tbuckley/cabot-search huggingface dataset:
Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer
Authors: Helen M. Mohan, Carol M. Aherne, Ailin C. Rogers, Alan W. Baird, Des C. Winter, Evelyn P. Murphy
Journal: Clinical Cancer Research (2012)

Abstract Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-κB, phosphoinositide 3-kinase/AKT, c-jun-NH2-kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-ϒ). The subcellular location of NR4A “nuclear receptors” is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation. Clin Cancer Res; 18(12); 3223–8. ©2012 AACR.
Vascular Endothelial Growth Factor-C Protects Prostate Cancer Cells from Oxidative Stress by the Activation of Mammalian Target of Rapamycin Complex-2 and AKT-1
Authors: Michael H. Muders, Heyu Zhang, Enfeng Wang, Donald J. Tindall, Kaustubh Datta
Journal: Cancer Research (2009)

Recurrence and subsequent metastatic transformation of cancer develops from a subset of malignant cells, which show the ability to resist stress and to adopt to a changing microenvironment. These tumor cells have distinctly different growth factor pathways and antiapoptotic responses compared with the vast majority of cancer cells. Long-term therapeutic success can only be achieved by identifying and targeting factors and signaling cascades that help these cells survive during stress. Both microarray and immunohistochemical analysis on human prostate cancer tissue samples have shown an increased expression of vascular endothelial growth factor-C (VEGF-C) in metastatic prostate cancer. We have discovered that VEGF-C acts directly on prostate cancer cells to protect them against oxidative stress. VEGF-C increased the survival of prostate cancer cells during hydrogen peroxide stress by the activation of AKT-1/protein kinase Balpha. This activation was mediated by mammalian target of rapamycin complex-2 and was not observed in the absence of oxidative stress. Finally, the transmembrane nontyrosine kinase receptor neuropilin-2 was found to be essential for the VEGF-C-mediated AKT-1 activation. Indeed, our findings suggest a novel and distinct function of VEGF-C in protecting cancer cells from stress-induced cell death, thereby facilitating cancer recurrence and metastasis. This is distinctly different from the known function of VEGF-C in inducing lymphangiogenesis.
The MUC gene family: their role in diagnosis and early detection of pancreatic cancer.
Authors: Jörg Ringel, Matthias Löhr
Journal: Molecular Cancer (2003)

The early diagnosis of pancreatic cancer, as well as distinguishing between chronic pancreatitis and malignant pancreatic disease, remains still a clinical problem. Presently, there is no specific tumor marker for diagnosing pancreatic cancer. Mucin-associated marker like CA 19-9 are the most widely available pancreatic cancer tumor marker, but its value as a screening marker is limited by its reduced specificity. Mucins (MUCs) are heavily glycosylated, high molecular weight glycoproteins with an aberrant expression profile in various malignancies. This review considers briefly the potential use of the mucin expression pattern in diagnosis of pancreatic neoplasm. The overview will point out the present knowledge about changes in the mucin gene expression in pancreatic intraepithelial neoplasia (PanINs) as precursor lesions and in pancreatic adenocarcinoma, compared to normal pancreas and chronic pancreatitis and the potential role for differentiating chronic pancreatitis from pancreatic cancer.Furthermore, the potential use of MUCs in the diagnosis and differentiation of intraductal papillary-mucinous neoplasm's (IPMNs) will be discussed.
The cytotoxicity of cadmium based, aqueous phase – Synthesized, quantum dots and its modulation by surface coating
Authors: Yuanyuan Su, Yao He, Haoting Lu, Liman Sai, Qingnuan Li, Wenxin Li, Lianhui Wang, Pingping Shen, Qing Huang, Chunhai Fan
Journal: Biomaterials (2008)
Intrinsic hazard of breech presentation.
Authors: A M Smith
Journal: BMJ (1980)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Intrinsic hazard of breech presentation. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Using prior knowledge and genome-wide association to identify pathways involved in multiple sclerosis
Authors: Marylyn D Ritchie
Journal: Genome Medicine (2009)

The efforts of the Human Genome Project are beginning to provide important findings for human health. Technological advances in the laboratory, particularly in characterizing human genomic variation, have created new approaches for studying the human genome - genome-wide association studies (GWAS). However, current statistical and computational strategies are taking only partial advantage of this wealth of information. In the quest for susceptibility genes for complex diseases in GWAS data, several different analytic strategies are being pursued. In a recent report, Baranzini and colleagues used a pathway- and network-based analysis to explore potentially interesting single locus association signals in a GWAS of multiple sclerosis. This and other pathway-based approaches are likely to continue to emerge in the GWAS literature, as they provide a powerful strategy to detect important modest single-locus effects and gene-gene interaction effects.
Growth Hormone Receptor Antagonists: Discovery, Development, and Use in Patients with Acromegaly
Authors: J. J. Kopchick, C. Parkinson, E. C. Stevens, P. J. Trainer
Journal: Endocrine Reviews (2002)

