tbuckley/cabot-search huggingface dataset:
Preferential Signaling and Induction of Allergy-promoting Lymphokines Upon Weak Stimulation of the High Affinity IgE Receptor on Mast Cells
Authors: Claudia Gonzalez-Espinosa, Sandra Odom, Ana Olivera, J. Peyton Hobson, Maria Eugenia Cid Martinez, Antonio Oliveira-dos-Santos, Lillian Barra, Sarah Spiegel, Josef M. Penninger, Juan Rivera
Journal: The Journal of Experimental Medicine (2003)

Mast cell degranulation and de novo cytokine production is a consequence of antigen-aggregation of the immunoglobulin E (IgE)-occupied high affinity receptor for IgE (Fc epsilon RI). Herein, we report that lymphokines that promote allergic inflammation, like MCP-1, were potently induced at low antigen (Ag) concentrations or at low receptor occupancy with IgE whereas some that down-regulate this response, like interleukin (IL)-10, required high receptor occupancy. Weak stimulation of mast cells caused minimal degranulation whereas a half-maximal secretory response was observed for chemokines and, with the exception of TNF-alpha, a weaker cytokine secretory response was observed. The medium from weakly stimulated mast cells elicited a monocyte/macrophage chemotactic response similar to that observed at high receptor occupancy. Weak stimulation also favored the phosphorylation of Gab2 and p38MAPK, while LAT and ERK2 phosphorylation was induced by a stronger stimulus. Gab2-deficient mast cells were severely impaired in chemokine mRNA induction whereas LAT-deficient mast cells showed a more pronounced defect in cytokines. These findings demonstrate that perturbation of small numbers of IgE receptors on mast cells favors certain signals that contribute to a lymphokine response that can mediate allergic inflammation.
Perinatal and Familial Risk Factors for Brain Tumors in Childhood through Young Adulthood
Authors: Casey Crump, Jan Sundquist, Weiva Sieh, Marilyn A. Winkleby, Kristina Sundquist
Journal: Cancer Research (2014)

Abstract Perinatal factors, including high birth weight, have been associated with childhood brain tumors in case–control studies. However, the specific contributions of gestational age and fetal growth remain unknown, and these issues have never been examined in large cohort studies with follow-up into adulthood. We conducted a national cohort study of 3,571,574 persons born in Sweden in 1973–2008, followed up for brain tumor incidence through 2010 (maximum age 38 years) to examine perinatal and familial risk factors. There were 2,809 brain tumors in 69.7 million person-years of follow-up. After adjusting for potential confounders, significant risk factors for brain tumors included high fetal growth [incidence rate ratio (IRR) per additional 1 SD, 1.04; 95% confidence interval (CI), 1.01–1.08, P = 0.02], first-degree family history of a brain tumor (IRR, 2.43; 95% CI, 1.86–3.18, P &amp;lt; 0.001), parental country of birth (IRR for both parents born in Sweden vs. other countries, 1.21; 95% CI, 1.09–1.35, P &amp;lt; 0.001), and high maternal education level (Ptrend = 0.01). These risk factors did not vary by age at diagnosis. The association with high fetal growth appeared to involve pilocytic astrocytomas, but not other astrocytomas, medulloblastomas, or ependymomas. Gestational age at birth, birth order, multiple birth, and parental age were not associated with brain tumors. In this large cohort study, high fetal growth was associated with an increased risk of brain tumors (particularly pilocytic astrocytomas) independently of gestational age, not only in childhood but also into young adulthood, suggesting that growth factor pathways may play an important long-term role in the etiology of certain brain tumor subtypes. Cancer Res; 75(3); 576–83. ©2014 AACR.
Involvement of Rho GTPases in the Transcriptional Inhibition of Preproendothelin-1 Gene Expression by Simvastatin in Vascular Endothelial Cells
Authors: Octavio Hernández-Perera, Dolores Pérez-Sala, Estrella Soria, Santiago Lamas
Journal: Circulation Research (2000)

