tbuckley/cabot-search huggingface dataset:
Relationship between 18F-Fluorodeoxyglucose Accumulation and <i>KRAS</i>/<i>BRAF</i> Mutations in Colorectal Cancer
Authors: Kenji Kawada, Yuji Nakamoto, Mayumi Kawada, Koya Hida, Takuya Matsumoto, Teppei Murakami, Suguru Hasegawa, Kaori Togashi, Yoshiharu Sakai
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has been widely used in the management of colorectal cancer (CRC). However, the relationship between FDG accumulation and KRAS/BRAF mutations has not yet been investigated. The purpose of this study was to investigate whether KRAS/BRAF mutations affect FDG accumulation in CRC. Experimental Design: Retrospective analysis was conducted in 51 patients with CRC who underwent FDG-PET/computed tomographic (CT) scans for staging before primary tumor resection. The maximum standardized uptake value (SUVmax) for the primary tumor and the tumor-to-liver ratio (TLR) were calculated from FDG accumulation and compared between KRAS/BRAF mutated and wild-type groups. Expression levels of glucose transporter-1 (GLUT1) and hexokinase type-II (HXK-II) were assessed by immunohistochemical analysis. Results: Both SUVmax and TLR were significantly higher in the KRAS/BRAF-mutated group compared with the wild-type group (P = 0.006 and 0.001, respectively). Multivariate analysis indicated that SUVmax and TLR remained significantly associated with KRAS/BRAF mutations (P = 0.016 and 0.01, respectively). KRAS/BRAF status could be predicted with an accuracy of 75% when a SUVmax cutoff value of 13 or 14 was used. GLUT1 expression in cancer cells was positively correlated with FDG accumulation and KRAS/BRAF status whereas HXK-II expression was not. Conclusion: FDG accumulation was higher in CRC with KRAS/BRAF mutations. FDG-PET/CT scans may be useful for predicting the KRAS/BRAF status of patients with CRC and thus aid in determination of therapeutic strategies for patients with CRC. Clin Cancer Res; 18(6); 1696–703. ©2012 AACR.
Quantitative DNA Methylation Analysis Identifies a Single CpG Dinucleotide Important for ZAP-70 Expression and Predictive of Prognosis in Chronic Lymphocytic Leukemia
Authors: Rainer Claus, David M. Lucas, Stephan Stilgenbauer, Amy S. Ruppert, Lianbo Yu, Manuela Zucknick, Daniel Mertens, Andreas Bühler, Christopher C. Oakes, Richard A. Larson, Neil E. Kay, Diane F. Jelinek, Thomas J. Kipps, Laura Z. Rassenti, John G. Gribben, Hartmut Döhner, Nyla A. Heerema, Guido Marcucci, Christoph Plass, John C. Byrd
Journal: Journal of Clinical Oncology (2012)

Increased ZAP-70 expression predicts poor prognosis in chronic lymphocytic leukemia (CLL). Current methods for accurately measuring ZAP-70 expression are problematic, preventing widespread application of these tests in clinical decision making. We therefore used comprehensive DNA methylation profiling of the ZAP-70 regulatory region to identify sites important for transcriptional control.High-resolution quantitative DNA methylation analysis of the entire ZAP-70 gene regulatory regions was conducted on 247 samples from patients with CLL from four independent clinical studies.Through this comprehensive analysis, we identified a small area in the 5' regulatory region of ZAP-70 that showed large variability in methylation in CLL samples but was universally methylated in normal B cells. High correlation with mRNA and protein expression, as well as activity in promoter reporter assays, revealed that within this differentially methylated region, a single CpG dinucleotide and neighboring nucleotides are particularly important in ZAP-70 transcriptional regulation. Furthermore, by using clustering approaches, we identified a prognostic role for this site in four independent data sets of patients with CLL using time to treatment, progression-free survival, and overall survival as clinical end points.Comprehensive quantitative DNA methylation analysis of the ZAP-70 gene in CLL identified important regions responsible for transcriptional regulation. In addition, loss of methylation at a specific single CpG dinucleotide in the ZAP-70 5' regulatory sequence is a highly predictive and reproducible biomarker of poor prognosis in this disease. This work demonstrates the feasibility of using quantitative specific ZAP-70 methylation analysis as a relevant clinically applicable prognostic test in CLL.
Distinct mPTP activation mechanisms in ischaemia–reperfusion: contributions of Ca2+, ROS, pH, and inorganic polyphosphate
Authors: Lea K. Seidlmayer, Vanessa V. Juettner, Sarah Kettlewell, Evgeny V. Pavlov, Lothar A. Blatter, Elena N. Dedkova
Journal: Cardiovascular Research (2015)

