tbuckley/cabot-search huggingface dataset:
Abstract LB-102: The p21Cip1/Waf1 cyclin-dependent kinase inhibitor is required for the activation of the FA-BRCA pathway
Authors: Meghan A. Rego, Maurizio Mauro, Julie A. Harney, Mae Shen, Frederick W. Kolling, Niall G. Howlett
Journal: Cancer Research (2010)

Abstract Fanconi anemia (FA) is a rare recessive disorder characterized in part by pronounced cancer susceptibility. The FA proteins, and the protein products of the major breast cancer susceptibility genes BRCA1 and BRCA2, function cooperatively in the FA-BRCA pathway, to repair damaged DNA and to prevent cellular transformation. A major step in the activation of the FA-BRCA pathway is the mono-ubiquitination of the FANCD2 and FANCI proteins, targeting these proteins to discrete chromatin-associated nuclear foci. Importantly, the regulation of FANCD2 (and FANCI) mono-ubiquitination remains poorly understood. To gain further insight into this important post-translational modification step, here we have examined the roles of p53 tumor suppressor as well its downstream target p21Cip1/Waf1 in the regulation of the mono-ubiquitination of FANCD2. In this study we have used the isogenic HCT116 p53+/+, p53−/−, p21+/+, and p21−/− cell lines, to determine that p21, and not p53, plays a key role in the regulation of the mono-ubiquitination of FANCD2 following exposure to DNA damaging agents. For example, robust FANCD2 mono-ubiquitination is observed in HCT116 p21+/+ cells 2 h following exposure to 20 J/m2 UV irradiation, while this effect is markedly attenuated in p21−/− cells. Using immunofluorescence microscopy we also demonstrate that p21 is necessary for the efficient recruitment of FANCD2 to nuclear foci following exposure to UV irradiation. Furthermore, preliminary protein-protein interaction analyses in COS-7 cells demonstrate that FLAG-p21 and 6xHis/V5-FANCD2 physically interact. Interestingly, despite a failure to efficiently activate the mono-ubiquitination of FANCD2 following exposure to DNA damaging agents, p21−/− cells are not hypersensitive to the cytotoxic effects of the DNA crosslinking agent mitomycin C (MMC). However, elevated levels of distinct chromosome aberrations, including telomere associations and dicentric chromosomes, are observed in p21−/− cells compared with p21+/+ cells following exposure to MMC. Taken together, our results demonstrate an important upstream role for the p21 cyclin-dependent-kinase inhibitor in the activation of the FA-BRCA pathway. A greater understanding of the regulation of this important tumor suppressor pathway will lead to improved diagnostic and therapeutic approaches to FA and enhance our understanding of the elevated cancer susceptibility of FA patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-102.
Abstract 1707: Androgen responsiveness of the <i>NKX3.1</i> gene is regulated by the proto-oncogene ETS1
Authors: Marc A. Thomas, Darren M. Preece, Jacqueline M. Bentel
Journal: Cancer Research (2010)

Abstract Expression of the prostatic homeodomain protein NKX3.1 is androgen-regulated in both the normal prostate and in prostate cancer cells. Androgen responsiveness of NKX3.1 is mediated in part by the 3’ untranslated region (3'UTR) of the NKX3.1 gene, within which we have isolated 3 discrete regions of androgen-induced transcriptional regulatory activity including 2 androgen response elements (AREs). The proximal ∼2kb of the 5’ promoter of the NKX3.1 gene is incompletely characterised, however it is not androgen-responsive using conventional luciferase reporter assays. Investigation of the NKX3.1 proximal promoter has identified regulation of promoter activity by the ETS transcription factor, ETS1, which is mediated by an ETS binding site (EBS) located at −1008 relative to the NKX3.1 transcription start site. Overexpression of ETS1 in the LNCaP prostate cancer cell line results in upregulation of NKX3.1 protein levels, supporting a functional role of ETS1 in the regulation of NKX3.1 expression. ETS1 has been reported previously to transactivate the androgen receptor (AR) in a ligand-dependent manner on a subset of androgen-responsive promoters, suggesting cooperativity or co-regulation of AR and ETS1 signalling in prostate cancer cells. Treatment of LNCaP cells with 10−8M 5α-dihydrotestosterone (DHT) results in upregulation of endogenous ETS1 protein levels, while overexpression of exogenous ETS1 causes a concomitant increase in AR expression. A cooperative interaction between ETS1 and the AR on the NKX3.1 promoter is evident in LNCaP cells whereby overexpression of ETS1 is able to induce androgen responsiveness of the initial ∼2kb of the NKX3.1 promoter sequence and in particular the 76bp region surrounding the EBS. Reversal of DHT effects by the antiandrogen bicalutamide indicates an AR-mediated mechanism. ETS1 is overexpressed in a high proportion of prostate cancers with its expression aberrantly localised in the cytoplasm of a subset of prostate tumour cells. Findings of the present study support a complex mechanism of AR-mediated regulation of NKX3.1 expression via multiple regions of the NKX3.1 gene and modified by additional transcription factors in prostate cancer cells. Abnormal expression and/or function of these factors may contribute to the transcriptional deregulation of NKX3.1 expression and the downregulation of NKX3.1 protein levels that is frequently observed in advanced prostate tumours. Similarly, it is also feasible that upregulation of ETS1 contributes to the deregulation of AR signalling in advanced prostate cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1707.
Case 11-1996
Authors: R.C. Stanton, V. Nickeleit, E.J. Mark
Journal: New England Journal of Medicine (1996)

