tbuckley/cabot-search huggingface dataset:
Abstract 1636: ErbB4 is a new therapeutic target for metastasis and anoikis resistance in Ewing's sarcoma
Authors: Ariadna Mendoza-Naranjo, Pitri Mistry, Nikola Lazic, Sandra J. Strauss, Poul HB Sorensen
Journal: Cancer Research (2011)

Abstract Most Ewing sarcoma (ES)-related deaths occur as a result of metastatic disease. As a barrier to metastases, cells normally undergo a form of cell death called ‘‘anoikis” after they lose contact with the extracellular matrix or neighboring cells. Tumor cells that acquire malignant potential develop mechanisms to suppress anoikis. We previously demonstrated that ES tumors suppress anoikis and show prolonged survival as multicellular spheroids, which mimic micrometastases under anchorage-independent conditions. Here we have used the paired CHLA-9 primary tumor line established at diagnosis and the metastatic CHLA-10 line established from the same patient after four cycles of induction chemotherapy with cisplatin, doxorubicin, cyclophosphamide, and etoposide, as well as high-throughput Affymetrix whole exon array platforms to screen for potential therapeutic targets to treat metastatic disease. We have identified ErbB4, a member of the epidermal growth factor receptor (EGFR) family, as a novel mediator of anoikis resistance in ES. We detected a 4-fold increase in ERBB4, along with enhanced ErbB4 protein expression and Tyr kinase activation (confirmed by P-Tyr kinase proteome arrays) in CHLA-10 cells grown under anchorage independent conditions, compared to CHLA-9 tumor cells under the same conditions. Upregulated ErbB4 expression was further confirmed in a panel of metastatic vs. primary ES cell lines at both the mRNA and protein levels. We are currently validating these findings in the clinical setting by analyzing ErbB4 expression in paired primary vs. metastatic biopsies from ES patients. shRNA-mediated knockdown of ErbB4, or treatment with the ErbB inhibitor Lapatinib, dramatically reduced proliferation, decelerated tumor invasion, and sensitized metastatic/chemoresistant ES tumors to chemotherapeutic drugs used to treat ES patients. Taken together, our findings identify ErbB4 as a novel target for metastasis and anoikis resistance in ES. 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 1636. doi:10.1158/1538-7445.AM2011-1636
Abstract 5220: Dclk1 labels quiescent pancreatic progenitor and cancer initiating cells
Authors: Christoph Benedikt Westphalen, Michael Quante, Daniel Worthley, Samuel Asfaha, Helen Remotti, Kenneth P. Olive, Timothy C. Wang
Journal: Cancer Research (2012)

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the US. Despite major efforts pancreatic cancer has the highest mortality rate of all major cancers with a 5-year survival rate below 5% while the survival rate for the disease has not improved substantially in nearly 40 years. Recently, doublecortin-like kinase 1 protein (Dclk1) was proposed as a marker of putative quiescent stem cells in the gastrointestinal tract and in the pancreas although no genetic fate mapping was performed. Additionally, it was demonstrated that Dclk1 cells expand in the setting of inflammation, hyperplasia and metaplasia. While clinical relevant mouse models of PDAC exist the identity of the cell of origin for pancreatic cancer is still debated. Aim: In order to investigate the role of Dclk1 cells in pancreatic health and disease we generated a BAC transgenic mouse line (Dclk1-CreERT) that expresses tamoxifen-inducible Cre recombinase under the control of the endogenous Dclk1 gene regulation. Results: Using genetic lineage tracing, we demonstrate that Dclk1 labels rare long-lived, quiescent progenitor cells in the pancreas that can give rise to ductal and acinar tissue. Furthermore, Dclk1 cells were found to expand in the setting of pancreatic inflammation and malignancy. Importantly, the Dclk1 lineage contributed significantly to pancreatic regeneration after caerulein-induced pancreatitis. Finally, expression of mutant K-Ras (G12D) in Dclk-1 cells leads to rapid onset (2-3 months) of invasive pancreatic ductal adenocarcinoma that could be further accelerated by caerulein-induced pancreatic injury (1-2 months). Conclusion: Dclk1 labels rare quiescent progenitor cells in the pancreas. These cells take part in the regeneration of the gland after injury and are capable of giving rise to pancreatic cancer. Therefore, we propose that Dclk1 could label the cell of origin in pancreatic cancer. 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 5220. doi:1538-7445.AM2012-5220
Abstract SY11-03: Mechanisms of ATM activation
Authors: Tanya T. Paull, Ji-Hoon Lee, Scott Ditch, Zhi Guo
Journal: Cancer Research (2012)

