tbuckley/cabot-search huggingface dataset:
Arsenic Methylation, Oxidative Stress and Cancer--Is There a Link?
Authors: M. F. Hughes
Journal: JNCI Journal of the National Cancer Institute (2009)

Arsenic is a multiorgan human carcinogen. The best-known example of this effect occurred in subgroups of the Taiwanese population who were chronically exposed to high levels of naturally occurring arsenic in drinking water and developed cancers of the skin, lung, urinary bladder, and potentially the kidney ( 1 ). Nonneoplastic effects that are attributed to arsenic exposure under similar conditions include vascular disease, hypertension, diabetes, and dermal lesions ( 2 , 3 ). Many countries today still have arseniccontaminated drinking water and are facing a potential public health crisis ( 4 ). Although the carcinogenicity of arsenic in humans has been known for more than 100 years, there is no defi nitive understanding of the mechanism of action for this effect. This gap in knowledge has been partly because of the lack of positive animal carcinogenicity studies for a number of years, because arsenic is not a point mutagen, and because the mechanism for the biotransformation of arsenic was not completely known. In the 1990s, attention became focused on the potential tumor-promoting and carcinogenic effects of the methylated metabolites of arsenic. Investigations found that dimethylarsinic acid [DMAs(V)], a pentavalent metabolite of inorganic arsenic, was a multiorgan tumor promoter in rodents ( 5 ) and was carcinogenic in rat urinary bladder following chronic dietary or drinking water exposure ( 6 , 7 ). Arsenic was also found to be carcinogenic in more recent studies using transgenic animals ( 5 ) or transplacental exposure in mice ( 8 ). In the 1940s, Challenger ( 9 ) proposed a pathway for arsenic metabolism that included reduction of a pentavalent (V) arsenical to a trivalent (III) arsenical by transfer of two electrons, followed by oxidative methylation using the methyl donor, S -adenosyl methionine. The pathway is shown below: Arsenate [iAs(V)] + 2 e → Arsenite [iAs(III)] + CH 3 → Monomethylarsonic acid [MAs(V)] + 2 e → Monomethylarsonous acid [MAs(III)] + CH 3 → Dimethylarsinic acid [DMAs(V)] + 2 e → Dimethylarsinous acid [DMAs(III)] + CH 3 → Trimethylarsine oxide [TMAsO(V)] For years, the methylation of arsenic was considered to be a detoxifi cation mechanism. The reasons for this hypothesis were that the pentavalent methylated arsenicals [MAs(V), DMAs(V), and TMAsO(V)] were less acutely toxic than either arsenate [iAs(V)] or arsenite [iAs(III)] and that these methylated metabolites were rapidly excreted by mammals ( 10 ). The exception is in the rat, which retains administered arsenic ( 10 ) and has hemoglobin that avidly binds DMAs(III) ( 11 ). Also, the trivalent methylated arsenicals, MAs(III) and DMAs(III), had never been detected in vitro or in vivo.
Epigenetic Repression of DNA Mismatch Repair by Inflammation and Hypoxia in Inflammatory Bowel Disease–Associated Colorectal Cancer
Authors: Robert A. Edwards, Mavee Witherspoon, Kehui Wang, Kambiz Afrasiabi, Trang Pham, Lutz Birnbaumer, Steven M. Lipkin
Journal: Cancer Research (2009)

Abstract Sporadic human mismatch repair (MMR)–deficient colorectal cancers account for ∼12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein α subunit Giα2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Giα2−/− colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Giα2−/− cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Giα2−/− colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Giα2−/− crypts. Treating Giα2−/− mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase–dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer. [Cancer Res 2009;69(16):6423–9]
Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials
Authors: Christopher E M Griffiths, Kristian Reich, Mark Lebwohl, Peter van de Kerkhof, Carle Paul, Alan Menter, Gregory S Cameron, Janelle Erickson, Lu Zhang, Roberta J Secrest, Susan Ball, Daniel K Braun, Olawale O Osuntokun, Michael P Heffernan, Brian J Nickoloff, Kim Papp
Journal: The Lancet (2015)
The shock index and the simplified PESI for identification of low-risk patients with acute pulmonary embolism
Authors: A. Sam, D. Sánchez, V. Gómez, C. Wagner, D. Kopecna, C. Zamarro, L. Moores, D. Aujesky, R. Yusen, D. Jiménez Castro
Journal: European Respiratory Journal (2010)

