tbuckley/cabot-search huggingface dataset:
Abstract 2154: CDCP1 links RAS and Src signaling pathways as a common effector for the promotion of tumor metastasis
Authors: Ryuichi Sakai, Takamasa Uekita
Journal: Cancer Research (2012)

Abstract The oncogenic RAS is one of the most intensively studied proteins which are well recognized as a master regulator of cancer initiation and progression, however rather limited information is available as for their contribution to the cell properties associated with tumor metastasis such as anoikis resistance, cell migration and invasion. We have revealed that CUB domain-containing protein 1 (CDCP1) protein, a substrate of Src family kinase (SFK), in solid cancers is involved in the regulation of anoikis resistance, cell migration and invasion. CDCP1 contributes significantly to the metastatic potential of various cancers including lung, stomach, and pancreatic cancers in a tyrosine phosphorylation dependent manner. It was recently observed that human lung cancer cell lines with K-RAS mutations show significantly higher expression of CDCP1 than those without, while the other common mutations such as EGFR, LKB1 and p53 did not show such relationship. The introduction of the activating mutation of K-RAS clearly induced the expression of CDCP1 and that this enhancement is also affected by the expression levels of Myc protein. Treatment of PD98059, an inhibitor of MEK downstream of Ras, as well as expression of dominant-negative Ras, reduced the expression of CDCP1, and at the same time suppressed cell survival in suspension culture, cell migration and invasion. However, these properties were rescued only when both CDCP1 and Fyn, a member of SFKs were expressed. On the contrary, metastatic potentials caused by expression of activated K-Ras in lung cancer cells was blocked by knockdown of in CDCP1 expression induced by Ras. Using three dimensional organotypic culture assay of human cervical keratinocytes (HCKs) which mimics in vivo tissue invasion of cervical cancers, marked expression of CDCP1 was detected at the site of cell invasion into the collagen raft. The treatment of CDCP1 siRNA or SFKs inhibitor PP2 repressed cell invasion into the collagen raft induced by Ras and Myc. As a summary, it was revealed that expression of CDCP1 is induced by oncogenic Ras, and upregulated CDCP1 triggers cancer invasion and metastasis when phosphorylated by SFKs. Metastatic potential induced by Ras is dependent on the CDCP1 induction, while CDCP1 is not responsive for proliferative change also induced by Ras. These findings demonstrated the central role of CDCP1 as the functional link between RAS and SFKs signaling during the progression of human malignant tumors. 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 2154. doi:1538-7445.AM2012-2154
Children with Normal-Variant Short Stature: Treatment with Human Growth Hormone for Six Months
Authors: Daniel Rudman, Michael H. Kutner, R. Dwain Blackston, Robert A. Cushman, Raymond P. Bain, Joseph H. Patterson
Journal: New England Journal of Medicine (1981)