Presentation of CaseA 69-year-old man was admitted to the hospital because of increasing dyspnea in the course of one day. The patient had a 12-year history of hypertension. He had had hyperlipidemia, with pancreatitis, five years before admission. During the year before admission, the creatinine concentration ranged between 1.3 and 1.7 mg per deciliter (110 and 115 μmol per liter). Six months before admission, the urea nitrogen concentration was 24 mg per deciliter (8.6 mmol per liter), and the creatinine concentration was 2.7 mg per deciliter (240 μmol per liter). “Nephrotic-range” proteinuria was noted; the results of serum protein . . .
AB0864 Extensive evaluation of biomarkers related with bone turnover in patients with ankylosing spondylitis:
Authors: A. Taylan, I. Sari, B. Akinci, S. Bilge, D.L. Kozaci, S. Akar, H. Yalcin, N. Gunay, N. Akkoc
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Ankylosing spondylitis (AS) is a chronic inflammatory disease of spine and sacroiliac joints and characterized by new bone formation. Osteoporosis is also accompanied with AS.Human nuclear factor κβ ligand (RANKL) stimulate osteoclasts. Osteoprotegrin (OPG), which is produced by osteoblasts, inhibits RANKL and plays an important role in bone formation. The Wnt signaling cascade and the secreted inhibitor of Wnts, Sclerostin, Dickkopfs (Dkks) and secreted frizzled related proteins (sFRP1) play important roles in bone turnover <h3>Objectives</h3> We investigated changes in bone mineral density (BMD) and the levels of various biomarkers related with bone turnover with regard to clinical parameters, disease activity and treatment regimen with/without anti TNFα drugs. <h3>Methods</h3> Fifty five AS patients (48Males) and 33 controls (24Males) were included in the study. Spinal mobility was assessed by the Bath Ankylosing Spondylitis Metrology Index (BASMI) and radiologic changes were scored by bath ankylosing spondylitis radiologic index (BASRI). Patients were also evaluated with the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).BMD of hip and spine and various bone turnover biomarkers were measured. <b>Results:</b> <h3>Conclusions</h3> OPG was lower and correlated with active disease state in AS patients. Wnt signal pathway inhibitors level did not altered in AS and ongoing ectopic bone formation may be related dysfunction of these molecules at cellular level.There is a complex interaction of anti TNF α drug with various cytokines. OPG is decreased but Dkk1 is increased on anti TNF α treatment in AS patients. Even clues of the osteoblastic effects of anti TNF α treatment, concrete role of these drugs both on osteoporosis and ectopic bone formation still need to be clarified. <h3>Disclosure of Interest</h3> None Declared
An Activating KIT Mutation Induces Crizotinib Resistance in ROS1-Positive Lung Cancer
Authors: Rafal Dziadziuszko, Anh T. Le, Anna Wrona, Jacek Jassem, D. Ross Camidge, Marileila Varella-Garcia, Dara L. Aisner, Robert C. Doebele
Journal: Journal of Thoracic Oncology (2016)
AB0064 Progranulin Antibodies (PGRN-ABS) in Rheumatoid Arthritis More Frequent than in Psoriatic Arthritis
Authors: G. Assmann, S. Zinke, M. Gerling, M. Pfreundschuh, L. Thurner, K. Preuss
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Until recently, most research on progranulin (PGRN) had been foccussed on its role in neurodegenerative diseases as frontotemporal demetia. However, we discovered antibodies against PGRN in a protein array-based screening of plasma from various different rheumatic diseases (1,2). Furthermore, PGRN-Abs have been proved to have neutralizing effect on PGRN plasma levels; PGRN itself showed antiinflammatory effects by its high-affinity to the TNFa receptor 1 and 2 causing a direct inhibition of the TNFa receptors. <h3>Objectives</h3> To evaluate the prevalence of PGRN-Abs in sera of patients with rheumatoid arthritis compared to psoriatic arthritis patients and healthy controls <h3>Methods</h3> PGRN-Abs were determined in sera of 201 patients of RA, 260 patients of PsA, and 97 healthy controls. The ELISA detecting PGRN-Abs were applied as previously described (2). The prevalence of PGRN-Abs in sera of RA were compared to PsA and healthy controls. Subgroup analyses has stratifyed the RA cohort according to gender, age, seropositivity of rheumatoid factor (RF) and ACPA, erosive course of disease, duration of disease, and the occurrence of anti-TNF treatment failure. The statistics was performed with the Mann-Whithney U test evaluating the differences between RA, PsA and healthy controls; the using the χ<sup>2</sup> test differences between the different RA subgroups were investigated. A p-value of &lt;0.5 was considered significant. <h3>Results</h3> PGRN-Abs was detected in 32.6% of the RA cohort with significant higher prevalence compared to PsA (19.2, p=0.014) and healthy controls (1.03, p=0.001). Among the RA subgroups patients on age elder than 60 years (versus younger than 60) and patients with disease duration longer than 5 years (versus shorter than 5 years) showed significantly more frequent PGRN-Abs in their sera. <h3>Conclusions</h3> Here we present the first study evaluating the PGRN-Abs in sera of patients with RA. Longer duration of disease seems to favor the occurrence of PGRN-Abs. PGRN-Abs could been detected significantly more frequent in RA than in PsA. <h3>References</h3> Thurner L &amp; Pfreundschuh M et al, PGRN in autoimmune diseases, J Autoimmunity, 2012 Thurner L &amp; Assmann G et al, PGRN in PsA, Arth Res Th, 2013 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5925
Press: Both sides now
Authors: T. Jackson
Journal: BMJ (2002)