AimsThe mitochondrial permeability transition pore (mPTP) plays a central role for tissue damage and cell death during ischaemia–reperfusion (I/R). We investigated the contribution of mitochondrial inorganic polyphosphate (polyP), a potent activator of Ca2+-induced mPTP opening, towards mPTP activation and cardiac cell death in I/R.
Nitric Oxide Regulates Gene Expression in Cancers by Controlling Histone Posttranslational Modifications
Authors: Divya Vasudevan, Jason R. Hickok, Rhea C. Bovee, Vy Pham, Lin L. Mantell, Neil Bahroos, Pinal Kanabar, Xing-Jun Cao, Mark Maienschein-Cline, Benjamin A. Garcia, Douglas D. Thomas
Journal: Cancer Research (2015)

Abstract Altered nitric oxide (•NO) metabolism underlies cancer pathology, but mechanisms explaining many •NO-associated phenotypes remain unclear. We have found that cellular exposure to •NO changes histone posttranslational modifications (PTM) by directly inhibiting the catalytic activity of JmjC-domain containing histone demethylases. Herein, we describe how •NO exposure links modulation of histone PTMs to gene expression changes that promote oncogenesis. Through high-resolution mass spectrometry, we generated an extensive map of •NO-mediated histone PTM changes at 15 critical lysine residues on the core histones H3 and H4. Concomitant microarray analysis demonstrated that exposure to physiologic •NO resulted in the differential expression of over 6,500 genes in breast cancer cells. Measurements of the association of H3K9me2 and H3K9ac across genomic loci revealed that differential distribution of these particular PTMs correlated with changes in the level of expression of numerous oncogenes, consistent with epigenetic code. Our results establish that •NO functions as an epigenetic regulator of gene expression mediated by changes in histone PTMs. Cancer Res; 75(24); 5299–308. ©2015 AACR.
Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state
Authors: Florent Ginhoux, Matthew P. Collin, Milena Bogunovic, Michal Abel, Marylene Leboeuf, Julie Helft, Jordi Ochando, Adrien Kissenpfennig, Bernard Malissen, Marcos Grisotto, Hans Snoeck, Gwendalyn Randolph, Miriam Merad
Journal: The Journal of Experimental Medicine (2007)

Langerin is a C-type lectin receptor that recognizes glycosylated patterns on pathogens. Langerin is used to identify human and mouse epidermal Langerhans cells (LCs), as well as migratory LCs in the dermis and the skin draining lymph nodes (DLNs). Using a mouse model that allows conditional ablation of langerin+ cells in vivo, together with congenic bone marrow chimeras and parabiotic mice as tools to differentiate LC- and blood-derived dendritic cells (DCs), we have revisited the origin of langerin+ DCs in the skin DLNs. Our results show that in contrast to the current view, langerin+CD8− DCs in the skin DLNs do not derive exclusively from migratory LCs, but also include blood-borne langerin+ DCs that transit through the dermis before reaching the DLN. The recruitment of circulating langerin+ DCs to the skin is dependent on endothelial selectins and CCR2, whereas their recruitment to the skin DLNs requires CCR7 and is independent of CD62L. We also show that circulating langerin+ DCs patrol the dermis in the steady state and migrate to the skin DLNs charged with skin antigens. We propose that this is an important and previously unappreciated element of immunosurveillance that needs to be taken into account in the design of novel vaccine strategies.
Age-Related Lobular Involution and Risk of Breast Cancer
Authors: Tia R. Milanese, Lynn C. Hartmann, Thomas A. Sellers, Marlene H. Frost, Robert A. Vierkant, Shaun D. Maloney, V. Shane Pankratz, Amy C. Degnim, Celine M. Vachon, Carol A. Reynolds, Romayne A. Thompson, L. Joseph Melton, Ellen L. Goode, Daniel W. Visscher
Journal: JNCI Journal of the National Cancer Institute (2006)