An understanding of the events that occur during GH receptor (GHR) signaling has facilitated the development of a GHR antagonist (pegvisomant) for use in humans. This molecule has been designed to compete with native GH for the GHR and to prevent its proper or functional dimerization-a process that is critical for GH signal transduction and IGF-I synthesis and secretion. Clinical trials in patients with acromegaly show GHR blockade to be an exciting new mode of therapy for this condition, and pegvisomant may have a therapeutic role in diseases, such as diabetes and malignancy, in which abnormalities of the GH/IGF-I axis have been observed. This review charts the discovery and development of GHR antagonists and details the experience gained in patients with acromegaly.
Development of the National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
Authors: Ethan Basch, Bryce B Reeve, Sandra A Mitchell, Steven B Clauser, Lori M Minasian, Amylou C Dueck, Tito R Mendoza, Jennifer Hay, Thomas M Atkinson, Amy P Abernethy, Deborah W Bruner, Charles S Cleeland, Jeff A Sloan, Ram Chilukuri, Paul Baumgartner, Andrea Denicoff, Diane St Germain, Ann M O'Mara, Alice Chen, Joseph Kelaghan, Antonia V Bennett, Laura Sit, Lauren Rogak, Allison Barz, Diane B Paul, Deborah Schrag
Journal: JNCI Journal of the National Cancer Institute (2014)

The standard approach for documenting symptomatic adverse events (AEs) in cancer clinical trials involves investigator reporting using the National Cancer Institute's (NCI's) Common Terminology Criteria for Adverse Events (CTCAE). Because this approach underdetects symptomatic AEs, the NCI issued two contracts to create a patient-reported outcome (PRO) measurement system as a companion to the CTCAE, called the PRO-CTCAE. This Commentary describes development of the PRO-CTCAE by a group of multidisciplinary investigators and patient representatives and provides an overview of qualitative and quantitative studies of its measurement properties. A systematic evaluation of all 790 AEs listed in the CTCAE identified 78 appropriate for patient self-reporting. For each of these, a PRO-CTCAE plain language term in English and one to three items characterizing the frequency, severity, and/or activity interference of the AE were created, rendering a library of 124 PRO-CTCAE items. These items were refined in a cognitive interviewing study among patients on active cancer treatment with diverse educational, racial, and geographic backgrounds. Favorable measurement properties of the items, including construct validity, reliability, responsiveness, and between-mode equivalence, were determined prospectively in a demographically diverse population of patients receiving treatments for many different tumor types. A software platform was built to administer PRO-CTCAE items to clinical trial participants via the internet or telephone interactive voice response and was refined through usability testing. Work is ongoing to translate the PRO-CTCAE into multiple languages and to determine the optimal approach for integrating the PRO-CTCAE into clinical trial workflow and AE analyses. It is envisioned that the PRO-CTCAE will enhance the precision and patient-centeredness of adverse event reporting in cancer clinical research.
European Society of Gastrointestinal Endoscopy (ESGE)Guideline: Prophylaxis of post-ERCP pancreatitis
Authors: J.-M. Dumonceau, A. Andriulli, J. Deviere, A. Mariani, J. Rigaux, T. Baron, P. Testoni
Journal: Endoscopy (2010)

Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Risk factors for post-ERCP pancreatitis (PEP) are both patient-related and procedure-related. Identification of patients at high risk for PEP is important in order to target prophylactic measures. Prevention of PEP includes administration of nonsteroidal inflammatory drugs (NSAIDs), use of specific cannulation techniques, and placement of temporary pancreatic stents. The aim of this guideline commissioned by the European Society of Gastrointestinal Endoscopy (ESGE) is to provide practical, graded, recommendations for the prevention of PEP.
Survival and Neurologic Outcomes in a Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation Therapy in Brain Metastases
Authors: Minesh P. Mehta, Patrick Rodrigus, C.H.J. Terhaard, Aroor Rao, John Suh, Wilson Roa, Luis Souhami, Andrea Bezjak, Mark Leibenhaut, Ritsuko Komaki, Christopher Schultz, Robert Timmerman, Walter Curran, Jennifer Smith, See-Chun Phan, Richard A. Miller, Markus F. Renschler
Journal: Journal of Clinical Oncology (2003)

