tbuckley/cabot-search huggingface dataset:
<i>TP53</i> mutation is an early event in breast cancer progression.
Authors: W Zhou, AA Muggerud, P Vu, EU Due, T Sørlie, A Børresen-Dale, F Wärnberg, A Langerød
Journal: Cancer Research (2009)

Abstract Abstract #1047 Background: In breast cancer, previous studies have shown that somatic TP53 mutations cause a more aggressive disease with poor clinical outcome and may impact treatment response. Although TP53 mutation is considered to be an early event in breast cancer, the timing of TP53 mutations is not known, and there are controversies regarding the cellular origin and linear model of breast cancer. The purpose of this study was to investigate whether TP53 mutations are early events in breast cancer progression.&amp;#x2028; Methods: From a population-based cohort of women diagnosed between 1986 and 2004 either with a pure ductal carcinoma in situ (DCIS), a pure invasive cancer (&amp;lt;15mm) or a mixed lesion (i.e. invasive cancer with a DCIS component), we included 118 women with stored frozen tissue. Mixed lesions were microdissected using LCM (laser capture microdissection) on a PALM slide to separate in situ and invasive tumor cells. DNA was isolated using phenol-chloroform extraction. The entire coding sequence of TP53 was analyzed for mutations by direct sequencing on a 3730 DNA analyzer.&amp;#x2028; Results: Of 118 tumor samples, 19 were detected with a TP53 mutation; five 5 of 32 (15.6%) pure DCIS, 4 of 38 (10.5%) pure invasive cancers and 10 of 48 (20.8%) mixed lesions. In the mixed lesions, both the invasive and the DCIS component showed the same mutation in all 5 cases where we successfully could microdissect the two components separately. Pure DCIS demonstrated missense mutations (4/5, 80%) more frequently than pure invasive cancers (2/4, 50%) and mixed lesions (4/10, 40%), although this difference was not statistically significant (p=0.3). Also, the frequency of missense mutations in the DNA binding domain was not statistically different between the three groups.&amp;#x2028; Conclusion: TP53 mutation is likely an early event in breast cancer, occurring previous to or in the in situ stage. Presence of the same mutation in both DCIS and invasive component from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression into invasive cancer is less clear and may vary between subtypes of breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1047.
Abstract LB-20: mTOR kinase inhibition relieves feedback suppression of receptor tyrosine kinase leading to a biphasic regulation of AKT signaling in breast cancer cells
Authors: Vanessa S. Rodrik-Outmezguine, Sarat Chandarlapaty, Nen C. Pagano, Poulikos I. Poulikakos, Maurizio Scaltriti, José Baselga, Sylvie Guichard, Neal Rosen
Journal: Cancer Research (2012)

Abstract Activation of mitogenic signaling by receptor tyrosine kinases (RTKs) is regulated by negative feedback. Feedback is in part mediated by mTORC1/S6K dependent downregulation of IRS proteins which downregulate IGF/insulin receptor signaling. We have found that mTORC1 inhibitors or rapalogs relieve feedback inhibition of receptor tyrosine kinases and cause mTORC2-dependent phosphorylation of AKT S473 leading to activation of AKT kinase and signaling. This relief of feedback inhibition of mTORC2/AKT signaling has been associated with the limited clinical efficacy of these compounds. mTOR kinase inhibitors have now been developed to circumvent these problems; they block mTORC1 and mTORC2 and thus do not cause the mTORC2-dependent activation of AKT observed with the mTORC1 inhibitors. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT S473 dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. Inhibition of mTOR kinase also relieves feedback suppression of RTKs leading to subsequent PI3K activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound inhibition of mTORC1 and accumulation of activated AKT phosphorylated on T308 but not S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regressions in vivo. These results highlight the possible need for combinatorial approaches to block feedback-regulated pathways. 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-20. doi:1538-7445.AM2012-LB-20
Tl-201 Uptake in an Intracranial Primary Malignant Melanoma
Authors: TAKAHIRO MIYAZAKI, TAKASHI OHNISHI, HIROAKI HOSHI, SEISHI JINNOUCHI, SHIGEMI FUTAMI, SHIGEKI NAGAMACHI, KATSUSHI WATANABE, RYOUICHI HAMASUNA, TAKASHI UEDA, SHINICHIRO WAKISAKA
Journal: Clinical Nuclear Medicine (1996)