Abstract The Ataxia-Telangiectasia Mutated (ATM) kinase initiates a rapid cascade of protein phosphorylation in response to double-strand breaks in chromosomal DNA. The critical targets of ATM during this response include many tumor suppressors involved in cell cycle progression and apoptosis. The DNA damage response is thus defective in cells lacking ATM; however, there are also many indications that cells lacking ATM are defective in responses to other forms of stress, particularly oxidative stress. Mammalian cells lacking ATM exhibit high levels of reactive oxygen species and indications of chronic oxidative stress. In addition, the shortened lifespan, haematopoietic stem cell loss, and increased lymphomagenesis seen in A-T mouse models can be suppressed by antioxidants, suggesting that oxidative stress constitutes an important part of the A-T phenotype and is important for cancer progression. We have observed robust ATM activation in human cell lines in response to oxidative stress, in the absence of apparent DNA damage. In addition, oxidation of purified recombinant ATM in vitro induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-crosslinked dimer containing several disulfide bonds. Mutation of a critical cysteine residue involved in disulfide bond formation specifically blocks activation via the oxidation pathway, both in vitro with purified components and in human cells. Identification of this pathway explains many observations of ATM activation under conditions of oxidative stress, and shows that ATM is an important sensor of reactive oxygen species (ROS) in vivo. Here we investigate how the oxidation pathway of ATM activation is affected by small molecules, specifically by resveratrol and related compounds, and how this affects cell cycle checkpoint responses in human cells. We also show in vitro that ATM is a direct target of these compounds and investigate the mechanism underlying the effects on ATM function. 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 SY11-03. doi:1538-7445.AM2012-SY11-03
AB0015 Association of BLK Polymorphism with Susceptibility to Rheumatoid Arthritis in an Algerian Population
Authors: R. Djidjik, I. Allam, S. Louahchi, N. Raaf, N. Ouikhlef, A. Boucharef, A. Abdessemed, N. Khaldoun, N. Behaz, K. Cherguelaine, A. Tahiat, A. Ladjouze Rezig, M. Ghaffor
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The B-cell lymphocyte kinase (BLK) is a src family protein tyrosine kinase expressed in B-lineage cells. BLK gene polymorphism was reported as a risk factor in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) susceptibility. <h3>Objectives</h3> To investigate whether the association of BLK gene polymorphism with RA is present in an Algerian population. <h3>Methods</h3> The BLK (rs13277113) single nucleotide polymorphism was directly genotyped in 223 RA patients and 200 healthy controls by real time -polymerase chain reaction method (TaqMan Assays). The relationships between anti-citrullinated peptide antibody (ACPA) positivity, rheumatoid factor (RF) positivity and BLK genotypes were analyzed statistically. Disease activity score (DAS28) and HAQ score were also assessed. <h3>Results</h3> Significant associations between RA and controls were observed for AG heterozygote genotype (21% vs 33%, P=0.004, OR=0.53) and recessive model (AA vs. AG+GG, 94% vs 99%, P=0.002, OR=0.08). Allele frequencies did not differ between patients and controls and between antibodies positive (ACPA, RF) and negative RA (P&gt;0.05). No significant difference in genotypes distribution was found after stratification according to parameters of disease activity (DAS 28 and HAQ, P&gt;0.05). <h3>Conclusions</h3> Our result indicates that polymorphism in BLK gene is associated with susceptibility to RA in Algerian population but not with the severity. <h3>References</h3> Génin E, Coustet B, Allanore Y, et al. Epistatic interaction between BANK1 and BLK in rheumatoid arthritis: results from a large trans-ethnic meta-analysis. PLoS One. 2013 Apr 30;8(4) Viatte S, Plant D, Bowes J, et al. Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients. Ann Rheum Dis. 2012 Dec;71(12) Zhang H, Wang L, Huang Y, et al. Influence of BLK polymorphisms on the risk of rheumatoid arthritis. Mol Biol Rep. 2012 Nov;39(11). <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1943
Three-Dimensional Virtual Neck Exploration before Parathyroidectomy
Authors: Jacopo D'Agostino, Michele Diana, Michel Vix, Luc Soler, Jacques Marescaux
Journal: New England Journal of Medicine (2012)

The authors found that three-dimensional virtual neck exploration may be a valuable adjunct to presurgical planning. It can detect inapparent anatomical variations that permit modification of the planned surgical approach.
Epidemiological and Economic Effects of Priming With the Whole-Cell<i>Bordetella pertussis</i>Vaccine
Authors: Haedi DeAngelis, Samuel V. Scarpino, Meagan C. Fitzpatrick, Alison P. Galvani, Benjamin M. Althouse
Journal: JAMA Pediatrics (2016)