This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd).Patients were randomly assigned to 30 Gy of WBRT +/- 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated.Four hundred one (251 non-small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P =.48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P =.95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P =.048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P =.018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P =.025). MGd improved neurocognitive function in lung cancer patients.The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.
Intragenic recombination in an E beta gene for a murine Ia antigen.
Authors: M L Plunkett, J E Coligan, C S David, J H Freed
Journal: The Journal of Experimental Medicine (1982)

The recombinant strain D2.GD was originally typed as I-Ad by serological methods. Indeed, the A alpha and A beta chains of the I-A antigens appear to exhibit normal behavior by the criteria of serology and two dimensional gel analysis. However, the E beta chain encoded by the I-A subregion of this strain, one of the two components of the plasma membrane located I-E antigens produced in D2.GD X A.TFR5)F1 animals, has been demonstrated to be the product of an intragenic recombinational event between E beta genes from the d and b haplotypes. Sequence analysis suggests that the amino-terminal portion of the Eg2 beta chain is derived from the d haplotype and, therefore, that the coding strand for this gene is oriented centromeric leads to telomeric (5' to 3' direction). Finally, these data combined with the data of Rose and Cullen (17) allow the ordering of the genes within the I-A subregion as (H-2K), A alpha, A beta, E beta ... (H-2D).
The amino acid composition of actin and myosin and Ca2+-activated myosin adenosine triphosphatase in chronic canine congestive heart failure.
Authors: R R Raszkowski, J D Welty, M B Peterson
Journal: Circulation Research (1977)

The Ca2+-activated myosin ATPase and the amino acid compositions of actin and myosin were determined for preparations from chronically failing dog hearts. Hypertrophy and congestive heart failure were produced by combined tricuspid valve insufficiency and pulmonary artery stenosis. Control, shamoperated, and noncardiac circulatory failure (inferior vena cava constriction) dogs also were studied. All hearts were divided into right ventricle, septum and left ventricle and each sample was individually analyzed. Calcium-activated ATPase decreased in the failing hearts and showed a distinct gradient of depression from right to left ventricles. There were no changes in ATPase activity among the other groups. The amino acid composition of actin was the same regardless of origin. The amino acid composition of myosin was unaltered except that cystine/2 residues were markedly decreased in failing heart myosin. The same gradient of depression was present as was found for Ca2+-activated myosin ATPase. This study suggests that protein metabolism is abnormal and that altered proteins are produced in hypertrophy and congestive heart failure. It appears that these changes do not affect all proteins, since actin was normal by the parameters studied. It is clear that the stressed ventricle is the most severely involved, but the entire heart is altered to some degree. Thus, we conclude that altered protein metabolism may be an important primary factor in the genesis of heart failure.
Hypoxia-Induced Down-regulation of <i>BRCA1</i> Expression by E2Fs
Authors: Ranjit S. Bindra, Shannon L. Gibson, Alice Meng, Ulrica Westermark, Maria Jasin, Andrew J. Pierce, Robert G. Bristow, Marie K. Classon, Peter M. Glazer
Journal: Cancer Research (2005)

Abstract Decreased BRCA1 expression in the absence of genetic mutation is observed frequently in sporadic cancers of the breast and other sites, although little is known regarding the mechanisms by which the expression of this gene can be repressed. Here, we show that activating and repressive E2Fs simultaneously bind the BRCA1 promoter at two adjacent E2F sites in vivo, and that hypoxia induces a dynamic redistribution of promoter occupancy by these factors resulting in the transcriptional repression of BRCA1 expression. Functionally, we show that hypoxia is associated with impaired homologous recombination, whereas the nonhomologous end-joining (NHEJ) repair pathway is unaffected under these conditions. Repression of BRCA1 expression by hypoxia represents an intriguing mechanism of functional BRCA1 inactivation in the absence of genetic mutation. We propose that hypoxia-induced decreases in BRCA1 expression and consequent suppression of homologous recombination may lead to genetic instability by shifting the balance between the high-fidelity homologous recombination pathway and the error-prone NHEJ pathway of DNA repair. Furthermore, these findings provide a novel link between E2Fs and the transcriptional response to hypoxia and provide insight into the mechanisms by which the tumor microenvironment can contribute to genetic instability in cancer. (Cancer Res 2005; 65(24): 11597-604)
Up-regulation of soluble vascular endothelial growth factor receptor-1 prevents angiogenesis in hypertrophied myocardium
Authors: E. Kaza, K. Ablasser, D. Poutias, E. R. Griffiths, F. A. Saad, J. G. Hofstaetter, P. J. del Nido, I. Friehs
Journal: Cardiovascular Research (2010)