A 32-year-old man had a giant pigmented nevus in general at birth in the head, face, chest, and back, and mental retardation and right hemiparesis (unknown cause) developed. A malignant melanoma was suspected on clinical evidence plus the images. At craniotomy, an intracranial primary malignant melanoma was diagnosed that originated in the pia matter with neurocutaneous melanosis.
THU0203 Equal Retention and Drug Survival Between Females and Males Requiring Biologic Therapy for Rheumatoid Arthritis
Authors: J. Lee, R. Mason, L. Martin, C. Barnabe
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Sex differences in RA prevalence, disease activity levels, and patient-reported outcomes are documented, but no studies have documented drug retention or drug-survival differences. <h3>Objectives</h3> To determine retention and drug-survival duration on first and subsequent biologic agents by sex. <h3>Methods</h3> Data source: Alberta Biologics Pharmacovigilance Program (ABioPharm), a population-based longitudinal registry. Analysis: Comparison of disease activity measures by sex over the treatment course, drug retention on the first and subsequent biologic agents, number of treatment switches required and drug survival using Kaplan-Meier survival curves. <h3>Results</h3> 572 patients (423 females, 74.0%) with established RA (11.8 years) were included. Disease activity indices were similar at baseline for females and males (swollen joints (28 joints) 3.1 vs 3.0, tender joints 4.3 vs 3.7, DAS28 5.83 vs 5.72). Females reported worse function (HAQ 1.64 vs 1.51 (P=0.037)) and more fatigue (6.7 vs 5.9, 0-10 scale (p=0.013)), but the same global score for disease activity as males (6.9 vs 6.8, 0-10 scale). No differences in disease activity measures or patient-reported outcomes developed, but females continued to report poorer function. The first biologic agents used were similar (etanercept 60.8% vs 61.1%; infliximab 20.3% vs 16.1%; adalimumab 17.0% versus 17.5%) as was retention on the first biologic agent (62.7% versus 70.5%, P=0.0866) with a median survival of 3.7 vs 3.3 years (logrank test p=0.25) (Figure 1). Frequency of switching and survival on subsequent biologics were the same. <h3>Image/graph</h3> <h3>Conclusions</h3> No sex differences were detected in drug retention and survival for patients requiring biologic therapy for RA. Females reported poorer function throughout the treatment course but disease activity measures were similar. <h3>Disclosure of Interest</h3> None Declared
The Risk of Stomach Cancer in Patients with Gastric or Duodenal Ulcer Disease
Authors: Lars-Erik Hansson, Olof Nyrén, Ann W. Hsing, Reinhold Bergström, Staffan Josefsson, Wong-Ho Chow, Joseph F. Fraumeni, Hans-Olov Adami
Journal: New England Journal of Medicine (1996)

Helicobacter pylori infection, now considered to be a cause of gastric cancer, is also strongly associated with gastric and duodenal ulcer disease. The discovery of these relations has brought the long-controversial connection between peptic ulcers and gastric cancer into focus.We estimated the risk of stomach cancer in a large cohort of hospitalized patients with gastric or duodenal ulcers, as recorded in the Swedish Inpatient Register between 1965 and 1983. Altogether, 57,936 patients were followed through 1989, for an average of 9.1 years. The standardized incidence ratio--the ratio of the observed number of cancers to the number expected on the basis of the incidence in the Swedish population at large--was used as a measure of relative risk.After peaking in the first 3 years of follow-up, the standardized incidence ratio for gastric cancer among 29,287 patients with gastric ulcers leveled off at 1.8 (95 percent confidence interval, 1.6 to 2.0) and remained significantly increased throughout follow-up, which was as long as 24 years for some patients. Prepyloric ulcer, diagnosed in 8646 patients, was not associated with a significant excess risk (standardized incidence ratio, 1.2; 95 percent confidence interval, 0.8 to 1.6). In the cohort of patients with duodenal ulcers (24,456 patients), the incidence of gastric cancer was significantly lower than expected. After the second year of follow-up, the standardized incidence ratio was only 0.6 (95 percent confidence interval, 0.4 to 0.7) and remained stable thereafter.Gastric ulcer disease and gastric cancer have etiologic factors in common. A likely cause of both is atrophic gastritis induced by H. pylori. By contrast, there appear to be factors associated with duodenal ulcer disease that protect against gastric cancer.
Abstract 5681: A high throughput soft agar assay on a panel of 60 tumor cell lines to study compounds for potential anti-oncogenic properties
Authors: Holger Weber, Melanie Mueller, Jan E. Ehlert
Journal: Cancer Research (2012)