Current acellular pertussis vaccines may not protect against transmission of Bordetella pertussis.To assess whether a priming dose of whole-cell pertussis (wP) vaccine is cost-effective at reducing pertussis infection in infants.Mathematical model of pertussis transmission fit to US incidence data in a simulation of the US population. In this simulation study conducted from June 2014 to May 2015, the population was divided into 9 age groups corresponding to the current pertussis vaccination schedule and fit to 2012 pertussis incidence.Inclusion of a priming dose of wP vaccine into the current acellular pertussis vaccination schedule.Reductions in symptomatic pertussis incidence by age group, increases in wP vaccine-related adverse effects, and quality-adjusted life-years owing to changing vaccine schedule.Switching to a wP-priming vaccination strategy could reduce whooping cough incidence by up to 95% (95% CI, 91-98), including 96% (95% CI, 92-98) fewer infections in neonates. Although there may be an increase in the number of vaccine adverse effects, we nonetheless estimate a 95% reduction in quality-adjusted life-years lost with a switch to the combined strategy and a cost reduction of 94% (95% CI, 91-97), saving more than $142 million annually.Our results suggest that an alternative vaccination schedule including 1 dose of wP vaccine may be highly cost-effective and ethically preferred until next-generation pertussis vaccines become available.
EFFECT OF TRANSCATHETER MITRAL REPAIR WITH THE CARDIOBAND DEVICE ON 3-DIMENSIONAL GEOMETRY OF THE MITRAL ANNULUS
Authors: Mani Arsalan, Eustachio Agricola, Ottavio Alfieri, Stephan Baldus, Antonio Colombo, Giovanni Filardo, Christoph Hammerstingl, Michael Huntgeburth, Felix Kreidel, Karl-Heinz Kuck, Giovanni La Canna, David Messika-Zeitoun, Francesco Maisano, Georg Nickenig, Benjamin D. Pollock, Bradley J. Roberts, Alec Vahanian, Paul Grayburn
Journal: Journal of the American College of Cardiology (2016)
Combining the Antidepressant Drugs
Authors: M. F. Lockett, G. Milner
Journal: BMJ (1965)

To compare the effects of epidermal growth factor (EGF) and betamethasone on the morphogenesis of the gas exchange region and the differentiation of the alveolar type II cell during fetal lung development, fetal rhesus monkeys (78% gestation) were treated in utero with EGF (5.33 mg/kg total dose), beta-methasone (2.6 mg/kg total dose) or the carrier, saline (control), every other day for 7 days. EGF-treated monkeys had significantly increased body and adrenal weights. Betamethasone-treated monkeys had significantly decreased body and adrenal weights. Exogenous EGF reduced cytoplasmic glycogen and increased the cytoplasmic organelle and SP-A content within alveolar type II cells. In contrast, exogenous betamethasone did not alter alveolar type II cell cytodifferentiation. Neither EGF nor betamethasone treatment significantly altered the structure of the gas exchange region as shown by a lack of change from controls in alveolar airspace size or in the fraction of the gas exchange region that was potential airspace. We conclude that at clinically relevant doses, EGF greatly accelerates the maturation of alveolar type II cells, whereas betamethasone does not. Exogenous EGF may act directly on alveolar type II cells because these cells contain EGF receptor. Neither EGF nor betamethasone had dramatic effects on the morphogenesis of the gas exchange region.
Abstract 1276: Application of high-throughput proteomics Micro-Western array in studying molecular mechanism of anticancer effect of liver X receptor agonists against human colon cancer cells
Authors: Ching-Yu Lin, Chiech Huo, Hui-Ping Lin, Shih Sheng Jiang, Chih-Pin Chuu
Journal: Cancer Research (2012)

