0 U/ micro g protein, illustrating the cumulative effect of low OGG activity and smoking.Low OGG activity is associated with an increased risk of lung cancer. Although prospective studies are needed to validate the results, they suggest that smoking cessation in individuals with reduced OGG activity might be an effective strategy in lung cancer prevention.
Desensitization of oxytocin receptors in human myometrium
Authors: S Phaneuf, G Asbóth, M P Carrasco, B R Liñares, T Kimura, A Harris, A L Bernal
Journal: Human Reproduction Update (1998)

In the present study, we investigated the possible mechanisms by which oxytocin might regulate oxytocin receptor (OTR) density. Exposure of cultured myometrial cells to oxytocin for a prolonged period caused desensitization: the steady-state level of oxytocin binding was 210 x 103 binding sites/cell, but this was time-dependently reduced to 20.1 x 103 sites/cell by exposing the cells to oxytocin for up to 20 h. In contrast, Western blotting data showed that the total amount of OTR protein was not affected by oxytocin treatment for up to 24 h. Flow cytometry experiments demonstrated that OTRs were not internalized during this treatment. However, RNase protection assays and Northern analysis showed that in cultured myometrial cells OTR mRNA was reduced by oxytocin treatment to reach a new low steady-state concentration. Analysis of this mRNA in myometrial biopsies from 17 patients undergoing emergency Caesarean section showed how it decreased with advancing labour. Samples obtained after 12 h of labour contained approximately 50 times less OTR mRNA than samples obtained from patients in labour for less than 12 h. We speculate that this decrease in OTR mRNA represents in-vivo OTR desensitization.