Background : As women age, the lobules in their breasts undergo involution or regression. We investigated whether lobular involution in women with benign breast disease was associated with subsequent breast cancer risk. Methods : We examined biopsy specimens of 8736 women in the Mayo Benign Breast Disease Cohort from whom biopsy samples were taken between January 1, 1967, and December 31, 1991. Median follow-up for breast cancer outcomes was 17 years. We classified lobular involution in the background breast tissue as none (0% involuted lobules), partial (1%–74%), or complete (≥75%). Subsequent breast cancer events and data on other risk factors were obtained from medical records and follow-up questionnaires. To estimate relative risks (RRs), standardized incidence ratios were calculated by use of incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) Registry. All statistical tests were two-sided. Results : Distribution of extent of involution was none among 1627 (18.6%) women, partial among 5197 (59.5%), and complete among 1912 (21.9%). Increased involution was positively associated with increased age and inversely associated with parity (both P <.001). The relative risk for the entire cohort of 8736 women, compared with the Iowa SEER population, was 1.40 (95% CI = 1.30 to 1.51). Risk of breast cancer was associated with the extent of involution (for no involution, RR [i.e., observed versus expected] = 1.88, 95% confidence interval [CI] = 1.59 to 2.21; for partial involution, RR = 1.47, 95% CI = 1.33 to 1.61; and for complete involution, RR = 0.91, 95% CI = 0.75 to 1.10; test for heterogeneity P <.001). Lobular involution modified risk in all subsets (e.g., among women with atypia, for no involution, RR = 7.79, 95% CI = 3.56 to 14.81; for partial involution, RR = 4.06, 95% CI = 3.03 to 5.33; and for complete involution, RR = 1.49, 95% CI = 0.41 to 3.82; P = .003). Conclusions : In this large cohort of women with benign breast disease, lobular involution was associated with reduced risk of breast cancer. Aberrant involution may be a biologically important phenomenon in breast cancer biology.
An fMRI Study of Facial Emotion Processing in Patients With Schizophrenia
Authors: Raquel E. Gur, Claire McGrath, Robin M. Chan, Lee Schroeder, Travis Turner, Bruce I. Turetsky, Christian Kohler, David Alsop, Joseph Maldjian, J. Daniel Ragland, Ruben C. Gur
Journal: American Journal of Psychiatry (2002)

Emotion processing deficits are notable in schizophrenia. The authors evaluated cerebral blood flow response in schizophrenia patients during facial emotion processing to test the hypothesis of diminished limbic activation related to emotional relevance of facial stimuli.Fourteen patients with schizophrenia and 14 matched comparison subjects viewed facial displays of happiness, sadness, anger, fear, and disgust as well as neutral faces. Functional magnetic resonance imaging was used to measure blood-oxygen-level-dependent signal changes as the subjects alternated between tasks of discriminating emotional valence (positive versus negative) and age (over 30 versus under 30) of the faces with an interleaved crosshair reference condition.The groups did not differ in performance on either task. For both tasks, healthy participants showed activation in the fusiform gyrus, occipital lobe, and inferior frontal cortex relative to the resting baseline condition. The increase was greater in the amygdala and hippocampus during the emotional valence discrimination task than during the age discrimination task. In the patients with schizophrenia, minimal focal response was observed for all tasks relative to the resting baseline condition. Contrasting patients and comparison subjects on the emotional valence discrimination task revealed voxels in the left amygdala and bilateral hippocampus in which the comparison subjects had significantly greater activation.Failure to activate limbic regions during emotional valence discrimination may explain emotion processing deficits in patients with schizophrenia. While the lack of limbic recruitment did not significantly impair simple valence discrimination performance in this clinically stable group, it may impact performance of more demanding tasks.
In vitro-induced human airway hyperresponsiveness to bradykinin
Authors: M Molimard, E Naline, E Boichot, P Devillier, V Lagente, B Begaud, C Advenier
Journal: European Respiratory Journal (1998)