In the quest for balanced reporting on issues such as MMR, journalists may be misleading the public

There has long been a tendency to blame the mass media, particularly tabloid newspapers, for public attitudes to and understanding of matters of scientific controversy, such as the MMR (measles, mumps, and rubella) vaccine. But how far do newspapers, and television and radio news, affect what people believe and know?

Researchers at the Cardiff School of Journalism, Media and Cultural Studies have been asking more than a thousand people what they think and know about MMR, human and animal …
Community Clinical Oncology Program Marks 10th Anniversary
Authors: N. S. Larsen
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Community Clinical Oncology Program Marks 10th Anniversary Get access Natalie S. Larsen Natalie S. Larsen Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 18, 15 September 1993, Pages 1456–1458, https://doi.org/10.1093/jnci/85.18.1456 Published: 15 September 1993
Analysis of the Role of Cancer Prevention and Control Measures in Reducing Cancer Mortality
Authors: K C Chu, B S Kramer, C R Smart
Journal: JNCI Journal of the National Cancer Institute (1991)

One goal of the war against cancer is to create declines in cancer mortality rates. A decrease in these rates can only occur in two ways: 1) a decrease in incidence rates and 2) a real increase in overall survival rates. Reductions in incidence rates can be envisioned to occur through three mechanisms (in order of the time course of cancer): 1) reduction or amelioration of environmental or lifestyle risk factors, 2) use of agents that prevent the occurrence of cancer by blocking the progression to cancer, and 3) early detection at a preneoplastic state combined with treatment that prevents or delays progression to invasive cancer. "True" increases in overall survival can occur by two mechanisms (in order of the time course of cancer): 1) early detection of cancer by screening tests and subsequent effective treatment and 2) advancements in treatment. Unique patterns or "fingerprints" of stage-specific incidence and overall incidence and of survival rates characterize the various cancer prevention and control mechanisms that can decrease mortality rates. The rates are presented for five organ sites that have shown reduced cancer mortality. The patterns of rates for breast cancer for women under the age of 65 years were most consistent with early detection. The testicular cancer fingerprints were most consistent with advances in treatment, whereas cervical cancer rates were most consistent with the detection of preneoplastic lesions. The stomach cancer fingerprints were indicative of reductions in lifestyle or environmental risks, and colorectal cancer rates were indicative of a combination of treatment advances and early detection. These fingerprint patterns can be extended to other situations in which mortality trends are changing in order to suggest possible causes of observed changes. Limitations of this model are also discussed.
OUTCOME IN MIDDLE-AGED INDIVIDUALS WITH ANOMALOUS CORONARY ARTERIES ORIGINATING FROM THE OPPOSITE SINUS: A CASE CONTROL STUDY
Authors: Christoph Gräni, Dominik Benz, Olivier Clerc, Christian Schmied, Dominik Steffen, Fran Mikulicic, Jan Vontobel, Mathias Possner, Aju Pazhenkottil, Oliver Gaemperli, Philipp Kaufmann, Ronny Buechel
Journal: Journal of the American College of Cardiology (2016)
Effects of methyl derivatives of the rexinoid UAB30 on methylnitrosourea (MNU) induced mammary cancers and on various indicators of toxicity.
Authors: DD Muccio, RA Lubet, VR Atigadda, WJ Brouillette, CJ Grubbs
Journal: Cancer Research (2009)

Abstract Abstract #1108 UAB30 is a RXR selective retinoid that has shown excellent activity in preventing chemically-induced mammary cancers with minimal toxicity (specifically not increasing serum triglycerides), and is currently undergoing a Phase I clinical trial. Several methyl analogs were synthesized in an attempt to obtain a more active preventive agent and to better understand the mechanisms of activity/toxicity of this class of agents. The retinoids included 4-methyl-UAB30, 5-methyl-UAB30, 6-methyl-UAB30, 7-methyl-UAB30, and 8-methyl-UAB30. The compounds were evaluated in the MNU-induced mammary cancer model using female Sprague-Dawley rats. MNU (75 mg/kg BW) was administered at 50 days of age and the animals observed for 120 days afterward for the development of ER+ mammary cancers. The retinoids were given at a dose of 200 mg/kg diet, except 7-methyl-UAB30 (given at 100 mg/kg diet). 