Abstract —Endothelial dysfunction is characterized by an impaired vasodilatory response to endothelial agonists as well as by alterations in adhesion and coagulation processes. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) have been shown to be useful in the reversal of endothelial dysfunction, an effect that may be independent of the reduction in cholesterol levels. Both the l -arginine–nitric oxide–cGMP and endothelin pathways are involved in the regulation of vascular tone. Here, we show that the basal transcription rate of the preproendothelin-1 gene was decreased by simvastatin (10 μmol/L) in bovine aortic endothelial cells. Transfection studies with the preproendothelin-1 gene promoter showed that mevalonate (100 μmol/L) was able to prevent the inhibitory effect mediated by simvastatin. Protein geranylgeranylation, but not farnesylation, proved to be crucial for a correct expression of the preproendothelin-1 gene. The C3 exotoxin from Clostridium botulinum that selectively inactivates Rho GTPases, the processing of which involves geranylgeranylation, reproduced the inhibitory effect of simvastatin on the expression of preproendothelin-1. Overexpression of dominant-negative mutants of RhoA and RhoB led to a significant reduction in the preproendothelin-1 promoter activity, whereas the expression of wild-type and constitutively active forms of these proteins resulted in an increase, in support that Rho proteins are required for the basal expression of the preproendothelin-1 gene. Finally, we show that the Rho-dependent activation of the preproendothelin-1 gene transcription was inhibited by simvastatin. Thus, the control of vascular tone and proliferative response mediated by endothelin-1 is regulated at multiple levels, among which the Rho proteins play an essential role.
Tackling Off-Label Use of Anticancer Drugs
Authors: Francesco Perrone, Filippo de Braud, Roberto Labianca, Carlo Tomino, Fausto Roila
Journal: Journal of Clinical Oncology (2012)

TO THEEDITOR:WereadwithinterestthearticlebyMullinsetal 1 reportingrecommendationsforclinicaltrialsofoff-labeldrugsusedto treat advanced-stage cancer. The 14 statements summarizing their recommendations are absolutely shareable and actually represent an excellentchecklistforimprovingqualityofclinicaltrials,nomatterthe field to which they are applied. However, we doubt that they can significantlyaffecttheoff-labelphenomenon,drivenbytheawareness ofsafety(atleastinthesettinginwhichthetreatmentisapproved)and the existence of true unmet medical needs. In 2006, we conducted a survey in 15 Italian centers, 2 collecting data on treatment of 644 patients corresponding to 1,053 prescriptions.Overall,199prescriptions(18.9%)wereofflabelbecauseofone of four reasons: drug used in a cancer different than that authorized (n 92; 46.2%), drug used within an inappropriate combination (n 41; 20.6%), drug used in a line of treatment different than the registeredone(n39;19.6%),anddrugusedinararetumor(n27; 13.6%). All the prescriptions of the first group had supporting scientific evidence (assessed by physicians different from those who wrote the prescription) from one or more randomized trials or several positivephaseIIstudiespublishedinmajoroncologyjournals.Therefore, clinical trials in this case had been performed but had not produced registration. In the second group, the only drug used in combination but approved as a single agent (at that time) was capecitabine (20 prescriptions; 10%). The remaining were drugs approved for use in combination that were instead used as single agents, possibly because of toxicity and consideration of patients’ conditions. From the perspectiveofMullinsetal, 1 thelattershouldprobablybetestedinclinical trials dedicated to unfit patients. The third group mostly (28 v 11 patient cases) included drugs that were used for lines of treatment subsequent to those for which they were registered, in common cancers such as breast and colorectal. It is hard to believe that proper randomized trials can be planned involving patients receiving their fourth or fifth line of treatment, primarily because of the difficulty of identifying a control arm that should probably be placebo or best supportive care. Finally, the fourth group included rare neoplasms, which represent a well-knownfield of debate because of the impossibility of applying common rules of clinical trial methodology. 3
Pancreatic cancer genomics: insights and opportunities for clinical translation
Authors: Alvin Makohon-Moore, Jacqueline A Brosnan, Christine A Iacobuzio-Donahue
Journal: Genome Medicine (2013)

