tbuckley/cabot-search huggingface dataset:
Abstract 209: Zinc is essential for the efficacy of p53 reactivating drugs
Authors: Asfar S. Azmi, Ammar Sukari, Philip A. Philip, Ramzi M. Mohammad
Journal: Cancer Research (2011)

Abstract According to the International Zinc Nutrition Consultative Group, 20% of the world's population lack sufficient Zinc in their diet. Zinc is required by &amp;gt;200 different proteins including the most extensively studied Zinc-finger protein p53 that is considered guardian of genome. Its crucial role in p53 core domain folding has been proven, as disruption of this interaction greatly reduces or abrogates p53 DNA binding and transactivation of target genes. Therefore, alterations in Zinc homeostasis may impair p53 activity and also reduce the efficacy of wt-p53 re-activating drugs. Recently, we have shown that Zinc is necessary for proper wt-p53 re-activation and cancer cell apoptosis by small molecule inhibitors of HDM2 such as MI-219 (Oncogene 2010). As a logical extension to our these results, in this clinically translatable study we show that Zinc is crucial for the activity of mutant p53 reactivated by PRIMA and provide evidence for using combination therapies with PRIMA that include supplemental Zinc for the treatment of mut-p53 tumors. ZnCl2 (64 µM) enhanced PRIMA (0-100 µM) anti-tumor activity (induced growth inhibition and apoptosis and suppressed colony formation) in multiple pancreatic, colon and breast cancer cell lines. Chelation of Zinc by chelex 100 resin not only blocked the activity of PRIMA, but also suppressed reactivation of the mut-p53 and its downstream effector molecules 14-33σ, Bax and p21 as detected by western blot analysis. N,N,N'N′-tetrakis(−)[2-pyridylmethyl]-ethylenediamine (TPEN), a specific Zinc chelator, but not 1,2-bis-(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid (Bapta-AM), a calcium chelator or desferroxamine, a iron chelator blocked PRIMA-induced apoptosis. Zinc chelation by TPEN suppressed p53 nuclear localization that is important for its transcriptional activity. Zinc did not affect PRIMA activity in p53 null cells, suggesting that this was indeed a p53 dependent phenomenon. Addition of Zinc suppressed the known p53 feedback MDM2 activation, which could be restored by TPEN. Before wt- or mut-p53 re-activating drugs such as MI-219 and PRIMA make their way into the clinic for cancer patients who usually have mild to moderate Zinc deficiency, we believe that the results of our findings will help in the design of novel combination strategies with Zinc for better survival outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 209. doi:10.1158/1538-7445.AM2011-209
Saccharin's Link to Human Cancer Questioned
Authors: F. X. Mahaney
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Saccharin‘s Link to Human Cancer Questioned Get access Francis X. Mahaney, Jr. Francis X. Mahaney, Jr. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 9, 6 May 1992, Page 665, https://doi.org/10.1093/jnci/84.9.665 Published: 06 May 1992
LESS OBSTRUCTIVE CORONARY ARTERY DISEASE, BUT NOT LESS DIFFUSE CORONARY ATHEROSCLEROTIC BURDEN IN WOMEN RELATIVE TO MEN REFERRED FOR CORONARY ANGIOGRAPHY
Authors: Viviany R. Taqueti, Venkatesh Murthy, Jon Hainer, Courtney Foster, Ron Blankstein, Sharmila Dorbala, Marcelo Di Carli
Journal: Journal of the American College of Cardiology (2015)
Chronic Postrheumatic-Fever (Jaccoud's) Arthritis
Authors: Nathan J. Zvaifler
Journal: New England Journal of Medicine (1962)

The relation of chronic deforming arthritis and valvular heart disease is complex and has been the source of a large number of investigations, both clinical and pathological. Earliest attention to this question followed the realization that the joint involvement in rheumatic fever was in some way related to the development of valvular heart disease. Later, the problem became one of distinguishing between the articular changes of acute rheumatic fever and chronic rheumatoid arthritis. This was simplified as knowledge of the course, the clinical characteristics, the x-ray features and, later, the serologic reactions of the two diseases became more familiar. Occasional . . .
Abstract LB-298: EGF induces EMT through PI3K/Akt and MAPK singnaling pathways in breast cancer cell lines
Authors: Jin Kyoung Kim, Jienan Kong, Youngseok Lee, Hoiseon Jeong, Aeree Kim
Journal: Cancer Research (2012)