4-Methyl-UAB30 and 7-methyl-UAB30 were highly active; reducing mammary cancer multiplicity by 74 and 61%, respectively. The retinoids 5-methyl-UAB30, 6-methyl-UAB30, and 8-methyl-UAB30 did not have chemopreventive activity in this model. The 8-methyl-UAB30 derivative actually caused a 108% increase in growth of the mammary cancers. As we have previously shown (Carcinogenesis 27, 1232-1239, 2006), serum triglycerides correlated with cancer preventive activity; i.e., high levels were observed with active retinoids. 4-methyl-UAB30 caused an initial large increase in body weight gain of the rats. Of interest, serum levels of 6-methyl-UAB30 and 7-methyl-UAB30 were high, while the other agents were low or could not be detected. All methyl derivatives caused varying decreases in liver retinyl palmitate levels. Structure-activity relationships are also being evaluated using crystallography of RXR/UAB-rexinoid complexes as a guide. Structure-based and dynamic-based approaches are used to facilitate the design of new rexinoids that fit into the LBD of RXRs. For example, 4-methyl-UAB30 had a 5-fold greater binding affinity to hRXR alpha LBD than 9-cis-retinoic-acid. These studies emphasize that minor modifications of a retinoid molecule can drastically change its absorption, metabolism, toxicity, binding affinities to receptors, and activity in preventing mammary cancers. (Supported by NCI Breast SPORE CA089019 and contract HHSN261200433001C). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1108.
IL-27 receptor signaling is critical for B cell differentiation in collagen induced arthritis
Authors: Odilia B J Corneth, Anne-Marie C Mus, atrick S Asmawidjaja, Rudi W Hendriks, Erik Lubberts
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> IL-27 receptor (IL-27R) signaling induces Th1 differentiation and IL-10 production and inhibits Th17 differentiation. In experimental autoimmune encephalomyelitis (EAE), IL-27R knock-out mice showed higher proliferation of draining lymph nodes with more production of IL-17, IL-6 and tumour necrosis factor α. The authors therefore hypothesised that collagen induced arthritis (CIA) would be enhanced in IL-27R knock-out mice compared to controls. <h3>Objective</h3> To investigate the role of IL-27R signaling in CIA. <h3>Methods</h3> IL-27R knock-out mice and controls were immunised with chicken collagen type II and complete Freunds adjuvant (CFA), and boosted again 21 days later. Mice were euthanised 10, 36 and 45 days after immunisation and B and T cell subsets in spleen, lymph nodes and joints were analysed using flow cytometry. Furthermore, auto-antibodies were determined in serum using ELISA and immunohistochemic analysis of the spleen was performed. For antigen induced arthritis, mice were immunised with methylated bovine serum albumin (mBSA) in CFA and a local injection of mBSA in the knee joint was given 1 week later. <h3>Results</h3> Interestingly, both the incidence of CIA and the arthritis score were significantly lower in IL-27R knock-out mice compared to controls. In addition, synovial inflammation was markedly decreased in IL-27R knock-out mice. Although the proportion of Th17 cells was increased in IL-27R knock-out mice, the total number of CD4+T cells was significantly lower. To assess whether Th17 cells were pathogenic the authors made use of the Th17 mediated antigen induced arthritis (AIA) model. Inflammation of the knee joints in IL-27R knock-out mice in AIA was comparable to controls, showing that the pathogenicity of these cells is normal. As B cells also play a significant role in CIA, the authors then analysed B cells by flow cytometry. The total number of B cells was lower in IL-27R knock-out mice. Also, IL-27R knock-out mice hardly develop germinal center B cells, which the authors confirmed by immunohistochemistry. In line with this, the authors found that collagen specific IgG antibody levels were lower in these mice suggesting a critical role for IL-27R signaling in further differentiation of mature B cells. <h3>Conclusion</h3> Our data show a critical role of the IL-27R signaling in the development of CIA. The development of germinal center B cells was significantly impaired. These data suggest that IL-27R signaling is involved in B cell differentiation and function and that the lack of germinal center B cells in the IL-27R deficient mice is most critical for the reduced expression of CIA.
Case 33-1967
Authors: Kurt J. Bloch, Benjamin Castleman
Journal: New England Journal of Medicine (1967)