Children with normal-variant short stature can be classified into four subgroups by measuring their anabolic and growth reactions to a 10-day course of human growth hormone. In Subgroup 1 there is no anabolic or growth reaction; in Subgroup 2 there is a weak anabolic reaction but no growth; Subgroups 3 and 4 have both reactions but Subgroup 4 is more responsive than Subgroup 3. We monitored growth rate and plasma immunoreactive somatomedin C concentrations in four to six children from each subgroup (age range, eight to 11 years) before, during, and after six months of injections of growth hormone (0.08 unit per kilogram of body weight per day). In children in Subgroups 3 and 4, the average somatomedin C level, which was subnormal before treatment, was restored to normal. Simultaneously, the average growth rate accelerated fivefold. In children in Subgroups 1 and 2, whose average pretreatment somatomedin C was normal, growth hormone had little effect on somatomedin level of growth rate. The somatomedin response in Subgroups 3 and 4 was apparent by the 10th day of treatment. This response provides a rapid method for identifying affected children who will benefit from longterm administration of human growth hormone.
INHIBITING INVASION AND STEMNESS IN GLIOBLASTOMA BY THYMOSIN BETA 4 GENE SILENCING: A POTENTIAL THERAPEUTIC TARGET?
Authors: G. Tabatabai, H.-G. Wirsching, S. Krishnan, A.-M. Florea, K. Frei, N. Krayenbuhl, K. Hasenbach, G. Reifenberger, M. Weller
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastoma is an incurable primary brain tumors with one of the worst 5-year survival rates among all cancers. Despite multimodal treatment involving neurosurgery, irradiation and temozolomide chemotherapy, the median overall survival is in the range of 15-16 months even in selected clinical trial populations. Thymosin beta 4 (TB4) is a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes. TB4 gene silencing promotes differentiation of neural progenitor cells whereas TB4 overexpression initiates cortical folding of developing brain hemispheres. Moreover, TB4 is involved in migration, invasion and epithelial to mesenchymal transition in other cancer entities, e.g. colon cancer. METHODS: We analyzed TB4 expression on tissue microarrays and performed REMBRANDT and TCGA database interrogations. We analyzed TB4 expression in 8 long-term glioma cell lines and 7 glioma-initiating cell lines. Using lentiviral transduction, we modulated TB4 expression in the long-term glioma cell lines LNT-229 and U87MG, and in the glioma-initiating cell line GS-2. We studied clonogenic survival, migration, invasion, sphere formation anddifferentiation capacity of TB4-depleted or TB4-overexpressing glioma cells in vitro, and tumorigenicity upon orthotopic implantation in vivo. Finally, we performed a genome wide mRNA expression analysis to unravel the molecular network of TB4 signaling effects. RESULTS: TB4 expression increased with the grade of malignancy in gliomas and correlated with patient survival in glioblastoma. In vitro, TB4 gene silencing by lentiviral transduction decreased migration, invasion, growth and self-renewal, and promoted differentiation and the susceptibility to undergo apoptotic cell death upon nutrient depletion in LNT-229, U87MG and the glioma stem-cell line GS-2, respectively. In vivo, survival of nude mice bearing tumors derived from TB4-depleted glioma cells was improved and the tumorigenicity of the GS-2 glioma stem-cell line was decreased. The gene expression pattern was shifted from the mesenchymal towards the pro-neural gene signature upon TB4 gene silencing, thereby modulating TGF-beta and p53 signaling networks. CONCLUSIONS: TB4 is involved in the regulation of key malignancy features in glioblastoma and may therefore be a novel candidate therapeutic target. SECONDARY CATEGORY: n/a.
Reply to V. Arena et al
Authors: Stefano Zurrida, Giuseppe Viale, Umberto Veronesi
Journal: Journal of Clinical Oncology (2009)

We thank Arena et al for their letter supporting our call to modify the present TNM breast cancer classification. We also appreciate their agreement with our main proposals for change: denoting T as exact size in cm, specifying N in relation to number of lymph nodes examined, and simplifying terminology. Their suggestion to include specific information on the sentinel lymph node—as already widely practiced—seems useful. It may not be easy to modify favorably patients’ psychological statuses, and there may be resistance to our proposals, but we feel it essential to move in a positive direction. We are concerned about the practice by Arena et al of splitting histopathologic data from biologic data and having it evaluated by separate pathologists, which we fear could lead to incongruities or even errors. We feel that the person who diagnoses the cancer should also be the one concerned with its biologic characterization: he or she would then be in a position to evaluate the coherence of the entire information set. With regard to our proposal to specify, in a new TNM classification, biologic characteristics pertinent to decision making, we agree that the techniques and reagents used to determine these characteristics vary markedly. Rather than rendering a classification unwieldy with excess detail, however, we believe the way forward is to standardize protocols (as ASCO/CAP has done with human epidermal growth factor receptor 2 [HER2] and is doing with estrogen receptors and progesterone receptors) and reagents (eg, US Food and Drug Administration approved). We also believe it would be sufficient to specify HER2 status, for example, in classes (0, 1 , 2 , and 3 ) including the number of positive cells in brackets (eg, HER2 3 [40%]).
Abstract 1154: Detection of aberrant methylation of the RASSF1A gene as a biomarker for hepatocellular carcinoma.
Authors: Surbhi Jain, Lijia Xie, Batbold Boldbaatar, Ying-Hsiu Su, Wei Song
Journal: Cancer Research (2013)