Abstract EMT, epithelial-mesenchymal transition, is defined by the loss of epithelial characteristics and the acquisition of mesenchymal properties, such as reduced cell to cell contact, spindle morphology, expression mesenchymal markers and migratory function. In carcinogenesis, EMT is known to be associated with increased aggressiveness, and invasive and metastatic potential. Although various factor, such as EGF signaling pathways, cytokines, miRNAs, Wnt signaling and TGF-ß signaling have been suggested as inducers of EMT signaling pathway, detailed mechanism haven't been clarified except TGF-ß induced EMT. This study was designed to evaluate if and how EGF can induce EMT in breast cancer cell lines. We showed EGF induced EMT, such as elongation of cancer cells, down regulation of E-cadherin, and upregulation of vimentin and fibronectin in MCF-7 and MDA-MB-231 cell lines. In addition, we confirmed that EMT by EGF was induced via MAPK and PI3K/Akt signaling pathway using LY294002 (PI3K inhibitor) and PD98059 (MAPK inhibitor). PI3K inhibitor and MAPK inhibitor also blocked phosphorylation of Smad2 and inhibited nuclear localization of p-Smad2. With using SB203580 (p-Smad2 inhibitor) inhibited expression of Snail. In summary, EGF induces EMT through PI3K/Akt and MAPK signaling pathways, which activate downstream of Smad2 and Sanil signaling in MCF-7 and MDA-MB-231 cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-298. doi:1538-7445.AM2012-LB-298
No clinical relevance of standardized immunocytological and molecular methods for detection of disseminated tumor cells in bone marrow of patients with primary breast cancer.
Authors: S Kaul, M Sonnauer, B Bartik, A Deckert, F Zeifang, G Bastert, N Fersis
Journal: Cancer Research (2009)