Lipopolysaccharide (LPS) and interleukin (IL)-1beta have been reported to induce airway hyperresponsiveness in several animal models. This study investigated the effect of LPS or IL-1beta on bradykinin-induced human isolated bronchi contraction. LPS (100 ng x mL(-1) for 3-6 h) and IL-1beta (3x10(-10) and 3x10(-9) M for 20 min to 3 h) time-dependently potentiated bradykinin-induced contraction. This contraction was abolished, as in control experiments, by indomethacin (10(-6) M) or by the thromboxane (Tx) receptor antagonist GR 32191 but not by the cyclo-oxygenase-2 inhibitor, CGP28238. In contrast, the Tx mimetic U46619-induced contraction of human bronchi was not enhanced IL-1beta pretreatment. In the presence of GR 32191 (10(-6) M), bradykinin induced a prostanoid dependent relaxation that was not significantly modified by IL-1beta pretreatment. Determination of prostanoids in the organ bath fluid showed that bradykinin induced TxB2, the stable metabolite of TxA2, and 6-keto prostaglandin F1alpha, the stable metabolite of PGI2, release. Only TxA2 release was potentiated by IL-1beta. Taken together our results suggest that interleukin-1beta (1-3 h)-induced potentiation of the effect of bradykinin is linked to an increased activity of thromboxane synthase and, in turn, to increased thromboxane synthesis.
The Effect of Inhaled IFN-β on Worsening of Asthma Symptoms Caused by Viral Infections. A Randomized Trial
Authors: Ratko Djukanović, Tim Harrison, Sebastian L. Johnston, Flic Gabbay, Peter Wark, Neil C. Thomson, Robert Niven, Dave Singh, Helen K. Reddel, Donna E. Davies, Richard Marsden, Christine Boxall, Sarah Dudley, Vincent Plagnol, Stephen T. Holgate, Phillip Monk
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-β. Exogenous IFN-β restores antiviral activity.To compare the efficacy and safety of inhaled IFN-β with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses.A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2-5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-β (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses.A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse (mean change in six-item Asthma Control Questionnaire <0.5) and IFN-β treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset of more difficult-to-treat, Step 4-5 people with asthma (n = 27 IFN-β; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-β (P = 0.004).Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-β is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the need for further, adequately powered, trials in this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).
Serological-diagnosis of chronic pulmonary aspergillosis (CPA) and aspergillus lateral-flow device (LFD)
Authors: Makoto Kobayashi, Christopher R. Thornton
Journal: European Respiratory Journal (2014)

[Background] Elderly people who suffer from chronic pulmonary aspergillosis (CPA) develop debilitating fever and exhaustion. It is often hard to confirm the diagnosis because invasive diagnostic procedures are difficult to perform.  [Materials and Methods] We reviewed medical records of eleven patients with CPA (80±8 years of age, F2/M9) that we had encountered for the past six years in our hospital. In parallel with the serological testing including the GM antigen and the precipitating antibody,  Aspergillus -LFD using monoclonal antibody JF5 was also tested for its utility.  [Results] (1) Of eleven patients in the present study, ten showed radiological cavitary changes with fungus ball in half of them, and the other one did bronchiectasis. (2) Of seven patients who had the tuberculosis sequela, five were positive for the precipitating antibody against  Aspergillus fumigatus  and six were positive for the GM antigen, respectively. (3) Of the remaining four patients without the past history of tuberculosis, three had been treated with oral corticosteroids, and the other one patient developed  Aspergillus  lung abscess after lung cancer surgery. The GM antigen was positive in three patients and the precipitating antibody was positive in one patient. (4) Of eight patients9 serum samples which were available, six samples were positive (3+; 1 sample, 2+; 2 samples, and 1+; 3 samples) and the other two were negative for LFD. (5) Serum beta-D-glucan values were negative in ten patients.  [Discussion] The  Aspergillus  antigen and antibody detection testing combined with LFD was useful for enabling early diagnosis and treatment of CPA, and then contributed to the improvement of patients9 QOL.
LXRs Regulate ER Stress and Inflammation through Dynamic Modulation of Membrane Phospholipid Composition
Authors: Xin Rong, Carolyn J. Albert, Cynthia Hong, Mark A. Duerr, Brian T. Chamberlain, Elizabeth J. Tarling, Ayaka Ito, Jie Gao, Bo Wang, Peter A. Edwards, Michael E. Jung, David A. Ford, Peter Tontonoz
Journal: Cell Metabolism (2013)
A Compendium of Challenges: Assessing the State of the Science on Occupational Carcinogens
Authors: M. Nathaniel Mead
Journal: Environmental Health Perspectives (2010)