Pancreatic cancer is a highly lethal tumor type for which there are few viable therapeutic options. It is also caused by the accumulation of mutations in a variety of genes. These genetic alterations can be grouped into those that accumulate during pancreatic intraepithelial neoplasia (precursor lesions) and thus are present in all cells of the infiltrating carcinoma, and those that accumulate specifically within the infiltrating carcinoma during subclonal evolution, resulting in genetic heterogeneity. Despite this heterogeneity there are nonetheless commonly altered cellular functions, such as pathways controlling the cell cycle, DNA damage repair, intracellular signaling and development, which could provide for a variety of drug targets. This review aims to summarize current knowledge of the genetics and genomics of pancreatic cancer from its inception to metastatic colonization, and to provide examples of how this information can be translated into the clinical setting for therapeutic benefit and personalized medicine.
Interactions Between Nitric Oxide and Lipid Oxidation Pathways
Authors: Valerie B. O’Donnell, Bruce A. Freeman
Journal: Circulation Research (2001)

Abstract —Nitric oxide ( · NO) signaling pathways and lipid oxidation reactions are of central importance in both the maintenance of vascular homeostasis and the progression of vascular disease. Because both of these pathways involve free radical species that can also react together at extremely fast rates, convergent interactions between these pathways are expected. Biochemical and cell biology studies have defined multiple interactions of · NO with oxidizing lipids that could lead to either vascular protection or potentiation of inflammatory vascular injury. For example, low levels of · NO generated by endothelial nitric oxide synthase can terminate propagating lipid radicals and inhibit lipoxygenases, reactions that would be protective. Alternatively, if generated at elevated levels, for example, after inducible nitric oxide synthase expression in inflammation, · NO can be converted to prooxidant species, such as peroxynitrite (ONOO – ) and nitrogen dioxide ( · NO 2 ), that can potentiate inflammatory injury to vascular cells. Finally, both enzymatic and nonenzymatic lipid oxidation reactions can influence · NO bioactivity by directly scavenging · NO or altering the induction and catalytic activity of nitric oxide synthase enzymes. In this review, we summarize the biochemical interactions between · NO and lipid oxidation reactions and discuss the recognized and potential roles of these reactions in the vasculature.
The Consult Guys - Spinal or General Anesthesia?
Authors: Geno J. Merli, Howard H. Weitz
Journal: Annals of Internal Medicine (2014)

Web Exclusives15 July 2014The Consult Guys - Spinal or General Anesthesia?FREEGeno J. Merli, MD and Howard H. Weitz, MDGeno J. Merli, MDSearch for more papers by this author and Howard H. Weitz, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G14-3007 SectionsSupplemental MaterialAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The Consult Guys bring a new perspective to the art and science of medicine with lively discussion and analysis of real-world cases and situations.For more videos from and information on The Consult Guys, visit www.annals.org/ConsultGuys. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Disclosures: Geno J. Merli, MD, reports the following: Research grants/contracts: Bristol-Myers Squibb, Bayer, sanofi-aventis; Consultancies: Bristol-Myers Squibb, Bayer, sanofi-aventis. Howard H. Weitz, MD, reports that he has no financial relationships or interests to disclose. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 July 2014Volume 161, Issue 2Page: CG7KeywordsConflicts of interestGeneral anesthesiaResearch grantsResearch reporting guidelines ePublished: 15 July 2014 Issue Published: 15 July 2014 Copyright & PermissionsCopyright © 2014 by American College of Physicians. All Rights Reserved.Loading ...
Employment, work disability, and work days lost in patients with ankylosing spondylitis: a cross sectional study of Dutch patients
Authors: A Boonen
Journal: Annals of the Rheumatic Diseases (2001)

To evaluate employment status, work disability, and work days lost in patients with ankylosing spondylitis (AS).A questionnaire was sent to 709 patients with AS aged 16-60. The results of 658 of the patients could be analysed.After adjustment for age, labour force participation was decreased by 15.4% in male patients and 5.2% in female patients compared with the general Dutch population. Work disability (all causes) was 15.7% and 16.9% higher than expected in the general population for male and female patients respectively. In particular, the proportion of those with a partial work disability pension was increased. Patients with a paid job lost 5.0% of work days as the result of having AS, accounting for a mean of 10.1 days of sick leave due to AS per patient per year in addition to the national average of 12.3 unspecified days of sick leave.This study on work status in AS provides data adjusted for age and sex, and the differences from the reference population were significant. The impact of AS on employment and work disability is considerable. Work status in patients with AS needs more attention as an outcome measure in future research.
Septic arthritis caused by treatment resistant Pseudomonas cepacia.
Authors: E L Matteson, W J McCune
Journal: Annals of the Rheumatic Diseases (1990)