Abstract Abstract #306 Background: Bone marrow samples from 2093 patients operated for primary breast cancer (stage T1-4, N0/N+, M0/M1) at the University Hospital Heidelberg between 1999 und 2007 were analysed for disseminated tumor cells (DTC) by standard cytology on cytospin slides. In parallel a subgroup of 250 samples was analysed by immunobead-RT-PCR methods for CK19 expression.&amp;#x2028; Material and Methods: Mononuclear cells were enriched by Ficoll density-gradient centrifugation. Cytospin-slides (mean 6) with 1x106 BM-cells were fixed in 3.5% buffered formalin at RT and endogenous AP and Ig were blocked with 10% acetic acid and 2.28% NaJO4. DTC were identified by CK antibodies 5D3 and A45-B/B3 (automated immunostainers, AP-techniques). Slides were analysed by automated picture analysis with the ACIS I and II systems (ChromaVision). Criteria for classification of disseminated tumor cells were in compliance with the publication of Fehm et al. (Cancer, Vol.107, 2006). 1x107 BM cells were used for immunomagnetic enrichment of epithelial cell types using antibodies targeting the cell membrane glycoproteins MUC1 and EpCAM. The markers cytokeratin 19 (CK19) and MG1 were analysed by real-time qRT-PCR using primers and FAM-labeled TaqMan probes of the UniversalProbeLibrary system (Roche AG, Basel, CH). The newly developed embedded tumor cell calibrator (ETC) technique was introduced for cell quantification.&amp;#x2028; Results: Small cells characterized by an excentrically located small and clear nucleus were detected in 56% of the bone marrow samples. These cytokeratin-positive cells were identified as bone marrow stroma stem cells. Identical cell types were present in 27 samples from normal BM-donors. In contrast, tumor cells were characterized by strong and irregular cytoplasmic cytokeratin staining, a granular nucleus and a clearly enlarged nuclear size. These DTC had a mean value for the parameter area of 309 (n=13) according to the ACIS picture analysis. Using published tumor classification critera 40 (1.9%) from 2093 patients with primary breast carcinoma were scored DTC positive. At the basis of 2x106 BM-cells the molecular detection methods of a) endpoint RT-PCR for CK19 and b) real-time RT-PCR for CK19 and MG1 had positivity rates of 3.5% and 3.8%, respectively.&amp;#x2028; Discussion: We have shown that bone marrow stroma cells are positive for various epithelial antigens including CK. Elimination of these cells either by size exclusion in picture analysis or by immunomagnetic separation results in tumor cell detection rates of less than 4% in 2x106 bone marrow cells. We conclude that cytological DTC analysis and the technique of immunomagnetic enrichment followed by molecular CK19 detection have no clinical relevance in patients with primary breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 306.
AB1240 Ultrasound evaluation of rheumatoid nodules and their correlation with disease activity:
Authors: A.M. Bertoli, M. Audisio, C. Pineda Villaseñor, C. Hernandez-Diaz
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Little is known about the correlation of rheumatoid nodules and disease activity; in fact, this has been evaluated neither in clinical trials nor in cohort studies. <h3>Objectives</h3> The purpose of this study is to correlate the degree of vascularization of rheumatoid nodules measured by a semi-quantitative scale of power Doppler (PD) signal with the degree of disease activity. <h3>Methods</h3> We evaluated 36 consecutive patients fulfilling the 1987 ACR criteria for rheumatoid arthritis who had rheumatoid nodules on the extensor aspect of the forearms. In the case the patient had more than one nodule, the largest was chosen for its evaluation. The correlation between the presence and intensity of vascularization of the nodule using a semi-quantitative (0-3) scale of PD signal with disease activity, as measured clinically (DAS28 and RAPID3) and ultrasonographically (German US7 gray scale and PD synovitis scores), were examined by the Mann-Whitney U test and the Spearman's rank order test. For the latter, a coefficient &lt;0.40 was considered poor, 0.40-0.59 moderate, 0.60-0.79 good and 0.80-1 excellent. <h3>Results</h3> Patients were predominantly females (67%) with a median (percentile 25-75) disease duration of 126 (61-261) months. Median PD signal of nodules was 1 (1-2), median DAS 28=4.24 (3.68 – 6.07), median RAPID 3=12.50 (5.48-15.15) and median German US7 gray scale synovitis=12.00 (9.00-19.75) and PD synovitis=9.00 (5.25-12.0). The correlation between the nodules PD vascularization with clinimetric and ultrasonographic indexes are shown in Table 1. <h3>Conclusions</h3> In this study, the presence and degree of vascularization of rheumatoid nodules, which can be taken as a surrogate measure of extraarticular inflammation, does not seem to parallel other clinical and ultrasonographic measures of disease activity at both, patient and joint levels. The Rapid3 was the only composite index that showed a moderate level of correlation with the nodule vascularization. Results suggest that different regulatory pathways may exist controlling the expression of rheumatoid nodules and synovitis. <h3>References</h3> Nalbant S, Corominas H, Hsu B, Chen LX, Schumacher HR, Kitumnuaypong T. Ultrasonography for assessment of subcutaneous nodules. J Rheumatol 2003; 30(6):1191-5. Backhaus M, Ohrndorf S, Kellner H, Strunk J, Backhaus TM, Hartung W et al. Evaluation of a novel 7-joint ultrasound score in daily rheumatologic practice: a pilot project Arthritis Rheum 2009; 61(9):1194-201. <h3>Disclosure of Interest</h3> None Declared
Sputum inflammatory cells in COPD patients classified according to GOLD 2011 guidelines
Authors: Maria Laura Bartoli, Francesco Costa, Laura Malagrinò, Dario Nieri, Sandra Antonelli, Giovanna Decusatis, Claudia De Simone, Sabrina Santerini, Silvana Cianchetti, Manuela Latorre, Barbara Vagaggini, Pierluigi Paggiaro
Journal: European Respiratory Journal (2016)

Recently the definition of chronic obstructive pulmonary disease (COPD) severity, stated in 2001 by Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines and based on forced expiratory volume in 1 s (FEV1) evaluation, has been considered inadequate to recognise all the multifaceted aspects of the disease. To overcome this limitation, 2011 GOLD recommendations suggested a new approach, which stratified COPD patients in four groups of severity (A, B, C, D) according to the level of symptoms (as assessed by either the modified Medical Research Council (mMRC) score or the COPD Assessment Test), the degree of airflow limitation (expressed as percentage of predicted forced expiratory volume in 1 s (FEV1) value) and the number of exacerbations in the previous year [1]. It is still matter of debate if this new classification helps to better understand the disease and improve COPD treatment and prognosis. Studies on the existing database have been published comparing the old with the new GOLD classifications, showing that GOLD 2011 classification adds new details on the phenotyping and on the prognosis of COPD [2–5]. Despite the many post hoc analyses performed on the large databases of the most important recent observational studies (ECLIPSE, CCLS, COPDgene), the demonstration that these different groups of GOLD 2011 classification are different for physiological and biological features is controversial. The A, B, C and D groups of the new GOLD classification are at least partly related to different COPD phenotypes <http://ow.ly/Xgr8q>
RADIOLOGIC PATTERN OF PULMONARY EMBOLISM IN PATIENTS WITH CIRRHOSIS
Authors: A Abu Shanab, N Starr, Z Hutchinson, J Hegarty, A McCormick, R Merriman
Journal: Gut (2013)