Sprawling Cities Have the Most Very Hot DaysThe urban heat island effect, the phenomenon in which a city has higher temperatures than surrounding countryside, is known to contribute to higher rates of heat-related mortality in summer months when temperatures soar.Although extreme heat events have become more common in large U.S. cities, a new study indicates that sprawling cities experience more than double the rate of extreme heat events in the summer compared with more compact urban areas [EHP 118( 10):1425-1428; Stone et al.].The authors considered 53 U.S. metropolitan areas for which data were available on sprawl and extreme heat event.Sprawl had been assessed in a 2003 study using an index based on land use data from the 2000 census along with measures of population density, average street block size, proximity of homes to businesses, and land use mix.Extreme heat events were defined as days on which the minimum, maximum, or average temperature exceeded the 85th percentile of a base period of 1961-1990.The authors compared the extent of sprawl for each metropolitan area with that area's average annual rate of extreme heat events from 1956 through 2005.Over the 50 years examined,
Depressed Ryanodine Receptor Activity Increases Variability and Duration of the Systolic Ca <sup>2+</sup> Transient in Rat Ventricular Myocytes
Authors: M.E. Díaz, D.A. Eisner, S.C. O’Neill
Journal: Circulation Research (2002)

Sarcoplasmic reticulum (SR) Ca2+ release, through the ryanodine receptor (RyR), is essential for the systolic Ca2+ transient and thus the cardiac contractile function. The aim of this study was to examine the effects on the spatial organization of the systolic Ca2+ transient of depressing RyR open probability (P(o)) with tetracaine or intracellular acidification. Voltage-clamped, fluo-3-loaded myocytes were studied using confocal microscopy. Depressing RyR P(o) increased the variability of the Ca2+ transient amplitude between different regions of the cell. This variability often produced alternans with a region producing large and small transients alternately. In addition, the raising phase of the Ca2+ transient became biphasic. The initial phase was constant but the second was variable and propagated as a wave through part of the cell. That both phases involved SR Ca2+ release was shown by their reduction by caffeine. Regional [Ca2+]i alternans was accompanied by a much smaller degree of alternans at the whole cell level. We suggest that, in tetracaine or acidosis, the initial phase of the Ca2+ transient results from Ca2+ release via RyRs directly activated by adjacent L-type Ca2+ channels. At some sites, this will activate neighboring RyRs and a Ca2+ wave will propagate via activation of other RyRs. This work is the first demonstration that decreased RyR P(o) alone can produce disarray of the Ca2+ release process and initiate alternans.
Staging and Functional Characterization of Pheochromocytoma and Paraganglioma by 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography
Authors: Henri J. L. M. Timmers, Clara C. Chen, Jorge A. Carrasquillo, Millie Whatley, Alexander Ling, Graeme Eisenhofer, Kathryn S. King, Jyotsna U. Rao, Robert A. Wesley, Karen T. Adams, Karel Pacak
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundPheochromocytomas and paragangliomas (PPGLs) are rare tumors of the adrenal medulla and extra-adrenal sympathetic chromaffin tissues; their anatomical and functional imaging are critical to guiding treatment decisions. This study aimed to compare the sensitivity and specificity of 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) for tumor localization and staging of PPGLs with that of conventional imaging by [123I]-metaiodobenzylguanidine single photon emission CT (123I-MIBG SPECT), CT, and magnetic resonance imaging (MRI).