A case of septic arthritis of the knee caused by Pseudomonas cepacia following an intraarticular corticosteroid injection in a patient with a history of osteoarthritis is presented. This is the second report of this agent causing infection in a diarthrodial joint, which proved difficult to eradicate despite in vitro antibiotic sensitivity.
Reversible and permanent effects of tobacco smoke exposure on airway epithelial gene expression
Authors: Jennifer Beane, Paola Sebastiani, Gang Liu, Jerome S Brody, Marc E Lenburg, Avrum Spira
Journal: Genome biology (2007)

Tobacco use remains the leading preventable cause of death in the US. The risk of dying from smoking-related diseases remains elevated for former smokers years after quitting. The identification of irreversible effects of tobacco smoke on airway gene expression may provide insights into the causes of this elevated risk.Using oligonucleotide microarrays, we measured gene expression in large airway epithelial cells obtained via bronchoscopy from never, current, and former smokers (n = 104). Linear models identified 175 genes differentially expressed between current and never smokers, and classified these as irreversible (n = 28), slowly reversible (n = 6), or rapidly reversible (n = 139) based on their expression in former smokers. A greater percentage of irreversible and slowly reversible genes were down-regulated by smoking, suggesting possible mechanisms for persistent changes, such as allelic loss at 16q13. Similarities with airway epithelium gene expression changes caused by other environmental exposures suggest that common mechanisms are involved in the response to tobacco smoke. Finally, using irreversible genes, we built a biomarker of ever exposure to tobacco smoke capable of classifying an independent set of former and current smokers with 81% and 100% accuracy, respectively.We have categorized smoking-related changes in airway gene expression by their degree of reversibility upon smoking cessation. Our findings provide insights into the mechanisms leading to reversible and persistent effects of tobacco smoke that may explain former smokers increased risk for developing tobacco-induced lung disease and provide novel targets for chemoprophylaxis. Airway gene expression may also serve as a sensitive biomarker to identify individuals with past exposure to tobacco smoke.
Nano-Enabled SERS Reporting Photosensitizers
Authors: Arash Farhadi, Áron Roxin, Brian C. Wilson, Gang Zheng
Journal: Theranostics (2015)

To impart effective cellular damage via photodynamic therapy (PDT), it is vital to deliver the appropriate light dose and photosensitizer concentration, and to monitor the PDT dose delivered at the site of interest. In vivo monitoring of photosensitizers has in large part relied on their fluorescence emission. Palladium-containing photosensitizers have shown promising clinical results by demonstrating near full conversion of light to PDT activity at the cost of having undetectable fluorescence. We demonstrate that, through the coupling of plasmonic nanoparticles with palladium-photosensitizers, surface-enhanced Raman scattering (SERS) provides both reporting and monitoring capability to otherwise quiescent molecules. Nano-enabled SERS reporting of photosensitizers allows for the decoupling of the therapeutic and imaging mechanisms so that both phenomena can be optimized independently. Most importantly, the design enables the use of the same laser wavelength to stimulate both the PDT and imaging features, opening the potential for real-time dosimetry of photosensitizer concentration and PDT dose delivery by SERS monitoring.
Lymphangiogenic Gene Therapy With Minimal Blood Vascular Side Effects
Authors: Anne Saaristo, Tanja Veikkola, Tuomas Tammela, Berndt Enholm, Marika J. Karkkainen, Katri Pajusola, Hansruedi Bueler, Seppo Ylä-Herttuala, Kari Alitalo
Journal: The Journal of Experimental Medicine (2002)