<h3>Introduction</h3> The liver plays the key role in haemostasis both primary and secondary. Pulmonary embolism (PE) has been observed in patients with cirrhosis despite associated coagulopathy. The radiologic pattern and risk factors of PE in patients with cirrhosis are poorly characterised. <h3>Aims/Background</h3> To study the radiologic pattern and possible risk factors of PE in cirrhotic patients. <h3>Method</h3> Retrospective cohort data of patients with PE and cirrhosis in a single center from was collected from our HIPE (Hospital Inpatient Enquiry) department between 2002–2012. Patients with active malignancy, recent (within 90 days) fracture or surgery or pregnancy were excluded. Clinical variables included severity of cirrhosis, symptoms of PE and laboratory tests and radiologic patterns were studied. <h3>Results</h3> Ten cirrhotic patients, M:F 1:1 with average age 59 years old, had PE during this period. Dyspnea was the predominant symptom in 90% of patients while chest pain or haemoptysis was present in only 20% and 10% respectively. The average platelet count and INR was 126 and 1.4 respectively. Sixty per cent had bilateral radiologic findings, 30% had PE in the right side while only 10% had left sided PE. Lower lobes emboli were significantly more common than upper lobe PEs (p=0.03). Pleural effusion was present on the ipsilateral side of PE in 60% while the rest did not have pleural effusion. <h3>Conclusion</h3> PE tends to occur bilaterally and mainly in lower lobes, particularly the right if unilateral. The presence of a measurable coagulopathy in a cirrhotic patient does not absolutely protect against PE.
Abstract 3635: Improved efficacy of HER2 targeted-immunotoxins using photochemical internalization (PCI)
Authors: Maria Eb Berstad, Kristian Berg, Michael Rosenblum, Yu Cao, James D. Marks, Anette Weyergang
Journal: Cancer Research (2011)

Abstract Human epidermal growth factor receptor 2 (HER2) is overexpressed in several cancers (breast, ovary, stomach, colon and esophagus) and is an attractive target for delivery of cancer therapeutics. However, both primary and acquired resistance to current anti-HER2 therapies is of major clinical concern and calls for more effective HER2 targeted treatment strategies. We here present photochemical internalization (PCI) of HER2 targeted immunotoxins (ITs) as a novel treatment strategy for HER2 positive cancers. PCI has been shown to result in release of macromolecular therapeutics entrapped in endocytic vesicles. The method is based on photosensitizers (PSs) which localize to the membranes of endocytic vesicles, and subsequent membrane rupture upon light exposure so that the drugs can escape into the cytosol. The purpose of this study was to evaluate photochemical internalization (PCI) of HER2 targeted immunotoxins (ITs) with various binding sites and affinities. ITs were constructed by chemically coupling the monoclonal HER2 antibody, trastuzumab, to a type I ribosome inactivating protein (RIP), saporin, through a biotin-streptavidin linkage, or by genetically fusing human single-chain antibodies (scFv) to recombinant gelonin, another type I RIP. The cytotoxic effect of PCI of the ITs was assessed against HER2 positive Zr-75-1 and BT-20 cells and HER2 negative MDA-MB231 cells. The present data confirm synergistic cytotoxicity of PCI of trastuzumab-based and HER2 scFv-based ITs compared to treatment with ITs and photodynamic therapy (PDT) alone (PS+light). At LD50-PDT a subtoxic dose of 100pM of the different ITs was sufficient to kill 75-85% of Zr-75-1 cells. LD95 of PCI of the recombinant fusions was detected between 1 and 10nM of all 4 ITs (subtoxic dosage) at a photodynamic dose reducing the viability of the BT-20 cells to 50%. PCI of the ITs was shown to be much more effective compared to PCI of the respective toxins alone, as no significant increase in toxicity was found by PCI of 0.1nM of the toxins. Animal model studies to assess the ability of PCI to augment the efficacy of immunotoxins are ongoing. These studies suggest that the selectivity of HER2-based ITs may be further improved by the addition of an independent, selective strategy such as PCI which augments efficacy only in tumor cells. Research Conducted, in part, by the Norwegian Cancer Society and the Clayton Foundation for Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3635. doi:10.1158/1538-7445.AM2011-3635
Breast MRI Screening of Women with a Prior High-Risk Lesion: Preliminary Results.
Authors: S. Brennan, L. Liberman, D. Dershaw, E. Morris
Journal: Cancer Research (2009)