Abstract In the course of drug development, analysis of cellular efficacy represents a critical stage before drugs proceed into in vivo studies. For anti-cancer drugs, one method of choice is to assess the drug's impact on tumor cell proliferation. Usually proliferation is analysed in 2D format, analysing cell growth on a flat surface. However, accumulating data suggest that cells behave in a more physiological manner when growing in a 3D matrix. In fact, the gold standard for analysing the transformed status of cells is growth in soft agar, a semi-solid medium in which epithelial cells grow in 3D due to their transformation-related anchorage-independent status. In order to allow a more physiological cellular drug screening for proliferation as well as for transformation, we have now established soft agar assays in 96 well format for 60 tumor cell lines derived from solid tumors. Our data show the multitude of outcomes that may be expected from such a comprehensive study, e.g. we present IC50 analyses indicating that the same compound can have seemingly contradictory, i.e. stimulatory as well as inhibitory activity on soft agar growth, depending on concentration and tested cell line. We propose screening of compounds for impact on cellular soft agar growth as a mandatory prerequisite before testing a drug in vivo. 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 5681. doi:1538-7445.AM2012-5681
Site-Selective 8 -Chloro- Cyclic Adenosine 3′,5′-Monophosphate as a Biologic Modulator of Cancer: Restoration of Normal Control Mechanisms
Authors: Y S Cho-Chung
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Site-Selective 8 -Chloro- Cyclic Adenosine 3′,5′-Monophosphate as a Biologic Modulator of Cancer: Restoration of Normal Control Mechanisms Get access Yoon Sang Cho-Chung Yoon Sang Cho-Chung Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 13, 5 July 1989, Pages 982–987, https://doi.org/10.1093/jnci/81.13.982 Published: 05 July 1989 Article history Received: 13 January 1989 Revision received: 01 May 1989 Accepted: 09 May 1989 Published: 05 July 1989
Abstract 5005: Deletion of bone morphogenetic protein receptor 1A impairs mammary gland development and tumor formation.
Authors: Philip Owens, Charli R. Bobbitt, Michael W. Pickup, Agnieszka E. Gorska, Sergey V. Novitskiy, Harold L. Moses
Journal: Cancer Research (2013)

Abstract Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) superfamily. BMP ligands have recently been shown to be overexpressed in human breast cancers. Normal breast and cancers display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 8. BMP signaling is a known morphogen, responsible for differentiation of many cell types. This led us to hypothesize that BMP signaling may be required for development of the mammary gland and tumors. We first utilized the mammary epithelial specific Cre recombinase driven by the MMTV promoter to remove conditionally floxed BMPR1a alleles. We found that mice lacking BMPR1a (cKO) had significant reduction in epithelial branching morphogenesis within the mammary gland. We further analyzed BMPR1a loss in lactating mice using WAP promoter driven Cre, which demonstrated a loss of milk production. We next combined the MMTV.PyVmT oncogene with mice lacking BMPR1a and found this deletion resulted in delayed tumor onset and extended survival significantly (p-value &amp;lt;.001). Furthering these studies, we investigated the morphology of BMPR1a deleted tumors and found a striking loss of luminal characteristics combined with a stromal desmoplasia. Immunofluorescence staining revealed that cKO tumors co-expressed cytokeratins and mesenchymal cell markers such as Vimentin. This indicated that epithelial-to-mesenchymal (EMT) like changes were occurring upon BMPR1a deletion. We performed a DNA microarray on these tumors and found unique changes, which supported a loss of mammary gland differentiation and resulted in EMT-like activation. We next examined human breast tumor cell lines that previously reported the molecular signature response to BMP stimulation and compared them to primary human mammary epithelial cells (HMEC). Comparing signatures, we found that BMP4 stimulation induced unique genes in HMECs compared to tumor cells. Interestingly, transcriptional targets that were absent from tumors and found in normal HMECs included differentiation related genes. These results suggest that BMP signaling is critically deregulated in tumors. In conclusion, we found that loss of the BMP pathway restricts mammary gland development and impairs tumor formation and progression. Citation Format: Philip Owens, Charli R. Bobbitt, Michael W. Pickup, Agnieszka E. Gorska, Sergey V. Novitskiy, Harold L. Moses. Deletion of bone morphogenetic protein receptor 1A impairs mammary gland development and tumor formation. [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 5005. doi:10.1158/1538-7445.AM2013-5005
Case 41-1991
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, A.K. Rustgi, C.C. Compton
Journal: New England Journal of Medicine (1991)