Abstract We recently developed a high-throughput proteomics technology, the Micro-Western arrays (Ciaccio MF, Nature Methods 2010). Micro-Western array is a nano-litter scale array-based Western blotting assay. This method allowed us to measure 96 to 384 different phosphosites on multiple proteins of a set of 6 to 15 different samples simultaneously. We applied this technology in investigating molecular mechanism of anticancer effect of small molecular compound. Colon cancer is the third leading cause of cancer-related death in the world. Previously, we reported that agonists for liver X receptors (LXRs) suppressed the proliferation of several human cancer cell lines. LXRβ and LXRβ are nuclear receptors and are important regulators of cholesterol, fatty acid, and glucose homeostasis. 96-well proliferation assay and colony formation assay showed that three commonly used LXR agonists 22(R)-hydroxycholesterol, T0901317, and GW3965 suppressed proliferation of HT-29 and HCT-116 human colon cancer cells dose-dependently. Flow cytometry analysis indicated that LXR agonists induced G1 cell cycle arrest but not apoptosis in colon cancer cells. We then used gene overexpression and shRNA/siRNA knockdown to verify that LXRβ and LXRβ were directly involved in the growth inhibition caused by LXR agonists. To understand the molecular mechanism, we used gene array and Micro-Western Array with more than 240 phosphorylated antibodies targeting signaling network regulating receptor tyrosine kinases (RTKs), cell cycle, cell stress, and PI3K/Akt to systematically investigate signaling proteins being affected by LXR agonists in multiple time points. With help of bioinformatics modeling, our result revealed a potential mechanism how nuclear receptor LXR regulating cell cycle in human colon cancer cells via EGFR/PI3K/Akt and ABCA1/SREBP-1/LDLR signaling. Effect of LXR agonists treatment with or without chemotherapy agents on HT-29 xenograft model and validation of target proteins for LXR agonists in patients’ tissues are currently ongoing. Our observations suggested that LXR agonists treatment may be a potential adjuvant therapy for colon cancers. 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 1276. doi:1538-7445.AM2012-1276
Shaken, Not Sonicated?
Authors: Colin L. Masters
Journal: New England Journal of Medicine (2014)

Investigators studying the infectious protein (prion protein, PrP) have long sought a sensitive and minimally invasive diagnostic tool that is specifically targeted to the particular protein that causes the disease. For all forms of Creutzfeldt–Jakob disease — sporadic, inherited, and acquired — such diagnostic tools are emerging, as illustrated by two similar technologies now reported in the Journal by Orrú et al.1 and Moda et al.2: a real-time quaking (shaking)-induced conversion (RT-QuIC) assay applied to nasal olfactory epithelial brushings1 and a sonicated protein misfolding cyclic amplification (PMCA) assay applied to urine.2 Both assays rely on imparting kinetic energy into . . .
Effects of Socioeconomic Status on Access to Invasive Cardiac Procedures and on Mortality after Acute Myocardial Infarction
Authors: David A. Alter, C. David Naylor, Peter Austin, Jack V. Tu
Journal: New England Journal of Medicine (1999)

Universal health care systems seek to ensure access to care on the basis of need rather than income and to improve the health status of all citizens. We examined the performance of the Canadian health system with respect to these goals in the province of Ontario by assessing the effects of neighborhood income on access to invasive cardiac procedures and on mortality one year after acute myocardial infarction.
Abstract 3003: Immune cell-related microRNA-155 is associated with human liver cirrhosis and hepatocellular carcinoma
Authors: Anuradha S. Budhu, Zhipeng Yu, Marshonna Forgues, Zhao You Tang, Carlo M. Croce, Xin Wei Wang
Journal: Cancer Research (2010)

Abstract Liver cirrhosis, a major hepatocellular carcinoma (HCC) risk factor, is caused by chronic liver disease (CLD) of various etiologies with ambiguous underlying mechanisms. Gene profiling has illustrated that CLD etiologies differ and are associated with cytokine up-regulation. Recently, microRNAs (miRNAs), noncoding-RNA gene regulators, have been utilized as effective molecular biomarkers in many cancer types, including HCC. We investigated whether unique miRNAs are associated with CLD and HCC. We examined miRNA array profiles of 58 human liver tissue specimens with end-stage CLD (hepatitis B virus, hepatitis C virus, Wilson's disease, autoimmune hepatitis, alcoholic liver disease and primary biliary cirrhosis) and a normal liver pool. We compared the differentially expressed miRNAs between CLDs and normal liver, among CLDs and between etiologically equivalent CLD and HCC. Significant differentially expressed CLD-miRNAs were validated by quantitative-real time PCR (qRT-PCR). MiRNA and immune cell expression was measured in CLD, HCC or human peripheral blood mononuclear cells (PBMC) by qRT-PCR or immunohistochemistry. Correlation analysis between etiology-specific miRNAs and mRNAs were performed, followed by pathway analysis of the correlating mRNAs. Statistical class comparison analyses revealed that unique miRNAs were associated with each CLD group and among CLD etiologies, with only one miRNA commonly altered among CLDs (p=0.05; 10 fold cross-validation; 10k permutation). miRNA expression correlated well between array and qRT-PCR analyses (spearman r= 0.53-0.83, p= 0.03-0.001). We also found that many CLD-miRNA alterations were maintained in HCC. In particular, immune-related miR-155 was significantly up-regulated in CLDs, HCC, nontumor tissue, metastasis tissue specimens and PBMC treated with pro-metastatic colony stimulating factor 1 (CSF1) or osteopontin (OPN). MiR-155 was associated with T regulatory cells (Treg) and both were elevated by pro-inflammatory cytokines. Moreover, high miR-155 expression in nontumor tissues was associated with poor overall HCC patient survival (p=0.0244). Correlation analysis revealed that miR-155 was associated with distinct gene expression pathways in each CLD etiology. In sum, CLD miRNAs are mainly etiologically distinct and are coupled to immune responses and tumorigenesis. Our work suggests that miR-155 may modulate Tregs and hence, functionally contribute to CLD and HCC progression. 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 3003.
Abstract 1676: Cytotoxicity of fenretinide and its metabolite 4-oxo-4-HPR in malignant lymphoid cells can be dependent and independent of reactive oxygen species (ROS)
Authors: Jason P. Cooper, Charles P. Reynolds, Robert W. Curley, Min H. Kang
Journal: Cancer Research (2010)