Inadequate capillary growth in pressure-overload hypertrophy impairs myocardial perfusion and substrate delivery, contributing to progression to failure.Capillary growth is tightly regulated by angiogenesis growth factors like vascular endothelial growth factor (VEGF) and endogenous inhibitors such as the splice variant of VEGF receptor-1, sVEGFR-1.We hypothesized that inadequate expression of VEGF and up-regulation of VEGFR-1 and its soluble splice variant, sVEGFR-1, restrict capillary growth in pressure-overload hypertrophy. Methods and resultsNeonatal New Zealand White rabbits underwent aortic banding.mRNA (qRT -PCR) and protein levels (immunoblotting) were determined in hypertrophied and control myocardium (7/group) for total VEGF, VEGFR-1, sVEGFR-1, VEGFR-2, and phospho-VEGFR-1 and -R-2.Free VEGF was determined by enzyme-linked immunoassay (ELISA) in hypertrophied myocardium, controls, and hypertrophied hearts following inhibition of sVEGFR-1 with placental growth factor (PlGF).VEGFR-1 and sVEGFR-1 mRNA (seven-fold up-regulation, P ¼ 0.001) and protein levels were significantly up-regulated in hypertrophied hearts vs. controls (VEGFR-1: 44 + 8 vs. 23 + 1, P ¼ 0.031; sVEGFR-1: 71 + 13 vs. 31 + 3, P ¼ 0.016).There was no change in VEGF and VEGFR-2 mRNA or protein levels in hypertrophied compared with controls hearts.A significant decline in free, unbound VEGF was found in hypertrophied myocardium which was reversed following inhibition of sVEGFR-1 with PlGF, which was accompanied by phosphorylation of VEGFR-1 and VEGFR-2. ConclusionUp-regulation of the soluble VEGFR-1 in pressure-loaded myocardium prevents capillary growth by trapping VEGF.Inhibition of sVEGFR-1 released sufficient VEGF to induce angiogenesis and preserved contractile function.These data suggest sVEGFR-1 as possible therapeutic targets to prevent heart failure.
Treatment of Primary and Secondary Syphilis
Authors: Nicholas J. Fiumara
Journal: JAMA (1980)

One hundred thirty-eight patients with primary syphilis and 161 patients with secondary syphilis were treated with penicillin G benzathine, 2.4 million units given intramuscularly weekly for two weeks, for a total of 4.8 million units. All 138 patients with primary syphilis had a rapid resolution of their lesions, and all became seronegative within one year. Similarly, the 161 patients with secondary syphilis were cured clinically, and all achieved seronegativity within 24 months. (<i>JAMA</i>243:2500-2502, 1980)
Cullin7: a new gene involved in liver carcinogenesis related to metabolic syndrome
Authors: Valerie Paradis, Miguel Albuquerque, Mouniya Mebarki, Lucie Hernandez, Stephane Zalinski, Samuel Quentin, Jacques Belghiti, Jean Soulier, Pierre Bedossa
Journal: Gut (2012)

<h3>Background</h3> Metabolic syndrome (MS) is an emerging risk factor in hepatocellular carcinoma (HCC). HCC related to MS may occur either in advanced fibrosis or before the development of cirrhosis, suggesting involvement of different molecular pathways according to the features of background liver. <h3>Objective</h3> To investigate genomic aberrations in HCC related to MS in order to identify new target genes involved in liver carcinogenesis. <h3>Methods</h3> Chromosomal aberrations of HCC obtained from 20 patients with MS (HCC/MS) were studied by comparative genomic hybridisation and compared with HCC related to hepatitis C virus (HCV) infection (HCC/HCV, n=10) and, within the group of HCC with MS, according to the condition of the background liver (presence or absence of significant fibrosis). <h3>Results</h3> Among the most frequent chromosomal alterations observed in HCC, 6p21.1 amplification had a higher incidence in HCC/MS than in HCC/HCV (60% vs 20%, p&lt;0.01). Advanced fibrosis/cirrhosis in the peritumoral liver was the only clinicopathological factor associated with the 6p21.1 amplicon in HCC/MS. Increased expression of cullin7 (CUL7), a gene located at the 6p21.1 locus, was demonstrated in HCC with the 6p21.1 amplicon, in parallel with a decrease in cyclin D1 expression. <i>CUL7</i> downregulation using siRNA transfection in hepatoma cell lines induced significant cyclin D1 expression (by promoting its degradation), decreased cell proliferation and increased apoptosis. <h3>Conclusions</h3> This study demonstrates specific genomic alterations in HCC/MS and points to <i>CUL7</i> as a novel gene potentially involved in liver carcinogenesis associated with MS, the amplification of which might influence cell proliferation.