Presentation of Case First admission. A 76-year-old man was admitted to the hospital because of recurrent gastrointestinal bleeding.There was a history of an ostium secundum atrial septal defect that was repaired five years before admission, with placement of a large patch over the defect. Warfarin was administered for six months, without complication. Thereafter the patient was well until 18 months before entry, when a transient cerebral ischemic attack occurred during atrial fibrillation, and warfarin was resumed. An echocardiographic study showed borderline left ventricular hypertrophy and diffuse hypokinesis, with a left ventricular ejection fraction of 48 percent; the left . . .
TRAIL POTENTIATES PANOBINOSTAT CYTOTOXICITY IN GLIOBLASTOMA MULTIFORME (GBM) IN VITRO
Authors: J. L. Darling, F. B. Rowther, A. L. Armesilla, T. P. Dawson, K. Ashton, T. Warr
Journal: Neuro-Oncology (2014)

BACKGROUND: (blind field). METHODS: Low passage short-term cultures derived from GBM previously extensively characterised at a molecular level were used in this study. RNA was extracted using RNeasy Mini Kit. Quantitative RT-PCR (Q-PCR) was carried out using Solaris qPCR gene expression assay with FAM reporter on an ABI 7500 Sequence Detection System and protein expression confirmed used Western blotting. Cytotoxicity was determined in vitro using a sulforhodamine B assay, drug interaction was measured using the median-effect principle proposed by Chou-Talalay and a Cignal™ 45-pathway reporter assay was used to screen pathway activity following drug treatment. RESULTS: Q-PCR showed that TRAIL ligand was preferentially expressed in cultures that contained a p53 mutation or deletion whilst expression was low or absent in cultures with wild-type p53. TRAIL death receptors 1 (DR4) and 2 (DR5) were expressed in cultures irrespective of p53 status. TRAIL decoy receptor 3, 1 and 2 (DcR2) were highly expressed in cultures with wild-type p53 and either absent or at low levels in p53 mutant cultures. The ID50 of cultures to TRAIL ranged from 0.18–15.1 ng/ml. Most cultures with mutant p53 were resistant to TRAIL although one wild-type culture that expressed high levels of DcR2 was very resistant to TRAIL. Knocking down DR5 receptor produced resistance to TRAIL and knocking down DcR2 decoy receptor augmented response to TRAIL. Treatment of cultures with a non-toxic dose of TRAIL enhanced toxicity to panobinostat between 2 and 40-fold and that this was associated with increased reporter activity of the nanog, retinoic acid, wnt and xenobiotic pathways. CONCLUSIONS: A combination of low dose TRAIL and panobinostat are significantly more toxic to GBM cells in vitro than the single agents. Combinations of TRAIL and HDAC inhibitors that affect both cell death pathways should be evaluated in vivo with a view to clinical application in GBM. SECONDARY CATEGORY: n/a.
Effect of Danazol in Immune Thrombocytopenic Purpura
Authors: Alan D. Schreiber, Paul Chien, Ann Tomaski, Douglas B. Cines
Journal: New England Journal of Medicine (1987)

Danazol and vinblastine are effective in many patients with chronic immune thrombocytopenic purpura (ITP). To evaluate the mechanism of action of these drugs, we studied six consecutive patients with chronic ITP treated with danazol and one treated with vinblastine. All the patients responded clinically without a notable change in the level of platelet-associated IgG. Instead, the clinical response to therapy was associated with a decrease in the number of monocyte binding sites for monomeric IgG (Fc receptors). In one patient, clinical relapse was associated with a spontaneous 2.7-fold increase in the number of monocyte Fc (IgG) receptors, without a change in the level of platelet-associated immunoglobulin. A decrease in the number of monocyte Fc (IgG) receptors following vinblastine infusion was associated with a clinical remission. We conclude that the clinical course of ITP may be influenced by the expression of monocyte or macrophage Fc (IgG) receptors. Danazol and vinblastine may mediate their clinical effect, at least in part, by influencing the number of available Fc (IgG) receptors on phagocytic cells.
Transcription-Factor Mutations and Disease
Authors: David S. Latchman
Journal: New England Journal of Medicine (1996)