We compared the test characteristics of the shock index (SI) and the simplified pulmonary embolism severity index (sPESI) for predicting 30-day outcomes in a cohort of 1,206 patients with objectively confirmed pulmonary embolism (PE). The primary outcome of the study was all-cause mortality. The secondary outcome was nonfatal symptomatic recurrent venous thromboembolism (VTE) or nonfatal major bleeding. Overall, 119 (9.9%) out of 1,206 patients died (95% CI 8.2–11.5%) during the first month of follow-up. The sPESI classified fewer patients as low-risk (369 (31%) out of 1,206 patients, 95% CI 28–33%) compared to the SI (1,024 (85%) out of 1,206 patients, 95% CI 83–87%) (p&lt;0.001). Low-risk patients based on the sPESI had a lower 30-day mortality than those based on the SI (1.6% (95% CI 0.3–2.9%) versus 8.3% (95% CI 6.6–10.0%)), while the 30-day rate of nonfatal recurrent VTE or major bleeding was similar (2.2% (95%CI 0.7–3.6%) versus 3.3% (95%CI 2.2–4.4%)). The net reclassification improvement with the sPESI was 13.4% (p = 0.07). The integrated discrimination improvement was estimated as 1.8% (p&lt;0.001). The sPESI quantified the prognosis of patients with PE better than the SI.
Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data
Authors: F. Favero, T. Joshi, A.M. Marquard, N.J. Birkbak, M. Krzystanek, Q. Li, Z. Szallasi, A.C. Eklund
Journal: Annals of Oncology (2014)

Exome or whole-genome deep sequencing of tumor DNA along with paired normal DNA can potentially provide a detailed picture of the somatic mutations that characterize the tumor. However, analysis of such sequence data can be complicated by the presence of normal cells in the tumor specimen, by intratumor heterogeneity, and by the sheer size of the raw data. In particular, determination of copy number variations from exome sequencing data alone has proven difficult; thus, single nucleotide polymorphism (SNP) arrays have often been used for this task. Recently, algorithms to estimate absolute, but not allele-specific, copy number profiles from tumor sequencing data have been described.
Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers.
Authors: Christina E Hoei-Hansen, Sigrid M Kraggerud, Vera M Abeler, Janne Kærn, Ewa Rajpert-De Meyts, Ragnhild A Lothe
Journal: Molecular Cancer (2007)

Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia. We examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2γ) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13–40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH. This study provides new data supporting two distinct but overlapping pathways in OGCT development; one involving spontaneous KIT mutation(s) leading to increased survival and proliferation of undifferentiated oogonia, the other related to presence of Y chromosome material and ensuing gonadal dysgenesis in phenotypic females.
Sicca symptoms and secondary Sjogren's syndrome in systemic lupus erythematosus: comparison with rheumatoid arthritis and correlation with disease variables
Authors: I-M Gilboe, T K Kvien, T Uhlig, G Husby
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> Firstly, to study the prevalence of ocular and oral sicca symptoms, reduced tear and saliva production, and the minimum frequency of secondary Sjögren9s syndrome (sSS) in systemic lupus erythematosus (SLE). Secondly, to compare sicca symptoms and findings with those of matched patients with rheumatoid arthritis (RA), and sicca symptoms with those in healthy controls. Finally, to study possible associations of clinical variables with sicca symptoms and sSS in SLE. <h3>METHODS</h3> Self reported sicca symptoms were recorded in 81 patients with SLE aged ⩽70, 81 matched patients with RA, and 81 matched healthy controls. Other study variables included Schirmer-I test (S1T), unstimulated whole saliva, health status measures (in SLE and RA), disease activity, accumulated organ damage, and serological markers (in SLE). <h3>RESULTS</h3> A significantly higher proportion of patients with SLE reported sicca symptoms than healthy controls. Further, a significantly higher proportion reported ocular sicca symptoms (43 and 21%, respectively) and had pathologically reduced S1T compared with RA (46 and 21%, respectively). No difference was seen in oral sicca symptoms and saliva production. In SLE, sicca symptoms were associated with fatigue, and sSS with anti-SSB or anti-SSA antibodies, or both. <h3>CONCLUSIONS</h3> An increased prevalence of sicca symptoms was found in patients with SLE compared with controls, and a higher prevalence of ocular sicca symptoms and reduced tear production in SLE compared with RA. Sicca problems should be considered in the care of patients with SLE, especially those with anti-SSB and/or anti-SSA antibodies who have sicca symptoms and fatigue.
Mesenchymal stem cells from Shwachman–Diamond syndrome patients display normal functions and do not contribute to hematological defects
Authors: V André, D Longoni, S Bresolin, C Cappuzzello, E Dander, M Galbiati, C Bugarin, A Di Meglio, E Nicolis, E Maserati, M Serafini, A J Warren, G te Kronnie, G Cazzaniga, L Sainati, M Cipolli, A Biondi, G D'Amico
Journal: Blood Cancer Journal (2012)