Abstract Fenretinide (4-HPR) is a cytotoxic retinoid that increases ROS and ceramides and has shown clinical activity against neuroblastoma and lymphoid malignancies. We compared the cytotoxicity, ROS generation, and sphingolipid synthesis of 4-oxo-4-HPR (a recently identified 4-HPR metabolite) with 4-HPR in malignant lymphoid cells. Cytotoxicity of 4-oxo-4-HPR and 4-HPR was measured in 14 malignant lymphoid cell lines using a DIMSCAN system. Median concentrations cytotoxic for 90% of cells (IC90) were 2.1 µM (range: 1.1 − 15.9) for 4-oxo-4-HPR and 4.4 µM (range: 0.7 − 29.2) for 4-HPR. In 2 of 3 cell lines tested, ROS generation (DCFDA by flow cytometry) was higher with 4-HPR vs. 4-oxo-4-HPR (table). Ascorbic acid (AA) abrogated ROS generation and significantly attenuated cytotoxicity of 4-oxo-4-HPR and 4-HPR in CCRF-CEM and COG-LL-317 cells. However, in GA-10 cells AA completely abrogated ROS generation, but not cytotoxicity, for both 4-oxo-4-HPR and 4-HPR. Intracellular sphingolipid (SL) changes, another suggested mechanism for 4-HPR cytotoxicity, were measured by tandem mass spectrometry in GA-10 cells at 48-hours, and both 4-oxo-4-HPR and 4-HPR treatment increased SL, with significantly higher (p &amp;lt; 0.05) increases by 4-oxo-4-HPR. The fold increase/control for 4-oxo-4-HPR vs. 4-HPR: ceramides = 2.1 ± 0.13 vs. 1.3 ± 0.11; dihydroceramides = 87.6 ± 7.1 vs. 34.0 ± 5.1; sphingomyelins = 4.1 ± 0.14 vs. 2.4 ± 0.04). Thus, 4-oxo-4-HPR is similar in cytotoxicity to 4-HPR, less active in generating ROS, but more active in increasing SL. The cytotoxicity of both 4-HPR and 4-oxo-4-HPR in the GA-10 cell line is independent of ROS, providing a novel in vitro model for identifying the role of SL in the cytotoxicity of these agents.Table.Cytotoxicity and ROS generation for 4-HPR and 4-oxo-4-HPR, and cell survival after ROS abrogation. Cell Line (Histopathology)CCRF-CEM (T ALL)COG-LL-317 (T ALL)GA-10 (B Burkitt lymphoma)IC90 (µM)4-oxo-4-HPR1.32.41.54-HPR1.01.57.3 ROS Generation‡ (fold increase/control)4-oxo-4-HPR2.3 ± 0.03***1.6 ± 0.02***1.7 ± 0.04**4-HPR8.3 ± 0.36***5.3 ± 0.26***2.2 ± 0.29** ROS abrogation‡ (% inhibition from drug alone)4-oxo-4-HPR + AA55%***31%*100%*4-HPR + AA83%***91%***100%*** Cell Survival at 20 hours‡AA102.5% ± 12.6107.3% ± 14.986.8% ± 14.94-oxo-4-HPR12.9% ± 2.926.3%± 2.010.9% ± 6.84-oxo-4-HPR + AA22.9% ± 3.5***63.1% ± 8.6***9.1% ± 3.74-HPR1.2% ± 0.69.1% ± 2.011.9% ± 6.24-HPR + AA27.9% ± 6.8***91.2% ± 11.4***12.6% ± 3.1‡ Treatments: 10 µM 4-oxo-4-HPR, 10 µM 4-HPR, 200 µM AA; * P &amp;lt; 0.05, ** P &amp;lt; 0.01, *** P &amp;lt; 0.001 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 1676.