Abstract Hepatocellular carcinoma (HCC) is an aggressive malignancy that is responsible for between 250,000 and 800,000 deaths annually worldwide. HCC has a poor prognosis with a 5-year survival rate of less than 15% mainly due to a lack of early detection. The current biomarker for HCC is the alpha-fetoprotein (AFP), which has a low sensitivity of 40-60%. There is a necessity for non-invasive, convenient, and sensitive methods to detect the cancer in its curative stages to improve prognosis. Previous studies from our laboratory showed that the location of the CpG site methylation studied could impact the marker performance in distinguishing HCC from other liver diseases. The aberrant methylation of the tumor-suppressor RASSF1A gene has been extensively studied as a marker for a variety of cancers, including liver cancer. However, some studies found that the gene was methylated even in non-cancerous liver tissues. Thus, in order to explore the possibility of detecting aberrant methylation of the tumor-suppressor RASSF1A gene as a biomarker for HCC screening, we analyzed the methylation profiles of 57 CpG sites in three regions of the promoter - P1, P2, and E1 - in normal, hepatitic, cirrhotic, adjacent non-HCC, and HCC tissue samples through bisulfite DNA sequencing. We discovered that the P1 region was most specifically methylated to HCC. We then confirmed the findings by developing a methylation specific PCR and analyzing a larger sample size. The data were analyzed and the P1 test was found to have an area under the curve (AUROC) of 0.90, whereas the E1 and P2 tests had AUROC of 0.84 and 0.72, respectively. At a cutoff of 10 copies for our analysis, the P1 MSP gave a sensitivity of 80.8% and specificity of 85.7%. Furthermore, we found that out of 62 AFP-negative samples, mRASSF1A detected 54 (87.1%). By combining AFP and mRASSF1A, 107 of 115 (93.0%) of HCC samples were detected as cancerous. Subsequently, we developed a PCR assay to detect the methylated RASSF1A gene in the urine of patients. This assay was then used to test the urine DNA isolated from patients with hepatitic, cirrhotic, or HCC after which the data were statistically evaluated. The potential of a urine DNA test for HCC screening is discussed. Citation Format: Surbhi Jain, Lijia Xie, Batbold Boldbaatar, Ying-Hsiu Su, Wei Song. Detection of aberrant methylation of the RASSF1A gene as a biomarker for hepatocellular carcinoma. [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 1154. doi:10.1158/1538-7445.AM2013-1154
Abstract 5338: A repressive EWS-FLI1 subsignature is the result of FOXO1 suppression and nuclear exclusion
Authors: Stephan Niedan, Maximilian Kauer, Gunhild Jug, Robert L. Walker, Paul S. Meltzer, Heinrich Kovar
Journal: Cancer Research (2011)

Abstract The EWS-FLI1 chimeric protein, characteristic of Ewing′s sarcoma (ESFT), constitutes the prototype of an aberrant oncogenic ETS transcription factor. The mechanisms of transcriptional regulation leading to ETS-driven tumorigenesis are poorly understood. In-silico analysis of time-resolved expression data revealed enrichment of ETS binding motifs in EWS-FLI1 activated target promoters, while EWS-FLI1 repressed promoters showed most prominently enrichment of recognition motifs for forkhead box (FOX) proteins. Several FOX genes were found to be bound by EWS-FLI1 in ChIP-seq and transcriptionally affected by EWS-FLI1 knockdown. We therefore hypothesized that EWS-FLI1 exerts an important part of its repressive activity via inhibition of FOX proteins. Upon silencing of EWS-FLI1, both FOXO1 and FOXO3 proteins were strongly induced in ESFT cells consistent with this hypothesis, but only FOXO1 translocated to the nucleus. However, in the presence of EWS-FLI1, ectopic FOXO1 was found excluded from the nucleus as consequence of phosphorylation. Nuclear translocation was restored by either inhibition of CDK2, a directly EWS-FLI1 activated kinase, augmented by chemical inhibition of PI3K, or by mutation of CDK2 phosphorylation sites. These results suggest an important role for CDK2 in FOXO1 repression by EWS-FLI1. To test the contribution of FOXO1 to the EWS-FLI1 repressive signature on the ESFT transcriptome, the overlap between genes activated by EWS-FLI1 knockdown and genes activated by ectopically expressed, nuclear directed FOXO1 was determined and compared to the effects of EWS-FLI1 knockdown under concomitant FOXO1 silencing. A significant overlap between FOXO1 activated and EWS-FLI1 repressed genes was identified (P&amp;lt;10e-20, hypergeometric test). Taken together, these data confirm our hypothesis that a repressive subsignature of EWS-FLI1 regulated genes is due to suppression of FOXO1. Functional restoration of nuclear FOXO1 expression in ESFT cells resulted in impaired proliferation and significantly reduced soft agar colony formation ability suggesting that FOXO1 plays an important role in ESFT oncogenesis. This study was supported by grant 22328-B09 from the Austrian Science Fund FWF. 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 5338. doi:10.1158/1538-7445.AM2011-5338
HIGH CENTER VOLUME IS ASSOCIATED WITH LOWER IN-HOSPITAL MORTALITY IN HEART FAILURE PATIENTS: A NEW YORK STATE WIDE ANALYSIS OF 300,000 ADMISSIONS
Authors: Shivank Madan, Daniel Sims, Omar Saeed, Snehal Patel, Jooyoung Shin, Sandhya Murthy, Ileana Pina, Mario Garcia, Ulrich Jorde
Journal: Journal of the American College of Cardiology (2016)
123I MIBG Appearance of Severe Renal Artery Stenosis
Authors: Alistair Jordan, Marc Seltzer, Alan Siegel
Journal: Clinical Nuclear Medicine (2014)