Presentation of Case First admission. A sixty-six-year-old woman was admitted to the hospital because of pain in the abdomen.For many years she had had severe rheumatoid arthritis involving all the extremities; the sole therapy had been aspirin. Two days before entry diffuse abdominal pain developed suddenly, with subsequent localization in the right lower quadrant. On the following day she vomited several times.The patient was an emaciated woman with rheumatoid deformities of the hands and feet and flexor contractures of the hips, knees and elbows. The heart was not enlarged; a Grade 2 precordial midsystolic murmur was audible. . . .
Case 18-2008
Authors: Margaret Seton, Misha Pless, Jay A. Fishman, Paul A. Caruso, E. Tessa Hedley-Whyte
Journal: New England Journal of Medicine (2008)

A 68-year-old man was admitted to the hospital because of headache and loss of vision in the right eye, 3 1/2 months after orthotopic liver transplantation. Four weeks after transplantation, headaches and jaw claudication developed, followed by blurred vision in the right eye. Two weeks before admission, an ophthalmologist began therapy with prednisone; symptoms improved and then worsened 2 days before admission. On admission, additional diagnostic studies were performed.
Abstract 767: RalGTPase regulation of p53 and its contribution to malignant transformation.
Authors: Awet Tecleab, Xiaolei Zhang, Said M. Sebti
Journal: Cancer Research (2013)

Abstract The regulation of the tumor suppressor p53 by Ral GTPases and its contribution to malignant transformation are not known. Here we demonstrate that the expression of K-Ras, Ral A and Ral B, but not Akt1/2 and c-Raf, is required for maintaining low levels of p53 in human cancer cells that harbor mutant K-Ras and wild type p53. Depletion of Ral A and Ral B increases p53 protein levels by increasing its stability and this results in p53-dependent up regulation of p21waf and mdm2. Furthermore, depletion of Ral A and / or Ral B leads to a p53-dependent decrease in the proportion of cells in the S-phase of the cell cycle, inhibition of anchorage-independent growth and suppression of invasion. Thus, expression of Ral proteins is critical to maintaining low levels of p53, and this appears to be critical to the ability of Ral GTPase to induce malignant transformation. Citation Format: Awet Tecleab, Xiaolei Zhang, Said M. Sebti. RalGTPase regulation of p53 and its contribution to malignant transformation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 767. doi:10.1158/1538-7445.AM2013-767