Shwachman–Diamond syndrome (SDS) is a rare inherited disorder characterized by bone marrow (BM) dysfunction and exocrine pancreatic insufficiency. SDS patients have an increased risk for myelodisplastic syndrome and acute myeloid leukemia. Mesenchymal stem cells (MSCs) are the key component of the hematopoietic microenvironment and are relevant in inducing genetic mutations leading to leukemia. However, their role in SDS is still unexplored. We demonstrated that morphology, growth kinetics and expression of surface markers of MSCs from SDS patients (SDS-MSCs) were similar to normal MSCs. Moreover, SDS-MSCs were able to differentiate into mesengenic lineages and to inhibit the proliferation of mitogen-activated lymphocytes. We demonstrated in an in vitro coculture system that SDS-MSCs, significantly inhibited neutrophil apoptosis probably through interleukin-6 production. In a long-term coculture with CD34+-sorted cells, SDS-MSCs were able to sustain CD34+ cells survival and to preserve their stemness. Finally, SDS-MSCs had normal karyotype and did not show any chromosomal abnormality observed in the hematological components of the BM of SDS patients. Despite their pivotal role in the hematopoietic stem cell niche, our data suggest that MSC themselves do not seem to be responsible for the hematological defects typical of SDS patients.
Phase I Drug and Light Dose-Escalation Trial of Motexafin Lutetium and Far Red Light Activation (Phototherapy) in Subjects With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention and Stent Deployment
Authors: Dean J. Kereiakes, Arthur M. Szyniszewski, Dennis Wahr, Howard C. Herrmann, Daniel I. Simon, Campbell Rogers, Paul Kramer, Wendy Shear, Alan C. Yeung, Kendrick A. Shunk, Tony M. Chou, Jeffrey Popma, Peter Fitzgerald, Tanya E. Carroll, David Forer, Daniel C. Adelman
Journal: Circulation (2003)

Motexafin lutetium (MLu; Antrin) is a photosensitizer that is taken up by atherosclerotic plaque and concentrated within macrophages and vascular smooth muscle cells. After photoactivation with far red light, MLu facilitates production of cytotoxic oxygen radicals that mediate apoptosis. We assessed the safety and tolerability of phototherapy (PT) with MLu in patients undergoing percutaneous coronary intervention with stent deployment.An open-label, phase I, drug and light dose-escalation clinical trial of MLu PT enrolled 80 patients undergoing de novo coronary stent deployment. MLu was administered to 79 patients by intravenous infusion 18 to 24 hours before procedure, and photoactivation was performed after balloon predilatation and before stent deployment. Clinical evaluation, serial quantitative angiography, and intravascular ultrasound were performed periprocedurally and at 6 months follow-up. MLu PT was well tolerated without serious dose-limiting toxicities, and side effects (paresthesia and rash) were minor. No adverse angiographic outcomes were attributed to phototherapy.This study demonstrates that coronary MLu PT seems safe, and the maximum well-tolerated MLu dose and range of tolerated light doses were identified. These data can be used in phase II efficacy trials of MLu PT for the treatment of coronary atherosclerosis or vulnerable plaque.
HSP47siRNA targeting to myofibroblasts attenuates bleomycin-induced pulmonary fibrosis
Authors: Mitsuo Otsuka, Masanori Shiratori, Koji Kuronuma, Hiroki Takahashi
Journal: European Respiratory Journal (2012)