We describe a patient with labile hypertension and elevated metanephrines who underwent 123Iodine metaiodobenzylguanidine (MIBG) for the detection of a possible paraganglioma. The scan revealed markedly abnormal diffusely increased activity in the right renal parenchyma. A CT angiogram showed severe renal artery stenosis of an atrophic-appearing right kidney and delayed enhancement of the right kidney, consistent with renal dysfunction due to renal artery stenosis.
Most people know little about the Affordable Care Act's provisions, US study finds
Authors: M. McCarthy
Journal: BMJ (2014)

Although almost all US residents have an opinion about the Affordable Care Act, few know very much about what the law does, a new study has shown.1

The study was an analysis of data from a survey conducted in September, just before the opening of the health insurance exchanges. It found that 82% of people surveyed had an opinion about the healthcare reform law (34% favorable and 48% unfavorable) but that under a third …
FRI0455 High intensity aerobic exercise in ankylosing spondylitis reduces arterial stiffness: results from a randomized controlled trial
Authors: I. J. Berg, A. G. Semb, S. Halvorsen, C. Fongen, H. Dagfinrud, T. K. Kvien, S. A. Provan
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Patients with ankylosing spondylitis (AS) are at increased risk of cardiovascular disease (CVD). However, we do not know etiological mechanism or how to reduce risk. Exercise is known to reduce cardiovascular (CV) risk in the general population. <h3>Objectives</h3> A proof of concept investigation to test whether high intensity aerobic exercise reduces CV risk factors and risk markers in AS patients. <h3>Methods</h3> A randomized controlled pilot study was carried out at Diakonhjemmet Hospital, Norway in 2011-2012. Inclusion criterion was active AS with BASDAI&gt;3.5. The patients were allocated to either the exercise group (EG) or a control group (CG). The exercise program consisted of aerobic high intensity training 40 minutes 3 days a week and muscular strength training 20 minutes twice a week. The training was supervised twice a week. The intervention lasted for 3 months. The control group received care as usual. Participants were assessed at baseline and at 3 months for CV risk factors (blood pressure, lipids, BMI) and arterial stiffness (using applanation tonometry, calculating augmentation Index (AIx) and pulse wave velocity (PWV)). Statistical analyses were performed using SPSS 20, using Mann-Whitney U test to compare median change (from baseline to 3 months) of the parameters between EG and CG. Analyses were performed pr protocol. <h3>Results</h3> 28 AS patients were recruited to the study. Two patients did not perform testing after 3 months, 1 in EG and 1 in CG, and two additional patients did not adhere to the exercise program. Thus 24 patients fulfilled the study, 10 in the EG and 14 in the CG. There were some differences in demographics (EG vs. CG): age, years (median (min-max)) 43 (30-67) vs. 50 (26-68), male gender: 20% vs. 71%. After the study period, arterial stiffness was reduced in the EG compared CG, both significant for AIx (%) median (min-max) -3.3 (-24.5-2.5) vs. 1.7 (-13.5-10.3), p=0.04 and for PWV (m/s) median (min-max) -0.4 (-1.9-0.1) vs. -0.1 (-1.5-0.1), p=0.05 (figure). There were no significant group differences in change of traditional CV risk factors (systolic blood pressure, diastolic blood pressure, total cholesterol, LDL, HDL, triglycerides, BMI). No adverse events were observed. <h3>Image/graph</h3> <h3>Conclusions</h3> This proof of concept study showed that intervention with high intensity aerobic exercise reduced arterial stiffness after 3 months compared to controls. The results of this small study need replication in larger RCT with longer follow-up. <h3>Disclosure of Interest</h3> None Declared
Abstract 5229: Single, pre-labeled metastatic melanoma cells can be detected in the mouse brain using MRI
Authors: Inderjit K. Daphu, Ingvild Wendelbo, Heike Immervoll, Eva Sykova, Pavla Jendelova, Michel Babic, Rolf Bjerkvig, Frits Thorsen
Journal: Cancer Research (2011)