Abstract Purpose: To determine the frequency of breast cancer detection in women at increased risk due to a prior high-risk lesion.Materials and methods: An IRB approved retrospective review was performed of the records of 2184 breast MRIs starting from 1999, to identify patients who commenced screening breast MRI who had a history of a prior high risk lesion. Eighty-three women were identified who had a prior biopsy demonstrating a high-risk lesion such as atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS). History, imaging, and pathologic findings were reviewed.Results: Histologies of prior high-risk lesions in these 83 women were ADH in 24, LCIS in 54 and ALH in 5. The median length of MRI follow-up was four (range, 1-9) years. Biopsies were recommended based on MRI findings in 39 (47%) of 83 women, yielding cancer in seven (8%) women (four of whom also had benign biopsies), and benign findings only in 32 (39%) women. Six of the seven women who developed a breast cancer also had a family history of breast cancer. Histologic findings in these seven cancers were ductal carcinoma in situ (DCIS) in 4 (57%) and invasive cancer in three (43%). Invasive cancer histologies (n=3) were ductal in one and lobular in two; maximal histologic size was 2.0 cm. This large invasive cancer had a mammographic, sonographic, and palpable correlate, and was node-positive; the other cancers were identified by MRI only. Among these seven cancers, two (29%) were detected in screening year 1, two (29%) in screening year 2, two (29%) in screening year 3 and one in screening year 4 (14%). Three (43%) of the seven cancers were in the contralateral breast. In these 83 women, the likelihood of detecting cancer by MRI was higher in those with, rather than without, a family history of breast cancer (6/54=11% vs. 1/29=3%) and in women with prior LCIS rather than prior ADH (6/54=11% vs. 1/24=4%).Conclusion: Breast MRI detected cancer in 7 (8%) of 83 women with a prior high-risk lesion, six (86%) of whom also had a family history of breast cancer. Among these cancers, all were detected during the first four years of screening and less than half were invasive (43%). Further work with more patients is needed to determine the utility of breast MRI screening in women with specific prior high-risk lesions, with and without additional risk factors. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4002.
Abstract 1063: The ErbB3/4 receptor ligand Heregulin negatively regulates ErbB2 and ErbB3 receptor levels
Authors: Smita Awasthi, Arundhati Ghosh, Gerald M. Wilson, Bret A. Hassel, Anne W. Hamburger
Journal: Cancer Research (2012)

Abstract ErbB2 is overexpressed in 30% of breast cancers and its overexpression is associated with poor prognosis. In addition, the ErbB2/3 heterodimer forms the most potent mitogenic receptor in vitro and is key to the proliferation of breast cancer cells. Despite the importance of this heterodimer in breast cancer progression, the negative regulation of these ErbB tyrosine kinases is still poorly understood. We demonstrate here for the first time that the ErbB3/4 ligand Heregulin (HRG) reduces mRNA and protein levels of both ErbB2 and ErbB3 in human breast cancer cell lines. We have found that after 24h of HRG treatment, ErbB2 expression decreased at both the RNA and protein levels in ErbB2 overexpressing AU565, BT474 and LTLT-Ca breast cancer cell lines. In contrast, EGFR levels were unaffected by HRG treatment. An initial decline in steady state mRNA levels was first noted at 1 hour after HRG treatment. ErbB3 levels also decreased in LTLT-Ca cells after HRG treatment. Lapatinib, which inhibits ErbB2 and EGFR kinase activity and HRG induced-ErbB3 phosphorylation, diminished the HRG- induced decrease in ErbB2 and ErbB3 in AU565 and LTLT-Ca cells. This finding suggests that the kinase activity of EGFR/ErbB2 may be involved in the HRG-induced down-regulation. HRG did not change the activity of ErbB2 promoter reporter constructs spanning 215 kb to 6007 kb upstream of the ErbB2 transcription start site as indicated by luciferase assays. An ongoing study suggests that HRG could be involved in decreasing ErbB2 mRNA stability. Our findings suggest that resistance to Lapatinib may be due in part to the fact that inhibition of ErbB2/ EGFR kinase activity dampens the negative effect of HRG on ErbB2 expression, resulting in elevated levels of ErbB2 in breast cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1063. doi:1538-7445.AM2012-1063