Rationale:  The 47-kDa heat shock protein 47 (HSP47) plays a role in the processing of procollagens as a collagen molecular chaperone. The HSP47-positive cells increase in lung fibrosis, which suggests an important role of HSP47 in the pathogenesis of lung fibrosis. It is expected that to control the expression of the HSP47 may reduce the lung fibrosis. Lung myofibroblasts are speculated vitamin A (VA)-storing cells in the lungs like hepatic stellate cells. Based on these properties of myofibroblasts, we prepared a VA-coupled liposomes carrying HSP47siRNA. The goal of this study is to investigate whether the inhibition of HSP47 for the myofibroblasts with siRNA influences to lung fibrosis.  Methods:  Sprague-Dawley male rats were treated with intra-tracheal bleomycin (BLM) or PBS. We injected VA-coupled liposomes carrying HSP47siRNA into rat tail vein three times in a week. We made 5 groups; PBS intratracheally & PBS intravenously, BLM & PBS, BLM & VA-HSP47siRNA, BLM & HSP47siRNA, and BLM & VA-randomRNA, respectively. We measured the contents of lung hydroxyproline, BAL cells counts, HSP47 expression, and cytokines.  Results:  Western blotting showed the expressions of HSP47 were reduced in rats treated with VA-coupled liposomes carrying HSP47siRNA. The liposomes with HSP47siRNA significantly improved lung fibrosis morphologically and the increases of hydroxyproline contents in the lungs, the inflammatory cytokines, and the number of BAL cells.  Conclusions:  These results suggest that HSP47siRNA improves bleomycin-induced lung fibrosis and this drug delivery system is useful methods.
The Physician-Scientist Workforce and Board Certification
Authors: David G. Nichols, George Lister
Journal: JAMA Pediatrics (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Induction of Lung Fibroblast Apoptosis by Soluble Fibronectin Peptides
Authors: HÉLÈNE LEVREY HADDEN, CRAIG A. HENKE
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Despite the importance of fibroproliferative lung disorders, no safe and effective therapies exist for reducing the size of the fibroblast population in existing fibrotic lesions. Recent work suggests that therapies that promote fibroblast apoptosis during the repair phase following lung injury may facilitate lung repair by eliminating excess fibrotic tissue. We report here our finding that three soluble fibronectin peptides (RGD, CS-1, and FN-C/H-V) induce apoptosis in lung fibroblasts. Fibroblast susceptibility to these peptides was dose and time dependent, with a maximal effect observed at 96 h (87 ± 16% [mean ± SEM] apoptosis). The peptides were able to induce fibroblast apoptosis in fibrin gels, an in vitro model of early fibroproliferative lesions. Fibroblasts were difficult to kill. All three peptides were required for maximal apoptosis of anchored cells. Apoptosis occurred by disruption of adhesion (anoikis). Treatment of fibroblasts with peptides caused proteolysis of pp125FAK, a tyrosine kinase involved in integrin-mediated signaling related to cell survival. These data show that soluble fibronectin peptides trigger nontransformed fibroblast apoptosis in routine culture and in fibrin gels by a mechanism that includes disruption of an integrin-mediated survival signaling pathway. The use of small fibronectin peptides to promote fibroblast apoptosis warrants further study as possible antifibrotic therapy.
Roles of Nitric Oxide Synthase Inhibition and Vascular Endothelial Growth Factor Receptor-2 Inhibition on Vascular Morphology and Function in an<i>In vivo</i>Model of Pancreatic Cancer
Authors: E. Ramsay Camp, Anthony Yang, Wenbiao Liu, Fan Fan, Ray Somcio, Daniel J. Hicklin, Lee M. Ellis
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Both nitric oxide (NO) and vascular endothelial growth factor (VEGF) mediate tumor vascular function. Because these molecules regulate one another's expression, we hypothesized that NO synthase (NOS) inhibition produces effects comparable to those of anti-VEGF therapy on human pancreatic cancer xenografts. Experimental Design: L3.6pl human pancreatic cancer cells were s.c. implanted in nude mice. On day 6, mice were randomized to receive (a) PBS (control), (b) DC101 [VEGF receptor 2 (VEGFR-2) antibody] by i.p. injection, (c) N-nitro-l-arginine (NNLA; NOS inhibitor) in the drinking water, or (d) both DC101 and NNLA. Mice were killed on day 20. Results: DC101 and NNLA as single agents inhibited tumor growth by ∼50% to 60% (P &amp;lt; 0.008 for both). Furthermore, combined therapy inhibited mean tumor growth by 89% (P &amp;lt; 0.008). Combined inhibition of VEGFR-2 and NOS also decreased mean vessel counts by 65% (P &amp;lt; 0.03) and vessel area by 80% versus controls (P &amp;lt; 0.001). In contrast to DC101 where vessel diameter was similar to control, NNLA decreased mean vessel diameter by 42% (P &amp;lt; 0.001). NNLA also led to a 54% (P &amp;lt; 0.03) decrease in tumor uptake of the perfusion marker Hoechst 33342 versus controls whereas DC101 decreased Hoechst 33342 staining by 43% (P &amp;lt; 0.03). The combination of inhibitors decreased perfusion by 73% (P &amp;lt; 0.03). Conclusions: Although VEGFR-2 can mediate NOS activity, the combination of VEGFR-2 and NOS inhibition significantly increased the antivascular effect over single agent therapy. The addition of NOS inhibition led to an even further alteration of tumor vessel morphology and vascular perfusion compared with VEGFR-2 blockade, suggesting that NO and VEGFR-2 have distinct but complementary effects on the tumor vasculature.
Pediatric Ventricular Assist Devices — First Steps for Babies
Authors: Linda J. Addonizio
Journal: New England Journal of Medicine (2012)

Patients with severe cardiac failure who are candidates for heart transplantation may require temporary mechanical cardiac support to survive until a donor heart becomes available. This clinical observation is true of children as well as adults. Although the numbers of children may be much smaller than the numbers of adults thus affected, the potential number of years of life saved for each person is much greater for children.Since the 1970s, the principal form of mechanical cardiac support for infants and children has been extracorporeal membrane oxygenation (ECMO). However, ECMO is designed for short-term support, and as waiting times for . . .