Abstract In metastatic melanoma, brain metastases are clinically diagnosed in 40-60% of patients during the disease, but can be found in up to 90% at autopsy. The prognosis for these patients is poor, due to ineffective treatments and development of multiple brain metastasis. There is a limited knowledge about the biological mechanisms behind this development of multiple metastasis in the brain, which necessitates the development of clinically more relevant animal models. The purpose of this study was to develop a multiple brain metastasis animal model which closely reflects the clinical setting, and specifically to determine the number of single melanoma cells able to arrest in the animal brain. The H1 brain metastatic melanoma cell line was established from a patient melanoma brain metastases obtained during surgery. The H1 cells were pre-labeled with superparamagnetic iron oxide particles (Fedex; Babic et al, Bioconjugate Chem 2008) at a concentration of 10 μg/ml for 24 hrs. The viability of labeled cells was studied in vitro using cell proliferation assays, and Scanning/Transmission Electron Microscopy (SEM/TEM). One million pre-labeled tumor cells were then injected into the left ventricle of the heart in nod scid mice. 24 hrs after injections, T1 weighted (T1w), T2 weighted (T2w) and T2* weighted (T2*w) MR imaging were performed. In addition, T1w and T2w MR images were obtained 5 weeks after injections. We also transfected the H1 melanoma cells with luciferase, and monitored the animals for up to 6 weeks using bioluminescence imaging (OI). Pre-labeling of melanoma cells with Fedex did not affect cell proliferation. The SEM and TEM studies showed iron oxide particle attachment to the tumor cell membrane, as well as localisation of the labelling agents within vesicles in the cytoplasm. By encapsulating pre-labeled tumor cells at various concentrations in soft agar, we were able to detect less than 50 cell/μl using T2 mapping MRI. By pre-labeling the melanoma cells with Fedex, we were able to detect single tumour cells in the animal brains. Imaging studies (OI, MR) 4-6 weeks after injections confirmed multiple metastatic spread to the brain. In conclusion, we have developed a melanoma metastasis model in immunodeficient mice, which reflects the metastatic tumor spread seen in patients. By using pre-labeling with Fedex, we were able to detect single tumour cells in the brain. 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 5229. doi:10.1158/1538-7445.AM2011-5229
ACUTE OPTIMIZATION OF LEFT VENTRICULAR PACING SITE PLUS MULTIPOINT PACING IMPROVE REMODELING AND CLINICAL RESPONSE OF CRT AT ONE YEAR FOLLOW UP
Authors: Francesco Zanon, Lina Marcantoni, Enrico Baracca, Gianni Pastore, Daniela Lanza, Silvio Aggio, Loris Roncon, Luca Conte, Claudio Picariello, Mauro Carraro, Franco Noventa, Frits W. Prinzen
Journal: Journal of the American College of Cardiology (2016)
A Double-Blind, Placebo-Controlled Multicenter Study of Tacrine for Alzheimer's Disease
Authors: K L Davis, L J Thal, E R Gamzu, C S Davis, R F Woolson, S I Gracon, D A Drachman, L S Schneider, P J Whitehouse, T M Hoover
Journal: New England Journal of Medicine (1992)

In Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease.
Endoscopic resection in the duodenum: current limitations and future directions
Authors: M. Bourke
Journal: Endoscopy (2013)

Duodenal lesions that should be considered for endoscopic resection comprise a heterogeneous group of disorders. Most are adenomas, primarily located in the descending duodenum. In comparison to lesions of a similar size elsewhere in the gastrointestinal tract, the risk of major complications from endoscopic resection of duodenal lesions is magnified. The unique anatomical features of the duodenum are largely responsible for this, but despite this we continue to apply conventional endoscopic therapies when a more sophisticated approach is required. Many other important clinical questions in relation to duodenal adenomas remain unanswered. This review aims to identify the gaps in the knowledge base and therapeutic approach and propose some solutions and directions for future research.