Correct regulation of gene expression, so that specific proteins are made by the appropriate organs at the appropriate times or in response to specific signals, is essential both to normal development and to the correct functioning of the adult organism. Such regulation is usually achieved at the level of DNA transcription, a process that controls which genes are transcribed into RNA by the enzyme RNA polymerase, although regulation also occurs after transcription.1 The transcription of specific genes is controlled by regulatory proteins known as transcription factors.2,3 These factors therefore have a vital function in both embryonic development and the . . .
Bone Densitometry Study in a Patient with Prior Kyphoplasty Variant of Vertebroplasty
Authors: Aline McAllister, Richard P Spencer, Aris D Yannopoulos
Journal: Clinical Nuclear Medicine (2002)

McALLISTER, ALINE C.N.M.T., A.R.R.T. (N)*; SPENCER, RICHARD P. M.D., Ph.D.*; YANNOPOULOS, ARIS D. M.D.† Author Information
Till receipts - a new approach for investigating outbreaks? Evaluation during a large Salmonella Enteritidis phage type 14b outbreak in a north west London takeaway restaurant, September 2009
Authors: D Zenner, J Zöllner, A Charlett, W Marmairis, C Lane, J Y Chow
Journal: Eurosurveillance (2014)

Binary file ES_Abstracts_Final_ECDC.txt matches
What's Preventing Us from Preventing Type 2 Diabetes?
Authors: Judith E. Fradkin, B. Tibor Roberts, Griffin P. Rodgers
Journal: New England Journal of Medicine (2012)

The Diabetes Prevention Program studies showed that certain interventions could prevent or substantially delay the onset of type 2 diabetes safely and cost-effectively. But despite the disease's toll, diabetes prevention is not widely practiced in the United States.
Abstract 4693: High expression levels of NOXA are important for p53-mediated hypersensitivity in testicular germ cell tumor (TGCT) cells
Authors: Matthias Gutekunst, Moshe Oren, Andrea Weilbacher, Michael A. Dengler, Walter E. Aulitzky, Heiko van der Kuip
Journal: Cancer Research (2011)

Abstract Consistent with the excellent clinical results in testicular germ cell tumors (TGCT), most cell lines derived from this cancer such as NTERA-2D1 show an exquisite sensitivity to Cisplatin. It is well accepted that the high susceptibility of TGCT cells to apoptosis is responsible for this hypersensitive phenotype. However, the role of the p53 pathway remains controversial. Using RNA interference-mediated gene silencing, we systematically investigated the impact of DNA damage kinases upstream of p53, p53 itself, as well as apoptosis-related p53 targets on this hypersensitivity. Unexpectedly, neither knockdown of ATM, ATR, or DNA-PK alone nor ATM/ATR double knockdown or ATM/ATR/DNA-PK triple knockdown had any significant protective effect on survival of NTERA-2D1 cells upon Cisplatin. However, siRNA-mediated silencing of p53 was sufficient to completely abrogate hypersensitivity demonstrating that in these cells p53 acts preferentially as a pro-apoptotic factor. This is also supported by the finding that NTERA-2D1 cells were not only hypersensitive to Cisplatin but also to non-genotoxic inducers of p53 such as the Mdm2 antagonist Nutlin-3 and the proteasome inhibitor Bortezomib. Screening of different p53 targets revealed that the pro-apoptotic function of p53 was dependent on NOXA, since silencing of this p53 target almost completely mimicked the effect of the p53 knockdown. Importantly, both constitutive and Cisplatin-induced levels of NOXA were significantly reduced in resistant NTERA-2D1 cells obtained by either short-term differentiation or cultivation with increasing Cisplatin concentrations. Furthermore, comparison of a panel of p53 wildtype tumor cell lines revealed exceptionally high NOXA levels in the most sensitive cell line NTERA-2D1. In conclusion, our data indicate that the hypersensitivity of TGCT cells is a result of their unique sensitivity to pro-apoptotic functions of p53 mediated by exceptionally high levels of NOXA. 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 4693. doi:10.1158/1538-7445.AM2011-4693