Recent work from many laboratories has demonstrated that the vascular endothelial growth factor-C/VEGF-D/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and that mutations of the Vegfr3 gene are associated with hereditary lymphedema. Furthermore, VEGF-C gene transfer to the skin of mice with lymphedema induced a regeneration of the cutaneous lymphatic vessel network. However, as is the case with VEGF, high levels of VEGF-C cause blood vessel growth and leakiness, resulting in tissue edema. To avoid these blood vascular side effects of VEGF-C, we constructed a viral vector for a VEGFR-3–specific mutant form of VEGF-C (VEGF-C156S) for lymphedema gene therapy. We demonstrate that VEGF-C156S potently induces lymphangiogenesis in transgenic mouse embryos, and when applied via viral gene transfer, in normal and lymphedema mice. Importantly, adenoviral VEGF-C156S lacked the blood vascular side effects of VEGF and VEGF-C adenoviruses. In particular, in the lymphedema mice functional cutaneous lymphatic vessels of normal caliber and morphology were detected after long-term expression of VEGF-C156S via an adeno associated virus. These results have important implications for the development of gene therapy for human lymphedema.
Folate Intake and the Risk of Incident Hypertension Among US Women
Authors: John P. Forman
Journal: JAMA (2005)

ContextFolate has important beneficial effects on endothelial function, but there is limited information about folate intake and risk of incident hypertension.ObjectiveTo determine whether higher folate intake is associated with a lower risk of incident hypertension.Design, Setting, and ParticipantsTwo prospective cohort studies of 93 803 younger women aged 27 to 44 years in the Nurses' Health Study II (1991-1999) and 62 260 older women aged 43 to 70 years in the Nurses' Health Study I (1990-1998), who did not have a history of hypertension. Baseline information on dietary folate and supplemental folic acid intake was derived from semiquantitative food frequency questionnaires and was updated every 4 years.Main Outcome MeasureRelative risk of incident self-reported hypertension during 8 years of follow-up.ResultsWe identified 7373 incident cases of hypertension in younger women and 12 347 cases in older women. After adjusting for multiple potential confounders, younger women who consumed at least 1000 μg/d of total folate (dietary plus supplemental) had a decreased risk of hypertension (relative risk [RR], 0.54; 95% confidence interval [CI], 0.45-0.66; P for trend <.001) compared with those who consumed less than 200 μg/d. Younger women's absolute risk reduction (ARR) was approximately 8 cases per 1000 person-years (6.7 vs 14.8 cases). The multivariable RR for the same comparison in older women was 0.82 (95% CI, 0.69-0.97; P for trend = .05). Older women's ARR was approximately 6 cases per 1000 person-years (34.7 vs 40.4 cases). When the analysis was restricted to women with low dietary folate intake (<200 μg/d), the multivariable RR for younger women with total folate intake at least 800 μg/d compared with less than 200 μg/d was 0.55 (95% CI, 0.32-0.94; P for trend = .03), and 0.61 (95% CI, 0.34-1.11; P for trend = .05) in the older cohort. Among women who did not take folic acid–containing supplements, dietary folate intake of 400 μg/d or more was not significantly associated with risk of hypertension.ConclusionHigher total folate intake was associated with a decreased risk of incident hypertension, particularly in younger women.
Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study
Authors: Erica Villa, Rosina Critelli, Barbara Lei, Guido Marzocchi, Calogero Cammà, Gianluigi Giannelli, Patrizia Pontisso, Giuseppe Cabibbo, Marco Enea, Stefano Colopi, Cristian Caporali, Teresa Pollicino, Fabiola Milosa, Aimilia Karampatou, Paola Todesca, Elena Bertolini, Livia Maccio, Maria Luz Martinez-Chantar, Elena Turola, Mariagrazia Del Buono, Nicola De Maria, Stefano Ballestri, Filippo Schepis, Paola Loria, Giorgio Enrico Gerunda, Luisa Losi, Umberto Cillo
Journal: Gut (2015)

The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide high-throughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC.Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V0 and V1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model.Calculated tumour doubling times ranged from 30 to 621 days (mean, 107±91 days; median, 83 days) and were divided into quartiles: ≤53 days (n=19), 54-82 days (n=20), 83-110 days (n=20) and ≥111 days (n=19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p<0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2 (ANGPT2), delta-like ligand 4 (DLL4), neuropilin (NRP)/tolloid (TLL)-like 2 (NETO2), endothelial cell-specific molecule-1 (ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p<0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p<0.0001).The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC.ClinicalTrials.gov Identifier: NCT01657695.